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"abstract": "A 50-year-old male presented to our hospital complaining of dry cough and slight fever. A chest CT scan showed a mass in the right upper lung lobe, pleural effusion on both sides, and multiple liver tumors. He was diagnosed with small cell lung cancer (SCLC), and then antitumor chemotherapy was started. Thereafter, his condition deteriorated rapidly, and died 2 days later. An autopsy revealed that the cause of death was ruptured liver metastases. SCLC is a highly invasive disease and often metastasizes to the liver, but the rupture of liver metastases is rare. Clinical features and imaging findings were of a great help in diagnosing ruptured hepatic metastasis. Physicians need to pay attention to this condition, especially after chemotherapy has initiated.",
"affiliations": "Department of Respiratory Medicine, Iizuka Hospital, 3-83 Yoshiomachi, Iizuka, Fukuoka, 820-0018, Japan.;Department of Respiratory Medicine, Iizuka Hospital, 3-83 Yoshiomachi, Iizuka, Fukuoka, 820-0018, Japan.;Department of Respiratory Medicine, Iizuka Hospital, 3-83 Yoshiomachi, Iizuka, Fukuoka, 820-0018, Japan.;Department of Respiratory Medicine, Iizuka Hospital, 3-83 Yoshiomachi, Iizuka, Fukuoka, 820-0018, Japan.;Department of Respiratory Medicine, Iizuka Hospital, 3-83 Yoshiomachi, Iizuka, Fukuoka, 820-0018, Japan.;Department of Respiratory Medicine, Iizuka Hospital, 3-83 Yoshiomachi, Iizuka, Fukuoka, 820-0018, Japan.;Department of Respiratory Medicine, Iizuka Hospital, 3-83 Yoshiomachi, Iizuka, Fukuoka, 820-0018, Japan.",
"authors": "Goto|Yuki|Y|;Tobino|Kazunori|K|;Yoshimine|Kohei|K|;Sueyasu|Takuto|T|;Okahisa|Masanobu|M|;Sakabe|Mitsukuni|M|;Tsuruno|Kosuke|K|",
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"doi": "10.1016/j.rmcr.2020.101039",
"fulltext": "\n==== Front\nRespir Med Case Rep\nRespir Med Case Rep\nRespiratory Medicine Case Reports\n2213-0071 Elsevier \n\nS2213-0071(20)30091-5\n10.1016/j.rmcr.2020.101039\n101039\nCase Report\nAn autopsy case of ruptured liver metastases from small cell lung cancer: A case report and literature review\nGoto Yuki ygotoh3@aih-net.coma∗ Tobino Kazunori ab Yoshimine Kohei a Sueyasu Takuto a Okahisa Masanobu a Sakabe Mitsukuni a Tsuruno Kosuke a a Department of Respiratory Medicine, Iizuka Hospital, 3-83 Yoshiomachi, Iizuka, Fukuoka, 820-0018, Japan\nb Department of Respiratory Medicine, Juntendo University, School of Medicine, 2-1-1 Hongo; Bunkyo-Ku, Tokyo, 113-8421, Japan\n∗ Corresponding author. ygotoh3@aih-net.com\n19 3 2020 \n2020 \n19 3 2020 \n30 1010394 3 2020 15 3 2020 © 2020 The Authors2020This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).A 50-year-old male presented to our hospital complaining of dry cough and slight fever. A chest CT scan showed a mass in the right upper lung lobe, pleural effusion on both sides, and multiple liver tumors. He was diagnosed with small cell lung cancer (SCLC), and then antitumor chemotherapy was started. Thereafter, his condition deteriorated rapidly, and died 2 days later. An autopsy revealed that the cause of death was ruptured liver metastases. SCLC is a highly invasive disease and often metastasizes to the liver, but the rupture of liver metastases is rare. Clinical features and imaging findings were of a great help in diagnosing ruptured hepatic metastasis. Physicians need to pay attention to this condition, especially after chemotherapy has initiated.\n\nKeywords\nSmall cell lung cancerLiver metastasesHemoperitoneum\n==== Body\n1 Introduction\nSCLC is highly invasive and the liver is the most common site of metastasis. However, the incidence of ruptured liver metastasis is rare in comparison to hepatocellular carcinoma. We herein describe an autopsy case of SCLC involving a patient who died of this condition, in order to make clinicians aware of patients with associated risk factors (see Fig. 3).\n\n1.1 Case presentation\nA 50-year-old man was referred to our department for further investigation of a chest X-ray abnormality (Fig. 1A). He complained of dry cough and slight fever, which had persisted for three weeks. Although he had bronchial asthma, he was not taking any medications. He had no history of blood transfusion, hepatitis, or alcohol abuse, but had a 37 pack-year history of cigarette smoking He had no known allergies. His consciousness level was clear. His heart rate was 128 beats/min and his blood pressure was 195/120 mmHg; his other vital signs were normal. He was sweaty and had bulbar conjunctiva and had many petechiae on his lower extremities. The results of cardiopulmonary and abdominal examinations were normal (see Fig. 2).Fig. 1 A chest radiograph showed a huge mass in the right upper lung field and enlargement of the right hilum.\n\nFig. 1Fig. 2 A: Chest CT revealed a mass in the right upper lung lobe, right hilar lymphadenopathy, and pleural effusion on both sides. B: Abdominal CT revealed multiple liver tumors, and some lesions were located at the subcapsular region.\n\nFig. 2Fig. 3 A: The liver was enlarged, weighing 3120 g. B: More than 60% of the liver was replaced by metastasis. C and D: Immunohistochemical staining of the metastatic liver tumor cells was diffusely positive for CD34 (C) and MIB1 (D).\n\nFig. 3\n\nA laboratory test revealed the following results: hemoglobin, 13.5 g/dL; leukocyte count, 11,150/mm3; platelet count, 77,000/mm3; prothrombin time, 92%; serum albumin, 3.0 g/dL; total bilirubin (T.Bil), 1.7 mg/dL; serum aspartate transaminase (AST), 115 IU/L; serum alanine transferase (ALT), 215 IU/L; alkaline phosphatase (ALP), 1209 IU/L; lactate dehydrogenase (LDH), 1277 IU/L; γGTP, 936 IU/L; and serum C-reactive protein, 2.84 mg/dL. The renal function and ionogram results were in the normal ranges. Tests for hepatitis B surface (HBs) antigen and HCV antibodies were negative. Tumor marker tests revealed the following results: carcino-embryonal antigen (CEA), 19.1 ng/ml; soluble cytokeratin 19 fragment (CYFRA), 4.3 ng/ml; and pro-gastrin releasing-peptide (proGRP), 72,098 pg/ml.\n\nA computed tomography (CT) scan revealed a mass in the right upper lung lobe (7.0 cm in diameter) that subsequently expanded to the right hilum, and pleural effusion on both sides (Fig. 1B). Multiple liver tumors were also detected and some were located at the subcapsular region (Fig. 1C). A histological examination of the tumor specimen obtained by bronchoscopy from the right upper lung lobe confirmed the diagnosis of small cell lung cancer (SCLC), and antitumor chemotherapy (carboplatin and etoposide) was started. Several hours after the completion of the chemotherapy, the patient suddenly complained of nausea and general malaise. Laboratory tests showed anemia (hemoglobin, 9.8 g/dL), coagulation abnormality (PT, 76%; APTT, 21.4 sec), elevation of hepatic and biliary enzymes (T.Bil, 5.2 mg/dL; AST, 562 IU/L; ALT, 723 IU/L; ALP 1802 IU/L; LDH 2013 IU/L; γGTP, 1517 IU/L), acute renal insufficiency (BUN, 46 mg/dL; Cre 1.48 mg/dL), and hyperpotassemia (5.0 mEq/L). After that, his condition deteriorated rapidly and he died the next morning.\n\nAn autopsy revealed a mass (6.0 cm by 7.0 cm) in the right upper lobe. A histological examination revealed small cell lung cancer. His liver was enlarged, weighing 3120 g. A subcapsular hematoma (6 cm) and 1600 ml of ascites were also detected. The cut surface of the liver showed widely distributed tumor nodules (SCLC) of varying sizes and necrotic tissue. More than 60% of the liver parenchyma was replaced with metastatic tumors (Fig. 1D). Immunohistochemical staining of his metastatic liver tumor cells was diffusely positive for CD34 and MIB1, suggesting hypervascularity and high proliferation (Fig. 1E). From these findings, hemoperitoneum was thought to have occurred due to the rupture of subcapsular liver metastasis from lung cancer. Cancer had also spread to the distant lymph nodes, spleen and bone marrow.\n\n2 Discussion\nWe described a case of hemoperitoneum due to the rupture of liver metastasis from SCLC. SCLC is a highly invasive disease and often metastasizes to the liver; however, the rupture of liver metastasis is rare. Hepatocellular carcinoma (HCC) is reported to be the most common cause of spontaneous rupture of liver tumors. HCC rupture is thought to occur due to its hypervascularity, high invasiveness, tendency to penetrate the liver capsule, and decreased coagulation factors due to underlying liver cirrhosis [1,2]. Other contributing factors have been proposed, including necrotic tendency, subcapsular location, congestion of the local hepatic vein, increased intra-abdominal pressure, and rapid tumor growth [3]. Our patient had some of these risk factors, and based on his clinical course, chemotherapy was also considered to be one of the triggers of this condition due to tumor necrosis. Rupture of liver metastasis of various tumors, including lung cancer, pancreatic cancer, skin cancer, prostate cancer, kidney tumor, testicular cancer, and gastric cancer, has been reported [4,5]. To the best of our knowledge, more than 50 cases of hemoperitoneum due to rupture of liver metastasis have been reported [2,4]. We comprehensively reviewed the relevant literature, and finally found 11 similar cases with rupture of liver metastasis from lung cancer (Table 1) [4,[6], [7], [8], [9], [10], [11], [12], [13], [14]].Table 1 Reported cases of liver rupture due to metastases from lung cancer.\n\nTable 1Ref.\tPathology\tAge\tSex\tLatest treatment\tInitial symptoms\tTreatment\tTime to death\t\nSakai M et al. [6]\tAd\t64\tM\tnone\tAbdominal discomfort hypotension\tTAE\tsurvival\t\nSchoedel KE et al. [7]\tAd\t57\tM\tnone\tConfusion tachycardia hypotension\tconservative\t6 days\t\nMittleman RE et al. [8]\tSm\t62\tM\tnone\tabdominal pain back pain tachycardia\toperation\t<1 day\t\nKadowaki T et al. [9]\tSq\t72\tM\tnone\tabdominal pain tachycardia hypotension\tconservative\t2 months\t\nFujikawa T et al. [10]\tSm\t69\tM\tamrubicin (8 weeks prior)\tdizziness\nnausea\nabdominal pain\tconservative\t3 days\t\nNishikawa S et al. [11]\tAd\t65\tF\terlotinib (current)\tabdominal pain\tconservative\t3 months\t\nNishikawa S et al. [11]\tSm\t79\tM\tamrubicin (current)\t(no data)\tconservative\t2 months\t\nUmemoto K et al. [12]\tAd\t60\tM\tenterectomy (6 days prior)\tshock\toperation\t7 days\t\nKadowaki T et al. [13]\tSq\t72\tM\tnone\tabdominal pain hypotension\tconservative\t2 months\t\nOdagiri H et al. [14]\tLa\t74\tM\tlung lobectomy\t(no data)\tconservative\t2–3 weeks\t\nMochimaru T et al. [4]\tSm\t65\tM\tCDDP + ETP (current)\tabdominal discomfort hypotension\tTAE\tsurvival\t\n\n\nLiver metastasis is found in 30–45% of cases of non-small cell lung cancer, and in 17–34% cases of small cell lung cancer on autopsy [15]. In our patient, >60% of the liver parenchyma had been replaced by metastasis, resulting in acute liver failure (ALF). ALF is defined as a rapid loss of the liver function in a patient with no preexisting liver disease. The most common cause of ALF is viral infection, followed by drugs and autoimmune hepatitis. SCLC often metastasizes to the liver, but metastatic liver lesions remain asymptomatic in most patients. Thus, ALF due to liver metastasis of SCLC is extremely rare. In a previous study, diffusely spread carcinoma cells were reported to destroy liver cells and cause hepatic ischemia, necrosis, and potal vein thrombosis [3].\n\nThe initial symptoms of spontaneous rupture of liver metastasis depend on the extent of bleeding and range from subtle abdominal discomfort to acute abdomen and hemorrhagic shock (Table 1). Although there have been no published reviews of the CT features of ruptured liver metastasis, Choi et al. reviewed the CT findings of 12 patients with ruptured hepatocellular carcinoma and reported that peripheral location, protruding contour, discontinuity of the hepatic surface, and surrounding hemoperitoneum are helpful diagnostic indicators of ruptured hepatocellular carcinoma [16]. In this case, CT revealed multiple liver metastases, and some of the metastatic lesions of the right lobe were located at the subcapsular region with discontinuity of the hepatic surface. Abdominal ultrasound is usually the first examination performed and shows free intraperitoneal fluid. In the case of pre-existing ascites, there are reports that contrast-enhanced ultrasonography can be used to confirm active bleeding and determine the location of a bleeding lesion if contrast media is present in the ascites [5]. CT angiography is the diagnostic modality of choice and may show signs of ongoing bleeding with extravasation of contrast media. It also offers useful information regarding the extent of the metastatic disease in the liver and treatment by transarterial embolization (TAE).\n\nThe short-term prognosis of spontaneous rupture of liver metastasis is determined by bleeding severity. In many of the reported cases, the patients received conservative therapy and died within three months. While the long-term prognosis depends on the cancer stage and the patient's performance status, treatment of hemoperitoneum secondary to rupture of liver metastasis depends on the tumor size, tumor location, and severity of bleeding, with control of the hemorrhage being the major objective [1]. Most patients are in shock or unstable, and therapeutic options are limited. Especially in cases of advanced cancer, therapy tends to be palliative rather than curative. The goal of treatment should be to control the hemorrhage quickly and effectively. The role of TAE is well established in HCC hemorrhage [17] and case reports describe its successful application in the treatment of ruptured liver metastasis [4,6]. Surgical resection of liver metastasis or ligation of the hepatic artery is ineffective in unstable patients but may be considered after haemostasis has been achieved, especially in cases of solitary liver metastasis [17,18].\n\nWe presented a rare case of hemoperitoneum secondary to the spontaneous rupture of hepatic metastasis from lung cancer. The clinical features and imaging findings were very useful in the diagnosis of ruptured hepatic metastasis. Physicians should pay attention to this condition, especially after the initiation of chemotherapy.\n\nCRediT authorship contribution statement\nYuki Goto: Data curation, Writing - original draft. Kazunori Tobino: Data curation. Kohei Yoshimine: Data curation. Takuto Sueyasu: Data curation. Masanobu Okahisa: Data curation. Mitsukuni Sakabe: Writing - original draft, Data curation.\n\nDeclaration of competing interest\nAll the authors have no conflict of interest about this case report.\n\nAppendix A Supplementary data\nThe following is the Supplementary data to this article:Multimedia component 1\nMultimedia component 1 \n\nAppendix A Supplementary data to this article can be found online at https://doi.org/10.1016/j.rmcr.2020.101039.\n==== Refs\nReferences\n1 Urdaneta L.F. Nielsen J.V. Massive hemoperitoneum secondary to spontaneous rupture of hepatic metastases: report of two cases and review of the literature J. Surg. Oncol. 31 1986 104 107 3713184 \n2 Akriviadis E.A. Hemoperitoneum in patients with ascites Am. J. Gastroenterol. 92 1997 567 575 9128301 \n3 van Marcke C. Coulier B. Gielen I. Maldague P. Acute liver failure secondary to metastatic liver infiltration: case report and review of the literature Acta Gastro-Enterol. Belg. 76 4 2013 436 438 \n4 Mochimaru T. Minematsu N. Ohsawa K. Hemoperitoneum secondary to rupture of a hepatic metastasis from small cell lung cancer during chemotherapy: a case with a literature review Intern. Med. 56 2017 695 699 28321073 \n5 Naganuma H. Funaoka M. Fujimori S. Rupture of liver metastasis: report of a case with an emphasis on contrast-enhanced US J. Med. Ultrason. 34 2007 113 116 \n6 Sakai M. Oguri T. Sato S. Spontaneous hepatic rupture due to metastatic tumor of lung adenocarcinoma Intern. Med. 44 2005 50 54 15704663 \n7 Schoedel K.E. Dekker A. Hemoperitoneum in the setting of metastatic cancer to the liver. A report of two cases with review of the literature Dig. Dis. Sci. 37 1992 153 154 1728523 \n8 Mittleman R.E. Hepatic rupture due to metastatic lung carcinoma Am. J. Clin. Pathol. 88 1987 506 509 2821795 \n9 Kadowaki T. Hamada H. Yokoyama A. Hemoperitoneum secondary to spontaneous rupture of hepatic metastasis from lung cancer Intern. Med. 44 2005 290 293 15897637 \n10 Fujikawa T. Nagahama K. Minakata K. A case of intraperito neal bleeding due to spontaneous rupture of liver metastases of small-cell lung carcinoma Jpn. J. Chest Dis. 57 2014 59 66 (in Japanese) \n11 Nishikawa S. Kiba H. Watanabe K. Two cases of adenocarcinoma with hepatic metastasis causing hemoperitoneum Jpn. J. Lung Canc. 54 2014 593 (in Japanese) \n12 Umemoto K. Oura T. Nakayama M. A case of ruptured hepatic metastasis from lung cancer Hokkaido J. Surg. 56 2011 60 (in Japanese) \n13 Kadowaki T. Hamada Y. Itoh R. A case of hemoperitoneum in the elderly secondary to rupture of a hepatic metastasis from lung cancer Nihon Ronen Igakkai Zasshi 41 2004 566 (in Japanese) \n14 Odagiri H. Sugimoto H. Hanada S. An autopsy case of large cell carcinoma of the lung with rhabdoid phenotype, causing rupture of a metastatic hepatoma in an early time after operation Jpn. J. Lung Canc. 50 2010 387 (in Japanese) \n15 Fishman A.P. Elias J.A. Fishman J.A. Fishman's Pulmonary Diseases and Disorders third ed. 1997 McGrow Hill New York 1770 1821 \n16 Choi B.G. Park S.H. Byun J.Y. The findings of ruptured hepatocellular carcinoma on helical CT Br. J. Radiol. 74 2001 142 146 11718385 \n17 Srinivasa S. Lee W.G. Aldameh A. Spontaneous hepatic haemorrhage: a review of pathogenesis, aetiology and treatment HPB 17 2015 872 880 26252245 \n18 Kim H.J. Park Y.E. Ki M.S. Spontaneous rupture of hepatic metastasis from a thymoma: a case report World J. Gastroenterol. 22 2016 9860 9864 27956811\n\n",
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{
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"literaturereference": "GOTO Y, TOBINO K, YOSHIMINE K, SUEYASU T, OKAHISA M, SAKABE M, ET AL. AN AUTOPSY CASE OF RUPTURED LIVER METASTASES FROM SMALL CELL LUNG CANCER: A CASE REPORT AND LITERATURE REVIEW. RESPIRAT-MED-CASE-REPORT 2020?NULL:NULL.. 2020",
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},
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},
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},
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},
{
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},
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"reactionoutcome": "5"
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{
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"reactionmeddraversionpt": "23.0",
"reactionoutcome": "5"
},
{
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"reactionmeddraversionpt": "23.0",
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{
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"reactionmeddraversionpt": "23.0",
"reactionoutcome": "6"
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{
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"reactionmeddraversionpt": "23.0",
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},
{
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] |
{
"abstract": "Allogeneic hematopoietic cell transplantation (alloHCT) with reduced-intensity conditioning is an appealing option for patients with high-risk multiple myeloma (MM). However, progression after alloHCT remains a challenge. Maintenance therapy after alloHCT may offer additional disease control and allow time for a graft-versus-myeloma effect. The primary objective of this clinical trial was to determine the tolerability and safety profile of maintenance lenalidomide (LEN) given on days 1 to 21 of 28 days cycles, with intrapatient dose escalation during 12 months/cycles after alloHCT. Thirty alloHCT recipients (median age, 54 years) with high-risk MM were enrolled at 8 centers between 2009 and 2012. The median time from alloHCT to LEN initiation was 96 days (range, 66 to 171 days). Eleven patients (37%) completed maintenance and 10 mg daily was the most commonly delivered dose (44%). Most common reasons for discontinuation were acute graft-versus-host disease (GVHD) (37%) and disease progression (37%). Cumulative incidence of grades III to IV acute GVHD from time of initiation of LEN was 17%. Outcomes at 18 months after initiation of maintenance were MM progression, 28%; transplantation-related mortality, 11%; and progression-free and overall survival, 63% and 78%, respectively. The use of LEN after alloHCT is feasible at lower doses, although it is associated with a 38% incidence of acute GVHD. Survival outcomes observed in this high-risk MM population warrant further study of this approach.",
"affiliations": "Department of Blood and Marrow Transplantation, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida. Electronic address: melissa.alsina@moffitt.org.;Division of Hematology, University of Washington School of Medicine/Fred Hutchinson Cancer Research Center, Seattle, Washington.;Department of Biostatistics, Mailman School of Public Health, Columbia University, New York, New York.;Prospective Research, Center for International Blood and Marrow Transplant Research, Minneapolis, Minnesota.;Center for International Blood and Marrow Transplant Research, Medical College of Wisconsin, Milwaukee, Wisconsin.;Blood and Marrow Stem Cell Transplantation Division, John Theurer Cancer Center at Hackensack University Medical Center, Hackensack, New Jersey.;Blood and Marrow Stem Cell Transplant Program, Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania.;Multiple Myeloma and Blood and Marrow Stem Cell Transplantation Divisions, John Theurer Cancer Center at Hackensack University Medical Center, Hackensack, New Jersey.;Center for International Blood and Marrow Transplant Research, Medical College of Wisconsin, Milwaukee, Wisconsin.;Division of Hematology, Oncology and Transplantation, Department of Medicine, University of Minnesota Medical Center, Minneapolis, Minnesota.;Division of Cancer Medicine, Department of Stem Cell Transplantation, The University of Texas MD Anderson Cancer Center, Houston, Texas.;Department of Hematology & Hematopoietic Cell Transplantation, City of Hope, Duarte, California.;Division of Hematology, Oncology and Transplantation, Department of Medicine, University of Minnesota Medical Center, Minneapolis, Minnesota.;Division of Hematology, University of Washington School of Medicine/Fred Hutchinson Cancer Research Center, Seattle, Washington.;Department of Blood and Marrow Transplantation, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida.;Division of Hematologic Oncology, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York.;Center for International Blood and Marrow Transplant Research, Medical College of Wisconsin, Milwaukee, Wisconsin.",
"authors": "Alsina|Melissa|M|;Becker|Pamela S|PS|;Zhong|Xiaobo|X|;Adams|Alexia|A|;Hari|Parameswaran|P|;Rowley|Scott|S|;Stadtmauer|Edward A|EA|;Vesole|David H|DH|;Logan|Brent|B|;Weisdorf|Daniel|D|;Qazilbash|Muzaffar|M|;Popplewell|Leslie L|LL|;McClune|Brian|B|;Bensinger|William|W|;Riches|Marcie|M|;Giralt|Sergio A|SA|;Pasquini|Marcelo C|MC|;|||",
"chemical_list": "D020533:Angiogenesis Inhibitors; D013792:Thalidomide; D000077269:Lenalidomide",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1083-8791",
"issue": "20(8)",
"journal": "Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation",
"keywords": "Allogeneic transplantation; Lenalidomide; Multiple myeloma",
"medline_ta": "Biol Blood Marrow Transplant",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D020533:Angiogenesis Inhibitors; D018572:Disease-Free Survival; D005260:Female; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D000077269:Lenalidomide; D008297:Male; D008875:Middle Aged; D009101:Multiple Myeloma; D011446:Prospective Studies; D013792:Thalidomide; D019172:Transplantation Conditioning; D014184:Transplantation, Homologous; D055815:Young Adult",
"nlm_unique_id": "9600628",
"other_id": null,
"pages": "1183-9",
"pmc": null,
"pmid": "24769014",
"pubdate": "2014-08",
"publication_types": "D017427:Clinical Trial, Phase II; D016428:Journal Article; D016448:Multicenter Study; D052061:Research Support, N.I.H., Extramural; D013485:Research Support, Non-U.S. Gov't; D013486:Research Support, U.S. Gov't, Non-P.H.S.; D013487:Research Support, U.S. Gov't, P.H.S.",
"references": "15976175;21239841;17209057;16258534;12384400;11994441;22571201;16855634;23648667;21410373;23872222;19626046;12296856;12176874;22571202;17593024;9516151;21146205;18971951;20644101;18612103;11830525;21690556;17360989;23440663;19135946;14982868;19919652;19203728",
"title": "Lenalidomide maintenance for high-risk multiple myeloma after allogeneic hematopoietic cell transplantation.",
"title_normalized": "lenalidomide maintenance for high risk multiple myeloma after allogeneic hematopoietic cell transplantation"
} | [
{
"companynumb": "US-CELGENEUS-163-21880-13022939",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "LENALIDOMIDE"
},
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"drugdosageform": "Capsules",
"drugdosagetext": "10 MG DAILY WITH 5 MG INCREMENTS TO 25 MG",
"drugenddate": null,
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"drugindication": "PLASMA CELL MYELOMA",
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"medicinalproduct": "REVLIMID"
}
],
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"reaction": [
{
"reactionmeddrapt": "Rash",
"reactionmeddraversionpt": "17.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Pain",
"reactionmeddraversionpt": "17.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Liver function test abnormal",
"reactionmeddraversionpt": "17.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Chronic graft versus host disease",
"reactionmeddraversionpt": "17.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Neutropenia",
"reactionmeddraversionpt": "17.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Transplantation complication",
"reactionmeddraversionpt": "17.1",
"reactionoutcome": "5"
},
{
"reactionmeddrapt": "Thrombocytopenia",
"reactionmeddraversionpt": "17.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Acute graft versus host disease",
"reactionmeddraversionpt": "17.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Syncope",
"reactionmeddraversionpt": "17.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Infection",
"reactionmeddraversionpt": "17.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Pyrexia",
"reactionmeddraversionpt": "17.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Plasma cell myeloma",
"reactionmeddraversionpt": "17.1",
"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "ALSINA M,BECKER P,ZHONG X,ADAMS A,HARI P,ROWLEY S. LENALIDOMIDE MAINTENANCE FOR HIGH RISK MULTIPLE MYELOMA AFTER ALLOGENEIC HEMATOPOIETIC CELL TRANSPLANTATION. BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION.",
"literaturereference_normalized": "lenalidomide maintenance for high risk multiple myeloma after allogeneic hematopoietic cell transplantation",
"qualification": "3",
"reportercountry": "US"
},
"primarysourcecountry": "US",
"receiptdate": "20140808",
"receivedate": "20130226",
"receiver": {
"receiverorganization": "FDA",
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},
"reporttype": "2",
"safetyreportid": 9119616,
"safetyreportversion": 2,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": 1,
"seriousnessdisabling": null,
"seriousnesshospitalization": null,
"seriousnesslifethreatening": null,
"seriousnessother": 1,
"transmissiondate": "20150326"
}
] |
{
"abstract": "Background: Ectopic pregnancy is the leading cause of gestation-related deaths during the first trimester. Cervical twin heterotopic pregnancies, when ectopic, constitute a small and rare part of gynecological surgery. Case Presentation: A 30-year-old pregnant woman (gravida 3, para 2) presented with mild pain in the lower abdomen and traces of bleeding per vaginum for three days. Transvaginal ultrasonography revealed a balloon-shaped cervical canal with a visible gestational sac measuring 3.5 × 3.9 cm. A second gestational sac was seen in the uterine cavity. The measurements of the gestational sacs corresponded to 7 + 4 weeks' pregnancy. A decision for medical abortion with mifepristone and misoprostol was made. However, due to an incomplete abortion and continuous bleeding, a curettage was performed. Conclusions: Spontaneous heterotopic pregnancy with the ectopic pregnancy located in the cervix is an extremely rare clinical condition requiring urgent treatment in order to reduce maternal mortality and morbidity and preserve fertility.",
"affiliations": "1st Department of Obstetrics and Gynecology, General Hospital of Athens 'ALEXANDRA', National and Kapodistrian University of Athens, Lourou and Vasilissis Sofias Ave., 11528 Athens, Greece.;1st Department of Obstetrics and Gynecology, General Hospital of Athens 'ALEXANDRA', National and Kapodistrian University of Athens, Lourou and Vasilissis Sofias Ave., 11528 Athens, Greece.;1st Department of Obstetrics and Gynecology, General Hospital of Athens 'ALEXANDRA', National and Kapodistrian University of Athens, Lourou and Vasilissis Sofias Ave., 11528 Athens, Greece.;1st Department of Surgery, Laikon General Hospital, National and Kapodistrian University of Athens, Agiou Thoma Str. 17, 11527 Athens, Greece.;Department of Obstetrics and Gynecology, General Hospital of Xanthi, Neapoli, 67100 Xanthi, Greece.;Department of Surgery, University Hospital of Larissa, Mezourlo, 41110 Larissa, Greece.;Department of Obstetrics and Gynecology, Democritus University of Thrace, Vasilissis Sofias Str. 12, 67100 Alexandroupolis, Greece.;1st Department of Obstetrics and Gynecology, General Hospital of Athens 'ALEXANDRA', National and Kapodistrian University of Athens, Lourou and Vasilissis Sofias Ave., 11528 Athens, Greece.;1st Department of Obstetrics and Gynecology, General Hospital of Athens 'ALEXANDRA', National and Kapodistrian University of Athens, Lourou and Vasilissis Sofias Ave., 11528 Athens, Greece.;1st Department of Obstetrics and Gynecology, General Hospital of Athens 'ALEXANDRA', National and Kapodistrian University of Athens, Lourou and Vasilissis Sofias Ave., 11528 Athens, Greece.;Department of Obstetrics and Gynecology, Democritus University of Thrace, Vasilissis Sofias Str. 12, 67100 Alexandroupolis, Greece.",
"authors": "Koutras|Antonios|A|;Fasoulakis|Zacharias|Z|0000-0003-0216-3420;Diakosavvas|Michail|M|0000-0003-1104-7739;Syllaios|Athanasios|A|;Pagkalos|Athanasios|A|;Samara|Athina A|AA|0000-0002-6177-7281;Tsatsaris|Georgios|G|0000-0001-8026-9795;Ntounis|Thomas|T|;Theodora|Marianna|M|;Sindos|Michael|M|;Kontomanolis|Emmanuel N|EN|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.3390/medicina57090969",
"fulltext": "\n==== Front\nMedicina (Kaunas)\nMedicina (Kaunas)\nmedicina\nMedicina\n1010-660X\n1648-9144\nMDPI\n\n10.3390/medicina57090969\nmedicina-57-00969\nCase Report\nCervical Twin Heterotopic Pregnancy: Overview of Ectopic Pregnancies and Scanning Detection Algorithm\nKoutras Antonios 1\nhttps://orcid.org/0000-0003-0216-3420\nFasoulakis Zacharias 1\nhttps://orcid.org/0000-0003-1104-7739\nDiakosavvas Michail 1\nSyllaios Athanasios 2\nPagkalos Athanasios 3\nhttps://orcid.org/0000-0002-6177-7281\nSamara Athina A. 4*\nhttps://orcid.org/0000-0001-8026-9795\nTsatsaris Georgios 5\nNtounis Thomas 1\nTheodora Marianna 1\nSindos Michael 1\nKontomanolis Emmanuel N. 5\nFerrero Simone Academic Editor\n1 1st Department of Obstetrics and Gynecology, General Hospital of Athens ‘ALEXANDRA’, National and Kapodistrian University of Athens, Lourou and Vasilissis Sofias Ave., 11528 Athens, Greece; antoniskoy@yahoo.gr (A.K.); hzaxos@gmail.com (Z.F.); mdiakosavvas@gmail.com (M.D.); thomasntounis@gmail.com (T.N.); martheodr@gmail.com (M.T.); sindosgyn@hotmail.com (M.S.)\n2 1st Department of Surgery, Laikon General Hospital, National and Kapodistrian University of Athens, Agiou Thoma Str. 17, 11527 Athens, Greece; nh_reas@hotmail.com\n3 Department of Obstetrics and Gynecology, General Hospital of Xanthi, Neapoli, 67100 Xanthi, Greece; sakispagkalos@gmail.com\n4 Department of Surgery, University Hospital of Larissa, Mezourlo, 41110 Larissa, Greece\n5 Department of Obstetrics and Gynecology, Democritus University of Thrace, Vasilissis Sofias Str. 12, 67100 Alexandroupolis, Greece; tsatsarisg3@gmail.com (G.T.); mek-2@otenet.gr (E.N.K.)\n* Correspondence: at.samara93@gmail.com; Tel.: +30-24-1350-1701\n15 9 2021\n9 2021\n57 9 96931 8 2021\n14 9 2021\n© 2021 by the authors.\n2021\nhttps://creativecommons.org/licenses/by/4.0/ Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).\nBackground: Ectopic pregnancy is the leading cause of gestation-related deaths during the first trimester. Cervical twin heterotopic pregnancies, when ectopic, constitute a small and rare part of gynecological surgery. Case Presentation: A 30-year-old pregnant woman (gravida 3, para 2) presented with mild pain in the lower abdomen and traces of bleeding per vaginum for three days. Transvaginal ultrasonography revealed a balloon-shaped cervical canal with a visible gestational sac measuring 3.5 × 3.9 cm. A second gestational sac was seen in the uterine cavity. The measurements of the gestational sacs corresponded to 7 + 4 weeks’ pregnancy. A decision for medical abortion with mifepristone and misoprostol was made. However, due to an incomplete abortion and continuous bleeding, a curettage was performed. Conclusions: Spontaneous heterotopic pregnancy with the ectopic pregnancy located in the cervix is an extremely rare clinical condition requiring urgent treatment in order to reduce maternal mortality and morbidity and preserve fertility.\n\nheterotopic pregnancy\ncervical twins\ngestation\n==== Body\npmc1. Introduction\n\nSpontaneous heterotopic pregnancy is a highly uncommon condition in which an intrauterine and extrauterine gestation occur simultaneously [1]. Cervical ectopic pregnancy (CEP) is an extremely rare condition, representing less than 0.1% of all ectopic pregnancies [2]. CEP is associated with high mother and embryo mortality and advanced pregnancies may require urgent surgical intervention, and in some cases, even a hysterectomy [3]. Diagnosis and management can be quite challenging, however, recent improvements in ultrasound resolution and earlier detection of these pregnancies have limited morbidity and preserved fertility [2,4]. As the treatment of choice (medical or surgical) for CEP remains controversial, factors such as gestational age, serum β-hCG (Beta Human Chorionic Gonadotropin) levels, fetal cardiac activity presence, and fertility preservation play a major role in individualization of each case [4].\n\nHerein, we present a rare case of a spontaneous unruptured cervical twin heterotopic pregnancy treated medically in order to preserve fertility.\n\n2. Case Presentation\n\nA 30-year-old pregnant Caucasian female (gravida 3, para 2) presented with mild pain located in the lower abdomen and traces of bleeding per vaginum for three days. During the gynecological examination, blood was found in the outer cervical os and the vagina. Conception was achieved spontaneously.\n\nHer previous menstrual cycle was normal and her gynecological history was unremarkable. She had no prior abdominal operations, and her past medical/surgical history revealed no allergies or co-morbidities; her blood group was Rhesus B (+) positive. Her obstetric history included two single pregnancies that were both delivered by a lower segment uterine section five and three years ago. Her infection profile was negative.\n\nUltrasonography examination was conducted thoroughly both transabdominally and transvaginally. The examination revealed a visible gestational sac measuring 3.5 × 3.9 cm and a yolk sac with a fetal pole. A second gestational sac with a yolk sac and fetal pole was seen in the uterine cavity surrounded by a thickened endometrium as expected. The measurements of both fetal poles corresponded to 7 + 4 weeks’ pregnancy. Positive cardiac activities were confirmed with the vaginal probe. In addition, magnetic resonance imaging (MRI) was requested to exclude uterine scar implantation.\n\nFollowing this, a decision was made for medical abortion with 200 mg of mifepristone (mifegyne), a synthetic steroid with anti-progesteronic action, and the day after, four tablets (800 mcg) of misoprostol (cytotec), an equivalent of the prostaglandin E1, which were administered orally. Heavy bleeding was observed by the patient and she reported immediately to the emergency room (ER). An ultrasound demonstrated incomplete expulsion of the products of conception.\n\nCurettage was performed to complete the abortion and control the bleeding originating from the network formed by the ascending branches of the vaginal artery and descending branches of the uterine artery. The bleeding was controlled with the use of a Foley balloon catheter in the cervical canal and simultaneous vaginal ligation of the branches of the cervical arteries in the vicinity of the external layer of the cervix.\n\n3. Discussion\n\nEctopic pregnancies make up a small part of gynecological surgery, but there is an increasing incidence worldwide, causing significant maternal morbidity and mortality, accompanied by pregnancy loss [5,6,7]. In the United Kingdom, there are around 11,000 cases reported annually (11.5 per 1000 pregnancies), with a mortality rate of 0.4 per 1000 ectopic pregnancies [7]. A ruptured ectopic pregnancy is a life-threatening medical condition that requires urgent surgical intervention [8]. Spontaneous extrauterine pregnancies are considered rare, and predisposing factors include pelvic inflammatory disease (often due to chlamydia trachomatis), tobacco smoking, prior tubal surgery, history of infertility, and increased age [9]. Most ectopic pregnancies are detected in the fallopian tubes (90%) and less than 1% are located in the cervix [1,5].\n\nClinical suspicion of extrauterine pregnancy is raised when the patient has a positive pregnancy test, bleeding, an adnexal mass, and a conglomeration of complex fluid (suggestive of blood) in the cul-de-sac anatomical area. Free fluid is a non-specific finding, although a large amount of fluid is suggestive of an ectopic pregnancy. Complex fluid is compatible with hemoperitoneum; this is associated with ectopic pregnancy but does not necessarily signify tubal rupture [10].\n\nEarly detection of an ectopic pregnancy is vital, and laboratory investigation has limited use. When an ectopic pregnancy ruptures, hemoperitoneum, a result of the rapid accumulation of blood under pressure within the peritoneum, is an emergency situation that can lead to hemodynamic instability and that requires urgent surgery [11]. Sonographic detection and “final” diagnosis of an ectopic pregnancy are definitely the most difficult steps of the management process. Transvaginal ultrasonography (U/S) is a more accurate tool compared to the abdominal alternative in cases of cervical ectopic pregnancies (CEP) [12]. The ‘sliding sign’ on transvaginal U/S can help with the differential diagnosis of an aborting intrauterine pregnancy residing in the cervix [12,13,14]. The presence of this kind of pregnancy becomes noticeable with obturator pain. Yet, despite improvements in ultrasonography, the consequences of misdiagnosis (unnecessary surgery, interruption of a normal and viable gestation) are still likely to result [15]. A diagnostic laparoscopy is the gold standard for the diagnosis of an ectopic gestation [16].\n\nThe uterine scar due to a previous cesarean section is closely located to the internal os. In our case, the patient had undergone two previous cesarean sections, which partially justified the presence of the cervical pregnancy without, however, being implanted in the previous scar. To exclude uterine scar implantation, an MRI was performed.\n\nTransvaginal U/S seems to be more sensitive in the definitive diagnosis of hemoperitoneum than culdocentesis f; we could otherwise conclude that transvaginal sonography has to a great extent replaced culdocentesis in the evaluation of ectopic pregnancy. Sonographic diagnosis of a cervical pregnancy is now established when a gestational sac surrounded by a peritrophoblastic flow is observable, or when a live embryo with positive cardiac activity is detected within the cervical canal. Moreover, the endometrium might have a pseudogestational sac with decidual cysts around it [17]. Neither type of pain nor the location of pain is specific for confirming the location of an ectopic pregnancy [18]. In our case, the patient presented to our external department with pain located in the lower abdomen and vaginal bleeding (spotting) for the past three days that she did not pay attention to, due to the fact that she had previously experienced the same symptom without any particular findings after gynecological examination.\n\nA negative hCG essentially excludes the diagnosis of a live pregnancy, although a chronic ectopic pregnancy may be present. Normally, serum beta-hCG becomes positive at around 23 menstrual days (nine days postconception). In a normal pregnancy, the hCG doubling time is two days. In a twin pregnancy, hCG rises rapidly from the very beginning of gestation. In ectopic pregnancy, the doubling time is prolonged. If hCG levels are abnormally elevated, the patient might have an ectopic pregnancy [19].\n\nApproximately 60% of surgically treated patients subsequently experience a term pregnancy.\n\nHeterotopic multifetal pregnancy is the co-existence of an intrauterine pregnancy with an ectopic pregnancy. All multiple gestations should be carefully evaluated for the possibility of an ectopic pregnancy [20]. The sac should be eccentric to the endometrial cavity. The earliest sign of an intrauterine pregnancy is a small fluid collection in the endometrium [21]. Ectopic pregnancy will eventually lead to adverse outcomes and a decision for the intrauterine pregnancy has to be made. In the literature, there have been described many cases of a live birth after a successfully treated heterotopy pregnancy [1]. In our case, where the heterotopy pregnancy was located in the cervix, the patient decided to stop both pregnancies, and misoprostol was administered followed by dilation and curettage due to severe bleeding.\n\nThe cervix is composed predominantly of fibrous tissue, and patients bleed profusely. Currently, conservative treatment includes sonographically introduced local potassium chloride injection, systemic or local methotrexate, or preoperative uterine artery embolization before dilatation and curettage, with the aim to preserve future reproductive potential [22].\n\n4. Conclusions\n\nCervical twin heterotopic pregnancies, when ectopic, constitute a small part of gynecological surgery; delayed diagnosis and treatment can lead to mothers’ mortality and embryo loss. Transvaginal scanning seems to be an accurate and safe way of detecting hemoperitoneum and gaining a better look at the endometrium, while sonographic diagnosis is not that clear in all cases. However, the most efficient method of diagnosing and managing ectopic pregnancies is still under investigation.\n\nAcknowledgments\n\nThe authors are grateful to all who provided assistance during the preparation of this manuscript.\n\nAuthor Contributions\n\nA.K., Z.F., M.D., T.N., A.S., A.A.S., M.T., M.S. and E.N.K. contributed to study conception and design. A.K., E.N.K. and A.S. were responsible for overall supervision. A.K., A.P., A.A.S. and G.T. drafted the manuscript, which was revised by E.N.K. All authors have read and agreed to the published version of the manuscript.\n\nFunding\n\nThis research did not receive any specific grant from funding agencies in the public, commercial or not-for-profit sectors.\n\nInstitutional Review Board Statement\n\nThe manuscript meets the all the criteria of the Declaration of Helsinki.\n\nInformed Consent Statement\n\nWritten informed consent was obtained from the patient for the publication of this case report.\n\nData Availability Statement\n\nData are available upon reasonable request.\n\nConflicts of Interest\n\nThe authors declare that they have no competing interest.\n\nPublisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n\n1. Ntounis T. Fasoulakis Z. Koutras A. Diakosavvas M. Bourazan A. Pagkalos A. Samara A.A. Kontomanolis E.N. Heterotopic tubal pregnancy with a naturally conceived live twin intrauterine pregnancy in a patient with systemic lupus erythematosus: A case report Case Rep. Women’s Health 2021 32 e00348 10.1016/j.crwh.2021.e00348 34401399\n2. Singh S. Diagnosis and management of cervical ectopic pregnancy J. Hum. Reprod. Sci. 2013 6 273 276 10.4103/0974-1208.126312 24672169\n3. Takeda K. Mackay J. Watts S. Successful Management of Cervical Ectopic Pregnancy with Bilateral Uterine Artery Embolization and Methotrexate Case Rep. Emerg. Med. 2018 2018 9593824 10.1155/2018/9593824 29854485\n4. Ozcivit I.B. Cepni I. Hamzaoğlu K. Erenel H. Madazlı R. Conservative management of 11 weeks old cervical ectopic pregnancy with transvaginal ultrasound-guided combined methotrexate injection: Case Report and Literature Review Int. J. Surg. Case Rep. 2020 67 215 218 10.1016/j.ijscr.2020.01.020 32066111\n5. Elmoheen A. Salem W.A. Eltawagny M. Elmoheen R. Bashir K. The Largest Tubal Pregnancy: 14th Week Case Rep. Obstet. Gynecol. 2020 2020 4728730 10.1155/2020/4728730 32518701\n6. Sivalingam V. Duncan W.C. Kirk E. Shephard L.A. Horne A.W. Diagnosis and management of ectopic pregnancy J. Fam. Plan. Reprod. Health Care 2011 37 231 240 10.1136/jfprhc-2011-0073\n7. Taheri M. Bharathan R. Subramaniam A. Kelly T. A United Kingdom national survey of trends in ectopic pregnancy management J. Obstet. Gynaecol. 2014 34 508 511 10.3109/01443615.2014.910181 24766292\n8. Hoover K.W. Tao G. Kent C.K. Trends in the Diagnosis and Treatment of Ectopic Pregnancy in the United States Obstet. Gynecol. 2010 115 495 502 10.1097/AOG.0b013e3181d0c328 20177279\n9. Marion L.L. Meeks G.R. Ectopic pregnancy: History, incidence, epidemiology, and risk factors Clin. Obstet. Gynecol. 2012 55 376 386 10.1097/GRF.0b013e3182516d7b 22510618\n10. Parker V.L. Srinivas M. Non-tubal ectopic pregnancy Arch. Gynecol. Obstet. 2016 294 19 27 10.1007/s00404-016-4069-y 27056054\n11. Alkatout I. Honemeyer U. Strauss A. Tinelli A. Malvasi A. Jonat W. Mettler L. Schollmeyer T. Clinical Diagnosis and Treatment of Ectopic Pregnancy Obstet. Gynecol. Surv. 2013 68 571 581 10.1097/OGX.0b013e31829cdbeb 23921671\n12. Rathod S. Samal S.K. Cervical ectopic pregnancy J. Nat. Sci. Biol. Med. 2015 6 257 260 10.4103/0976-9668.149221 25810679\n13. Jurkovic D. Hacket E. Campbell S. Diagnosis and treatment of early cervical pregnancy: A review and a report of two cases treated conservatively Ultrasound Obstet. Gynecol. 1996 8 373 380 10.1046/j.1469-0705.1997.08060373.x 9014275\n14. Hajenius P.J. Mol F. Mol B.W.J. Bossuyt P.M. Ankum W.M. Van Der Veen F. Interventions for tubal ectopic pregnancy Cochrane Database Syst. Rev. 2007 2007 CD000324 10.1002/14651858.CD000324.pub2 17253448\n15. Chetty M. Elson J. Treating non-tubal ectopic pregnancy Best Pract. Res. Clin. Obstet. Gynaecol. 2009 23 529 538 10.1016/j.bpobgyn.2008.12.011 19230785\n16. Murray H. Baakdah H. Bardell T. Tulandi T. Diagnosis and treatment of ectopic pregnancy Can. Med. Assoc. J. 2005 173 905 912 10.1503/cmaj.050222 16217116\n17. American College of Obstetricians and Gynecologists’ Committee on Practice Bulletins—Gynecology ACOG Practice Bulletin No. 193: Tubal Ectopic Pregnancy Obstet. Gynecol. 2018 131 e91 e103 Erratum in Obstet. Gynecol. 2019, 133, 1059 10.1097/AOG.0000000000002560 29470343\n18. Long Y. Zhu H. Hu Y. Shen L. Fu J. Huang W. Interventions for non-tubal ectopic pregnancy Cochrane Database Syst. Rev. 2020 7 CD011174 10.1002/14651858.cd011174.pub2 32609376\n19. Gun M. Mavrogiorgis M. Cervical ectopic pregnancy: A case report and literature review Ultrasound Obstet. Gynecol. 2002 19 297 301 10.1046/j.1469-0705.2002.00559.x 11896956\n20. Talbot K. Simpson R. Price N. Jackson S.R. Heterotopic pregnancy J. Obstet. Gynaecol. 2011 31 7 12 10.3109/01443615.2010.522749 21280985\n21. Soriano D. Shrim A. Seidman D.S. Goldenberg M. Mashiach S. Oelsner G. Diagnosis and treatment of heterotopic pregnancy compared with ectopic pregnancy J. Am. Assoc. Gynecol. Laparosc. 2002 9 353 358 10.1016/S1074-3804(05)60416-1\n22. Goldstein J.S. Ratts V.S. Philpott T. Dahan M. Risk of Surgery After Use of Potassium Chloride for Treatment of Tubal Heterotopic Pregnancy Obstet. Gynecol. 2006 107 506 508 10.1097/01.AOG.0000175145.23512.5e 16449166\n\n",
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"abstract": "A female with massive PTE and absolute contraindication for thrombolytic did not meet guidelines due to unavailability of catheter or surgical embolectomy and giving thrombolytic as a last resort to save a life. In such cases, physicians should consider to act outside of the guidelines to save a life.",
"affiliations": "Cardiology Department of Shohaday-e-Tajrish Hospital Shahid Beheshti University of Medical Sciences Tehran Iran.;Cardiology Department of Shohaday-e-Tajrish Hospital Shahid Beheshti University of Medical Sciences Tehran Iran.;Cardiology Department of Shohaday-e-Tajrish Hospital Shahid Beheshti University of Medical Sciences Tehran Iran.;Internal Department of Shohaday-e-Tajrish Hospital Shahid Beheshti University of Medical Sciences Tehran Iran.;Internal Department of Shohaday-e-Tajrish Hospital Shahid Beheshti University of Medical Sciences Tehran Iran.",
"authors": "Alirezaei|Toktam|T|0000-0002-4473-7093;Hajimoradi|Behzad|B|;Pishgahi|Mehdi|M|;Nekooghadam|Seyyed Mojtaba|SM|;Golmohamadi|Mohamad|M|",
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"fulltext": "\n==== Front\nClin Case RepClin Case Rep10.1002/(ISSN)2050-0904CCR3Clinical Case Reports2050-0904John Wiley and Sons Inc. Hoboken 10.1002/ccr3.1629CCR31629Case ReportCase ReportsSuccessful systemic thrombolytic therapy for massive pulmonary embolism in a patient with breast cancer, brain metastasis, and thrombocytopenia: A case report ALIREZAEI et al.Alirezaei Toktam http://orcid.org/0000-0002-4473-7093alirezaei.toktam@sbmu.ac.ir \n1\nHajimoradi Behzad \n1\nPishgahi Mehdi \n1\nNekooghadam Seyyed Mojtaba \n2\nGolmohamadi Mohamad \n2\n\n1 \nCardiology Department of Shohaday‐e‐Tajrish Hospital\nShahid Beheshti University of Medical Sciences\nTehran\nIran\n\n2 \nInternal Department of Shohaday‐e‐Tajrish Hospital\nShahid Beheshti University of Medical Sciences\nTehran\nIran\n* Correspondence\n\nToktam Alirezaei, Cardiology Department of Shohaday‐e‐Tajrish Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran.\n\nEmail: alirezaei.toktam@sbmu.ac.ir\n05 6 2018 8 2018 6 8 10.1002/ccr3.2018.6.issue-81431 1435 18 2 2018 26 4 2018 08 5 2018 © 2018 The Authors. Clinical Case Reports published by John Wiley & Sons Ltd.This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.Key Clinical Message\nA female with massive PTE and absolute contraindication for thrombolytic did not meet guidelines due to unavailability of catheter or surgical embolectomy and giving thrombolytic as a last resort to save a life. In such cases, physicians should consider to act outside of the guidelines to save a life.\n\nbrain metastasismassive pulmonary embolismsystemic thrombolysisthrombocytopenia source-schema-version-number2.0component-idccr31629cover-dateAugust 2018details-of-publishers-convertorConverter:WILEY_ML3GV2_TO_NLMPMC version:version=5.4.4 mode:remove_FC converted:19.08.2018\n\n\nAlirezaei \nT \n, \nHajimoradi \nB \n, \nPishgahi \nM \n, \nNekooghadam \nSM \n, \nGolmohamadi \nM \n. Successful systemic thrombolytic therapy for massive pulmonary embolism in a patient with breast cancer, brain metastasis, and thrombocytopenia: A case report . Clin Case Rep . 2018 ;6 :1431 –1435 . 10.1002/ccr3.1629\n==== Body\n1 INTRODUCTION\nVenous thromboembolism (VTE) is a common complication of cancer and is a major cause of morbidity and one of the leading causes of mortality in terminal cancer patients.\n\nTreatment of thromboembolic disease especially life‐threatening conditions such as massive pulmonary embolism in cancer patients is challenging.\n\nIt is common for clinicians to be faced with the dilemma of how to manage cancer patients with massive pulmonary embolism in life‐threatening settings. In the present case, the problem was further complicated by brain metastasis and thrombocytopenia both of which have a dramatic impact in the risk of intracranial hemorrhage after thrombolysis.\n\n2 CLINICAL CASE REPORT\nA 65‐year‐old female, known case of metastatic breast cancer with brain involvement, presented to our emergency department because of dyspnea, tachypnea, tachycardia and hypotension since 2 hours ago.\n\nShe had history of triple positive (ER+, PR+, HER2+) breast cancer and left radical mastectomy 15 years ago after which systemic chemotherapy and hormone therapy (Letrozole/Tamoxifen) was implemented. Three years before current presentation, bilateral hystero‐salpingo‐ovoforectomy, was performed. About 2 months ago, routine clinical examination by her oncologists revealed left axillary lymphadenopathy (2 × 3 cm) with fixed, firm and nontender node and an additional fixed mass (1 × 3 cm) in the anterior left forearm. Both lesions were excisionally biopsied. Further Imaging showed bilateral hilar lymphadenopathy and multiple metastatic lesions in the liver & abdomen and chest. PET scan showed 2 metastatic lesions in brain.\n\nPathologic examination of excised node revealed metastatic breast cancer (ER+/HER2+) and salvage chemotherapy with Paclitaxel 100 mg and Gemcitabin 1000 mg weekly plus Herceptin (Trastuzumab) 440 mg and Perjecta (Pertuzumab) 14 mg/kg tri weekly was initiated. One day after the first dose of Herceptin and Perjecta and the fourth dose of Gemcitabin and Paclitaxel, the right lower extremity swelling developed and subsequent Compression ultrasound and Doppler studies revealed acute extensive thrombus formation in the superficial femoral vein of the right leg. The patient was admitted and anticoagulation therapy with LMVH (60 mg BID) was initiated under the supervision of an oncologist at a private hospital. Preliminary laboratory tests revealed mild pancytopenia with a platelet count of 60 000 that was attributed to recent chemotherapy.\n\nTwo days after anticoagulation initiation she was discharged home.\n\nShortly after discharge, she presented to our emergency department with complaint of severe shortness of breath beginning abruptly 2 hours ago.\n\nHer vital signs upon arrival to the emergency department showed a systolic blood pressure of 70 mm Hg, a heart rate of 155 beats per minute, a respiratory rate of 40 per minute & oxygen saturation of 70% in ambient air. She was apparently pale, agitated, diaphoretic and unable to speak in full sentence. Jugular veins were distended and cardiac exam showed moderate tachycardia and a right ventricular heave.\n\nPulmonary examination was unremarkable except for decreased breath sounds at the mid‐zone of the left lung and the base of right lung.\n\nRadial pulses were very weak bilaterally with no palpable pulse in lower extremities. The initial electrocardiogram showed sinus tachycardia at a rate of 135 per minute, right bundle branch block with a QRS duration of 130 ms and right axis deviation of 110 degrees (Figure 1).\n\nFigure 1 \nECG shows sinus tachycardia and right bundle branch block\n\nBedside echocardiography performed despite severe agitation of the patient demonstrated preserved EF (EF = 50%‐55%), severe right ventricular (RV) dilation and estimated pulmonary artery pressure (PAP) of 45‐50 mm Hg.\n\nRepeat laboratory findings showed Hemoglobin: 8 (g/dL), Platelets count: 50/mm3.\n\nImmediately a 500 cc bolus of normal saline was administered and norepinephrine was initiated as vasopressor of choice.\n\nPulmonary CT angiography (CTA) confirmed large bilateral pulmonary thromboemboli with radiological evidence of RV strain (Figure 2).\n\nFigure 2 Pulmonary CT angiography demonstrates bilateral pulmonary thromboemboli with RV strain\n\nAccording to hemodynamic compromise resulting from the massive pulmonary embolism and absolute contraindication for thrombolytic therapy due to brain metastases and concurrent thrombocytopenia, she became candidate for emergent catheter or surgical embolectomy. Surgical consult with cardiothoracic surgeon was requested but due to critical condition of the patient complicated by refractory hypoxia and unstable hemodynamic parameters surgery and anesthesiology team declared the patient as inoperable and there was no equipment and specialist for catheter embolectomy in our center.\n\nUltimately the critical decision was made, despite absolute contraindications, to treat the patient with systemic thrombolysis. Alteplase was selected as thrombolytic of choice and was prescribed according to approved dosage for massive PTE (100 mg infusion over a 2 hours’ period).\n\nApproximately 1 hour after termination of thrombolytic therapy, the norepinephrine was discontinued. Blood pressure returned to 110/70 mm Hg, with a heart rate of 100 beats per minute and a respiratory rate of 20 per minute with an oxygen saturation of 90% in ambient air. Electrocardiogram now shows sinus tachycardia at a rate of 100 per minute, normal QRS duration and normal axis, Figure 3.\n\nFigure 3 \nECG shows normal sinus tachycardia\n\nHeparin infusion was initiated with half‐dose because of concurrent thrombocytopenia.\n\nAfter 30 hours, heparin infusion stopped due to a drop in platelet count (platelet count: 23 000/mm3), consulted with hematologist colleagues, they believed it was due to recent chemotherapy, so 10 units of platelets were transfused. One day later platelet count reached 123 000/mm3, heparin infusion was resumed, and after 24 hours it changed to a therapeutic dose of subcutaneous enoxaparin (LMWH with a dose of 60 mg twice a day). The patient continued to improve clinically and was discharged from hospital after 5 days with LMWH. Last echocardiography performed immediately before discharge demonstrated mild RV enlargement & dysfunction and pulmonary artery pressure of 20‐25 mm Hg. One week after discharge, laboratory findings showed Hemoglobin: 11.5 (g/dL), Platelet count: 227/mm.\n\n3 DISCUSSION\nVenous thromboembolism (pulmonary embolism and deep venous thrombosis) is a common complication of various cancers and their treatments.1, 2 Malignancies are associated with a 4‐fold increase in VTE incidence3 and VTE affects up to 20% of cancer patients, such that it is one of the major causes of morbidity and mortality in these population.4\n\n\nMetastatic disease at the time of diagnosis is considered to be the strongest predictor of VTE within the first year of diagnosis and is associated with a 1.4‐21.5‐fold higher risk of VTE according to the type of cancer.5, 6, 7, 8, 9, 10\n\n\nCancer‐related VTE is associated with higher rates of mortality or morbidity, in part due to increased bleeding complications imposed by anticoagulation/fibrinolytic therapy compared with VTE in patients without cancer4, 11 it is also a marker of more advanced disease and portends a poor prognosis.12\n\n\nMetastatic brain lesions are more prone to spontaneous intracranial hemorrhage compared with primary brain tumors.13 However, the risk of intracranial hemorrhage from breast cancers brain metastases is relatively low (1%‐5%).14, 15\n\n\nIn recent decades, owing to striking developments in the field of treatment of metastatic breast cancer, long‐term survival can be achieved in many patients.16 Furthermore, the increased prevalence of brain metastases is becoming a major impediment to improve quality of life for many breast cancer patients.\n\nInternational society guidelines addressing management of pulmonary embolism, generally propose 2 viable options in the management of massive PTE: (i) thrombolysis, (ii) surgical embolectomy. Systemic thrombolysis leads to rapid resolution of thrombi and improves hemodynamic instability.17, 18 Despite this recommendations, in a study of 108 patients with massive pulmonary embolism, 2‐thirds of the patients did not receive thrombolysis or embolectomy.19\n\n\nImprovement in the survival of cancer patients may lead to an increase in malignancy‐associated VTE episodes, many of which are complicated by concomitant metastatic involvement of brain. In conditions such as massive pulmonary embolism, the patients need emergency treatments. Systemic thrombolysis has absolute contraindication in the cases of brain metastases and emergency embolectomy is not available in all hospitals ‐and if available‐ many surgeons and anesthesiologists are reluctant to accept the risk of surgery. Act outside of the guidelines to save a life, Therefore, in life‐threatening conditions, clinicians may be faced with the question of how to manage patient with massive pulmonary embolism and they have to act outside of the guidelines to lifesaving.20\n\n\nIn the current case, we encountered a management crisis in a patient with massive pulmonary embolism who was at extremely high risk for bleeding complications of thrombolytic therapy and at the same time, no other acceptable recourse was available. Ultimately the patient survived the jeopardy of this double‐edge remedy. By this case report, we reported successful outcome of thrombolytic therapy as a last resort in massive PTE despite its contraindication.\n\nCONFLICT OF INTEREST\nThe authors have no conflict of interests to declare.\n\nAUTHORSHIP\nTA: analyzed data, drafted, did background research, and revised the manuscript. BH and MP: involved in patient management. SMN: reviewed results and revised the manuscript. MG: collected history.\n==== Refs\nREFERENCES\n1 \n\nStein \nPD \n, \nBeemath \nA \n, \nMeyers \nFA \n, \nSkaf \nE \n, \nSanchez \nJ \n, \nOlson \nRE \n. Incidence of venous thromboembolism in patients hospitalized with cancer . Am J Med . 2006 ;119 :60 ‐68 .16431186 \n2 \n\nKhorana \nAA \n, \nFrancis \nCW \n, \nCulakova \nE \n, \nFisher \nRI \n, \nKuderer \nNM \n, \nLyman \nGH \n. Thromboembolism in hospitalized neutropenic cancer patients . J Clin Oncol . 2006 ;24 :484 ‐490 .16421425 \n3 \n\nHeit \nJA \n, \nSilverstein \nMD \n, \nMohr \nDN \n, \nPetterson \nTM \n, \nO’Fallon \nWM \n, \nMelton \nLJ \n3rd\n. Risk factors for deep vein thrombosis and pulmonary embolism: a population‐based case‐control study . Arch Intern Med . 2000 ;160 :809 ‐815 .10737280 \n4 \n\nKhorana \nAA \n, \nFrancis \nCW \n, \nCulakova \nE \n, \nKuderer \nNM \n, \nLyman \nGH \n. Thromboembolism is a leading cause of death in cancer patients receiving outpatient chemotherapy . J Thromb Haemost . 2007 ;5 :632 ‐634 .17319909 \n5 \n\nChew \nHK \n, \nWun \nT \n, \nHarvey \nD \n, \nZhou \nH \n, \nWhite \nRH \n. Incidence of venous thromboembolism and its effect on survival among patients with common cancers . Arch Intern Med . 2006 ;166 :458 ‐464 .16505267 \n6 \n\nAlcalay \nA \n, \nWun \nT \n, \nKhatri \nV \n, et al. Venous thromboembolism in patients with colorectal cancer: incidence and effect on survival . J Clin Oncol . 2006 ;24 :1112 ‐1118 .16505431 \n7 \n\nChew \nHK \n, \nWun \nT \n, \nHarvey \nDJ \n, \nZhou \nH \n, \nWhite \nRH \n. Incidence of venous thromboembolism and the impact on survival in breast cancer patients . J Clin Oncol . 2007 ;25 :70 ‐76 .17194906 \n8 \n\nRodriguez \nAO \n, \nWun \nT \n, \nChew \nH \n, \nZhou \nH \n, \nHarvey \nD \n, \nWhite \nRH \n. Venous thromboembolism in ovarian cancer . Gynecol Oncol . 2007 ;105 :784 ‐790 .17408726 \n9 \n\nBlom \nJW \n, \nVanderschoot \nJP \n, \nOostindier \nMJ \n, \nOsanto \nS \n, \nvan der Meer \nFJ \n, \nRosendaal \nFR \n. Incidence of venous thrombosis in a large cohort of 66,329 cancer patients: results of a record linkage study . J Thromb Haemost . 2006 ;4 :529 ‐535 .16460435 \n10 \n\nChew \nHK \n, \nDavies \nAM \n, \nWun \nT \n, \nHarvey \nD \n, \nZhou \nH \n, \nWhite \nRH \n. The incidence of venous thromboembolism among patients with primary lung cancer . J Thromb Haemost . 2008 ;6 :601 ‐608 .18208538 \n11 \n\nPrandoni \nP \n, \nLensing \nAW \n, \nPiccioli \nA \n, et al. Recurrent venous thromboembolism and bleeding complications during anticoagulant treatment in patients with cancer and venous thrombosis . Blood . 2002 ;100 :3484 ‐3488 .12393647 \n12 \n\nSorensen \nHT \n, \nMellemkjaer \nL \n, \nOlsen \nJH \n, \nBaron \nJA \n. Prognosis of cancers associated with venous thromboembolism . N Engl J Med . 2000 ;343 :1846 ‐1850 .11117976 \n13 \n\nMaiuri \nF \n, \nD’Andrea \nF \n, \nGallicchio \nB \n, \nCarandente \nM \n. Intracranial hemorrhages in metastatic brain tumors . J Neurosurg Sci . 1985 ;29 :37 ‐41 .4067634 \n14 \n\nSo \nW \n, \nHugenholtz \nH \n, \nRichard \nMT \n. Complications of anticoagulant therapy in patients with known central nervous system lesions . Can J Surg . 1983 ;26 :181 ‐183 .6825010 \n15 \n\nGerber \nDE \n, \nGrossman \nSA \n, \nStreiff \nMB \n. Management of venous thromboembolism in patients with primary and metastatic brain tumors . J Clin Oncol . 2006 ;24 :1310 ‐1318 .16525187 \n16 \n\nTabouret \nE \n, \nChinot \nO \n, \nMetellus \nP \n, \nTallet \nA \n, \nViens \nP \n, \nGoncalues \nA \n. Recent trends in epidemiology of brain metastases: an over view . Anticancer Res . 2012 ;32 :4655 ‐4662 .23155227 \n17 \n\nKearon \nC \n, \nKahn \nSR \n, \nAgnelli \nG \n, et al. Antithrombotic therapy for venous thromboembolic disease: American College of Chest Physicians Evidence‐Based Clinical Practice Guidelines (8th Edition) . Chest \n2008 ;133 :454 ‐545 . These antithrombotic recommendations set the standard of care of the use of anticoagulation in patients including those with cancer in the USA.\n18 \n\nKucher \nN \n, \nGoldhaber \nSZ \n. Management of massive pulmonary embolism . Circulation . 2005 ;112 :e28 ‐e32 .16009801 \n19 \n\nKucher \nN \n, \nRossi \nE \n, \nDe Rosa \nM \n, \nGoldhaber \nSZ \n. Massive pulmonary embolism . Circulation . 2006 ;113 :577 ‐582 .16432055 \n20 \n\nPishgahi \nM \n, \nAlirezaei \nT \n, \nHajimoradi \nB \n, \nNekooghadam \nSM \n, \nShahi \nS \n. Systemic fibrinolytic therapy in the presence of absolute contraindication; a case series . Emergency . 2018 ;6 :e25 .30009227\n\n",
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"issue": "6(8)",
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"keywords": "brain metastasis; massive pulmonary embolism; systemic thrombolysis; thrombocytopenia",
"medline_ta": "Clin Case Rep",
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"pages": "1431-1435",
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"references": "12393647;17319909;16525187;16432055;18574272;16431186;6825010;16009801;23155227;18208538;16505267;4067634;11117976;17408726;16460435;16505431;17194906;16421425;30009227;10737280",
"title": "Successful systemic thrombolytic therapy for massive pulmonary embolism in a patient with breast cancer, brain metastasis, and thrombocytopenia: A case report.",
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{
"abstract": "Whole-arm translocations are relatively rare among hematological malignancies. There are a few reports on myeloid malignancies harboring der(1;21)(q10;q10). A 65-year-old male was referred to our hospital due to squamous cell carcinoma of the lung. Pembrolizumab monotherapy resulted in progression, and so chemotherapy involving nab-paclitaxel and carboplatin was administered thereafter. The patient developed cytopenia, and his bone marrow exhibited dysplasia. Chromosomal analysis revealed a whole-arm translocation, der(1;21)(q10;q10). Thus, the patient was diagnosed with myelodysplastic syndrome. The der(1;21)(q10;q10) translocation is a rare variant of the der(1;7)(q10;p10) translocation, which is an adverse prognostic factor for myeloid neoplasms. Clarifying the clinical features of myeloid neoplasms in patients with der(1;21)(q10;q10) would facilitate the elucidation of their tumorigenic mechanisms.",
"affiliations": "Osaka General Hospital of West Japan Railway Company 1-2-22 Matsuzaki-cho, Abeno-ku, Osaka 545-0053, Japan.;Osaka General Hospital of West Japan Railway Company 1-2-22 Matsuzaki-cho, Abeno-ku, Osaka 545-0053, Japan.;Osaka General Hospital of West Japan Railway Company 1-2-22 Matsuzaki-cho, Abeno-ku, Osaka 545-0053, Japan.;Osaka General Hospital of West Japan Railway Company 1-2-22 Matsuzaki-cho, Abeno-ku, Osaka 545-0053, Japan.;Osaka General Hospital of West Japan Railway Company 1-2-22 Matsuzaki-cho, Abeno-ku, Osaka 545-0053, Japan.;Osaka General Hospital of West Japan Railway Company 1-2-22 Matsuzaki-cho, Abeno-ku, Osaka 545-0053, Japan.;Osaka General Hospital of West Japan Railway Company 1-2-22 Matsuzaki-cho, Abeno-ku, Osaka 545-0053, Japan.;Osaka General Hospital of West Japan Railway Company 1-2-22 Matsuzaki-cho, Abeno-ku, Osaka 545-0053, Japan.;Osaka General Hospital of West Japan Railway Company 1-2-22 Matsuzaki-cho, Abeno-ku, Osaka 545-0053, Japan.;Osaka General Hospital of West Japan Railway Company 1-2-22 Matsuzaki-cho, Abeno-ku, Osaka 545-0053, Japan.",
"authors": "Manabe|Masahiro|M|;Tamagaki|Gakuya|G|;Shimizu|Keiji|K|;Michimoto|Koichi|K|;Hagiwara|Yuuji|Y|;Asada|Reiko|R|;Momose|Dai|D|;Sugano|Yasuyoshi|Y|;Mazaki|Takeshi|T|;Koh|Ki-Ryang|KR|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2160-1992",
"issue": "8(3)",
"journal": "American journal of blood research",
"keywords": "der(1;21)(q10;q10); myelodysplastic syndrome; whole-arm translocation",
"medline_ta": "Am J Blood Res",
"mesh_terms": null,
"nlm_unique_id": "101569577",
"other_id": null,
"pages": "17-20",
"pmc": null,
"pmid": "30498621",
"pubdate": "2018",
"publication_types": "D002363:Case Reports",
"references": "8975709;10706455;9593284;21039422;12816870;8527385;16527611;3706291;17321329;10862050;17315020;12454741;8502563",
"title": "An isolated der(1;21)(q10;q10) translocation in a patient with myelodysplastic syndrome: a case report.",
"title_normalized": "an isolated der 1 21 q10 q10 translocation in a patient with myelodysplastic syndrome a case report"
} | [
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{
"reactionmeddrapt": "Pancytopenia",
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"reactionoutcome": "3"
}
],
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},
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"literaturereference": "MANABE M, TAMAGAKI G, SHIMIZU K, MICHIMOTO K, HAGIWARA Y, ASADA R, ET AL.. AN ISOLATED DER(1?21)(Q10?Q10) TRANSLOCATION IN A PATIENT WITH MYELODYSPLASTIC SYNDROME: A CASE REPORT.. AM-J-BLOOD-RES. 2018?8(3):17-20.",
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},
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},
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"transmissiondate": "20190417"
}
] |
{
"abstract": "Opioids are currently offered as first-line treatment for chronic pain from cancer. Continuous regional analgesia could be an alternative to opioids. However, the required duration of catheterization and the sustained analgesic effects of this technique after catheter removal have yet to be clarified.\n\n\n\nWe report the case of a patient with a shoulder desmoid tumour for which monitoring of tumour progression was the sole therapeutic strategy. Analgesia took the form of patient-controlled infusion of local anaesthetics through an interscalene catheter. Due to the need of an MRI control 45 days later, the pump was stopped. The persistence of pain relief 48 hr later led to the decision to remove the perineural catheter. No pain was reported by the patient over the following 42 days.\n\n\n\nIn this patient, it would seem that continuous analgesia allowed for a sustained resolution of pain from the shoulder-located tumour. One hypothesis is that local anaesthetics play a direct role in the erasure of pain memory. This hypothesis needs to be tested with a large patient cohort.\n\n\n\nThis case report provides new insights into the treatment of cancer pain. The most interesting finding is that the pain did remained absent after 45 days of continuous infusion of local anaesthetics through an interscalene catheter. We postulated that local anaesthetic drugs have an impact on pain memory.",
"affiliations": "Department of Anesthesiology, Institut Claudius Regaud, IUCT-O, Toulouse, France.;Department of Anesthesiology, Institut Claudius Regaud, IUCT-O, Toulouse, France.;Department of Anesthesiology, Institut Claudius Regaud, IUCT-O, Toulouse, France.;Department of Anesthesiology, Institut Claudius Regaud, IUCT-O, Toulouse, France.;Department of Anesthesiology, Institut Claudius Regaud, IUCT-O, Toulouse, France.",
"authors": "Fuzier|Régis|R|;Izard|Philippe|P|;Daboussi|Amelle|A|;Pouymayou|Jacques|J|;Pierre|Sébastien|S|",
"chemical_list": "D000779:Anesthetics, Local; D000077212:Ropivacaine",
"country": "England",
"delete": false,
"doi": "10.1002/ejp.1295",
"fulltext": null,
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"issn_linking": "1090-3801",
"issue": "23(1)",
"journal": "European journal of pain (London, England)",
"keywords": null,
"medline_ta": "Eur J Pain",
"mesh_terms": "D000698:Analgesia; D000779:Anesthetics, Local; D000072716:Cancer Pain; D059350:Chronic Pain; D005260:Female; D018222:Fibromatosis, Aggressive; D018718:Home Infusion Therapy; D006801:Humans; D008875:Middle Aged; D009407:Nerve Block; D010147:Pain Measurement; D017060:Patient Satisfaction; D000077212:Ropivacaine; D012782:Shoulder; D020069:Shoulder Pain",
"nlm_unique_id": "9801774",
"other_id": null,
"pages": "31-34",
"pmc": null,
"pmid": "30074669",
"pubdate": "2019-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "A case report of sustained resolution of cancer pain by continuous perineural infusion of local anaesthetic.",
"title_normalized": "a case report of sustained resolution of cancer pain by continuous perineural infusion of local anaesthetic"
} | [
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}
],
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"reaction": [
{
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"reactionmeddraversionpt": "21.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Nausea",
"reactionmeddraversionpt": "21.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Dizziness",
"reactionmeddraversionpt": "21.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Sensory disturbance",
"reactionmeddraversionpt": "21.1",
"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "FUZIER R, IZARD P, DABOUSSI A, POUYMAYOU J, PIERRE S. A CASE REPORT OF SUSTAINED RESOLUTION OF CANCER PAIN BY CONTINUOUS PERINEURAL INFUSION OF LOCAL ANAESTHETIC. EUR-J-PAIN 2019?23(1):31-34.",
"literaturereference_normalized": "a case report of sustained resolution of cancer pain by continuous perineural infusion of local anaesthetic",
"qualification": "3",
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},
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},
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},
{
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"fulfillexpeditecriteria": "1",
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{
"abstract": "BACKGROUND\nThe mean age of patients included in clinical trials does not reflect the current clinical practice for patients with B-cell non-Hodgkin lymphoma (B-NHL). We compared our outcomes for patients with B-NHL aged < 65 and > 65 years who were treated with 90-yttrium-ibritumomab tiuxetan therapy ((90)Y-IT).\n\n\nMETHODS\nA total of 108 patients who had received (90)Y-IT according to the hospital protocol (ISCRTN36210045) were eligible. A quality of life (QoL) assessment using the Medical Outcomes Study short form 36-item survey was performed for patients aged > 65 years.\n\n\nRESULTS\nOf the 108 patients, 43 were aged > 65 years (mean age, 73.4 years; men 46.15%); 37 had follicular NHL (86.0%). Also, 27 patients had previously undergone < 2 therapy regimens (62.8%). The mean follow-up period was 45.2 months. The mean progression-free survival (PFS) period was 71.3 months, and the mean overall survival was 78.2 months. The median values were not reached. The overall response rate was 90.5%, and a complete response was observed in 36 of the 43 patients aged > 65 years (85.7%). Neutropenia (43.3%) and thrombocytopenia (45.2%) were the most frequent grade 3 and 4 toxicities. Five patients required a red blood cell transfusion and 11, a platelet transfusion. Five patients aged > 65 years (11.6%) developed a second tumor. These outcomes were similar to those for the younger patients. The QoL assessment showed scores similar to those of general population for general health and social functioning.\n\n\nCONCLUSIONS\nThis is the largest cohort of NHL treated with RIT in a single institution in Spain. We observed a high response rate and prolonged PFS in patients with B-NHL, independent of patient age. Thus, consolidation RIT offers better outcomes with manageable toxicity.",
"affiliations": "Department of Hematology, Miguel Servet University Hospital, Zaragoza, Spain; Translational Research Unit, Miguel Servet University Hospital-Instituto Aragonés de Ciencias de la Salud, Zaragoza, Spain; Centro de Investigación Biomédica en Red (CIBERER) Instituto de Salud Carlos III, Zaragoza, Spain.;Department of Hematology, Miguel Servet University Hospital, Zaragoza, Spain.;Department of Hematology, Miguel Servet University Hospital, Zaragoza, Spain.;Department of Nuclear Medicine, Miguel Servet University Hospital, Zaragoza, Spain.;Department of Hematology, Royo Villanova Hospital, Zaragoza, Spain.;Department of Nuclear Medicine, Miguel Servet University Hospital, Zaragoza, Spain.;Translational Research Unit, Miguel Servet University Hospital-Instituto Aragonés de Ciencias de la Salud, Zaragoza, Spain; Centro de Investigación Biomédica en Red (CIBERER) Instituto de Salud Carlos III, Zaragoza, Spain. Electronic address: giraldocastellano@gmail.com.",
"authors": "Andrade-Campos|Marcio M|MM|;Montes-Limón|Anel E|AE|;Soro-Alcubierre|Gloria|G|;Lievano|Paola|P|;López-Gómez|Luis|L|;Baringo|Teresa|T|;Giraldo|Pilar|P|",
"chemical_list": "D000911:Antibodies, Monoclonal; C422802:ibritumomab tiuxetan",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2152-2669",
"issue": "15(8)",
"journal": "Clinical lymphoma, myeloma & leukemia",
"keywords": "Elderly; Indolent NHL; Quality of life; Radioimmunotherapy; Safety",
"medline_ta": "Clin Lymphoma Myeloma Leuk",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000911:Antibodies, Monoclonal; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D008228:Lymphoma, Non-Hodgkin; D008297:Male; D008875:Middle Aged; D016499:Radioimmunotherapy",
"nlm_unique_id": "101525386",
"other_id": null,
"pages": "464-71",
"pmc": null,
"pmid": "25823889",
"pubdate": "2015-08",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Patients Older Than 65 Years With Non-Hodgkin Lymphoma Are Suitable for Treatment With (90)Yttrium-Ibritumumab Tiuxetan: A Single-Institution Experience.",
"title_normalized": "patients older than 65 years with non hodgkin lymphoma are suitable for treatment with 90 yttrium ibritumumab tiuxetan a single institution experience"
} | [
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],
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}
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},
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}
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}
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},
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},
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] |
{
"abstract": "Alemtuzumab, approved for multiple sclerosis (MS), can cause secondary autoimmune adverse events including thyroid disorders, immune thrombocytopenia (ITP), and glomerular nephropathies. Non-ITP autoimmune cytopenias are rarely reported.\n\n\n\nTo report a case of autoimmune hemolytic anemia (AIHA) and nephropathy in a MS patient treated with alemtuzumab.\n\n\n\nA 34-year-old man with MS developed albuminuria and AIHA after the first and only alemtuzumab treatment, with positive Coombs' direct and indirect tests and IgG autoantibodies. Both AIHA and nephropathy resolved 1 month after treatment with steroids and intravenous immunoglobulins.\n\n\n\nOur report adds to literature on AIHA and nephropathy after alemtuzumab treatment and suggests to add Coombs' tests to the screening panel required for alemtuzumab treatment.",
"affiliations": "MS Center, Neurologic Clinic, SS. Annunziata Hospital, Chieti, Italy/Department of Neuroscience, Imaging and Clinical Sciences, \"G. d'Annunzio\" University, Chieti, Italy.;MS Center, Neurologic Clinic, SS. Annunziata Hospital, Chieti, Italy/Department of Neuroscience, Imaging and Clinical Sciences, \"G. d'Annunzio\" University, Chieti, Italy.;MS Center, Neurologic Clinic, SS. Annunziata Hospital, Chieti, Italy/Department of Neuroscience, Imaging and Clinical Sciences, \"G. d'Annunzio\" University, Chieti, Italy.;MS Center, Neurologic Clinic, SS. Annunziata Hospital, Chieti, Italy.;MS Center, Neurologic Clinic, SS. Annunziata Hospital, Chieti, Italy/Department of Neuroscience, Imaging and Clinical Sciences, \"G. d'Annunzio\" University, Chieti, Italy.;MS Center, Neurologic Clinic, SS. Annunziata Hospital, Chieti, Italy/Department of Neuroscience, Imaging and Clinical Sciences, \"G. d'Annunzio\" University, Chieti, Italy.;MS Center, Neurologic Clinic, SS. Annunziata Hospital, Chieti, Italy.",
"authors": "di Ioia|Maria|M|;Farina|Deborah|D|;di Tommaso|Valeria|V|;Travaglini|Daniela|D|;Pietrolongo|Erika|E|;Onofrj|Marco|M|;de Luca|Giovanna|G|",
"chemical_list": "D007155:Immunologic Factors; D000074323:Alemtuzumab",
"country": "England",
"delete": false,
"doi": "10.1177/1352458517743093",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1352-4585",
"issue": "24(6)",
"journal": "Multiple sclerosis (Houndmills, Basingstoke, England)",
"keywords": "Multiple sclerosis; albuminuria; alemtuzumab; autoimmune hemolytic anemia; glomerular nephropathy",
"medline_ta": "Mult Scler",
"mesh_terms": "D000328:Adult; D000419:Albuminuria; D000074323:Alemtuzumab; D000744:Anemia, Hemolytic, Autoimmune; D006801:Humans; D007155:Immunologic Factors; D008297:Male; D020529:Multiple Sclerosis, Relapsing-Remitting",
"nlm_unique_id": "9509185",
"other_id": null,
"pages": "813-815",
"pmc": null,
"pmid": "29359617",
"pubdate": "2018-05",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Simultaneous early-onset severe autoimmune hemolytic anemia and albuminuria during alemtuzumab treatment for multiple sclerosis.",
"title_normalized": "simultaneous early onset severe autoimmune hemolytic anemia and albuminuria during alemtuzumab treatment for multiple sclerosis"
} | [
{
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{
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"activesubstance": {
"activesubstancename": "ALEMTUZUMAB"
},
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},
{
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},
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},
{
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},
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"drugdosagetext": "15 MG,QD",
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"drugindication": "INSOMNIA",
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"medicinalproduct": "MIRTAZAPINE."
}
],
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"patientonsetageunit": "801",
"patientsex": "1",
"patientweight": "70",
"reaction": [
{
"reactionmeddrapt": "Coombs indirect test positive",
"reactionmeddraversionpt": "21.1",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Hypercreatininaemia",
"reactionmeddraversionpt": "21.1",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Haemoglobin decreased",
"reactionmeddraversionpt": "21.1",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Coombs direct test positive",
"reactionmeddraversionpt": "21.1",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Red blood cell count decreased",
"reactionmeddraversionpt": "21.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Hyperhidrosis",
"reactionmeddraversionpt": "21.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Proteinuria",
"reactionmeddraversionpt": "21.1",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Tachycardia",
"reactionmeddraversionpt": "21.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Thrombocytopenia",
"reactionmeddraversionpt": "21.1",
"reactionoutcome": "2"
},
{
"reactionmeddrapt": "Glomerulonephropathy",
"reactionmeddraversionpt": "21.1",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Albuminuria",
"reactionmeddraversionpt": "21.1",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Asthenia",
"reactionmeddraversionpt": "21.1",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Haptoglobin decreased",
"reactionmeddraversionpt": "21.1",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Blood lactate dehydrogenase increased",
"reactionmeddraversionpt": "21.1",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Pallor",
"reactionmeddraversionpt": "21.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Autoimmune haemolytic anaemia",
"reactionmeddraversionpt": "21.1",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Palpitations",
"reactionmeddraversionpt": "21.1",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Anaemia",
"reactionmeddraversionpt": "21.1",
"reactionoutcome": "1"
}
],
"summary": {
"narrativeincludeclinical": "CASE EVENT DATE: 20170410"
}
},
"primarysource": {
"literaturereference": "IOIA MD, FARINA D, TOMMASO VD, TRAVAGLINI D, PIETROLONGO E, ONOFRJ M ET AL. SIMULTANEOUS EARLY-ONSET SEVERE AUTOIMMUNE HEMOLYTIC ANEMIA AND ALBUMINURIA DURING ALEMTUZUMAB TREATMENT FOR MULTIPLE SCLEROSIS. MULT. SCLER. J.. 2017?1-3",
"literaturereference_normalized": "simultaneous early onset severe autoimmune hemolytic anemia and albuminuria during alemtuzumab treatment for multiple sclerosis",
"qualification": "1",
"reportercountry": "IT"
},
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},
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},
"serious": 1,
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},
{
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},
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"summary": null
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},
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},
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},
{
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},
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},
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"drugtreatmentdurationunit": null,
"medicinalproduct": "GILENYA"
}
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"reaction": [
{
"reactionmeddrapt": "Tachycardia",
"reactionmeddraversionpt": "21.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Palpitations",
"reactionmeddraversionpt": "21.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Autoimmune haemolytic anaemia",
"reactionmeddraversionpt": "21.0",
"reactionoutcome": "1"
},
{
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"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Thrombocytopenia",
"reactionmeddraversionpt": "21.0",
"reactionoutcome": "2"
},
{
"reactionmeddrapt": "Red blood cell count decreased",
"reactionmeddraversionpt": "21.0",
"reactionoutcome": "6"
},
{
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"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Proteinuria",
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"reactionoutcome": "1"
},
{
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"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Nephropathy",
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"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Albuminuria",
"reactionmeddraversionpt": "21.0",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Asthenia",
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"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Hypercreatininaemia",
"reactionmeddraversionpt": "21.0",
"reactionoutcome": "1"
}
],
"summary": {
"narrativeincludeclinical": "CASE EVENT DATE: 20170410"
}
},
"primarysource": {
"literaturereference": "IOIA MD, FARINA D, TOMMASO VD, TRAVAGLINI D, PIETROLONGO E, ONOFRJ M ET AL. SIMULTANEOUS EARLY-ONSET SEVERE AUTOIMMUNE HEMOLYTIC ANEMIA AND ALBUMINURIA DURING ALEMTUZUMAB TREATMENT FOR MULTIPLE SCLEROSIS. MULTIPLE SCLEROSIS JOURNAL.1-3. DOI: 10.1177/1352458517743093",
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},
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}
] |
{
"abstract": "Present study carried out in a tertiary referral hospital in North India attempts to determine the maternal and neonatal outcomes of metformin therapy in patients of gestational diabetes mellitus.\nTo evaluate maternal and neonatal outcomes in patients of GDM on metformin therapy and to study its adverse effects.\nIn this prospective observational study, all women diagnosed with GDM not controlled by medical nutrition therapy were started on metformin therapy and the maternal and neonatal outcomes were studied.\nA total of 104 patients of GDM, not controlled on MNT and requiring pharmacotherapy, were enrolled for the study. An important clinical data from the study were that in 63.5% of patients there was no family history of diabetes mellitus. Average weight gain during pregnancy ranged from 6 to 10 kg. Glycemic control was achieved in 96.2% of patients with varying doses of metformin therapy, and it reached statistical significance. Duration of metformin therapy ranged from a minimum of 2 months to a maximum of 6 months. No serious side effects were noted except for hypoglycemia in one patient. Patient acceptability toward metformin intake was good. Mean birth weight of newborns was 2972 ± 280 g, and no case of fetal macrosomia was seen. Neonatal hypoglycemia was seen in 3.8% of the babies and 6.7% required NICU admission. No case of congenital malformation was reported.\nMetformin is a clinically effective, inexpensive and safe drug for treating gestational diabetes mellitus.",
"affiliations": "JISNH Sector 20D, Chandigarh, 160020 India.;Department of Obstetrics and Gynecology, D Block, Level IV, GMCH, Sector 32, Chandigarh, 160030 India.;Department of Obstetrics and Gynecology, D Block, Level IV, GMCH, Sector 32, Chandigarh, 160030 India.",
"authors": "Gupta|Shubhi|S|0000-0002-5800-5029;Takkar|Navneet|N|;Goel|Poonam|P|",
"chemical_list": null,
"country": "India",
"delete": false,
"doi": "10.1007/s13224-019-01216-4",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0975-6434",
"issue": "69(6)",
"journal": "Journal of obstetrics and gynaecology of India",
"keywords": "Gestational diabetes mellitus; Maternal and neonatal outcomes; Metformin",
"medline_ta": "J Obstet Gynaecol India",
"mesh_terms": null,
"nlm_unique_id": "0374763",
"other_id": null,
"pages": "490-494",
"pmc": null,
"pmid": "31844362",
"pubdate": "2019-12",
"publication_types": "D016428:Journal Article",
"references": "25467617;23524173;26117686;23068960;18463376;25688819;25315294",
"title": "Maternal and Neonatal Outcomes in Patients of Gestational Diabetes Mellitus on Metformin Therapy.",
"title_normalized": "maternal and neonatal outcomes in patients of gestational diabetes mellitus on metformin therapy"
} | [
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"activesubstancename": "METFORMIN HYDROCHLORIDE"
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"reaction": [
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"reactionmeddrapt": "Postpartum sepsis",
"reactionmeddraversionpt": "22.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Maternal exposure during pregnancy",
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"reactionoutcome": "6"
}
],
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},
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},
{
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"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Foetal hypokinesia",
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"reactionoutcome": "6"
}
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},
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"activesubstance": {
"activesubstancename": "METFORMIN HYDROCHLORIDE"
},
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"medicinalproduct": "METFORMIN"
}
],
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"reaction": [
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"reactionmeddraversionpt": "22.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Stillbirth",
"reactionmeddraversionpt": "22.1",
"reactionoutcome": "6"
}
],
"summary": null
},
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],
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"patientsex": "2",
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"reaction": [
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"reactionmeddraversionpt": "23.0",
"reactionoutcome": "6"
},
{
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"reactionmeddraversionpt": "23.0",
"reactionoutcome": "6"
}
],
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"literaturereference_normalized": "maternal and neonatal outcomes in patients of gestational diabetes mellitus on metformin therapy",
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},
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},
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"seriousnessdeath": null,
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"seriousnesshospitalization": null,
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"seriousnessother": 1,
"transmissiondate": "20200713"
},
{
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"activesubstancename": "METFORMIN HYDROCHLORIDE"
},
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"reactionmeddraversionpt": "22.1",
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{
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},
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"literaturereference_normalized": "maternal and neonatal outcomes in patients of gestational diabetes mellitus on metformin therapy",
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{
"abstract": "Sodium voltage-gated channel alpha subunit 2 (SCN2A) gene encodes the Nav1.2 subunit of voltage-gated sodium channel in pyramidal neurons. SCN2A gain-of-function mutations are identified more and more often with gene panels and whole exome sequencing. Phenotype ranges from benign neonatal or infantile seizures to severe epileptic encephalopathy. Although large series of patients targeting genetic background point out two main phenotypes with SCN2A encephalopathy, Ohtahara syndrome and malignant migrating partial seizures in infancy (EMPSI), we noticed that in fact, a peculiar clinical and electroencephalogram (EEG) sequence distinct from these syndromes should suggest the diagnosis early.\n\n\n\nWe report three new cases with de novo SCN2A mutations - 166237617C>A p.(Asp1487Glu), c.407T>G p.(Met136Arg), and c.4633A>G p.(Met1545Val) - diagnosed by direct sequencing or genes panel, their follow-up ranging from 4 to 5 years.\n\n\n\nFor all three patients, seizures started at two days of life and consisted of apnea and cyanosis with partial clonic or tonic, alternating on both sides with, up to 100/day, evolving to generalized tonic-clonic seizures (GTCS) and epileptic spasms by three months. First EEG showed a discontinuous pattern, evolving to multifocal spikes, by 3 (two patients) and 6 months (one). Seizure frequency decreased progressively by the middle or end of the first year of life. Only less frequent GTCS persisted during the second year of life for two patients. Improvement was observed in two patients with sodium channel blocker (phenytoin) used at age of 1 month for one patient and at 2 years for another one. All patients remained with severe psychomotor delay.\n\n\n\nAll three infants share a condition different from Ohtahara syndrome in which tonic spasms predominate and suppression-burst pattern is obvious, and from EMPSI, in which partial migrating discharges involve successively the various parts of the brain including occipital regions with oculoclonic seizures, but there is neither discontinuous pattern nor therapeutic response to sodium channel blockers.\n\n\n\nNeonatal SCN2A encephalopathy has a recognizable phenotype starting soon after birth with alternating partial motor seizures evolving to infantile spasms and a discontinuous EEG pattern. Seizures improve spontaneously in the first year of life. This electroclinical sequence should indicate the search of SCN2A mutation and suggest the administration of sodium channel blockers.",
"affiliations": "Department of Pediatrics, MediClubGeorgia Medical Center, Tbilisi, Georgia.;AdPueriVitam, Antony, France.;Services d'explorations fonctionnelles, Centre de médecine du sommeil, Hôpital Antoine-Béclère, AP-HP, Clamart, France; Service de pédiatrie, Centre hospitalier intercommunal André Grégoire, Montreuil, France. Electronic address: svetlana.gataullina@aphp.fr.",
"authors": "Melikishvili|Gia|G|;Dulac|Olivier|O|;Gataullina|Svetlana|S|",
"chemical_list": "D062551:NAV1.2 Voltage-Gated Sodium Channel; C568251:SCN2A protein, human; D026941:Sodium Channel Blockers; D010672:Phenytoin",
"country": "United States",
"delete": false,
"doi": "10.1016/j.yebeh.2020.107187",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1525-5050",
"issue": "111()",
"journal": "Epilepsy & behavior : E&B",
"keywords": "Discontinuous tracing; Epileptic spasms; Migrating partial seizures in infancy; Neonatal seizures; Ohtahara syndrome",
"medline_ta": "Epilepsy Behav",
"mesh_terms": "D001921:Brain; D002648:Child; D002675:Child, Preschool; D004569:Electroencephalography; D005260:Female; D006801:Humans; D007231:Infant, Newborn; D008297:Male; D062551:NAV1.2 Voltage-Gated Sodium Channel; D010672:Phenytoin; D026941:Sodium Channel Blockers; D013036:Spasms, Infantile",
"nlm_unique_id": "100892858",
"other_id": null,
"pages": "107187",
"pmc": null,
"pmid": "32603808",
"pubdate": "2020-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Neonatal SCN2A encephalopathy: A peculiar recognizable electroclinical sequence.",
"title_normalized": "neonatal scn2a encephalopathy a peculiar recognizable electroclinical sequence"
} | [
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] |
{
"abstract": "OBJECTIVE\nThere is a sound theoretical basis but little clinical evidence substantiating the benefits of concurrent chemoradiotherapy with two-drug chemotherapy for locally advanced soft tissue sarcomas. Our five-year data on the feasibility and effectiveness of neoadjuvant chemoradiotherapy with systemically effective doses of adriamycin and ifosfamide combined is presented here.\n\n\nMETHODS\nBetween 2000 and 2011, 53 patients with UICC (2010) stage I (n=1, 1.9%), II (n=12, 22.7%) or III (n=40, 75.5%) nonmetastatic soft tissue sarcoma received neoadjuvant chemoradiotherapy with ifosfamide (1.5 g/m(2)/day, d1-5, q28) and doxorubicin (50mg/m(2)/day, d3, q28) plus concurrent radiotherapy with a target dose of 50-64 Gy (median 60 Gy). The treatment of 34 patients (64.2%) was combined with hyperthermia.\n\n\nRESULTS\nAt five years, the local control rate was 89.9% (± 5.7%), distant metastasis-free survival 66.6% (± 7.6%), and survival 83.3% (± 6%). The R0 resection rate was 81.1%. Radiotherapy was completed as planned in all patients and chemotherapy in 42/53 (70.2%). Grades III (n=21, 29.6%) and IV (n=18, 34%) leukopenia was the main acute adverse event. All acute and chronic non-hematologic toxicities were moderate.\n\n\nCONCLUSIONS\nNeoadjuvant chemoradiotherapy for soft tissue sarcoma is associated with good feasibility, manageable acute and late toxicities, and high local efficacy.",
"affiliations": "Department of Radiation Oncology, University of Erlangen-Nurnberg, Universitätsstraße 27, 91054 Erlangen, Germany.;Pathology Institute, University of Erlangen-Nurnberg, Krankenhausstraße 8-10, 91054 Erlangen, Germany.;Department of Radiation Oncology, University of Erlangen-Nurnberg, Universitätsstraße 27, 91054 Erlangen, Germany.;Department of Radiation Oncology, University of Erlangen-Nurnberg, Universitätsstraße 27, 91054 Erlangen, Germany.;Department of Surgery, University of Erlangen-Nurnberg, Krankenhausstraße 12, 91054 Erlangen, Germany.;Department of Surgery, University of Erlangen-Nurnberg, Krankenhausstraße 12, 91054 Erlangen, Germany.;Department of Surgery, University of Erlangen-Nurnberg, Krankenhausstraße 12, 91054 Erlangen, Germany.;Department of Radiation Oncology, University of Erlangen-Nurnberg, Universitätsstraße 27, 91054 Erlangen, Germany.;Department of Radiation Oncology, University of Erlangen-Nurnberg, Universitätsstraße 27, 91054 Erlangen, Germany. Electronic address: sabine.semrau@uk-erlangen.de.",
"authors": "Stubbe|F|F|;Agaimy|A|A|;Ott|O|O|;Lettmaier|S|S|;Vassos|N|N|;Croner|R|R|;Hohenberger|W|W|;Fietkau|R|R|;Semrau|S|S|",
"chemical_list": "D004317:Doxorubicin; D007069:Ifosfamide",
"country": "France",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1278-3218",
"issue": "20(1)",
"journal": "Cancer radiotherapie : journal de la Societe francaise de radiotherapie oncologique",
"keywords": "Chemoradiotherapy; Chemotherapy; Chimioradiothérapie; Neoadjuvant; Néoadjuvant; Radiotherapy; Recurrence; Récidive; Sarcoma; Sarcomes des tissus mous; Survie; Survival; Toxicity; Toxicité",
"medline_ta": "Cancer Radiother",
"mesh_terms": "D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D059186:Chemoradiotherapy, Adjuvant; D004317:Doxorubicin; D005240:Feasibility Studies; D005260:Female; D006801:Humans; D006979:Hyperthermia, Induced; D007069:Ifosfamide; D007970:Leukopenia; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D011879:Radiotherapy Dosage; D012074:Remission Induction; D012509:Sarcoma; D012983:Soft Tissue Neoplasms; D055815:Young Adult",
"nlm_unique_id": "9711272",
"other_id": null,
"pages": "6-13",
"pmc": null,
"pmid": "26700874",
"pubdate": "2016-02",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Effective local control of advanced soft tissue sarcoma with neoadjuvant chemoradiotherapy and surgery: A single institutional experience.",
"title_normalized": "effective local control of advanced soft tissue sarcoma with neoadjuvant chemoradiotherapy and surgery a single institutional experience"
} | [
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}
],
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},
{
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}
],
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"literaturereference": "STUBBE F, AGAIMY A, OTT O, LETTMAIER S, VASSOS N, CRONER R, ET AL. EFFECTIVE LOCAL CONTROL OF ADVANCED SOFT TISSUE SARCOMA WITH NEOADJUVANT CHEMORADIOTHERAPY AND SURGERY: A SINGLE INSTITUTIONAL EXPERIENCE. CANCER-RADIOTHER 2016;20(1):6-13.",
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{
"abstract": "Opioids remain the mainstay of treatment for severe cancer pain, but up to 20% of patients have persistent or refractory pain despite rapid and aggressive opioid titration, or develop refractory pain after long-term opioid use. In these scenarios, alternative agents and mechanisms for analgesia should be considered. This case report describes a 28-year-old man with metastatic pancreatic neuroendocrine cancer with severe, intractable pain despite high-dose opioids including methadone and a hydromorphone patient-controlled analgesia (PCA). After treatment with short-course, low-dose ketamine, his opioid requirements decreased by 99% and pain ratings by 50%, with the majority of this decrease occurring in the first 48 hours. As this patient's pain and opioid regimen escalated, he likely experienced some component of central sensitization and hyperalgesia. Administration of ketamine reduced opioid consumption by 99% and potentially \"reset\" neuronal hyperexcitability and reduced pain signaling, allowing for improved pain control.",
"affiliations": null,
"authors": "Waldfogel|Julie M|JM|;Nesbit|Suzanne|S|;Cohen|Steven P|SP|;Dy|Sydney M|SM|",
"chemical_list": "D000700:Analgesics; D000701:Analgesics, Opioid; D007649:Ketamine",
"country": "England",
"delete": false,
"doi": "10.1080/15360288.2016.1231732",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1536-0288",
"issue": "30(4)",
"journal": "Journal of pain & palliative care pharmacotherapy",
"keywords": "NMDA; cancer pain; ketamine; opioid-refractory",
"medline_ta": "J Pain Palliat Care Pharmacother",
"mesh_terms": "D000328:Adult; D000700:Analgesics; D000701:Analgesics, Opioid; D000072716:Cancer Pain; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007649:Ketamine; D008297:Male; D009362:Neoplasm Metastasis; D018358:Neuroendocrine Tumors; D010148:Pain, Intractable; D010190:Pancreatic Neoplasms; D016896:Treatment Outcome",
"nlm_unique_id": "101125608",
"other_id": null,
"pages": "294-297",
"pmc": null,
"pmid": "27754734",
"pubdate": "2016-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Successful Treatment of Opioid-Refractory Cancer Pain with Short-Course, Low-Dose Ketamine.",
"title_normalized": "successful treatment of opioid refractory cancer pain with short course low dose ketamine"
} | [
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},
{
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},
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{
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},
{
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{
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},
{
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"reactionoutcome": "1"
},
{
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"reactionoutcome": "6"
}
],
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},
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},
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},
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},
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},
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"drugdosagetext": "50 MG/H WITH 25 MG BOLUS DOSES, SEE TEXT",
"drugenddate": null,
"drugenddateformat": null,
"drugindication": null,
"drugintervaldosagedefinition": null,
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},
{
"actiondrug": "6",
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"activesubstancename": "HYDROCODONE"
},
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"drugadministrationroute": "065",
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"drugcharacterization": "1",
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"drugdosageform": null,
"drugdosagetext": "UNK UNK, SEE TEXT",
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "CANCER PAIN",
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
"drugrecurreadministration": "3",
"drugrecurrence": null,
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"drugstartdateformat": null,
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"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "HYDROCODONE"
},
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "HYDROMORPHONE HYDROCHLORIDE"
},
"drugadditional": null,
"drugadministrationroute": "065",
"drugauthorizationnumb": "019892",
"drugbatchnumb": null,
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": null,
"drugdosagetext": "UNK",
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "CANCER PAIN",
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
"drugrecurreadministration": "3",
"drugrecurrence": null,
"drugseparatedosagenumb": null,
"drugstartdate": null,
"drugstartdateformat": null,
"drugstructuredosagenumb": null,
"drugstructuredosageunit": null,
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "HYDROMORPHONE HYDROCHLORIDE."
}
],
"patientagegroup": null,
"patientonsetage": "28",
"patientonsetageunit": "801",
"patientsex": "1",
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Hyperaesthesia",
"reactionmeddraversionpt": "20.0",
"reactionoutcome": "2"
},
{
"reactionmeddrapt": "Central pain syndrome",
"reactionmeddraversionpt": "20.0",
"reactionoutcome": "2"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "WALDFOGEL JM, NESBIT S, COHEN SP, DY SM. SUCCESSFUL TREATMENT OF OPIOID-REFRACTORY CANCER PAIN WITH SHORT-COURSE, LOW-DOSE KETAMINE. JOURNAL OF PAIN + PALLIATIVE CARE PHARMACOTHERAPY. 2016;30:4:294-297",
"literaturereference_normalized": "successful treatment of opioid refractory cancer pain with short course low dose ketamine",
"qualification": "2",
"reportercountry": "US"
},
"primarysourcecountry": "US",
"receiptdate": "20170418",
"receivedate": "20170331",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 13392021,
"safetyreportversion": 2,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
"seriousnessdisabling": null,
"seriousnesshospitalization": null,
"seriousnesslifethreatening": null,
"seriousnessother": 1,
"transmissiondate": "20170830"
}
] |
{
"abstract": "With the introduction of potent immunosuppressive and chemotherapeutic medications for various diseases, there is an increased incidence of therapy-related myeloid neoplasms. They are the result of mutational rearrangement and historically, have a grave prognosis compared with de novo myeloid neoplasms. We did a short review on various types of myeloid leukaemias reported after therapy with antitumour necrosis factor and also report, to the best of our knowledge, one among the very few cases of therapy-related acute promyelocytic leukaemia in a patient on infliximab therapy for refractory Crohn's disease. The patient responded well to the traditional treatment and is in complete remission for more than 5 years.",
"affiliations": "Department of Medicine/Hematology-Oncology, Staten Island University Hospital, Staten Island, New York, USA.;Department of Medicine/Hematology-Oncology, Staten Island University Hospital, Staten Island, New York, USA.;Department of Medicine/Hematology-Oncology, Staten Island University Hospital, Staten Island, New York, USA.;Department of Pathology, Staten Island University Hospital, Staten Island, New York, USA.;Department of Pathology, Staten Island University Hospital, Staten Island, New York, USA.;Department of Medicine/Hematology-Oncology, Staten Island University Hospital, Staten Island, New York, USA.",
"authors": "Mohammad|Farhan|F|;Vivekanandarajah|Abhirami|A|;Haddad|Housam|H|;Shutty|Christopher M|CM|;Hurford|Matthew T|MT|;Dai|Qun|Q|",
"chemical_list": "D000911:Antibodies, Monoclonal; D000069285:Infliximab",
"country": "England",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "2014()",
"journal": "BMJ case reports",
"keywords": null,
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000328:Adult; D000911:Antibodies, Monoclonal; D000971:Antineoplastic Combined Chemotherapy Protocols; D001707:Biopsy, Needle; D001856:Bone Marrow Examination; D003424:Crohn Disease; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007150:Immunohistochemistry; D000069285:Infliximab; D015473:Leukemia, Promyelocytic, Acute; D018570:Risk Assessment; D012720:Severity of Illness Index; D016896:Treatment Outcome",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "24842356",
"pubdate": "2014-05-19",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": "20332773;23488881;17190640;15831904;19005432;16120759;12826706;10338381;17654504;14638375;12623843;12483718;19259097;3463495;20149321;19357394",
"title": "Acute promyelocytic leukaemia (APL) in a patient with Crohn's disease and exposure to infliximab: a rare clinical presentation and review of the literature.",
"title_normalized": "acute promyelocytic leukaemia apl in a patient with crohn s disease and exposure to infliximab a rare clinical presentation and review of the literature"
} | [
{
"companynumb": "US-JNJFOC-20140612083",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "INFLIXIMAB"
},
"drugadditional": null,
"drugadministrationroute": "042",
"drugauthorizationnumb": "103772",
"drugbatchnumb": null,
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": "LYOPHILIZED POWDER",
"drugdosagetext": "0,2, 6 AND 8 WEEKS FOR APPROXIAMTELY FOR 24 MONTHS.",
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "CROHN^S DISEASE",
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
"drugrecurreadministration": "3",
"drugrecurrence": null,
"drugseparatedosagenumb": null,
"drugstartdate": null,
"drugstartdateformat": null,
"drugstructuredosagenumb": "5",
"drugstructuredosageunit": "007",
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "INFLIXIMAB, RECOMBINANT"
}
],
"patientagegroup": "5",
"patientonsetage": "42",
"patientonsetageunit": "801",
"patientsex": "2",
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Acute promyelocytic leukaemia",
"reactionmeddraversionpt": "18.0",
"reactionoutcome": "2"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "MOHAMMAD F, VIVEKANANDARAJAH A, HADDAD H, SHUTTY CM, HURFORD MT, DAI Q. ACUTE PROMYELOCYTIC LEUKAEMIA (APL) IN A PATIENT WITH CROHN?S DISEASE AND EXPOSURE TO INFLIXIMAB: A RARE CLINICAL PRESENTATION AND REVIEW OF THE LITERATURE. BMJ CASE REP 2014:1-4.",
"literaturereference_normalized": "acute promyelocytic leukaemia apl in a patient with crohn s disease and exposure to infliximab a rare clinical presentation and review of the literature",
"qualification": "1",
"reportercountry": "US"
},
"primarysourcecountry": "US",
"receiptdate": "20141231",
"receivedate": "20140624",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 10255265,
"safetyreportversion": 3,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
"seriousnessdisabling": null,
"seriousnesshospitalization": 1,
"seriousnesslifethreatening": null,
"seriousnessother": 1,
"transmissiondate": "20150528"
}
] |
{
"abstract": "OBJECTIVE\nFentanyl is a synthetic opioid available therapeutically as an intravenous, transbucal, or transdermal preparation. It is also used as a drug of abuse through a variety of different methods, including the oral abuse of transdermal fentanyl patches. This is a series of patients with oral fentanyl patch exposure reported to our center and represents the first series of oral fentanyl patch exposures collected outside of the postmortem setting.\n\n\nMETHODS\nIn this series, we examined the New York Poison Control Center database for all cases of oral abuse of fentanyl reported between January 2000 and April 2008.\n\n\nRESULTS\nTwenty cases were reported, nine were asymptomatic or had symptoms of opioid withdrawal; 11 had symptoms of opioid intoxication. Eight patients were administered naloxone and all showed improvement in clinical status. Only one case resulted in a confirmed fatality-this patient had an orally adherent patch discovered at intubation.\n\n\nCONCLUSIONS\nOral exposure may result in life-threatening toxicity. Patients should be closely assessed and monitored for the opioid toxidrome, and if symptomatic, should be managed with opioid antagonists and ventilatory support.",
"affiliations": "Division of Emergency Medicine, Weill Cornell Medical College, New York Presbyterian Hospital, 525 E. 68th St. M130, New York, NY 10065, USA. jprosser100@gmail.com",
"authors": "Prosser|Jane M|JM|;Jones|Brent E|BE|;Nelson|Lewis|L|",
"chemical_list": "D000701:Analgesics, Opioid; D009292:Narcotic Antagonists; D009270:Naloxone; D005283:Fentanyl",
"country": "United States",
"delete": false,
"doi": "10.1007/s13181-010-0092-8",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1556-9039",
"issue": "6(4)",
"journal": "Journal of medical toxicology : official journal of the American College of Medical Toxicology",
"keywords": null,
"medline_ta": "J Med Toxicol",
"mesh_terms": "D000284:Administration, Oral; D000328:Adult; D000701:Analgesics, Opioid; D016208:Databases, Factual; D005260:Female; D005283:Fentanyl; D006801:Humans; D008297:Male; D008875:Middle Aged; D009270:Naloxone; D009292:Narcotic Antagonists; D011041:Poisoning; D012121:Respiration, Artificial; D019966:Substance-Related Disorders; D013406:Suicide, Attempted; D057968:Transdermal Patch; D016896:Treatment Outcome",
"nlm_unique_id": "101284598",
"other_id": null,
"pages": "443-7",
"pmc": null,
"pmid": "20532845",
"pubdate": "2010-12",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Complications of oral exposure to fentanyl transdermal delivery system patches.",
"title_normalized": "complications of oral exposure to fentanyl transdermal delivery system patches"
} | [
{
"companynumb": "US-JNJFOC-20130807402",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "FENTANYL"
},
"drugadditional": null,
"drugadministrationroute": "048",
"drugauthorizationnumb": "019813",
"drugbatchnumb": null,
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": "UNSPECIFIED",
"drugdosagetext": null,
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "PRODUCT USED FOR UNKNOWN INDICATION",
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
"drugrecurreadministration": "3",
"drugrecurrence": null,
"drugseparatedosagenumb": null,
"drugstartdate": null,
"drugstartdateformat": null,
"drugstructuredosagenumb": null,
"drugstructuredosageunit": null,
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "FENTANYL TRANSDERMAL SYSTEM"
},
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "FENTANYL"
},
"drugadditional": null,
"drugadministrationroute": "048",
"drugauthorizationnumb": null,
"drugbatchnumb": null,
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": "UNSPECIFIED",
"drugdosagetext": null,
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "PRODUCT USED FOR UNKNOWN INDICATION",
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
"drugrecurreadministration": "3",
"drugrecurrence": null,
"drugseparatedosagenumb": null,
"drugstartdate": null,
"drugstartdateformat": null,
"drugstructuredosagenumb": null,
"drugstructuredosageunit": null,
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "FENTANYL TRANSDERMAL SYSTEM"
}
],
"patientagegroup": null,
"patientonsetage": null,
"patientonsetageunit": null,
"patientsex": null,
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Drug abuse",
"reactionmeddraversionpt": "19.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Toxicity to various agents",
"reactionmeddraversionpt": "19.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Completed suicide",
"reactionmeddraversionpt": "19.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Respiratory failure",
"reactionmeddraversionpt": "19.0",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Drug diversion",
"reactionmeddraversionpt": "19.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Intentional product use issue",
"reactionmeddraversionpt": "19.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Incorrect route of drug administration",
"reactionmeddraversionpt": "19.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Drug dependence",
"reactionmeddraversionpt": "19.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Loss of consciousness",
"reactionmeddraversionpt": "19.0",
"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "PROSSER JM, JONES BE, NELSON L. COMPLICATIONS OF ORAL EXPOSURE TO FENTANYL TRANSDERMAL DELIVERY SYSTEM PATCHES. JOURNAL OF MEDICAL TOXICOLOGY: OFFICIAL JOURNAL OF THE AMERICAN COLLEGE OF MEDICAL TOXICOLOGY 2010;6 (4):443-447. PROSSER JM, HOWLAND MA, JONES BE, HOFFMAN RS, NELSON LS. COMPLICATIONS OF FENTANYL PATCH INGESTION. CLINICAL TOXICOLOGY 2009;47 (5):449.",
"literaturereference_normalized": "complications of oral exposure to fentanyl transdermal delivery system patches",
"qualification": "3",
"reportercountry": "US"
},
"primarysourcecountry": "US",
"receiptdate": "20160530",
"receivedate": "20130826",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 9476287,
"safetyreportversion": 2,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
"seriousnessdisabling": null,
"seriousnesshospitalization": 1,
"seriousnesslifethreatening": 1,
"seriousnessother": 1,
"transmissiondate": "20160815"
},
{
"companynumb": "US-JNJFOC-20090900073",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "FENTANYL"
},
"drugadditional": null,
"drugadministrationroute": "048",
"drugauthorizationnumb": null,
"drugbatchnumb": null,
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": "PATCH",
"drugdosagetext": null,
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "SUICIDE ATTEMPT",
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
"drugrecurreadministration": "3",
"drugrecurrence": null,
"drugseparatedosagenumb": null,
"drugstartdate": null,
"drugstartdateformat": null,
"drugstructuredosagenumb": null,
"drugstructuredosageunit": null,
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "FENTANYL."
},
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "FENTANYL"
},
"drugadditional": null,
"drugadministrationroute": "048",
"drugauthorizationnumb": "019813",
"drugbatchnumb": null,
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": "PATCH",
"drugdosagetext": null,
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "DRUG ABUSE",
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
"drugrecurreadministration": "3",
"drugrecurrence": null,
"drugseparatedosagenumb": null,
"drugstartdate": null,
"drugstartdateformat": null,
"drugstructuredosagenumb": null,
"drugstructuredosageunit": null,
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "FENTANYL."
}
],
"patientagegroup": "5",
"patientonsetage": "28",
"patientonsetageunit": "801",
"patientsex": null,
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Intentional product misuse",
"reactionmeddraversionpt": "18.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Loss of consciousness",
"reactionmeddraversionpt": "18.0",
"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "PROSSER JM, JONES BE, NELSON L. COMPLICATIONS OF ORAL EXPOSURE TO FENTANYL TRANSDERMAL DELIVERY SYSTEM PATCHES. JOURNAL OF MEDICAL TOXICOLOGY 08-JUN-2010;6 (4):443-447. PROSSER JM, HOWLAND MA, JONES BE, HOFFMAN RS, NELSON LS. COMPLICATIONS OF FENTANYL PATCH INGESTION. CLINICAL TOXICOLOGY 2009;47 (5):449.",
"literaturereference_normalized": "complications of oral exposure to fentanyl transdermal delivery system patches",
"qualification": "3",
"reportercountry": "US"
},
"primarysourcecountry": "US",
"receiptdate": "20150524",
"receivedate": "20150328",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 10963817,
"safetyreportversion": 2,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
"seriousnessdisabling": null,
"seriousnesshospitalization": 1,
"seriousnesslifethreatening": null,
"seriousnessother": 1,
"transmissiondate": "20150821"
},
{
"companynumb": "US-JNJFOC-20090900066",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "FENTANYL"
},
"drugadditional": null,
"drugadministrationroute": "048",
"drugauthorizationnumb": "019813",
"drugbatchnumb": null,
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": "PATCH",
"drugdosagetext": null,
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "DRUG ABUSE",
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
"drugrecurreadministration": "3",
"drugrecurrence": null,
"drugseparatedosagenumb": null,
"drugstartdate": null,
"drugstartdateformat": null,
"drugstructuredosagenumb": null,
"drugstructuredosageunit": null,
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "FENTANYL."
}
],
"patientagegroup": "5",
"patientonsetage": null,
"patientonsetageunit": null,
"patientsex": null,
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Drug abuse",
"reactionmeddraversionpt": "18.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Intentional product misuse",
"reactionmeddraversionpt": "18.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Feeling abnormal",
"reactionmeddraversionpt": "18.0",
"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "PROSSER JM, JONES BE, NELSON L. COMPLICATIONS OF ORAL EXPOSURE TO FENTANYL TRANSDERMAL DELIVERY SYSTEM PATCHES. JOURNAL OF MEDICAL TOXICOLOGY 08-JUN-2010;6 (4):443-7. PROSSER JM, HOWLAND MA, JONES BE, HOFFMAN RS, NELSON LS. COMPLICATIONS OF FENTANYL PATCH INGESTION. CLINICAL TOXICOLOGY 2009;47 NO.5:449.",
"literaturereference_normalized": "complications of oral exposure to fentanyl transdermal delivery system patches",
"qualification": "3",
"reportercountry": "US"
},
"primarysourcecountry": "US",
"receiptdate": "20150524",
"receivedate": "20150327",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 10959727,
"safetyreportversion": 2,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
"seriousnessdisabling": null,
"seriousnesshospitalization": null,
"seriousnesslifethreatening": null,
"seriousnessother": 1,
"transmissiondate": "20150821"
},
{
"companynumb": "US-JNJFOC-20090900069",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "FENTANYL"
},
"drugadditional": null,
"drugadministrationroute": "048",
"drugauthorizationnumb": "019813",
"drugbatchnumb": null,
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": "PATCH",
"drugdosagetext": null,
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "DRUG ABUSE",
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
"drugrecurreadministration": "3",
"drugrecurrence": null,
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{
"abstract": "Linezolid, an oxazolidinone antibiotic, has been reported to increase the risk of lactic acidosis and peripheral neuropathy because it disrupts mitochondrial function. This case report describes the development of lactic acidosis in a 63-year-old man who had received 3 months of treatment with intravenous linezolid for pulmonary nocardiasis, and correction of the acidotic state with sustained low-efficiency dialysis. This case demonstrates that renal replacement therapy can be an alternative to discontinuation alone for rapid reversal of linezolid-induced lactic acidosis.",
"affiliations": "Huntsville Hospital, Huntsville, AL. Electronic address: adam.sawyer@hhsys.org.;Huntsville Hospital, Huntsville, AL. Electronic address: haley0513@gmail.com.;Huntsville Hospital, Huntsville, AL.;Huntsville Hospital, Huntsville, AL.;Huntsville Hospital, Huntsville, AL.",
"authors": "Sawyer|Adam J|AJ|;Haley|Heather L|HL|;Baty|Sharon R|SR|;McGuffey|Grant E|GE|;Eiland|Edward H|EH|",
"chemical_list": "D000081:Acetamides; D000890:Anti-Infective Agents; D023303:Oxazolidinones; D000069349:Linezolid",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0272-6386",
"issue": "64(3)",
"journal": "American journal of kidney diseases : the official journal of the National Kidney Foundation",
"keywords": "Linezolid; Zyvox; dialysis; lactic acidosis; oxazolidinone antibiotic; renal replacement therapy; sustained low-efficiency dialysis (SLED)",
"medline_ta": "Am J Kidney Dis",
"mesh_terms": "D000081:Acetamides; D000140:Acidosis, Lactic; D000890:Anti-Infective Agents; D006801:Humans; D000069349:Linezolid; D008297:Male; D008875:Middle Aged; D023303:Oxazolidinones; D006435:Renal Dialysis",
"nlm_unique_id": "8110075",
"other_id": null,
"pages": "457-9",
"pmc": null,
"pmid": "24961626",
"pubdate": "2014-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Linezolid-induced lactic acidosis corrected with sustained low-efficiency dialysis: a case report.",
"title_normalized": "linezolid induced lactic acidosis corrected with sustained low efficiency dialysis a case report"
} | [
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{
"reactionmeddrapt": "Lactic acidosis",
"reactionmeddraversionpt": "18.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Dyspnoea",
"reactionmeddraversionpt": "18.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Atrial fibrillation",
"reactionmeddraversionpt": "18.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Abdominal pain",
"reactionmeddraversionpt": "18.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Anaemia",
"reactionmeddraversionpt": "18.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Muscular weakness",
"reactionmeddraversionpt": "18.0",
"reactionoutcome": "6"
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{
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},
{
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"reactionmeddraversionpt": "18.0",
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},
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"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Gait disturbance",
"reactionmeddraversionpt": "18.0",
"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "SAWYER AJ, HALEY HL, BATY SR, MCGUFFEY GE, EILAND EH. LINEZOLID-INDUCED LACTIC ACIDOSIS CORRECTED WITH SUSTAINED LOW-EFFICIENCY DIALYSIS:A CASE REPORT. AM J KIDNEY DIS 2014;64 (3):457-459.",
"literaturereference_normalized": "linezolid induced lactic acidosis corrected with sustained low efficiency dialysis a case report",
"qualification": "1",
"reportercountry": "US"
},
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"receiptdate": "20150325",
"receivedate": "20150325",
"receiver": {
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},
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"sendertype": "2"
},
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"seriousnesslifethreatening": null,
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}
] |
{
"abstract": "BACKGROUND\nTransplantation is not only the best method for treating end-stage failure of many organs but also the way to improve the quality of life of patients. For women of childbearing age, an organ transplant often brings a restoration of regular reproductive functions, which means, among other things, the possibility of having biological offspring.\n\n\nOBJECTIVE\nThe aim of the study was to analyze the medical records and assess the impact of a liver transplant on the course of pregnancy and labor.\n\n\nMETHODS\nThe research was carried out from March to May 2019 in the Nephrology and Transplant Clinic Medical University of Warsaw. The study group consisted of 19 women after liver transplantation. Medical records were analyzed, and laboratory test results routinely performed on patients were also used for the study.\n\n\nRESULTS\nThe mean age of conception of the patients following transplantation was 30 ± 4 years old. In the analyzed period, 6 patients gave birth to 2 children each, and 8 patients to 1 child each. Only 3 patients experienced premature birth. Twelve patients gave birth by caesarean delivery. Fourteen patients took tacrolimus.\n\n\nCONCLUSIONS\nPregnancy is possible in patients following a liver transplant and does not appear to have a damaging effect on liver functionality. There is an increased risk of pre-eclampsia, intensified hypertension, and premature birth among patients following a transplant, which is why it is essential for these patients to remain under the care of a specialistic therapeutic team.",
"affiliations": "Department of Nephrologic Nursing, Medical University of Warsaw, Warsaw, Poland. Electronic address: m.saran@op.pl.;Department of Nephrologic Nursing, Medical University of Warsaw, Warsaw, Poland.;Department of Transplant Medicine, Nephrology and Internal Diseases, Medical University of Warsaw, Warsaw, Poland.;University Centre of Health and Women, Gynecology Department, Clinic for Women with Organ Failure, Warsaw, Poland.;Department of Nephrologic Nursing, Medical University of Warsaw, Warsaw, Poland.",
"authors": "Pendraszewska|Monika|M|;Krucińska|Brygida|B|;Pazik|Joanna|J|;Jabiry-Zieniewicz|Zoulikha|Z|;Wyzgał|Janusz|J|",
"chemical_list": "D016559:Tacrolimus",
"country": "United States",
"delete": false,
"doi": "10.1016/j.transproceed.2020.03.034",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0041-1345",
"issue": "52(8)",
"journal": "Transplantation proceedings",
"keywords": null,
"medline_ta": "Transplant Proc",
"mesh_terms": "D000328:Adult; D005260:Female; D006801:Humans; D006973:Hypertension; D016031:Liver Transplantation; D011183:Postoperative Complications; D011225:Pre-Eclampsia; D011247:Pregnancy; D011248:Pregnancy Complications; D011256:Pregnancy Outcome; D047928:Premature Birth; D011788:Quality of Life; D016559:Tacrolimus; D016896:Treatment Outcome",
"nlm_unique_id": "0243532",
"other_id": null,
"pages": "2512-2516",
"pmc": null,
"pmid": "32471631",
"pubdate": "2020-10",
"publication_types": "D023362:Evaluation Study; D016428:Journal Article",
"references": null,
"title": "A Long-term Evaluation of Treatment Results of Pregnant Patients Following a Liver Transplant.",
"title_normalized": "a long term evaluation of treatment results of pregnant patients following a liver transplant"
} | [
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"companynumb": "NVSC2020PL151445",
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},
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"drugindication": "FOETAL EXPOSURE DURING PREGNANCY",
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"medicinalproduct": "CYCLOSPORINE."
}
],
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"reaction": [
{
"reactionmeddrapt": "Premature baby",
"reactionmeddraversionpt": "23.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Foetal exposure during pregnancy",
"reactionmeddraversionpt": "23.0",
"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "PENDRASZEWSKA M, KRUCIINSKAA B, PAZIK J, JABIRY-ZIENIEWICZ Z, WYZGAL J. A LONG-TERM EVALUATION OF TREATMENT RESULTS OF PREGNANT PATIENTS FOLLOWING A LIVER TRANSPLANT. TRANSPLANTATION PROCEEDINGS. 2020?1-5",
"literaturereference_normalized": "a long term evaluation of treatment results of pregnant patients following a liver transplant",
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},
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}
] |
{
"abstract": "A 42-year-old woman with a history of acute myeloid leukaemia status postallogeneic stem cell transplant presented with fevers, altered mental status, pulmonary infiltrates and septic shock that further progressed to thrombocytopenia and purpura fulminans. Laboratory studies were consistent with a diagnosis of thrombotic thrombocytopenic purpura (TTP). Blood cultures grew Streptococcus pneumoniae On chart review, our patient had a history of low immunoglobulin levels following stem cell transplant, which may have predisposed her to pneumococcal infection. The patient responded to therapy with ceftriaxone, plasma exchange, rituximab and caplacizumab. This is the fourth-documented case of pneumococcal induced TTP and, to the best of our knowledge, the first-describing pneumococcal induced TTP with purpura fulminans. We conclude that patients with TTP should be evaluated for infectious aetiologies and empiric antibiotics should be considered. Clinicians should be aware of the possibility for TTP to lead to purpura fulminans.",
"affiliations": "Internal Medicine, University of Virginia School of Medicine, Charlottesville, Virginia, USA lfw4z@virginia.edu.;Division of Infectious Diseases and International Health, University of Virginia, Charlottesville, Virginia, USA.;Division of Infectious Diseases and International Health, University of Virginia, Charlottesville, Virginia, USA.",
"authors": "Walsh|Laura Frances|LF|;Sherbuk|Jacqueline E|JE|;Wispelwey|Brian|B|",
"chemical_list": "D000900:Anti-Bacterial Agents; D005343:Fibrinolytic Agents; D005938:Glucocorticoids; D007155:Immunologic Factors; D061905:Single-Domain Antibodies; C585343:caplacizumab; D000069283:Rituximab; D002443:Ceftriaxone",
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2020-235580",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "14(1)",
"journal": "BMJ case reports",
"keywords": "immunology; infections; malignant disease and immunosuppression; purpura fulminans; thrombotic thrombocytopenic purpura",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000328:Adult; D000900:Anti-Bacterial Agents; D016470:Bacteremia; D002443:Ceftriaxone; D003937:Diagnosis, Differential; D005260:Female; D005343:Fibrinolytic Agents; D005385:Fingers; D005734:Gangrene; D005938:Glucocorticoids; D006086:Graft vs Host Disease; D006801:Humans; D007155:Immunologic Factors; D015470:Leukemia, Myeloid, Acute; D009666:Nose; D010951:Plasma Exchange; D011008:Pneumococcal Infections; D055665:Purpura Fulminans; D011697:Purpura, Thrombotic Thrombocytopenic; D000069283:Rituximab; D012772:Shock, Septic; D061905:Single-Domain Antibodies; D033581:Stem Cell Transplantation; D014034:Toes",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "33500295",
"pubdate": "2021-01-26",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Pneumococcal induced thrombotic thrombocytopenic purpura with features of purpura fulminans.",
"title_normalized": "pneumococcal induced thrombotic thrombocytopenic purpura with features of purpura fulminans"
} | [
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},
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}
],
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"reaction": [
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"reactionmeddraversionpt": "23.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Autoimmune haemolytic anaemia",
"reactionmeddraversionpt": "23.1",
"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "WALSH LF, SHERBUK JE, WISPELWEY B.. PNEUMOCOCCAL INDUCED THROMBOTIC THROMBOCYTOPENIC PURPURA WITH FEATURES OF PURPURA FULMINANS.. BMJ CASE REPORTS. 2021?14 (1)",
"literaturereference_normalized": "pneumococcal induced thrombotic thrombocytopenic purpura with features of purpura fulminans",
"qualification": "1",
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},
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},
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},
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"transmissiondate": "20210420"
},
{
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},
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"medicinalproduct": "TACROLIMUS."
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],
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"reaction": [
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},
{
"reactionmeddrapt": "Autoimmune haemolytic anaemia",
"reactionmeddraversionpt": "23.1",
"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "WALSH LF, SHERBUK JE, WISPELWEY B. PNEUMOCOCCAL INDUCED THROMBOTIC THROMBOCYTOPENIC PURPURA WITH FEATURES OF PURPURA FULMINANS. BMJ CASE REPORTS.2021?14(1):ARTICLE NUMBER E235580. DOI: 10.1136/BCR?2020?235580",
"literaturereference_normalized": "pneumococcal induced thrombotic thrombocytopenic purpura with features of purpura fulminans",
"qualification": "1",
"reportercountry": "US"
},
"primarysourcecountry": "US",
"receiptdate": "20210301",
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"drugindication": "GRAFT VERSUS HOST DISEASE IN LIVER",
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"medicinalproduct": "TACROLIMUS."
}
],
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"patientsex": "2",
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"reaction": [
{
"reactionmeddrapt": "Microangiopathic haemolytic anaemia",
"reactionmeddraversionpt": "23.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Autoimmune haemolytic anaemia",
"reactionmeddraversionpt": "23.1",
"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "WALSH LF, SHERBUK JE, WISPELWEY B. PNEUMOCOCCAL INDUCED THROMBOTIC THROMBOCYTOPENIC PURPURA WITH FEATURES OF PURPURA FULMINANS. BMJ CASE REPORTS. 2021?14(1):E235580",
"literaturereference_normalized": "pneumococcal induced thrombotic thrombocytopenic purpura with features of purpura fulminans",
"qualification": "3",
"reportercountry": "US"
},
"primarysourcecountry": "NL",
"receiptdate": "20210223",
"receivedate": "20210223",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 18926611,
"safetyreportversion": 1,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
"seriousnessdisabling": null,
"seriousnesshospitalization": null,
"seriousnesslifethreatening": null,
"seriousnessother": 1,
"transmissiondate": "20210420"
}
] |
{
"abstract": "BACKGROUND\nTakotsubo cardiomyopathy (TC) is characterized by the abrupt onset of cardiac dysfunction, with transient apical and midventricular hypo-/akinesia with a compensatory hypercontractility of the remaining segments. The clinical presentation appears to be similar to acute myocardial infarction (AMI). However, the myocardial dysfunction is reversible.\n\n\nMETHODS\nWe report on the case of a 58-year-old man with acute myeloid leukemia (AML) who was admitted to our hospital to receive the second course of consolidation chemotherapy with intravenous cytarabine. Subsequently, the patient developed severe dyspnea at rest, with cardiogenic shock after the central venous catheter was removed. Echocardiography revealed severe dyskinesia of the mid and apical portions of both ventricles, accompanied by a highly reduced left ventricular function (LVF). 5 months later, 12-lead electrocardiography (ECG) did not show any evidence of repolar-ization disorders and echocardiographic evaluation revealed a normal LVF. We suppose that the underlying mechanism was TC.\n\n\nCONCLUSIONS\nTC can occur in patients with AML under systemic chemotherapy, which possibly represents a triggering factor for TC development. Cardiogenic shock is a serious life-threatening complication of TC. Nevertheless, the prognosis of TC is favorable and a complete recovery of the LVF is possible.",
"affiliations": "First Department of Medicine, Faculty of Medicine Mannheim, University Medical Center Mannheim (UMM), University of Heidelberg, Mannheim, Germany.",
"authors": "Baumann|Stefan|S|;Huseynov|Aydin|A|;Goranova|Diana|D|;Faust|Melanie|M|;Behnes|Michael|M|;Nolte|Florian|F|;Heidenreich|Daniela|D|;Hofmann|Wolf-Karsten|WK|;Borggrefe|Martin|M|;Akin|Ibrahim|I|;Klein|Stefan|S|",
"chemical_list": "D000964:Antimetabolites, Antineoplastic; D003561:Cytarabine",
"country": "Netherlands",
"delete": false,
"doi": "10.1159/000365536",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2296-5270",
"issue": "37(9)",
"journal": "Oncology research and treatment",
"keywords": null,
"medline_ta": "Oncol Res Treat",
"mesh_terms": "D000964:Antimetabolites, Antineoplastic; D060830:Consolidation Chemotherapy; D003561:Cytarabine; D006801:Humans; D007275:Injections, Intravenous; D015470:Leukemia, Myeloid, Acute; D008297:Male; D008875:Middle Aged; D054549:Takotsubo Cardiomyopathy; D016896:Treatment Outcome",
"nlm_unique_id": "101627692",
"other_id": null,
"pages": "487-90",
"pmc": null,
"pmid": "25231689",
"pubdate": "2014",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Takotsubo cardiomyopathy after systemic consolidation therapy with high-dose intravenous cytarabine in a patient with acute myeloid leukemia.",
"title_normalized": "takotsubo cardiomyopathy after systemic consolidation therapy with high dose intravenous cytarabine in a patient with acute myeloid leukemia"
} | [
{
"companynumb": "DE-MYLANLABS-2015M1017411",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
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{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "VANCOMYCIN"
},
"drugadditional": null,
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{
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"drugindication": "ACUTE MYELOID LEUKAEMIA",
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"medicinalproduct": "CYTARABINE."
},
{
"actiondrug": "5",
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"activesubstancename": "PIPERACILLIN SODIUM\\TAZOBACTAM SODIUM"
},
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},
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"drugdosageform": "INJECTION",
"drugdosagetext": "ON DAYS 1, 3, AND 5",
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"drugintervaldosagedefinition": "804",
"drugintervaldosageunitnumb": "1",
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"drugstructuredosageunit": "009",
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"drugtreatmentdurationunit": null,
"medicinalproduct": "CYTARABINE."
}
],
"patientagegroup": null,
"patientonsetage": null,
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"reaction": [
{
"reactionmeddrapt": "Cardiogenic shock",
"reactionmeddraversionpt": "18.0",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Stress cardiomyopathy",
"reactionmeddraversionpt": "18.0",
"reactionoutcome": "1"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "BAUMANN S, HUSEYNOV A, GORANOVA D, FAUST M, BEHNES M, NOLTE F, ET AL. TAKOTSUBO CARDIOMYOPATHY AFTER SYSTEMIC CONSOLIDATION THERAPY WITH HIGH-DOSE INTRAVENOUS CYTARABINE IN A PATIENT WITH ACUTE MYELOID LEUKEMIA. ONCOL-RES-TREAT 2014; 37(9):487-490.",
"literaturereference_normalized": "takotsubo cardiomyopathy after systemic consolidation therapy with high dose intravenous cytarabine in a patient with acute myeloid leukemia",
"qualification": "1",
"reportercountry": "DE"
},
"primarysourcecountry": "DE",
"receiptdate": "20150528",
"receivedate": "20150528",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 11142832,
"safetyreportversion": 1,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
"seriousnessdisabling": null,
"seriousnesshospitalization": 1,
"seriousnesslifethreatening": 1,
"seriousnessother": null,
"transmissiondate": "20150821"
}
] |
{
"abstract": "BACKGROUND\nAcetaminophen Psi Parameter (APP) is a composite of acetaminophen (paracetamol) level and lag time before N-acetylcysteine (NAC) therapy. The APP is a significant predictor of hepatotoxicity secondary to acute acetaminophen overdose. Acetaminophen Psi Nomogram (APN) was invented as a graphic analog of the APP for use in predicting individual patient's risk of hepatotoxicity. Clinical accuracy of the APN has never been validated\n\n\nOBJECTIVE\nThe authors are reporting the validity of APN in predicting hepatotoxicity secondary to acute acetaminophen overdose at Siriraj Hospital.\n\n\nMETHODS\nThis present study is a retrospective review of medical records of patients with acute acetaminophen overdose at Siriraj Hospital between January 2004 and June 2009. Each case was classified by APN into an appropriate risk group. The outcome of interest was hepatotoxicity. The validity of the APN is reported as sensitivity and specificity. Secondary outcomes include serum acetaminophen concentrations, delay to NAC therapy, and APP for each APN's risk group.\n\n\nRESULTS\nOne hundred and sixty-one patients were enrolled Higher APN risk classifications are associated with a trend towards higher acetaminophen levels, longer delayed to NAC initiation, and larger APP. Twenty five patients (15.5%) developed hepatotoxicity. The number of patients who were above the APN's risk lines, 1% and 50% were 88 (54.7%) and 17 (10.6%), respectively, with corresponding sensitivities of 100.0% (95% CI 186.6, 100.0) and 40.0% (95% C121.2, 61.3). APN's risk lines 50% had specificity of 94.9% (95% CI 89.7, 97.9).\n\n\nCONCLUSIONS\nAcetaminophen Psi Nomogram is a sensitive and specific tool for prediction of hepatotoxicity secondary to acute acetaminophen overdose. By application of the APN, a significant proportion of patients may not require either further follow-up after the completion of NAC therapy or prolongation of NAC therapy. Patients in high APN's risk ranges may be treated and monitored more intensively with confidence.",
"affiliations": null,
"authors": "Chomchai|Summon|S|;Lawattanatrakul|Nongnuch|N|;Chomchai|Chulathida|C|",
"chemical_list": "D018712:Analgesics, Non-Narcotic; D000931:Antidotes; D000082:Acetaminophen; D000111:Acetylcysteine",
"country": "Thailand",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0125-2208",
"issue": "97(2)",
"journal": "Journal of the Medical Association of Thailand = Chotmaihet thangphaet",
"keywords": null,
"medline_ta": "J Med Assoc Thai",
"mesh_terms": "D000082:Acetaminophen; D000111:Acetylcysteine; D018712:Analgesics, Non-Narcotic; D000931:Antidotes; D056486:Chemical and Drug Induced Liver Injury; D062787:Drug Overdose; D006801:Humans; D049451:Nomograms; D011237:Predictive Value of Tests; D012189:Retrospective Studies; D018570:Risk Assessment; D012307:Risk Factors; D012680:Sensitivity and Specificity; D013785:Thailand",
"nlm_unique_id": "7507216",
"other_id": null,
"pages": "165-72",
"pmc": null,
"pmid": "24765894",
"pubdate": "2014-02",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Acetaminophen Psi Nomogram: a sensitive and specific clinical tool to predict hepatotoxicity secondary to acute acetaminophen overdose.",
"title_normalized": "acetaminophen psi nomogram a sensitive and specific clinical tool to predict hepatotoxicity secondary to acute acetaminophen overdose"
} | [
{
"companynumb": "TH-JNJFOC-20120712526",
"fulfillexpeditecriteria": "1",
"occurcountry": "TH",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "ALPRAZOLAM"
},
"drugadditional": null,
"drugadministrationroute": "065",
"drugauthorizationnumb": null,
"drugbatchnumb": null,
"drugcharacterization": "2",
"drugcumulativedosagenumb": null,
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"drugdosageform": "Unspecified",
"drugdosagetext": null,
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"drugindication": "PRODUCT USED FOR UNKNOWN INDICATION",
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"medicinalproduct": "ALPRAZOLAM."
},
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "LORATADINE"
},
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"medicinalproduct": "LORATADINE."
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{
"actiondrug": "5",
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},
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"medicinalproduct": "ACETAMINOPHEN."
},
{
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"activesubstancename": "ACETAMINOPHEN"
},
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"medicinalproduct": "ACETAMINOPHEN."
},
{
"actiondrug": null,
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"activesubstancename": "AMITRIPTYLINE"
},
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"drugdosageform": "Unspecified",
"drugdosagetext": null,
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"drugenddateformat": null,
"drugindication": "PRODUCT USED FOR UNKNOWN INDICATION",
"drugintervaldosagedefinition": null,
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"drugtreatmentdurationunit": null,
"medicinalproduct": "AMITRIPTYLINE"
},
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "CHLORPHENIRAMINE"
},
"drugadditional": null,
"drugadministrationroute": "065",
"drugauthorizationnumb": null,
"drugbatchnumb": null,
"drugcharacterization": "2",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": "Unspecified",
"drugdosagetext": null,
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "PRODUCT USED FOR UNKNOWN INDICATION",
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
"drugrecurreadministration": null,
"drugrecurrence": null,
"drugseparatedosagenumb": null,
"drugstartdate": null,
"drugstartdateformat": null,
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"drugstructuredosageunit": null,
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "CHLORPHENIRAMINE"
}
],
"patientagegroup": null,
"patientonsetage": null,
"patientonsetageunit": null,
"patientsex": null,
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Overdose",
"reactionmeddraversionpt": "18.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Hepatotoxicity",
"reactionmeddraversionpt": "18.0",
"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "LAWATTANATRAKUL N. ACETAMINOPHEN PSI NOMOGRAM: A SENSITIVE AND SPECIFIC CLINICAL TOOL TO PREDICT HEPATOTOXICITY SECONDARY TO ACUTE ACETAMINOPHEN OVERDOSE.. JOURNAL OF THE MEDICAL ASSOCIATION OF THAILAND 2014;97 (2):165-72. CHOMCHAI S, CHOMCHAI C, ANUSORNSUWAN T. ACETAMINOPHEN PSI PARAMETER: A USEFUL TOOL TO QUANTIFY HEPATOTOXICITY RISK IN ACUTE ACETAMINOPHEN OVERDOSE. CLINICAL TOXICOLOGY 2011;49:664-667.",
"literaturereference_normalized": "acetaminophen psi nomogram a sensitive and specific clinical tool to predict hepatotoxicity secondary to acute acetaminophen overdose",
"qualification": "3",
"reportercountry": "TH"
},
"primarysourcecountry": "TH",
"receiptdate": "20141003",
"receivedate": "20120801",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 8696750,
"safetyreportversion": 3,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
"seriousnessdisabling": null,
"seriousnesshospitalization": null,
"seriousnesslifethreatening": null,
"seriousnessother": 1,
"transmissiondate": "20150529"
}
] |
{
"abstract": "The effect of sofosbuvir and daclatasvir in treatment of genotype 4 Hepatitis C Virus (HCV) is not well documented. This study investigated the safety and efficacy of sofosbuvir plus daclatasvir with or without ribavirin in treatment of HCV genotype 4 patients. The impact of therapy on liver fibrosis as well as the role of IL18 polymorphism in therapeutic outcome was assessed.\nOne hundred HCV genotype 4 patients were categorized into 2 groups. The group 1 comprised treatment naïve patients, with total serum bilirubin ≤ 1.2 mg/10-1 L, serum albumin ≥ 3.5 g/10-1 L, INR ≤ 1.2, and platelet count ≥ 150 × 109/L. This group was treated with sofosbuvir plus daclatasvir for 12 weeks. The group 2 included Peg-IFN-α-or sofosbuvir treatment experienced, or patients with at least 2 of the following findings: total serum bilirubin > 1.2 mg/10-1 L, serum albumin < 3.5 g/10-1 L, INR > 1.2, and platelet count < 150 × 109 L-1. Group 2 was treated with sofosbuvir-daclatasvir + ribavirin for 12 weeks, with the exception of sofosbuvir treatment experienced patients, who were treated with sofosbuvir/daclatasvir + ribavirin for 24 weeks.\nSustained Virological Response (SVR12) (undetectable viremia12 weeks post-treatment), was 93.3% in group 1 and 87.5% in group 2 (total = 91%). Such high efficacy was accompanied with tolerable adverse effects as well as with significant improvement in liver fibrosis. No significant association was observed between IL18 polymorphism (rs1946518) at position -607 and achievement of SVR12 in HCV patients after treatment.\nSofosbuvir plus daclatasvir, with or without ribavirin achieved high efficacy and safety in HCV genotype 4 patients. Their effects were accompanied with attenuation of liver fibrosis. Further wider-scale studies are needed to evaluate the actual role of IL18 polymorphisms in treatment response with sofosbuvir/daclatasvir.",
"affiliations": "Department of Pharmacology, Faculty of Medicine, Minia University, 61511 Minia, Egypt.;Department of Pharmacology, Faculty of Medicine, Minia University, 61511 Minia, Egypt.;Department of Pharmacology, Faculty of Medicine, Minia University, 61511 Minia, Egypt.;Department of Pharmacology, Faculty of Medicine, Minia University, 61511 Minia, Egypt.;Department of Biochemistry, Faculty of Medicine, Minia University, 61511 Minia, Egypt.;Department of Biochemistry, Faculty of Medicine, Minia University, 61511 Minia, Egypt.;Department of Internal Medicine, Faculty of Medicine, Minia University, 61511 Minia, Egypt.",
"authors": "Abdel-Aziz|Asmaa M|AM|;Ibrahim|Mohamed A|MA|;El-Sheikh|Azza A|AA|;Kamel|Maha Y|MY|;Zenhom|Nagwa M|NM|;Abdel-Raheim|Salam|S|;Abdelhaleem|Hisham|H|",
"chemical_list": null,
"country": "India",
"delete": false,
"doi": "10.1016/j.jceh.2017.06.006",
"fulltext": null,
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"issn_linking": "0973-6883",
"issue": "8(1)",
"journal": "Journal of clinical and experimental hepatology",
"keywords": "DAA, Direct Acting Anti-viral; FIB 4, Fibrosis Score 4; HCV; HCV, Hepatitis C Virus; IL-18 polymorphism; IL-18, Interleukin 18; INF, Interferon; NS, Non-Structural; PCR, Polymerase Chain Reaction; RFLP, Restriction Fragment Length Polymorphism; RNA, Ribonucleic Acid; SNPs, Single-Nucleotide Polymorphisms; SVR12, Sustained Virologic Response 12 Week Post Treatment; daclatasvir; sofosbuvir",
"medline_ta": "J Clin Exp Hepatol",
"mesh_terms": null,
"nlm_unique_id": "101574137",
"other_id": null,
"pages": "15-22",
"pmc": null,
"pmid": "29743792",
"pubdate": "2018-03",
"publication_types": "D016428:Journal Article",
"references": "25822283;18781864;26486291;24428467;25911336;28261822;26313445;25114601;28121921;19455410;21186531;16729309;24725239;26514736;26325535;17963291;25553890;26890629;24816173;26754432;26042207;23490375;22212578;26933517;24468783;27352267;2182076;24204123;24790644;24387618",
"title": "Effect of Sofosbuvir Plus Daclatasvir in Hepatitis C Virus Genotype-4 Patients: Promising Effect on Liver Fibrosis.",
"title_normalized": "effect of sofosbuvir plus daclatasvir in hepatitis c virus genotype 4 patients promising effect on liver fibrosis"
} | [
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"literaturereference": "ABDEL-AZIZ A, IBRAHIM M, EL-SHEIKH A, KARNEL M, ZENHOM N, ABDEL-RAHEIM S, ABDELLHALEEM H. EFFECT OF SOFOSBUVIR PLUS DACLATASVIR IN HEPATITIS C VIRUS GENOTYPE-4 PATIENTS: PROMISING EFFECT ON LIVER FIBROSIS. JOURNAL OF CLINICAL AND EXPERIMENTAL HEPATOLOGY. 2017;UNKNOWN:1-8",
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{
"abstract": "BACKGROUND\nPlacenta percreta is associated with maternal morbidity and mortality. A hysterectomy is often needed to control the bleeding in such cases. However, it has been advocated that placenta percreta be managed conservatively to avoid massive pelvic bleeding and to preserve the patient's fertility. Here, we present a case of placenta percreta diagnosed by magnetic resonance imaging, and treated with systemic administration of methotrexate.\n\n\nMETHODS\nA 27-year-old nulliparous Japanese woman at 39 gestational weeks had an uncomplicated vaginal delivery of a 3244-g infant. However, her placenta was not delivered, and we could not remove it manually. Contrast-enhanced magnetic resonance imaging indicated deep myometrial invasion by placental tissue and the whole placenta was strongly enhanced. Seven days post-partum, her serum human chorionic gonadotropin level was 12,656IU/L. Our patient hoped to preserve her uterus for a future pregnancy. She therefore received 13 courses of methotrexate (50mg/week, intravenous injection). Her serum human chorionic gonadotropin level was undetectable 97 days after the first methotrexate injection. At 117 days post-partum, she had a labor-like pain every three minutes and delivered the placenta. Our patient regained normal menses and at follow-up remained in good health. Two years later, she delivered a healthy daughter.\n\n\nCONCLUSIONS\nWe should try to detect placenta percreta in high-risk patients by any means. For low-risk patients, we should give a diagnosis swiftly and control any intrauterine infection and massive bleeding.",
"affiliations": "Department of Obstetrics and Gynecology, Sapporo Medical University Hospital, South 1, West 16, Chuo-ku, Sapporo, Hokkaido, 060-8543, Japan. mtamate@sapmed.ac.jp.;Department of Obstetrics and Gynecology, Sapporo Medical University Hospital, South 1, West 16, Chuo-ku, Sapporo, Hokkaido, 060-8543, Japan.;Department of Obstetrics and Gynecology, Sapporo Medical University Hospital, South 1, West 16, Chuo-ku, Sapporo, Hokkaido, 060-8543, Japan.;Department of Obstetrics and Gynecology, Sapporo Medical University Hospital, South 1, West 16, Chuo-ku, Sapporo, Hokkaido, 060-8543, Japan.;Department of Obstetrics and Gynecology, Sapporo Medical University Hospital, South 1, West 16, Chuo-ku, Sapporo, Hokkaido, 060-8543, Japan.;Department of Obstetrics and Gynecology, Sapporo Medical University Hospital, South 1, West 16, Chuo-ku, Sapporo, Hokkaido, 060-8543, Japan.;Department of Obstetrics and Gynecology, Sapporo Medical University Hospital, South 1, West 16, Chuo-ku, Sapporo, Hokkaido, 060-8543, Japan.;Department of Obstetrics and Gynecology, Sapporo Medical University Hospital, South 1, West 16, Chuo-ku, Sapporo, Hokkaido, 060-8543, Japan.",
"authors": "Tamate|Masato|M|;Matsuura|Motoki|M|;Habata|Shutaro|S|;Akashi|Yushi|Y|;Tanaka|Ryoichi|R|;Ishioka|Shinichi|S|;Endo|Toshiaki|T|;Saito|Tsuyoshi|T|",
"chemical_list": "D006063:Chorionic Gonadotropin; D010120:Oxytocics; D008727:Methotrexate",
"country": "England",
"delete": false,
"doi": "10.1186/s13256-015-0716-3",
"fulltext": "\n==== Front\nJ Med Case RepJ Med Case RepJournal of Medical Case Reports1752-1947BioMed Central London 71610.1186/s13256-015-0716-3Case ReportPreservation of fertility and subsequent childbirth after methotrexate treatment of placenta percreta: a case report Tamate Masato mtamate@sapmed.ac.jp Matsuura Motoki Habata Shutaro Akashi Yushi Tanaka Ryoichi Ishioka Shinichi Endo Toshiaki Saito Tsuyoshi Department of Obstetrics and Gynecology, Sapporo Medical University Hospital, South 1, West 16, Chuo-ku, Sapporo, Hokkaido 060-8543 Japan 19 10 2015 19 10 2015 2015 9 23231 3 2015 28 9 2015 © Tamate et al. 2015\nOpen AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Introduction\nPlacenta percreta is associated with maternal morbidity and mortality. A hysterectomy is often needed to control the bleeding in such cases. However, it has been advocated that placenta percreta be managed conservatively to avoid massive pelvic bleeding and to preserve the patient’s fertility. Here, we present a case of placenta percreta diagnosed by magnetic resonance imaging, and treated with systemic administration of methotrexate.\n\nCase presentation\nA 27-year-old nulliparous Japanese woman at 39 gestational weeks had an uncomplicated vaginal delivery of a 3244-g infant. However, her placenta was not delivered, and we could not remove it manually. Contrast-enhanced magnetic resonance imaging indicated deep myometrial invasion by placental tissue and the whole placenta was strongly enhanced. Seven days post-partum, her serum human chorionic gonadotropin level was 12,656IU/L. Our patient hoped to preserve her uterus for a future pregnancy. She therefore received 13 courses of methotrexate (50mg/week, intravenous injection). Her serum human chorionic gonadotropin level was undetectable 97 days after the first methotrexate injection. At 117 days post-partum, she had a labor-like pain every three minutes and delivered the placenta. Our patient regained normal menses and at follow-up remained in good health. Two years later, she delivered a healthy daughter.\n\nConclusion\nWe should try to detect placenta percreta in high-risk patients by any means. For low-risk patients, we should give a diagnosis swiftly and control any intrauterine infection and massive bleeding.\n\nKeywords\nCritical care obstetricsHuman chorionic gonadotropinMethotrexatePlacenta percretaPreservation of fertilityissue-copyright-statement© The Author(s) 2015\n==== Body\nIntroduction\nPlacenta percreta, where the chorionic villi invade the myometrium, represents a major cause of obstetric hemorrhage and is associated with maternal morbidity and mortality. A hysterectomy is often needed to control the bleeding in such cases [1]. Even if the bleeding can be controlled, a hysterectomy is often chosen to prevent profuse bleeding and infection during the infant-rearing period. However, it has been advocated that placenta percreta should be managed conservatively to avoid massive pelvic bleeding and preserve the patient’s fertility. Methotrexate (MTX) has been suggested as a possible treatment for placenta percreta to avoid hysterectomy. For such patients, it is also important to diagnose the condition swiftly and not to miss any patients at high risk. Contrast-enhanced magnetic resonance imaging (MRI) technology offers a valuable tool for an early diagnosis and assessment of the treatment outcomes [2]. There has been a paradigm shift in terms of treatment to more conservative methods of management, involving uterine conservation and leaving the placenta in situ with adjuvant treatment of MTX in some cases or simply awaiting spontaneous resorption of the placenta. Here, we present a case of placenta percreta diagnosed by MRI, and treated with systemic administration of MTX.\n\nCase presentation\nOur patient was a 27-year-old Japanese woman, gravida 1 para 0 (G1P0010). Her obstetric history was not significant except for a spontaneous abortion requiring curettage 10 years previously. There was no history of any other pelvic or abdominal surgical intervention.\n\nShe was admitted to our hospital with premature rupture of the membranes and had undergone induction of labor at 39 gestational weeks. Two days later, she had an uncomplicated vaginal delivery of a 3244-g male infant with a good Apgar score. However, her placenta was not delivered. We tried manual removal of the placenta, but felt resistance during traction of the umbilical cord. Subsequent Doppler ultrasonography (US) examinations showed a progressive vascular flow to the placental mass in her uterus. We suspected placenta accreta, so we left the whole placenta in her uterus. Fortunately, postpartum bleeding was not severe and the total amount of bleeding was 850mL, even though the umbilical cord was torn during delivery.\n\nWe cared for the bleeding and possible infections. At 7 days post-partum, her serum human chorionic gonadotropin (hCG) level was 12,656IU/L. Gadolinium-enhanced MRI also indicated deep myometrial invasion by placental tissues, and the whole placenta was strongly enhanced (Fig. 1a). A general physical examination revealed no abnormalities. Her medical and gynecological histories were unremarkable.Fig. 1 \na Magnetic resonance imaging scan taken 7 days post-partum. Myometrial invasion by placental tissue is shown and the whole placenta (13.4×11.6×8.6cm) was strongly enhanced. b After 13 courses of methotrexate therapy, placental tissue was reduced and none of the placenta (7.0×6.8×6.6cm) was enhanced\n\n\n\nOur patient hoped to preserve her uterus for a future pregnancy so we decided to administer 50mg MTX by intravenous injection after obtaining informed consent relevant to surgical and other treatment strategies. Hematological, hepatic, and renal functions were evaluated and found to be normal before the MTX injections. Our patient experienced no untoward effects following MTX administration, and her vaginal bleeding diminished gradually over four weeks. To avoid intrauterine manipulation with surgical equipment and subsequent infection (that is, diagnostic hysteroscopy), follow-up MRI using an identical technique was performed every four weeks to assess the treatment response. MTX therapy (50mg/week) was administered 13 times. During the course of this therapy, our patient had an intrauterine infection and took three separate course of antibiotics. Complete resolution of the uterine lesion was confirmed by MRI scans (Fig. 1b). Her serum hCG level was undetectable (<5IU/L) 97 days after the first MTX injection (Fig. 2). At 117 days post-partum, she had a labor-like pain every three minutes and delivered the remnant of the placenta with a little bleeding. The vestigial mass weighed 80g (10×6×4cm) and histopathology indicated placental tissue with necrosis. Her menses resumed 181 days after the first MTX injection, and a follow-up hysteroscopy showed no abnormal findings (Fig. 3).Fig. 2 Serum human chorionic gonadotropin (HCG) levels were attenuated exponentially by methotrexate (MTX) treatment. Our patient had an intrauterine infection, and took three courses of antibiotics. CLDM clindamycin, CPFN-PI cefcapene pivoxil, CPFX ciprofloxacin, CTM cefotiam, FMOX flomoxef, MRI magnetic resonance imaging, PIPC piperacillin, SBTPC sultamicillin\n\nFig. 3 Hysteroscopy image by transvaginal ultrasonography showing a small defect in the endometrium of the posterial wall measuring 8 mm. Another region of the endometrium was defect-free\n\n\n\nTwo years later, our patient (G2P1011) became pregnant spontaneously. We did not detect any placental lacunae or clear spaces on transabdominal US, nor did we see any depletion of decidua in her uterus on MRI. She underwent an uncomplicated vaginal delivery of a 3304-g female infant with a good Apgar score. Postpartum bleeding was not active and the total bleeding was 910mL. We did not find any thinning of the posterior uterine muscular layer on transabdominal US, and there was no bleeding with the dislodging of the placenta. The placenta had histopathological features of marginal infarction and chorioamnionitis stage 2 by the Blanc category. Two independent pathologists did not note any deficiency in the decidua.\n\nDiscussion\nThis case illustrates a successful nonsurgical management strategy for placenta percreta utilizing MTX, which resulted in near-complete placental atrophy, as demonstrated by a comparison of pre-treatment and post-treatment MRI scans using gadolinium contrast. In this case, gray-scale US and Doppler imaging were effective for the detection of placental blood flow.\n\nAbnormal placental adherence is believed to result from pathological absence of the normally intervening uterine decidua basalis and Nitabuch’s fibrinoid layer [3, 4]. Superficial invasion of the basalis layer is termed placenta accreta (approximately 75% of cases); deeper invasion of the myometrium is termed placenta increta (approximately 15% of cases); and even deeper invasion involving the serosa or adjacent pelvic organs is termed placenta percreta [5]. This abnormal adherence of the placenta to the uterus can result in catastrophic intrapartum hemorrhage at the time of placental delivery, often necessitating emergency hysterectomy. The prevalence of placenta accreta has increased more than tenfold in the past 30 years to approximately 1 in 2500 deliveries in the USA [6]. This increase appears to relate to the increasing incidence of uterine surgery, which results in a decidual defect that allows abnormal placental ingrowth [7]. However, our patient did not have this risk factor. It is also possible that placenta percreta is associated with an abnormal position of implantation in early pregnancy, for example, cornual and angular pregnancies [8].\n\nPlacenta percreta is associated with considerable maternal morbidity and mortality. Indeed, most cases of placenta percreta require a hysterectomy to achieve adequate hemostasis [9]. Although a hysterectomy remains the definitive therapy for placenta increta, some women (such as in our case) desire conservation of the uterus to ensure future fertility. For this reason, less-extreme surgical approaches, including wedge resection of the affected myometrium, have been proposed as a method of permitting subsequent pregnancy. MTX is a potent antimetabolite, with mechanisms of action that include inhibition of trophoblast cells, reduction of placental neovascularization, and attenuation of placental growth factors [10]. In this case, MTX was effective in reducing the blood flow in her placenta diagnosed by MRI and US. Placenta previa and prior intrauterine manipulation have been identified as significant synergistic factors for the development of placenta accreta or percreta, with rates as high as 50–67% in patients with a combination of more than two prior Cesarean deliveries and a placenta previa [11]. However, our patient did not have a history of prior Cesarean delivery.\n\nMRI and US are effective diagnostic tools. The overall sensitivity and specificity of US for the diagnosis of placenta accreta have been reported to be 77–93% and 71–96%, respectively [11]. The US features of placenta accreta include loss of the normal retroplacental clear space, anomalies of the bladder–myometrium interface, prominent placental lacunae, and increased vascularity at the interface of the uterus and bladder [11, 12]. By contrast, the overall sensitivity and specificity of MRI have been reported as 80–88% and 65–100%, respectively. MRI features considered diagnostic of placenta accreta include abnormal uterine bulging, heterogeneous placental signal intensity on T2-weighted images, and the presence of dark intraplacental bands associated with lacunae on such images [11, 12]. In our case, MRI in puerperium showed the absence of dark intraplacental bands.\n\nOur patient had risk factors for placental abnormality, including a previous abortion, and dilatation and curettage. However, if dilatation and curettage become a risk of placenta accreta, she may have a repeat placenta accreta. Previous placenta previa, submucosal fibroids, prior Cesarean delivery, and multiparity are other recognized risk factors for placenta increta and percreta. Recent studies have shown that patients with placenta accreta or percreta have high serum alpha-fetoprotein and serum hCG levels.\n\nIt took 117 days from the initial delivery for our patient to achieve a satisfactory therapeutic response to MTX, shown by her declining serum hCG levels and confirmed by contrast-enhanced MRI. This successful response obviated the need for diagnostic hysteroscopy and possible hysterectomy to remove the residual placenta.\n\nPlacental invasion of the myometrium may be difficult to discern using routine US. Accordingly, use of contrast-enhanced MRI to confirm any abnormal placentation warrants consideration in such clinical settings [13].\n\nConclusions\nWe should try to detect placenta accreta and percreta in high-risk cases using US and MRI. For low-risk cases, we should give a diagnosis swiftly and control any intrauterine infection and massive bleeding. Early diagnosis is important so that the patient can be prepared and adequately counselled with regard to the treatment options and their possible consequences. Fever may also represent an inflammatory response to tissue necrosis in the absence of any infectious source. Infectious morbidity can be reduced by use of prophylactic broad-spectrum antibiotic therapy [14] and the patient in our case had a successful subsequent live delivery after placenta percreta.\n\nConsent\nWritten informed consent was obtained from the patient for publication of this case and accompanying images. A copy of the written consent is available for review by the Editor-in- Chief of this journal.\n\nAbbreviations\nhCGhuman chorionic gonadotropin\n\nMRImagnetic resonance imaging\n\nMTXmethotrexate\n\nUSultrasonography\n\nCompeting interests\n\nThe authors declare that they have no competing interests.\n\nAuthors’ contributions\n\nMT drafted the manuscript and MM and SI assessed the quality of the paper. MT, MM, SH and YA treated the patient. TB and SI were witness to the birth. RT, TE and TS revised the manuscript critically for its content. All authors read and approved the final manuscript.\n==== Refs\nReferences\n1. Chan BC Lam HS Yuen JH Lam TP Tso WK Pun TC Conservative management of placenta praevia with accreta Hong Kong Med J. 2008 14 479 84 19060348 \n2. Elsayes KM Trout AT Friedkin AM Liu PS Bude RO Platt JF Imaging of the placenta: a multimodality pictorial review Radiographics. 2009 29 1371 91 10.1148/rg.295085242 19755601 \n3. Zaki ZM Bahar AM Ali ME Albar HA Gerais MA Risk factors and morbidity in patients with placenta previa accreta compared to placenta previa non-accreta Acta Obstet Gynecol Scand. 1998 77 391 4 10.1080/j.1600-0412.1998.00015.x 9598946 \n4. Zelop CM Harlow BL Frigelleto FD Jr Safon LE Saltzman DH Emergency peripartum hysterectomy Am J Obstet Gynecol. 1993 168 1443 8 10.1016/S0002-9378(11)90779-0 8498425 \n5. Mazouni C Gorincour G Juhan V Bretelle F Placenta accreta: a review of current advances in prenatal diagnosis Placenta. 2007 28 599 603 10.1016/j.placenta.2006.06.011 16959315 \n6. ACOG Committee on Obstetric Practice ACOG committee opinion number 266: placenta accreta Obstet Gynecol. 2002 99 169 70 10.1016/S0029-7844(01)01748-3 11777527 \n7. Benirschke K The placenta: structure and function NeoReviews. 2004 5 252 61 10.1542/neo.5-6-e252 \n8. Breen JL A 21 year survey of 654 ectopic pregnancies Am J Obstet Gynecol. 1970 106 1004 19 5461630 \n9. Breen JL Neubecker R Gregoli CA Franklin JE Jr Placenta accreta, increta and percreta. A survey of 40 cases Obstet Gynecol 1977 49 43 7 299782 \n10. Flam F Karlstrom PO Carlsson B Garoff L Methotrexate treatment for retained placental tissue Eur J Obstet Gynecol Reprod Biol. 1999 83 127 9 10.1016/S0301-2115(98)00270-X 10391520 \n11. Warshak CR Eskander R Hull AD Scioscia AL Mattrey RF Benirschke K Accuracy of ultrasonography and magnetic resonance imaging in the diagnosis of placenta accreta Obstet Gynecol. 2006 108 573 81 10.1097/01.AOG.0000233155.62906.6d 16946217 \n12. Dwyer BK Belogolovkin V Tran L Prenatal diagnosis of placenta accreta: sonography or magnetic resonance imaging? J Ultrasound Med. 2008 27 1275 81 18716136 \n13. Wehbe SA Ghulmiyyah LM Carroll KT Perloe M Schwartzberg DG Sills ES Correlations from gadopentetate dimeglumine-enhanced magnetic resonance imaging after methotrexate chemotherapy for hemorrhagic placenta increta Biomagn Res Technol. 2003 1 3 10.1186/1477-044X-1-3 14617375 \n14. Khan M Sachdeva P Arora R Bhasin S Conservative management of morbidly adherant placenta - a case report and review of literature Placenta. 2013 34 963 6 10.1016/j.placenta.2013.04.016 23937959\n\n",
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"mesh_terms": "D000328:Adult; D006063:Chorionic Gonadotropin; D005260:Female; D005298:Fertility; D006801:Humans; D008279:Magnetic Resonance Imaging; D008727:Methotrexate; D010120:Oxytocics; D010921:Placenta Accreta; D049590:Postpartum Period; D011247:Pregnancy; D047929:Term Birth",
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"title": "Preservation of fertility and subsequent childbirth after methotrexate treatment of placenta percreta: a case report.",
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"abstract": "Respiratory viruses are an important yet underestimated cause of infectious morbidity and mortality in immunocompromised children and adolescents. Here, we report the occurrence of fatal lower respiratory tract disease associated with human metapneumovirus (HMPV) infection in a 10-year-old girl with chronic graft-versus-host disease following allogeneic hematopoietic stem cell transplantation (HSCT) for secondary chronic myeloid leukemia. Symptoms occurred 8 months after HSCT while on immunosuppression with 0.2 mg/kg/day of prednisone, and presented as dry cough, bilateral pneumonitis, and progressive respiratory distress. Non-invasive and invasive microbiological investigations revealed HMPV type B as the sole pathogen. Histopathological findings showed interstitial and intra-alveolar pneumonitis with profound alveolar cell damage. The patient was treated with intravenous and oral ribavirin and polyvalent immunoglobulins, but ultimately died from respiratory failure. The case reflects the potentially fatal impact of infections by respiratory viruses in immunocompromised patients and the need for effective approaches to their prevention and treatment.",
"affiliations": "Infectious Disease Research Program, Center for Bone Marrow Transplantation, University Children's Hospital Münster, Münster, Germany.",
"authors": "Dokos|C|C|;Masjosthusmann|K|K|;Rellensmann|G|G|;Werner|C|C|;Schuler-Lüttmann|S|S|;Müller|K-M|KM|;Schiborr|M|M|;Ehlert|K|K|;Groll|A H|AH|",
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"medline_ta": "Transpl Infect Dis",
"mesh_terms": "D002648:Child; D017809:Fatal Outcome; D005260:Female; D006086:Graft vs Host Disease; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D016867:Immunocompromised Host; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive; D029121:Metapneumovirus; D018184:Paramyxoviridae Infections; D012141:Respiratory Tract Infections; D014184:Transplantation, Homologous",
"nlm_unique_id": "100883688",
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"pages": "E97-E101",
"pmc": null,
"pmid": "23551689",
"pubdate": "2013-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Fatal human metapneumovirus infection following allogeneic hematopoietic stem cell transplantation.",
"title_normalized": "fatal human metapneumovirus infection following allogeneic hematopoietic stem cell transplantation"
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{
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{
"abstract": "OBJECTIVE\nTo report a case of optic neuropathy secondary to Linezolid, second line anti tuberculosis agent.\n\n\nMETHODS\n22 year Indian male with multidrug resistant spinal tuberculosis and TB meningitis was started on second line anti tuberculosis drugs. Within one month of onset of second line anti TB drug, he was noted to have optic neuropathy in both eyes. Visual field and electro diagnostics suggested optic neuropathy.\n\n\nCONCLUSIONS\nLinezolid is a synthetic oxazolidinone broad spectrum antibiotic and has been in off label use for multidrug resistant tuberculosis (MDR-TB). There are very scattered case reports of optic neuropathy secondary to use of this off label drug. In our case, the optic neuropathy was however reversible on stoppage of the drug.\n\n\nCONCLUSIONS\nIt seems prudent that baseline ophthalmological evaluation to be done for all patients to be subjected for treatment with this drug for any short term or long term therapy.",
"affiliations": "Moorfields Eye Hospital NHS Foundation Trust , London , UK and.",
"authors": "Agrawal|Rupesh|R|;Addison|Peter|P|;Saihan|Zubin|Z|;Pefkianaki|Maria|M|;Pavesio|Carlos|C|",
"chemical_list": "D000081:Acetamides; D000890:Anti-Infective Agents; D023303:Oxazolidinones; D000069349:Linezolid",
"country": "England",
"delete": false,
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"issue": "23(1)",
"journal": "Ocular immunology and inflammation",
"keywords": "Linezolid; MDR TB; optic neuropathy; second-line anti-TB drugs",
"medline_ta": "Ocul Immunol Inflamm",
"mesh_terms": "D000081:Acetamides; D000890:Anti-Infective Agents; D006801:Humans; D000069349:Linezolid; D008297:Male; D009901:Optic Nerve Diseases; D023303:Oxazolidinones; D018088:Tuberculosis, Multidrug-Resistant; D014399:Tuberculosis, Spinal; D055815:Young Adult",
"nlm_unique_id": "9312169",
"other_id": null,
"pages": "90-2",
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"pmid": "24432953",
"pubdate": "2015-02",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Optic neuropathy secondary to Linezolid for multidrug-resistant mycobacterial spinal tuberculosis.",
"title_normalized": "optic neuropathy secondary to linezolid for multidrug resistant mycobacterial spinal tuberculosis"
} | [
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{
"abstract": "Diphenoxylate-atropine (Lomotil) intoxication incidence was significantly high in the past, but seeing such cases in the present day of modern and advanced medicine, hints about the gaps in the practice of medicine. In our case, a general physician maltreated an infant for diarrhea with an adult dose of diphenoxylate-atropine (Lomotil), a Food and Drug Administration (FDA) unapproved drug, which caused labored breathing and pinpoint pupils. After being maltreated, at the time of presentation to the emergency room (ER), she was being misdiagnosed as a case of dehydration until doctors noticed miosis and reached the diagnosis of diphenoxylate-atropine (Lomotil) toxicity. Her condition completely reversed with a single dose of naloxone. Hence, this case highlights the need for basic knowledge about the dosage of drugs for different age groups, especially infants, along with the importance of adherence to the evaluation protocols for accurate management.",
"affiliations": "Internal Medicine, Quaid-e-Azam Medical College, Bahawalpur, PAK.;Internal Medicine, Dow University of Health Sciences, Karachi, PAK.;Internal Medicine, Quaid-e-Azam Medical College, Bahawalpur, PAK.;Internal Medicine, Dow University of Health Sciences, Karachi, PAK.;Pediatrics, Dow University of Health Sciences, Karachi, PAK.",
"authors": "Khan|Hamza R|HR|;Ali Asghar|Sarrah|S|;Kanwal|Sharfa|S|;Qadar|Laila Tul|LT|;Qadri|Kashif H|KH|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.7759/cureus.5875",
"fulltext": "\n==== Front\nCureusCureus2168-8184Cureus2168-8184Cureus Palo Alto (CA) 10.7759/cureus.5875Preventive MedicineInternal MedicinePediatricsDiphenoxylate-atropine (Lomotil) Toxicity in Infantile Diarrhea: A Case Report of Therapeutic Failure Muacevic Alexander Adler John R Khan Hamza R 1Ali Asghar Sarrah 2Kanwal Sharfa 1Qadar Laila Tul 2Qadri Kashif H 3\n1 \nInternal Medicine, Quaid-e-Azam Medical College, Bahawalpur, PAK \n2 \nInternal Medicine, Dow University of Health Sciences, Karachi, PAK \n3 \nPediatrics, Dow University of Health Sciences, Karachi, PAK \nHamza R. Khan hrk151@outlook.com9 10 2019 10 2019 11 10 e587527 9 2019 9 10 2019 Copyright © 2019, Khan et al.2019Khan et al.This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.This article is available from https://www.cureus.com/articles/23718-diphenoxylate-atropine-lomotil-toxicity-in-infantile-diarrhea-a-case-report-of-therapeutic-failureDiphenoxylate-atropine (Lomotil) intoxication incidence was significantly high in the past, but seeing such cases in the present day of modern and advanced medicine, hints about the gaps in the practice of medicine. In our case, a general physician maltreated an infant for diarrhea with an adult dose of diphenoxylate-atropine (Lomotil), a Food and Drug Administration (FDA) unapproved drug, which caused labored breathing and pinpoint pupils. After being maltreated, at the time of presentation to the emergency room (ER), she was being misdiagnosed as a case of dehydration until doctors noticed miosis and reached the diagnosis of diphenoxylate-atropine (Lomotil) toxicity. Her condition completely reversed with a single dose of naloxone. Hence, this case highlights the need for basic knowledge about the dosage of drugs for different age groups, especially infants, along with the importance of adherence to the evaluation protocols for accurate management.\n\ndiphenoxylate-atropine toxicitydrug contraindicationsdiarrheadosagenaloxonelomotilThe content published in Cureus is the result of clinical experience and/or research by independent individuals or organizations. Cureus is not responsible for the scientific accuracy or reliability of data or conclusions published herein. All content published within Cureus is intended only for educational, research and reference purposes. Additionally, articles published within Cureus should not be deemed a suitable substitute for the advice of a qualified health care professional. Do not disregard or avoid professional medical advice due to content published within Cureus.\n==== Body\nIntroduction\nDiarrhea is a dangerous sign for the health of a child. Hence, it requires appropriate and timely management. The first-line approach for managing a case of diarrhea is physiological, which includes rehydration, either orally or through the intravenous route. The pharmacological method comprising antidiarrheals as adjuvant therapy is also used [1]. The most common antidiarrheals prescribed by general physicians in our country are diphenoxylate-atropine (Lomotil) and loperamide [2].\n\nLomotil is a synthetic substance that is chemically related to meperidine. A subtherapeutic dosage of atropine, an anticholinergic, is added to the preparation, to discourage deliberate overdose. It has the role of an antisecretory agent when it acts on enteric μ-opioid receptors, resulting in the release of noradrenaline as a final mediator. It also acts as a spasmogenic to prolong gastric emptying and decrease bowel frequency, thus rendering the gut atonic [3-4]. The use of diphenoxylate-atropine (Lomotil) in higher than the prescribed dosage can cause toxicity. Clinical presentations in a case of toxicity vary in terms of which a component of the drug (opioid or anticholinergic) will dominate first. The metabolism of diphenoxylate involves rapid and extensive conversion by ester hydrolysis into difenoxin, which is biologically five times more active and a major metabolite in the blood [5]. Antidiarrheal diphenoxylate-atropine (Lomotil) is available in forms like tablets and syrup. The composition of a single pill of diphenoxylate-atropine (Lomotil) is 2.5 mg of diphenoxylate and 0.025 mg of atropine sulfate. The dose of usually two tablets, which is prescribed to adults only produces required opioid effects locally in the gut to control diarrhea. However, the same treatment can cause central nervous system (CNS) and respiratory depression in an infant or child.\n\nDespite well-documented risks and toxicities of this drug as well as contraindications of its use at an age of fewer than two years by the Food and Drug Administration (FDA) [6], doctors of our locality still prescribe it with no important instructions to parents. Herein, we present a case of diphenoxylate-atropine (Lomotil) toxicity in a 10-month-old infant treated for diarrhea.\n\nCase presentation\nA 10-month-old female child presented in the emergency room (ER) of Dr. Ruth KM Pfau, Civil Hospital Karachi (CHK), with an altered level of consciousness and shallow breathing. The child was vaccinated according to the expanded program on immunization (EPI) but was malnourished, with an unsubstantial history of family illnesses. The patient was accompanied by her mother. She weighed 6.6 kg, is the fourth-born child to her parents and was delivered at term to a 37-year-old G4P4 (gravida 4 para 4) mother via normal vaginal delivery. The mother did not disclose any complications during pregnancy. \n\nThe patient developed respiratory distress since that morning accompanied by low-grade intermittent fever on the day of presentation. She had a history of loose, watery diarrhea for one day. There were 12 episodes of watery motions, not blood-stained, for which treatment was taken by the nearby general physician, including antibiotics, zinc supplements, and two tablets of diphenoxylate-atropine after which diarrhea was resolved. Past medical history revealed the child is developmentally delayed and is being treated for maculopapular rash. The mother also noticed weight loss and altered bowel habits, although micturition was normal.\n\nOn examination, the patient was lying on the bed, irritated and lethargic, having labored breathing. Initial vitals included blood pressure (BP) 129/103 mmHg, a regular pulse of 201 beats/min, a respiratory rate of 15 breaths/min, and a low-grade fever of 99.7° F. The patient was anemic and dehydrated, with no visible signs of clubbing, cyanosis, edema, and lymphadenopathy. Various lab investigations were ordered, which include complete blood count (CBC) (Table 1), urea creatinine electrolytes (UCE) (Table 2), and arterial blood gas (ABG) (Table 3). All other systems were unremarkable.\n\nTable 1 CBC of our patient\nCBC: Complete blood count\n\nParameters\tResult\tNormal Value\t\nHemoglobin (g/dL)\t12.3\t11-16\t\nMean corpuscular volume (fl)\t91.6\t82-95\t\nMean corpuscular hemoglobin (pg)\t32.2\t27-31\t\nMean corpuscular hemoglobin concentration (g/dL)\t35.1\t32-36\t\nTotal leukocyte count (109/L)\t10.7\t4-11\t\nNeutrophils (%)\t32.7\t40-70\t\nLymphocytes (%)\t46.7\t20-45\t\nPlatelets (103/μl)\t370\t150-450\t\nTable 2 Values of UCE in our patient\nUCE: Urea creatinine electrolytes \n\nParameters\tResult\tNormal Value\t\nBlood urea nitrogen (mg/dL)\t6\t7-20\t\nCreatinine (mmol/L)\t0.3\t0.6-0.12\t\nNa (mmol/L)\t137\t135-145\t\nK (mmol/L)\t4.6\t3.5-5.1\t\nCl (mmol/L)\t103\t98-107\t\nTable 3 An ABG test values of our patient\nABG: Arterial blood gas\n\n\nParameters\n\t\nResult\n\t\nNormal Value\n\t\n\npH\n\t\n7.35\n\t\n7.35-7.45\n\t\n\npCO2 (mmHg)\n\t\n48\n\t\n35-45\n\t\n\nHCO3- (mmol/L)\n\t\n20\n\t\n22-26\n\t\nOn chest auscultation, harsh vesicular breathing and equal air entry were heard; the breathing pattern was abnormal and shallow. The presumptive diagnosis of dehydration was made. However, when reflexes were found to be brisk, with a pinpoint pupil, the diagnosis of opioid (diphenoxylate-atropine) toxicity was made, which was completely reversed by a single naloxone dose of 0.6 mg. The child responded immediately after the administration of naloxone and the breathing pattern also improved. The pinpointed pupil got settled toward dilation and became reactive. The level of consciousness was also regained.\n\nDiscussion\nDiphenoxylate-atropine (Lomotil) ranks seventh on the list of deadly drugs that cause severe intoxication in children with just a single dose [7]. Anticholinergic overdose symptoms, from the most to the least common, include tachycardia, restlessness/anxiety, flushing, urinary retention, and diminished reflexes, while overdose symptoms due to the diphenoxylate component of diphenoxylate-atropine (Lomotil), from the most to the least common, are drowsiness, vomiting, respiratory depression, coma, and abdominal pain/constipation [7]. Miosis, seizures, or paralytic ileus may also be seen. Our patient exhibited many symptoms; however, the only point of diagnosis was the presence of miosis whereas other reports show that ocular toxicity, ototoxicity, and cardiac conduction defects like arrhythmias can occur [8].\n\nOur infant patient was also given a single adult dose of two tablets for the treatment of diarrhea, which was controlled at the time of presentation to the ER. Presenting complaints were delayed sensorium, altered level of consciousness, and other signs and symptoms (S/S) mentioned above. Initially, the doctor thought that the patient is a simple case of dehydration, so she was being managed for it until her pupils were found to be pinpoint, which, on further inquiry from the mother, shifted the diagnosis to diphenoxylate-atropine (Lomotil) toxicity.\n\nAs per reports, there are usually two phases of diphenoxylate-atropine (Lomotil) intoxication [5]. The first phase, which attributed to the dominant effects of atropine, shows S/S such as flushing, high fever, and tachypnea followed by the second phase of opioid dominance due to diphenoxylate mainly comprises CNS and respiratory depression along with miosis. Although our patient presented after almost 24 hours of taking diphenoxylate-atropine (Lomotil) when the phase of atropine was over, she still showed overlapping atropine effects, such as fever and severe tachycardia, co-occurring with bradypnea and miosis, which is an opioid overdose symptom. Moreover, reflexes are diminished as part of atropine effects, but our patient had normal muscle tone and brisk reflexes.\n\nMedical complications seen in this type of toxicity are aspiration pneumonia, cortical blindness, and cerebral edema [5]. In the early stage of diphenoxylate poisoning in children, there is a report of multiple and extensive edema-necrosis in various areas of the brain observed through magnetic resonance imaging (MRI), which also supports the risk of complications [9]. This patient, however, did not suffer any complications.\n\nVarious modalities of treatment were adopted in the past like emetics, gastric lavage, activated charcoal, forced diuresis, and, finally, the drug of choice, naloxone [5]. Whereas, in cases of the dependence of diphenoxylate combination therapy of buprenorphine 2 mg and naloxone 0.5 mg is also documented [10]. Our patient’s condition was reversed by just one dose of naloxone.\n\nToxicity reports for this drug fall under both accidental ingestion and therapeutic administration. The risk of accidental ingestion remains whereas intoxication due to therapeutic administration is not frequently encountered due to education and awareness among doctors. However, to our dismay, cases of toxicity are still seen due to malpractice of some primary care providers mainly to satisfy distressed parents. However, the lack of proper education of parents by the physician regarding dosage and intoxication can sometimes lead to instances where parents overdose the children due to a lack of knowledge about drugs [6]. In our case, the infant was maltreated by the general practitioner of the locality.\n\nTherefore, we find it necessary to report this to educate general practitioners and improve the careful and appropriate management of common pediatric illnesses. We also emphasize the lesson that proper and thorough physical evaluation must be carried out before reaching any diagnosis and starting any treatment. If this infant had been misdiagnosed initially as a case of severe dehydration at the time of presentation to the ER because of missing an essential step of evaluating the pupils, her condition would have remained the same or deteriorated, and she might have died due to intoxication. Hence, this case is different, after considering the therapeutic errors in drugs of known toxicity due to a lack of awareness among general practitioners regarding pediatric dosage and contraindications, evaluation protocols, and approach to management.\n\nConclusions\nUp-to-date information about the new drugs for common illnesses, along with knowledge of known toxicities of conventional drugs, must be known to the doctors. Apart from that, the dosage of drugs must always be correctly determined and prescribed to the pediatric age group since they are very susceptible to dosage intoxication. For this, all doctors should regularly check FDA guidelines for the drugs that are commonly used for treating such diseases. Moreover, ER care doctors must strictly adhere to evaluation protocols and thoroughly examine patients before deciding because they have a narrow margin of error.\n\nThe authors have declared that no competing interests exist.\n\nHuman Ethics\nConsent was obtained by all participants in this study\n==== Refs\nReferences\n1 Management strategies in the treatment of neonatal and pediatric gastroenteritis Infect Drug Resist Ciccarelli S Stolfi I Caramia G 133 161 6 2013 24194646 \n2 Prescription patterns of general practitioners in Peshawar, Pakistan Pak J Med Sci Raza UA Khursheed T Irfan M Abbas M Irfan UM 462 465 30 2014 24948959 \n3 Acute anticholinergic poisoning in children Hong Kong Med J Lee AC So KT 520 523 11 2005 https://pdfs.semanticscholar.org/9320/8b3da88c59f76db7787eba491a5ad9f1621e.pdf 16340032 \n4 Pharmacologic management of diarrhea in patients with short bowel syndrome JPEN J Parenter Enteral Nutr Kumpf VJ 38 44 38 2014 \n5 Diphenoxylate-atropine (Lomotil) overdose in children: an update (report of eight cases and review of the literature) Pediatrics McCarron MM Challoner KR Thompson GA 694 700 87 1991 https://pediatrics.aappublications.org/content/87/5/694.abstract 2020516 \n6 What is Lomotil (atropine & diphenoxylate)? 9 2019 2014 https://www.everydayhealth.com/drugs/lomotil \n7 Re: \"Are one or two dangerous? Diphenoxylate-atropine exposure in toddlers\" J Emerg Med Farmer BM Prosser JM Hoffman RS 384 38 2010 \n8 Lomotil Pediatrics 9 2019 Rosenstein G Freeman M Standard AL Weston N 132 134 51 2019 https://www.webmd.com/drugs/2/drug-6876/lomotil-oral/details \n9 MRI findings in 6 cases of children by inadvertent ingestion of diphenoxylate-atropine Eur J Radiol Xiao L Lin X Cao J Wang X Wu L 432 436 79 2011 https://doi.org/10.1016/j.ejrad.2010.03.021 20395092 \n10 Diphenoxylate dependence treated with buprenorphine and naloxone combination Ann Indian Psychiatry Nemlekar SS Mehta RY Shah ND 63 64 2 2018\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2168-8184",
"issue": "11(10)",
"journal": "Cureus",
"keywords": "diarrhea; diphenoxylate-atropine toxicity; dosage; drug contraindications; lomotil; naloxone",
"medline_ta": "Cureus",
"mesh_terms": null,
"nlm_unique_id": "101596737",
"other_id": null,
"pages": "e5875",
"pmc": null,
"pmid": "31763098",
"pubdate": "2019-10-09",
"publication_types": "D002363:Case Reports",
"references": "20395092;4684435;24948959;19545964;16340032;24463352;2020516;24194646",
"title": "Diphenoxylate-atropine (Lomotil) Toxicity in Infantile Diarrhea: A Case Report of Therapeutic Failure.",
"title_normalized": "diphenoxylate atropine lomotil toxicity in infantile diarrhea a case report of therapeutic failure"
} | [
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{
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},
{
"reactionmeddrapt": "Overdose",
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"literaturereference": "KHAN, H.. DIPHENOXYLATE-ATROPINE (LOMOTIL) TOXICITY IN INFANTILE DIARRHEA: A CASE REPORT OF THERAPEUTIC FAILURE. CUREUS. 2019?11(10): E5875:10.7759/CUREUS.5875",
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] |
{
"abstract": "Acute toxic leukoencephalopathy (ATL) is a rare adverse effect of 5-Fluorouracil (5-FU) chemotherapeutic agent. It is imperative for the radiologist to confidently identify the white matter changes caused by this agent in case of toxicity. This will help in early detection and appropriate management of patient, as the condition is reversible both clinically and on imaging. We report a case of a 29 years old gentleman, known case of carcinoma of esophagus who suffered from acute toxic leukoencephalopathy secondary to leukotoxic therapeutic agent 5-FU, and illustrate the reversible imaging findings of this condition on withdrawal of the inciting agent.",
"affiliations": "Department of Radiology, The Aga Khan University Hospital, Karachi.;Department of Radiology, The Aga Khan University Hospital, Karachi.;Department of Radiology, The Aga Khan University Hospital, Karachi.;Department of Radiology, The Aga Khan University Hospital, Karachi.",
"authors": "Maheen Anwar|Shayan Sirat|SS|;Mubarak|Fatima|F|;Sajjad|Zafar|Z|;Azeemuddin|Muhammad|M|",
"chemical_list": "D000964:Antimetabolites, Antineoplastic; D005472:Fluorouracil",
"country": "Pakistan",
"delete": false,
"doi": "03.2014/JCPSP.S8S10",
"fulltext": null,
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"issue": "24 Suppl 1()",
"journal": "Journal of the College of Physicians and Surgeons--Pakistan : JCPSP",
"keywords": null,
"medline_ta": "J Coll Physicians Surg Pak",
"mesh_terms": "D000208:Acute Disease; D000328:Adult; D000964:Antimetabolites, Antineoplastic; D038524:Diffusion Magnetic Resonance Imaging; D004938:Esophageal Neoplasms; D005472:Fluorouracil; D006801:Humans; D056784:Leukoencephalopathies; D008297:Male",
"nlm_unique_id": "9606447",
"other_id": null,
"pages": "S8-10",
"pmc": null,
"pmid": "24718016",
"pubdate": "2014-03",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "5-FU induced acute toxic leukoencephalopathy: early recognition and reversibility on DWI-MRI.",
"title_normalized": "5 fu induced acute toxic leukoencephalopathy early recognition and reversibility on dwi mri"
} | [
{
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},
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"medicinalproduct": "5-FLUOROURACIL"
}
],
"patientagegroup": null,
"patientonsetage": "29",
"patientonsetageunit": "801",
"patientsex": "1",
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"reaction": [
{
"reactionmeddrapt": "Ventricular tachycardia",
"reactionmeddraversionpt": "18.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Blood creatinine increased",
"reactionmeddraversionpt": "18.0",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Hemianopia",
"reactionmeddraversionpt": "18.0",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Leukoencephalopathy",
"reactionmeddraversionpt": "18.0",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Arteriospasm coronary",
"reactionmeddraversionpt": "18.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Left ventricular dysfunction",
"reactionmeddraversionpt": "18.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Discomfort",
"reactionmeddraversionpt": "18.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Acute myocardial infarction",
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"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Aphasia",
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},
{
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"reactionoutcome": "6"
}
],
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"literaturereference": "ANWAR SSM, MUBARAK F, SAJJAD Z, AZEEMUDDIN M.. 5-FU INDUCED ACUTE TOXIC LEUKOENCEPHALOPATHY: EARLY RECOGNITION AND REVERSIBILITY ON DWI-MRI.. J-COLL-PHYSICIANS-SURG-PAK. 2014;24:S8-S10",
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"reactionmeddraversionpt": "18.0",
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},
{
"reactionmeddrapt": "Acute kidney injury",
"reactionmeddraversionpt": "18.0",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Left ventricular dysfunction",
"reactionmeddraversionpt": "18.0",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Ventricular tachycardia",
"reactionmeddraversionpt": "18.0",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Myocardial infarction",
"reactionmeddraversionpt": "18.0",
"reactionoutcome": "1"
}
],
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},
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"literaturereference": "ANWAR S.S.M., MUBARAK F., SAJJAD Z., AZEEMUDDIN M.. 5-FU INDUCED ACUTE TOXIC LEUKOENCEPHALOPATHY: EARLY RECOGNITION AND REVERSIBILITY ON DWI-MRI. JOURNAL OF THE COLLEGE OF PHYSICIANS AND SURGEONS PAKISTAN. 2014;24:S8-S10",
"literaturereference_normalized": "5 fu induced acute toxic leukoencephalopathy early recognition and reversibility on dwi mri",
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},
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"transmissiondate": "20150529"
},
{
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{
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{
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{
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},
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}
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"reaction": [
{
"reactionmeddrapt": "Leukoencephalopathy",
"reactionmeddraversionpt": "18.0",
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},
{
"reactionmeddrapt": "Acute kidney injury",
"reactionmeddraversionpt": "18.0",
"reactionoutcome": "2"
},
{
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"reactionmeddraversionpt": "18.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Acute myocardial infarction",
"reactionmeddraversionpt": "18.0",
"reactionoutcome": "6"
},
{
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"reactionmeddraversionpt": "18.0",
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}
],
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{
"abstract": "We report 3 cases of successful pregnancies in women with a history of surgeries for gynecological malignancies and postoperative infertility, achieved by in vitro fertilization-embryo transfer (IVF-ET) with controlled ovarian hyperstimulation. All the 3 patients had clinical pregnancies without cancer recurrence. In such cancer survivors with infertility, the ovarian reserve is severely impaired by cancer therapies and assisted reproductive techniques should be the primary option.",
"affiliations": "Assisted Reproduction Centre, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China. E-mail: wang_nan_lucky@163.com.",
"authors": "Wang|Nan|N|;Chen|Xin|X|;Ye|Desheng|D|;Xu|Lijuan|L|;Tian|Xiaolong|X|;Tao|Ting|T|;Chen|Shiling|S|",
"chemical_list": null,
"country": "China",
"delete": false,
"doi": null,
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"fulltext_license": null,
"issn_linking": "1673-4254",
"issue": "35(6)",
"journal": "Nan fang yi ke da xue xue bao = Journal of Southern Medical University",
"keywords": null,
"medline_ta": "Nan Fang Yi Ke Da Xue Xue Bao",
"mesh_terms": "D004624:Embryo Transfer; D005260:Female; D005307:Fertilization in Vitro; D013509:Gynecologic Surgical Procedures; D006801:Humans; D007247:Infertility, Female; D009369:Neoplasms; D011247:Pregnancy; D027724:Reproductive Techniques, Assisted",
"nlm_unique_id": "101266132",
"other_id": null,
"pages": "838-43",
"pmc": null,
"pmid": "26111681",
"pubdate": "2015-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't; D016454:Review",
"references": null,
"title": "Successful pregnancy in women with infertility following surgeries for gynecological malignancies: report of 3 cases and literature review.",
"title_normalized": "successful pregnancy in women with infertility following surgeries for gynecological malignancies report of 3 cases and literature review"
} | [
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}
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"reactionoutcome": "6"
}
],
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},
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},
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] |
{
"abstract": "OBJECTIVE\nTo evaluate outcome predictors of aflibercept in neovascular age-related macular degeneration pretreated with ranibizumab based on a treat-and-extend regimen (TER).\n\n\nMETHODS\nWe performed a retrospective evaluation of 18-month follow-up of 45 consecutive patients with limited response to ranibizumab.\n\n\nRESULTS\nAt month 18, mean central retinal thickness and intraretinal fluid (IRF) height were significantly reduced. The recurrence-free treatment interval (RFTI) increased from 7.0 ± 1.8 to 8.5 ± 2.4 weeks (p = 0.01); visual acuity remained stable. At month 18, 58.1% of patients showed a longer RFTI. At month 12, eyes with baseline subretinal fluid (SRF) had a shorter RFTI than those without SRF (p = 0.032). Eyes with baseline IRF showed a longer RFTI than those without IRF (p = 0.037). Baseline hyperreflective foci (HRF) presence indicated improvement in SRF (p = 0.024) and IRF at month 12 (p = 0.049).\n\n\nCONCLUSIONS\nBaseline HRF presence predicted better morphological outcome, while SRF predicted a shorter RFTI and IRF a longer RFTI after switching from ranibizumab to aflibercept within a TER.",
"affiliations": "Vista Klinik, Binningen, Switzerland.",
"authors": "Türksever|Cengiz|C|;Prünte|Christian|C|;Hatz|Katja|K|",
"chemical_list": "D020533:Angiogenesis Inhibitors; D011993:Recombinant Fusion Proteins; C533178:aflibercept; D040262:Receptors, Vascular Endothelial Growth Factor; D000069579:Ranibizumab",
"country": "Switzerland",
"delete": false,
"doi": "10.1159/000477856",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0030-3755",
"issue": "238(3)",
"journal": "Ophthalmologica. Journal international d'ophtalmologie. International journal of ophthalmology. Zeitschrift fur Augenheilkunde",
"keywords": "Aflibercept; Anti-vascular endothelial growth factor; Hyperreflective foci; Neovascular age-related macular degeneration; Optical coherence tomography; Ranibizumab",
"medline_ta": "Ophthalmologica",
"mesh_terms": "D020533:Angiogenesis Inhibitors; D057915:Drug Substitution; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D058449:Intravitreal Injections; D008266:Macula Lutea; D008297:Male; D000069579:Ranibizumab; D040262:Receptors, Vascular Endothelial Growth Factor; D011993:Recombinant Fusion Proteins; D012189:Retrospective Studies; D013997:Time Factors; D041623:Tomography, Optical Coherence; D016896:Treatment Outcome; D014792:Visual Acuity; D057135:Wet Macular Degeneration",
"nlm_unique_id": "0054655",
"other_id": null,
"pages": "172-178",
"pmc": null,
"pmid": "28772268",
"pubdate": "2017",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Baseline Optical Coherence Tomography Findings as Outcome Predictors after Switching from Ranibizumab to Aflibercept in Neovascular Age-Related Macular Degeneration following a Treat-and-Extend Regimen.",
"title_normalized": "baseline optical coherence tomography findings as outcome predictors after switching from ranibizumab to aflibercept in neovascular age related macular degeneration following a treat and extend regimen"
} | [
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"companynumb": "CH-REGENERON PHARMACEUTICALS, INC.-2017-21211",
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}
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"activesubstancename": "AFLIBERCEPT"
},
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"drugdosagetext": "DOSE, FREQUENCY OR TOTAL NUMBER OF INJECTIONS WERE NOT REPORTED",
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"reactionmeddraversionpt": "20.1",
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},
{
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"reactionoutcome": "1"
}
],
"summary": {
"narrativeincludeclinical": "CASE EVENT DATE: 20141120"
}
},
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"drugdosagetext": "0.05 ML, ONCE",
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{
"reactionmeddrapt": "Retinal haemorrhage",
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}
],
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},
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"literaturereference": "TUERKSEVER C; PRUENTE C; HATZ K.. BASELINE OPTICAL COHERENCE TOMOGRAPHY FINDINGS AS OUTCOME PREDICTORS AFTER SWITCHING FROM RANIBIZUMAB TO AFLIBERCEPT IN NEOVASCULAR AGE-RELATED MACULAR DEGENERATION FOLLOWING A TREAT-AND-EXTEND REGIMEN. OPHTHALMOLOGICA. 2017;XX:XX",
"literaturereference_normalized": "baseline optical coherence tomography findings as outcome predictors after switching from ranibizumab to aflibercept in neovascular age related macular degeneration following a treat and extend regimen",
"qualification": "3",
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},
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"receivedate": "20170901",
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},
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},
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}
] |
{
"abstract": "OBJECTIVE\nA case of capecitabine-associated cerebellar ataxia is presented.\n\n\nCONCLUSIONS\nA 65-year-old white woman with stage IV colorectal cancer with liver metastasis was started on a chemotherapy regimen of capecitabine, oxaliplatin, and bevacizumab, given every three weeks. She tolerated the first two treatment cycles fairly well without major toxicities. The capecitabine dosage was started at 2000 mg daily for 14 days during the first cycle and increased to 2500 and 3000 mg daily during the second and the third cycles, respectively. On day 5 of the third cycle, the patient reported increased nausea, fatigue, and sleepiness, and the dosage of capecitabine was subsequently reduced to 2500 mg daily. On day 12 of the fourth treatment cycle, she reported ongoing lightheadedness and progressive gait disturbance with worsening ataxia over the past 3 days. Her capecitabine dosage was further reduced to 2000 mg daily, and the time between treatment intervals was increased to four weeks. The patient continued to experience intermittent, but less severe, ataxia during the fifth treatment cycle. On the day before the seventh cycle was to begin, she had ataxic gait and could not walk without assistance. Subsequent magnetic resonance imaging of the brain revealed no evidence of brain metastasis or cerebellar abnormality. The chemotherapy was postponed for a total of six weeks until the ataxia completely resolved. Her chemotherapy was ultimately discontinued due to disease progression. Her neurologic symptoms did not recur.\n\n\nCONCLUSIONS\nA patient receiving capecitabine-containing chemotherapy developed persistent but reversible cerebellar ataxia.",
"affiliations": "Hematology/Oncology Infusion Clinic, Kaiser Permanente Antioch Medical Center, Antioch, CA 94531, USA. sin.h.lam@kp.org",
"authors": "Lam|Masha S H|MS|;Kaufman|Douglas A|DA|;Russin|Michael P|MP|",
"chemical_list": "D000964:Antimetabolites, Antineoplastic; D003841:Deoxycytidine; D000069287:Capecitabine; D005472:Fluorouracil",
"country": "England",
"delete": false,
"doi": "10.2146/ajhp080094",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1079-2082",
"issue": "65(21)",
"journal": "American journal of health-system pharmacy : AJHP : official journal of the American Society of Health-System Pharmacists",
"keywords": null,
"medline_ta": "Am J Health Syst Pharm",
"mesh_terms": "D000368:Aged; D000964:Antimetabolites, Antineoplastic; D000069287:Capecitabine; D002524:Cerebellar Ataxia; D003841:Deoxycytidine; D005260:Female; D005472:Fluorouracil; D006801:Humans",
"nlm_unique_id": "9503023",
"other_id": null,
"pages": "2032-5",
"pmc": null,
"pmid": "18945862",
"pubdate": "2008-11-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Capecitabine-associated cerebellar ataxia.",
"title_normalized": "capecitabine associated cerebellar ataxia"
} | [
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"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
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"drugdosageform": null,
"drugdosagetext": "2500 MG, DAILY (RECEIVING CAPECITABINE 2500 MG DAILY)",
"drugenddate": null,
"drugenddateformat": null,
"drugindication": null,
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
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"drugstartdateformat": null,
"drugstructuredosagenumb": "2500",
"drugstructuredosageunit": "003",
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"drugtreatmentdurationunit": null,
"medicinalproduct": "CAPECITABINE."
},
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "LOVASTATIN"
},
"drugadditional": null,
"drugadministrationroute": "048",
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"drugcharacterization": "2",
"drugcumulativedosagenumb": null,
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"drugdosageform": null,
"drugdosagetext": "40 MG, DAILY",
"drugenddate": null,
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"drugstartdateformat": null,
"drugstructuredosagenumb": "40",
"drugstructuredosageunit": "003",
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "LOVASTATIN."
}
],
"patientagegroup": null,
"patientonsetage": "65",
"patientonsetageunit": "801",
"patientsex": "2",
"patientweight": "71.66",
"reaction": [
{
"reactionmeddrapt": "Cerebellar ataxia",
"reactionmeddraversionpt": "22.1",
"reactionoutcome": "1"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "LAM, M.. CAPECITABINE-ASSOCIATED CEREBELLAR ATAXIA. AMERICAN JOURNAL OF HEALTH-SYSTEM PHARMACY. 2008?65 (21):10.2146/AJHP080094",
"literaturereference_normalized": "capecitabine associated cerebellar ataxia",
"qualification": "2",
"reportercountry": "US"
},
"primarysourcecountry": "US",
"receiptdate": "20200120",
"receivedate": "20200120",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 17288972,
"safetyreportversion": 1,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
"seriousnessdisabling": null,
"seriousnesshospitalization": null,
"seriousnesslifethreatening": null,
"seriousnessother": 1,
"transmissiondate": "20200409"
}
] |
{
"abstract": "OBJECTIVE\nStage 4A retinopathy of prematurity (ROP) is a critical phase where retinal detachment develops, but fovea is preserved. The present study aims to evaluate the effect of the first treatment choice (laser photocoagulation (LPC) or intravitreal ranibizumab (IVR)) applied in this critical phase on the prognosis of the disease.\n\n\nMETHODS\nRecords of patients diagnosed with stage 4A ROP and whose first treatment was applied in our clinic were evaluated retrospectively. All patients were referred to our clinic for the treatment of advanced ROP . While group 1 was composed of the patients who were administered LPC as first treatment, group 2 included patients where IVR was applied as first treatment. The patients in both groups were referred to surgical treatment in the presence of progression.\n\n\nRESULTS\nThe present study included a total of 31 eyes in 16 patients with stage 4A ROP. Eighteen eyes of nine patients in group 1 were first applied LPC, and 13 eyes of seven patients in group 2 were first applied intravitreal ranibizumab. While anatomic outcomes of ten eyes in both groups were favorable, eight eyes in group 1 and three eyes in group 2 displayed progression and were referred to vitreoretinal surgery.\n\n\nCONCLUSIONS\nLaser and/or IVR treatment may be effective as a non-surgical treatment for stage 4A ROP. Especially stage 4A ROP until 6 clock hours can regress without surgical treatment. However, in stage 4A with involvement wider than 6 clock hours, non-surgical regression is difficult. Prospective controlled large series studies are necessary.",
"affiliations": "Department of Ophthalmology, Adana Numune Training and Research Hospital, Ege Bagatur Caddesi Adana Numune Eğitim ve Araştırma Hastanesi Yüreğir, Adana, Turkey, 06520. esukgen@gmail.com.;Department of Ophthalmology, Adana Numune Training and Research Hospital, Ege Bagatur Caddesi Adana Numune Eğitim ve Araştırma Hastanesi Yüreğir, Adana, Turkey, 06520.",
"authors": "Sukgen|Emine Alyamaç|EA|;Koçluk|Yusuf|Y|",
"chemical_list": "D020533:Angiogenesis Inhibitors; D000069579:Ranibizumab",
"country": "Germany",
"delete": false,
"doi": "10.1007/s00417-016-3443-6",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0721-832X",
"issue": "255(2)",
"journal": "Graefe's archive for clinical and experimental ophthalmology = Albrecht von Graefes Archiv fur klinische und experimentelle Ophthalmologie",
"keywords": "Intravitreal ranibizumab; Laser photocoagulation; Retinopathy of prematurity (ROP); Stage 4A",
"medline_ta": "Graefes Arch Clin Exp Ophthalmol",
"mesh_terms": "D020533:Angiogenesis Inhibitors; D018450:Disease Progression; D005260:Female; D005500:Follow-Up Studies; D005865:Gestational Age; D006801:Humans; D007231:Infant, Newborn; D058449:Intravitreal Injections; D017075:Laser Coagulation; D008297:Male; D011379:Prognosis; D011446:Prospective Studies; D000069579:Ranibizumab; D012178:Retinopathy of Prematurity; D016896:Treatment Outcome",
"nlm_unique_id": "8205248",
"other_id": null,
"pages": "263-269",
"pmc": null,
"pmid": "27495302",
"pubdate": "2017-02",
"publication_types": "D016428:Journal Article",
"references": "20673589;18621796;25851862;15097884;16009843;25313709;9823344;26265249;18635152;12860803;18317348;18398359;19700197;19371954;17965108;14662586;22818800;25569026;25886603;21976936;9787350;21911664;22575901;18320201",
"title": "Treatment for stage 4A retinopathy of prematurity: laser and/or ranibizumab.",
"title_normalized": "treatment for stage 4a retinopathy of prematurity laser and or ranibizumab"
} | [
{
"companynumb": "TR-ROCHE-1898542",
"fulfillexpeditecriteria": "1",
"occurcountry": "TR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "RANIBIZUMAB"
},
"drugadditional": "3",
"drugadministrationroute": "031",
"drugauthorizationnumb": "125156",
"drugbatchnumb": null,
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": "SOLUTION FOR INJECTION",
"drugdosagetext": "0.25 MG, UNK (BOTH EYES)",
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "RETINOPATHY OF PREMATURITY",
"drugintervaldosagedefinition": null,
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"medicinalproduct": "RANIBIZUMAB"
}
],
"patientagegroup": null,
"patientonsetage": "29",
"patientonsetageunit": "803",
"patientsex": "1",
"patientweight": "1.25",
"reaction": [
{
"reactionmeddrapt": "Off label use",
"reactionmeddraversionpt": "19.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Disease progression",
"reactionmeddraversionpt": "19.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Drug ineffective",
"reactionmeddraversionpt": "19.1",
"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "SUKGEN E, KOCLUK Y. TREATMENT FOR STAGE 4A RETINOPATHY OF PREMATURITY: LASER AND/OR RANIBIZUMAB... GRAEFES ARCHIVE FOR CLINICAL AND EXPERIMENTAL OPHTHALMOLOGY. 2017;9:255-263.",
"literaturereference_normalized": "treatment for stage 4a retinopathy of prematurity laser and or ranibizumab",
"qualification": "3",
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},
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"receiptdate": "20170228",
"receivedate": "20170228",
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},
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},
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"transmissiondate": "20170428"
}
] |
{
"abstract": "Derinöz-Güleryüz O. Doxylamine succinate overdose: Slurred speech and visual hallucination. Turk J Pediatr 2018; 60: 439-442. Doxylamine succinate is a commonly used antihistamine for respiratory allergies including allergic rhinitis as well as for the management of insomnia. As it is available over-the-counter like other nonprescription antihistamines and sleep aids, there is a risk of overdose. It is believed that doxylamine succinate has both peripheral and central activity with its anticholinergic properties. Delirium, seizures, and coma are among the central adverse effects that are rare. This case was presented since it is the first case in the literature who developed slurred speech and visual hallucination after high dose doxylamine succinate use and received antidotal therapy for anticholinergic side effects.",
"affiliations": "Department of Pediatric Emergency, Gazi University Faculty of Medicine, Ankara, Turkey.",
"authors": "Derinöz-Güleryüz|Okşan|O|",
"chemical_list": "D002800:Cholinesterase Inhibitors; D006634:Histamine H1 Antagonists; D004319:Doxylamine; D010830:Physostigmine; C035385:doxylamine succinate",
"country": "Turkey",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0041-4301",
"issue": "60(4)",
"journal": "The Turkish journal of pediatrics",
"keywords": "doxylamine; overdose; slurred speech; visual hallucination",
"medline_ta": "Turk J Pediatr",
"mesh_terms": "D000293:Adolescent; D002800:Cholinesterase Inhibitors; D004319:Doxylamine; D062787:Drug Overdose; D005260:Female; D006212:Hallucinations; D006634:Histamine H1 Antagonists; D006801:Humans; D010830:Physostigmine; D013060:Speech; D013064:Speech Disorders",
"nlm_unique_id": "0417505",
"other_id": null,
"pages": "439-442",
"pmc": null,
"pmid": "30859772",
"pubdate": "2018",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Doxylamine succinate overdose: Slurred speech and visual hallucination.",
"title_normalized": "doxylamine succinate overdose slurred speech and visual hallucination"
} | [
{
"companynumb": "TR-SA-2019SA092201",
"fulfillexpeditecriteria": "1",
"occurcountry": "TR",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "DOXYLAMINE SUCCINATE"
},
"drugadditional": null,
"drugadministrationroute": "048",
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"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
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"drugdosageform": null,
"drugdosagetext": "25 MG/ PILLS, TOTAL DOSE 40MG/KG",
"drugenddate": null,
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"drugindication": "SUICIDE ATTEMPT",
"drugintervaldosagedefinition": null,
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"drugstructuredosagenumb": "80",
"drugstructuredosageunit": "032",
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "DOXYLAMINE SUCCINATE."
}
],
"patientagegroup": "4",
"patientonsetage": "15",
"patientonsetageunit": "801",
"patientsex": "2",
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Seizure",
"reactionmeddraversionpt": "22.0",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Hallucination, visual",
"reactionmeddraversionpt": "22.0",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Tachycardia",
"reactionmeddraversionpt": "22.0",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Overdose",
"reactionmeddraversionpt": "22.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Mydriasis",
"reactionmeddraversionpt": "22.0",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Hallucination",
"reactionmeddraversionpt": "22.0",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Flushing",
"reactionmeddraversionpt": "22.0",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Rhabdomyolysis",
"reactionmeddraversionpt": "22.0",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Dysarthria",
"reactionmeddraversionpt": "22.0",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Generalised tonic-clonic seizure",
"reactionmeddraversionpt": "22.0",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Agitation",
"reactionmeddraversionpt": "22.0",
"reactionoutcome": "1"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "DERINOZ-GULERYUZ O.. DOXYLAMINE SUCCINATE OVERDOSE: SLURRED SPEECH AND VISUAL HALLUCINATION.. TURKISH JOURNAL OF PEDIATRICS. 2018?60(4):439-442",
"literaturereference_normalized": "doxylamine succinate overdose slurred speech and visual hallucination",
"qualification": "3",
"reportercountry": "TR"
},
"primarysourcecountry": "TR",
"receiptdate": "20190409",
"receivedate": "20190409",
"receiver": {
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"receivertype": "6"
},
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"safetyreportversion": 1,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
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"seriousnessdeath": null,
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"seriousnesshospitalization": 1,
"seriousnesslifethreatening": null,
"seriousnessother": 1,
"transmissiondate": "20190711"
},
{
"companynumb": "TR-PERRIGO-19TR004886",
"fulfillexpeditecriteria": "1",
"occurcountry": "TR",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "DOXYLAMINE SUCCINATE"
},
"drugadditional": "1",
"drugadministrationroute": "048",
"drugauthorizationnumb": "040167",
"drugbatchnumb": "UNKNOWN",
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": "TABLET",
"drugdosagetext": "2000 MG, SINGLE",
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "SUICIDE ATTEMPT",
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
"drugrecurreadministration": null,
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"drugstartdateformat": null,
"drugstructuredosagenumb": "2000",
"drugstructuredosageunit": "003",
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "DOXYLAMINE SUCCINATE."
}
],
"patientagegroup": null,
"patientonsetage": "15",
"patientonsetageunit": "801",
"patientsex": "2",
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Dysarthria",
"reactionmeddraversionpt": "22.0",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Seizure",
"reactionmeddraversionpt": "22.0",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Intentional overdose",
"reactionmeddraversionpt": "22.0",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Hallucination, visual",
"reactionmeddraversionpt": "22.0",
"reactionoutcome": "1"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "DERINOZ-GULERYUZ O. DOXYLAMINE SUCCINATE OVERDOSE: SLURRED SPEECH AND VISUAL HALLUCINATION. TURK J PEDIATR. 2018?60:439-42",
"literaturereference_normalized": "doxylamine succinate overdose slurred speech and visual hallucination",
"qualification": "1",
"reportercountry": "TR"
},
"primarysourcecountry": "TR",
"receiptdate": "20190422",
"receivedate": "20190422",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 16224296,
"safetyreportversion": 1,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
"seriousnessdisabling": null,
"seriousnesshospitalization": 1,
"seriousnesslifethreatening": null,
"seriousnessother": null,
"transmissiondate": "20190711"
}
] |
{
"abstract": "A 68-year-old female with severe aplastic anemia (SAA) refractory to initial immunosuppressive therapy, including anti-thymocyte globulin (ATG) and cyclosporine, received a reduced-intensity cord blood transplant (CBT) in June 2015. Tacrolimus (TAC) and mycophenolate mofetil were administered for graft-versus-host disease (GVHD) prophylaxis, and she received prolonged TAC and prednisolone to treat chronic GVHD. The patient presented with progressive ataxia 14 months after CBT. A brain magnetic resonance image (MRI, FLAIR) detected a high-intensity lesion in the left cerebellar hemisphere, which suggested infarction. Her consciousness level gradually continued to deteriorate and another brain MRI (T2) revealed that the size of the cerebellar lesion had increased and had involved the pons. A cerebrospinal fluid (CSF) examination showed normal cell count and protein levels; however, polymerase chain reaction (PCR) analysis of CSF was positive for JC virus (JCV). Therefore, she was eventually diagnosed with progressive multifocal leukoencephalopathy (PML) and treated with mefloquine. The symptoms were reduced after 3 months, and JCV in CSF disappeared without new lesions after 6 months. This is an unusual case of PML initially involving the cerebellum, and we report here PML after an immunosuppressive therapy and CBT in the patient with SAA.",
"affiliations": "Department of Hematology, Mishuku Hospital.;Department of Hematology, Mishuku Hospital.;Department of Neurology, Mishuku Hospital.;Department of Hematology, Mishuku Hospital.;Department of Hematology, Mishuku Hospital.;Department of Neurology, Mishuku Hospital.",
"authors": "Masuoka|Kazuhiro|K|;Akagawa|Yuri|Y|;Hanashiro|Rii|R|;Yamaguchi|Mariko|M|;Oota|Hikari|H|;Kiyozuka|Tetsuto|T|",
"chemical_list": "D007166:Immunosuppressive Agents; D015767:Mefloquine",
"country": "Japan",
"delete": false,
"doi": "10.11406/rinketsu.60.93",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0485-1439",
"issue": "60(2)",
"journal": "[Rinsho ketsueki] The Japanese journal of clinical hematology",
"keywords": "JCV; Mefloquine; PML; SAA",
"medline_ta": "Rinsho Ketsueki",
"mesh_terms": "D000368:Aged; D000741:Anemia, Aplastic; D036101:Cord Blood Stem Cell Transplantation; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents; D007577:JC Virus; D007968:Leukoencephalopathy, Progressive Multifocal; D015767:Mefloquine",
"nlm_unique_id": "2984782R",
"other_id": null,
"pages": "93-98",
"pmc": null,
"pmid": "30842386",
"pubdate": "2019",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Progressive multifocal leukoencephalopathy developing subsequent to cord blood transplantation in a patient with severe aplastic anemia.",
"title_normalized": "progressive multifocal leukoencephalopathy developing subsequent to cord blood transplantation in a patient with severe aplastic anemia"
} | [
{
"companynumb": "JP-ACCORD-156227",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "CYCLOSPORINE"
},
"drugadditional": "1",
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"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
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"drugdosagetext": null,
"drugenddate": "201612",
"drugenddateformat": "610",
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"medicinalproduct": "CICLOSPORIN"
},
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "FLUDARABINE PHOSPHATE"
},
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"drugindication": "APLASTIC ANAEMIA",
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"drugtreatmentdurationunit": null,
"medicinalproduct": "FLUDARABINE"
},
{
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"activesubstance": {
"activesubstancename": "MELPHALAN"
},
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"medicinalproduct": "MELPHALAN."
},
{
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"activesubstancename": "TACROLIMUS"
},
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"abstract": "BACKGROUND\nMost patients with hepatocellular carcinoma (HCC) have lost the chance of radical treatment at the time of their visit, and the prognosis of metastatic HCC is even worse. Sorafenib is currently regarded as a first-line systemic therapy in patients with advanced and metastatic HCC. Apatinib is a new inhibitor of vascular endothelial growth factor receptor 2 tyrosine kinase, which has been reported to be effective in some solid tumors. We herein report a case of apatinib in the treatment of the patient with metastatic HCC who was resistant to sorafenib.\nA 41-year-old Chinese man with a history of chronic hepatitis B had undergone an emergency partial hepatectomy for tumor ruptured. Despite the treatment with transcatheter arterial chemoembolization and sorafenib, the progression of tumor failed to control.\nAlthough the patient had been treated with sorafenib (400 mg, twice daily) for 10 months, computed tomography documented radiological progression.\n\n\nMETHODS\nDue to disease progression, failure of sorafenib and positive expression of vascular endothelial growth factor (VEGF), the drug regimen was changed to apatinib 250 mg once daily. Due to some degree of resistance, the dose was increased up to 425 mg once daily.\n\n\nRESULTS\nThe patient had a disease-free progression of 7 months at 250 mg apatinib. The dosage was adjusted to 425 mg due to drug resistance and the side effects were tolerable. The patient has survived a total of 19 months under apatinib.\n\n\nCONCLUSIONS\nApatinib may be a substitute for the HCC patients with sorafenib resistance in the future, especially for those with high expression of VEGF.",
"affiliations": "Department of Interventional Radiology, the First People's Hospital of Changzhou, 185# Juqian Street, Changzhou, Jiangsu Province, China.",
"authors": "Han|Zonghong|Z|;He|Zhongming|Z|;Wang|Caoye|C|;Wang|Qi|Q|",
"chemical_list": "D000970:Antineoplastic Agents; D011725:Pyridines; C553458:apatinib; D000077157:Sorafenib",
"country": "United States",
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"fulltext": "\n==== Front\nMedicine (Baltimore)Medicine (Baltimore)MEDIMedicine0025-79741536-5964Wolters Kluwer Health 30544412MD-D-18-0426610.1097/MD.0000000000013388133884500Research ArticleClinical Case ReportThe effect of apatinib in the treatment of sorafenib resistant metastatic hepatocellular carcinoma A case reportHan Zonghong MDHe Zhongming MDWang Caoye PhDWang Qi MD∗NA. Department of Interventional Radiology, the First People's Hospital of Changzhou, 185# Juqian Street, Changzhou, Jiangsu Province, China.∗ Correspondence: Qi Wang, The First People's Hospital of Changzhou, Changzhou, Jiangsu, China. (e-mail: czwangqi666@sina.com).12 2018 10 12 2018 97 49 e1338824 6 2018 30 10 2018 Copyright © 2018 the Author(s). Published by Wolters Kluwer Health, Inc.2018This is an open access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. http://creativecommons.org/licenses/by-nc-nd/4.0Abstract\nRationale:\nMost patients with hepatocellular carcinoma (HCC) have lost the chance of radical treatment at the time of their visit, and the prognosis of metastatic HCC is even worse. Sorafenib is currently regarded as a first-line systemic therapy in patients with advanced and metastatic HCC. Apatinib is a new inhibitor of vascular endothelial growth factor receptor 2 tyrosine kinase, which has been reported to be effective in some solid tumors. We herein report a case of apatinib in the treatment of the patient with metastatic HCC who was resistant to sorafenib.\n\nPatient concerns:\nA 41-year-old Chinese man with a history of chronic hepatitis B had undergone an emergency partial hepatectomy for tumor ruptured. Despite the treatment with transcatheter arterial chemoembolization and sorafenib, the progression of tumor failed to control.\n\nDiagnoses:\nAlthough the patient had been treated with sorafenib (400 mg, twice daily) for 10 months, computed tomography documented radiological progression.\n\nInterventions:\nDue to disease progression, failure of sorafenib and positive expression of vascular endothelial growth factor (VEGF), the drug regimen was changed to apatinib 250 mg once daily. Due to some degree of resistance, the dose was increased up to 425 mg once daily.\n\nOutcomes:\nThe patient had a disease-free progression of 7 months at 250 mg apatinib. The dosage was adjusted to 425 mg due to drug resistance and the side effects were tolerable. The patient has survived a total of 19 months under apatinib.\n\nLessons:\nApatinib may be a substitute for the HCC patients with sorafenib resistance in the future, especially for those with high expression of VEGF.\n\nKeywords\napatinibdrug resistancehepatocellular carcinomasorafenibtargeted therapyOPEN-ACCESSTRUE\n==== Body\n1 Introduction\nHepatocellular carcinoma (HCC) is the fifth most common cancer and the third leading cause of cancer-related deaths worldwide.[1] Sorafenib is uniquely recommended as the first line treatment for advanced HCC, but only a modest increase in overall survival. Furthermore, a subgroup of HCC is resistant to sorafenib, and the majority of these patients show disease progression even after an initial satisfactory response.[2] Apatinib is a new inhibitor of vascular endothelial growth factor receptor (VEGFR)-2 tyrosine kinase, which has been reported to be effective in various solid tumors.[3,4] We report a case of apatinib in the treatment of patient with metastatic HCC who was resistant to sorafenib. Written informed consent was provided by the patient to publish the case details and the study was approved by The Ethics Committee of the First People's Hospital of Changzhou.\n\n2 Case report\nOn July 26, 2015, a 41-year-old Chinese man complained of mild pain in his right upper quadrant for 3 days before he visited our hospital. He had a history of chronic hepatitis B for more than 20 years. Abdominal computed tomography (CT) scan revealed tumors located in segment V (S5) and S6 (10.5 cm × 9.8 cm), S7 (3.2 cm × 2.9 cm) with thrombi in the right branch of portal vein (BCLC stage C). The concentration of serum alpha-fetoprotein (AFP) was >1210 ng/ml (normal range <8 ng/ml). Unfortunately, the patient suffered tumor (S5, S6) ruptured two days later, then an emergency partial hepatectomy (S5, S6 resection, and S7 tumor resection) with removal of portal vein tumor thrombi was performed on July 28, 2015. Postoperative pathology showed HCC with portal vein tumor thrombi but negative margin. Interestingly, the degree of differentiation of HCC was moderate-poor in S5 and S6 while moderate in S7. Immunohistochemical analysis showed that vascular endothelial growth factor (VEGF) was moderate positive (++) in S5 and S6 while weak (+) in S7. The perioperative course was uneventful, and AFP dropped to 3.61 ng/ml on September 01, 2015. From September 11, 2015, to October 13, 2016, the patient suffered from an intrahepatic relapse and metastases in hilar lymph node, peritoneum, abdominal wall, and lung, although he was treated by 3 times of transcatheter arterial chemoembolization (TACE) and sorafenib (400 mg, twice daily). Except for intrahepatic nodules were well controlled by TACE, extrahepatic metastases progressed continuously and showed no response to sorafenib (Table 1). AFP gradually increased to >1210 ng/ml, and never dropped below 1210 ng/ml in the following treatments. At the same time, the patient could touch a hard and ill-defined border mass in abdominal wall and felt the changes of the mass.\n\nTable 1 Changes in extrahepatic nodules size on CT-scans during treatments.\n\nWith disease progression, failure of sorafenib and positive expression of VEGF in tumor, the regimen was changed to apatinib at a dosage of 250 mg once daily (BCLC stage C, Child-Pugh A) on October 13, 2016. Regrettably, CT-scan was not given to the patient before taking apatinib, but the patient felt the abdominal wall mass softer than before just a week after taking apatinib. CT-scan showed that the intrahepatic nodule was still stable and non-enhanced areas of necrosis within the metastases in hilar lymph node, peritoneum and abdominal wall 1 month later. It was puzzling that the metastases in lung didn’t show similar changes (Fig. 1A, Table 1). On March 7, 2017, CT showed that the metastases in the hilar lymph nodes, peritoneum and abdominal wall were significantly smaller and less enhanced compared with before, while the lung nodules kept stable (Fig. 1B, Table 1). Meanwhile, the patient felt a shrinkage of the abdominal wall mass. Unfortunately, the patient complained that the abdominal mass began to grow again from May 2017. Later CT-scan (June 08, 2017) showed that the metastases in the peritoneum, abdominal wall, and lung significantly enlarged compared with before except for the hepatic hilar lymph node (Fig. 1C, Table 1). As apatinib was effective on the patient and well tolerated, the patient was recommended to adjust the dosage to 425 mg once daily. The patient felt the mass in abdominal wall shrank again after two weeks of dosage adjustment. On September 29, 2017, CT-scan showed that the hilar lymph node remained steady, and the metastases in peritoneum and abdominal wall shrank again, while lung nodules continued to progress (Table 1). Surprisingly, not only the metastases in the peritoneum and abdominal wall continued to shrink with the hilar lymph nodes remained stable, but also the lung nodules kept stable again on the followed CT-scans On December 14, 2017, and all of them maintained stably in the followed CT-scans on March 29, 2018 (Fig. 1D, Table 1).\n\nFigure 1 Contrast enhanced CT images of the metastases in abdominal wall treated by apatinib. 1A One month after apatinib 250 mg. 1B Five months after apatinib 250 mg. 1C Eight months after apatinib 250 mg. 1D Nine months after apatinib 425 mg. (white arrow).\n\nUp to now, the patient is still alive and has survived for 19 months since taking apatinib. The adverse events were mild fatigue, hand-foot skin toxicities, and hypertension when taking apatinib 250 mg, which could be tolerated well. When the dose was adjusted to 425 mg, the patient suffered severe diarrhea (7–8 times daily, grade 3) and he had to be relieved by loperamide.\n\n3 Discussion\nThe therapy options are limited and relapse and metastasis are common in advanced HCC. The patients with metastatic HCC often cannot survive more than 1 year. Sorafenib is a recommended systemic therapy for advanced HCC with a favorable safety profile but only 3 months more of survival gain compared to placebo.[2]\n\nAngiogenesis is today universally considered as a cancer hallmark, as it supplies for the increased request of oxygen and nutrients which is typical of the fast-growing microenvironment of solid tumors. As is well known, angiogenesis is mediated by VEGF, which gives rise to a significantly more robust kinase activity when binding with VEGFR-2. Some studies have shown that high expression of VEGF in HCC is closely related to sorafenib resistance and worse prognosis.[5,6] TACE is an important treatment of HCC, but can potentially cause hypoxic changes in tumors as well as in the surrounding liver tissue due to the anti-cancer effects of chemotherapy infusions and embolization of feeding arteries. These can eventually induce the upregulation of circulating VEGF.[7] However high expression of VEGF makes it an appealing target for novel anti-cancer therapies. Apatinib abrogates the interaction of VEGF with VEGFR-2 and directly inhibits angiogenesis.[3] As to this case, the patient has achieved an unexpected effective result by anti-angiogenic therapy with apatinib as described above, even though his pathogenetic condition had been progressing for 10 months treated by sorafenib. Comparing the targets and their IC50 of apatinib with sorafenib, we can find that the significant advantage of apatinib over sorafenib is its high affinity to VEGFR-2 (IC50 to VEGFR-2 of apatinib and sorafenib is 1 nmol/L and 90 nmol/L respectively),[3,8] so we believe that the difference in affinity to VEGFR-2 would have the different outcomes. Interestingly, the metastases in peritoneum and abdominal wall were sensitive to apatinib, whereas the metastases in lung were relatively insensitive. Gershtein et al [9] demonstrated that an increase in expression of VEGF and VEGFR-2 correlates with the degree of histological differentiation and the stage of the tumor by histological analysis. Therefore, we speculate that the metastases in peritoneum and abdominal wall were caused by the rupture of the tumor in S5 and S6, whereas the lung metastases may originated from the tumor in S7, for the difference in pathological differentiation and expression of VEGF. Some studies have shown that apatinib combined with TACE or alone in treating HCC achieved promising prospects for its anti-angiogenic effect.[4,10] And this is the first case report about apatinib in the treatment of patient with metastatic HCC after failure to sorafenib. It should be noted that apatinib had a certain degree of resistance after a disease-free progression of 7 months at 250 mg, although it could be temporarily overcome by dosage adjusted to 425 mg. The adverse events of the patient were mild fatigue, hand-foot skin toxicities and hypertension which could be tolerated well when the dose was 250 mg. However, the patient suffered severe diarrhea when the dose was adjusted to 425 mg. The adverse events with apatinib could be tolerated and managed as described in previous studies.[4]\n\nAs to our case, it is regrettable that there was a lack of pathological differentiation, quantitative detection of VEGF or genetic testing for intraperitoneal and intrapulmonary metastases before and during the treatment with apatinib. Apatinib may be a substitute for the HCC patients with sorafenib resistance or as a first-line treatment for the patients with high expression of VEGF, but further prospective studies are still needed to optimize the treatment.\n\nAuthor contributions\nConceptualization: Zonghong Han, Zhongming He, and Qi Wang.\n\nFormal analysis: Zonghong Han.\n\nInvestigation: Zonghong Han, Zhongming He, and Caoye Wang.\n\nProject administration: Qi Wang.\n\nSupervision: Qi Wang.\n\nValidation: Qi Wang.\n\nVisualization: Zonghong Han and Caoye Wang.\n\nWriting – original draft: Zonghong Han.\n\nWriting – review, and editing: Qi Wang.\n\nAbbreviations: AFP = alpha-fetoprotein, CT = computed tomography, HCC = hepatocellular carcinoma, S5/6/7 = segment V/VI/VII, TACE = transcatheter arterial chemoembolization, VEGF = vascular endothelial growth factor, VEGFR-2 = vascular endothelial growth factor receptor 2.\n\nThe authors have no conflicts of interest to disclose.\n==== Refs\nReferences\n[1] Torre LA Bray F Siegel RL \nGlobal cancer statistics, 2012 . CA Cancer J Clin \n2015 ;65 :87–108 .25651787 \n[2] Finn RS Zhu AX Farah W \nTherapies for advanced stage hepatocellular carcinoma with macrovascular invasion or metastatic disease: a systematic review and meta-analysis . Hepatology \n2018 ;67 :422–35 .28881497 \n[3] Tian S Quan H Xie C \nYN968D1 is a novel and selective inhibitor of vascular endothelial growth factor receptor-2 tyrosine kinase with potent activity in vitro and in vivo . Cancer Sci \n2011 ;102 :1374–80 .21443688 \n[4] Yu WC Zhang KZ Chen SG \nEfficacy and Safety of apatinib in patients with intermediate/advanced hepatocellular carcinoma: a prospective observation study . Medicine (Baltimore) \n2018 ;97 :e9704.29505026 \n[5] Choi SB Han HJ Kim WB \nVEGF overexpression predicts poor survival in hepatocellular carcinoma . Open Med (Wars) \n2017 ;12 :430–9 .29318189 \n[6] Tsuchiya K Asahina Y Matsuda S \nChanges in plasma vascular endothelial growth factor at 8 weeks after sorafenib administration as predictors of survival for advanced hepatocellular carcinoma . Cancer \n2014 ;120 :229–37 .24122122 \n[7] Ranieri G Ammendola M Marech I \nVascular endothelial growth factor and tryptase changes after chemoembolization in hepatocarcinoma patients . World J Gastroenterol \n2015 ;21 :6018–25 .26019468 \n[8] Ranieri G Gadaleta-Caldarola G Goffredo V \nSorafenib (BAY 43-9006) in hepatocellular carcinoma patients: from discovery to clinical development . Curr Med Chem \n2012 ;19 :938–44 .22214462 \n[9] Gershtein ES Dubova EA Shchegolev AI \nVascular endothelial growth factor and its type 2 receptor in hepatocellular carcinoma . Bull Exp Biol Med \n2010 ;149 :749–52 .21165437 \n[10] Liu C Xing W Si T \nEfficacy and safety of apatinib combined with transarterial chemoembolization for hepatocellular carcinoma with portal venous tumor thrombus: a retrospective study . Oncotarget \n2017 ;8 :100734–45 .29246017\n\n",
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"mesh_terms": "D000328:Adult; D000970:Antineoplastic Agents; D006528:Carcinoma, Hepatocellular; D018450:Disease Progression; D019008:Drug Resistance, Neoplasm; D019694:Hepatitis B, Chronic; D006801:Humans; D008113:Liver Neoplasms; D008297:Male; D011725:Pyridines; D000077157:Sorafenib",
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}
],
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},
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}
],
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},
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"literaturereference": "HAN Z, HE Z, WANG C, WANG Q. THE EFFECT OF APATINIB IN THE TREATMENT OF SORAFENIB RESISTANT METASTATIC HEPATOCELLULAR CARCINOMA: A CASE REPORT. MEDICINE. 2018?97:49:E13388",
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},
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}
] |
{
"abstract": "A 69-year-old woman presented with shivering and pain in the lower extremities on 5 April 2006; she was referred to the dermatology division of our hospital on the following day with difficulty in walking. She had been suffering from non-viral, non-alcoholic liver cirrhosis, and was being treated by the Division of Internal Medicine. Physical examination showed edema in the lower extremities and light purpuras on the groin and legs. Low blood pressure had been observed since admission. Necrotizing fasciitis (NF) was suspected on the basis of the skin symptoms, systemic conditions, and magnetic resonance imaging. During surgical debridement under general anesthesia, cardiopulmonary arrest occurred, and the patient died 12 h after admission. NF, in its early stages, exhibits few skin changes. In order to differentiate it from other skin infections, it is necessary to take into account blood pressure, abnormal systemic conditions, and severe pain out of proportion to its minor skin changes. In the present case, Streptococcus pneumoniae was detected by blood culture. Soft tissue infectious diseases caused by S. pneumoniae, especially NF, are very rare. We have reviewed reported cases of NF caused by S. pneumoniae.",
"affiliations": "Division of Dermatology, Okinawa Kyoudo Hospital, 593 Madanbashi Tomishiro, Okinawa 901-0201, Japan. hihuka@jim.u-ryukyu.ac.jp",
"authors": "Yamashiro|Etsuko|E|;Asato|Yutaka|Y|;Taira|Kiyohito|K|;Awazawa|Ryoko|R|;Yamamoto|Yu-Ichi|Y|;Hagiwara|Keisuke|K|;Tamaki|Hajime|H|;Uezato|Hiroshi|H|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1111/j.1346-8138.2009.00643.x",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0385-2407",
"issue": "36(5)",
"journal": "The Journal of dermatology",
"keywords": null,
"medline_ta": "J Dermatol",
"mesh_terms": "D000368:Aged; D019115:Fasciitis, Necrotizing; D017809:Fatal Outcome; D005260:Female; D006801:Humans; D008279:Magnetic Resonance Imaging; D011008:Pneumococcal Infections; D013296:Streptococcus pneumoniae",
"nlm_unique_id": "7600545",
"other_id": null,
"pages": "298-305",
"pmc": null,
"pmid": "19383002",
"pubdate": "2009-05",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Necrotizing fasciitis caused by Streptococcus pneumoniae.",
"title_normalized": "necrotizing fasciitis caused by streptococcus pneumoniae"
} | [
{
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],
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] |
{
"abstract": "Idarubicin (IDR) is a new anthracycline that can be administered orally. Oral IDR was given at a dose of 30 mg/m2 daily for 3 d in 20 patients aged 65 to 79 yr with previously untreated acute myeloid leukemia (AML). 5 patients whose marrow remained blastic at d 14 received a second course. 8 patients achieved complete remission (6 after one single course). There were: 1 early death, 4 deaths in aplasia, 7 failures. The hematologic toxicity was high. All but 1 patient had to stay in hospital and the duration of neutropenia was 12 to 34 d (median 19). Oral IDR is an effective therapy for AML in elderly patients but the total dose of 90 mg/m2 is too aggressive to be administered safely outside the hospital.",
"affiliations": "Department of Hematology, Nantes, France.",
"authors": "Harousseau|J L|JL|;Rigal-Huguet|F|F|;Hurteloup|P|P|;Guy|H|H|;Milpied|N|N|;Pris|J|J|",
"chemical_list": "D015255:Idarubicin",
"country": "England",
"delete": false,
"doi": "10.1111/j.1600-0609.1989.tb01208.x",
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"issn_linking": "0902-4441",
"issue": "42(2)",
"journal": "European journal of haematology",
"keywords": null,
"medline_ta": "Eur J Haematol",
"mesh_terms": "D000284:Administration, Oral; D000368:Aged; D005260:Female; D006801:Humans; D015255:Idarubicin; D015470:Leukemia, Myeloid, Acute; D008297:Male",
"nlm_unique_id": "8703985",
"other_id": null,
"pages": "182-5",
"pmc": null,
"pmid": "2917635",
"pubdate": "1989-02",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Treatment of acute myeloid leukemia in elderly patients with oral idarubicin as a single agent.",
"title_normalized": "treatment of acute myeloid leukemia in elderly patients with oral idarubicin as a single agent"
} | [
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}
],
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},
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},
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},
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}
] |
{
"abstract": "Antidepressant drug choice in pregnancy is a complex problem especially for new drugs. Among 590 cases exposed to drugs during pregnancy who were followed by our center, 21 cases used newer antidepressants, i.e., venlafaxine, mirtazapine, nefazodone. We present the gestational findings and fetal outcomes of these cases. Ten cases had used venlafaxine, one case had used both venlafaxine and mirtazapine, eight had used mirtazapine alone or with some other drugs and two had used nefazodone, in the first trimester. Of the 21 cases, 17 (80.9%) had healthy babies, 3 (14.3%) decided to terminate the pregnancy, and 1 (4.8%) spontaneous abortion was observed in a case exposed to mirtazapine, alprazolam, diazepam and trifluoperazine. All obstetrical findings were normal during the pregnancy of each case. No congenital abnormality and developmental problem was observed in the babies followed up for 12 months. The aim of the present study is to contribute the data to the limited knowledge available in the literature regarding human pregnancy.",
"affiliations": "Department of Family Medicine, School of Medicine, Karadeniz Technical University, TR-61187 Trabzon, Turkey. fyaris@meds.ktu.edu.tr",
"authors": "Yaris|Fusun|F|;Kadioglu|Mine|M|;Kesim|Murat|M|;Ulku|Cunay|C|;Yaris|Ersin|E|;Kalyoncu|Nuri Ihsan|NI|;Unsal|Mesut|M|",
"chemical_list": "D018687:Antidepressive Agents, Second-Generation; D000929:Antidepressive Agents, Tricyclic; D003511:Cyclohexanols; D010879:Piperazines; D013723:Teratogens; D014230:Triazoles; D008803:Mianserin; C051752:nefazodone; D000069470:Venlafaxine Hydrochloride; D000078785:Mirtazapine",
"country": "United States",
"delete": false,
"doi": "10.1016/j.reprotox.2004.07.004",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0890-6238",
"issue": "19(2)",
"journal": "Reproductive toxicology (Elmsford, N.Y.)",
"keywords": null,
"medline_ta": "Reprod Toxicol",
"mesh_terms": "D000014:Abnormalities, Drug-Induced; D000328:Adult; D018687:Antidepressive Agents, Second-Generation; D000929:Antidepressive Agents, Tricyclic; D003511:Cyclohexanols; D004359:Drug Therapy, Combination; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008803:Mianserin; D000078785:Mirtazapine; D010879:Piperazines; D011247:Pregnancy; D011248:Pregnancy Complications; D011256:Pregnancy Outcome; D011446:Prospective Studies; D013723:Teratogens; D014230:Triazoles; D014421:Turkey; D000069470:Venlafaxine Hydrochloride",
"nlm_unique_id": "8803591",
"other_id": null,
"pages": "235-8",
"pmc": null,
"pmid": "15501389",
"pubdate": "2004-12",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Newer antidepressants in pregnancy: prospective outcome of a case series.",
"title_normalized": "newer antidepressants in pregnancy prospective outcome of a case series"
} | [
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{
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"activesubstancename": "VENLAFAXINE HYDROCHLORIDE"
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{
"abstract": "OBJECTIVE\nTo report two cases of ciliochoroidal effusion after the usage of topiramate.\n\n\nMETHODS\nTwo middle-aged women experienced sudden onset of acute glaucoma and acquired myopia after taking topiramate. Ultrasound biomicroscopy demonstrated bilateral ciliochoroidal effusion and angle closure. The A-scan ultrasonography revealed shallow anterior chamber and thick lens. After the treatment and drug withdrawal, intraocular pressure, refractive status and angle anatomy returned to normal and there was resolution of ciliochoroidal effusion. During the clinical course, the anterior chamber depth (ACD) increased from 2.02 to 3.30 mm (1.28 mm of changes) OD and from 1.94 to 3.36 mm (1.42 mm of changes) OS. The lens thickness (LT) became thinner from 4.53 to 4.31 mm (0.22 mm of changes) OD and from 4.59 to 4.30 mm (0.29 mm of changes) OS in the first case. In the second case, the ACD increased from 2.33 to 3.07 mm (0.74 mm of changes) OD and from 2.30 to 3.05 mm (0.75 mm of changes) OS. The LT became thinner from 4.42 to 4.27 mm (0.15 mm of changes) OD and from 4.38 to 4.26 mm (0.12 mm of changes) OS. The forward displacement of the lens-iris diaphragm contributed more to the shallowness of the anterior chamber than the thickening of the lens itself (only accounting for 20%).\n\n\nCONCLUSIONS\nTopiramate-induced bilateral acute angle closure glaucoma and myopic shift was due to ciliochoroidal effusion which resulted in thicker lens and shallow anterior chamber. The later was mainly due to anterior displacement of the lens-iris diaphragm.",
"affiliations": "Department of Ophthalmology, MacKay Memorial Hospital, No. 92, Sec. 2, Chung Shan N. Rd., Taipei, 104, Taiwan. yu_wen_66@yahoo.com.;Department of Ophthalmology, MacKay Memorial Hospital, No. 92, Sec. 2, Chung Shan N. Rd., Taipei, 104, Taiwan.",
"authors": "Lan|Yu-Wen|YW|http://orcid.org/0000-0002-7871-536X;Hsieh|Jui-Wen|JW|",
"chemical_list": "D000927:Anticonvulsants; D007004:Hypoglycemic Agents; D000077236:Topiramate",
"country": "Netherlands",
"delete": false,
"doi": "10.1007/s10792-017-0740-y",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0165-5701",
"issue": "38(6)",
"journal": "International ophthalmology",
"keywords": "Acute angle closure glaucoma; Ciliochoroidal effusion; Myopic shift; Topiramate",
"medline_ta": "Int Ophthalmol",
"mesh_terms": "D000927:Anticonvulsants; D015862:Choroid Diseases; D005260:Female; D015812:Glaucoma, Angle-Closure; D006801:Humans; D007004:Hypoglycemic Agents; D008875:Middle Aged; D009216:Myopia; D000077236:Topiramate",
"nlm_unique_id": "7904294",
"other_id": null,
"pages": "2639-2648",
"pmc": null,
"pmid": "29063980",
"pubdate": "2018-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": "15234126;19933218;15129841;21252671;20952855;21058272;9578038;18091456;21269432;16797716;19514879;16517439;19365189;5344324;21800704;14700673;22265151;16705522;12805393;18201514;11438067;6829690;23632405;18301283;18632523;12578783;20005660;19171058;12470170;19298900;12850232;12583802;25114497;526462;19412496;20606870;16765687;3963117;14711721;23022160;22275816;19001233;17927286",
"title": "Bilateral acute angle closure glaucoma and myopic shift by topiramate-induced ciliochoroidal effusion: case report and literature review.",
"title_normalized": "bilateral acute angle closure glaucoma and myopic shift by topiramate induced ciliochoroidal effusion case report and literature review"
} | [
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},
{
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"reactionmeddraversionpt": "21.1",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Flat anterior chamber of eye",
"reactionmeddraversionpt": "21.1",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Myopia",
"reactionmeddraversionpt": "21.1",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Lens disorder",
"reactionmeddraversionpt": "21.1",
"reactionoutcome": "1"
}
],
"summary": null
},
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"literaturereference": "LAN YW, HSIEH JW. BILATERAL ACUTE ANGLE CLOSURE GLAUCOMA AND MYOPIC SHIFT BY TOPIRAMATE-INDUCED CILIOCHOROIDAL EFFUSION: CASE REPORT AND LITERATURE REVIEW. INT OPHTHALMOL. 2017?1-10",
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},
{
"companynumb": "TW-CIPLA LTD.-2017TW19406",
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},
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"reactionmeddraversionpt": "20.1",
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},
{
"reactionmeddrapt": "Choroidal effusion",
"reactionmeddraversionpt": "20.1",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Nasopharyngitis",
"reactionmeddraversionpt": "20.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Myopia",
"reactionmeddraversionpt": "20.1",
"reactionoutcome": "1"
}
],
"summary": null
},
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"literaturereference": "LAN YW, HSIEH JW. BILATERAL ACUTE ANGLE CLOSURE GLAUCOMA AND MYOPIC SHIFT BY TOPIRAMATE-INDUCED CILIOCHOROIDAL EFFUSION: CASE REPORT AND LITERATURE REVIEW. INT OPHTHALMOL. 2017",
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},
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"reactionmeddrapt": "Choroidal effusion",
"reactionmeddraversionpt": "21.1",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Myopia",
"reactionmeddraversionpt": "21.1",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Angle closure glaucoma",
"reactionmeddraversionpt": "21.1",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Product use in unapproved indication",
"reactionmeddraversionpt": "21.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Off label use",
"reactionmeddraversionpt": "21.1",
"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "LAN Y, HSIEH J. BILATERAL ACUTE ANGLE CLOSURE GLAUCOMA AND MYOPIC SHIFT BY TOPIRAMATE-INDUCED CILIOCHOROIDAL EFFUSION: CASE REPORT AND LITERATURE REVIEW. INT OPHTHALMOL 2018?38(6):2639-2648.",
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] |
{
"abstract": "Chronic hypotony is not uncommon following deep sclerectomy (DS), but only a minor proportion of patients develop hypotony-associated complications. Numerical hypotony does not affect the visual outcomes. This study identifies factors associated with hypotony.\n\n\n\nTo investigate the incidence and risk factors of hypotony and hypotony-associated complications after DS.\n\n\n\nRetrospective cohort study of 1765 eyes (1385 patients) undergoing DS with or without cataract extraction between 2001 and 2020 in 2 UK centers. Chronic hypotony was defined as intraocular pressure (IOP) ≤5 mm Hg in ≥2 consecutive visits lasting >90 days or as any IOP ≤5 mm Hg associated with hypotony-related complications or requiring surgical intervention. Clinical hypotony was defined as the presence of: serous or hemorrhagic choroidal detachment, hypotony maculopathy, flat anterior chamber requiring reformation, decompression retinopathy. The incidence of hypotony was calculated with Kaplan-Meier statistics, and Cox regression was used to identify risk factors.\n\n\n\nThe median (interquartile range) age and follow-up were 76 (67 to 82) years and 45.4 (20.9 to 79.8) months, respectively. The incidence (95% confidence interval) of chronic and clinical hypotony at 5 years was 13.4% (11.5%-15.3%) and 5.6% (4.3%-6.9%), respectively. Sixteen eyes (15.7%) with hypotony-associated complications had IOP >5 mm Hg. Male sex (hazard ratio [HR]: 1.89, P=0.018), non-Caucasian ethnicity (HR: 2.49, P=0.046), intraoperative bevacizumab (HR: 3.96, P=0.01), pigmentary glaucoma (HR: 3.59, P=0.048), previous vitreoretinal surgery (HR: 5.70, P=0.009), intraoperative microperforation (HR: 4.17, P<0.001) and macroperforation (HR: 20.76, P<0.001), and avascular bleb (HR: 1.80, P=0.036) were associated with clinical hypotony.\n\n\n\nChronic hypotony is not uncommon following DS, but clinical hypotony is infrequent. Hypotony associated-complications can occur in eyes without statistical hypotony.",
"affiliations": "Department of Ophthalmology, Gloucestershire Hospitals NHS Foundation Trust, Cheltenham.;Department of Ophthalmology, Gloucestershire Hospitals NHS Foundation Trust, Cheltenham.;Department of Ophthalmology, Gloucestershire Hospitals NHS Foundation Trust, Cheltenham.",
"authors": "Rabiolo|Alessandro|A|;Leadbetter|Duncan|D|;Anand|Nitin|N|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1097/IJG.0000000000001882",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1057-0829",
"issue": "30(7)",
"journal": "Journal of glaucoma",
"keywords": null,
"medline_ta": "J Glaucoma",
"mesh_terms": "D006801:Humans; D015994:Incidence; D007429:Intraocular Pressure; D008297:Male; D011183:Postoperative Complications; D012189:Retrospective Studies; D012307:Risk Factors; D014130:Trabeculectomy",
"nlm_unique_id": "9300903",
"other_id": null,
"pages": "e314-e326",
"pmc": null,
"pmid": "34115726",
"pubdate": "2021-07-01",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Hypotony-associated Complications After Deep Sclerectomy: Incidence, Risk Factors, and Long-term Outcomes.",
"title_normalized": "hypotony associated complications after deep sclerectomy incidence risk factors and long term outcomes"
} | [
{
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"actiondrug": "6",
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"activesubstancename": "BEVACIZUMAB"
},
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"drugdosagetext": "2.5 MG OF BEVACIZUMAB IN 0.1 ML WAS INJECTED SUBCONJUNCTIVALLY",
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}
],
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"reaction": [
{
"reactionmeddrapt": "Off label use",
"reactionmeddraversionpt": "24.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Choroidal detachment",
"reactionmeddraversionpt": "24.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Hypotony maculopathy",
"reactionmeddraversionpt": "24.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Hypotony of eye",
"reactionmeddraversionpt": "24.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Retinopathy",
"reactionmeddraversionpt": "24.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Choroidal effusion",
"reactionmeddraversionpt": "24.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Choroidal haemorrhage",
"reactionmeddraversionpt": "24.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Anterior chamber disorder",
"reactionmeddraversionpt": "24.0",
"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "RABIOLO A, LEADBETTER D AND ANAND N. HYPOTONY?ASSOCIATED COMPLICATIONS AFTER DEEP SCLERECTOMY: INCIDENCE, RISK FACTORS, AND LONG?TERM OUTCOMES. JOURNAL OF GLAUCOMA 2021 JUL?30 (7):E314?26.",
"literaturereference_normalized": "hypotony associated complications after deep sclerectomy incidence risk factors and long term outcomes",
"qualification": "1",
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},
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"receiptdate": "20210802",
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},
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},
"serious": 1,
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"seriousnessother": 1,
"transmissiondate": "20211014"
}
] |
{
"abstract": "BACKGROUND Chronic myeloid leukemia (CML) is usually a tri-phasic myeloproliferative neoplasm, characterized by the presence of the BCR-ABL1 fusion gene, derived from a balanced translocation, t(9;22)(q34;q11). BCR-ABL tyrosine kinase inhibitors (TKI) are used to treat patients with CML. The addition of pegylated interferon-alpha2b to imatinib or dasatinib results in promising deep molecular responses. Because imatinib shows poor penetration into the central nervous system (CNS), the CNS may become a sanctuary site in patients on prolonged imatinib therapy for CML. It is extremely rare for the blast phase in patients with chronic phase CML to affect the CNS without concomitant bone marrow involvement. CASE REPORT This report describes a 57-year-old woman who was diagnosed with accelerated phase (AP) CML and failed high dose imatinib therapy. Despite achieving an excellent molecular response to dasatinib in 6 months, she developed recurrent isolated CNS blast crisis. Survival was prolonged after treatment with intrathecal chemotherapy and whole-brain radiation therapy combined with dasatinib. After achieving long and deep molecular remission with dasatinib and a few months of pegylated interferon-alpha2a, she lived for 18 months in treatment-free-remission (TFR). At age 65 years, she died of progressive rectal carcinoma with septic shock, cancer-related venous thromboembolism, and a possible autoimmune disorder. CONCLUSIONS This patient with accelerated phase CML and 2 isolated CNS blast crises died in TFR 8.5 years after her initial diagnosis and 7.5 years after her first isolated CNS blast crisis. Survival resulted from tailoring of therapies around her comorbidities.",
"affiliations": "Department of Adult Hematology/Bone Marrow Transplantation (BMT), King Fahad Medical City, Riyadh, Saudi Arabia.;Department of Adult Hematology/Bone Marrow Transplantation (BMT), King Fahad Medical City, Riyadh, Saudi Arabia.;Department of Adult Hematology/Bone Marrow Transplantation (BMT), King Fahad Medical City, Riyadh, Saudi Arabia.;Department of Adult Hematology/Bone Marrow Transplantation (BMT), King Fahad Medical City, Riyadh, Saudi Arabia.;Department of Adult Hematology/Bone Marrow Transplantation (BMT), King Fahad Medical City, Riyadh, Saudi Arabia.;Department of Adult Hematology/Bone Marrow Transplantation (BMT), King Fahad Medical City, Riyadh, Saudi Arabia.;Department of Adult Hematology/Bone Marrow Transplantation (BMT), King Fahad Medical City, Riyadh, Saudi Arabia.",
"authors": "Bin Salman|Ahmed A|AA|;Zaidi|Abdul Rehman Zia|ARZ|;Altaf|Syed Yasir|SY|;AlShehry|Nawal F|NF|;Tailor|Imran K|IK|;Motabi|Ibraheem H|IH|;Zaidi|Syed Ziauddin A|SZA|",
"chemical_list": "D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors",
"country": "United States",
"delete": false,
"doi": "10.12659/AJCR.922971",
"fulltext": "\n==== Front\nAm J Case Rep\nAm J Case Rep\namjcaserep\nThe American Journal of Case Reports\n1941-5923 International Scientific Literature, Inc. \n\n32920590\n10.12659/AJCR.922971\n922971\nArticles\nProlonged Survival of a Patient with Chronic Myeloid Leukemia in Accelerated Phase with Recurrent Isolated Central Nervous System Blast Crisis\nBin Salman Ahmed A. ABCDEF1 Zaidi Abdul Rehman Zia ABCDEF12 Altaf Syed Yasir E1 AlShehry Nawal F. E1 Tailor Imran K. E1 Motabi Ibraheem H. E1 Zaidi Syed Ziauddin A. ABCDEF1 \n1 Department of Adult Hematology/Bone Marrow Transplantation (BMT), King Fahad Medical City, Riyadh, Saudi Arabia\n\n2 College of Medicine, Alfaisal University, Riyadh, Saudi Arabia\nCorresponding Author: Ahmed A. Bin Salman, e-mail: bensalman_a@hotmail.comAuthors’ Contribution:\n\nA Study Design\n\nB Data Collection\n\nC Statistical Analysis\n\nD Data Interpretation\n\nE Manuscript Preparation\n\nF Literature Search\n\nG Funds Collection\n\nConflict of interest: None declared\n\n\n2020 \n13 9 2020 \n21 e922971-1 e922971-9\n19 1 2020 16 7 2020 10 8 2020 © Am J Case Rep, 20202020This work is licensed under Creative Common Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)Patient: Female, 57-year-old\n\nFinal Diagnosis: CML accelerated phase with two isolated CNS blast crisis\n\nSymptoms: Headache\n\nMedication:—\n\nClinical Procedure: —\n\nSpecialty: Hematology\n\nObjective:\nUnusual clinical course\n\nBackground:\nChronic myeloid leukemia (CML) is usually a tri-phasic myeloproliferative neoplasm, characterized by the presence of the BCR-ABL1 fusion gene, derived from a balanced translocation, t(9;22)(q34;q11). BCR-ABL tyrosine kinase inhibitors (TKI) are used to treat patients with CML. The addition of pegylated interferon-α2b to imatinib or dasatinib results in promising deep molecular responses. Because imatinib shows poor penetration into the central nervous system (CNS), the CNS may become a sanctuary site in patients on prolonged imatinib therapy for CML. It is extremely rare for the blast phase in patients with chronic phase CML to affect the CNS without concomitant bone marrow involvement.\n\nCase Report:\nThis report describes a 57-year-old woman who was diagnosed with accelerated phase (AP) CML and failed high dose imatinib therapy. Despite achieving an excellent molecular response to dasatinib in 6 months, she developed recurrent isolated CNS blast crisis. Survival was prolonged after treatment with intrathecal chemo-therapy and whole-brain radiation therapy combined with dasatinib. After achieving long and deep molecular remission with dasatinib and a few months of pegylated interferon-α2a, she lived for 18 months in treatment-free-remission (TFR). At age 65 years, she died of progressive rectal carcinoma with septic shock, cancer-related venous thromboembolism, and a possible autoimmune disorder.\n\nConclusions:\nThis patient with accelerated phase CML and 2 isolated CNS blast crises died in TFR 8.5 years after her initial diagnosis and 7.5 years after her first isolated CNS blast crisis. Survival resulted from tailoring of therapies around her comorbidities.\n\nMeSH Keywords:\nBlast CrisisCentral Nervous SystemChemoradiotherapyInjections, SpinalLeukemia, Myelogenous, Chronic, BCR-ABL Positive\n==== Body\nBackground\nChronic myeloid leukemia (CML), a myeloproliferative neoplasm, is usually a triphasic disease, consisting of chronic, accelerated, and blastic phases. CML is characterized by the BCR-ABL1 fusion gene, which is generally derived from a balanced translocation between the long arms of chromosomes 9 and 22, t(9;22)(q34;q11), resulting in a derivative chromosome known as the Philadelphia (Ph) chromosome. Globally, CML has an incidence of 1–2 patients per 100 000 adults and accounts for approximately 15% of newly diagnosed cases of leukemia in adults [1]. CML accounts for 12.5% of all leukemias in the adult population of Saudi Arabia [2].\n\nBlast crisis in CML may be myeloid, lymphoid, or of mixed lineage. Myeloid blast crisis is twice as common as lymphoid blast crisis. Approximately 20% of patients who have CML blast crisis and are treated with imatinib experience a relapse in the central nervous system (CNS), despite a complete response in the peripheral blood and bone marrow (BM). This observation suggests that imatinib has poor penetration through the blood-brain barrier [3].\n\nSeveral studies have evaluated whether tyrosine kinase inhibitors (TKIs) can be safely discontinued in patients who have achieved long-term deep molecular responses, including the Stop Imatinib (STIM) [4], TWISTER [5], STOP 2G-TKI [6], ENEST freedom [7] and EURO-SKI [8] trials, the latter being the largest trial to date on TKI discontinuation in CML patients.\n\nThe addition of pegylated interferon-α2b to imatinib or dasatinib results in promising deep molecular responses that compare favorably with those observed with either TKI alone, suggesting that these combinations may increase the likelihood of treatment-free-remission (TFR) [9,10].\n\nThis report describes the prolonged survival of a CML patient in accelerated phase (AP) who experienced recurrent isolated CNS relapses and was treated successfully. After initial diagnosis, she showed minimal response to imatinib doses as high as 600 mg/day. Treatment with dasatinib for 4.5 years resulted in an early molecular response, followed by treatment with dasatinib and pegylated interferon (Pegasys®) for 20 months (interrupted). She then remained off treatment in deep molecular remission for 18 months before dying of a rectosigmoid adenocarcinoma, septic shock, cancer-related venous thromboembolism, and possible autoimmune disorder. To our knowledge, this is the longest survival reported to date in a patient with CML-AP and double isolated CNS blast crises.\n\nCase Report\nThe patient provided written informed consent for all described treatments. The Institutional Review Board (IRB) of our institution provided an exemption from approval for the purposes of publication.\n\nA 57-year-old woman from Syria initially presented at our institution with an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 1. She had diabetes, for which she was being treated with metformin, and a vitamin D deficiency. She was diagnosed in April 2008 in Syria with Philadelphia positive (Ph+) CML in AP with hepatosplenomegaly. Ultrasonography at the referring hospital at the time of diagnosis showed that her spleen was 25-cm in diameter, and her liver was 22-cm in size. As suggested by the referral report, she was initially treated with imatinib for 2 years and went into hematological remission, but later showed clinical resistance to imatinib. Her imatinib dose was increased to 600 mg/day, but she was intolerant to this dose without any significant response. After 19 months, she presented again to the referring hospital with pallor and hepatosplenomegaly. Laboratory findings showed a hemoglobin concentration of 7 g/dL, a platelet count of 194 000/μL, a white blood cell (WBC) count of 26 000/μL with 0% basophils, 1%, eosinophils and 10% blasts.\n\nShe was referred to our tertiary care hospital with CML in AP. A BM test on March 1, 2010, showed hypercellular BM (90% cellularity) with 11% blasts, which were positive for CD45, CD34, CD33, and CD117 and negative for CD56. Her karyotype was 47,XX,+7,t(9,22)(q34,q11.2). Fluorescence in situ hybridization (FISH) analysis showed that 5% of 200 cells screened had BCR/ABL fusion signals. Hence, on March 7, 2010, she was switched to a second-line TKI, dasatinib, at a dose of 100 mg/day. After starting dasatinib, she showed minimal interruption of treatment, as well as occasionally receiving granulocyte-colony stimulating factor (GCSF) and blood product transfusions.\n\nIn June 2010, she presented with progressive shortness of breath, lung infiltrates, and abdominal pain. A computed tomography (CT) scan of her abdomen and pelvis revealed mild hepatosplenomegaly with portal venous hypertension and a small hypo-attenuated splenic lesion. There was no evidence of lymphadenopathy in the abdomen or pelvis, and her bowels were unremarkable. Within 6 months, she experienced complete cytogenetic remission with the disappearance of the Philadelphia chromosome and trisomy 7 (her karyotype was 46, XX). FISH was negative, and molecular analysis for BCRABL p210 did not show a detectable transcript. She was also negative for the JAK-2 V617F mutation.\n\nShe experienced 2 episodes of isolated CNS relapse, accompanied by normal BM findings. On the first occasion, in late June 2010, while she was in complete cytogenetic and molecular remission, she presented with severe headache, nausea, and a history of 2 generalized tonic-clonic seizures. A brain MRI demonstrated abnormal signal intensity within the cortical sulci of both cerebral hemispheres, along with contrast signal enhancement and abnormal signal intensity of the subjacent cortical structures. The latter was more pronounced on the left side, highly suggestive of leptomeningeal infiltration in the context of leukemia (Figure 1). Cerebrospinal fluid (CSF) examination showed 130 WBCs/μL with 51% blasts and immature cells (Figure 2). Flow cytometry confirmed that 43% of myeloblasts were positive for CD34, CD117, and CD33; but all myoblasts were negative for HLA-DR, CD3, and CD13. She was treated with dasatinib and 10 doses of triple intrathecal (TIT) chemotherapy, consisting of methotrexate (15 mg), cytarabine (50 mg), and hydrocortisone (50 mg). Her CSF became clear after 5 rounds of TIT chemotherapy. After 10 rounds, she refused further TIT chemotherapies. She was also not ready to undergo allogeneic stem cell transplantation (allo-SCT) because of its potential toxicities.\n\nEight months later, in February 2011, the patient again presented with a severe headache and was diagnosed with a second CNS relapse. Brain MRI showed interval improvement regarding the diffuse leukemic leptomeningeal infiltration and almost complete resolution of the previously observed diffuse pachymeningeal enhancement in the supra- and infratentorial locations (Figure 3). However, there was notable interval development of new, non-enhancing patchy T2 hyperintensity at the temporopolar regions bilaterally and in the frontal sub-cortical white matter, which was considered to be a sequela of leukemic infiltration. CSF showed a blast population (52%) expressing CD34, CD117, CD33, CD13, and CD7.\n\nThe second isolated CNS relapse was treated with whole-brain radiation therapy (30 Gy in 10 fractions). The patient was maintained on 100 mg/day dasatinib as she had shown remarkable response to it, with deep molecular remission in both peripheral blood and BM samples. However, she continued to have significant fluctuating hepatosplenomegaly, with a CT scan in March 2012 showing a spleen size of 18 cm. A repeat BM biopsy in June 2012 showed BM cellularity of 50%, characterized by trilineage hematopoiesis with <1% blasts, indicating that her relapse was controlled. Cytogenetic analysis was normal (46,XX). The combination of apparent molecular remission but ongoing hepatosplenomegaly was intriguing.\n\nIn July 2013, she was diagnosed with hypothyroidism and started on levothyroxine. Although minimal pleural effusion was ongoing, she was effectively managed with diuretics and occasional GCSF support, which was required to maintain a reasonable neutrophil count. Dasatinib was decreased to 70 mg/day because of these signs and symptoms but increased to 100 mg/day in February 2014. Dasatinib treatment was halted in September 2014 because of diarrhea and edema. Quantitative RT-PCR showed that BCR-ABL transcripts were undetectable. She was started on pegylated interferon-α2a (PegINF-α2a; Pegasys; Hoffman-LaRoche), at doses ranging from 45 to 135 μg. Although hepatosplenomegaly was resolved, she was unable to tolerate PegINF-α2a. Because she remained persistently negative for BCR-ABL, PegINF-α2a was discontinued in June 2016. Her spleen, however, again started to grow slowly. This was most likely an aspect of a new autoimmune disorder, as she also had joint pains, minimal left-sided pleural effusion, and chronic diarrhea. Tests in November 2016 showed that she was positive for lupus anticoagulant, antinu-clear antibody (ANA), anticardiolipin IgG and IgM antibodies, B2GP1, and anti-dsDNA antibodies. The patient refused prophylactic anticoagulation. She was referred to the rheumatology department but could not be seen due to compliance/logistic issues. Ultrasonography on 29 January 2017 showed that her spleen size had reached 17.1 cm. At this point, CML therapy had been on hold since June 2016, and she was in continuous deep molecular remission, as evidenced by undetectable BCR-ABL transcripts on 8 October 2017. During this period, she was successfully treated for 2 isolated CNS relapses while maintaining a deep systemic response.\n\nUnfortunately, due to insurance coverage issues, her file was closed. In late August 2017, the patient developed bloody diarrhea. An endoscopic biopsy in an outside facility in September 2017 showed that she had developed an adenocarcinoma of the rectum with invasion of the uterus.\n\nFinally, she returned to our institution with septic shock and was admitted to the intensive care unit. CT imaging of her abdomen and pelvis on 27 November 2017 (Figure 4) showed a wedge-shaped splenic infarct at the lower pole measuring 5.8×3 cm, along with interval development of moderate to massive ascites, and omental thickening with peritoneal deposits. The adnexal mass on her left side had increased in size, to 7.7×6 cm, and she had developed a new adnexal mass on her right side, measuring 6×6.7 cm. CT also showed that a diffuse long segment of the rectal mass had infiltrated into the anal canal and surrounding soft tissue, and nodules were noted. Bilateral inguinal lymph nodes showed an interval increase in size, with one reference left inguinal node measuring 2.3×2.1 cm, suggesting disease progression. A non-occlusive thrombosis of the left external iliac and visualized common femoral veins was observed. Bilateral minimal pleural effusions with basilar atelectasis and minor traction bronchiectasis in the left lower lobe basal segment were also observed. Another CT scan showed pulmonary embolism with bilateral pulmonary nodules. The patient was seen by our medical oncology team and deemed unfit for chemotherapy. She was provided with palliative supportive care.\n\nThe patient died on 28 December 2017 of septic shock, cancer-related venous thromboembolism, a possible autoimmune disorder, and progressive adenocarcinoma of the rectum for which only supportive therapy could be offered. Of note, this patient with AP CML and 2 episodes of isolated CNS relapse and died at age 65 years in treatment-free remission of 18 months, which began 8.5 years after initial diagnosis and 7.5 years after first isolated CNS relapse due to the tailoring of therapies around her comorbidities (Table 1, Figure 5).\n\nDiscussion\nThis study describes a 57-year-old woman with accelerated phase CML who failed high dose imatinib. Despite showing an excellent molecular response to dasatinib treatment for 6 months, she developed recurrent isolated CNS blast crises. Her survival was prolonged by treatment with dasatinib plus intrathecal chemotherapies at first relapse and dasatinib plus whole-brain radiation therapy at second relapse. Long and deep molecular remission was achieved by treatment with dasatinib and PegINF-α2a for a few months, followed by treatment-free remission. She died at age 65 years of septic shock, cancer-related venous thromboembolism, a possible autoimmune disorder, and progressive adenocarcinoma of the rectum for which only supportive therapies could be offered. In standard practice, TKIs are discontinued during the first chronic phase of CML after maintenance of deep molecular remission for 2–3 years. This was demonstrated feasible in our patient with CML in AP during deep molecular remission [11–13].\n\nTo our knowledge, this is the first case report of a CML patient who survived after 2 CNS blast crises and then died in complete molecular remission (CMR) while off therapy.\n\nThe TKIs commonly used to treat CML are imatinib, nilotinib, dasatinib, bosutinib, and ponatinib. Imatinib produces complete cytogenetic responses (CCRs) in about 76.2% of patients [14]. Nevertheless, it does not penetrate well into the CNS [15,16], Several studies have assessed whether TKIs can be successfully discontinued in patients with CML who have achieved CCR and deep molecular remission lasting a few years [4–8].\n\nFew studies to date have described patients who developed isolated CNS blast crisis during the course of CML. Dasatinib has been reported to cross the blood-brain barrier and to be effective for treating Ph+ leukemia in the CNS [17]. Dasatinib maintenance following allo-SCT has the potential to prevent CNS relapse, as shown in a patient with sustained CMR in both BM and CNS for 8 months after allogeneic HSCT [18]. Other studies have suggested, however, that dasatinib may fail to prevent CNS relapse [19,20].\n\nAn effective approach to increase the potential for treatment-free remission (TFR) may be the addition of PegINF-α2a to imatinib or dasatinib, as combination treatment results in deep molecular responses, comparable to those observed with TKIs alone [9,10]. Intrathecal chemotherapies have also been shown effective in treating CNS blast crises [21].\n\nA report of a patient with an isolated CNS blast crisis and review of 23 other patients found that 5 of these patients developed an isolated CNS relapse at a median 3.1 years after allo-SCT [22]. In addition, a 64-year-old woman with blast crises CML who was treated with unrelated allo-SCT developed an isolated CNS relapse 18 months later, which was treated with triple intrathecal chemotherapy and dasatinib. She survived for 3 years but later died of advanced vulva carcinoma [23]. One patient diagnosed with chronic phase CML in October 2014 and treated with 100 mg/day dasatinib experienced 2 CNS relapses, the first in June 2015, which was successfully treated with 140 mg/day dasatinib plus intrathecal chemotherapy while BM was in chronic phase; and the second in September 2015, which was treated with 24 Gy radiation followed by unrelated 10/10 matched donor allo-SCT [24]. Another study described a patient with chronic phase CML who initially presented with extramedullary CNS and lymph node blast crises that were treated with dasatinib 70 mg orally twice daily and a standard AML induction regimen along with 16 doses of intrathecal methotrexate/cytarabine/hydrocortisone and 24 Gy of radiation [25]. Because of the patient’s poor general condition, allo-SCT was not advisable. The patient remained in complete cytogenetic and molecular remission, on single-agent dasatinib for 4 years with no evidence of active extramedullary disease according to his most recent brain MRI performed 4 months prior to the writing of this report [25]. Splenomegaly persisted for some time in our patient, despite her being in CMR, and disappeared following treatment with PegINF-α2a, which acts as an immunotherapeutic agent.\n\nConclusions\nIn conclusion, we report the longest survival to date of a patient who experienced 2 episodes of isolated CNS blast crises during her course of CML in AP. She was treated successfully with individually tailored therapy, surviving for 116 months after the diagnosis of CML in AP. She died in treatment-free remission of 18 months, 90 months after her first isolated CNS relapse, without employing allo-SCT. Discontinuation of TKI is currently recommended as standard practice in the first chronic phase of CML. The feasibility of this approach was demonstrated in our patient while she was in deep molecular remission.\n\nIsolated CNS relapses can occur in patients with BCR-ABL-positive CML while receiving imatinib or a next-generation TKI. Achievement of complete cytogenetic and molecular responses in BM may not be sufficient to prevent CNS relapse. Clinical vigilance is required to detect isolated CNS blast crisis in CML patients, even if they are in deep molecular remission. Patients with vague CNS symptoms should undergo CSF analysis and brain MRI. Aggressive intrathecal chemotherapy and craniospinal irradiation can effectively control CNS disease and significantly prevent mortality. Concurrent continuation of an appropriate TKI with better CNS penetration and/or pegylated interferon, as well as consideration of allo-SCT, are potential therapeutic modalities in preventing relapse and possible achievement of cure.\n\nWe are in the process of systematically analyzing the demographic characteristics of similar patients and therapeutic strategies used in their treatment, to provide further insight into the management of isolated blast crises during CML.\n\nThe authors thank and acknowledge King Fahad Medical City (KFMC) and its Research Center for their support, and the IRB of KFMC for ethical approval of the study. The authors would also like to thank Dr. Mohammed Salman Qureshi for providing the radiological images.\n\nConflict of interests\n\nNone.\n\nFigure 1. Composite radiological images of MRI of the brain (A: Axial T2 FSE, B: FLAIR, and C: T1 post Gadolinium) at first CNS relapse in June 2010. Abnormal signal intensities were observed within the swollen cortical and subcortical regions in the right posterior parietal location, along with subtle leptomeningeal enhancement highly suggestive of leptomeningeal infiltration in the context of leukemia (red circles).\n\nFigure 2. Microphotograph of the CSF, showing many blasts characterized by flow cytometry as myeloblasts (Giemsa stain, magnification 400×).\n\nFigure 3. (A–D) Composite radiological images of MRI of the brain (axial FLAIR and post gadolinium T1 WI) at second CNS relapse in February 2011. Interval improvements in signal abnormalities and leptomeningeal enhancement observed in the right posterior parietal location in images A and B were due to leukemic leptomeningeal infiltration (red circles). New non-enhancing hyperintensities in image C were more marked in the left temporopolar regions. Bilateral frontal subcortical white matter was thought to indicate new leukemic infiltrations, as these were not seen in the previous MRI (red circle).\n\nFigure 4. Composite radiological images comparing abdomen and pelvic CT scans at the time of diagnosis in June 2010 (left) and 7 years later in November 2017 when the patient was in treatment-free remission (right), showing the disappearance over time of splenomegaly.\n\nFigure 5. Timeline of the clinical course of this patient, showing treatments and events from the diagnosis of accelerated phase CML to death in treatment-free remission due to advanced stage rectal cancer. Overall survival was greater than 9.5 years (116 months) from diagnosis and 7.5 years from first CNS blast crisis. * TIT – triple intrathecal rherapies; WBRT – whole-brain radiation therapy.\n\nTable 1. Hematological and molecular response of patient during the course of treatment.\n\nCourse of treatment\tWhite blood cells (×109/L)\tHemoglobin (g/dL)\tPlatelets (×109/L)\tBone marrow blasts (%)\tKaryotype/FISH for BCR: ABL\tRTQ-PCR for BCR: ABL p210\tOverall systematicand CNS remission status\t\nAt diagnosis\t26×109/L with (Eosinophils: 1% Basophils: 0% Blasts: 10%)\t7 g/dL\t194×109/L\t11% blasts with increased eosinophilic & basophilic precursors\t47,XX, +7, t(9,22) (q34,q11.2) FISH showing BCR-ABL fusion signals in 5% scored nuclei\t86.7%\tCML – Accelerated Phase\t\nAt 24 months (on Imatinib)\t2.36×109/L No immature cells\t9.48 g/dL\t85.4×109/L\t1% blasts with normal myeloid immuno-phenotype\t46, XX[20] FISH negative for BCR-ABL fusion signal\t0.001048 (IS)\tCML in deep molecular remission\t\nAt 1st CNS Blast Crisis (on TITs and Dasatinib)\t4.84×109/L No immature cells\t9.82 g/dL\t145×109/L\t<1% blasts with hypocellular bone marrow with a cellularity of 30%\t46, XX[20] FISH negative for BCR-ABL fusion signal\t0.000131 (IS)\tIsolated CNS Blast Crisis (CSF had 31% blasts by morphology and 43% of myeloblasts by flow cytometry) with deep molecular remission in bone marrow\t\nAt 2nd CNS Blast Crisis (On WBR and Dasatinib)\t1.32×109/L No immature cells\t10.1 g/dL\t151×109/L\t1% blasts with marrow cellularity of 50%\t46, XX[20] FISH negative for BCR-ABL fusion signal\t0.00019% (IS)\tIsolated CNS Blast Crisis (CSF had 50% blasts by morphology and 52% of myeloblasts co-expressing CD7 by flowcytometry) with deep molecular remission in bone marrow\t\nOn start of PEG-Interferon α\t1.42×109/L No immature cells\t8.9 g/dL\t115×109/L\tPatient refused bone marrow biopsy\t46, XX[20] FISH negative for BCR-ABL fusion signal\t0.0012% (IS)\tIn deep molecular remission, and CNS clear\t\nOn end of PEG-Interferon α\t1.12×109/L No immature cells\t9.1 g/dL\t195×109/L\tPatient refused bone marrow biopsy\t46, XX[20] FISH negative for BCR-ABL fusion signal\tNot detected\tIn deep molecular remission, No CNS manifestations\t\nDuring treatment free remission\t5.53×109/L No immature cells\t9.3 g/dL\t330×109/L\t\t46, XX[20] FISH negative for BCR-ABL fusion signal\tNot detected\tIn deep molecular remission, No CNS manifestations\n==== Refs\nReferences:\n1. American Cancer Society Cancer Facts & Figures Atlanta American Cancer Society Available from: https://www.cancer.org/research/cancer-facts-statistics/all-cancer-facts-figures/cancer-facts-figures-2017.html \n2. Registry SC Cancer Incidence Report, Saudi Arabia – 2014 Saudi Health Council Available from:https://nhic.gov.sa/eServices/Documents/2014.pdf \n3. Leis JF Stepan DE Curtin PT Central nervous system failure in patients with chronic myelogenous leukemia lymphoid blast crisis and Philadelphia chromosome positive acute lymphoblastic leukemia treated with imatinib (STI-571) Leuk Lymphoma 2004 45 4 695 98 15160941 \n4. Mahon FX Rea D Guilhot J Intergroupe Français des Leucémies Myéloïdes Chroniques: Discontinuation of imatinib in patients with chronic myeloid leukaemia who have maintained complete molecular remission for at least 2 years: The prospective, multicentre Stop Imatinib (STIM) trial Lancet Oncol 2010 11 11 1029 35 20965785 \n5. Ross DM Branford S Seymour JF Safety and efficacy of imatinib cessation for CML patients with stable undetectable minimal residual disease: results from the TWISTER study Blood 2013 122 4 515 22 23704092 \n6. Rea D Nicolini FE Tulliez M France Intergroupe des Leucémies Myéloïdes Chroniques: Discontinuation of dasatinib or nilotinib in chronic myeloid leukemia: Interim analysis of the STOP 2G-TKI study Blood 2017 129 7 846 54 27932374 \n7. Hochhaus A Masszi T Giles FJ Treatment-free remission following frontline nilotinib in patients with chronic myeloid leukemia in chronic phase: results from the ENESTfreedom study Leukemia 2017 31 7 1525 31 28218239 \n8. Saussele S Richter J Guilhot J EURO-SKI investigators: Discontinuation of tyrosine kinase inhibitor therapy in chronic myeloid leukaemia (EUROSKI): A prespecified interim analysis of a prospective, multicentre, non-randomised, trial Lancet Oncol 2018 19 6 747 57 29735299 \n9. Simonsson B Gedde-Dahl T Markevarn B Combination of pegylated IFN-α2b with imatinib increases molecular response rates in patients with low- or intermediate-risk chronic myeloid leukemia Blood 2011 118 12 3228 35 21685374 \n10. Hjorth-Hansen H Stentoft J Richter J Safety and efficacy of the combination of pegylated interferon-α2b and dasatinib in newly diagnosed chronic-phase chronic myeloid leukemia patients Leukemia 2016 30 9 1853 60 27133821 \n11. National Comprehensive Cancer Network Chronic Myeloid Leukemia (Version 4.2018) 2018 Available from: https://www.nccn.org/professionals/physician_gls/pdf/cml.pdf \n12. Hochhaus A Saussele S Rosti G ESMO Guidelines Committee Chronic myeloid leukaemia: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up Ann Oncol 2017 28 Suppl. 4 iv41 iv51 \n13. Rea D Ame S Berger M French Chronic Myeloid Leukemia Study Group Discontinuation of tyrosine kinase inhibitors in chronic myeloid leukemia: Recommendations for clinical practice from the French Chronic Myeloid Leukemia Study Group Cancer 2018 124 14 2956 63 29723417 \n14. O’Brien SG Guilhot F Larson RA IRIS Investigators Imatinib compared with interferon and low-dose cytarabine for newly diagnosed chronic-phase chronic myeloid leukemia N Engl J Med 2003 348 11 994 1004 12637609 \n15. Petzer AL Gunsilius E Hayes M Low concentrations of STI571 in the cerebrospinal fluid: A case report Br J Haematol 2002 117 3 623 25 12028032 \n16. Takayama N Sato N O’Brien SG Imatinib mesylate has limited activity against the central nervous system involvement of Philadelphia chromosome-positive acute lymphoblastic leukaemia due to poor penetration into cerebrospinal fluid Br J Haematol 2002 119 1 106 8 12358909 \n17. Porkka K Koskenvesa P Lundan T Dasatinib crosses the blood-brain barrier and is an efficient therapy for central nervous system Philadelphia chromosome-positive leukemia Blood 2008 112 4 1005 12 18477770 \n18. Nishimoto M Nakamae H Koh KR Dasatinib maintenance therapy after allogeneic hematopoietic stem cell transplantation for an isolated central nervous system blast crisis in chronic myelogenous leukemia Acta Haematol 2013 130 2 111 14 23548721 \n19. Papageorgiou SG Pappa V Economopoulou C Dasatinib induces long-term remission in imatinib-resistant Philadelphia chromosome-positive acute megakaryoblastic leukemia but fails to prevent development of central nervous system progression Leuk Res 2010 34 9 e254 56 20392492 \n20. Frigeri F Arcamone M Luciano L Systemic dasatinib fails to prevent development of central nervous system progression in a patient with BCRABL unmutated Philadelphia chromosome-positive leukemia Blood 2009 113 20 5028 29 19443672 \n21. Rajappa S Uppin SG Raghunadharao D Isolated central nervous system blast crisis in chronic myeloid leukemia Hematol Oncol 2004 22 4 179 81 15995975 \n22. Jain A Gupta N Isolated CNS blast crises in chronic myeloid leukaemia presenting as hypertrophic pachymeningitis and bilateral optic neuritis: A case report J Clin Diagn Res 2016 10 1 OE01 5 \n23. Fuchs M Reinhofer M Ragoschke-Schumm A Isolated central nervous system relapse of chronic myeloid leukemia after allogeneic hematopoietic stem cell transplantation BMC Blood Disord 2012 12 9 22871019 \n24. Al-blooshi R Vergidis D Lipton JH Isolated CNS blast crisis of CML in a patient on dasatinib therapy J Leuk 2016 4 2 212 \n25. Abuelgasim KA Alshieban S Almubayi NA An atypical initial presentation of chronic myeloid leukemia with central nervous system and lymph node blast crises Case Rep Oncol 2016 9 2 415 21 27721761\n\n",
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"mesh_terms": "D000368:Aged; D000970:Antineoplastic Agents; D001752:Blast Crisis; D001932:Brain Neoplasms; D002490:Central Nervous System; D016371:Cranial Irradiation; D005260:Female; D006801:Humans; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive; D008875:Middle Aged; D047428:Protein Kinase Inhibitors",
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"title": "Prolonged Survival of a Patient with Chronic Myeloid Leukemia in Accelerated Phase with Recurrent Isolated Central Nervous System Blast Crisis.",
"title_normalized": "prolonged survival of a patient with chronic myeloid leukemia in accelerated phase with recurrent isolated central nervous system blast crisis"
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"literaturereference": "BIN SALMAN AA, ZAIDI ARZ, ALTAF SY, AISHEHRY NF, TAILOR IK, MOTABI IH., ET AL. PROLONGED SURVIVAL OF A PATIENT WITH CHRONIC MYELOID LEUKEMIA IN ACCELERATED PHASE WITH RECURRENT ISOLATED CENTRAL NERVOUS SYSTEM BLAST CRISIS. AM J CASE REP. 2020?21:E922971-9",
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"abstract": "Mild elevation of creatine kinase (CK) is common in untreated hypothyroidism, but severe myositis and overt rhabdomyolysis are rare. Similarly, muscle pain and CK elevation are potential side effects of statin therapy, yet rhabdomyolysis is likewise rare in the absence of medication interactions adversely affecting statin metabolism. The coexistence of statin therapy and hypothyroid states may synergistically increase the risk of myopathy. We describe a case of rhabdomyolysis attributable to induced hypothyroidism in a patient on chronic statin medication who was anticipating adjuvant radioiodine ((131)I) therapy for a thyroid carcinoma.",
"affiliations": "Boonshoft School of Medicine, Wright State University, Dayton, Ohio, USA.;Boonshoft School of Medicine, Wright State University, Dayton, Ohio, USA.",
"authors": "Jbara|Yaser|Y|;Bricker|Dean|D|",
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"keywords": "Induced hypothyroidism; Recombinant human thyrotropin; Rhabdomyolysis; Statin therapy",
"medline_ta": "Eur Thyroid J",
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"title": "Rhabdomyolysis in the setting of induced hypothyroidism and statin therapy: a case report.",
"title_normalized": "rhabdomyolysis in the setting of induced hypothyroidism and statin therapy a case report"
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{
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},
{
"reactionmeddrapt": "Myositis",
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},
{
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{
"reactionmeddrapt": "Rhabdomyolysis",
"reactionmeddraversionpt": "18.1",
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],
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},
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"literaturereference": "JBARA Y, BRICKER D.. RHABDOMYOLYSIS IN THE SETTING OF INDUCED HYPOTHYROIDISM AND STATIN THERAPY: A CASE REPORT.. EUR-THYROID-J. 2015?4(1):62-64",
"literaturereference_normalized": "rhabdomyolysis in the setting of induced hypothyroidism and statin therapy a case report",
"qualification": "1",
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},
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}
] |
{
"abstract": "A 45-year-old hypertensive Japanese woman presented with epigastric pain on inspiration, fever, complete atrioventricular block and polyarthritis. Her antistreptolysin O levels were markedly elevated. A diagnosis of rheumatic fever was made according to the modified Jones criteria. She was prescribed loxoprofen sodium, which was partially effective for her extracardiac clinical symptoms. However, she had syncope due to complete atrioventricular block with asystole longer than 10 seconds. Consequently, we implanted a permanent pacemaker. Although we prescribed prednisolone, the efficacy of which was limited for the patient's conduction disturbance, the complete atrioventricular block persisted. In our systematic review of 12 similar cases, the duration of complete heart block was always transient and there was no case requiring a permanent pacemaker. We thus encountered a very rare case of adult-onset acute rheumatic fever with persistent complete atrioventricular block necessitating permanent pacemaker implantation.",
"affiliations": "Division of Cardiovascular Medicine, Department of Medicine, Jichi Medical University.",
"authors": "Oba|Yusuke|Y|;Watanabe|Hiroaki|H|;Nishimura|Yoshioki|Y|;Ueno|Shuichi|S|;Nagashima|Takao|T|;Imai|Yasushi|Y|;Shimpo|Masahisa|M|;Kario|Kazuomi|K|",
"chemical_list": "D000893:Anti-Inflammatory Agents; D010666:Phenylpropionates; C040656:loxoprofen; D000989:Antistreptolysin; D011239:Prednisolone",
"country": "Japan",
"delete": false,
"doi": "10.1536/ihj.15-091",
"fulltext": null,
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"issn_linking": "1349-2365",
"issue": "56(6)",
"journal": "International heart journal",
"keywords": null,
"medline_ta": "Int Heart J",
"mesh_terms": "D000893:Anti-Inflammatory Agents; D000989:Antistreptolysin; D054537:Atrioventricular Block; D002304:Cardiac Pacing, Artificial; D005260:Female; D006801:Humans; D008875:Middle Aged; D010138:Pacemaker, Artificial; D010666:Phenylpropionates; D011239:Prednisolone; D012213:Rheumatic Fever; D013575:Syncope; D016896:Treatment Outcome",
"nlm_unique_id": "101244240",
"other_id": null,
"pages": "664-7",
"pmc": null,
"pmid": "26549396",
"pubdate": "2015",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "A Case of Adult-Onset Acute Rheumatic Fever With Long-Lasting Atrioventricular Block Requiring Permanent Pacemaker Implantation.",
"title_normalized": "a case of adult onset acute rheumatic fever with long lasting atrioventricular block requiring permanent pacemaker implantation"
} | [
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},
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},
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},
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},
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{
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},
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}
] |
{
"abstract": "Invasive fungal infections, usually Aspergillus and Candida, represent a major cause of morbidity and mortality in patients with malignant haematological diseases, but in the last years rare fungal infections have more frequently been reported. Here, we report the clinical history of three patients affected with haematological malignancies who developed an infection caused by Geotrichum (G.) clavatum. Two out of three patients were affected by acute myeloid leukaemia (AML), and one by mantle cell lymphoma (MCL). All patients received cytarabine-based chemotherapeutic regimens and developed G. clavatum infection within 3 weeks from therapy initiation. In all cases, G. clavatum was isolated from central venous catheter and peripheral blood cultures. In vitro susceptibility test confirmed an intrinsic resistance to echinocandins and, in all cases, visceral localisations (spleen, liver and lung) were documented by total body computed tomography (CT) scan. A prolonged antifungal therapy with high doses liposomal amphotericin-B was necessary to obtain fever resolution. Only the patient with MCL died while the other two AML recovered, and one of them after received an allogeneic stem cell transplantation. We consecutively reviewed all published cases of infection caused by G. clavatum. Our experience and literature review indicate that G. clavatum can cause invasive infection in haematological patients, mainly in those with acute leukaemia.",
"affiliations": "Cattedra di Ematologia, Dipartimento di Biomedicina e Prevenzione, Università degli studi di Roma \"Tor Vergata\", Roma, Italia.;Clinica di Malattie Infettive, Dipartimento di Medicina dei Sistemi, Università Tor Vergata, Roma, Italia.;Cattedra di Ematologia, Dipartimento di Biomedicina e Prevenzione, Università degli studi di Roma \"Tor Vergata\", Roma, Italia.;Dipartimento di Medicina e Chirurgia, Università Tor Vergata, Roma, Italia.;Cattedra di Ematologia, Dipartimento di Biomedicina e Prevenzione, Università degli studi di Roma \"Tor Vergata\", Roma, Italia.;Cattedra di Ematologia, Dipartimento di Biomedicina e Prevenzione, Università degli studi di Roma \"Tor Vergata\", Roma, Italia.;Cattedra di Ematologia, Dipartimento di Biomedicina e Prevenzione, Università degli studi di Roma \"Tor Vergata\", Roma, Italia.;Cattedra di Ematologia, Dipartimento di Biomedicina e Prevenzione, Università degli studi di Roma \"Tor Vergata\", Roma, Italia.;Cattedra di Ematologia, Dipartimento di Biomedicina e Prevenzione, Università degli studi di Roma \"Tor Vergata\", Roma, Italia.;Istituto di Farmacologia Translazionale, Dipartimento di Medicina, CNR, Roma, Italia.;Cattedra di Ematologia, Dipartimento di Biomedicina e Prevenzione, Università degli studi di Roma \"Tor Vergata\", Roma, Italia.;Istituto di Microbiologia, Università Cattolica del Sacro Cuore, Roma, Italia.;Cattedra di Ematologia, Dipartimento di Biomedicina e Prevenzione, Università degli studi di Roma \"Tor Vergata\", Roma, Italia.;Istituto di Ematologia, Università Cattolica del Sacro Cuore, Roma, Italia.;Cattedra di Ematologia, Dipartimento di Biomedicina e Prevenzione, Università degli studi di Roma \"Tor Vergata\", Roma, Italia.",
"authors": "Del Principe|Maria Ilaria|MI|;Sarmati|Loredana|L|;Cefalo|Mariagiovanna|M|;Fontana|Carla|C|;De Santis|Giovanna|G|;Buccisano|Francesco|F|;Maurillo|Luca|L|;De Bellis|Eleonora|E|;Postorino|Massimiliano|M|;Sconocchia|Giuseppe|G|;Del Poeta|Giovanni|G|;Sanguinetti|Maurizio|M|;Amadori|Sergio|S|;Pagano|Livio|L|;Venditti|Adriano|A|",
"chemical_list": "D000935:Antifungal Agents; D054714:Echinocandins; C068538:liposomal amphotericin B; D000666:Amphotericin B",
"country": "Germany",
"delete": false,
"doi": "10.1111/myc.12508",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0933-7407",
"issue": "59(9)",
"journal": "Mycoses",
"keywords": "(1→3)-β-d-glucan; Geotrichum clavatum; acute myeloid leukaemia; emerging yeast infections; fungaemia; liposomal amphotericin-B; susceptibility tests",
"medline_ta": "Mycoses",
"mesh_terms": "D000328:Adult; D000666:Amphotericin B; D000935:Antifungal Agents; D062905:Central Venous Catheters; D025141:Drug Resistance, Fungal; D054714:Echinocandins; D017809:Fatal Outcome; D005260:Female; D005847:Geotrichosis; D005848:Geotrichum; D019337:Hematologic Neoplasms; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D000072742:Invasive Fungal Infections; D007558:Italy; D015470:Leukemia, Myeloid, Acute; D008099:Liver; D008168:Lung; D020522:Lymphoma, Mantle-Cell; D008297:Male; D008826:Microbial Sensitivity Tests; D008875:Middle Aged; D013154:Spleen; D014057:Tomography, X-Ray Computed; D055815:Young Adult",
"nlm_unique_id": "8805008",
"other_id": null,
"pages": "594-601",
"pmc": null,
"pmid": "27061932",
"pubdate": "2016-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "A cluster of Geotrichum clavatum (Saprochaete clavata) infection in haematological patients: a first Italian report and review of literature.",
"title_normalized": "a cluster of geotrichum clavatum saprochaete clavata infection in haematological patients a first italian report and review of literature"
} | [
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"literaturereference": "DEL PRINCIPE MI, SARMATI L, CEFALO M, FONTANA C, DE SANTIS G, BUCCISANO F, ET AL. A CLUSTER OF GEOTRICHUM CLAVATUM (SAPROCHAETE CLAVATA) INFECTION IN HAEMATOLOGICAL PATIENTS: A FIRST ITALIAN REPORT AND REVIEW OF LITERATURE. MYCOSES 2016;59(9):594-601.",
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"abstract": "Acetaminophen (APAP) is the leading cause of drug overdose and hepatotoxicity worldwide, including in Thailand. Patterns of overdose and hospital management are known to have significant impacts on the outcomes of APAP overdose, and these factors vary from country to country. Therefore, this study aimed to analyze clinical characteristics of Thai patients with APAP overdose in terms of overdose patterns, clinical presentation, treatment and outcomes. In this retrospective analytical study, medical records of adult patients hospitalized with a diagnosis of APAP overdose at Rajavithi Hospital, Bangkok, between January 2013 and December 2017 were reviewed. A total of 184 patients diagnosed with APAP overdose were included. The median age was 22 (15-76) years and the majority were female (79.9%). Most overdoses were intended self-poisoning ingestion (90.8%) with a median dose of 10.5 g (4.5-50). A total of 121 patients were treated with N-acetylcysteine with a median visit-to-N-acetylcysteine time of 2 (0.5-15) h. Overall, 15.6% developed mild hepatotoxicity (aspartate aminotransferase or alanine aminotransferase >3 times the upper limit of normal), 6.4% developed severe hepatotoxicity (aspartate aminotransferase or alanine aminotransferase >10 times the upper limit of normal and international normalized ratio >2.0) and 3 patients developed acute liver failure (1 patient resolved spontaneously and 2 patients, neither of whom had a liver transplant, died). Significant predictors for hepatotoxicity included older age, chronic alcohol drinking, repeated taking of medication for more than 8 h (staggered ingestion), long duration between ingestion and hospital visit, alcohol coingestion, abdominal pain symptoms, and acute kidney injury. Most cases of APAP overdose in Thailand appear to be young women with intentional ingestion. With prompt management, most patients (76.4%) did not develop significant hepatotoxicity; nevertheless, despite N-acetylcysteine therapy, hepatotoxicity including acute liver failure was observed in a small proportion of patients, particularly those with unintentional overdose and chronic alcohol drinking.",
"affiliations": "Division of Gastroenterology and Hepatology, Department of Medicine, Rajavithi Hospital, Bangkok, Thailand.;Division of Gastroenterology and Hepatology, Department of Medicine, Rajavithi Hospital, Bangkok, Thailand.",
"authors": "Pholmoo|Natthiya|N|;Bunchorntavakul|Chalermrat|C|",
"chemical_list": null,
"country": "China",
"delete": false,
"doi": "10.14218/JCTH.2018.00066",
"fulltext": "\n==== Front\nJ Clin Transl HepatolJ Clin Transl HepatolJCTHJournal of Clinical and Translational Hepatology2225-07192310-8819XIA & HE Publishing Inc. JCTH.2018.0006610.14218/JCTH.2018.00066Original ArticleCharacteristics and Outcomes of Acetaminophen Overdose and Hepatotoxicity in Thailand Pholmoo N. et al: Acetaminophen hepatotoxicity in ThailandPholmoo Natthiya Bunchorntavakul Chalermrat *Division of Gastroenterology and Hepatology, Department of Medicine, Rajavithi Hospital, Bangkok, Thailand*Correspondence to: Chalermrat Bunchorntavakul, Division of Gastroenterology and Hepatology, Department of Internal Medicine, Rajavithi Hospital, College of Medicine, Rangsit University, Rajavithi Road, Ratchathewi, Bangkok 10400, Thailand. Tel: +662-3548081, Fax: +662-3548179, E-mail: dr.chalermrat@gmail.comThe authors have no conflict of interests related to this publication.\n\nData acquisition, analysis and interpretation, drafting and approval of the final manuscript (NP), conceptualization, analysis and interpretation of data, critical revision and approval of the final manuscript (CB).\n\n14 6 2019 28 6 2019 7 2 132 139 19 12 2018 15 5 2019 16 5 2019 © 2019 Authors.2019This article has been published under the terms of Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0), which permits noncommercial unrestricted use, distribution, and reproduction in any medium, provided that the following statement is provided. “This article has been published in Journal of Clinical and Translational Hepatology at DOI: 10.14218/JCTH.2018.00066 and can also be viewed on the Journal’s website at http://www.jcthnet.com”.Abstract\nBackground and Aims: Acetaminophen (APAP) is the leading cause of drug overdose and hepatotoxicity worldwide, including in Thailand. Patterns of overdose and hospital management are known to have significant impacts on the outcomes of APAP overdose, and these factors vary from country to country. Therefore, this study aimed to analyze clinical characteristics of Thai patients with APAP overdose in terms of overdose patterns, clinical presentation, treatment and outcomes.\n\nMethods: In this retrospective analytical study, medical records of adult patients hospitalized with a diagnosis of APAP overdose at Rajavithi Hospital, Bangkok, between January 2013 and December 2017 were reviewed.\n\nResults: A total of 184 patients diagnosed with APAP overdose were included. The median age was 22 (15–76) years and the majority were female (79.9%). Most overdoses were intended self-poisoning ingestion (90.8%) with a median dose of 10.5 g (4.5–50). A total of 121 patients were treated with N-acetylcysteine with a median visit-to-N-acetylcysteine time of 2 (0.5–15) h. Overall, 15.6% developed mild hepatotoxicity (aspartate aminotransferase or alanine aminotransferase >3 times the upper limit of normal), 6.4% developed severe hepatotoxicity (aspartate aminotransferase or alanine aminotransferase >10 times the upper limit of normal and international normalized ratio >2.0) and 3 patients developed acute liver failure (1 patient resolved spontaneously and 2 patients, neither of whom had a liver transplant, died). Significant predictors for hepatotoxicity included older age, chronic alcohol drinking, repeated taking of medication for more than 8 h (staggered ingestion), long duration between ingestion and hospital visit, alcohol coingestion, abdominal pain symptoms, and acute kidney injury.\n\nConclusions: Most cases of APAP overdose in Thailand appear to be young women with intentional ingestion. With prompt management, most patients (76.4%) did not develop significant hepatotoxicity; nevertheless, despite N-acetylcysteine therapy, hepatotoxicity including acute liver failure was observed in a small proportion of patients, particularly those with unintentional overdose and chronic alcohol drinking.\n\nAcetaminophenParacetamolOverdoseDrug-induced hepatotoxicityLiver failure\n==== Body\nIntroduction\nAcetaminophen (APAP) is an over-the-counter medicine which is commonly used worldwide, either as a single-ingredient medication or as a component of numerous combination products for analgesia and antipyresis. In Thailand, APAPs are widely available as over-the-counter drugs, which can be sold without restriction in terms of quantities and the number of tablets per bottle. Although APAP is generally considered to be safe at the usual therapeutic doses recommended by the manufacturer (1–4 g/day), concerns about its use have emerged over the past decade as APAP has been increasingly recognized as a major cause of acute liver failure (ALF) in adults in the United States and many other countries worldwide.1,2 In contrast, Asia-Pacific countries have a higher incidence of ALF, due to hepatitis viruses and drugs, with fewer cases of APAP overdose being observed.3\n\nAccording to a recent systematic review, about one quarter of patients with drug-induced liver injury in China are associated with traditional Chinese medicine.4 Notably, APAP is a classic cause of drug-induced hepatotoxicity in a dose-dependent manner. Single-overdose ingestion typically occurs in attempted suicide, and doses exceeding 15–25 g may cause severe liver injury, resulting in death in up to 25% of cases. However, it should be noted that 30–50% of cases of hospitalized APAP hepatotoxicity nowadays result from “unintentional overdose” or a “therapeutic misadventure”, whereby the daily dose may not have greatly exceeded the recommended safe limits but where certain risk factors are present, such as concomitant alcohol use, obesity, malnutrition state, and medications that interact with the cytochrome (CYP) system.3,5\n\nPatterns of overdose and hospital management are known to have significant impacts on the outcomes of APAP overdose, and these factors vary between countries, but in Southeast Asia the data on APAP overdose and hepatotoxicity are limited. Previous studies from Malaysia and Singapore have reported somewhat different characteristics and better outcomes in patients with APAP overdose compared to those of studies from Western countries.6–10 Therefore, this study aimed to describe the clinical characteristics of Thai patients with APAP overdose in terms of overdose patterns, clinical presentation, treatment, and outcomes. In addition, the features and predictive factors of APAP-induced hepatotoxicity were also analyzed.\n\nMethods\nStudy oversight\nMedical records of consecutive adult patients hospitalized with diagnosis of APAP overdose at Rajavithi Hospital, Bangkok over a five-year period from January 2013 to December 2017 were retrospectively reviewed, and the results were matched with the International Statistical Classification of Disease and Related Health Problems, 10th revision T39.1 (poisoning by non-opioid analgesics, antipyretics, and antirheumatics [4-aminophenol derivatives]). The study protocol was reviewed and approved by the Medical Ethics Committee of Rajavithi Hospital.\n\nStudy population\nAdult patients (>15 years of age) who presented at the Emergency Department of the hospital with a diagnosis of APAP overdose were consecutively included. Patients with incomplete or unclear records were excluded. Patient demographics were reviewed and recorded as follows: age, gender, length of stay, cost, comorbid diseases, history of alcohol intake, dose and pattern of ingestion, time to hospital visit, coingestants, clinical presentations, physical examination, laboratory data (e.g., aspartate aminotransferase (AST), alanine aminotransferase (ALT), total bilirubin (TB), prothrombin time (PT), international normalized ratio (INR), creatinine (Cr), platelet count, hematocrit), treatments, and clinical outcomes. Intentionality of overdose was also noted and compared.\n\nTerm definitions\nAPAP overdose was defined as an ingestion of supratherapeutic dose of >4 g per day, >2 g per day for alcoholic patients, or levels higher than therapeutic ones (>20 mcg/L) for patients with chronic liver disease. Acute overdose was defined as an ingestion of APAP overdose within an 8-h period. Supratherapeutic doses ingested over a time period of over 8 h were considered as a staggered overdose or a repeated supratherapeutic ingestion, which is referred to as a “staggered ingestion” in this study. Unintentional overdose was defined as an ingestion of supratherapeutic dose for pain/fever reduction without the intention of self-harm. Mild hepatotoxicity was defined as present when either the AST or ALT reading was 3 times higher than the upper limit of normal (xULN) but not more than 10 xULN.\n\nSevere hepatotoxicity was defined as present when either the AST or ALT reading was 10 xULN with an INR >2.11 ALF was defined as hepatotoxicity with an INR >1.5 with any degree of hepatic encephalopathy.12 Acute kidney injury (AKI) was defined as an absolute increase in serum Cr of 0.3 mg/dL or a percentage increase in serum Cr of 50% within 48 h.13\n\nStatistical analysis\nAll results were analyzed using the Statistical Package for Social Scientists (SPSS version 23.0). Data values were presented as median and range (minimum to maximum). Demographic data and baseline characteristics were summarized using descriptive statistics such as mean ± standard deviation or median (min-max). Categorical variables were compared using the chi-square test or Fisher’s exact test, while comparison of continuous variables was performed using the independent t-test or the Mann-Whitney U test. Logistic regression analysis was used to analyze the significant predictors of hepatotoxicity and severe hepatotoxicity, and results are presented by odds ratio. All statistical examinations were two-tailed with p-value <0.05 defined as statistically significant.\n\nResults\nBaseline demographic data and patterns of ingestion\nA total of 184 patients with APAP overdose were included (17 unintentional and 167 intentional overdose ingestions). The median age was 22 (15–76) years, and 79.9% were female. Among the 57 patients whose complete history of alcohol consumption was obtained, 15.8% were chronic alcohol drinkers. The median amount of APAP ingestion was 10.5 (4.5–50) g. Alcohol coingestion was reported in 10 patients (5.4%) and drug/substance coingestion was reported in 28 (15.2%) patients (14 antihistamines, 7 nonsteroidal anti-inflammatory drugs, 2 sleeping pills, 2 antibiotics, 1 antacid, 1 unknown drug, and 2 toilet cleaning liquids). Comparison of the two groups showed that patients with unintentional overdose were more likely to be male, older, and have history of alcohol abuse, underlying cirrhosis, longer duration of APAP ingestions (staggered ingestion), and longer time between ingestion and hospital visit (Table 1).\n\nTable 1. Baseline demographics and clinical characteristics\n\tAll, n=184\tUnintentional, n=17\tIntentional, n=167\tp-value\t\nVariable\t\t\t\t\t\n Age in years\t22 [15, 76]\t33 [15, 50]\t21 [15, 76]\t<0.001\t\n Female gender\t147 (79.9%)\t11 (64.7%)\t136 (81.4%)\t0.115\t\n Length of stay in days\t2 [1, 21]\t5 [1, 21]\t2 [1, 14]\t0.014\t\nComorbid disease\t\t\t\t\t\n None\t177 (96.2%)\t14 (82.4%)\t163 (97.6%)\t0.018\t\n Cirrhosis\t2 (1.1%)\t2 (11.8%)\t0 (0%)\t0.008\t\n Psychiatric disease\t3 (1.6%)\t0 (0%)\t3 (1.8%)\t1.000\t\nHistory of alcohol use*\t\t\t\t\t\n Chronic drinker\t9/57 (15.8%)\t5/11 (45.4%)\t4/46 (8.7%)\t<0.001\t\n Social drinker\t17/57 (29.8%)\t4/11 (36.4%)\t13/46 (28.3%)\t0.056\t\n None/rare\t31/57 (54.4%)\t2/11 (18.2%)\t29/46 (63.0%)\t0.742\t\nTime of ingestion\t\t\t\t\t\n Acute (< 8 h)\t170 (92.4%)\t4 (23.5%)\t166 (99.4%)\t <0.001\t\n Staggered (> 8 h)\t11 (6%)\t11 (64.7%)\t0 (0%)\t<0.001\t\n Unknown\t3 (1.6%)\t2 (11.8%)\t1 (0.6%)\t0.023\t\nTime to hospital in h\t6 [1, 1008]\t72 [1, 1008]\t6 [1, 84]\t<0.001\t\nIngested dose in g\t10.5 [4.5, 50]\t12 [4.5, 30]\t10.5 [4.5, 50]\t0.332\t\nCoingestants\t36 (19.6%)\t2 (11.8%)\t34 (20.4%)\t 0.532\t\n Alcohol\t10 (5.4%)\t2 (11.8%)\t8 (4.8%)\t0.233\t\n Other drug(s)\t28 (15.2%)\t0 (0%)\t28 (16.8%)\t0.080\t\nValues are presented as number (%) and median [range].\n\n* missing data 69%.\n\nClinical presentation and laboratory findings\nThe common symptoms reported at presentation were nausea/vomiting (66.8%) and abdominal pain (31.5%). Five patients, all of whom were cases of unintentional overdose, had jaundice. Laboratory data are summarized in Table 2. Most patients had serum AST, ALT, TB, Cr, PT, INR and complete blood count within the normal ranges throughout hospitalization. In those with documented hepatotoxicity, the peak AST and ALT levels were 15,616 IU/L and 7,726 IU/L respectively, with median duration of 10–18 (1–105) h after acute overdose. Eleven patients (6%) had AKI, with maximum Cr of 5.37 mg/dL. Comparison of the two groups showed that patients with unintentional overdose were more likely to have jaundice, hepatotoxicity and AKI, whereas those with intentional overdose were likely to have nausea and vomiting at presentation.\n\nTable 2. Clinical presentation, physical examination and laboratory data\n\tAll, n = 184\tUnintentional, n = 17\tIntentional, n = 167\tp-value\t\nClinical presentation\t\t\t\t\t\nAsymptomatic\t36 (19.6%)\t5 (29.4%)\t31 (18.6%)\t0.283\t\nNausea/vomiting\t123 (66.8%)\t8 (47.1%)\t115 (68.9%)\t0.102\t\nAbdominal pain\t58 (31.5%)\t6 (35.3%)\t52 (31.1%)\t0.786\t\nDizziness\t16 (8.7%)\t0 (0%)\t16 (9.6%)\t0.369\t\nDrowsiness\t10 (5.4%)\t2 (11.8%)\t8 (4.8%)\t0.233\t\nPhysical examination\t\t\t\t\t\nNormal\t120 (65.2%)\t6 (35.3%)\t114 (68.3%)\t0.007\t\nJaundice\t5 (2.7%)\t5 (29.4%)\t0 (0%)\t<0.001\t\nHepatomegaly\t1 (0.5%)\t1 (5.9%)\t0 (0%)\t0.092\t\nAbdominal pain\t59 (32.1%)\t6 (35.3%)\t53 (31.7%)\t0.788\t\nEncephalopathy\t1 (0.5%)\t1 (5.9%)\t0 (0%)\t0.092\t\nLaboratory findings\t\t\t\t\t\nPeak AST as U/L\t24 [12, 15616]\t899 [12, 15616]\t23 [12, 8615]\t0.001\t\nTime in h\t10.5 [1, 1018]\t78 [1, 1018]\t10 [1, 88]\t0.001\t\nPeak ALT as U/L\t19 [6, 7726]\t583 [9, 4945]\t18 [6, 7726]\t0.003\t\nTime in h\t10.5 [1, 1018]\t78 [1, 1018]\t10 [1, 105]\t0.001\t\nPeak INR\t1.13 [0.8, 6.14]\t1.79 [1.02, 5.24]\t1.12 [0.8, 6.14]\t0.001\t\nTime in h\t13 [1, 1009]\t85 [1, 1009]\t12 [1, 105]\t0.001\t\nPeak TB as mg/dL\t0.76 [0.1, 37.7]\t4.87 [0.25, 37.7]\t0.74 [0.1, 12.28]\t0.004\t\nTime in h\t14.5 [1, 1009]\t117 [1, 1009]\t13.5 [1, 134]\t0.003\t\nPeak creatinine as mg/dL\t0.64 [0.27, 5.37]\t0.93 [0.34, 5.37]\t0.63 [0.27, 4]\t0.013\t\nTime in h\t8 [1, 1009]\t90.5 [1, 1009]\t8 [1, 129]\t0.001\t\nPlatelet as /uL)\t286000 [16000, 523000]\t204000 [74000, 363000]\t288000 [16000, 523000]\t0.005\t\nHematocrit as %\t38.8 [25.6, 53.1]\t39 [31.1, 50.6]\t38.8 [25.6, 53.1]\t0.958\t\nAcute kidney injury\t11 (6%)\t6 (35.3%)\t5 (3%)\t<0.001\t\nValues are presented as number (%) and median [range].\n\nAbbreviations: AST, aspartate aminotransferase; ALT, alanine aminotransferase; TB, total bilirubin; INR, international normalized ratio.\n\nHospital management and clinical outcomes\nPatients with intentional APAP overdose underwent gastric lavage and activated charcoal administration, involving 70 (41%) and 71 (42.5%) cases respectively. Most patients (65.8%) had average interval from ingestion to N-acetylcysteine (NAC) administration of 10 (1–337) h and were treated with intravenous NAC. The average interval from hospital arrival to NAC administration was 2 (0.5–15) h. Serum for APAP concentration was obtained from 121 of 128 patients (94%) who presented <24 hours after ingestion. Fifty-nine patients had serum APAP concentration above the “treatment line” of the Rumack-Matthew Nomogram, and fifty-eight of these (98%) received NAC. Sixty-two patients had serum APAP concentration below the treatment line, and twenty-one of them (34%) received NAC (Fig. 1).\n\nFig. 1. Individual value plot: acetaminophen concentration versus time after single acute overdose.\nSloped lines are the “probable toxicity line” and the “treatment line” according to the Rumack-Matthew nomogram and corresponding to 200 and 500 µg/mL at 4 h post-ingestion respectively.\n\nIn terms of clinical outcomes, 132 of the 173 patients (76.3%) had no significant hepatotoxicity on admission. Overall, 27 patients (15.6%) developed mild hepatotoxicity, 11 (6.4%) developed severe hepatotoxicity, and 3 (1.7%) developed ALF (1 spontaneously resolved, and 2 deaths without liver transplant). Treatment outcome was unable to be documented in 11 patients in the intentional overdose group, due to entering and leaving the hospital within a very short period of time for personal reasons (e.g., refusing treatment or changing hospital). Patients with unintentional overdose were more likely to develop hepatotoxicity and ALF than those who had intentionally overdosed (Table 3). Among the 121 patients whose serum APAP concentration was documented, all patients who developed hepatotoxicity had serum APAP concentration above the treatment line of the Rumack-Matthew Nomogram (Fig. 1).\n\nTable 3. Hospital management and outcomes\n\tAll, n = 184\tUnintentional, n = 17\tIntentional, n = 167\tp-value\t\nTreatment\t\t\t\t\t\nGastric lavage\t70 (38%)\t0 (0%)\t70 (41.9%)\t<0.001\t\nActivated charcoal\t71 (38.6%)\t0 (0%)\t71 (42.5%)\t<0.001\t\nIntravenous NAC\t121 (65.8%)\t12 (70.6%)\t109 (65.3%)\t0.792\t\nIngestion-to-NAC time in h\t10 [1, 337]\t78 [9, 337]\t9 [1, 93]\t<0.001\t\nVisit-to-NAC time in h\t2 [0.5, 15]\t4 [0.5, 15]\t2 [0.5, 11]\t0.034\t\nAcetaminophen level as mcg/mL\t50.3 [0, 335.3]\t17.8 [0, 218.3]\t57.65 [0, 335.3]\t0.002\t\nTime in h\t7 [1, 1018]\t76.5 [1, 1018]\t7 [1, 87]\t<0.001\t\nOutcome\t\t\t\t\t\nNo hepatotoxic injury\t132/173 (76.3%)\t6/17 (35.3%)\t126/156 (80.8%)\t0.001\t\nMild hepatotoxic injury\t27/173 (15.6%)\t5/17 (29.4%)\t22/156 (14.1%)\t0.140\t\nSevere hepatotoxic injury\t11/173 (6.4%)\t3/17 (17.6%)\t8/156 (5.1%)\t0.068\t\nAcute liver failure\t3/173 (1.7%)\t3/17 (17.6%)\t0/156 (0%)\t0.001\t\nDeath\t2/173 (1.2%)\t2/17 (11.8%)\t0/156 (0%)\t0.008\t\nValues presented as number (%) and median [range].\n\nAbbreviation: NAC, N-acetylcysteine.\n\nPredictive factors for APAP-induced hepatotoxicity\nBased on univariate logistic regression analysis, significant predictors of APAP-induced hepatotoxicity included older age, male gender, chronic alcohol drinking, unintentional overdose, staggered ingestion, alcohol coingestion, late presentation, and presence of abdominal pain. Patients with hepatotoxicity more frequently developed AKI (17.1% vs. 3% respectively) and required longer hospital stay (5 days vs. 1 day respectively) compared to those without it (Table 4). Significant predictors of severe hepatotoxicity included older age, chronic alcohol drinking, underlying cirrhosis, unintentional overdose, staggered ingestion, alcohol coingestion, late presentation, and presence of abdominal pain and jaundice. Patients with hepatotoxicity more frequently developed AKI (42.9% vs. 3.1% respectively) and required longer hospital stay (7.5 days vs. 2 days, respectively) than those without it (Table 5). Multivariate analysis did not identify any significant independent predictors of hepatotoxicity, whereas the presence of abdominal pain was an independent predictor of severe hepatotoxicity (adjusted odds ratio: 12.61, 95% confidence interval: 1.91–83.27; p=0.009).\n\nTable 4. Univariate logistic regression analysis: predictive factors of APAP-induced hepatotoxicity\n\tNo hepatotoxicity, n = 132\tHepatotoxicity, n = 41\tOR (95%CI)\tp-value\t\nAge in years\t21 [15, 76]\t26 [16, 50]\t1.05 (1.01, 1.09)\t0.007\t\nFemale gender\t110 (83.3%)\t27 (65.9%)\t0.39 (0.18, 0.85)\t0.018\t\nChronic alcohol drinker\t1 (0.8%)\t8 (19.5%)\t4.42 (3.01, 6.48)\t<0.001*\t\nUnderlying cirrhosis\t0 (0%)\t2 (4.9%)\t4.38 (3.33, 5.78)\t0.055\t\nIntentional overdose\t126 (95.5%)\t30 (73.2%)\t0.3 (0.18, 0.48)\t<0.001*\t\nUnintentional overdose\t6 (4.5%)\t11 (26.8%)\t3.36 (2.09, 5.42)\t<0.001*\t\nAcute ingestion\t129 (97.7%)\t30 (73.2%)\t0.24 (0.16, 0.37)\t<0.001*\t\nStaggered ingestion\t3 (2.3%)\t8 (19.5%)\t3.57 (2.22, 5.73)\t0.001*\t\nIngested dose in g\t10 [4.5, 50]\t15 [4.5, 50]\t1.03 (1, 1.06)\t0.079\t\nTime to hospital in h\t5 [1, 96]\t37 [1, 1008]\t1.05 (1.03, 1.07)\t<0.001*\t\nAlcohol coingestion\t4 (3%)\t5 (12.2%)\t4.44 (1.13, 17.42)\t0.032*\t\nAbdominal pain\t38 (28.8%)\t20 (48.8%)\t2.36 (1.15, 4.84)\t0.019*\t\nAcute kidney injury\t4 (3%)\t7 (17.1%)\t6.63 (1.83, 24.01)\t0.004*\t\nGastric lavage\t60 (45.5%)\t6 (14.6%)\t0.21 (0.08, 0.52)\t0.001*\t\nActivated charcoal\t62 (47%)\t6 (14.6%)\t0.19 (0.08, 0.49)\t0.001*\t\nIntravenous NAC\t82 (62.1%)\t38 (92.7%)\t7.72 (2.26, 26.34)\t0.001*\t\nTime from ingestion to NAC\t8.5 [1, 100]\t40 [6, 337]\t1.08 (1.04, 1.11)\t<0.001*\t\nLength of stay in days\t1 [1, 5]\t5 [1, 21]\t2.57 (1.84, 3.57)\t<0.001*\t\nValues are presented as number (%) and median [range].\n\nAbbreviations: CI, confidence interval; NAC, N-acetylcysteine; OR, odds ratio.\n\nTable 5. Univariate logistic regression analysis: predictive factors of APAP-induced severe hepatotoxicity\n\tNo severe hepatotoxicity,* n = 159\tSevere hepatotoxicity, ** n = 14\tOR (95%CI)\tp-value\t\nAge in years\t21 [15, 76]\t33.5 [18, 50]\t1.08 (1.03, 1.13)\t0.001*\t\nFemale gender\t131 (78.9%)\t11 (78.6%)\t0.98 (0.24, 5.76)\t1.0\t\nChronic alcohol drinker\t2 (1.3%)\t7 (50%)\t18.22 (8.15, 40.74)\t<0.001*\t\nUnderlying cirrhosis\t0 (0%)\t2 (14.3%)\t14.25 (8.26, 24.59)\t0.006*\t\nIntentional overdose\t148 (93.1%)\t8 (57.1%)\t0.15 (0.06, 0.37)\t0.001*\t\nUnintentional overdose\t11 (6.9%)\t6 (42.9%)\t6.88 (2.71, 17.49)\t0.001*\t\nAcute ingestion\t151 (95%)\t8 (57.1%)\t0.12 (0.05, 0.29)\t<0.001*\t\nStaggered ingestion\t7 (4.4%)\t4 (28.6%)\t5.89 (2.2, 15.79)\t0.007*\t\nAlcohol coingestion\t6 (3.8%)\t3 (21.4%)\t6.95 (1.53, 31.64)\t0.012*\t\nAbdominal pain\t49 (30.8%)\t9 (64.3%)\t4.04 (1.29, 12.68)\t0.017*\t\nAcute kidney injury\t5 (3.1%)\t6 (42.9%)\t22.5 (5.64, 89.76)\t<0.001*\t\nGastric lavage\t62 (39%)\t4 (28.6%)\t0.63 (0.19, 2.08)\t0.445\t\nActivated charcoal\t65 (40.9%)\t3 (21.4%)\t0.39 (0.11, 1.47)\t0.166\t\nIntravenous NAC\t106 (66.7%)\t14 (100%)\tNA\t0.997\t\nTime from ingestion to NAC\t9 [1, 337]\t56 [11, 111]\t1.02 (1, 1.03)\t0.034*\t\nLength of stay in days\t2 [1, 21]\t7.5 [3, 14]\t1.4 (1.2, 1.62)\t<0.001*\t\nValues are presented as number (%) and median [range].\n\nAbbreviations: CI, confidence interval; NAC, N-acetylcysteine; OR, odds ratio.\n\nDiscussion\nOur study comprehensively depicted the patient characteristics, patterns, and outcomes of APAP overdose in Thailand. Rajavithi Hospital is a referral hospital under the Ministry of Public Health of Thailand, located in central Bangkok, and the authors believe that the clinical characteristics of patients included in this study can be a good representation of APAP overdose patients who present at secondary/tertiary medical centers in Bangkok. Similar to the findings of previous reports from Asia-Pacific regions (e.g., Singapore,10 Malaysia,9 and Australia)14 the majority of APAP overdose cases were female (80%) with an average age of 22–25 years, and up to 90% of cases were deliberate overdose with the intent of self-harm. Histories of chronic alcohol drinking, substance coingestion, and significant medical comorbidities were relatively uncommon in this study, and this is in keeping with the results of other reports from the Asia-Pacific region.9,10,14\n\nNotably, patient characteristics and patterns of acute overdose in this study are somewhat different from those reported from Western countries. In the USA, national surveillance systems assessed rates of APAP-related events identified in different settings, including calls to poison centers, emergency department visits, and in-patient hospitalizations, and estimated that the prevalence of female gender with APAP overdose was 62–69%, and that 16–67% of cases were unintentional overdoses.15 A higher prevalence of unintentional APAP overdose among all cases has also been observed in European countries.16 In addition, substance coingestion seems to be more common in Western countries than in Asia-Pacific ones.15,16\n\nOn presentation, abdominal symptoms, most commonly nausea and vomiting, were reported in more than 60% of cases. Interestingly, abdominal pain corresponding with mild abdominal tenderness, either at the epigastric (most cases) or right upper quadrant area, was observed in about 32% of our patients with acute overdose and appeared to be associated with the subsequent development of APAP-induced hepatotoxicity (2.4-fold increased risk); to the best of our knowledge, this observation has never been previously reported elsewhere. The exact explanation is unclear but abdominal pain may be related to gastric irritation or inflammation induced by APAP exposure at higher doses, or, in rare instances, may be related to distension of the liver capsule associated with hepatocyte injury. Although this observation needs to be confirmed in future studies, the presence of abdominal pain could be another simple clinical predictor of APAP-induced hepatotoxicity, particularly when the ingested dose is uncertain and serum APAP is not readily available.\n\nOf patients with intentional overdose, only 14.1% and 5.1% developed mild or severe hepatotoxicity respectively. There was no incidence of ALF or death. Notably, 8 patients who developed severe hepatotoxicity from intentional overdose came to the hospital late after ingestion, and only 2 received NAC therapy within 24 h. The good outcomes in this group of patients may be due to: (1) patient characteristics, including young age, lack of underlying liver disease, and early presentation to the hospital (median time 6 h from ingestion); and (2) hospital management, particularly prompt NAC therapy (median time of not >2 h after presentation). In cases of unintentional overdose, 35.3%, 29.4%, and 17.6% of patients developed mild hepatotoxicity, ALF, or died respectively. The poorer outcomes in this group may be mainly due to comorbidities and late presentation to the hospital (many of the patients came to the hospital when evident hepatotoxicity had already developed).\n\nThe differences between the characteristics of patients with intentional versus unintentional APAP overdose were similar to those in previous reports.5,8,17 It should be noted that the overall incidence of severe APAP-induced hepatotoxicity among patients with APAP overdose in our cohort (6.4%) was quite low compared to other reports worldwide: 31% in UK (n = 80)6; 32% in Texas, USA (n = 71)8; 15% in multi-states, USA (n = 157)7; 14% in Australia (n = 188)18; 7.3% in Malaysia (n = 1024)9; 5.6% in Singapore (n = 177)10; and 6% in Hong Kong (n = 104).19 Although the definition of severe hepatotoxicity may vary in different studies, it appears that the incidence of APAP-induced hepatotoxicity among patients with APAP overdose is lower in Asia than in Western countries. One possible explanation for this observation is the difference in the total dose of APAP ingestion, mostly with intent of self-harm, which was higher among studies from the UK and USA (median: 15–18 g)6–8 than in studies from Asia-Pacific regions (median 10–12 g).9,10,18,19\n\nApart from overdose intention, several other factors have been found to predict the subsequent development of hepatotoxicity, including older age, chronic alcohol drinking, staggered ingestion, long duration between ingestion and hospital visit, alcohol coingestion, abdominal pain symptoms, and AKI. These factors, with the exception of abdominal pain (discussed above), have been found to be associated with APAP-induced hepatotoxicity.2,9,17,20 The interaction between ethanol, a competitive substrate of CYP2E1, and APAP is complex. Acute alcohol ingestion is not a risk factor for APAP hepatotoxicity and may actually be protective by competing with APAP for CYP2E1.20,21 Chronic alcohol ingestion potentiates APAP-induced hepatotoxicity by up-regulating CYP2E1 and decreasing glutathione synthesis. Most available data have concluded that chronic alcohol consumption is associated with an increased risk of APAP-induced hepatotoxicity in patients with repeated overdoses (mostly therapeutic misadventure), particularly in those who have underlying cirrhosis; however, alcoholics do not seem to be at an increased risk of hepatotoxicity at a therapeutic dose or in a single overdose setting.2,21,22 Nonetheless, our study found that both acute and chronic alcohol drinking were risk factors of APAP-induced hepatotoxicity.\n\nAccording to recent guidelines for the management of APAP poisoning in Australia and New Zealand, APAP concentration should be used to assess the need for NAC administration in all patients presenting with deliberate self-poisoning with APAP, regardless of the stated dose.23 In this study, serum was obtained for measuring APAP concentration from 94% of patients who presented within 24 h after ingestion and from 58 of 59 patients (98%) who had APAP concentrations above the treatment line who had received NAC therapy (all intravenously). All patients who developed hepatotoxicity had serum APAP concentration levels above the treatment line, supporting the recommendation of the use of APAP concentration and the Rumack-Matthew Nomogram for NAC treatment justification in Thai populations. Notably, NAC therapy tended to be overutilized in our hospital, as 21 of 62 patients (34%) who had serum APAP concentration below the treatment line also received NAC. In addition, anaphylactoid reaction was observed in only 2/121 patients (1.7%) in this study, which appeared to be much lower than in previous literature (10–20%).2\n\nThis study had several limitations, including its retrospective nature, its single-center design and relatively small number of patients, especially in the unintentional overdose group. It is also possible that the total dose of APAP intake estimated by the patients could have been inaccurate, and data on the amount of alcohol consumption was not clearly documented (missing or incomplete) in 69% of patients. Furthermore, utilization of the Roussel Uclaf Causality Assessment Method (referred to as RUCAM) and biomarkers would have helped to improve the causality assessment in suspected cases of hepatotoxicity from drugs, including APAP.24,25 However, the RUCAM scale was not performed routinely for diagnosis of APAP hepatotoxicity in this study. In future cases, the prospective use of the updated RUCAM is recommended in order to harmonize the causality assessment of drug- and herb-induced liver injury.26 Despite these limitations, we did our best to complete the data collection and analysis. It should be noted that this retrospective study has detailed data on the clinical progression of patients, particularly in the hepatotoxicity aspect, and we believe that these data provide valuable insights and may be used as a reference in future related research.\n\nIn conclusion, most cases of APAP overdose in Thailand appeared to be young women with intentional ingestion. With prompt management, most patients did not develop significant hepatotoxicity. Even so, despite NAC therapy, hepatotoxicity, including ALF, was observed in a small proportion of patients, and clinical predictors included unintentional overdose, staggered ingestion, older age, chronic alcohol drinking, late presentation, and having abdominal pain.\n\nAbbreviations\nAKIacute kidney injury\n\nALFacute liver failure\n\nAPAPacetaminophen\n\nALTalanine aminotransferase\n\nASTaspartate aminotransferase\n\nCrcreatinine\n\nCYPcytochrome\n\nINRinternational normalized ratio\n\nNACN-acetylcysteine\n\nPTprothrombin time\n\nRUCAMRoussel Uclaf Causality Assessment Method\n\nTBtotal bilirubin\n\nxULNtimes higher than the upper limit of normal\n==== Refs\nReferences\n1 Lee WM Acetaminophen and the U.S. Acute Liver Failure Study Group: lowering the risks of hepatic failure Hepatology 2004 40 6 9 10.1002/hep.20293 15239078 \n2 Bunchorntavakul C Reddy KR Acetaminophen-related hepatotoxicity Clin Liver Dis 2013 17 587 607 10.1016/j.cld.2013.07.005 24099020 \n3 Bunchorntavakul C Reddy KR Acetaminophen (APAP or N-Acetyl-p-Aminophenol) and acute liver failure Clin Liver Dis 2018 22 325 346 10.1016/j.cld.2018.01.007 29605069 \n4 Wang R Qi X Yoshida EM Méndez-Sánchez N Teschke R Sun M Clinical characteristics and outcomes of traditional Chinese medicine-induced liver injury: a systematic review Expert Rev Gastroenterol Hepatol 2018 12 425 434 10.1080/17474124.2018.1427581 29323538 \n5 Larson AM Polson J Fontana RJ Davern TJ Lalani E Hynan LS Acetaminophen-induced acute liver failure: results of a United States multicenter, prospective study Hepatology 2005 42 1364 1372 10.1002/hep.20948 16317692 \n6 Hawton K Ware C Mistry H Hewitt J Kingsbury S Roberts D Paracetamol self-poisoning. Characteristics, prevention and harm reduction Br J Psychiatry 1996 168 43 48 10.1192/bjp.168.1.43 8770427 \n7 James LP Capparelli EV Simpson PM Letzig L Roberts D Hinson JA Acetaminophen-associated hepatic injury: evaluation of acetaminophen protein adducts in children and adolescents with acetaminophen overdose Clin Pharmacol Ther 2008 84 684 690 10.1038/clpt.2008.190 18923390 \n8 Schiødt FV Rochling FA Casey DL Lee WM Acetaminophen toxicity in an urban county hospital N Engl J Med 1997 337 1112 1117 10.1056/NEJM199710163371602 9329933 \n9 Marzilawati AR Ngau YY Mahadeva S Low rates of hepatotoxicity among Asian patients with paracetamol overdose: a review of 1024 cases BMC Pharmacol Toxicol 2012 13 8 10.1186/2050-6511-13-8 23021009 \n10 Tan CJ Sklar GE Characterisation and outcomes of adult patients with paracetamol overdose presenting to a tertiary hospital in Singapore Singapore Med J 2017 58 695 702 10.11622/smedj.2016170 27752704 \n11 Koch DG Speiser JL Durkalski V Fontana RJ Davern T McGuire B The natural history of severe acute liver injury Am J Gastroenterol 2017 112 1389 1396 10.1038/ajg.2017.98 28440304 \n12 Wendon J Cordoba J Dhawan A Larsen FS Manns M Samuel D EASL Clinical Practical Guidelines on the management of acute (fulminant) liver failure J Hepatol 2017 66 1047 1081 10.1016/j.jhep.2016.12.003 28417882 \n13 Khwaja A KDIGO clinical practice guidelines for acute kidney injury Nephron Clin Pract 2012 120 c179 c184 10.1159/000339789 22890468 \n14 Singer AJ Carracio TR Mofenson HC The temporal profile of increased transaminase levels in patients with acetaminophen-induced liver dysfunction Ann Emerg Med 1995 26 49 53 10.1016/S0196-0644(95)70237-7 7793720 \n15 Major JM Zhou EH Wong HL Trinidad JP Pham TM Mehta H Trends in rates of acetaminophen-related adverse events in the United States Pharmacoepidemiol Drug Saf 2016 25 590 598 10.1002/pds.3906 26530380 \n16 Tittarelli R Pellegrini M Scarpellini MG Marinelli E Bruti V di Luca NM Hepatotoxicity of paracetamol and related fatalities Eur Rev Med Pharmacol Sci 2017 21 95 101 \n17 Lee WM Acetaminophen (APAP) hepatotoxicity-Isn’t it time for APAP to go away? J Hepatol 2017 67 1324 1331 10.1016/j.jhep.2017.07.005 28734939 \n18 Ayonrinde OT Phelps GJ Hurley JC Ayonrinde OA Paracetamol overdose and hepatotoxicity at a regional Australian hospital: a 4-year experience Intern Med J 2005 35 655 660 10.1111/j.1445-5994.2005.00947.x 16248859 \n19 Chan TY Chan AY Critchley JA Paracetamol poisoning and hepatotoxicity in Chinese–the Prince of Wales Hospital (Hong Kong) experience Singapore Med J 1993 34 299 302 8266197 \n20 Lee WM Drug-induced hepatotoxicity N Engl J Med 2003 349 474 485 10.1056/NEJMra021844 12890847 \n21 Schmidt LE Dalhoff K Poulsen HE Acute versus chronic alcohol consumption in acetaminophen-induced hepatotoxicity Hepatology 2002 35 876 882 10.1053/jhep.2002.32148 11915034 \n22 Kuffner EK Dart RC Bogdan GM Hill RE Casper E Darton L Effect of maximal daily doses of acetaminophen on the liver of alcoholic patients: a randomized, double-blind, placebo-controlled trial Arch Intern Med 2001 161 2247 2252 10.1001/archinte.161.18.2247 11575982 \n23 Chiew AL Fountain JS Graudins A Isbister GK Reith D Buckley NA Summary statement: new guidelines for the management of paracetamol poisoning in Australia and New Zealand Med J Aust 2015 203 215 218 10.5694/mja15.00614 26852051 \n24 Teschke R Schulze J Eickhoff A Danan G Drug induced liver injury: Can biomarkers assist RUCAM in causality assessment? Int J Mol Sci 2017 18 803 10.3390/ijms18040803 \n25 Teschke R Zhu Y Paracetamol (acetaminophen), alcohol and liver injury: Biomarkers, clinical issues, and experimental aspects SL Pharmacology and Toxicology 2018 1 131 \n26 Danan G Teschke R RUCAM in drug and herb induced liver injury: The update Int J Mol Sci 2015 17 14 10.3390/ijms17010014\n\n",
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"issue": "7(2)",
"journal": "Journal of clinical and translational hepatology",
"keywords": "Acetaminophen; Drug-induced hepatotoxicity; Liver failure; Overdose; Paracetamol",
"medline_ta": "J Clin Transl Hepatol",
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"title": "Characteristics and Outcomes of Acetaminophen Overdose and Hepatotoxicity in Thailand.",
"title_normalized": "characteristics and outcomes of acetaminophen overdose and hepatotoxicity in thailand"
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"abstract": "Nosocomial Klebsiella pneumoniae infection is associated with a high mortality in neonates and antimicrobial therapy of these infections has been complicated by the emergence of multiresistant strains. These organisms remain susceptible to only a few antimicrobial agents, and some of these are not recommended for use in children. In this study the antimicrobial agents used in the treatment of 33 neonates with Klebsiella pneumoniae (K. pneumonia) infection in our tertiary neonatal unit, during an outbreak were: piperacillin/tazobactam (13), imipenem/cilastatin (17), cefotaxime (2), and ciprofloxacin (1). Extended-spectrum beta-lactamase production was detected in K. pneumoniae isolates from 18 of 33 (54.5%) neonates. All-cause mortality was 13 of 33 (39.4%) and there was no significant difference in mortality between neonates treated with imipenem/cilastatin (6 of 17 or 35.3%) and neonates treated with piperacillin/tazobactam (6 of 13 or 46.2%). The duration of antimicrobial therapy and total hospital stay was similar between neonates who received imipenem/cilastatin and those that received piperacillin/tazobactam. This report suggests that piperacillin/tazobactam may be a useful antimicrobial agent in neonatal infections caused by beta-lactamase-producing organisms.",
"affiliations": "Department of Paediatrics, University of Natal, South Africa.",
"authors": "Pillay|T|T|;Pillay|D G|DG|;Adhikari|M|M|;Sturm|A W|AW|",
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"mesh_terms": "D000890:Anti-Infective Agents; D015377:Cilastatin; D002939:Ciprofloxacin; D003428:Cross Infection; D004338:Drug Combinations; D004352:Drug Resistance, Microbial; D018432:Drug Resistance, Multiple; D004791:Enzyme Inhibitors; D005260:Female; D006801:Humans; D015378:Imipenem; D007231:Infant, Newborn; D007710:Klebsiella Infections; D007711:Klebsiella pneumoniae; D008297:Male; D008826:Microbial Sensitivity Tests; D010397:Penicillanic Acid; D010406:Penicillins; D010878:Piperacillin; D011480:Protease Inhibitors; D012189:Retrospective Studies; D000078142:Tazobactam; D013845:Thienamycins; D065093:beta-Lactamase Inhibitors",
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"title": "Piperacillin/tazobactam in the treatment of Klebsiella pneumoniae infections in neonates.",
"title_normalized": "piperacillin tazobactam in the treatment of klebsiella pneumoniae infections in neonates"
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"literaturereference": "PILLAY, T.. PIPERACILLIN/TAZOBACTAM IN THE TREATMENT OF KLEBSIELLA PNEUMONIAE INFECTIONS IN NEONATES. AMERICAN JOURNAL OF PERINATOLOGY. 1998?15 (1):47?51",
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{
"abstract": "A syndrome of low renin hypertension in childhood with apparent mineralocorticoid excess associated with a defect in the peripheral metabolism of cortisol has been described previously in 2 patients. In these patients, decreased secretion rates of glucocorticoids, mineralocorticoids, and sex steroids have been demonstrated. In a 10(10/12)-yr-old girl with this disorder, continuous iv administration of hydrocortisone in doses of 5, 10, 15, and 20 mg/day resulted in an increase in blood pressure and a decrease in serum potassium concentration. The addition of spironolactone during the continued administration of 20 mg/day hydrocortisone did not result in a decrease in blood pressure. Withdrawal of hydrocortisone and continued administration of spironolactone alone resulted in a decrease in blood pressure, a rise in serum potassium concentration, and a fall in serum sodium concentrations. These studies suggest that an abnormality in cortisol action or metabolism causing cortisol to behave as a potent mineralocorticoid may account for this syndrome of apparent mineralocorticoid excess.",
"affiliations": null,
"authors": "Oberfield|S E|SE|;Levine|L S|LS|;Carey|R M|RM|;Greig|F|F|;Ulick|S|S|;New|M I|MI|",
"chemical_list": "D006914:Hydroxysteroids; D008901:Mineralocorticoids; D013148:Spironolactone; D000450:Aldosterone; D000324:Adrenocorticotropic Hormone; D012083:Renin; D011188:Potassium; D006854:Hydrocortisone; D008797:Metyrapone",
"country": "United States",
"delete": false,
"doi": "10.1210/jcem-56-2-332",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0021-972X",
"issue": "56(2)",
"journal": "The Journal of clinical endocrinology and metabolism",
"keywords": null,
"medline_ta": "J Clin Endocrinol Metab",
"mesh_terms": "D000324:Adrenocorticotropic Hormone; D000450:Aldosterone; D001794:Blood Pressure; D002648:Child; D005260:Female; D006801:Humans; D006854:Hydrocortisone; D006914:Hydroxysteroids; D006973:Hypertension; D008797:Metyrapone; D008901:Mineralocorticoids; D011188:Potassium; D012083:Renin; D013148:Spironolactone; D013577:Syndrome",
"nlm_unique_id": "0375362",
"other_id": null,
"pages": "332-9",
"pmc": null,
"pmid": "6296185",
"pubdate": "1983-02",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't; D013487:Research Support, U.S. Gov't, P.H.S.",
"references": null,
"title": "Metabolic and blood pressure responses to hydrocortisone in the syndrome of apparent mineralocorticoid excess.",
"title_normalized": "metabolic and blood pressure responses to hydrocortisone in the syndrome of apparent mineralocorticoid excess"
} | [
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] |
{
"abstract": "Allopurinol, a common drug for treating hyperuricemia, is associated with cutaneous adverse drug reactions ranging from mild maculopapular exanthema to life-threatening severe cutaneous adverse reactions, including drug reaction with eosinophilia and systemic symptoms, Stevens-Johnson syndrome, and toxic epidermal necrolysis. We have previously reported that HLA-B*58:01 is strongly associated with allopurinol-induced severe cutaneous adverse reactions in Han Chinese, but the associations of the HLA-B*58:01 genotype in an allopurinol-induced hypersensitivity phenotype remain unclear. To investigate the comprehensive associations of HLA-B*58:01, we enrolled 146 patients with allopurinol-induced cutaneous adverse drug reactions (severe cutaneous adverse reactions, n = 106; maculopapular exanthema, n = 40) and 285 allopurinol-tolerant control subjects. Among these allopurinol-induced cutaneous adverse drug reactions, HLA-B*58:01 was strongly associated with severe cutaneous adverse reactions (odds ratio [OR] = 44.0; 95% confidence interval = 21.5-90.3; P = 2.6 × 10(-41)), and the association was correlated with disease severity (OR = 44.0 for severe cutaneous adverse reactions, OR = 8.5 for maculopapular exanthema). The gene dosage effect of HLA-B*58:01 also influenced the development of allopurinol-induced cutaneous adverse drug reactions (OR = 15.25 for HLA-B*58:01 heterozygotes and OR = 72.45 for homozygotes). Furthermore, coexistence of HLA-B*58:01 and renal impairment increased the risk and predictive accuracy of allopurinol-induced cutaneous adverse drug reactions (heterozygous HLA-B*58:01 and normal renal function: OR = 15.25, specificity = 82%; homozygous HLA-B*58:01 and severe renal impairment: OR = 1269.45, specificity = 100%). This HLA-B*58:01 correlation study suggests that patients with coexisting HLA-B*58:01 and renal impairment (especially estimated glomerular filtration rate < 30ml/minute/1.73 m(2)) should be cautious and avoid using allopurinol.",
"affiliations": "Department of Dermatology, Drug Hypersensitivity Clinical and Research Center, Chang Gung Memorial Hospital, Taipei, Linko and Keelung, Taiwan; School of Medicine, College of Medicine, Chang Gung University, Taoyuan, Taiwan.;Department of Dermatology, Drug Hypersensitivity Clinical and Research Center, Chang Gung Memorial Hospital, Taipei, Linko and Keelung, Taiwan; School of Medicine, College of Medicine, Chang Gung University, Taoyuan, Taiwan.;Department of Dermatology, Drug Hypersensitivity Clinical and Research Center, Chang Gung Memorial Hospital, Taipei, Linko and Keelung, Taiwan; Chang Gung Immunology Consortium, Chang Gung Memorial Hospital and Chang Gung University, Taoyuan, Taiwan.;Institute of Pharmacology, School of Medicine, National Yang-Ming University, Taipei, Taiwan.;Department of Dermatology, Drug Hypersensitivity Clinical and Research Center, Chang Gung Memorial Hospital, Taipei, Linko and Keelung, Taiwan; School of Medicine, College of Medicine, Chang Gung University, Taoyuan, Taiwan.;Department of Dermatology, Drug Hypersensitivity Clinical and Research Center, Chang Gung Memorial Hospital, Taipei, Linko and Keelung, Taiwan; School of Medicine, College of Medicine, Chang Gung University, Taoyuan, Taiwan.;Institute of Pharmacology, School of Medicine, National Yang-Ming University, Taipei, Taiwan.;Graduate Institute of Clinical Medical Science, Clinical Informatics and Medical Statistics Research Center, Chang Gung University, Taoyuan, Taiwan; Biostatistical Center for Clinical Research, Chang Gung Memorial Hospital, Linkou, Taiwan.;Graduate Institute of Clinical Medical Science, Clinical Informatics and Medical Statistics Research Center, Chang Gung University, Taoyuan, Taiwan; Biostatistical Center for Clinical Research, Chang Gung Memorial Hospital, Linkou, Taiwan.;Department of Dermatology, Drug Hypersensitivity Clinical and Research Center, Chang Gung Memorial Hospital, Taipei, Linko and Keelung, Taiwan; Whole-Genome Research Core Laboratory of Human Diseases, Chang Gung Memorial Hospital, Keelung, Taiwan.;Whole-Genome Research Core Laboratory of Human Diseases, Chang Gung Memorial Hospital, Keelung, Taiwan.;Department of Rheumatology, Taichung Veterans General Hospital, Taichung, Taiwan.;School of Medicine, College of Medicine, Chang Gung University, Taoyuan, Taiwan; Division of Allergy, Immunology and Rheumatology, Department of Medicine, Chang Gung Memorial Hospital, Keelung, Taiwan.;Department of Nephrology, Kidney Research Center, Chang Gung Memorial Hospital, Chang Gung University, Taoyuan, Taiwan.;Department of Dermatology, Drug Hypersensitivity Clinical and Research Center, Chang Gung Memorial Hospital, Taipei, Linko and Keelung, Taiwan; School of Medicine, College of Medicine, Chang Gung University, Taoyuan, Taiwan. Electronic address: ba1128@adm.cgmh.org.tw.;Department of Dermatology, Drug Hypersensitivity Clinical and Research Center, Chang Gung Memorial Hospital, Taipei, Linko and Keelung, Taiwan; School of Medicine, College of Medicine, Chang Gung University, Taoyuan, Taiwan; Chang Gung Immunology Consortium, Chang Gung Memorial Hospital and Chang Gung University, Taoyuan, Taiwan; Whole-Genome Research Core Laboratory of Human Diseases, Chang Gung Memorial Hospital, Keelung, Taiwan. Electronic address: wenhungchung@yahoo.com.",
"authors": "Ng|Chau Yee|CY|;Yeh|Yu-Ting|YT|;Wang|Chuang-Wei|CW|;Hung|Shuen-Iu|SI|;Yang|Chih-Hsun|CH|;Chang|Ya-Ching|YC|;Chang|Wan-Chun|WC|;Lin|Yu-Jr|YJ|;Chang|Chee-Jen|CJ|;Su|Shih-Chi|SC|;Fan|Wen-Lang|WL|;Chen|Der-Yuan|DY|;Wu|Yeong-Jian Jan|YJ|;Tian|Ya-Chung|YC|;Hui|Rosaline Chung-Yee|RC|;Chung|Wen-Hung|WH|;|||",
"chemical_list": "D015235:HLA-B Antigens; C500126:HLA-B*58:01 antigen; D000493:Allopurinol",
"country": "United States",
"delete": false,
"doi": "10.1016/j.jid.2016.02.808",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0022-202X",
"issue": "136(7)",
"journal": "The Journal of investigative dermatology",
"keywords": null,
"medline_ta": "J Invest Dermatol",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D000493:Allopurinol; D002648:Child; D002681:China; D003875:Drug Eruptions; D004802:Eosinophilia; D005076:Exanthema; D005260:Female; D005838:Genotype; D005919:Glomerular Filtration Rate; D015235:HLA-B Antigens; D006720:Homozygote; D006801:Humans; D033461:Hyperuricemia; D007668:Kidney; D008297:Male; D008875:Middle Aged; D016017:Odds Ratio; D012372:ROC Curve; D012306:Risk; D012680:Sensitivity and Specificity; D012867:Skin; D013262:Stevens-Johnson Syndrome; D055815:Young Adult",
"nlm_unique_id": "0426720",
"other_id": null,
"pages": "1373-1381",
"pmc": null,
"pmid": "26996548",
"pubdate": "2016-07",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Impact of the HLA-B(*)58:01 Allele and Renal Impairment on Allopurinol-Induced Cutaneous Adverse Reactions.",
"title_normalized": "impact of the hla b 58 01 allele and renal impairment on allopurinol induced cutaneous adverse reactions"
} | [
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"companynumb": "TW-SEBELA IRELAND LIMITED-2016SEB01455",
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"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ALLOPURINOL"
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"reaction": [
{
"reactionmeddrapt": "Drug reaction with eosinophilia and systemic symptoms",
"reactionmeddraversionpt": "19.1",
"reactionoutcome": "5"
},
{
"reactionmeddrapt": "Stevens-Johnson syndrome",
"reactionmeddraversionpt": "19.1",
"reactionoutcome": "5"
},
{
"reactionmeddrapt": "Toxic epidermal necrolysis",
"reactionmeddraversionpt": "19.1",
"reactionoutcome": "5"
}
],
"summary": null
},
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"literaturereference": "NG CY, YEH Y-T, WANG C-W, ET AL.. IMPACT OF THE HLA-B*58:01 ALLELE AND RENAL IMPAIRMENT ON ALLOPURINOL-INDUCED CUTANEOUS ADVERSE REACTIONS. J INVEST DERMATOL (DOI: 10.1016/J.JID.2016.02.808). 2016;136:1373-1381",
"literaturereference_normalized": "impact of the hla b 58 01 allele and renal impairment on allopurinol induced cutaneous adverse reactions",
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"reportercountry": "TW"
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"receiptdate": "20160906",
"receivedate": "20160906",
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"receiverorganization": "FDA",
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"seriousnessdeath": 1,
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"seriousnesshospitalization": null,
"seriousnesslifethreatening": null,
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"transmissiondate": "20161109"
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{
"abstract": "BACKGROUND\nWe present an unusual bleeding complication in a patient with severe acute respiratory distress syndrome in coronavirus disease 2019.\n\n\nMETHODS\nThe patient, a 63-year-old Caucasian man, received venovenous extracorporeal membrane oxygenation support after rapid deterioration of lung function on day 6 after admission to hospital. After initial stabilization on lung protective ventilation and prone positioning, he started to develop mild bleeding complications until he went into occult profound hemorrhagic shock. Causative was a massive hemothorax of the right hemithorax with mediastinal shifting due to spontaneous bleeding from a pulmonal artery in a heavily remodeled right inferior lobe. Histopathological examination of the resected tissue showed signs of an organizing fibrinous pneumonia with focal parenchyma necrosis. After surviving a massive bleeding event caused by necrotizing pneumonia, the patient made a swift recovery and was discharged to rehabilitation 31 days after initial hospital admission.\n\n\nCONCLUSIONS\nThe combination of severely elevated inflammatory markers and pulmonary hemorrhage should arouse suspicion of necrotizing pneumonia. In necrotizing pneumonia, the possibility of severe intrathoracic bleeding complications should be kept in mind if it comes to sudden deterioration of the patient.",
"affiliations": "Department of Anaesthesiology and Intensive Care Medicine, Medical School Hannover, Carl-Neuberg-Str. 1, 30625, Hannover, Germany. jung.carolin@mh-hannover.de.;Department of Anaesthesiology and Intensive Care Medicine, Medical School Hannover, Carl-Neuberg-Str. 1, 30625, Hannover, Germany.;Department of Anaesthesiology and Intensive Care Medicine, Medical School Hannover, Carl-Neuberg-Str. 1, 30625, Hannover, Germany.;Department of Anaesthesiology and Intensive Care Medicine, Medical School Hannover, Carl-Neuberg-Str. 1, 30625, Hannover, Germany.",
"authors": "Jung|Carolin|C|http://orcid.org/0000-0003-4672-8403;Gillmann|Hans-Joerg|HJ|;Stueber|Thomas|T|;Hinken|Lukas|L|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1186/s13256-021-03032-9",
"fulltext": "\n==== Front\nJ Med Case Rep\nJ Med Case Rep\nJournal of Medical Case Reports\n1752-1947\nBioMed Central London\n\n3032\n10.1186/s13256-021-03032-9\nCase Report\nSpontaneous massive hemothorax as a complication of necrotizing pneumonia in a patient with severe acute respiratory syndrome coronavirus 2 induced acute respiratory distress syndrome: a case report\nhttp://orcid.org/0000-0003-4672-8403\nJung Carolin jung.carolin@mh-hannover.de\n\nGillmann Hans-Joerg\nStueber Thomas\nHinken Lukas\ngrid.10423.34 0000 0000 9529 9877 Department of Anaesthesiology and Intensive Care Medicine, Medical School Hannover, Carl-Neuberg-Str. 1, 30625 Hannover, Germany\n3 9 2021\n3 9 2021\n2021\n15 44417 5 2021\n28 7 2021\n© The Author(s) 2021\nhttps://creativecommons.org/licenses/by/4.0/ Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.\nBackground\n\nWe present an unusual bleeding complication in a patient with severe acute respiratory distress syndrome in coronavirus disease 2019.\n\nCase presentation\n\nThe patient, a 63-year-old Caucasian man, received venovenous extracorporeal membrane oxygenation support after rapid deterioration of lung function on day 6 after admission to hospital. After initial stabilization on lung protective ventilation and prone positioning, he started to develop mild bleeding complications until he went into occult profound hemorrhagic shock. Causative was a massive hemothorax of the right hemithorax with mediastinal shifting due to spontaneous bleeding from a pulmonal artery in a heavily remodeled right inferior lobe. Histopathological examination of the resected tissue showed signs of an organizing fibrinous pneumonia with focal parenchyma necrosis. After surviving a massive bleeding event caused by necrotizing pneumonia, the patient made a swift recovery and was discharged to rehabilitation 31 days after initial hospital admission.\n\nConclusions\n\nThe combination of severely elevated inflammatory markers and pulmonary hemorrhage should arouse suspicion of necrotizing pneumonia. In necrotizing pneumonia, the possibility of severe intrathoracic bleeding complications should be kept in mind if it comes to sudden deterioration of the patient.\n\nSupplementary Information\n\nThe online version contains supplementary material available at 10.1186/s13256-021-03032-9.\n\nKeywords\n\nCOVID-19\nNecrotizing pneumonia\nHemothorax\nARDS\nCase report\nMedizinische Hochschule Hannover (MHH) (3118)Open Access funding enabled and organized by Projekt DEAL.\n\nissue-copyright-statement© The Author(s) 2021\n==== Body\npmcBackground\n\nPulmonary hemorrhage is a recurring finding in patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections and has been reported in 17% of cases with severe coronavirus disease 2019 (COVID-19) on extracorporeal support [1]. Necrotizing pneumonia is strongly associated with the occurrence of pulmonary hemorrhage and severely elevated inflammatory markers and comes with a poor prognosis [2, 3]. It can induce profound parenchyma damage and lead to severe complications such as spontaneous hemothorax. Awareness of the possibility of this complication can lead to timely diagnostic and therapy.\n\nWe report a case of spontaneous hemothorax as a complication of necrotizing pneumonia in a patient with severe COVID-19, that took a favorable course after surgical resection of the necrotic tissue.\n\nCase presentation\n\nA 63-year-old Caucasian male with a background of arterial hypertension and mild obesity (BMI 30.5 kg/m2) was admitted to hospital with dyspnea under COVID-19. He initially tested positive for SARS-CoV-2 via a polymerase chain reaction swab conducted in the ambulatory setting. When he arrived at the primary care hospital, he displayed a reduced general condition. Admission observations revealed: blood pressure 100/40 mmHg, heart rate 115 beats/minute, peripheral oxygen saturation 71%, body temperature 40 °C. His breathing noises were reduced, and there were rattling noises over his lungs bilaterally. He was cooperative and orientated, and showed no focal neurological deficit. His renal function markers were elevated [creatinine 1.66 mg/dl, estimated glomerular filtration rate (eGFR) 45 ml/minute], and the liver function markers were in the normal range. He was admitted to intensive care unit (ICU) 5 days later owing to worsening of respiratory symptoms. After 1 day of noninvasive ventilation, the patient decompensated into global respiratory insufficiency, and endotracheal intubation was required. Because of persistent global respiratory insufficiency under exhausted conservative therapy, the patient was transferred to our university hospital for venovenous extracorporeal support (vvECMO) in severe acute respiratory distress syndrome (ARDS). Computed tomographic (CT) imaging before transferal showed diffuse bilateral ground-glass opacities. On admission at our hospital, his acute phase reactants were elevated: white blood cell count 20,400/µl (normal range 3600–10,000/µl), CRP 316.5 mg/l (normal range < 5 mg/l), IL-6 420 ng/l (normal range < 7 ng/l), soluble IL-2-receptor 1549 kU/l (normal range 223–710 kU/l), ferritin 916 µg/l (normal range 27–365 µg/l), and fibrinogen > 9 g/l (normal range 1.8–3.5 g/l). He showed lymphocytopenia with a cell count of 470/µl (2.3%). SARS-CoV-2-PCR diagnostic was repeated from tracheal aspirate on arrival at our hospital and remained positive (cycle threshold 25). His medical treatment taken at home included valsartan, bisoprolol, amlodipine, and chlorthalidone as well as atorvastatin and mirtazapine. The patient did not smoke or consume alcohol regularly. He is married and has been working as a specialist in internal medicine until his recent retirement.\n\nHe received therapeutic anticoagulation with unfractionated heparin (UFH). Monitoring of anticoagulation was done by measurement of activated partial thromboplastin time (aPTT) every 6 hours with a target of 50–60 seconds. Preexisting treatment with acetylsalicylic acid was continued. Sedation proved to be difficult even under a multimodal intravenous sedative regime. First signs of pulmonary hemorrhage were noticed on day 11. Because of a suspected hyperinflammatory syndrome [4], dosage of dexamethasone was increased from 6 to 18 mg per day. For a detailed depiction of events, see timeline (Fig. 1 and Additional file 1).Fig. 1 Timeline\n\nOver the following days, the patient continuously produced extensive aqueous and slightly bloody discolored tracheal secretion. Chest x-ray on day 15 in supine position showed a progressive extensive opacity projecting to the right inferior lobe (Fig. 2). This corresponded with a heavy decline in pulmonary gas exchange. A diagnostic bronchoscopy on the same day revealed hemorrhagic pneumonia with extremely vulnerable mucosa and plenty of viscous mucus as well as extensive coagulum in segment 9. After removal of the coagulum, gas exchange improved at first. Because pulmonary hemorrhage remained persistent and gas exchange declined yet again alarmingly, the patient underwent a second bronchoscopy on the following day. Here, another extensive coagulum in right lung segment nine was cautiously and, due to high risk of bleeding, incompletely recovered. Dependence of extracorporeal support remained very high, and the patient became increasingly unstable. On day 17, the patient developed profound hemorrhagic shock (Table 1) without evident source of bleeding. The patient required extensive doses of norepinephrine, epinephrine, and vasopressin as well as a massive transfusion of red blood cells, plasma, and platelets for stabilization. At the same time, a severe acute decrease of pulmonary compliance was noticed.Fig. 2 Chest x-ray on day 15\n\nTable 1 Blood gas analysis over the days of hospitalization\n\n\tDay 6\n(after\nECMO implantation)\tDay 17\n(occult shock)\tDay 18\n(time of CT diagnostic)\tDay 18\n(thoracotomy)\tDay 18\n(revisional surgery)\tDay 19\n(first postoperative day)\tDay 31\n(referral to rehabilitation clinic)\t\nFiO2%\t100%\t100%\t100%\t100%\t100%\t30%\t2 LPM\t\npH\t7.47\t7.22\t7.42\t7.17\t7.19\t7.48\t7.49\t\nSpO2 (%)\t97\t96\t97\t96\t90\t95\t92\t\nPaO2 (mmHg)\t88\t101\t89\t107\t67\t77\t64\t\nPaCO2 (mmHg)\t29\t55\t41\t76\t67\t39\t41\t\nHemoglobin (g/dl)\t12.7\t5.3\t11.2\t13.9\t6.7\t9.8\t10.2\t\nPotassium (mmol/l)\t3.9\t5.8\t5.7\t6.5\t6.1\t3.7\t3.5\t\nLactate (mmol/l)\t1.2\t3.7\t1.7\t1.8\t3.7\t1.4\t0.6\t\nBase excess (mmol/l)\t1.3\t−5.7\t1.9\t−3.8\t−3.0\t4.4\t7.4\t\nFiO2 fraction of inspired oxygen, SpO2 oxygen saturation at periphery, PaO2 partial pressure of oxygen, PaCO2 partial pressure of carbon dioxide, LPM liters of oxygen per minute.\n\nDiagnostic focus and assessment/investigations\n\nSince the patient showed multiple bleeding complications, we suspected an ECMO-associated coagulopathy. Acquired von Willebrand syndrome was ruled out (vWF-activity 246%, vWF antigen 441%), as well as a clotting factor deficiency (factors II 107%, V > 180%, XIII 64.1%). Point-of-care coagulation diagnostic on day 13 showed no signs of fibrinolysis but displayed a rather hypercoagulable state (see Additional file 2) despite anticoagulant therapy with unfractionated heparin and acetylsalicylic acid. The patient had a normal platelet count until the day he developed hemorrhagic shock. At the time of the massive bleeding event, aPTT ranged between 38 and 50 seconds. Occurrence of bloody discolored tracheal secretion was thought to be the result of a possible aspiration event of blood in the hypopharynx due to nasal bleeding. Since the bloody discolored tracheal secretion remained persistent and was of very aqueous consistence, the working diagnosis changed to lung edema. The patient required large amounts of sedatives and was repeatedly disharmonic to the respirator, so that we suspected a self-inflicted lung injury as causal to the potential lung edema. On day 18, when the patient was in manifest shock, serum transaminases were severely elevated, indicative of a severe liver damage. Renal parameters displayed acute kidney injury KDIGO stage 2. Focused assessment with sonography revealed a large pleural effusion in the right hemithorax; transthoracic echocardiography led to the conclusion of hypovolemic shock. After stabilization of the patient, a CT scan of head, thorax, abdomen, and pelvis was done, revealing a massive hemothorax in the right hemithorax with complete compression of the ipsilateral lung, mediastinal shift, and signs of acute bleeding from a pulmonary artery (Fig. 3). There were also extensive low-contrast lesions in liver segments 6, 7, and 4a, indicative of low perfusion of these segments due to compression of the liver parenchyma in effusion-associated phrenoptosis at the right side (Fig. 4). On thoracic CT angiography, no signs of pulmonal arterial aneurysm were seen.Fig. 3 Axial slice from arterial phase computed tomography (Se:8, lm:59)\n\nFig. 4 Coronal slice from multiplanar reformation computed tomography (Se:904, lm82). Phrenoptosis due to massive hemothorax of the right hemithorax\n\nTherapeutic focus and assessment\n\nAfter CT scan, a posterolateral thoracotomy through the fifth intercostal space with evacuation of a massive hematoma of approximately 4–5 L blood was executed. The right inferior lobe was confirmed as the source of the bleeding. It presented itself imbibed and starkly altered and had to be resected to stop the bleeding. After lobectomy, the patient stabilized temporarily. A few hours after initial surgery, a second hemorrhagic shock due to a massive intrathoracic bleeding occurred. Revisional surgery revealed another massive hemothorax supplied by another approximate 5 L of blood originating from an intercostal artery located in the intercostal space below the recent thoracotomy.\n\nAccording to the pathology report of the removed lung tissue, the dorsal inferior lobe presented itself with extensive hemorrhage in an area of 10 × 12 cm. In bled-in areas, there was subpleural focal necrosis with a maximum diameter of 2 cm.\n\nHistopathology revealed an organizing fibrinous focal pneumonia (Figs. 5, 6, 7a and b) with focal parenchymal necrosis (Fig. 8) and extensive hemorrhage of lung parenchyma as well as multifocal alveolar capillary microthrombi (Figs. 9 and 10). The morphological finding was seen to be in accordance with the pattern of acute viral pneumonia.Fig. 5 Pneumonitis\n\nFig. 6 Edema\n\nFig. 7 a Fibrinous pneumonia. b Fibrinous pneumonia\n\nFig. 8 Necrosis\n\nFig. 9 Intracapillary megakaryocyte\n\nFig. 10 Intracapillary thrombi\n\nOutcome and follow-up\n\nAfter emergency lobectomy of the right inferior lobe, evacuation of the hemothorax, and sufficient hemostasis, the patient underwent a fast recovery. ECMO support was terminated 2 days after lobectomy. The patient was able to breath constantly without respirator support on postoperative day 11. A tracheal culture taken on day 25 revealed bacterial superinfection with Pseudomonas aeruginosa, which was treated with ceftazidime. After cessation of sedation, ICU-acquired weakness with proximal flaccid tetraparesis became evident. He was discharged to rehabilitation 31 days after initial hospital admission.\n\nDiscussion\n\nBrief review of the literature\n\nThis is, to the best of our knowledge, the second reported case of a spontaneous intrathoracic bleeding in a patient with COVID-19 [5]. In both cases, evidence of parenchymal necrosis of the lungs as a complication of the SARS-CoV-2-induced pneumonia was found. This pattern is in accordance with past findings that the occurrence of hemoptysis in nontuberculous lower respiratory tract infections is strongly associated with necrotizing pneumonia [2]. Pulmonary hemorrhage seems to be a rare but still recurring complication of SARS-CoV-2-infection. In a systematic review, 22% of ante- or postmortem dissected lungs displayed macroscopic hemorrhagic changes. Histopathologically, alveolar hemorrhage was seen in 33% and partial hemorrhagic necrosis in 0.3% of cases [6]. Clinically evident pulmonary hemorrhage has been described in patients with SARS-CoV-2-associated pneumonia with and without therapeutic anticoagulation [7, 8]. In COVID-19 patients with severe ARDS and therapeutic anticoagulation under vvECMO therapy, incidence of pulmonary hemorrhage seems to occur in a substantial number of cases. In a monocentric observation study, 17% of COVID-19 patients with ECMO support developed pulmonary hemorrhage that required intervention. Three cases were successfully controlled by temporary disruption of heparin for few days, and in one case successful embolization of a pulmonary artery was performed [1]. Murgo et al. reported another case of severe pulmonary hemorrhage in a patient with COVID-19 on ECMO therapy. Seven days after initiation of vvECMO therapy, the patient developed profound pulmonary bleeding. Several bronchoscopic interventions were required because of recurrent formation of obstructive clots. Since the endobronchial bleeding kept recurring and the patient was in a critical condition, complete bilateral embolization was performed as ultima ratio. Endobronchial bleeding stopped after the procedure, but the patient died nonetheless from nonhemorrhagic shock 3 days after the embolization [9]. Goursaud et al. reported a case of necrotizing pneumonia with spontaneous hemothorax in a patient with COVID-19 under ECMO support. After management of the bleeding complication with a thoracic drainage and massive transfusion, the patient died from refractory vasoplegic shock related to a massive systemic inflammatory response syndrome [5]. Necrotizing pneumonia is a rare complication in lung parenchyma infections and is defined by the development of parenchymal necrosis. Risk factors for the development of necrotizing pneumonia involve the inflammatory response of the host and thrombosis of the pulmonary vasculature. A further risk factor is coinfection of the lungs with bacterial and viral pathogens [3]. Necrotizing pneumonia is usually associated with bacterial infections, especially with Klebsiella species, Streptococcus pneumoniae, and Staphylococcus aureus [13]. Rapidly progressing necrotizing pneumonia has been reported in patients with bacterially superinfected influenza pneumonia [3]. In patients with necrotizing pneumonia, affection of pulmonal artery vasculature was seen in about 40% of the cases [2]. Considering the high prevalence of capillary microthrombosis and high inflammatory burden as well as a significant rate of bacterial coinfection in patients suffering from severe COVID-19, the ideal basis for necrotizing pneumonia is given. It still seems to be a rare complication that develops only in the most affected patients. In cases of necrotizing pneumonia, profound parenchymal injury and necrosis can lead to complications such as spontaneous pneumothorax or erosion of pulmonal vasculature resulting in pulmonary bleeding, or, as in our case, even in intrathoracic bleeding.\n\nCase discussion\n\nPathophysiology of SARS-CoV-2-induced lung damage is still incompletely understood. There is, however, accumulating evidence of profound damage to the lung parenchyma in severe cases [10–12]. In our patient, there was no mechanical trauma that could explain the occurrence of the pulmonal vascular injury leading to the massive intrathoracic bleeding. Intraoperatively, the right inferior lobe stood out as severely altered and imbibed. Histopathologically, the changes of the tissue were consistent with those of an acute viral pneumonia in the organizing phase with focal parenchymal necrosis.\n\nIt has been described that patients with necrotizing pneumonia show pronouncedly elevated inflammatory markers [13]. In our patient, d-dimer, ferritin, and white blood cell count were rising parallel to the occurrence of bloody tracheal secretions and remained massively elevated in the days before the hemorrhagic shock (Fig. 11). The massive elevation of d-dimer was not associated with clinically or radiologically evident thrombosis. Nevertheless, elevated d-dimer, ferritin, and inflammation markers are not specific for a distinct complication but are known to be associated with a poor prognosis in COVID-19 generally [14, 15]. The exact biological mechanism of the markedly elevated d-dimer and the interindividual variations in patients with COVID-19 remain unclear [14]. After resection of the right inferior lobe in our patient, d-dimer and white blood cell count fell instantly and remained only slightly elevated henceforth. Severely elevated inflammatory markers in combination with occurrence of pulmonary hemorrhage in a critically ill COVID-19 patient should alert to the possible development of an otherwise rare necrotizing pneumonia.Fig. 11 Time course of inflammation markers and d-dimer during the ICU stay. Red line indicates day of emergency right lower lobe lobectomy\n\nTherapeutic approach to necrotizing pneumonia consists of mainly conservative anti-infective and symptomatic treatment. Surgical interventions are reserved for cases not responsive to medical treatment or in case of severe bleeding complications that cannot be controlled by embolization of the affected vessels.\n\nSome aspects of our case management can be discussed. Even though we saw bleeding complications several days before the arterial bleeding, we did not deescalate our anticoagulation regime. In the face of the persistent hypercoagulability even under high UFH dosage and a consecutive oxygenator thrombosis with the necessity of an ECMO system change on day 16, we weighed the risk of a life-threatening thrombotic event higher than that of persistent mild bleeding. When it came to the occult hemorrhagic shock, we reduced UFH dosage to 4 units/kg/hour. Retrospectively, earlier thoracic computed tomographic imaging could have revealed the necrotic conversion of the right inferior lobe before it became evident by arrosion of the pulmonal artery.\n\nRegarding the extent of the hemothorax and computed tomographic signs of active arterial bleeding, we primarily performed open thoracotomy to evaluate the source of the bleeding. Resection of the severely altered right inferior lobe led to a rapid stabilization not only of the hemodynamics, but also of the respiratory situation. After days of persistent complete dependence from the extracorporeal support due to a profound hypoxemia, the patient underwent a surprisingly rapid ECMO weaning and was decannulated 2 days postoperatively (Table 1). This case demonstrates the pathophysiological principle that impaired oxygenation in ARDS is not per se caused by impaired diffusion across the alveolar–capillary membrane but is predominantly caused by right-to-left shunting due to regions where perfusion exceeds ventilation [16]. The fast sequence from high ECMO dependence to ECMO weaning only shortly after the surgical intervention leads to the conclusion that the necrotic right inferior lobe was responsible for a significant amount of right-to-left shunting in this patient. A similar observation was made by Ashkenazi et al., who reported a lobectomy in a toddler on vvECMO therapy due to necrotizing pneumonia without clinical improvement under conservative management. After resection of the problematic lobe, the toddler could be weaned off vvECMO support immediately and was discharged home 2 weeks later [17]. In a monocentric observation study, all patients that underwent surgery for therapy-refractory pulmonary bleeding in necrotizing pneumonia survived and were discharged alive from the ICU [2].\n\nConclusion\n\nThe combination of severely elevated inflammatory markers and pulmonary hemorrhage should arouse suspicion of necrotizing pneumonia and lead to timely diagnostic. In COVID-19 cases with progression to necrotizing pneumonia that do not respond well to conventional therapy, surgical intervention is an interesting option that warrants further exploration.\n\nPatient’s perspective\n\n“I fully recovered and now am able to live the life I had before the infection, including sportive activity and being able to take care of my dog. The most persistent problem turned out to be a hypoglossal nerve palsy, which eventually resolved almost completely under speech therapy. I am very thankful to the intensive care team for not giving up on me.”\n\nSupplementary Information\n\nAdditional file 1. Detailed timeline of events and medication taken during the stay.\n\nAdditional file 2. Viscelastometic point-of-care diagnostic (Haemonetics ClotProⓇ) on day 13.\n\nAbbreviations\n\nARDS Acute respiratory distress syndrome\n\naPTT Activated partial thromboplastin time\n\nBMI Body mass index\n\nCOVID-19 Coronavirus disease 2019\n\nCRP C-reactive protein\n\nCT Computed tomography\n\nFiO2 Fraction of inspired oxygen\n\nICU Intensive care unit\n\nIL Interleukin\n\nKDIGO Kidney Disease: Improving Global Outcomes\n\nLPM Liters oxygen per minute\n\nMPR Multiplanar reformation\n\nPaCO2 Partial pressure of carbon dioxide\n\nPaO2 Partial pressure of oxygen\n\nPCR Polymerase chain reaction\n\nSARS-CoV-2 Severe acute respiratory syndrome coronavirus type 2\n\nSpO2 Oxygen saturation at periphery\n\nUFH Unfractionated heparin\n\nvvECMO Venovenous extracorporeal membrane oxygenation\n\nvWF von Willebrand factor\n\nAcknowledgements\n\nWe would like to thank Dr. Florian Laenger, senior physician at the institute of pathology at Medical School Hannover, for providing anatomo-pathological images of the resected lung tissue.\n\nAuthors’ contributions\n\nCJ and LH analyzed and interpreted the patient data regarding the case and were major contributors in writing the manuscript. HJG and TS have made a substantial contribution to the conception and revision of the manuscript. All authors read and approved the final manuscript.\n\nFunding\n\nOpen Access funding enabled and organized by Projekt DEAL.\n\nAvailability of data and materials\n\nAll data generated or analyzed during this case report are included in this published article.\n\nDeclarations\n\nEthics approval and consent to participate\n\nNot applicable.\n\nConsent for publication\n\nWritten informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal. \n\nCompeting interests\n\nThe authors declare that they have no competing interests.\n\nPublisher’s Note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n\n1. Guihaire J Owyang CG Madhok J Laverdure F Gaillard M Girault A Specific considerations for venovenous extracorporeal membrane oxygenation during coronavirus disease 2019 pandemic ASAIO J 2020 66 10 1069 1072 10.1097/MAT.0000000000001251 33136589\n2. Carteaux G Contou D Voiriot G Khalil A Carette MF Antoine M Severe hemoptysis associated with bacterial pulmonary infection: clinical features, significance of parenchymal necrosis, and outcome Lung 2018 196 1 33 42 10.1007/s00408-017-0064-8 29026982\n3. Krutikov M Rahman A Tiberi S Necrotizing pneumonia (aetiology, clinical features and management) Curr Opin Pulm Med 2019 25 3 225 232 10.1097/MCP.0000000000000571 30844921\n4. Webb BJ Peltan ID Jensen P Hoda D Hunter B Silver A Clinical criteria for COVID-19-associated hyperinflammatory syndrome: a cohort study Lancet Rheumatol 2020 2 12 e754 e763 10.1016/S2665-9913(20)30343-X 33015645\n5. Goursaud S Mombrun M du Cheyron D COVID-19 necrotising pneumonia and extracorporeal membrane oxygenation: a challenge for anticoagulation ERJ Open Res 2020 10.1183/23120541.00182-2020 32665949\n6. Polak SB Van Gool IC Cohen D von der Thusen JH van Paassen J A systematic review of pathological findings in COVID-19: a pathophysiological timeline and possible mechanisms of disease progression Mod Pathol 2020 33 11 2128 2138 10.1038/s41379-020-0603-3 32572155\n7. Peys E Stevens D Weygaerde YV Malfait T Hermie L Rogiers P Haemoptysis as the first presentation of COVID-19: a case report BMC Pulm Med 2020 20 1 275 10.1186/s12890-020-01312-6 33092563\n8. Al-Samkari H Gupta S Leaf RK Wang W Rosovsky RP Brenner SK Thrombosis, bleeding, and the observational effect of early therapeutic anticoagulation on survival in critically ill patients with COVID-19 Ann Intern Med 2021 174 5 622 32 10.7326/M20-6739 33493012\n9. Murgo S Lheureux O Taccone F Vouche M Golzarian J Haemoptysis treated by bronchial artery embolisation in severe acute respiratory syndrome coronavirus 2: case report CVIR Endovasc 2020 3 1 61 10.1186/s42155-020-00154-x 32889589\n10. Kommoss FKF Schwab C Tavernar L Schreck J Wagner WL Merle U The pathology of severe COVID-19-related lung damage Dtsch Arztebl Int 2020 117 29–30 500 506 32865490\n11. Borczuk AC Pulmonary pathology of COVID-19: a review of autopsy studies Curr Opin Pulm Med 2021 27 3 184 192 10.1097/MCP.0000000000000761 33399353\n12. Bosmuller H Matter M Fend F Tzankov A The pulmonary pathology of COVID-19 Virchows Arch 2021 478 1 137 150 10.1007/s00428-021-03053-1 33604758\n13. Seo H Cha SI Shin KM Lim JK Yoo SS Lee J Clinical relevance of necrotizing change in patients with community-acquired pneumonia Respirology 2017 22 3 551 558 10.1111/resp.12943 27862706\n14. McGonagle D O'Donnell JS Sharif K Emery P Bridgewood C Immune mechanisms of pulmonary intravascular coagulopathy in COVID-19 pneumonia Lancet Rheumatol 2020 2 7 e437 e445 10.1016/S2665-9913(20)30121-1 32835247\n15. Yao Y Cao J Wang Q Shi Q Liu K Luo Z D-dimer as a biomarker for disease severity and mortality in COVID-19 patients: a case control study J Intensive Care 2020 8 49 10.1186/s40560-020-00466-z 32665858\n16. Radermacher P Maggiore SM Mercat A Fifty years of research in ARDS. Gas exchange in acute respiratory distress syndrome Am J Respir Crit Care Med 2017 196 8 964 84 10.1164/rccm.201610-2156SO 28406724\n17. Ashkenazi S Ben-Nun A Pessach I Rubinshtein M Paret G Lobectomy on ECMO as a life-saving procedure following necrotizing pneumonia in a toddler: a case study J Pediatr Intensive Care 2018 7 4 207 209 10.1055/s-0038-1636507 31073496\n\n",
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"abstract": "Increased serum C-protein (CRP) levels reduce fecundity in healthy eumenorrheic women with 1-2 pregnancy losses. Subclinical systemic inflammation may impede maternal immune tolerance toward the fetal semi-allograft, compromising implantation and early embryonic development. Some miscarriages with normal karyotypes could, therefore, be caused by inflammation. Whether pre-pregnancy CRP relates to karyotypes of spontaneously aborted products of conception (POCs) was investigated.\n\n\n\nA study cohort of 100 infertile women with missed abortions who underwent vacuum aspirations followed by cytogenetic analysis of their products of conception tissue was evaluated at an academically affiliated fertility center. Since a normal female fetus cannot be differentiated from maternal cell contamination (MCC) in conventional chromosomal analyses, POC testing was performed by chromosomal microarray analysis. MCC cases and incomplete data were excluded. Associations of elevated CRP with first trimester pregnancy loss in the presence of a normal fetal karyotype were investigated.\n\n\n\nMean patients' age was 39.9 ± 5.8 years; they demonstrated a BMI of 23.9 ± 4.6 kg/m2 and antiMullerian hormone (AMH) of 1.7 ± 2.4 ng/mL; 21.3% were parous, 19.1% reported no prior pregnancy losses, 36.2% 1-2 and 6.4% ≥ 3 losses. Karyotypes were normal in 34% and abnormal in 66%. Adjusted for BMI, women with elevated CRP were more likely to experience euploid pregnancy loss (p = 0.03). This relationship persisted when controlled for female age and AMH.\n\n\n\nWomen with elevated CRP levels were more likely to experience first trimester miscarriage with normal fetal karyotype. This relationship suggests an association between subclinical inflammation and miscarriage.",
"affiliations": "Department of Obstetrics and Gynecology, Medical University of Vienna, Vienna, Austria. andrea.weghofer@meduniwien.ac.at.;The Center for Human Reproduction, New York, N.Y., USA.;The Center for Human Reproduction, New York, N.Y., USA.;Department of Obstetrics and Gynecology, Wake Forest University, Winston Salem, N.C., USA.;The Center for Human Reproduction, New York, N.Y., USA.;Department of Obstetrics and Gynecology, Medical University of Vienna, Vienna, Austria.",
"authors": "Weghofer|Andrea|A|http://orcid.org/0000-0002-2306-5910;Barad|David H|DH|;Darmon|Sarah K|SK|;Kushnir|Vitaly A|VA|;Albertini|David F|DF|;Gleicher|Norbert|N|",
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"fulltext": "\n==== Front\nArch Gynecol Obstet\nArch. Gynecol. Obstet\nArchives of Gynecology and Obstetrics\n0932-0067 1432-0711 Springer Berlin Heidelberg Berlin/Heidelberg \n\n5461\n10.1007/s00404-020-05461-1\nGynecologic Endocrinology and Reproductive Medicine\nEuploid miscarriage is associated with elevated serum C-reactive protein levels in infertile women: a pilot study\nhttp://orcid.org/0000-0002-2306-5910Weghofer Andrea andrea.weghofer@meduniwien.ac.at 12 Barad David H. 23 Darmon Sarah K. 2 Kushnir Vitaly A. 4 Albertini David F. 2 Gleicher Norbert 1235 1 grid.22937.3d0000 0000 9259 8492Department of Obstetrics and Gynecology, Medical University of Vienna, Vienna, Austria \n2 grid.417602.60000 0004 0585 2042The Center for Human Reproduction, New York, N.Y. USA \n3 The Foundation for Reproductive Medicine, New York, N.Y. USA \n4 grid.241167.70000 0001 2185 3318Department of Obstetrics and Gynecology, Wake Forest University, Winston Salem, N.C. USA \n5 grid.134907.80000 0001 2166 1519Stem Cell Biology and Molecular Embryology Laboratory, The Rockefeller University, New York, N.Y USA \n27 2 2020 \n27 2 2020 \n2020 \n301 3 831 836\n17 4 2019 13 2 2020 © The Author(s) 2020Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.Purpose\nIncreased serum C-protein (CRP) levels reduce fecundity in healthy eumenorrheic women with 1–2 pregnancy losses. Subclinical systemic inflammation may impede maternal immune tolerance toward the fetal semi-allograft, compromising implantation and early embryonic development. Some miscarriages with normal karyotypes could, therefore, be caused by inflammation. Whether pre-pregnancy CRP relates to karyotypes of spontaneously aborted products of conception (POCs) was investigated.\n\nMethods\nA study cohort of 100 infertile women with missed abortions who underwent vacuum aspirations followed by cytogenetic analysis of their products of conception tissue was evaluated at an academically affiliated fertility center. Since a normal female fetus cannot be differentiated from maternal cell contamination (MCC) in conventional chromosomal analyses, POC testing was performed by chromosomal microarray analysis. MCC cases and incomplete data were excluded. Associations of elevated CRP with first trimester pregnancy loss in the presence of a normal fetal karyotype were investigated.\n\nResults\nMean patients’ age was 39.9 ± 5.8 years; they demonstrated a BMI of 23.9 ± 4.6 kg/m2 and antiMullerian hormone (AMH) of 1.7 ± 2.4 ng/mL; 21.3% were parous, 19.1% reported no prior pregnancy losses, 36.2% 1–2 and 6.4% ≥ 3 losses. Karyotypes were normal in 34% and abnormal in 66%. Adjusted for BMI, women with elevated CRP were more likely to experience euploid pregnancy loss (p = 0.03). This relationship persisted when controlled for female age and AMH.\n\nConclusions\nWomen with elevated CRP levels were more likely to experience first trimester miscarriage with normal fetal karyotype. This relationship suggests an association between subclinical inflammation and miscarriage.\n\nKeywords\nC-reactive protein (CRP)EuploidInfertilityInflammationMiscarriageissue-copyright-statement© Springer-Verlag GmbH Germany, part of Springer Nature 2020\n==== Body\nIntroduction\nThe detrimental effects of chronic subclinical inflammation on human health are increasingly becoming apparent. Mediating vascular remodeling, inflammation was recently recognized to induce and promote cardiovascular disease [1]. Biomarkers of micro-inflammation, such as C-reactive protein (CRP), serve as predictive tools for the development and monitoring of the acute coronary syndrome, as inflammation is considered a target that can be therapeutically improved [3, 13]. These insights have improved the understanding of how inflammation promotes a variety of pregnancy-induced disorders, such as gestational diabetes and pre-eclampsia [23, 29]. Anti-inflammatory drugs, such as aspirin, have proven beneficial in preventing and mitigating pre-eclampsia-associated adverse pregnancy outcomes in expectant mothers at risk [17].\n\nPreconception and inflammation play an important physiological role in ovulation and implantation [14, 24] but, increasingly, thus also appear to exert potentially detrimental effects on reproductive success. To allow for implantation and proper development of the embryonic semi-allograft, the female immune system must induce tolerance. In the presence of micro-inflammation, induction of fetal–maternal tolerance may be derailed, increasing risks of subfertility, repeated implantation failure and pregnancy loss [6, 10, 12].\n\nRadin et al. [20] recently reported impaired fecundity in eumenorrheic women with increased CRP levels. Their findings are supported by the reported effects of aspirin in the Gestation and Reproduction (EAGER) trial which demonstrated that low-dose aspirin restored pregnancy and live birth rates among eumenorrheic women with one or two pregnancy losses and abnormally high preconception CRP [25]. Subclinical inflammations could, thus, serve as a causative factor for the substantial proportion of miscarriages that reveal normal karyotypes after the analysis of products of conception (POCs) [8]. If this were, indeed, the case, normal POC karyotypes should be more prevalent in women with abnormally high CRP levels.\n\nConventional chromosomal analyses of POC-karyotypes do not allow discrimination between normal female karyotypes and maternal cell contaminations (MCCs). The introduction of chromosomal microarray analysis, featuring single nucleotide polymorphism technology (Anora®, Natera, San Carlos, CA), however, now facilitates correct differentiation.\n\nThis study was initiated to shed further light on the relationship between maternal micro-inflammation, reflected in pre-pregnancy CRP levels, and POC karyotypes.\n\nMethods\nWe retrospectively evaluated 100 consecutive infertile women who presented with missed abortions and underwent dilatation and curettage (D and C) with cytogenetic analysis of POCs at The Center for Human Reproduction (CHR) in New York City, NY. Patients with abnormal parental karyotypes, genetic disorders, uterine malformations, autoimmune disorders, such as antiphospholipid syndrome, chronic endometritis or clinical signs of spontaneous abortion were not eligible for enrollment.\n\nIn the course of routine workup for fertility treatment, women underwent vaginal sonography, baseline hormone testing of follicle stimulating (FSH) and antiMullerian hormone (AMH), estradiol and androgen serum levels on cycle days 2/3. As part of their routine workup for fertility treatment, patients at our center also undergo CRP assessments. Fertility treatment was performed as previously reported [11]. Five to six weeks after the first positive serum human chorionic gonadotropin (hCG), vaginal ultrasound was performed. Missed abortions were diagnosed by the presence of at least one gestational sac and absence of fetal heart activity. Before surgical evacuation, all women signed case-specific informed consents for surgery and chromosomal analyses of POCs. Evacuation was performed by suction aspiration within days from diagnosis. Patients’ blood and POCs were collected under sterile conditions, processed and shipped to a national reference laboratory as indicated in the test provider’s instructions of the sample kit (Anora®, Natera, San Carlos, CA). Testing was performed by microarray analysis, featuring single nucleotide polymorphism technology (Anora®, Natera, San Carlos, CA).\n\nSerum CRP levels increase with age and body mass index (BMI) [15]. The EAGER trial assessed preconception CRP levels in healthy women attempting pregnancy. In this large US trial, women without low-grade inflammation (i.e., low CRP tertile) were defined as CRP < 0.73 mg/L [25]. In this study, area under the curve (AUC) for CRP of aneuploid pregnancy loss was 0.66 ± 0.09 (p = 0.07) (Fig. 1). Based on this ROC curve, the maximal inflection point (81% sensitivity, 51.6% specificity) was around CRP 0.75 mg/L and, therefore, practically identical to the EAGER trial [13]. In this study, patients with CRP of 0.75 mg/L were, therefore, considered to have an elevated CRP. Study subjects with incomplete data sets (i.e., n = 35) and/or POC analyses that revealed MCC (i.e., n = 16) or inconclusive results (i.e., n = 2) were excluded from further analysis. This resulted in 47 women with complete data for final analysis.Fig. 1 CRP and fetal karyotype. ROC curve demonstrating the relationship between CRP and fetal karyotype\n\n\n\nContinuous data were expressed as mean ± SD and compared via ANOVA. Outcome parameters are presented as proportions. The association of elevated CRP with euploid pregnancy loss was tested using logistic regression, adjusting for appropriate covariates. All statistical analyses were carried out with use of the Statistical Package for the Social Sciences 21.0 (SPSS). A p < 0.05 was considered statistically significant.\n\nAt initial consultation, patients at our center sign an informed consent, which allows for the use of their anonymized electronic medical records and, where needed, of their paper records, if the patient’s identity remains protected and the medical record remains confidential. Since here-presented data only involved retrospective review of the center’s anonymized electronic research database, also used to report the center’s annual IVF outcomes to national registries, these conditions were met. The Center for Human Reproduction Institutional Review Board approved such medical record studies.\n\nResults\nThe women studied were 39.9 ± 5.8 years old. They presented with a BMI of 23.5 ± 4.7 kg/m2, AMH of 1.7 ± 2.4 ng/mL and CRP of 2.0 ± 2.7 mg/L. There was no significant difference in age, BMI, AMH levels, semen analysis parameters or white blood cell counts between couples with euploid and aneuploid pregnancy loss (Table 1). All women were taking prednisone during pregnancy and, thus, WBC counts while pregnant were significantly higher than when not pregnant. Within the study cohort, 29/47 (61.7%) had previous pregnancies, 10/47 (21.3%) had a previous live birth, 9/47 (19.1%) had no prior pregnancy losses, 17/47 (36.2%) had 1–2 prior first trimester miscarriages and 3/47 (6.4%) had a history of three or more losses. Thirty-three women presented with normal BMI, ten were overweight and four suffered from obesity.Table 1 Patient characteristics according to fetal karyotype in 47 women with first trimester miscarriage\n\n\tAll\tEuploid\tAneuploid\t\n(n = 47)\t(n = 16)\t(n = 31)\t\nFemale age (years)\t39.9 ± 5.8\t39.1 ± 7.3\t40.3 ± 4.9\t\nBMI (kg/m2)\t23.6 ± 4.6\t23.7 ± 4.3\t23.6 ± 4.9\t\nAMH (ng/mL)\t1.7 ± 2.4\t2.1 ± 3.3\t1.5 ± 1.8\t\nCRP (mg/L)\t2.2 ± 3.0\t2.9 ± 3.3\t1.9 ± 2.7\t\nSemen analysis\t\n Vol\t1.9 ± 1.3\t1.9 ± 1.7\t2.0 ± 1.3\t\n Count (× 106)\t58.0 ± 63.1\t50.3 ± 46.4\t62.0 ± 72.0\t\n Motility (%)\t43.0 ± 21.0\t46.0 ± 17.4\t62.0 ± 72.0\t\n Morphology(%)\t11 ± 19\t8 ± 5\t12 ± 24\t\nWBC\t\n Before pregnancy\t4.4 ± 6.3\t4.7 ± 7\t3.8 ± 6.4\t\n During SAB\t8.8 ± 11.5\t7.3 ± 11.8\t8.7 ± 12.3\t\nValues are presented as means ± SD\n\n\n\nIndications for fertility treatment were diminished ovarian reserve in 40 women, male factor infertility in 10 and tubal factor in 4 couples, 2 patients suffered from polycystic ovary syndrome (PCOS) and one had endometriosis (some patients had multiple diagnoses). None of the study subjects suffered from hypertension or diabetes. Within the study cohort, 43 women conceived via assisted reproduction (i.e., IVF or ICSI), 2 in the course of controlled ovarian hyperstimulation and intrauterine insemination (IUI) and the remaining 2 conceived spontaneously during work up for fertility treatment. Sixteen patients (34%) showed a normal fetal karyotype in their POC analysis, while 31 patients (66%) presented with aneuploid pregnancy losses. Details on karyotypes of women with aneuploid conceptions are presented in Table 2.Table 2 Karyotypes of product of conception analyses in women undergoing miscarriage\n\nKaryotype\tCount\t%\t\n46,XY\t9\t14.29\t\n46,XX\t7\t11.11\t\n46,XX UPD 1–22,X\t1\t1.59\t\n45,X0\t1\t1.59\t\n47,XX + 7\t1\t1.59\t\n47,XX + 8\t1\t1.59\t\n47,XX + 11\t1\t1.59\t\n47,XX + 15\t2\t3.17\t\n47,XX + 16\t2\t3.17\t\n47,XX + 22\t1\t1.59\t\n47,XY + 3\t3\t4.76\t\n47,XY + 9\t1\t1.59\t\n47,XY + 15\t1\t1.59\t\n47,XY + 16\t2\t3.17\t\n47,XY + 16 mosaic\t1\t1.59\t\n47,XY + 22\t1\t1.59\t\n48,XX + 4, + 16\t1\t1.59\t\n48,XY + 10, + 18\t1\t1.59\t\n48,XY + 14, + 22\t1\t1.59\t\n48,XY + 21, + 22\t1\t1.59\t\n49,XX + 9, + 18, + 20\t1\t1.59\t\n69,XX + 2\t1\t1.59\t\n69,XXX maternal\t3\t4.76\t\n69,XXY maternal\t2\t3.17\t\n72,XXY + 5, + 6, + 21\t1\t1.59\t\nMCC\t16\t25.4\t\n\n\nAge, BMI and AMH have all been previously reported to be associated with changes in CRP levels [18]. To evaluate a possible association between CRP, age, BMI and AMH, regression analyses were performed. Only BMI demonstrated a significant positive relationship with CRP levels (p < 0.01) and was, therefore, included in the multi-regression model. After adjustment for BMI, POCs of women with elevated CRP levels were significantly more likely to demonstrate normal fetal karyotypes (p = 0.03). Odds of having a euploid embryo loss were 5.5 (95 CI 1.2–25.2) in women with elevated CRP levels and this association remained significant when further adjusted for female age and AMH levels.\n\nDiscussion\nIn this study, patients with elevated preconception CRP concentrations were more likely to demonstrate normal karyotypes than women with normal CRP levels. These findings suggest that subclinical inflammation may create challenges for the maternal immune system to reprogram itself towards tolerance. Similar conclusions were also reached by Barad et al. [2], when discussing a recent miscarriage study by Feichtinger et al. [9] who reported patients with recurrent miscarriage demonstrated less aneuploidy than those with sporadic miscarriage. Repeat aborters, therefore, appeared to have more non-chromosomal causes for pregnancy loss, likely mostly immune-mediated losses.\n\nMost recent studies suggest that aneuploidy maximally represent about 50% of causes of fetal demise [26]. A considerable number of pregnancies with normal karyotypes, thus, result in miscarriages. In this study, practically two-third of miscarriages were aneuploid, though this number is, likely, consequence of above average age of our center’s patient population. While associations between miscarriages and specific conditions, such as antiphospholipid syndrome or uterine malformations, are well established [19, 28], underlying mechanisms for most other non-chromosomal miscarriages are still only poorly understood.\n\nIncreased miscarriage rates in women with overt autoimmune conditions offer support for inflammation potentially impeding the crosstalk between fetus and maternal immune system at the maternal–fetal interface [5, 21]. If even subclinical inflammation, reflected in elevated CRP levels in absence of systemic inflammatory symptoms, impairs fetal growth and development, any excessive degree of inflammatory response may hinder timely induction of tolerance.\n\nA number of observations suggest that the timeline for physiological tolerance pathways starts prior to conception: before human embryos implant, they spend about 2 days within the uterine cavity. This time frame, therefore, likely defines a period of crucially important crosstalk between embryo, endometrium and the maternal immune system. Embryos, however, also are able to implant extrauterine and even in vitro [7]. It, thus, seems likely that the initial signal that creates a welcoming implantation environment may come from the embryo.\n\nEndometrium (or other sites in cases of extrauterine pregnancies), in turn, must react properly by abandoning its absolute hostility toward the invasion of any kind (an absolutely essential quality of the endometrium that routinely must protect women from trans-endometrial bacterial, viral and parasitic infections), and, instead, creates a welcoming microenvironment for invasiveness (i.e., implantation). Since implantation sites never demonstrate allogeneic immune responses, the process must include development of an initial level of tolerance by the maternal immune system that prevents immediate rejection of the invading embryo. This concept of required timely induction of tolerance pathways is supported by improved fecundity in chronically infected females with distinct helminthic infections, which likely induce common tolerance pathways to implanting embryos [4].\n\nIf induction of pregnancy tolerance, indeed, follows a prefixed timeline, one can also assume that some miscarriages reflect insufficient tolerance induction, with the consequence of allogeneic immune responses of the maternal immune system against the implanting embryo. As hyperactive immune systems are known to hamper induction of tolerance pathways, increased miscarriage risk (and, possibly, implantation failure) with laboratory evidence of inflammation should not surprise. All inflammatory markers may, however, not denote identical risks, just as all helminths do not induce the same tolerance pathways [4].\n\nIf subclinical inflammation can lead to insufficient induction of tolerance, anti-inflammatory drugs should increase reproductive health by improving pregnancy rates, reducing miscarriage and, maybe, even ameliorating pre-eclampsia in women at risk. Large double-blind placebo-controlled trials support this hypothesis. Sjaarda et al. recently reported increased implantation and live birth chances after low-dose aspirin treatment among eumenorrheic women with a history of one or two pregnancy losses and increased preconception CRP levels. In contrast, such an impact was absent with normal preconception CRP [25]. Similar results are also reported after low-dose prenatal aspirin treatment in women at risk for pre-eclampsia. Rolnik et al. [22] described a 62% risk reduction for preterm preeclampsia after low-dose aspirin treatment in at risk populations.\n\nThat timing of when anti-inflammatory treatment should be started is crucial for its success, further supports the timeline concept of tolerance induction: Tempfer et al. [27] reported higher live birth rates in women with idiopathic recurrent miscarriage after prednisone, low-dose aspirin and progesterone treatment initiated preconceptionally. Moore et al. [16] demonstrate similar effects with pre-eclampsia: low-dose aspirin significantly reduced pre-eclampsia risk when treatment was initiated before week 17, long before initial symptoms of pre-eclampsia became apparent. That aspirin exerts benefits where vascular remodeling and chronic inflammation interphase, emphasizes their close interplay and its importance for implantation and the exponential growth of products of conception during gestation.\n\nHere-presented evidence, thus, further suggests that preconception assessments of CRP, a widely available and low-cost blood test, may in infertile women be useful in identifying those at increased risk for immune system-induced miscarriages which, in turn, may allow for timely pharmaceutical interventions. Prospectively randomized studies are, however, required to confirm this hypothesis.\n\nThe retrospective nature of this study is an obvious weakness. Though reflecting an unselected patient population, retrospective studies can never be absolutely free of selection biases. This weakness is, however, compensated by the fact that patients with and without abnormally high CRP levels were similar in important patient characteristics.\n\nThis study raises two immediate challenges: first, the question arises whether other inflammatory markers are equally or, maybe, even more predictive of treatment outcomes in infertility. Second, prospective randomized studies are necessary to determine in women with abnormally high CRP (and potentially other inflammatory markers) which anti-inflammatory medications will be most effective in counteracting adverse effects on female reproduction. In conclusion, women with elevated CRP levels were more likely to experience first trimester miscarriage with normal fetal karyotype. This relationship suggests an association between subclinical inflammation and miscarriage.\n\nPublisher's Note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n\nAcknowledgements\nOpen access funding provided by Medical University of Vienna.\n\nAuthor contributions\nAW: study design, execution, manuscript drafting and critical discussion; SD: execution, analysis and critical discussion; VAK: execution and critical discussion; DFA: execution and critical discussion; DHB: study design, analysis and critical discussion; NG: study design, manuscript drafting and critical discussion.\n\nFunding\nIntramural funds from The Center for Human Reproduction and The Foundation for Reproductive Medicine.\n\nCompliance with ethical standards\nConflict of interest\nAW, VAK, DFA, DHB and NG have received research grant support, travel funds and speaker honoraria from various pharmaceutical and medical device companies, none, however, related to the here-presented topic. DHB and NG are listed as inventors on already awarded and still pending U.S. patents, claiming beneficial effects on diminished ovarian reserve and embryo ploidy from DHEA supplementation. SD has no conflict of interest to report.\n==== Refs\nReferences\n1. Anzai T Inflammatory mechanisms of cardiovascular remodeling Circ J 2018 82 629 635 10.1253/circj.CJ-18-0063 29415911 \n2. Barad DH Kushnir VA Gleicher N Focus on recurrent miscarriage phenotypes Fertil Steril 2017 107 64 65 10.1016/j.fertnstert.2016.10.034 27887715 \n3. Berger JS Roncaglioni MC Avanzini F Pangrazzi I Tognoni G Brown DL Aspirin for the primary prevention of cardiovascular events in women and men: a sex-specific meta-analysis of randomized controlled trials JAMA 2006 295 306 313 10.1001/jama.295.3.306 16418466 \n4. Blackwell AD Tamayo MA Beheim B Trumble BC Stieglitz J Hooper PL Martin M Kaplan H Gurven M Helminth infection, fecundity, and age of first pregnancy in women Science 2015 350 970 972 10.1126/science.aac7902 26586763 \n5. Busnelli A Paffoni A Fedele L Somigliana E The impact of thyroid autoimmunity on IVF/ICSI outcome: a systematic review and meta-analysis Hum Reprod Update 2016 22 793 794 10.1093/humupd/dmw034 27671830 \n6. Chen X Liu Y Cheung WC Zhao Y Huang J Chung JPW Wang CC Li TC Increased expression of angiogenic cytokines in CD56+ uterine natural killer cells from women with recurrent miscarriage Cytokine 2018 110 272 276 10.1016/j.cyto.2018.01.013 29396049 \n7. Deglincerti A Croft GF Pietila LN Zernicka-Goetz M Siggia ED Brivanlou AH Self-organization of the in vitro attached human embryo Nature 2016 533 251 254 10.1038/nature17948 27144363 \n8. Ebina Y Nishino Y Deguchi M Maesawa Y Nakashima Y Yamada H Natural killer cell activity in women with recurrent miscarriage: Etiology and pregnancy outcome J Reprod Immunol 2017 120 42 47 10.1016/j.jri.2017.04.005 28441552 \n9. Feichtinger M Wallner E Hartmann B Reiner A Philipp T Transcervical embryoscopic and cytogenetic findings reveal distinctive differences in primary and secondary recurrent pregnancy loss Fertil Steril 2017 107 144 149 10.1016/j.fertnstert.2016.09.037 27743696 \n10. Galgani M Insabato L Cali G Della Gatta AN Mirra P Papaccio F Santopaolo M Alviggi C Mollo A Strina I Matarese G Beguinot F De Placido G Ulianich L Regulatory T cells, inflammation, and endoplasmic reticulum stress in women with defective endometrial receptivity Fertil Steril 2015 103 1579 1586 10.1016/j.fertnstert.2015.03.014 25935494 \n11. Gleicher N Kim A Weghofer A Shohat-Tal A Lazzaroni E Lee HJ Barad DH Starting and resulting testosterone levels after androgen supplementation determine at all ages in vitro fertilization (IVF) pregnancy rates in women with diminished ovarian reserve (DOR) J Assist Reprod Genet 2013 30 49 62 10.1007/s10815-012-9890-z 23212832 \n12. Kushnir VA Solouki S Sarig-Meth T Vega MG Albertini DF Darmon SK Deligdisch L Barad DH Gleicher N Systemic inflammation and autoimmunity in women with chronic endometritis Am J Reprod Immunol 2016 75 672 677 10.1111/aji.12508 26952510 \n13. Libby P Current concepts of the pathogenesis of the acute coronary syndromes Circulation 2001 104 365 372 10.1161/01.CIR.104.3.365 11457759 \n14. Macklon NS Brosens JJ The human endometrium as a sensor of embryo quality Biol Reprod 2014 91 98 10.1095/biolreprod.114.122846 25187529 \n15. Michaud M Balardy L Moulis G Gaudin C Peyrot C Vellas B Cesari M Nourhashemi F Proinflammatory cytokines, aging, and age-related diseases J Am Med Dir Assoc 2013 14 877 882 10.1016/j.jamda.2013.05.009 23792036 \n16. Moore GS Allshouse AA Post AL Galan HL Heyborne KD Early initiation of low-dose aspirin for reduction in preeclampsia risk in high-risk women: a secondary analysis of the MFMU High-Risk Aspirin Study J Perinatol 2015 35 328 331 10.1038/jp.2014.214 25474553 \n17. Ortved D Hawkins TL Johnson JA Hyett J Metcalfe A The cost-effectiveness of first trimester screening and early preventative use of aspirin in women at high risk of early onset pre-eclampsia Ultrasound Obstet Gynecol 2018 53 2 239 244 10.1002/uog.19076 \n18. Paepegaey AC Genser L Bouillot JL Oppert JM Clement K Poitou C High levels of CRP in morbid obesity: the central role of adipose tissue and lessons for clinical practice before and after bariatric surgery Surg Obes Relat Dis 2015 11 148 154 10.1016/j.soard.2014.06.010 25393045 \n19. Pinar MH Gibbins K He M Kostadinov S Silver R Early pregnancy losses: review of nomenclature, histopathology, and possible etiologies Fetal Pediatr Pathol 2018 37 3 191 209 10.1080/15513815.2018.1455775 29737906 \n20. Radin RG Sjaarda LA Silver RM Nobles CJ Mumford SL Perkins NJ Wilcox BD Pollack AZ Schliep KC Plowden TC Schisterman EF C-Reactive protein in relation to fecundability and anovulation among eumenorrheic women Fertil Steril 2018 109 232 239 10.1016/j.fertnstert.2017.10.025 29317123 \n21. Rai R Cohen H Dave M Regan L Randomised controlled trial of aspirin and aspirin plus heparin in pregnant women with recurrent miscarriage associated with phospholipid antibodies (or antiphospholipid antibodies) BMJ 1997 314 253 257 10.1136/bmj.314.7076.253 9022487 \n22. Rolnik DL Wright D Poon LC O'Gorman N Syngelaki A de Paco MC Akolekar R Cicero S Janga D Singh M Molina FS Persico N Jani JC Plasencia W Papaioannou G Tenenbaum-Gavish K Meiri H Gizurarson S Maclagan K Nicolaides KH Aspirin versus placebo in pregnancies at high risk for preterm preeclampsia N Engl J Med 2017 377 613 622 10.1056/NEJMoa1704559 28657417 \n23. Sheu A Chan Y Ferguson A Bakhtyari MB Hawke W White C Chan YF Bertolino PJ Woon HG Palendira U Sierro F Lau SM A proinflammatory CD4(+) T cell phenotype in gestational diabetes mellitus Diabetologia 2018 61 7 1633 1643 10.1007/s00125-018-4615-1 29691600 \n24. Sirois J Sayasith K Brown KA Stock AE Bouchard N Dore M Cyclooxygenase-2 and its role in ovulation: a 2004 account Hum Reprod Update 2004 10 373 385 10.1093/humupd/dmh032 15205395 \n25. Sjaarda LA Radin RG Silver RM Mitchell E Mumford SL Wilcox B Galai N Perkins NJ Wactawski-Wende J Stanford JB Schisterman EF Preconception low-dose aspirin restores diminished pregnancy and live birth rates in women with low-grade inflammation: a secondary analysis of a randomized trial J Clin Endocrinol Metab 2017 102 1495 1504 10.1210/jc.2016-2917 28323989 \n26. Sugiura-Ogasawara M Ozaki Y Katano K Suzumori N Kitaori T Mizutani E Abnormal embryonic karyotype is the most frequent cause of recurrent miscarriage Hum Reprod 2012 27 2297 2303 10.1093/humrep/des179 22661547 \n27. Tempfer CB Kurz C Bentz EK Unfried G Walch K Czizek U Huber JC A combination treatment of prednisone, aspirin, folate, and progesterone in women with idiopathic recurrent miscarriage: a matched-pair study Fertil Steril 2006 86 145 148 10.1016/j.fertnstert.2005.12.035 16716321 \n28. Tincani A Bazzani C Zingarelli S Lojacono A Lupus and the antiphospholipid syndrome in pregnancy and obstetrics: clinical characteristics, diagnosis, pathogenesis, and treatment Semin Thromb Hemost 2008 34 267 273 10.1055/s-0028-1082270 18720306 \n29. Zeisler H Llurba E Chantraine F Vatish M Staff AC Sennstrom M Olovsson M Brennecke SP Stepan H Allegranza D Dilba P Schoedl M Hund M Verlohren S Predictive value of the sFlt-1:PlGF ratio in women with suspected preeclampsia N Engl J Med 2016 374 13 22 10.1056/NEJMoa1414838 26735990\n\n",
"fulltext_license": "CC BY",
"issn_linking": "0932-0067",
"issue": "301(3)",
"journal": "Archives of gynecology and obstetrics",
"keywords": "C-reactive protein (CRP); Euploid; Infertility; Inflammation; Miscarriage",
"medline_ta": "Arch Gynecol Obstet",
"mesh_terms": "D000022:Abortion, Spontaneous; D000328:Adult; D002097:C-Reactive Protein; D005260:Female; D006801:Humans; D007247:Infertility, Female; D010865:Pilot Projects; D011247:Pregnancy; D055815:Young Adult",
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"pubdate": "2020-03",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
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"title": "Euploid miscarriage is associated with elevated serum C-reactive protein levels in infertile women: a pilot study.",
"title_normalized": "euploid miscarriage is associated with elevated serum c reactive protein levels in infertile women a pilot study"
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{
"abstract": "Weekly rifapentine and isoniazid therapy (3HP) is the most frequent treatment for latent tuberculosis infection (LTBI). However, the association between major adverse drug reactions (ADRs) and drug metabolic enzyme single-nucleotide polymorphisms (SNPs) remains unclear. In this study, 377 participants who received the 3HP regimen were recruited and examined for genotyping of CYP5A6, CYP2B6, CYP2C19, CYP2E1, and NAT2 SNPs. In our study, 184 participants (48.4%) developed ADRs. Moreover, CYP2C19 rs4986893 (TT vs. CC+CT, odds ratio [OR] [95% CI]: 2.231 [1.015-4.906]), CYP2E1 rs2070676 (CC vs. CG+GG, OR [95% CI]: 1.563 [1.022-2.389]), and CYP2E1 rs2515641 (CC vs. CT+TT, OR [95% CI]: 1.903 [1.250-2.898]) were associated with ADR development. In conclusion, CYP2C19 and CYP2E1 SNPs may provide useful information regarding ADRs in LTBI patients receiving the 3HP regimen.",
"affiliations": "Institute of Medicine, Chung Shan Medical University, Taichung 402, Taiwan.;Division of Chest, Department of Internal Medicine, Chung Shan Medical University Hospital, Taichung 402, Taiwan.;Department of Internal Medicine, Taichung Hospital, Ministry of Health and Welfare, Taichung 403, Taiwan.;Division of Chest Medicine, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung 407, Taiwan.;Division of Chest, Changhua Christian Hospital, Changhua 500, Taiwan.;Department of Health, Pulmonary and Critical Care Unit, Changhua Hospital, Changhua 500, Taiwan.;Institute of Medicine, Chung Shan Medical University, Taichung 402, Taiwan.;School of Medical Laboratory and Biotechnology, Chung Shan Medical University, Taichung 402, Taiwan.;Institute of Medicine, Chung Shan Medical University, Taichung 402, Taiwan.",
"authors": "Yu|Ya-Yen|YY|;Tsao|Shih-Ming|SM|;Yang|Wen-Ta|WT|;Huang|Wei-Chang|WC|0000-0002-9733-5899;Lin|Ching-Hsiung|CH|;Chen|Wei-Wen|WW|;Yang|Shun-Fa|SF|0000-0002-0365-7927;Chiou|Hui-Ling|HL|;Huang|Yi-Wen|YW|0000-0001-6097-3910",
"chemical_list": "D000995:Antitubercular Agents; D003577:Cytochrome P-450 Enzyme System; D001191:Arylamine N-Acetyltransferase; C478900:NAT2 protein, human; D007538:Isoniazid; D012293:Rifampin; C018421:rifapentine",
"country": "Switzerland",
"delete": false,
"doi": "10.3390/ijerph17010210",
"fulltext": "\n==== Front\nInt J Environ Res Public HealthInt J Environ Res Public HealthijerphInternational Journal of Environmental Research and Public Health1661-78271660-4601MDPI 10.3390/ijerph17010210ijerph-17-00210ArticleAssociation of Drug Metabolic Enzyme Genetic Polymorphisms and Adverse Drug Reactions in Patients Receiving Rifapentine and Isoniazid Therapy for Latent Tuberculosis Yu Ya-Yen 12Tsao Shih-Ming 34Yang Wen-Ta 5https://orcid.org/0000-0002-9733-5899Huang Wei-Chang 6789Lin Ching-Hsiung 10Chen Wei-Wen 11https://orcid.org/0000-0002-0365-7927Yang Shun-Fa 112Chiou Hui-Ling 1314*https://orcid.org/0000-0001-6097-3910Huang Yi-Wen 111*1 Institute of Medicine, Chung Shan Medical University, Taichung 402, Taiwan; yy68642@gmail.com (Y.-Y.Y.); ysf@csmu.edu.tw (S.-F.Y.)2 Department of Clinical Laboratory, Changhua Hospital, Changhua 513, Taiwan3 Division of Chest, Department of Internal Medicine, Chung Shan Medical University Hospital, Taichung 402, Taiwan; tsmhwy@ms24.hinet.net4 Institute of Biochemistry, Microbiology and Immunology, Chung Shan Medical University, Taichung 402, Taiwan5 Department of Internal Medicine, Taichung Hospital, Ministry of Health and Welfare, Taichung 403, Taiwan; taic3057@gmail.com6 Division of Chest Medicine, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung 407, Taiwan; huangweichangtw@gmail.com7 Department of Medical Technology, Jen-Teh Junior College of Medicine, Nursing and Management, Miaoli 356, Taiwan8 Department of Life Sciences, National Chung Hsing University, Taichung 402, Taiwan9 Department of Industrial Engineering and Enterprise Information, Tunghai University, Taichung 407, Taiwan10 Division of Chest, Changhua Christian Hospital, Changhua 500, Taiwan; 47822@cch.org.tw11 Department of Health, Pulmonary and Critical Care Unit, Changhua Hospital, Changhua 500, Taiwan; sweefa818@gmail.com12 Department of Medical Research, Chung Shan Medical University Hospital, Taichung 402, Taiwan13 School of Medical Laboratory and Biotechnology, Chung Shan Medical University, Taichung 402, Taiwan14 Department of Clinical Laboratory, Chung Shan Medical University Hospital, Taichung 402, Taiwan* Correspondence: hlchiou@csmu.edu.tw (H.-L.C.); hiwen1533@gmail.com (Y.-W.H.)27 12 2019 1 2020 17 1 21011 11 2019 25 12 2019 © 2019 by the authors.2019Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).Weekly rifapentine and isoniazid therapy (3HP) is the most frequent treatment for latent tuberculosis infection (LTBI). However, the association between major adverse drug reactions (ADRs) and drug metabolic enzyme single-nucleotide polymorphisms (SNPs) remains unclear. In this study, 377 participants who received the 3HP regimen were recruited and examined for genotyping of CYP5A6, CYP2B6, CYP2C19, CYP2E1, and NAT2 SNPs. In our study, 184 participants (48.4%) developed ADRs. Moreover, CYP2C19 rs4986893 (TT vs. CC+CT, odds ratio [OR] [95% CI]: 2.231 [1.015–4.906]), CYP2E1 rs2070676 (CC vs. CG+GG, OR [95% CI]: 1.563 [1.022–2.389]), and CYP2E1 rs2515641 (CC vs. CT+TT, OR [95% CI]: 1.903 [1.250–2.898]) were associated with ADR development. In conclusion, CYP2C19 and CYP2E1 SNPs may provide useful information regarding ADRs in LTBI patients receiving the 3HP regimen.\n\ndrug metabolic enzymespolymorphismlatent tuberculosisadverse drug reaction\n==== Body\n1. Introduction\nTuberculosis (TB) is still prevalent worldwide. Up to one-third of the world’s population is estimated to be infected with Mycobacterium tuberculosis [1]. Additionally, although infected individuals have no signs or symptoms of TB disease and are not infectious, they still have a risk of active TB infection and becoming infectious. In Taiwan, TB ranks the highest for the number of new cases and is the main cause of death annually from communicable diseases in Taiwan.\n\nA comprehensive effort to control TB by implementing directly observed therapy (DOT), a short-course program, for all patients with TB has been implemented since 2006 in Taiwan to reduce the incidence to half, from 67.4 per 100,000 population to 33.7 per 100,000 population, by 2016. Although the incidence rate has declined, it gradually slowed down to 43.9 per 100,000 population by 2016, less than half of the target. Thus, intensified efforts to reduce TB morbidity and transmission by implementing more laboratory diagnoses, active-TB case identification, and latent TB infection (LTBI) treatment have been commenced since 2016.\n\nApart from the traditional LTBI treatment regimen, that is, isoniazid (INH) 300 mg daily for 9 months (9H), in 2011 the Centers for Disease Control and Prevention recommended a short-course combination regimen of once-weekly INH and rifapentine for 12 weeks (3HP) through DOT [2,3]. Compared with other regimens, the 3HP regimen has practical advantages, such as a shorter treatment period, higher completion rate, and cost effectiveness [4]. Typically, the hepatotoxicity risk during LTBI treatment is much lower in the 3HP regimen than in the 9H regimen [5]. Therefore, the 3HP regimen was initiated in Taiwan in 2013, as it is in one of the high prevalence areas for viral hepatitis. However, the incidence of flu-like syndrome, one of the side effects of the 3HP regimen, is much higher in Taiwan (8% vs. 2.2%) [6,7] than in other countries. The occurrence of flu-like syndrome is also the common reason for the noncompliance of patients with the 3HP regimen.\n\nFlu-like syndrome is one of the adverse reactions of rifapentine. Rifapentine induces cytochrome P450 enzymes and can also accelerate the metabolism of certain drugs, such as birth control pills and antiretroviral drugs [8]. By contrast, INH is the inhibitor of cytochrome P450 enzymes [9,10]. Therefore, clinicians should pay more attention to drug–drug interactions. Another study reported that women, Caucasians, elderly individuals, and individuals with a low body mass index (BMI) have a higher risk of developing systemic drug reactions after the administration of the 3HP regimen; however, the mechanism underlying this increased risk remains unclear [6]. Therefore, in this study, eight polymorphisms of drug metabolic enzyme genes, namely CYP5A6 rs28399433, CYP2B6 rs8192709, CYP2C19 rs4986893, CYP2C19 rs12248560, CYP2E1 rs2070676, CYP2E1 rs2515641, NAT2 rs1495741, and NAT2 rs1799930, were examined to study their associations with susceptibility to adverse drug reactions (ADRs) in the 3HP regimen in patients with latent TB infection in Taiwan.\n\n2. Materials and Methods\n2.1. Study Design\nThis was a multicenter observational study including close contacts aged >12 years and selecting individuals not resistant to INH and rifampin between February 2017 and October 2018. Participants received 15 mg/kg of INH (maximum dose of 900 mg) and rifapentine (maximum dose of 900 mg). Basic information, namely age, sex, BMI, ethnicity, education, comorbidities, medications, occupation, and compliance with therapy, were recorded for each participant. Dose adherence was assessed by DOT, and ADR monitoring was based on patients’ self-report. ADRs were recorded after receiving the first dose each week until two weeks after the treatment. The onset time, duration, and severity of ADRs, such as flu-like syndrome and skin symptoms, were recorded. Severity was defined by the common toxicity criteria of the Cancer Therapy Evaluation Program. The association between the cause of incomplete treatment and single-nucleotide polymorphisms (SNPs) was analyzed on the basis of the aforementioned data. Written informed consent was obtained from each participant enrolled in this study. This study was approved by the Institutional Review Board of Chung Shan Medical University Hospital (CSMUH No: CS16131).\n\n2.2. Sample Preparation and DNA Extraction\nPeripheral blood specimens were collected from patients with LTBI for genomic DNA extraction. Whole blood samples were placed in ethylenediaminetetraacetic (EDTA)-containing tubes and were centrifuged at 3000 rpm for 10 min. Genomic DNA extraction was performed using QIAamp DNA blood mini kits (Qiagen, Valencia, CA, USA) as previously described [11]. Extracted DNA was dissolved in Tris-EDTA (TE) buffer and was applied as DNA template in the following process of polymerase chain reactions.\n\n2.3. Drug Metabolic Enzyme SNP Genotyping\nAssessment of allelic discrimination for CYP5A6 rs28399433 (assay ID: C_30634332_10), CYP2B6 rs8192709 (assay ID: C_2818162_20), CYP2C19 rs4986893 (assay ID: C_27861809_10), CYP2C19 rs12248560 (assay ID: C_469857_10), CYP2E1 rs2070676 (assay ID: C_16026001_20), CYP2E1 rs2515641 (assay ID: C_16026002_10), NAT2 rs1495741 (assay IDs: C_8684110_10), and NAT2 rs1799930 (assay IDs: C_1204091_10) SNPs were performed using the TaqMan assay with an ABI StepOne Software v2.3 Real-Time PCR System. The real-time PCR consisted of initial denaturation at 95 °C for 10 min, followed by 40 cycles at 95 °C for 15 s and finally 1 min at 60 °C. Generated data were collected and further evaluated using the SDS 7000 series software (Applied Biosystems, Foster City, CA, USA).\n\n2.4. Statistical Analysis\nContinuous variables were determined using Student’s t-test, and categorical variables were determined using the chi-squared test or Fisher’s exact test. The chi-squared test was also applied to determine the prevalence of all drug metabolic enzyme gene polymorphisms, such as CYP2E1 genotype, between the non-ADR and ADR group. Multiple unconditional logistic regression analyses were performed to estimate odds ratios and their 95% confidence intervals. Two-tailed p values < 0.05 were considered to be statistically significant.\n\n3. Results\nA total of 377 TB patients were recruited and administered the 3HP regimen. Of these 377 participants, 337 (89.3%) completed the treatment, 29 (7.7%) discontinued treatment owing to ADRs, 8 (2.1%) switched to the 9H regimen due to ADRs, and 3 (0.8%) transferred to another facility or refused further treatment (Table 1). In the total sample, the mean age was 45.7 years, 208 participants (55.2%) were women, 144 participants (38.2%) had comorbidities, and 184 (48.8%) developed ADRs (Table 2). ADRs occurred in 184 participants (48.4%), and 596 adverse drug events were reported. Most of the ADRs were Grade 1 (77.68%), followed by Grade 2 ADRs (20.63%). Grade 3 ADRs were observed most frequently in patients with flu-like symptoms (80%), one patient with urticaria, and one patient with hepatotoxicity.\n\nThe genotypes of CYP5A6, CYP2B6, CYP2C19, CYP2E1, and NAT2 SNPs in the non-ADR and ADR groups are shown in Table 3. In the non-ADR and ADR groups, the highest distribution frequencies of the drug metabolic enzyme genetic polymorphisms rs28399433, rs8192709, rs4986893, rs12248560, rs2070676, rs2515641, rs1495741, and rs1799930 were homozygous for AA, TT, GG, CC, CC, CC, GA, and GG, respectively. As shown in Table 3, patients with CYP2B6 polymorphic rs8192709 TC or TC+CC, CYP2E1 polymorphic rs2070676 CG or CG+GG, CYP2E1 polymorphic rs2515641 CT or CT+TT genotypes exhibited significantly (p < 0.05) higher frequencies, 2.355-fold (95% CI: 1.037–5.351), 2.231-fold (95% CI: 1.015–4.906), 1.594-fold (95% CI: 1.031–2.464), 1.563-fold (95% CI: 1.022–2.389), 1.850-fold (95% CI: 1.193–2.870), and 1.903-fold (95% CI: 1.250–2.898) respectively, of developing ADRs compared with their corresponding wild type (WT) homozygotes.\n\nThe allele frequencies of CYP5A6, CYP2B6, CYP2C19, CYP2E1, and NAT2 SNPs in patients in the non-ADR and ADR groups are shown in Table 4. Results indicated that patients with the CYP2E1 polymorphic rs2515641 T allele and NAT2 polymorphic rs1495741 A allele exhibited significantly (p < 0.05) higher frequencies, 1.704-fold (95% CI: 1.200–2.421) and 1.415-fold (95% CI: 1.062–1.885), respectively, of developing ADRs compared with their corresponding WT homozygotes (Table 4).\n\n4. Discussion\nIn this study, we investigated the significance of the relationship between ADR in patients with LTBI receiving the 3HP regimen and several drug metabolic enzyme gene polymorphisms of CYP5A6, CYP2B6, CYP2C19, CYP2E1, and NAT2 in the Taiwanese population. Results showed that almost half of the participants (184/377, 48.8%) experienced ADRs (98.3% were <Grade 2), and the most common presentation was flu-like symptoms, accounting for 80.2% of ADR episodes, which is much higher than that reported in a previous study [6]. Our study results indicated that the high incidence of flu-like symptoms is the major problem associated with the prescription of 3HP short-term treatment for LTBI cases. This is another aspect that should be further investigated.\n\nINH is an inhibitor of cytochrome P450 [9,10]; by contrast, rifapentine is an inducer of cytochrome P450 [8,12], which may result in pharmacodynamic reduction in the treatment regimen. Our study showed that cytochrome P450 enzymes, such as CYP2B6 and CYP2E1, were associated with the incidence of ADR (p < 0.05). Some of these enzymes are involved in the metabolic pathway of INH, such as CYP2E1 and NAT2 [13,14], and some have direct or indirect effects on INH, such as CYP2B6 [15]. Based on our study results, the occurrence of side effects appeared to be more related to INH. Thus, the relationship between INH and flu-like symptoms is worth examining because the major side effects of the 3HP treatment are flu-like symptoms.\n\nThe 3HP regimen contained 3 times higher doses, especially for INH, when compared with other regimens. However, based on animal studies, high doses of INH have no greater efficacy than standard doses (300 mg) [16]. By contrast, significant differences in drug tolerance, ADRs, and safety were not observed between the high and normal doses of rifapentine [17,18,19,20]. Rifapentine acts as an inducer of many metabolic enzymes, especially in antiretroviral drugs; thus, interactions between INH and rifapentine have been evaluated in many studies [21,22]. In 2018, Brooks et al. indicated that serious drug side effects are associated with endogenous cytokines [23]. Therefore, we speculate that high doses of INH can induce side effects of rifapentine, coupled with the effects of certain genotypes, resulting in more drug side effects in many cases. However, this hypothesis must be explored and confirmed by conducting additional molecular biology, pharmacokinetics, and pharmacodynamics studies, and even animal experiments.\n\nThis study aimed to determine whether the side effects of LTBI 3HP treatment (INH and rifapentine) are associated with SNPs. Many studies have discussed the association between genotypes and drug side effects [24,25,26]; with the rise of pharmacogenetics and pharmacogenomics in recent years [27,28,29], in addition to the current focus on personalized medicine, the results of this study are expected to be personalized in TB.\n\nSeveral genotypes (rs8192709 TC, rs2070676 CG, rs2515641 CT, and rs1495741 AA) showed an association with side effects to LTBI in our study. The results indicate that for patients with the rs8192709 TC genotype, the risk of side effects is 2.355 folds higher than that for patients with the TT genotype. Furthermore, patients with the rs2070676 CG genotype, rs2515641 CT genotype, and rs1495741 AA genotype had higher risks of side effects (p = 0.036, p = 0.006, and p = 0.018, respectively) than did patients with other genotypes (Table 3). Additionally, rs2515641 T and rs1495741 A allele carriers belong to a high-risk group for side effects (p = 0.003 and p = 0.018, respectively) (Table 4). Hiratsuka et al. have suggested that SNPs of NAT2 enzymes can predict the side effects of INH [30]. Similarly, Sotsuka et al. indicated that hepatotoxicity caused by INH is related to the genotype of its drug-metabolizing enzyme [31]. Additionally, the genotype of NAT2 is associated with failure or recurrence of TB treatment [21]. Most of the studies have investigated the relationship between INH and genotypes. By contrast, few studies have focused on the relationship between rifapentine and genotypes; this may be due to the metabolic pathway of rifapentine, which is still unclear, thus hindering further research on genetic polymorphisms.\n\n5. Conclusions\nIn summary, we found that CYP2C19 rs4986893, CYP2E1 rs2070676, and CYP2E1 rs2515641 were associated with ADR development. Since CYP2C19 and CYP2E1 have been proven to be involved in the metabolic pathway of INH, their association with ADR development is a rational supposition. The results of this study can provide an improved strategy for identifying people with increased TB risk.\n\nAuthor Contributions\nConceptualization: Y.-Y.Y., S.-M.T., H.-L.C., and Y.-W.H.; methodology: W.-W.C. and S.-F.Y.; formal analysis: S.-F.Y.; resources: S.-M.T., W.-T.Y., W.-C.H., C.-H.L., and Y.-W.H.; writing—original draft preparation: Y.-Y.Y., S.-M.T., W.-W.C., H.-L.C., and Y.-W.H.; writing—review and editing; Y.-Y.Y., S.-M.T., S.-F.Y., H.-L.C., and Y.-W.H. All authors have read and agreed to the published version of the manuscript.\n\nFunding\nThis research received no external funding.\n\nConflicts of Interest\nThe authors declare no conflict of interest.\n\nijerph-17-00210-t001_Table 1Table 1 Characteristics and treatment outcomes of the enrolled participants.\n\n(n = 377)\tTreatment Completed\tInterrupted Due to Side Effects\tSwitched to 9H Due to Side Effects\tOther *\t\nNumber\t337\t29\t8\t3\t\n%\t89.4%\t7.7%\t2.1%\t0.8%\t\n* Transferred to other medical facility, refused further treatment.\n\nijerph-17-00210-t002_Table 2Table 2 Clinical characteristics and laboratory data in 377 patients.\n\nVariable\t(n = 377)\tNon-ADR\n(n = 193)\tADR\n(n = 184)\t\nAge (year)\t\n\t\n\t\n\t\n≦35\t96\t53\t43\t\n36–55\t169\t88\t81\t\n56–64\t83\t37\t46\t\n≧65\t29\t15\t14\t\nGender\t\n\t\n\t\n\t\nMale\t169\t101\t68\t\nFemale\t208\t92\t116\t\nBody mass index (kg/m2)\t24.9\t25\t24.7\t\nAST (U/L)\t25.11\t24.95\t25.32\t\nALT (U/L)\t27.08\t26.98\t27.1\t\nComorbidity (n = 144)\t\n\t\n\t\n\t\nHypertension\t46\t22\t24\t\nDiabetes mellitus\t21\t12\t9\t\nHBV infection\t17\t11\t6\t\nHeart disease\t8\t4\t4\t\nThalassemias\t5\t1\t4\t\nHyperlipidemia\t4\t2\t2\t\nAllergic rhinitis\t4\t4\t0\t\nInsomnia\t3\t0\t3\t\nHyperthyroidism\t3\t2\t1\t\nGastric ulcer\t4\t0\t4\t\nHyperthyroidism\t3\t2\t1\t\nHepatitis C\t2\t0\t2\t\nGout\t2\t0\t2\t\nLung cancer\t2\t0\t2\t\nDementia\t1\t0\t1\t\nBreast cancer\t2\t1\t1\t\nProctitis\t1\t0\t1\t\nFatty liver\t1\t0\t1\t\nHyperuricemia\t1\t1\t0\t\nOthers\t14\t8\t6\t\nADR: adverse drug reaction; AST: aspartate transaminase; ALT: alanine transaminase. HBV: Hepatitis B virus; Others: epilepsy, urticaria, cerebral neurasthenia, cerebral palsy, fibromyalgia, anemia, aplastic anemia, gall stone, hemochromatosis. Data are number. \n\nijerph-17-00210-t003_Table 3Table 3 Single nucleotide polymorphism frequencies of five drug-metabolic genes in 377 patients.\n\nVariable\tALL\n(n = 377)\tNon-ADR (n = 193)\tADR\n(n = 184)\tOR (95% C.I.)\tp Value\t\nCYP5A6 (rs28399433)\t\n\t\n\t\n\t\n\t\n\t\nA/A\t235 (62.3%)\t116 (60.1%)\t119 (64.7%)\t1.000 (reference)\t\n\t\nC/A\t100 (26.5%)\t54 (28.0%)\t46 (25.0%)\t0.830 (0.519–1.327)\tp = 0.437\t\nC/C\t42 (11.2%)\t23 (11.9%)\t19 (10.3%)\t0.805 (0.417–1.557)\tp = 0.520\t\nC/A+C/C\t142 (37.7%)\t77 (39.9%)\t65 (35.3%)\t0.823 (0.542–1.249)\tp = 0.360\t\nCYP2B6 (rs8192709)\t\n\t\n\t\n\t\n\t\n\t\nT/T\t347 (92.0%)\t183 (94.8%)\t164 (89.1%)\t1.000 (reference)\t\n\t\nT/C\t28 (7.5%)\t9 (4.7%)\t19 (10.3%)\t\n2.355 (1.037–5.351)\n\t\np = 0.041 *\n\t\nC/C\t2 (0.5%)\t1 (0.5%)\t1 (0.6%)\t1.116 (0.069–17.983)\tp = 0.938\t\nT/C+C/C\t30 (8.0%)\t10 (5.2%)\t20 (10.9%)\t\n2.231 (1.015–4.906)\n\t\np = 0.046 *\n\t\nCYP2C19 (rs4986893)\t\n\t\n\t\n\t\n\t\n\t\nG/G\t342 (90.7%)\t180 (93.3%)\t162 (88.0%)\t1.000 (reference)\t\n\t\nG/A\t34 (9.0%)\t12 (6.2%)\t22 (12.0%)\t2.037 (0.977–4.247)\tp = 0.058\t\nA/A\t1 (0.3%)\t1 (0.5%)\t0 (0.0%)\t-\t-\t\nG/A+A/A\t35 (9.3%)\t13 (6.7%)\t22 (12.0%)\t1.880 (0.917–3.854)\tp = 0.085\t\nCYP2C19 (rs12248560)\t\n\t\n\t\n\t\n\t\n\t\nC/C\t375 (99.5%)\t191 (99.0%)\t184 (100.0%)\t1.000 (reference)\t\n\t\nT/C\t2 (0.5%)\t2 (1.0%)\t0 (0.0%)\t-\t-\t\nT/T\t0 (0%)\t0 (0.0%)\t0 (0.0%)\t-\t-\t\nT/C+T/T\t2 (0.5%)\t2 (1.0%)\t0 (0.0%)\t-\t-\t\nCYP2E1 (rs2070676)\t\n\t\n\t\n\t\n\t\n\t\nC/C\t243 (64.5%)\t134 (69.4%)\t109 (59.3%)\t1.000 (reference)\t\n\t\nC/G\t124 (32.9%)\t54 (28.0%)\t70 (38.0%)\t\n1.594 (1.031–2.464)\n\t\np = 0.036 *\n\t\nG/G\t10 (2.6%)\t5 (2.6%)\t5 (2.7%)\t1.229 (0.347–4.356)\tp = 0.749\t\nC/G+G/G\t134 (35.5%)\t59 (30.6%)\t75 (40.8%)\t\n1.563 (1.022–2.389)\n\t\np = 0.039 *\n\t\nCYP2E1 (rs2515641)\t\n\t\n\t\n\t\n\t\n\t\nC/C\t232 (61.5%)\t133 (68.9%)\t99 (53.8%)\t1.000 (reference)\t\n\t\nC/T\t126 (33.4%)\t53 (27.5%)\t73 (39.7%)\t\n1.850 (1.193–2.870)\n\t\np = 0.006 *\n\t\nT/T\t19 (5.1%)\t7 (3.6%)\t12 (6.5%)\t2.303 (0.875–6.062)\tp = 0.091\t\nC/T+T/T\t145 (38.5%)\t60 (31.1%)\t85 (46.2%)\t\n1.903 (1.250–2.898)\n\t\np = 0.003 *\n\t\nNAT2 (rs1495741)\t\n\t\n\t\n\t\n\t\n\t\nG/G\t116 (30.8%)\t63 (32.6%)\t53 (28.8%)\t1.000 (reference)\t\n\t\nG/A\t166 (44.0%)\t94 (48.7%)\t72 (39.1%)\t0.910 (0.565–1.467)\tp = 0.700\t\nA/A\t95 (25.2%)\t36 (18.7%)\t59 (32.1%)\t\n1.948 (1.121–3.385)\n\t\np = 0.018 *\n\t\nG/A+A/A\t261 (69.2%)\t130 (67.4%)\t131 (71.2%)\t1.198 (0.773–1.857)\tp = 0.420\t\nNAT2 (rs1799930)\t\n\t\n\t\n\t\n\t\n\t\nG/G\t219 (58.1%)\t112 (58.0%)\t107 (58.1%)\t1.000 (reference)\t\n\t\nG/A\t128 (33.9%)\t62 (32.1%)\t66 (35.9%)\t1.114 (0.720–1.724)\tp = 0.627\t\nA/A\t30 (8.0%)\t19 (9.9%)\t11 (6.0%)\t0.606 (0.275–1.333)\tp = 0.213\t\nG/A+A/A\t158 (41.9%)\t81 (42.0%)\t77 (41.8%)\t0.995 (0.661–1.498)\tp = 0.981\t\nNote: * and bold text indicate a significant association with p-value < 0.05.\n\nijerph-17-00210-t004_Table 4Table 4 Single nucleotide polymorphism frequencies of five drug-metabolic genes in 377 patients.\n\nVariable\tALL\n(n = 754)\tNon-ADR (n = 386)\tADR\n(n = 368)\tOR (95% C.I.)\tp Value\t\nCYP5A6 (rs28399433)\t\n\t\n\t\n\t\n\t\n\t\nA allele\t570 (75.6%)\t286 (74.1%)\t284 (77.2%)\t1.000 (reference)\t\n\t\nC allele\t184 (24.4%)\t100 (25.9%)\t84 (22.8%)\t0.846 (0.606–1.181)\tp = 0.325\t\nCYP2B6 (rs8192709)\t\n\t\n\t\n\t\n\t\n\t\nT allele\t722 (95.8%)\t375 (97.2%)\t347 (94.3%)\t1.000 (reference)\t\n\t\nC allele\t32 (4.2%)\t11 (2.8%)\t21 (5.7%)\t2.063 (0.980–4.341)\tp = 0.056\t\nCYP2C19 (rs4986893)\t\n\t\n\t\n\t\n\t\n\t\nG allele\t718 (95.2%)\t372 (96.4%)\t346 (94.0%)\t1.000 (reference)\t\n\t\nA allele\t36 (4.8%)\t14 (3.6%)\t22 (6.0%)\t1.690 (0.851–3.355)\tp = 0.134\t\nCYP2C19 (rs12248560)\t\n\t\n\t\n\t\n\t\n\t\nC allele\t752 (99.7%)\t384 (99.5%)\t368 (100.0%)\t1.000 (reference)\t\n\t\nT allele\t2 (0.3%)\t2 (0.5%)\t0 (0.0%)\t-\t-\t\nCYP2E1 (rs2070676)\t\n\t\n\t\n\t\n\t\n\t\nC allele\t610 (80.9%)\t322 (83.4%)\t288 (78.3%)\t1.000 (reference)\t\n\t\nG allele\t144 (19.1%)\t64 (16.6%)\t80 (21.7%)\t1.398 (0.970–2.013)\tp = 0.072\t\nCYP2E1 (rs2515641)\t\n\t\n\t\n\t\n\t\n\t\nC allele\t590 (78.3%)\t319 (82.6%)\t271 (73.6%)\t1.000 (reference)\t\n\t\nT allele\t164 (21.7%)\t67 (17.4%)\t97 (26.4%)\t\n1.704 (1.200–2.421)\n\t\np = 0.003 *\n\t\nNAT2 (rs1495741)\t\n\t\n\t\n\t\n\t\n\t\nG allele\t398 (52.8%)\t220 (57.0%)\t178 (48.4%)\t1.000 (reference)\t\n\t\nA allele\t356 (47.2%)\t166 (43.0%)\t190 (51.6%)\t\n1.415 (1.062–1.885)\n\t\np = 0.018 *\n\t\nNAT2 (rs1799930)\t\n\t\n\t\n\t\n\t\n\t\nG allele\t566 (75.1%)\t286 (74.1%)\t280 (76.1%)\t1.000 (reference)\t\n\t\nA allele\t188 (24.9%)\t100 (25.9%)\t88 (23.9%)\t0.899 (0.646–1.251)\tp = 0.528\t\nNote: * and bold text indicated a significant association with p-value < 0.05.\n==== Refs\nReferences\n1. 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Cost-effectiveness of 3 months of weekly rifapentine and isoniazid compared with other standard treatment regimens for latent tuberculosis infection: A decision analysis study J. Antimicrob. Chemother. 2019 74 218 227 10.1093/jac/dky403 30295760 \n5. Bliven-Sizemore E.E. Sterling T.R. Shang N. Benator D. Schwartzman K. Reves R. Drobeniuc J. Bock N. Villarino M.E. Three months of weekly rifapentine plus isoniazid is less hepatotoxic than nine months of daily isoniazid for LTBI Int. J. Tuberc. Lung Dis. 2015 19 1039 1044 10.5588/ijtld.14.0829 26260821 \n6. Sterling T.R. Moro R.N. Borisov A.S. Phillips E. Shepherd G. Adkinson N.F. Weis S. Ho C. Villarino M.E. Flu-like and other systemic drug reactions among persons receiving weekly rifapentine plus isoniazid or daily isoniazid for treatment of latent tuberculosis infection in the prevent tuberculosis study Clin. Infect. Dis. Off. Publ. Infect. Dis. Soc. Am. 2015 61 527 535 10.1093/cid/civ323 \n7. Huang Y.W. Yang S.F. Yeh Y.P. Tsao T.C. Tsao S.M. Impacts of 12-dose regimen for latent tuberculosis infection: Treatment completion rate and cost-effectiveness in Taiwan Medicine 2016 95 e4126 10.1097/MD.0000000000004126 27559940 \n8. Baciewicz A.M. Chrisman C.R. Finch C.K. Self T.H. Update on rifampin, rifabutin, and rifapentine drug interactions Curr. Med Res. Opin. 2013 29 1 12 10.1185/03007995.2012.747952 \n9. Desta Z. Soukhova N.V. Flockhart D.A. Inhibition of cytochrome p450 (cyp450) isoforms by isoniazid: Potent inhibition of cyp2c19 and cyp3a Antimicrob. Agents Chemother. 2001 45 382 392 10.1128/AAC.45.2.382-392.2001 11158730 \n10. Wen X. Wang J.S. Neuvonen P.J. Backman J.T. Isoniazid is a mechanism-based inhibitor of cytochrome p450 1a2, 2a6, 2c19 and 3a4 isoforms in human liver microsomes Eur. J. Clin. Pharmacol. 2002 57 799 804 10.1007/s00228-001-0396-3 11868802 \n11. Tung M.C. Wen Y.C. Wang S.S. Lin Y.W. Chow J.M. Yang S.F. Chien M.H. Impact of long non-coding RNA hotair genetic variants on the susceptibility and clinicopathologic characteristics of patients with urothelial cell carcinoma J. Clin. Med. 2019 8 282 10.3390/jcm8030282 30813594 \n12. Williamson B. Dooley K.E. Zhang Y. Back D.J. Owen A. Induction of influx and efflux transporters and cytochrome p450 3a4 in primary human hepatocytes by rifampin, rifabutin, and rifapentine Antimicrob. Agents Chemother. 2013 57 6366 6369 10.1128/AAC.01124-13 24060875 \n13. Perwitasari D.A. Atthobari J. Wilffert B. Pharmacogenetics of isoniazid-induced hepatotoxicity Drug Metab. Rev. 2015 47 222 228 10.3109/03602532.2014.984070 26095714 \n14. Wang P. Pradhan K. Zhong X.B. Ma X. Isoniazid metabolism and hepatotoxicity Acta Pharm. Sin. B 2016 6 384 392 10.1016/j.apsb.2016.07.014 27709007 \n15. Fernandes D.C. Santos N.P. Moraes M.R. Braga A.C. Silva C.A. Ribeiro-dos-Santos A. Santos S. Association of the cyp2b6 gene with anti-tuberculosis drug-induced hepatotoxicity in a brazilian amazon population Int. J. Infect. Dis. 2015 33 28 31 10.1016/j.ijid.2014.04.011 25271170 \n16. Cynamon M.H. Zhang Y. Harpster T. Cheng S. DeStefano M.S. High-dose isoniazid therapy for isoniazid-resistant murine mycobacterium tuberculosis infection Antimicrob. Agents Chemother. 1999 43 2922 2924 10.1128/AAC.43.12.2922 10582883 \n17. Weiner M. Burman W. Vernon A. Benator D. Peloquin C.A. Khan A. Weis S. King B. Shah N. Hodge T. Low isoniazid concentrations and outcome of tuberculosis treatment with once-weekly isoniazid and rifapentine Am. J. Respir. Crit. Care. Med. 2003 167 1341 1347 10.1164/rccm.200208-951OC 12531776 \n18. Bock N.N. Sterling T.R. Hamilton C.D. Pachucki C. Wang Y.C. Conwell D.S. Mosher A. Samuels M. Vernon A. 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Chemother. 2014 69 1079 1085 10.1093/jac/dkt483 24343893 \n22. Podany A.T. Bao Y. Swindells S. Chaisson R.E. Andersen J.W. Mwelase T. Supparatpinyo K. Mohapi L. Gupta A. Benson C.A. Efavirenz pharmacokinetics and pharmacodynamics in hiv-infected persons receiving rifapentine and isoniazid for tuberculosis prevention Clin. Infect. Dis. 2015 61 1322 1327 10.1093/cid/civ464 26082504 \n23. Brooks K.M. George J.M. Pau A.K. Rupert A. Mehaffy C. De P. Dobos K.M. Kellogg A. McLaughlin M. McManus M. Cytokine-mediated systemic adverse drug reactions in a drug-drug interaction study of dolutegravir with once-weekly isoniazid and rifapentine Clin. Infect. Dis. 2018 67 193 201 10.1093/cid/ciy082 29415190 \n24. Guzey C. Spigset O. Genotyping of drug targets: A method to predict adverse drug reactions? Drug Saf. 2002 25 553 560 10.2165/00002018-200225080-00002 12113641 \n25. Guzey C. Spigset O. Genotyping as a tool to predict adverse drug reactions Curr. Top. Med. Chem. 2004 4 1411 1421 10.2174/1568026043387791 15379654 \n26. Wilke R.A. Lin D.W. Roden D.M. Watkins P.B. Flockhart D. Zineh I. Giacomini K.M. Krauss R.M. Identifying genetic risk factors for serious adverse drug reactions: Current progress and challenges Nat. Rev. Drug Discov. 2007 6 904 916 10.1038/nrd2423 17971785 \n27. Rioux P.P. Clinical trials in pharmacogenetics and pharmacogenomics: Methods and applications Am. J. Health. Syst. Pharm. 2000 57 887 901 887–898; quiz 899–901 10.1093/ajhp/57.9.887 10840530 \n28. Daly A.K. Pharmacogenomics of adverse drug reactions Genome Med. 2013 5 5 10.1186/gm409 23360680 \n29. Relling M.V. Evans W.E. Pharmacogenomics in the clinic Nature 2015 526 343 350 10.1038/nature15817 26469045 \n30. Hiratsuka M. Kishikawa Y. Takekuma Y. Matsuura M. Narahara K. Inoue T. Hamdy S.I. Endo N. Goto J. Mizugaki M. Genotyping of the n-acetyltransferase2 polymorphism in the prediction of adverse drug reactions to isoniazid in japanese patients Drug Metab. Pharmacokinet. 2002 17 357 362 10.2133/dmpk.17.357 15618686 \n31. Sotsuka T. Sasaki Y. Hirai S. Yamagishi F. Ueno K. Association of isoniazid-metabolizing enzyme genotypes and isoniazid-induced hepatotoxicity in tuberculosis patients In Vivo (Athens, Greece) 2011 25 803 812\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1660-4601",
"issue": "17(1)",
"journal": "International journal of environmental research and public health",
"keywords": "adverse drug reaction; drug metabolic enzymes; latent tuberculosis; polymorphism",
"medline_ta": "Int J Environ Res Public Health",
"mesh_terms": "D000328:Adult; D000995:Antitubercular Agents; D001191:Arylamine N-Acetyltransferase; D003577:Cytochrome P-450 Enzyme System; D004334:Drug Administration Schedule; D004359:Drug Therapy, Combination; D064420:Drug-Related Side Effects and Adverse Reactions; D005260:Female; D006801:Humans; D007538:Isoniazid; D055985:Latent Tuberculosis; D008297:Male; D016017:Odds Ratio; D020641:Polymorphism, Single Nucleotide; D012293:Rifampin",
"nlm_unique_id": "101238455",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "31892222",
"pubdate": "2019-12-27",
"publication_types": "D016428:Journal Article",
"references": "25904367;25489785;27559940;12531776;26095714;23136913;15618686;21753138;29415190;23360680;22150035;17971785;15379654;26082504;30295760;11158730;10840530;30813594;25635488;24343893;26469045;11868802;27709007;26260821;25271170;24060875;10582883;12113641;10517722;22157884;12045127",
"title": "Association of Drug Metabolic Enzyme Genetic Polymorphisms and Adverse Drug Reactions in Patients Receiving Rifapentine and Isoniazid Therapy for Latent Tuberculosis.",
"title_normalized": "association of drug metabolic enzyme genetic polymorphisms and adverse drug reactions in patients receiving rifapentine and isoniazid therapy for latent tuberculosis"
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"literaturereference": "YU YY, TSAO SM, YANG WT, HUANG WC, LIN CH, CHEN WW ET AL.. ASSOCIATION OF DRUG METABOLIC ENZYME GENETIC POLYMORPHISMS AND ADVERSE DRUG REACTIONS IN PATIENTS RECEIVING RIFAPENTINE AND ISONIAZID THERAPY FOR LATENT TUBERCULOSIS. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH. 2020?17(1):1-9",
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"abstract": "Hidradenitis suppurativa is a chronic inflammatory skin disorder associated with inflammatory bowel disease. However, it can arise as a paradoxical side effect of anti-TNF treatment.\nThe article reports on three patients with Crohn's disease who developed hidradenitis suppurativa during the treatment with adalimumab.\nCase 1: A 38-year-old female exhibited an infiltrative lesion in the inguinal region and vulva, consistent with hidradenitis suppurativa, after three months of adalimumab. These lesions were treated with partial vulvectomy. Case 2: After adalimumab treatment, a 27-year-old female, originally diagnosed with ileocolonic Crohn's disease, went into clinical and endoscopic remission. The patient eventually presented two hyperchromic nodules in the inguinal region, which were diagnosed as hidradenitis suppurativa. The patient showed improvement after treatment with oral doxycycline and local therapy. Case 3: A 34-year-old female with fistulizing and stenosing ileocolonic Crohn's disease, started adalimumab in 2010, with optimization in 2015. One year after, the patient developed bilateral, erythematous, hardened, inguinal nodulations with purulent drainage, consistent with hidradenitis suppurativa. Treatment with oral doxycycline, fusidic acid, and infiltration with triamcinolone resulted in partial improvement of the lesions. In 2018, the lesions deteriorate. The patient underwent surgical treatment.\nPatients with inflammatory bowel disease are more likely to the development of other mediated inflammatory diseases, such as hidradenitis suppurativa. Hidradenitis suppurativa may appear as a paradoxical reaction to anti-TNF therapy. Clinical teams must be aware of this type of complication. Early diagnosis and treatment are essential for controlling the disease and preventing the onset of complications.",
"affiliations": "Department of Internal Medicine, São Paulo State University (Unesp), Medical School, Botucatu, Brazil.;Department of Internal Medicine, São Paulo State University (Unesp), Medical School, Botucatu, Brazil.;Department of Internal Medicine, São Paulo State University (Unesp), Medical School, Botucatu, Brazil.;Department of Internal Medicine, São Paulo State University (Unesp), Medical School, Botucatu, Brazil.;Inflammatory Bowel Disease Unit, Saint Mark's Hospital, London, UK.;Department of Surgery, São Paulo State University (Unesp), Medical School, Botucatu, Brazil.;Department of Internal Medicine, São Paulo State University (Unesp), Medical School, Botucatu, Brazil.",
"authors": "Beraldo|Rodrigo Fedatto|RF|0000-0002-8398-5014;Marcondes|Mariana Barros|MB|0000-0001-5011-9542;Baima|Julio Pinheiro|JP|0000-0002-4035-3113;Barros|Jaqueline Ribeiro|JR|0000-0003-1451-8794;Ramdeen|Madhoor|M|0000-0003-4213-2899;Saad-Hossne|Rogerio|R|0000-0002-8166-0304;Sassaki|Ligia Yukie|LY|0000-0002-7319-8906",
"chemical_list": null,
"country": "New Zealand",
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"doi": "10.2147/CEG.S263685",
"fulltext": "\n==== Front\nClin Exp Gastroenterol\nClin Exp Gastroenterol\nceg\nceg\nClinical and Experimental Gastroenterology\n1178-7023 Dove \n\n263685\n10.2147/CEG.S263685\nCase Series\nHidradenitis Suppurativa as a Paradoxical Side Effect to the Use of Adalimumab in Patients with Crohn’s Disease?\nBeraldo et alBeraldo et alhttp://orcid.org/0000-0002-8398-5014Beraldo Rodrigo Fedatto 1 http://orcid.org/0000-0001-5011-9542Marcondes Mariana Barros 1 http://orcid.org/0000-0002-4035-3113Baima Julio Pinheiro 1 http://orcid.org/0000-0003-1451-8794Barros Jaqueline Ribeiro 1 http://orcid.org/0000-0003-4213-2899Ramdeen Madhoor 2 http://orcid.org/0000-0002-8166-0304Saad-Hossne Rogerio 3 http://orcid.org/0000-0002-7319-8906Sassaki Ligia Yukie 1 1 Department of Internal Medicine, São Paulo State University (Unesp), Medical School, Botucatu, Brazil\n2 Inflammatory Bowel Disease Unit, Saint Mark’s Hospital, London, UK\n3 Department of Surgery, São Paulo State University (Unesp), Medical School, Botucatu, Brazil\nCorrespondence: Ligia Yukie Sassaki Email ligiasassaki@gmail.com\n19 8 2020 \n2020 \n13 293 298\n28 5 2020 23 7 2020 © 2020 Beraldo et al.2020Beraldo et al.This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms (https://www.dovepress.com/terms.php).Background\nHidradenitis suppurativa is a chronic inflammatory skin disorder associated with inflammatory bowel disease. However, it can arise as a paradoxical side effect of anti-TNF treatment.\n\nMethods\nThe article reports on three patients with Crohn’s disease who developed hidradenitis suppurativa during the treatment with adalimumab.\n\nResults\nCase 1: A 38-year-old female exhibited an infiltrative lesion in the inguinal region and vulva, consistent with hidradenitis suppurativa, after three months of adalimumab. These lesions were treated with partial vulvectomy. Case 2: After adalimumab treatment, a 27-year-old female, originally diagnosed with ileocolonic Crohn’s disease, went into clinical and endoscopic remission. The patient eventually presented two hyperchromic nodules in the inguinal region, which were diagnosed as hidradenitis suppurativa. The patient showed improvement after treatment with oral doxycycline and local therapy. Case 3: A 34-year-old female with fistulizing and stenosing ileocolonic Crohn’s disease, started adalimumab in 2010, with optimization in 2015. One year after, the patient developed bilateral, erythematous, hardened, inguinal nodulations with purulent drainage, consistent with hidradenitis suppurativa. Treatment with oral doxycycline, fusidic acid, and infiltration with triamcinolone resulted in partial improvement of the lesions. In 2018, the lesions deteriorate. The patient underwent surgical treatment.\n\nConclusion\nPatients with inflammatory bowel disease are more likely to the development of other mediated inflammatory diseases, such as hidradenitis suppurativa. Hidradenitis suppurativa may appear as a paradoxical reaction to anti-TNF therapy. Clinical teams must be aware of this type of complication. Early diagnosis and treatment are essential for controlling the disease and preventing the onset of complications.\n\nKeywords\nhidradenitis suppurativaCrohn’s diseaseadalimumabinflammatory bowel diseasedid not receive any specific grant from funding agenciesThis research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.\n==== Body\nPlain Language Summary\nCrohn’s disease is a disabling disease which impairs the patient’s quality of life. Anti-TNF drugs, such as adalimumab, are widely used for treating Crohn’s disease and can have promising results. Hidradenitis suppurative is a chronic inflammatory skin disorder associated with inflammatory bowel disease, that can arise as a paradoxical side effect of anti-TNF treatment. The use of antibiotics, such as tetracycline, clindamycin and even rifampicin, have been shown to improve the lesions, however advanced lesions require surgical intervention. This study reports on three separate Crohn’s disease patients who develop hidradenitis suppurative while receiving adalimumab. Two patients were submitted to surgical treatment and one patient improved after clinical treatment. This case series highlighted the importance of early diagnosis and treatment of this disabling condition. A multidisciplinary approach is essential for the proper management of IBD patients, including the evaluation of other specialists such as dermatologists, rheumatologists, surgeons, and professionals from other areas such as nursing, nutritionists and psychologists, among others. \n\nIntroduction\nAdalimumab is an anti-TNF agent used for inducing and maintaining remission in moderate to severe Crohn’s disease (CD).1,2 However, hidradenitis suppurativa (HS) has been described as a possible paradoxical effect of adalimumab.3–5\n\nHS is an immune-mediated inflammatory disease, that involves the pilosebaceous structure, and typically presents as phlogistic, deep, and painful lesions.6 Nodes, recurrent painful abscesses, fistulas and scars have also been associated with HS.6 Circumstantially, the lesions may extend to adjacent areas such as the perianal, gluteus, and/or breasts.6 A clinical diagnosis may be complemented with a biopsy in refractory or atypical cases.6 An estimated 1% of the population is affected by this pathology.6\n\nPatients with inflammatory bowel disease are more likely to present other autoimmune disease, such as HS.7 Similarly, patients with HS are at increased risk of having IBD compared to the general population.8 However, cases of paradoxical HS secondary to the use of biological agents have been described in the literature.3–5 This study reports on three patients with CD, who were treated with adalimumab, and subsequently exhibited HS.\n\nCase Report\nCase 1\nA 38-year-old, non-smoking female was diagnosed with colonic and fistulizing CD (Montreal Classification A2, L2, B3p) in 2006. A colonoscopy in 2012 revealed that, despite the use of infliximab (5mg/kg) and azathioprine (2mg/kg), the patient had superficial ulcers in the rectum and sigmoid. The patient had ulcerations in the vaginal lips and in the perianal region, including a perianal fistula and rectovaginal fistula. Curettage was performed on the entire raw surface. Passage of the seton showed improvement. In 2015, surgery of the rectovaginal fistula leads to complete restoration of the lesion. In February 2016, the patient presented with moderate clinical disease activity, bloody vaginal discharge, and pain in the perineum. Physical examination revealed an ulcerated lesion in the perineum and fecaloid drainage from the vagina (Figure 1). The patient was subjected to antibiotic therapy and local debridement. In June 2016, the patient presented with clinical disease activity, including an increased number of bowel movements, the presence of liquid stools with mucus and blood, and abdominal pain. Furthermore, perianal lesions appeared, which prompted optimization of infliximab (10 mg/kg). In 2017, the patient underwent surgery for treatment of the perianal lesions, along with drainage of perineal abscesses and curettage of fistulous paths (Figure 2). The lack of adequate control for the patient’s perianal CD prompted a switch from infliximab to adalimumab treatment. Three months later, the patient identified a red, painful, and infiltrative nodular lesion in the inguinal region. The lesion displayed no drainage. A biopsy of the lesion showed epithelioid microgranulomas, which are consistent with cutaneous CD and HS (Hurley’s stage III) (Figure 3). The patient received doxycycline and adalimumab optimization was elected for treatment of both diseases. A colonoscopy, performed in February 2019, showed endoscopic remission of CD. The serum dosage of adalimumab was 35 mcg/mL (normal 5–12 mcg/mL), which was reduced to the usual dosage (40 mg every other week). Despite drug treatment, the HS lesions progressed. In April 2019, the patient underwent partial vulvectomy and skin graft from the hip (Figure 4). Anatomopathological study indicated results that were consistent with chronic vulvitis, such as superficial ulcerations, inflammatory lymphoplasmacytic infiltrates, presence of multinucleated giant cells, and reactional lymphadenitis. Adalimumab treatment was suspended due to suspected paradoxical HS. In July 2019, a new skin graft was performed in the vulvar area and displayed good healing (Figure 5). Currently, the patient is receiving ustekinumab for the treatment of CD, with no recurrence of HS lesions.Figure 1 Ulcerated lesion in the perineal region, consistent with perianal Crohn’s disease.\n\nFigure 2 Abscess in the region of the large left vulvar lip and perianal fistulas, consistent with perianal Crohn´s disease.\n\nFigure 3 Nodular and infiltrative lesions in the inguinal region consistent with hidradenitis suppurative Hurley stage III.\n\nFigure 4 Partial vulvectomy surgery to treat hidradenitis suppurative.\n\nFigure 5 Appearance of the vulvar region after skin grafting and wound healing.\n\n\n\nCase 2\nA 27-year-old, non-smoking female was diagnosed with ileocolonic CD (Montreal classification A2, L3, B1) in March 2017. She presented with liquid diarrhea associated with abdominal pain, fatigue, and weight loss. A colonoscopy showed longitudinal ulcerations in the terminal ileum and ileocecal valve and deep ulcerations in the sigmoid colon. The patient started adalimumab in April 2017, which resolved the symptoms. In February 2018, the patient exhibited 2 painful hyperchromic nodules in the left inguinal region. The nodules produced no secretion and were diagnosed as HS (Hurley’s stage I). Treatment consisted of oral doxycycline and local therapy with clindamycin, 5% benzoyl peroxide, and infiltration with triamcinolone, which showed partial improvement. In April 2018, a colonoscopy showed moderate disease activity (SES-CD = 7), and azathioprine was initiated in combination with adalimumab (serum dosage: 19.6 mcg/mL [normal 5–12 mcg/mL]). After 5 months, another colonoscopy showed mild disease activity (SES-CD = 3). Therapy was maintained because of the lack of access to other biological therapies. HS lesions were present, with no drainage. In November 2019, the patient exhibited stenosis of the ileocecal valve, with symptoms of abdominal pain, distention, and diarrhea. The patient underwent elective hemicolectomy surgery with anastomosis right ascending ileum.\n\nCase 3\nA 34-year-old, non-smoking female presented with fistulizing and stenosing ileocolonic CD (Montreal classification A2, L3, B3p) since 2005. She received azathioprine and infliximab, which resulted in clinical and endoscopic remission. Due to a late anaphylactic reaction to infliximab, the medication was changed to adalimumab in 2010. The adalimumab dosage was optimized in 2015 due to clinical disease activity. In 2016, the patient presented bilateral, erythematous, hardened, inguinal nodules with purulent drainage, consistent with HS (Hurley I). Treatment consisted of oral doxycycline (100 mg/day), topical fusidic acid, and local application of triamcinolone + lincomycin, resulting in partial lesion improvement. In 2018, the lesions worsened and were resected in the bilateral inguinal region and perivulvar region, with good local healing. Moderate, inflammatory CD activity prompted a change in therapy to vedolizumab. The serum dosage of adalimumab was 12.7 mcg/mL (normal 5–12 mcg/mL). The patient underwent a segmental enterectomy and ileostomy in September 2018. The patient started treatment with ustekinumab to prevent post-surgical recurrence, resulting in an i0 Rutgeerts score. In December 2019, the patient exhibited cicatricial lesions in the inguinal region, with no specific treatment for HS.\n\nDiscussion\nHS is a chronic, inflammatory, recurrent, and debilitating skin disease that mainly affects the armpits, perineum and inframammary regions.9 Although HS pathogenesis is not completely understood, research suggests that it is a multifocal disease in which the atrophy of sebaceous glands precedes lymphocytic inflammation and pilosebaceous hyperkeratosis. Subsequent hair follicle occlusion provokes hair follicle destruction, which results in the formation of granulomas. HS is rarely triggered by infection and does not originate in the apocrine sweat glands.10 HS lesions are classified in 3 stages11 according to the severity of the disease.\n\nThe use of antibiotics, such as tetracycline, clindamycin and even rifampicin, have been shown to benefit HS patients with lesion improvement.6 Advanced HS requires surgical intervention, since non-surgical methods rarely result in a definitive cure.12 Radical surgical methods have low recurrence rates.13,14 However, one study suggests a recurrence rate of up to 33% in HS patients who were monitored over a period of 1–19 years.13 For recurrent cases, reconstruction with flap repair has been utilized, and has resulted in a recurrence rate of 18.75% over a period of 2 years.14\n\nSeveral studies indicate the interleukin-12 (IL-12),6,10 interleukin-17 (IL-17),10 interleukin-23 (IL-23)6,9 and tumor necrosis factor-alpha (TNF-alpha)6,9 are involved in HS pathogenesis. Prior studies report increased concentrations of TNF-alpha in HS patient serum and skin,15,16 which justifies the use of TNF-alpha inhibitors such as infliximab17 and adalimumab in treatment.18 In contrast, other studies19,20 have demonstrated reduced expression of the TNF-alpha protein, suggesting that HS appears as a paradoxical anti-TNF effect.\n\nTNF-α inhibits the overproduction of interferon-α in the skin of healthy individuals.21 Anti-TNF drugs lead to increased production of interferon-α,21 which promotes T-helper cell activation and higher production of IL-17. Interestingly, enhanced IL-17 and IL-23 levels were found in CD patients who developed skin lesions (psoriforms and eczemas) during treatment with anti-TNF-α.22\n\nA relationship between the use of adalimumab and the appearance of HS as a paradoxical effect of the medication has previously been reported.3–5 Faivre et al3 conducted a retrospective study on 25 patients with auto-immune diseases (9 CD). In this study, 12 patients, who were treated with adalimumab, developed HS. Furthermore, patients who restarted adalimumab exhibited HS relapse. Delobeau et al4 published a series of four cases for patients with differing autoimmune diseases including CD, juvenile idiopathic arthritis, severe plaque psoriasis and ankylosing spondylitis who developed HS as a paradoxical reaction to adalimumab. Analogous to our results, females were the dominant gender in these studies.3–5 Other adalimumab risk factors, such as smoking and obesity,23 were not observed in the present study.\n\nDespite the reports of HS as a secondary event to anti-TNF therapy, it should be remembered that patients with immune-mediated diseases have an increased risk of developing associated autoimmune diseases,7,8 as emphasized by Phan et al,8 in a systematic review that demonstrated the prevalence of IBD in HS cohorts with a significant association with CD (OR 2.25; 95% CI 1.52–3.32; P < 0.0001, I2 = 92%) and ulcerative colitis (OR 1.56; 95% CI 1.26–1.94; P < 0.0001; I2 = 36%).\n\nAlthough we have observed several reported cases of the association between CD and HS in the literature,7,8 we would like to highlighted that HS could appear as a paradoxical effect to the use of adalimumab, even though we are aware of the difficulty in differentiating the two situations in clinical practice. In these cases, it is indicated to switch or stop the anti-TNF.5 Anti-TNF should be maintained only in cases where the therapy is essential or exchange is not possible.5 In all cases, specific treatment for HS must be added.\n\nCytokines other than TNF alpha are also involved in the pathogenesis of HS. An increase in IL-1b16,24 and IL-1016,19,24,25 has been reported in both lesions and the contours of the HS site. IL-10 is produced by macrophages, activated T cells, B cells and mast cells. Such cells are found in abundance in injured tissues, correlating with the inflammatory status of HS. Other interleukins found in greater proportion were IL-17 and IL-23.16,24,26 IL-23 is present in the formation of the Th17 cell, which has been found in the injured skin of patients with\\z HS.26 IL-1b, IL-23 and IL-17 pathways have been identified in the pathogenesis of HS, which supports the use of anti-interleukins as a treatment for the disease.\n\nConclusion\nHS is a chronic inflammatory disease that can be associated with inflammatory bowel disease. However, it can arise as a paradoxical effect due to anti-TNF agents, specifically adalimumab. A multidisciplinary evaluation, inclusive of a dermatologist with an interest in IBD, is crucial to accurately diagnose and treat this disabling condition aiming at controlling the inflammatory process and restoring the patient’s quality of life.\n\nAbbreviations\nCD, Crohn’s disease; HS, hidradenitis suppurativa.\n\nEthics Approval and Informed Consent\nThe study was approved by the Botucatu Medical School Research Ethics Committee (protocol number 20350119.8.0000.5411). All participants received explanations about the study objectives and expected results and were enrolled in the study only after signing the informed consent form.\n\nConsent for Publication\nPatients signed informed consent regarding publishing their data and photographs.\n\nAuthor Contributions\nAll authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.\n\nDisclosure\nThe authors have no competing interests to disclose in relationship to the work presented here.\n==== Refs\nReferences\n1. Gomollón \nF , Dignass \nA , Annese \nV , et al. 3rd European evidence-based consensus on the diagnosis and management of Crohn’s disease 2016: part 1: diagnosis and medical management\n. J Crohns Colitis . 2017 ;11 (1 ):3 –25\n. doi:10.1093/ecco-jcc/jjw168 27660341 \n2. Samaan \nM , Campbell \nS , Cunningham \nG , Tamilarasan \nAG , Irving \nPM , McCartney \nS . Biologic therapies for Crohn’s disease: optimising the old and maximising the new\n. F1000 Res . 2019 ;8 :1210 . doi:10.12688/f1000research.18902.1 \n3. Faivre \nC , Villani \nAP , Aubin \nF , et al. Hidradenitis suppurativa (HS): an unrecognized paradoxical effect of biologic agents (BA) used in chronic inflammatory diseases\n. J Am Acad Dermatol . 2016 ;74 (6 ):1153 –1159\n. doi:10.1016/j.jaad.2016.01.018 26965410 \n4. Delobeau \nM , Abdou \nA , Puzenat \nE , et al. Observational case series on adalimumab-induced paradoxical hidradenitis suppurativa\n. J Dermatolog Treat . 2016 ;27 :251 –253\n. doi:10.3109/09546634.2015.1094179 26368546 \n5. Salvador-Rodriguez \nL , Montero-Vílchez \nT , Arias-Santiago \nS , Molina-Leyva \nA . Paradoxical hidradenitis suppurativa in patients receiving TNF-α inhibitors: case series, systematic review, and case meta-analysis\n. Dermatology . 2020 ;236 :307 –313\n. doi:10.1159/000506074 32135533 \n6. Jemec \nGB . Clinical practice. Hidradenitis suppurativa\n. N Engl J Med . 2012 ;366 (2 ):158 –164\n. doi:10.1056/NEJMcp1014163 22236226 \n7. Yadav \nS , Singh \nS , Edakkanambeth Varayil \nJ , et al. Hidradenitis suppurativa in patients with inflammatory bowel disease: a population-based cohort study in Olmsted County, Minnesota\n. Clin Gastroenterol Hepatol . 2016 ;14 (1 ):65 –70\n. doi:10.1016/j.cgh.2015.04.173 25952308 \n8. Phan \nK , Tatian \nA , Woods \nJ , Cains \nG , Frew \nJW . Prevalence of inflammatory bowel disease (IBD) in hidradenitis suppurativa (HS): systematic review and adjusted meta-analysis\n. Int J Dermatol . 2020 ;59 (2 ):221 –228\n. doi:10.1111/ijd.14697 31631340 \n9. Alikhan \nA , Lynch \nPJ , Eisen \nDB . Hidradenitis suppurativa: a comprehensive review\n. J Am Acad Dermatol . 2009 ;60 (4 ):539 –561\n. doi:10.1016/j.jaad.2008.11.911 19293006 \n10. Prens \nE , Deckers \nI . Pathophysiology of hidradenitis suppurativa: an update\n. J Am Acad Dermatol . 2015 ;73 (5 Suppl 1 ):S8 –S11\n. doi:10.1016/j.jaad.2015.07.045 26470623 \n11. Hurley \nH . Axillary hyperhidrosis, apocrine bromhidrosis, hidradenitis suppurativa, and familial benign pemphigus: surgical approach In: Roenigh \nRRH , editor. Dermatologic Surgery . New York : Marcel Dekker ; 1989 :729 –739\n.\n12. Ellis \nLZ . Hidradenitis suppurativa: surgical and other management techniques\n. Dermatol Surg . 2012 ;38 (4 ):517 –536\n. doi:10.1111/j.1524-4725.2011.02186.x 22092698 \n13. Bohn \nJ , Svensson \nH . Surgical treatment of hidradenitis suppurativa\n. Scand J Plast Reconstr Surg Hand Surg . 2001 ;35 (3 ):305 –309\n. doi:10.1080/028443101750523230 11680401 \n14. Alharbi \nZ , Kauczok \nJ , Pallua \nN . A review of wide surgical excision of hidradenitis suppurativa\n. BMC Dermatol . 2012 ;12 :9 . doi:10.1186/1471-5945-12-9 22734714 \n15. Matusiak \nL , Bieniek \nA , Szepietowski \nJC . Increased serum tumour necrosis factor-alpha in hidradenitis suppurativa patients: is there a basis for treatment with anti-tumour necrosis factor-alpha agents?\n\nActa Derm Venereol . 2009 ;89 (6 ):601 –603\n. doi:10.2340/00015555-0749 19997690 \n16. Van der Zee \nHH , de Ruiter \nL , Van den Broecke \nDG , Dik \nWA , Laman \nJD , Prens \nEP . Elevated levels of tumour necrosis factor (TNF)-alpha, interleukin (IL)-1beta and IL-10 in hidradenitis suppurativa skin: a rationale for targeting TNF-alpha and IL-1beta\n. Br J Dermatol . 2011 ;164 (2 ):1292 –1298\n. doi:10.1111/j.1365-2133.2011.10254.x 21332464 \n17. Grant \nA , Gonzalez \nT , Montgomery \nMO , Cardenas \nV , Kerdel \nFA . Infliximab therapy for patients with moderate to severe hidradenitis suppurativa: a randomized, double-blind, placebo-controlled crossover trial\n. J Am Acad Dermatol . 2010 ;62 (2 ):205 –217\n. doi:10.1016/j.jaad.2009.06.050 20115947 \n18. Miller \nI , Lynggaard \nCD , Lophaven \nS , Zachariae \nC , Dufour \nDN , Jemec \nGB . A double-blind placebo-controlled randomized trial of adalimumab in the treatment of hidradenitis suppurativa\n. Br J Dermatol . 2011 ;165 (2 ):391 –398\n. doi:10.1111/j.1365-2133.2011.10339.x 21457202 \n19. Dreno \nB , Khammari \nA , Brocard \nA , et al. Hidradenitis suppurativa: the role of deficient cutaneous innate immunity\n. Arch Dermatol . 2012 ;148 (2 ):182 –186\n. doi:10.1001/archdermatol.2011.315 22004878 \n20. Giamarellos-Bourboulis \nEJ , Antonopoulou \nA , Petropoulou \nC , et al. Altered innate and adaptive immune responses in patients with hidradenitis suppurativa\n. Br J Dermatol . 2007 ;156 (1 ):51 –56\n. doi:10.1111/j.1365-2133.2006.07556.x 17199566 \n21. Cullen \nG , Kroshinsky \nD , Cheifetz \nAS , Korzenik \nJR . Psoriasis associated with anti-tumour necrosis factor therapy in inflammatory bowel disease: a new series and a review of 120 cases from the literature\n. Aliment Pharmacol Ther . 2011 ;34 (11–12 ):1318 –1327\n. doi:10.1111/j.1365-2036.2011.04866.x 21957906 \n22. Wlodarczyk \nM , Sobolewska \nA , Wojcik \nB , Loga \nK , Fichna \nJ , Wisniewska-Jarosinska \nM . Correlations between skin lesions induced by anti-tumor necrosis factor-alpha and selected cytokines in Crohn’s disease patients\n. World J Gastroenterol . 2014 ;20 (22 ):7019 –7026\n. doi:10.3748/wjg.v20.i22.7019 24944497 \n23. Zouboulis \nCC , Desai \nN , Emtestam \nL , et al. European S1 guideline for the treatment of hidradenitis suppurativa/acne inversa\n. J Eur Acad Dermatol Venereol . 2015 ;29 (4 ):619 –644\n. doi:10.1111/jdv.12966 25640693 \n24. Wolk \nK , Warszawska \nK , Hoeflich \nC , et al. Deficiency of IL-22 contributes to a chronic inflammatory disease: pathogenetic mechanisms in acne inversa\n. J Immunol . 2011 ;186 (2 ):1228 –1239\n. doi:10.4049/jimmunol.0903907 21148041 \n25. Van der Zee \nHH , Laman \nJD , de Ruiter \nL , Dik \nWA , Prens \nEP . Adalimumab (antitumour necrosis factor-alpha) treatment of hidradenitis suppurativa ameliorates skin inflammation: an in situ and ex vivo study\n. Br J Dermatol . 2012 ;166 (2 ):298 –305\n. doi:10.1111/j.1365-2133.2011.10698.x 22013960 \n26. Schlapbach \nC , Hanni \nT , Yawalkar \nN , Hunger \nRE . Expression of the IL-23/Th17 pathway in lesions of hidradenitis suppurativa\n. J Am Acad Dermatol . 2011 ;65 (4 ):790 –798\n. doi:10.1016/j.jaad.2010.07.010 21641076\n\n",
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"issn_linking": "1178-7023",
"issue": "13()",
"journal": "Clinical and experimental gastroenterology",
"keywords": "Crohn’s disease; adalimumab; hidradenitis suppurativa; inflammatory bowel disease",
"medline_ta": "Clin Exp Gastroenterol",
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"nlm_unique_id": "101532800",
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"pages": "293-298",
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"pmid": "32943900",
"pubdate": "2020",
"publication_types": "D002363:Case Reports",
"references": "25640693;21332464;22092698;20115947;17199566;22004878;22734714;26470623;26965410;24944497;32135533;21457202;21148041;26368546;22236226;25952308;27660341;11680401;31631340;21957906;19997690;22013960;21641076;19293006;31448080",
"title": "Hidradenitis Suppurativa as a Paradoxical Side Effect to the Use of Adalimumab in Patients with Crohn's Disease?",
"title_normalized": "hidradenitis suppurativa as a paradoxical side effect to the use of adalimumab in patients with crohn s disease"
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{
"abstract": "BACKGROUND\nPulmonary involvement is relatively frequent in adult and juvenile patients with Systemic Lupus Erythematosus (SLE), but its occurrence in newborns with Neonatal Lupus Erythematosus (NLE) is exceedingly rare.\n\n\nMETHODS\nA mother with SLE and positive anti-SSA/Ro and anti-SSB/La delivered a preterm newborn with third-degree heart block and positive anti-SSA/Ro confirmed postnatally. A temporary pacemaker was placed at D3 and a definitive pacemaker only at D15 due to sepsis with concurrent mild respiratory failure. Despite adequate antibiotic therapy, negative cultures and decreasing inflammatory parameters, at D17 severe respiratory failure ensued, requiring mechanical ventilation. Chest x-ray showed symmetrical interstitial infiltrates. Acute Lupus Pneumonitis (ALP) and Pulmonary Embolism were suspected and the chest angio-CT revealed diffuse ground glass opacities. After 3 methylprednisolone pulses he improved rapidly.\n\n\nCONCLUSIONS\nThe diagnosis of ALP in NLE, mostly one of exclusion, is a challenge. A high degree of suspicion and a multidisciplinary approach to these patients are fundamental in order not to delay establishing a diagnosis. Although few reports in the literature, early aggressive treatments are probably crucial for a favorable outcome without long-term sequelae.",
"affiliations": "Centro Hospitalar São João (CHSJ).;Neonatal Intensive Care Unit.",
"authors": "Pereira|Sandra|S|;Flor-de-Lima|Filipa|F|;Soares|Henrique|H|;Vilan|Ana|A|;Ferraz|Catarina|C|;Rodrigues|Mariana|M|;Moura|Cláudia|C|;Rocha|Gustavo|G|;Guimarães|Hercília|H|;Brito|Iva|I|",
"chemical_list": null,
"country": "Portugal",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0303-464X",
"issue": "43(3)",
"journal": "Acta reumatologica portuguesa",
"keywords": null,
"medline_ta": "Acta Reumatol Port",
"mesh_terms": "D006801:Humans; D007231:Infant, Newborn; D017563:Lung Diseases, Interstitial; D008180:Lupus Erythematosus, Systemic; D008297:Male",
"nlm_unique_id": "0431702",
"other_id": null,
"pages": "230-234",
"pmc": null,
"pmid": "30414372",
"pubdate": "2018",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Pulmonary involvement in neonatal lupus: a challenging diagnosis - case report and literature review.",
"title_normalized": "pulmonary involvement in neonatal lupus a challenging diagnosis case report and literature review"
} | [
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{
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"reactionmeddraversionpt": "22.0",
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},
{
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"reactionmeddraversionpt": "22.0",
"reactionoutcome": "6"
},
{
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},
{
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},
{
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},
{
"reactionmeddrapt": "Leukopenia",
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},
{
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},
{
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},
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},
{
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},
{
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},
{
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"reactionoutcome": "3"
},
{
"reactionmeddrapt": "Cardiomegaly",
"reactionmeddraversionpt": "22.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Lung infiltration",
"reactionmeddraversionpt": "22.0",
"reactionoutcome": "1"
},
{
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"reactionmeddraversionpt": "22.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Acute respiratory failure",
"reactionmeddraversionpt": "22.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Hypoxia",
"reactionmeddraversionpt": "22.0",
"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "S PEREIRA ET AL. PULMONARY INVOLVEMENT IN NEONATAL LUPUS: A CHALLENGING DIAGNOSIS - CASE REPORT AND LITERATURE REVIEW. ACTA REUMATOL PORT. 2018?43:230-4",
"literaturereference_normalized": "pulmonary involvement in neonatal lupus a challenging diagnosis case report and literature review",
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},
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},
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},
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"seriousnesscongenitalanomali": 1,
"seriousnessdeath": null,
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"seriousnesshospitalization": 1,
"seriousnesslifethreatening": null,
"seriousnessother": 1,
"transmissiondate": "20190711"
},
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"companynumb": "PT-MYLANLABS-2018M1005012",
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"reactionmeddraversionpt": "22.1",
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},
{
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"reactionmeddraversionpt": "22.1",
"reactionoutcome": "3"
},
{
"reactionmeddrapt": "Heart block congenital",
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"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Rash erythematous",
"reactionmeddraversionpt": "22.1",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Lupus pneumonitis",
"reactionmeddraversionpt": "22.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Pulmonary embolism",
"reactionmeddraversionpt": "22.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "C-reactive protein increased",
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"reactionoutcome": "3"
},
{
"reactionmeddrapt": "Sepsis",
"reactionmeddraversionpt": "22.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Premature baby",
"reactionmeddraversionpt": "22.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Leukopenia",
"reactionmeddraversionpt": "22.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Acute respiratory failure",
"reactionmeddraversionpt": "22.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Lung infiltration",
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"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Respiratory failure",
"reactionmeddraversionpt": "22.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Thrombocytopenia",
"reactionmeddraversionpt": "22.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Tachypnoea",
"reactionmeddraversionpt": "22.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Hypoxia",
"reactionmeddraversionpt": "22.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Foetal exposure during pregnancy",
"reactionmeddraversionpt": "22.1",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Patent ductus arteriosus",
"reactionmeddraversionpt": "22.1",
"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "PEREIRA S, FLOR-DE-LIMA F, SOARES H, VILAN A, FERRAZ C, RODRIGUES M ET AL... PULMONARY INVOLVEMENT IN NEONATAL LUPUS: A CHALLENGING DIAGNOSIS - CASE REPORT AND LITERATURE REVIEW.. ACTA REUMATOL. PORT... 2018?43:230-4",
"literaturereference_normalized": "pulmonary involvement in neonatal lupus a challenging diagnosis case report and literature review",
"qualification": "3",
"reportercountry": "PT"
},
"primarysourcecountry": "PT",
"receiptdate": "20191115",
"receivedate": "20180129",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 14454685,
"safetyreportversion": 2,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": 1,
"seriousnessdeath": null,
"seriousnessdisabling": null,
"seriousnesshospitalization": 1,
"seriousnesslifethreatening": null,
"seriousnessother": 1,
"transmissiondate": "20200122"
}
] |
{
"abstract": "The prevalence of D alloimmunization occurs between 0.15% and 0.4%. The anti-D can cross the placenta and cause hemolysis and fetal anemia. At present, a Doppler study of the middle cerebral artery allows the monitoring of the degree of fetal anemia. The treatment in cases of moderate to severe anemia in fetuses of less than 34-35 weeks of gestation is intrauterine transfusion via cordocentesis. However, with high titers of anti-D, in the absence of fetal anemia it is possible to modulate the maternal immune response by plasmapheresis and intravenous immunoglobulin administration. We present a case report of an Rh(D) alloimmunized pregnancy treated with plasmapheresis followed by intravenous immunoglobulin administration. We performed a caesarean section at 31 weeks, 5 days of gestation. The hemoglobin at birth was 13.8 g/dl and hematocrit 40.8%. Intrauterine transfusion was not necessary.",
"affiliations": "Department of Obstetrics and Gynecology, University Hospital of Puerto Real, Cádiz, Spain. Electronic address: jjesus.fernandez@uca.es.;Department of Obstetrics and Gynecology, University Hospital of Puerto Real, Cádiz, Spain.;Department of Obstetrics and Gynecology, University Hospital of Puerto Real, Cádiz, Spain.;Department of Hematology, University Hospital of Puerto Real, Cádiz, Spain.;Department of Obstetrics and Gynecology, University Hospital of Puerto Real, Cádiz, Spain.;Department of Obstetrics and Gynecology, University Hospital of Puerto Real, Cádiz, Spain.;Department of Obstetrics and Gynecology, University Hospital of Puerto Real, Cádiz, Spain.",
"authors": "Fernández Alba|Juan J|JJ|;León|Raquel|R|;González-Macías|Carmen|C|;Paz|Antonio|A|;Prado|Fabiana|F|;Moreno|Luis J|LJ|;Torrejón|Rafael|R|",
"chemical_list": "D016756:Immunoglobulins, Intravenous; D007155:Immunologic Factors; D007518:Isoantibodies; D012204:Rh-Hr Blood-Group System; C026410:Rho(D) antigen",
"country": "England",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1473-0502",
"issue": "51(1)",
"journal": "Transfusion and apheresis science : official journal of the World Apheresis Association : official journal of the European Society for Haemapheresis",
"keywords": "Alloimmunization; Hemolytic disease of the newborn; Intravenous immunoglobulin; Therapeutic plasma exchange",
"medline_ta": "Transfus Apher Sci",
"mesh_terms": "D000328:Adult; D004899:Erythroblastosis, Fetal; D005260:Female; D006801:Humans; D016756:Immunoglobulins, Intravenous; D007155:Immunologic Factors; D007518:Isoantibodies; D010956:Plasmapheresis; D011247:Pregnancy; D012204:Rh-Hr Blood-Group System",
"nlm_unique_id": "101095653",
"other_id": null,
"pages": "70-2",
"pmc": null,
"pmid": "25312036",
"pubdate": "2014-08",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Treatment of D alloimmunization in pregnancy with plasmapheresis and intravenous immune globulin: case report.",
"title_normalized": "treatment of d alloimmunization in pregnancy with plasmapheresis and intravenous immune globulin case report"
} | [
{
"companynumb": "ES-SHIRE-ES201846013",
"fulfillexpeditecriteria": "1",
"occurcountry": "ES",
"patient": {
"drug": [
{
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"activesubstance": {
"activesubstancename": "ALBUMIN HUMAN"
},
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"drugdosagetext": "5% CONCENTRATON",
"drugenddate": null,
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"drugindication": "ALLOIMMUNISATION",
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"medicinalproduct": "HUMAN ALBUMIN"
},
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "HUMAN IMMUNOGLOBULIN G"
},
"drugadditional": "3",
"drugadministrationroute": "042",
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"drugcharacterization": "1",
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"drugdosageform": "SOLUTION FOR INFUSION",
"drugdosagetext": "1G/ KG",
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "ALLOIMMUNISATION",
"drugintervaldosagedefinition": null,
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"medicinalproduct": "KIOVIG"
}
],
"patientagegroup": null,
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"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Premature baby",
"reactionmeddraversionpt": "21.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Foetal exposure during pregnancy",
"reactionmeddraversionpt": "21.1",
"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "FERNANDEZ ALBA, J? LEON, R? GONZALEZ-MACIAS, C? PAZ, A? PRADO, F. ET. AL.. TREATMENT OF D ALLOIMMUNIZATION IN PREGNANCY WITH PLASMAPHERESIS AND INTRAVENOUS IMMUNE GLOBULIN: CASE REPORT. TRANSFUSION AND APHERESIS SCIENCE. 2014?51(1):70-72",
"literaturereference_normalized": "treatment of d alloimmunization in pregnancy with plasmapheresis and intravenous immune globulin case report",
"qualification": "3",
"reportercountry": "ES"
},
"primarysourcecountry": "ES",
"receiptdate": "20181205",
"receivedate": "20181205",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 15690870,
"safetyreportversion": 1,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
"seriousnessdisabling": null,
"seriousnesshospitalization": 1,
"seriousnesslifethreatening": null,
"seriousnessother": null,
"transmissiondate": "20190205"
}
] |
{
"abstract": "Endopyelotomy is a minimally invasive option for treatment of ureteropelvic junction (UPJ) obstruction. Although largely supplanted by laparoscopic or robot-assisted laparoscopic pyeloplasty, it retains efficacy and utility in the absence of a crossing vessel in patients not fit for laparoscopy, patients with secondary obstructions or strictures, or those with stones requiring simultaneous treatment. Antegrade endopyelotomy is most commonly performed with scissors, cold knife, or more recently, using a Holmium laser. Herein we present the first reported case of simultaneous antegrade endopyelotomy and percutaneous nephrolithotomy (PCNL) using a thulium fiber laser (TFL). A 72-year-old male with surgical history of open abdominal aortic aneurysm repair at age 43 years, colon resection, bilateral popliteal artery aneurysms, 5-vessel coronary artery bypass grafting, recent thoracic endovascular aortic repair, and celiac/superior mesenteric artery/bilateral renal stents on Coumadin was referred for gross hematuria and CT urography demonstrating a high-insertion UPJ obstruction without a crossing vessel and 4 caliceal stones, the largest being 2 cm. Given his multiple comorbidities and prior abdominal and retroperitoneal surgeries, he was offered simultaneous PCNL and endopyelotomy to treat both urological conditions with a single procedure. The procedure was accomplished bloodlessly with TFL PCNL and endopyelotomy as an ambulatory procedure with minimal morbidity, immediate resumption of anticoagulation, and rapid convalescence using a special method to convert the high insertion to a dependent insertion. The TFL provides a new effective and efficient tool for the simultaneous endoscopic management of stones and obstructions with minimal bleeding and rapid recovery in select situations.",
"affiliations": "Department of Urology, Montefiore Medical Center, The Bronx, New York, USA.;Department of Urology, Icahn School of Medicine, Mount Sinai Medical Center, New York, New York, USA.;Department of Urology, Icahn School of Medicine, Mount Sinai Medical Center, New York, New York, USA.",
"authors": "Gupta|Kavita|K|;Gupta|Kasmira Radha|KR|;Gupta|Mantu|M|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1089/cren.2020.0101",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2379-9889",
"issue": "6(4)",
"journal": "Journal of endourology case reports",
"keywords": "endopyelotomy; percutaneous nephrolithotomy; thulium fiber laser",
"medline_ta": "J Endourol Case Rep",
"mesh_terms": null,
"nlm_unique_id": "101684114",
"other_id": null,
"pages": "297-301",
"pmc": null,
"pmid": "33457658",
"pubdate": "2020",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "A Novel Technique Using a Thulium Fiber Laser for Simultaneous Percutaneous Nephrolithotomy and Transpelvic Endopyelotomy for High-Insertion Ureteropelvic Junction Obstruction.",
"title_normalized": "a novel technique using a thulium fiber laser for simultaneous percutaneous nephrolithotomy and transpelvic endopyelotomy for high insertion ureteropelvic junction obstruction"
} | [
{
"companynumb": "US-BRISTOL-MYERS SQUIBB COMPANY-BMS-2021-005214",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "WARFARIN SODIUM"
},
"drugadditional": "3",
"drugadministrationroute": "065",
"drugauthorizationnumb": "009218",
"drugbatchnumb": null,
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": null,
"drugdosagetext": null,
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "PRODUCT USED FOR UNKNOWN INDICATION",
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
"drugrecurreadministration": null,
"drugrecurrence": null,
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"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "WARFARIN SODIUM."
}
],
"patientagegroup": null,
"patientonsetage": "72",
"patientonsetageunit": "801",
"patientsex": "1",
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Haematuria",
"reactionmeddraversionpt": "23.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Procedural haemorrhage",
"reactionmeddraversionpt": "23.1",
"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "GUPTA K, GUPTA KR, GUPTA M. A NOVEL TECHNIQUE USING A THULIUM FIBER LASER FOR SIMULTANEOUS PERCUTANEOUS NEPHROLITHOTOMY AND TRANSPELVIC ENDOPYELOTOMY FOR HIGH?INSERTION URETEROPELVIC JUNCTION OBSTRUCTION. JOURNAL OF ENDOUROLOGY CASE REPORTS. 2020?6(4):297?301",
"literaturereference_normalized": "a novel technique using a thulium fiber laser for simultaneous percutaneous nephrolithotomy and transpelvic endopyelotomy for high insertion ureteropelvic junction obstruction",
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},
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},
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] |
{
"abstract": "The few studies performed in adults with T cell-mediated hypersensitivity to penicillins have found a rate of cross-reactivity with cephalosporins ranging from 2.8% to 31.2% and an absence of cross-reactivity with aztreonam.\n\n\n\nWe sought to evaluate the possibility of using cephalosporins and aztreonam in subjects with documented delayed hypersensitivity to penicillins who especially require them.\n\n\n\nWe conducted a prospective study of 214 consecutive subjects who had 307 nonimmediate reactions to penicillins (almost exclusively aminopenicillins) and had positive patch test and/or delayed-reading skin test responses to at least 1 penicillin reagent. To assess cross-reactivity with cephalosporins and aztreonam and the tolerability of such alternative β-lactams, all subjects underwent skin tests with cephalexin, cefaclor, cefadroxil, cefuroxime, ceftriaxone, and aztreonam. Subjects with negative responses were challenged with the alternative β-lactams concerned.\n\n\n\nAll subjects had negative skin test results to cefuroxime, ceftriaxone, and aztreonam and tolerated challenges. Forty (18.7%) of the 214 subjects had positive skin test responses to at least 1 aminocephalosporin. Of the 174 subjects with negative responses, 170 underwent challenges; 1 reacted to cefaclor.\n\n\n\nThese data demonstrate a rate of cross-reactivity between aminopenicillins and aminocephalosporins (ie, cephalexin, cefaclor, and cefadroxil) of around 20%, as well as the absence of cross-reactivity between penicillins and cefuroxime, ceftriaxone, and aztreonam in all subjects with T cell-mediated hypersensitivity to penicillins, almost exclusively aminopenicillins. Therefore these subjects could be treated with cefuroxime, ceftriaxone, and aztreonam. In those who especially require cephalosporin or aztreonam treatment, however, we recommend pretreatment skin tests because negative responses indicate tolerability.",
"affiliations": "Allergy Unit, Complesso Integrato Columbus, Rome, Italy; IRCCS Oasi Maria S.S., Troina, Italy. Electronic address: aromano.allergy@gmail.com.;Allergy Unit, Complesso Integrato Columbus, Rome, Italy.;Allergy Unit, Complesso Integrato Columbus, Rome, Italy.;Allergy Unit, Complesso Integrato Columbus, Rome, Italy.;Allergy Unit, Complesso Integrato Columbus, Rome, Italy.;Ambulatorio di Allergologia, IDI-IRCCS, Capranica, Italy.",
"authors": "Romano|Antonino|A|;Gaeta|Francesco|F|;Valluzzi|Rocco Luigi|RL|;Maggioletti|Michela|M|;Caruso|Cristiano|C|;Quaratino|Donato|D|",
"chemical_list": "D002511:Cephalosporins; D010406:Penicillins; D007073:Immunoglobulin E; D001398:Aztreonam",
"country": "United States",
"delete": false,
"doi": "10.1016/j.jaci.2016.01.025",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0091-6749",
"issue": "138(1)",
"journal": "The Journal of allergy and clinical immunology",
"keywords": "Aztreonam; cephalosporins; challenges; cross-reactivity; nonimmediate reactions; penicillins; skin tests; tolerability",
"medline_ta": "J Allergy Clin Immunol",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D001398:Aztreonam; D002511:Cephalosporins; D003429:Cross Reactions; D004342:Drug Hypersensitivity; D005260:Female; D006801:Humans; D006968:Hypersensitivity, Delayed; D007108:Immune Tolerance; D007073:Immunoglobulin E; D008297:Male; D008875:Middle Aged; D010328:Patch Tests; D010406:Penicillins; D010641:Phenotype; D012882:Skin Tests; D013601:T-Lymphocytes; D055815:Young Adult",
"nlm_unique_id": "1275002",
"other_id": null,
"pages": "179-186",
"pmc": null,
"pmid": "27016799",
"pubdate": "2016-07",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Cross-reactivity and tolerability of aztreonam and cephalosporins in subjects with a T cell-mediated hypersensitivity to penicillins.",
"title_normalized": "cross reactivity and tolerability of aztreonam and cephalosporins in subjects with a t cell mediated hypersensitivity to penicillins"
} | [
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{
"abstract": "Despite increasing use of targeted therapies to treat cancer, anemia remains a common complication of cancer therapy. Physician concerns about the safety of intravenous (IV) iron products and erythropoiesis-stimulating agents (ESAs) have resulted in many patients with cancer receiving no or suboptimal anemia therapy. In this article, we present 4 patient cases that illustrate both common and complex clinical scenarios. We first present a review of erythropoiesis and then describe our approach to cancer-associated anemia by identifying the contributing causes before selecting specific treatments. We summarize clinical trial data affirming the safety and efficacy of currently available IV iron products used to treat cancer-associated anemia and illustrate how we use commonly available laboratory tests to assess iron status during routine patient management. We compare adverse event rates associated with IV iron vs red cell transfusion and discuss using first-line IV iron monotherapy to treat anemic patients with cancer, which decreases the need for ESAs. A possible mechanism behind ESA-induced tumor progression is discussed. Finally, we review the potential of novel therapies such as ascorbic acid, prolyl hydroxylase inhibitors, activin traps, hepcidin, and bone morphogenetic protein antagonists in treating cancer-associated anemia.",
"affiliations": "Department of Pharmacotherapy, University of Utah College of Pharmacy, and.;Division of Hematology and Hematologic Malignancies, Huntsman Cancer Institute at University of Utah, Salt Lake City, UT.",
"authors": "Gilreath|Jeffrey A|JA|;Rodgers|George M|GM|",
"chemical_list": "D006397:Hematinics; D007501:Iron",
"country": "United States",
"delete": false,
"doi": "10.1182/blood.2019004017",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0006-4971",
"issue": "136(7)",
"journal": "Blood",
"keywords": null,
"medline_ta": "Blood",
"mesh_terms": "D061605:Administration, Intravenous; D000740:Anemia; D018450:Disease Progression; D017707:Erythrocyte Transfusion; D004920:Erythropoiesis; D006397:Hematinics; D006801:Humans; D007501:Iron; D009369:Neoplasms",
"nlm_unique_id": "7603509",
"other_id": null,
"pages": "801-813",
"pmc": null,
"pmid": "32556170",
"pubdate": "2020-08-13",
"publication_types": "D016428:Journal Article; D016454:Review",
"references": null,
"title": "How I treat cancer-associated anemia.",
"title_normalized": "how i treat cancer associated anemia"
} | [
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"abstract": "A 67-year-old male suffering from depressive symptomatology was admitted to the inpatient clinic at Firat University School of Medicine; and his psychiatric evaluation revealed major depressive episode according to DSM-IV. He developed chest discomfort, chest pain and shortness of breath of acute onset accompanying pulseless ventricular tachycardia (VT) leading to cardiac arrest following sertraline and mirtazapine combination treatment. He died after two days in the Intensive Care Unit. The present case suggests that psychiatrists should be aware of unexpected cardiac events, especially when they use combination treatments.",
"affiliations": "University, School of Medicine, Department of Psychiatry,Elazig, TURKEY.;University, School of Medicine, Department of Psychiatry,Elazig, TURKEY.",
"authors": "Atmaca|Murad|M|;Mermi|Osman|O|",
"chemical_list": null,
"country": "Iran",
"delete": false,
"doi": null,
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"issn_linking": "1735-4587",
"issue": "9(1)",
"journal": "Iranian journal of psychiatry",
"keywords": "Cardiac arrest; Mirtazapine; Sertraline",
"medline_ta": "Iran J Psychiatry",
"mesh_terms": null,
"nlm_unique_id": "101302041",
"other_id": null,
"pages": "45-6",
"pmc": null,
"pmid": "25561949",
"pubdate": "2014-03",
"publication_types": "D016428:Journal Article",
"references": "11866318;2690162;8573661;10832857;12088171;9715336;11037308;12169073;14399272",
"title": "A case of Ventricular Tachycardia and Cardiac Arrest Associated with Sertraline and Mirtazapine Combination.",
"title_normalized": "a case of ventricular tachycardia and cardiac arrest associated with sertraline and mirtazapine combination"
} | [
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{
"abstract": "This retrospective, case series describes our experience with the use of telavancin in patients with methicillin-resistant Staphylococcus aureus (MRSA) osteomyelitis and prosthetic joint infection. The primary objectives were clinical outcomes and adverse events (AEs), and a secondary outcome described microbiological susceptibility. Fourteen patients were enrolled. Median duration of therapy was 58 days, and four patients had concurrent bacteremia. End-of-treatment outcomes were available in 78% of patients, with a clinical success rate of 91%. Thirty-day and 12-month outcomes were also obtained. Seven patients experienced AEs. Infusion-related reactions were most common, and three AEs required discontinuation of therapy. All MRSA isolates had a telavancin MIC ≤0.06μg/ml, which is susceptible. This study indicates that telavancin may have a role in treatment of MRSA osteomyelitis and prosthetic joint infection. Our study describes clinical success and adverse events for long duration of therapy, up to 8 weeks.",
"affiliations": "Sullivan University College of Pharmacy, Louisville, KY; Division of Infectious Diseases, University of Louisville School of Medicine, University Hospital, Louisville, KY. Electronic address: jharting@sullivan.edu.;Division of Infectious Diseases, University of Louisville School of Medicine, University Hospital, Louisville, KY.;Division of Infectious Diseases, University of Louisville School of Medicine, University Hospital, Louisville, KY.;Division of Infectious Diseases, University of Louisville School of Medicine, University Hospital, Louisville, KY.;Division of Infectious Diseases, University of Louisville School of Medicine, University Hospital, Louisville, KY.;Division of Infectious Diseases, University of Louisville School of Medicine, University Hospital, Louisville, KY.",
"authors": "Harting|Julie|J|;Fernandez|Francisco|F|;Kelley|Rob|R|;Wiemken|Tim|T|;Peyrani|Paula|P|;Ramirez|Julio|J|",
"chemical_list": "D000617:Aminoglycosides; D000900:Anti-Bacterial Agents; D000077427:Lipoglycopeptides; C487637:telavancin",
"country": "United States",
"delete": false,
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"issue": "89(4)",
"journal": "Diagnostic microbiology and infectious disease",
"keywords": "Bone; MRSA; Osteomyelitis; Prosthetic joint; Telavancin",
"medline_ta": "Diagn Microbiol Infect Dis",
"mesh_terms": "D000328:Adult; D000368:Aged; D000617:Aminoglycosides; D000900:Anti-Bacterial Agents; D016470:Bacteremia; D015992:Body Mass Index; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007592:Joint Diseases; D000077427:Lipoglycopeptides; D008297:Male; D055624:Methicillin-Resistant Staphylococcus aureus; D008826:Microbial Sensitivity Tests; D008875:Middle Aged; D010019:Osteomyelitis; D012189:Retrospective Studies; D013203:Staphylococcal Infections",
"nlm_unique_id": "8305899",
"other_id": null,
"pages": "294-299",
"pmc": null,
"pmid": "29137718",
"pubdate": "2017-12",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Telavancin for the treatment of methicillin-resistant Staphylococcus aureus bone and joint infections.",
"title_normalized": "telavancin for the treatment of methicillin resistant staphylococcus aureus bone and joint infections"
} | [
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"literaturereference": "HARTING J, FERNANDEZ F, KELLEY R, WIEMKEN T, PEYRANI P, RAMIREZ J.. TELAVANCIN FOR THE TREATMENT OF METHICILLIN-RESISTANT STAPHYLOCOCCUS AUREUS BONE AND JOINT INFECTIONS. DIAGNOSTIC MICROBIOLOGY AND INFECTIOUS DISEASE. 2017?89:294-299",
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] |
{
"abstract": "BACKGROUND\nThe management of recurrent ischemic priapism (RIP) is not clearly defined. Ketoconazole (KTZ) is used to treat RIP and produces a temporary hypogonadal state to suppress sleep-related erections (SREs), which often evolve into episodes of ischemic priapism in this population.\n\n\nOBJECTIVE\nWe review our experience to prevent RIP using KTZ and present our outcomes using a decreased dose regimen.\n\n\nMETHODS\nA retrospective chart review and phone survey of 17 patients with RIP was performed. KTZ inhibits adrenal and gonadal testosterone production with a half-life of 8 hours. By suppressing testosterone levels, SREs are interrupted. We compared our previous protocol of three times daily (TID) KTZ dosing with prednisone for 6 months with our current regimen of initiating KTZ 200 mg TID with prednisone 5 mg daily for 2 weeks and then tapering to KTZ 200 mg nightly for 6 months.\n\n\nMETHODS\nThe primary outcome was the prevention of RIP using KTZ. Secondary outcomes included side effects secondary to KTZ use and patient satisfaction.\n\n\nRESULTS\nAll men experienced daily or almost daily episodes of prolonged, painful erections prior to starting KTZ. The mean number of emergency room (ER) visits per patient prior to starting KTZ was 6.5. No patient required an ER visit for RIP while on KTZ. Sixteen of 17 patients (94%) had complete resolution of priapism while on KTZ with effects noted immediately after starting therapy and no reported sexual side effects attributed to KTZ. One man stopped therapy after 4 days because of nausea/vomiting. Fourteen of 16 men eventually discontinued KTZ after a median duration of 7 months. Twenty-nine percent reported no recurrent priapic episodes after discontinuing. A total of 78.6% had partial or complete resolution of symptoms persisting after KTZ was discontinued with a mean post-treatment follow-up of 36.7 months.\n\n\nCONCLUSIONS\nNo reliable effective preventative therapy has been identified for RIP. In our relatively sizable single-center experience, KTZ appears to be a reasonably effective, safe, and inexpensive treatment to prevent RIP while preserving sexual function. We now recommend our tapered dose regimen listed above. After 6 months, we recommend stopping the medication as we have found a majority of patients will not need to resume nightly KTZ.",
"affiliations": "Department of Urology, Rush University Medical Center, Chicago, IL, USA.",
"authors": "Hoeh|Michael P|MP|;Levine|Laurence A|LA|",
"chemical_list": "D058888:14-alpha Demethylase Inhibitors; D013739:Testosterone; D007654:Ketoconazole",
"country": "Netherlands",
"delete": false,
"doi": "10.1111/jsm.12359",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1743-6095",
"issue": "11(1)",
"journal": "The journal of sexual medicine",
"keywords": "Induced Hypogonadal State and Recurrent Priapism; Ketoconazole; Priapism; Recurrent Ischemic Priapism; Sleep-Related Erections; Stuttering Priapism",
"medline_ta": "J Sex Med",
"mesh_terms": "D058888:14-alpha Demethylase Inhibitors; D000293:Adolescent; D000328:Adult; D000755:Anemia, Sickle Cell; D002985:Clinical Protocols; D004636:Emergency Service, Hospital; D006801:Humans; D007511:Ischemia; D007654:Ketoconazole; D008297:Male; D008875:Middle Aged; D010410:Penile Erection; D011317:Priapism; D012008:Recurrence; D012189:Retrospective Studies; D013739:Testosterone; D055815:Young Adult",
"nlm_unique_id": "101230693",
"other_id": null,
"pages": "197-204",
"pmc": null,
"pmid": "24433561",
"pubdate": "2014-01",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Prevention of recurrent ischemic priapism with ketoconazole: evolution of a treatment protocol and patient outcomes.",
"title_normalized": "prevention of recurrent ischemic priapism with ketoconazole evolution of a treatment protocol and patient outcomes"
} | [
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{
"abstract": "Patients on dialysis have an increased incidence of tuberculosis (TB). Rifampicin, a first-line antitubercular therapy (ATT) drug, is a potent inducer of hepatic cytochrome P450 (CYP). There is potential for pharmacokinetic interaction between rifampicin and anti-hypertensives that are CYP substrates: amlodipine and metoprolol. Therefore, hypertensive patients receiving rifampicin-based ATT are at risk for worsening of hypertension. However, this hypothesis has not yet been systematically studied. In this prospective study, hypertensive CKD 5D patients with TB were followed after rifampicin initiation. Blood pressure (BP) was ≤140/90 mmHg with stable anti-HT requirement at inclusion. Serum amlodipine, metoprolol, and prazosin levels were estimated by high-performance liquid chromatography at baseline and 3, 7, 10, and 14 days after rifampicin initiation. BP and anti-HT requirement were monitored for 2 weeks or until stabilization. All 24 patients in the study had worsening of hypertension after rifampicin and 83.3% required increase in drugs to maintain BP <140/90 mmHg. Serial amlodipine levels were estimated in 16 patients; metoprolol and prazosin in four patients each. Drug levels declined by >50% in all patients and became undetectable in 50-75%. Drug requirement increased from 4.5 ± 3.6 to 8.5 ± 6.4 units (P < 0.0001). Mean time to first increase in dose was 6.5 ± 3.6 days. Eleven (46%) patients experienced a hypertensive crisis at 9.1 ± 3.8 days. Three of them had a hypertensive emergency with acute pulmonary edema. In two patients, rifampicin had to be discontinued to achieve BP control. In conclusion, rifampicin caused a significant decrease in blood levels of commonly used anti hypertensives. This decrease in levels correlated well with worsening of hypertension. Thus, we suggest very close BP monitoring in CKD patients after rifampicin initiation.",
"affiliations": "Department of Nephrology, All India Institute of Medical Sciences, New Delhi, India.;Department of Nephrology, All India Institute of Medical Sciences, New Delhi, India.;Department of Pharmacology, All India Institute of Medical Sciences, New Delhi, India.;Department of Pharmacology, All India Institute of Medical Sciences, New Delhi, India.",
"authors": "Agrawal|A|A|;Agarwal|S K|SK|;Kaleekal|T|T|;Gupta|Y K|YK|",
"chemical_list": null,
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"doi": "10.4103/0971-4065.176145",
"fulltext": "\n==== Front\nIndian J NephrolIndian J NephrolIJNIndian Journal of Nephrology0971-40651998-3662Medknow Publications & Media Pvt Ltd India IJN-26-32210.4103/0971-4065.176145Original ArticleRifampicin and anti-hypertensive drugs in chronic kidney disease: Pharmacokinetic interactions and their clinical impact Agrawal A. Agarwal S. K. Kaleekal T. 1Gupta Y. K. 1Department of Nephrology, All India Institute of Medical Sciences, New Delhi, India1 Department of Pharmacology, All India Institute of Medical Sciences, New Delhi, IndiaAddress for correspondence: Dr. A. Agrawal, Department of Nephrology, All India Institute of Medical Sciences, New Delhi, India. E-mail: akansha.a@gmail.com9 2016 26 5 322 328 Copyright: © Indian Journal of Nephrology2016This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 3.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as the author is credited and the new creations are licensed under the identical terms.Patients on dialysis have an increased incidence of tuberculosis (TB). Rifampicin, a first-line antitubercular therapy (ATT) drug, is a potent inducer of hepatic cytochrome P450 (CYP). There is potential for pharmacokinetic interaction between rifampicin and anti-hypertensives that are CYP substrates: amlodipine and metoprolol. Therefore, hypertensive patients receiving rifampicin-based ATT are at risk for worsening of hypertension. However, this hypothesis has not yet been systematically studied. In this prospective study, hypertensive CKD 5D patients with TB were followed after rifampicin initiation. Blood pressure (BP) was ≤140/90 mmHg with stable anti-HT requirement at inclusion. Serum amlodipine, metoprolol, and prazosin levels were estimated by high-performance liquid chromatography at baseline and 3, 7, 10, and 14 days after rifampicin initiation. BP and anti-HT requirement were monitored for 2 weeks or until stabilization. All 24 patients in the study had worsening of hypertension after rifampicin and 83.3% required increase in drugs to maintain BP <140/90 mmHg. Serial amlodipine levels were estimated in 16 patients; metoprolol and prazosin in four patients each. Drug levels declined by >50% in all patients and became undetectable in 50-75%. Drug requirement increased from 4.5 ± 3.6 to 8.5 ± 6.4 units (P < 0.0001). Mean time to first increase in dose was 6.5 ± 3.6 days. Eleven (46%) patients experienced a hypertensive crisis at 9.1 ± 3.8 days. Three of them had a hypertensive emergency with acute pulmonary edema. In two patients, rifampicin had to be discontinued to achieve BP control. In conclusion, rifampicin caused a significant decrease in blood levels of commonly used anti hypertensives. This decrease in levels correlated well with worsening of hypertension. Thus, we suggest very close BP monitoring in CKD patients after rifampicin initiation.\n\nKey words\nAnti-hypertensive drugschronic kidney diseasedrug interactionhypertensionrifampicin\n==== Body\nIntroduction\nChronic kidney disease (CKD) leads to an immunocompromised state with enhanced susceptibility to infections. The increased incidence of tuberculosis (TB) in patients on maintenance hemodialysis (MHD) was noted as early as the 1970s.[1] It is reported to be 4-15%, which is 6-16 times that of the general population.[234] Further, as majority are hypertensive (HT),[5] it can be inferred that a significant number require simultaneous treatment with antitubercular therapy (ATT) and anti-HT drugs. This clinical scenario is especially relevant in TB endemic countries.\n\nRifampicin, a first-line antitubercular drug, exhibits pharmacokinetic interactions with numerous drugs. It is a potent inducer of cytochrome P450 (CYP) 3A4 in the liver and small intestine.[6] Rifampicin also induces intestinal and hepatic P-glycoprotein, which function as cellular efflux pumps.[7] Full induction of drug metabolizing enzymes is reached in about 1 week after starting rifampicin treatment and the induction dissipates in approximately 2 weeks after discontinuing rifampicin.[8]\n\nIt has been our experience that hypertensive CKD patients with previously controlled blood pressure (BP) develop worsening hypertension after initiation of rifampicin as part of ATT. There is evidence that rifampicin induces anti-HT drug metabolism and decreases their potency. Pharmacokinetic studies in healthy volunteers and case studies of hypertensive patients have described significant interactions of beta-blockers (BB) and calcium-channel blockers (CCB) with rifampicin.[910111213] However, the interaction could be unpredictable in the presence of renal dysfunction due to factors such as decreased renal excretion of anti-HTs, decreased serum rifampicin levels, the tendency for fluid retention, renin-mediated hypertension and clearance of drugs during dialysis.\n\nSo far, this issue has not been systematically addressed in the clinical setting. In our study, we aimed to correlate the change in the degree of hypertension, anti-HT drug requirements and serum levels of commonly used anti-HTs in CKD 5D patients initiated on rifampicin-based ATT.\n\nSubjects and Methods\nStudy design\nThis was a single-center, prospective observational cohort study conducted at a tertiary care hospital in India between September 2012 and December 2013. Adult (≥18 years) hypertensive CKD 5D patients recently diagnosed with TB and planned for initiation of rifampicin-based daily ATT were screened for eligibility. Patients enrolled had controlled hypertension (BP ≤140/90 mmHg) with stable anti-HT drug requirement for ≥4 weeks before recruitment. All patients were receiving regular thrice-weekly MHD. Patients were excluded if they were receiving concomitant drugs which could influence CYP450 metabolism; had a current history of smoking or alcohol abuse; were inadequately dialyzed; had fluid overload, or were poorly compliant to treatment. The study protocol was approved by the Institutional Ethics Committee and written informed consent was sought from all participants.\n\nBaseline evaluation included a detailed medical and drug history, physical examination, urine analysis, complete hemogram, liver and renal function tests, renal ultrasound, electrocardiography, echocardiography, and assessment of comorbid conditions such as cardiac disease. Serum samples for baseline estimation of anti-HT drug levels were drawn in all patients before start of rifampicin. Baseline levels of particular anti-HT were measured in patients who were receiving the drug for at least 4 weeks prior to recruitment. After the introduction of rifampicin-based ATT, patients were followed regularly for 2 weeks or until stabilization of BP and anti-HT requirement, whichever was longer. Data collected included BP recording, episodes of uncontrolled hypertension (>140/90 mmHg) and change in anti-HT drug prescription with regard to number, dosage, and frequency of medication. Hypertensive crises were defined as per the Joint National Committee 7 guidelines.[14]\n\nEstimation of serum anti-hypertensive drug levels\nSerum levels of amlodipine besylate, metoprolol succinate, and prazosin hydrochloride were measured using high-performance liquid chromatography (HPLC) technique. Blood samples for estimation were drawn at baseline (day 0) and days 3, 7, 10, and 14 days after starting rifampicin. Samples were also taken whenever there was uncontrolled hypertension or change in anti-HT drug requirement. Blood was centrifuged and supernatant serum was stored at −80°C until analysis.\n\nThe Shimadzu UFLC model HPLC system with fluorescence detector (Shimadzu Corporation, Kyoto, Japan) was used to measure the drug levels. All solvents used were of HPLC-grade while other chemicals were of analytical grade and were obtained for Merck (India). HPLC standards for amlodipine besylate, metoprolol succinate, and prazosin hydrochloride were supplied by Sun Pharma, India. Calibration curves were plotted using five-point calibration standards prepared by plotting peak area against various known concentrations of the drugs. Linear calibration curves were used to estimate drug level in patient samples. The procedure was validated to ensure the suitability and accuracy of the method in terms of linearity of the chromatographic response, accuracy, precision, sensitivity, specificity, and recovery.\n\nStatistical analysis\nOutcome parameters assessed were change in BP, anti-HT drug requirement, and serum levels of amlodipine, metoprolol, and prazosin after initiation of rifampicin. Anti-HT drug prescription in terms of number of drugs, dosage, and frequency of administration was computed into unit scores. Minimum dose or increments in dose of individual anti-HTs used was considered as 1 unit equivalent. These were then algebraically added to derive the total anti-HT drug requirement at a given time point. One unit was taken as amlodipine 5 mg, metoprolol succinate or tartarate 25 mg, prazosin XL 2.5 mg, clonidine 0.1 mg, nifedipine SR 20 mg, atenolol 25 mg, ramipril 5 mg, and minoxidil 5 mg.\n\nCategorical variables were summarized by frequency (%) and quantitative variables were expressed as a mean ± standard deviation. Paired t-test was used to compare changes in baseline and post-rifampicin values of quantitative variables. All statistical analyses were performed using SPSS® Statistics version 22.0 (IBM® Corp., Armonk, New York) and P < 0.05 was considered as statistically significant.\n\nResults\nStudy population\nTwenty-four Asian Indian patients on MHD with newly diagnosed TB were recruited for the study. They were all planned for initiation of daily rifampicin-based ATT. Nineteen patients were male (79%) and mean age of the cohort was 41.1 ± 13.1 years (range: 20–74). Mean body mass index was 20.1 ± 3.3 kg/m2(range: 15–27.8) and serum albumin level was 3.9 ± 0.6 g/dl (range: 2.9-5.2). Mean systolic and diastolic BPs at baseline were 132 ± 9 and 82 ± 8 mmHg, respectively with stable anti-HT requirement for at least 4 weeks prior to recruitment. Distribution of various anti-HT drug classes, as well as concomitant medications, are shown in Table 1. Prior to initiation of rifampicin-based ATT, 79% of the study group required ≤2 anti-HT drugs for maintaining BP ≤140/90 mmHg. Most patients (87.5%) required <10 units of anti-HT drugs at baseline and 75% required ≤5 units. Most commonly prescribed drugs were amlodipine, clonidine, metoprolol, and prazosin.\n\nTable 1 Baseline medication history of the study population (n=24)a\n\nDiagnosis of TB and decision to treat with daily rifampicin-based ATT was per standard clinical practice. All patients were initiated on daily four-drug ATT with isoniazid, rifampicin, pyrazinamide, and ethambutol. The dose of rifampicin used was 450 mg/day for patients weighing ≤60 kg and 600 mg/day for patients >60 kg.\n\nChange in blood pressure and anti-hypertensive drug requirement\nAfter initiation of rifampicin, 20 patients (83.3%) required an increase in anti-HT drugs to maintain BP ≤140/90 mmHg. The overall increase in anti-HT drug requirement from 4.5 ± 3.6 units to 8.5 ± 6.4 units was statistically significant (P < 0.0001) [Figure 1]. The mean time to first increase in anti-HT drugs was 6.5 ± 3.6 (range: 2-14) days. The other four patients also had increase in systolic and diastolic BP by mean of 24 ± 10 mmHg (P = 0.017) and 15 ± 2 mmHg (P = 0.001), respectively, which was both clinically and statistically significant. Eleven of the 24 (46%) patients experienced a hypertensive crisis. Three patients had a hypertensive emergency with the development of acute left ventricular failure and pulmonary edema. The mean time to a crisis was 9.1 + 3.8 days, with a range of 3-14 days.\n\nFigure 1 Increase in anti-hypertensive requirement (expressed in units) with time after rifampicin initiation\n\nIn two patients, BP could not be controlled despite maximal doses of anti-HTs including amlodipine/nifedipine, metoprolol, prazosin, clonidine, minoxidil, and ramipril. They had frequent hypertensive urgencies during hemodialysis, requiring intravenous nitroglycerine infusion, and labetalol. Both these patients had well-controlled BP on three anti-HT drugs prior to initiation of rifampicin. Ultimately, rifampicin was withdrawn and fluoroquinolone was started instead. Three days after withdrawal, the anti-HT requirement began decreasing and by the 10-12th day they were back to requiring only three drugs to maintain BP ≤140/90 mmHg.\n\nAnti-hypertensive drug levels\nThe serial serum concentrations of amlodipine were available in 16 patients, 5 of whom were on 5 mg/day and the other 11 were on 10 mg/day of amlodipine. With the 5 mg/day dose of amlodipine, baseline levels ranged from 10.8 ng/mL to 392 ng/mL. The median level was 27.6 ng/mL and mean was 109.7 ± 161 ng/mL. In the patients who were on 10 mg/day amlodipine, the baseline serum concentration varied from 7.3 to 332.8 ng/mL with median and mean of 37.7 ng/mL and 95.5 ± 100.8 ng/mL, respectively [Table 2]. There was a decrease in serum amlodipine levels in all 16 patients after initiation of rifampicin [Figure 2]. The mean % decline from the baseline was 81.7 ± 20.6% with a range of 52-100%. In 8 of the 16 patients, the levels became undetectable by HPLC.\n\nTable 2 Anti-hypertensive drug requirement and serial anti.hypertensive drug levels after rifampicin initiation\n\nFigure 2 Serial serum amlodipine levels after rifampicin initiation\n\nOf four patients on metoprolol succinate, 2 were receiving 50 mg/day and one each was receiving 25 mg/day and 100 mg/day. The baseline serum concentrations of metoprolol were 27.2 ng/mL (25 mg/day), 45.9 ng/mL and 84 ng/mL (50 mg/day) and 49.5 ng/mL (100 mg/day) [Table 2]. Unlike amlodipine, the decrease in serum metoprolol level was not a steady decline. All four patients however, had a decrease in drug concentration from the baseline [Figure 3]. The mean % decline was 91.9 ± 16.2% (range: 67.6-100%) and three patients (75%) had decline to undetectable levels.\n\nFigure 3 Serial serum metoprolol levels after rifampicin initiation\n\nPrazosin was prescribed to five patients prior to initiation of rifampicin and serum levels estimated in 4 of them. Two patients were on 5 mg/day and one each was receiving 10 mg/day and 15 mg/day. The baseline serum concentrations of prazosin varied markedly [Table 2]. They were 7.9 ng/mL and 4208.3 ng/mL (5 mg/day), 4398.6 ng/mL (10 mg/day), and 923.2 ng/mL (15 mg/day). Although prazosin and rifampicin are not described to interact pharmacokinetically, we observed a decrease in drug concentration from baseline in all four patients [Figure 4]. Levels declined by 98.1 ± 2.7% (range: 94.3–100%) and became undetectable in two patients (50%).\n\nFigure 4 Serial serum prazosin levels after rifampicin initiation\n\nDiscussion\nOurs is a systematic study to address the important issue of interaction of rifampicin with antihypertensive medications in CKD patients. All 24 CKD-5D patients experienced worsening hypertension after initiation of rifampicin-based ATT and twenty patients had a significant increase in their anti-HT drug requirement. It is also noteworthy that eleven patients suffered a hypertensive crisis and in two, rifampicin ultimately had to be stopped to achieve BP control.\n\nIn the only other study on this issue, Sharma et al. analysed the effect of antitubercular medications on BP control in a predialysis CKD cohort.[15] They compared 62 CKD patients with TB with 73 CKD controls. They also observed an increase in anti-HT medications in 60% of patients in the TB group and a two-fold increase in drug requirement (P < 0.0001). They inferred that the temporal relationship between starting antitubercular medications and increase in anti-HT medications suggested a cause and effect relationship. However, they did not perform pharmacokinetic profiling as in our study.\n\nSerum levels of anti-HTs were serially estimated in our study and the decline of drug level correlated clinically with increased BP. The variations in the baseline concentrations of the drugs may be attributed to difference in time of sampling with respect to drug ingestion, meals or hemodialysis and individual patient characteristics. However, each patient in our study served as his own control and we attempted to circumvent this problem by drawing the sample at the same time each day prior to the hemodialysis session.\n\nAll patients showed a decline in serum amlodipine and metoprolol concentrations. Studies in healthy volunteers have shown that rifampicin decreases the bioavailability, plasma levels, and pharmacological effects of beta-blockers and calcium channel blockers by induction of CYP2D6 and CYP3A4, respectively. Bennet PN et al. reported that rifampin reduced the plasma concentrations of metoprolol causing a 33% mean decrease in the area under the curve.[9] Within 15 days after discontinuation, these changes had reverted to the initial values. Similarly, Holtbecker et al. demonstrated decreased bioavailability of oral nifedipine from 41.2% to 5.3% after 7 days of rifampin.[12] Exacerbation of angina and development of uncontrolled hypertension after rifampicin in patients previously well-controlled on nifedipine have also been reported by Tsuchihashi et al.[11] and Tada et al.,[13] respectively. As far as prazosin is concerned, there is no known interaction described with rifampicin in literature. However, we observed a significant decrease in serum prazosin levels with rifampicin. Thus, this interaction warrants further investigation.\n\nTwo of our patients actually required withdrawal of rifampicin due to uncontrolled hypertension despite maximal anti-HT drug prescription. After substitution of rifampicin with a fluoroquinolone, their anti-HT requirement decreased back to baseline in 10-12 days. Singh described a similar occurrence in two dialysis-dependent patients 14-15 days after initiation of rifampicin.[16]\n\nThough small in terms of number of cases, the strength of our study is that it is well-designed, prospective, and the first study to demonstrate the pharmacokinetic effects and clinical significance of the interaction of rifampicin with anti-HTs in patients with renal dysfunction. It provides a proof of concept that rifampicin induces the metabolism of anti-HT drugs, resulting in clinically significant increases in BP. This interaction may be of increased significance in the setting of CKD, and leads to a high incidence of hypertensive crises. In extreme situations, when BP remains uncontrolled despite maximal anti-HT drugs, discontinuation of rifampicin may be the only feasible option. Whether administration of supramaximal doses of anti-HT drugs with rifampicin would counteract the pharmacokinetic interaction and help in better control of hypertension needs further study.\n\nThere are three clear messages from our study for handling such clinical situations. First, avoid rifampicin in patients of CKD with hypertension as far as possible. Caution needs to be exercised in patients with poorly controlled BP and fluoroquinolones may be used instead of rifampicin. Second, if rifampicin is being used, it is essential to ensure strict BP monitoring. This is especially so in first 2 weeks, when there is maximum induction of liver enzymes. Third, patients as well as the primary care physicians must be made aware of the potential risk of uncontrolled hypertension or a hypertensive crisis and should be more watchful in patients at risk for these emergencies.\n\nThe limitations of our study are small sample size and single centre study in a specific subgroup of CKD 5D patients. However, we have no reason to believe that similar findings will not be there in milder degree of CKD. Further, there is a caveat to conversion of anti-HT drugs to unit scores. For example, 1 unit of amlodipine (5 mg) might not be equivalent to 1 unit of clonidine (0.1 mg). Finally, we did our best to enforce compliance with frequent counseling; however, variation of drug and dietary compliance in the same patient with time may also contribute to change in BP.\n\nConclusion\nRifampicin is a potent inducer of cytochrome p450 enzymes and decreases serum levels of commonly used antihypertensive drugs – amlodipine, metoprolol, and prazosin. This interaction is of significant clinical importance in hypertensive CKD 5D patients initiated on rifampicin-based antitubercular treatment. They experience significant lowering of anti-HT drug levels and corresponding worsening of hypertension. Given the clinical impact of our findings and ease of applicability, we feel it would be prudent to monitor patients closely for worsening of hypertension after initiation of rifampicin or use an alternative antitubercular drug in place of rifampicin.\n\nFinancial support and sponsorship\nIntramural Research Grant from All India Institute of Medical Sciences, New Delhi.\n\nConflicts of interest\nThere are no conflicts of interest.\n==== Refs\nReferences\n1 Pradhan RP Katz LA Nidus BD Matalon R Eisinger RP Tuberculosis in dialyzed patients JAMA 1974 229 798 800 4407820 \n2 Andrew OT Schoenfeld PY Hopewell PC Humphreys MH Tuberculosis in patients with end-stage renal disease Am J Med 1980 68 59 65 7350806 \n3 Lundin AP Adler AJ Berlyne GM Friedman EA Tuberculosis in patients undergoing maintenance hemodialysis Am J Med 1979 67 597 602 495629 \n4 Malhotra KK Parashar MK Sharma RK Bhuyan UN Dash SC Kumar R Tuberculosis in maintenance haemodialysis patients. Study from an endemic area Postgrad Med J 1981 57 492 8 7301697 \n5 Rao MV Qiu Y Wang C Bakris G Hypertension and CKD: Kidney Early Evaluation Program (KEEP) and National Health and Nutrition Examination Survey (NHANES), 1999-2004 Am J Kidney Dis 2008 51 4 Suppl 2 S30 7 18359406 \n6 Rae JM Johnson MD Lippman ME Flockhart DA Rifampin is a selective, pleiotropic inducer of drug metabolism genes in human hepatocytes: Studies with cDNA and oligonucleotide expression arrays J Pharmacol Exp Ther 2001 299 849 57 11714868 \n7 Brinkmann U Roots I Eichelbaum M Pharmacogenetics of the human drug-transporter gene MDR1: Impact of polymorphisms on pharmacotherapy Drug Discov Today 2001 6 835 9 11495756 \n8 Niemi M Backman JT Fromm MF Neuvonen PJ Kivistö KT Pharmacokinetic interactions with rifampicin: Clinical relevance Clin Pharmacokinet 2003 42 819 50 12882588 \n9 Bennett PN John VA Whitmarsh VB Effect of rifampicin on metoprolol and antipyrine kinetics Br J Clin Pharmacol 1982 13 387 91 7059439 \n10 Herman RJ Nakamura K Wilkinson GR Wood AJ Induction of propranolol metabolism by rifampicin Br J Clin Pharmacol 1983 16 565 9 6639842 \n11 Tsuchihashi K Fukami K Kishimoto H Sumiyoshi T Haze K Saito M A case of variant angina exacerbated by administration of rifampicin Heart Vessels 1987 3 214 7 3453828 \n12 Holtbecker N Fromm MF Kroemer HK Ohnhaus EE Heidemann H The nifedipine-rifampin interaction. Evidence for induction of gut wall metabolism Drug Metab Dispos 1996 24 1121 3 8894514 \n13 Tada Y Tsuda Y Otsuka T Nagasawa K Kimura H Kusaba T Case report: Nifedipine-rifampicin interaction attenuates the effect on blood pressure in a patient with essential hypertension Am J Med Sci 1992 303 25 7 1345893 \n14 Chobanian AV Bakris GL Black HR Cushman WC Green LA Izzo JL Jr The seventh report of the Joint National Committee on prevention, detection, evaluation, and treatment of high blood pressure: The JNC 7 report JAMA 2003 289 2560 72 12748199 \n15 Sharma AP Sural S Gupta A Garg AX Gulati S Sharma RK Effect of antitubercular medications on blood pressure control in chronic kidney disease patients with tuberculosis: A prospective cohort study J Nephrol 2006 19 771 7 17173251 \n16 Singh B Singh G Uncontrolled blood pressure in tubercular patients on hemodialysis: Think rifampicin Hemodial Int 2012 16 324 5 22099181\n\n",
"fulltext_license": "CC BY-NC-SA",
"issn_linking": "0971-4065",
"issue": "26(5)",
"journal": "Indian journal of nephrology",
"keywords": "Anti-hypertensive drugs; chronic kidney disease; drug interaction; hypertension; rifampicin",
"medline_ta": "Indian J Nephrol",
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"nlm_unique_id": "8914356",
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"pages": "322-328",
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"pmid": "27795624",
"pubdate": "2016-09",
"publication_types": "D016428:Journal Article",
"references": "495629;3453828;7301697;4407820;1345893;7059439;6639842;11714868;11495756;12882588;18359406;7350806;8894514;12748199;17173251;22099181",
"title": "Rifampicin and anti-hypertensive drugs in chronic kidney disease: Pharmacokinetic interactions and their clinical impact.",
"title_normalized": "rifampicin and anti hypertensive drugs in chronic kidney disease pharmacokinetic interactions and their clinical impact"
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},
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] |
{
"abstract": "OBJECTIVE\nTo compare the healthcare expenditure associated with mycophenolate mofetil (MMF)-based immunosuppression in contrast to conventional therapy in patients with lupus nephritis.\n\n\nMETHODS\nOur retrospective single-center study compared the major healthcare costs during the first 24 months of treatment incurred by immunosuppressive medications, hospitalization, and complications in patients with severe lupus nephritis who had been treated with prednisolone and either MMF or sequential cyclophosphamide induction followed by azathioprine maintenance (CTX-AZA).\n\n\nRESULTS\nForty-four patients were studied (22 in each group). Baseline demographic and clinical measures, and remission rates after treatment, were similar between the 2 groups. Immunosuppressive drug cost was 13.6-fold higher in the MMF group (US$4168.3+/-1176.5 per patient, compared with $285.0+/-70.6 in the CTX-AZA group, mean difference $3883.2+/-251.3; p<0.001). MMF treatment was associated with a lower incidence of infections (12.0 episodes/1000 patient-months, compared with 32.4 in the CTX-AZA group; p=0.035). Combined cost of hospitalization and treatment of infections was 82.5% lower in the MMF group (mean difference -2208.7+/-1700.6; p=0.120). Overall treatment expenditure on immunosuppressive drugs, hospitalization, and treatment of infections was 1.57-fold higher in the MMF group (mean US $4635.9 compared with $2961.5 in the CTX-AZA group; p<0.001).\n\n\nCONCLUSIONS\nWhile the cost of MMF treatment for severe lupus nephritis is much higher compared with CTX-AZA, the increased drug cost is partially offset by savings from the reduced incidence of complications.",
"affiliations": "Department of Medicine, University of Hong Kong, Queen Mary Hospital, Pokfulam Road, Hong Kong, China.",
"authors": "Tse|Kai Chung|KC|;Tang|Colin S O|CS|;Lam|Man Fai|MF|;Yap|Desmond Y H|DY|;Chan|Tak Mao|TM|",
"chemical_list": "D007166:Immunosuppressive Agents; D003520:Cyclophosphamide; D009173:Mycophenolic Acid; D001379:Azathioprine",
"country": "Canada",
"delete": false,
"doi": "10.3899/jrheum.080517",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0315-162X",
"issue": "36(1)",
"journal": "The Journal of rheumatology",
"keywords": null,
"medline_ta": "J Rheumatol",
"mesh_terms": "D000328:Adult; D001379:Azathioprine; D003520:Cyclophosphamide; D016527:Drug Costs; D005260:Female; D017721:Hospital Costs; D006801:Humans; D016867:Immunocompromised Host; D007166:Immunosuppressive Agents; D015994:Incidence; D007239:Infections; D008181:Lupus Nephritis; D008297:Male; D008875:Middle Aged; D009173:Mycophenolic Acid; D011014:Pneumonia; D055815:Young Adult",
"nlm_unique_id": "7501984",
"other_id": null,
"pages": "76-81",
"pmc": null,
"pmid": "19004041",
"pubdate": "2009-01",
"publication_types": "D003160:Comparative Study; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Cost comparison between mycophenolate mofetil and cyclophosphamide-azathioprine in the treatment of lupus nephritis.",
"title_normalized": "cost comparison between mycophenolate mofetil and cyclophosphamide azathioprine in the treatment of lupus nephritis"
} | [
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"abstract": "Seizure is a common manifestation of the many neurological conditions faced by primary care physicians. This study aims to determine the prevalence, etiology, and predictors of immediate noncompliance of adult patients presenting with seizures to the department of emergency (ED).\nWe conducted this study in the ED of CMC, Vellore from November 2015 to February 2016. Retrospective chart review was used to gather specific data regarding these consecutive cases.\nDuring the study period, 477 patients presented with seizures. The prevalence of nontrauma seizures in the ED was 2.3% [Figure 1]. The mean age was 41.4 ± 17.25 years. There was a male predominance (63.1%). About 11.7% had active seizures at presentation to the ED and less than a quarter (21.8%) were determined to have status epilepticus. Nearly 41% had new-onset seizures with common etiologies being idiopathic generalized epilepsy (22.6%), metabolic causes (17.9%), acute febrile illnesses (14.42%), and space-occupying lesions (12.3%). Among those with a history of seizures (58.9%), 87.9% were advised regular medications but 58.5% of them were immediately noncompliant. Phenytoin (58.6%), sodium valproate (20.5%), and levetiracetam (18%) were the most commonly used antiepileptics with 23% on multidrug therapy. About 60% were discharged stable from the ED. Univariate analysis showed chronic alcohol consumption (OR: 2.78; 95% CI: 1, 7.7) and female sex (OR: 1.45; 95% CI: 1-2.5) to be predictors of immediate noncompliance to antiepileptics.\nCommon etiologies of new-onset seizures in the ED are idiopathic generalized epilepsy, metabolic causes, and acute febrile illnesses. More than half the patients with a known seizure disorder are immediately noncompliant to the advised medications. Knowledge among primary healthcare physicians about the importance of emphasizing compliance will greatly reduce the burden of seizures.",
"affiliations": "Department of Emergency Medicine, Christian Medical College, Vellore, Tamil Nadu, India.;Department of Emergency Medicine, Christian Medical College, Vellore, Tamil Nadu, India.;Department of Emergency Medicine, Christian Medical College, Vellore, Tamil Nadu, India.;Department of Emergency Medicine, Christian Medical College, Vellore, Tamil Nadu, India.;Department of Biostatistics, Christian Medical College, Vellore, Tamil Nadu, India.;Department of Emergency Medicine, Christian Medical College, Vellore, Tamil Nadu, India.",
"authors": "Honavar|Abhijit G|AG|;Anuranjana|Abhipsha|A|;Markose|Annsmol P|AP|;Dani|Kapil|K|;Yadav|Bijesh|B|;Abhilash|Kundavaram P P|KPP|",
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"fulltext": "\n==== Front\nJ Family Med Prim CareJ Family Med Prim CareJFMPCJournal of Family Medicine and Primary Care2249-48632278-7135Wolters Kluwer - Medknow India JFMPC-8-397710.4103/jfmpc.jfmpc_864_19Original ArticleProfile of patients presenting with seizures as emergencies and immediate noncompliance to antiepileptic medications Honavar Abhijit G. 1Anuranjana Abhipsha 1Markose Annsmol P. 1Dani Kapil 1Yadav Bijesh 2Abhilash Kundavaram P. P. 11 Department of Emergency Medicine, Christian Medical College, Vellore, Tamil Nadu, India2 Department of Biostatistics, Christian Medical College, Vellore, Tamil Nadu, IndiaAddress for correspondence: Dr. Kundavaram P. P. Abhilash, Department of Emergency Medicine, Christian Medical College, Vellore - 632 004, Tamil Nadu, India. E-mail: kppabhilash@gmail.com12 2019 10 12 2019 8 12 3977 3982 07 10 2019 08 10 2019 10 10 2019 Copyright: © 2019 Journal of Family Medicine and Primary Care2019This is an open access journal, and articles are distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 4.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as appropriate credit is given and the new creations are licensed under the identical terms.Introduction:\nSeizure is a common manifestation of the many neurological conditions faced by primary care physicians. This study aims to determine the prevalence, etiology, and predictors of immediate noncompliance of adult patients presenting with seizures to the department of emergency (ED).\n\nMaterials and Methods:\nWe conducted this study in the ED of CMC, Vellore from November 2015 to February 2016. Retrospective chart review was used to gather specific data regarding these consecutive cases.\n\nResults:\nDuring the study period, 477 patients presented with seizures. The prevalence of nontrauma seizures in the ED was 2.3% [Figure 1]. The mean age was 41.4 ± 17.25 years. There was a male predominance (63.1%). About 11.7% had active seizures at presentation to the ED and less than a quarter (21.8%) were determined to have status epilepticus. Nearly 41% had new-onset seizures with common etiologies being idiopathic generalized epilepsy (22.6%), metabolic causes (17.9%), acute febrile illnesses (14.42%), and space-occupying lesions (12.3%). Among those with a history of seizures (58.9%), 87.9% were advised regular medications but 58.5% of them were immediately noncompliant. Phenytoin (58.6%), sodium valproate (20.5%), and levetiracetam (18%) were the most commonly used antiepileptics with 23% on multidrug therapy. About 60% were discharged stable from the ED. Univariate analysis showed chronic alcohol consumption (OR: 2.78; 95% CI: 1, 7.7) and female sex (OR: 1.45; 95% CI: 1–2.5) to be predictors of immediate noncompliance to antiepileptics.\n\nConclusion:\nCommon etiologies of new-onset seizures in the ED are idiopathic generalized epilepsy, metabolic causes, and acute febrile illnesses. More than half the patients with a known seizure disorder are immediately noncompliant to the advised medications. Knowledge among primary healthcare physicians about the importance of emphasizing compliance will greatly reduce the burden of seizures.\n\nComplianceemergency departmentetiologyprofileseizures\n==== Body\nIntroduction\nSeizures are a common presentation of many neurological conditions that are faced by primary healthcare physicians. It is associated with significant morbidity among families, as well as being associated with many superstitious beliefs in the population.[12] The prevalence of epilepsy in low-income and middle-income countries is about twice that of high-income countries.[13] Less than half of epilepsy cases have an identifiable cause and the etiology of seizures varies from place to place. In the developed world, trauma and space-occupying lesions (SOL) predominate, while the central nervous system (CNS) infections are the main causes of seizures in the developing world.[45] Antiepileptic drugs (AEDs) are indicated for most cases and need to be taken for many years. Compliance to these medications is a major concern and noncompliance is probably the most common cause of recurrent seizures.[67] Primary care physicians are often the first to prescribe these drugs and counsel patients about compliance with them. The WHO envisages care for epilepsy as a joint effort coordinated between primary and secondary care, with primary care physicians performing the tasks of case finding, adequate referral and follow-up, and secondary care providers delegated the duties of diagnostic and investigative services and instituting interventions.[89] However, in low- and middle-income countries like India, several barriers exist in implementing such a system. One of the most important of these is a dearth of trained physicians, which in turn defaults the care of epilepsy patients to primary care providers.\n\nMost of the studies on seizures in India have been done on hospital in-patients or on out-patients from neurology or neurosurgery departments, the profile of whom varies significantly from those who present to an emergent primary care setting.[4510] There is limited data of the etiology and outcome of seizures presenting to the ED's in India. Hence, we conducted this study in our ED to determine the prevalence and etiology of nontrauma seizures and to determine the predictors of immediate noncompliance to antiepileptics among those prescribed medications earlier.\n\nMaterials and Methods\nStudy design\nRetrospective cross-sectional.\n\nSetting\nDepartment of Emergency Medicine of Christian Medical College, Vellore.\n\nInclusion criteria\n\nAdult patients (Age >15 years)\n\nPresented to the emergency department with seizures between November 2015 and April 2016.\n\n\n\n\nExclusion criteria\n\nPatients aged <15 years\n\nPatients with seizures due to acute trauma and pseudo-seizures\n\nMissing charts or with inadequate data.\n\n\n\n\nVariables\nPatient data was obtained through the hospital's electronic database. Details of history and physical examination findings and demographic details were recorded on a standard data collection sheet. The variables collected include age, sex, type of seizure, and duration of the seizure.\n\nThe variables were defined as follows:\n\n\nStatus epilepticus was defined as a continuous seizure lasting more than 30 min or two or more seizures without full recovery of consciousness between any of them.\n\nImmediate noncompliance was defined as omitting a single dose of antiepileptic drug within the 24 h period preceding a seizure.\n\nTriage priority was categorized as priority 1, 2, and 3 based on the Canadian Triage and Acuity Scale.\n\n\n\n\nRadiological investigations\nRadiological imaging in the form of computerized tomography (CT) or magnetic resonance imaging (MRI) was performed in all patients with new-onset seizures and in some patients with recurrent seizures based on the clinical indication.\n\nLaboratory tests\nAll patients were administered intravenous or oral AEDs. Serum levels of AEDs were sent only among those on regular medications.\n\nStatistical analysis\nThe data was then transferred into the Microsoft excel (version 16) and analyzed using Statistical Package for Social Sciences for Windows (SPSS Inc. Released 2007, version 16.0. Chicago). Continuous variables are presented as mean (standard deviation). Categorical and nominal variables are presented as percentages. Chi-square test or Fisher exact test was used to compare dichotomous variables and t-test or Mann–Whitney test was used for continuous variables as appropriate. The predictors of immediate noncompliance was analyzed by univariate analysis and their 95% confidence intervals (CI) were calculated. For all tests, a two-sided P < 0.05 was considered statistically significant.\n\nThis study was approved by the institutional review board (IRB Min. No. 9986 dated 2nd March 2016). Patient confidentiality was maintained using unique identifiers and by password-protected data entry software with restricted users.\n\nResults\nDuring the study period, 20832 patients presented to the ED. The prevalence of nontrauma seizures was 2.3% (477/20,832) [Figure 1]. The mean age at presentation was 41.4 ± 17.25 years. There was a male predominance (63.1%). The baseline characteristics and clinical presentation are shown in Table 1. Only 11.7% of the patients had active seizures at presentation to the ED. Less than a quarter (21.8%) were determined to have status epilepticus. A majority (80.5%) had generalized tonic-clonic seizures (GTCS) while 17% had focal seizures.\n\nFigure 1 Strobe statement of patients presenting with seizures\n\nTable 1 Baseline characteristics (n=477)\n\nVariable\tNumber\tPercentage\t\nMean Age (years)\t41.4±17.25\t-\t\nMales\t304\t63.7\t\nDiabetes Mellitus\t83\t17.4\t\nHypertension\t71\t14.9\t\nChronic alcohol consumption\t62\t13\t\nPast cerebrovascular accident\t35\t7.3\t\nTriage Priority 1\t111\t23.2\t\nTriage Priority 2\t348\t73\t\nTriage Priority 3\t18\t3.8\t\nStatus epilepticus\t104\t21.8\t\nActively seizuring at presentation\t56\t11.7\t\nNew onset seizures\t195\t41.1\t\nPatients with known seizure disorder\t282\t58.9\t\nPatients advised medications for seizures\t248/282\t87.9\t\nPatients compliant to medications\t103/248\t41.5\t\nPatients not compliant to medications\t145/248\t58.4\t\nMultiple drug therapy\t56/248\t23\t\nMonotherapy\t192/248\t77\t\nType of seizure\t\nGeneralized Tonic Clonic Seizure (GTCS)\t384\t80.5\t\nFocal seizure\t81\t17\t\nMyoclonic seizure\t6\t1.25\t\nAbsence seizure\t6\t1.25\t\nAbout 41% of the patients had new-onset seizures with common etiologies being idiopathic seizure disorder (22.6%), metabolic causes (17.9%), and acute febrile illness (14.4%) [Table 2]. Metabolic causes included hyponatremia, hypoglycemia, hyperglycemia, and uremia. Among those with a history of seizures, 98% were advised regular medications but 58.5% of them were immediately noncompliant. Phenytoin (58.6%), sodium valproate (20.5%), and levetiracetam (18%) were the most commonly used antiepileptics with 23% on multidrug therapy. Among the patients immediately compliant to medications, only 35.6% had serum AEDs levels in the therapeutic range. Univariate analysis showed chronic alcohol consumption (OR: 2.78; 95% CI: 1, 7.7) to be a predictor of immediate noncompliance to antiepileptics. Choice of the antiepileptic, age, sex, and other comorbidities did not have any association with immediate compliance [Table 3].\n\nTable 2 Etiology of new onset seizures (n=195)\n\nEtiology\tNumber\tPercentage\t\nIdiopathic Generalized Epilepsy\t44\t22.6%\t\nMetabolic causes\t35\t17.9%\t\nAcute febrile illness\t28\t14.4%\t\nSpace Occupying Lesion (SOL)\t24\t12.3%\t\nCerebrovascular accident\t22\t11.2%\t\nAlcohol related\t14\t7.2%\t\nScar Epilepsy\t10\t5.1%\t\nEclampsia\t6\t3.1%\t\nOthers\t12\t6.2%\t\nTotal\t195\t\t\nOther Causes: Poisoning-5, Drug-induced-4, Autoimmune Encephalitis-1, Vasculitis-1, Wilsoneizurescross. Metabolic Causes: Hyponatremia-18, Uremia-9, Hyperglycemia-4, Hypoglycemia-4\n\nTable 3 Univariate analysis for predictors of immediate noncompliance\n\nVariable\tImmediately Compliant (n=103)\tImmediately Noncompliant (n=145)\tOdds Ratio (95% CI)\tP\t\nAge <65 years\t94\t137\t1.63 (0.6, 4.4)\t0.32\t\nFemale sex\t27\t50\t1.45 (1, 2.5)\t0.18\t\nChronic Alcohol Consumption\t5\t18\t2.78 (1.1, 7.7)\t<0.05\t\nDiabetes Mellitus\t8\t15\t1.37 (0.5, 3.3)\t0.5\t\nHypertension\t8\t14\t1.27 (0.5, 3.1)\t0.6\t\nPhenytoin Sodium\t46\t62\t0.61 (0.3, 1.1)\t0.11\t\nSodium Valproate\t13\t12\t0.63 (0.3, 1.5)\t0.28\t\nLeviteracetam\t11\t10\t0.64 (0.3, 1.6)\t0.35\t\nOn Multidrug Therapy\t33\t23\t0.41 (0.2, 0.7)\t<0.05\t\nCT scan of the brain was performed in 46.7% and MRI brain was performed in 20.3% of patients. CT brain was normal in 64% of patients and the radiological findings were shown in Figure 2. More than half (60%) were discharged stable from the ED after controlling the seizures and optimizing antiepileptic dosage.\n\nFigure 2 CT and MRI brain findings\n\nDiscussion\nOur study is one of the few done in the ED setting of a hospital and throws light on the spectrum of etiologies commonly encountered by primary care physicians. The prevalence of seizures (2.3%) is consistent with other studies done in the EDs of the developed world.[361112] Population-based studies probably have higher and more accurate incidence estimates than hospital-based studies but are more difficult to conduct. Hence, hospital-based prevalence studies like ours is a practical way to understand the burden of a common disease like seizures.\n\nAfter an extensive evaluation for etiology, almost half of our patients (221 of 477, or 46.3%) were labelled as having idiopathic generalized epilepsy and a quarter (22.6%) of new-onset episodes were idiopathic. The percentage of idiopathic generalized epilepsy is consistent with that reported from the West.[6] Indian studies also report etiology as idiopathic in 31–66% of patients.[1314] The percentage of new-onset seizures in the ED as reported by Huff et al. was 26% and 62% as reported by Chhabra et al.[613] We noted that 41% of our patients had new-onset seizures.\n\nThe definition of status epilepticus has constantly been changing over the last few decades. Until the 1960s, the term was used to define only persistent generalized clonic seizures. Many forms of status have been recognized by experts thereafter and currently there exist as many types of status epilepticus as there are types of seizures.[15] Studies in the past have reported status epilepticus to be present in 3–30% of patients presenting with seizures.[461314] The 21.8% rate of status epilepticus in our study is comparable to the rate seen in the literature.\n\nPerforming imaging studies in patients with seizures is a crucial decision at the primary care level, as a combination of a limited supply of centers that can provide such services and constrained financial resources of patients themselves. Our study found that nearly half of all patients had a CT or MRI scan done, which closely resembles the use of imaging studies elsewhere.[16] Almost two-thirds of CT scans were reported normal and did not affect management in any form. Limiting the use of imaging to patients who have acute head trauma, prolonged alteration of consciousness, or focal neurological deficit at the examination may increase the yield of emergent neuroimaging.[16]\n\nAEDs are a major treatment consideration for patients with epilepsy with an effective seizure-free period of 3–5 years being the main target. In our study, 59% of the patients who presented with seizures were known epileptics. Therapy with these drugs is started at a low dose and slowly titrated up to the maintenance dose. In addition to metabolic and organic causes, suboptimal drug levels are a major factor in the recurrence of seizures.\n\nWe found that 58% of known epileptics who were advised AEDs were not immediately compliant, and hence presented with recurrences. Joseph et al. from Karnataka, found 90.6% compliance among patients on monotherapy and 75.7% compliance among patients with multiple AED therapy whereas Gurumurthy et al. noted a 72.3% rate of compliance.[1417] Dose omissions are common among patients with epilepsy and are reported in up to 71% of patients with 45% of patients reporting a seizure after a missed dose, at some time during the treatment.[18] Studies have shown that patients on monotherapy have a higher compliance rate to AED than those on polytherapy (90.6% versus 75.7%).[19] Surprisingly, in our study, patients on multiple AEDs were found to be more compliant. We postulate that this is because patients on multiple AEDs were referred to epilepsy clinic multiple times and were more extensively counselled.\n\nSeveral factors in the community may contribute to the low compliance to medication. While we found chronic alcohol consumption to be a significant predictor of noncompliance, other possible factors include socioeconomic status and even type of seizure.[17] Due to the accident and trauma-inducing nature of seizures, which has been known to cause burns, scalds, head and dental injuries, patients' counselling to improve their compliance should be given paramount importance by physicians at all levels.\n\nThe development of adequate primary care systems is the need of the hour. Knowledge among primary caregivers, often the first point of contact and counsel of the poor compliance of epileptics to their medications, risk factors for noncompliance, and the serious consequences that follow will reduce the prevalence of seizures. Further steps include the use of home-based approaches, which primary healthcare workers are in a uniquely qualified position to deliver.[20]\n\nA developing country like India, where healthcare facilities are few and far between to access, needs to improve its healthcare system, particularly at the primary care level. Increased knowledge among primary healthcare physicians of the common reversible and easily treatable causes of seizures could go a long way in improving its outcome at a community level. It would also help the direct relevant investigation and focused management in resource-strapped settings.\n\nOur study has certain limitations. As it was conducted at a single medical centre, the patient population may be biased by patient selection and referral pattern. Since this study was a retrospective survey, some data was missing. Nonetheless, the study provides useful information about the profile and outcome of patients presenting with seizures to the ED.\n\nConclusion\nContrary to the notion among medical professionals that the most common cause of seizures in India is neurocysticercosis; this study suggests that the common etiologies for new-onset seizures in the ED are idiopathic generalized epilepsy, metabolic causes, acute febrile illnesses, and space-occupying lesions. Awareness of these etiologies will guide management of seizures among primary healthcare physicians. More than half of the patients with a seizure disorder are immediately noncompliant, with several socioeconomic factors at play. Hence effective counseling at first contact is needed to prevent recurrent episodes of seizures and reduce its burden on the community.\n\nResearch quality and ethics statement\nThe authors of this manuscript declare that this scientific work complies with reporting quality, formatting and reproducibility guidelines set forth by the EQUATOR Network. The authors also attest that this clinical investigation was determined to require Institutional Review Board/Ethics Committee review, and the corresponding protocol/approval number is IRB Min. No. 9986 dated 2nd March, 2016. We also certify that we have not plagiarized the contents in this submission and have done a Plagiarism Check.\n\nFinancial support and sponsorship\nNil.\n\nConflicts of interest\nThere are no conflicts of interest.\n\nAcknowledgements\nNone\n==== Refs\n1 Ngugi AK Bottomley C Kleinschmidt I Sander JW Newton CR Estimation of the burden of active and lifetime epilepsy: A meta-analytic approach Epilepsia 2010 51 883 90 20067507 \n2 Sridharan R Murthy BN Prevalence and pattern of epilepsy in India Epilepsia 1999 40 631 6 10386533 \n3 Ngugi AK Kariuki SM Bottomley C Kleinschmidt I Sander JW Newton CR Incidence of epilepsy: A systematic review and meta-analysis Neurology 2011 77 1005 12 21893672 \n4 Kafle DR Oli KK Clinical profile of patients with recurrent seizure in tertiary care hospital in Nepal Kathmandu Univ Med J 2014 12 202 6 \n5 Rao BS Vani MS Varma GAR The study of etiological profile in new onset seizures in Indian scenario Int J Adv Med 2015 2 6 12 \n6 Huff JS Morris DL Kothari RU Gibbs MA Emergency department management of patients with seizures: A multicenter study Acad Emerg Med 2001 8 622 8 11388937 \n7 Asadi-Pooya AA Drug compliance of children and adolescents with epilepsy Seizure 2005 14 393 5 15978849 \n8 World Health Organization Global burden of epilepsy and the need for coordinated action at the country level to address its health, social and public knowledge implications 2015 Available from: http://www.who.int/mental_health/neurology/epilepsy/resolution_68_20/en/ \n9 World Health Organization 2005 Atlas Epilepsy care in the world Available from: http://www.who.int/mental_health/neurology/Epilepsy_atlas_r1.pdf \n10 Murthy JMK Yangala R Acute symptomatic seizures-incidence and etiological spectrum: A hospital-based study from South India Seizure 1999 8 162 5 10356374 \n11 Krumholz A Grufferman S Orr ST Stern BJ Seizures and seizure care in an emergency department Epilepsia 1989 30 175 81 2924743 \n12 Dickson JM Jacques R Reuber M Hick J Campbell MJ Morley R The clinical profile of seizures in emergency setting J Dent Med Sci 2016 15 98 102 \n13 Chhabra V Gothwal SK Gupta D Sharma S Bajaj P Saini A The clinical profile of seizures in emergency setting J Dent Med Sci 2016 15 98 102 \n14 Joseph N Kumar GS Nelliyanil M Pattern of seizure cases in tertiary care hospitals in Karnataka state of India Ann Indian Acad Neurol 2013 16 347 51 24101814 \n15 Rona S Rosenow F Arnold S Carreño M Diehl B Ebner A A semiological classification of status epilepticus Epileptic Disord 2005 7 5 12 15741134 \n16 Salinsky M Wong VSS Motika P Meuse J Nguyen J Emergency department neuroimaging for epileptic seizures Epilepsia 2018 59 1676 83 30019464 \n17 Gurumurthy R Chanda K Sarma GRK An evaluation of factors affecting adherence to antiepileptic drugs in patients with epilepsy: A cross-sectional study Singapore Med J 2017 58 98 102 26805666 \n18 Waterhouse E Towne A Seizures in the elderly: Nuances in presentation and treatment Cleve Clin J Med 2005 72 Suppl 3 S26 37 16265941 \n19 Cramer JA Glassman M Rienza V The relationship between poor medication compliance and seizures Epilepsy Behav 2002 3 338 42 12609331 \n20 Singh G Sharma S Bansal RK Setia RK Sharma S Bansal N A home-based, primary-care model for epilepsy care in India: Basis and design Epilepsia Open 2019 4 264 74 Published 2019 Mar 6. doi: 10.1002/epi4.12311 31168493\n\n",
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"journal": "Journal of family medicine and primary care",
"keywords": "Compliance; emergency department; etiology; profile; seizures",
"medline_ta": "J Family Med Prim Care",
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"title": "Profile of patients presenting with seizures as emergencies and immediate noncompliance to antiepileptic medications.",
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}
],
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{
"reactionmeddrapt": "Partial seizures",
"reactionmeddraversionpt": "22.1",
"reactionoutcome": "6"
},
{
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},
{
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},
{
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}
],
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},
"primarysource": {
"literaturereference": "HONAVAR AG, ANURANJANA A, MARKOSE AP, DANI K, YADAV B, ABHILASH KP. PROFILE OF PATIENTS PRESENTING WITH SEIZURES AS EMERGENCIES AND IMMEDIATE NONCOMPLIANCE TO ANTIEPILEPTIC MEDICATIONS. JOURNAL OF FAMILY MEDICINE AND PRIMARY CARE. 2019?8(12):3977-82",
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},
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},
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}
] |
{
"abstract": "Wernicke's encephalopathy (WE) caused by thiamine deficiency is an acute neurological disorder. Clinically, the classic triad of WE consists of ophthalmoplegia, ataxia, and mental status changes. Thiamine deficiency is known to occur commonly in chronic alcoholic patients. Sometimes, it can occur in patients after gastrointestinal surgery and in those with malabsorption. In addition, patients undergoing renal dialysis, suffering from hyperemesis gravidarum, receiving total parenteral nutrition (TPN), and being treated with chemotherapeutic agents are also prone to develop thiamine deficiency. Herein, we report two cases of WE that developed following simultaneous 5-fluorouracil (5-FU) chemotherapy and TPN in colon cancer patients which was successfully treated with thiamine administration.",
"affiliations": "Department of Internal Medicine, Seoul Red Cross Hospital, Seoul, Korea.;Department of Internal Medicine, Seoul Red Cross Hospital, Seoul, Korea.;Department of Internal Medicine, Seoul Red Cross Hospital, Seoul, Korea.;Department of Internal Medicine, Seoul Red Cross Hospital, Seoul, Korea.;Department of Internal Medicine, Seoul Red Cross Hospital, Seoul, Korea.;Department of Internal Medicine, Seoul Red Cross Hospital, Seoul, Korea.;Division of Public Health Medical Service, Seoul National University Hospital, Seoul, Korea.;Division of Public Health Medical Service, Seoul National University Hospital, Seoul, Korea.",
"authors": "Cho|Kyung Pyo|KP|;Lee|Jae Sung|JS|;Seong|Ji Seok|JS|;Woo|Yong Moon|YM|;Cho|Young Jun|YJ|;Jeong|Beom Jin|BJ|;Sohn|Jee Hoon|JH|;Kim|Su-Jung|SJ|",
"chemical_list": "D000964:Antimetabolites, Antineoplastic; D014803:Vitamin B Complex; D005472:Fluorouracil; D013831:Thiamine",
"country": "Korea (South)",
"delete": false,
"doi": "10.4166/kjg.2014.64.3.158",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1598-9992",
"issue": "64(3)",
"journal": "The Korean journal of gastroenterology = Taehan Sohwagi Hakhoe chi",
"keywords": "Colonic neoplasms; Fluorouracil; Thiamine; Total parenteral nutrition; Wernicke encephalopathy",
"medline_ta": "Korean J Gastroenterol",
"mesh_terms": "D000328:Adult; D000964:Antimetabolites, Antineoplastic; D001921:Brain; D003110:Colonic Neoplasms; D005472:Fluorouracil; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D010289:Parenteral Nutrition, Total; D011859:Radiography; D013831:Thiamine; D014803:Vitamin B Complex; D014899:Wernicke Encephalopathy",
"nlm_unique_id": "101189416",
"other_id": null,
"pages": "158-63",
"pmc": null,
"pmid": "25252865",
"pubdate": "2014-09-25",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Two cases of Wernicke´s encephalopathy that developed during total parenteral nutrition in colon cancer patients treated with 5-fluorouracil-based chemotherapy.",
"title_normalized": "two cases of wernicke s encephalopathy that developed during total parenteral nutrition in colon cancer patients treated with 5 fluorouracil based chemotherapy"
} | [
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],
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},
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},
{
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{
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"activesubstancename": "LEUCOVORIN"
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"medicinalproduct": "FOLINIC ACID"
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"medicinalproduct": "BEVACIZUMAB"
},
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "FLUOROURACIL"
},
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"drugadministrationroute": "065",
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"medicinalproduct": "FLUOROURACIL."
},
{
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"activesubstancename": "OXALIPLATIN"
},
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"medicinalproduct": "OXALIPLATIN."
}
],
"patientagegroup": null,
"patientonsetage": "35",
"patientonsetageunit": "801",
"patientsex": "1",
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Wernicke^s encephalopathy",
"reactionmeddraversionpt": "19.0",
"reactionoutcome": "2"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "CHO K, LEE J, SEONG J, WOO Y, CHO Y, JEONG B, SOHN J, KIM S. TWO CASES OF WERNICKE^S ENCEPHALOPATHY THAT DEVELOPED DURING TOTAL PARENTERAL NUTRITION IN COLON CANCER PATIENTS TREATED WITH 5-FLUOROURACIL -BASED CHEMOTHERAPY.. KOREAN JOURNAL OF GASTROENTEROLOGY. 2014;64 (3):156-163.",
"literaturereference_normalized": "two cases of wernicke s encephalopathy that developed during total parenteral nutrition in colon cancer patients treated with 5 fluorouracil based chemotherapy",
"qualification": "3",
"reportercountry": "KR"
},
"primarysourcecountry": "KR",
"receiptdate": "20160531",
"receivedate": "20160525",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 12405015,
"safetyreportversion": 2,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
"seriousnessdisabling": null,
"seriousnesshospitalization": 1,
"seriousnesslifethreatening": null,
"seriousnessother": null,
"transmissiondate": "20160815"
},
{
"companynumb": "KR-SPECTRUM PHARMACEUTICALS, INC.-14-F-KR-00273",
"fulfillexpeditecriteria": "1",
"occurcountry": "KR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "FLUOROURACIL"
},
"drugadditional": null,
"drugadministrationroute": null,
"drugauthorizationnumb": "087792012209",
"drugbatchnumb": "UNK",
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
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"drugdosageform": "INJECTION",
"drugdosagetext": "UNK",
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"drugenddateformat": null,
"drugindication": "COLON CANCER",
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
"drugrecurreadministration": "3",
"drugrecurrence": null,
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"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "FLUOROURACIL."
}
],
"patientagegroup": null,
"patientonsetage": "60",
"patientonsetageunit": "801",
"patientsex": "1",
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Wernicke^s encephalopathy",
"reactionmeddraversionpt": "18.0",
"reactionoutcome": "2"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "CHO KP, LEE JS, SEONG JS,WOO YM, CHO YJ, JEONG BJ, ET AL.. TWO CASES OF WERNICKE^S ENCEPHALOPATHY THAT DEVELOPED DURING TOTAL PARENTERAL NUTRITION IN COLON CANCER PATIENTS TREATED WITH 5-FLUOROURACIL-BASED CHEMOTHERAPY. THE KOREAN JOURNAL OF GASTROENTEROLOGY. 2014;64 NO 3:158-163",
"literaturereference_normalized": "two cases of wernicke s encephalopathy that developed during total parenteral nutrition in colon cancer patients treated with 5 fluorouracil based chemotherapy",
"qualification": null,
"reportercountry": "COUNTRY NOT SPECIFIED"
},
"primarysourcecountry": "KR",
"receiptdate": "20141015",
"receivedate": "20141015",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 10520751,
"safetyreportversion": 1,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
"seriousnessdisabling": null,
"seriousnesshospitalization": null,
"seriousnesslifethreatening": null,
"seriousnessother": 1,
"transmissiondate": "20150528"
}
] |
{
"abstract": "An autoantibody against carbonic anhydrase II was identified in a case of acute tubulointerstitial nephritis induced by famotidine, which inhibits carbonic anhydrase II in addition to the gastric proton pump. The patient's serum reacted with distal nephron homogenates at the same molecular weight as purified carbonic anhydrase II, and immunohistochemistry using the patient's serum showed staining at the distal nephron. Carbonic anhydrase II may be a causative antigen in the famotidine-induced acute tubulointerstitial nephritis.",
"affiliations": "Division of Nephrology and Endocrinology, University of Tokyo, Tokyo, Japan. akitojo-tky@umin.ac.jp",
"authors": "Tojo|Akihiro|A|;Miyashita|Kazuhisa|K|;Kinugasa|Satoshi|S|;Takemura|Tamiko|T|;Goto|Atsuo|A|",
"chemical_list": "D001323:Autoantibodies; D024402:Carbonic Anhydrase II",
"country": "United States",
"delete": false,
"doi": "10.1097/MAJ.0b013e318272f1a6",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0002-9629",
"issue": "345(5)",
"journal": "The American journal of the medical sciences",
"keywords": null,
"medline_ta": "Am J Med Sci",
"mesh_terms": "D001323:Autoantibodies; D024402:Carbonic Anhydrase II; D005260:Female; D006801:Humans; D008875:Middle Aged; D009395:Nephritis, Interstitial",
"nlm_unique_id": "0370506",
"other_id": null,
"pages": "407-8",
"pmc": null,
"pmid": "23221519",
"pubdate": "2013-05",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Acute tubulointerstitial nephritis with an autoantibody response against carbonic anhydrase II.",
"title_normalized": "acute tubulointerstitial nephritis with an autoantibody response against carbonic anhydrase ii"
} | [
{
"companynumb": "JP-RANBAXY-2013R1-69767",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "4",
"activesubstance": {
"activesubstancename": "DOXAZOSIN\\DOXAZOSIN MESYLATE"
},
"drugadditional": null,
"drugadministrationroute": "065",
"drugauthorizationnumb": null,
"drugbatchnumb": null,
"drugcharacterization": "2",
"drugcumulativedosagenumb": null,
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"drugdosagetext": "UNK",
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"drugindication": "PRODUCT USED FOR UNKNOWN INDICATION",
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"medicinalproduct": "DOXAZOSIN"
},
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "FAMOTIDINE"
},
"drugadditional": null,
"drugadministrationroute": "065",
"drugauthorizationnumb": "090283",
"drugbatchnumb": null,
"drugcharacterization": "1",
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"drugindication": "PRODUCT USED FOR UNKNOWN INDICATION",
"drugintervaldosagedefinition": null,
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"drugstructuredosageunit": null,
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "FAMOTIDINE."
},
{
"actiondrug": "4",
"activesubstance": {
"activesubstancename": "ASPIRIN"
},
"drugadditional": null,
"drugadministrationroute": "065",
"drugauthorizationnumb": null,
"drugbatchnumb": null,
"drugcharacterization": "2",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": null,
"drugdosagetext": "UNK",
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "PRODUCT USED FOR UNKNOWN INDICATION",
"drugintervaldosagedefinition": null,
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"drugstartdate": null,
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"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "ASPIRIN."
}
],
"patientagegroup": null,
"patientonsetage": "63",
"patientonsetageunit": "801",
"patientsex": "2",
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Tubulointerstitial nephritis",
"reactionmeddraversionpt": "18.0",
"reactionoutcome": "2"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "TOJO A, MIYASHITA K, KINUGASA S, TAKEMURA T, GOTO A. ACUTE TUBULOINTERSTITIAL NEPHRITIS WITH AN AUTOANTIBODY RESPONSE AGAINST CARBONIC ANHYDRASE II. AM J MED SCI. 2013;MAY;345(5):407-8",
"literaturereference_normalized": "acute tubulointerstitial nephritis with an autoantibody response against carbonic anhydrase ii",
"qualification": "1",
"reportercountry": "JP"
},
"primarysourcecountry": "JP",
"receiptdate": "20141021",
"receivedate": "20130606",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 9335326,
"safetyreportversion": 2,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
"seriousnessdisabling": null,
"seriousnesshospitalization": 1,
"seriousnesslifethreatening": null,
"seriousnessother": null,
"transmissiondate": "20150529"
}
] |
{
"abstract": "The aims were to review the diagnosis, testing and presentation of acute hepatitis C (HCV) in patients initially diagnosed to have drug-induced liver injury (DILI) enrolled in the US DILI Network.\n\n\n\nAll patients with suspected DILI underwent testing for competing causes of liver injury and returned for 6-month follow-up. Causality was adjudicated by consensus expert opinion.\n\n\n\nBetween 2004 and 2016, 1518 patients were enrolled and adjudicated and underwent 6 months of follow-up. Initial locally acquired anti-HCV results were available in 1457 (96%), but HCV RNA in only 795 (52%). Stored sera were available for repeat testing, so that results were available on all 1518 patients (1457 for anti-HCV and 1482 for HCV RNA). A total of 104 subjects (6.9%) had evidence of HCV infection-10 positive for HCV RNA alone, 16 for anti-HCV alone and 78 for both. All 104 HCV-positive cases were reviewed, and 23 cases were adjudicated as acute HCV. All presented with acute hepatocellular injury with median ALT 1448 U/L, alkaline phosphatase 232 U/L and total bilirubin 10.8 mg/dL. Twenty-two (96%) patients were jaundiced. While all 23 cases initially had been suspected of having DILI, 19 were adjudicated as acute HCV and not DILI at the 6-month follow-up; while 4 were still considered DILI.\n\n\n\nTwenty-three of 1518 (1.5%) cases of suspected DILI were due to acute HCV infection. We recommend that initial and follow-up HCV RNA testing should be performed to exclude HCV in patients with acute hepatocellular injury and suspected DILI.",
"affiliations": "Division of Liver Diseases, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA. jawad.ahmad@mountsinai.org.;Division of Gastroenterology and Hepatology, University of Pennsylvania, Philadelphia, USA.;Division of Gastroenterology, Hepatology and Nutrition, East Carolina University, Greenville, USA.;Division of Gastroenterology and Hepatology, University of North Carolina School of Medicine, Chapel Hill, USA.;Division of Gastroenterology and Hepatology, Indiana University School of Medicine, Indianapolis, USA.;Division of Gastroenterology and Hepatology, University of Michigan Medical School, Ann Arbor, USA.;Einstein Medical Center, Philadelphia, USA.;Division of Gastrointestinal and Liver Diseases, Keck School of Medicine of University of Southern California, Los Angeles, USA.;Duke Clinical Research Institute, Duke University, Durham, USA.;Volwiler Society, Head Infectious Disease Research, Abbott Laboratories, Lake Bluff, USA.;National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), Bethesda, USA.",
"authors": "Ahmad|Jawad|J|0000-0003-1384-2349;Reddy|K Rajender|KR|;Tillmann|Hans L|HL|;Hayashi|Paul H|PH|;Chalasani|Naga|N|;Fontana|Robert J|RJ|;Navarro|Victor J|VJ|;Stolz|Andrew|A|;Barnhart|Huiman|H|;Cloherty|Gavin A|GA|;Hoofnagle|Jay H|JH|",
"chemical_list": "D018937:Hepatitis C Antibodies; D012367:RNA, Viral; D000410:Alanine Transaminase; D000469:Alkaline Phosphatase; D001663:Bilirubin",
"country": "United States",
"delete": false,
"doi": "10.1007/s10620-019-05591-w",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0163-2116",
"issue": "64(9)",
"journal": "Digestive diseases and sciences",
"keywords": "Acute hepatitis C; Drug-induced liver injury; Hepatitis C RNA",
"medline_ta": "Dig Dis Sci",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000410:Alanine Transaminase; D000469:Alkaline Phosphatase; D001663:Bilirubin; D056486:Chemical and Drug Induced Liver Injury; D003937:Diagnosis, Differential; D005260:Female; D016174:Hepacivirus; D006526:Hepatitis C; D018937:Hepatitis C Antibodies; D006801:Humans; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D012367:RNA, Viral; D055815:Young Adult",
"nlm_unique_id": "7902782",
"other_id": null,
"pages": "2645-2652",
"pmc": null,
"pmid": "30927209",
"pubdate": "2019-09",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study; D064888:Observational Study; D052061:Research Support, N.I.H., Extramural; D052060:Research Support, N.I.H., Intramural; D013485:Research Support, Non-U.S. Gov't",
"references": "19132805;20512999;21855518;23202418;23322703;24681128;25754159;25808284;26171595;27253181;27613441;29244000;29267061;8229111",
"title": "Importance of Hepatitis C Virus RNA Testing in Patients with Suspected Drug-Induced Liver Injury.",
"title_normalized": "importance of hepatitis c virus rna testing in patients with suspected drug induced liver injury"
} | [
{
"companynumb": "US-BAYER-2019-169184",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "NAPROXEN"
},
"drugadditional": null,
"drugadministrationroute": null,
"drugauthorizationnumb": "020204",
"drugbatchnumb": null,
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": "FILM-COATED TABLET",
"drugdosagetext": "UNK",
"drugenddate": null,
"drugenddateformat": null,
"drugindication": null,
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
"drugrecurreadministration": null,
"drugrecurrence": null,
"drugseparatedosagenumb": null,
"drugstartdate": null,
"drugstartdateformat": null,
"drugstructuredosagenumb": null,
"drugstructuredosageunit": null,
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "NAPROXEN."
}
],
"patientagegroup": "5",
"patientonsetage": "52",
"patientonsetageunit": "801",
"patientsex": "1",
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Acute hepatitis C",
"reactionmeddraversionpt": "22.0",
"reactionoutcome": null
},
{
"reactionmeddrapt": "Drug-induced liver injury",
"reactionmeddraversionpt": "22.0",
"reactionoutcome": null
}
],
"summary": null
},
"primarysource": {
"literaturereference": "AHMAD J, REDDY KR, TILLMANN HL, HAYASHI PH, CHALASANI N, FONTANA RJ, ET AL.. IMPORTANCE OF HEPATITIS C VIRUS RNA TESTING IN PATIENTS WITH SUSPECTED DRUG-INDUCED LIVER INJURY. DIGESTIVE DISEASES AND SCIENCES. 2019?64:9:2645-2652",
"literaturereference_normalized": "importance of hepatitis c virus rna testing in patients with suspected drug induced liver injury",
"qualification": "3",
"reportercountry": "US"
},
"primarysourcecountry": "US",
"receiptdate": "20190918",
"receivedate": "20190918",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "2",
"safetyreportid": 16823470,
"safetyreportversion": 1,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
"seriousnessdisabling": null,
"seriousnesshospitalization": 1,
"seriousnesslifethreatening": null,
"seriousnessother": null,
"transmissiondate": "20191005"
}
] |
{
"abstract": "BACKGROUND\nThe association between inhibition of tumour necrosis factor alpha (TNF-α) and new onset of neurological adverse events (AEs) is unclear.\n\n\nOBJECTIVE\nTo evaluate neurological AEs with TNF-α inhibitors reported to the Food and Drug Administration Adverse Event Reporting System (FAERS) utilising a standardised scoring tool for drug-induced AEs.\n\n\nMETHODS\nA search of FAERS for neurological AEs (January 1, 2000 to December 31, 2009) reported with infliximab, adalimumab, certolizumab and etanercept was performed. Full-text reports were accessed using the Freedom of Information Act and scored using Naranjo score, while accounting for temporal association, previous conclusive reports of the neurological AE with any TNF-α inhibitor, and alternate explanations including underlying disease, concomitant medications and comorbidities, such as diabetes mellitus.\n\n\nRESULTS\nThere were 772 reports. Most were in patients who had rheumatoid arthritis (393, 50.9%) followed by inflammatory bowel disease (140, 18.1%). No significant differences in age or gender were seen between IBD patients compared with rheumatological diseases (P = 0.584 and P = 0.055 respectively). Etanercept was reported most (327, 42.4%) followed by infliximab (276, 35.8%) (P = 0.008). Peripheral neuropathy was the most common neurological AE (296 reports, 38.3%) followed by central nervous system and/or spinal cord demyelination (153 reports, 19.8%). Majority (551, 71.4%) of the reports were of 'possible' AE with the remaining 'probable' AE and none identified as 'definite' AE.\n\n\nCONCLUSIONS\nWhile several neurological AEs have been described, definite association between de novo development of these AEs and exposure to TNF-α inhibitors was not established using the Naranjo score.",
"affiliations": "Department of Gastroenterology, Research Institute, NorthShore University Health System, Evanston, IL 60201, USA.",
"authors": "Deepak|P|P|;Stobaugh|D J|DJ|;Sherid|M|M|;Sifuentes|H|H|;Ehrenpreis|E D|ED|",
"chemical_list": "D014409:Tumor Necrosis Factor-alpha",
"country": "England",
"delete": false,
"doi": "10.1111/apt.12385",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0269-2813",
"issue": "38(4)",
"journal": "Alimentary pharmacology & therapeutics",
"keywords": null,
"medline_ta": "Aliment Pharmacol Ther",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D016907:Adverse Drug Reaction Reporting Systems; D001172:Arthritis, Rheumatoid; D002648:Child; D064420:Drug-Related Side Effects and Adverse Reactions; D005260:Female; D006801:Humans; D015212:Inflammatory Bowel Diseases; D008297:Male; D008875:Middle Aged; D009422:Nervous System Diseases; D014409:Tumor Necrosis Factor-alpha; D014481:United States; D014486:United States Food and Drug Administration; D055815:Young Adult",
"nlm_unique_id": "8707234",
"other_id": null,
"pages": "388-96",
"pmc": null,
"pmid": "23802849",
"pubdate": "2013-08",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
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"abstract": "Background Amlodipine is used for the treatment of hypertension, but reports on its use in early pregnancy are limited. Methods and Results In the present study, we recruited 231 women with chronic hypertension, including those who received amlodipine or other antihypertensives during early pregnancy, and investigated frequencies of morphologic abnormalities in their 231 offspring. Specifically, we evaluated 48 neonates exposed to amlodipine in the first trimester (amlodipine group, Group A), 54 neonates exposed to antihypertensives other than amlodipine (other antihypertensive group, Group O), and 129 neonates not exposed to antihypertensives (no-antihypertensive group, Group N). The number of morphologic abnormalities of offspring in each group were 2 in Group A (4.2%; 95% CI, 0.51-14.25); 3 in Group O (5.6%; 95% CI, 1.16-15.39) and 6 in Group N (4.7%; 95% CI, 1.73-9.85). The odds ratio of the primary outcome comparing Group A and Group O was 0.74 (95% CI: 0.118-4.621) and Group A and Group N was 0.89 (95% CI: 0.174-4.575). Conclusions The odds of birth defects in Group A in the first trimester were not significantly different from those with or without other antihypertensives.",
"affiliations": "Drug Information Institute in Pregnancy Tokyo Japan.;Drug Information Institute in Pregnancy Tokyo Japan.;Department of Obstetric Medicine Osaka Women's and Children's Hospital Osaka Japan.;Department of Internal Medicine (I) Osaka Medical College Osaka Japan.;Department of Perinatology and Gynecology National Cerebral and Cardiovascular Center Osaka Japan.;Department of Obstetric Medicine Osaka Women's and Children's Hospital Osaka Japan.;Department of Perinatology and Gynecology National Cerebral and Cardiovascular Center Osaka Japan.;Drug Information Institute in Pregnancy Tokyo Japan.;Drug Information Institute in Pregnancy Tokyo Japan.;Drug Information Institute in Pregnancy Tokyo Japan.;Drug Information Institute in Pregnancy Tokyo Japan.;Division of Biostatistics Clinical Research Center National Center for Child Health and Development Tokyo Japan.;Motherisk Program Division of Clinical Pharmacology and Toxicology Department of Paediatrics The Hospital for Sick Children University of Toronto Toronto Canada.",
"authors": "Mito|Asako|A|;Murashima|Atsuko|A|;Wada|Yoshinao|Y|;Miyasato-Isoda|Mai|M|;Kamiya|Chizuko A|CA|;Waguri|Masako|M|;Yoshimatsu|Jun|J|;Yakuwa|Naho|N|;Watanabe|Omi|O|;Suzuki|Tomo|T|;Arata|Naoko|N|;Mikami|Masashi|M|;Ito|Shinya|S|",
"chemical_list": "D000959:Antihypertensive Agents; D017311:Amlodipine",
"country": "England",
"delete": false,
"doi": "10.1161/JAHA.119.012093",
"fulltext": "\n==== Front\nJ Am Heart AssocJ Am Heart Assoc10.1002/(ISSN)2047-9980JAH3ahaoaJournal of the American Heart Association: Cardiovascular and Cerebrovascular Disease2047-9980John Wiley and Sons Inc. Hoboken 3134508310.1161/JAHA.119.012093JAH34232Original ResearchOriginal ResearchHypertensionSafety of Amlodipine in Early Pregnancy Mito et alMito Asako MD, PhD\n1\n\n2\nmito-a@ncchd.go.jp Murashima Atsuko MD, PhD\n1\n\n2\nWada Yoshinao MD, PhD\n3\nMiyasato‐Isoda Mai MD, PhD\n4\nKamiya Chizuko A. MD, PhD\n5\nWaguri Masako MD, PhD\n3\nYoshimatsu Jun MD, PhD\n5\nYakuwa Naho BPh\n1\nWatanabe Omi MD\n1\nSuzuki Tomo MD\n1\n\n6\nArata Naoko MD, PhD\n1\n\n2\nMikami Masashi MS\n7\nIto Shinya MD\n8\n\n1 \nDrug Information Institute in Pregnancy\nTokyo\nJapan\n\n2 \nDivision of Maternal Medicine\nCenter for Maternal‐Fetal‐Neonatal and Reproductive Medicine\nNational Center for Child Health and Development\nTokyo\nJapan\n\n3 \nDepartment of Obstetric Medicine\nOsaka Women's and Children's Hospital\nOsaka\nJapan\n\n4 \nDepartment of Internal Medicine (I)\nOsaka Medical College\nOsaka\nJapan\n\n5 \nDepartment of Perinatology and Gynecology\nNational Cerebral and Cardiovascular Center\nOsaka\nJapan\n\n6 \nDivision of Obstetrics\nCenter for Maternal‐Fetal‐Neonatal and Reproductive Medicine\nNational Center for Child Health and Development\nTokyo\nJapan\n\n7 \nDivision of Biostatistics\nClinical Research Center\nNational Center for Child Health and Development\nTokyo\nJapan\n\n8 \nMotherisk Program\nDivision of Clinical Pharmacology and Toxicology\nDepartment of Paediatrics\nThe Hospital for Sick Children\nUniversity of Toronto\nToronto\nCanada\n* Correspondence to: Asako Mito, MD, PhD, Drug Information Institute in Pregnancy/Division of Maternal Medicine, Center for Maternal‐Fetal‐Neonatal and Reproductive Medicine, National Center for Child Health and Development, 2‐10‐1 Okura Setagaya, Tokyo 157‐8535, Japan. E‐mail: mito-a@ncchd.go.jp26 7 2019 06 8 2019 8 15 10.1002/jah3.2019.8.issue-15e01209323 1 2019 28 5 2019 © 2019 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley.This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.Background\nAmlodipine is used for the treatment of hypertension, but reports on its use in early pregnancy are limited.\n\nMethods and Results\nIn the present study, we recruited 231 women with chronic hypertension, including those who received amlodipine or other antihypertensives during early pregnancy, and investigated frequencies of morphologic abnormalities in their 231 offspring. Specifically, we evaluated 48 neonates exposed to amlodipine in the first trimester (amlodipine group, Group A), 54 neonates exposed to antihypertensives other than amlodipine (other antihypertensive group, Group O), and 129 neonates not exposed to antihypertensives (no‐antihypertensive group, Group N). The number of morphologic abnormalities of offspring in each group were 2 in Group A (4.2%; 95% CI, 0.51–14.25); 3 in Group O (5.6%; 95% CI, 1.16–15.39) and 6 in Group N (4.7%; 95% CI, 1.73–9.85). The odds ratio of the primary outcome comparing Group A and Group O was 0.74 (95% CI: 0.118–4.621) and Group A and Group N was 0.89 (95% CI: 0.174–4.575).\n\nConclusions\nThe odds of birth defects in Group A in the first trimester were not significantly different from those with or without other antihypertensives.\n\nSee Editorial Malha and August\n\n\namlodipinechronic hypertensionfirst trimesterpregnancySubject Categories\nHigh Blood PressureHypertensionPregnancyJapan Agency for Medical Research and DevelopmentJP17mk0101086 source-schema-version-number2.0component-idjah34232cover-date06 August 2019details-of-publishers-convertorConverter:WILEY_ML3GV2_TO_NLMPMC version:5.6.7 mode:remove_FC converted:06.08.2019\n(J Am Heart Assoc . 2019 ;8 :e012093 DOI: 10.1161/JAHA.119.012093 .)31345083\n==== Body\nClinical Perspective\nWhat Is New?\n\nThe number of cases is greater than those in any previous study on amlodipine use in early pregnancy.\n\n\n\n\nWhat Are the Clinical Implications?\n\nThe incidence of morphologic abnormalities in the offspring of hypertensive mothers treated with amlodipine in early pregnancy was not higher than in mothers treated with or without other antihypertensives.\n\n\n\n\n\n\n\nIntroduction\nPregnancies with chronic hypertension have become increasingly common, partly because of the upward shift of pregnancy ages as well as increasing rates of obesity. Chronic hypertension during pregnancy is a risk factor for various adverse outcomes,1, 2 including perinatal complications such as superimposed preeclampsia, premature birth, and low birth weight.\n\nAmlodipine, a calcium channel blocker, is long‐acting and causes relatively few adverse drug reactions associated with vasodilation. Because of these advantages, amlodipine is frequently used for the treatment of hypertension, except for pregnant women. A few studies reported that calcium channel blockers as a group may not pose a significant teratogenic risk even in early pregnancy,3, 4, 5 although information on specific calcium channel blockers is limited.\n\nIt was recently reported that hypertension itself may be teratogenic.6, 7 In this study, therefore, we compared the pregnancy outcomes of 48 women with amlodipine exposure during the first trimester with those of hypertensive women who received nonamlodipine antihypertensives, as well as those who did not receive any antihypertensive drugs.\n\nMethods\nThe authors declare that all supporting data are available within the article and its online supplementary files.\n\nStudy Subject\nIn this retrospective study, we examined birth outcomes of pregnant women with chronic hypertension whose deliveries resulted in live births from April 2008 to July 2016 at the National Center for Child Health and Development (NCCHD, Tokyo), Osaka Women's and Children's Hospital (OWCH, Osaka), and National Cerebral and Cardiovascular Center (NCCC, Osaka). We extracted the data of singletons whose mothers’ electronic health records were coded “Hypertension” during pregnancy and of those with “Chronic hypertension” documented in the delivery records. We then excluded those who did not meet the criteria for chronic hypertension8 and the remainder were included in the final analyses.\n\nEthics Committee Approval\nThis study has been approved by the research ethics boards of these hospitals (NCCHD: 1243, OWCH: 1010, NCCC: M29‐073). The requirement for informed consent was waived. All personal identifying data were removed from the study database so that the individuals could not be identified.\n\nUse of Antihypertensives\nThe first trimester was defined in this study as the period from estimated conception to 11 weeks and 6 days’ gestation. We classified women and neonates exposed to amlodipine in the first trimester into the amlodipine group (Group A), those exposed to antihypertensives other than amlodipine (including other calcium channel blockers) into the other antihypertensive group (Group O), and those not exposed to antihypertensives into the no‐antihypertensive group (Group N).\n\nClinical Diagnosis\nWe confirmed the diagnosis of hypertension in pregnancy, according to the International Society for the Study of Hypertension in Pregnancy Classification, Diagnosis, and Management Recommendations for International Practice.8 In this study, therefore, hypertension in pregnancy was defined as “chronic hypertension” if the patient was diagnosed with hypertension before pregnancy, or if hypertension was noted before 20 weeks’ gestation. Hypertension was defined as a systolic blood pressure ≥140 mm Hg or a diastolic blood pressure ≥90 mm Hg. These measurements were made on at least 2 different occasions. Abnormal proteinuria in pregnancy was defined as the excretion of ≥300 mg of protein in 24 hours or a protein/creatinine ratio of ≥0.30 g/g·Cr. Superimposed preeclampsia was diagnosed if a woman with chronic hypertension developed new‐onset proteinuria in the setting of a rise in blood pressure or a sudden increase in pre‐existing proteinuria.\n\nData Analysis Framework\nPrimary outcome\nIn accordance with the European Surveillance of Congenital Anomalies Guide 1.4 and the Reference Documents9 developed by European Surveillance of Congenital Anomalies, neonates who exhibited “major anomalies” were considered to have morphologic abnormalities (Table S1).\n\nStudy Participant Characteristics\nClinical information, such as birth date, underlying disease, past medical history, previous pregnancy complications, family history, as well as information on the course of the index pregnancy and the newborn, were obtained from electronic medical records.\n\nStatistical Analysis\nA 95% CI was calculated for the incidence of malformations. P<0.05 was considered statistically significant. The χ2 test was used for analyzing primary outcome and discrete variables. Mean values of continuous variables were compared by 1‐way ANOVA. As a subgroup analysis, we repeated the comparison among the 3 groups after excluding 10 women with diabetes mellitus, which is a known risk factor for adverse pregnancy outcomes including congenital anomalies. All analyses were performed with SAS software, version 9.4 (SAS Institute, Cary, NC).\n\nResults\nThere were 25 485 live births delivered in this period. Among them, there were 1624 singletons with “Hypertension” documented in their mothers’ electronic medical records or “Chronic hypertension” in the delivery records. We excluded preeclampsia and gestational hypertension (n=457), postpartum hypertension (n=683), white coat hypertension, and those who did not meet criteria of hypertension (n=244). We also excluded a case of pulmonary hypertension (n=1) and those without data on blood pressure before 20 weeks’ gestations (n=8). A total of 231 Japanese women met the definition of chronic hypertension, and they were included in the final analyses (Figure 1).\n\nFigure 1 Flow chart representing the recruiting process of study subjects. There were 25 485 live births delivered in this period. Among them, there were 1624 singletons with “Hypertension” documented in their mothers’ electronic medical records or “Chronic hypertension” in the delivery records. After excluding those who did not meet criteria of chronic hypertension, a total of 231 neonates were included in the final analyses.\n\nForty‐eight neonates were classified into Group A, 54 neonates into Group O, and 129 neonates into Group N. No clear difference in patient background characteristics was observed between groups except that Group A showed a high proportion of women with thyroid disease as the underlying disease, a history of hypertensive disorders of pregnancy and those with a history of fetal growth restriction and that Group O showed a higher age at delivery than Group N (Table 1).\n\nTable 1 Maternal Baseline Characteristics\n\n\tAmlodipine (n=48)\tOther Antihypertensives (n=54)\tNo Antihypertensives (n=129)\t\nP Value\t\nAge at delivery (y)—mean (SD)\t37.5 (4.04)\t37.9 (5.04)\t36.3 (4.27)\t0.047\t\nHeight, cm—mean (SD)\t158.3 (4.62)\t159.0 (4.64)\t159.0 (5.98)\t0.727\t\nPrepregnancy body weight, kg—mean (SD)\t62.2 (13.03)\t66.4 (14.92)\t67.9 (17.10)\t0.107\t\nPrepregnancy BMI, kg/m2—mean (SD)\t24.8 (5.02)\t26.4 (6.34)\t26.8 (6.42)\t0.153\t\nNulliparous, N (%)\t20 (41.7)\t26 (48.1)\t70 (54.3)\t0.310\t\nUnderlying disease\t\nDiabetes mellitus, N (%)\t3 (6.3)\t1 (1.9)\t6 (4.7)\t0.533\t\nThyroid disease, N (%)\t7 (14.6)\t4 (7.4)\t5 (3.9)\t0.044\t\nKidney disease, N (%)\t3 (6.3)\t0 (0.0)\t4 (3.1)\t0.184\t\nCollagen disease, N (%)\t4 (8.3)\t2 (3.7)\t2 (1.6)\t0.090\t\nCongenital heart disease, N (%)\t0 (0.0)\t0 (0.0)\t1 (0.8)\t0.672\t\nPrevious pregnancy complications\t\nHypertensive disorders of pregnancy, N (%)\t19 (39.6)\t10 (18.5)\t28 (21.7)\t0.024\t\nFetal growth restriction, N (%)\t10 (20.8)\t5 (9.3)\t7 (5.4)\t0.008\t\nSmoking during pregnancy, N (%)\t0 (0.0)\t3 (5.6)\t5 (3.9)\t0.287\t\nAlcohol consumption during pregnancy, N (%)\t0 (0.0)\t1 (1.9)\t2 (1.6)\t0.662\t\nBMI indicates body mass index.\n\nThere was no statistically significant difference between groups in all delivery outcomes (Table 2).\n\nTable 2 Delivery Outcomes\n\n\tAmlodipine (n=48)\tOther Antihypertensives (n=54)\tNo Antihypertensives (n=129)\t\nP Value\t\nMaternal outcomes\t\nSuperimposed preeclampsia, N (%)\t15 (31.3)\t14 (25.9)\t43 (33.3)\t0.615\t\nGestational diabetes mellitus, N (%)\t3 (6.3)\t8 (14.8)\t24 (18.6)\t0.125\t\nNewborn outcomes\t\nGestational age, wks—mean (SD)\t37.7 (2.14)\t36.9 (3.43)\t37.1 (3.65)\t0.417\t\nDelivery weight, g—mean (SD)\t2778.4 (619.54)\t2520.1 (800.09)\t2536.0 (759.40)\t0.123\t\nPreterm birth (<37 wks), N (%)\t10 (20.8)\t12 (22.2)\t41 (31.8)\t0.221\t\nLow birth weight (<2500 g), N (%)\t12 (25.0)\t24 (44.4)\t49 (38.0)\t0.116\t\nApgar score\t\n1 min, mean (SD)\t8.0 (0.99)\t7.4 (1.97)\t7.6 (1.69)\t0.165\t\n5 min, mean (SD)\t8.9 (0.43)\t8.5 (1.30)\t8.7 (1.22)\t0.203\t\nBirth defects, N (%)\t2 (4.2)\t3 (5.6)\t6 (4.7)\t0.944\t\nThere was no statistically significant difference among the groups.\n\nMorphologic abnormalities were observed in 11 of the 231 neonates: 2 of 48 neonates in Group A (4.2%; 95% CI, 0.51–14.25), 3 of 54 neonates in Group O (5.6%; 95% CI, 1.16–15.39), and 6 of 129 neonates in Group N (4.7%; 95% CI, 1.73–9.85) (Table 2: P=0.944). The odds ratio of the primary outcome comparing Group A and Group O was 0.74 (95% CI: 0.118–4.621) and Group A and Group N was 0.89 (95% CI: 0.174–4.575). Details of observed birth defects are summarized in Table 3. We were unable to identify any specific pattern of birth defects in this group.\n\nTable 3 Details of Cases of Morphologic Abnormalities\n\nCase\tGroup\tBirth Defects\tAge at Delivery/Underlying Disease\tDelivery Outcome\tSuperimposed Preeclampsia\tAntihypertensive Agents\tOther Drugs\t\n1\tA\tPVS\t\n41 y.o.\n\nEssential hypertension\n\t\n35w4d\n\n1872 g\n\t−\tPrepregnancy to 4w6d\tAm\t12w0d to 28w0d: LDA\t\n34w5d to 35w0d\tMe\t\n35w1d to delivery\tMe, Nif\t\n2\tA\tVSD\t\n36 y.o.\n\nPrimary aldosteronism\n\t\n38w0d\n\n3217 g\n\t−\tPrepregnancy to 6w4d\tAm\t8w3d to 28w0d: LDA\t\n6w5d to 8w0d\tHy\t\n8w1d to delivery\tAm\t\n3\tO\tLow‐lying conus medullaris/hypospadias/inguinal hernia\t\n42 y.o.\n\nEssential hypertension\n\t\n29w1d\n\n521 g\n\t+\tPrepregnancy to 8w2d\tLa\t12w6d to delivery: LDA\t\n9w4d to 12w0d\tMe\t\n12w1d to 12w5d\tMe, La\t\n12w6d to 17w5d\tMe, La, Am\t\n17w6d to delivery\tMe, Am\t\n4\tO\tVSD\t\n38 y.o.\n\nEssential hypertension\n\nRA\n\t\n25w6d\n\n382 g\n\t−\tPrepregnancy to delivery\tNic, La\t\nPrepregnancy to delivery: PSL\n\n3w to delivery: LDA\n\t\n5\tO\tHypospadias\t\n39 y.o.\n\nEssential hypertension\n\t\n39w4d\n\n2912 g\n\t+\t8w4d to 30w2d\tMe\tNone\t\n30w3d to delivery\tMe, Am\t\n6\tN\tHypospadias\t\n33 y.o.\n\nEssential hypertension\n\t\n27w1d\n\n506 g\n\t+\t13w2d to 18w2d\tHy\t12w0d to delivery: LDA\t\n18w2d to delivery\tLa\t\n7\tN\tPatent foramen ovale/low‐lying conus medullaris\t\n40 y.o.\n\nEssential hypertension\n\t\n35w4d\n\n1351 g\n\t+\t16w0d to 24w6d\tMe\tNone\t\n25w0d to delivery\tMe, Nif\t\n8\tN\tLow anorectal anomaly/low‐lying conus medullaris\t\n42 y.o.\n\nEssential hypertension\n\t\n26w0d\n\n379 g\n\t+\t21w0d to 21w1d\tMe\tNone\t\n21w2d to delivery\tMe, Am\t\n9\tN\tLow‐lying conus medullaris\t\n37 y.o.\n\nEssential hypertension\n\t\n34w3d\n\n2108 g\n\t−\t16w4d to 28w5d\tMe\tNone\t\n28w6d to delivery\tMe, Am\t\n10\tN\tPotter syndrome\t\n40 y.o.\n\nEssential hypertension\n\t\n33w6d\n\n1836 g\n\t−\tNone\t\tNone\t\n11\tN\tColpocephaly\t\n32 y.o.\n\nEssential hypertension\n\t\n40w4d\n\n3396 g\n\t−\tNone\t\tNone\t\nA indicates amlodipine group; Am, amlodipine; Hy, hydralazine; La, labetalol; LDA, low‐dose aspirin; Me, methyldopa; N, No antihypertensive group; Nic, nicardipine; Nif, nifedipine; O, Other antihypertensive group; PSL, prednisolone; PVS, pulmonary valve stenosis; RA, rheumatoid arthritis; VSD, ventricular septal defect; y.o., years old.\n\nWe have calculated total dose to quantify the exposure (Table S2). Total dose was obtained by amlodipine daily dose times the total number of days of amlodipine uses during the first trimester. The average of total dose±SD and the total number of days±SD of amlodipine use for all cases were 363.6±257.9 mg and 65.0±25.9 days. Those of cases with birth defects were 175 mg, 35 days (Case 1 in Table 3) and 740 mg, 74 days (Case 2 in Table 3).\n\nOur study cohort included 10 women with diabetes mellitus, a known risk factor for congenital anomalies: 3 in group A, 1 in group O, and 6 in group N, although there were no birth defects among them. We performed a subgroup analysis after excluding these subjects, but group differences remained not statistically significant (P=0.960): morphologic abnormalities were observed in 11 of the 221 neonates: 2 of 45 neonates in Group A (4.4%; 95% CI, 0.54–15.15), 3 of 53 neonates in Group O (5.7%; 95% CI, 1.18–15.66), and 6 of 123 neonates in Group N (4.9%; 95% CI, 1.81–10.32) (Table S3). In this subgroup analysis, the odds ratio of the primary outcome comparing Group A and Group O was 0.78 (95% CI: 0.124–4.857) and Group A and Group N was 0.91 (95% CI: 0.176–4.666).\n\nA pair of twins who were excluded from the final analysis were exposed to amlodipine in early pregnancy. We listed delivery outcomes including the twins in Group A in Table S4.\n\nDiscussion\nIn this study, the rate of chronic hypertension was 0.9% and the rate of preeclampsia and gestational hypertension was 1.8%. These rates are lower than those expected from previous data in Japan, which are 0.6% to 3.5% (0.6%; age 30–34, 1.2%; age 35–39, 2.0%; age 40–44, 3.5%; age ≥45)10 for chronic hypertension, 2.3% for preeclampsia, and 2.3% for gestational hypertension.11\n\n\nAmlodipine Use and Morphologic Abnormalities\nIn this study, fetal morphologic abnormalities associated with exposure to amlodipine in the first trimester were investigated in pregnant women with chronic hypertension in Japan. Previous studies reported a total of 41 cases in which amlodipine was administered during the first trimester of pregnancy, and our dataset has added an additional 48 amlodipine‐exposed cases in the literature. In our study, morphologic abnormalities were observed in 2 neonates in Group A (4.2%). In this group, 26 women were exposed to only amlodipine in the first trimester. Our findings indicate that the point estimates of the odds of major malformations are not significantly different among the groups. However, the 95% CI was wide because of the small sample size. While our exploratory data are reassuring, further research effort is clearly needed.\n\nUse of Antihypertensives and Morphologic Abnormalities\nThe use of antihypertensives in the first trimester has generally been found not to increase the risk of morphologic abnormalities in offspring,3, 4, 12, 13, 14, 15, 16 although studies exist showing potential associations with birth defects such as heart malformation,6, 17, 18, 19 hypospadias,20, 21 and central nervous system malformation.17 In our study, abnormalities were observed in 5 of 102 (4.9%) neonates whose mothers used antihypertensives in the first trimester (Group A+Group O) and 6 of 129 (4.7%) whose mothers did not use antihypertensives (Group N). Among the 5 offspring in the antihypertensive groups (Group A+Group O), 3 had heart malformations, and 2 had hypospadias. There was no increase in the risk of morphologic abnormalities in the exposed groups, compared with the group that did not take antihypertensives (Group N) (P=0.929), although the relatively frequent occurrence of heart malformations and hypospadias was consistent with previous reports.6, 17, 18, 19, 20, 21 In the present study, the women whose offspring had heart malformations or hypospadias did not use any nonantihypertensive drugs that are associated with heart malformations22 or hypospadias.23\n\n\nMaternal Hypertension and Morphologic Abnormalities\nAs Shepard proposed,24 one of the essential criteria for a human teratogen is a specific phenotype(s) of the adverse effects. An association between maternal hypertension and specific birth defects was recently reported.6, 19, 21, 25, 26 Anomalies in the kidney, limbs, lips, and palate were frequently observed in the offspring of women with chronic hypertension.7 Maternal hypertension was also found to be associated with heart malformation,6, 19, 21, 25, 26, 27 hypospadias,28 and esophageal atresia or stenosis.29 In our study, consistent with the previous reports, the following abnormalities (including overlap) occurred in the offspring of women with chronic hypertension: heart malformation in 3 cases, hypospadias in 3, central nervous system abnormalities in 5, and renal abnormality (Potter syndrome) in 1. Possible teratogenicity of maternal hypertension itself cannot be ruled out or confirmed from the current study framework, mainly because of the absence of nonhypertensive control.\n\nImportantly, 5 of 11 women in this study whose offspring showed morphologic abnormalities had superimposed preeclampsia (2 women in Group O and 3 women in Group N). Of these 5 women, 3 demonstrated hypospadias and 3 exhibited low‐lying conus medullaris. van Gelder et al reported a high risk of ventricular septal defect and atrial septal defect in chronic hypertension women who developed superimposed preeclampsia (antihypertensives were not used).21 Maternal hypertension is speculated to directly affect fetal growth via vascular disruption or teratogenic mechanisms.30 Physiological changes in early pregnancy that progress to preeclampsia or gestational hypertension in late pregnancy are also speculated to be associated with morphologic abnormalities in some cases.21 Whether these observations reflect the teratogenic nature of maternal hypertension requires further studies.\n\nLimitations\nWe conducted a simulation about the unmeasured confounding factors that could have effects on birth defects in the comparison of Group A and Group N as a sensitivity analysis. We set a confounder‐birth defects odds ratio equal to 0.1, and the prevalence of confounding factors among Group N was equal to 0.05. We estimated the odds ratio of group‐birth defects depending on the prevalence of confounding factors among Group A. Within the condition of our sample size, when the prevalence of confounding factors among Group A was 0.95, the lower limit of 95% CI exceeds 1 (Figure 2). These results indicate that we cannot draw a conclusion regarding the difference in birth defects in this study. Because of this limitation, the effects of confounding maternal background factors such as age, body mass index, alcohol, smoking, underlying diabetes mellitus, and underlying congenital heart disease could not be examined.\n\nFigure 2 Unmeasured confounder‐birth defects odds ratio. The 95% CI was estimated by the range of 2.5 and 97.5 percentile points of exp (log [odds ratio]+error), which was calculated by Monte Carlo simulations. The error term was randomly sampled from the Normal distribution with mean 0 and the SD, which was substituted by the SE of unadjusted log odds ratio.\n\nSources of Funding\nThis research was supported by the Japan Agency for Medical Research and Development (AMED) under Grant Number JP17mk0101086.\n\nDisclosures\nNone.\n\nSupporting information\n\nTable S1. All Anomalies\n\n\nTable S2. Details of Cases Using Amlodipine During the First Trimester (Group A)\n\n\nTable S3. Delivery Outcomes Excluding Diabetes Mellitus\n\n\nTable S4. Delivery Outcomes Including a Pair of Twins in Group A\n\nClick here for additional data file.\n\n Acknowledgments\nOur sincere thanks to Dr Toru Kobayashi for reviewing this report. Also, thanks to Dr Tadasu Shionoiri for collecting the cases presented in this article. 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Maternal hypertension, medication use, and hypospadias in the National Birth Defects Prevention Study . Obstet Gynecol . 2014 ;123 :309 –317 .24402588 \n29 \n\nBanhidy \nF \n, \nAcs \nN \n, \nPuho \nEH \n, \nCzeizel \nAE \n. Chronic hypertension with related drug treatment of pregnant women and congenital abnormalities in their offspring: a population‐based study . Hypertens Res . 2011 ;34 :257 –263 .21107325 \n30 \n\nvan Gelder \nMM \n, \nvan Rooij \nIA \n, \nMiller \nRK \n, \nZielhuis \nGA \n, \nde Jong‐van den Berg \nLT \n, \nRoeleveld \nN \n. Teratogenic mechanisms of medical drugs . Hum Reprod Update . 2010 ;16 :378 –394 .20061329\n\n",
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"issue": "8(15)",
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"medline_ta": "J Am Heart Assoc",
"mesh_terms": "D000014:Abnormalities, Drug-Induced; D000368:Aged; D017311:Amlodipine; D000959:Antihypertensive Agents; D002908:Chronic Disease; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D006973:Hypertension; D007231:Infant, Newborn; D008297:Male; D008875:Middle Aged; D011247:Pregnancy; D011249:Pregnancy Complications, Cardiovascular; D011261:Pregnancy Trimester, First; D011446:Prospective Studies",
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{
"abstract": "Thrombolytic treatment with intravenous recombinant tissue plasminogen activator (rtPA) is an effective treatment for acute ischemic stroke. However, its effectiveness and risks in patients with hypothyroidism have not been reported. Here, we report the case of hemorrhagic transformation after intravenous rtPA thrombolysis treatment in a patient with acute ischemic stroke and hypothyroidism. An apparent edema formed around the hematoma and progressively worsened. He also developed lung infection, electrolyte imbalance, and abnormal liver and kidney functions, and eventually died within 1 month of symptom onset. Thus, our observations suggest that caution should be exercised for the administration of intravenous rtPA thrombolysis to patients with hypothyroidism.",
"affiliations": "Neurology Department, Tianjin Huanhu Hospital, Tianjin, China.;Neurology Department, Tianjin Huanhu Hospital, Tianjin, China.;Neurology Department, Tianjin Huanhu Hospital, Tianjin, China.;Neurology Department, Tianjin Huanhu Hospital, Tianjin, China. Electronic address: hhyyxxl@163.com.",
"authors": "Gu|Furong|F|;Qin|Jie|J|;Chen|Rongjie|R|;Xu|Xiaolin|X|",
"chemical_list": "D010959:Tissue Plasminogen Activator",
"country": "Poland",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0028-3843",
"issue": "49(4)",
"journal": "Neurologia i neurochirurgia polska",
"keywords": "Acute ischemic stroke; Edema; Hypothyroidism; Recombinant tissue plasminogen activator; Thrombolysis",
"medline_ta": "Neurol Neurochir Pol",
"mesh_terms": "D002545:Brain Ischemia; D002543:Cerebral Hemorrhage; D017809:Fatal Outcome; D006801:Humans; D007037:Hypothyroidism; D008297:Male; D008875:Middle Aged; D020521:Stroke; D015912:Thrombolytic Therapy; D010959:Tissue Plasminogen Activator",
"nlm_unique_id": "0101265",
"other_id": null,
"pages": "290-4",
"pmc": null,
"pmid": "26188947",
"pubdate": "2015",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Post-thrombolysis hemorrhage in a patient with hypothyroidism and acute ischemic stroke: Case report.",
"title_normalized": "post thrombolysis hemorrhage in a patient with hypothyroidism and acute ischemic stroke case report"
} | [
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"literaturereference": "GU F, QIN J, CHEN R, XU X. POST-THROMBOLYSIS HEMORRHAGE IN A PATIENT WITH HYPOTHYROIDISM AND ACUTE ISCHEMIC STROKE: CASE REPORT. NEURCLOGIA I NEUROCI-ITRURGIA-POLSKA. 2015 JAN 01;49:290-294.",
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{
"abstract": "Gastropericardial fistula, a connection between the upper gastrointestinal tract and pericardium, is a rare clinical finding most commonly associated with postsurgical complications, as well as direct tissue invasion from gastric cancer. Case Report. We report a case of a 58-year-old Caucasian woman with metastatic colon cancer treated with FOLFOX, a combination chemotherapy regimen, and bevacizumab who presented with chest pain. She was ruled out for acute coronary syndrome, aortic dissection, or pulmonary embolism. A computed tomography (CT) scan of her chest showed pneumopericardium. A barium swallow ruled out esophageal ulceration, and esophagogastroduodenoscopy (EGD) showed a large penetrating gastric ulcer with no evidence of gastric dysplasia or malignancy or evidence of Helicobacter pylori (H. pylori). The patient underwent median sternotomy with gastric ulcer resection and repair, as well as pericardial washout and pericardial chest tube placement. After an uncomplicated course, she was safely discharged home.\nGiven that gastrointestinal ulceration and perforation are known phenomena in patients taking vascular endothelial growth factor (VEGF) inhibitors, surveillance endoscopy may be beneficial to discover them before they result in potentially fatal complications such as gastropericardial fistulas.",
"affiliations": "Department of Cardiology, HCA Healthcare/USF Morsani College of Medicine GME Programs/Largo Medical Center, Largo, FL, USA.;Department of Cardiology, HCA Healthcare/USF Morsani College of Medicine GME Programs/Largo Medical Center, Largo, FL, USA.;Department of Cardiology, HCA Healthcare/USF Morsani College of Medicine GME Programs/Largo Medical Center, Largo, FL, USA.;Department of Cardiology, HCA Healthcare/USF Morsani College of Medicine GME Programs/Largo Medical Center, Largo, FL, USA.",
"authors": "Rathur|Abdullah|A|https://orcid.org/0000-0002-0258-9758;Al-Mohamad|Hussein|H|https://orcid.org/0000-0001-8781-3204;Steinhoff|Jeffrey|J|https://orcid.org/0000-0001-9017-8416;Walsh|Ronald|R|https://orcid.org/0000-0002-5285-7837",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1155/2021/5143608",
"fulltext": "\n==== Front\nCase Rep Cardiol\nCase Rep Cardiol\nCRIC\nCase Reports in Cardiology\n2090-6404\n2090-6412\nHindawi\n\n10.1155/2021/5143608\nCase Report\nChest Pain from Pneumopericardium with Gastropericardial Fistula\nhttps://orcid.org/0000-0002-0258-9758\nRathur Abdullah abdullah.rathur@hcahealthcare.com\n\nhttps://orcid.org/0000-0001-8781-3204\nAl-Mohamad Hussein\nhttps://orcid.org/0000-0001-9017-8416\nSteinhoff Jeffrey\nhttps://orcid.org/0000-0002-5285-7837\nWalsh Ronald\nDepartment of Cardiology, HCA Healthcare/USF Morsani College of Medicine GME Programs/Largo Medical Center, Largo, FL, USA\nAcademic Editor: Luigi Sciarra\n\n2021\n14 7 2021\n2021 514360815 5 2021\n27 6 2021\nCopyright © 2021 Abdullah Rathur et al.\n2021\nhttps://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.\nIntroduction\n\nGastropericardial fistula, a connection between the upper gastrointestinal tract and pericardium, is a rare clinical finding most commonly associated with postsurgical complications, as well as direct tissue invasion from gastric cancer. Case Report. We report a case of a 58-year-old Caucasian woman with metastatic colon cancer treated with FOLFOX, a combination chemotherapy regimen, and bevacizumab who presented with chest pain. She was ruled out for acute coronary syndrome, aortic dissection, or pulmonary embolism. A computed tomography (CT) scan of her chest showed pneumopericardium. A barium swallow ruled out esophageal ulceration, and esophagogastroduodenoscopy (EGD) showed a large penetrating gastric ulcer with no evidence of gastric dysplasia or malignancy or evidence of Helicobacter pylori (H. pylori). The patient underwent median sternotomy with gastric ulcer resection and repair, as well as pericardial washout and pericardial chest tube placement. After an uncomplicated course, she was safely discharged home.\n\nConclusion\n\nGiven that gastrointestinal ulceration and perforation are known phenomena in patients taking vascular endothelial growth factor (VEGF) inhibitors, surveillance endoscopy may be beneficial to discover them before they result in potentially fatal complications such as gastropericardial fistulas.\n==== Body\n1. Introduction\n\nPneumopericardium is the presentation of air within the pericardial cavity and can be caused by trauma, thoracic surgery, thoracentesis, infectious pericarditis, foreign body aspiration, cocaine inhalation, and fistula formation between the pericardium and other structures [1]. Gastropericardial fistula, a rare condition caused by pathological communication between the upper gastrointestinal tract and the pericardium, is one of the causes of pneumopericardium. The gastropericardial fistula is associated with significant morbidity and mortality, reaching as high as 69% in one study [2]. The presentation of gastropericardial fistulas varies, with acute dyspnea, chest pain, hemodynamic instability from cardiac tamponade, or even cardiac arrest from tension pneumopericardium [3]. Conditions most commonly associated with gastropericardial fistulas include prior gastroesophageal surgery such as Nissen fundoplication or hernia repair, gastroesophageal cancer [2], and even ulcers associated with gastroesophageal reflux disease, NSAID use, and Zollinger-Ellison syndrome [4–6]. This case highlights a very rare diagnosis of gastropericardial fistula in a patient on VEGF-inhibitor chemotherapy for metastatic colon cancer, in the absence of gastric cancer, prior gastroesophageal surgery, or significant risk factors for peptic ulcer disease.\n\n2. Case Presentation\n\nA 58-year-old Caucasian woman with a past medical history of stage IV colon cancer being treated actively with FOLFOX and bevacizumab presented to the emergency department (ED) with complaint of left-sided chest pain and left shoulder pain which started over a year ago but acutely increased in intensity and frequency over the past three weeks. The pain was inconsistently worse with position, associated with dyspnea, left-sided neck pain, and belching, without fever, chills, cough, abdominal pain, nausea, vomiting, diarrhea, dysphagia, melena, or hematochezia. Her last chemotherapy treatment was five days prior. She was initially diagnosed with the cancer 2.5 years ago with metastasis to the liver and was treated initially with diverting colostomy and chemotherapy with bevacizumab, later modified to include FOLFOX. The patient denied nonsteroidal anti-inflammatory drug (NSAID) use or alcohol or illicit drug abuse.\n\nIn the ED, initial vital signs showed blood pressure 174/83 mmHg, heart rate 101/minute, respiratory rate 24/minute, SpO2 97% on room air, temperature 96.9°F. Physical examination was unremarkable except for decreased breath sounds and regular tachycardia. Labs showed hemoglobin (16 g/dL), alkaline phosphatase (299 U/L), and negative urine drug screen. Serial troponins six hours apart were negative, and initial ECG showed sinus rhythm without ischemic changes. Thoracic CT angiogram ruled out pulmonary embolism and showed pneumopericardium, gastropericardial fistula, and three liver lesions suspicious for metastatic disease, as shown in Figure 1.\n\nA transthoracic echocardiogram showed a left ventricular (LV) ejection fraction of 55-60%, no valvular disease, and a normal pulmonary pressure and suggested the presence of pericardial air due to significant acoustic attenuation in otherwise previously normal windows. A barium swallow was performed with no visible esophageal stricture or ulceration, but the field of view did not include the stomach.\n\nAn EGD was done and showed a normal esophagus and 3 cm penetrating gastric cardia ulcer with surrounding edema and nonbleeding vessel in the center; biopsy was negative for dysplasia, metaplasia, malignancy, or H. pylori.\n\nSurgical intervention was performed by cardiothoracic and general surgery teams, including median sternotomy, laparotomy, intraoperative transesophageal echocardiogram (TEE) to delineate the area of ulceration, posterior pericardial debridement of tissue adhesions, gastric ulcer resection and primary repair with omental patch, gastrojejunostomy feeding tube insertion, diaphragmatic patch with mesh, pericardial washout, and pericardial/pleural chest tube placement. She was transferred to the intensive care unit (ICU) and placed on total parenteral nutrition. After a few days, she was discharged home without any postoperative complications.\n\n3. Discussion\n\nGastropericardial fistula is a rare condition typically associated with prior gastroesophageal surgery or gastroesophageal cancer [2]. Presentation is highly variable, ranging from benign left shoulder pain to cardiac arrest from tension pneumopericardium [3].\n\nOur patient presented with chest pain and long-standing left shoulder pain, initially attributed to rotator cuff pathology. However, long-standing shoulder pain is an important symptom associated with nontraumatic gastric perforation into the pericardium [7], and chest or left shoulder pain is the presenting symptom in 66% of cases of gastropericardial fistula [2]. Overall, the prognosis is typically poor with this condition due to late recognition in an acute chest pain setting. Gastropericardial fistula is frequently associated with infection and sepsis, requiring surgical intervention for repair [8, 9]. Pneumopericardium is often first diagnosed by chest X-ray, but the finding is nonspecific in identifying the etiology. Contrast CT imaging is useful for identifying a fistulous tract between the GI tract and the pericardium [3]. Endoscopy allows diagnosis and localization of a fistula by direct visualization and is beneficial in those unidentified by contrast imaging, and it also allows for biopsy of the ulcer to look for malignancy. Per literature review by Davidson et al., fluoroscopic contrast studies to detect gastropericardial fistula should be reserved for cases with negative initial CT or in equivocal cases. Transthoracic echocardiography is not usually effective for diagnosing pneumopericardium due to air attenuation artifact [10].\n\nGastrointestinal perforation is a known side effect of bevacizumab, a humanized monoclonal antibody against the vascular endothelial growth factor (VEGF). Vasoactive agents such as prostaglandins and nitrous oxide are activated by VEGF, and inhibition of growth factors can lead to weakened mucosal defense [11]. Animal models showed the regression of capillaries of intestinal villi which could contribute to perforation if exacerbated by other pathologic processes [12]. In a study by Hendrick et al., 1.7% of patients being concomitantly treated with bevacizumab and first-line chemotherapy had gastrointestinal perforation, with 68% occurring in the first 60 days. Our literature review did not show any prior reported cases of gastropericardial fistula in the setting of VEGF-inhibitor usage without any other risk factors.\n\nGastropericardial fistula in the absence of gastric malignancy, prior gastrointestinal surgery, or combination chemotherapy and radiation therapy is a very rare clinical syndrome. In one previously reported case, the patient had no prior gastric malignancy or surgery, and the only risk factor for gastric ulceration was alcohol abuse [13], which has been shown to be a risk factor for ulcer perforation [13]. Despite having metastatic colon cancer, our patient's gastric biopsy was negative for malignancy or H. pylori, and she denied a history of significant NSAID or alcohol use, making peptic ulcer disease a less likely cause. Gastropleural, gastropericardial, and gastropleuropericardial fistula formations have been reported with combination radiation therapy and chemotherapeutic agents such as fluorouracil, oxaliplatin, and sunitinib [14]. Radiation treatment results in vessel destruction and tumor necrosis, causing endothelial cytotoxicity and potential adhesion between the gastric fundus and diaphragm, leading to possible gastropericardial fistula formation [15–17]. As per standard of care, our patient did not need to receive radiation therapy. Pericardial metastasis can cause pericardial effusion, clinical pericarditis, and sometimes tamponade, but this was not the case in our patient as per biopsy. Again, based on literature review, our case appears to be the first reported case of gastropericardial fistula as a result of VEGF-inhibitor use in a patient without prior gastroesophageal surgery, invading gastroesophageal or pericardial cancer, or any significant risk factors for peptic ulcer disease.\n\n4. Conclusion\n\nClinical presentation of gastropericardial fistulas can vary from mild chest pain and shortness of breath to cardiac arrest from tension pneumopericardium, and there is usually little to no clinical suspicion for such an uncommon diagnosis. Given that this clinical diagnosis can be difficult, a more useful approach may be prevention before a gastropericardial fistula can form. Although there are currently no such guidelines, it may be prudent to consider surveillance endoscopy in patients taking combination VEGF inhibitors and other chemotherapeutic agents to assess for gastrointestinal ulceration in order to intervene before complications like gastropericardial fistula can occur.\n\nConflicts of Interest\n\nThe authors have no conflicts to declare.\n\nSupplementary Materials\n\nSupplementary Materials Included in the supplementary files are additional CT images of the pneumopericardium in the transverse section (Figure S1) and gastropericardial fistula in the coronal section (Figure S2).\n\nClick here for additional data file.\n\nFigure 1 Sagittal view of chest CT showing pneumopericardium (yellow arrow) and gastropericardial fistula (red arrow).\n==== Refs\n1 Chopra V. Garg N. Mrigpuri P. Spontaneous pneumopericardium an unusual complication in a patient of HIV and pulmonary tuberculosis Lung India 2013 30 2 148 150 10.4103/0970-2113.110425 2-s2.0-84876932369 23741097\n2 Azzu V. Gastropericardial fistula: getting to the heart of the matter BMC Gastroenterology 2016 16 1 p. 96 10.1186/s12876-016-0510-8 2-s2.0-84982315642 27542946\n3 Hervik K. Vognild I. Bjerke L. M. Almdahl S. M. Gastropericardial fistula presenting with cardiac arrest: a case report European Heart Journal-Case Reports 2018 2 2 10.1093/ehjcr/yty057 2-s2.0-85073524037 31020136\n4 Farkas Z. C. Pal S. Jolly G. P. Lim M. M. D. Malik A. Malekan R. Esophagopericardial fistula and pneumopericardium from caustic ingestion and esophageal stent The Annals of Thoracic Surgery 2019 107 3 e207 e208 10.1016/j.athoracsur.2018.06.087 2-s2.0-85061652875 30179624\n5 Park S. Kim J.-H. Lee Y. C. Chung J. B. Gastropericardial fistula as a complication in a refractory gastric ulcer after esophagogastrostomy with gastric pull-up Yonsei Medical Journal 2010 51 2 270 272 10.3349/ymj.2010.51.2.270 2-s2.0-77649210917 20191021\n6 Grandhi T. M. Rawlings D. Morran C. G. Gastropericardial fistula: a case report and review of literature Emergency Medicine Journal 2004 21 5 644 645 10.1136/emj.2003.007765 2-s2.0-4544318563 15333561\n7 Sailing N. Falensteen A. M. Larsen L. G. Non-traumatic perforation of gastric ulcer in a hiatal hernia to the pericardium Acta Medica Scandinavica 1983 213 3 225 226 10.1111/j.0954-6820.1983.tb03722.x 2-s2.0-0020577175 6846066\n8 Weng M. Wu J. Chiu K. Gastropericardial fistula-caused pneumopericardium Clinical Gastroenterology and Hepatology 2013 11 9 e64 e65 10.1016/j.cgh.2012.12.021 2-s2.0-84882816578 23333703\n9 Azam S. A. Wilcox A. G. King K. G. Whang G. Gastropericardial fistula Surgery 2020 167 4 e3 e4 10.1016/j.surg.2019.07.006\n10 Davidson J. P. Connelly T. M. Libove E. Tappouni R. Gastropericardial fistula: radiologic findings and literature review Journal of Surgical Research 2016 203 1 174 182 10.1016/j.jss.2016.03.015 2-s2.0-84965144859\n11 Schmidinger M. Understanding and managing toxicities of vascular endothelial growth factor (VEGF) inhibitors EJC Supplements 2013 11 2 172 191 10.1016/j.ejcsup.2013.07.016 2-s2.0-84884952345 26217127\n12 Kamba T. McDonald D. M. Mechanisms of adverse effects of anti-VEGF therapy for cancer British Journal of Cancer 2007 96 12 1788 1795 10.1038/sj.bjc.6603813 2-s2.0-34250365240 17519900\n13 Andersen I. B. Jørgensen T. Bonnevie O. Grønbæk M. Sørensen T. I. A. Smoking and alcohol intake as risk factors for bleeding and perforated peptic ulcers: a population-based cohort study Epidemiology 2000 11 4 434 439 10.1097/00001648-200007000-00012 2-s2.0-0033933533 10874551\n14 Neri A. Lambert Y. Marrelli D. Gastro-pleuro-pericardial fistula following combined radiation and chemotherapy for lung metastases from renal cell carcinoma: report of a case Surgery Today 2013 43 12 1457 1460 Epub 2013 Jan 12 10.1007/s00595-012-0475-3 2-s2.0-84892364378 23307297\n15 Emmanouilides C. Sfakiotaki G. Androulakis N. Front-line bevacizumab in combination with oxaliplatin, leucovorin and 5-fluorouracil (FOLFOX) in patients with metastatic colorectal cancer: a multicenter phase II study BMC Cancer 2007 7 1, article 91 10.1186/1471-2407-7-91 2-s2.0-34347236908\n16 Colon cancer treatment, by stage| how to treat colon cancer 2020 November 2020, https://www.cancer.org/cancer/colon-rectal-cancer/treating/by-stage-colon.html\n17 Jang S. J. Cha Y. K. Kim J. S. Kim D. Y. Kim D. B. A gastro-pleuro-pericardial fistula that occurred following palliative chemoradiotherapy for tongue cancer: a case report Journal of the Korean Society of Radiology 2019 80 4 p. 815 10.3348/jksr.2019.80.4.815\n\n",
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"title": "Chest Pain from Pneumopericardium with Gastropericardial Fistula.",
"title_normalized": "chest pain from pneumopericardium with gastropericardial fistula"
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"abstract": "BACKGROUND\nTo prevent mother-to-child transmission (MTCT) of HIV in developing countries, new World Health Organization (WHO) guidelines recommend maternal combination antiretroviral therapy (cART) during pregnancy, throughout breastfeeding for 1 year and then cessation of breastfeeding (COB). The efficacy of this approach during the first six months of exclusive breastfeeding has been demonstrated, but the efficacy of this approach beyond six months is not well documented.\n\n\nMETHODS\nA prospective observational cohort study of 279 HIV-positive mothers was started on zidovudine/3TC and lopinavir/ritonavir tablets between 14 and 30 weeks gestation and continued indefinitely thereafter. Women were encouraged to exclusively breastfeed for six months, complementary feed for the next six months and then cease breastfeeding between 12 and 13 months. Infants were followed for transmission to 18 months and for survival to 24 months. Text message reminders and stipends for food and transport were utilized to encourage adherence and follow-up.\n\n\nRESULTS\nTotal MTCT was 9 of 219 live born infants (4.1%; confidence interval (CI) 2.2-7.6%). All breastfeeding transmissions that could be timed (5/5) occurred after six months of age. All mothers who transmitted after six months had a six-month plasma viral load >1,000 copies/ml (p<0.001). Poor adherence to cART as noted by missed dispensary visits was associated with transmission (p=0.04). Infant mortality was lower after six months of age than during the first six months of life (p=0.02). The cumulative rate of infant HIV infection or death at 18 months was 29/226 (12.8% 95 CI: 7.5-20.8%).\n\n\nCONCLUSIONS\nMaternal cART may limit MTCT of HIV to the UNAIDS target of <5% for eradication of paediatric HIV within the context of a clinical study, but poor adherence to cART and follow-up can limit the benefit. Continued breastfeeding can prevent the rise in infant mortality after six months seen in previous studies, which encouraged early COB.",
"affiliations": "Department of Paediatrics and Child Health, University of Zambia, Lusaka, Zambia; Profngoma09@gmail.com.;Department of Pediatrics, Western University, London, Canada.;Department of Public Health, University of Zambia, Lusaka, Zambia.;Department of Epidemiology and Biostatistics, McGill University, Montreal, Canada.;Department of Epidemiology and Biostatistics, McGill University, Montreal, Canada.;Department of Medicine, University of Toronto, Toronto, Canada.;Department of Obstetrics and Gynecology, University of Zambia, Lusaka, Zambia.;Department of Anesthesiology, University of Zambia, Lusaka, Zambia.;Department of Paediatrics, Arthur Davison Children's Hospital, Ndola, Zambia.;Department of Nursing, Chelstone Clinic, Lusaka, Zambia.;Department of Paediatrics and Child Health, University of Zambia, Lusaka, Zambia.;Public Health Agency of Canada, Ottawa, Canada.;Public Health Agency of Canada, Ottawa, Canada.;Harvard Medical School, Cambridge, Mass.;Grand Challenges, Ottawa, Canada.;Department of Medicine, University of Toronto, Toronto, Canada.",
"authors": "Ngoma|Mary S|MS|;Misir|Amita|A|;Mutale|Wilbroad|W|;Rampakakis|Emmanuoil|E|;Sampalis|John S|JS|;Elong|Angela|A|;Chisele|Sam|S|;Mwale|Abel|A|;Mwansa|Jonathan K|JK|;Mumba|Scholastica|S|;Chandwe|Mula|M|;Pilon|Richard|R|;Sandstrom|Paul|P|;Wu|Samantha|S|;Yee|Kristen|K|;Silverman|Michael S|MS|",
"chemical_list": "D019380:Anti-HIV Agents",
"country": "Switzerland",
"delete": false,
"doi": "10.7448/IAS.18.1.19352",
"fulltext": "\n==== Front\nJ Int AIDS SocJ Int AIDS SocJIASJournal of the International AIDS Society1758-2652International AIDS Society 1935210.7448/IAS.18.1.19352Research ArticleEfficacy of WHO recommendation for continued breastfeeding and maternal cART for prevention of perinatal and postnatal HIV transmission in Zambia Ngoma Mary S §*1Misir Amita *2Mutale Wilbroad 3Rampakakis Emmanuoil 45Sampalis John S 45Elong Angela 6Chisele Sam 7Mwale Abel 8Mwansa Jonathan K 9Mumba Scholastica 10Chandwe Mula 1Pilon Richard 11Sandstrom Paul 11Wu Samantha 12Yee Kristen 13Silverman Michael S §6141 Department of Paediatrics and Child Health, University of Zambia, Lusaka,, Zambia2 Department of Pediatrics, Western University, London, Canada3 Department of Public Health, University of Zambia, Lusaka, Zambia4 Department of Epidemiology and Biostatistics, McGill University, Montreal, Canada5 JSS Medical Research, Montreal, Canada6 Department of Medicine, University of Toronto, Toronto, Canada7 Department of Obstetrics and Gynecology, University of Zambia, Lusaka, Zambia8 Department of Anesthesiology, University of Zambia, Lusaka, Zambia9 Department of Paediatrics, Arthur Davison Children's Hospital, Ndola, Zambia10 Department of Nursing, Chelstone Clinic, Lusaka, Zambia11 Public Health Agency of Canada, Ottawa, Canada12 Harvard Medical School, Cambridge, Mass13 Grand Challenges, Ottawa, Canada14 Division of Infectious Diseases, Western University, London, Canada§ Corresponding author: Michael S Silverman, 268 Grosvenor ST B3-414, London, ON, Canada N6A4V2. Tel: 1(519)6466311. (Michael.Silverman@sjhc.london.on.ca); Mary S Ngoma, P.O. Box 50110, Lusaka, 10101, Zambia. Tel: 011260977310638. (Profngoma09@gmail.com)* These authors contributed equally to this work.01 7 2015 2015 18 1 1935212 7 2014 08 3 2015 13 4 2015 © 2015 Ngoma MS et al; licensee International AIDS Society2015This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Introduction\nTo prevent mother-to-child transmission (MTCT) of HIV in developing countries, new World Health Organization (WHO) guidelines recommend maternal combination antiretroviral therapy (cART) during pregnancy, throughout breastfeeding for 1 year and then cessation of breastfeeding (COB). The efficacy of this approach during the first six months of exclusive breastfeeding has been demonstrated, but the efficacy of this approach beyond six months is not well documented.\n\nMethods\nA prospective observational cohort study of 279 HIV-positive mothers was started on zidovudine/3TC and lopinavir/ritonavir tablets between 14 and 30 weeks gestation and continued indefinitely thereafter. Women were encouraged to exclusively breastfeed for six months, complementary feed for the next six months and then cease breastfeeding between 12 and 13 months. Infants were followed for transmission to 18 months and for survival to 24 months. Text message reminders and stipends for food and transport were utilized to encourage adherence and follow-up.\n\nResults\nTotal MTCT was 9 of 219 live born infants (4.1%; confidence interval (CI) 2.2–7.6%). All breastfeeding transmissions that could be timed (5/5) occurred after six months of age. All mothers who transmitted after six months had a six-month plasma viral load >1,000 copies/ml (p<0.001). Poor adherence to cART as noted by missed dispensary visits was associated with transmission (p=0.04). Infant mortality was lower after six months of age than during the first six months of life (p=0.02). The cumulative rate of infant HIV infection or death at 18 months was 29/226 (12.8% 95 CI: 7.5–20.8%).\n\nConclusions\nMaternal cART may limit MTCT of HIV to the UNAIDS target of <5% for eradication of paediatric HIV within the context of a clinical study, but poor adherence to cART and follow-up can limit the benefit. Continued breastfeeding can prevent the rise in infant mortality after six months seen in previous studies, which encouraged early COB.\n\nbreastfeeding transmission of HIVvertical transmissionoption B+infant survivalefficacy of WHO guidelinesperinatal transmission of HIV\n==== Body\nIntroduction\nThe Joint United Nations Programme on HIV/AIDS (UNAIDS) has set a global plan to reduce HIV infections among HIV-exposed children to below 5% by 2015 and to keep their HIV-positive mothers alive through the provision of antiretroviral medication [1]. Despite the risk of mother-to-child transmission (MTCT) of HIV, in many developing countries, no acceptable, feasible, affordable, sustainable or safe alternative to breastfeeding exists [2–4]. Reaching the 5% target will require prevention of antepartum, intrapartum and postpartum transmission.\n\nIn the absence of antiretroviral prophylaxis, MTCT is lower during the first six months of life in exclusively breastfed (EBF) infants compared to those who mixed feed [5, 6]. Multiple studies have shown that maternal combination antiretroviral therapy (cART) can reduce postpartum MTCT for up to six months of EBF [7–9].\n\nIn HIV-exposed children, infant mortality and morbidity (e.g. failure to thrive (FTT), diarrhoea, pneumonia, malaria and tuberculosis) are increased after early cessation of breastfeeding (COB) (at 4–6 months) [9–13]. Therefore, in 2010 the World Health Organization (WHO) issued new recommendations which include EBF for 6 months followed by complementary feeding (CF) (defined as continued breastfeeding with the addition of solid or semi-solid foods) to 12 months of age and followed by gradual COB [2, 14]. Maternal cART is recommended during pregnancy and postpartum breastfeeding to prevent MTCT (PMTCT). For women whose CD4 cells are <500 cells/µl, on-going maternal cART after COB is recommended to protect the mothers health [15]. For women whose CD4 >500 cells/µl, the WHO recommends either option B where maternal cART is discontinued after COB or Option B+ where maternal cART is continued indefinitely [15]. Unfortunately, there are only limited data on the impact of maternal cART on infant adverse events and PMTCT while breastfeeding beyond six months of age. Therefore, the quality of the supporting evidence for the new WHO guidelines is still noted as low to moderate [2, 14, 15]. We, therefore, carried out a study to assess the efficacy and safety of continued breastfeeding while the mother receives cART.\n\nMethods\nThis was a prospective observational cohort study. Recruitment took place from December 2008 to December 2009 at the Chelstone Public Clinic in Lusaka, Zambia.\n\nInclusion criteria were: age ≥15 years, HIV seropositivity, confirmed pregnancy with the ability to initiate cART at 14–30 weeks gestation, intention to EBF for six months, ability to give informed consent and to attend follow-up visits. Exclusion criteria were previous cART (other than single-dose nevirapine or ≤1 month of zidovudine for PMTCT prophylaxis, which were not contraindications), known major illness likely to influence pregnancy outcome or place the participant at increased risk for adverse events from cART, including diabetes, severe renal, liver or heart disease, active tuberculosis, severe anaemia (Hgb <8 g/dl) or continuing therapy with medications, which are contraindicated for co-administration with ritonavir/lopinavir.\n\nAll mothers received zidovudine (ZDV) 300 mg/lamivudine (3TC) 150 mg (Combivir®, ViiV healthcare, Middlesex, UK) bid and lopinavir 200 mg/ritonavir 50 mg (trade name Aluvia® in Zambia, Abbvie, Chicago, IL) two tablets bid initiated between gestational age (GA) 14 and 30 weeks, and continued during labour, breastfeeding and COB. Women were enrolled in the national cART programme upon COB and were continued indefinitely on cART regardless of CD4 count (as per WHO option B+). Lopinavir/ritonavir was used, as efavirenz was not recommended during pregnancy at the time of this study [16], and nevirapine was contraindicated for the majority of women due to high baseline CD4 [17]. This approach allowed rapid initiation of therapy prior to CD4 results. Infants received oral ZDV for five days postpartum. EBF was encouraged to 6 months, with CF starting at 6 months and continued to 12 months, followed by the recommendation to cease breastfeeding between 12 and 13 months. Women received on-going counselling regarding medication adherence, text message reminders for clinic visits and stipends for food and transport (30,000 kwacha, equivalent to ~$6US/visit). Mothers were screened antepartum for syphilis using a non-treponemal test and were given multivitamins. Sexually transmitted diseases were diagnosed and treated syndromically as per national guidelines. Mothers received counselling on infant nutrition. GA dating was based on recall of last menstrual period. Follow-up visits took place antepartum at 4 weeks after enrolment, 36 weeks gestation; at birth; at postpartum infant ages 2, 6 weeks and 3, 6, 9, 12, 15 and 18 months. Infant dried blood spots for PCR were obtained at all postpartum visits. Infant survival data were also obtained at 24 months. Maternal plasma viral loads and drug resistance genotyping were assayed on all transmitting mother-infant pairs using standard techniques [18, 19] (see Supplementary files). Maternal plasma viral load was also assayed at birth and six months on a convenience sample of 96 non-transmitting mothers.\n\nStandard breastfeeding definitions were used for the study and were obtained from UNICEF [20]:\nExclusive breastfeeding (EBF): Only breast milk+medicines/vitamins.\n\n\nMixed feeding: Breast milk and non-human milk (including formula) and/or semi-solid/solid foods before six months.\n\n\nComplementary feeding (CF): Continued breastfeeding with the addition of solid or semi-solid foods beyond six months.\n\n\nReplacement feeding: No breast milk at all, fed only non-human milk or semi-solids/solids.\n\n\n\n\nEthical approval for the study was obtained from the research ethics boards of the University of Zambia in Lusaka and also Lakeridge Health Corporation in Canada. All mothers provided written informed consent. The study funders had no role in the design of the protocol, conduct of the study, the analysis of data or the writing of the manuscript.\n\nStatistical methods\nThe primary outcome of interest was the rate of HIV-free survival after an extended period (i.e. 12 months) of breastfeeding followed by gradual COB. Secondary outcomes of interest included HIV transmission rates and mortality particularly as they corresponded to the different time periods of exclusive breastfeeding (0–6 months), CF (6–12 months) and COB (12–18 months). The incidence of HIV transmission and death was described with the corresponding incidence rates up to 18 months post-partum for the above time periods. Denominators for these incidence rates include only those infants who remained at risk for transmission (i.e. were known to be HIV-uninfected and surviving) at the beginning of each relevant time period.\n\nFor all analyses, patients who were lost to follow-up were not included in the analysis for the periods when they were not available. This was decided in order to prevent these patients from being inadvertently considered as non-transmitting or surviving and thus artificially inflating efficacy.\n\nCategorical variables were summarized using frequency distributions and percentages, whereas continuous variables were described with the mean and standard deviation. We used independent samples t-test to assess statistical differences in (i) maternal age, maternal CD4 at birth and infant GA at birth between women lost to follow-up postpartum and those completing 24 months of follow-up and (ii) mean viral load between transmitting and non-transmitting mothers. We used Pearson's chi-square test to assess statistical differences in (i) the viral load categories at six months between transmitting and non-transmitting mothers; (ii) infant mortality based on presence or absence of low birthweight and (iii) HIV transmission between women missing vs. not missing a dispensary visit. Changes in viral load and viral load detection over six months of treatment were assessed with the paired t-test and the McNemar test, respectively. The incidence of HIV transmission and death was described with the incidence rate and the incidence rate ratio and the corresponding 95% confidence intervals (95% CI). A comparison of different time intervals with respect to these outcomes was performed using the person-time chi-square (χ2\nP-T) test [21, 22].\n\nPredictors of adverse event count by time interval were investigated using a saturated Poisson regression model where time interval and individual person follow-up time were incorporated as adjusting covariates. Given that this was a saturated model, goodness of fit was not assessed. Over dispersion was examined by dividing the Pearson statistic by its degrees of freedom and was corrected, as required, by inflating accordingly the covariance matrix.\n\nAll analyses were performed using SAS 9.2 (SAS Institute, Cary, NC), and all analyses were performed using a 0.05 significance level.\n\nResults\nStudy population\nClinical baseline characteristics of the cohort are presented in Table 1.\n\nTable 1 Maternal baseline characteristics (live born infants only)\n\nMaternal baseline characteristics\tAvailable n\n\t(N=231)\t\nMaternal age, years, mean (SD)\t226\t28.1 (5.5)\t\nGestational age (GA) at birth, weeks, mean (SD)\t229\t38 (3.5)\t\nSexually transmitted infections (STIs), n (%)\t225\t41 (18%)\t\nMultiple birth, n (%)\t225\t7 (3%)\t\nCD4 <350 at study entry, n (%)\t209\t125 (60%)\t\nCD4 <200 at study entry, n (%)\t209\t45 (22%)\t\nCD4 count, mean (SD)\t209\t353.8 (207.1)\t\nAnaemia (haemoglobin <10 g/dl), n (%)\t225\t55 (24%)\t\n\nNote: Detailed socio-demographic data are available in Supplementary Table 1.\n\nTransmission\nTransmission status at follow-up is presented in Figure 1. Overall, when considering all 231 live births, HIV status was known at 18 months or at the last scheduled test interval before their death (whichever came first) for 201/231 (87.0%). There was no difference between the women who were lost to follow-up postpartum and those who completed 24 months of follow-up when compared by maternal age (p=0.55), maternal CD4 at birth (p=0.89) or infant GA at birth (p=0.946). A total of 9/219 (4.1%; 95% CI: 2.2–7.6%) infants acquired HIV during the study period. There was a trend towards a higher transmission rate/100 person-weeks during 6–18 months (0.0529/100 person-weeks) when compared to six weeks to six months (0/100 person-weeks; p=0.167).\n\nFigure 1 Transmission status follow-up on livebirths and survivors.\n\n\n†Three hundred and eighty-four pregnant women were approached, of which 80 were not eligible (due to presentation outside of 14–30 weeks gestation) and 25 declined enrolment, leaving 279 women who were recruited. Of the 279 enrolled women, 45 of 279 (15%) defaulted before birth, leaving 234 women. Of these 234 women, 8 had stillbirths and 226 had livebirths. These 226 mothers delivered 231 liveborn infants (five pairs of twins were included). *Two infants HIV positive at birth so no longer at-risk for transmission at start of time interval, therefore removed from denominator. **Infant became HIV positive+1 infant died between birth and 6 weeks, so no longer at-risk for transmission at start of time interval, therefore removed from denominator.\n\nDetails of the individual transmissions are found in Supplementary Table 2. Baseline maternal CD4 count (<200 vs. >200; odds ratio, OR <350 vs. >350, OR <500 vs. >500) was not correlated with infant mortality or postpartum transmission (data not shown).\n\nTreatment failure and late HIV transmission\nFive of five women who transmitted after six months had a plasma viral load (VL) >1,000 at six months (range 3,252–459,866; mean 4.75 log10, SD 0.82). In comparison, mean viral loads at six months in the 96 non-transmitting mothers tested were lower (mean 0.61 log10 SD 1.4; p<0.0001). Twelve of 96 (12.5%) non-transmitting mothers had a VL >1,000 (p<0.001) and 16/96 (16.7%) had a VL >50 at six months (p<0.001). Including all transmitting and non-transmitting mothers, more mothers had a detectable VL (>50) at birth (40 of 99 (40.4%)) than at six months (p=0.002), and mean Log10 viral load at six months (1.21, SD 1.94) was not higher than at birth (1.25, SD1.73; p=0.86). Data available on seven of nine transmissions showed one transmission (antepartum) to be associated with resistance to the cART regimen (K65R in mother and infant; Supplementary Table 3).\n\nMortality\nFour of 279 (1.4%) mothers died including one maternal death with accompanying miscarriage/foetal death. Details of individual infant and maternal deaths are given in Supplementary Tables 4 and 5.\n\nTwo hundred and eleven of 231 (91.3%) live born infants had 24-month survival data, the remainder being lost to follow-up. Cumulative postnatal mortality was 25/231 live births (10.8%; 95% CI: 6.8–14.8%). Data on cumulative rate of HIV infection and/or death were available for 226 infants with a cumulative rate of 29/226 (12.8%; 95% CI: 7.5–20.8%) (includes 20 deaths of HIV-uninfected infants, 5 deaths in HIV-infected infants and 4 transmissions in surviving infants).\n\nHIV-uninfected infant death rate was highest in the first six months of life, falling during the second six months with no evidence of any rise after COB at 1 year (Table 2).\n\nTable 2 Death incidence rate ratio by time to event for infants who were HIV uninfected\n\nTime interval (month)a\n\tNumber of deaths\tIncidence rate (per 100 person-week)\tIncidence rate ratio\t95% CI of IRR\t\np\n\t\n(0–6)\t12\t0.2346\t1.0000\tNA\tNA\t\n(6–12)\t4\t0.0838\t0.3570\t(0.1148, 1.1102)\t0.03952\t\n(12–18)\t2\t0.0433\t0.1847\t(0.0412, 0.8284)\t0.00160\t\n(18–24)\t2\t0.0457\t0.1947\t(0.0434, 0.8735)\t0.00228\t\na \nNote: Patients contributed the respective person-time corresponding to each time period provided they were known to be remaining at risk of death during that time period. Therefore, those who were lost to follow-up at any point did not contribute person-time for subsequent time periods. Mortality at each time interval is compared with that at the first time interval (0–6 months). Confidence intervals were determined considering a Poisson distribution for the number of deaths. NA, not applicable.\n\nUsing the same intervals as in the recent BAN study, which showed an increase in HIV-uninfected infant mortality with COB at 28 weeks [9], HIV-uninfected infant mortality in our cohort fell from 0.2183/100 person-weeks (95% CI: 0.1162–0.626) during the first 28 weeks of life to 0.0755/100 person-weeks (95% CI: 0.0156–0.2016) during weeks 29–48 (incidence rate ratio =0.346 (95% CI: 0.0983–1.22); p=0.04).\n\nTotal mortality (HIV-infected and -uninfected infants) was also higher in the first six months of life 0.2839/100 person-weeks (95% CI: 0.1589–0.4564) than between 6 and 12 months 0.0813/100 person-weeks (95% CI: 0.022–0.1933; incidence rate ratio=0.286 (95% CI: 0.069, 0.8989) (p=0.02)).\n\nMaternal adherence\nSelf-reported adherence to breastfeeding recommendations was requested at each visit with full data to COB or death being available on 205/231 infants (88.7%). Adherence was high with 92.8% EBF until six months and 79% CF thereafter. Only 4.5% had ceased breastfeeding completely at 6 months and 97.8% had ceased breastfeeding by 15 months (Figure 2) (age range of COB 1.5–17 months).\n\nFigure 2 Type of feeding over time.\n\nNote: definitions for feeding types [24].\n\nSelf-reported adherence to taking cART was unreliable as it correlated poorly with attendance at dispensary visits (data not shown). Thirty-six of 226 women (15.9%) missed at least one dispensary visit (i.e. were greater than two weeks late for a scheduled visit and therefore would have had a drug holiday due to medication shortage). Four of 35 (11.4%) women who missed a visit vs. 5 of 184 (2.7%) women who did not miss a visit transmitted HIV (p=0.038).\n\nMaternal and infant adverse events\nIn order to compare adverse events during different time periods, HIV-infected and HIV-uninfected infants are analyzed separately as in previous studies [9]. In HIV-uninfected infants (Table 3), FTT was greatest in the first six months of life (p<0.001), the rates of diarrhoea rose after six months of age (during the period of CF) when compared with the first six months of life (EBF; p<0.001) and the rates of respiratory tract infections rose during the period of COB (12–18 months of age) when compared with the periods of EBF (0–6 months) and CF (6–12 months; p<0.001 for both comparisons). The number of HIV-infected infants was small making estimates of the incidence of adverse effects in this group unreliable (see Supplementary Table 6). Maternal adverse events are in Supplementary Table 7.\n\nTable 3 Total infant adverse events (excluding HIV-infected infants)\n\n\tTime perioda\n\t\np\nb\n\t\n\t\n\n\t\n\n\t\nAdverse event\t0–6 months\n(n, R)\t6–12 months\n(n, R)\t12–18 months\n(n, R)\t0–18 months\n(n, R)\t6–12 vs. 0–6 months\t12–18 vs. 0–6 months\t12–18 vs. 6–12 months\t\nDiarrhoea\t18 (0.36)\t55 (1.16)\t61 (1.33)\t134 (0.94)\t0.00002\t<0.00001\t0.45966\t\nRespiratory infection\t12 (0.24)\t11 (0.23)\t57 (1.24)\t80 (0.56)\t0.94240\t<0.00001\t<0.00001\t\nFailure to thrive\t88 (1.75)\t34 (0.72)\t33 (0.72)\t155 (1.09)\t0.00001\t0.00001\t0.98412\t\nRash\t71 (1.42)\t15 (0.32)\t14 (0.30)\t100 (0.70)\t<0.00001\t<0.00001\t0.92923\t\nCandidiasis\t14 (0.28)\t6 (0.13)\t0 (0.00)\t20 (0.14)\t0.11281\t0.02262\t0.08464\t\nMalaria\t6 (0.12)\t2 (0.04)\t9 (0.20)\t17 (0.12)\t0.22568\t0.35831\t0.05407\t\nNonspecific infection\t14 (0.28)\t0 (0.00)\t3 (0.07)\t17 (0.12)\t0.02125\t0.02517\t0.19028\t\nTuberculosis\t0 (0.00)\t2 (0.04)\t0 (0.00)\t2 (0.01)\t0.28298\t0.96486\t0.30926\t\n\nNote: Rates are based on per 100 person-weeks.\n\na Patients contributed the respective person-time corresponding to each time period.\n\nb \np-Values were computed using a Poisson regression.\n\nDiscussion\nThis study provides an estimate of the real-world efficacy of continued maternal cART. The government of Malawi reviewed their experience of the efficacy of Option B+, but HIV status was documented at 12 months or beyond on only 54% of infants leading to an inability to make a reliable estimate of efficacy [23]. Furthermore, a recent review did not find any reports which were able to assess late MTCT through the end of 12 months of breastfeeding using option B or B+ [24]. We believe that our study is the first to report rates of MTCT at 18 months of age.\n\nPredictive models to estimate the efficacy of different national programmes to lead to population wide HIV MTCT rates <5% have suggested that very high population coverage with maternal ARVs will be necessary [25, 26]. Our data showing 4.1% MTCT using continued maternal cART within the context of a clinical study suggest that even at 90% enrolment in ARV programmes nationally, achieving a population wide MTCT rate of less than 5% may be challenging [25]. Furthermore, loss to follow-up antepartum (15%) and postpartum (13%) would have led to a significant number of women discontinuing cART. This occurred despite using adherence counselling, food and transportation stipends and text messaging reminders to enhance follow-up. Therefore, the true intent-to-treat transmission rate would likely be higher than 5% even within this study cohort. Very high “real-world” rates of loss to follow-up in pregnant and breastfeeding women on cART have been found in other studies [27–29] and so we feel that our data reflect real-world efficacy. The 95% CI for the MTCT rate was 2.2–7.6%, and so further studies with larger cohorts will be required to confirm the rate of MTCT using continued maternal cART.\n\nSix episodes of post-partum transmissions occurred and of these, all five for which data were available to determine timing occurred after six months of age. Adherence to maternal cART was poor or questionable in all five women in our cohort who transmitted after six months (Supplementary Table 2). The transmission of a K65R resistance mutation leading to potential failure of future cART in one infant is concerning. A meta-analysis of 51 studies found that only 53% of women had adequate adherence to ARVs in the postpartum period [30].\n\nWhen analyzed as a continuous variable, CD4 count was not found to be correlated to HIV transmission or infant death in the postpartum period (data not shown). Our low event rate likely led to a lack of sensitivity in identifying a relationship. Only the maternal VL measured at six months was predictive of subsequent HIV transmission. This is consistent with data involving heterosexual transmission of HIV, which demonstrated the importance of viral load in risk of transmission [31]. Our data suggest that measurement of maternal VL at six months of age may help to identify infants at higher risk of late transmission. Patients displaying virologic failure, or patients who have missed dispensary visits, may benefit from further counselling regarding ARV adherence, both for the mother's health and to prevent MTCT although this approach would require further study to confirm. Maternal adherence to treatment may have been improved by using a daily rather than a twice daily cART regimen [32]. It is notable, however, that twice daily ZDV/3TC is still a preferred option in both the US and British treatment guidelines for pregnant women [33, 34].\n\nOur data support the logical premise that poor adherence leading to an elevated maternal viral load appears to be the main factor responsible for post-partum transmission. We base this on the observation that not only elevated maternal viral load but also missed dispensary visits were associated with transmission. However, the hypothesis that there may be something inherently different about the EBF (0–6 months) vs. the CF and COB (6–18 months) periods that makes the latter particularly susceptible to MTCT in the setting of an elevated viral load is also possible. The trend towards a higher transmission rate/100 person-weeks during 6–18 months when compared to 6 weeks to 6 months (p=0.167) is suggestive. In addition, when including transmitting and non-transmitting mothers, more mothers had a detectable VL (>50) at birth than at six months (p=0.002), and mean Log10 viral load at six months was not different from that obtained at birth, which would lead one to expect that there would be equivalent or more transmissions in the 0 to 6 months vs. 6 to 18 months period if VL level was the sole factor responsible for MTCT, which was not seen in our results. The mechanism of this potential inherent difference between the EBF (0–6 months) and CF/COB (6–18 months) period remains speculative but may include ingestion of contaminated water, fluids and food, which may lead to gut mucosal injury and disruption of immune barriers which has been proposed for the increased MTCT seen in previous studies [35, 36] that identified a higher transmission rate with mixed feeding compared with EBF. This hypothesis should be interpreted with caution, however, given our low event rate, our VL comparator convenience sample being limited to 96 non-transmitting mothers and that there was a trend but not a statistically significant difference in transmissions in the 0 to 6 months vs. 6 to 18 months time periods.\n\nOur HIV-uninfected infant mortality rate was highest in the 0 to 6 months’ time period (12 deaths) vs. any other time period (8 deaths in 6–18 months time period). Worldwide, a child's risk of dying is highest in the first 28 days of life [37]; our results were consistent with this, with 8 of 12 HIV-uninfected infant deaths in the 0–6 month time period occurring in the first 28 days of life (Supplementary Table 5). In addition, the well-known ‘survivor bias’ would also predict this drop in mortality as time advances. Comparison of mortality rates in a specific time period (i.e. 6–18 months) to a historic time period (i.e. 0–6 months) is biased in the direction of making the later mortality rate appear lower even though it is being compared within the same population. This is because of the premise that the population that is remaining at the later time period is actually a substantively different population by virtue of the fact that infants who have survived >6 months have already been selected out as being healthier/more resistant to mortality. The fact that this survivor bias was not seen in previous studies is interpreted as a complication of the early COB in those studies [9, 12]. By contrast, in our cohort, the total and HIV-uninfected infant mortality rates fell significantly after six months, which suggests a protective effect of on-going breastfeeding.\n\nOur absolute rate of infant mortality in the first six months of life was higher than that seen in the recently published BAN study in Malawi [9]. This difference may reflect the reported higher under-5 mortality rate in Zambia when compared to Malawi, the aetiology of which is probably multifactorial [38]. This fact, however, should not change the within-populations comparison of under and over 28-week death rates seen, which showed a significant increase in mortality after 28 weeks in the Malawi population which utilized early COB (from 0.065 to 0.12/100 person-weeks) vs. a decrease in mortality after 28 weeks in our cohort (from 0.2183 to 0.0755/100 person-weeks; p=0.007). Overall, this would suggest that the difference in infant-feeding practices between the two studies is a very plausible explanation for the demonstrated reversal in pattern of the change in mortality at six months. Nevertheless, comparisons in outcomes between different cohorts need caution in their interpretation.\n\nOur infant FTT was significantly higher during EBF when compared to later time periods (Table 3). We believe that this is also likely due to a survivor bias, and this also impacts early death rates as about 45% of all child deaths are linked to malnutrition [37]. After infants are developmentally advanced enough to accept significant amounts of semi-solid/solid foods (typically after six months), the available options to provide safe, high-caloric and nutrient-rich foods expand significantly.\n\nConclusions\nContinued maternal cART can achieve the global UNAIDS target of <5% MTCT for eradication of paediatric HIV within the context of a clinical study but loss to follow-up and poor adherence to therapy may limit the benefit. Continued breastfeeding may prevent the rise in infant mortality at six months seen with early COB. These data will help to inform policy decisions regarding implementation of the new WHO guidelines.\n\nSupplementary Material\nEfficacy of WHO recommendation for continued breastfeeding and maternal cART for prevention of perinatal and postnatal HIV transmission in Zambia\nClick here for additional data file.\n\n Acknowledgements\nWe thank B. Picov for his strong support of this study. We also thank N. Ackad, M. Martinez, K. Vermeulen, A. Kopinska, M. Chipili, K. Semaru, R. Mahone, M. Nsowa, R.K. Silverman, P. Godfrey and N. Mbewe for their contributions. Finally, thank you to the women, children and staff of the Chelstone Clinic.\n\n\nFunding\nThis study was supported by The Rotary Foundation, The Stephen Lewis Foundation, The Mount Sinai Hospital Foundation, ViiV Healthcare and AbbVie. The funding agencies had no role in the design, analysis and conduct of the study or writing of the manuscript.\n\nCompeting interests\nThis study was partially funded by unrestricted grants from Abbvie and ViiV Healthcare. None of the study funders had any role in study design, conduct of the study, study analysis or manuscript preparation.\n\nAuthors' contributions\nAll authors have read and approved the final version.\n==== Refs\nReferences\n1 UNAIDS Countdown to zero: global plan towards the elimination of new HIV infections among children by 2015 and keeping their mothers alive, 2011–2015 2011 Geneva Joint United Nations Programme on HIV/AIDS \n2 WHO Guidelines on HIV and infant feeding 2010: principles and recommendations for infant feeding in the context of HIV and summary of evidence 2010 Geneva World Health Organization \n3 Mofenson LM Protecting the next generation – eliminating perinatal HIV-1 infection N Engl J Med 2010 362 2316 18 10.1056/NEJMe1004406 20554987 \n4 WHO Programmatic update: use of antiretroviral drugs for treating pregnant women and preventing HIV infection in infants 2012 Geneva World Health Organization \n5 Kuhn L Sinkala M Kankasa C Semrau K Kasonde P Scott N High uptake of exclusive breastfeeding and reduced early post-natal HIV transmission PLoS One 2007 2 12 e1363 10.1371/journal.pone.0001363 18159246 \n6 Coovadia HM Rollins NC Bland RM Little K Coutsoudis A Bennish ML Mother-to-child transmission of HIV-1 infection during exclusive breastfeeding in the first 6 months of life: an intervention cohort study Lancet 2007 369 9567 1107 16 17398310 \n7 Kesho Bora Study Group Triple antiretroviral compared with zidovudine and single-dose nevirapine prophylaxis during pregnancy and breastfeeding for prevention of mother-to-child transmission of HIV-1 (Kesho Bora Study): a randomised controlled trial Lancet Infect Dis 2011 11 3 171 80 10.1016/S1473-3099(10)70288-7 21237718 \n8 Thomas TK Masaba R Borkowf CB Ndivo R Zeh C Misore A Triple-antiretroviral prophylaxis to prevent mother-to-child HIV transmission through breastfeeding—the Kisumu Breastfeeding Study, Kenya: a clinical trial PLoS Med 2011 8 3 e1001015 10.1371/journal.pmed.1001015 21468300 \n9 Jamieson DJ Chasela CS Hudgens MG King CC Kourtis AP Kayira D Maternal and infant antiretroviral regimens to prevent postnatal HIV-1 transmission: 48-week follow-up of the BAN randomised controlled trial Lancet 2012 379 9835 2449 58 10.1016/S0140-6736(12)60321-3 22541418 \n10 Kuhn L Aldrovandi GM Sinkala M Kankasa C Semrau K Mwiya M Effects of early, abrupt weaning on HIV-free survival of children in Zambia N Engl J Med 2008 359 2 130 41 10.1056/NEJMoa073788 18525036 \n11 Kuhn L Sinkala M Semrau K Kankasa C Kasonde P Mwiya M Elevations in mortality due to weaning persist into the second year of life among uninfected children born to HIV-infected mothers Clin Infect Dis 2010 50 3 437 44 10.1086/649886 20047479 \n12 Taha TE Hoover DR Chen S Kumwenda NI Mipando L Nkanaunena K Effects of cessation of breastfeeding in HIV-1-exposed, uninfected children in Malawi Clin Infect Dis 2011 53 4 388 95 10.1093/cid/cir413 21810754 \n13 Kafulafula G Hoover DR Taha TE Thigpen M Li Q Fowler MG Frequency of gastroenteritis and gastroenteritis-associated mortality with early weaning in HIV-1-uninfected children born to HIV-infected women in Malawi J Acquir Immune Defic Syndr 2010 53 1 6 13 10.1097/QAI.0b013e3181bd5a47 19844183 \n14 WHO Antiretroviral drugs for treating pregnant women and preventing HIV infection in infants: recommendations for a public health approach 2010 Geneva World Health Organization \n15 WHO Consolidated guidelines on the use of antiretroviral drugs for treating and preventing HIV infection: recommendations for a public health approach 2013 Geneva World Health Organization \n16 WHO technical update on treatment optimization Use of Efavirenz during pregnancy: a public health perspective 2012 [cited 2014 Jan 9]. Available from: http://www.who.int/hiv/pub/treatment2/efavirenz/en/ \n17 Viramune package insert [cited 2014 Jan 7]. Available from: http://bidocs.boehringer-ingelheim.com/BIWebAccess/ViewServlet.ser?docBase=renetnt&folderPath=/Prescribing+Information/PIs/Viramune/Viramune.pdf \n18 Kerr RJ Player G Fiscus SA Nelson JA Qualitative human immunodeficiency virus RNA analysis of dried blood spots for diagnosis of infections in infants J Clin Microbiol 2009 47 1 220 2 10.1128/JCM.01521-08 19005148 \n19 WHO Manual for HIV drug resistance testing using dried blood spots 2010 Geneva World Health Organization \n20 UNICEF Breastfeeding [cited 2013 Sep 28]. Available from: http://www.unicef.org/nutrition/index_24824.html \n21 Oleckno WA Epidemiology: concepts and methods 2008 Longrove, IL Waveland Press \n22 Steenland K Case studies in occupational epidemiology 1992 Oxford, UK Oxford University Press \n23 Government of Malawi Ministry of Health. Integrated HIV program report July – September 2012 [cited 2013 Aug 25]. Available from: http://www.hivunitmohmw.org/uploads/Main/Quarterly_HIV_Programme_Report_2012_Q3.pdf \n24 Ahmed S Kim MH Abrams EJ Risks and benefits of lifelong antiretroviral treatment for pregnant and breastfeeding women. A review of the evidence for the Option B+ approach Curr Opin HIV AIDS 2013 8 474 89 23925003 \n25 Ciaranello AL Perez F Keatinge J Park J-E Engelsmann B Maruva M What will it take to eliminate pediatric HIV? Reaching WHO target rates of mother-to-child HIV transmission in Zimbabwe: a model-based analysis PLoS Med 2012 9 1 e1001156 10.1371/journal.pmed.1001156 22253579 \n26 Fasawe O Avila C Shaffer N Schouten E Chimbwandira F Hoos D Cost-effectiveness analysis of option B+ for HIV prevention and treatment of mothers and children in Malawi PLoS One 2013 8 3 e57778 10.1371/journal.pone.0057778 23554867 \n27 Clouse K Maskew M Fox MP Bassett J Larson B Delayed diagnosis of HIV and high rates of loss to follow-up among pregnant women receiving antenatal services at a primary healthcare clinic in Johannesburg, South Africa [Abstract 1004] 2012 Paper presented at: Conference on Retroviruses and Opportunistic Infections 2012 Mar 6 Seattle, WA \n28 Myer L Cornell M Fox M Garone D Wood R Prozesky H Loss to follow-up and mortality among pregnant and non-pregnant women initiating ART: South Africa 2012 [abstract 22] CROI 2012 Mar 6 Seattle, WA \n29 Wang B Losina E Stark R Munro A Walensky RP Wilke M Loss to follow-up in a community clinic in South Africa. Roles of Gender, Pregnancy and CD4 count S Afr Med J 2011 101 4 253 7 21786730 \n30 Nachega JB Uthman OA Anderson J Peltzer K Wampold S Cotton MF Adherence to antiretroviral therapy during and after pregnancy in low-income, middle-income, and high- income countries: a systematic review and meta-analysis AIDS 2012 26 2039 52 22951634 \n31 Cohen MS Chen YQ McCauley M Gamble T Hosseinipour MC Kumarasamy N Prevention of HIV-1 infection with early antiretroviral therapy N Engl J Med 2011 365 493 505 21767103 \n32 Buscher A Hartman C Kallen MA Giordano TP Impact of antiretroviral dosing frequency and pill burden on adherence among newly diagnosed antiretroviral-naive HIV patients Int J STD AIDS 2012 23 351 5 22648890 \n33 Department of Health and Human Services Recommendations for use of antiretroviral drugs in pregnant HIV-1-infected women for maternal health and interventions to reduce perinatal HIV transmission in the United States [cited 2014 Jul 7]. Available from: http://aidsinfo.nih.gov/contentfiles/lvguidelines/perinatalgl.pdf \n34 Taylor GP Clayden P Dhar J Gandi K Gilleece Y Harding K British HIV Association guidelines for the management of HIV infection in pregnant women HIV Med 2012 13 Suppl 2 87 157 10.1111/j.1468-1293.2012.01030 22830373 \n35 Coutsoudis A Pillay K Spooner E Kuhn L Coovadia H for the South African Vitamin A Study Group Influence of infant-feeding patterns on early mother-to-child transmission of HIV-1 in Durban, South Africa: a prospective cohort study Lancet 1999 354 471 6 10465172 \n36 Preble EA Piwoz EG HIV and infant feeding: a chronology of research and policy advances and their implications for programs. The LINKAGES Project 1995 Washington, DC Support for Analysis and Research in Africa (SARA) Project \n37 The WHO media centre Children: reducing mortality [cited 2014 Dec 10]. Available from: http://www.who.int/mediacentre/factsheets/fs178/en/ \n38 The World Bank Data [cited 2012 Jun 24]. Available from: http://data.worldbank.org/indicator/SH.DYN.MORT\n\n",
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"mesh_terms": "D019380:Anti-HIV Agents; D001942:Breast Feeding; D015331:Cohort Studies; D004359:Drug Therapy, Combination; D005260:Female; D015658:HIV Infections; D006801:Humans; D007223:Infant; D018445:Infectious Disease Transmission, Vertical; D011247:Pregnancy; D011251:Pregnancy Complications, Infectious; D011446:Prospective Studies; D014944:World Health Organization; D015024:Zambia",
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{
"abstract": "BACKGROUND\nProgressive outer retinal necrosis (PORN) is a rare but devastating infectious retinitis associated with varicella zoster virus (VZV) and responsible for severe visual loss.\n\n\nMETHODS\nA 59-year-old man treated for generalized myasthenia with oral azathioprine and prednisone presented with severe unilateral necrotizing retinitis. Polymerase chain reaction of the aqueous and vitreous humors was diagnostic for VZV PORN.\n\n\nCONCLUSIONS\nVZV PORN is a severe potential ocular complication of immunosuppression, prompting urgent diagnosis and appropriate treatment.",
"affiliations": "Service d'Ophtalmologie, Centre Hospitalier Universitaire d'Angers, Université d'Angers, LUNAM, Angers, France.;Service d'Ophtalmologie, Centre Hospitalier Universitaire d'Angers, Université d'Angers, LUNAM, Angers, France.;Service d'Ophtalmologie, Centre Hospitalier Universitaire d'Angers, Université d'Angers, LUNAM, Angers, France ; Singapore National Eye Centre, Singapore Eye Research Institute and Duke-NUS, Singapore, Singapore.",
"authors": "Coisy|Solène|S|;Ebran|Jean-Marc|JM|;Milea|Dan|D|",
"chemical_list": null,
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"fulltext": "\n==== Front\nCase Rep OphthalmolCase Rep OphthalmolCOPCase Reports in Ophthalmology1663-2699S. Karger AG Allschwilerstrasse 10, P.O. Box · Postfach · Case postale, CH–4009, Basel, Switzerland · Schweiz · Suisse, Phone: +41 61 306 11 11, Fax: +41 61 306 12 34, karger@karger.ch 10.1159/000362662cop-0005-0132Published online: April, 2014Progressive Outer Retinal Necrosis and Immunosuppressive Therapy in Myasthenia Gravis Coisy Solène a*Ebran Jean-Marc aMilea Dan abaService d'Ophtalmologie, Centre Hospitalier Universitaire d'Angers, Université d'Angers, LUNAM, Angers, FrancebSingapore National Eye Centre, Singapore Eye Research Institute and Duke-NUS, Singapore, Singapore*Solène Coisy, Service d'Ophtalmologie, CHU d'Angers, 4 rue Larrey, FR–49933 Angers Cedex 09 (France), E-Mail socoisy@gmail.comJan-Apr 2014 22 4 2014 22 4 2014 5 1 132 137 Copyright © 2014 by S. Karger AG, Basel2014This is an Open Access article licensed under the terms of the Creative Commons Attribution-NonCommercial 3.0 Unported license (CC BY-NC) (www.karger.com/OA-license), applicable to the online version of the article only. Users may download, print and share this work on the Internet for noncommercial purposes only, provided the original work is properly cited, and a link to the original work on http://www.karger.com and the terms of this license are included in any shared versions.Introduction\nProgressive outer retinal necrosis (PORN) is a rare but devastating infectious retinitis associated with varicella zoster virus (VZV) and responsible for severe visual loss.\n\nCase Report\nA 59-year-old man treated for generalized myasthenia with oral azathioprine and prednisone presented with severe unilateral necrotizing retinitis. Polymerase chain reaction of the aqueous and vitreous humors was diagnostic for VZV PORN.\n\nConclusion\nVZV PORN is a severe potential ocular complication of immunosuppression, prompting urgent diagnosis and appropriate treatment.\n\nKey words\nRetinitisProgressive outer retinal necrosisVaricella zoster retinitis\n==== Body\nIntroduction\nVaricella zoster virus (VZV) progressive outer retinal necrosis (PORN) is a devastating ocular complication responsible for severe visual loss, occurring almost exclusively in patients with AIDS. Affected patients complain of blurring vision or vague visual loss (54%), constriction of the visual field or loss of peripheral vision (28%), floaters (1%), pain (6%), or are asymptomatic (11%) [1]. The fundoscopic examination is characterized by multifocal retinal opacities starting at the peripheral retina, involving the posterior pole in 30% of cases, being rapidly coalescent and progressing to complete retinal necrosis [1, 2]. The retinitis tends to be bilateral with time (61% of patients), i.e. within 4 weeks in the study by Engstrom et al. [1]. Intraocular inflammation and vasculitis are usually absent, which differentiates PORN from VZV acute retinal necrosis affecting non-immunosuppressed patients [3]. The diagnosis is based on isolating VZV DNA by polymerase chain reaction in the aqueous and/or vitreous humor [3]. Even if this affection was first described in a human immunodeficiency virus (HIV)-positive patient in 1990 by Forster et al. [4], a few cases have been reported in HIV-negative patients treated with immunosuppressive therapies.\n\nHere we report a case of VZV PORN in a patient treated with immunosuppressive therapies for a generalized myasthenia.\n\nCase Report\nA 59-year-old man was admitted with unilateral progressive visual loss in the right eye occurring over the last 7 days and evolving to counting fingers. He had been diagnosed with generalized myasthenia 2 years earlier and during the last 20 months he had been treated with oral prednisone (60 mg/day at first for 4 weeks with subsequent tapering down to 20 mg/day, which was his regimen during 14 months). Oral azathioprine (150 mg/day) was added 1 month prior to visual loss to treat complete ophthalmoplegia and ptosis in the left eye. The right eye's intraocular pressure was 18 mm Hg. There was no corneal opacity and no iris anomaly. Ophthalmic examination of the right eye disclosed no anterior chamber inflammation and no retinal vasculitis; however, mild vitritis, an optic disc edema and macular and peripheral necrotizing retinitis in the right eye (fig. 1, fig. 2). Visual acuity of the left eye was 20/20, and the remainder of the ophthalmic examination was normal. Polymerase chain reaction of the aqueous and vitreous humors performed in the right eye was positive for VZV and negative for cytomegalovirus and herpes simplex virus 1 and 2. The diagnosis was consistent with VZV PORN. HIV serology was negative, and the CD4 lymphocyte count (1,389/mm3) and CD4/CD8 ratio (1.74) were normal. Lumbar puncture and cerebral MRI found no signs of central nervous system zoster meningitis, encephalitis or vasculitis. Oral azathioprine therapy was discontinued, and steroid doses were progressively decreased. Two intravitreal injections of ganciclovir were followed by 10 intravitreal injections of foscarnet. High doses of intravenous foscarnet (180 mg/kg/day) and acyclovir (30 mg/kg/day) were also administered. As acute renal failure occurred after 2 weeks, foscarnet was discontinued and half of the dose of acyclovir was given for one more week. The patient was then discharged on oral acyclovir (15 mg/kg/day) for 3 months. After 10 months of follow-up, his best vision was counting fingers in the right eye and 20/20 in the left eye. The patient had no other ocular complications such as retinal detachment.\n\nDiscussion\nThe main finding of this report is that VZV PORN can occur in a patient affected by another ophthalmic condition, i.e. ocular myasthenia gravis. The retinal symptoms could have been initially misleading, but the immunosuppressed status of the patient prompted the exploration of PORN in this non-HIV-infected patient. The patient's symptoms (painless rapidly progressive visual loss), the appearance of retinal lesions (multifocal, coalescent and peripheral), the lack of anterior and posterior inflammation, the lack of response to treatment and the presence of VZV in aqueous and vitreous humors without another herpes virus (cytomegalovirus, herpes simplex virus) were typical of PORN [1, 2, 3, 4], in a context of immunosuppressive treatments recently introduced with azathioprine and prednisone. The context of recently introduced azathioprine associated with corticosteroids supports this diagnosis. It is well known that the use of azathioprine and/or steroids is associated with an increased risk of herpes zoster, and that this association is stronger among new users than persistent users of these drugs [5, 6].\n\nIndeed, this case is illustrative of a rare but serious complication of immunosuppressive therapy. To our knowledge, no other case of VZV PORN in a patient with another ophthalmic condition and/or with azathioprine has been reported. Only 10 other cases secondary to immunosuppressive therapies have been described (table 1) [6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17], but none secondary to azathioprine and none in a patient treated for myasthenia. The patients described in table 1 were treated for allogeneic stem cell transplants [7, 8, 9, 10], idiopathic thrombocytopenic purpura [11], cutaneous non-Hodgkin's lymphoma [12], rheumatoid arthritis [13, 14], multiple sclerosis [13], nephrotic syndrome [15] and lymphocytic lymphoma [16]. Another case has been reported on a non-HIV patient with a transient decrease in CD4 lymphocyte count and CD4/CD8 ratio, who has been treated at first with prednisolone only (table 1) [17]. The reports on patients after stem cell transplantation were all bilateral and associated with disseminated cutaneous herpes zoster or local cutaneous VZV (table 1) [7, 8, 9, 10]. The reports on patients with rheumatoid arthritis and on the one patient with idiopathic thrombocytopenic purpura were also bilateral [11, 13, 14]. PORN tends to be bilateral with time in HIV patient series (61–70% of patients) [1, 2], which was not the case in our patient. In addition, our patient could not report a previous or concurrent extraocular VZV manifestation, unlike 67–75% of patients in HIV patient series [1, 2]. Unfortunately, no VZV PORN cases in non-HIV patient series are available, probably because they are too rare. No accurate data as in HIV patients is available to assess how often the retinitis is bilateral in these patients. However, a careful monitoring of the other eye seems essential to detect PORN and to treat it early.\n\nThe current recommendations for PORN include antiviral intravitreal injections 3 times a week for 2 weeks (ganciclovir or foscarnet), followed by injections once or twice a week until the retinitis is stabilized. High doses of intravenous antiviral double therapy (ganciclovir or valganciclovir at induction doses for 3 weeks and foscarnet at induction doses for 2 weeks) are required to protect the other eye and the central nervous system, followed by maintenance antiviral therapy (oral valganciclovir and intravenous foscarnet) until complete healing. Oral valganciclovir or valacyclovir can then be continued [18]. Our patient was treated twice a week with intravitreal antiviral injections and intravenous high doses of antivirals (foscarnet and acyclovir) during 2 weeks and with half of the doses of intravenous acyclovir for 1 additional week. The visual outcome in HIV-patients is poor: 67 and 49% of patients had a final visual acuity of ‘no light perception’ within 4 weeks and 6 months after the initial diagnosis, respectively [1, 2]. The visual outcome may be better in patients treated with more than 1 intravenous antiviral agent, and even more so when using both intravenous and intravitreal antiviral agents [18]. In Scott et al.'s study, 45% of eyes treated with both intravitreal and intravenous antivirals had a final visual acuity of 20/80 or better [18].\n\nOne of the aims of the treatment in our patient was to prevent the involvement of the left eye and to preserve the right eye from retinal detachment. Indeed, about 70% of eyes develop rhegmatogenous retinal detachment [1, 2] within a median time of 30 days to 3 months after presentation [3]. Without laser treatment, our patient did not develop retinal detachment after 10 months; indeed, prophylactic demarcating laser treatment is controversial in this setting [3, 18].\n\nConclusion\nVZV PORN is a devastating ocular complication, typically occurring in severely immunosuppressed patients (in particular HIV patients) and characterized by multifocal peripheral and posterior retinal lesions which rapidly coalesce without anterior inflammation and vasculitis. In a patient with visual loss, while on longstanding immunosuppressive therapy, PORN is a rare albeit possible cause, beyond several common diagnoses (i.e. keratitis, uveitis, toxoplasmosis, syphilitic chorioretinitis), which needs prompt treatment. Thus, a careful examination of the peripheral retina is required for an early diagnosis. A delayed diagnosis may result in retinal necrosis and detachment, affecting both eyes and potentially leading to irreversible blindness. The treatment requires antiviral intravitreous injections and intravenous therapy.\n\nTable 1 Case reports of PORN in non-HIV patients treated with immunosuppressive therapies\n\nRef.\tCases, n\tUnilateral/bilateral\tDiagnosis\tImmunosuppressive therapy\tPORN treatment\t\n[10]\t1\tBilateral\tAcute lymphoblastic leukemia\tHematopoietic stem cell transplantation and steroids\tIntravenous ganciclovir and foscarnet, followed by intravenous cidofovir and intravitreous foscarnet\t\n[7]\t1\tBilateral\tAcute myeloid leukemia\tMethylprednisolone, ciclosporin, mycophenolate mofetil, anti-thymocyte globulin for stem cell transplantation\tIntravitreal ganciclovir and intravenous high-dose acyclovir\t\n[9]\t1\tBilateral\tRefractory anemia with excess blasts type 1\tCiclosporin, prednisolone, mycophenolate mofetil after stem cell transplantation\tIntravenous foscarnet, ganciclovir and cidofovir, intravitreal foscarnet injections and 1 dose of human immunoglobulin (0.4 g/kg)\t\n[8]\t1\tBilateral\tT-lymphoblastic lymphoma\tThiotepa, fludarabine and anti-thymocyte globulin for stem cell transplantation\tIntravenous and intravitreal foscarnet\t\n[17]\t1\tUnilateral\tTransient immune deviation\tPrednisolone\tIntravitreal foscarnet injection, intravenous acyclovir\t\n[13]\t2\tUnilateral/bilateral\tMultiple sclerosis/rheumatoid arthritis\tSteroids\tIntravenous acyclovir, intravitreal injections of ganciclovir and foscarnet\t\n[16]\t1\tUnilateral\tSmall lymphocytic lymphoma\tCorticosteroids and alkylating agent therapy (chlorambucil and cyclophosphamide)\tIntravenous foscarnet and ganciclovir, intravenous gammaglobulin (0.5 mg/kg/day) for 5 days and oral decadron (16 mg/day)\t\n[15]\t1\tUnilateral\tNephrotic syndrome\tPrednisolone\tIntravenous high-dose acyclovir\t\n[11]\t1\tBilateral\tIdiopathic thrombocytopenic purpura\tMethylprednisolone, gammaglobulin, vincristine\tIntravenous acyclovir\t\n[12]\t1\tUnilateral\tCutaneous non-Hodgkin's T-cell lymphoma\tChlorambucil and prednisone\tIntravenous acyclovir\t\n[14]\t1\tBilateral\tRheumatoid arthritis\tChlorambucil and prednisone\tIntravenous acyclovir\t\nFig. 1 Fundus appearance of the right eye showing multifocal retinal opacities and superficial retinal hemorrhages involving the posterior pole. There is an associated optic disc swelling and mild vitritis.\n\nFig. 2 Right retinal photograph showing multifocal and coalescent retinal opacities in the temporal retina.\n==== Refs\n1 Engstrom RE Jr Holland GN Margolis TP Muccioli C Lindley JI Belfort R Jr Holland SP Johnston WH Wolitz RA Kreiger AE The progressive outer retinal necrosis syndrome: a variant of necrotizing herpetic retinopathy in patients with AIDS Ophthalmology 1994 101 1488 1502 8090452 \n2 Moorthy RS Weinberg DV Teich SA Berger BB Minturn JT Kumar S Rao NA Fowell SM Loose IA Jampol LM Management of varicella zoster virus retinitis in AIDS Br J Ophthalmol 1997 81 189 194 9135381 \n3 Austin RB Progressive outer retinal necrosis syndrome: a comprehensive review of its clinical presentation, relationship to immune system status, and management Clin Eye Vis Care 2000 12 119 129 11137426 \n4 Forster DJ Dugel PU Frangieh GT Liggett PE Rao NA Rapidly progressive outer retinal necrosis in the acquired immunodeficiency syndrome Am J Ophthalmol 1990 110 341 348 2220967 \n5 Kim MJ Choe YH Monitoring and safety of azathioprine therapy in inflammatory bowel disease Pediatr Gastroenterol Hepatol Nutr 2013 16 65 70 24010109 \n6 Gupta G Lautenbach E Lewis JD Incidence and risk factors for herpes zoster among patients with inflammatory bowel disease Clin Gastroenterol Hepatol 2006 4 1483 1490 17162240 \n7 Gill H Cheung J Wong I Lie AK Kwong YL Varicella zoster virus progressive outer retinal necrosis after allogeneic haematopoietic stem cell transplantation Br J Haematol 2012 157 279 22329673 \n8 Kalpoe JS van Dehn CE Bollemeijer JG Vaessen N Claas EC Barge RM Willemze R Kroes AC Beersma MF Varicella zoster virus (VZV)-related progressive outer retinal necrosis (PORN) after allogeneic stem cell transplantation Bone Marrow Transplant 2005 36 467 469 15995710 \n9 Khot A Dignan F Taylor S Potter M Cubitt D Treleaven JG Another case of PORN (bilateral progressive outer retinal necrosis) after allogeneic stem cell transplantation Bone Marrow Transplant 2006 37 113 114 16247414 \n10 Patel A Olavarria E Optic neuritis preceding progressive outer retinal necrosis in an immunocompromised patient after allogeneic stem cell transplantation Ann Hematol 2013 92 1427 1429 23404584 \n11 Doi M Matsui K Akamine T Sasoh M Uji Y Taniguchi H Progressive outer retinal necrosis in a human immunodeficiency virus-negative patient Retina 1999 19 468 470 10546952 \n12 Njoo FL Rothova A Van Der Lelij A Progressive outer retinal necrosis in a patient with cutaneous non-Hodgkin's T cell lymphoma (Sézary syndrome) Br J Ophthalmol 1998 82 1218 1219 9924317 \n13 Benz MS Glaser JS Davis JL Progressive outer retinal necrosis in immunocompetent patients treated initially for optic neuropathy with systemic corticosteroids Am J Ophthalmol 2003 135 551 553 12654381 \n14 Bryan RG Myers FL Progressive outer retinal necrosis in a patient with rheumatoid arthritis Arch Ophthalmol 1998 116 1249 9747694 \n15 Shinoda K Inoue M Ishida S Kawashima S Wakabayashi T Suzuki S Katsura H Progressive outer retinal necrosis in a patient with nephrotic syndrome Ophthalmic Surg Lasers 2001 32 67 72 11195746 \n16 Foster RE Petersen MR Neuss MN Osher RH Progressive outer retinal necrosis syndrome in a lymphoma patient with good visual outcome Am J Ophthalmol 2001 132 117 120 11438070 \n17 Lim WK Chee SP Nussenblatt RB Progression of varicella-zoster virus necrotizing retinopathy in an HIV-negative patient with transient immune deviation Graefes Arch Clin Exp Ophthalmol 2005 243 607 609 15657772 \n18 Scott IU Luu KM Davis JL Intravitreal antivirals in the management of patients with acquired immunodeficiency syndrome with progressive outer retinal necrosis Arch Ophthalmol 2002 120 1219 1222 12215102\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1663-2699",
"issue": "5(1)",
"journal": "Case reports in ophthalmology",
"keywords": "Progressive outer retinal necrosis; Retinitis; Varicella zoster retinitis",
"medline_ta": "Case Rep Ophthalmol",
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"nlm_unique_id": "101532006",
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"pages": "132-7",
"pmc": null,
"pmid": "24926266",
"pubdate": "2014-01",
"publication_types": "D002363:Case Reports",
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"title": "Progressive outer retinal necrosis and immunosuppressive therapy in myasthenia gravis.",
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"literaturereference": "COISY S,EBRAN J,MILEA D. PROGRESSIVE OUTER RETINAL NECROSIS AND IMMUNOSUPPRESSIVE THERAPY IN MYASTHENIA GRAVIS. CASE REPORTS IN OPHTHALMOLOGY 2014 JAN;5:1:132-137.",
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"abstract": "BACKGROUND\nMalignant catatonia (MC) is a movement disorder syndrome characterized by immobility, rigidity, and consciousness disorders that develops in association with mental and physical diseases. It is often fatal due to hyperthermia, rhabdomyolysis, and acute kidney injury. Its clinical symptoms are similar to those of another disorder, neuroleptic malignant syndrome (NMS), and it is often difficult to distinguish between the 2 disorders.\nAn Asian woman in her 60s with history of schizophrenia. She was admitted to our hospital because of symptoms such as fever, unconsciousness, and muscle rigidity. Blood tests showed kidney injury and high creatinine kinase levels.\nAt the time of admission, she had been diagnosed with NMS complicated by pulmonary aspergillosis and was undergoing treatment although there was no improvement.\n\n\nMETHODS\nSubsequently, the administration of propofol, a gamma-aminobutyric acid A agonist, markedly improved the symptoms, and the diagnosis was corrected to MC. At the beginning of her hospitalization, she received dantrolene, bromocriptine, amantadine, and L-3,4-dihydroxyphenylalanine as treatment for NMS, but her symptoms did not improve. With propofol, which is used for sedation, her catatonic symptoms improved markedly. Quetiapine administration further improved the symptoms, and it eventually resolved completely.\n\n\nRESULTS\nThe patient's MC was in remission. Prolonged intensive care management resulted in a decline in activities of daily living, and she required rehabilitation at another hospital.\n\n\nCONCLUSIONS\nThis is the first report of MC with suspected involvement of pulmonary aspergillosis. MC differs from NMS, in that it is treated more effectively with gamma-aminobutyric acid A agonists. Although benzodiazepines are the first choice for the diagnosis and treatment of MC, they are ineffective for majority of patients with schizophrenia. However, even in such cases, propofol and quetiapine are effective, and they facilitate diagnosis and treatment.",
"affiliations": "Department of Emergency Medicine, Sapporo Medical University Hospital, Sapporo-shi.;Department of Emergency Medicine, Hakodate Municipal Hospital, Hakodate-shi.;Department of Emergency Medicine, Hakodate Municipal Hospital, Hakodate-shi.;Department of Neurosurgery, Sunagawa City Medical Center, Sunagawa-shi.;Department of Emergency Medicine, Sapporo Medical University Hospital, Sapporo-shi.;Department of Emergency Medicine, Teine Keijinkai Hospital, Sapporo-shi, Hokkaido, Japan.;Department of Emergency Medicine, Hakodate Municipal Hospital, Hakodate-shi.;Department of Emergency Medicine, Sapporo Medical University Hospital, Sapporo-shi.;Department of Emergency Medicine, Sapporo Medical University Hospital, Sapporo-shi.",
"authors": "Nomura|Kazuhito|K|0000-0001-8532-0166;Sakawaki|Sonoko|S|;Sakawaki|Eiji|E|;Yamaoka|Ayumu|A|;Aisaka|Wakiko|W|;Okamoto|Hiroyuki|H|;Takeyama|Yoshihiro|Y|;Uemura|Shuji|S|;Narimatsu|Eichi|E|",
"chemical_list": "D006993:Hypnotics and Sedatives; D000069348:Quetiapine Fumarate; D015742:Propofol",
"country": "United States",
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"doi": "10.1097/MD.0000000000025967",
"fulltext": "\n==== Front\nMedicine (Baltimore)\nMedicine (Baltimore)\nMEDI\nMedicine\n0025-7974\n1536-5964\nLippincott Williams & Wilkins Hagerstown, MD\n\nMD-D-20-12022\n10.1097/MD.0000000000025967\n25967\n3900\nResearch Article\nClinical Case Report\nSuccessful diagnosis and treatment of pulmonary aspergillosis-related malignant catatonia using propofol and quetiapine\nA case report\nhttp://orcid.org/0000-0001-8532-0166\nNomura Kazuhito MD, PhD a∗\nSakawaki Sonoko MD b\nSakawaki Eiji MD b\nYamaoka Ayumu MD c\nAisaka Wakiko MD a\nOkamoto Hiroyuki MD d\nTakeyama Yoshihiro MD b\nUemura Shuji MD, PhD a\nNarimatsu Eichi MD, PhD a\nSaranathan. Maya\na Department of Emergency Medicine, Sapporo Medical University Hospital, Sapporo-shi\nb Department of Emergency Medicine, Hakodate Municipal Hospital, Hakodate-shi\nc Department of Neurosurgery, Sunagawa City Medical Center, Sunagawa-shi\nd Department of Emergency Medicine, Teine Keijinkai Hospital, Sapporo-shi, Hokkaido, Japan.\n∗ Correspondence: Kazuhito Nomura, Department of Emergency Medicine, Sapporo Medical University Hospital, Minami 1-jo Nishi 16 Chome 291, Chuo-ku, Sapporo-shi, Hokkaido 060-8543, Japan (e-mail: kanomura@sapmed.ac.jp, sufjan_beirut@yahoo.co.jp).\n14 5 2021\n14 5 2021\n100 19 e2596715 12 2020\n9 4 2021\n28 4 2021\nCopyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc.\n2021\nhttps://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. http://creativecommons.org/licenses/by/4.0\n\nAbstract\n\nIntroduction:\n\nMalignant catatonia (MC) is a movement disorder syndrome characterized by immobility, rigidity, and consciousness disorders that develops in association with mental and physical diseases. It is often fatal due to hyperthermia, rhabdomyolysis, and acute kidney injury. Its clinical symptoms are similar to those of another disorder, neuroleptic malignant syndrome (NMS), and it is often difficult to distinguish between the 2 disorders.\n\nPatient concerns:\n\nAn Asian woman in her 60s with history of schizophrenia. She was admitted to our hospital because of symptoms such as fever, unconsciousness, and muscle rigidity. Blood tests showed kidney injury and high creatinine kinase levels.\n\nDiagnoses:\n\nAt the time of admission, she had been diagnosed with NMS complicated by pulmonary aspergillosis and was undergoing treatment although there was no improvement.\n\nInterventions:\n\nSubsequently, the administration of propofol, a gamma-aminobutyric acid A agonist, markedly improved the symptoms, and the diagnosis was corrected to MC. At the beginning of her hospitalization, she received dantrolene, bromocriptine, amantadine, and L-3,4-dihydroxyphenylalanine as treatment for NMS, but her symptoms did not improve. With propofol, which is used for sedation, her catatonic symptoms improved markedly. Quetiapine administration further improved the symptoms, and it eventually resolved completely.\n\nOutcomes:\n\nThe patient's MC was in remission. Prolonged intensive care management resulted in a decline in activities of daily living, and she required rehabilitation at another hospital.\n\nConclusion:\n\nThis is the first report of MC with suspected involvement of pulmonary aspergillosis. MC differs from NMS, in that it is treated more effectively with gamma-aminobutyric acid A agonists. Although benzodiazepines are the first choice for the diagnosis and treatment of MC, they are ineffective for majority of patients with schizophrenia. However, even in such cases, propofol and quetiapine are effective, and they facilitate diagnosis and treatment.\n\nKeywords\n\ndeep-seated mycosis\ndiagnostic test\nmalignant catatonia\npharmacology\npropofol\npulmonary aspergillosis\nquetiapine\nOPEN-ACCESSTRUE\n==== Body\n1 Introduction\n\nBoth neuroleptic malignant syndrome (NMS) and malignant catatonia (MC) are dyskinetic syndromes characterized by abnormalities such as high fever, muscle rigidity, and altered consciousness.[1] Cases of MC were reported before the development of antipsychotic drugs, and this type of catatonia can advance regardless of the administration of such drugs. In contrast, NMS differs in that it has always been associated with the administration of antipsychotic drugs. However, it is not uncommon for patients receiving antipsychotic drugs to develop MC, as has been reported previously.[2] Since they exhibit similar symptoms and there is no disease-specific test, it is extremely difficult to distinguish MC from NMS, and treatment is often difficult without a correct diagnosis.[3] In this report, we discuss the case of a patient who was initially diagnosed with refractory NMS complicated by deep Aspergillus infection, but in whom the diagnosis was subsequently corrected to MC due to the unexpected positive effect of propofol followed by quetiapine.\n\n2 Case presentation\n\nThe patient was an Asian woman in her 60s. She had a history of schizophrenia and cholelithiasis Fig. 1. She received brotizolam 0.25 mg/d, flunitrazepam 4 mg/d, quetiapine 600 mg/d, olanzapine 20 mg/d, powdered rhubarb (a type of Japanese herbal laxative) 9 g/d, magnesium oxide 9 g/d, rebamipide 300 mg/d, and bromazepam 15 mg/d. There was no change in the type or amount of drugs taken within the 6 months before her admission to our hospital. During the summer, she was transferred to a local hospital because she had a fever of 40°C and exhibited symptoms of malaise. She was hospitalized with a diagnosis of suspected urinary tract infection because she had a slightly elevated white blood cell count in her urine. Her blood test on the day after hospitalization revealed abnormalities in serum creatine kinase (154,000 IU/L) and serum creatinine (4.3 mg/dL). The attending physician diagnosed her with NMS and acute kidney injury, following which she was referred to our hospital for treatment.\n\nFigure 1 The time course from admission to discharge. CAFG = caspofungin, GM = galactomannan, ICU = intensive care unit, L-AMB = liposomal amphotericin B, MCFG = micafungin, VCZ = voriconazole.\n\nOn day 1, she was admitted to the intensive care unit (ICU). Her level of consciousness was Glasgow Coma Scale E3V4M6, and she was able to respond to simple commands. Strong rigidity was observed in the upper and lower limbs. Other vital signs were as follows: blood pressure, 130/84 mm Hg; heart rate, 92 bpm; respiratory rate, 15/min; percutaneous oxygen saturation: 100% (O2 administered at 5 L/min); and body temperature, 38.5°C (axillary temperature). She was diagnosed with NMS because she exhibited the major symptoms outlined in Levenson diagnostic criteria,[4] including hyperthermia, muscle rigidity, elevation of serum creatine kinase, as well as changes in the state of consciousness. Initially, we administered dantrolene (40 mg/d) and bromocriptine (7.5 mg/d). Given the presence of infiltrative shadows in both lungs on computed tomography (CT) (Fig. 2A), her poor general condition, and her consciousness disorder, we also performed endotracheal intubation and mechanical ventilation, intravenous rehydration, cooling, and continuous renal replacement therapy. Head and abdominal CT examinations did not reveal any findings related to the patient's symptoms.\n\nFigure 2 CT findings. (A) Lung CT on day 1. An infiltrative shadow due to pneumonia can be observed spreading to both lung fields. (B) Lung CT on day 84. An inflammatory ground glass opacity can be observed extending into the left lung field. CT = computed tomography.\n\nOn day 5, her blood tests and respiratory function improved, following which she was extubated and mechanical ventilation was terminated. On day 6, dantrolene was increased to 60 mg/d because her rigidity and hyperthermia had not improved. Treatment with diazepam (5 mg/d) and flunitrazepam (5 mg/d) was initiated for her prominent insomnia.\n\nOn day 13, she left the ICU because her renal function had improved, and she no longer needed blood purification. On day 14, she was diagnosed with pulmonary mycosis due to the infiltrative shadow observed on CT on day 1 (Fig. 2A) and an elevated β-D glucan level from her blood sampling on day 2. The delay in diagnosis occurred because the β-D glucan test in our hospital requires 1 to 2 weeks before results are available. We began to give her micafungin (MCFG) for the treatment of pulmonary mycosis.\n\nFrom day 16 to day 24, since her rigidity and hyperthermia had not improved, the doses of medications were increased as follows: MCFG to 150 mg/d, dantrolene to 100 mg/d, and bromocriptine to 17.5 mg/d. Amantadine (300 mg/d) and L-3,4-dihydroxyphenylalanine (L-DOPA) (25 mg/d) were also added.\n\nOn day 29, the patient's day 23 β-D glucan level had increased to 11.43 pg/mL, and her Aspergillus antigen test was also positive. She was thus diagnosed with a deep-seated Aspergillus infection. We considered MCFG to be ineffective and changed the antifungal drug to voriconazole (800 mg/d, lowered to 600 mg/d on the following day).\n\nOn day 34, she became restless due to extreme excitement and was unable to respond to directions. She was unable to communicate, shouted incomprehensibly, and refused to undergo medical treatment. She exhibited continuous movement in bed and could no longer rest. She would often stare diagonally upward with what appeared to be a startled expression on her face, although she did not make eye contact with the medical staff. Benzodiazepines were ineffective for her symptoms, and her respiratory status further worsened with decreased percutaneous oxygen saturation. We determined that she was in septic shock and delirium due to exacerbation of a deep-seated fungal infection. Consequently, we transferred her to the ICU and again performed tracheal intubation and mechanical ventilation. Intravenous administration of 100 mg of propofol for sedation during tracheal intubation immediately relieved her muscle rigidity, and she became able to comply with instructions. Before propofol administration, the patient's Bush-Francis Catatonia Rating Scale score[5] was 25 points (Table 1). Her diagnosis was revised from NMS to MC because she met the 4 criteria for the diagnosis of MC (severe catatonia symptoms, hyperthermia, hemodynamic instability, and increased muscle rigidity)[6,7] and because she did not respond to NMS treatment. Since dantrolene, bromocriptine, amantadine, and L-DOPA have side effects when the administration is stopped abruptly, we decided to discontinue administration after gradually decreasing the dose.\n\nTable 1 The patient's Bush-Francis Catatonia Rating Scale scores on day 34 (before propofol administration).\n\nExcitement\t+3\t\nImmobility/stupor\t0\t\nMutism\t0\t\nStaring\t+1\t\nPosturing/catalepsy\t0\t\nGrimacing\t+3\t\nEchopraxia/echolalia\t0\t\nStereotypy\t0\t\nMannerisms\t0\t\nVerbigeration\t+3\t\nRigidity\t+3\t\nNegativism\t+3\t\nWaxy flexibility\t0\t\nWithdrawal\t+3\t\nImpulsivity\t0\t\nAutomatic obedience\t0\t\nMitgehen\t0\t\nGegenhalten\t0\t\nAmbitendency\t0\t\nGrasp reflex\t0\t\nPerseveration\t+3\t\nCombativeness\t0\t\nAutonomic abnormality\t+3\t\n\nOn day 46, her β-D glucan results remained positive. We judged voriconazole to be ineffective and changed the antifungal drug to liposomal amphotericin B (L-AMB) (150 mg/d).\n\nOn day 86, we replaced L-AMB with caspofungin (70 mg/d) (50 mg/d from the following day) because her β-D glucan results remained positive despite prolonged administration of L-AMB. In addition, we observed a ground glass opacity in the left lung (Fig. 2B).\n\nOn day 91, we initiated treatment with quetiapine at 12.5 mg/d because propofol treatment alone did not result in amelioration of symptoms. Its effects had in fact diminished, and consent modified electroconvulsive therapy could not be obtained from the patient and her relatives. Administration of quetiapine did not cause exacerbation of hyperthermia or muscle rigidity.\n\nOn day 93, the β-D glucan level became negative. On day 95, the patient's consciousness was Glasgow Coma Scale E4V5M6. She was able to participate in a conversation through the use of a tracheostomy tube with a speaking valve. Her muscle rigidity had been nearly eliminated, and since we determined that the patient's MC was almost in remission, administration of propofol was terminated. On day 96, the β-D glucan remained negative, and her C-reactive protein level decreased. Thus, we concluded that the deep-seated aspergillosis had been cured, and administration of caspofungin was terminated.\n\nOn day 119, the patient's general condition and consciousness were stable. There were no abnormalities in consciousness or behavior reminiscent of excitement, stupor, or negativism. She was left with a walking disability and skilled finger movement disorder due to long-term bed rest and was transferred to another hospital for rehabilitation and treatment for schizophrenia.\n\n3 Discussion\n\nThe present report is the first to suggest an association between pulmonary aspergillosis and the development of MC. Recent studies have reported that MC develops in combination with various inflammatory diseases such as infections and autoimmune diseases.[8] Our patient was diagnosed with pulmonary aspergillosis based on a pulmonary CT image of pneumonia, elevated β-D glucan levels in her blood, and positive findings from an Aspergillus antigen test. As the duration of illness was nearly identical for her MC and deep-seated aspergillosis, we strongly suspect that these diseases were associated.\n\nIn our patient, we observed no inflammatory disease outside the lungs, including meningitis and sinusitis. She did not meet the diagnostic criteria outlined by the European Organization for Research and Treatment of Cancer Mycoses Study Group Criteria.[9] However, this is not uncommon in cases of invasive aspergillosis in patients with uncomplicated hematologic neoplastic disease.[9]\n\nAlthough samples (sputum, urine, blood) were collected several times, fungal culture tests were not successful in our patient, and failure to conduct antifungal susceptibility tests made the selection of the best antifungal drug difficult. However, enzyme-linked immunosorbent assays for the Aspergillus galactomannan (GM) antigen (enzyme-linked immunosorbent assay, PLATELIA ASPERGILLUS Ag) were strongly positive on days 23, 34, 49. In contrast, Candida antigen tests (latex agglutination reaction, CAND-TEC, LSI Medience, Tokyo, Japan) on these days were negative. Furthermore, polymerase chain reaction analyses for Pneumocystis jirovecii on day 37 (sputum) and day 38 (bronchoalveolar lavage fluid) were negative. Conditions that can lead to false-positive GM antigens include the use of some penicillins and the establishment of GM-producing microorganisms.[9]\n\nOur patient's β-D glucan level was measured using a β-glucan test (Waco Pure Chemical Industries, Osaka, Japan, cutoff value: 11 pg/mL). β-D glucan can increase due to the administration of drugs containing β-D glucan, renal replacement therapy using cellulose membranes, and sepsis caused by Alcaligenes faecalis.[10,11] However, none of these were observed in our patient.\n\nThe patient had no concomitant immunodeficiency diseases, including hematological malignancies, and no history of immunosuppressive drug use. This patient was not tested for human immunodeficiency virus (HIV), as there was no drop in lymphocyte count, and she had no history of repeated infections. Since the prevalence of HIV in Japan is low, and the patient had no history of sexual contact with an unspecified number of people, we concluded that it was extremely unlikely that the patient had HIV infection. However, her aspergillosis was refractory and required multiple antifungal drug changes. In recent years, the development of voriconazole resistance in Aspergillus has become a worldwide problem, and 1 multicenter study reported that approximately 20% of patients with pulmonary aspergillosis were infected with voriconazole-resistant strains.[12]\n\nPrevious studies have also reported that MCFG and L-AMB are only about 60% and 40% effective against Aspergillus species, respectively.[13,14] The Aspergillus strain in this case may have been such a strain with low drug sensitivity.\n\nIn addition to MC and NMS, delirium due to invasive Aspergillus infection represents a differential cause of psychiatric symptoms in our patient. However, this is unlikely because propofol administration, a risk factor for delirium,[15,16] greatly improved her psychiatric symptoms and involuntary movements (eg, muscle rigidity).\n\nAs in our case, patients with schizophrenia receiving antipsychotics often develop symptoms of catatonia. A common link in many of these cases is that determining correct treatment can be challenging due to the difficulty in distinguishing MC from NMS.[17,18] Recent studies have revealed that gamma-aminobutyric acid A (GABAA) receptor activity is decreased in the lateral orbital cortex of patients with catatonia, which is thought to be deeply involved in the mechanism of catatonia development. It is well known that the GABAA agonist benzodiazepine is highly effective against MC, but it does not work well against NMS.[19,20] We strongly suspected MC rather than NMS because the GABAA agonist propofol was very effective in this case, while dopamine agonists – which are used successfully against NMS – were ineffective. However, our patient did not respond to benzodiazepines, which may be because benzodiazepines are only 20% to 30% effective in patients with schizophrenic catatonia.[19]\n\nTwo studies have reported unintentional improvement of catatonia symptoms when propofol was used for sedation in patients with catatonia.[21,22] Hyperactivity of N-methyl-D-aspartate receptors is also considered among the causes leading to the development of MC.[8] Propofol not only acts as a GABAA receptor agonist but also expresses antagonistic action at N-methyl-D-aspartate receptors,[23] which may explain its significant effects in this case. Therefore, to aid in diagnosis and treatment, we propose that a propofol challenge test be performed in patients with catatonia symptoms who have not responded to NMS treatment and benzodiazepine administration.\n\nIn our case, remission was not achieved using propofol alone. Addition of quetiapine finally eliminated the catatonia symptoms. One study has suggested that, although catatonia is more likely to occur in patients with schizophrenia, it is a different condition than schizophrenia itself, in which antipsychotics are ineffective.[24] Certainly, first-generation antipsychotics are not recommended for use in patients with catatonia due to the high risk of developing NMS.[3,4] However, several reports have indicated that second-generation antipsychotics such as quetiapine can be successful.[20,25]\n\nQuetiapine acts as GABAA receptor agonist. In our case, we considered the GABAA agonistic effect of quetiapine to be associated with remission of MC. Separately, the remission of MC coincided with the resolution of refractory deep-seated aspergillosis. It is possible that recovery from the inflammatory condition further facilitated the remission of MC.\n\nIn summary, the present case is the first to show that various inflammatory diseases are involved in the development of MC, and that deep-seated aspergillosis is among them. Our findings suggest that, when a patient with schizophrenia treated with an antipsychotic drug or benzodiazepine develops MC, the GABAA agonist propofol can aid in diagnosis and treatment.\n\nAcknowledgments\n\nThe authors would like to express their sincere appreciation and gratitude to the nurses for their dedicated care of this patient.\n\nAuthor contributions\n\nConceptualization: Kazuhito Nomura.\n\nData curation: Kazuhito Nomura, Sonoko Sakawaki.\n\nInvestigation: Kazuhito Nomura, Sonoko Sakawaki.\n\nSupervision: Sonoko Sakawaki, Eiji Sakawaki, Ayumu Yamaoka, Wakiko Aisaka, Hiroyuki Okamoto, Yoshihiro Takeyama, Shuji Uemura, Eichi Narimatsu.\n\nWriting – original draft: Kazuhito Nomura.\n\nAbbreviations: CT = computed tomography, GABAA = gamma-aminobutyric acid A, GM = galactomannan, ICU = intensive care unit, L-AMB = liposomal amphotericin B, MC = malignant catatonia, MCFG = micafungin, NMS = neuroleptic malignant syndrome.\n\nHow to cite this article: Nomura K, Sakawaki S, Sakawaki E, Yamaoka A, Aisaka W, Okamoto H, Takeyama Y, Uemura S, Narimatsu E. Successful diagnosis and treatment of pulmonary aspergillosis-related malignant catatonia using propofol and quetiapine: a case report. Medicine. 2021;100:19(e25967).\n\nThe authors explained the case report submission and publication process to the patient herself and received verbal permission. However, since she had difficulty writing due to disuse syndrome, written consent could not be obtained. The patient is already deceased and has no relatives with the ability to make surrogate decisions. The patient's information has been completely anonymized. The Hakodate Municipal Hospital institutional review board (Takahiro Sato, Yoshiya Yamamoto, Hirohito Naruse, Kazuaki Nakanishi, Yoshihito Ujike, and Kiyofumi Morishita) has determined that the submission and publication of this article is appropriate.\n\nThe authors have no conflicts of interest to disclose.\n\nThe datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.\n==== Refs\nReferences\n\n[1] Johnson RA . NMS, and why we should call it (malignant) catatonia. J J P 2006;20 : Article 1.\n[2] Chiou YJ Lee Y Lin CC Huang TL . A case report of catatonia and neuroleptic malignant syndrome with multiple treatment modalities: short communication and literature review. Medicine 2015;94 :e1752.26512569\n[3] Caroff SN Mann SC Keck PE . Specific treatment of the neuroleptic malignant syndrome. Biol Psychiatry 1998;44 :378–81.9777166\n[4] Levenson JL . Neuroleptic malignant syndrome. Am J Psychiatry 1985;142 :1137–45.2863986\n[5] Bush G Fink M Petrides G Dowling F Francis A . Catatonia. I. Rating scale and standardized examination. Acta Psychiatr Scand 1996;93 :129–36.8686483\n[6] Häfner H Kasper S . Acute life-threatening catatonia. Nervenarzt 1982;53 :385–94.6126826\n[7] Philbrick KL Rummans TA . Malignant catatonia. J Neuropsychiatry Clin Neurosci 1994;6 :1–3.7908547\n[8] Rogers JP Pollak TA Blackman G David AS . Catatonia and the immune system: a review. Lancet Psychiatry 2019;6 :620–30.31196793\n[9] De Pauw B Walsh TJ Donnelly JP . Revised definitions of invasive fungal disease from the European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group (EORTC/MSG) consensus group. Clin Infect Dis 2008;46 :1813–21.18462102\n[10] Verweij PE Mennink-Kersten MASH . Issues with galactomannan testing. Med Mycol 2006;44 :S179–83.30408901\n[11] Wright WF Overman SB Ribes JA . (1-3)-β-D-glucan assay: a review of its laboratory and clinical application. Lab Med 2011;42 :679–85.\n[12] Lestrade PP Bentvelsen RG Schauwvlieghe AFAD . Voriconazole resistance and mortality in invasive aspergillosis: a multicenter retrospective cohort study. Clin Infect Dis 2019;68 :1463–71.30307492\n[13] Kohno S Masaoka T Yamaguchi H . A multicenter, open-label clinical study of micafungin (FK463) in the treatment of deep-seated mycosis in Japan. Scand J Infect Dis 2004;36 :372–9.15287383\n[14] Walsh TJ Hiemenz JW Seibel NL . Amphotericin B lipid complex for invasive fungal infections: analysis of safety and efficacy in 556 cases. Clin Infect Dis 1998;26 :1383–96.9636868\n[15] Pandharipande P Cotton BA Shintani A . Prevalence and risk factors for development of delirium in surgical and trauma ICU patients. J Trauma 2008;65 :34–41.18580517\n[16] Pandharipande PP Pun BT Herr DL . Effect of sedation with dexmedetomidine vs lorazepam on acute brain dysfunction in mechanically ventilated patients: the MENDS randomized controlled trial. JAMA 2007;298 :2644–53.18073360\n[17] Komatsu T Nomura T Takami H . Catatonic symptoms appearing before autonomic symptoms help distinguish neuroleptic malignant syndrome from malignant catatonia. Intern Med 2016;55 :2893–7.27725556\n[18] Fukai M Hirosawa T Takahashi T Kaneda R Kikuchi M Minabe Y . Clonazepam improves dopamine supersensitivity in a schizophrenia patient: a case report. Ther Adv Psychopharmacol 2017;7 :113–7.28348731\n[19] Rosebush PI Mazurek MF . Caroff SN Mann SC Francis A Fricchione G . Pharmacotherapy. Catatonia: From Psychopathology to Neurobiology. Washington DC: American Psychiatric Publishing; 2004. 141–50.\n[20] Pelzer AC van der Heijden FM den Boer E . Systematic review of catatonia treatment. Neuropsychiatr Dis Treat 2018;14 :317–26.29398916\n[21] Alfson ED Awosika OO Singhal T Fricchione GL . Lysis of catatonic withdrawal by propofol in a bone-marrow transplant recipient with adenovirus limbic encephalitis. Psychosomatics 2013;54 :192–5.22705183\n[22] Heekin RD Bradshaw K Calarge CA . First known case of catatonia due to cyclosporine A-related neurotoxicity in a pediatric patient with steroid-resistant nephrotic syndrome. BMC Psychiatry 2019;19 :123.31014303\n[23] Orser BA Bertlik M Wang LY MacDonald JF . Inhibition by propofol (2,6 di-isopropylphenol) of the N-methyl-D-aspartate subtype of glutamate receptor in cultured hippocampal neurones. Br J Pharmacol 1995;116 :1761–8.8528557\n[24] Ohi K Kuwata A Shimada T . Response to benzodiazepines and the clinical course in malignant catatonia associated with schizophrenia: a case report. Medicine 2017;96 :e6566.28422845\n[25] Yoshimura B Hirota T Takaki M Kishi Y . Is quetiapine suitable for treatment of acute schizophrenia with catatonic stupor?. A case series of 39 patients. Neuropsychiatr Dis Treat 2013;9 :1565–71.24143105\n\n",
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"mesh_terms": "D002389:Catatonia; D003937:Diagnosis, Differential; D005260:Female; D006801:Humans; D006993:Hypnotics and Sedatives; D008875:Middle Aged; D009459:Neuroleptic Malignant Syndrome; D015742:Propofol; D055732:Pulmonary Aspergillosis; D000069348:Quetiapine Fumarate; D051437:Renal Insufficiency; D012559:Schizophrenia",
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"title": "Successful diagnosis and treatment of pulmonary aspergillosis-related malignant catatonia using propofol and quetiapine: A case report.",
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{
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"primarysource": {
"literaturereference": "Nomura K, Sakawaki S, Sakawaki E, Yamaoka A, Aisaka W, Okamoto H, et al. Successful diagnosis and treatment of pulmonary aspergillosis-related malignant catatonia using propofol and quetiapine: A case report. Medicine. 2021;100(19):1-5",
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"abstract": "BACKGROUND\nWe know very little about the genetic factors affecting susceptibility to drug-induced central nervous system (CNS) toxicities, and this has limited our ability to optimally utilize existing drugs or to develop new drugs for CNS disorders. For example, haloperidol is a potent dopamine antagonist that is used to treat psychotic disorders, but 50% of treated patients develop characteristic extrapyramidal symptoms caused by haloperidol-induced toxicity (HIT), which limits its clinical utility. We do not have any information about the genetic factors affecting this drug-induced toxicity. HIT in humans is directly mirrored in a murine genetic model, where inbred mouse strains are differentially susceptible to HIT. Therefore, we genetically analyzed this murine model and performed a translational human genetic association study.\n\n\nRESULTS\nA whole genome SNP database and computational genetic mapping were used to analyze the murine genetic model of HIT. Guided by the mouse genetic analysis, we demonstrate that genetic variation within an ABC-drug efflux transporter (Abcb5) affected susceptibility to HIT. In situ hybridization results reveal that Abcb5 is expressed in brain capillaries, and by cerebellar Purkinje cells. We also analyzed chromosome substitution strains, imaged haloperidol abundance in brain tissue sections and directly measured haloperidol (and its metabolite) levels in brain, and characterized Abcb5 knockout mice. Our results demonstrate that Abcb5 is part of the blood-brain barrier; it affects susceptibility to HIT by altering the brain concentration of haloperidol. Moreover, a genetic association study in a haloperidol-treated human cohort indicates that human ABCB5 alleles had a time-dependent effect on susceptibility to individual and combined measures of HIT. Abcb5 alleles are pharmacogenetic factors that affect susceptibility to HIT, but it is likely that additional pharmacogenetic susceptibility factors will be discovered.\n\n\nCONCLUSIONS\nABCB5 alleles alter susceptibility to HIT in mouse and humans. This discovery leads to a new model that (at least in part) explains inter-individual differences in susceptibility to a drug-induced CNS toxicity.",
"affiliations": "Department of Anesthesia, Stanford University School of Medicine, Stanford, California, United States of America.;Department of Anesthesia, Stanford University School of Medicine, Stanford, California, United States of America.;Computer Science, Stanford University, Stanford, California, United States of America.;Veterans Affairs Palo Alto Health Care System, Palo Alto, California, United States of America.;Computer Science, Stanford University, Stanford, California, United States of America.;Department of Genetics, Stanford University School of Medicine, Stanford, California, United States of America.;Department of Genetics, Stanford University School of Medicine, Stanford, California, United States of America.;Department of Genetics, Stanford University School of Medicine, Stanford, California, United States of America.;Department of Psychiatry, University Of Halle, Halle, Germany.;Department of Anesthesia, Stanford University School of Medicine, Stanford, California, United States of America.;Center for Cancer Research, National Cancer Institute, Frederick, Maryland, United States of America.;Laboratory of Cell Biology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America.;Laboratory of Cell Biology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America.;Department of Pathology, Stanford University, Stanford, California, United States of America.;Department of Chemistry, Stanford University, Stanford, California, United States of America.;Department of Chemistry, Stanford University, Stanford, California, United States of America.;Laboratory of Molecular Cancer Biology, Molecular Physiology Research Unit (URPhyM), Namur Research Institute for Life Sciences (NARILIS), Faculty of Medicine, University of Namur, Belgium.;Laboratory of Molecular Cancer Biology, Molecular Physiology Research Unit (URPhyM), Namur Research Institute for Life Sciences (NARILIS), Faculty of Medicine, University of Namur, Belgium.;Department of Genetics, Stanford University School of Medicine, Stanford, California, United States of America.;Department of Anesthesia, Stanford University School of Medicine, Stanford, California, United States of America.",
"authors": "Zheng|Ming|M|;Zhang|Haili|H|;Dill|David L|DL|;Clark|J David|JD|;Tu|Susan|S|;Yablonovitch|Arielle L|AL|;Tan|Meng How|MH|;Zhang|Rui|R|;Rujescu|Dan|D|;Wu|Manhong|M|;Tessarollo|Lino|L|;Vieira|Wilfred|W|;Gottesman|Michael M|MM|;Deng|Suhua|S|;Eberlin|Livia S|LS|;Zare|Richard N|RN|;Billard|Jean-Martin|JM|;Gillet|Jean-Pierre|JP|;Li|Jin Billy|JB|;Peltz|Gary|G|",
"chemical_list": "C480744:ABCB5 protein, human; C573563:ABCB5 protein, mouse; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D018528:ATP-Binding Cassette Transporters; D014150:Antipsychotic Agents; D006220:Haloperidol",
"country": "United States",
"delete": false,
"doi": "10.1371/journal.pmed.1001782",
"fulltext": "\n==== Front\nPLoS MedPLoS MedplosplosmedPLoS Medicine1549-12771549-1676Public Library of Science San Francisco, CA USA 2564761210.1371/journal.pmed.1001782PMEDICINE-D-13-02788Research ArticleThe Role of Abcb5 Alleles in Susceptibility to Haloperidol-Induced Toxicity in Mice and Humans Abcb5 Alleles and Haloperidol-Induced ToxicityZheng Ming \n1\n\n‡\nZhang Haili \n1\n\n‡\nDill David L. \n2\nClark J. David \n3\nTu Susan \n2\nYablonovitch Arielle L. \n4\nTan Meng How \n4\nZhang Rui \n4\nRujescu Dan \n5\nWu Manhong \n1\nTessarollo Lino \n6\nVieira Wilfred \n7\nGottesman Michael M. \n7\nDeng Suhua \n8\nEberlin Livia S. \n9\nZare Richard N. \n9\nBillard Jean-Martin \n10\nGillet Jean-Pierre \n10\nLi Jin Billy \n4\n*Peltz Gary \n1\n*\n1 \nDepartment of Anesthesia, Stanford University School of Medicine, Stanford, California, United States of America\n\n2 \nComputer Science, Stanford University, Stanford, California, United States of America\n\n3 \nVeterans Affairs Palo Alto Health Care System, Palo Alto, California, United States of America\n\n4 \nDepartment of Genetics, Stanford University School of Medicine, Stanford, California, United States of America\n\n5 \nDepartment of Psychiatry, University Of Halle, Halle, Germany\n\n6 \nCenter for Cancer Research, National Cancer Institute, Frederick, Maryland, United States of America\n\n7 \nLaboratory of Cell Biology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America\n\n8 \nDepartment of Pathology, Stanford University, Stanford, California, United States of America\n\n9 \nDepartment of Chemistry, Stanford University, Stanford, California, United States of America\n\n10 \nLaboratory of Molecular Cancer Biology, Molecular Physiology Research Unit (URPhyM), Namur Research Institute for Life Sciences (NARILIS), Faculty of Medicine, University of Namur, Belgium\nPirmohamed Munir Academic Editor\nUniversity of Liverpool, UNITED KINGDOM\nThe authors have declared that no competing interests exist.\n\nConceived and designed the experiments: GP HZ MMG JPG. Performed the experiments: HZ DLD ALY MHT RZ MW LT WV SD LSE RNZ JMB JPG JBL. Analyzed the data: MZ JDC ST DR MG RNZ. Contributed reagents/materials/analysis tools: JBL JPG. Wrote the paper: GP HZ LSE. Enrolled patients: DR. ICMJE criteria for authorship read and met: MZ HZ DLD JDC ST ALY MHT RZ DR MW LT WV MMG SD LSE JMB JPG JBL RNZ GP. Agree with manuscript results and conclusions: MZ HZ DLD JDC ST ALY MHT RZ DR MW LT WV MMG SD LSE RNZ JMB JPG JBL GP.\n\n‡ These authors contributed equally to this work.\n\n* E-mail: gpeltz@stanford.edu (GP); jin.billy.li@stanford.edu (JBL)3 2 2015 2 2015 12 2 e100178229 8 2013 17 12 2014 © 2015 Zheng et al2015Zheng et alThis is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.Background\nWe know very little about the genetic factors affecting susceptibility to drug-induced central nervous system (CNS) toxicities, and this has limited our ability to optimally utilize existing drugs or to develop new drugs for CNS disorders. For example, haloperidol is a potent dopamine antagonist that is used to treat psychotic disorders, but 50% of treated patients develop characteristic extrapyramidal symptoms caused by haloperidol-induced toxicity (HIT), which limits its clinical utility. We do not have any information about the genetic factors affecting this drug-induced toxicity. HIT in humans is directly mirrored in a murine genetic model, where inbred mouse strains are differentially susceptible to HIT. Therefore, we genetically analyzed this murine model and performed a translational human genetic association study.\n\nMethods and Findings\nA whole genome SNP database and computational genetic mapping were used to analyze the murine genetic model of HIT. Guided by the mouse genetic analysis, we demonstrate that genetic variation within an ABC-drug efflux transporter (Abcb5) affected susceptibility to HIT. In situ hybridization results reveal that Abcb5 is expressed in brain capillaries, and by cerebellar Purkinje cells. We also analyzed chromosome substitution strains, imaged haloperidol abundance in brain tissue sections and directly measured haloperidol (and its metabolite) levels in brain, and characterized Abcb5 knockout mice. Our results demonstrate that Abcb5 is part of the blood-brain barrier; it affects susceptibility to HIT by altering the brain concentration of haloperidol. Moreover, a genetic association study in a haloperidol-treated human cohort indicates that human ABCB5 alleles had a time-dependent effect on susceptibility to individual and combined measures of HIT. Abcb5 alleles are pharmacogenetic factors that affect susceptibility to HIT, but it is likely that additional pharmacogenetic susceptibility factors will be discovered.\n\nConclusions\n\nABCB5 alleles alter susceptibility to HIT in mouse and humans. This discovery leads to a new model that (at least in part) explains inter-individual differences in susceptibility to a drug-induced CNS toxicity.\n\nGary Peltz and colleagues examine the role of ABCB5 alleles in haloperidol-induced toxicity in a murine genetic model and humans treated with haloperidol.\n\nEditors' Summary\nBackground\nThe brain is the control center of the human body. This complex organ controls thoughts, memory, speech, and movement, it is the seat of intelligence, and it regulates the function of many organs. The brain comprises many different parts, all of which work together but all of which have their own special functions. For example, the forebrain is involved in intellectual activities such as thinking whereas the hindbrain controls the body’s vital functions and movements. Messages are passed between the various regions of the brain and to other parts of the body by specialized cells called neurons, which release and receive signal molecules known as neurotransmitters. Like all the organs in the body, blood vessels supply the brain with the oxygen, water, and nutrients it needs to function. Importantly, however, the brain is protected from infectious agents and other potentially dangerous substances circulating in the blood by the “blood-brain barrier,” a highly selective permeability barrier that is formed by the cells lining the fine blood vessels (capillaries) within the brain.\n\nWhy Was This Study Done?\nAlthough drugs have been developed to treat various brain disorders, more active and less toxic drugs are needed to improve the treatment of many if not most of these conditions. Unfortunately, relatively little is known about how the blood-brain barrier regulates the entry of drugs into the brain or about the genetic factors that affect the brain’s susceptibility to drug-induced toxicities. It is not known, for example, why about half of patients given haloperidol—a drug used to treat psychotic disorders (conditions that affect how people think, feel, or behave)—develop tremors and other symptoms caused by alterations in the brain region that controls voluntary movements. Here, to improve our understanding of how drugs enter the brain and impact its function, the researchers investigate the genetic factors that affect haloperidol-induced toxicity by genetically analyzing several inbred mouse strains (every individual in an inbred mouse strain is genetically identical) with different susceptibilities to haloperidol-induced toxicity and by undertaking a human genetic association study (a study that looks for non-chance associations between specific traits and genetic variants).\n\nWhat Did the Researchers Do and Find?\nThe researchers used a database of genetic variants called single nucleotide polymorphisms (SNPs) and a computational genetic mapping approach to show first that variations within the gene encoding Abcb5 affected susceptibility to haloperidol-induced toxicity (indicated by changes in the length of time taken by mice to move their paws when placed on an inclined wire-mesh screen) among inbred mouse strains. Abcb5 is an ATP-binding cassette transporter, a type of protein that moves molecules across cell membranes. The researchers next showed that Abcb5 is expressed in brain capillaries, which is the location of the blood-brain barrier. Abcb5 was also expressed in cerebellar Purkinje cells, which help to control motor (intentional) movements. They also measured the measured the effect of haloperidol and the haloperidol concentration in brain tissue sections in mice that were genetically engineered to make no Abcb5 (Abcb5 knockout mice). Finally, the researchers investigated whether specific alleles (alternative versions) of ABCB5 are associated with haloperidol-induced toxicity in people. Among a group of 85 patients treated with haloperidol for a psychotic illness, one specific ABCB5 allele was associated with haloperidol-induced toxicity during the first few days of treatment.\n\nWhat Do These Findings Mean?\nThese findings indicate that Abcb5 is a component of the blood-brain barrier in mice and suggest that genetic variants in the gene encoding this protein underlie, at least in part, the differences in susceptibility to haloperidol-induced toxicity seen among inbred mice strains. Moreover, the human genetic association study indicates that a specific ABCB5 allele also affects the susceptibility of people to haloperidol-induced toxicity. The researchers note that other ABCB5 alleles or other genetic factors that affect haloperidol-induced toxicity in people might emerge if larger groups of patients were studied. However, based on their findings, the researchers propose a new model for the genetic mechanisms that underlie inter-individual and cell type-specific differences in susceptibility to haloperidol-induced brain toxicity. If confirmed in future studies, this model might facilitate the development of more effective and less toxic drugs to treat a range of brain disorders.\n\nAdditional Information\nPlease access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001782.\n\nThe US National Institute of Neurological Disorders and Stroke provides information about a wide range of brain diseases (in English and Spanish); its fact sheet “Brain Basics: Know Your Brain” is a simple introduction to the human brain; its “Blueprint Neurotherapeutics Network” was established to develop new drugs for disorders affecting the brain and other parts of the nervous system\n\nMedlinePlus provides links to additional resources about brain diseases and their treatment (in English and Spanish)\n\nWikipedia provides information about haloperidol, about ATP-binding cassette transporters and about genetic association (note that Wikipedia is a free online encyclopedia that anyone can edit; available in several languages)\n\nGP and MZ were partially supported by funding from a transformative RO1 award (1R01DK090992-01) DLD was supported by a King Abdullah University of Science and Technology (KAUST) research grant under the KAUST Stanford Academic Excellence Alliance program. ST was supported by Stanford’s CURIS program for summer research interns. LSE was supported by a postdoctoral fellowship from the Center for Molecular Analysis and Design (CMAD). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.\n==== Body\nIntroduction\nRelatively little is known about the mechanisms regulating the entry of many drugs into the brain, or about the genetic mechanisms affecting susceptibility to many drug-induced central nervous system (CNS) toxicities. Because of this lack of information, candidate drugs affecting the CNS have the lowest rate of survival during clinical development (<2%), and drug distribution across the blood-brain barrier has been identified as a contributing cause for drug candidate failure [1]. The blood-brain barrier is a very complex multicellular vascular structure, which separates the brain from the peripheral blood by actively controlling the entry and efflux of drugs [2]. Therefore, the mechanistic insight obtained by identification of genetic factors affecting a drug-induced CNS toxicity could aid in the development of new medicines and could improve our ability to optimally utilize existing treatments. For example, haloperidol is a potent dopamine receptor antagonist that is used to treat psychotic disorders [3]. However, haloperidol-induced alterations in the extrapyramidal motor system depress the ability to initiate voluntary movements. This effect triggers the characteristic extrapyramidal symptoms (EPS) that develop in 40%–76% of chronically treated human patients, which include tremors, Parkinsonian rigidity, and decreased spontaneous movement [4,5]. The same symptoms appear in some (but not all) of the 27 inbred strains that were treated with haloperidol [6]. In this murine genetic model, the time required (latency) for a mouse to move all four paws after being placed on an inclined wire-mesh screen was measured as an index of the haloperidol-induced Parkinsonian rigidity that is observed in haloperidol-treated human patients. Although all strains had plasma drug levels that were similar to those measured in human patients, the extent of the haloperidol-induced toxicity (HIT) varied in a highly (85%) heritable manner [6] among the inbred strains.\n\nBecause no pharmacogenetic factors for HIT have previously been identified in humans or mice, we wanted to analyze this murine genetic model of HIT. Of concern, mouse genetic studies have, overall, produced rather disappointing results; they have definitively identified <1% of the genes affecting the studied traits [7]. Beyond the well described problems associated with murine linkage studies [8], several analyses have predicted that the conventional methods used to analyze genome wide association studies (GWAS) using inbred mouse strains will produce even more disappointing results, owing to their low power and a high false positive rate [7,9,10]. However, the availability of next generation sequence (NGS) data, which can provide complete genome-wide variant information for an expanded number of inbred strains [11], could enable murine GWAS to identify causative genetic factors for many biomedical traits [12]. The detailed genetic variation information obtained using NGS has increased power for pinpointing underlying causal variants relative to studies using SNP array data [13]. Unlike the conventional murine GWAS methods, haplotype-based computational genetic mapping (HBCGM) [14] has provided an alternative method for analysis of murine GWAS data that has identified causative genetic factors for many biomedical traits (reviewed in [12]). HBCGM first organizes the allelic information into haplotype blocks, which facilitates the identification of the causative genetic factors through correlation of the phenotypic data with the haplotype-based pattern of genetic variation. Since our prior studies analyzed much less complex datasets, which had fewer SNPs and haplotype blocks, we did not know if HBCGM could analyze the far more complex datasets produced using NGS data. To determine if HBCGM could be successfully combined with an SNP database generated from whole genome sequence data, we analyzed a murine genetic model of HIT in order to identify causative genetic factors. A translational human genetic association study was then performed to determine if similar genetic factors affected human susceptibility to HIT.\n\nMethods\nNext-Generation Sequencing of the Genome of Nine Inbred Mouse Strains\nGenomic DNA was obtained from the Jackson Laboratory (http://www.jax.org). A total of 3 μg of DNA from each of nine inbred mouse strains was sonicated using a Covaris instrument with the following settings: duty cycle, 10%; intensity, 4; cycles per burst, 200; and time, 60 seconds. After end repair of the DNA fragments and addition of “A” base to the 3′ ends, standard Illumina genomic DNA sequencing adaptors were ligated. The samples were run on a 3% agarose gel, gel slices between 300–500 bp were excised, and the DNA was purified with a Qiagen column. The DNA was divided into three aliquots of equal quantity, and amplified separately using one of the following three DNA polymerases: Phusion HF (Finnzymes), Kapa HiFi (Kapa Biosystems), and Herculase (Agilent). For analysis of the SJL strain, Phusion GC (Finnzymes) was also used to amplify a separate aliquot. The PCR conditions for amplification were as follows: 98°C for 3 minutes, followed by nine cycles of 98°C for 20 seconds, 62°C for 30 seconds, and 72°C for 45 seconds, and then a final 72°C for 5 minutes. The amplified products were separated on an agarose gel, slices between 400 and 600 bp were excised, and the DNA was eluted from the gel slices and sequenced on an Illumina HiSeq 2000 instrument.\n\nSequence Analysis and Variant Calling\nThe quality statistics for the allele calls at each position were evaluated using the FASTX-Toolkit (http://hannonlab.cshl.edu/fastx_toolkit/). A rapid decay in sequence quality was observed toward the end of each read, usually within the last 10 (or sometimes 20) bps. To avoid artifacts caused by low quality sequence data, the last 10 or 20 bps of each read were trimmed, based upon a visual inspection of the quality statistics plot for the reads in each lane. The extent of trimming was designed to ensure that the quality scores should be ≥30 in the 1st quartile and ≥20 in the 5th percentile. All sequences were trimmed by 10 bps; with the exceptions being one of the three lanes for the MA/MyJ and MRL, and two of the three SM/J lanes. Since a much larger number of sequences were obtained for SJL, SJL sequences were trimmed by 20 bps to ensure the overall quality of the base calls. The read sequences were then aligned to the reference C57BL/6J mouse genome sequence (MGSCv37 assembly) using BWA [15]. Optical and PCR duplicates were then marked using the Picard tool (http://picard.sourceforge.net/). The sequence variants (SNPs and INDELs) for each strain were identified using Samtools [16], and the default settings were applied. The raw sequence data for the 17 inbred mouse strains described in [11] were obtained from the European Nucleotide Archive (http://www.ebi.ac.uk/ena/), and the same data processing procedures were applied, but these sequences were not trimmed.\n\nTo ensure high quality variant calls, the variants were further filtered using two additional criteria. (i) To ensure a high level of confidence in the existence of the variant, we require the QUAL score, which represents the (Phred-scaled) probability that all observed samples are homozygous reference alleles, should be ≥50. (ii) To ensure a high level of confidence that the variant allele is indeed homozygous, the genotype call (the “GT” value) must be a homozygous alternative call, and that the Phred-scaled genotype likelihood (the “PL” value) for the homozygous alternative call is at least 20 units above that of any other PL value. If the variant allele call for a strain does not meet these criteria, the call is converted to an “N” (undetermined) instead of being disregarded, which ensures that we don’t mistakenly assume that it is the reference allele. Information about the fold-coverage and other aspects of the sequencing methods are provided in S1 Text.\n\nHaplotype Block Construction and Genetic Mapping in Mice\nHBCGM utilizes bi-allelic SNPs that are polymorphic among the strains. Only bi-allelic SNPs with at least one definitive homozygous alternative call among the 23 strains were included, while all other variants (including INDELs) were marked and excluded from HBCGM analysis. The locations and potential codon-changes caused by the SNPs are then annotated relative to the encoded genes using predictive gene models from Ensembl version 65. Only SNPs meeting the following criteria were used for haplotype block construction: (i) polymorphic among the strains with input trait data; and (ii) there were at least eight strains (or one-half of the number of input strains) with unambiguous allele calls. Haplotype blocks with 2, 3, 4, or haplotypes were then dynamically produced as described in [17], and the correlation between the input phenotypic data and the haplotype pattern within each identified block was evaluated as described [14]. The genes are then sorted based upon the ANOVA p-value (in increasing order) for numeric data or by the F statistic (in decreasing order) for categorical data. For a gene that is covered by multiple blocks, the smallest p-value (or the largest F statistic) obtained for all blocks within that gene was used.\n\nThe genetic effect size is calculated using our previously described method [18]:\nGenetic effect size = (SSB − (k − 1) * MSE)/(SStotal + MSE),\nwhere SSB is the between-group sum-of-squares of the ANOVA model, SStotal is the total sum-of-squares, k is the number of groups, and MSE is within-group sum-of-squares divided by (n − k), where n is the total number of objects in the model. Given the very large number of haplotype blocks produced by the HBCGM method, all results were automatically filtered according to pre-determined criteria using software that selected the correlated genes that were expressed in a designated target organ and had missense SNPs.\n\nRobustness Assessment\nTo assess the robustness of the HBCGM output obtained using the data obtained from different sets of input strains, we developed software that would automatically perform a re-sampling analysis. For each iteration, a number (1, 2, or 3) was randomly selected to indicate the number of strains whose data would be randomly excluded from the 17 strains with available latency data. Next, the selected number of strains (and each of the individual strains to be deleted were also randomly selected) was excluded for this iteration. Then, HBCGM were run on this re-sampled data and the result was recorded (using p = 0.01 as the cutoff). This process was repeated 100 times. If a re-sampled strain panel was identical to one that had already been re-sampled, this iteration was disregarded, and another subset was randomly chosen using the same procedure. To measure the overall association of a gene with the phenotype among the 100 random re-sampled sets of output, we defined a robustness score based on the p-values obtained, which was calculated as: Score=∑i=1100-log10(pi), where p\ni was the resulting p-value for that gene in the ith re-sampled experiment (if the p-value was bigger than the cutoff and therefore censored in the result, p\ni was set to 0.01, i.e., the cutoff). Genes with a larger robustness index have stronger overall correlation among the different subsets analyzed. Their calculated scores then were used to rank the genes, and those with the highest scores were output.\n\nStatistical Analysis of Haloperidol Latency Data in Mice\nThe haloperidol-induced latency data measured on days 0, 3, 7, 30, 60, and 120 (MPD datasets: 39407, 39408, 39409, 39410, 39411, and 39445, respectively) and the plasma haloperidol concentrations measured on days 30, 60, 90, and 120 (MPD numbers: 39403–39406, respectively) were obtained from the Mouse PHENOME Database (http://phenome.jax.org/). The correlation analyses were performed using the phenotypic data for all 27 strains that were evaluated. The non-parametric Spearman’s correlation coefficient (rho) was calculated [19], and the statistical significance of the correlation between the tested datasets was evaluated using this result. This non-parametric test was used to avoid producing spurious results that could be caused by the non-normal distribution of the data and by the presence of extreme outlying values. The p-values were then adjusted for multiple testing using the Benjamin-Hochberg method [20]. To minimize the effect produced by the strain with an extreme outlying value and to better visualize the relationship of the variables, the haloperidol-induced latency data from day 7 and day 30 were log-transformed (10-based). (It should be noted that the log-transformation has no effect on the Spearman’s rho, nor did it affect the corresponding test result.)\n\nHaloperidol Toxicity Measurements\nAll animal experiments were performed according to protocols approved by the Stanford Institutional Animal Care and Use Committee. All mice were obtained from Jackson Labs, and were used at 10–12 weeks of age, and the results are reported according to the ARRIVE guidelines (S1 Text) [21]. Haloperidol was administered to the mice by one of two methods: (i) a haloperidol pellet (Innovative Research of America) was subcutaneously implanted, which continuously released a dosage equivalent to 3 mg/kg/day, using published methods [22]; or (ii) with 10 mg/kg haloperidol (Sigma) IP qd for measurement of drug and metabolite concentrations. The haloperidol-induced latency was measured as the time required for a mouse to move all four paws after being placed on a vertical metal mesh screen as previously described [22].\n\nHaloperidol Quantitation\nHaloperidol was purchased from Sigma-Aldrich; haloperidol-d4 was purchased from Toronto Research Chemicals Inc.; HPLC grade acetonitrile and water were from Honeywell Burdick and Jackson International Inc.; and formic acid was purchased from Pierce Thermo Scientific.\n\nMouse brain tissues of known weight were homogenized in methanol using a Precelly 24 (Bertin Technologies) homogenizer. 50 μl of homogenate was aliquoted, and haloperidol-d4 was added as internal standard to a final concentration of 100 ng/ml. After the mixture was incubated with three volumes of cold acetonitrile at −20°, it was centrifuged at 14,000 rpm for 10 minutes. The supernatant was dried in a speed vacuum and re-suspended in the original volume. A standard curve was prepared using brain homogenate from an untreated mouse in a linear range from 0.5 ng/ml to 250 ng/ml. Quantitative analysis of haloperidol and its metabolite (HPP+) was performed on an Agilent accurate mass QTOF 6520A coupled with an UHPLC Infinity 1290. The analytes were separated on a Phenomenex Kinetex XB-C18 column 2.1 × 100 mm. The flow rate was 0.5 ml/min with a gradient of solvent B (acetonitrile with 0.1% formic acid; solvent A is 0.1% formic acid) from 5% to 35% in 10 minutes, then 35% to 95% in 5 minutes. Positive electrospray full scan in the range of m/z 110–1,000 spectra were collected. Data analysis was done using Agilent quantitative analysis software.\n\nDesorption Electrospray Ionization Mass Spectrometroscopic Imaging\nHigh mass resolution/high mass accuracy mass spectrometry tissue imaging was performed using a lab-built desorption electrospray ionization mass spectrometry imaging (DESI-MSI) source coupled to an LTQ-Orbitrap XL mass spectrometer (Thermo Scientific). DESI-MSI was performed in the positive ion mode from m/z 200–500, using the orbitrap as the mass analyzer at a resolving power of 60,000. The spatial resolution of the imaging experiments was of 150 μm. A histologically compatible solvent system dimethylformamide:acetonitrile (DMF:ACN) 1:1 (v/v) was used for analysis [23] at a flow rate of 0.8 μl/min. The N2 pressure was set to 175 psi. After DESI-MSI, the same tissue section was subjected to hematoxylin–eosin (HE) staining. The software ImgGenerator (freeware, http://www.msimaging.net/) was used for converting raw files into 2-D images. Spatially accurate ion images were assembled using BioMap software (freeware, http://www.maldi-msi.org/). The protonated form of haloperidol was detected in the tissue sections at m/z 376.14679 (mass error of −1.7 ppm). The isotopic distribution of the ion at m/z 376.14679 was also found to agree with the molecular formula of haloperidol. DESI-MS ion images of haloperidol were compared to optical images of the same tissue in HE-stained tissue sections. The total abundance of haloperidol in each pixel from a DESI-MS ion image was extracted and averaged to obtain the average abundance of haloperidol per tissue section. This procedure was performed for each tissue section analyzed for each strain of mice. Based on the average total abundance of haloperidol for each strain, the fold change was then calculated.\n\nRNA In Situ Hybridization\n\nAbcb5 and Drd2 probes were designed to hybridize to their corresponding mRNAs. The 741 bp Abcb5 probe was PCR amplified from RIKEN_cDNA_clone B020023O04 using the primer set: AGGCCAGAAACAGAGGATTG; and CCTGGTAGAGCATGGCTTTG. The 1,126 bp Drd2 probe was PCR amplified from total cDNA from a C57BL/6J mouse using the primer set: CCGTGAACCCCATCATCTAT and GGTTTGGTGCATGTATGGTG. PCR reactions were performed using Phusion High-fidelity DNA polymerase (Thermo Scientific) and the products were cloned into pCR-BluntII-TOPO vector (Life Technology). Clones with correct insertions were linearized using either BamHI or NotI (New England Biolabs) for in vitro transcription. Anti-sense and sense RNA probes were then in vitro transcribed using Riboprobe System-SP6/T7 (Promega) and DIG RNA labeling mix (Roche), DNase treated, precipitated in lithium chloride (Ambion), and stored at −80°C in aliquots. Freshly dissected mouse brain was immediately bisected sagittally, and fixed in 4% paraformaldehyde in DEPC treated phosphate buffered saline at 4°C overnight. Fixed tissues were then saturated in DEPC-treated 20% sucrose at 4°C overnight, then flash frozen in OCT compound (Tissue-Tek) and stored at −80°C. The brain sections were cut at 20 μm thickness, and serial sections were collected on Superfrost Plus glass slides (Fisher Scientific). Sets of serial sections across the whole brain were then hybridized anti-sense probes, and adjacent sections were hybridized with the sense probe (as negative controls), at 63°C in a moist chamber overnight. After washing and blocking, tissue sections were then incubated with AP-conjugated anti-DIG antibody (Roche) at 4°C overnight. Tissue sections were then washed and chromogenic reactions were then performed by incubation with the AP substrate BM Purple (Roche) at room temperature. The sections were then examined using a light microscope, and a purple/blue color indicates the localization of the targeted mRNA within the tissue.\n\nStatistical Analysis of Data Obtained from Inbred and Chromosome Substitution Strains\nThe latency measurements from chromosome substitution strain (CSS) mice were log-transformed, and a two-sample t-test was applied to compare the latency of CSS12 to that of C57BL/6. The differences between the latency on the log-scale and the corresponding 95% confidence intervals were evaluated, and then transformed back to the original scale. Similarly, the measured haloperidol and HPP+ concentrations were log-transformed and a two-sample t-test was applied to compare the concentration in A/J to that in C57BL/6. The differences between the latency on the log-scale and the corresponding 95% confidence intervals were evaluated and then transformed back to the original scale. For comparison of the HPP+ levels in A/J, CSS12, and C57BL/6 strains, the concentrations were log-transformed and an F-test was applied. The differences between the latency on the log-scale and the corresponding 95% confidence intervals were evaluated using SAS (version 9.3), and were then transformed back to the original scale.\n\nAnalysis of Abcb5 Knockout Mice\nMice with a homozygous Abcb5 gene deletion were prepared and bred onto the C57BL/6 by nine backcrosses, and these mice did not express Abcb5 mRNA (JPG, MMG, and colleagues, personal communication). The latency in control wild-type littermate and Abcb5 knockout mice were analyzed after 0 to 7 days of haloperidol 10 mg/kg/day IP administration. The statistical significance of the difference in the latency measurements between wild-type and Abcb5 knockout mice was determined using a two-sample two-sided t-test on log-transformed data for each day as described in the preceding paragraph. Since gender could affect the haloperidol response, we performed a two-way ANOVA to assess the effect of gender. However, the gender effect was only significant on day 4 (p = 0.046) and was not significant for all of the other days. Therefore, an adjustment for the gender effect was not performed.\n\nHuman Genetic Association Analysis: Human ABCB5 Alleles and Haloperidol Toxicity\nThe study was approved by the ethics committee at the University of Munich, and was carried out in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and later revisions (S2 Text). Additional description of these participants and their characteristics can be found elsewhere [24]. Written informed consent was obtained at the time of recruitment for each participant. In brief, this human cohort consists of 101 patients of European descent that were treated with haloperidol as a monotherapy for a period of one month during the acute phase of their psychotic illness. The patients were enrolled over a 3-year period (1999–2002) at the Department of Psychiatry, Ludwig-Maximilians-University of Munich, Germany. Patients were excluded if they had a known contra-indication for treatment with haloperidol, had tardive dyskinesia previously, or severe neurological or medical disorders, organic brain diseases, pregnancy, or acute suicidal tendencies. Furthermore, the patients were excluded if they received a co-medication, such as beta blockers, or antidepressants that could possibly influence the antipsychotic treatment or its side effects. The patients were treated with haloperidol during the first phase of the illness’s episode, and then shifted to another antipsychotic treatment if there was a lack of response or if severe side effects developed. Patients were treated with haloperidol according to clinical need without any dose limitation during the acute phase of the illness. The mean dose of haloperidol was 8.76 mg/d (SD = 4.4) for day 1, 10.54 mg/d (SD = 6.0) for day 3, 10.88 mg/d (SD = 5.9) for day 7, 10.43 mg/d (SD = 6.2) for day 14, 10.95 mg/d (SD = 7.3) for day 21. As this was a naturalistic study doses were adapted to clinical requirements. Diagnosis was obtained through the Structured Clinical Interview for DSM-IV (SCID-I) interview, and psychopathological measurements were administered by two psychiatrists with highly reliable inter-rater evaluation results (k > 0.80). Haloperidol plasma levels, positive and negative syndrome scale (PANSS), ESRS, and UKU scores were assessed at baseline and on days 3, 7, 12, 21, and 28 as described [24]. Since genotyping was performed after the clinical part of the study was closed, it was not possible for any of the evaluators to be aware of the genetic results.\n\nThe alleles at 38 SNPs in ABCB5 were genotyped on a MassARRAY platform (Sequenom) for 85 patients, which represents all of the available DNA samples obtained from the individuals in this cohort. Briefly, after a multiplex PCR and shrimp alkaline phosphatase treatment, a single base extension reaction was performed. Following the de-salting of extension products with SpectroCLEAN resin (Sequenom), samples were spotted on SpecroCHIPs GenII (Sequenom), and analyzed with a MassARRAY MALDI-TOF mass spectrometer. Allele specific extension products and the resulting genotypes were identified using Typer 3.4 Software (Sequenom). For genotyping quality assurance, the CEU HapMap Trios (Coriell Institute for Medical Research) were included and compared with the HapMap database (www.hapmap.org). Nine of the SNPs were not polymorphic in these 85 patients, and were excluded from further analysis. None of the remaining 29 SNPs violated the HWE condition, since the smallest p-value obtained using a traditional Chi-squared test [25] was 0.11. Of note, 26 SNPs exhibited all three possible genotypes (i.e., homozygous major allele, heterozygous and homozygous minor allele), while three SNPs had only two genotypes. For the 26 SNPs with all three possible genotypes, we used an additive model to assess the association using ANOVA model. For the three SNPs with only two observed genotypes (homozygous major allele and heterozygous), only one grouping was tested using two-sample t-test. For each patient, the degree of parkinsonoid toxicity was rated as 0 (absent), 1 (mild), 2 (moderate), or 3 (severe) for each time point. A patient was classified as exhibiting parkinsonoid toxicity if the score was ≥2, as not exhibiting this toxicity if the score was ≤1 at each time point. Patients were similarly rated and classified for dyskinesia and akathesia, the other two toxicities. A combined measure of HIT at each time point was defined as follows: a patient was designated as exhibiting toxicity for (i.e., 1) if any of the three toxicity measurements was ≥2, and as non-toxic (i.e., 0) if the three toxicity measurements were all ≤1. Finally, as a cumulative index of the toxic effect of haloperidol, the area-under-curve (AUC) of the combined toxicity measures for days 0, 1, 3, and 7 was calculated. This value represents the cumulative toxicity induced by haloperidol over the indicated period, and it assumes one of the following values: 0, 1, 2, 3, or 4.\n\nResults\nWhole Genome-Genetic Association Mapping of Susceptibility to HIT\nAs described in S1 Text, we analyzed NGS data to produce a 16 million SNP database with alleles covering 26 strains, including the 12 strains sequenced here, 13 strains analyzed in [11], and the reference C57BL/6 strain (S1 Fig.; S1 Table). Since our prior studies analyzed much less complex datasets with fewer SNPs and blocks, we did not know if HBCGM could analyze this far more complex (~900-fold more blocks) whole genome NGS-based dataset. However, we found that whole genome HBCGM could identify the known genetic factors for four biomedical traits (S2 Fig.; S2 Table; S3 Text). Moreover, we also found that its performance was superior to that of another genetic association method, which analyzed the correlation with a selected set of individual SNPs, especially when the inbred strains exhibited three or more distinct phenotypic responses (S3 Table).\n\nWe then examined available data on HIT (measured after 3, 7, 30, 60, or 120 days of haloperidol treatment) for the 17 strains with available genomic sequence (S2B Table). As described in the S2B Table, our analysis of these data indicated that the prolonged latency appearing in some of the inbred strains (i) was due to haloperidol treatment; (ii) was not correlated with plasma drug levels; and (iii) had its relative magnitude in the strains maintained across all treatment periods (ranging from 3 to 120 days) analyzed. The lack of correlation between latency and plasma haloperidol level was expected, since the effect of CNS-acting drugs is dependent upon the brain (and not the plasma) drug concentration. HBCGM analysis indicated that genetic variation within Abcb5 had the highest correlation (p = 8.3 × 10−11) with the day 30 latency values (Fig. 1A). HBCGM analysis also indicated that Abcb5 was highly correlated with the latencies measured after 60 (rank number 3, p-value 2.9 × 10−13) or 120 (rank number 2, p-value 1.7 × 10−10) days of haloperidol treatment. Several other factors also indicated that Abcb5 was a likely candidate gene: (i) When the robustness of the mapping results were assessed by randomly deleting sets of strains and iteratively repeating the analysis, Abcb5 was among the top genes identified after the latency data were analyzed for treatment days 30, 60, or 120 (S4 Table). (ii) Among the 440 SNPs within or near Abcb5, eight missense SNPs divided the 17 strains into three haplotypic groupings with different latencies: group 1 (range: 3–44 seconds; 14 strains); group 2 (144–171 seconds; NZW, NZO); and group 3 (234 seconds, A/J). The three strains with extreme latency values share alleles at three missense SNPs that are within a nucleotide-binding region of the protein (Fig. 1B). Also, another codon changing SNP (cSNP) (rs30781912) converted a serine, which is conserved in all vertebrates, to an alanine in the strain (A/J) with the highest latency. (iii) We investigated whether Abcb5 alleles could predict the measured latency for two inbred strains with extreme latency values (NON/ShiLtJ, 2.8 seconds; and NZL/LtJ, 211 seconds) whose genomic sequence was not yet characterized. After characterizing their Abcb5 alleles, we found that their measured latencies were well within the range predicted by their Abcb5 haplotype (Table 1). Lastly, genetic variation within Abcb5 could affect susceptibility to HIT, since it is a member of the ABC-transporter gene family. Although little is known about murine Abcb5, its human homologue (ABCB5) is an energy-dependent efflux transporter that mediates the resistance to multiple drugs and chemotherapeutic agents [26–30]. Drug efflux pumps located at the luminal membrane of capillary endothelial cells in the brain, which export a drug back into the circulating blood after it has entered the brain, are major determinants of drug levels in the brain [31].\n\n10.1371/journal.pmed.1001782.g001Fig 1 A pharmacogenetic factor for HIT.\n(A) The average latency measured after 30 days of haloperidol administration to 17 inbred strains is shown in the top panel. The bottom panel shows ten genes whose genetic pattern was most highly correlated with the latency data by the HBCGM program. The genes within correlated haplotype blocks are indicated by their symbol; an orange, yellow, or white background indicates whether SNPs causing a significant, minor, or no amino acid change are present, respectively. (A blue background indicates a SNP that affects a potential splice site alteration is present.) The haplotypic pattern is shown as colored rectangles that are arranged in the same order as the input data. Strains with the same colored rectangle have the same haplotype within the block. The p-values and genetic effect size were calculated as previously described [14]. (B) Missense SNPs in Abcb5. The 1,255 amino acids in Abcb5 contain two transmembrane (shaded blocks) and two ATP binding transporter domains (solid blocks). The alleles in eight missense SNPs in the 17 analyzed strains are shown, and the alleles that differ from the C57BL/6 reference strain are highlighted. The Gly170Cys is within the first transmembrane domain, and Gly491Ser and Lys493Glu are within the first transporter domain. These three SNPs divide the strains into three haplotypic groupings (each indicated by a different color) that correspond with the haloperidol-induced latency.\n\n10.1371/journal.pmed.1001782.t001Table 1 \nAbcb5 alleles predict haloperidol-induced latency.\nSNP\tNON/ShiLtJ\tNZL/LtJ\t\nT7A\tT\tT\t\nL10S\tL\tS\t\nV27A\tV\t—\t\nG170C\tG\tC\t\nG491S\tG\tS\t\nK493E\tK\tE\t\nS619F\tS\tF\t\nK1206R\tK\tR\t\nHaplotype\t1\t2–3\t\nPredicted latency\t0–44\t147–234\t\nMeasured latency\t2.75\t211\t\nThe alleles for eight missense SNPs in Abcb5 that were determined for two inbred strains are shown. The alleles place NON/ShiLtJ mice in haplotypic group 1, and NZL/LtJ mice in haplotypic group 2–3. The measured haloperidol-induced latencies on treatment day 30 are well within the range (based upon data in Fig. 2) predicted by their haplotype.\n\nAnalysis of Chromosome Substitution Strains and Brain Haloperidol Levels\nA series of C57BL/6J-A/J CSS have been produced where each strain is homosomic for a single specified A/J chromosome on an otherwise C57BL/6 genetic background [32]. Since A/J and C57BL/6 exhibited extreme latency values, we tested the haloperidol-induced latency in four CSS. Of these, only CSS12 (which have A/J alleles for every gene on Chromosome 12) had a significantly increased latency after 5 (6.7-fold, t value = 12.98, p < 0.0001, 95% CI 4.9–9.3) and 10 days (8.5-fold, t = 8.41, p < 0.0001, 95% CI 4.8–14.8) of haloperidol treatment (Fig. 2A). Among the 34 genes on Chromosome 12 that were correlated with susceptibility to HIT, Abcb5 had the highest level of correlation and was the most plausible candidate based on its biological function (S5 Table).\n\n10.1371/journal.pmed.1001782.g002Fig 2 (A) HIT in C57BL/6J, A/J, and four chromosome substitution strains.\nThe time (latency) required for a mouse to make a coordinated movement on a vertical mesh screen after treatment with haloperidol (3 mg/kg/day IP) for the indicated number of days is shown. Each bar represents the average ± SEM for three to four mice per strain. Only CSS12 mice (which have A/J alleles for every gene on Chromosome 12) had a significantly increased latency (p < 0.005) after 5 and 10 days of haloperidol treatment. (B) The amount of haloperidol and its metabolite (HPP+) in brain tissue obtained from A/J and C57BL/6 mice after 4 days of treatment with haloperidol (10 mg/kg/day IP) was assessed in two independent experiments. Each bar represents the average ± SEM of the LC/MS determined abundance (molecules per unit mass of brain tissue) for n = 4 mice per strain. (C) The brain level of the oxidative metabolite of haloperidol (HPP+) was measured after 10 days of haloperidol administration (3 mg/kg/day) to A/J (n = 6), C57BL/6 (n = 6), and Chromosome 12 substitution strain (CSS12) (n = 8) mice. Each bar shows the average ± standard error for the six to eight measurements for each strain, and the p-value is calculated using the Student’s t test on log2-transformed relative abundance data. Of note, CSS12 mice have a significantly higher (1.3-fold, p = 0.004) brain HPP+ level than C57BL/6J mice, but this level is below that in A/J mice.\n\nHaloperidol is oxidatively metabolized to a pyridinium species (HPP+) that is present in brain tissue obtained from haloperidol-treated humans [33] or rodents [34]. HPP+ is a structural analog of the oxidative metabolite (MPP+) of a Parkinson-inducing neurotoxin N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), and HPP+ has been shown to induce toxicity in dopaminergic neurons [33,35,36]. To determine if differences in brain drug (or metabolite) levels were associated with susceptibility, we measured the concentration of haloperidol and HPP+ in brain tissue obtained from C57BL/6J and A/J mice after treatment with haloperidol 10 mg/kg/day for 4 days. This higher dose of haloperidol was used to ensure that we could measure the brain concentrations of both haloperidol and HPP+, since the metabolite is present at much lower (~100-fold) concentrations than the parent drug. C57BL/6 mice treated with this haloperidol dose do not exhibit an increased latency (see below). Consistent with HIT occurring in A/J but not C57BL/6J mice, the brain levels of haloperidol (2.2-fold and 2.3-fold, t values 4.88 and 4.99, p-values 0.008 and 0.002, 95% CI 1.4–3.5 and 1.5–3.5, respectively) and HPP+ (1.4-fold and 1.7-fold, t values 4.75 and 2.39, p-values 0.009 and 0.05, 95% CI 1.1–1.7 and 1.0–2.6, respectively) were both higher in A/J than in C57BL/6J mice in two independently performed experiments (Fig. 2B).\n\nWe also examined HPP+ levels in brains obtained from A/J, C57BL/6J, and CSS12 mice after a prolonged period (10 days) of haloperidol administration (3 mg/kg/day). The brain HPP+ level in CSS12 mice was significantly above (1.3-fold, t = 3.22, p = 0.004, 95% CI 1.1–1.5) that in C57BL/6 mice, but was below that of A/J mice, which had 1.9-fold (t = 7.65, p = 3 × 10−5, 95% CI 1.6–2.2) increase in HPP+ relative to C57BL/6 (Fig. 2C). These results suggest that the differential strain susceptibility to HIT could result from differences in Abcb5-regulated drug transport, and that an A/J Chromosome 12 on an otherwise C57BL/6 genetic background increases brain HPP+ levels. The correlation between the relative brain abundance of HPP+ in A/J, C57BL/6, and CSS12 mice and their haloperidol-induced latencies (Fig. 2A) is consistent with the other studies [33,35,36] indicating that HPP+ is causative of HIT.\n\nDesorption Electrospray Ionization-Mass Spectrometry Imaging of Haloperidol Abundance in Brain Sections\nIn DESI-MSI, thin tissue sections are bombarded with solvent microdroplets to dissolve hundreds of chemicals from the sample surface; the secondary microdroplets formed enter a mass spectrometer, and are analyzed for their chemical content. A movable stage enables multiple pixels (in a row by column matrix) encompassing the entire thin section to be sampled, which generates a detailed 2-D chemical map of the distribution of molecules within the sample surface. The relative amount of haloperidol in each region was analyzed by this method to produce a 2-D ion image of its relative abundance throughout the entire brain section. We analyzed independently prepared sagittal brain sections (two per mouse) from A/J and C57BL/6 mice (three per strain) after treatment with haloperidol (10 mg/kg/d IP) for 5 days. This analysis revealed that haloperidol was diffusely distributed throughout all brain regions, but the amount of haloperidol in A/J brain tissue was consistently greater (~6-fold) than in C57BL/6 brain tissue (Fig. 3). Because of its low abundance, we could not detect the oxidative metabolite by this method. The inter-strain differences indicated by DESI-MSI were greater than those identified by quantitative MS analysis of extracted whole brain. This difference could be attributed to the fact that DESI-MSI was performed on tissue sections in a specific sagittal plane, which does not account for the abundance of haloperidol in other brain regions that were sampled by quantitative MS analysis of extracted whole brain. Nevertheless, direct analysis of brain tissue and DESI-MS imaging both clearly show that haloperidol was more abundant in A/J mouse brain.\n\n10.1371/journal.pmed.1001782.g003Fig 3 DESI-MSI of haloperidol in brain tissue.\nA/J and C57BL/6J mice (n = 3 per strain) were treated with haloperidol (10 mg/kg/day IP) for 5 days. Two sagittal sections, which were separated by a distance of 120 μm, were prepared the same brain region of haloperidol-treated mice. The amount of haloperidol was analyzed DESI-MSI, and the relative abundance of haloperidol is indicated by the color shown in the scale bar. The HE-stained brain section shown at the bottom shows the sagittal plane analyzed, and the location of the frontal cortex (FC) and cerebellum (CB) are indicated for orientation. Haloperidol was diffusely present in the brain tissue obtained from both strains. Although the amount of haloperidol in brain tissue varied among different mice, A/J brain tissue had remarkably increased amount of haloperidol relative to C57BL/6J brain tissue.\n\n\nAbcb5 mRNA Is Expressed near Brain Capillaries and by Purkinje Cells\nSince we did not know if Abcb5 is expressed in brain, in situ hybridization studies were performed on tissue sections from mouse brain. The hybridizations were performed using an anti-sense probe that hybridizes to Abcb5 mRNA, and with an Abcb5 sense probe that serves as a negative control. Abcb5 mRNA expression was observed in the perivascular region of brain capillaries (Fig. 4A). Since this is the anatomic location of the blood-brain barrier function, this expression pattern is consistent with Abcb5 having a role in regulating brain haloperidol levels. Of importance, Purkinje cells in the cerebellum also expressed Abcb5 mRNA; and these cells also expressed dopamine receptor D2 (Drd2) mRNA, which encodes the receptor that binds haloperidol (Fig. 4B). Interestingly, Abcb5 mRNA was not detected in the substantia nigra (S3 Fig.). A low level of Abcb5 mRNA expression was also detected in regions of the hippocampus and frontal cortex (S4 Fig.), but not by the Drd2-positive cells in the substantia nigra (S3 Fig.).\n\n10.1371/journal.pmed.1001782.g004Fig 4 \nAbcb5 mRNA expression in mouse brain.\nIn situ hybridization was performed using anti-sense probes for Abcb5 and Drd2 mRNA on C57BL/6 mouse brain sections. For each anti-sense probe, negative-control hybridizations were also performed using the corresponding sense RNA probe on adjacent tissue sections. (A) Abcb5 mRNA was specifically expressed in the perivascular regions, as shown in two separate views of cortical and cerebellar regions. (B) Purkinje cells in cerebellum express Abcb5 mRNA, and these cells also express the dopamine receptor D2 (Drd2) that is bound by haloperidol. The left and right images are shown at 4× magnification, and magnified views (20×) of the boxed regions are shown in the center image.\n\n\nAbcb5 Knockout Mice Have a Prolonged Haloperidol-Induced Latency and Increased Brain Haloperidol Levels\nTo more precisely determine whether Abcb5 plays a role in HIT, we measured the latencies in homozygous Abcb5 knockout mice (on a C57BL/6 background) before and after treatment with haloperidol (10 mg/kg/day IP). Before drug treatment, there was no difference in the latency of Abcb5 knockout mice relative to wild-type littermates (t = 1.54, p = 0.185) (Fig. 5A). Although there were only marginal differences on treatment day 4 (t = 2.15, p = 0.05), the latencies in Abcb5 knockout mice were significantly prolonged after 5 (10.1-fold, t = 3.09, p-value = 0.03, 95% CI 1.5–69.2), 6 (13.6-fold, t = 4.79, p-value = 0.005, 95% CI 3.5–55.1), and 7 (50.3-fold, t = 7.91, p-value = 0.0005, 95% CI 14.1–179.6) days of haloperidol treatment relative to wild-type mice (Fig. 5). In a second independently performed experiment, haloperidol treatment induced a markedly prolonged latency in Abcb5 knockout mice (Fig. 5B). In contrast, the latencies measured in wild-type littermates did not increase with haloperidol treatment and were comparable to those of C57BL/6 mice. Furthermore, DESI-MSI revealed that the amount of haloperidol in brain tissue obtained from Abcb5 knockout mice (n = 3, 6,282 ± 2,279) was 6.8-fold higher than in wild-type littermates (n = 3, 935 ± 200, p = 0.02) (Fig. 5C). The prolonged latency and increased brain haloperidol levels observed in Abcb5 knockout mice confirms that Abcb5 affects susceptibility to HIT by increasing brain haloperidol levels.\n\n10.1371/journal.pmed.1001782.g005Fig 5 (A, B) Abcb5 knockout mice have a prolonged haloperidol-induced latency.\nIn two independent experiments shown in (A) and (B), Abcb5 knockout mice and wild-type littermates (gender indicated by male or female) were treated with haloperidol (10 mg/kg IP) for 7 days, and the haloperidol-induced latency was measured on the indicated days. In both experiments, the latencies in Abcb5 knockout mice were significantly prolonged relative to wild-type mice after 4, 5, 6, and 7 days of haloperidol treatment. The p-values comparing the latencies measured in the Abcb5 knockout and wild-type groups are shown for each treatment day. (C) DESI-MSI of haloperidol in brain tissues of Abcb5 knockout (n = 3) and wild-type littermate (n = 3) mice. The mice were treated with haloperidol (10mg/kg/day IP) for 4 days, and brain tissues were collected 4 hours after the last treatment. The amount of haloperidol was analyzed by DESI-MSI on 20 μm brain sections, and the relative abundance of haloperidol is indicated by the color shown in the scale bar. The HE-stained brain section shown at the bottom shows the sagittal plane analyzed. Abcb5 knockout mice have a 7-fold increased brain haloperidol level relative to wild-type littermates (p = 0.02).\n\nHuman ABCB5 Alleles Associate with Haloperidol Toxicity\nA human cohort with 85 patients of European descent was treated with haloperidol as a monotherapy for one month during the acute phase of their psychotic illness, and their response to therapy and the appearance of HIT was assessed at baseline and after 1, 3, 7, 14, and 21 days of treatment as described [24]. Their clinical and demographic characteristics are described in Table 2. We investigated whether ABCB5 SNP alleles were associated with the appearance of the three types of symptoms of HIT (Parkinsonoid, Dyskinesia, and Akathisia scores) that were measured in this cohort. Of the 29 SNPs analyzed: six were codon changing (cSNPs), three were in the 5′ UTR, and the others were intronic (Table 3). We first examined the effect that treatment duration had on the incidence of each of the three types of HIT toxicities throughout the course of treatment (S6 Table). The incidence of akathesia and parkinsonoid features increased through day 14, while dyskinesia decreased after day 3 (Fig. 6A), which may be due to fact that the onset of the other toxicities masked the dyskinesia. Therefore, we analyzed a composite index of all three symptoms of HIT, since our mouse genetic analysis identified a genetic factor that alters the brain haloperidol concentration, which will affect susceptibility to all of these symptoms. In examining the allelic associations, we found a clear time-dependent allelic effect on HIT that was maximal on days 1, 3, and 7 (Figs. 6B and S5). Therefore, it is likely that the protective allelic effect would dissipate after prolonged dosing owing to haloperidol (or metabolite) accumulation, but individuals with a protective ABCB5 allele would exhibit less toxicity during the early treatment period (i.e., days 3–7).\n\n10.1371/journal.pmed.1001782.g006Fig 6 Human ABCB5 alleles and HIT.\n(A) The average of three toxicity measurements (± SEM) for 85 patients determined after the indicated time of haloperidol treatment is shown. Of note, the average Dyskinesia score peaked at 3 days post treatment and then declined, while the two other toxicity measurements (akathesia and parkinsonoid) increased with time after treatment until day 14. For this analysis, the toxicity measurement data for days 0, 1, 3, 7, 14, and 21 were available for 85, 85, 85, 85, 81, and 54, respectively, of the 85 patients in this cohort. (B) The graph shows the combined toxicity measurement (y-axis) relative to the time (x-axis) for ABCB5 SNP rs17143212. The average combined toxicity measurement was calculated for each genotype at each SNP, and then plotted (± SEM) according to the colors shown in the legend. (C) The LD map for genetic variants in ABCB5, which was compiled using data obtained from the International HapMap project (http://hapmap.ncbi.nlm.nih.gov/). The three regions where the alleles have a high level of LD are enclosed in boxes. Region 2 contains a cluster of four SNPs with alleles that were associated with HIT, and arrows in the diagram at the top of the figure indicate their relative positions.\n\n10.1371/journal.pmed.1001782.t002Table 2 Demographic and clinical data for the 85 patients.\nVariable\tResults\t\nAge (y) (mean SD)\t35.4 11.7 (Range: 18–64)\t\nSex\tM = 45 (53%); F = 40 (47%)\t\nDiagnosis\tSchizophrenia, paranoid type = 46 (54.1%)\t\nSchizophrenia, undifferentiated type = 2 (2.4%)\t\nSchizophrenia, residual type = 2 (2.4%)\t\nSchizophrenia, catatonic type = 4 (4.7%)\t\nSchizophrenia, disorganized type = 3 (3.5%)\t\nSchizoaffective disorder = 15 (17.6%)\t\nBrief psychotic disorder = 7 (8.2%)\t\nDelusional disorder = 1 (1.2%)\t\nSchizophreniform disorder = 5 (5.9%)\t\nCo-medication (till day 7)\tLevomepromazin/ppromethazin = 52 (61.2%)\t\nCholinergic (biperiden/amitriptylin) = 26 (30.6%)\t\nβ-blocking agents = 8 (9.4%)\t\nGabaergic agents and benzodiazepine = 45 (52.9%)\t\nComorbid illness\tPhobia = 2 (2.4%)\t\nAlcoholism = 3 (3.5%)\t\nDepression = 3 (3.5%)\t\nSuicide attempt = 5 (5.8%)\t\nReason for dropout\t\t\nDay 14\t4 discharged after good recovery (4.7%)\t\nDay 21\t1 discharged after good recovery (1.1%)\t\n7 switched to other meds after good recovery (8.2%)\t\n7 switched after good recovery but with side effects (8.2%)\t\n3 without recovery (3.5%)\t\n9 intolerable side effects (10.5%)\t\n10.1371/journal.pmed.1001782.t003Table 3 Genetic association results for alleles at 29 SNPs with the area under curve calculated by summing the combined toxicity measures on days 0–7.\nSNP ID\tPosition\tAnnotation\tRegion\tMAF\tAUC\tPermutation p-Value\t\nrs2106562\t20655268\t5′UTR\t\t0.35\t0.044\t0.523\t\nrs73076550\t20655392\t5′UTR\t\t0.11\t0.272\t0.988\t\nrs78414512\t20668277\tINTRON\t\t0.16\t0.005\t0.086\t\nrs17143212\t20682884\tT131I\t1\t0.03\t0.002\t0.034\t\nrs2893006\t20687181\t5′UTR / Synonymous\t1\t0.24\t0.308\t0.995\t\nrs75784515\t20687332\tINTRON\t1\t0.24\t0.287\t0.992\t\nrs61732039\t20687604\tD370G\t1\t0.14\t0.03\t0.402\t\nrs3213622\t20690885\tINTRON\t1\t0.34\t0.434\t0.999\t\nrs34603556\t20691047\tAlternative start codon / M446T\t1\t0.24\t0.308\t0.995\t\nrs61227829\t20691219\tSynonymous\t1\t0.15\t0.038\t0.459\t\nrs17816709\t20691860\tINTRON\t1\t0.24\t0.287\t0.992\t\nrs2301641\t20698270\tK115E / K560E\t1\t0.36\t0.588\t1\t\nrs6952128\t20700361\tINTRON\t1\t0.36\t0.463\t1\t\nrs17143258\t20726621\tINTRON\t1\t0.18\t0.531\t1\t\nrs12700229\t20729931\tINTRON\t2\t0.26\t0.719\t1\t\nrs2190409\t20732020\tINTRON\t2\t0.19\t0.961\t1\t\nrs17218211\t20740648\tINTRON\t2\t0.21\t0.011\t0.195\t\nrs10488579\t20741343\tINTRON\t2\t0.24\t0.021\t0.316\t\nrs17218839\t20745418\tINTRON\t2\t0.26\t0.026\t0.361\t\nrs2108259\t20745756\tINTRON\t2\t0.26\t0.024\t0.338\t\nrs62453384\t20762646\tG365V / G810V\t\t0.38\t0.478\t1\t\nrs62453385\t20762937\tINTRON\t\t0.38\t0.478\t1\t\nrs6461513\t20763907\tINTRON\t\t0.32\t0.031\t0.402\t\nrs4719626\t20768794\tINTRON\t\t0.26\t0.102\t0.798\t\nrs6960186\t20773995\tINTRON\t3\t0.31\t0.478\t1\t\nrs6461515\t20778646\tE970K / E525K / E137K\t3\t0.19\t0.117\t0.853\t\nrs6461516\t20778773\tINTRON\t3\t0.17\t0.189\t0.961\t\nrs6461517\t20787273\tINTRON\t3\t0.38\t0.706\t1\t\nrs1015646\t20793720\tINTRON\t3\t0.39\t0.681\t1\t\nThe SNP ID, genomic position (based on NCBI Build 37), minor allele frequency (MAF), and the p-value (uncorrected for multiple testing) for the allelic association with the combined toxicity measure are shown. The annotation indicates the location of the SNP (intron, 5′ or 3′ UTR), and the amino acid residue altered by the SNP (because of alternative ABCB5 transcripts, more than one location is indicated for some SNPs). All p-values < 0.05 are in bold. To account for multiple testing a permutation test was performed for each SNP, and the p-value is shown in a separate column. Of note, rs17143212 is a missense SNP (Thr131ILE) that it is the only SNP with a significant p-value in the permutation test. This indicates that its association with the area under the curve (AUC) remains significant even after accounting for the fact that 29 SNPs were simultaneously tested.\n\nSince each of these three different toxicities could all be caused by an increased drug (or drug metabolite) concentration in the brain, we examined whether ABCB5 alleles were associated with a combined toxicity index, which indicated whether a patient manifested any of the three measured toxicities on a given day. To reduce the number of hypotheses that were tested simultaneously, the area under the curve (AUC) for the cumulative toxicity measurements on days 0 to 7 was calculated, and its association with each of the 29 SNPs was tested. (A truncated dataset was used because many of the values for day 14 and 21 were not available for many patients.) Remarkably, a SNP (rs17143212) that was a missense SNP (Thr131Ile) had a particularly strong association (raw p = 0.002) with the toxicity index, and a total of ten (out of 29) SNPs showed a plausible association (with raw p < 0.05) with the toxicity index (Table 2). Among these SNPs, four were consecutive SNPs within the second identified region of linkage disequilibrium in the ABCB5 gene (Fig. 6C). The probability that ten SNPs would randomly have these p-values (< 0.05) is <8 × 10−7, indicating that it is highly unlikely that all of these associations were false positives resulting from a random match. Since the AUC values didn’t follow a Gaussian distribution and the sample size may not be large enough, the resulting p-values from the ANOVA models could be biased. Therefore, we performed a permutation test, which accounts for multiple testing and makes no assumption about the data distribution, to rigorously assess the statistical significance of each association. To do this, the combined toxicity value for the 85 patients was permutated, while their genotypes remained unchanged; this enabled the linkage disequilibrium among the SNPs to be retained. The distribution of the minimum p-value for the 29 SNPs was evaluated by performing this permutation experiment 1,000 times. The observed raw p-value for each SNP was then compared to this distribution to obtain the true p-value for that SNP under the null hypothesis that this region was not associated with HIT. Strikingly, rs17143212, which caused a significant (131Thr → ILE) amino acid change in the predicted protein, still exhibited a significant association (permutation test p-value = 0.034) after the permutation test. The four consecutive SNPs that had significant raw p-values didn’t have significant permutation test p-values. However, if additional patients were available for analysis, we would be able to better assess the significance of their associations. Nevertheless, at least one human ABCB5 SNP shows a significant association (after correction for multiple testing) with a combined measure of HIT.\n\nDiscussion\nThis study identifies murine Abcb5 alleles as pharmacogenetic factors affecting susceptibility to HIT. Because Abcb5 is expressed in brain capillaries, it can function as part of the blood-brain barrier to regulate the level of drugs in the brain [37]. This function is consistent with the measured differences in the brain levels of haloperidol and its metabolite (HPP+) in inbred and chromosome substitution strains. These findings suggest a new model for the genetic mechanisms underlying inter-individual and cell type-specific differences in susceptibility to haloperidol-induced CNS toxicity (Fig. 7).\n\nAfter haloperidol enters the brain (because of its lipophilicity or other intrinsic properties), the brain concentrations of haloperidol and its toxic metabolite will be affected by Abcb5 function at the brain-blood barrier. Thus, a strain with an Abcb5 allele with reduced transporter function is more susceptible to HIT because of the increased haloperidol concentration in the brain. Like the causative toxins (MPTP, rotenone) used in the other animal models of toxin-induced Parkinson’s disease [38–41], the oxidative metabolite of haloperidol (HPP+) is a potent inhibitor of NADH-linked mitochondrial respiration [36]. Brain enzymes convert the Parkinsonian neurotoxin MPTP to its toxic metabolite [42–44], which is concentrated in cells with a high affinity dopamine uptake system [41,45], which causes the Parkinsonian-like symptoms to develop. HPP+ is a more potent inhibitor of mitochondrial electron transport than the oxidative metabolite of MPTP [36]. The toxicity of paraquat, which is another neurotoxin that selectively damages dopaminergic neurons, is also dependent upon dopamine transporter activity [46]. Thus, we propose that haloperidol in Drd2-expressing dopaminergic neurons is converted to its oxidative metabolite HPP+ by the drug metabolizing enzymes present in these neurons [47,48]; and the mitochondrial toxicity induced by this metabolite produces the Parkinsonian-like symptoms.\n\nOf interest, we found that Abcb5 and Drd2 were also expressed in cerebellar Purkinje cells. Given their large size, high metabolic requirements, and Drd2 expression, Purkinje cells should also be affected by HIT, since they are particularly susceptible to toxin-induced injury [49]. However, the symptoms of HIT observed in mice and humans are predominantly extrapyramidal and do not have a substantial cerebellar component. Why does HIT produce Parkinsonian symptoms, but not cerebellar toxicity? We believe that Abcb5 expression by Purkinje cells protects them from HIT by their ability to transport haloperidol out of the cells. In contrast, haloperidol-targeted neurons in the substantia nigra, which lack Abcb5 expression, will be susceptible to HIT (Fig. 7).\n\n10.1371/journal.pmed.1001782.g007Fig 7 A diagram of the effect of Abcb5-mediated haloperidol transport on HIT.\nAbcb5 is expressed in brain capillaries and by cerebellar Purkinje cells. Haloperidol will enter the brain due to its intrinsic properties, but vectorial transport by perivascular Abcb5 will reduce the brain concentration of haloperidol. An individual with alleles that reduce Abcb5 activity are more susceptible to HIT because they will have an increased brain haloperidol concentration. Cerebellar Purkinje cells and dopaminergic neurons in the substantia nigra both express the Drd2 receptor that is bound by haloperidol. In Drd2-expressing dopaminergic neurons haloperidol is converted to its oxidative metabolite (HPP+), which inhibits mitochondrial energy generation and causes the characteristic Parkinsonian-like symptoms to develop. Although Purkinje cells express Drd2, they also express Abcb5, which exports of haloperidol from these cells and protects them from HIT.\n\nAlthough a relatively small cohort of patients who were treated with haloperidol was evaluated here, a human ABCB5 SNP, which causes a significant amino acid change in the protein, was also associated with susceptibility to HIT. However, the human allelic affect is exerted during the early period of drug treatment. The time-dependent effect observed in humans may be caused by the fact that continued haloperidol treatment may overwhelm the ability of the protective allele to clear the toxic metabolite. Despite some evidence for familial clustering [50] and scattered reports (from studies that evaluated a small number of patients) of candidate gene associations [51,52], we did not have any solid information about human pharmacogenetic factors for HIT. A recently completed, large human GWAS did not reveal any significant associations with antipsychotic drug-induced toxicities [53]. However, this study did not perform the detailed analysis of HIT that was performed here. Our results suggest that an examination of the time dependence of individual and the aggregation of cumulative toxicity measurements may be required to identify pharmacogenetic factors for antipsychotic agents. Like the murine gene, human ABCB5 is also highly polymorphic; alleles at ten codon changing SNPs (cSNPs) are predicted to affect human ABCB5 transporter function, including two (Iso648Thre, Glu679Lys) within the nucleotide-binding region [54]. So, it is certainly possible that analysis of a larger cohort could identify other human ABCB5 alleles that also affect ABCB5 function, and possibly susceptibility to drug toxicity. It is also possible that analysis of a larger human cohort could reveal SNP alleles in other genes that also affect susceptibility to HIT. Although haloperidol is a first-generation antipsychotic agent, the more commonly used second-generation antipsychotics (aripiprazole, clozapine, olanzapine, risperidone) are also associated with a significant incidence of EPS-related toxicities, which is higher than was originally appreciated [55]. It would be of interest to determine whether genetic variation in ABCB5, or other efflux transporters, could affect susceptibility to their toxicity. Simulation studies have convincingly demonstrated that using pharmacogenetic information for drug selection [56] or dose adjustment [57] could reduce drug toxicity. Characterization of genetic factors affecting the toxicity caused by haloperidol (or second-generation antipsychotics) could lead to pharmacogenetic strategies that would improve the outcome for patients taking these drugs.\n\nLastly, analysis of chromosomal substitution strains indicated that the presence of A/J alleles on Chromosome 12 could partially induce susceptibility to HIT. However, the magnitude of the haloperidol-induced latency and the brain HPP+ levels in CSS12 mice were significantly below those of A/J mice. Thus, other genetic factors could also affect susceptibility to HIT in mice, which raises the possibility that there are other human pharmacogenetic factors to be found.\n\nConclusions\nThese findings indicate that Abcb5 is a component of the blood-brain barrier in mice and suggest that genetic variants in this gene underlie, at least in part, the differences in susceptibility to haloperidol-induced toxicity among inbred mice strains. Moreover, the human genetic association study indicates that a specific ABCB5 allele also affects the susceptibility of people to haloperidol-induced toxicity.\n\nSupporting Information\nS1 Checklist ARRIVE checklist.\n(DOCX)\n\nClick here for additional data file.\n\n S2 Checklist STROBE statement.\n(DOCX)\n\nClick here for additional data file.\n\n S1 Fig The effect of incorporating SNP data obtained from additional strains on the haplotype map.\n(A) The number of total (left panel) and added (right panel) SNPs identified after analysis of the genomic sequence obtained from the indicated number of additional strains. Beginning with the 12.6 M SNPs present in 14 strains, additional SNPs were identified by analyzing the sequence of 11 additional strains in a random order. This procedure was repeated 50 times, and the order of the added strains was varied. The left panel shows the total number of SNPs ± SEM from for each additional strain; while the right panel shows the number of added SNPs ± SEM for each added strain. Of note, the total number of SNPs increased significantly for each added strain. However, the number of new SNPs identified per additional strain analyzed decreased in an exponential fashion (blue line) as additional strains were evaluated. (B) The total number (± SEM) of haplotype blocks identified after inclusion of SNPs that were identified by analysis of the NGS sequence data obtained from the 15th through 25th strains that were analyzed is shown. These numbers were determined using the simulation described in (A). (C) The total numbers of additional haplotype blocks (± SEM) that were identified after incorporation of SNP data from the indicated number of additional analyzed strains are shown as diamonds. The numbers of added blocks (± SEM) that were produced as a result of new SNPs present in the additional analyzed strains are shown as circles. Of note, 30%–53% of new haplotype blocks are produced from newly identified SNPs, while the remainder are produced by new recombinations occurring in regions with previously known SNPs. (D) The average size of a haplotype block (± SEM) decreases as the additional allelic data are incorporated into the genetic map. (E) A density plot of the quality (QUAL) score for the SNP calls, which were determined by analysis of the sequence of each indicated strain using Samtools. The QUAL score reflects the likelihood that there is a genetic variant at each identified position. One criterion for inclusion of a SNP in the database was a QUAL score ≥ 50. Since the SJL strain had 55-fold whole genome sequence coverage, it is noteworthy that 68% of SJL SNPs have a QUAL score > 150; while the other strains, with 20- to 31-fold sequence coverage, had only ~50%–60% of their SNPs above the same cutoff. However, regardless of the extent of sequence coverage, ~87% of the SNP calls for all strains are above the desired cutoff of 50.\n\n(TIF)\n\nClick here for additional data file.\n\n S2 Fig The input phenotypic data and the HBCGM results for the aryl hydrocarbon response and macrophage susceptibility to Bacillus anthracis lethal toxin (A), the major histocompatibility complex (MHC) H2 response (B), albino skin type (C), and survival after fungal infection (E) are shown.\nThe p-value, and Genetic Effect Size were determined as previously described [8]. The genes within correlated haplotype blocks are indicated by their symbol; a blue, orange, yellow, or white background indicates whether SNPs altering a splice site, or causing a significant, minor, or no amino acid change within the predicted protein sequence are present, respectively. The haplotypic pattern is shown as colored rectangles arranged in the same order as the input data. Strains with the same colored rectangle have the same haplotype within the block at the indicated chromosome and position. The presence (y) or absence (n) of albinism in each strain is indicated in (C). (D) The association between SNP alleles in two candidate genes and albino status are shown for four additional strains: one strain (P/J) is non-albino (green) and three are albino (red). The alleles for each SNP are indicated by letter and by box color. Only the Cys103Ser alleles in the Tyr gene segregate with the albino status of these four strains.\n\n(TIF)\n\nClick here for additional data file.\n\n S3 Fig DRD2+ cells in the substantia nigra do not express Abcb5.\nIn situ hybridizations were performed using anti-sense probes for Abcb5 and Drd2. The dashed box region shows the substantia nigra region. The images of sagittal brain sections were obtained from a C57BL/6 mouse, and are shown at 1× magnification.\n\n(TIFF)\n\nClick here for additional data file.\n\n S4 Fig \nAbcb5 mRNA is expressed in the hippocampus (A) and in frontal cortex (B).\nIn situ hybridization was performed using anti-sense probes for Abcb5 on C57BL/6 mouse brain sections. As a negative-control, hybridizations were also performed using the sense probe on adjacent tissue sections. Abcb5 mRNA was expressed in a linear pattern within the hippocampus (arrows). In addition, Abcb5 was also faintly expressed in the frontal cortex. The images are shown at 4× magnification, and a magnified view (20×) of the boxed region in (A) is shown in the center image.\n\n(TIFF)\n\nClick here for additional data file.\n\n S5 Fig The graphs show the combined toxicity measurement (y-axis) relative to the time (x-axis) for each of the four consecutive ABCB5 SNPs located between 20.740 and 20.746 MB.\nThe average combined toxicity measurement was calculated for each genotype at each SNP, and then plotted according to the colors shown in the legend.\n\n(TIFF)\n\nClick here for additional data file.\n\n S1 Table The sequence coverage and SNP variants identified by analysis of NGS data for 26 mouse genomes.\nThe amount of genomic sequence (Gb), fold coverage, numbers of SNPs, or indels relative to the C57BL/6 reference sequence (or uniquely present in each strain) are shown. The sequence data for the first 12 strains was obtained at Stanford, C57BL6 is the reference sequence, and Keane and colleagues [1] produced the sequence data for the other 13 strains. The sequence coverage and SNP variants identified by analysis of NGS data for 26 mouse genomes. The amount of genomic sequence (Gb), fold coverage, numbers of SNPs, or indels relative to the C57BL/6 reference sequence (or uniquely present in each strain) are shown.\n\n(DOCX)\n\nClick here for additional data file.\n\n S2 Table (A) The phenotypic data used for HBCGM of five traits.\nThe aryl hydrocarbon response (AHR), major histocompatibility complex (MHC) H2 haplotypes (MHC H2), litter size (MPD: 31408), and macrophage susceptibility to the Bacillus anthracis lethal toxin (Anthrax MPD: 1501) were obtained from [8] and from the Mouse Phenome Database (http://phenome.jax.org/). Since the MHC H2 haplotypes for NOD/ShiLtJ (g7), SJL/J (s), and SM/J (v) are unique and each is distinct from that of the other 18 strains; they were not used for the HBCGM results shown in this paper. We can include no more than five different phenotypes in a mapping experiment since haplotype blocks with up to five haplotypes are analyzed. The albino status (Albino) was obtained from the Jackson Laboratory description of mouse strains (http://www.jax.org/). The Candida albicans (C. albicans) survival data was obtained from [11]. (B) The phenotypic dataset used for analysis of haloperidol-induced latency. The measured haloperidol-induced latencies (seconds) on days 0 (MPD: 39407), 3 (MPD: 39408), 7 (MPD: 39409), 30 (MPD: 39410), 60 (MPD: 39411), and 120 (MPD: 39445); and the plasma haloperidol levels on day 30 (MPD: 39403) were obtained from the Mouse Phenome Database (MPD) (http://phenome.jax.org). The number of mice examined, average measurement, and the standard deviation are shown for each of the 16 indicated strains.\n\n(DOCX)\n\nClick here for additional data file.\n\n S3 Table The results obtained using the EMMA method [5] for evaluating the phenotypic data for five traits.\nGenetic variation within the indicated causative genes was among the most highly correlated candidates identified by HBCGM. After EMMA analyzed the same phenotypic data, its results were evaluated by examining all of the SNPs within a 10 kB neighborhood surrounding the indicated causative genes. The smallest p-value obtained using the EMMA method for a SNP within this neighborhood serves as the “minimum p-value” for the causative gene. We also show the number of other SNPs in the mouse genome that had an equivalent or smaller p-value for each trait. The size of the genomic regions and the number of genes within 10 kB of these SNPs are shown, which provides an indication of the number of “false positive” correlations. The numbers of genes with codon changes are also shown. For the three binary response traits (AH response, Anthrax, and albinism), EMMA identified the causative gene. For the two quantitative traits tested, EMMA identified over 21,691 SNPs (corresponding to 66.1 MB encoding 922 genes) or 12,113 SNPs (64.7 MB, 1064 genes), with an equivalent or higher correlation than the known causative variants for survival after C. albicans infection (C5), or haloperidol-induced latency on day 30 (Abcb5), respectively. The causative genes for these quantitative traits had three or more distinct phenotypic responses, which indicates that methods that analyze only one SNP at a time are not optimal for analyzing traits where the causative genetic variants have more than two distinctive haplotypic groupings.\n\n(DOCX)\n\nClick here for additional data file.\n\n S4 Table The top 10 genes (indicated by symbol) from the robustness analyses performed using the day 30, 60, and 120 latency data are shown.\n\nAbcb5 (highlighted) ranked number 1, number 4, and number 3 on days 30, 60, and 120, respectively. Of note, if the small olfactory genes (Olfr392–398) and pseudogenes (Gm12329) were excluded, Abcb5 would rank number 1 and number 2 on days 60 and 120, respectively.\n\n(DOCX)\n\nClick here for additional data file.\n\n S5 Table Genes on Chromosome 12 whose genetic pattern was identified by HBCGM as having some level of correlation with the day 30 haloperidol-induced latency measurements for 17 inbred strains.\nThe symbol, starting and ending position on Chromosome 12, and the calculated p-value and genetic effect size are shown for each gene. Three genes with SNPs that significantly altered an amino acid in the predicted protein sequence are indicated in orange, while two with minor amino acid substitutions are shown in yellow. Abcb5 and Sp8 are collinear genes that had the highest correlation. Sp8 is a zinc finger transcription factor affecting limb development that is only expressed in liver and blood cells. Another gene of potential interest was Kcns3, which is a potassium voltage gated channel. However, Kcns3 is expressed in kidney, does not have any SNPs causing amino acid changes, and has a >10-fold lower level of correlation than does Abcb5.\n\n(DOCX)\n\nClick here for additional data file.\n\n S1 Text Whole genome sequencing of inbred mouse strains facilitates genetic trait analysis.\n(DOCX)\n\nClick here for additional data file.\n\n Abbreviations:\nCNScentral nervous system\n\nCSSchromosome substitution strain\n\nDESI-MSIdesorption electrospray ionization mass spectroscopic imaging\n\nGWASgenome wide association studies\n\nHBCGMhaplotype-based computational genetic mapping\n\nHEhematoxylin and eosin\n\nHIThaloperidol-induced toxicity\n\nMPTPN-methyl-4-phenyl-1,2,3,6-tetrahydropyridine\n\nNGSnext generation sequencing\n\nSEMstandard error of the mean\n==== Refs\nReferences\n1 \nOhtsuki S , Terasaki T (2007 ) Contribution of carrier-mediated transport systems to the blood-brain barrier as a supporting and protecting interface for the brain; importance for CNS drug discovery and development . 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"fulltext_license": "CC BY",
"issn_linking": "1549-1277",
"issue": "12(2)",
"journal": "PLoS medicine",
"keywords": null,
"medline_ta": "PLoS Med",
"mesh_terms": "D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D018528:ATP-Binding Cassette Transporters; D000293:Adolescent; D000328:Adult; D000483:Alleles; D000818:Animals; D014150:Antipsychotic Agents; D001812:Blood-Brain Barrier; D001921:Brain; D005260:Female; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D006220:Haloperidol; D006801:Humans; D008297:Male; D051379:Mice; D008875:Middle Aged; D020258:Neurotoxicity Syndromes; D020641:Polymorphism, Single Nucleotide; D055815:Young Adult",
"nlm_unique_id": "101231360",
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"pages": "e1001782",
"pmc": null,
"pmid": "25647612",
"pubdate": "2015-02",
"publication_types": "D016428:Journal Article; D052061:Research Support, N.I.H., Extramural; D013485:Research Support, Non-U.S. Gov't",
"references": "21623707;22143804;22118772;22306008;22251459;21079646;22207321;24037378;24309662;18332662;10700173;10932178;11722319;12491573;12960149;15499019;6611553;6332988;6335692;2861548;2868716;3486869;3545764;8301579;8071874;8090363;8847965;9042387;15803197;15899824;16296948;17390261;17277361;17549063;17619998;17982890;18180754;18791257;19135557;19451168;19505943;19875103;20135320;20613859;20729912;21298007;21079921;21652540;21827890;21793152;21921910;21875959;22037040",
"title": "The role of Abcb5 alleles in susceptibility to haloperidol-induced toxicity in mice and humans.",
"title_normalized": "the role of abcb5 alleles in susceptibility to haloperidol induced toxicity in mice and humans"
} | [
{
"companynumb": "US-JNJFOC-20150809455",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
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{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "HALOPERIDOL"
},
"drugadditional": null,
"drugadministrationroute": "065",
"drugauthorizationnumb": "015923",
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"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": "UNSPECIFIED",
"drugdosagetext": null,
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "PRODUCT USED FOR UNKNOWN INDICATION",
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
"drugrecurreadministration": "3",
"drugrecurrence": null,
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"drugstructuredosagenumb": null,
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"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "HALOPERIDOL."
}
],
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"patientonsetage": null,
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"patientsex": null,
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"reaction": [
{
"reactionmeddrapt": "Parkinsonism",
"reactionmeddraversionpt": "18.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Toxicity to various agents",
"reactionmeddraversionpt": "18.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Akathisia",
"reactionmeddraversionpt": "18.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Dyskinesia",
"reactionmeddraversionpt": "18.1",
"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "ZHENG M, ZHANG H, DILL DL, DAVID JC, TU S, YABLONOVITCH AL, ET AL. THE ROLE OF ABCB5 ALLELES IN SUSCEPTIBILITY TO HALOPERIDOL-INDUCED TOXICITY IN MICE AND HUMANS. PLOS MEDICINE 2015;12 (2):1-29.",
"literaturereference_normalized": "the role of abcb5 alleles in susceptibility to haloperidol induced toxicity in mice and humans",
"qualification": "3",
"reportercountry": "US"
},
"primarysourcecountry": "US",
"receiptdate": "20150902",
"receivedate": "20150902",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 11447693,
"safetyreportversion": 1,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 2,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
"seriousnessdisabling": null,
"seriousnesshospitalization": null,
"seriousnesslifethreatening": null,
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"transmissiondate": "20151125"
}
] |
{
"abstract": "The use of thrombopoietin-receptor agonists (TPO-RAs) has increased as a second-line therapy in ITP, but the efficacy and safety of such drugs has not been evaluated in SLE-associated ITP.\nThis was a multicentre retrospective cohort study from 2009 to 2016. Participating centres (n = 11) were secondary- or tertiary-care hospitals belonging to the French national network for adult ITP.\nWe included 18 patients with SLE-ITP treated with TPO-RAs; 10 (55%) had aPL, 5 (27%) showing definite APS. Except for one patient, all (94%) achieved response with TPO-RAs overall. After a median follow-up of 14.7 months with TPO-RAs, four arterial thrombosis events (including one catastrophic APS) occurred in four patients. Two venous thrombosis events occurred in a patient without APS or aPLs.\nOur results suggest that aPLs should be systematically screened before TPO-RA initiation in patients with SLE. With aPL positivity, alternative therapy should be discussed (if possible), especially in patients with definite APS or suboptimal adherence to anti-coagulation therapy.",
"affiliations": "Département de Médecine Interne et Immunologie Clinique, CHU Lille, Lille, France.;Département de Médecine Interne et Immunologie Clinique, CHU Lille, Lille, France.;Department of Internal Medecine, CHRU Lyon, Lyon, France.;Department of Internal Medecine, CHRU Lyon, Lyon, France.;Department of Internal Medicine, Pitie-Salpetriere University Hospital, Paris, France.;Department of Internal Medicine, Pitie-Salpetriere University Hospital, Paris, France.;Weill Cornell Medicine, New York, NY, USA.;Department of Internal Medicine, Hôtel Dieu University Hospital, Nantes, France.;Weill Department of Medicine, Internal Medecine, CHRU Nice, Nice, France.;Department of Internal Medicine, Bretonneau University Hospital, Tours, France.;Department of Internal Medicine, CHRU Toulouse, Toulouse, France.;Hematology, CHRU Réunion, Saint-Pierre, France.;Internal Medecine, CHRU Besançon, Besançon, France.;Internal Medicine, French Referral Centre for Adult Immune Cytopenia, Henri Mondor Hospital, AP-HP, UPEC University, Créteil, France.;Department of Internal Medicine, Dijon University Hospital, Dijon, France.;Internal Medicine, French Referral Centre for Adult Immune Cytopenia, Henri Mondor Hospital, AP-HP, UPEC University, Créteil, France.;Internal Medicine, French Referral Centre for Adult Immune Cytopenia, Henri Mondor Hospital, AP-HP, UPEC University, Créteil, France.",
"authors": "Guitton|Zelie|Z|;Terriou|Louis|L|;Lega|Jean-Christophe|JC|;Nove-Josserand|Raphaele|R|;Hie|Miguel|M|;Amoura|Zahir|Z|;Bussel|James B|JB|;Hamidou|Mohamed|M|;Rosenthal|Eric|E|;Lioger|Bertrand|B|;Chauveau|Dominique|D|;Chaminade|Axel|A|;Magy-Bertrand|Nadine|N|;Michel|Marc|M|;Audia|Sylvain|S|;Godeau|Bertrand|B|;Mahevas|Matthieu|M|",
"chemical_list": "D001565:Benzoates; D006834:Hydrazines; D011720:Pyrazoles; D011961:Receptors, Fc; D053628:Receptors, Thrombopoietin; D011993:Recombinant Fusion Proteins; D013926:Thrombopoietin; C488777:romiplostim; C520809:eltrombopag",
"country": "England",
"delete": false,
"doi": "10.1093/rheumatology/key119",
"fulltext": null,
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"issn_linking": "1462-0324",
"issue": "57(8)",
"journal": "Rheumatology (Oxford, England)",
"keywords": null,
"medline_ta": "Rheumatology (Oxford)",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D016736:Antiphospholipid Syndrome; D001565:Benzoates; D005260:Female; D005500:Follow-Up Studies; D005602:France; D006801:Humans; D006834:Hydrazines; D015994:Incidence; D008180:Lupus Erythematosus, Systemic; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D011720:Pyrazoles; D011961:Receptors, Fc; D053628:Receptors, Thrombopoietin; D011993:Recombinant Fusion Proteins; D012189:Retrospective Studies; D013926:Thrombopoietin; D013927:Thrombosis; D055815:Young Adult",
"nlm_unique_id": "100883501",
"other_id": null,
"pages": "1432-1438",
"pmc": null,
"pmid": "29757439",
"pubdate": "2018-08-01",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study",
"references": null,
"title": "Risk of thrombosis with anti-phospholipid syndrome in systemic lupus erythematosus treated with thrombopoietin-receptor agonists.",
"title_normalized": "risk of thrombosis with anti phospholipid syndrome in systemic lupus erythematosus treated with thrombopoietin receptor agonists"
} | [
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{
"abstract": "Transient left ventricular apical ballooning syndrome, also known as Takotsubo Cardiomyopathy (Broken Heart Syndrome) is increasingly being reported in the medical literature. Its clinical picture resembles of an acute coronary syndrome with transient apical dyskinesia and normal coronary arteries. We report here a case of Takotsubo cardiomyopathy in a patient with Addison disease with reversible cardiomyopathy. To the best of our knowledge there has been only one other reported case of this syndrome with Addison disease but with a different outcome.",
"affiliations": null,
"authors": "Punnam|Sujeeth Reddy|SR|;Gourineni|Nandu|N|;Gupta|Vishal|V|",
"chemical_list": null,
"country": "Netherlands",
"delete": false,
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"issn_linking": "0167-5273",
"issue": "144(2)",
"journal": "International journal of cardiology",
"keywords": null,
"medline_ta": "Int J Cardiol",
"mesh_terms": "D000224:Addison Disease; D000368:Aged; D005260:Female; D006801:Humans; D054549:Takotsubo Cardiomyopathy",
"nlm_unique_id": "8200291",
"other_id": null,
"pages": "e34-6",
"pmc": null,
"pmid": "19217174",
"pubdate": "2010-10-08",
"publication_types": "D002363:Case Reports; D016422:Letter",
"references": null,
"title": "Takotsubo cardiomyopathy in a patient with Addison disease.",
"title_normalized": "takotsubo cardiomyopathy in a patient with addison disease"
} | [
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{
"abstract": "BACKGROUND\nScleromyxedema is a progressive, systemic connective tissue disorder characterized by fibro-mucous skin lesions and increased serum monoclonal immunoglobulin levels. Pulmonary involvement occurs in a subset of patients, though the overall prevalence of pulmonary lesions in scleromyxedema is unknown. Since pulmonary hypertension presumably occurs in these patients due to disease progression and development of additional conditions, treatment of the underlying plasma cell dyscrasia and connective tissue disorder may improve pulmonary hypertension symptoms.\n\n\nMETHODS\nAn elderly patient with scleromyxedema developed pulmonary hypertension refractory to vasodilator and diuretic therapy and subsequently multiple myeloma that responded to a combination therapy of bortezomib, cyclophosphamide, and dexamethasone treatment.\n\n\nCONCLUSIONS\nTreatment of the underlying disease(s) that contributed to pulmonary hypertension development with anti-neoplastic agents like bortezomib may improve cardiopulmonary symptoms secondary to reducing abnormal blood cell counts and paraprotein levels.",
"affiliations": "Department of Pulmonary and Critical Care Medicine, Marshfield Clinic, Marshfield, WI, USA. mazenkreidy@hotmail.com.;Department of Internal Medicine, Marshfield Clinic, Marshfield, WI, USA.;Department of Rheumatology, Ronald Reagan UCLA Medical Center, Santa Monica, California, USA.;Department of Pathology, Marshfield Clinic, Marshfield, WI, USA.",
"authors": "Kreidy|Mazen|M|http://orcid.org/0000-0002-5123-8823;Al-Hilli|Ali|A|;Yachoui|Ralph|R|;Resnick|Jeffrey|J|",
"chemical_list": "D000069286:Bortezomib; D003907:Dexamethasone; D003520:Cyclophosphamide",
"country": "England",
"delete": false,
"doi": "10.1186/s12890-019-1020-6",
"fulltext": "\n==== Front\nBMC Pulm MedBMC Pulm MedBMC Pulmonary Medicine1471-2466BioMed Central London 102010.1186/s12890-019-1020-6Case ReportSevere but reversible pulmonary hypertension in scleromyxedema and multiple myeloma: a case report http://orcid.org/0000-0002-5123-8823Kreidy Mazen mazenkreidy@hotmail.com 15Al-Hilli Ali Al-hilli.ali@marshfieldclinic.org 2Yachoui Ralph Ralph_yachoui@hotmail.com 3Resnick Jeffrey Resnick.jeffrey@marshfieldclinic.org 41 0000 0000 9274 7048grid.280718.4Department of Pulmonary and Critical Care Medicine, Marshfield Clinic, Marshfield, WI USA 2 0000 0000 9274 7048grid.280718.4Department of Internal Medicine, Marshfield Clinic, Marshfield, WI USA 3 Department of Rheumatology, Ronald Reagan UCLA Medical Center, Santa Monica, California, USA 4 0000 0000 9274 7048grid.280718.4Department of Pathology, Marshfield Clinic, Marshfield, WI USA 5 0000 0004 0444 1241grid.414316.5Present affiliation: Christiana Care Health System, PO Box 1668, Wilmington, DE 19899 USA 9 1 2020 9 1 2020 2020 20 826 3 2019 6 12 2019 © The Author(s). 2020Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Background\nScleromyxedema is a progressive, systemic connective tissue disorder characterized by fibro-mucous skin lesions and increased serum monoclonal immunoglobulin levels. Pulmonary involvement occurs in a subset of patients, though the overall prevalence of pulmonary lesions in scleromyxedema is unknown. Since pulmonary hypertension presumably occurs in these patients due to disease progression and development of additional conditions, treatment of the underlying plasma cell dyscrasia and connective tissue disorder may improve pulmonary hypertension symptoms.\n\nCase presentation\nAn elderly patient with scleromyxedema developed pulmonary hypertension refractory to vasodilator and diuretic therapy and subsequently multiple myeloma that responded to a combination therapy of bortezomib, cyclophosphamide, and dexamethasone treatment.\n\nConclusions\nTreatment of the underlying disease(s) that contributed to pulmonary hypertension development with anti-neoplastic agents like bortezomib may improve cardiopulmonary symptoms secondary to reducing abnormal blood cell counts and paraprotein levels.\n\nKeywords\nScleromyxedemaPulmonary hypertensionMultiple myelomaBortezomibCyclophosphamideDexamethasoneissue-copyright-statement© The Author(s) 2020\n==== Body\nBackground\nScleromyxedema (papular mucinosis, generalized lichen myxedematous, Arndt-Gordon disease) is a rare, chronic, progressive disorder characterized by skin lesions with mucinous material deposition, fibrosis, increased population of fibroblasts, and high levels of immunoglobulins (monoclonal gammopathy of unknown significance [MGUS]) in serum without a corresponding thyroid abnormality [1–11]. In a subset of cases described by Rongioletti et al., immune cell infiltrates may also be present in skin lesions in a “granuloma annulare-like pattern” [7]. Scleromyxedema is a multi-organ disorder that can involve the nervous system, lungs, heart, kidneys, esophagus, larynx, eyes, muscles, bone marrow, and skin [2–11]. Death can occur due to organ involvement or evolution into a blood malignancy or other cancer [2–4, 6, 8, 10–19]. In a 2013 retrospective study of 30 scleromyxedema cases, two patients died from Hodgkin lymphoma or myeloid leukemia at 22 months and 11 years post-scleromyxedema diagnosis, respectively, without undergoing melphalan treatment (a chemotherapeutic agent associated with development of hematological malignancies) [2, 3, 6, 8, 12]. Treatment generally involves modulating the immune system, decreasing the population of plasma cells, and/or improving dermatological manifestations of the disease; pharmacological and surgical treatments include intravenous immunoglobulin (IVIG), thalidomide/thalidomide derivative lealidomide, systemic glucocorticoids, melphalan, bortezomib plus dexamethasone, and autologous stem cell transplantation among others [2–6, 8–14, 16–41].\n\nAs a dermatological condition with disease characteristics similar to scleroderma, scleromyxedema is generally classified as a connective tissue disorder with associated immune system/inflammatory responses, but due to the abnormal amounts of monoclonal immunoglobulin produced (paraproteinemia) and associated abnormal plasma cell populations, scleromyxedema is also considered a paraneoplastic and hematologic disorder [1–11, 36]. In these contexts, many scleromyxedema-associated syndromes can develop, including pulmonary hypertension (PH), myeloproliferative neoplasms (MPN), leukemia/lymphoma, and multiple myeloma [1, 6, 8–22, 24–27, 29, 31–33, 35–37, 39–41]. PH, defined by a mean pulmonary arterial pressure of ≥25 mmHg at rest, can also occur in patients with MPN and other paraneoplastic conditions, and it is demonstrated in the medical literature that PH symptoms improve in response to treatment when the underlying MPN is targeted [25, 42–63]. Therefore, prescribing treatment regimens that target the overlapping pathophysiological characteristics of these associated conditions may simultaneously improve symptomology in patients with multi-system scleromyxedema [2, 13, 17, 19–22, 24–26, 36].\n\nIn this case report, we describe the diagnosis, treatment, and progression of PH in a patient who had scleromyxedema and developed multiple myeloma refractory to triple PH treatment that resolved with a combination treatment of bortezomib, cyclophosphamide, and dexamethasone. We propose that combination therapy with the anti-neoplastic agent bortezomib is an important adjuvant therapy to reverse vasodilator resistant PH in patients with scleromyxedema and plasma cell dyscrasias.\n\nCase presentation\nA 77-year-old male nonsmoker with a history of atrial fibrillation and sick sinus syndrome post-pacemaker placement experienced edema, skin rash, and skin tightening. During the initial physical examination, yellow-brown papules and indurated and pendulous skin folds were evident on his face, neck, retroauricular area, chest, trunk, upper extremities, and thighs; he also had difficulty opening his mouth. No gross changes were observed in the digital nail beds (i.e., pitting and capillary loops) but were present in the lower extremities. Edema was present in the lower extremities. Skin biopsies revealed fibrosis and benign fibrocytic proliferation consistent with scleromyxedema (Fig. 1a). Colloidal iron staining for mucin deposition detected minimal interstitial mucin deposition in one biopsy, although Verhoeff van Gieson elastic stain highlighted fragmentation of superficial dermal collagen bundles (Fig. 1b and c). Congo red stain for amyloid deposition was negative. Aside from telangiectasia, there was no evidence of vasculopathy or thrombosis associated with these lesions. Laboratory testing of serum and urine samples detected an elevated level of immunoglobulin G (IgG) production, consistent with a diagnosis of MGUS. Electrophoresis of serum proteins revealed a total IgG level of 1500 mg/dL. Elevated levels of two IgG lambda monoclonal antibodies (~ 0.4 g/dL each) with a kappa to lambda ratio of 0.28 were detected by immunofixation of serum samples. The remaining blood values were normal for hemoglobin and calcium levels, but the patient’s kidney function was slightly above normal (creatinine level was 1.4 mg/dL and estimated glomerular filtration rate [eGFR] was 54 mL/min/1.73 m2). A 24-h urine sample was positive for lambda Bence-Jones protein at levels too low to quantitate by immunofixation. Although a skeletal survey was negative for lytic lesions, bone marrow biopsies contained 4.7% of mature looking plasma cells.\nFig. 1 Pathology analysis of skin biopsies highlighting fibrosis and fibrocytic proliferation indicative of scleromyxedema using a Hematoxylin and Eosin stain, b colloidal iron staining for mucin deposition, and c Verhoeff van Gieson elastic stain\n\n\n\nAdditional diagnostic work-up did not suggest multi-organ involvement with scleromyxedema; initial spirometry testing and diffusion lung capacity for carbon monoxide (DLCO) were within normal limits. An echocardiogram indicated the patient had diastolic dysfunction but otherwise normal right and left cardiac function and size with a normal pulmonary artery systolic pressure of 27 mmHg. He was placed on intravenous immunoglobulin G therapy at a dosage of 40 g/mL administered every 6 weeks, with a daily regimen of 60 mg prednisone and 200 mg hydroxychloroquine twice daily. There was significant improvement in the patient’s skin symptoms, and 8 weeks later, his prednisone regimen was weaned down to 5 mg per day. The patient was also started on a thalidomide regimen with an initial dose of 100 mg per day. His IgG levels decreased to 600 mg/dL after one year of maintenance therapy with this regimen.\n\nOver the following 4 years post-scleromyxedema diagnosis, the patient had three recurrences of dermatological symptoms of increasing severity. Episodes of acute symptoms were managed by a burst dose and tapering of steroid medication (prednisone at 60 mg daily until resolution of symptoms then a rapid taper to a maintenance dose of 5 mg daily) and increased dose of IVIG. Thalidomide treatment was discontinued 2 years later due to neuropathy, and hydroxychloroquine treatment was considered inefficient for ameliorating symptoms. During this period of time, the patient’s total IgG levels slowly increased to 1700 mg/dL with concurrent elevations in lambda monoclonal proteins ranging from 0.4–0.5 mg/dL and 0.6–0.7 mg/dL.\n\nAt 4 years post-diagnosis, he experienced an acute episode of skin symptoms and severe dyspnea. Severely elevated levels of brain natriuretic peptide (BNP) (2650 pg/mL), indicative of cardiac strain, were detected in serum, and echocardiographic analysis revealed an enlarged right heart with depressed systolic function and an elevated pulmonary arterial systolic pressure estimated at 70 mmHg. Left ventricular function and size was normal. Abnormal pulmonary hemodynamics (in mm Hg) were measured by right heart catheterization, specifically, pulmonary artery pressures of 66/30/42, wedge pressure of 12, right ventricular pressures at 66/15, and right atrial pressure at 13. The pulmonary vascular resistance was estimated at 8.2 international units (IU), while the cardiac output was elevated at 3.65 L/min. Pulmonary function testing revealed a low DLCO at 50%. A chest computed tomography (CT) scan excluded embolism and parenchymal lung disease as contributing factors to elevated right heart dimensions and pulmonary hemodynamics. Additional laboratory testing of serum proteins detected elevated levels of IgG proteins (3670 mg/dL) and the two lambda monoclonal proteins (1.6 g/dL and 1.3 g/dL). A follow-up bone marrow biopsy revealed an ~ 10% normal appearing population of plasma cells that were considered reactive to the patient’s underlying scleromyxedema.\n\nBased on the cardiovascular, pulmonary, and hematological analyses, the patient was diagnosed with a scleromyxedema flare with associated pulmonary arterial hypertension (PAH). He was initially placed on a dual treatment regimen for PAH consisting of 40 mg tadalafil once daily and ambrisentan 5 mg daily that was later increased to 10 mg daily. In addition to increasing the ambrisentan dosage, a daily dose of 40 mg lasix was added to the PAH treatment. Scleromyxedema treatment was optimized with the addition of intravenous chimeric antibodies against CD20 (rituximab) at a dosage and frequency similar to a protocol for rheumatoid arthritis, specifically 1 g of rituximab on days 1 and 15 of the treatment cycle over a period of 24 weeks for a total regimen of three cycles. A burst-taper dose of prednisone was also administered (60 mg, tapered over the next 8 weeks). Over the following year, inhaled trepostinil (vasodilator) was added to the PAH regimen for persistently elevated pulmonary arterial systolic pressure at 42 mmHg and right heart strain on cardiac echography.\n\nOn this treatment regimen, the patient’s acute symptoms improved, and he maintained a New York Heart Association (NYHA) functional status of class II. Although the patient’s serum BNP levels decreased to 300 pg/mL, echocardiographic analysis continued to show depressed right heart function and elevated pulmonary arterial pressure at 43 mmHg. A polysomnographic analysis indicated the patient had developed obstructive sleep apnea (Apnea–Hypopnea Index [AHI] of 24 events/hour), and he was subsequently treated with continuous positive airway pressure (CPAP) at 10 cmH2O. Intravenous prostacyclin therapy was considered for PAH, but the patient declined. Follow-up immunoglobulin analysis revealed decreased IgG levels (2060 mg/dL).\n\nDespite maintenance therapy with IVIG and rituximab, the patient developed another severe recurrence of his skin symptoms and worsening dyspnea at 6 years post-scleromyxedema diagnosis (2 years post-PAH diagnosis). Follow-up echocardiography revealed a new left ventricular cardiomyopathy with an ejection fraction of 40%, persistent elevated pulmonary arterial pressure at 44 mmHg, and persistent right ventricular dilation. Serum BNP levels were elevated at 631 pg/mL, and IgG levels had increased to 3420 mg/dL with concurrent elevations of the two monoclonal lambda proteins at 1.48 and 0.37 g/dL. A follow-up bone marrow biopsy revealed an abnormal plasma cell population of 60% consistent with a hematological abnormality. The patient was diagnosed with multiple myeloma associated with an acute episode of scleromyxedema flare up with multi-organ involvement. A treatment regimen of bortezomib (2 mg; dose adjusted per cycle depending on patient-related factors as denoted in Table 1) and dexamethasone (20 mg) (4 weeks per cycle of therapy) was initiated to decrease the plasma cell population, and IVIG treatment was continued to alleviate dermatological symptoms. Over the following 2 years, the patient received a total of seven cycles of bortezomib and dexamethasone (Table 1). There was a dramatic improvement in his PAH, cardiovascular, and dermatological symptoms. Serum analysis revealed decreased BNP and IgG levels at 100 pg/mL and 1300 mg, respectively. A repeat echocardiogram revealed significant improvement in right ventricular size and function as well as left ventricular function, but pulmonary arterial systolic pressure was still elevated at 51 mmHg. However, bortezomib had to be discontinued after the seventh cycle due to worsening neuropathy. A treatment regimen with a lenalidomide derivative (Revlimid) was attempted but also discontinued after 2 months of treatment due to adverse side effects. The patient elected to halt the inhaled trepostinil regimen.\nTable 1 Chemotherapeutic regimens administered with bortezomib for treatment of multiple myeloma and pre-existing scleromyxedema with pulmonary symptoms\n\nCycle #\tAgent 1\tDose\tAgent 2\tDose\tAgent 3\tDose\tAgent 4\tDose\t\n1\tBortezomib D1, D8, D15\t2.5 IV\tDexamethasone Weekly\t20 mg PO\tIVIG Weekly\t40 g IV\t–\t–\t\n2\tBortezomib D1, D8, D15\t2.6 S/Q\tDexamethasone Weekly\t20 mg PO\tIVIG Weekly\t40 g IV\t–\t–\t\n3\tBortezomib D1, D8, D15\t2.6 S/Q\tDexamethasone Weekly\t20 mg PO\tIVIG Weekly\t40 g IV\t–\t–\t\n4\tBortezomib D1, D8, D15\t2.6 S/Q\tDexamethasone Weekly\t20 mg PO\tIVIG Weekly\t40 g IV\t–\t–\t\n5\tBortezomib D1, D8, D15\t2.6 S/Q\tDexamethasone Weekly\t20 mg PO\tIVIG Weekly\t40 g IV\t–\t–\t\n6\tBortezomib D1, D8, D15\t2.6 S/Q\tDexamethasone Weekly\t20 mg PO\tIVIG Weekly\t40 g IV\t–\t–\t\n7\tBortezomib D1 only, developed neuropathy\t2.6 S/Q\tDexamethasone Weekly\t20 mg PO\tIVIG Weekly\t40 g IV\t\t\t\n1\tBortezomib D1, D8, D15\t1.5 mg IV\tDexamethasone Weekly\t20 mg PO\tCyclophosphamide D1, D8, D15\t300 mg IV\tIVIG Weekly\t40 g IV\t\n2\tBortezomib D1, D8, D15\t1.5 mg IV\tDexamethasone Weekly\t20 mg PO\tCyclophosphamide D1, D8, D15\t300 mg IV\tIVIG Weekly\t40 g IV\t\n3\tBortezomib D1, D8, D15\t1.6 mg IV\tDexamethasone Weekly\t20 mg PO\tCyclophosphamide D1, D8, D15\t600 mg IV\tIVIG Weekly\t40 g IV\t\n4\tBortezomib D1, D8, D15\t1.6 mg IV\tDexamethasone Weekly\t20 mg PO\tCyclophosphamide D1, D8, D15\t600 mg IV\tIVIG Weekly\t40 g IV\t\nChemotherapy break–\t–\tDexamethasone Weekly\t20 mg PO\t–\t–\tIVIG Weekly\t40 g IV\t\n5\tBortezomib D1, D8, D15\t1.2 mg IV\tDexamethasone Weekly\t20 mg PO\tCyclophosphamide D1, D8, D15\t600 mg IV\tIVIG Weekly\t40 g IV\t\n6\tBortezomib D1, D8, D15\t1.5 mg IV\tDexamethasone Weekly\t20 mg PO\tCyclophosphamide D1, D8, D15\t480 mg IV\tIVIG Weekly\t40 g IV\t\n7\tBortezomib D1, D8, D15\t2 mg IV\tDexamethasone Weekly\t20 mg PO\tCyclophosphamide D1, D8, D15\t600 mg IV\tIVIG Weekly\t40 g IV\t\n8\tBortezomib D1, D8, D15\t1.6 mg IV\tDexamethasone Weekly\t20 mg PO\tCyclophosphamide D1, D8, D15\t600 mg IV\tIVIG Weekly\t40 g IV\t\n9\tBortezomib D1, D8, D15\t2 mg IV\tDexamethasone Weekly\t20 mg PO\tCyclophosphamide D1, D8, D15\t500 mg IV\tIVIG Weekly\t40 g IV\t\n\tIron infusion\t510 mg IV\t–\t–\t–\t–\t–\t–\t\n\tPassed away\tN/A\tN/A\tN/A\tN/A\tN/A\tN/A\tN/A\t\nAbbreviations: D# Day of treatment cycle, IV Intravenous Injection, IVIG Intravenous Immunoglobulin, N/A Not applicable, PO Per Os (oral), S/Q Subcutaneos Injection, − unknown\n\n\n\nThe patient was observed for ~ 14 months before he experienced a recurrence of symptoms and cardiopulmonary decline. His IgG levels had again increased to 2000 mg/dL. The patient was placed on a weekly regimen of 3 mg bortezomib, 20 mg dexamethasone, and 600 mg of cyclophosphamide (Cytoxan) (4 weeks per cycle, last dose omitted because of pancytopenia), and IVIG maintenance therapy was continued at a dosage of 40 g/mL (see Table 1 for dose adjustments per cycle). After four cycles, the patient’s symptoms improved, and his IgG levels decreased to the lowest concentration of 1100 mg/dL. Only one monoclonal lambda protein was detected at 0.52 mg/dL. An echocardiogram revealed normalization of left and right ventricular size and function as well as normalization of pulmonary arterial systolic pressure at 23 mmHg.\n\nAfter a treatment break of 6 months, the patient’s symptoms recurred, and his IgG levels increased above 2000 mg/dL. The patient underwent five additional cycles of bortezomib, dexamethasone, and cyclophosphamide. His IgG levels stabilized between 2000 and 2500 mg/dL, and a repeat bone marrow biopsy revealed a decrease in the abnormal plasma cell population to 22%. A follow-up echocardiogram revealed normal right and left ventricular size and function and a mildly elevated pulmonary arterial systolic pressure at 38 mmHg. Future plans for the patient’s care involved slowly weaning him from his vasodilator medications; however, he suffered a sudden and fatal out-of-hospital cardiac arrest of unclear etiology at 9 years post-scleromyxedema diagnosis. No autopsy was performed.\n\nDiscussion\nPulmonary hypertension has occurred in association with various hematologic malignancies, particularly those with underlying plasma cell dyscrasias [25, 42–63]. The first case of reversible PH in response to antineoplastic treatment for a scleromyxedema-like condition and hematological malignancy was described by Yaqub et al. in 2004, and in 2015, Feyereisn described the diagnosis, treatment, and outcome of four cases of reversible PH in the setting of plasma cell dyscrasias one of which had scleromyxedema [24, 25]. The overall frequency and spectrum of PH in this setting remains largely undefined.\n\nIn our patient with scleromyxedema, multiple anti-neoplastic and immunomodulatory treatment regimens were used to alleviate dermatological and cardiopulmonary symptoms. Immunomodulatory treatments like IVIG, glucocorticoids, and hydroxychloroquine were administered over the entire course of the disease but were unable to produce a complete remission of skin and cardiopulmonary symptoms. Administration of anti-neoplastic agents like thalidomide and bortezomib led to decreased paraprotein levels on multiple occasions and corresponded to improved pulmonary dynamics in a manner similar to previously published cases [24, 25, 27, 60]. Close monitoring and treatment alteration was necessary to prevent unanticipated clinical events. Thalidomide or thalidomide derivatives were used at two points over the course of this patient’s history but were halted due to development of neuropathy and other adverse side effects. Although anti-neoplastic/chemotherapeutic agents can be associated with the development of PH, pulmonary injury, and hematological malignancies, we do not believe this occurred based on the temporal progression of scleromyxedema from a localized cutaneous condition to a generalized disease with multiple phenotypes over a period of 9 years [2–4, 6, 8, 10–12, 47, 53, 64–80]. Furthermore, PH developed 2 years after thalidomide treatment was stopped, and cardiopulmonary symptoms for the most part resolved in response to multiple myeloma treatment. Despite a partial therapeutic response with respect to abnormal plasma cell populations and IgG production, this patient experienced excellent recovery of cardiopulmonary function when on anti-neoplastic treatment regimens. Thus, a complete remission of scleromyxedema and associated plasma cell dyscrasia and paraprotein levels does not appear to be necessary to obtain a significant improvement in PH symptoms.\n\nAlthough the physiopathology of PH development in response to plasma cell dyscrasias has not been fully elucidated, the reversibility of hemodynamics in response to treatment with chemotherapeutic and immunomodulatory agents offers hope for PAH patients [24, 25, 27, 42, 43, 45, 50, 53, 57–60, 62, 63, 81–103]. Improvements in hematopoietic cell populations, paraprotein levels, and hemodynamic functions in our patient and other cases of reversible PH suggest that abnormal plasma cell populations play a central role in the development of PH [24, 25, 27, 43, 45, 50, 53, 57–60, 62, 63, 81, 84–86, 91]. Furthermore, patients with scleromyxedema and related conditions who received treatments traditionally used for multiple myeloma have exhibited decreases in IgG and paraprotein levels that co-occurred with clinical improvements, as in our patient [17, 20–25, 31, 35, 60, 61]. This may also indicate a direct link between decreased paraprotein levels and hemodynamic improvements by way of improved hyperviscosity and associated microvascular dysfunction [8]. However, detectable paraprotein levels are not always present nor correspond to the severity, progression, and response of scleromyxedema to standard treatments for this condition; therefore, the relative contribution of scleromyxedema progression and paraprotein levels to PH development is unclear [3, 5, 6, 8, 9, 13, 14, 16–18, 20–25, 31, 35, 60, 61]. Other pathobiological mechanisms invoked in the development of scleromyxedema and/or associated with plasma cell dyscrasias may also contribute to the development of PAH. These include increased secretion and expression of cytokines, dysregulation of immune system activities, and/or abnormal pulmonary fibroblasts, mucin deposition in the pulmonary vasculature, and direct invasion of the pulmonary vasculature by abnormal plasma cells [2–4, 8, 11, 14–16, 18, 27, 29, 31–38, 41, 57, 62, 63, 81, 86, 87, 96, 104–111]. Alternatively, a direct effect of chemotherapeutic agents on the pulmonary vasculature and associated abnormal humoral milieus may also have played a role in this reversibility. Due to the multifaceted nature of PH development and reversibility in response to treatment, it is also possible that a multi-hit model, as in idiopathic pulmonary arterial hypertension (IPAH), is plausible [106]. Regardless of the underlying etiology, patients with concurrent PH and MPN or vice versa have demonstrated hemodynamic improvements in response to chemotherapeutic agents; thus, patients with vasodilator-resistant PH may derive benefit from cancer treatments [25, 27, 42–63].\n\nEvidence for a cancer-like pathology and direct effects of immunosuppressive and anti-proliferative agents on PH development and progression is present in case reports for patients with PAH [24, 25, 42, 43, 45–55, 57, 58, 60–63, 76, 81, 85–87, 90–96, 105–107, 110–113]. According to Price et al., “Pathologic specimens from patients with PAH demonstrate an accumulation of perivascular inflammatory cells,” and laboratory analysis of serum from patients with PAH revealed increased levels of cytokines, chemokines as well as autoantibodies to endothelial cells and fibroblasts [105, 108, 109]. In parallel to those abnormalities, the pulmonary vascular cells of patients with PAH exhibit many features of cancerous cells from dysregulated metabolism to increased cell proliferation and resistance to apoptosis [106, 109]. These observations combined with the occurrence of PAH in various connective tissue diseases support the role of inflammation, autoimmunity, and a neoplastic-like dysregulation at the center of the pathogenesis of PAH [105–107, 110–113]. This model could provide a mechanistic explanation for the hemodynamic improvements noted in our patient and in many patients with PAH in response to immunosuppressive and anti-proliferative agents [24, 25, 27, 42–63]. The following paragraphs provide a description of currently used agents for multiple myeloma and/or scleromyxedema that have proven effective for patients with PAH.\n\nGlucocorticoids have an inhibitory effect on multiple types of immune cells and produce broad anti-inflammatory and immunosuppressive effects [114]. Glucocorticoids have been used as a treatment for scleromyxedema with positive effects reported in single case reports, and its efficacy against collagen disease-associated PAH is well known [31–35, 84, 88–90, 112–114]. Glucocorticoids are also used as a first line therapy for multiple myeloma in combination with other chemotherapy regimens in patients ineligible for autologous stem cell transplantation [115]. Improvements post-prednisolone treatment have been noted in adult and pediatric patients with iPAH as well as in monocrotaline-induced pulmonary arterial hypertension in rodents [88–90, 96, 97].\n\nRituximab is an FDA-approved chimeric anti-CD20 monoclonal antibody for various malignancies and autoimmune disorders [116]. It exerts its immunosuppressive and anti-proliferative effects through antibody- and complement-mediated dependent cellular toxicity and apoptosis and has been used anecdotally for mixed connective tissue disorders [91, 112, 116]. Previously published case reports demonstrated improvements in collagen vascular disease-associated PAH in response to rituximab treatment, and a large randomized placebo controlled clinical trial of rituximab for the treatment of scleroderma-associated PAH is currently underway (ClinicalTrials.gov identifier NCT01086540) [92, 93]. In a presumed case of iPAH, rituximab co-treatment with chemotherapy for lymphoma lead to symptom resolution, and PAH in the setting of Castleman lymphoma was also noted to respond to rituximab [63, 85]. However, in two instances, rituximab use was associated with the development of PH [79, 80].\n\nPlasma exchange or plasmapheresis is an automated technique that permits the selective therapeutic exchange of patient plasma with another fluid. Plasma exchange has been suggested as a treatment for scleromyxedema and was noted to improve PAH in association with various connective tissue diseases [37, 38, 86]. Immunoadsorption (IA), another extracorporeal automated technique to selectively remove immunoglobulins from the plasma of PAH patients via high affinity absorbers, is a promising treatment for iPAH; in 5 patients with severe iPAH awaiting transplant, IA improved symptoms associated with iPAH [94]. IA as an add-on to targeted medical therapy also led to improvements in mean PVR and CI in 10 patients with iPAH though these hemodynamic improvements did not correlate to substantial improvements in the 6 mn walk test [95].\n\nBortezomib is a proteasome inhibitor that is FDA-approved for the treatment of multiple myeloma [117, 118]. In the medical literature, patients with multiple myeloma and PH can experience reversal of PH symptoms with bortezomib treatment, although adverse pulmonary effects have also been reported in association with this drug [25, 64–71, 73, 75, 76]. Steroid co-treatments can prevent bortezomib-induced lung injury, though additional studies are needed to assess both the adverse pulmonary side effects as well as the protective effect of an adjuvant steroid regimen for bortezomib treatment [64–71, 73, 75, 76]. In animal models of pulmonary disease, bortezomib treatment reverses adverse cardiopulmonary effects and can improve survival post-monocrotaline-induced PH/PAH [98–103]. In a mouse model of hypoxia-induced PH, bortezomib treatment prevented an increase in right ventricular systolic pressure, ratio of right ventricular weight to left ventricular weight and septum (right ventricular hypertrophy index), percent medial wall thickness, and muscularization of pulmonary vessels and inhibited vascular smooth muscle proliferation [98]. A similar treatment effect was observed in rats with monocrotaline- or left-to-right shunt-induced PAH, and bortezomib treatment also enhanced survival in monocrotaline-injected rats compared to monocrotaline-injected rats without bortezomib treatment [98–102]. In a chronic hypoxia-induced PAH rat model, Ibrahim and colleagues noted that anti-tumor agents, specifically bortezomib, MG-132, and daunorubicin, decreased pulmonary vessel thickness and, in the case of daunorubicin and MG-132, improved pulmonary response to vasodilator treatment [103]. Together, these results suggest that proteasome inhibitors alone or in combination with vasodilators could potentially prevent and/or reverse PAH-induced pulmonary vessel remodeling and hemodynamic response in PAH afflicted patients [98–103].\n\nRegardless of the agent selected, it is clear from our and previous cases that PH/PAH can be improved by the addition of anti-neoplastic agents to the overall treatment regimen of patients with conditions that produce plasma cell dyscrasias, abnormal protein levels, and increased extracellular matrix deposition [24, 25, 27, 43, 45, 50, 53, 57–60, 62, 63, 81–103]. However, these therapies can produce adverse side effects that may potentially limit the number and type of treatments available for PH, multiple myeloma, and other conditions associated with multi-system scleromyxedema [2–4, 6, 8, 10–12, 47, 53, 64–80]. Careful monitoring is necessary to mitigate adverse treatment effects in this patient population.\n\nConclusion\nAlthough bortezomib and cyclophosphamide are generally used as second- and third-line treatments for scleromyxedema and related cutaneous mucinoses, these agents may be an effective primary therapy for these conditions in combination with glucocorticoids and/or proteasome inhibitors [4, 6, 8, 10, 13, 14, 16–18, 22–24, 26, 27, 30, 69, 87] especially in the presence of plasma cell dyscrasia-associated PAH. Treatment of our patient’s underlying plasma cell abnormality with a combination treatment of cyclophosphamide, bortezomib, and dexamethasone not only reduced the population of abnormal plasma cells in the bone marrow but also improved the dermatological, cardiopulmonary, and paraprotein effects of scleromyxedema and multiple myeloma-induced PH as well similar to a few other previously reported cases [24, 25, 27, 60]. Therefore, a combination regimen of cyclophosphamide, dexamethasone, and bortezomib may be an effective multi-target treatment for patients with PH refractory to vasodilator treatment, in the setting of plasma cell dyscrasias and elevated paraprotein levels. Additional work is necessary to understand the physiology of chemotherapeutic agents for PAH-associated plasma cell dyscrasias and develop treatment regimens to maximize clinical response with minimal side effects.\n\nAbbreviations\nAHIApnea–Hypopnea Index\n\nBNPBrain natriuretic peptide\n\nCPAPContinuous positive airway pressure\n\nCTComputed tomography\n\nDLCODiffusion lung capacity for carbon monoxide\n\neGFREstimated glomerular filtration rate\n\nIgGImmunoglobulin G\n\nIUInternational units\n\nIVIGIntravenous immunoglobulin\n\nMGUSMonoclonal gammopathy of unknown significance\n\nMPNMyeloproliferative neoplasms\n\nNYHANew York Heart Association\n\nPAHPulmonary Arterial Hypertension\n\nPHPulmonary Hypertension\n\nPOEMSPolyneuropathy, organomegaly, endocrinopathy/edema, M-protein, skin changes\n\nPublisher’s Note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n\nAcknowledgements\nThe authors would like to thank Emily Andreae, PhD, and Marie Fleisner for manuscript preparation and submission.\n\nAuthors’ contributions\nAll authors contributed to the preparation of this manuscript and have read and approved the final manuscript. Individual contributions: MK managed the patient’s pulmonary hypertension and led the preparation, writing, and revising of the manuscript. AAH tracked the patient’s chemotherapy schedule and generated the treatment tables for this manuscript. RY is the rheumatologist representing the department who managed the patient’s scleromyxedema and provided input from a rheumatological standpoint for the manuscript. JR prepared, analyzed, and interpreted pathology specimens.\n\nFunding\nThis work did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.\n\nAvailability of data and materials\nData sharing is not applicable to this article, as no datasets were generated or analyzed during the current study. A complete listing of data from the patient’s electronic medical record is unavailable for viewing, sharing, or dissemination per HIPAA guidelines.\n\nEthics approval and consent to participate\nAs this manuscript meets the definition of a case report, Institutional Review Board (IRB) review was not required for publication; the Marshfield Clinic Health System’s IRB does not require written patient consent unless identifiable information (i.e., facial photographs) is published. Care was provided in accordance with standard-of-care procedures and best-practice recommendations at the health care system. Convenience.\n\nConsent for publication\nWe confirm that we have obtained verbal consent to publish from the patient/participant to report the individual patient’s data and medical images. Verbal consent was obtained from the patient. 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"fulltext_license": "CC BY",
"issn_linking": "1471-2466",
"issue": "20(1)",
"journal": "BMC pulmonary medicine",
"keywords": "Bortezomib; Cyclophosphamide; Dexamethasone; Multiple myeloma; Pulmonary hypertension; Scleromyxedema",
"medline_ta": "BMC Pulm Med",
"mesh_terms": "D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D000069286:Bortezomib; D003520:Cyclophosphamide; D003907:Dexamethasone; D018450:Disease Progression; D006801:Humans; D006976:Hypertension, Pulmonary; D008297:Male; D009101:Multiple Myeloma; D053718:Scleromyxedema",
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"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "16200212;20335791;23622421;10898077;16198811;26897387;26177174;16861361;21431360;21719499;25071283;24293470;16014687;24789952;22451584;9486700;14583573;23251183;25540889;28712039;17301973;25643063;16394362;25497573;17189220;24092351;26695547;16705455;11260022;17851555;16410442;16620228;21719421;20385792;21193794;26763365;20977988;28300892;22842494;22679007;22215829;22416898;2592130;22404151;6416712;3570589;7942794;15132415;17325874;18480066;15699271;17113967;10319080;11555513;27413173;27468853;22429092;25992284;14096371;16908401;16264059;17664489;23357166;11868596;16172450;15280830;10092701;24100255;28787715;2767291;7601944;11568755;23867624;3689684;18572979;20350658;12181050;17134751;24881743;19118232;24572252;16135682;22026006;9929105;24270576;28212825;23453242;20693255;12810524;813582;18625655;1247293;2347969;16230566;3336281;22278389;28506331;26621899;26324801;28786499;16774952;26401262;9266900;20559888;25638299;8432180;17122539;18204366;28597757;21831425;23771811;15392092;11493100",
"title": "Severe but reversible pulmonary hypertension in scleromyxedema and multiple myeloma: a case report.",
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"abstract": "Hypnic jerks or sleep starts are benign myoclonic jerks that usually occur on falling asleep. Various factors like excessive caffeine intake, physical, and emotional stress can increase their frequency. Here we report a case of a female who suffered from hypnic jerks with use of selective serotonin reuptake inhibitor drug escitalopram and responding to treatment with clonazepam.",
"affiliations": "Department of Psychiatry, Lokmanya Tilak Municipal Medical College, Mumbai, Maharashtra, India.;Department of Psychiatry, Lokmanya Tilak Municipal Medical College, Mumbai, Maharashtra, India.;Department of Psychiatry, Lokmanya Tilak Municipal Medical College, Mumbai, Maharashtra, India.;Department of Psychiatry, Lokmanya Tilak Municipal Medical College, Mumbai, Maharashtra, India.",
"authors": "Sathe|Harshal|H|;Karia|Sagar|S|;Desousa|Avinash|A|;Shah|Nilesh|N|",
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"fulltext": "\n==== Front\nJ Neurosci Rural PractJ Neurosci Rural PractJNRPJournal of Neurosciences in Rural Practice0976-31470976-3155Medknow Publications & Media Pvt Ltd India JNRP-6-42310.4103/0976-3147.158797Case ReportHypnic jerks possibly induced by escitalopram Sathe Harshal Karia Sagar Desousa Avinash Shah Nilesh Department of Psychiatry, Lokmanya Tilak Municipal Medical College, Mumbai, Maharashtra, IndiaAddress for correspondence: Dr. Avinash Desousa, Carmel, 18, St. Francis Road, Off S.V. Road, Santacruz West, Mumbai - 400 054, Maharashtra, India. E-mail: avinashdes888@gmail.comJul-Sep 2015 6 3 423 424 Copyright: © Journal of Neurosciences in Rural Practice2015This is an open-access article distributed under the terms of the Creative Commons Attribution-Noncommercial-Share Alike 3.0 Unported, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Hypnic jerks or sleep starts are benign myoclonic jerks that usually occur on falling asleep. Various factors like excessive caffeine intake, physical, and emotional stress can increase their frequency. Here we report a case of a female who suffered from hypnic jerks with use of selective serotonin reuptake inhibitor drug escitalopram and responding to treatment with clonazepam.\n\nEscitalopramhypnic jerksselective serotonin reuptake inhibitor\n==== Body\nIntroduction\nHypnic jerks or sleep starts are benign myoclonic jerks that everyone experiences sometimes in a lifetime. Although they resemble the jerks of myoclonic seizures, they occur on falling asleep and are just benign nonepileptic phenomena. They occur at all ages and the patient complaining of hypnic jerks is often given a thorough epileptic evaluation.[1] They are easily identified on video electroencephalography (EEG) or normal EEG monitoring by the fact that they occur in wake to stage 1 sleep and have no epileptic correlates on EEG, but rather show a muscle artefact pattern. Furthermore, known as predormital myoclonus, hypnic jerks usually consist of a single contraction that often affects the body asymmetrically.[2] The jerk may be either spontaneous or induced by stimuli. Sleep starts are sometimes associated with the subjective impression of falling, a visual sleep start (sensation of blinding light coming from inside the eyes or head), an auditory sleep start (loud snapping noise that seems to come from inside the head) or a visual hypnagogic dream or hallucination.[3] Pure sensory phenomena in the absence of a body jerk (so-called “sensory sleep starts”) can also occur. Excessive caffeine or other stimulant intake, prior intense physical work or exercise, and emotional stress can increase the frequency and severity of sleep starts.[34] Here we report a case of a female, who suffered from hypnic jerks with use of selective serotonin reuptake inhibitor drug Escitalopram and responding to treatment with Clonazepam.\n\nCase Report\nA 45-year-old housewife had come to our outpatient department with complaints of persistent sadness of mood and decreased interest in daily activities since 2 months. She would not find pleasure in activities like watching television or talking to neighbors, which she used to like previously. She also would occasionally have crying spells without any reasons. She would feel that her life is a waste and that it was better to die rather than live such a life. However, there was no history of any suicidal attempt or any self-harm behavior. Her sleep and appetite had also decreased. She also started remaining withdrawn, not talking much, and not taking part in household activities. These complaints had started 2 months back when she got separated with her husband due to an altercation with him. She claimed that there used to be constant verbal altercations between them since the past 20 years of their marital life over varied issues. But this time, the fight led her to leave his house and stay with her mother, though they had not filed for a divorce. There was no previous history of similar complaints. She did not have any manic features, delusions, hallucinations or obsessive-compulsive symptoms. Her past medical and surgical history was also insignificant. There was no history of psychiatric illness in her family. On mental status examination, she was groomed normally and demonstrated occasional crying for a few minutes during the interview. Her mood was sad and she conveyed ideas of hopelessness, helplessness, and worthlessness. We diagnosed her as having Major Depressive Disorder as per Diagnostic and Statistical Manual 5 criteria and started her on escitalopram 10 mg/day in divided doses. On regular follow-up, in 2 weeks she showed 40% improvement in her symptoms, so we continued the same. 6 weeks after being on escitalopram therapy, she reported that she noticed jerky movements of her leg that occurred just as she was beginning to fall asleep often causing her to awaken suddenly for a moment. The jerky movement would characteristically occur in 15–30 min after falling asleep. Initially they would occur once a night, but later the frequency increased to twice or thrice every night. She also started having difficulty in falling asleep and would not get proper sleep. She thus developed daytime fatigability and sleepiness. There was no history of accompanying unconsciousness or any frothing at the mouth or uprolling of the eyeballs or any abnormal involuntary movements during daytime. She denied any history of nightmares or night terrors or other parasomnias. She was diagnosed as having sleep starts or hypnic jerks. She was reassured and was started on clonazepam 0.5 mg at night. After 10 days of starting Clonazepam, she reported a significant reduction in her jerky limb movements. We have tried to reduce clonazepam and take patient off clonazepam but the patient was very much apprehensive of recurrence of jerks so requested us to let her be on same, so she is still on clonazepam and well maintained.\n\nDiscussion\nVarious hypotheses have been proposed in the etiology of hypnic jerks. One of them states that these jerks are a natural step in the transition from alertness to sleep made via the reticular activating system, where some of the nerves of the hands and legs misfire. Yet another theory states that it is a basic protective reflex. Complete relaxation of the muscles is interpreted by the brain as falling and in order to prevent this the brain orders the muscle to twitch.[5] Polysomnography can be helpful in confirming the diagnosis which can also be done clinically.[5] Differential diagnosis of hypnic jerks includes myoclonic seizures, rapid eye movement behavior sleep disorder, rhythmic movement disorder, benign sleep myoclonus of infancy, etc. From a prognostic perspective, these are benign phenomena, but they need to be treated if they interfere with one's sleep. The management includes nonpharmacological methods such as reducing caffeine intake, exercise in moderation during the daytime, and improved sleep hygiene with most importantly psychological reassurance to the patient. If needed, rapid onset benzodiazepines are the drugs of choice.[6] On a thorough literature search, we did not find any case report on escitalopram induced hypnic jerks and this is a rare, but unique side effect that clinical psychiatrists need to be cognizant of.\n\nSource of Support: Nil.\n\nConflict of Interest: None declared.\n==== Refs\n1 Derry CP Duncan JS Berkovic SF Paroxysmal motor disorders of sleep: The clinical spectrum and differentiation from epilepsy Epilepsia 2006 47 1775 91 17116016 \n2 Fryer J Hypnic reflex: A spinal perspective J Sleep Disord Ther 2014 3 5 6 \n3 Frenette E Guilleminault C Nonepileptic paroxysmal sleep disorders Handb Clin Neurol 2013 112 857 60 23622294 \n4 Lozsadi D Myoclonus: A pragmatic approach Pract Neurol 2012 12 215 24 22869763 \n5 Vetrugno R Montagna P Sleep-to-wake transition movement disorders Sleep Med 2011 12 Suppl 2 S11 6 22136891 \n6 Avidan AY Parasomnias and movement disorders of sleep Semin Neurol 2009 29 372 92 19742413\n\n",
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"keywords": "Escitalopram; hypnic jerks; selective serotonin reuptake inhibitor",
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"pubdate": "2015",
"publication_types": "D002363:Case Reports",
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"title": "Hypnic jerks possibly induced by escitalopram.",
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"abstract": "Contrast-enhanced spectral detector-based computed tomography (SDCT) allows for the comprehensive and retrospective analysis. We report a case of pulmonary thromboembolism (PE) accompanied by non-ST-segment elevation myocardial infarction (NSTEMI) diagnosed by SDCT.\nA 72-year-old man with diabetes mellitus, hypertension, and prostate cancer suddenly developed chest and back pain and had difficulty in breathing at rest. Electrocardiography showed a right bundle branch block without significant ST-segment change. The initial serum troponin I level was 0.05 ng/mL, and the d-dimer level was 14.7 μg/mL. Spectral detector-based computed tomography showed bilateral scattered PE. After admission, his chest pain persisted, and the serum troponin I level 3 h after admission was elevated to 0.90 ng/mL. Reconstruction of SDCT images showed a perfusion defect of the posterolateral left ventricle myocardium. A coronary angiogram showed total occlusion of the obtuse marginal branch (OM); percutaneous coronary intervention was performed. Furthermore, we administered him with oral anticoagulants (OACs) for PE. Spectral detector-based computed tomography tests performed 6 months after the treatment was initiated, until when the dual antiplatelet therapy and OAC therapy were continued, showed improvement in perfusion defects of both pulmonary fields and the myocardium. His treatment was deescalated to single antiplatelet therapy and OAC, and the patient has had a good course.\nNon-ST-segment elevation myocardial infarction is sometimes difficult to diagnose accurately, especially in the hyper-acute phase or in the OM branch. The reconstruction of spectral images from enhanced SDCT was helpful to diagnose this unique combination of PE and NSTEMI and may be useful for evaluating therapeutic effects in such patients.",
"affiliations": "Department of Cardiology, Tokyo Metropolitan Geriatric Hospital, 35-2 Sakaechou, Itabashi-ku, Tokyo 173-0015, Japan.;Department of Cardiology, Tokyo Metropolitan Geriatric Hospital, 35-2 Sakaechou, Itabashi-ku, Tokyo 173-0015, Japan.;Department of Cardiology, Tokyo Metropolitan Geriatric Hospital, 35-2 Sakaechou, Itabashi-ku, Tokyo 173-0015, Japan.;Department of Cardiology, Tokyo Metropolitan Geriatric Hospital, 35-2 Sakaechou, Itabashi-ku, Tokyo 173-0015, Japan.",
"authors": "Aoyama|Rie|R|0000-0001-8018-1726;Murata|Teppei|T|;Ishikawa|Joji|J|;Harada|Kazumasa|K|",
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"fulltext": "\n==== Front\nEur Heart J Case Rep\nEur Heart J Case Rep\nehjcr\nEuropean Heart Journal: Case Reports\n2514-2119 Oxford University Press \n\n10.1093/ehjcr/ytaa284\nytaa284\nCase Reports\nCardiac Imaging (Echocardiography / Cardiac MRI / Nuclear Cardiology)\nAcademicSubjects/MED00200\nCase report of non-ST-segment elevation myocardial infarction diagnosed in spectral detector-based computed tomography performed for the diagnosis of acute pulmonary embolism\nhttp://orcid.org/0000-0001-8018-1726Aoyama Rie \nDepartment of Cardiology, Tokyo Metropolitan Geriatric Hospital, 35-2 Sakaechou, Itabashi-ku, Tokyo 173-0015, Japan\n Murata Teppei \nDepartment of Cardiology, Tokyo Metropolitan Geriatric Hospital, 35-2 Sakaechou, Itabashi-ku, Tokyo 173-0015, Japan\n Ishikawa Joji \nDepartment of Cardiology, Tokyo Metropolitan Geriatric Hospital, 35-2 Sakaechou, Itabashi-ku, Tokyo 173-0015, Japan\n Harada Kazumasa \nDepartment of Cardiology, Tokyo Metropolitan Geriatric Hospital, 35-2 Sakaechou, Itabashi-ku, Tokyo 173-0015, Japan\n Brown Richard Alexander Handling Editor Monika Aranauskaite Editor Piotr Nikodem Rudzínski Editor Alberto Bouzas-Mosquera Editor Parham Eshterhardi Editor Simovic Stefan Editor Peregrine Green Editor Corresponding author. Tel: +81 3 3964 1141, Email: r-aoyama@nms.ac.jp\n10 2020 \n09 9 2020 \n09 9 2020 \n4 5 1 7\n21 3 2020 15 4 2020 29 7 2020 © The Author(s) 2020. Published by Oxford University Press on behalf of the European Society of Cardiology.2020This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.comAbstract\nBackground\nContrast-enhanced spectral detector-based computed tomography (SDCT) allows for the comprehensive and retrospective analysis. We report a case of pulmonary thromboembolism (PE) accompanied by non-ST-segment elevation myocardial infarction (NSTEMI) diagnosed by SDCT.\n\nCase summary\nA 72-year-old man with diabetes mellitus, hypertension, and prostate cancer suddenly developed chest and back pain and had difficulty in breathing at rest. Electrocardiography showed a right bundle branch block without significant ST-segment change. The initial serum troponin I level was 0.05 ng/mL, and the d-dimer level was 14.7 μg/mL. Spectral detector-based computed tomography showed bilateral scattered PE. After admission, his chest pain persisted, and the serum troponin I level 3 h after admission was elevated to 0.90 ng/mL. Reconstruction of SDCT images showed a perfusion defect of the posterolateral left ventricle myocardium. A coronary angiogram showed total occlusion of the obtuse marginal branch (OM); percutaneous coronary intervention was performed. Furthermore, we administered him with oral anticoagulants (OACs) for PE. Spectral detector-based computed tomography tests performed 6 months after the treatment was initiated, until when the dual antiplatelet therapy and OAC therapy were continued, showed improvement in perfusion defects of both pulmonary fields and the myocardium. His treatment was deescalated to single antiplatelet therapy and OAC, and the patient has had a good course.\n\nDiscussion\nNon-ST-segment elevation myocardial infarction is sometimes difficult to diagnose accurately, especially in the hyper-acute phase or in the OM branch. The reconstruction of spectral images from enhanced SDCT was helpful to diagnose this unique combination of PE and NSTEMI and may be useful for evaluating therapeutic effects in such patients.\n\nCase reportContrast medium-enhanced spectral detector-based computed tomographyAcute coronary syndromePulmonary thromboembolism\n==== Body\nLearning points\nNon-ST-segment elevation acute coronary syndrome (ACS) can be difficult to diagnose accurately, especially in the hyper-acute phase or in the obtuse marginal branch where changes in physiological tests are less likely to be reflected.\n\nThe reconstruction of spectral images from contrast medium-enhanced spectral detector-based computed tomography even without electrocardiogram synchronization may be helpful to improve the diagnostic accuracy of ACS and may be useful for evaluating the therapeutic effects.\n\n\n\n\nIntroduction\nAcute chest pain is one of the most important clinical symptoms and one of the main reasons for presentation to the emergency department. Patients with acute coronary syndrome (ACS), aortic dissection, or pulmonary thromboembolism (PE) may present with similar symptoms, and the diagnosis of the latter two diseases is usually made with contrast-enhanced computed tomography (CT) without electrocardiogram (ECG) synchronization. Although coronary CT angiography (CCTA) provides accurate diagnosis for coronary artery lesions, the diagnostic value of non-ECG-synchronized CT, which is often performed in the emergency department, is not as high when compared to CCTA.1–5 Besides, ECG synchronization is needed to obtain CCTA images and the heart rate must be within the optimal range. Reperfusion time is especially important in ACS, and therefore it is often difficult to obtain CCTA images. The evaluation of myocardial perfusion in non-ECG-synchronized CT may sometimes detect myocardial infarction; however, if the infarcted region is small, this may be overlooked.6,7 Thus multiple imaging techniques are performed to make a differential diagnosis; however, we sometimes meet cases that are difficult to diagnose.\n\nContrast medium-enhanced spectral detector-based computed tomography (SDCT) has the potential for comprehensive analysis of the coronary artery morphology as well as changes in myocardial perfusion.6,8–10 Tissues in the human body and iodine-based contrast media have unique absorption characteristics when penetrated with different X-ray energy levels, which enables mapping of the iodine and blood distribution. SDCT can retrospectively reconstruct images to clarify the iodine and blood distribution.\n\nWe experienced a case of PE accompanied by ACS in the obtuse marginal branch (OM) which is sometimes difficult to diagnose. If the patient is initially scanned with SDCT, adding the retrospective valuation of the images made a clear diagnose possible.\n\nTimeline\nTime\tEvents\t\n2 years previously\tDiagnosed with diabetes mellitus, hypertension, and prostate cancer accompanied by multiple bone metastasis. Medication therapy was started\t\nDay 1\t\t\n 13:00\tThe patient had sudden-onset chest pain and dyspnoea\t\n 15:00\tHe was transferred to our emergency department and diagnosed with pulmonary thromboembolism by enhanced computed tomography\t\n 18:00\tHis chest pain persisted and his serum troponin I level, 3 h after the admission was elevated to 0.90 ng/mL. Reconstruction of the spectral detector-based computed tomography (SDCT) images showed a perfusion defect of the posterolateral left ventricle myocardium\t\n 18:30\tA coronary angiogram was performed, which showed total occlusion of the obtuse marginal branch. Consequently, percutaneous coronary intervention (PCI) was performed at the occlusion site. After thrombectomy, two drug-eluting stents were deployed\t\n\tPeak post-PCI creatine kinase was 2034 IU/L. Dual antiplatelet therapy (aspirin 100 mg and clopidogrel 75 mg/day) and oral anticoagulant (OAC) therapy (rivaroxaban 30 mg/day for 3 weeks and 15 mg/day after 3 weeks) were started\t\nDay 14\tHe had a good clinical course and was discharged\t\n6 months after the treatment started\t\nThe SDCT showed an improvement in the perfusion defects of both pulmonary fields and the myocardium\n\n\nSingle antiplatelet therapy (clopidogrel 75 mg/day) and OAC therapy (rivaroxaban 15 mg/day) were continued, and the patient felt well without any recurrence\n\n\n\t\nCase presentation\nA 72-year-old man with diabetes mellitus, hypertension, and prostate cancer accompanied by multiple bone metastasis had sudden chest and back pain and difficulty in breathing at rest. His chest pain was accompanied by heaviness, squeezing, and discomfort. His prostate cancer had been treated with bicalutamide (80 mg/day) for ∼2 years, and his cancer stage was stable. He was brought to our hospital by ambulance and his vital signs were as follows: heart rate 72/min, respiratory rate 24/min, an axillary temperature 36.2°C, saturation of percutaneous oxygen under room air 90%, and peak blood pressure of 190/108 mmHg. There was no pleural effusion or congestion in the chest radiograph (Figure 1A). Electrocardiography showed sinus rhythm with a complete right bundle branch block (CRBBB) and no significant ST-segment changes (Figure 1B). His initial serum troponin I level was 0.05 ng/mL (normal value: <0.04 ng/mL) and the d-dimer level was 14.7 μg/mL (normal value: <1.0 μg/mL). White blood cell count was 12 900/μL (normal value: 4000–7500/μL) and brain natriuretic peptide was 110 pg/mL (normal value: <18.4 pg/mL); other laboratory values were within normal range. The echocardiogram did not show any wall motion abnormality, significant valve disease, right ventricle dilation, or obvious congenital heart disease such as a patent foramen ovale. His chest CT with contrast showed bilateral scattered PE and left deep vein thrombus (from popliteal vein to soleus vein) (Figure 2). After admission, his chest pain persisted, and the serum troponin I level and ECG were checked repeatedly. Although his serial ECG did not show no significant changes (Figure 1C), his serum troponin I level 3 h after the admission was elevated to 0.90 ng/mL. Furthermore, reconstruction of the SDCT (IQon Spectral CT; Philips healthcare) images clearly showed a perfusion defect of the posterolateral left ventricle myocardium (Figure 4C), suggesting a combination of PE and non-ST-segment elevation myocardial infarction (NSTEMI).\n\n\nFigure 1 (A) Chest X-ray images in the anteroposterior view demonstrating no congestion and pleural effusion. (B) Electrocardiogram demonstrating sinus rhythm with complete right bundle branch block and no significant ST-segment change. (C) Serial electrocardiogram tests demonstrating no significant ST-segment change.\n\nFigure 2 Enhanced computed tomography scan in the axial plane and in the soft tissue window demonstrating bilateral scattered pulmonary thromboembolism and left deep vein thrombus in the soleus vein (red arrows).\n\nFollowing these findings, coronary angiogram was then performed which showed total occlusion of the OM branch. Although atherosclerotic plaques were seen in multiple coronary arteries, significant stenosis was not observed except for the OM branch (Figure 3A and Video 1). Consequently, percutaneous coronary intervention (PCI) was performed to the occlusion site. After thrombectomy, intracoronary imaging using intravascular ultrasound was performed, and atherosclerotic plaque lesions were observed (Figure 3B). Two drug-eluting stents were deployed (Synergy 2.75/28 mm and Synergy 2.25/20 mm), and Thrombolysis in Myocardial Infarction 3 flow was achieved (Figure 3C and Video 2). The creatine kinase (CK) and CK-MB peaked at 2034 and 278 IU/L (normal values: CK 60–287 IU/L and CK-MB <25 IU/L) 8 h after the admission.\n\nFigure 3 (A) Coronary angiography demonstrating atherosclerotic plaques in multiple coronary arteries and total occlusion of the obtuse marginal branch (white triangles). (B) Intravascular ultrasound after thrombectomy demonstrating atherosclerotic plaque lesions in the middle of the obtuse marginal branch. (C) Percutaneous coronary intervention was performed to the occlusion site and two drug-eluting stents were deployed, and Thrombolysis in Myocardial Infarction 3 flow was achieved.\n\nFollowing treatment of ACS, we began treatment for PE with an oral anticoagulant (OAC, rivaroxaban 30 mg/day).11 He was relieved of his chest symptoms and was rescued from a hypoxic state. He was discharged on the 14th day after admission. Enhanced SDCT and associated reconstructed images of effective atomic number (Z-effective) 6 months after the treatment started, until when dual antiplatelet therapy (aspirin 100 mg and clopidogrel 75 mg/day) and OAC therapy (rivaroxaban 30 mg/day for 3 weeks and 15 mg/day after 3 weeks) were continued, showed improvement in perfusion defects in both pulmonary fields (Figure 4A and B) and the myocardium (Figure 4C and D). His treatment was deescalated to single antiplatelet therapy (clopidogrel 75 mg/day) and OAC,12 and he has had a good course without recurrence.\n\nFigure 4 The reconstructed effective atomic number (Z-effective) images of enhanced spectral detector-based computed tomography demonstrating the improvement of the perfusion defects both pulmonary fields (red circles) and posterolateral left ventricle myocardium (yellow triangles). (A) Pulmonary fields at the admission. (B) Pulmonary fields 6 months after the treatment started. (C) Myocardium at the admission. (D) Myocardium 6 months after the treatment started.\n\nDiscussion\nGenerally, the risk of PE as venous thrombosis and the risk of ischaemic heart disease, which is mainly due to plaque rupture or atherosclerosis, do not necessarily match. In this case, he had a cancer-bearing status as a risk factor of PE, with multiple coronary risk factors. Furthermore, his prostate cancer had been treated with bicalutamide, a non-steroidal anti-androgen. Although the risk of thrombosis with this drug is lower than that with conventional steroid-based drugs, we cannot deny the thrombotic effects of the drug. The presence of multiple coronary risk factors and arteriosclerotic lesions might be related to the coronary plaque rupture. We believe that the presence of multiple risk factors and the anti-androgen therapy led to the onset of the rare combination in our patient.\n\nAcute chest pain is one of the main reasons for presentation to the emergency department. The diagnostic usefulness of CCTA for patients presenting with acute chest pain to the emergent department has been established.13 This case showed sinus rhythm within normal heart rate range which might enable to take CCTA and it might be possible to take less time for reperfusion. Since D-dimer level was high and ECG and the serum troponin I level were within normal range, we did not strongly doubt ACS. If SDCT was taken in ECG synchronization, it might be possible to reduce reperfusion time.\n\nClinical applications of SDCT have been widely reported, and the usefulness of its application in cardiovascular disease has also been documented.14–16 Reconstruction yields a colour map of iodine content within tissues. The iodine distribution is determined based on the unique X-ray absorption characteristics at different kilovoltage levels. The reconstruction of the image was helpful for the recognition of the perfusion defect and may be beneficial for diagnosis of myocardial infarction.\n\nWe could not diagnose ACS immediately due to the lack of a troponin level elevation in the initial test or ECG changes in the serial tests, and CRBBB made it more difficult to detect ST-segment changes. Moreover, PEs show similar symptoms to ACS. Although biomarkers such as CK, CK-MB, and troponin I are measured in patients with chest pain, troponin I becomes positive 3–4 h after the onset and CK becomes positive 4–6 h after the onset. Therefore, it is not necessarily useful for diagnosis of the hyper-acute phase of ACS. The diagnosis of ACS is sometimes challenging when ECG does not show any significant ST-segment changes, especially when the culprit lesion is in the left circumflex artery and/or in the side branch of a main coronary artery.17,18 We thought that this case was an ACS of the OM branch, which did not have a comparatively large perfusion area. We also thought that this was not a case of Type 2 myocardial infarction due to acute PE, because (i) there was further increase in myocardial deviant enzymes, (ii) thrombectomy in PCI improved the coronary flow of the OM branch, and (iii) the perfusion defect corresponding to the region of the OM branch improved in the chronic phase. These facts support that the complete blockage of coronary flow from the thrombotic formation by a plaque rupture of OM branch, rather than myocardial injury due to hypoxia; furthermore, we think that it occurred at approximately the same time as the onset of PE.\n\nAssessment of myocardial perfusion may enhance the ability of CT to detect ACS in patients with acute chest pain.19 In this case, Figure 2 shows a mild perfusion defect in the posterolateral region of the myocardium; but we cannot deny the possibility of contrast non-uniformity and cannot definitely diagnose a myocardial infarction. By incorporating the reconstruction of effective atomic number images of the thoracic region, it is possible to arrive at a diagnosis.\n\nFurthermore, the PE lesions were significantly improved by the administration of OAC and we could confirm the remarkable improvement of the perfusion defects in the SDCT images. Spectral detector-based CT was also able to identify pulmonary perfusion defects. The diagnostic accuracy of SDCT in PE has also been reported.20,21\n\nNon-ST-segment elevation myocardial infarction ACS can sometimes be difficult to diagnose accurately, especially in the hyper-acute phase or in the OM branch where changes in physiological tests are less likely to be reflected. The reconstruction of spectral images from contrast medium-enhanced SDCT even without ECG synchronization was helpful to diagnose this unique combination of PE and NSTEMI and may be useful for evaluating the therapeutic effects.\n\nLead author biography\nRie Aoyama is a head physician in the Cardiology Department of Tokyo Metropolitan Geriatric Hospital and an interventional cardiologist with over 15 years of experience in the field. Her clinical interests include complex PCI, coronary imaging, TAVR, and interventional approach for hypertrophic cardiomyopathy. She was graduated from Nippon Medical graduate school in 2016, PhD in Coronary imaging and interventional approach for hypertrophic cardiomyopathy. Her research interests include intra-left ventricular blood flow and myocardium metabolism in hypertrophic cardiomyopathy and valvular heart disease and exploring sex-based differences in valvular heart disease.\n\nSupplementary material\n\nSupplementary material is available at European Heart Journal - Case Reports online.\n\n\nSlide sets: A fully edited slide set detailing this case and suitable for local presentation is available online as Supplementary data.\n\n\nConsent: The author/s confirm that written consent for submission and publication of this case report including image(s) and associated text has been obtained from the patient in line with COPE guidance.\n\n\nConflict of interest: none declared.\n\nSupplementary Material\nytaa284_Supplemntary_Data Click here for additional data file.\n==== Refs\nReferences\n1 \nMano Y , Anzai T , Yoshizawa A , Itabashi Y , Ohki T. \nRole of non-electrocardiogram-gated contrast-enhanced computed tomography in the diagnosis of acute coronary syndrome\n. Heart Vessels 2015 ;30 :1 –8\n.24221182 \n2 \nWatanabe T , Furuse Y , Ohta Y , Kato M , Ogawa T , Yamamoto K. \nThe effectiveness of non-ECG-gated contrast-enhanced computed tomography for the diagnosis of non-ST segment elevation acute coronary syndrome\n. Int Heart J 2016 ;57 :558 –564\n.27593539 \n3 \nSchepis T , Achenbach S , Marwan M , Muschiol G , Ropers D , Daniel WG \net al\nPrevalence of first-pass myocardial perfusion defects detected by contrast-enhanced dual-source CT in patients with non-ST segment elevation acute coronary syndromes\n. Eur Radiol 2010 ;20 :1607 –1614\n.20155270 \n4 \nBudoff MJ , Dowe D , Jollis JG , Gitter M , Sutherland J , Halamert E \net al\nDiagnostic performance of 64-multidetector row coronary computed tomographic angiography for evaluation of coronary artery stenosis in individuals without known coronary artery disease: results from the prospective multicenter ACCURACY (Assessment by Coronary Computed Tomographic Angiography of Individuals Undergoing Invasive Coronary Angiography) trial\n. J Am Coll Cardiol 2008 ;52 :1724 –1732\n.19007693 \n5 \nMeijboom WB , Mollet NR , Van Mieghem CA , Weustink AC , Pugliese F , van Pelt N \net al\n64-Slice CT coronary angiography in patients with non-ST elevation acute coronary syndrome\n. Heart 2007 ;93 :1386 –1392\n.17344332 \n6 \nRubinshtein R , Miller TD , Williamson EE , Kirsch J , Gibbons RJ , Primak AN \net al\nDetection of myocardial infarction by dual-source coronary computed tomography angiography using quantitated myocardial scintigraphy as the reference standard\n. Heart 2009 ;95 :1419 –1422\n.19196731 \n7 \nBranch KR , Busey J , Mitsumori LM , Strote J , Caldwell JH , Busch JH \net al\nDiagnostic performance of resting CT myocardial perfusion in patients with possible acute coronary syndrome\n. AJR Am J Roentgenol 2013 ;200 :W450 –W457\n.23617513 \n8 \nKerl JM , Deseive S , Tandi C , Kaiser C , Kettner M , Korkusuz H \net al\nDual energy CT for the assessment of reperfused chronic infarction—a feasibility study in a porcine model\n. Acta Radiol 2011 ;52 :834 –839\n.21873508 \n9 \nHan R , Sun K , Lu B , Zhao R , Li K , Yang X. \nDiagnostic accuracy of coronary CT angiography combined with dual-energy myocardial perfusion imaging for detection of myocardial infarction\n. Exp Ther Med 2017 ;14 :207 –213\n.28672916 \n10 \nPatino M , Prochowski A , Agrawal MD , Simeone FJ , Gupta R , Hahn PF \net al\nMaterial separation using dual-energy CT: current and emerging applications\n. Radiographics 2016 ;36 :1087 –1105\n.27399237 \n11 \nYamada N , Hirayama A , Maeda H , Sakagami S , Shikata H , Prins MH \net al\nOral rivaroxaban for Japanese patients with symptomatic venous thromboembolism—the J-EINSTEIN DVT and PE program\n. Thromb J 2015 ;13 :2 .25717286 \n12 \nValgimigli M , Bueno H , Byrne RA , Collet J-P , Costa F , Jeppsson A \net al; ESC Scientific Document Group; ESC Committee for Practice Guidelines (CPG); ESC National Cardiac Societies. \n2017 ESC focused update on dual antiplatelet therapy in coronary artery disease developed in collaboration with EACTS: the Task Force for dual antiplatelet therapy in coronary artery disease of the European Society of Cardiology (ESC) and of the European Association for Cardio-Thoracic Surgery (EACTS)\n. Eur Heart J 2018 ;39 :213 –260\n.28886622 \n13 \nRaff GL , Chinnaiyan KM , Cury RC , Garcia MT , Hecht HS , Hollander JE \net al\nSCCT guidelines on the use of coronary computed tomographic angiography for patients presenting with acute chest pain to the emergency department: a report of the Society of Cardiovascular Computed Tomography Guidelines Committee\n. J Cardiovasc Comput Tomogr 2014 ;8 :254 –271\n.25151918 \n14 \nMachida H , Tanaka I , Fukui R , Shen Y , Ishikawa T , Tate E \net al\nDual-energy spectral CT: various clinical vascular applications\n. Radiographics 2016 ;36 :1215 –1232\n.27399244 \n15 \nParakh A , Macri F , Sahani D. \nDual-energy computed tomography: dose reduction, series reduction, and contrast load reduction in dual-energy computed tomography\n. Radiol Clin North Am 2018 ;56 :601 –624\n.29936950 \n16 \nVliegenthart R , Pelgrim GJ , Ebersberger U , Rowe GW , Oudkerk M , Schoepf UJ. \nDual-energy CT of the heart\n. AJR Am J Roentgenol 2012 ;199 :S54 –S63\n.23097168 \n17 \nArai R , Fukamachi D , Ebuchi Y , Akutsu N , Okumura Y. \nPotential utility of non-gated enhanced computed tomography for an early diagnosis of myocardial infarctions\n. Intern Med 2020 ;59 :215 –219\n.31511486 \n18 \nMovahed A , Becker LC. \nElectrocardiographic changes of acute lateral wall myocardial infarction: a reappraisal based on scintigraphic localization of the infarct\n. J Am Coll Cardiol 1984 ;4 :660 –666\n.6481007 \n19 \nBezerra HG , Loureiro R , Irlbeck T , Bamberg F , Schlett CL , Rogers I \net al\nIncremental value of myocardial perfusion over regional left ventricular function and coronary stenosis by cardiac CT for the detection of acute coronary syndromes in high-risk patients: a subgroup analysis of the ROMICAT trial\n. J Cardiovasc Comput Tomogr 2011 ;5 :382 –391\n.22146497 \n20 \nSi-Mohamed S , Moreau-Triby C , Tylski P , Tatard-Leitman V , Wdowik Q , Boccalini S \net al\nHead-to-head comparison of lung perfusion with dual-energy CT and SPECT-CT\n. Diagn Interv Imaging 2020 ;101 :299 –310\n.32173289 \n21 \nThieme SF , Graute V , Nikolaou K , Maxien D , Reiser MF , Hacker M \net al\nDual energy CT lung perfusion imaging–correlation with SPECT/CT\n. Eur J Radiol 2012 ;81 :360 –365\n.21185141\n\n",
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"issue": "4(5)",
"journal": "European heart journal. Case reports",
"keywords": "Acute coronary syndrome; Case report; Contrast medium-enhanced spectral detector-based computed tomography; Pulmonary thromboembolism",
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"title": "Case report of non-ST-segment elevation myocardial infarction diagnosed in spectral detector-based computed tomography performed for the diagnosis of acute pulmonary embolism.",
"title_normalized": "case report of non st segment elevation myocardial infarction diagnosed in spectral detector based computed tomography performed for the diagnosis of acute pulmonary embolism"
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{
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],
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"literaturereference": "AOYAMA R, MURATA T, ISHIKAWA J, HARADA K. CASE REPORT OF NON?ST?SEGMENT ELEVATION MYOCARDIAL INFARCTION DIAGNOSED IN SPECTRAL DETECTOR?BASED COMPUTED TOMOGRAPHY PERFORMED FOR THE DIAGNOSIS OF ACUTE PULMONARY EMBOLISM. EUROPEAN HEART JOURNAL ? CASE REPORTS. 2020?4(5):1?7.",
"literaturereference_normalized": "case report of non st segment elevation myocardial infarction diagnosed in spectral detector based computed tomography performed for the diagnosis of acute pulmonary embolism",
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{
"abstract": "An 83-year-old Caucasian man with cutaneous T-cell lymphoma developed an aggressive squamous cell carcinoma of the left forearm, which recurred and metastasized after Mohs micrographic surgery and systemic chemotherapy with cis-platin and 5-fluorouracil. He was treated with extracorporeal photopheresis, radiation therapy, PUVA photochemotherapy, and interferon therapy for cutaneous T-cell lymphoma. Aggressive squamous cell carcinoma can occur in the setting of extracorporeal photopheresis.",
"affiliations": "Department of Dermatology, New York-Presbyterian Hospital, Columbia Presbyterian Center, New York, USA.",
"authors": "Gmyrek|R|R|;Beer|R|R|;Elizeri|Y|Y|;Oster|M W|MW|;Silvers|D N|DN|;Schneiderman|P|P|;Grossman|M E|ME|",
"chemical_list": "D002945:Cisplatin; D005472:Fluorouracil",
"country": "United States",
"delete": false,
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"fulltext": null,
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"issn_linking": "0011-4162",
"issue": "64(4)",
"journal": "Cutis",
"keywords": null,
"medline_ta": "Cutis",
"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D000671:Amputation; D000971:Antineoplastic Combined Chemotherapy Protocols; D002294:Carcinoma, Squamous Cell; D002945:Cisplatin; D003131:Combined Modality Therapy; D018450:Disease Progression; D017809:Fatal Outcome; D005472:Fluorouracil; D006801:Humans; D008207:Lymphatic Metastasis; D016410:Lymphoma, T-Cell, Cutaneous; D008297:Male; D015580:Mohs Surgery; D009364:Neoplasm Recurrence, Local; D017893:Photopheresis; D012878:Skin Neoplasms; D012883:Skin Ulcer",
"nlm_unique_id": "0006440",
"other_id": null,
"pages": "261-4",
"pmc": null,
"pmid": "10544882",
"pubdate": "1999-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Invasive squamous cell carcinoma with sporotrichoid metastasis in a patient with cutaneous T cell lymphoma treated with chronic extracorporeal photopheresis.",
"title_normalized": "invasive squamous cell carcinoma with sporotrichoid metastasis in a patient with cutaneous t cell lymphoma treated with chronic extracorporeal photopheresis"
} | [
{
"companynumb": "US-MALLINCKRODT-T201703409",
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],
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"reaction": [
{
"reactionmeddrapt": "Thrombosis",
"reactionmeddraversionpt": "20.1",
"reactionoutcome": "5"
},
{
"reactionmeddrapt": "Skin squamous cell carcinoma metastatic",
"reactionmeddraversionpt": "20.1",
"reactionoutcome": "3"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "GMYREK R; BEER R; ELIZERI Y; OSTER MW; SILVERS DN; SCHNEIDERMAN P, GROSSMAN ME. INVASIVE SQUAMOUS CELL CARCINOMA WITH SPOROTRICHOID METASTASIS IN A PATIENT WITH CUTANEOUS T CELL LYMPHOMA TREATED WITH CHRONIC EXTRACORPOREAL PHOTOPHERESIS. CUTIS. 1999;64:261-4",
"literaturereference_normalized": "invasive squamous cell carcinoma with sporotrichoid metastasis in a patient with cutaneous t cell lymphoma treated with chronic extracorporeal photopheresis",
"qualification": "1",
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},
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{
"abstract": "When treating HIV-infected patients with hemophilia, adverse drug reactions and interactions and the effect of treatment on bleeding disorders must be considered. Raltegravir is the first HIV integrase inhibitor, but its use in patients with hemophilia is rarely reported. Nine HIV-positive patients with hemophilia were retrospectively studied with a focus on the virological response, changes in the CD4 count, the tendency to bleed, and the response to replacement therapy before and after raltegravir-based antiretroviral therapy (ART). The nine patients were highly treatment-experienced patients and they received raltegravir-based ART for at least nine months. The patients had their own reasons for changing to raltegravir-based ART. During treatment, the CD4 count increased progressively in four patients, with a median absolute increase of 233 cells/mm(3), while the count stabilized in the remaining five patients. Two previous recipients of lopinavir/ritonavir (LPV/r) who failed to respond to lamivudine (3TC) + zidovudine (ZDV) + efavirenz (EFV) had a viral rebound. Genotyping indicated multidrug resistance to nucleoside reverse transcriptase inhibitors (NRTIs) and non-nucleoside reverse transcriptase inhibitors (NNRTIs). A pattern of resistance to raltegravir was evident, including the primary mutation N155H and the secondary mutation T97A. In the two patients, the tendency to bleed decreased markedly and monthly usage of clotting factor VIII decreased significantly decreased. In the remaining seven patients, the viral load remained < 40 copies/mL, there was no evidence of an increased tendency to bleed, and no evidence of changes in the response to replacement therapy. All of the patients had a stable condition with no signs of disease progression and no serious adverse reactions. Results indicated that Raltegravir-based therapy offered a safe and well-tolerated option for HIV-positive patients with hemophilia.",
"affiliations": "Department of Infectious Diseases, Shanghai Public Health Clinical Center, Fudan University.",
"authors": "Xiao|Hong|H|;Xue|Yile|Y|;Gu|Shiming|S|;Wang|Jiangrong|J|;Sun|Hongqing|H|;Lu|Hongzhou|H|",
"chemical_list": "D019380:Anti-HIV Agents; D000068898:Raltegravir Potassium; D019426:Integrases",
"country": "Japan",
"delete": false,
"doi": "10.5582/bst.2015.01180",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1881-7815",
"issue": "10(1)",
"journal": "Bioscience trends",
"keywords": null,
"medline_ta": "Biosci Trends",
"mesh_terms": "D000328:Adult; D019380:Anti-HIV Agents; D023241:Antiretroviral Therapy, Highly Active; D024882:Drug Resistance, Viral; D015658:HIV Infections; D006467:Hemophilia A; D006801:Humans; D019426:Integrases; D008875:Middle Aged; D009154:Mutation; D000068898:Raltegravir Potassium; D016896:Treatment Outcome",
"nlm_unique_id": "101502754",
"other_id": null,
"pages": "42-6",
"pmc": null,
"pmid": "26911541",
"pubdate": "2016-02",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Efficacy and safety of antiretroviral regimens including raltegravir to treat HIV-infected patients with hemophilia.",
"title_normalized": "efficacy and safety of antiretroviral regimens including raltegravir to treat hiv infected patients with hemophilia"
} | [
{
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{
"abstract": "High-dose antibiotic-loaded bone cement (ALBC) spacers are commonly used to treat prosthetic joint infections following total hip and knee arthroplasties. This methodology can provide high local antibiotic concentrations while minimizing systemic exposure and toxicity. The occurrence of acute kidney injury (AKI) is rarely reported. Available literature suggests that the rate may be higher than previously thought. We report a case of significant systemic tobramycin absorption with concomitant acute renal failure in a 69-year-old female following the implantation of a high-dose ALBC spacer containing both tobramycin and vancomycin. The tobramycin level 24 h post-surgery was 5.8 mcg/mL. Due to concomitant renal failure, antibiotic clearance was poor and resulted in prolonged exposure to elevated aminoglycoside levels. Recovery of renal function occurred, but clinicians should be vigilant in considering the potential impact ALBC spacers can have on post-operative renal function if antibiotic elution is higher than expected.",
"affiliations": "a Banner Health , Mesa , AZ , USA.;a Banner Health , Mesa , AZ , USA.",
"authors": "James|Alexia|A|;Larson|Trent|T|",
"chemical_list": "D001843:Bone Cements; D014031:Tobramycin",
"country": "England",
"delete": false,
"doi": "10.3109/0886022X.2015.1052949",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0886-022X",
"issue": "37(6)",
"journal": "Renal failure",
"keywords": "Acute kidney injury; arthroplasty; bone cement; knee; prosthesis-related infections; replacement; tobramycin/adverse effects",
"medline_ta": "Ren Fail",
"mesh_terms": "D058186:Acute Kidney Injury; D000368:Aged; D019645:Arthroplasty, Replacement, Knee; D001806:Blood Urea Nitrogen; D001843:Bone Cements; D004305:Dose-Response Relationship, Drug; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007677:Kidney Function Tests; D018570:Risk Assessment; D014031:Tobramycin; D016896:Treatment Outcome",
"nlm_unique_id": "8701128",
"other_id": null,
"pages": "1061-6",
"pmc": null,
"pmid": "26056733",
"pubdate": "2015-07",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Acute renal failure after high-dose antibiotic bone cement: case report and review of the literature.",
"title_normalized": "acute renal failure after high dose antibiotic bone cement case report and review of the literature"
} | [
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},
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},
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},
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],
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}
},
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"literaturereference": "JAMES A, LARSON T. ACUTE RENAL FAILURE AFTER HIGH-DOSE ANTIBIOTIC BONE CEMENT:CASE REPORT AND REVIEW OF THE LITERATURE. RENAL FAILURE. 2015;37 (6):1061-1066.",
"literaturereference_normalized": "acute renal failure after high dose antibiotic bone cement case report and review of the literature",
"qualification": "2",
"reportercountry": "US"
},
"primarysourcecountry": "US",
"receiptdate": "20170112",
"receivedate": "20151005",
"receiver": {
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},
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},
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] |
{
"abstract": "OBJECTIVE\nTo describe 3 cases of advanced refractory penile cancer treated with targeted therapy against the epidermal growth factor receptor (EGFR).\n\n\nMETHODS\nWe identified 3 patients with advanced penile cancer who had disease progression after platinum chemotherapy refractory and who subsequently received EGFR-targeted therapy. Their tumor tissue was evaluated for expression of EGFR by immunohistochemistry and messenger ribonucleic acid quantitation and was also tested for the presence of human papillomavirus deoxyribonucleic acid by line hybridization. K-ras mutation was evaluated by polymerase chain reaction for 6 mutations in codon 12 and 1 mutation in codon 13.\n\n\nRESULTS\nOne patient responded to cetuximab and remains disease-free 42 months after presentation. One patient responded to panitumumab, then suffered relapse. One other progressed through EGFR-targeted therapy. EGFR expression by immunohistochemistry was 1-2+ in all cases, and messenger ribonucleic acid expression ranged from 4.08 to 7.33. No K-ras mutations or human papillomavirus deoxyribonucleic acid was detected.\n\n\nCONCLUSIONS\nWe report 3 cases in which EGFR-targeted therapy was used to treat platinum-refractory penile cancer patients. Because 2 of the 3 had clinical benefit, future prospective trials of EGFR-targeted therapy in penile cancer are warranted.",
"affiliations": "Department of Medicine, University of Southern California, Keck School of Medicine, Los Angeles, CA.;Department of Pathology, University of Southern California, Keck School of Medicine, Los Angeles, CA.;University of Southern California, Keck School of Medicine, University of Southern California Institute of Urology, Los Angeles, CA.;Department of Medicine, University of Southern California, Keck School of Medicine, Los Angeles, CA.;University of Texas, MD Anderson Cancer Center, Houston, TX.;Department of Medicine, University of Southern California, Keck School of Medicine, Los Angeles, CA.;Department of Medicine, University of Southern California, Keck School of Medicine, Los Angeles, CA. Electronic address: dorff@usc.edu.",
"authors": "Brown|Alev|A|;Ma|Yanling|Y|;Danenberg|Kathleen|K|;Schuckman|Anne K|AK|;Pinski|Jacek K|JK|;Pagliaro|Lance C|LC|;Quinn|David I|DI|;Dorff|Tanya B|TB|",
"chemical_list": "D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D000077544:Panitumumab; D066246:ErbB Receptors; D000068818:Cetuximab",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0090-4295",
"issue": "83(1)",
"journal": "Urology",
"keywords": null,
"medline_ta": "Urology",
"mesh_terms": "D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D002294:Carcinoma, Squamous Cell; D000068818:Cetuximab; D066246:ErbB Receptors; D006801:Humans; D008297:Male; D008875:Middle Aged; D000077544:Panitumumab; D010412:Penile Neoplasms; D012189:Retrospective Studies",
"nlm_unique_id": "0366151",
"other_id": null,
"pages": "159-65",
"pmc": null,
"pmid": "24238569",
"pubdate": "2014-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D052061:Research Support, N.I.H., Extramural; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Epidermal growth factor receptor-targeted therapy in squamous cell carcinoma of the penis: a report of 3 cases.",
"title_normalized": "epidermal growth factor receptor targeted therapy in squamous cell carcinoma of the penis a report of 3 cases"
} | [
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"drugdosagetext": "25 MILLIGRAM/SQ. METER, CYCLICAL",
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "PENILE SQUAMOUS CELL CARCINOMA",
"drugintervaldosagedefinition": null,
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"drugrecurrence": null,
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"drugstructuredosagenumb": "25",
"drugstructuredosageunit": "009",
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"drugtreatmentdurationunit": null,
"medicinalproduct": "CISPLATIN."
},
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PANITUMUMAB"
},
"drugadditional": "3",
"drugadministrationroute": "042",
"drugauthorizationnumb": "125147",
"drugbatchnumb": null,
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": "UNKNOWN FORMULATION",
"drugdosagetext": "9 MILLIGRAM/KILOGRAM, Q3WK",
"drugenddate": null,
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"drugintervaldosagedefinition": "803",
"drugintervaldosageunitnumb": "3",
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"medicinalproduct": "PANITUMUMAB"
}
],
"patientagegroup": "5",
"patientonsetage": "43",
"patientonsetageunit": "801",
"patientsex": "1",
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "EGFR gene mutation",
"reactionmeddraversionpt": "22.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Penile squamous cell carcinoma",
"reactionmeddraversionpt": "22.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Off label use",
"reactionmeddraversionpt": "22.1",
"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "DANENBERG K. EPIDERMAL GROWTH FACTOR RECEPTOR-TARGETED THERAPY IN SQUAMOUS CELL CARCINOMA OF THE PENIS: A REPORT OF 3 CASES. UROLOGY. 2014?83(1):159-166",
"literaturereference_normalized": "epidermal growth factor receptor targeted therapy in squamous cell carcinoma of the penis a report of 3 cases",
"qualification": "3",
"reportercountry": "US"
},
"primarysourcecountry": "US",
"receiptdate": "20200120",
"receivedate": "20200120",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 17288003,
"safetyreportversion": 1,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
"seriousnessdisabling": null,
"seriousnesshospitalization": null,
"seriousnesslifethreatening": null,
"seriousnessother": 1,
"transmissiondate": "20200409"
}
] |
{
"abstract": "OBJECTIVE\nTo report a case of acute reversible pancreatitis associated with metronidazole-treated aspiration pneumonia.\n\n\nMETHODS\nA 61-year-old white woman requiring coronary artery bypass surgery developed acute pancreatitis following treatment with metronidazole for suspected postsurgical aspiration pneumonia. The patient developed moderate to severe bilateral upper quadrant abdominal pain; laboratory studies revealed elevated amylase and lipase concentrations four days following the initiation of metronidazole therapy. After discontinuation of metronidazole, the patient's abdominal pain subsequently improved, and both amylase and lipase concentrations immediately declined and were within normal limits within one week.\n\n\nCONCLUSIONS\nAn acute attack of pancreatitis is characterized by moderate to severe abdominal pain that may radiate to the back, accompanied by increased concentrations of pancreatic enzymes and few morphologic changes in the pancreas. Metronidazole is reported as having a probable association with acute pancreatitis, although the mechanism of drug-induced pancreatitis is not known. One speculative mechanism of metronidazole-induced pancreatitis is that, under aerobic conditions, metronidazole may undergo redox cycling and yield hydrogen peroxide, superoxide, and other free radicals. Such redox-active compounds are toxic to pancreatic beta-cells, and oxygen-centered free radicals have been implicated in the induction of pancreatitis. Other suggested mechanisms include immune-mediated inflammatory response, pancreatic duct constriction, and metabolic effects.\n\n\nCONCLUSIONS\nVery few cases of metronidazole-associated pancreatitis have been reported, and the long-term sequelae are unknown. However, if metronidazole or any other drug is suspected as the causative agent in pancreatitis, it should be discontinued and rechallenge should be avoided.",
"affiliations": "Evanston Northwestern Healthcare-Evanston Hospital, IL 60201, USA. msuraENH@hotmail.com",
"authors": "Sura|M E|ME|;Heinrich|K A|KA|;Suseno|M|M|",
"chemical_list": "D000890:Anti-Infective Agents; D008795:Metronidazole",
"country": "United States",
"delete": false,
"doi": "10.1345/aph.10021",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1060-0280",
"issue": "34(10)",
"journal": "The Annals of pharmacotherapy",
"keywords": null,
"medline_ta": "Ann Pharmacother",
"mesh_terms": "D000890:Anti-Infective Agents; D005260:Female; D006801:Humans; D008795:Metronidazole; D008875:Middle Aged; D010084:Oxidation-Reduction; D010195:Pancreatitis; D011015:Pneumonia, Aspiration; D006435:Renal Dialysis",
"nlm_unique_id": "9203131",
"other_id": null,
"pages": "1152-5",
"pmc": null,
"pmid": "11054984",
"pubdate": "2000-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Metronidazole-associated pancreatitis.",
"title_normalized": "metronidazole associated pancreatitis"
} | [
{
"companynumb": "US-STRIDES ARCOLAB LIMITED-2017SP010795",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
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{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "METRONIDAZOLE"
},
"drugadditional": "3",
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"drugauthorizationnumb": "208162",
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"medicinalproduct": "METRONIDAZOLE."
}
],
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"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Pancreatitis acute",
"reactionmeddraversionpt": "20.1",
"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "SANFORD KA, MAYLE JE, DEAN HA, GREENBAUM DS. METRONIDAZOLE ASSOCIATED PANCREATITIS.. ANN INTERN MED. 1988;109 (9):756?757",
"literaturereference_normalized": "metronidazole associated pancreatitis",
"qualification": "3",
"reportercountry": "US"
},
"primarysourcecountry": "US",
"receiptdate": "20170901",
"receivedate": "20170901",
"receiver": {
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"receivertype": "6"
},
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"safetyreportversion": 1,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
"seriousnessdisabling": null,
"seriousnesshospitalization": null,
"seriousnesslifethreatening": null,
"seriousnessother": 1,
"transmissiondate": "20171127"
},
{
"companynumb": "US-STRIDES ARCOLAB LIMITED-2017SP010797",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "METRONIDAZOLE"
},
"drugadditional": null,
"drugadministrationroute": "065",
"drugauthorizationnumb": "208162",
"drugbatchnumb": null,
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
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"drugdosageform": null,
"drugdosagetext": "UNK",
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "PNEUMONIA ASPIRATION",
"drugintervaldosagedefinition": null,
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"medicinalproduct": "METRONIDAZOLE."
}
],
"patientagegroup": null,
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"patientonsetageunit": null,
"patientsex": null,
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"reaction": [
{
"reactionmeddrapt": "Pancreatitis acute",
"reactionmeddraversionpt": "20.1",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Amylase increased",
"reactionmeddraversionpt": "20.1",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Lipase increased",
"reactionmeddraversionpt": "20.1",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Abdominal pain upper",
"reactionmeddraversionpt": "20.1",
"reactionoutcome": "1"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "SURA ME, HEINRICH KA, SUSENO M.. METRONIDAZOLE-ASSOCIATED PANCREATITIS.. ANN PHARMACOTHER.. 2000;34(10):1152-5",
"literaturereference_normalized": "metronidazole associated pancreatitis",
"qualification": "3",
"reportercountry": "US"
},
"primarysourcecountry": "US",
"receiptdate": "20170901",
"receivedate": "20170901",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 13929555,
"safetyreportversion": 1,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
"seriousnessdisabling": null,
"seriousnesshospitalization": null,
"seriousnesslifethreatening": null,
"seriousnessother": 1,
"transmissiondate": "20171127"
}
] |
{
"abstract": "OBJECTIVE\nTo assess long-term outcomes of ALA-PDT in treating recalcitrant laryngeal leukoplakia.\n\n\nMETHODS\nRetrospective Case-Control.\n\n\nMETHODS\nWe reviewed all laryngeal leukoplakia patients treated with ALA-PDT compared with angiolytic laser treatment alone (585 nm PDL or 532 nm KTP laser) from 2000 to 2019. Patients with laryngeal cancer (or a history of laryngeal cancer), leukoplakia previously treated with radiation and no pathologic report were excluded. Patient demographics, procedure details and outcomes were examined including histopathologic diagnosis, procedures performed, ALA usage, recurrence of leukoplakia and the development of cancer.\n\n\nRESULTS\nWe identified 132 patients with laryngeal leukoplakia: 42 were treated with ALA-PDT and 90 were treated with an angiolytic laser alone (Laser group). The proportion of cases of high-grade dysplasia was 57.1% in the ALA-PDT group compared to 32.2% in the Laser group. In high-grade dysplasia cases, there was a statistically significant better recurrence-free survival (RFS) at 12 months and 60 months in those who underwent ALA-PDT 71.4% and 7.1% vs Laser 25% and 0% (p = .01). However, for overall groups, there was no difference in RFS (p = .25). Voice outcomes (patient subjective report) improved or were stable in 75% of subjects with no serious side effects reported.\n\n\nCONCLUSIONS\nALA-PDT for recalcitrant and high-grade dysplasia is highly effective with improved recurrence-free survival compared to laser alone. ALA-PDT may be an appropriate therapy in patients who have failed prior angiolytic laser alone.",
"affiliations": "Department of Otorhinolaryngology, Faculty of Medicine, Srinakharinwirot University, Bangkok, Thailand.;Department of Otolaryngology, Massachusetts Eye and Ear, Boston, Massachusetts, USA.;Department of Otolaryngology-Head and Neck Surgery, Icahn School of Medicine at Mount Sinai Hospital, New York, New York, USA.;Department of Otolaryngology, Massachusetts Eye and Ear, Boston, Massachusetts, USA.",
"authors": "Santeerapharp|Alena|A|https://orcid.org/0000-0001-5592-0849;Song|Sungjin A|SA|https://orcid.org/0000-0002-4335-1236;Woo|Peak|P|;Franco|Ramon A|RA|https://orcid.org/0000-0002-4549-6017",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1111/coa.13878",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1749-4478",
"issue": null,
"journal": "Clinical otolaryngology : official journal of ENT-UK ; official journal of Netherlands Society for Oto-Rhino-Laryngology & Cervico-Facial Surgery",
"keywords": "KTP; Laryngeal leukoplakia; PDL; dysplasia; laryngeal cancer; leukoplakia; photodynamic therapy",
"medline_ta": "Clin Otolaryngol",
"mesh_terms": null,
"nlm_unique_id": "101247023",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "34662496",
"pubdate": "2021-10-18",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Long-term outcomes of aminolevulinic acid photodynamic therapy for treatment of recalcitrant laryngeal premalignant lesions.",
"title_normalized": "long term outcomes of aminolevulinic acid photodynamic therapy for treatment of recalcitrant laryngeal premalignant lesions"
} | [
{
"companynumb": "TH-SUN PHARMACEUTICAL INDUSTRIES LTD-2022R1-327692",
"fulfillexpeditecriteria": "1",
"occurcountry": "TH",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "AMINOLEVULINIC ACID HYDROCHLORIDE"
},
"drugadditional": "3",
"drugadministrationroute": "061",
"drugauthorizationnumb": "20965",
"drugbatchnumb": null,
"drugcharacterization": "1",
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"drugdosageform": "TOPICAL SOLUTION",
"drugdosagetext": "UNK",
"drugenddate": null,
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"drugindication": "Laryngeal leukoplakia",
"drugintervaldosagedefinition": null,
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"medicinalproduct": "LEVULAN KERASTICK"
}
],
"patientagegroup": "5",
"patientonsetage": null,
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"patientsex": null,
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Therapy partial responder",
"reactionmeddraversionpt": "24.1",
"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "Santeerapharp A, Song SA, Woo P, Franco RA. Long-term outcomes of aminolevulinic acid photodynamic therapy for treatment of recalcitrant laryngeal premalignant lesions. Clin Otolaryngol. 2022;47:153-159",
"literaturereference_normalized": "long term outcomes of aminolevulinic acid photodynamic therapy for treatment of recalcitrant laryngeal premalignant lesions",
"qualification": "3",
"reportercountry": "TH"
},
"primarysourcecountry": "TH",
"receiptdate": "20220303",
"receivedate": "20220303",
"receiver": {
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},
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"safetyreportversion": 1,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": 2,
"seriousnessdeath": 2,
"seriousnessdisabling": 2,
"seriousnesshospitalization": 2,
"seriousnesslifethreatening": 2,
"seriousnessother": 1,
"transmissiondate": "20220423"
}
] |
{
"abstract": "BACKGROUND\nRapid scale-up of antiretroviral therapy rollout in Sub-Saharan African countries faces the challenge of virological failure. This could be the consequence of transmitted drug-resistant human immunodeficiency virus strains at the population level. While a pre-antiretroviral therapy genotypic test has been a major component of the human immunodeficiency virus management programme in developed nations, it is yet to be incorporated into the antiretroviral therapy programme in resource-poor countries.\n\n\nMETHODS\nA 32-year-old Black African woman was seen for her six-month routine review. Her viral load after initiation of fixed drug combination of tenofovir, emtricitabine and efavirenz was 31,397 RNA copies/mL. Adherence was assessed to be good based on pharmacy pick-up dates, on-time clinic appointment records, medical file review, self-reporting and treatment supporter's report. Her viral load was repeated after another two months of close monitoring; the result showed viral load of 31,159 RNA copies/mL. She was assessed as virological failure to her first-line antiretrovirals and commenced on second-line antiretrovirals: zidovudine/lamivudine/Aluvia(®) (lopinavir and ritonavir). A human immunodeficiency virus drug genotypic testing showed she was only susceptible to zidovudine and protease inhibitors. At third month on the new regimen, her viral load was suppressed.\n\n\nCONCLUSIONS\nThis case report demonstrates the possibility of a silent epidemic within the human immunodeficiency virus pandemic in resource-poor settings like Eastern Cape, South Africa. We described a case of early virological failure in a highly motivated young woman. Although, a pre-antiretroviral therapy genotypic test is yet to be incorporated into a human immunodeficiency virus programme in resource-poor countries, the need for it might become evident as the programme expands. Close monitoring of the viral load of patients according to national guidelines will enable early detection of a failing regimen and prompt intervention can be instituted to prevent morbidity and mortality. There is an urgent need to strengthen the human immunodeficiency virus programme in resource-poor countries to prevent the emergence of an epidemic of transmitted drug-resistant human immunodeficiency virus strains within the existing human immunodeficiency virus pandemic.",
"affiliations": "Department of Family Medicine, Division of HIV Care, Cecilia Makiwane Hospital, East London Hospital Complex, East London, Eastern Cape Province, South Africa. dudumela@yahoo.com.;Department of Family Medicine, Division of HIV Care, Cecilia Makiwane Hospital, East London Hospital Complex, East London, Eastern Cape Province, South Africa. vincoladele@gmail.com.;Department of Family Medicine, Division of HIV Care, Cecilia Makiwane Hospital, East London Hospital Complex, East London, Eastern Cape Province, South Africa. yusilanof@gmail.com.;School of Health Sciences, University of Fort Hare, East London, South Africa. dgoon@ufh.ac.za.",
"authors": "Sogbanmu|Olufunso Oladipo|OO|;Adeniyi|Oladele Vincent|OV|;Fuentes|Yusimi Ordaz|YO|;Ter Goon|Daniel|D|",
"chemical_list": "D019380:Anti-HIV Agents; D017320:HIV Protease Inhibitors; D015215:Zidovudine",
"country": "England",
"delete": false,
"doi": "10.1186/s13256-015-0557-0",
"fulltext": "\n==== Front\nJ Med Case RepJ Med Case RepJournal of Medical Case Reports1752-1947BioMed Central London 55710.1186/s13256-015-0557-0Case ReportVery early virological failure and drug resistance mutations in a woman on antiretroviral therapy in Eastern Cape, South Africa: a case report Sogbanmu Olufunso Oladipo dudumela@yahoo.com Adeniyi Oladele Vincent vincoladele@gmail.com Fuentes Yusimi Ordaz yusilanof@gmail.com Goon Daniel Ter dgoon@ufh.ac.za Department of Family Medicine, Division of HIV Care, Cecilia Makiwane Hospital, East London Hospital Complex, East London, Eastern Cape Province South Africa School of Health Sciences, University of Fort Hare, East London, South Africa 7 5 2015 7 5 2015 2015 9 10616 12 2014 26 2 2015 © Sogbanmu et al.; licensee BioMed Central. 2015This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Introduction\nRapid scale-up of antiretroviral therapy rollout in Sub-Saharan African countries faces the challenge of virological failure. This could be the consequence of transmitted drug-resistant human immunodeficiency virus strains at the population level. While a pre-antiretroviral therapy genotypic test has been a major component of the human immunodeficiency virus management programme in developed nations, it is yet to be incorporated into the antiretroviral therapy programme in resource-poor countries.\n\nCase presentation\nA 32-year-old Black African woman was seen for her six-month routine review. Her viral load after initiation of fixed drug combination of tenofovir, emtricitabine and efavirenz was 31,397 RNA copies/mL. Adherence was assessed to be good based on pharmacy pick-up dates, on-time clinic appointment records, medical file review, self-reporting and treatment supporter’s report. Her viral load was repeated after another two months of close monitoring; the result showed viral load of 31,159 RNA copies/mL. She was assessed as virological failure to her first-line antiretrovirals and commenced on second-line antiretrovirals: zidovudine/lamivudine/Aluvia® (lopinavir and ritonavir). A human immunodeficiency virus drug genotypic testing showed she was only susceptible to zidovudine and protease inhibitors. At third month on the new regimen, her viral load was suppressed.\n\nConclusions\nThis case report demonstrates the possibility of a silent epidemic within the human immunodeficiency virus pandemic in resource-poor settings like Eastern Cape, South Africa. We described a case of early virological failure in a highly motivated young woman. Although, a pre-antiretroviral therapy genotypic test is yet to be incorporated into a human immunodeficiency virus programme in resource-poor countries, the need for it might become evident as the programme expands. Close monitoring of the viral load of patients according to national guidelines will enable early detection of a failing regimen and prompt intervention can be instituted to prevent morbidity and mortality. There is an urgent need to strengthen the human immunodeficiency virus programme in resource-poor countries to prevent the emergence of an epidemic of transmitted drug-resistant human immunodeficiency virus strains within the existing human immunodeficiency virus pandemic.\n\nKeywords\nGenotypicGuidelinesHIVPrimary HIV resistanceTransmitted drug-resistant virusissue-copyright-statement© The Author(s) 2015\n==== Body\nIntroduction\nAccording to the 2013 Global Report of the Joint United Nations Programme on HIV and AIDS (UNAIDS), 35.3 million people were living with human immunodeficiency virus (HIV) by the end of 2012 and 70.8% of the global burden reside in Sub-Saharan Africa. South Africa has the highest burden of the HIV epidemic (6.4 million people living with HIV/acquired immunodeficiency syndrome) [1]. The global response to the epidemic has seen more than 60% of eligible individuals already initiated on antiretroviral therapy (ART) using World Health Organization (WHO) criteria of 2010 (CD4 count ≤350 cells/mL) and approximately 34% using WHO 2013 criteria (CD4 count ≤500 cells/mL) [2].\n\nThe impact of the scale-up of ART includes 4.2 million deaths averted, 800,000 child infections averted with the Prevention of Mother-to-Child Transmission of HIV programme and a decrease in the incidence of HIV infections in 2012 [2]. The probable challenges of rapid scale-up of ART include loss to follow up, virological failures and drug resistance (acquired and transmitted). These have not been fully investigated in resource-poor settings; however, their possibility has been documented [3]. While acquired resistance has received attention in the national programmes of most resource-poor countries of Sub-Saharan Africa [4], transmitted resistance has not received similar attention.\n\nThis is the first case report to the best of our knowledge to describe a patient who experienced a primary virological failure possibly secondary to transmitted drug-resistant HIV (TDRHIV) strain in Eastern Cape, South Africa.\n\nCase presentation\nSix months ago, a 32-year-old Black African woman was seen for her routine review. She was asymptomatic. Approximately 13 to 14 months earlier, she was referred to our HIV Unit because of a low CD4 count for ART initiation. She was antiretroviral (ARV)-naïve with WHO clinical stage 3 (oral candidiasis) and a baseline CD4 count of 14 cells/mL. Reflex laboratory serum Cryptococcal Latex Antigen Test serology was negative. The results of other baseline investigations were within normal limits. Her symptom screen for tuberculosis was negative. Alcohol and substance use were excluded. There was no history of depression or any comorbid chronic illnesses. She disclosed her status to her partner. She was nulliparous.\n\nHer medications during preparation for ARVs included co-trimoxazole, multivitamins and oral nystatin. She was commenced on a fixed dose combination of tenofovir, emtricitabine and efavirenz daily (according to the South African National Department of Health Guideline, 2013) [4]. She was followed up at 2, 4 and 8 weeks for immune reconstitution inflammatory syndrome and adverse effects. At each visit, adherence was reviewed and further counselling was provided. Isoniazid prophylaxis was initiated; her estimated glomerular filtration rate was normal at three months (glomerular filtration rate >60 mL/minute/1.73m2).\n\nShe was again reviewed at six months in 2014: viral load (VL) of 31,397 ribonucleic acid (RNA) copies/mL; a log value of 4 was obtained. Poor adherence was considered despite her and the treatment supporter’s account of good adherence. A thorough evaluation of the medical files for clinic attendance, pharmacy records for pick-up of medications and pill count charts was conducted. She was deemed to have a relatively good adherence. There were no drug–drug interactions; no herbal or alternative therapies were used during the period of treatment. She was not treated for diarrhoea or vomiting during the preceding 6 months. Further questions about her new sexual partner and HIV status of previous sexual partners did not yield any new information and she had not been sexually active since diagnosis of HIV. Adherence was consolidated for another two months with intense monthly review. Her VL at eight month remained 31,159 RNA copies/mL in spite of excellent adherence. We confirmed virological failure. An assessment of a probable primary virological failure from TDRHIV was considered. A decision was made to switch to a second-line regimen of zidovudine (AZT)/lamivudine/lopinavir and ritonavir at standard doses.\n\nAfter analysing the case we decided to do an HIV drug genotypic test outside the National guideline to understand the pattern of resistant mutation in our patient.\n\nThe genotypic test result showed susceptibility to protease inhibitors and AZT (Table 1).Table 1 \nMutation score of patient\n\n\n\nRT\n\t\n3TC\n\t\nABC\n\t\nAZT\n\t\nD4T\n\t\nDDI\n\t\nFTC\n\t\nTDF\n\t\nEFV\n\t\nETR\n\t\nNVP\n\t\nRPV\n\t\nK65R\t30\t45\t−15\t45\t60\t30\t60\t−\t−\t−\t−\t\nM184I\t60\t15\t−10\t−10\t10\t60\t−10\t−\t−\t−\t−\t\nK103S\t−\t−\t−\t−\t−\t−\t−\t45\t0\t60\t0\t\nV106M\t−\t−\t−\t−\t−\t−\t−\t60\t0\t60\t0\t\nM230L\t−\t−\t−\t−\t−\t−\t−\t45\t30\t60\t45\t\nK653+M184I\t−\t−\t−\t10\t−\t−\t10\t−\t−\t−\t−\t\n\nAbbreviations: 3TC lamivudine, ABC abacavir, AZT zidovudine, D4T stavudine, DDI didanosine, EFV efavirenz, ETR etravirine, FTC emtricitabine, NVP nevirapine, RPV rilpivirine, RT reverse transcriptase, TDF tenofovir.\n\n\n\nThe HIV subtype isolated in the genotypic testing was subtype C. The K65R mutation was noted as part of the nucleoside/nucleotide reverse-transcriptase inhibitor mutation; however, AZT remains active.\n\nShe was reviewed monthly and a blood sample for VL was taken at third month of commencing second-line ARVs. The result confirmed viral suppression (VL=25 RNA copies/mL). She is presently doing well.\n\nThe timeline of the case is shown in Figure 1.Figure 1 Timeline of important clinical events during management of patient. Abbreviations: 3TC, lamivudine; ARV, antiretroviral; AZT, zidovudine; EFV, efavirenz; FTC, emtricitabine; HIV, human immunodeficiency virus; RNA, ribonucleic acid; TDF, tenofovir; VL, viral load; WHO, World Health Organization. Aluvia® is lopinavir and ritonavir.\n\n\n\nDiscussion\nThe case report suggests the possibility of yet another epidemic that may be emanating from the HIV pandemic; awareness of its existence is a reality in resource-poor countries. Whether our case represents a part of the rising prevalence of TDRHIV remains uncertain. A pre-ART genotypic test is a prerequisite for initiation of treatment in resource-rich nations [5], whereas a genotypic test is reserved for second-line regimen failures in resource-constrained settings like ours [4,6,7]. The difference between the two models of HIV care could result in a minimum of ≥eight months’ delay in initiating effective ART in patients with TDRHIV which was the case in this patient.\n\nThe two VLs taken according to the South African ART guideline [4] confirmed virological failure. What remains applicable in our practice setting is the role of VL monitoring, which was adhered to strictly in our patient. Hence, VL monitoring may remain the only tool to determine early ARV failure in the resource-poor setting where we practice. However, it is worth noting that TDRHIV is one of the documented causes of virological failure on a first-line regimen [8] which is a possibility in this patient. Safe sexual practice should be advocated in all patients to prevent the spread of TDRHIV strains at a community level [9,10]. Of importance in our patient is her being ARV naïve with no past obstetrics history.\n\nSimilar to a meta-analysis conducted by Gupta et al., our patient has acquired many mutations (Table 1) [11]. However, we found that she remained susceptible to AZT as mutations found in combination with K65R in our case enhance susceptibility to AZT (M184V as well as K65R) [12]. Therefore, we expect that AZT would remain active against such viruses. The latest VL of 25 RNA copies/mL from her confirmed an effective ART after an initial delay of 8 months.\n\nLimitations of current practice\nIt remains a challenge that a pre-ART genotypic resistance testing could not be undertaken in patients with HIV infection in a resource-constrained setting as this would have provided information on the baseline ARV drug resistance. Also, the inability to conduct ARV drug levels in the partner of the patient should be noted.\n\nConclusions\nAlthough, a pre-ART genotypic test is yet to be incorporated into an HIV programme in resource-poor countries, the need for its incorporation into clinical care may become more evident as the prevalence of TDR rises. Meanwhile, close monitoring of VL of patients according to the national guidelines is very important. This will enable early detection of a failing regimen and prompt intervention can be instituted to prevent accumulation of resistant strains, virological failure, morbidity and mortality. There is an urgent need to strengthen the HIV programme in resource-poor settings to prevent the emergence of a silent epidemic of TDRHIV within the HIV pandemic.\n\nConsent\nWritten informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.\n\nAbbreviations\nARTAntiretroviral therapy\n\nARVAntiretroviral\n\nAZTZidovudine\n\nHIVHuman immunodeficiency virus\n\nRNARibonucleic acid\n\nTDRHIVTransmitted drug-resistant HIV\n\nUNAIDSJoint United Nations Programme on HIV and AIDS\n\nVLViral load\n\nWHOWorld Health Organization\n\nCompeting interests\n\nThe authors declare that they have no competing interests.\n\nAuthors’ contributions\n\nOOS, OVA, YOF and DTG: conducted expert analysis of the case and prepared the manuscript. All the authors read and approved the final draft.\n\nAuthors’ information\n\nOOS – MBChB (Ogun, NGA), PGDip (Clinical HIV/AIDS Mgt, UKZN), MMed (Family Medicine), MMed SC (Clinical HIV/AIDS Mgt, UKZN).\n\nSpecialist family physician, Division of HIV care, Department of Family Medicine, Cecilia Makiwane Hospital, Mdantsane, East London, South Africa.\n\nPhD Candidate, University of Fort Hare, East London, South Africa.\n\nOVA – MBBS, MPhil (HIV/AIDS Mgt, STELL), FCFP (SA), Dip HIV Man (SA), Higher Dip in Sexual Health & HIV Medicine (SA), Dip Obst (SA).\n\nSpecialist family physician, Division of HIV Care, Department of Family Medicine, Cecilia Makiwane Hospital, Mdantsane, East London, South Africa.\n\nPhD Candidate, University of Fort Hare, East London, South Africa.\n\nYOF – Family physician, 1st Degree University of Havana, MSc Women Health Care, University of Havana, Cuba.\n\nChief Medical Officer, Division of HIV Care, Department of Family Medicine, Cecilia Makiwane Hospital, Mdantsane, East London, South Africa.\n\nDTG – Senior Research Fellow, Associate Professor, School of Health Sciences, University of Fort Hare, East London, South Africa.\n\nAcknowledgements\nWe thank the staffs of the Division of HIV Care (Ward 5), Department of Family Medicine, Cecilia Makiwane Hospital and National Health Laboratory Service, Cecilia Makiwane Hospital for the quick turnaround time of all the results on the patient.\n==== Refs\nReferences\n1. Global report. UNAIDS report on the global AIDS epidemic: UNAIDS. 2012.\n2. HSRC. South African National HIV Prevalence, Incidence and Behaviour Survey, 2012 Available on URL: http://heaids.org.za/site/assets/files/1267/sabssm_iv_leo_final.pdf. Assessed on 15th April 2014.\n3. Kuritzkes DR Extending antiretroviral therapy to resource-poor settings: implications for drug resistance AIDS. 2004 18 S45 8 10.1097/00002030-200406003-00009 15322484 \n4. South Africa Department of Health National Antiretroviral Treatment Guidelines Pretoria, National Department of Health 2013 \n5. Panel on Antiretroviral Guidelines for Adult and Adolescents. Guideline for the use of antiretroviral agents in HIV 1-infected adults and adolescents. Department of Health and Human Services. May 2014. Available at http://aidsinfo.nih.gov/contentfiles/lvguidelines/adultandadolescentgl.pdf. Accessed on 17th September 2014.\n6. Conradie F Wilson D Basson A De Oliveria T Hunt G The 2012 Southern African ARV drug resistance guidelines: Guideline S Afr J HIV Med 2012 13 4 162 7 \n7. World Health Organization. Antiretroviral treatment guidelines for adult and adolescents. 2013. Available at http://www.who.int/hiv/pub/guidelines/adolescents/en/. Accessed on 16th September 2014.\n8. Wittkop L Gunthard H de Wolf F Effects of transmitted drug resistance on virological and immunological response to initial combination antiretroviral therapy for HIV. (EuroCoord-CHAIN joint project). A European multi-cohort study Lancets Infect Dis 2011 11 363 71 10.1016/S1473-3099(11)70032-9 \n9. Grant RM Hecht FM Warmerdam M Liu L Liegler T Petropoulos CJ Time trends in primary HIV-1 drug resistance among recently infected persons JAMA. 2002 288 181 8 10.1001/jama.288.2.181 12095382 \n10. Van de Vijver DAMC, Wensing AMJ, Asjo B, et al. Patterns of predicted drug susceptibility and its change over time among 2000 isolates across Europe: the CAPTURE study. In: Abstracts of the Fourth European HIV Drug Resistance Workshop, Monaco. Utrecht, The Netherlands: Virology Education; 2006. p. 5. Abstract 4.\n11. Gupta R Hill A Sawyer A Pillay D Emergence of drug resistance in HIV type 1-infected patients after receipt of first-line highly active antiretroviral therapy: a systematic review of clinical trials Clin Infect Dis. 2008 47 5 712 22 10.1086/590943 18662137 \n12. Sunpath H High rate of K65R for ART naïve patients with subtype C HIV infection failing a TDF-containing first-line regimen in South Africa AIDS 2012 26 13 1679 84 10.1097/QAD.0b013e328356886d 22739389\n\n",
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"title": "Very early virological failure and drug resistance mutations in a woman on antiretroviral therapy in Eastern Cape, South Africa: a case report.",
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{
"abstract": "Background: Intravenous injection of oral opioid substitution drugs (OSD) is widespread among injecting drug users. Several OSDs contain the polymer polyvinylpyrrolidone (PVP) as an excipient. Parenterally administered PVP of high molecular weight may accumulate in tissues and organs. This phenomenon was first described in the 1950s, when PVP was utilised in medication for parenteral use. We report a case of an opioid-addicted patient with extensive PVP-deposition caused by repeated injections of OSDs. Case presentation: A 30-year-old male drug addicted patient in opioid substitution therapy (OST) was repeatedly referred to his local hospital in a poor general condition. Work-up revealed severe normocytic anaemia, renal insufficiency, pancreas insufficiency and pathological fractures. Biopsies from fractured bones, bone marrow and gastric mucosa showed extensive infiltrates of histiocytes with intracytoplasmic vacuoles. Vacuole content stained slightly bluish in hematoxylin and eosin stain, red in Congo red stain and black in periodic acid methenamine silver stain. The morphological appearance and staining properties were in accordance with the diagnosis of PVP deposition. The patient had been injecting both buprenorphine tablets and a specific methadone syrup for several years. The methadone syrup contained large amounts of high molecular weight PVP, making it the most likely cause of the deposition. His health quickly deteriorated and he died, impaired by multi-organ failure and cachexia, five years after the first diagnosis of PVP-deposition. The autopsy revealed extensive PVP-deposition in all sampled organs and tissues. Conclusions: Histological investigation and the correct identification of PVP in the biopsies led to the discovery of a severe adverse effect from long-standing misuse of a drug. The disseminated PVP deposition likely contributed to multi-organ dysfunction and cachexia with a fatal outcome. The deposited PVP likely originated from repeated injections of a certain methadone syrup.",
"affiliations": "Department of Pathology, Haukeland University Hospital, Post box 1, 5021 Bergen, Norway.;Department of Medicine, Haukeland University Hospital, Post box 1, 5021 Bergen, Norway.;Department of Pathology, Haukeland University Hospital, Post box 1, 5021 Bergen, Norway.;Department of Medical Biochemistry and Pharmacology, Haukeland University Hospital, Post box 1, 5021 Bergen, Norway.;Kvam Municipality, Grovagjelet 16, 5600 Norheimsund, Norway.;Department of Clinical Medicine, University of Bergen, Jonas Lies vei 87, 5021 Bergen, Norway.;Department of Pathology, Haukeland University Hospital, Post box 1, 5021 Bergen, Norway.",
"authors": "Stalund|Ida Viken|IV|0000-0002-2466-355X;Riise|Gro Nygard|GN|;Leh|Friedemann|F|;Bjånes|Tormod Karlsen|TK|0000-0002-0221-7807;Riise|Lars|L|;Svarstad|Einar|E|;Leh|Sabine|S|0000-0002-0764-2941",
"chemical_list": "D000701:Analgesics, Opioid; D004364:Pharmaceutical Preparations; D002047:Buprenorphine; D011205:Povidone",
"country": "England",
"delete": false,
"doi": "10.12688/f1000research.51927.2",
"fulltext": "\n==== Front\nF1000Res\nF1000Res\nF1000Research\n2046-1402\nF1000 Research Limited London, UK\n\n10.12688/f1000research.51927.2\nCase Report\nArticles\nCase Report: Polyvinylpyrrolidone deposition disease from repeated injection of opioid substitution drugs: report of a case with a fatal outcome\n[version 2; peer review: 2 approved]\n\nStalund Ida Viken Investigation Visualization Writing – Original Draft Preparation https://orcid.org/0000-0002-2466-355X\na12\nRiise Gro Nygard Conceptualization Investigation Writing – Original Draft Preparation 3\nLeh Friedemann Conceptualization Investigation Writing – Review & Editing 1\nBjånes Tormod Karlsen Investigation Writing – Review & Editing https://orcid.org/0000-0002-0221-7807\n4\nRiise Lars Investigation Writing – Review & Editing 5\nSvarstad Einar Conceptualization Writing – Review & Editing 2\nLeh Sabine Conceptualization Funding Acquisition Investigation Supervision Writing – Review & Editing https://orcid.org/0000-0002-0764-2941\n12\n1 Department of Pathology, Haukeland University Hospital, Post box 1, 5021 Bergen, Norway\n2 Department of Clinical Medicine, University of Bergen, Jonas Lies vei 87, 5021 Bergen, Norway\n3 Department of Medicine, Haukeland University Hospital, Post box 1, 5021 Bergen, Norway\n4 Department of Medical Biochemistry and Pharmacology, Haukeland University Hospital, Post box 1, 5021 Bergen, Norway\n5 Kvam Municipality, Grovagjelet 16, 5600 Norheimsund, Norway\na ida.viken.stalund@helse-bergen.no\nNo competing interests were disclosed.\n\n7 7 2021\n2021\n10 30029 6 2021\nCopyright: © 2021 Stalund IV et al.\n2021\nhttps://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution Licence, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.\n\nBackground: Intravenous injection of oral opioid substitution drugs (OSD) is widespread among injecting drug users. Several OSDs contain the polymer polyvinylpyrrolidone (PVP) as an excipient. Parenterally administered PVP of high molecular weight may accumulate in tissues and organs. This phenomenon was first described in the 1950s, when PVP was utilised in medication for parenteral use. We report a case of an opioid-addicted patient with extensive PVP–deposition caused by repeated injections of OSDs.\n\nCase presentation: A 30-year-old male drug addicted patient in opioid substitution therapy (OST) was repeatedly referred to his local hospital in a poor general condition. Work-up revealed severe normocytic anaemia, renal insufficiency, pancreas insufficiency and pathological fractures. Biopsies from fractured bones, bone marrow and gastric mucosa showed extensive infiltrates of histiocytes with intracytoplasmic vacuoles. Vacuole content stained slightly bluish in hematoxylin and eosin stain, red in Congo red stain and black in periodic acid methenamine silver stain. The morphological appearance and staining properties were in accordance with the diagnosis of PVP deposition. The patient had been injecting both buprenorphine tablets and a specific methadone syrup for several years. The methadone syrup contained large amounts of high molecular weight PVP, making it the most likely cause of the deposition. His health quickly deteriorated and he died, impaired by multi-organ failure and cachexia, five years after the first diagnosis of PVP-deposition. The autopsy revealed extensive PVP-deposition in all sampled organs and tissues.\n\nConclusions: Histological investigation and the correct identification of PVP in the biopsies led to the discovery of a severe adverse effect from long-standing misuse of a drug. The disseminated PVP deposition likely contributed to multi-organ dysfunction and cachexia with a fatal outcome. The deposited PVP likely originated from repeated injections of a certain methadone syrup.\n\nPolyvinylpyrrolidone\nPVP\npovidone\nopioid substitution therapy\nopioid substitution drugs\nmethadone\nadverse effect\ncase report\nThe Western Norway Health Authority 912001 Ida Viken Stalund was funded by The Western Norway Health Authority [grant number 912001]. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Revised Amendments from Version 1\n\nBased on the review reports from the reviewers, we have revised sections of the text and added a reference. Key words: Case report removed. Foreign material and histiocytic storage added. Result section: Under the sub-heading “Biopsy findings”: We have added “in Congo red stain or any other stain.” to the last sentence. Under the sub-heading “Further development”: We have added a sentence about thrombocytopenia and leukocytopenia. Under the subheading “Autopsy findings”: We have added a sentence about the absence of symptoms of cardiac dysfunction. Sentences about findings in the pancreatic tissue altered for clarification. Sentence added about glomerular findings. Sentence added about signs of acute inflammation. For clarification, we have made a minor revision to the legend for Figure 4. Discussion section: In the second paragraph of the discussion: We have added a sentence about differentiating PVP deposits from deposits of crospovidone. New reference added: Ganesan S, Felo J, Saldana M, Kalasinsky VF, Lewin-Smith MR, Tomashefski JF, Jr. (2003) Embolized crospovidone (poly[N-vinyl-2-pyrrolidone]) in the lungs of intravenous drug users. Mod Pathol 16(4):286-92. https://doi.org/10.1097/01.mp.0000062653.65441.da\n==== Body\nBackground\n\nInjection of oral opioid substitution drugs (OSD) is a concern in the treatment of opioid dependency. An Australian study found that 7–13% of clients in opioid substitution therapy (OST) injected their medication weekly or more often. 1 The OSDs may also be sold on the illegal drug market, and 26.6% of out-of-treatment intravenous drug users in a Norwegian study reported having injected methadone during the past 4 weeks. 2 Injection of oral or sublingual drug formulations may lead to vascular and soft tissue damage with a range of secondary complications. 3\n\nSeveral OSDs contain the excipient polyvinylpyrrolidone (PVP), 4 a water-soluble polymer with a wide variety of applications in the pharmaceutical industry. 5 When orally ingested, PVP is not absorbed, and causes no harm. 6, 7 When injected, PVP is not metabolized, and the only way of excretion is via glomerular filtration. 6 While low molecular weight (MW) PVP is freely filtered by the glomerulus, PVP with moderate or high MW will be partly or completely retained in the body. 6, 8 In the middle part of the last century, PVP was utilized as a plasma expander 9 and as a retarding agent in hormone preparations for injection. 10 Reports from this time described storage in multiple tissues following repeated parenteral administrations of PVP-containing preparations. 9– 11\n\nWe report a case of extensive PVP-deposition disease with a fatal outcome following long-term injection of PVP-containing OSDs.\n\nCase presentation\n\nFirst admission\n\nA male, 30-year-old drug addicted patient in OST was admitted to the local hospital. He was hepatitis C positive and had a history of hospitalisations for skin infection. At admittance, he was in a poor general condition with nausea, vomiting, abdominal pain and muscle aches. Physical examination revealed a diffusely tender abdomen and poor dental status. Laboratory investigations disclosed non-specific inflammatory signs with an increased erythrocyte sedimentation rate (83 mm/h) and C-reactive protein (CRP, 90 mg/L), severe normocytic anaemia with a haemoglobin of 7.8 g/dL and renal insufficiency (serum creatinine 133 μmol/L, estimated glomerular filtration rate 60.1 mL/min/1.73m 2) with microalbuminuria. Blood cultures were negative. Radiological examinations of the thorax and abdomen showed splenomegaly and a pancreatic cyst, but otherwise no radiologic signs of infection, malignancy or kidney pathology. His CRP and serum creatinine levels fell spontaneously, and he left the hospital against the doctor’s advice after four days.\n\nSecond admission\n\nTwo months later, the patient fractured his right clavicle. After a two-week delay, he was admitted to hospital with a fever and a swollen and erythematous clavicular region. His general condition and nutritional status had worsened, nausea and vomiting persisted and anaemia and renal insufficiency had relapsed. Blood cultures were positive for Staphylococcus aureus, and antibiotic treatment against suspected osteomyelitis was initiated. Magnetic resonance imaging (MRI) of the clavicular region and the upper arm showed mottled signal changes with a high signal intensity in the lateral clavicle, the humeral bone and the acromion ( Figure 1a). The diagnoses considered at this time were osteomyelitis or malignancy. Biopsies from the fractured bone, bone marrow and gastric mucosa were performed in the work-up of this complex symptomatology.\n\nFigure 1. Radiological and biopsy findings.\n\n(a) MRI (T2-blade-sag-FS) of the right humerus showing mottled signal changes. (b) Clavicular bone (H&E): The marrow space is infiltrated by histiocytes with bluish transparent bubbles. (c) Bone marrow (H&E): Massive infiltration of histiocytes and scarce remaining hematopoietic tissue. (d) Gastric mucosa (H&E): Infiltration of vacuolated histiocytes in an extended lamina propria. All scale-bars 50 μm.\n\nBiopsy findings\n\nThe biopsies all showed similar infiltrates of histiocytes with a cytoplasm extended by vacuoles of different sizes ( Figure 1b– d) and eccentrically located nuclei.\n\nBiopsies from the fractured bone revealed reactive changes with ongoing fibrosis. The fibrotic tissue contained the multivacuolated histiocytes as singular cells, small groups or sheets of cells ( Figure 1b). The bone marrow biopsy showed massive histiocytic infiltrates ( Figure 1c). There was reduced fat cell content, and there was almost no visible hematopoietic tissue. The gastric biopsy showed antrum mucosa with elongated gastric pits and aggregates of multivacuolated histiocytes in both the superficial and deep lamina propria ( Figure 1d). A gastric biopsy taken two years previously was re-examined. It showed the same histiocytic infiltrates; however, the findings did not lead to the correct diagnosis at the time.\n\nIn the hematoxylin and eosin (H &E) stain, the vacuoles had distinct membranes and a bluish, transparent looking content. Vacuole content did not stain in the periodic acid Schiff (PAS), Prussian blue or Alcian blue stain. The cells were positive for CD68/PGM1 confirming the histiocytic nature ( Figure 2a). The vacuoles stained red in Congo red stain and black in the periodic acid methenamine silver (PASM) stain ( Figure 2b and c). The vacuoles did not show birefringence in Congo red stain or other stains.\n\nFigure 2. Staining properties.\n\nAll micrographs are from the same bone marrow biopsy. (a) CD 68/PGM1: The vacuolated cells are CD68-positive histiocytes. (b): Congo red stain: Vacuole content stains faintly red. (b) PASM: Vacuole content stains grey or black. All scale bars 50 μm.\n\nInterpretation\n\nThe microscopic appearance of the vacuolated histiocytes and the histochemical staining properties were consistent with PVP deposition. 12, 13 At that time, several of the OSDs marketed in Norway contained PVP. 4 Our patient had injected both buprenorphine tablets and methadone syrup regularly over several years. The buprenorphine tablets contained PVP K30 (MW 44–54 kDa). The specific methadone syrup he had been injecting contained large amounts of PVP K90 (MW 1 000–1 500 kDa). 14 While much of the PVP K30 is expected to be excreted within weeks, PVP K90 will not be excreted and consequently accumulates in the body. 6 It is therefore plausible that injections of the PVP K90-containing methadone syrup were the cause of the PVP-deposition disease in this patient. Based on the history of this patient and other similar cases, 15, 16 the European Medicines Agency suspended this methadone syrup in 2014. 14\n\nFurther development\n\nAfter the diagnosis was made, the patient’s health gradually declined, in part due to his poor self-care and underlying chronic drug addiction. There is no specific treatment for PVP deposition disease. His persistent anaemia was treated with regular blood transfusions and erythropoietin-stimulating agents with limited effect. He had short episodes of mild thrombocytopenia and leukocytopenia, and, in general, his leukocyte response to infection was weak. The kidney failure was managed by supportive treatment, and serum creatinine levels fluctuated between 150 and 450 μmol/L.\n\nWithin the first year of the diagnosis, the patient suffered a left sided pathological femoral neck fracture with impaired fracture healing, complicated by chronic osteomyelitis. In the right hip, he developed severe bone destruction of the acetabulum with dislocation of the femoral head and a subsequent femoral neck fracture ( Figure 3a). MRI scans of both hips and the pelvis (not shown) revealed the same changes as those detected in the shoulder region. Biopsies from the greater trochanter region showed extensive histiocytic infiltrates ( Figure 3b). Surgical treatments were unsuccessful. Henceforth his mobility deteriorated to such a degree that he needed a wheelchair and required daily activity support and care in a palliative care centre. Furthermore, he developed endocrine pancreas insufficiency with insulin-dependent diabetes mellitus. He had a gradual weight loss of 22 kg during four years despite adequate food intake. Malabsorption due to exocrine pancreas insufficiency was suspected, but supplementation of pancreas enzymes had little effect on the weight loss.\n\nFigure 3. Pathological fractures and bone destruction: radiological and biopsy findings.\n\n(a) Pelvic radiograph. Left hip: The hip prosthesis has been removed due to loosening and replaced by a Girdlestone hip. Right hip: Extensive lytic and sclerotic changes in the proximal femur and acetabulum leading to medial dislocation of the femoral head. (b) Biopsy from the right greater trochanter (H&E): The marrow space is filled with histiocytes with the bluish vacuoles characteristic of PVP-deposition. The bone trabecula has empty lacunar spaces and contains a bluish material. Scale bar 50 μm.\n\nFive years after the diagnosis of PVP deposition disease, the patient died, impaired by multi-organ failure and advanced cachexia with a body mass index below 15 kg/m 2.\n\nAutopsy\n\nThe autopsy concluded that the immediate cause of death was multi organ failure due to PVP deposition disease, which in turn was a consequence of the patient’s illicit substance abuse. The following organs and tissues were sampled during the autopsy: the pericardium and myocardium, the pleura and lungs, kidneys, liver, pancreas, gastric mucosa, adrenal glands, peritoneum and abdominal adipose tissue, the spleen, lymph nodes, and femoral bone and bone marrow. Microscopically, we observed PVP-deposition in all sampled organs and tissues ( Figure 4). The PVP-containing histiocytes were partly scattered in the interstitium, e.g. in the myocardium ( Figure 4a), and partly organised like larger, nodular lesions, e.g. in the pleura ( Figure 4b). Peri- and intra-neural distribution was seen in several organs including the heart. However, there were no clinical, echocardiographic or electocardiographic evidence of impaired cardiac output or arrhythmias prior to his death. Autopsy findings corresponded well with the clinically observed pancreas and kidney insufficiency. There was little preserved exocrine and endocrine pancreas parenchyma. The pancreatic tissue was dominated by dense fibrosis interspersed by heavy infiltrations of histiocytes ( Figure 4c). The kidney showed moderate to severe interstitial fibrosis and tubular atrophy, and only minor glomerular changes. There were infiltrates of PVP-containing histiocytes in the interstitium, mostly in atrophic areas ( Figure 4d). In glomeruli, we observed a slightly increased number of histiocytes and occasional PVP-containing vacuoles. There were no amyloid depositions or signs of other renal diseases. The autopsy revealed no evidence of infection besides minor foci of acute inflammation in the pancreas.\n\nFigure 4. Autopsy findings (H&E).\n\nInfiltrates of histiocytes with the bluish vacuoles characteristic of PVP in all organs. (a) Myocardium: Interstitial fibrosis and histiocytic infiltrates. Scale bar 50 μm. (b) Pleura: Nodular lesion composed of fibrotic tissue and histiocytes. We found similar lesions in the pericardium and peritoneum. These were macroscopically visible. Scale bar 200 μm. (c) Pancreas: Pronounced fibrosis with histiocytic infiltrates. Poorly preserved ductal structures. Scale bar 50 μm. (d) Kidney: Cortical tissue showing interstitial fibrosis, tubular atrophy, and an infiltrate of histiocytes in the extended interstitium. Scale bar 50 μm.\n\nDiscussion\n\nWe present the case of a drug-addicted patient with widespread PVP-deposition disease. We describe the patient’s clinical course from the first diagnosis of PVP-deposition to his death five years later and present biopsy and autopsy findings. The PVP deposition disease in this patient was likely caused by repeated intravenous injections of a methadone syrup containing high MW PVP.\n\nThe characteristic appearance and staining properties of PVP in tissue samples are well known. 17 Positivity for Congo red and PASM and negativity for PAS distinguishes PVP deposits from those seen in hereditary storage diseases. The histiocytic nature of the cells and the PAS negativity rule out metastatic signet ring cell carcinoma as a differential diagnosis. 17 PVPs light blue color in H&E and the typical localization of the deposits differentiates it from the non-water soluble variant of PVP, crospovidone. 18 Furthermore, PVP is not birefringent, unlike most other foreign materials commonly observed in tissue samples from injecting drug users. 19 Hence, making the diagnosis of PVP deposition is straightforward if this option is considered.\n\nWhether PVP deposition causes disease was controversial for a long time. The first reports of PVP- deposition described storage in the tissue that persisted years after the administration of PVP, but disputed whether the storage was harmful to the functioning of the target organs. 20 Later reports described clinically relevant adverse effects. Those most frequently reported were cytopenias, bone destruction, polyneuropathy and granulomatous lesions of the skin. 17, 21– 24 PVP deposition in internal organs such as the liver, kidneys, pancreas and the gastrointestinal tract has also been described, but the adverse effect of the deposition in these organs is less well known. 25, 26\n\nOur patient experienced a complex clinical syndrome and rapidly deteriorating health. The reason for his health decline was multifactorial, and his continued drug addiction likely aggravated the clinical course. Many of the clinical conditions associated with the fatal outcome correspond to findings in biopsies and the autopsy showing extensive PVP deposition. We believe that the extensive PVP deposition contributed to his health decline through several mechanisms. The widespread PVP deposition in bone and bone marrow was likely the main reason for the patient’s anaemia, pathological fractures and impaired fracture healing, fitting well with previous reports. 21, 23, 24 The impaired mobility and chronic osteomyelitis that resulted from these fractures gravely affected his health and quality of life. Furthermore, progressive cachexia was an important part of his health decline. The reason for the weight loss was not established during his lifetime, but his continued drug use likely contributed. Other possible contributing factors were pancreas insufficiency, progressive kidney failure, malabsorption, chronic infections and continued problems with vomiting, all likely related to the extensive PVP deposition. In summary, the PVP deposition probably played a major role in causing the patients’ multiple organ dysfunction ultimately leading to the fatal outcome.\n\nInjection of oral OSDs is common among injecting drug users and has long been a concern in the treatment of opioid addiction. 2 As an attempt to prevent injections, the previously mentioned methadone syrup was made highly viscous. 14 However, the increased viscosity did not prevent such unintended use. As a consequence, the choice of high MW PVP as thickener caused further severe adverse effects from injection.\n\nConclusions\n\nThis case revealed an unanticipated explanation for anaemia and pathological fractures in a drug-addicted patient. The correct identification of the observed foreign material as PVP revealed that injection of a certain methadone syrup containing PVP probably caused the patient’s deposition disease. Based on the clinical history, biopsy and autopsy findings, we conclude that the widespread PVP deposition likely contributed to the patient’s severe morbidity and death.\n\nList of abbreviations\n\nPVP: Polyvinylpyrrolidone\n\nOSD: Opioid substitution drug\n\nOST: Opioid substitution therapy\n\nH&E: Hematoxylin and eosin stain\n\nPASM: Periodic acid methenamine silver stain\n\nPAS: Periodic acid Schiff stain\n\nCRP: C-reactive protein\n\nMRI: Magnetic resonance imaging\n\nMW: Molecular weight\n\nData availability\n\nAll data underlying the results are available as part of the article and no additional source data are required.\n\nReporting guidelines\n\nZenodo: CARE checklist for “Polyvinylpyrrolidone deposition disease from repeated injection of opioid substitution drugs: report of a case with a fatal outcome”. https://doi.org/10.5281/zenodo.4667989. 27\n\nData are available under the terms of the Creative Commons Zero “No rights reserved” data waiver ( CC0 1.0 Universal).\n\nConsent for publication\n\nWritten informed consent for publication of the patient’s clinical details and clinical images was obtained from the patient prior to his death and from the closest relative.\n\nAcknowledgements\n\nWe appreciate the contributions of the patient and his family in allowing us to discuss his care and findings. We thank Ingrid Vallevik and Stine Kristoffersen for performing the autopsy and Anna Emilia Kozak for valuable comments on the radiologic images.\n\n10.5256/f1000research.58229.r89200\nReviewer response for version 2\nBüttner-Herold Maike 1Referee https://orcid.org/0000-0002-9974-6683\n\n1 Department of Nephropathology, Institute of Pathology, Friedrich-Alexander University Erlangen-Nuremberg (FAU), Erlangen, Germany\n8 7 2021 Copyright: © 2021 Büttner-Herold M\n2021\nhttps://creativecommons.org/licenses/by/4.0/ This is an open access peer review report distributed under the terms of the Creative Commons Attribution Licence, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.\nVersion 2recommendationapprove\nThe authors addressed all points I had to my perfect satisfaction and I have no further questions. Thank you for the opportunity to review this very interesting case.\n\nAre enough details provided of any physical examination and diagnostic tests, treatment given and outcomes?\n\nPartly\n\nIs the case presented with sufficient detail to be useful for other practitioners?\n\nYes\n\nIs sufficient discussion included of the importance of the findings and their relevance to future understanding of disease processes, diagnosis or treatment?\n\nYes\n\nIs the background of the case’s history and progression described in sufficient detail?\n\nYes\n\nReviewer Expertise:\n\nNephropathology, GvHD, immunology\n\nI confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard.\n\n10.5256/f1000research.55139.r85062\nReviewer response for version 1\nColvin Robert Barnes 1Referee\n1 Department of Pathology, Massachusetts General Hospital, Boston, MA, USA\n26 5 2021 Copyright: © 2021 Colvin RB\n2021\nhttps://creativecommons.org/licenses/by/4.0/ This is an open access peer review report distributed under the terms of the Creative Commons Attribution Licence, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.\nVersion 1recommendationapprove\nThe paper shows no new information, but the problem is a major one, with missed diagnoses and serious consequences. I think the paper will receive some attention with the major opioid crisis we have.\n\nI have no specific suggestions, other than a careful editing of the prose and the addition of at least on other major publication which has embolized material (EM) - e.g., Ganesan et al. (2003) 1 .\n\nAre enough details provided of any physical examination and diagnostic tests, treatment given and outcomes?\n\nYes\n\nIs the case presented with sufficient detail to be useful for other practitioners?\n\nYes\n\nIs sufficient discussion included of the importance of the findings and their relevance to future understanding of disease processes, diagnosis or treatment?\n\nYes\n\nIs the background of the case’s history and progression described in sufficient detail?\n\nYes\n\nReviewer Expertise:\n\nNA\n\nI confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard.\n\nStalund Ida Viken Haukeland University Hospital, Norway\n\n28 6 2021 We thank you for your thorough review of our manuscript.\n\nTo address your comment, we have added the following sentence in the second paragraph of the discussion: “PVPs light blue color in H&E and the typical localization of the deposits differentiates it from the non-water soluble variant of PVP, crospovidone.” and added your suggested reference.\n\n10.5256/f1000research.55139.r83519\nReviewer response for version 1\nBüttner-Herold Maike 1Referee https://orcid.org/0000-0002-9974-6683\n\n1 Department of Nephropathology, Institute of Pathology, Friedrich-Alexander University Erlangen-Nuremberg (FAU), Erlangen, Germany\n28 4 2021 Copyright: © 2021 Büttner-Herold M\n2021\nhttps://creativecommons.org/licenses/by/4.0/ This is an open access peer review report distributed under the terms of the Creative Commons Attribution Licence, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.\nVersion 1recommendationapprove-with-reservations\nThe present case report illustrates a very impressive case of PVP deposition in histiocytes in a large number of organs in a patient who repeatedly injected oral opioid substitution drugs. The description of such a finding is very valuable as the identification of foreign material can be very difficult for a pathologist, if the histological picture has not previously been seen. The illustration of the findings is very nicely done.\n\nSome minor points could be addressed: Besides the reported anaemia did the patient also have thrombopenia and leukopenia, which could explain the infectious complications?\n\nWas the patient free of infectious complications when he died?\n\nCan a loss of pancreatic islets be shown by immunhohistochemistry? In Figure 4C one wonders whether remaining islets are depicted.\n\nAs PVP is filtered in the glomeruli, were histiocytes detecable in the glomeruli? Was the distribution of PVP-loaden histiocytes in the kidneys dependent on the renal compartment?\n\nDid the cardiac infiltration by histiocytes lead to functional impairment of the cardiac output or to arrhythmias?\n\nIs their a possible explanation why PVP should interfer with the structure of the bone in such a destructive way?\n\nDoes the lack of birefringence of PVP also apply to the Congo red staining?\n\nKeywords: It would maybe be helpful to include \"foreign material\" and \"histiocytic storage\" to facilitate search for a pathologist finding PVP in a patient without being able to assign the finding to the right cause.\n\nAre enough details provided of any physical examination and diagnostic tests, treatment given and outcomes?\n\nPartly\n\nIs the case presented with sufficient detail to be useful for other practitioners?\n\nYes\n\nIs sufficient discussion included of the importance of the findings and their relevance to future understanding of disease processes, diagnosis or treatment?\n\nYes\n\nIs the background of the case’s history and progression described in sufficient detail?\n\nYes\n\nReviewer Expertise:\n\nNephropathology, GvHD, immunology\n\nI confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however I have significant reservations, as outlined above.\n\nStalund Ida Viken Haukeland University Hospital, Norway\n\n28 6 2021 We thank you for your thorough review of our manuscript. We have addressed your comments point by point.\n\nBesides the reported anemia, did the patient also have thrombocytopenia and leukopenia, which could explain the infectious complications? The patient had episodes of mild thrombocytopenia and leukopenia. In general, his leukocyte response to infection was weak. We added the following sentence in the section “Further development” to address this question: “He had short episodes of mild thrombocytopenia and leukocytopenia, and in general, his leukocyte response to infection was weak.”\n\nWas the patient free of infectious complications when he died? In the days and weeks prior to his death, he had stable, moderately increased CRP. Clinically, he showed no signs of acute infection and he did not receive antibiotic treatment. The autopsy revealed small foci of acute inflammation in the pancreas, but otherwise there were no signs of an acute infection. We added the following sentence in the section “Autopsy” to address this question: \"The autopsy revealed no evidence of infection besides minor foci of acute inflammation in the pancreas.\"\n\nCan a loss of pancreatic islets be shown by immunohistochemistry? In Figure 4C, one wonders whether remaining islets are depicted. Based on H&E morphology there was little preserved pancreatic parenchyma, both pancreatic acini and islets. Synaptophysin and Chromogranin A staining revealed a marked loss of pancreatic islets. CK-19 staining revealed areas of some preserved ductal structures, though the morphology was impaired by autolysis.\n\nWe changed the following sentence in the section “Autopsy” to address this question: \"There was little preserved exocrine and endocrine pancreas parenchyma. The pancreatic tissue was dominated by dense fibrosis interspersed by heavy infiltrations of histiocytes (Figure 4c).\"\n\nFigure 4C depicts fibrosis, PVP-containing histiocytes and ductal structures impaired by autolysis. Synaptophysin and Chromogranin A staining could not detect islets in this area. We changed the legend to figure 4C accordingly: (c) Pancreas: Pronounced fibrosis with histiocytic infiltrates. Poorly preserved ductal structures.\n\nAs PVP is filtered in the glomeruli, were histiocytes detecable in the glomeruli? Was the distribution of PVP-loaden histiocytes in the kidneys dependent on the renal compartment? In H&E, we observed occasional PVP-containing vacuoles in glomeruli. With CD68 staining, we detected histiocytes in most glomeruli. The number of histiocytes per glomerulus cross section was variable, but always less than ten. We added the following sentence in the section “Autopsy” to address this question: In glomeruli, we observed a slightly increased number of histiocytes and occasional PVP-containing vacuoles. \n\nThe vast majority of PVP-containing histiocytes were seen in the tubulointerstitial compartment, as stated in the “Autopsy” section. \n\nDid the cardiac infiltration by histiocytes lead to functional impairment of the cardiac output or to arrhythmias? The autopsy revealed infiltrates of PVP-containing histiocytes in the myocardium. We also observed peri- and intraneural distribution of the histiocytes. It is possible that such infiltrates could induce arrhythmias or other forms of cardiac impairments. Our patient did not show signs of such organ dysfunction, neither clinically nor in echocardiographic and electrocardiographic evaluations. We added the following sentence in the section “Autopsy” to address this question: “Peri- and intra-neural distribution was seen in several organs, including the heart. However, there were never any clinical, echocardiographic or electrocardiographic evidence of impaired cardiac output or arrhythmias prior to his death.” \n\nIs there a possible explanation why PVP should interfere with the structure of the bone in such a destructive way? The only mentioning of a possible cause for the bone destruction is in in a case report from 1993: Kepes et al. suggested that cells containing engulfed PVP would undergo mucoid alterations as a result of interactions between the engulfed material and the cytoplasm. The authors argue that in bone, the PVP-induced mucoid changes cause “softening of the bone” and interfere with the structural integrity of the bone trabeculae. One could also speculate that the massive infiltration of histiocytes in the marrow space could affect the blood supply to the osseous tissue, causing a form of avascular necrosis.\n\nWe think a discussion of this unresolved matter is out of focus for this case report.\n\nDoes the lack of birefringence of PVP also apply to the Congo red staining? Yes, the lack of birefringence of PVP also apply to the Congo red. We changed the following sentence in the section “Biopsy findings” to address this question: “The vacuoles did not show birefringence in Congo red stain or any other stains.”\n\nKeywords: It would maybe be helpful to include \"foreign material\" and \"histiocytic storage\" to facilitate search for a pathologist finding PVP in a patient without being able to assign the finding to the right cause Good point. We added these keywords.\n\nCompeting interests: Maike Büttner-Herold is involved in an European initiative working on a harmonized Kidney biopsy coding (KBC) system, which is coordinated by S. Leh. It is a project in which a large number of European Nephropathologists are involved discussing in meetings of how to best construct a coding system. From time to time we also have Zoom-meetings or email correspondence. This, however, has nothing to do with the case report submitted.\n\nCompeting interests: No competing interests were disclosed.\n\nCompeting interests: No competing interests were disclosed.\n\nCompeting interests: Maike Büttner-Herold is involved in an European initiative working on a harmonized Kidney biopsy coding (KBC) system, which is coordinated by S. Leh. It is a project in which a large number of European Nephropathologists are involved discussing in meetings of how to best construct a coding system. From time to time we also have Zoom-meetings or email correspondence. This, however, has nothing to do with the case report submitted.\n\nCompeting interests: No competing interests were disclosed.\n==== Refs\nReferences\n\n1 Degenhardt L Larance BK Bell JR : Injection of medications used in opioid substitution treatment in Australia after the introduction of a mixed partial agonist-antagonist formulation. Med J Aust. 2009;191 (3 ):161–165. 10.5694/j.1326-5377.2009.tb02729.x 19645647\n2 Bretteville-Jensen AL Lillehagen M Gjersing L : Illicit use of opioid substitution drugs: prevalence, user characteristics, and the association with non-fatal overdoses. Drug Alcohol Depend. 2015;147 :89–96. 10.1016/j.drugalcdep.2014.12.002 25543167\n3 Yeo AK Chan CY Chia KH : Complications relating to intravenous buprenorphine abuse: a single institution case series. Ann Acad Med Singap. 2006;35 (7 ):487–91. 16902725\n4 European Medicines Agency: Methadone medicinal products for oral use containing povidone. 2014 Reference SourceAccessed 07.11.2015.\n5 Buehler V : Polyvinylpyrrolidone Excipients for Pharmaceuticals: Povidone, Crospovidone and Copovidone. Berlin: Springer;2005.\n6 Robinson BV Sullivan FM Borzelleca JF : PVP - A Critical Review of the Kinetics and Toxicology of Polyvinylpyrrolidone (Povidone). Michigan: Lewis Publishers;1990.\n7 Siber GR Mayer RJ Levin MJ : Increased gastrointestinal absorption of large molecules in patients after 5-fluorouracil therapy for metastatic colon carcinoma. Cancer Res. 1980;40 (10 ):3430–6. 7438030\n8 Ravin HA Seligman AM Fine J : Polyvinyl pyrrolidone as a plasma expander: studies on its excretion, distribution and metabolism. N Engl J Med. 1952;247 (24 ):921–9. 10.1056/NEJM195212112472403 13002648\n9 Honda K Motoki R Sakuma H : Complications following the use of plasma expander, especially polyvinylpyrrolidone. Int Surg. 1966;45 :539–47.\n10 Christensen M Johansen P Hau C : Storage of polyvinylpyrrolidone (PVP) in tissues following long-term treatment with a PVP-containing vasopressin preparation. Acta Med Scand. 1978;204 (4 ):295–8. 10.1111/j.0954-6820.1978.tb08442.x 696429\n11 Wessel W Schoog M Winkler E : Polyvinylpyrrolidone (PVP), its diagnostic, therapeutic and technical application and consequences thereof. Arzneimittelforschung. 1971;21 (10 ):1468–82. 4945248\n12 Reske-Nielsen E Bojsen-Moller M Vetner M : Polyvinylpyrrolidone-storage disease. Light microscopical, ultrastructural and chemical verification. Acta Pathol Microbiol Scand A. 1976;84 (5 ):397–405. 970128\n13 Weiss SW Goldblum JR : Benign fibrohistiocytic and histiocytic tumors. In: Enzinger and Weiss’s Soft Tissue Tumors. 6ed. Philadelphia: Mosby Elsevier;2014. p.378–80.\n14 European Medicines Agency: Assessment report for methadone medicinal products for oral use containing povidone. 2014. Reference SourceAccessed 07.11.2015\n15 Kaur P Bergrem A Gerlyng P : A methadone user with anaemia, skeletal pain and altered appearance. Tidsskr Nor Laegeforen. 2016;136 (10 ):925–9. 10.4045/tidsskr.15.0692 27272371\n16 Kristoffersen AH Bjanes TK Jordal S : Polyvinylpyrrolidone induced artefactual prolongation of activated partial thromboplastin times in intravenous drug users with renal failure. J Thromb Haemost. 2016;14 (5 ):936–9. 10.1111/jth.13299 26921123\n17 Kuo TT Hsueh S : Mucicarminophilic histiocytosis. A polyvinylpyrrolidone (PVP) storage disease simulating signet-ring cell carcinoma. Am J Surg Pathol. 1984;8 (6 ):419–28. 10.1097/00000478-198406000-00002 6203415\n18 Ganesan S Felo J Saldana M Kalasinsky VF : Embolized crospovidone (poly[N-vinyl-2-pyrrolidone]) in the lungs of intravenous drug users. Mod Pathol. 2003;16 (4 ):286–92. 10.1097/01.mp.0000062653.65441.da 12692192\n19 Kringsholm B Christoffersen P : The nature and the occurrence of birefringent material in different organs in fatal drug addiction. Forensic Sci Int. 1987;34 (1-2 ):53–62. 10.1016/0379-0738(87)90083-1 3036675\n20 Altemeier WA Schiff L Galle A : Physiological and pathological effects of long-term polyvinylpyrrolidone retention. AMA Arch Surg. 1954;69 (3 ):308–14. 13188506\n21 Kepes JJ Chen WY Jim YF : 'Mucoid dissolution' of bones and multiple pathologic fractures in a patient with past history of intravenous administration of polyvinylpyrrolidone (PVP). A case report. Bone Miner. 1993;22 (1 ):33–41. 10.1016/s0169-6009(08)80079-7 8219936\n22 Kuo TT Hu S Huang CL : Cutaneous involvement in polyvinylpyrrolidone storage disease: a clinicopathologic study of five patients, including two patients with severe anemia. Am J Surg Pathol. 1997;21 (11 ):1361–7. 10.1097/00000478-199711000-00011 9351574\n23 Dunn P Kuo T Shih LY : Bone marrow failure and myelofibrosis in a case of PVP storage disease. Am J Hematol. 1998;57 (1 ):68–71. 10.1002/(SICI)1096-8652(199801)57:1<68::AID-AJH12>3.0.CO;2-5 9423820\n24 Huang WC Chang CH Tsai CC : Polyvinylpyrrolidone storage disease presenting as pathologic fracture and anemia: report of a case with imprint cytology. Diagn Cytopathol. 2012;40 (1 ):69–72. 10.1002/dc.21607 22180241\n25 Kojima M Takahashi K Honda K : Morphological study on the effect of polyvinyl pyrrolidone infusion upon the reticuloendothelial system. Tohoku J Exp Med. 1967;92 (1 ):27–54. 10.1620/tjem.92.27 6059659\n26 Edelmann U Johansen P Pedersen AB : PVP storage as the cause of specific organ symptoms. Ugeskr Laeger. 1977;139 (39 ):2309–12. 906128\n27 Stalund IV Riise GN Leh F : CARE checklist for “Polyvinylpyrrolidone deposition disease from repeated injection of opioid substitution drugs: report of a case with a fatal outcome”. Zenodo. 2021. 10.5281/zenodo.4667989\n\n",
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"keywords": "PVP; Polyvinylpyrrolidone; adverse effect; case report; methadone; opioid substitution drugs; opioid substitution therapy; povidone",
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"mesh_terms": "D000328:Adult; D000701:Analgesics, Opioid; D002047:Buprenorphine; D006801:Humans; D008297:Male; D004364:Pharmaceutical Preparations; D011205:Povidone",
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"title": "Case Report: Polyvinylpyrrolidone deposition disease from repeated injection of opioid substitution drugs: report of a case with a fatal outcome.",
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"abstract": "Varicella-zoster virus vaccination is recommended for virtually all young children in the United States, Canada, and several other countries. Varicella vaccine is a live attenuated virus that retains some of its neurotropic properties. Herpes zoster caused by vaccine virus still occurs in immunized children, although the rate is much lower than in children who had wild-type varicella. It was commonly thought that 2 varicella vaccinations would protect children against the most serious complication of meningitis following herpes zoster; however, 2 meningitis cases have already been published. We now report a third case of varicella vaccine meningitis and define risk factors shared by all 3 immunized adolescents. The diagnosis in cerebrospinal fluid in this third case was verified by amplifying and sequencing portions of the viral genome, to document fixed alleles found only in the vaccine strain. Viral antibody was also detected in the cerebrospinal fluid by confocal microscopy. When compared with the other 2 cases, remarkably all 3 were 14 years old when meningitis occurred. All 3 were treated with intravenous acyclovir, with complete recovery. The adolescent in our case report also had recurrent asthma, which was treated with both prednisone tablets and beclomethasone inhaler before onset of meningitis. When the 3 cases were considered together, they suggested that immunity to varicella-zoster virus may be waning sufficiently in some twice-immunized adolescents to make them vulnerable to varicella vaccine virus reactivation and subsequent meningitis. This complication rarely happens in children after wild-type varicella.",
"affiliations": "Division of Infectious Diseases, 23195Blank Children's Hospital, Des Moines, IA, USA.;Division of Hematology-Oncology, 23195Blank Children's Hospital, Des Moines, IA, USA.;Clinical Microbiology Laboratory, 23195Blank Children's Hospital, Des Moines, IA, USA.;Department of Neurology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.;Division of Pulmonary Diseases, University of Iowa Children's Hospital, 4083University of Iowa, Iowa City, IA, USA.;Division of Infectious Diseases/Virology, University of Iowa Children's Hospital, 4083University of Iowa, Iowa City, IA, USA.;Division of Infectious Diseases/Virology, University of Iowa Children's Hospital, 4083University of Iowa, Iowa City, IA, USA.;Division of Infectious Diseases/Virology, University of Iowa Children's Hospital, 4083University of Iowa, Iowa City, IA, USA.;Division of Child Neurology, University of Iowa Children's Hospital, 4083University of Iowa, Iowa City, IA, USA.",
"authors": "Ramachandran|Veena|V|;Elliott|Stephen C|SC|;Rogers|Kathie L|KL|;Cohrs|Randall J|RJ|;Weinberger|Miles|M|;Jackson|Wallen|W|;Carpenter|John E|JE|;Grose|Charles|C|0000-0001-6884-6668;Bonthius|Daniel J|DJ|",
"chemical_list": "D000998:Antiviral Agents; D019433:Chickenpox Vaccine; D000077483:Valacyclovir; D000212:Acyclovir",
"country": "United States",
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"doi": "10.1177/0883073820938597",
"fulltext": "\n==== Front\nJ Child Neurol\nJ Child Neurol\nJCN\nspjcn\nJournal of Child Neurology\n0883-0738 1708-8283 SAGE Publications Sage CA: Los Angeles, CA \n\n10.1177/0883073820938597\n10.1177_0883073820938597\nOriginal Articles\nVaricella Vaccine Meningitis as a Complication of Herpes Zoster in\nTwice-Immunized Immunocompetent Adolescents\nRamachandran Veena MD1 Elliott Stephen C. DO, PhD2 Rogers Kathie L. PhD3 Cohrs Randall J. PhD4 Weinberger Miles MD5 Jackson Wallen BA6 Carpenter John E. PhD6 https://orcid.org/0000-0001-6884-6668Grose Charles MD6 Bonthius Daniel J. MD, PhD7 \n1 Division of Infectious Diseases, 23195Blank Children’s Hospital, Des Moines, IA, USA\n\n2 Division of Hematology-Oncology, 23195Blank Children’s Hospital, Des Moines, IA, USA\n\n3 Clinical Microbiology Laboratory, 23195Blank Children’s Hospital, Des Moines, IA, USA\n\n4 Department of Neurology, University of Colorado Anschutz Medical\nCampus, Aurora, CO, USA\n\n5 Division of Pulmonary Diseases, University of Iowa Children’s\nHospital, 4083University of Iowa, Iowa City, IA, USA\n\n6 Division of Infectious Diseases/Virology, University of Iowa\nChildren’s Hospital, 4083University of Iowa, Iowa City, IA, USA\n\n7 Division of Child Neurology, University of Iowa Children’s Hospital, 4083University of Iowa, Iowa City, IA, USA\nCharles Grose, MD, Division of Infectious\nDiseases/Virology, University of Iowa Hospital, room BT2001, 200 Hawkins Drive,\nIowa City, IA 52242, USA. Email: charles-grose@uiowa.edu\n17 7 2020 \n11 2020 \n35 13 889 895\n25 3 2020 12 5 2020 3 6 2020 © The Author(s) 20202020SAGE PublicationsThis article is distributed under the terms of the Creative Commons\nAttribution-NonCommercial 4.0 License (https://creativecommons.org/licenses/by-nc/4.0/) which\npermits non-commercial use, reproduction and distribution of the work\nwithout further permission provided the original work is attributed as\nspecified on the SAGE and Open Access pages (https://us.sagepub.com/en-us/nam/open-access-at-sage).Varicella-zoster virus vaccination is recommended for virtually all young\nchildren in the United States, Canada, and several other countries. Varicella\nvaccine is a live attenuated virus that retains some of its neurotropic\nproperties. Herpes zoster caused by vaccine virus still occurs in immunized\nchildren, although the rate is much lower than in children who had wild-type\nvaricella. It was commonly thought that 2 varicella vaccinations would protect\nchildren against the most serious complication of meningitis following herpes\nzoster; however, 2 meningitis cases have already been published. We now report a\nthird case of varicella vaccine meningitis and define risk factors shared by all\n3 immunized adolescents. The diagnosis in cerebrospinal fluid in this third case\nwas verified by amplifying and sequencing portions of the viral genome, to\ndocument fixed alleles found only in the vaccine strain. Viral antibody was also\ndetected in the cerebrospinal fluid by confocal microscopy. When compared with\nthe other 2 cases, remarkably all 3 were 14 years old when meningitis occurred.\nAll 3 were treated with intravenous acyclovir, with complete recovery. The\nadolescent in our case report also had recurrent asthma, which was treated with\nboth prednisone tablets and beclomethasone inhaler before onset of meningitis.\nWhen the 3 cases were considered together, they suggested that immunity to\nvaricella-zoster virus may be waning sufficiently in some twice-immunized\nadolescents to make them vulnerable to varicella vaccine virus reactivation and\nsubsequent meningitis. This complication rarely happens in children after\nwild-type varicella.\n\nvaricellavaccineacyclovirasthmacerebrospinal fluidprednisoneNational Institutes of Healthhttps://doi.org/10.13039/100000002HL126667typesetterts3\n==== Body\nMeningitis as a complication of herpes zoster is extraordinarily unusual in\nimmunocompetent children and adolescents who have had wild-type varicella after their\nfirst birthday.1 No cases of associated meningitis were documented in a 22-year retrospective\nsurvey of herpes zoster cases in otherwise healthy children (through age 19 years) seen\nby pediatricians at the Mayo Clinic before approval of varicella vaccination.2 In a prior report, we described 3 children with severe cutaneous herpes zoster\ncaused by the varicella vaccine virus.3 In this report, we extend that observation to include an even more serious and\nunusual complication of varicella vaccination and herpes zoster, namely, varicella\nvaccine meningitis. The live attenuated varicella vaccine (strain Oka; Varivax) was\napproved for administration to children in the United States by the Food and Drug\nAdministration in 1995.4 Extensive clinical trials had been carried out in both Japan and the United States.5 The first trials were carried out in Japan because the vaccine was developed by\nthe Takahashi virology laboratory in Osaka.6 The vaccine effectiveness is high, and the disease varicella has nearly\ndisappeared from the United States because of high immunization rates.7,8 The safety profile has also been excellent.9\n\n\nThe varicella vaccine virus is a live attenuated virus. Therefore, like its wild-type\ncounterpart, the vaccine virus can enter neurons after local replication in the skin.\nThe vaccine virus can also establish latency in the dorsal root ganglia and occasionally\nreactivate to cause herpes zoster.10 Herpes zoster after varicella vaccination is generally less common and less\nsevere than herpes zoster after wild-type varicella disease.11 Vaccine-related herpes zoster can also lead to meningitis.12,13 Because these earlier cases of varicella vaccine meningitis have occurred\nfollowing herpes zoster in children who have received only a single varicella\nvaccination, it was thought that 2 varicella vaccinations would effectively protect\nagainst subsequent varicella vaccine meningitis.14 However, we now present the third case of viral meningitis caused by varicella\nvaccine virus in a twice-immunized and otherwise healthy adolescent. We also review the\n2 prior varicella vaccine meningitis cases in twice-immunocompetent adolescents, both of\nwhich are very similar to our case.15,16 Altogether, these 3 cases elucidate risk factors for varicella vaccine meningitis\nin older children who have received 2 varicella vaccinations.\n\nMethods\nWe measured levels of varicella antibody in cerebrospinal fluid by an adaption of the\nvaricella fluorescent antibody to membrane antigen test, in which we substituted\nconfocal microscopy for conventional fluorescence microscopy.17,18 Confocal microscopy is several-fold more sensitive than conventional\nfluorescence microscopy for detection of antibody. The 3-D confocal images were\nprepared with the Imaris software program. Likewise, methods for varicella-specific\nsequencing have been described in earlier publications from this virology laboratory.3,19,20 Our methods follow guidelines among varicella laboratories for identifying\nfixed alleles specific to the genome of the varicella vaccine virus (strain Oka).21-24 Briefly, the cerebrospinal fluid sample was stored frozen after aliquots were\nremoved for the initial screening tests (cell count, glucose, protein, bacterial\nculture, screening PCR). Subsequently, the sample was thawed for the first time in\norder to perform partial sequencing of the viral genome known to be present in\ncerebrospinal fluid after the varicella-positive screening PCR test.\n\nBecause the varicella open reading frame (ORF) 62 contains the most single nucleotide\npolymorphisms specific to the vaccine strain, regions of ORF62 were PCR-amplified\nfrom the sample of cerebrospinal fluid using previously described primers and the\nExpand Hi Fidelity DNA polymerase (Roche Diagnostics, 11732641001).25 The PCR amplicons were then sequenced by Sanger methodology at the University\nof Iowa Core Facility. The generated sequences were then aligned to either the\nvaricella wild-type reference sequence (Dumas, GenBank X04370.1) or the varicella\nvaccine virus sequence (vOka, Genbank AB097932) to provide a consensus sequence\nusing a locally written computer program.\n\nResults\nIllustrative Case Report\nThe patient was a 14-year-old female adolescent admitted to hospital in 2019\nbecause of increasingly severe headaches. The headaches were accompanied by\ndizziness, nausea, vomiting, and confusion. When she first presented in the\nemergency department late in the evening, she was noted to be febrile. Her\nweight was 72 kg, with a body mass index of 23. A complete blood cell count and\nmetabolic panel were unremarkable. A head computed tomogram was performed and\nread as normal. Thereafter, a lumbar puncture was performed, with the following\nresults on cerebrospinal fluid: colorless; protein, 132 mg/dL; glucose, 45\nmg/dL; red blood cells, 5/mm3; and nucleated cell count,\n775/mm3, with 82% lymphocytes. A Biofire Filmarray\nencephalitis/meningitis multiplex panel test on the cerebrospinal fluid was\npositive for varicella-zoster virus. Within 12 hours after admission, therapy\nwith intravenous acyclovir (30 mg/kg/d) was initiated. Later in the same day, a\nsmall cluster of vesicles was observed over her right knee (see Discussion and\nFigure 2, panel C).\nFluid from one vesicle was tested by Focus Integrated Cycler for both herpes\nsimplex virus and varicella virus DNA; only varicella was positive. Head\nmagnetic resonance imaging was performed and was normal except for increased\nenhancement along the leptomeningeal surface, consistent with meningitis.\n\nOn further questioning after admission, the patient revealed that she had been\nhaving intermittent but less severe headaches as well as abdominal pain and back\npain for 2 weeks. She had gone to a different medical clinic, where a computed\ntomogram of the abdomen/pelvis with contrast was performed 10 days before the\ncurrent admission. That scan did not show any abnormalities. During her\nhospitalization, she completed a 7-day course of intravenous acyclovir, followed\nby 2 weeks of valacyclovir tablets (1 g thrice daily), with complete resolution\nof symptoms.\n\nHer past medical history was also notable for recurrent bouts of asthma since age\n3 years; the asthma attacks were induced by viral respiratory infections.\nBecause of continued exacerbations up to the present time, she was\nintermittently using an oral metered-dose inhaler of beclomethasone (80 µg twice\ndaily). Four weeks before her current admission, her asthma worsened and she had\nsought treatment at a third medical facility. At that clinic, prednisone tablets\n20 mg daily for 5 days were prescribed. She had never taken prednisone tablets\nin the past. Four days later, she refilled her prescription for the\nbeclomethasone inhaler, which she had continued to use until admission to the\nhospital.\n\nShe had received all recommended childhood immunizations, including a live\nattenuated varicella vaccine at ages 1 and 5 years. She had received a\nmeasles-mumps-rubella vaccination on the same 2 days. Neither she nor her mother\nrecalled any family member with varicella or herpes zoster rashes in the month\npreceding onset of meningitis. Therefore, there was no possibility of a recent\ntransmission of varicella vaccine virus to the adolescent. Also see further\ninformation in the Discussion.\n\nOne month after discharge, she returned for an immunology evaluation. Serum\nlevels of immunoglobulins IgM, IgA, and IgG were within normal limits, as were\nlevels of the 4 IgG subclasses. Similarly, the levels of IgG antibodies to both\ntetanus toxoid and diphtheria toxoid were within normal ranges for a child who\nhad previously received 4 tetanus-diphtheria-pertussis vaccinations. The total\nserum complement level was normal. The B-cell phenotyping profile for\nimmunodeficiency and immune competence assessment was normal. The percentages of\nCD3, CD4, CD8, and CD16 + CD56 lymphocytes were normal by flow cytometry\nanalysis. Likewise, a CD8 immune competence assessment was normal as measured by\ngamma interferon level and CD107a/CD107b markers. All immunology testing was\nperformed by Mayo Medical Laboratories, Rochester, MN.\n\nVaricella Antibody in Cerebrospinal Fluid\nIn prior studies, the presence of varicella antibody in cerebrospinal fluid has\nbeen a sensitive indicator of central nervous system infection, sometimes more\nsensitive than measuring varicella DNA.26-28 To confirm the result of the multiplex assay, we tested for varicella\nantibody in the cerebrospinal fluid of our patient and the test was positive\n(Figure 1). Four\nrepresentative images are shown in panels A to D; arrows designate the presence\nof fluorescent-labeled varicella antibody in the cerebrospinal fluid reacting\nwith virus-infected cells. Panels A and B include 2-D images and panels C and D\ninclude renderings of 3-D images; panels E and F are positive and negative\ncontrol images, respectively.\n\nFigure 1. Detection of antibody to varicella virus in the cerebrospinal fluid of\nmeningitis case. The patient’s antibody that attaches to virus-infected\ncells is stained fluorescent green; these positive areas are designated\nby yellow arrows (A-D). Positive and negative controls (E, F). Nuclei\nwithin the cells are stained dark blue (For interpretation of the\nreferences to colours in this figure legend, refer to the online version\nof this article).\n\nViral Sequencing Data\nThe commercial Biofire Filmarray screening test of cerebrospinal fluid is both\nsensitive and specific.29 The test was positive for varicella DNA. However, the test kit does not\ndifferentiate wild-type from vaccine-type varicella strains. Therefore, further\nsequencing was necessary to amplify specific varicella genes in the\ncerebrospinal fluid sample. The viral genome contains around 70 individual\ngenes. A very informative sequence is ORF62, because there are\nseveral single nucleotide polymorphisms in ORF62 that are\nalways found in vaccine-type ORF62 genes but are never found in\nwild-type varicella ORF62 genes.30,31 The viral sequencing data demonstrated that the patient’s isolate was\nvaccine-type and not wild-type. For example, the polymorphism at nucleotide\nposition 107252, which is always found in vaccine-type virus but never in\nwild-type virus, was present in the viral DNA of our patient.21 Thus, our varicella sequencing results confirmed that the vaccine strain\nwas responsible for the meningitis. These results were very similar to those\npreviously reported in cases from 2017 and 2019 (Table 1).\n\nTable 1. Prominent Features Among 3 Immunized and Immunocompetent Adolescents With\nVaricella Vaccine Meningitis and Herpes Zoster.\n\nCategory\tCurrent Case\tCase\nRef 15\tCase\nRef 16\t\nGeography\tDes Moines, IA\tBoston, MA\tSeattle, WA\t\nGender\tFemale\tFemale\tMale\t\nAge 1st vaccine, y\t1.3\t1.5\t∼1\t\nAge 2nd vaccine, y\t5\t12\t4\t\nAge of meningitis, y\t14\t14\t14\t\nLocation of zoster\tL4\tT5\tL1/L2\t\nYears after 1st vaccine\t13\t13\t13\t\nYears after 2nd vaccine\t9\t2\t10\t\nCSF screening PCR\tYes\tYes\tYes\t\nCSF cell count\t775\t568\t140\t\nCSF VZV antibody\tYes\tNot done\tNo\t\nAcyclovir IV, d\t7\t7\t7\t\nValacyclovir, d\t14\t14\t0\t\nFollow-up\tYes\tNo\tYes\t\nAbbreviations: CSF, cerebrospinal fluid; IV, intravenous; PCR,\npolymerase chain reaction; VZV, varicella zoster virus.\n\nComparison With 2 Prior Cases\nBased on our review of the literature, we have diagnosed the third case of\nvaricella vaccine meningitis in a twice-immunized immunocompetent adolescent.\nThere are strikingly similarities among the 3 cases, as shown in Table 1. First, all 3\npatients were aged 14 years.15,16 Second, the 3 patients have likely had latent vaccine virus in their\ndorsal root ganglia for 13 years, since their first varicella vaccination.\nThird, 2 of the 3 patients had herpes zoster in their lower extremities. Note\nthat we did not include another patient described in reference 16, because that\npatient was immunocompromised when he developed herpes zoster. As mentioned in\nthe Introduction, we also did not include any meningitis cases that occurred in\nchildren who had received only 1 varicella vaccination.\n\nMost varicella vaccinations in children under the age of 2 years are administered\nby injection into the thigh. Thus, the location of herpes zoster in our\npatient’s lower extremity was most likely secondary to local viral replication\nin the thigh following her initial varicella vaccination and subsequent\northograde transport of vaccine virus via sensory nerves to lumbar dorsal root\nganglia innervating the L2-L4 dermatomes, followed by re-emergence of the virus\nin the lower extremity years later. The location of thoracic herpes zoster\nfollowing immunization is easily explained, based on early data from Japan that\nshowed about a 50% likelihood of viremia after the first varicella vaccination.32 During the viremia, the virus either directly entered thoracic dorsal\nroot ganglia after exiting their segmental artery blood supply or the virus\nexited capillaries beneath the truncal skin and caused a few tiny unrecognized\nvesicles with sequent spread of virus to thoracic dorsal root ganglia.\n\nDiscussion\nIn a Medline literature search between 1960 and 2004, we found 1 case report of\nherpes zoster meningitis in an otherwise healthy 12-year-old boy who had had\nwild-type varicella and no varicella vaccination.1,2 We now present data from 3 patients described in Table 1, suggesting that some vaccine\nrecipients who have received 2 varicella vaccinations beginning after their first\nbirthday already are exhibiting waning immunity by age 14 years, sufficient to allow\nreactivation with varicella vaccine meningitis as a complication of herpes zoster.\nThe phenomenon that twice-immunized children could lose immunity within 9-10 years\nafter their second immunization had not been anticipated. But there are similarities\nto laboratory findings in older adults who have herpes zoster. Clinical studies\nperformed decades ago in the United States and Finland revealed that 38% to 46% of\nadult herpes zoster patients will have a pleocytosis in the cerebrospinal fluid, an\ninflammatory response highly suggestive of viral meningitis.33,34 In the 3 cases of vaccinated adolescents (Table 1), all 3 patients had headache and\nall 3 had pleocytosis with detectable varicella DNA in the cerebrospinal fluid. We\nknow that vaccine virus reactivates less frequently than wild-type virus,11,35 but we may never know the percentage of children with abnormal cerebrospinal\nfluid values after vaccine-related herpes zoster without clinical meningitis.\n\nIn our patient, one prior risk factor came to particular attention. The patient has\nhad a diagnosis of asthma since 2007 and frequently used bronchodilating inhalers,\nbut never systemic corticosteroids until 2019. She exhibited the most common\nclinical asthma phenotype with bronchial hyperresponsiveness following viral\nrespiratory infection.36 We have shown an increased risk of herpes zoster in children with asthma,\nirrespective of inhaled corticosteroid usage37,38; most of these children would have had wild-type varicella. In our 2019\nreport of 3 cases of severe herpes zoster caused by varicella vaccine virus, one of\nthe 3 children developed asthma after he recovered from the shingles.3 Other groups have shown an increased risk of herpes zoster in both children\nand adults with asthma.39-42 In our current case, a precipitating risk factor for herpes zoster may have\nbeen the addition of prednisone tablets to her standard inhaled beclomethasone\nregimen for treatment of recurrent asthma. There was no information about an asthma\nhistory in the other 2 case reports (Table 1).\n\nSystemic corticosteroid regimens have been known to precipitate herpes zoster in\nchildren with cancer and other chronic diseases since the 1950s.43,44 Based on studies examining the risk of herpes zoster in patients being\ntreated for various rheumatologic diseases, dosages of prednisone of over 7.5 mg per\nday were sufficient to increase the likelihood of developing herpes zoster.45-47 Many of these children with chronic rheumatologic diseases were taking\nprednisone for long periods. However, some of the cases of herpes zoster occurred\nwithin weeks of starting prednisone therapy.48 Of further interest, data from the older literature suggests that children\nwith asthma who were recently treated with corticosteroids were particularly\nvulnerable to adverse events following primary varicella infection.49-51 In spite of the concerns listed in the preceding sentences, we note that the\ndosage of prednisone received by our patient was not high when her weight was taken\ninto consideration.\n\nFurther, we propose a pathogenesis model for varicella vaccine meningitis, based not\nonly on a varicella animal model52 but also on data from a closely related herpesvirus of swine, namely,\npseudorabies virus (Figure\n2). Zosteriform rashes during pseudorabies disease are secondary to virus\ntraveling in itch and pain sensory fibers.53 In our adolescent patient, vaccine virus entered the dorsal root ganglia\nafter the first varicella vaccination at age 1 year (A). At age 14 years, vaccine\nvirus acquired at age 1 year reactivated from latency (B) and traveled in sensory\nfibers to both the skin over the right leg (C) and also to the gray matter of the\nadjacent spinal cord.54 Viral replication in the spinal cord led to meningitis (D). We postulate that\nrapid initiation of intravenous acyclovir therapy may have prevented a progression\nfrom meningitis to meningoencephalitis (E). Finally, although this report is meant\nto raise awareness of varicella vaccine meningitis, we note the rarity of this\nneurologic infectious disease in the United States.\n\nFigure 2. Model for pathogenesis of varicella vaccine meningitis following herpes\nzoster in an immunized adolescent. This figure includes a photo of the\nherpes zoster rash on the right leg of our case of meningitis (panel C).\nDRG, dorsal root ganglia.\n\nAuthor Contributions: VR, SCE, KLR, and MW provided clinical management; WJ, JEC, and CG carried out\nthe virology assays and prepared the figures; RJC reviewed the methodology from\nthe virology assays; VR, CG, and DJB prepared the manuscript.\n\nDeclaration of Conflicting Interests: The authors declared no potential conflicts of interest with respect to the\nresearch, authorship, and/or publication of this article.\n\nFunding: The authors disclosed receipt of the following financial support for the\nresearch, authorship, and/or publication of this article: Research by Dr Grose\nis funded in part by NIH grant AI153817, which supports research to advance\nvaccine safety.\n\nORCID iD: Charles Grose, MD \nhttps://orcid.org/0000-0001-6884-6668\n\n\nEthical Approval: This case study was approved by the University of Iowa Institutional Review\nBoard, Iowa City, IA, USA.\n==== Refs\nReferences\n1 \nJhaveri R Sankar R Yazdani S Cherry JD \nVaricella-zoster virus: an overlooked cause of\naseptic meningitis\n. 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Nat Rev Neurosci .\n2010 ;11 (12 ):823 –836\n.21068766\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "0883-0738",
"issue": "35(13)",
"journal": "Journal of child neurology",
"keywords": "acyclovir; asthma; cerebrospinal fluid; prednisone; vaccine; varicella",
"medline_ta": "J Child Neurol",
"mesh_terms": "D000212:Acyclovir; D000293:Adolescent; D000998:Antiviral Agents; D019433:Chickenpox Vaccine; D005260:Female; D006562:Herpes Zoster; D006801:Humans; D007121:Immunocompetence; D008297:Male; D008581:Meningitis; D000077483:Valacyclovir",
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"pages": "889-895",
"pmc": null,
"pmid": "32677551",
"pubdate": "2020-11",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D052061:Research Support, N.I.H., Extramural",
"references": "23792686;7964642;13335332;4285450;15911422;12553305;30496366;14998778;31943220;26018115;16474115;8308520;889481;17287447;30290892;20225010;12388706;3339190;25087224;24162921;32234797;1850506;25134101;18789098;6273449;8559621;30187216;21068766;27078099;23183312;26821966;29202939;18419392;22889542;3863086;23587434;29939802;24805130;31692250;13400603;9818869;28332418;17069870;11162813;14513413;24470276;2828948;30628536;30103646;3018124;22205584;17279082;5845441",
"title": "Varicella Vaccine Meningitis as a Complication of Herpes Zoster in Twice-Immunized Immunocompetent Adolescents.",
"title_normalized": "varicella vaccine meningitis as a complication of herpes zoster in twice immunized immunocompetent adolescents"
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],
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},
"primarysource": {
"literaturereference": "RAMACHANDRAN V, ELLIOTT SC, ROGERS KL, COHRS RJ, WEINBERGER M, JACKSON W, ET AL. VARICELLA VACCINE MENINGITIS AS A COMPLICATION OF HERPES ZOSTER IN TWICE?IMMUNIZED IMMUNOCOMPETENT ADOLESCENTS. J?CHILD?NEUROL 2020?:.",
"literaturereference_normalized": "varicella vaccine meningitis as a complication of herpes zoster in twice immunized immunocompetent adolescents",
"qualification": "1",
"reportercountry": "US"
},
"primarysourcecountry": "US",
"receiptdate": "20200826",
"receivedate": "20200826",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "1",
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"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
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}
] |
{
"abstract": "OBJECTIVE\nTo observe the retinopathy of the patients who received interferon/ribavirin for treatment of chronic hepatitis C.\n\n\nMETHODS\nWe observed 6 patients(5 males and 1 female) who received interferon/ribavirin for treatment of chronic hepatitis C. Visual acuity tests and detailed fundus examinations were performed monthly during 6 months of interferon/ribavirin therapy.\n\n\nRESULTS\nAll patients developed soft retinal exudate and 5 developed retinal blot hemorrhage. None of the patients exhibited visual impairment or subjective symptoms during the treatment period, and the retinopathy disappeared or decreased in all patients. All of the patients in this study developed interferon retinopathy while undergoing interferon/ribavirin combination therapy.\n\n\nCONCLUSIONS\nBecause the combination of ribavirin with interferon may increase the incidence of interferon retinopathy, and cases of severe retinal complications have also been reported, careful fundus examinations should be performed during combination therapy, just as they are performed during conventional interferon therapy.",
"affiliations": "Department of Ophthalmology, Showa University Northern Yokohama Hospital. 3 5 1 Chigasakichuo, Tsuzuki-ku, Yokohama 224 8503, Japan.",
"authors": "Nakamura|Toru|T|;Takahashi|Haruo|H|;Koike|Noboru|N|;Mitsutaka|Minami|M|;Soda|Mitsutaka|M|;Kimu|Myonsugi|M|",
"chemical_list": "D000998:Antiviral Agents; D000077190:Interferon alpha-2; D016898:Interferon-alpha; D011994:Recombinant Proteins; D012254:Ribavirin",
"country": "Japan",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0029-0203",
"issue": "109(11)",
"journal": "Nippon Ganka Gakkai zasshi",
"keywords": null,
"medline_ta": "Nippon Ganka Gakkai Zasshi",
"mesh_terms": "D000368:Aged; D000998:Antiviral Agents; D004359:Drug Therapy, Combination; D005260:Female; D019698:Hepatitis C, Chronic; D006801:Humans; D000077190:Interferon alpha-2; D016898:Interferon-alpha; D008297:Male; D008875:Middle Aged; D011994:Recombinant Proteins; D012164:Retinal Diseases; D012166:Retinal Hemorrhage; D012254:Ribavirin",
"nlm_unique_id": "7505716",
"other_id": null,
"pages": "748-52",
"pmc": null,
"pmid": "16363669",
"pubdate": "2005-11",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Retinopathy during interferon treatment in combination with ribavirin for chronic hepatitis C.",
"title_normalized": "retinopathy during interferon treatment in combination with ribavirin for chronic hepatitis c"
} | [
{
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{
"actiondrug": "5",
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"drugindication": "CHRONIC HEPATITIS C",
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"drugdosagetext": "600-800MG EVERY DAY.",
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}
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"reactionmeddrapt": "Retinal exudates",
"reactionmeddraversionpt": "18.1",
"reactionoutcome": "3"
},
{
"reactionmeddrapt": "Retinal haemorrhage",
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"reactionoutcome": "3"
},
{
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}
],
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"drugdosagetext": "600-800MG EVERY DAY.",
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"medicinalproduct": "RIBAVIRIN."
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"actiondrug": "5",
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},
{
"reactionmeddrapt": "Retinopathy",
"reactionmeddraversionpt": "18.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Retinal haemorrhage",
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}
],
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},
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"literaturereference_normalized": "retinopathy during interferon treatment in combination with ribavirin for chronic hepatitis c",
"qualification": "1",
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},
"primarysourcecountry": "JP",
"receiptdate": "20151028",
"receivedate": "20151028",
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},
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},
{
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}
],
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},
{
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{
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}
],
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},
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],
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{
"reactionmeddrapt": "Retinopathy",
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},
{
"reactionmeddrapt": "Retinal exudates",
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},
{
"reactionmeddrapt": "Retinal haemorrhage",
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}
],
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},
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},
{
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},
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{
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{
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"reactionoutcome": "3"
}
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"literaturereference_normalized": "retinopathy during interferon treatment in combination with ribavirin for chronic hepatitis c",
"qualification": "1",
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},
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] |
{
"abstract": "In this report, we describe the first successful case of microvascular free tissue transfer in a patient with Evans Syndrome (ES), a rare form of idiopathic thrombocytopenic purpura (ITP) and associated autoimmune hemolytic anemia (AIHA). Microvascular surgery in the setting of ES is likely to have higher complication rates because of the increased risk of postoperative bleeding and free flap thrombosis. The case presented here opens up to the feasibility of microvascular reconstruction of patients with coagulation disorders like ES. Every effort should be made to control for hemolytic, thrombocytopenic, and thrombophilic states associated with ES. In the absence of evidence-based treatment guidelines for ES, personalized treatment protocols with high-dose corticosteroids, immunoglobulin, and postoperative anticoagulation regimen are highly recommended.",
"affiliations": "Unit of Oral and Maxillofacial Surgery, Department of Surgery, Azienda Ospedaliera Universitaria Integrata Verona, Verona, Italy.",
"authors": "Bedogni|Alberto|A|;Anesi|Alexandre|A|;Fior|Andrea|A|;Bettini|Giordana|G|;Nocini|Pier Francesco|PF|",
"chemical_list": "D000305:Adrenal Cortex Hormones",
"country": "United States",
"delete": false,
"doi": "10.1055/s-0033-1348898",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0743-684X",
"issue": "29(8)",
"journal": "Journal of reconstructive microsurgery",
"keywords": null,
"medline_ta": "J Reconstr Microsurg",
"mesh_terms": "D000293:Adolescent; D000305:Adrenal Cortex Hormones; D000744:Anemia, Hemolytic, Autoimmune; D005260:Female; D006801:Humans; D063175:Mandibular Reconstruction; D008866:Microsurgery; D016038:Skin Transplantation; D013921:Thrombocytopenia; D014057:Tomography, X-Ray Computed",
"nlm_unique_id": "8502670",
"other_id": null,
"pages": "545-50",
"pmc": null,
"pmid": "23804021",
"pubdate": "2013-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Microsurgical reconstruction of the mandible in a patient with evans syndrome: a case report and review of the literature.",
"title_normalized": "microsurgical reconstruction of the mandible in a patient with evans syndrome a case report and review of the literature"
} | [
{
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}
],
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"reaction": [
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"reactionmeddrapt": "Cushingoid",
"reactionmeddraversionpt": "18.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Giant cell epulis",
"reactionmeddraversionpt": "18.0",
"reactionoutcome": "1"
}
],
"summary": {
"narrativeincludeclinical": "CASE EVENT DATE: 200701"
}
},
"primarysource": {
"literaturereference": "BEDOGNI A,ANESI A,FIOR A,BETTINI G,NOCINI P. MICROSURGICAL RECONSTRUCTION OF THE MANDIBLE IN A PATIENT WITH EVANS SYNDROME: A CASE REPORT AND REVIEW OF THE LITERATURE. JOURNAL OF RECONSTRUCTIVE MICROSURGERY 2013 OCT;29:8:545-550.",
"literaturereference_normalized": "microsurgical reconstruction of the mandible in a patient with evans syndrome a case report and review of the literature",
"qualification": "3",
"reportercountry": "COUNTRY NOT SPECIFIED"
},
"primarysourcecountry": "IT",
"receiptdate": "20150415",
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},
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},
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"transmissiondate": "20150821"
}
] |
{
"abstract": "Tumor lysis syndrome (TLS) is an oncological emergency that results from massive cytolysis of malignant cells with a sudden release of their contents into the systemic circulation. TLS was rarely described in patients with malignant melanoma. In this article, we describe two patients with malignant melanoma who developed this syndrome. In one of them, the syndrome occurred spontaneously, and this is the second description of spontaneous tumor lysis in a patient with melanoma. We reviewed the previous patients with melanoma-induced TLS and discussed the manifestations and the pathophysiology of the syndrome in our patients.",
"affiliations": "Department of Medicine E, Sheba Medical Center and Sackler School of Medicine, Tel-Aviv University, Tel-Hashomer 52621, Israel. mouallem@post.tau.ac.il",
"authors": "Mouallem|Meir|M|;Zemer-Wassercug|Noa|N|;Kugler|Eitan|E|;Sahar|Nadav|N|;Shapira-Frommer|Ronnie|R|;Schiby|Ginette|G|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1007/s12032-012-0364-z",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1357-0560",
"issue": "30(3)",
"journal": "Medical oncology (Northwood, London, England)",
"keywords": null,
"medline_ta": "Med Oncol",
"mesh_terms": "D000368:Aged; D006801:Humans; D008297:Male; D008545:Melanoma; D015275:Tumor Lysis Syndrome",
"nlm_unique_id": "9435512",
"other_id": null,
"pages": "364",
"pmc": null,
"pmid": "23673985",
"pubdate": "2013",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "19570088;11908861;2154576;8092128;3501039;19646138;14979478;9934768;11209026;8274754;12764356;6894477;18509186;12544084;12655435;1958906;10091788;21561350;8430709;17204864;3724704",
"title": "Tumor lysis syndrome and malignant melanoma.",
"title_normalized": "tumor lysis syndrome and malignant melanoma"
} | [
{
"companynumb": "IL-STRIDES ARCOLAB LIMITED-2021SP027111",
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"occurcountry": "IL",
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"actiondrug": "6",
"activesubstance": {
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},
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"medicinalproduct": "ALDOSPIRONE"
},
{
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"activesubstancename": "FUROSEMIDE"
},
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"drugindication": "OEDEMA PERIPHERAL",
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"medicinalproduct": "FUROSEMIDE."
},
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "DACARBAZINE"
},
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"drugcharacterization": "1",
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"drugdosagetext": "UNK, CYCLICAL, THREE COURSES WERE COMPLETED",
"drugenddate": null,
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"drugindication": "METASTATIC MALIGNANT MELANOMA",
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},
{
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"drugdosagetext": "20 MILLIGRAM, RECEIVED ABOUT 1 MONTH PRIOR TO THE CURRENT PRESENTATION",
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"drugindication": "GUILLAIN-BARRE SYNDROME",
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"medicinalproduct": "PREDNISOLONE."
}
],
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"reaction": [
{
"reactionmeddrapt": "Anuria",
"reactionmeddraversionpt": "24.0",
"reactionoutcome": "5"
},
{
"reactionmeddrapt": "Tumour lysis syndrome",
"reactionmeddraversionpt": "24.0",
"reactionoutcome": "5"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "MOUALLEM M, ZEMER?WASSERCUG N, KUGLER E, SAHAR N, SHAPIRA?FROMMER R, SCHIBY G.. TUMOR LYSIS SYNDROME AND MALIGNANT MELANOMA.. MED?ONCOL. 2013?30(3):364",
"literaturereference_normalized": "tumor lysis syndrome and malignant melanoma",
"qualification": "3",
"reportercountry": "IL"
},
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},
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},
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"seriousnesslifethreatening": null,
"seriousnessother": null,
"transmissiondate": "20211014"
}
] |
{
"abstract": "OBJECTIVE\nThe purpose of this report is to describe a case of lipemia retinalis due to decompensating hyperlipidemia that occurred during chemotherapy in a patient with metastatic colon carcinoma.\n\n\nMETHODS\nRetrospective case report.\n\n\nRESULTS\nA 55-year-old non-insulin-dependent diabetic man with well-controlled hyperlipidemia presented himself with temporarily blurred vision in both eyes occurring during chemotherapy. He was found to have lipemia retinalis in his both eyes. Blood tests revealed elevated cholesterol and triglyceride levels exceeding 8,200 mg/dL. He received six cycles of FOLFIRI/bevacizumab and accompanying dexamethasone because of colon cancer with pulmonary metastases. Lipemia retinalis had resolved after a 6-week follow-up when chemotherapy was finished, and the patients' triglyceride and glucose levels decreased to normal values.\n\n\nCONCLUSIONS\nLipemia retinalis associated with visual impairment may occur during chemotherapy under accompanying treatment with dexamethasone. Even if patients with hyperlipidemia are metabolically well-controlled with oral medication, treatment with dexamethasone can potentially lead to decompensation of hyperlipidemia causing secondary lipemia retinalis.",
"affiliations": "Department of Ophthalmology, Academic Teaching Hospital of St. John of God, Vienna, Austria.;Department of Ophthalmology, Academic Teaching Hospital of St. John of God, Vienna, Austria.;Department of Internal Medicine, Academic Teaching Hospital of St. John of God, Vienna, Austria.;Department of Ophthalmology, Academic Teaching Hospital of St. John of God, Vienna, Austria.;Department of Ophthalmology, Academic Teaching Hospital of St. John of God, Vienna, Austria.;Department of Ophthalmology, Academic Teaching Hospital of St. John of God, Vienna, Austria.",
"authors": "Wetzel|Barbara|B|;Mylonas|Georgios|G|;Puntus|Thomas|T|;Prager|Franz|F|;Bernhart|Clemens|C|;Amon|Michael|M|",
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"fulltext": "\n==== Front\nRetin Cases Brief Rep\nRetin Cases Brief Rep\ncabr\nRetinal Cases & Brief Reports\n1935-1089\n1937-1578\nRetinal Cases & Brief Reports\n\n30074937\nCABR-217-1592\n10.1097/ICB.0000000000000814\n00024\nCase Report\nLIPEMIA RETINALIS DURING CHEMOTHERAPY WITH ADJUNCTIVE GLUCOCORTICOID TREATMENT IN A PATIENT WITH COLON CARCINOMA\nWetzel Barbara MD *†\nMylonas Georgios MD *†\nPuntus Thomas MD ‡\nPrager Franz MD *†\nBernhart Clemens MD *†\nAmon Michael MD *†\n* Department of Ophthalmology, Academic Teaching Hospital of St. John of God, Vienna, Austria;\n† Sigmund Freud University Vienna, Campus Prater, Vienna, Austria; and\n‡ Department of Internal Medicine, Academic Teaching Hospital of St. John of God, Vienna, Austria.\nReprint requests: Georgios Mylonas, MD, Department of Ophthalmology, Academic Teaching Hospital of St. John of God, Johannes von Gott Platz 1, 1020 Vienna, Austria; e-mail: mylonasgio@yahoo.com\n7 2021\n02 8 2018\n15 4 450452\nCopyright © 2018 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the Opthalmic Communications Society, Inc.\n2018\nhttps://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.\n\nWe report the case of a 55-year-old non–insulin-dependent diabetic man with well-controlled hyperlipidemia who presented himself with temporarily blurred vision in both eyes occurring during chemotherapy with adjunctive glucocorticoid treatment for colon carcinoma. Fundus examination revealed lipemia retinalis in his both eyes that resolved after 6 weeks when the chemotherapy was finished, and the patients' triglyceride and glucose levels decreased.\n\nPurpose:\n\nThe purpose of this report is to describe a case of lipemia retinalis due to decompensating hyperlipidemia that occurred during chemotherapy in a patient with metastatic colon carcinoma.\n\nMethods:\n\nRetrospective case report.\n\nResults:\n\nA 55-year-old non–insulin-dependent diabetic man with well-controlled hyperlipidemia presented himself with temporarily blurred vision in both eyes occurring during chemotherapy. He was found to have lipemia retinalis in his both eyes. Blood tests revealed elevated cholesterol and triglyceride levels exceeding 8,200 mg/dL. He received six cycles of FOLFIRI/bevacizumab and accompanying dexamethasone because of colon cancer with pulmonary metastases. Lipemia retinalis had resolved after a 6-week follow-up when chemotherapy was finished, and the patients' triglyceride and glucose levels decreased to normal values.\n\nConclusion:\n\nLipemia retinalis associated with visual impairment may occur during chemotherapy under accompanying treatment with dexamethasone. Even if patients with hyperlipidemia are metabolically well-controlled with oral medication, treatment with dexamethasone can potentially lead to decompensation of hyperlipidemia causing secondary lipemia retinalis.\n\nKey words:\n\nchemotherapy\ncolon carcinoma\ncortisone\nhyperlipidemia\nlipemia retinalis\nOPEN-ACCESSTRUE\n==== Body\nHyperlipidemia is characterized by increased levels of serum concentrations of cholesterol or triglycerides and known as a major factor of premature vessel atherosclerosis. Lipemia retinalis is a rare retinal manifestation of hypertriglyceridemia. Retinal vessels appear creamy whitish colored due to the effect of light scattering by triglyceride-laden chylomicrons.1 In clinical practice, lipemia retinalis caused by chylomicronemia in hyperlipidemia is often observed in patients with metabolic syndrome. However, associations with primary hyperlipidemia or secondary factors causing high levels of triglycerides are also well-documented.2,3\n\nCase Report\n\nA 55-year-old white man presented to our department with temporarily blurred vision in both eyes. Ocular history of the patient was unremarkable, and his best-corrected visual acuity was 100/100 in both eyes. Slit-lamp examination demonstrated normal anterior segments, and intraocular pressures were measured at 16 mmHg in both eyes. His medical history included metastatic colon cancer treated with surgery and chemotherapy, diabetes mellitus, and hyperlipidemia well-controlled with statins (atorvastatin 40 mg once per day).\n\nDilated funduscopic examination revealed normal optic discs, white creamy retinal vessels, and arterial narrowing with arteriovenous crossing abnormalities but no signs of diabetic retinopathy. Furthermore, optical coherence tomography was unremarkable, and there was no evidence for diabetic macular edema. The clinical picture was consistent with lipemia retinalis (Figure 1, A and B).\n\nFig. 1. Fundus photograph of right (A) and left (B) eye with signs of lipemia retinalis. Characteristic white creamy vessels are visible, making it difficult to distinguish the arteries from the veins.\n\nBefore our ophthalmologic examination, the patient was treated with six cycles of chemotherapy with FOLFIRI/bevacizumab because of newly occurring pulmonary metastases. The chemotherapy consisted of bevacizumab, irinotecan, and 5-fluorouracil. In addition, he received intravenous therapy with dexamethasone (8 mg every 2 weeks) for treatment of the side effects of the chemotherapy. The patient was referred to the Department of Internal Medicine to perform further diagnosis and treatment; were laboratory evaluation revealed highly increased levels of cholesterol (681 mg/dL) and triglycerides (8,258 mg/dL). It seems the chemotherapy with concomitant treatment with dexamethasone led to metabolic decompensation in hyperlipidemia.\n\nThe patient presented himself again to our department 6 weeks later, reporting that his visual problems had vanished. Fundus examination revealed reversion of the alterations of the retinal vessels due to lipemia (Figure 2, A and B). Metabolic control of the triglycerides was achieved (triglycerides were 605 mg/dL and cholesterol was 167 mg/dL on the day of examination) since he quitted chemotherapy and intravenous dexamethasone. In addition, his lipid-lowering therapy had been re-evaluated and changed to cholib 145/40 mg tablets once per day (combination of simvastatin and fenofibrate).\n\nFig. 2. Fundus photograph of right (A) and left (B) eye, 6 weeks after initial presentation and under appropriate lipid-lowering medication. The lipemia retinalis had resolved, and the retinal vessels abnormalities returned to normal appearance.\n\nDiscussion\n\nLipemia retinalis is a rare ocular finding characterized by creamy white colored retinal blood vessels, which was first described in 1880 by Heyl.4 It is associated with elevated levels of plasma triglycerides and occurs in certain types of both primary and secondary hyperlipidemia. In early stages of lipemia retinalis (triglyceride levels of 2,500–3,499 mg/dL), only the peripheral retinal vessels appear creamy and thin. As triglyceride levels increase (3,500–5,000 mg/dL), lipemia spreads out to the posterior pole and the creamy color of the vessels extends toward the optic disc. With triglyceride levels exceeding 5,000 mg/dL, the retina becomes salmon-colored with creamy whitish arteries and veins distinguishable only by size.1,2\n\nAlthough the exact correlation of the incidence of lipemia retinalis and the level of plasma triglycerides is not completely understood, the retinal changes are known as a direct consequence of the elevated levels of circulating chylomicrons in the retinal vessels. Chylomicrons are large lipoproteins, which serve to transport triglycerides in the circulatory system after intestinal absorption. The slightly smaller macromolecules very low-density lipoproteins also play an important role. These lipoproteins are involved in the process of transportation of fat in the metabolism but do not seem to contribute to the fundal appearance.5\n\nHowever, it has been observed that not all patients with even highly elevated levels of chylomicrons and triglycerides present lipemia retinalis, suggesting that other factors, such as changes in hematocrit and difference in translucency of the retinal and choroidal vessels, have to be considered.5 Rayner et al1 assumed the light-scattering effect of chylomicrons is responsible for the clinical picture of lipemia retinalis in the fundi.\n\nMost lipemia retinalis cases are asymptomatic, but in fact, also patients with initially deteriorated visual acuity were reported.6 In general, only advanced and persistent lipemia is known to cause decrease in visual acuity or might even lead to complete loss of vision after massive irreversible lipid exsudation.1\n\nRegarding current literature, several cases of lipemia retinalis caused by chylomicronemia in hyperlipidemia due to uncontrolled diabetes mellitus or due to primary hyperlipidemia or even caused by impairment of lipid metabolism during a viral illness were described.1,3\n\nThis is the first report to our knowledge of an association between symptomatic lipemia retinalis and decompensated hyperlipidemia related to treatment with chemotherapy and accompanying treatment with dexamethasone in a patient with metastatic colon cancer. The present data do not reveal any causal linkage between chemotherapy with FOLFOX/bevacizumab and secondary hyperlipidemia, so lipemia retinalis in our patient is believed to be a consequence of decompensated hyperlipidemia after chronic therapy with dexamethasone over a period of 5 months.\n\nPreviously, Chahande et al described a case of a 14-year-old diabetic boy developing lipemia retinalis because of intravenous treatment with prednisolone (1 mg/kg for 5 days) for multiple intracranial neurocysticerci with perilesional edema. The authors also assume the lipemia in this case was caused by administration of steroids.7\n\nSecondary hypertriglyceridemia is known as a result of the supply of glucocorticoids. Glucocorticoid substitution is associated with hypertriglyceridemia, elevated glucose, and higher non–high-density lipoprotein cholesterol levels and can lead to metabolic syndrome, which was proved in a study with GH- and glucocorticoid-replaced hypopituitary patients.8\n\nSuggesting underlying mechanisms, studies reported that pharmacological doses of glucocorticoids lead to an increased endogenous glucose production in healthy people by stimulating hepatic gluconeogenic enzymes and augmenting supply of substrates to the liver for gluconeogenesis by peripheral lipolysis and proteolysis.9,10\n\nUsually no treatment is required for lipemia retinalis. Once triglyceride levels return to normal, the retinal appearance of lipemia retinalis should quickly resolve without causing decrease in visual acuity or permanent retinal disease.11 However, lipemia retinalis is a very important sign of a potential life-threatening systemic metabolic disorder, and it is essential to recognize it as a sign of a profound lipid abnormality.\n\nWe present the first documentation of lipemia retinalis associated with visual symptoms because of decompensating hyperlipidemia in a patient undergoing chemotherapy with concomitant treatment with dexamethasone, and we want to raise awareness of this probably often underdiagnosed retinal condition. Lipid-lowering therapy is believed to normalize fundal appearance and leads to restoration of visual acuity. It is important to adapt the lipid-lowering medication to obtain appropriate management of the lipid metabolism in patients receiving dexamethasone therapy.\n\nNone of the authors has any financial/conflicting interests to disclose.\n==== Refs\nReferences\n\n1. Rayner S Lee N Leslie D . Lipaemia retinalis: a question of chylomicrons? Eye 1996;10 :603–608.8977790\n2. Park YH Lee YC . Lipemia retinalis associated with secondary hyperlipidemia. New Engl J Med 2007;357 :10.\n3. Gayathri K Ramalingam PK Santhakumar R . Lipemia retinalis due to secondary hyperlipidemia in type 1 diabetes mellitus. J Assoc Physicians India 2016;64 :83–84.\n4. Heyl AG . Intraocular lipaemia. Trans Am Ophthalmol Soc 1880;3 :55.\n5. Vinger PF Sachs BA . Ocular manifestations of hyperlipoproteinaemia. Am J Ophthalmol 1970;70 :563–572.5505473\n6. Rymarz E Matysik-Woyniak A Baltaziak L . Lipemia retinalis—an unusual cause of visual acuity deterioration. Med Sci Monit 2012;18 :CS72–CS75.22847206\n7. Chahande S Murthy R . Lipemia retinalis following systemic steroids for neurocysticercosis in a juvenile diabetic. Indian J Pediatr 2015;82 :298–299.25186570\n8. Dullaart RPF Schols JL Van Der Steege G . Glucocorticoid replacement is associated with hypertriglycerdiaemia, elevated glucose and higher non-HDL cholesterol and may diminish the association of HDL cholesterol with the -629C>A CETP promoter polymorphism in GH-receiving hypopituitary patients. Clin Endocrinol 2008;69 :359–366.\n9. Kraus-Friedmann N . Hormonal regulation of hepatic gluconeogenesis. Physiol Rev 1984;64 :170–259.6141578\n10. Vander Kooi BT Onuma H Oeser JK . The glucose-6-phosphatase catalytic subunit gene promoter contains both positive and negative glucocorticoid response elements. Mol Endocrinol 2005;19 :3001–3022.16037130\n11. Horton M Thompson K . Lipemia retinalis preceding acute pancreatitis. Optometry 2011;82 :475–480.21570360\n\n",
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{
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] |
{
"abstract": "Secondary malignancies are relatively common and clinically important phenomena following both chemotherapy and radiotherapy. The majority of these cases are acute leukemias, the occurrence of which have been thoroughly documented and studied. More rarely, chronic myeloid leukemias (CML) may arise subsequent to treatment of a primary malignancy. Literature review on such developments following treatment of Hodgkin's Lymphoma (HL) is scant. Herein, the authors present three cases of CML diagnosed within five years of treatment initiation for Hodgkin's Lymphoma (HL); one of the three patients had CML with atypical variant carrying a rare mutation with BCR-JAK2 fusion.",
"affiliations": "The George Washington University School of Medicine, Washington, DC, U.S.A.;The Department of Veteran Affairs Medical Center, Washington, DC, U.S.A.;The George Washington University School of Medicine, Washington, DC, U.S.A.;The George Washington University School of Medicine, Washington, DC, U.S.A. Samahnd@gwu.edu.",
"authors": "Millett|Ralph|R|;Aggarwal|Anita|A|;Tabbara|Imad|I|;Nassereddine|Samah|S|",
"chemical_list": "D016044:Fusion Proteins, bcr-abl; C507924:JAK2 protein, human; D053614:Janus Kinase 2; C496613:BCR protein, human; D051562:Proto-Oncogene Proteins c-bcr",
"country": "Greece",
"delete": false,
"doi": "10.21873/anticanres.13600",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0250-7005",
"issue": "39(8)",
"journal": "Anticancer research",
"keywords": "CML; Hodgkin lymphoma; secondary malignancy",
"medline_ta": "Anticancer Res",
"mesh_terms": "D016044:Fusion Proteins, bcr-abl; D006689:Hodgkin Disease; D006801:Humans; D053614:Janus Kinase 2; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive; D008297:Male; D008875:Middle Aged; D009154:Mutation; D016609:Neoplasms, Second Primary; D051562:Proto-Oncogene Proteins c-bcr",
"nlm_unique_id": "8102988",
"other_id": null,
"pages": "4333-4335",
"pmc": null,
"pmid": "31366526",
"pubdate": "2019-08",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Chronic Myeloid Leukemia as Secondary Malignancy Following the Treatment of Hodgkin Lymphoma: A Case Series.",
"title_normalized": "chronic myeloid leukemia as secondary malignancy following the treatment of hodgkin lymphoma a case series"
} | [
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] |
{
"abstract": "Hemophagocytic Lymphohistiocytosis (HLH), is an uncommon, aggressive and life threatening syndrome of excessive immune activation. We report an unusual case of HLH, in a 34 year old male, who was admitted with Subarachnoid hemorrhage and cerebellar contusion in a Neurosurgical Intensive care unit, whose trigger is not clear.",
"affiliations": "Post Graduate.;Senior Resident.;Associate Professor.;Professor.;Professor and Head of Department, Sri Ramachandra University and Research Institute, Chennai, Tamil Nadu.",
"authors": "Duruvasal|Aravind|A|;Lakshmi|||;Srinivasan|||;Sowmya|||;Arthur|Preetam|P|",
"chemical_list": "D000927:Anticonvulsants; D010672:Phenytoin",
"country": "India",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0004-5772",
"issue": "66(3)",
"journal": "The Journal of the Association of Physicians of India",
"keywords": null,
"medline_ta": "J Assoc Physicians India",
"mesh_terms": "D000328:Adult; D000927:Anticonvulsants; D000070624:Brain Contusion; D006801:Humans; D051359:Lymphohistiocytosis, Hemophagocytic; D008297:Male; D010322:Parvoviridae Infections; D010672:Phenytoin; D013345:Subarachnoid Hemorrhage",
"nlm_unique_id": "7505585",
"other_id": null,
"pages": "90-1",
"pmc": null,
"pmid": "30341881",
"pubdate": "2018-03",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "HLH - Unusual Trigger and Positive Outcome.",
"title_normalized": "hlh unusual trigger and positive outcome"
} | [
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{
"abstract": "Spontaneous coronary artery dissection (SCAD) is thought to be a rare condition that is hard to predict due to the lack of easily identifiable warning signs. We report the case of a 49-year-old woman with a locally advanced Stage IIIB anal squamous cell carcinoma who presented with chest pain and a positive stress test, ST elevations in her inferior echocardiogram leads, and induced chest pain with exercise without heart perfusion defects. Coronary catheterization revealed a right coronary artery dissection, which led to the diagnosis of SCAD. Our patient was diagnosed while undergoing a combination treatment of fluorouracil (5-FU), mitomycin, and pelvic radiotherapy. We reviewed the current literature and update the etiologies that have been proposed since the publication of this case report.",
"affiliations": "Radiation Oncology, The Karmanos Cancer Center's Gershenson Radiation Oncology Center, Wayne State University School of Medicine, Detroit, USA.;Radiation Oncology, The Karmanos Cancer Center's Gershenson Radiation Oncology Center, Wayne State University School of Medicine, Detroit, USA.;Radiation Oncology, The Karmanos Cancer Center's Gershenson Radiation Oncology Center, Wayne State University School of Medicine, Detroit, USA.",
"authors": "Hart|Kimberly|K|;Patel|Suketu|S|;Kovoor|Joshua|J|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.7759/cureus.4979",
"fulltext": "\n==== Front\nCureusCureus2168-8184Cureus2168-8184Cureus Palo Alto (CA) 10.7759/cureus.4979CardiologyRadiation OncologyOncologySpontaneous Coronary Artery Dissection Associated with Anal Cancer Management with Fluorouracil and Radiotherapy Muacevic Alexander Adler John R Hart Kimberly 1Patel Suketu 1Kovoor Joshua 1\n1 \nRadiation Oncology, The Karmanos Cancer Center's Gershenson Radiation Oncology Center, Wayne State University School of Medicine, Detroit, USA \nJoshua Kovoor ez9565@wayne.edu23 6 2019 6 2019 11 6 e497916 4 2019 21 6 2019 Copyright © 2019, Hart et al.2019Hart et al.This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.This article is available from https://www.cureus.com/articles/18138-spontaneous-coronary-artery-dissection-associated-with-anal-cancer-management-with-fluorouracil-and-radiotherapySpontaneous coronary artery dissection (SCAD) is thought to be a rare condition that is hard to predict due to the lack of easily identifiable warning signs. We report the case of a 49-year-old woman with a locally advanced Stage IIIB anal squamous cell carcinoma who presented with chest pain and a positive stress test, ST elevations in her inferior echocardiogram leads, and induced chest pain with exercise without heart perfusion defects. Coronary catheterization revealed a right coronary artery dissection, which led to the diagnosis of SCAD. Our patient was diagnosed while undergoing a combination treatment of fluorouracil (5-FU), mitomycin, and pelvic radiotherapy. We reviewed the current literature and update the etiologies that have been proposed since the publication of this case report.\n\nradiotherapyanal canceranal squamous cell carcinoma5-fluorouracilspontaneous coronary artery dissectionscadThe content published in Cureus is the result of clinical experience and/or research by independent individuals or organizations. Cureus is not responsible for the scientific accuracy or reliability of data or conclusions published herein. All content published within Cureus is intended only for educational, research and reference purposes. Additionally, articles published within Cureus should not be deemed a suitable substitute for the advice of a qualified health care professional. Do not disregard or avoid professional medical advice due to content published within Cureus.\n==== Body\nIntroduction\nSpontaneous coronary artery dissection (SCAD) describes a phenomenon where layers of the coronary arterial wall disrupt and fill with blood without evidence of atherosclerotic disease. This can interrupt blood flow to the cardiac muscle, resulting in acute coronary syndromes, including myocardial infarction and sudden death [1].\n\nThe standard treatment for squamous cell anal cancer after 1980 has been chemoradiotherapy (CRT). The Nigro trials showed there was greater local control of the malignancy with CRT versus radiotherapy (RT) alone [2]. Chemoradiotherapy also allows surgical procedures that resect part of the colon to be avoided in the majority of patients and withheld to only a minority of patients that have recurrent or persistent disease after CRT [3]. Our patient received mitomycin-C, fluorouracil (5-FU), and pelvic radiotherapy, which increased risk factors that cause mechanical stress on heart vessels. We report the rare case of SCAD secondary to the treatment of anal cancer.\n\nCase presentation\nPatient profile\n\nThis study involved a 49-year-old woman who presented with a Stage IIIB locally advanced anal squamous cell carcinoma with no prior cardiovascular risk factors. Her treatment regimen consisted of 5-FU (7,200 mg/96 hours), mitomycin (18 mg), and 5,400 cGy delivered by RapidArc® intensity-modulated radiation therapy (IMRT) (Varian Medical Systems, Inc., Palo Alto, CA). She presented with sharp left-sided chest pain with exertional dyspnea and nausea four days after receiving chemotherapy and two cycles of RT for a total dose of 360 cGy. After treatment, she had protracted emesis and sharp retrosternal pain that radiated to the back, which increased with deep inspiration and cough. The pain was exaggerated by changing position and ameliorated with rest. She was admitted and treated with catheter angiography for myocardial infarction (MI). The causative lesion was coronary artery dissection evaluated by myocardial perfusion imaging, as shown in Figure 1, and identified using coronary catheterization which revealed an ostial right coronary artery that was 70% dissected.\n\nFigure 1 Myocardial Perfusion Imaging of Spontaneous Coronary Artery Dissection (SCAD)\nThe yellow circled areas on the scans in the regions labeled STRESS and REST in the figure highlight the region of the heart hypoperfused by the SCAD. The region of the figure labeled STRESS illustrates the myocardial perfusion while the patient's heart is under stress. The region of the figure labeled REST illustrates the myocardial perfusion while the patient is at rest. Both sets of scans show how the hypoperfused region, in the yellow circles, does not change with activity.\n\nHLA: horizontal long axis; VLA: vertical long axis\n\nAfter the patient was diagnosed with SCAD, she underwent catheterization with a drug-eluting stent and was placed on ticagrelor, aspirin, and pravastatin. Radiotherapy was resumed; however, during the second cycle of chemotherapy, the patient was admitted for chest pain again. She was monitored by troponin biomarkers and electrocardiograms (EKGs); however, there were no changes in cardiac function. The patient’s chest discomfort was attributed to anxiety and she was, therefore, treated with lorazepam. The patient developed a neutropenic fever of 38.7 degrees Celsius secondary to chemotherapy. The radiotherapy was stopped for 10 days secondary to the neutropenia. The SCAD continued to be monitored by the patient’s chest symptoms and by single photon emission computed tomography (SPECT) imaging. Her SPECT myocardial perfusion scan six months after the completion of her radiotherapy and chemotherapy treatment noted the left ventricle had a normal ejection fraction of 66% and there were no abnormal left ventricle wall thickenings or motions. It also revealed there were no myocardial perfusion defects.\n\nDiscussion\nA case study from 2003 described a similar presentation in which a woman receiving 5-FU chemotherapy and pelvic radiotherapy presented with hyperemesis [4]. The proposed risk factors, in that case, included 5-FU-related vasoconstrictive effects and the Valsalva stress of protracted vomiting.\n\nEpidemiology\n\nThe true incidence of SCAD is difficult to determine. There are no biochemical markers that differentiate SCAD from other acute coronary syndromes. Although the relationship between hormonal change and SCAD is not fully understood, there is a high prevalence of SCAD in pregnancy which may be related to the rapid changes in circulating estrogen and gonadotropins [4]. Historically, SCAD was thought to be rare, but increasing use of early angiography have revealed SCAD to be more common than believed [5]. SCAD affects young to middle-aged women with 90% of the cases reported in this group [6-7]. The mean age is between 44 - 55 years old. SCAD can be triggered by events that cause increased cardiovascular stress, such as childbirth or emotional stress. Excess progesterone also leads to impaired collagen synthesis which weakens the coronary vasculature. Women on hormonal therapy would be at an increased risk for SCAD [8]. One in 10 women under 50 years old presenting with the acute coronary syndrome will be observed to have SCAD. Pregnancy-associated SCAD has been found to be a smaller proportion of events than early case series indicated [9-10].\n\nPathophysiology\n\nThere are two mechanisms for the pathophysiology of SCAD. The first is an accumulation of blood in the vessel wall by rupture of the vasa vasorum. The vasa vasorum are small blood vessels that travel and supply blood to the walls that make up arteries and veins. If those vasa vasorum rupture, they create a false-lumen between the walls. The second is the direct disruption of the tunica intima, the innermost wall, leading to a collection of blood between the tunica intima and tunica media. The tunica media is the muscular layer in arteries and veins. This layer is larger in arteries, so once the intima is disrupted, it instead dissects the intima rather than piercing through [8].\n\nPrecipitating factors\n\nOur patient had two factors related to mechanical stress on the wall of the artery which could precipitate an intimal tear and subsequent hematoma formation [8]. The first was the protracted vomiting. The second was the myocardial ischemia induced by the vasoconstrictive effects of the 5-FU. The vasoconstriction induces chest pain associated with effort, rest, or a variant between the two levels of activity. It presents as a sudden onset chest pain similar to an acute heart attack once the 5-FU reaches peak systemic levels [11].\n\nConclusions\nSCAD is an unusual complication but one that should be monitored for in patients undergoing 5-FU treatment, especially if they have protracted emesis. The vasoconstrictive effects of 5-FU, combined with the action of emesis, risk stressing the heart and its blood vessels beyond their compliance limit. This eventually can lead to a tear in the intimal layer of a coronary vessel, leading to SCAD. We believe this was the case with our patient, who had both risk factors. If SCAD is suspected, physicians should monitor these patients with myocardial perfusion imaging to note areas of hypoperfusion and decreased myocardial activity. Overall, physicians should keep a high suspicion for SCAD if a patient undergoing 5-FU presents with heart-related symptoms.\n\nThe authors have declared that no competing interests exist.\n\nHuman Ethics\nConsent was obtained by all participants in this study\n==== Refs\nReferences\n1 Spontaneous coronary artery dissection in women: what is known and what is yet to be understood Clin Cardiol Tweet MS Kok SN Hayes SN 203 210 41 2018 29493808 \n2 Combined therapy for cancer of the anal canal Dis Colon Rectum Nigro ND Vaitkevicius VK Buroker T Bradley GT Considine B 73 75 24 1981 7215078 \n3 Clinical trials in the management of anal cancer Clin Colon Rectal Surg Sana S Khan AU 115 119 22 2009 20436836 \n4 Spontaneous coronary artery dissection in a woman receiving 5-fluorouracil--a case report Angiology Abbott JD Curtis JP Murad K Kramer HM Remetz MS Setaro JF Brennan JJ 721 724 54 2003 14666962 \n5 Spontaneous coronary artery dissection Heart Al-Hussaini A Adlam D 1043 1051 103 2017 28363899 \n6 Clinical presentation of patients with spontaneous coronary artery dissection Catheter Cardiovasc Interv Luong C Starovoytov A Heydari M Sedlak T Aymong E Saw J 1149 1154 89 2017 28244197 \n7 Prevalence, therapeutic management and medium-term prognosis of spontaneous coronary artery dissection: results from a database of 11,605 patients Eur J Cardiothorac Surg Vanzetto G Berger-Coz E Barone-Rochette G 250 254 35 2009 19046896 \n8 Alternative causes of myocardial ischemia in women: an update on spontaneous coronary artery dissection, vasospastic angina and coronary microvascular dysfunction Vasc Med Ahmed B Creager MA 146 160 22 2017 28429664 \n9 Spontaneous coronary artery dissection: current state of the science: a scientific statement from the American Heart Association Circulation Hayes SN Kim ESH Saw J 523 557 137 2018 \n10 Spontaneous coronary artery dissection in a young woman precipitated by retching J Invasive Cardiol Velusamy M Fisherkeller M Keenan ME Kiernan FJ Fram DB 198 201 14 2002 http://www.ncbi.nlm.nih.gov/pubmed/11923575 11923575 \n11 Vascular toxicities of cancer therapies: the old and the new-an evolving avenue Circulation Herrmann J Yang EH Iliescu CA 1272 1289 133 2016 27022039\n\n",
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"title": "Spontaneous Coronary Artery Dissection Associated with Anal Cancer Management with Fluorouracil and Radiotherapy.",
"title_normalized": "spontaneous coronary artery dissection associated with anal cancer management with fluorouracil and radiotherapy"
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"abstract": "Patients with rheumatologic diseases might be more susceptible to COVID-19 and carry a poorer prognosis. The aim of this study is to examine the incidence and outcomes of all COVID-19 patients with rheumatologic conditions in Hong Kong.\n\n\n\nThis is a population-based retrospective study. All patients tested positive for SARS-CoV-2 by PCR with a previous diagnosis of rheumatologic diseases were reviewed. The incidence of COVID-19 in patients with rheumatologic conditions was calculated and compared to the general population in Hong Kong. Descriptive data of those rheumatologic patients with COVID-19 and the clinical course of the index infection were presented.\n\n\n\nUp till 27 May 2020, there were 1067 cases of COVID-19 diagnosed in Hong Kong which had a population of 7.5 million. Out of the 39,835 patients with underlying rheumatologic diseases, we identified 5 PCR confirmed COVID-19 cases. The estimated incidence of COVID-19 was 0.0126% patients with rheumatologic diseases, compared to 0.0142% in the general population. All 5 patients had inflammatory arthropathies. One patient was on hydroxychloroquine and sulphasalazine, and one was on methotrexate. None of the 3534 patients on b/tsDMARDs was infected. Four patients had leucopenia/lymphopenia and stool viral PCR was positive in 3 patients. All patients made uneventful recovery without complications or flare of underlying diseases.\n\n\n\nWe found no alarming signals of increased frequency or severity of COVID-19 in patients with rheumatologic diseases, although extrapolation of the results to other populations with different infection control strategies should be made with caution.",
"affiliations": "Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong. Electronic address: hoso@cuhk.edu.hk.;Institute of Digestive Disease, Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong.;Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong.;Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong.;Institute of Digestive Disease, Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong.;Department of Medicine, Alice Ho Miu Ling Nethersole Hospital, Hong Kong.;Department of Medicine, Queen Mary Hospital, Hong Kong.;Department of Medicine, Queen Mary Hospital, Hong Kong.;Department of Medicine and Geriatrics, Princess Margaret Hospital, Hong Kong.;Department of Medicine and Geriatrics, United Christian Hospital, Hong Kong.;Department of Medicine and Geriatrics, United Christian Hospital, Hong Kong.;Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong.",
"authors": "So|Ho|H|;Mak|Joyce Wing-Yan|JW|;So|Jacqueline|J|;Lui|Grace|G|;Lun|Frankie|F|;Lee|Jolly|J|;Chan|Shirley|S|;Ho|Carmen|C|;Chan|Jacky Man-Chun|JM|;Kong|Shing-Pak|SP|;Ng|Woon-Leung|WL|;Tam|Lai-Shan|LS|",
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"mesh_terms": "D000328:Adult; D018501:Antirheumatic Agents; D000073640:Betacoronavirus; D000086382:COVID-19; D000086742:COVID-19 Testing; D019411:Clinical Laboratory Techniques; D015897:Comorbidity; D018352:Coronavirus Infections; D005260:Female; D006723:Hong Kong; D006801:Humans; D015994:Incidence; D007592:Joint Diseases; D008297:Male; D008875:Middle Aged; D017063:Outcome Assessment, Health Care; D058873:Pandemics; D011024:Pneumonia, Viral; D011379:Prognosis; D012189:Retrospective Studies; D012216:Rheumatic Diseases; D018570:Risk Assessment; D012307:Risk Factors; D000086402:SARS-CoV-2",
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"title": "Incidence and clinical course of COVID-19 in patients with rheumatologic diseases: A population-based study.",
"title_normalized": "incidence and clinical course of covid 19 in patients with rheumatologic diseases a population based study"
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"abstract": "OBJECTIVE\nIn lung cancer (LC) patients, pre-existing interstitial lung disease (ILD) is a risk of chemotherapy-associated acute exacerbation of ILD (AE-ILD). AE-ILD shows a diverse clinical course varying from fatal respiratory failure to asymptomatic event, and the prognostic impact is still unclear.\n\n\nMETHODS\nWe retrospectively evaluated the association between the prognosis and AE-ILD in 86 LC patients with pre-existing ILD who were treated with cytotoxic chemotherapy, especially focusing on histological types of LC.\n\n\nRESULTS\nThirty (34.9%) patients had AE-ILD, that was significantly associated with a poor prognosis in LC patients with ILD. When analyzed by histological types, a significant association of AE-ILD with shorter survival was observed only in the small cell LC (SCLC) group, but not in the non-small cell LC group.\n\n\nCONCLUSIONS\nThe development of AE-ILD by cytotoxic chemotherapy is associated with poor prognosis in LC patients with ILD, especially in patients with SCLC.",
"affiliations": "Department of Respiratory Internal Medicine, Hiroshima University Hospital, Hiroshima, Japan.;Department of Respiratory Internal Medicine, Hiroshima University Hospital, Hiroshima, Japan yamaguchikakuhiro@gmail.com.;Department of Respiratory Internal Medicine, Hiroshima University Hospital, Hiroshima, Japan.;Department of Respiratory Internal Medicine, Hiroshima University Hospital, Hiroshima, Japan.;Department of Respiratory Internal Medicine, Hiroshima University Hospital, Hiroshima, Japan.;Department of Respiratory Internal Medicine, Hiroshima University Hospital, Hiroshima, Japan.;Department of Respiratory Internal Medicine, Hiroshima University Hospital, Hiroshima, Japan.;Department of Respiratory Internal Medicine, Hiroshima University Hospital, Hiroshima, Japan.;Department of Respiratory Internal Medicine, Hiroshima University Hospital, Hiroshima, Japan.;Department of Respiratory Internal Medicine, Hiroshima University Hospital, Hiroshima, Japan.;Department of Respiratory Internal Medicine, Hiroshima University Hospital, Hiroshima, Japan.",
"authors": "Nakao|Satoshi|S|;Yamaguchi|Kakuhiro|K|;Sakamoto|Shinjiro|S|;Horimasu|Yasushi|Y|;Masuda|Takeshi|T|;Miyamoto|Shintaro|S|;Nakashima|Taku|T|;Iwamoto|Hiroshi|H|;Fujitaka|Kazunori|K|;Hamada|Hironobu|H|;Hattori|Noboru|N|",
"chemical_list": "D000970:Antineoplastic Agents",
"country": "Greece",
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"keywords": "Advanced lung cancer; acute exacerbation; chemotherapy; interstitial lung disease; prognosis",
"medline_ta": "Anticancer Res",
"mesh_terms": "D000368:Aged; D000970:Antineoplastic Agents; D002289:Carcinoma, Non-Small-Cell Lung; D005260:Female; D006801:Humans; D017563:Lung Diseases, Interstitial; D008175:Lung Neoplasms; D008297:Male; D011379:Prognosis; D012189:Retrospective Studies; D055752:Small Cell Lung Carcinoma",
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"title": "Chemotherapy-associated Acute Exacerbation of Interstitial Lung Disease Shortens Survival Especially in Small Cell Lung Cancer.",
"title_normalized": "chemotherapy associated acute exacerbation of interstitial lung disease shortens survival especially in small cell lung cancer"
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{
"abstract": "Kaposi sarcoma (KS) caused by human herpes virus type-8 is the most frequent immunosuppression-associated malignancy worldwide and its treatment is still controversial. We report on the clinical management of a patient who developed oral KS after liver transplantation. The disease appeared 1 month after the transplant and recurred after 4 months. The patient represents, to our knowledge, a rare case that was treated successfully only by shifting a conventional immunosuppressive therapy to everolimus alone.",
"affiliations": "*Division of Maxillofacial Surgery†Pathology Division, University of Torino, Torino, Italy.",
"authors": "Garzino-Demo|Paolo|P|;Mettus|Arianna|A|;Passalacqua|Fabio|F|;Vittone|Federico|F|;Ramieri|Guglielmo|G|",
"chemical_list": "D007166:Immunosuppressive Agents",
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"delete": false,
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"issn_linking": "1049-2275",
"issue": "28(6)",
"journal": "The Journal of craniofacial surgery",
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"medline_ta": "J Craniofac Surg",
"mesh_terms": "D000072700:Conservative Treatment; D058625:End Stage Liver Disease; D019288:Herpesvirus 8, Human; D006801:Humans; D007165:Immunosuppression Therapy; D007166:Immunosuppressive Agents; D008103:Liver Cirrhosis; D016031:Liver Transplantation; D008297:Male; D008875:Middle Aged; D009062:Mouth Neoplasms; D009364:Neoplasm Recurrence, Local; D012514:Sarcoma, Kaposi",
"nlm_unique_id": "9010410",
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"pages": "e545-e547",
"pmc": null,
"pmid": "28708648",
"pubdate": "2017-09",
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"title": "Oral Localization of Kaposi Sarcoma: Clinical Presentation and Conservative Management.",
"title_normalized": "oral localization of kaposi sarcoma clinical presentation and conservative management"
} | [
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{
"abstract": "We describe two patients who developed gastrointestinal bleeding due to cytomegalovirus (CMV) colitis after placement of a HeartMate II left ventricular assist device (LVAD). We aim to raise awareness of CMV colitis as a possible cause of gastrointestinal bleeding after LVAD placement and discuss potential mechanisms for CMV reactivation and areas for future research.",
"affiliations": "Division of Infectious Diseases, University of Nebraska Medical Center, Omaha, NE, USA. usandkovsky@unmc.edu",
"authors": "Sandkovsky|Uriel|U|;Florescu|Diana F|DF|;Um|John Y|JY|;Raichlin|Eugenia|E|;Lowes|Brian D|BD|;Kapalis|Matthew|M|;Hewlett|Alexander|A|;Duncan|Kim F|KF|;Ryan|Timothy|T|;Dimaio|Dominick|D|;Wedel|Whitney|W|;Kalil|Andre C|AC|",
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"issue": "17(5)",
"journal": "International journal of infectious diseases : IJID : official publication of the International Society for Infectious Diseases",
"keywords": null,
"medline_ta": "Int J Infect Dis",
"mesh_terms": "D006348:Cardiac Surgical Procedures; D003092:Colitis; D003587:Cytomegalovirus; D003586:Cytomegalovirus Infections; D006471:Gastrointestinal Hemorrhage; D006333:Heart Failure; D006353:Heart-Assist Devices; D006801:Humans; D008297:Male; D008875:Middle Aged; D012307:Risk Factors; D014775:Virus Activation",
"nlm_unique_id": "9610933",
"other_id": null,
"pages": "e348-51",
"pmc": null,
"pmid": "23313155",
"pubdate": "2013-05",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Cytomegalovirus reactivation and colitis after left ventricular assist device placement.",
"title_normalized": "cytomegalovirus reactivation and colitis after left ventricular assist device placement"
} | [
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],
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{
"abstract": "Mantle cell lymphoma (MCL) is a distinct type of non-Hodgkin's lymphoma that commonly affects extranodal sites. The most commonly affected sites are bone marrow, gastrointestinal tract and Waldeyer's ring, however, skin is rarely involved. We reported a 62-year-old Japanese patient with MCL, exhibiting multiple small dome-shaped red nodules and skin ulcers. Histopathological examination demonstrated numerous atypical lymphoid cells in the dermis and subcutis. Immunohistochemically, tumor cells were positive for CD20 (L26), CD5, CD43 and cyclin D1, but negative for CD45RO (UCHL-1), CD3, CD10 and CD23. Our patient showed a significant improvement of skin lesions and lymphadenopathy with a combination chemotherapy. Awareness of skin manifestations of MCL is essential for dermatologists to establish an early diagnosis and perform appropriate treatment.",
"affiliations": "Department of Dermatology, Gunma University Graduate School of Medicine, 3-39-22 Showa-machi, Maebashi, Gunma 371-8511, Japan. smotegi@showa.gunma-u.ac.jp",
"authors": "Motegi|Sei-Ichiro|S|;Okada|Etsuko|E|;Nagai|Yayoi|Y|;Tamura|Atsushi|A|;Ishikawa|Osamu|O|",
"chemical_list": null,
"country": "France",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1167-1122",
"issue": "16(4)",
"journal": "European journal of dermatology : EJD",
"keywords": null,
"medline_ta": "Eur J Dermatol",
"mesh_terms": "D006801:Humans; D020522:Lymphoma, Mantle-Cell; D008297:Male; D008875:Middle Aged; D012878:Skin Neoplasms",
"nlm_unique_id": "9206420",
"other_id": null,
"pages": "435-8",
"pmc": null,
"pmid": "16935806",
"pubdate": "2006",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Skin manifestation of mantle cell lymphoma.",
"title_normalized": "skin manifestation of mantle cell lymphoma"
} | [
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},
{
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},
{
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},
{
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"reactionoutcome": "1"
},
{
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"reactionoutcome": null
},
{
"reactionmeddrapt": "Cough",
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"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Muscle spasms",
"reactionmeddraversionpt": "21.0",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Thrombocytopenia",
"reactionmeddraversionpt": "21.0",
"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "STOLARZ SKIZYPEK. SKIN MANIFESTATION OF MANTLE CELL LYMPHOMA ? CASE REPORT AND LITERATURE REVIEW. MANAGEMENT OF A PATIENT WITH MULTIPLE ANTIHYPERTENSIVE DRUG INTOLERANCE.. KARDIOLOGIA PO DYPLOMIE. 2017?6:29200",
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"qualification": "3",
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},
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"receiver": {
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"receivertype": "6"
},
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"sendertype": "2"
},
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"seriousnesslifethreatening": null,
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}
] |
{
"abstract": "A 78-year-old woman diagnosed with rheumatoid arthritis without a history of skin tumors or immunosuppressive medication, started treatment with leflunomide. One month after the introduction of the drug, and for two consecutive years, she developed multiple crateriform nodules and papules on her lower extremities . Biopsy specimens showed keratoacanthomas and squamous-cell carcinomas. Owing to suspicion that the drug could be implicated in the appearance of these tumors, the patient decided to suspend the drug. No new skin lesions have appeared in seventeen months of clinical follow-up. There have been several published case reports of multiple keratoacanthomas associated with immunosuppressive therapy such as sorafenib and imiquimod. However, we found no mention in the literature of the eruption of multiple keratoacanthomas in patients with rheumatoid arthritis treated with leflunomide. We suggest, that the the sudden appearance of skin tumors in our patient is related to the introduction of leflunomide, but additional case reports are required to confirm this association.",
"affiliations": null,
"authors": "Frances|Laura|L|;Guijarro|Jaime|J|;Marin|Irene|I|;Leiva-Salinas|Maria del Carmen|Mdel C|;Bouret|Angelica Maria|AM|",
"chemical_list": "D000894:Anti-Inflammatory Agents, Non-Steroidal; D007555:Isoxazoles; D000077339:Leflunomide",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1087-2108",
"issue": "19(7)",
"journal": "Dermatology online journal",
"keywords": null,
"medline_ta": "Dermatol Online J",
"mesh_terms": "D000368:Aged; D000894:Anti-Inflammatory Agents, Non-Steroidal; D001172:Arthritis, Rheumatoid; D002294:Carcinoma, Squamous Cell; D003875:Drug Eruptions; D005260:Female; D006801:Humans; D007555:Isoxazoles; D007636:Keratoacanthoma; D000077339:Leflunomide; D012878:Skin Neoplasms",
"nlm_unique_id": "9610776",
"other_id": null,
"pages": "18968",
"pmc": null,
"pmid": "24010514",
"pubdate": "2013-07-14",
"publication_types": "D002363:Case Reports; D016422:Letter",
"references": null,
"title": "Multiple eruptive keratoacanthomas associated with leflunomide.",
"title_normalized": "multiple eruptive keratoacanthomas associated with leflunomide"
} | [
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{
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},
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"medicinalproduct": "LEFLUNOMIDE."
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},
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],
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"reaction": [
{
"reactionmeddrapt": "Skin mass",
"reactionmeddraversionpt": "18.0",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Skin lesion",
"reactionmeddraversionpt": "18.0",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Actinic keratosis",
"reactionmeddraversionpt": "18.0",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Keratoacanthoma",
"reactionmeddraversionpt": "18.0",
"reactionoutcome": "1"
},
{
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},
{
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"reactionoutcome": "1"
},
{
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"reactionoutcome": "1"
}
],
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},
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"literaturereference": "FRANCES L, GUIJARRO J, MARIN I, LEIVA-SALINAS MC, BOURET AM. MULTIPLE ERUPTIVE KERATOACANTHOMAS ASSOCIATED WITH LEFLUNOMIDE. DERMATOLOGY ONLINE JOURNAL. 2013;19(7):16",
"literaturereference_normalized": "multiple eruptive keratoacanthomas associated with leflunomide",
"qualification": "3",
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},
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"receiptdate": "20150429",
"receivedate": "20130823",
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},
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},
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"seriousnessother": 1,
"transmissiondate": "20150821"
}
] |
{
"abstract": "Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has become a highly prevalent infectious disease. Currently, organs are not being transplanted from donors who are SARS-CoV-2 positive. It remains unclear as to how to differentiate active from recovered patients. We report our recent experience of a 3-month-old deceased organ donor who died as the result of an anoxic brain injury after a cardiopulmonary arrest (presumed sudden infant death syndrome). The child was born to a mother presumed to have coronavirus disease 2019. The donor tested negative for SARS-CoV-2 reverse transcriptase-polymerase chain reaction and positive for SARS-CoV-2 immunoglobulin A antibodies. We suspect this is the first known report of its kind and noteworthy for the organ donation and transplantation community.",
"affiliations": "LifeGift, Fort Worth, Texas. Electronic address: snelson@lifegift.org.;LifeGift, Fort Worth, Texas.;Children's Health Dallas, Dallas, Texas.;Division of Abdominal Transplantation and Advance Hepatobiliary Surgery, Department of Surgery, University of Utah, Salt Lake City, Utah.;Department of Pediatrics, Division of Infectious Diseases, Duke University School of Medicine, Durham, North Carolina.;LifeGift, Fort Worth, Texas.;LifeGift, Fort Worth, Texas.",
"authors": "Nelson|Susan|S|;Curran|Christopher C|CC|;Sutcliffe|David L|DL|;Rofaiel|George|G|;Chang|Yeh-Chung|YC|;Easterling|Larry|L|;Wood|R Patrick|RP|",
"chemical_list": "D000914:Antibodies, Viral",
"country": "United States",
"delete": false,
"doi": "10.1016/j.transproceed.2021.06.028",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0041-1345",
"issue": "53(8)",
"journal": "Transplantation proceedings",
"keywords": null,
"medline_ta": "Transplant Proc",
"mesh_terms": "D000914:Antibodies, Viral; D000086382:COVID-19; D006801:Humans; D007223:Infant; D016377:Organ Transplantation; D000086402:SARS-CoV-2; D014019:Tissue Donors; D009927:Tissue and Organ Procurement",
"nlm_unique_id": "0243532",
"other_id": null,
"pages": "2435-2437",
"pmc": null,
"pmid": "34301402",
"pubdate": "2021-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "SARS-CoV-2 Antibody Serology Testing in a 3-Month-Old Organ Donor: A Case Report and Review of Available Literature.",
"title_normalized": "sars cov 2 antibody serology testing in a 3 month old organ donor a case report and review of available literature"
} | [
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"literaturereference": "Nelson S, Curran C, Sutcliffe D, Rofaiel G, Chang Y, Easterling L, Wood R. SARS-CoV-2 Antibody Serology Testing in a 3-Month-Old Organ Donor: A Case Report and Review of Available Literature. Transpl Proc. 2021;53(8):2435-7. doi:10.1016/j.transproceed.2021.06.028",
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{
"abstract": "Severely ill COVID-19 patients may end in acute respiratory distress syndrome (ARDS) and multi-organ failure. Some of them develop a systemic hyperinflammatory state produced by the massive release of inflammatory agents, known as cytokine storm syndrome (CSS). Inhibition of IL-1 by Anakinra (ANK) is a potential life-saving therapy for severe CSS cases. We propose a rationale for the use of subcutaneous ANK and review our initial experience in a small cohort of severe COVID-19 CSS patients.\n\n\n\nRetrospective cohort study of COVID-19 patients developing ARDS (PaO2/FiO2 <300) and exhibiting signs of hyperinflammation (ferritin >1000 ng/mL and/or d-dimers > 1.5 μg/mL, plus IL-6 < 40 mg/mL) that received ANK. For comparison, a propensity score matched historical cohort of patients treated with IL-6 inhibitor Tocilizumab (TCZ) was used. Patients had previously received combinations of azithromycin, hydroxy-chloroquine, and methyl-prednisolone. Laboratory findings, respiratory function and adverse effects were monitored. Resolution of ARDS within the first 7 days of treatment was considered a favorable outcome.\n\n\n\nSubcutaneous ANK (100 mg every 6 h) was given to 9 COVID-19 ARDS CSS patients (77.8% males). Median age was 62 years (range, 42 to 87). A TCZ cohort of 18 patients was selected by propensity score matching and treated with intravenous single dose of 600 mg for patients weighing >75 Kg, or 400 mg if < 75 Kg. Prior to treatment, median PaO2/FiO2 ratio of the ANK and TCZ cohorts were 193 and 249, respectively (p = 0.131). After 7 days of treatment, PaO2/FiO2 ratio improved in both groups to 279 (104-335) and 331 (140-476, p = 0.099) respectively. On day 7, there was significant reduction of ferritin (p = 0.046), CRP (p = 0.043), and IL-6 (p = 0.043) levels in the ANK cohort but only of CRP (p = 0.001) in the TCZ group. Favorable outcome was achieved in 55.6% and 88.9% of the ANK and TCZ cohorts, respectively (p = 0.281). Two patients that failed to respond to TCZ improved after ANK treatment. Aminotransferase levels significantly increased between day 1 and day 7 (p = 0.004) in the TCZ group. Mortality was the same in both groups (11%). There were not any opportunistic infection in the groups nor other adverse effects attributable to treatment.\n\n\n\nOverall, 55.6% of COVID-19 ARDS CSS patients treated with ANK exhibited favorable outcome, not inferior to a TCZ treated matched cohort. ANK may be a potential alternative to TCZ for patients with elevated aminotransferases, and may be useful in non-responders to TCZ.",
"affiliations": "Systemic Autoimmune Diseases Unit, Department of Internal Medicine, Burgos University Hospital, Spain. Electronic address: eiglesiasjulian@gmail.com.;Systemic Autoimmune Diseases Unit, Department of Internal Medicine, Burgos University Hospital, Spain.;Systemic Autoimmune Diseases Unit, Department of Internal Medicine, Burgos University Hospital, Spain.;Systemic Autoimmune Diseases Unit, Department of Internal Medicine, Burgos University Hospital, Spain.;Department of Neurosurgery, Burgos University Hospital, Spain.;Department of Rheumatology, Burgos University Hospital, Spain.;Department of Pharmacy, Burgos University Hospital, Spain.;Department of Intensive Care Medicine, Burgos University Hospital, Spain.;Department of Rheumatology, Burgos University Hospital, Spain.;Department of Pneumology, Burgos University Hospital, Spain.;Department of Pneumology, Burgos University Hospital, Spain.;Department of Anesthesiology, Burgos University Hospital, Spain.;Department of Pharmacy, Burgos University Hospital, Spain.;Department of Internal Medicine, Burgos University Hospital, Spain.;Infectious Diseases Unit, Department of Internal Medicine, Burgos University Hospital, Spain.",
"authors": "Iglesias-Julián|Enrique|E|;López-Veloso|María|M|;de-la-Torre-Ferrera|Noelia|N|;Barraza-Vengoechea|Julio Cesar|JC|;Delgado-López|Pedro David|PD|;Colazo-Burlato|María|M|;Ubeira-Iglesias|Marta|M|;Montero-Baladía|Miguel|M|;Lorenzo-Martín|Andrés|A|;Minguito-de-la-Iglesia|Javier|J|;García-Muñoz|Juan Pablo|JP|;Sanllorente-Sebastián|Rodrigo|R|;Vicente-González|Blanca|B|;Alemán-Alemán|Ana|A|;Buzón-Martín|Luis|L|",
"chemical_list": "D061067:Antibodies, Monoclonal, Humanized; D018501:Antirheumatic Agents; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1; D015850:Interleukin-6; C502936:tocilizumab",
"country": "England",
"delete": false,
"doi": "10.1016/j.jaut.2020.102537",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0896-8411",
"issue": "115()",
"journal": "Journal of autoimmunity",
"keywords": "Acute respiratory distress syndrome; Anakinra; COVID-19; Cytokine storm syndrome; IL-1; SARS-CoV2; Tocilizumab",
"medline_ta": "J Autoimmun",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D061067:Antibodies, Monoclonal, Humanized; D018501:Antirheumatic Agents; D000086382:COVID-19; D015331:Cohort Studies; D000080424:Cytokine Release Syndrome; D018450:Disease Progression; D005260:Female; D006801:Humans; D007279:Injections, Subcutaneous; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1; D015850:Interleukin-6; D008297:Male; D008875:Middle Aged; D012128:Respiratory Distress Syndrome; D000086402:SARS-CoV-2; D013030:Spain",
"nlm_unique_id": "8812164",
"other_id": null,
"pages": "102537",
"pmc": null,
"pmid": "32843231",
"pubdate": "2020-12",
"publication_types": "D016428:Journal Article",
"references": "32203709;32207255;32217556;22797452;32602262;28614216;28631531;32222466;32501454;32376398;32475759;20693540;32376392;32376597;24157572;22418018;32835257;32579985;32835233;32482538;31986264;26584195;32979572;24583503;32362390;32007143;31182982;32317220",
"title": "High dose subcutaneous Anakinra to treat acute respiratory distress syndrome secondary to cytokine storm syndrome among severely ill COVID-19 patients.",
"title_normalized": "high dose subcutaneous anakinra to treat acute respiratory distress syndrome secondary to cytokine storm syndrome among severely ill covid 19 patients"
} | [
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{
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"literaturereference_normalized": "high dose subcutaneous anakinra to treat acute respiratory distress syndrome secondary to cytokine storm syndrome among severely ill covid 19 patients",
"qualification": "3",
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},
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