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{ "abstract": "Epidiolex® (cannabidiol, aka CBD) is a recently approved FDA prescription drug for the treatment of epilepsy associated with Lennox-Gastaut and Dravet syndromes, and is increasingly used for treatment-resistant epilepsy. Rash was rarely reported in Epidiolex® clinical trial data. We report a case of Epidiolex®-related skin rash that developed in a delayed fashion in a 23-year-old female with medically refractory epilepsy. We also review the potential mechanism of Epidiolex®-related skin rash.", "affiliations": "The Ohio State University Wexner Medical Center, Neurology department, Columbus, Ohio, USA.;The Ohio State University Wexner Medical Center, Neurology department, Columbus, Ohio, USA.", "authors": "Singh|Jaysingh|J|;Antimisiaris|Marika-Foteni|MF|", "chemical_list": "D063386:Cannabinoid Receptor Agonists; D002185:Cannabidiol", "country": "France", "delete": false, "doi": "10.1684/epd.2020.1189", "fulltext": null, "fulltext_license": null, "issn_linking": "1294-9361", "issue": "22(4)", "journal": "Epileptic disorders : international epilepsy journal with videotape", "keywords": "CBD; Epidiolex; Epidiolex® (cannabidiol); antiepileptics; cannabinoid; drug interaction; hypersensitivity reaction; rash; skin", "medline_ta": "Epileptic Disord", "mesh_terms": "D000328:Adult; D002185:Cannabidiol; D063386:Cannabinoid Receptor Agonists; D000069279:Drug Resistant Epilepsy; D005076:Exanthema; D005260:Female; D006801:Humans; D055815:Young Adult", "nlm_unique_id": "100891853", "other_id": null, "pages": "511-514", "pmc": null, "pmid": "32729550", "pubdate": "2020-08-01", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Epidiolex-induced skin rash.", "title_normalized": "epidiolex induced skin rash" }

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"drugstructuredosagenumb": "5.8", "drugstructuredosageunit": "012", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "EPIDIOLEX" } ], "patientagegroup": null, "patientonsetage": "23", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug interaction", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Rash morbilliform", "reactionmeddraversionpt": "23.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "SINGH J, ANTIMISIARIS M. EPIDIOLEX-INDUCED SKIN RASH. EPILEPTIC DISORDERS. 2020?22:4:511-514. 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EPIDIOLEX-INDUCED SKIN RASH. EPILEPTIC-DISORD 2020?22(4):511-514.", "literaturereference_normalized": "epidiolex induced skin rash", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20201022", "receivedate": "20201022", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 18414735, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20210114" }, { "companynumb": "US-LUNDBECK-DKLU3022804", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "CLOBAZAM" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "202067", "drugbatchnumb": null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "30", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CLOBAZAM." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "CANNABIDIOL" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "100 MG/ML SOLUTION", "drugenddate": null, "drugenddateformat": null, "drugindication": "LENNOX-GASTAUT SYNDROME", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "2", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "2.9", "drugstructuredosageunit": "012", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "EPIDIOLEX" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "LACOSAMIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PARTIAL SEIZURES", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "2", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "150", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LACOSAMIDE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CLOBAZAM" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "202067", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PARTIAL SEIZURES", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "25", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CLOBAZAM." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "CANNABIDIOL" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "2", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "5.8", "drugstructuredosageunit": "012", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "EPIDIOLEX" } ], "patientagegroup": null, "patientonsetage": "23", "patientonsetageunit": "801", "patientsex": "2", "patientweight": "117", "reaction": [ { "reactionmeddrapt": "Drug interaction", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Rash morbilliform", "reactionmeddraversionpt": "23.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "SINGH J, ANTIMISIARIS M. EPIDIOLEX-INDUCED SKIN RASH. EPILEPTIC DISORD. 2020 AUG?22 (4):511-514.", "literaturereference_normalized": "epidiolex induced skin rash", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20201119", "receivedate": "20201023", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 18422801, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20210114" }, { "companynumb": "US-TARO-2020TAR01739", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "CLOBAZAM" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "209440", "drugbatchnumb": null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "30 MG PM", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "30", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CLOBAZAM." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CLOBAZAM" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "209440", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "25 MG AM", "drugenddate": null, "drugenddateformat": null, "drugindication": "STATUS EPILEPTICUS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "25", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CLOBAZAM." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "TOPIRAMATE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "200 MG, BID", "drugenddate": null, "drugenddateformat": null, "drugindication": "STATUS EPILEPTICUS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "200", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TOPIRAMATE." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "CANNABIDIOL" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "2.9 ML, BID (100 MG/ML SOLUTION)", "drugenddate": null, "drugenddateformat": null, "drugindication": "STATUS EPILEPTICUS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "2.9", "drugstructuredosageunit": "012", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "EPIDIOLEX" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "LACOSAMIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "150 MG, BID", "drugenddate": null, "drugenddateformat": null, "drugindication": "STATUS EPILEPTICUS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "150", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LACOSAMIDE." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "CANNABIDIOL" 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"reactionmeddrapt": "Drug interaction", "reactionmeddraversionpt": "23.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Dyspnoea", "reactionmeddraversionpt": "23.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Diarrhoea", "reactionmeddraversionpt": "23.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "SINGH J, ANTIMISIARIS M-F. 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{ "abstract": "Haemorrhage is the primary complication of anticoagulation therapy with the gastrointestinal, urinary and nasal tracts the most common sites of bleeding. Haematoma within solid organs is uncommon especially in the absence of blunt trauma. We describe two patients on long term Warfarin therapy who developed focal haematomas within the pancreas. To the best of our knowledge these are the first isolated unprovoked focal pancreatic hematoma cases reported in the literature. The non-specific clinical symptoms and confusing radiological features mimicked pancreatic malignancy and this led to misdiagnosis in the one patient who underwent unnecessary surgical exploration. The haematoma was correctly identified in the second patient who was managed conservatively and had an uneventful recovery.", "affiliations": "Radiology Department, Hull and East Yorkshire NHS Trust, Hull Royal Infirmary, Anlaby Road, Hull HU3 2JZ, UK. keith.chiu@hey.nhs.uk.", "authors": "Chiu|Keith|K|;Razack|Abdul|A|;Maraveyas|Anthony|A|", "chemical_list": null, "country": "England", "delete": false, "doi": "10.1186/1477-9560-11-20", "fulltext": "\n==== Front\nThromb JThromb JThrombosis Journal1477-9560BioMed Central 1477-9560-11-202422874010.1186/1477-9560-11-20Case ReportIsolated pancreatic heamorrhage in association with anticoagulation Chiu Keith 1keith.chiu@hey.nhs.ukRazack Abdul 1abdul.razack@hey.nhs.ukMaraveyas Anthony 2anthony.maraveyas@hey.nhs.uk1 Radiology Department, Hull and East Yorkshire NHS Trust, Hull Royal Infirmary, Anlaby Road, Hull HU3 2JZ, UK2 The Queen’s Centre for Oncology and Haematology, Hull and York Medical School, Castle Hill Hospital, Castle Road, Hull HU16 5JQ, UK2013 1 10 2013 11 20 20 15 6 2013 21 8 2013 Copyright © 2013 Chiu et al.; licensee BioMed Central Ltd.2013Chiu et al.; licensee BioMed Central Ltd.This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Haemorrhage is the primary complication of anticoagulation therapy with the gastrointestinal, urinary and nasal tracts the most common sites of bleeding. Haematoma within solid organs is uncommon especially in the absence of blunt trauma. We describe two patients on long term Warfarin therapy who developed focal haematomas within the pancreas. To the best of our knowledge these are the first isolated unprovoked focal pancreatic hematoma cases reported in the literature. The non-specific clinical symptoms and confusing radiological features mimicked pancreatic malignancy and this led to misdiagnosis in the one patient who underwent unnecessary surgical exploration. The haematoma was correctly identified in the second patient who was managed conservatively and had an uneventful recovery.\n==== Body\nBackground\nAnticoagulation therapy is essential in preventing many thromboembolic events and warfarin is the most commonly prescribed oral anticoagulation therapy. Unfortunately, the pharmacokinetics and pharmacodynamics of Warfarin are complex and its usage requires regular monitoring. Haemorrhagic complications associated with warfarin can cause significant morbidity and mortality to patients [1].\n\nWe report two cases of isolated pancreatic haemorrhage mimicking pancreatic malignancy and discuss the challenges in correctly diagnosing these two cases as well as how to differentiate pancreatic malignancy and haemorrhage from its mimics.\n\nCase presentation\nThe first patient was a 66 year-old male who presented acutely to the surgical admissions unit in January 2011. The patient had 4 episodes of fresh rectal bleeding within 48 hours and non-specific abdominal pain. The patient had had mechanical aortic valve replacement four years previously for aortic stenosis. The patient had also suffered from abdominal aortic aneurysm rupture and had undergone an emergency open abdominal aorta repair three years prior to this admission. The patient was on multiple medications including amiodarone, perindopril and long term Warfarin therapy.\n\nOn admission, the patient had a raised serum lactate of 5.0 mmol/L, white cell count of 17.6 × 10^12/L (neutophilia), a chronic normocytic anaemia of 9.4 g/dl but no acute drop in haemoglobin level. The patient’s anticoagulation was well controlled and had an international normalised Ratio (INR) of 3.1 that was within therapeutic range for the patient. Other blood examination was normal. The surgical team was concerned that there may be an aorto-enteric fistula in view of previous aortic surgery. A Computed Tomography (CT) scan was carried out and an unexpected 3 cm mass in the head of pancreas was identified (Figure 1A). The patient underwent an oesophagogastroduodenoscopy (OGD) and a colonoscopy which were normal. The case was referred to the hepato-pancreatico-biliary multidisciplinary meeting (MDT) and the lesion was presumed to be a potentially operable pancreatic adenocarcinoma. An MRI had been suggested for further assessment of this lesion but this was overlooked and decision was made for trial dissection with a view to perform a curative Whipple’s procedure. In July 2011, the patient underwent a laparotomy and intra-operatively, the hepatobiliary surgeon was unable to identify the pancreatic lesion. An intra-operative ultrasound was carried out by two experienced cross-sectional radiologists that also failed to identify the lesion. The laparotomy was abandoned.\n\nFigure 1 CT images of the first patient. (A) An 3 cm lesion was seen on initial post contrast venous phase CT (white arrow). This was mis-interpreted as a pancreatic malignancy. (B) Patient underwent a laparotomy which failed to identify a mass in the pancreas. Post operatively, he developed a wound site abscess (black arrow).\n\nThe patient was clinically septic during the post-operative period and a follow-up CT scan 2 weeks post-surgery showed that the pancreatic lesion had resolved completely (Figure 1B). The patient went on to develop an abscess in the wound site. He had debridement and wash-out of the abscess under general anesthesia and made an uneventful recovery thereafter.\n\nThe second patient was a 67 year-old female who was admitted to the medical admissions unit in November 2011 with abdominal pain. The patient had mitral valve repair nine months prior for mitral stenosis and had been on Warfarin therapy since. The patient also suffered from rheumatoid arthritis and was on methotrexate and prednisolone. Initial blood examination showed a raised white cell count of 17.6 × 10^12/L and a normocytic anaemia of 10.9 g/dl. Patient’s anticoagulation was poorly controlled since beginning Warfarin therapy and on admission had an INR of 9.5.\n\nThe patient’s anticoagulation therapy was stopped and INR reversed back to normal while put on intravenous heparin. She also underwent an ultrasound scan that demonstrated a large heterogeneous mass arising from the pancreatic head. A CT scan was then carried out that confirmed the presence of a pancreatic mass which was thought to be a malignant lesion (Figure 2A).\n\nFigure 2 CT and MRI images of the second patient. (A) A large heterogenous mass (white arrow) was identified at the head of pancreas. This was identified as a haematoma. (B) Follow-up MRI showed the pancreatic mass (black arrow) had decreased in size and demonstrated characteristic signals for a haematoma.\n\nThe case was discussed in the hepato-pancreatico-biliary MDT and on review the lesion was thought to be a haematoma rather than a malignant lesion. A decision to ‘watch and wait’ was adopted. The patient’s symptoms settled with conservative management and was discharged home. An interval Magnetic Resonance Imaging (MRI) scan one month after discharge showed the pancreas mass had decreased in size and showed MR characteristics of a haematoma (Figure 2B). A further follow-up CT 3 months later showed complete resolution of the pancreatic mass. The patient was discharged from the care of the hepato-pancreatico-biliary service.\n\nDiscussion\nTo our knowledge, this is the first descriptions of isolated focal haemorrhage in the pancreas as a result of oral anticoagulation. The periampullary region is anatomically and physiologically complex, thus focal haemorrhage involving any of its structures can mimic the presentation of a neoplasm. Although at times challenging, they can be differentiated by various imaging modalities from their enhancement pattern, signal characteristics or metabolic activities [2,3]. What is unique in these two cases is that the patients had isolated focal pancreatic parenchymal haemorrhage in the absence of a neoplasm, pancreatitis or trauma.\n\nPerhaps it is not surprising that our two cases were initially misinterpreted as pancreatic malignancies as the presence of a pancreatic mass is the most common direct sign of a pancreatic tumour. The most common type of pancreatic cancer, accounting for over 85% of these tumours is ductal adenocarcinoma. They often cause distortion to the contour of the gland, dilated pancreatic and common bile ducts, atrophy of the gland, invasion of local vasculature as well as metastases to regional lymph nodes, liver and the peritoneal cavity [4]. However, haemorrhage can also occur within a pancreatic tumour and is common in neoplasms such as solid pseudopapillary tumours and acinar cell carcinoma [5,6]. Therefore, only by recognizing the lack of indirect features, other lesions such as haematomas can be distinguished from a pancreatic tumour.\n\nTumoural haemorrhage is not only cause of haemorrhage within the pancreas. Pancreatic haemorrhage is also often associated within pancreatitis, occuring in 20% of cases [7]. Although serum amylase is the most widely used biochemical test to diagnose acute pancreatitis [8], CT plays an ever increasing role in aiding diagnosis and predicting clinical outcome [9]. In general, haemorrhage associated with pancreatitis also exhibit other signs of pancreatitis, including focal or diffuse pancreatic enlargement, pseudoaneurysms, inflammatory changes in the surrounding peripancreatic space, fluid collection formation and necrosis of the parenhcyma. The absence of these signs was not recognized which resulted in the misinterpretation of the radiological findings. If the CT scan had been performed with a non-contrast phase followed by arterial and venous phase study, the high Hounsfield (HU) values on the non-contrast images along with the lack of increase in HU values following contrast injection would have helped in making the correct diagnosis.\n\nOther causes of pancreatic haemorrhage include pancreatic injury secondary to trauma or iatrogenic cause (such as biopsy) [10,11]. In these circumstances, although radiological appearances may be similar to these two cases, there is usually a clear history for making the diagnosis.\n\nThe two cases illustrate the potential morbidity of anticoagulation therapy. It is estimated that around 1% of the UK population is on oral anticoagulation therapy (source IMS Health) and haemorrhage is the most common complication of Warfarin therapy [12]. The risk of major bleeding is thought to be around 2% in clinical trials although the incidence of major haemorrhage is unknown due to the varying dosage used, patient characteristics and differential definitions used by various studies [13]. Multiple factors such as the intensity of anticoagulation, time from starting anticoagulation therapy, quality of monitoring, genetic factors, age, gender, co-morbidities, polypharmacy and patient compliance have all been identified to be associated with anticoagulation bleeding complications [14].\n\nThe importance of recognizing the potential complications of anticoagulation therapy cannot be understated. Only by increasing the awareness amongst physicians, surgeons and radiologists, unnecessary procedures as in one of our patients who underwent laparotomy and had a prolonged hospital stay could be avoided.\n\nConclusion\nHaemorrhage secondary to anticoagulation therapy is common although focal haemorrhage in a solid organ is rare. These two cases provide a timely reminder of the potential complications of anticoagulation therapy. Careful analyses of radiological images and an awareness of the complications of anticoagulation therapy can reduce morbidity of patients.\n\nConsent\nWritten informed consent was obtained from the patients 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\nCompeting interests\nThe authors declare that they have no competing interests.\n\nAuthors’ contributions\nAM and AR were involved in the management of the patient. KC prepared the initial manuscript. All three authors reviewed and approved the final manuscript.\n==== Refs\nHorton JD Bushwick BM Warfarin therapy: evolving strategies in anticoagulation Am Fam Physician 1999 59 3 635 646 10029789 \nSutherland T Galvin A Little AF Part 2: CT characterisation of pancreatic neoplasm: tumour mimics Insights Imaging 2011 2 4 389 397 10.1007/s13244-011-0103-6 22347960 \nTo'o KJ Raman SS Yu NC Kim YJ Crawford T Kadell BM Pancreatic and peripancreatic diseases mimicking primary pancreatic neoplasia Radiographics 2005 25 4 949 965 10.1148/rg.254045167 16009817 \nRosewicz S Wiedenmann B Pancreatic carcinoma Lancet 1997 349 9050 485 489 10.1016/S0140-6736(96)05523-7 9040589 \nBuetow PC Buck JL Pantongrag-Brown L Beck KG Ros PR Adair CF Solid and papillary epithelial neoplasm of the pancreas: imaging-pathologic correlation on 56 cases Radiology 1996 199 3 707 711 8637992 \nTatli S Mortele KJ Levy AD Glickman JN Ros PR Banks PA CT and MRI features of pure acinar cell carcinoma of the pancreas in adults AJR Am J Roentgenol 2005 184 2 511 519 10.2214/ajr.184.2.01840511 15671372 \nBalthazar EJ Complications of acute pancreatitis: clinical and CT evaluation Radiol Clin North Am 2002 40 6 1211 1227 10.1016/S0033-8389(02)00043-X 12479707 \nGumaste VV Diagnostic tests for acute pancreatitis Gastroenterologist 1994 2 2 119 130 8055237 \nBalthazar EJ Acute pancreatitis: assessment of severity with clinical and CT evaluation Radiology 2002 223 3 603 613 10.1148/radiol.2233010680 12034923 \nGlancy KE Review of pancreatic trauma West J Med 1989 151 1 45 51 2669347 \nSahni VA Mortele KJ The bloody pancreas: MDCT and MRI features of hypervascular and hemorrhagic pancreatic conditions AJR Am J Roentgenol 2009 192 4 923 935 10.2214/AJR.08.1602 19304696 \nLinkins LA Choi PT Douketis JD Clinical impact of bleeding in patients taking oral anticoagulant therapy for venous thromboembolism: a meta-analysis Ann Intern Med 2003 139 11 893 900 10.7326/0003-4819-139-11-200312020-00007 14644891 \nSchulman S Beyth RJ Kearon C Levine MN Hemorrhagic complications of anticoagulant and thrombolytic treatment: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition) Chest 2008 133 6 Suppl 257S 298S 18574268 \nPalareti G Cosmi B Bleeding with anticoagulation therapy - who is at risk, and how best to identify such patients Thromb Haemost 2009 102 2 268 278 19652877\n\n", "fulltext_license": "CC BY", "issn_linking": "1477-9560", "issue": "11(1)", "journal": "Thrombosis journal", "keywords": null, "medline_ta": "Thromb J", "mesh_terms": null, "nlm_unique_id": "101170542", "other_id": null, "pages": "20", "pmc": null, "pmid": "24228740", "pubdate": "2013-10-01", "publication_types": "D002363:Case Reports", "references": "10029789;15671372;8637992;9040589;19652877;18574268;12479707;22347960;14644891;19304696;16009817;2669347;12034923;8055237", "title": "Isolated pancreatic heamorrhage in association with anticoagulation.", "title_normalized": "isolated pancreatic heamorrhage in association with anticoagulation" }

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{ "abstract": "Immune-checkpoint inhibitors are emerging as revolutionary drugs for certain malignancies. However, blocking the co-inhibitory signals may lead to immune-related adverse events, mainly in the spectrum of autoimmune diseases including colitis, endocrinopathies and nephritis. Here, we report a case of a 75-year-old man with metastatic malignant melanoma treated with a combination of nivolumab (anti-PD1-antibody) and ipilimumab (anti-CTLA-4 antibody) who developed systemic rash along with severe acute tubulointerstitial nephritis after two doses of combination therapy. Kidney biopsy and peripheral blood immune profile revealed highly proliferative and cytotoxic T cell features. Herein, we discuss the pathophysiology and management of immune checkpoint blockade-related adverse events.", "affiliations": "Renal Division, Brigham & Women's Hospital , Harvard Medical School , Boston, MA , USA.;Renal Division, Brigham & Women's Hospital , Harvard Medical School , Boston, MA , USA.;Department of Pathology, Brigham and Women's Hospital , Harvard Medical School , Boston, MA , USA.;Renal Division, Brigham& Women's Hospital, Harvard Medical School, Boston, MA, USA; Transplantation Research Center, Brigham and Women's Hospital, Harvard Medical School, Boston, USA.", "authors": "Murakami|Naoka|N|;Borges|Thiago J|TJ|;Yamashita|Michifumi|M|;Riella|Leonardo V|LV|", "chemical_list": null, "country": "England", "delete": false, "doi": "10.1093/ckj/sfw024", "fulltext": "\n==== Front\nClin Kidney JClin Kidney JckjndtplusClinical Kidney Journal2048-85052048-8513Oxford University Press 10.1093/ckj/sfw024sfw024OnconephrologySevere acute interstitial nephritis after combination immune-checkpoint inhibitor therapy for metastatic melanoma Murakami Naoka 1*Borges Thiago J. 1*Yamashita Michifumi 2Riella Leonardo V. 131 Renal Division, Brigham& Women's Hospital, Harvard Medical School, Boston, MA, USA2 Department ofPathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA3 Transplantation Research Center, Brigham and Women's Hospital, Harvard Medical School, Boston, USACorrespondence and offprint requests to: Leonardo V. Riella; E-mail: lriella@bwh.harvard.edu* These authors contributed equally to this work.\n\n6 2016 4 5 2016 4 5 2016 9 3 411 417 16 2 2016 8 3 2016 © The Author 2016. Published by Oxford University Press on behalf of ERAEDTA2016This 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.comImmune-checkpoint inhibitors are emerging as revolutionary drugs for certain malignancies. However, blocking the co-inhibitory signals may lead to immune-related adverse events, mainly in the spectrum of autoimmune diseases including colitis, endocrinopathies and nephritis. Here, we report a case of a 75-year-old man with metastatic malignant melanoma treated with a combination of nivolumab (anti-PD1-antibody) and ipilimumab (anti-CTLA-4 antibody) who developed systemic rash along with severe acute tubulointerstitial nephritis after two doses of combination therapy. Kidney biopsy and peripheral blood immune profile revealed highly proliferative and cytotoxic T cell features. Herein, we discuss the pathophysiology and management of immune checkpoint blockade-related adverse events.\n\nacute kidney injuryimmune-checkpoint blockadeinterstitial nephritisNational Institutes of Health http://dx.doi.org/10.13039/100000002T32DK00752712FTF120070328American Heart Association http://dx.doi.org/10.13039/100000968\n==== Body\nBackground\nImmune-checkpoint inhibitors are increasingly used as anti-cancer agents as more efficacies have been proved in multiple cancer species, such as melanoma, non-small-cell lung carcinoma and renal cell carcinoma [1–4]. On the other hand, the therapy comes with a price: immune-related adverse events (irAE) occur in up to 60% of treated patients, usually mild to moderate in grade. The pathophysiology of irAE is considered similar to that of autoimmune diseases, wherein activated lymphocytes target self-antigens [5]. Here we report a case of a patient with metastatic melanoma treated with immune-checkpoint inhibitor combination therapy, who developed acute kidney injury (AKI), systemic maculopapular rash and fever.\n\nCase report\nClinical history and initial laboratory data\nA 75-year-old Caucasian male with essential hypertension and recurrent metastatic melanoma presented with systemic morbilliform rash and AKI. The patient was initially diagnosed with invasive cutaneous melanoma of the left nasolabial fold [American Joint Committee of Cancer (AJCC) Stage IIc; T4b, N0, M0. BRAF V600/NRAS-wild-type] and underwent local excision with clear margins. Seven months later, he presented with significant weight loss and a palpable mass in his left submandibular area. PET-CT revealed an FDG-avid left submandibular lymph node and a liver lesion without any brain metastasis [AJCC Stage IV, M1c; Eastern Cooperative Oncology Group (ECOG) performance status 0]. Biopsy confirmed recurrence of malignant melanoma and combination therapy of nivolumab (1 mg/kg) and ipilimumab (3 mg/kg) was initiated. Routine blood test after his second cycle of treatment revealed a creatinine of 3.96 mg/dL, compared with a baseline of 0.91 mg/dL 3 weeks prior, indicating AKI (Table 1). Urinalysis revealed 2+ protein (albumin/creatinine ratio 42.4 mg/gCre), RBC 8/hpf and WBC 9/hpf. Urine sediments showed granular casts and WBC casts (Figure 1A and B). There was no history suggestive of dehydration or exposure to nephrotoxic agents such as antibiotics, contrast or analgesics. His only medications were nivolumab and ipilimumab. He was allergic to sulfa and ciprofloxacin.\nTable 1. Laboratory parameters\n\n\tTime since last dose of nivolumab/ipilimumab\t\n\tBaseline\t3 weeks\t5 weeks\t(Reference range)\t\nSodium (mEq/L)\t139\t141\t137\t136–145\t\nPotassium (mEq/L)\t4.2\t4.1\t4.1\t3.4–5.0\t\nChloride (mEq/L)\t108\t114\t101\t98–107\t\nBicarbonate (mmol/L)\t24\t18\t16\t22–31\t\nBUN (mg/dL)\t13\t65\t73\t6–23\t\nCre (mg/dL)\t0.91\t3.96\t4.64\t0.50–1.20\t\nTotal bilirubin (mg/dL)\t0.7\t0.6\t0.7\t0.0–1.0\t\nLDH (U/L)\t188\t189\t536\t135–225\t\nTotal protein (g/dL)\t9.3\t\t5.1\t6.4–8.3\t\nAlbumin (g/dL)\t3.2\t\t2.6\t3.5–5.2\t\nALT (U/L)\t25\t\t33\t10–50\t\nAST (U/L)\t22\t\t31\t10–50\t\nAlkaline phosphatase (U/L)\t96\t\t67\t35–130\t\nWBC (1000/µL)\t7.05\t7.52\t7.18\t4.0–10.0\t\nHemoglobin (g/dL)\t15.6\t11.9\t10.5\t13.5–18.0\t\nPlatelets (1000/µL)\t250\t252\t61\t150–450\t\nANA\t\t1:40 (diffuse, speckled)\t\t\t\ndsDNA Ab (IU)\t\t25\t\t0–25\t\nHistone Ab (U)\t\t0.7\t\t<1.0\t\nC3 (mg/dL)\t\t120\t\t90–180\t\nC4 (mg/dL)\t\t31\t\t10–40\t\nPPD\t\tNegative\t\t\t\nCortisol (in AM, µg/dL)\t\t21.3\t\t6–24\t\nTSH (µIU/mL)\t1.35\t\t0.09\t0.50–5.70\t\nFT4 (ng/dL)\t1.1\t\t1.1\t0.9–1.7\t\nTHBR\t\t\t1.17\t0.80–1.20\t\nTPO Ab (IU/mL)\t\t\t<10.0\t0.0–33.9\t\nANA, anti-nuclear antibody; PPD, purified protein derivative; TSH, thyroid-stimulating hormone; FT4, free thyroxine; THBR, thyroid hormone binding ratio; TPO Ab, thyroid peroxidase antibody.\n\n\nFig. 1. (A and B) Urine sediment analysis revealed granular cast (A) and WBC cast (B). (C) Non-pruritic morbilliform erythematous rash on patient's chest and abdomen.\n\n\n\nOn physical examination, vitals revealed a temperature of 36.4°C, a pulse of 93/min, a blood pressure at 178/80 mmHg, a respiratory rate of 20/min and body weight of 73.1 kg (an increase of 5 kg from his pre-treatment weight). A non-tender submandibular mass was palpable. His lungs were clear to auscultation and 1+ bilateral lower extremity edema were noted. A morbilliform eruption rash was noted on his chest, abdomen and back (Figure 1C). There was no change in the oral mucosa. A renal ultrasound showed no evidence of hydronephrosis, although the kidneys were slightly enlarged bilaterally (right 12.4 cm and left 13.0 cm). The decision was then made to pursue a kidney biopsy to further define the etiology of the patient's severe AKI.\n\nKidney biopsy\nThe kidney biopsy contained 34 glomeruli, of which 4 were globally sclerosed. The remaining glomeruli showed wrinkled glomerular capillary loops and narrowing of Bowman's space, suggestive of hypoperfusion. Cellularity and architecture was normal and no active inflammation of the tuft, necrotizing lesions or cellular crescents was noted (not shown). There was diffuse extensive interstitial inflammation associated with moderate interstitial edema (Figure 2A). The infiltrates were primarily composed of lymphocytes and plasma cells with admixed eosinophils and neutrophils. Granuloma or granulomatous lesions were not noted. There were frequent tubulitis and various degenerative changes, with focal flattening of the epithelium and occasional mitoses. Several tubules contained necrotic cellular debris, granular casts and periodic acid–Schiff-positive hyaline casts.\nFig. 2. Light microscopy of the kidney biopsy: (A) Periodic acid–Schiff staining showed severe interstitial infiltration of inflammatory cells, mainly lymphocytes and neutrophils. (B–F) Immunohistochemistry revealed extensive T-cell infiltration of CD4+ (B) and CD8+ T cells (C). Ten to 20% of the infiltrates were positive for granzyme B (D) and perforin (E). Foxp3-positive regulatory T cells were also present (F). Scale bars, 100 μm.\n\n\n\nImmunofluorescence staining revealed no significant immune deposits in the glomeruli. Tubular basement membranes showed focal fine granular deposition of C3 (1+). The interstitium revealed intense fibrin deposits (not shown). Immunohistochemistry showed extensive T-cell-dominant infiltrates (Figure 2B and C), of which ∼10–20% were strongly positive for cytotoxic enzymes including granzyme B (Figure 2D) and perforin (Figure 2E). Foxp3+ regulatory T cells were also present in the interstitium (Figure 2F).\n\nClinical follow-up\nThe patient was treated with a steroid pulse [solumedrol 500 mg intravenous (IV) × 3 days] followed by a taper (prednisone 60 mg daily). Although his creatinine initially improved to 2.41 mg/dL over the course of a week, it had increased to 4.64 mg/dL when he was readmitted the following week with symptoms of a fever and a rash (Table 1 and Figure 3). There was no laboratory evidence of hypophysitis or hepatitis at the time (Table 1). Skin biopsy revealed interface dermatitis involving adnexal structures with superficial perivascular lymphohistiocytic infiltrates. Peripheral immune characterization revealed highly proliferative circulating CD4+ and CD8+ T cells (measured by the percentage of Ki67+ cells, Figure 4A–C) in combination with an expansion of effector memory T cells (TEM, CD45RA-negative CCR7-negative, Figure 4D and E). Furthermore, serum cytokine analysis revealed a strikingly high level of pro-inflammatory cytokines (IL-1Ra, CXCL10 and TNF-α) (Figure 4F–H) and soluble IL-2 receptor (32 400 pg/mL; reference range <1033 pg/mL). Due to these findings, the patient's steroid dose was increased (solumedrol 140 mg IV twice a day) and mycophenolate mofetil (MMF; 1000 mg twice a day) was added to intensify treatment. Creatinine peaked at 7.31 mg/dL and then improved to 3.37 mg/dL over 10 days (Figure 3). The patient's rash dramatically improved and eventually resolved. Two weeks later, the patient was again admitted with a fever of 38.4°C and 3 days of bloody diarrhea. While his creatinine had remained stable, he was found to be pancytopenic (WBC 1.25 × 103/µL with 92% neutrophils, hemoglobin 9.2 g/dL, platelets 37 × 103/µL). The patient subsequently developed septic shock and deceased in spite of aggressive treatment with broad-spectrum antibiotics and vasopressor support. Blood culture turned out to be positive for pan-sensitive Pseudomonas aeruginosa. Autopsy demonstrated hemorrhagic colitis with no histological evidence of viable tumor in his liver.\nFig. 3. Clinical course of the patient. Serum creatinine, timing of nivolumab and ipilimumab administration, kidney biopsy procedure and treatment course are shown. Time course was described as weeks after the first dose of nivolumab/ipilimumab.\n\n\nFig. 4. Immunological characterization of T cells upon anti-PD-1/anti-CTLA-4 therapy. (A) Gating strategy of peripheral blood mononuclear cells (PBMCs) in flow cytometry analysis. Patient's CD8+ or CD4+ T cells carried an extremely proliferative phenotype recognized as Ki67+ cells (B and C), and more effector-memory (TEM) T cells identified as CD45RA-negative CCR7-negative population (D and E) compared with healthy controls. Serum cytokine profile was analyzed using Luminex multiplex panel. Pro-inflammatory cytokines (IL-1Ra, CXCL10 and TNF-α) were strikingly higher in the patient (F–H). HC; healthy controls.\n\n\n\nDiscussion\nImmune-checkpoint molecules play important roles in tolerance and cancer immunity. One of the mechanisms by which cancer cells evade immune surveillance and destruction is cell surface expression of co-inhibitory molecules such as PD-L1. Immune-checkpoint inhibitors exhibit immense tumor immunity via enhancing effector lymphocyte functions to target cancer cells by uncovering these molecular ‘shields’ [6]. Nevertheless, this immune enhancement comes at the expense of an increased risk of irAE (Table 2) [7]. A recent study of nivolumab and ipilimumab combination therapy for melanoma reported higher treatment-related severe adverse events rates [Common Terminology Criteria for Adverse Events (CTCAE) grade 3 or 4] for dual therapy (55%) compared with nivolumab or ipilimumab alone (16.3 and 27.3%, respectively) [8]. However, severe renal adverse events (grade 3–4) were still rare (6 cases out of 313) in the combination therapy group.\nTable 2. Immune-related adverse events associated with immune-checkpoint inhibitors in melanoma patients\n\n\tNivolumab\tIpilimumab\tNivolumab + ipilimumab\t\nAll grade\tGrade 3/4\tAll grade\tGrade 3/4\tAll grade\tGrade 3/4\t\nSkin\t\n Pruritus (%)\t9–23\t<1\t24–36\t0–1\t33–47\t2\t\n Rash (%)\t9–26\t0–1\t15–33\t0–2\t28–55\t3–5\t\n Vitiligo (%)\t3–11\t0\t2–4\t0\t7\t0\t\nGastro-intestinal\t\n Colitis (%)\t1–3\t<1–2\t7–12\t5–9\t9–23\t4–17\t\n Diarrhea (%)\t8–20\t0–2\t23–33\t3–10\t34–45\t6–11\t\nEndocrinopathy\t\n Hypothyroidism (%)\t2–9\t<1\t1.5–4\t0\t15–16\t<1\t\n Hyperthyroidism (%)\t1–5\t<1\t1–2\t<1\t10\t1\t\n Hypophysitis (%)\t<1\t<1\t2–4\t2\t8–12\t2–7\t\nPneumonitis (%)\t1–9\t0–1\t0–2\t<1\t0–6\t1–2\t\nRenal injury (%)\t0–1\t0–1\t0–1\t<1\t<1\t<1\t\n\n\nTo our knowledge, this is the first report of biopsy-proven acute interstitial nephritis (AIN) caused by combination immune-checkpoint inhibitor therapy. Seven cases of ipilimumab-associated AIN were reported in the literature [9–14], which were recently reviewed by Izzedine et al. [13]. Most of the cases presented with minimally symptomatic elevation of creatinine with mild proteinuria 6–12 weeks after initiation of ipilimumab. Of the four cases where biopsy was available, three had granulomatous tubulointerstitial nephritis while one had membranous lupus nephritis. Unlike these patients, who responded well to steroid therapy, our patient relapsed 2 weeks later with a more severe presentation accompanied by systemic rash and fever. Further immune suppression with combination of high dose steroid and MMF was required to control the disease activity. What made our case different from previous cases of AIN?\n\nOne possibility is related to the dual immune-checkpoint inhibition. CTLA-4 regulates peripheral tolerance by modulating the interaction between antigen-presenting cells and T cells in secondary lymphoid organs, and CTLA-4 deficiency was reported to trigger early-onset severe lymphoproliferative autoimmune syndromes both in human and mouse [15–18] via tissue self-antigen-specific T-cell activation [19]. On the other hand, PD-1 contributes to tolerance primarily at the level of target organs. PD-L1 or PD-1 deficient animals do develop autoimmune phenotype, but in a milder form and later in life [20, 21], which corroborates data in humans showing that anti-PD-1 therapy was associated with distinct and less severe irAE profile compared with anti-CTLA-4 therapy [22]. Blocking both pathways could synergistically potentiate antigen recognition and T-cell proliferation at lymph nodes [23], and provoke untethered cytotoxic T-cell effects in the periphery, not only against tumor but also against normal tissues (Figure 5). This mechanism is particularly relevant given mounting evidence that the clonal deletion of auto-reactive T-cell clones in the thymus is incomplete, and a few auto-reactive T cells remain dormant in all individuals [24, 25].\nFig. 5. Dual PD-1/CTLA-4 blockade synergistically breaks the tolerance by unleashing quiescent tissue-specific self-reactive T cells, which express high levels of PD-1. In the draining lymph nodes (right), regulatory T cells (Tregs) suppress T cells/APCs in a CTLA-4-dependent manner. With CTLA-4 blockade, Tregs lose their suppressive capacity and an uncontrolled activation of auto-reactive T cells occurs. Those cells then migrate and infiltrate the target tissue (e.g. kidney). In the renal tissue (left, top), IFN-γ triggers the upregulation of PD-L1 by renal cells, which will bind and signal through PD-1 expressed by T cells, trying to prevent those cells from proliferating and damaging the tissue. However, when the self-reactive T cells have their PD-1 receptor blocked by the antibody, the PD-1/PD-L1 signaling will be interrupted and T cells will further proliferate and mature. These T cells will then produce perforin and granzyme B (GrzB), feeding the pathogenic cycle further.\n\n\n\nIn our patient, a highly proliferative effector-memory T-cell phenotype along with aggressive cytotoxic T-cell infiltration in the kidney (Figures 2 and 4) raises the intriguing possibility that immune-checkpoint inhibitors unleashed these dormant auto-reactive T cells, leading to selective tissue injury (Figure 5).\n\nThere are unanswered questions on clonality and antigen-specificity of tissue-infiltrating cells. The observation that certain tissues seem more prone to irAE while others are spared [5] suggests tissue-antigen specificity as shown in CTLA-4-deficient animals [19]. Moreover, some patients develop irAE while others do not. T-cell receptor repertoire analyses and detailed immune profile characterization may enable us to risk-stratify patients and better manage these complications in the future.\n\nThe mainstay of irAE management is immune suppression, including high-dose steroids, MMF and potentially TNF-α inhibitors [5], interventions which do not seem to worsen cancer-specific outcomes [26]. Nevertheless, as our patient tragically demonstrated, one must be vigilant about the possibility of severe systemic infections in these patients.\n\nIn summary, our case highlights the aggressive T-cell-mediated pathophysiology of irAE, in the setting of immune-checkpoint inhibitor combination therapy. Early intervention and fine adjustment of immune modulatory agents is the key to the management of these complications.\n\nConflict of interest statement\nNone declared.\n\nAcknowledgements\nN.M. is supported by a grant from the National Institutes of Health (T32DK007527) and L.V.R is supported by a Research Grant (12FTF120070328) from the American Heart Association.\n==== Refs\nReferences\n1 Hodi FS , O'Day SJ , McDermott DF et al \nImproved survival with ipilimumab in patients with metastatic melanoma . N Engl J Med \n2010 ; 363 : 711 –723 20525992 \n2 Brahmer J , Reckamp KL , Baas P et al \nNivolumab versus docetaxel in advanced squamous-cell non-small-cell lung cancer . N Engl J Med \n2015 ; 373 : 123 –135 26028407 \n3 Garon EB , Rizvi NA , Hui R et al \nPembrolizumab for the treatment of non-small-cell lung cancer . N Engl J Med \n2015 ; 372 : 2018 –2028 25891174 \n4 Motzer RJ , Escudier B , McDermott DF et al \nNivolumab versus everolimus in advanced renal-cell carcinoma . N Engl J Med \n2015 ; 373 : 1803 –1813 26406148 \n5 Weber JS , Kahler KC , Hauschild A \nManagement of immune-related adverse events and kinetics of response with ipilimumab . J Clin Oncol \n2012 ; 30 : 2691 –2697 22614989 \n6 Murakami N , Riella LV \nCo-inhibitory pathways and their importance in immune regulation . Transplantation \n2014 ; 98 : 3 –14 24978034 \n7 Spain L , Diem S , Larkin J \nManagement of toxicities of immune checkpoint inhibitors . Cancer Treat Rev \n2016 ; 44 : 51 –60 26874776 \n8 Larkin J , Chiarion-Sileni V , Gonzalez R et al \nCombined nivolumab and ipilimumab or monotherapy in untreated melanoma . N Engl J Med \n2015 ; 373 : 23 –34 26027431 \n9 Beck KE , Blansfield JA , Tran KQ et al \nEnterocolitis in patients with cancer after antibody blockade of cytotoxic T-lymphocyte-associated antigen 4 . J Clin Oncol \n2006 ; 24 : 2283 –2289 16710025 \n10 Fadel F , El Karoui K , Knebelmann B \nAnti-CTLA4 antibody-induced lupus nephritis . N Engl J Med \n2009 ; 361 : 211 –212 19587352 \n11 Forde PM , Rock K , Wilson G et al \nIpilimumab-induced immune-related renal failure—a case report . Anticancer Res \n2012 ; 32 : 4607 –4608 23060594 \n12 Voskens CJ , Goldinger SM , Loquai C et al \nThe price of tumor control: an analysis of rare side effects of anti-CTLA-4 therapy in metastatic melanoma from the ipilimumab network . PLoS One \n2013 ; 8 : e53745 23341990 \n13 Izzedine H , Gueutin V , Gharbi C et al \nKidney injuries related to ipilimumab . Invest New Drugs \n2014 ; 32 : 769 –773 24687600 \n14 Thajudeen B , Madhrira M , Bracamonte E et al \nIpilimumab granulomatous interstitial nephritis . Am J Ther \n2015 ; 22 : e84 –e87 24067875 \n15 Waterhouse P , Penninger JM , Timms E et al \nLymphoproliferative disorders with early lethality in mice deficient in Ctla-4 . Science \n1995 ; 270 : 985 –988 7481803 \n16 Tivol EA , Borriello F , Schweitzer AN et al \nLoss of CTLA-4 leads to massive lymphoproliferation and fatal multiorgan tissue destruction, revealing a critical negative regulatory role of CTLA-4 . Immunity \n1995 ; 3 : 541 –547 7584144 \n17 Kuehn HS , Ouyang W , Lo B et al \nImmune dysregulation in human subjects with heterozygous germline mutations in CTLA4 . Science \n2014 ; 345 : 1623 –1627 25213377 \n18 Schubert D , Bode C , Kenefeck R et al \nAutosomal dominant immune dysregulation syndrome in humans with CTLA4 mutations . Nat Med \n2014 ; 20 : 1410 –1416 25329329 \n19 Ise W , Kohyama M , Nutsch KM et al \nCTLA-4 suppresses the pathogenicity of self antigen-specific T cells by cell-intrinsic and cell-extrinsic mechanisms . Nat Immunol \n2010 ; 11 : 129 –135 20037585 \n20 Nishimura H , Nose M , Hiai H et al \nDevelopment of lupus-like autoimmune diseases by disruption of the PD-1 gene encoding an ITIM motif-carrying immunoreceptor . Immunity \n1999 ; 11 : 141 –151 10485649 \n21 Nishimura H , Okazaki T , Tanaka Y et al \nAutoimmune dilated cardiomyopathy in PD-1 receptor-deficient mice . Science \n2001 ; 291 : 319 –322 11209085 \n22 Robert C , Schachter J , Long GV et al \nPembrolizumab versus ipilimumab in advanced melanoma . N Engl J Med \n2015 ; 372 : 2521 –2532 25891173 \n23 Das R , Verma R , Sznol M et al \nCombination therapy with anti-CTLA-4 and anti-PD-1 leads to distinct immunologic changes in vivo . J Immunol \n2015 ; 194 : 950 –959 25539810 \n24 Malhotra D , Linehan JL , Dileepan T et al \nTolerance is established in polyclonal CD4T cells by distinct mechanisms, according to self-peptide expression patterns . Nat Immunol \n2016 ; 17 : 187 –195 26726812 \n25 Kuchroo VK , Ohashi PS , Sartor RB et al \nDysregulation of immune homeostasis in autoimmune diseases . 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J Clin Oncol \n2015 ; 33 : 3193 –3198 26282644\n\n", "fulltext_license": "CC BY-NC", "issn_linking": "2048-8505", "issue": "9(3)", "journal": "Clinical kidney journal", "keywords": "acute kidney injury; immune-checkpoint blockade; interstitial nephritis", "medline_ta": "Clin Kidney J", "mesh_terms": null, "nlm_unique_id": "101579321", "other_id": null, "pages": "411-7", "pmc": null, "pmid": "27274826", "pubdate": "2016-06", "publication_types": "D016428:Journal Article", "references": "20037585;24067875;19587352;24978034;16710025;7481803;22614989;22227671;26282644;11209085;25539810;26406148;20525992;7584144;26726812;10485649;25891173;24687600;25329329;25213377;26028407;25891174;26874776;23060594;26027431;23341990", "title": "Severe acute interstitial nephritis after combination immune-checkpoint inhibitor therapy for metastatic melanoma.", "title_normalized": "severe acute interstitial nephritis after combination immune checkpoint inhibitor therapy for metastatic melanoma" }

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SEVERE ACUTE INTERSTITIAL NEPHRITIS AFTER COMBINATION IMMUNE-CHECKPOINT INHIBITOR THERAPY FOR METASTATIC MELANOMA. 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SEVERE ACUTE INTERSTITIAL NEPHRITIS AFTER COMBINATION?IMMUNE-CHECKPOINT INHIBITOR THERAPY FOR METASTATIC?MELANOMA. CKJ 2016;9(3):411-417.?", "literaturereference_normalized": "severe acute interstitial nephritis after combination immune checkpoint inhibitor therapy for metastatic melanoma", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20160829", "receivedate": "20160829", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 12692656, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20161109" }, { "companynumb": "US-MYLANLABS-2016M1034349", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "MYCOPHENOLATE MOFETIL" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "065520", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "1000 MG, BID", "drugenddate": null, "drugenddateformat": null, "drugindication": "TUBULOINTERSTITIAL NEPHRITIS", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": "2", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "1000", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MYCOPHENOLATE MOFETIL." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "IPILIMUMAB" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "3 MG/KG", "drugenddate": null, "drugenddateformat": null, "drugindication": "METASTATIC MALIGNANT MELANOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "IPILIMUMAB" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "METHYLPREDNISOLONE SODIUM SUCCINATE" }, "drugadditional": "3", "drugadministrationroute": "042", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "500MG FOR 3 DAYS; LATER DOSE WAS INCREASED TO 140MG TWICE A DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": "TUBULOINTERSTITIAL NEPHRITIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "SOLU-MEDROL" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "METHYLPREDNISOLONE SODIUM SUCCINATE" }, "drugadditional": "3", "drugadministrationroute": "042", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "140 MG, BID", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": "2", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "140", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "SOLU-MEDROL" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "NIVOLUMAB" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "1 MG/KG", "drugenddate": null, "drugenddateformat": null, "drugindication": "METASTATIC MALIGNANT MELANOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "NIVOLUMAB" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "PREDNISONE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "60 MG, QD", "drugenddate": null, "drugenddateformat": null, "drugindication": "TUBULOINTERSTITIAL NEPHRITIS", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "60", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISONE." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Septic shock", "reactionmeddraversionpt": "19.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Pseudomonas infection", "reactionmeddraversionpt": "19.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Tubulointerstitial nephritis", "reactionmeddraversionpt": "19.1", "reactionoutcome": "2" }, { "reactionmeddrapt": "Enterocolitis haemorrhagic", "reactionmeddraversionpt": "19.1", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "MURAKAMI N, BORGES TJ, YAMASHITA M, RIELLA LV. SEVERE ACUTE INTERSTITIAL NEPHRITIS AFTER COMBINATION IMMUNE-CHECKPOINT INHIBITOR THERAPY FOR METASTATIC MELANOMA. CLIN-KIDNEY-J 2016;9(3):411-417.", "literaturereference_normalized": "severe acute interstitial nephritis after combination immune checkpoint inhibitor therapy for metastatic melanoma", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20160817", "receivedate": "20160817", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 12660485, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20161109" }, { "companynumb": "US-TEVA-687806USA", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "NIVOLUMAB" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "1 MG/KG", "drugenddate": null, "drugenddateformat": null, "drugindication": "METASTATIC MALIGNANT MELANOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "NIVOLUMAB" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "METHYLPREDNISOLONE SODIUM SUCCINATE" }, "drugadditional": "3", "drugadministrationroute": "042", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "TUBULOINTERSTITIAL NEPHRITIS", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "2", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "140", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "SOLU-MEDROL" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "IPILIMUMAB" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "3 MG/KG", "drugenddate": null, "drugenddateformat": null, "drugindication": "METASTATIC MALIGNANT MELANOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "IPILIMUMAB" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "MYCOPHENOLATE MOFETIL" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "65457", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "TUBULOINTERSTITIAL NEPHRITIS", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "2", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "1000", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MYCOPHENOLATE MOFETIL." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "METHYLPREDNISOLONE SODIUM SUCCINATE" }, "drugadditional": "3", "drugadministrationroute": "042", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "500MG FOR 3 DAYS; 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SEVERE ACUTE INTERSTITIAL NEPHRITIS AFTER COMBINATION IMMUNE-CHECKPOINT INHIBITOR THERAPY FOR METASTATIC MELANOMA. CLIN-KIDNEY-J 2016;9(3):411-417.", "literaturereference_normalized": "severe acute interstitial nephritis after combination immune checkpoint inhibitor therapy for metastatic melanoma", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20160826", "receivedate": "20160826", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 12691663, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20161109" } ]

{ "abstract": "BACKGROUND\nCardiotoxicity from anthracycline-based chemotherapy is an important cause of early and late morbidity and mortality in breast cancer patients. Left ventricular (LV) function is assessed for patients receiving anthracycline-based chemotherapy to identify cardiotoxicity. However, animal studies suggest that right ventricular (RV) function may be a more sensitive measure to detect LV dysfunction. The purpose of this pilot study was to determine if breast cancer patients undergoing anthracycline-based chemotherapy experience RV dysfunction.\n\n\nMETHODS\nForty-nine breast cancer patients undergoing anthracycline-based chemotherapy at the Ottawa Hospital between November 2007 and March 2013 and who had 2 echocardiograms performed at least 3months apart were retrospectively identified. Right atrial area (RAA), right ventricular fractional area change (RV FAC) and RV longitudinal strain of the free wall (RV LSFW) were evaluated according to the American Society of Echocardiography guidelines.\n\n\nRESULTS\nThe majority (48/49) of patients were females with an average age of 53.4 (95% CI: 50.1-56.7years). From baseline to follow-up study, average LV ejection fraction (LVEF) decreased from 62.22 (95% CI: 59.1-65.4) to 57.4% (95% CI: 54.0-60.9) (P=0.04). During the same time period, the mean RAA increased from 12.1cm(2) (95% CI: 11.1-13.0cm(2)) to 13.8cm(2) (95% CI: 12.7-14.9cm(2)) (P=0.02), mean RV FAC decreased (P=0.01) from 48.3% (95% CI: 44.8-51.74) to 42.1% (95% CI: 38.5-45.6%), and mean RV LSFW worsened from -16.2% (95% CI: -18.1 to -14.4%) to -13.81% (95% CI: -15.1 to -12.5%) (P=0.04).\n\n\nCONCLUSIONS\nThis study demonstrates that breast cancer patients receiving anthracycline-based chemotherapy experience adverse effects on both right atrial size and RV function. Further studies are required to determine the impact of these adverse effects on right heart function and whether this represents an earlier marker of cardiotoxicity.", "affiliations": "Department of Medicine (Cardiology), University of Ottawa Heart Institute, Ottawa, Ontario, Canada.;Department of Medicine (Oncology), The Ottawa Hospital, University of Ottawa, Ottawa, Ontario, Canada.;Department of Medicine (Oncology), The Ottawa Hospital, University of Ottawa, Ottawa, Ontario, Canada.;Department of Medicine (Cardiology), The Ottawa Hospital, Ottawa, Ontario, Canada.;Department of Medicine (Cardiology), University of Ottawa Heart Institute, Ottawa, Ontario, Canada.;Department of Medicine (Cardiology), The Ottawa Hospital, Ottawa, Ontario, Canada.;Department of Medicine (Oncology), The Ottawa Hospital, University of Ottawa, Ottawa, Ontario, Canada.;Department of Medicine (Cardiology), University of Ottawa Heart Institute, Ottawa, Ontario, Canada gdwivedi@ottawaheart.ca.", "authors": "Boczar|Kevin Emery|KE|;Aseyev|Olexiy|O|;Sulpher|Jeffrey|J|;Johnson|Christopher|C|;Burwash|Ian G|IG|;Turek|Michele|M|;Dent|Susan|S|;Dwivedi|Girish|G|", "chemical_list": null, "country": "England", "delete": false, "doi": "10.1530/ERP-16-0020", "fulltext": "\n==== Front\nEcho Res PractEcho Res PractechoEcho Research and Practice2055-0464Bioscientifica Ltd Bristol 2745796610.1530/ERP-16-0020ERP160020ResearchRight heart function deteriorates in breast cancer patients undergoing anthracycline-based chemotherapy K E Boczar and othersRight heart function in chemotherapy patientsBoczar Kevin Emery MD1Aseyev Olexiy MD PhD2Sulpher Jeffrey MD FRCPC2Johnson Christopher MD FRCPC3Burwash Ian G MD FRCPC1Turek Michele MD FRCPC3Dent Susan MD FRCPC2Dwivedi Girish DM PhD (UK) MRCP (UK)11 Department of Medicine (Cardiology), University of Ottawa Heart Institute, Ottawa, Ontario, Canada2 Department of Medicine (Oncology), The Ottawa Hospital, University of Ottawa, Ottawa, Ontario, Canada3 Department of Medicine (Cardiology), The Ottawa Hospital, Ottawa, Ontario, CanadaCorrespondence should be addressed to G Dwivedi; Email: gdwivedi@ottawaheart.ca9 2016 9 2016 3 3 79 84 14 7 2016 22 7 2016 © 2016 The authors2016The authorsThis work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.Background\nCardiotoxicity from anthracycline-based chemotherapy is an important cause of early and late morbidity and mortality in breast cancer patients. Left ventricular (LV) function is assessed for patients receiving anthracycline-based chemotherapy to identify cardiotoxicity. However, animal studies suggest that right ventricular (RV) function may be a more sensitive measure to detect LV dysfunction. The purpose of this pilot study was to determine if breast cancer patients undergoing anthracycline-based chemotherapy experience RV dysfunction.\n\nMethods\nForty-nine breast cancer patients undergoing anthracycline-based chemotherapy at the Ottawa Hospital between November 2007 and March 2013 and who had 2 echocardiograms performed at least 3months apart were retrospectively identified. Right atrial area (RAA), right ventricular fractional area change (RV FAC) and RV longitudinal strain of the free wall (RV LSFW) were evaluated according to the American Society of Echocardiography guidelines.\n\nResults\nThe majority (48/49) of patients were females with an average age of 53.4 (95% CI: 50.1–56.7years). From baseline to follow-up study, average LV ejection fraction (LVEF) decreased from 62.22 (95% CI: 59.1–65.4) to 57.4% (95% CI: 54.0–60.9) (P=0.04). During the same time period, the mean RAA increased from 12.1cm2 (95% CI: 11.1–13.0cm2) to 13.8cm2 (95% CI: 12.7–14.9cm2) (P=0.02), mean RV FAC decreased (P=0.01) from 48.3% (95% CI: 44.8–51.74) to 42.1% (95% CI: 38.5–45.6%), and mean RV LSFW worsened from −16.2% (95% CI: −18.1 to −14.4%) to −13.81% (95% CI: −15.1 to −12.5%) (P=0.04).\n\nConclusion\nThis study demonstrates that breast cancer patients receiving anthracycline-based chemotherapy experience adverse effects on both right atrial size and RV function. Further studies are required to determine the impact of these adverse effects on right heart function and whether this represents an earlier marker of cardiotoxicity.\n\nKeywords\nright heart functionchemotherapycardiotoxicityechocardiography\n==== Body\nIntroduction\nBreast cancer patients undergoing chemotherapy have an increased risk of developing cardiovascular complications including heart failure (1, 2). Of the various chemotherapeutic agents used in breast cancer treatment, anthracyclines and their related compounds are some of the most frequently implicated agents (1, 2). Anthracycline-based chemotherapy is associated with a dose-dependent risk of congestive heart failure that can occur years after completion of chemotherapy. The clinical impact of this latent toxicity can be significant. A study carried out in older women (>66years of age) who had been treated for breast cancer demonstrated a higher risk of death from cardiovascular disease than recurrence of breast cancer 7–8years after completion of breast cancer treatment (2). Although a number of studies have reported the adverse impact of anthracycline-based agents on left ventricular (LV) systolic and diastolic function, limited data exists on their impact on right ventricular (RV) function. Preliminary human and animal studies have suggested that the detrimental/toxic effect of doxorubicin provokes global cardiac injury that extends to both the left and right ventricles (3, 4, 5). Importantly, RV function is a strong incremental predictor of prognosis in patients with LV systolic dysfunction and various LV pathologies (6, 7). The evaluation of RV function using traditional echocardiographic methods, as well as novel methods such as deformation imaging (strain, strain rate imaging), as recommended in the recent multimodality guidelines to detect subclinical LV dysfunction, may provide evidence of associated right ventricular cardiotoxicity (8).\n\nIn our study, we hypothesized that breast cancer patients undergoing anthracycline-based chemotherapy would show evidence of right ventricular dysfunction identifiable using transthoracic echocardiography and currently available echocardiographic techniques.\n\nMaterials and methods\nUsing the University of Ottawa Local Breast Cancer Registry, we retrospectively identified 49 patients with early-stage human epidermal growth factor receptor 2 negative breast cancer (stage I–III) who underwent anthracycline-based chemotherapy at the Ottawa Hospital between November 2007 and March 2013. All of these 49 patients had undergone at least two echocardiograms performed at least 3months apart. The majority of patients (i.e., 80%) had undergone echocardiogram before the completion of first cycle of chemotherapy (mean: 30days; 95% CI: 3–57days before chemotherapy). All patients had their follow-up echocardiography after the completion of chemotherapy cycle (mean: 125days; 95% CI: 107–142days). The Breast Cancer Registry was approved by the Human Research Ethics Board, and all patients provided written informed consent for the use of their data.\n\nEchocardiography and image analysis\nComprehensive echocardiographic examinations were carried out according to the standard recommendations of the American Society of Echocardiography (ASE) (9, 10). All echocardiographic images were digitally stored and conventional echocardiographic parameters were measured. The parameters of cardiac structure and function were measured as per the guidelines of ASE (9, 10).\n\nRight atrial area (RAA) measurements were performed in the apical four-chamber view. RAA was estimated by planimetry at the end of ventricular systole (largest atrial volume), tracing the RA endocardium from the lateral aspect of the tricuspid annulus to the septal aspect, excluding the area between the leaflets and annulus, and the right atrial appendage.\n\nRight ventricular fractional area change (RVFAC) was calculated from the apical four-chamber view using the percentage change in the RV end-diastolic and end-systolic areas.\n\nRV longitudinal strain of the free wall (RV LSFW) was measured offline using speckle-tracking method and dedicated TomTec software (TomTec Imaging Systems, Unterschleissheim, Germany). In brief, the endocardial border of the RV was manually traced (approximately 10 points) over 1 frame, and endocardial borders were automatically tracked throughout the cardiac cycles by the software. The software determines myocardial velocity as the ratio between frame-to-frame displacement of the speckles and the time interval, and derives the systolic longitudinal strain. Longitudinal strain (LS) of the RV free wall was measured as the average of three segmental strain values (base, mid and apex) (Fig. 1).\nFigure 1 Panel A is a pre-chemotherapy image depicting normal right ventricle free wall longitudinal strain. Panel B is a post-chemotherapy image from the same patient showing reduced right ventricle free wall longitudinal strain.\n\n\n\n\nImages were reviewed and analyzed offline by two independent observers blinded to the clinical characteristics of the study population. Reproducibility analysis for right heart parameters was performed in a subset of patients (n=10) and intra-class correlation coefficient value was 0.81 (95% CI: 0.58–0.91).\n\nStatistical analysis\nMedCalc for Windows version 12.0 (MedCalc Software, Ostend, Belgium) was used for analysis of the data. For the continuous variables, parametric test conditions were first tested. The Shapiro–Wilk test was used to determine whether the continuous variables were normally distri­buted. Descriptive statistics were shown as mean±s.d. or median (minimum–maximum), where appropriate. To compare the echocardiography variables, paired t-test was used and statistical significance was defined as two-tailed probability value of P<0.05.\n\nResults\nBaseline characteristics\nBaseline characteristics of study population are provided in Table 1. The mean age was 53.4years (95% CI: 50.2–56.6years) and the majority of patients had no pre-existing cardiovascular disease. All but one (n=48) patients were female and most were nonsmokers and had no history of hypertension or hyperlipidemia. A total of 15 patients received doxorubicin-based chemotherapy (doxorubicin/cyclophosphamide every 3weeks×4 cycles±paclitaxel). The mean total dose of doxorubicin was 232mg/m2 (95% CI: 214.84–249.16mg/m2). A total of 34 patients received epirubicin-containing chemotherapy (fluorouracil/epirubicin/cyclophosphamide every 3weeks×3±docetaxel). The average total dose of epirubicin was 294.12mg/m2 (95% CI: 285.78–302.46mg/m2).\nTable 1 Baseline characteristics of study population.\n\n\tn=49\t\nAge (years)\t53.4±3.3 (50.1–56.7)\t\nWomen\t48 (98.0%)\t\nBody mass index (kg/m2)\t25.9±1.3 (24.6–27.2)\t\nCardiac risk factors\t\n Smoker/ex-smoker\t21 (42.9%)\t\n Hypertension\t12 (24.5%)\t\n Dyslipidemia\t7 (14.3 %)\t\n Diabetes\t7 (14.3%)\t\n Family history of coronary artery disease\t2 (4.1%)\t\nCardiac history\t\n Prior coronary artery disease\t2 (4.1%)\t\n\n\n\nEchocardiographic variables\nThe average LV ejection fraction (LVEF) decreased from 62.2% (95% CI: 59.1–65.4) at their first echocardiogram to 57.4% (95% CI: 54.0–60.9) on follow-up echocardiogram (P=0.04) (Table 2). Similarly, the mean LV global LS decreased from −15.4% (95% CI: −16.3 to −14.5) to −12.8 (95% CI: −13.8 to −11.9) on follow-up (P<0.0001).\nTable 2 Echocardiography parameters.\n\n\tBaseline\tFollow-up\tSignificance\nP\t\nLVEF\t62.2% (95% CI: 59.1–65.4)\t57.4% (95% CI: 54.0–60.9)\t0.04\t\nLV GLS\t−15.4 (95% CI: −16.3 to −14.5)\t−12.8 (95% CI: −13.8 to −11.9)\t<0.0001\t\nLV diastole (cm)\t4.6 (95% CI: 4.5–4.7)\t4.9 (95% CI: 4.8–5.1)\t<0.0001\t\nLV systole (cm)\t3.0 (95% CI: 2.9–3.2)\t4.0 (95% CI: 2.9–5.1)\t0.10\t\nIV septum (cm)\t0.84 (95% CI: 0.80–0.89)\t0.84 (95% CI: 0.80–0.87)\t0.75\t\nPosterior wall (cm)\t0.87 (95% CI: 0.83–0.91)\t0.87 (95% CI: 0.83–0.90)\t0.96\t\nFractional shortening (%)\t33.9 (95% CI: 31.8–36.0)\t30.3 (95% CI: 27.8–32.7)\t0.003\t\nMitral valve E Max velocity (cm/s)\t74.9 (95% CI: 70.7–79.2)\t73.8 (95% CI: 69.0–78.6)\t0.60\t\nMitral valve A Max velocity (cm/s)\t71.1 (95% CI: 64.6–77.7)\t73.8 (95% CI: 68.4–79.1)\t0.20\t\nMitral valve E/A\t1.14 (95% CI: 1.02–1.30)\t1.08 (95% CI: 0.95–1.21)\t0.15\t\nLeft atrium (cm)\t3.3 (95% CI: 3.1–3.5)\t3.4 (95% CI: 3.2–3.5)\t0.12\t\nAortic root (cm)\t2.8 (95% CI: 2.6–2.9)\t2.9 (95% CI: 2.7–3.0)\t0.14\t\nRV FAC\t48.3% (95% CI: 44.8–51.7)\t42.1% (95% CI: 38.5–45.6%)\t0.01\t\nRAA\t12.7cm2 (95% CI: 11.1–13.1cm2)\t13.8cm2 (95% CI: 12.7–14.9cm2)\t0.02\t\nLS RVFW\t−16.2% (95% CI: −18.1 to −14.4%)\t−13.8% (95% CI: −15.1 to −12.5%)\t0.04\t\nHeart rate (beats/min)\t83 (95% CI: 74–92)\t79 (95% CI: 74–84)\t0.32\t\nLS RVFW, longitudinal strain of the RV free wall; LV GLS, longitudinal strain of the LV; LVEF, LV ejection fraction; RAA, right atrial area; RV FAC, right ventricular fractional area change.\n\n\n\n\nMean RAA significantly increased from 12.1cm2 (95% CI: 11.1–13.0cm2) to 13.8cm2 on follow-up echocardiogram (95% CI: 12.7–14.9cm2) (P=0.02). Mean RV FAC significantly decreased from 48.3% (95% CI: 44.8–51.7) to 42.1% on follow-up (P=0.01). Mean RV LSFW worsened from −16.2% (95% CI: −18.1 to −14.4%) to −13.8% on follow-up (95% CI: −15.1 to −12.5%) (P=0.04).\n\nDiscussion\nWhereas previous studies involving anthracycline-based chemotherapy in breast cancer patients have identified clinical and subclinical LV dysfunction, we have demonstrated that anthracycline-based chemotherapy can adversely affect right heart function. Moreover, in this study we have identified a previously unreported abnormality in RV function (RV LSFW) evident in breast cancer patients receiving anthracycline-based chemotherapy using myocardial deformation parameters, the latter considered an important marker of subclinical dysfunction for the left ventricle (8).\n\nRight heart assessment and its implications\nIt is increasingly recognized that RV function plays an important role in determining prognosis in conditions that have typically been regarded as largely related to LV pathologies, including congestive heart failure and coronary artery disease (6, 7, 11, 12, 13). Despite advancement in echocardiographic techniques, the assessment of the right ventricle by conventional two-dimensional echocardiography remains challenging due to its complex shape and systolic mechanics (9). Right atrial assessment is of clinical importance as its enlargement can reflect abnormalities in RV function, and right atrial enlargement has been shown to be strongly associated with adverse clinical outcomes (14, 15). We measured RAA in our study as it is consi­dered an accurate and reliable technique for evaluating right atrial size (9, 14).\n\nOf the many different echocardiographic indices of RV function, RVFAC is the most commonly used two-dimensional method to assess RV function (9). It is considered to be a robust predictor of heart failure, sudden death, stroke and mortality in patients with right and left heart conditions (16, 17, 18). However, like LVEF, RVFAC change may be a late manifestation of RV dysfunction. In the setting of cardiotoxicity from cancer therapy, early detection of subclinical cardiotoxicity is desirable to permit modification of cancer treatment or optimization of cardiac function.\n\nDeformation imaging (strain or strain rate imaging) was initially developed to measure LV mechanics. However, recent studies have established its usefulness for the assessment of the RV in disease states where RV function can be adversely affected (19, 20, 21, 22). As the bulk of RV muscle fibers run longitudinally, longitudinal shortening assessed by strain imaging has the potential to reveal early stages of myocardial dysfunction not evident on routine RV parameters (23). Similar to LV strain, RV assessment by speckle-tracking method allows the assessment in a nongeometrical manner, relatively independent of tethering or translational motion (24, 25). Importantly, strain-based assessment is less affected by loading conditions, which may be particularly important in patients receiving chemotherapy, who are prone to changing fluid and weight status during the course of therapy. These factors suggest that deformation imaging of the RV using speckle-tracking echocardiography may be a promising modality for detection of subclinical cardiotoxicity during cancer therapy.\n\nMechanism of right heart abnormalities\nIn our study we found that RAA, RVFAC and RV LSFW (in addition to LVEF) were adversely affected by anthracycline-based chemotherapy. Previous histological studies have indicated that cardiotoxic damage is more prominent in the sub-endocardial part of the cardiac walls (26). Intuitively, a thinner RV may be more sensitive to the toxic effects of chemotherapy compared with the thicker muscular LV, although data to support this premise are limited. Prospective nonhuman studies with histological analysis to test whether the right ventricle is involved at an earlier time than the left ventricle would lend support to this hypothesis. We have identified both LV and RV dysfunction in our patients, but we are unable to determine if the RV is more sensitive to the cardiotoxic effects.\n\nRV cardiotoxicity as a result of chemotherapy has not been adequately studied and previous studies have revealed divergent results. Belham et al. observed no change in RV myocardial performance index when patients were evaluated following administration of low-dose anthracycline (27). Similarly, Cottin et al. reported no alterations in the RV function at 1 and 12months after anthracycline therapy using multiple-gated acquisitions (28). However, Yildirim et al. reported abnormalities in the RV tissue Doppler velocities at rest and during dobutamine stress echocardiography following anthracycline administration (29) and Tanindi et al. reported a decrease in the RVFAC during chemotherapy in a study carried out in 37 patients (3). Our results reveal similar findings and add to the growing evidence by demonstrating abnormalities in RV function using deformation imaging – an important technique to identify subclinical LV dysfunction that has been incorporated into the most recent multimodality imaging guidelines to assess cardio-oncologic patients (8).\n\nLimitations\nBecause of the retrospective aspect of this study we were unable to evaluate the utility of RV tissue Doppler and tricuspid annular plane septal excursion measurements as they were not systematically recorded. Another limitation of the study is the absence of cardiac biomarkers as they were not collected. Due to the limited number of patients in our study, we were unable to determine if the RV functional impairment was independent of or preceded a fall in LV function. However, this study clearly demonstrates, using multiple measures, that the RV may be adversely impacted by anthracycline-based chemotherapy regimens. Further studies will be required to evaluate the potential of RV parameters to identify cardiotoxicity before the current LV parameters. To determine the impact of these RV parameters on patient prognosis, a larger prospective multicenter study with a more objective comparison method, such as cardiac magnetic resonance imaging, will be needed to confirm these correlations and the clinical impacts of our results.\n\nConclusions\nOur pilot study confirms that the right side of the heart is adversely affected in breast cancer patients undergoing anthracycline-based chemotherapy. 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(10.1093/ejechocard/jeq071 )20562426\n\n", "fulltext_license": "CC BY-NC-ND", "issn_linking": "2055-0464", "issue": "3(3)", "journal": "Echo research and practice", "keywords": "cardiotoxicity; chemotherapy; echocardiography; right heart function", "medline_ta": "Echo Res Pract", "mesh_terms": null, "nlm_unique_id": "101664713", "other_id": null, "pages": "79-84", "pmc": null, "pmid": "27457966", "pubdate": "2016-09", "publication_types": "D016428:Journal Article", "references": "11923049;22789916;23965488;25677889;8698054;20176715;16455426;20620859;26140151;21880609;20190280;24679740;22294683;22618330;25577444;20562426;2341055;25172399;18308007;25309687;16923465;11153735;24161324;11985906;17577017;25559473;17145230;10080447", "title": "Right heart function deteriorates in breast cancer patients undergoing anthracycline-based chemotherapy.", "title_normalized": "right heart function deteriorates in breast cancer patients undergoing anthracycline based chemotherapy" }

[ { "companynumb": "CA-JNJFOC-20161206636", "fulfillexpeditecriteria": "1", "occurcountry": "CA", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "DOXORUBICIN HYDROCHLORIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "050718", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "LIPOSOME INJECTION", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "BREAST CANCER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "232", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DOXORUBICIN HYDROCHLORIDE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "PACLITAXEL" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNSPECIFIED", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "BREAST CANCER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PACLITAXEL." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CYCLOPHOSPHAMIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNSPECIFIED", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "BREAST CANCER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYCLOPHOSPHAMIDE." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Cardiotoxicity", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Right ventricular ejection fraction decreased", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Cardiac disorder", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "BOCZAR KE, ASEYEV O, SULPHER J, JOHNSON C, BURWASH IG, TUREK M, ET AL. RIGHT HEART FUNCTION DETERIORATES IN BREAST CANCER PATIENTS UNDERGOING ANTHRACYCLINE-BASED CHEMOTHERAPY. ECHO RESEARCH AND PRACTICE 01-SEP-2016;3/3:79-84.", "literaturereference_normalized": "right heart function deteriorates in breast cancer patients undergoing anthracycline based chemotherapy", "qualification": "1", "reportercountry": "CA" }, "primarysourcecountry": "CA", "receiptdate": "20161212", "receivedate": "20161212", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 13017503, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170207" } ]

{ "abstract": "We experienced two cases of dipeptidyl peptidase-4 (DPP-4) inhibitor-associated bullous pemphigoid (BP) showing an unfavorable course despite its discontinuation. Clinicians should carefully monitor the course of DPP-4 inhibitor-associated BP even after withdrawal of DPP-4 inhibitor therapy, especially in very elderly patients.", "affiliations": "Department of Endocrinology and Metabolism Dokkyo Medical University Tochigi Japan.;Department of Endocrinology and Metabolism Dokkyo Medical University Tochigi Japan.;Department of Endocrinology and Metabolism Dokkyo Medical University Tochigi Japan.;Department of Endocrinology and Metabolism Dokkyo Medical University Tochigi Japan.;Department of Endocrinology and Metabolism Dokkyo Medical University Tochigi Japan.;Department of Dermatology Dokkyo Medical University Tochigi Japan.;Department of Endocrinology and Metabolism Dokkyo Medical University Tochigi Japan.;Department of Dermatology Dokkyo Medical University Tochigi Japan.;Department of Endocrinology and Metabolism Dokkyo Medical University Tochigi Japan.", "authors": "Shinohara|Yasutake|Y|;Iijima|Toshie|T|https://orcid.org/0000-0002-4613-3744;Sakurai|Shintaro|S|;Jojima|Teruo|T|https://orcid.org/0000-0002-2907-261X;Ohira|Eriko|E|;Hayashi|Shujiro|S|;Usui|Isao|I|;Igawa|Ken|K|;Aso|Yoshimasa|Y|", "chemical_list": null, "country": "England", "delete": false, "doi": "10.1002/ccr3.3047", "fulltext": "\n==== Front\nClin Case Rep\nClin Case Rep\n10.1002/(ISSN)2050-0904\nCCR3\nClinical Case Reports\n2050-0904 John Wiley and Sons Inc. Hoboken \n\n10.1002/ccr3.3047\nCCR33047\nCase Report\nCase Reports\nBullous pemphigoid associated with dipeptidyl peptidase‐4 inhibitor showing unfavorable outcomes despite immediate discontinuation of medication\nSHINOHARA et al.Shinohara Yasutake \n1\n Iijima Toshie https://orcid.org/0000-0002-4613-3744\n1\ntoshie@dokkyomed.ac.jp Sakurai Shintaro \n1\n Jojima Teruo https://orcid.org/0000-0002-2907-261X\n1\n Ohira Eriko \n1\n Hayashi Shujiro \n2\n Usui Isao \n1\n Igawa Ken \n2\n Aso Yoshimasa \n1\n \n1 \nDepartment of Endocrinology and Metabolism\nDokkyo Medical University\nTochigi\nJapan\n\n\n2 \nDepartment of Dermatology\nDokkyo Medical University\nTochigi\nJapan\n\n* Correspondence\n\nToshie Iijima, Department of Endocrinology and Metabolism, Dokkyo Medical University, Mibu, Shimotsuga, Tochigi 321‐0293, Japan.\n\nEmail: toshie@dokkyomed.ac.jp\n\n30 8 2020 \n10 2020 \n8 10 10.1002/ccr3.v8.102007 2012\n03 4 2020 13 5 2020 28 5 2020 © 2020 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.Abstract\nWe experienced two cases of dipeptidyl peptidase‐4 (DPP‐4) inhibitor‐associated bullous pemphigoid (BP) showing an unfavorable course despite its discontinuation. Clinicians should carefully monitor the course of DPP‐4 inhibitor‐associated BP even after withdrawal of DPP‐4 inhibitor therapy, especially in very elderly patients.\n\nWe experienced two cases of dipeptidyl peptidase‐4 (DPP‐4) inhibitor‐associated bullous pemphigoid (BP) showing an unfavorable course despite its discontinuation. Clinicians should carefully monitor the course of DPP‐4 inhibitor‐associated BP even after withdrawal of DPP‐4 inhibitor therapy, especially in very elderly patients.\n\n\nbullous pemphigoiddipeptidyl peptidase‐4 inhibitortype 2 diabetes source-schema-version-number2.0cover-dateOctober 2020details-of-publishers-convertorConverter:WILEY_ML3GV2_TO_JATSPMC version:5.9.2 mode:remove_FC converted:16.10.2020\n\n\nShinohara \nY \n, \nIijima \nT \n, \nSakurai \nS \n, et al. Bullous pemphigoid associated with dipeptidyl peptidase‐4 inhibitor showing unfavorable outcomes despite immediate discontinuation of medication\n. Clin Case Rep . 2020 ;8 :2007 –2012\n. 10.1002/ccr3.3047\n==== Body\n1 INTRODUCTION\nWe report three cases of dipeptidyl peptidase‐4 (DPP‐4) inhibitor‐associated bullous pemphigoid (BP), two cases of which had an unfavorable course despite its discontinuation. Therefore, clinicians should pay close attention to the clinical course of DPP‐4 inhibitor‐associated BP, even after withdrawal of these drugs.\n\nBullous pemphigoid (BP) is a bullous autoimmune skin disease that is characterized by autoantibodies targeting BP180 and BP230, which are two hemidesmosomal proteins localized at the epidermal‐dermal junction.\n1\n BP is relatively common among elderly people, mainly affecting the trunk, lower limbs, and face.\n1\n Various drugs have been reported to show an association with BP.\n2\n DPP‐4 inhibitors are oral antidiabetic drugs that inhibit degradation of incretins (gastric inhibitory peptide and glucagon‐like inhibitory peptide −1). Recently, there have been several reports that use of dipeptidyl peptidase‐4 (DPP‐4) inhibitors is associated with an increased risk of BP, with the highest risk being noted for vildagliptin among these drugs.\n3\n, \n4\n, \n5\n, \n6\n A recent report has demonstrated clinical features and pathophysiology of BP associated with DPP‐4 inhibitors in Japanese patients,\n7\n suggesting that noninflammatory BP may be associated with DPP‐4 inhibitors. Several studies have shown that the clinical outcome is better if DPP‐4 inhibitor therapy is discontinued when BP is diagnosed.\n8\n, \n9\n, \n10\n\n\n\nHowever, we experienced two cases of BP associated with DPP‐4 inhibitor therapy showing unfavorable outcomes despite immediate discontinuation of the relevant drugs. Here, we report a total of three cases of DPP‐4 inhibitor‐associated BP in patients with type 2 diabetes, summarizing their characteristics and the clinical course of BP after discontinuation of DPP‐4 inhibitors. Patients provided informed consent for publication of these cases.\n\n2 CASE REPORTS\nCase 1: An 82‐year‐old woman with a long history of type 2 diabetes started to take linagliptin (5 mg/d) in addition to the combination of basal insulin and a glinide. Nine months later, linagliptin was switched to teneligliptin (20 mg/d) at a different hospital. After a further six months, she presented with pruritic erythema on the trunk and limbs, followed by development of blisters on the left arm (Figure 1A). She consulted a dermatologist at our university hospital. Examination revealed diffuse bullae and generalized edematous erythema. Histological examination of a skin biopsy specimen with hematoxylin and eosin (H‐E) staining showed subepidermal blisters and scanty eosinophil infiltration (Figure 1B). Direct immunofluorescence demonstrated linear deposits of immunoglobulin G (IgG) along the epidermal basement membrane (Figure 1C; yellow arrows). The serum level of anti‐BP180 antibody (noncollagen 16A domain; NC16A) was elevated to 328 U/mL. BP was diagnosed from these findings. HbA1c was 7.0% at the diagnosis of DPP‐4 inhibitor‐associated BP.\n\nFigure 1 A, Clinical features of skin in Case 1‐3. B, Histopathological findings with hematoxylin and eosin staining of skin biopsy in Case 1‐3. C, Direct immunofluorescence for IgG of skin biopsy in Case 1‐3\n\nAfter hospitalization, treatment with prednisolone (40 mg/d) and cyclosporine (150 mg/d) was initiated, while teneligliptin was discontinued because it was suspected to be the cause of BP. However, her skin lesions did not improve and serum anti‐BP 180 antibody increased to 10 000 U/mL on January 10, 2017. Intravenous steroid pulse therapy was commenced, as well as administration of intravenous immunoglobulin (IVIG) and plasmapheresis on several occasions. Subsequently, her skin lesions improved and anti‐BP180 antibody decreased to 109 U/mL on March 13, 2017. However, her symptoms showed repeated exacerbation after discharge from hospital. Therefore, the patient was readmitted and received intravenous steroid pulse therapy, IVIG, and plasmapheresis, but her skin lesions did not respond. After multiple courses of intravenous steroid pulse therapy followed by a high dose of oral glucocorticoid, HbA1c was increased to 8.4%. After that, she had a fall and developed confusion. Emergency head computed tomography revealed new bleeding into an existing chronic subdural hematoma (Figure 2A). The patient died two weeks later, possibly from cerebral herniation.\n\nFigure 2 A, Computed tomography of brain in Case 1; chronic subdural hematoma. B, Computed tomography of lungs in Case 2; multiple nodular lesions in the middle to lower lobes of both lung. C, Computed tomography of abdomen in Case 2; suspected ascending colon cancer (red arrow) and para‐aortic lymphadenopathy (yellow arrows)\n\nCase 2: An 89‐year‐old woman with long‐standing type 2 diabetes started treatment with sitagliptin (50 mg/d), which was switched to vildagliptin (100 mg/d) at a different hospital. Three years after initiation of vildagliptin therapy, she presented with erythema and small tense blisters on her limbs and trunks. She visited a local dermatology clinic and was referred to the department of dermatology at our university hospital. On examination, she had tense bullae and erythema on her chest and limbs (Figure 1A), along with scars due to scratching on her back. Histological examination of a skin biopsy specimen from the right leg with H‐E staining revealed blisters with fibrin precipitates and infiltration of eosinophils into the epidermis and dermis (Figure 1B). Direct immunofluorescence showed linear staining for IgG along the epidermal basement membrane (Figure 1C; yellow arrows). Serum anti‐BP180 NC16A antibody was elevated to 3450 U/mL. BP was diagnosed on the basis of these findings. HbA1c was 7.9% at the diagnosis of DPP‐4 inhibitor‐associated BP. Vildagliptin was discontinued immediately, and treatment was started with prednisolone (30 mg/d), doxycycline (100 mg/d), and niceritrol (500 mg/d). Despite this regimen, new blisters continued to appear, so cyclosporine (150 mg/d) was added to her therapy. Subsequently, the skin lesions gradually improved and did not relapse when prednisolone and cyclosporine were tapered. She continued prednisolone at a dose of 10 mg/d with no recurrence of blistering and erythema. HbA1c was gradually increased and remained at a high level of 8 to 9%. Three months later, she became unconsciousness after a history of poor health for several days. Cardiopulmonary arrest occurred when she was transported to the emergency department of our university hospital. Although emergency treatment was initiated, the patient could not be revived. Laboratory tests performed upon arrival showed leukocytosis of 27 400/µL and elevation of serum C‐reactive protein to 11.91 mg/dL. Whole body computed tomography revealed multiple nodular lesions in the middle to lower lobes of both lung (Figure 2B) and suspected ascending colon cancer (Figure 2C; red arrow) with para‐aortic lymphadenopathy (Figure 2C: yellow arrows).\n\nCase 3: A 67‐year‐old man with type 2 diabetes commenced treatment with alogliptin (12.5 mg/d). The dose of alogliptin was subsequently increased to 25 mg/d and metformin (500 mg/d) was added. After 3.5 years, he developed generalized blisters on his skin and intraorally. He presented to the department of dermatology at our university hospital. On examination, several areas of edematous erythema without blistering were found on his thigh and in the oral cavity (Figure 1A). Histological examination of a skin biopsy specimen with H‐E staining showed subepidermal blisters with scanty eosinophil infiltration into the skin (Figure 1B). Direct immunofluorescence demonstrated linear deposits of IgG along the epidermal basement membrane (Figure 1C; yellow arrows). Serum anti‐BP180 antibody was negative, but BP was diagnosed from the other findings. HbA1c was 7.2% at the diagnosis of DPP‐4 inhibitor‐associated BP. Alogliptin was discontinued immediately and treatment with prednisolone (20 mg/d) was started. The dose of prednisolone was tapered to 4 mg/day as his symptoms gradually improved, and he currently remains in remission. Although HbA1c was increased to 8.6% after treatment with oral glucocorticoids, it was decreased to 6.9% by the initiation of insulin therapy.\n\n3 DISCUSSION\nBP is an autoimmune disease that causes bullae, erosions, and erythema on the skin and mucosal surfaces. It is characterized by autoantibodies targeting hemidesmosomal proteins BP180 and BP230 involved in adhesion at the epidermal‐dermal junction.\n1\n A wide variety of drugs (diuretics, spironolactone, furosemide, antihypertensives, and antibiotics) have been associated with development of BP in elderly persons.\n2\n Recently, there have been increasing reports that use of DPP‐4 inhibitors is also associated with the development of BP.\n3\n, \n4\n, \n5\n, \n6\n The rate of DPP‐4 inhibitors use is markedly higher in Japanese people with type 2 diabetes than in Caucasian people,\n11\n which may explain why more DPP‐4i‐associated BP cases are reported from Japan.\n7\n Several retrospective case‐control studies have compared the frequency of DPP‐4 inhibitor use between BP patients with diabetes and control diabetes patients without BP, demonstrating an association of DPP‐4 inhibitors with the development of BP.\n9\n, \n10\n, \n12\n Accordingly, patients who are using DPP‐4 inhibitors should be warned to report new‐onset diffuse itching, urticarial lesions, or blisters.\n\nWe experienced 3 patients with type 2 diabetes who presented BP after treatment with DPP‐4 inhibitors. We confirmed our three cases developed BP as an adverse effect of DPP‐4 inhibitor based on Naranjo scale (an adverse drug reaction probability scale). However, it cannot be denied that amlodipine may be associated with development of BP in Case 1 and 2, because amlodipine is known to be a risk of drug‐induced BP.\n2\n\n\n\nIzumi et al reported that DPP‐4 inhibitor‐associated BP featured less prominent erythema clinically and showed little evidence of histological inflammation with scanty infiltration of eosinophils into the skin, suggesting it was an atypical form of noninflammatory BP.\n13\n It was also suggested that drug‐induced BP could have a relatively favorable outcome compared with typical BP. Our Cases 1 and 3 were examples of this noninflammatory phenotype of DPP‐4 inhibitor‐associated BP, presenting with less erythema and minor infiltration of eosinophils into the skin on histological examination (Figure 1 and Table 1). On the other hand, there have been reports that most patients with DPP‐4 inhibitor‐associated BP have typical clinical manifestations and histological features of this disease.\n10\n, \n14\n\n\n\nTable 1 Clinical characteristics at the bullous pemphigoid associated with dipeptidyl peptidase‐4 inhibitors in three patients with type 2 diabetes\n\n\tCase 1\tCase 2\tCase 3\t\nAge (yrs)/sex\t82/female\t89/female\t67/male\t\nDPP4‐inhibitors\t\nlinagliptin→\n\n\nteneligliptin\n\n\n\t\nsitagliptin→\n\n\nvildagliptin\n\n\n\t\nalogliptin\n\n\n\t\nNaranjo scale (points)\t3\t4\t7\t\nOther drugs (/day)\tmetformin 250 mg\t\t\t\nmiglitol 75 mg\t\t\t\namlodipine 5 mg\tamlodipine 5 mg\tmetformin 500 mg\t\ncandesartan 4 mg\tcandesartan 1 mg\t\t\nloxoprofen 60 mg\t\t\t\netizolam 5 mg\t\t\t\netizolam 0.5 mg\t\t\t\nDiabetic retinopathy\tNone\tnone\tnone\t\nHbA1c at the onset of BP (%)\t7.0\t7.9\t7.2\t\neGFR (mL/min/1.73 m2)/UAE (mg/gCr)\t50.6/–\t60.5/–\t57.2/3.0\t\nComorbidity\tHypertension, Cerebral infarction, Intestinal obstruction\tHypertension\tGastric ulcer, Hypertension, Gallstones\t\nPeriod of DPP‐4 inhibitors administration until onset of BP\t16 mo\t38 mo\t6 mo\t\nanti‐BP180 autoantibody\t328 U/mL\t3450 U/mL\t–\t\nerythema/ blisters\t＋/＋\t＋/＋\t＋/＋\t\nEosinophil infiltration into the skin\tmild\tsevere\tmild\t\nRelapse\t＋\t–\t–\t\nHLA(DQB1*03:01)\t–\tnot examined\t＋\t\nTherapy for BP\tprednisolone, minocycline, cyclosporine, Steroid pulse therapy, intravenous immunoglobulin therapy\tprednisolone, tetracycline, cyclosporine, niceritrol\tprednisolone, tetracycline, niceritrol, nicotinamide\t\nOutcomes/Cause\tDeath: Acute subdural hematoma\tDeath: Pulmonary metastasis?\tRemission\t\nJohn Wiley & Sons, LtdBenzaquen et al reported that discontinuation of DPP‐4 inhibitor therapy had a favorable impact on the outcome of BP in 19 patients with diabetes, because 95% of them achieved clinical remission after stopping DPP‐4 inhibitors and receiving first‐line treatment for BP.\n9\n A retrospective case‐control study also demonstrated that clinical outcomes were less favorable among 13 patients with diabetes who continued DPP‐4 inhibitors compared with 19 patients who discontinued DPP‐4 inhibitors, with eight of the 13 patients who continued DPP‐4 inhibitors dying between 2 months and 4.9 years after the initial diagnosis of BP.\n10\n These findings suggested that discontinuation of DPP‐4 inhibitor therapy may be associated with better clinical outcomes. Taking the results from these studies together,\n9\n, \n10\n it can be suggested that administration of DPP‐4 inhibitors should be discontinued immediately when a diagnosis of BP is made. However, we experienced two cases of DPP‐4 inhibitor‐associated BP with unfavorable outcomes despite immediate withdrawal of DPP‐4 inhibitor therapy and initiation of first‐line treatment for BP with an oral steroid and a high‐potency topical steroid. Both patients were elderly women over 80 years old.\n\nIn Case 1, skin lesions showed multiple relapses despite discontinuation of DPP‐4 inhibitor therapy and initiation of treatment for BP. She received intravenous steroid pulse therapy, IVIG, and plasmapheresis in hospital on several occasions. Eventually, she died after a fall, probably from cerebral herniation associated with a subdural hematoma. In Case 2, symptoms of BP were improved by treatment with oral prednisolone and cyclosporine, but the patient died after deterioration of her general condition. She may have died of lung metastasis from primary colon cancer, although the possibility that opportunistic pulmonary infection was associated with her death cannot be excluded. It was recently reported that control of BP and relapse of this condition did not differ between patients who stopped or continued treatment with DPP‐4 inhibitors.\n15\n This report and our experience suggest that it is important for clinicians to pay close attention to the clinical course of DPP‐4 inhibitor‐associated BP, even after discontinuation of DPP‐4 inhibitor therapy.\n\nThe mechanisms responsible for BP associated with DPP‐4 inhibitor therapy remain to be determined. DPP‐4 (CD26) is highly expressed by T cells, especially CD4+ T cells. It is possible that inhibition of DPP‐4 may be associated with development of autoimmune skin diseases, because autoreactive T cells are involved in the pathogenesis of BP.\n16\n A previous study demonstrated that the HLA‐DQB1*03:01 allele is a biomarker for genetic susceptibility to BP associated with DPP‐4 inhibitors in a Japanese population,\n17\n suggesting an association between HLA class II and this drug‐induced autoimmune disease. Our Case 3 was positive for the HLA‐DQB1*03:01 allele, in agreement with this report (Table 1). We previously demonstrated that sitagliptin, another DPP‐4 inhibitor, reduced circulating CD4 + T cells in patients with type 2 diabetes, especially causing a decline of regulatory T cells.\n18\n In fact, a very recent study demonstrated that dysfunction of regulatory T cells is associated with induction of autoantibodies to bullous pemphigoid antigens in mice and humans.\n19\n Another possibility is that inhibition of DPP‐4 augments the activity of eotaxin (CCL11), a DPP‐4 substrate, resulting in recruitment of eosinophils to the skin.\n20\n\n\n\nIn conclusion, we experienced 3 patients with type 2 diabetes who developed DPP‐4 inhibitor‐associated BP. Despite prompt discontinuation of DPP‐4 inhibitor therapy and initiation of first‐line treatment for BP, the outcome was unfavorable in two patients. Accordingly, clinicians should carefully monitor the course of DPP‐4 inhibitor‐associated BP even after withdrawal of DPP‐4 inhibitor therapy, especially in very elderly patients.\n\nCONFLICT OF INTEREST\nNone declared.\n\nAUTHOR CONTRIBUTIONS\nYS: treated the patient and drafted the manuscript. TI: wrote the manuscript. EO, SS, and SH: treated the patients. TJ, IU, and KI: reviewed the manuscript. YA: wrote the manuscript. All authors read and approved the final manuscript.\n\nACKNOWLEDGMENTS\nPublished with written consent of the patient.\n==== Refs\nREFERENCES\n1 \n\nSchmidt \nE \n, \nZillikens \nD \n. Pemphigoid diseases\n. Lancet . 2013 ;381 :320 ‐332\n.23237497 \n2 \n\nStavropoulos \nPG \n, \nSoura \nE \n, \nAntoniou \nC \n. Drug‐induced pemphigoid: a review of the literature\n. J Eur Acad Dermatol Venereol . 2014 ;28 :1133 ‐1140\n.24404939 \n3 \n\nPasmatzi \nE \n, \nMonastirli \nA \n, \nHabeos \nJ \n, \nGeorgiou \nS \n, \nTsambaos \nD \n. Dipeptidyl peptidase‐4 inhibitors cause bullous pemphigoid in diabetic patients: report of two cases\n. Diabetes Care . 2011 ;34 :133 .\n4 \n\nSkandalis \nK \n, \nSpirova \nM \n, \nGaitanis \nG \n, \nTsartsarakis \nA \n, \nBassukas \nID \n. Drug‐induced bullous pemphigoid in diabetes mellitus patients receiving dipeptidyl peptidase‐IV inhibitors plus metformin\n. J Eur Acad Dermatol Venereol . 2012 ;26 :249 ‐253\n.21466592 \n5 \n\nAttaway \nA \n, \nMersfelder \nTL \n, \nVaishnav \nS \n, \nBaker \nJK \n. Bullous pemphigoid associated with dipeptidyl peptidase IV inhibitors. A case report and review of literature\n. J Dermatol Case Rep . 2014 ;8 :24 ‐28\n.24748908 \n6 \n\nGarcía \nM \n, \nAranburu \nMA \n, \nPalacios‐Zabalza \nI \n, \nLertxundi \nU \n, \nAguirre \nC \n. Dipeptidyl peptidase‐IV inhibitors induced bullous pemphigoid: a case report and analysis of cases reported in the European pharmacovigilance database\n. J Clin Pharm Ther . 2016 ;41 :368 ‐370\n.27191539 \n7 \n\nMurakami \nT \n, \nYabe \nD \n, \nInagaki \nN \n. Bullous pemphigoid with dipeptidyl peptidase‐4 inhibitors: Clinical features and pathophysiology\n. J Diabetes Investig . 2019 ;10 (5 ):1168 ‐1170\n.\n8 \n\nBéné \nJ \n, \nMoulis \nG \n, \nBennani \nI \n, et al. Bullous pemphigoid and dipeptidyl peptidase IV inhibitors: a case‐noncase study in the French Pharmacovigilance Database\n. Br J Dermatol . 2016 ;175 (2 ):296 ‐301\n.27031194 \n9 \n\nBenzaquen \nM \n, \nBorradori \nL \n, \nBerbis \nP \n, et al. Dipeptidyl peptidase IV inhibitors, a risk factor for bullous pemphigoid: Retrospective multicenter case‐control study from France and Switzerland\n. J Am Acad Dermatol . 2018 ;78 :1090 ‐1096\n.29274348 \n10 \n\nKridin \nK \n, \nBergman \nR \n. Association of bullous pemphigoid with dipeptidyl‐peptidase 4 inhibitors in patients with diabetes: estimating the risk of the new agents and characterizing the patients\n. JAMA Dermatol . 2018 ;154 :1152 ‐1158\n.30090931 \n11 \n\nSeino \nY \n, \nKuwata \nH \n, \nYabe \nD \n. Incretin‐based drugs for type 2 diabetes: Focus on East Asian perspectives\n. J Diabetes Investig . 2016 ;7 :102 ‐109\n.\n12 \n\nVarpuluoma \nO \n, \nFörsti \nAK \n, \nJokelainen \nJ \n, et al. Vildagliptin significantly increases the risk of bullous pemphigoid: A Finnish nationwide registry study\n. J Invest Dermatol . 2018 ;138 :1659 ‐1661\n.29427585 \n13 \n\nIzumi \nK \n, \nNishie \nW \n, \nMai \nY \n, et al. Autoantibody profile differentiates between inflammatory and noninflammatory bullous pemphigoid\n. J Invest Dermatol . 2016 ;136 :2201 ‐2210\n.27424319 \n14 \n\nPatsatsi \nA \n, \nKyriakou \nA \n, \nMeltzanidou \nP \n, et al. Βullous pemphigoid in patients with DPP‐4 inhibitors at the onset of disease: does this differ from common bullous pemphigoid?\n\nEur J Dermatol . 2018 ;28 :711 ‐713\n.30325322 \n15 \n\nLindgren \nO \n, \nVarpuluoma \nO \n, \nTuusa \nJ \n, et al. Gliptin‐associated bullous pemphigoid and the expression of dipeptidyl peptidase‐4/CD26 in bullous pemphigoid\n. Acta Dermato Venereol . 2019 ;99 (6 ):602 ‐609\n.\n16 \n\nKasperkiewicz \nM \n. Zillikens D The pathophysiology of bullous pemphigoid\n. Clin Rev Allergy Immunol . 2007 ;33 :67 ‐77\n.18094948 \n17 \n\nUjiie \nH \n, \nMuramatsu \nK \n, \nMushiroda \nT \n, et al. HLA‐DQB1*03:01 as a biomarker for genetic susceptibility to bullous pemphigoid induced by DPP‐4 inhibitors\n. J Invest Dermatol . 2018 ;138 :1201 ‐1204\n.29203362 \n18 \n\nAso \nY \n, \nFukushima \nM \n, \nSagara \nM \n, et al. Sitagliptin, a DPP‐4 inhibitor, alters the subsets of circulating CD4+ T cells in patients with type 2 diabetes\n. Diabetes Res Clin Pract . 2015 ;110 :250 ‐256\n.26508675 \n19 \n\nMuramatsu \nK \n, \nUjiie \nH \n, \nKobayashi \nI \n, et al. Regulatory T‐cell dysfunction induces autoantibodies to bullous pemphigoid antigens in mice and human subjects\n. J Allergy Clin Immunol . 2018 ;142 :1818 ‐1830\n.29704593 \n20 \n\nForssmann \nU \n, \nStoetzer \nC \n, \nStephan \nM \n, et al. Inhibition of CD26/dipeptidyl peptidase IV enhances CCL11/eotaxin‐mediated recruitment of eosinophils in vivo\n. J Immunol . 2008 ;181 :1120 ‐1127\n.18606664\n\n", "fulltext_license": "CC BY", "issn_linking": "2050-0904", "issue": "8(10)", "journal": "Clinical case reports", "keywords": "bullous pemphigoid; dipeptidyl peptidase‐4 inhibitor; type 2 diabetes", "medline_ta": "Clin Case Rep", "mesh_terms": null, "nlm_unique_id": "101620385", "other_id": null, "pages": "2007-2012", "pmc": null, "pmid": "33088540", "pubdate": "2020-10", "publication_types": "D002363:Case Reports", "references": "21466592;30848289;27031194;24404939;30989811;21788636;29274348;26508675;18094948;30090931;29203362;24748908;27186364;29704593;27191539;18606664;30325322;23237497;29427585;27424319", "title": "Bullous pemphigoid associated with dipeptidyl peptidase-4 inhibitor showing unfavorable outcomes despite immediate discontinuation of medication.", "title_normalized": "bullous pemphigoid associated with dipeptidyl peptidase 4 inhibitor showing unfavorable outcomes despite immediate discontinuation of medication" }

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BULLOUS PEMPHIGOID ASSOCIATED WITH DIPEPTIDYL PEPTIDASE-4 INHIBITOR SHOWING UNFAVORABLE OUTCOMES DESPITE IMMEDIATE DISCONTINUATION OF MEDICATION. CLINICAL CASE REPORTS.2020?8(10):2007-2012. 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"patientonsetage": "89", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Pemphigoid", "reactionmeddraversionpt": "23.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Glycosylated haemoglobin increased", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "SHINOHARA Y, IIJIMA T, SAKURAI S, JOJIMA T, OHIRA E, HAYASHI S, ET AL. BULLOUS PEMPHIGOID ASSOCIATED WITH DIPEPTIDYL PEPTIDASE-4 INHIBITOR SHOWING UNFAVORABLE OUTCOMES DESPITE IMMEDIATE DISCONTINUATION OF MEDICATION. CLIN-CASE-REP 2020?8(10):2007-2012.", "literaturereference_normalized": "bullous pemphigoid associated with dipeptidyl peptidase 4 inhibitor showing unfavorable outcomes despite immediate discontinuation of medication", "qualification": "3", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20201110", "receivedate": "20201110", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 18484796, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20210114" }, { "companynumb": "JP-PFIZER INC-2020459011", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "LINAGLIPTIN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "5 MG, 1X/DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": "TYPE 2 DIABETES MELLITUS", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "5", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LINAGLIPTIN" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "MIGLITOL" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", 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BULLOUS PEMPHIGOID ASSOCIATED WITH DIPEPTIDYL PEPTIDASE-4 INHIBITOR SHOWING UNFAVORABLE OUTCOMES DESPITE IMMEDIATE DISCONTINUATION OF MEDICATION. CLINICAL CASE REPORTS. 2020?8(10):2007-2012", "literaturereference_normalized": "bullous pemphigoid associated with dipeptidyl peptidase 4 inhibitor showing unfavorable outcomes despite immediate discontinuation of medication", "qualification": "1", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20201130", "receivedate": "20201124", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 18540879, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210114" }, { "companynumb": "JP-PFIZER INC-2020459012", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "VILDAGLIPTIN" }, "drugadditional": "1", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "100 MG, 1X/DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": "TYPE 2 DIABETES MELLITUS", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "100", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VILDAGLIPTIN" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "AMLODIPINE BESYLATE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": "019787", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "5 MG", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "5", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "AMLODIPINE BESILATE" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "SITAGLIPTIN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "50 MG, 1X/DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": "TYPE 2 DIABETES MELLITUS", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "50", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "SITAGLIPTIN" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "CANDESARTAN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "1 MG", "drugenddate": null, "drugenddateformat": null, "drugindication": "TYPE 2 DIABETES MELLITUS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "1", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CANDESARTAN." } ], "patientagegroup": null, "patientonsetage": "89", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Pemphigoid", "reactionmeddraversionpt": "23.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "SHINOHARA, Y.. BULLOUS PEMPHIGOID ASSOCIATED WITH DIPEPTIDYL PEPTIDASE-4 INHIBITOR SHOWING UNFAVORABLE OUTCOMES DESPITE IMMEDIATE DISCONTINUATION OF MEDICATION.. CLINICAL CASE REPORTS.. 2020?8(10):2007-2012", "literaturereference_normalized": "bullous pemphigoid associated with dipeptidyl peptidase 4 inhibitor showing unfavorable outcomes despite immediate discontinuation of medication", "qualification": "1", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20201130", "receivedate": "20201124", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 18538742, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210114" }, { "companynumb": "JP-TEVA-2020-JP-1846177", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": 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BULLOUS PEMPHIGOID ASSOCIATED WITH DIPEPTIDYL PEPTIDASE-4 INHIBITOR SHOWING UNFAVORABLE OUTCOMES DESPITE IMMEDIATE DISCONTINUATION OF MEDICATION. 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BULLOUS PEMPHIGOID ASSOCIATED WITH DIPEPTIDYL PEPTIDASE-4 INHIBITOR SHOWING UNFAVORABLE OUTCOMES DESPITE IMMEDIATE DISCONTINUATION OF MEDICATION. CLINICAL CASE REPORTS.2020?8(10):2007-2012. DOI: 10.1002/CCR3.3047", "literaturereference_normalized": "bullous pemphigoid associated with dipeptidyl peptidase 4 inhibitor showing unfavorable outcomes despite immediate discontinuation of medication", "qualification": "1", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20201128", "receivedate": "20201128", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 18556431, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210114" }, { "companynumb": "JP-STRIDES ARCOLAB LIMITED-2020SP013384", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": 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null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "50", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "SITAGLIPTIN" } ], "patientagegroup": null, "patientonsetage": "89", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Pemphigoid", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Scar", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Blister", "reactionmeddraversionpt": "23.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Skin lesion", "reactionmeddraversionpt": "23.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Erythema", "reactionmeddraversionpt": "23.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "SHINOHARA Y, IIJIMA T, SAKURAI S, JOJIMA T, OHIRA E, HAYASHI S, ET AL.. BULLOUS PEMPHIGOID ASSOCIATED WITH DIPEPTIDYL PEPTIDASE-4 INHIBITOR SHOWING UNFAVORABLE OUTCOMES DESPITE IMMEDIATE DISCONTINUATION OF MEDICATION. CLINICAL CASE REPORTS. 2020?8(10):2007-2012", "literaturereference_normalized": "bullous pemphigoid associated with dipeptidyl peptidase 4 inhibitor showing unfavorable outcomes despite immediate discontinuation of medication", "qualification": "3", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20201106", "receivedate": "20201106", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 18472981, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210114" } ]

{ "abstract": "Spinal cord trauma can occur during subarachnoid blockade and can result in significant morbidity for the patient. Careful attention to lumbar insertion level is essential to prevent injury.", "affiliations": "From the Department of Anesthesiology, University of Arizona College of Medicine, Tucson, Arizona.;Department of Anesthesiology, Vanderbilt University School of Medicine, Nashville, Tennessee.", "authors": "Palmer|Craig M|CM|;Baysinger|Curtis L|CL|", "chemical_list": null, "country": "United States", "delete": false, "doi": "10.1213/XAA.0000000000000966", "fulltext": null, "fulltext_license": null, "issn_linking": "2575-3126", "issue": "12(11)", "journal": "A&A practice", "keywords": null, "medline_ta": "A A Pract", "mesh_terms": "D000773:Anesthesia, Obstetrical; D000775:Anesthesia, Spinal; D002585:Cesarean Section; D005260:Female; D006801:Humans; D007049:Iatrogenic Disease; D008279:Magnetic Resonance Imaging; D008318:Malpractice; D011247:Pregnancy; D011263:Pregnancy Trimester, Third; D013119:Spinal Cord Injuries; D055815:Young Adult", "nlm_unique_id": "101714112", "other_id": null, "pages": "452-454", "pmc": null, "pmid": "30640276", "pubdate": "2019-06-15", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Spinal Cord Trauma During Subarachnoid Anesthesia for Cesarean Delivery: A Case Report.", "title_normalized": "spinal cord trauma during subarachnoid anesthesia for cesarean delivery a case report" }

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{ "abstract": "BACKGROUND\nNocardia species is known as conditional pathogenic bacteria. Disseminated infection caused by Nocardia species is rare and occurs primarily in immunosuppressed patients. Signs and symptoms of this infection are frequently nonspecific making early diagnosis and treatment difficult.\nWe report a case of subcutaneous and pulmonary nocardiosis due to Nocardia farcinica (N farcinica) in a patient with nephrotic syndrome who is undergoing long-term corticosteroid therapy. In this patient, systemic and pulmonary symptoms (usually found in nocaria infection) such as fever, cough, and expectoration were absent.\nEarly diagnosis was made by pus culture from subcutaneous abscesses and 16S rRNA gene sequencing, which confirm the diagnosis of N farcinica infection.\n\n\nMETHODS\nThe patient was treated with combination therapy of cefatriaxone and trimethoprim-sulfamethoxazole (TMP-SMX) for 2 weeks, and the treatment with TMP-SMX continued to 6 months.\n\n\nRESULTS\nThe abscesses were cured in 4 weeks and a lesion in the upper lobe of left lung resolved in 3 months.\n\n\nCONCLUSIONS\nThis case indicates that disseminated infection due to N farcinica could occur in patients with nephrotic syndrome, even during the period of maintenance therapy with a low-dose corticosteroid and common signs and symptoms of infections could be absent.", "affiliations": "Department of Cardiology Department of Nephrology, The Third Clinical College of Wenzhou Medical University, Wenzhou People's Hospital, Wenzhou, Zhejiang Province, PR China.", "authors": "Zhu|Ning|N|;Zhu|Yuan|Y|;Wang|Yi|Y|;Dong|Shaoshao|S|", "chemical_list": "D000305:Adrenal Cortex Hormones; D000900:Anti-Bacterial Agents; D007166:Immunosuppressive Agents", "country": "United States", "delete": false, "doi": "10.1097/MD.0000000000007211", "fulltext": "\n==== Front\nMedicine (Baltimore)Medicine (Baltimore)MEDIMedicine0025-79741536-5964Wolters Kluwer Health 28614268MD-D-17-0017510.1097/MD.0000000000007211072114900Research ArticleClinical Case ReportPulmonary and cutaneous infection caused by Nocardia farcinica in a patient with nephrotic syndrome A case reportZhu Ning MDa∗Zhu Yuan MDbWang Yi MDaDong Shaoshao MDbOkpechi. Ikechi a Department of Cardiologyb Department of Nephrology, The Third Clinical College of Wenzhou Medical University, Wenzhou People's Hospital, Wenzhou, Zhejiang Province, PR China.∗ Correspondence: Ning Zhu, The Third Clinical College of Wenzhou Medical University, Wenzhou People's Hospital, No. 57 Canghou Street, Wenzhou 325000, Zhejiang Province, PR China (e-mail: zhuningccc@126.com).6 2017 16 6 2017 96 24 e721112 1 2017 13 5 2017 16 5 2017 Copyright © 2017 the Author(s). Published by Wolters Kluwer Health, Inc.2017This is an open access article distributed under the terms of the Creative Commons Attribution-Non Commercial License 4.0 (CCBY-NC), where it is permissible to download, share, remix, transform, and buildup the work provided it is properly cited. The work cannot be used commercially without permission from the journal. http://creativecommons.org/licenses/by-nc/4.0Abstract\nRationale:\nNocardia species is known as conditional pathogenic bacteria. Disseminated infection caused by Nocardia species is rare and occurs primarily in immunosuppressed patients. Signs and symptoms of this infection are frequently nonspecific making early diagnosis and treatment difficult.\n\nPatient concerns:\nWe report a case of subcutaneous and pulmonary nocardiosis due to Nocardia farcinica (N farcinica) in a patient with nephrotic syndrome who is undergoing long-term corticosteroid therapy. In this patient, systemic and pulmonary symptoms (usually found in nocaria infection) such as fever, cough, and expectoration were absent.\n\nDiagnoses:\nEarly diagnosis was made by pus culture from subcutaneous abscesses and 16S rRNA gene sequencing, which confirm the diagnosis of N farcinica infection.\n\nInterventions:\nThe patient was treated with combination therapy of cefatriaxone and trimethoprim-sulfamethoxazole (TMP-SMX) for 2 weeks, and the treatment with TMP-SMX continued to 6 months.\n\nOutcomes:\nThe abscesses were cured in 4 weeks and a lesion in the upper lobe of left lung resolved in 3 months.\n\nLessons:\nThis case indicates that disseminated infection due to N farcinica could occur in patients with nephrotic syndrome, even during the period of maintenance therapy with a low-dose corticosteroid and common signs and symptoms of infections could be absent.\n\nKeywords\nnephrotic syndromeNocardia farcinicapulmonary and cutaneous infectionOPEN-ACCESSTRUE\n==== Body\n1 Introduction\nNocardia infections are uncommon and occur mostly in patients receiving immunosuppressive therapy, organ transplant recipients, or patients infected with human immunodeficiency virus (HIV).[1–3] Recognition of clinical isolates is vital because Nocardia species differ in the clinical spectrum of the disease they can cause and their susceptibility to antimicrobial agents.[4] Patients with nephrotic syndrome are at a high risk of infections, for example, Cryptococcus,[5] cytomegalovirus,[6] toxoplasmosis,[7] often augmented by the need for immunosuppressive therapy. Here, we present an unusual case of Nocardia farcinica in a patient with nephrotic syndrome on long-term corticosteroid therapy.\n\n1.1 Case presentation\nThis case report has been approved by the ethics committee of Wenzhou People's Hospital. A 60-year-old man was admitted to Wenzhou People's Hospital with a 1-week history of a subcutaneous abscess on his left lower limb. He reported no constitutional symptoms or cough and had not incurred any trauma to his leg. On admission, the patient was tachycardic but not in septic shock and had a normal systems examination. The largest subcutaneous abscess on his left lower limb was 9 cm∗10 cm and was warm and tender with intact overlying skin. He later developed further abscesses on his buttock, which were 3 cm∗3 cm in diameter.\n\nThe patient had a background history of idiopathic membranous nephropathy diagnosed on renal 14 months before admission. He was initially treated with oral methylprednisolone and Tacrolimus and achieved a complete remission. However, he later relapsed and was treated with intravenous (IV) methylprednisolone and oral Tacrolimus. Due to a lack of clinical response cyclophosphamide, he was started on oral Cyclophosphamide with an accumulated dosage of approximately 8 g. Subsequently, his renal disease was stable and the dose of oral methylprednisolone was slowly tapered down.\n\nOn blood tests, the total white cell count was 8.4 x 10^9/L with 85.5% neutrophils and 8.1% lymphocytes. The subset of lymphocytes was almost normal: CD3+ 72.5%, CD4+ 28.6%, CD8+ 41.9%, CD4+/CD8+ 0.68, CD19+ 4.7%. His erythrocyte sedimentation rate (ESR) was elevated at 113 mm/h and C-reactive protein (CRP) was mildly elevated at 12.2 mg/L. He was found to still be nephrotic: 24-hour urine protein was raised at 8.23 g low serum albumin 18.4 g/L and cholesterol with mild renal impairment (creatinine 131 μmol/L). A computed tomography (CT) brain scan was normal while patient's pulmonary CT scan showed an inflammatory nodule in the upper lobe of left lung (Figure 1A). Ultrasound of abscesses revealed subcutaneous anechoic lesions. Blood cultures were sterile.\n\nFigure 1 Changes of the lesion after treatments. (A) The lesion in the upper lobe of left lung. (B) The lesion after treatment with TMP-SMX for 4 weeks. (C) The lesion disappeared following treatment for 4 months.\n\nThe abscesses were drained and the patient was empirically treated with IV penicillin and oral trimethoprim-sulfamethoxazole (TMP-SMX). Culture subsequently yielded Nocardia, later identified as N farcinica on rRNA gene sequencing (Figure 2). Combination therapy of IV cefatriaxone (2 g/day) and oral TMP-SMX (1.92 g/d) was used according to drug sensitivity. The patient's inflammatory markers and clinical state improved and IV ceftriaxone was stopped after a 2 weeks oral. After 4 weeks, the subcutaneous abscesses disappeared and the lesion in the upper lobe of left lung had improved (Figure 1B). The patient was discharged on a 5-month course of oral TMP-SMX therapy. Oral methylprednisolone was stopped 2 months later and his nephrotic syndrome had improved. A follow-up CT after 3 months showed that the lesion in the upper lobe of left lung completely disappeared (Figure 1C) and his renal disease was stable.\n\nFigure 2 Gene sequence of N farcinica identified from the pus.\n\n2 Discussion\nNocardia farcinica is a gram-positive, partially acid-fast, methenamine silver-positive aerobic actinomycete.[8] The genus-Nocardia contains more than 100 species that have been identified by phenotypic and molecular methods and 16S RNA gene sequencing. Nocardiae are common in the environment and can be found worldwide in water, soil, dust, decaying vegetation, and organic matter. After inhalation or percutaneous inoculation, particularly in immunocompromised hosts, Nocardia can induce multisystem infection that can be life-threatening.[9]\n\nN farcinica is characterized by higher pathogenicity [10] and also known to be resistant to multiple antibiotics.[11] Timely diagnosis of the infection is important, as appropriate treatment can be lifesaving.\n\nOn the whole, early diagnosis of N farcinica infections remain a challenge and treatment is often empiric. This patient's clinical presentation was atypical.[12] This may be explained by long-term corticosteroid therapy masking the symptoms and signs of infection. Because of the absence of history of percutaneous inoculation, it was assumed that the patient may had inhaled N farcinica initially with dissemination to the skin. The patient's blood cultures were negative, which is consistent with literature, as blood cultures for patients with Nocardia infection are rarely positive.[13] Therefore, other tests, in this case the pus culture and gene sequencing, are necessary for diagnosis.\n\nStandard treatment for this infection includes Ceftriaxone, Cefotaxime and, more commonly, TMP-SMX. Sulfonamides have been extensively used, with good outcomes; however, some strains of Nocardia, including N farcinica, may be resistant.[13,14] Although the duration of therapy required remains controversial, reports in the literature recommend 6 months to 1 year in disseminated Nocardiosis.[15] In our case, the patient received the treatment of TMP-SMX for 6 months and was completely cured.\n\nIn conclusion, this is the first report of pulmonary and cutaneous infection caused by N farcinica in a patient with nephrotic syndrome. Our case highlights that even on maintenance immunosuppression, patients can develop opportunistic infections such as Nocardia and can present atypically. Early diagnosis and treatment is the key to curing such patients, which may also avoid prolonged antimicrobial therapy.\n\nAbbreviations: N farcinica = Nocardia farcinica, TMP-SMX = trimethoprim-sulfamethoxazole.\n\nThe authors confirm that there are no conflicts of interests.\n==== Refs\nReferences\n[1] Ambrosioni J Lew D Garbino J \nNocardiosis: updated clinical review and experience at a tertiary center . Infection \n2010 ;38 :89 –97 .20306281 \n[2] Lebeaux D Morelon E Suarez F \nNocardiosis in transplant recipients . Eur J Clin Microbiol Infect Dis \n2013 ;33 :689 –702 .24272063 \n[3] Anderson M Kuz ’niar TJ \nPulmonary nocardiosis in a patient with chronic obstructive pulmonary disease; case report and literature review . Pol Pneumonol Allergol \n2012 ;80 :565 –9 .\n[4] Beaman BL Beaman L \nNocardia farcinica bacteraemia presenting as a prostate abscess . Clin Microbiol Rev \n1994 ;7 :213 –64 .8055469 \n[5] Liu Y Qunpeng H Shutian X \nFatal primary cutaneous cryptococcosis: case report and review of published literature . Ir J Med Sci \n2016 ;185 :959 –63 .26246081 \n[6] Lopez-Lluva MT de la Nieta-Garcia MD Piqueras-Flores J \nChlorambucil-induced cytomegalovirus infection: a case report . J Med Case Rep \n2014 ;8 :280 .25142684 \n[7] Barrios JE Duran Botello C Gonzalez Velasquez T \nNephrotic syndrome with a nephritic component associated with toxoplasmosis in an immunocompetent young man . Colomb Med (Cali) \n2012 ;43 :226 –9 .24893197 \n[8] Boamah H Puranam P Sandre RM \nDisseminated Nocardia farcinica in an immunocompetent patient . IDCases \n2016 ;6 :9 –12 .27617207 \n[9] Schiff TA McNeil MM Brown JM \nCutaneous Nocardia farcinica infection in a nonimmunocompromised patient: case report and review . Clin Infect Dis \n1993 ;16 :756 –60 .8329506 \n[10] Torres OH Domingo P Pericas R \nInfection caused by Nocardia farcinica: case report and review . Eur J Clin Microbiol Infect Dis \n2000 ;19 :205 –12 .10795594 \n[11] Anil KV Deepthi A Dilip P \nNocardia farcinica brain abscess: epidemiology pathophysiology, and literature review . Surg Infect \n2014 ;15 :640 –6 .\n[12] Coussement J Lebeaux D van Delden C \nNocardia infection in solid organ transplant recipients: a multicenter European case-control study . Clin Infect Dis \n2016 ;63 :338 –45 .27090987 \n[13] Peters BR Saubolle MA Costantino JM \nDisseminated and cerebral infection due to Nocardia farcinica: diagnosis by blood culture and cure with antibiotics alone . Clin Infect Dis \n1996 ;23 :1165 –7 .8922819 \n[14] Wilson JW \nNocardiosis: updates and clinical overview . Mayo Clin Proc \n2012 ;87 :403 –7 .22469352 \n[15] Menéndez R1 Cordero PJ Santos M \nPulmonary infection with Nocardia species: a report of 10 cases and review . Eur Respir J \n1997 ;10 :1542 –6 .9230244\n\n", "fulltext_license": "CC BY-NC", "issn_linking": "0025-7974", "issue": "96(24)", "journal": "Medicine", "keywords": null, "medline_ta": "Medicine (Baltimore)", "mesh_terms": "D000305:Adrenal Cortex Hormones; D000900:Anti-Bacterial Agents; D042241:Early Diagnosis; D006801:Humans; D007166:Immunosuppressive Agents; D008171:Lung Diseases; D008297:Male; D008875:Middle Aged; D009404:Nephrotic Syndrome; D009617:Nocardia Infections; D017192:Skin Diseases, Bacterial", "nlm_unique_id": "2985248R", "other_id": null, "pages": "e7211", "pmc": null, "pmid": "28614268", "pubdate": "2017-06", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Pulmonary and cutaneous infection caused by Nocardia farcinica in a patient with nephrotic syndrome: A case report.", "title_normalized": "pulmonary and cutaneous infection caused by nocardia farcinica in a patient with nephrotic syndrome a case report" }

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PULMONARY AND CUTANEOUS INFECTION CAUSED BY NOCARDIA FARCINICA IN A PATIENT WITH NEPHROTIC SYNDROME: A CASE REPORT. MEDICINE. 2017;96 (24):E7211", "literaturereference_normalized": "pulmonary and cutaneous infection caused by nocardia farcinica in a patient with nephrotic syndrome a case report", "qualification": "1", "reportercountry": "CN" }, "primarysourcecountry": "CN", "receiptdate": "20170719", "receivedate": "20170719", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 13768314, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": 1, "seriousnessother": null, "transmissiondate": "20171127" } ]

{ "abstract": "Chemotherapeutic induction of radiation recall (RR) is a rare event in which a chemotherapeutic agent given days to years after radiation therapy causes an inflammation reaction of the tissues within the irradiated area-\"recalling\" increased radiation effects to that area. In this unique case, a 14-year-old girl with a synovial sarcoma of the forearm was treated with neoadjuvant chemotherapy and radiation therapy. Gemcitabine was administered in an adjuvant setting inducing a RR reaction. The severity of the inflammation resulted in a forearm myositis secondarily causing a compartment syndrome that was treated with several prolonged courses of corticosteroids. The symptoms of RR and compartment syndrome have resolved 1 year postonset, although magnetic resonance imaging continues to show myositis and soft-tissue edema. This case highlights the need to maintain a heightened awareness to recognizing the signs and symptoms of RR and the potential severity of RR in pediatric cancer patients in conjunction with chemotherapeutic agents used more frequently in adults.", "affiliations": "Department of Medicine, David Geffen School of Medicine, UCLA, Los Angeles, CA, USA.", "authors": "Eckardt|Mark A|MA|;Bean|Adrienne|A|;Selch|Michael T|MT|;Federman|Noah|N|", "chemical_list": "D000964:Antimetabolites, Antineoplastic; D003841:Deoxycytidine; C056507:gemcitabine", "country": "United States", "delete": false, "doi": "10.1097/MPH.0b013e31827e4c28", "fulltext": null, "fulltext_license": null, "issn_linking": "1077-4114", "issue": "35(2)", "journal": "Journal of pediatric hematology/oncology", "keywords": null, "medline_ta": "J Pediatr Hematol Oncol", "mesh_terms": "D000293:Adolescent; D000964:Antimetabolites, Antineoplastic; D003131:Combined Modality Therapy; D003161:Compartment Syndromes; D003841:Deoxycytidine; D005260:Female; D006801:Humans; D011855:Radiodermatitis; D013584:Sarcoma, Synovial", "nlm_unique_id": "9505928", "other_id": null, "pages": "156-61", "pmc": null, "pmid": "23274380", "pubdate": "2013-03", "publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't", "references": null, "title": "A child with gemcitabine-induced severe radiation recall myositis resulting in a compartment syndrome.", "title_normalized": "a child with gemcitabine induced severe radiation recall myositis resulting in a compartment syndrome" }

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A CHILD WITH GEMCITABINE INDUCED SEVERE RADIATION RECALL MYOSITIS RESULTING IN A COMPARTMENT SYNDROME. 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"drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "GEMCITABINE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "IFOSFAMIDE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "IFOSFAMIDE." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Infection", "reactionmeddraversionpt": "17.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Cardiac tamponade", "reactionmeddraversionpt": "17.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Sepsis", "reactionmeddraversionpt": "17.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Disease progression", "reactionmeddraversionpt": "17.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Recall phenomenon", "reactionmeddraversionpt": "17.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Deep vein thrombosis", "reactionmeddraversionpt": "17.1", "reactionoutcome": "6" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 200305" } }, "primarysource": { "literaturereference": "ECKARDT MA, BEAN A, SELCH MT, FEDERMAN N. A CHILD WITH GEMCITABINE-INDUCED SEVERE RADIATION RECALL MYOSITIS RESULTING IN A COMPARTMENT SYNDROME. J PEDIATRIC HEMATOLOGY/ ONCOLOGY. 2013;35:156-61", "literaturereference_normalized": "a child with gemcitabine induced severe radiation recall myositis resulting in a compartment syndrome", "qualification": null, "reportercountry": "COUNTRY NOT SPECIFIED" }, "primarysourcecountry": "US", "receiptdate": "20140925", "receivedate": "20140925", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 10474663, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20150326" } ]

{ "abstract": "We describe a case of tinnitus occurred during a bleomycin monotherapy for Kaposi's sarcoma.", "affiliations": "Centre Régional de Pharmacovigilance d'Amiens, Amiens, France.;Service de Dermatologie, Centre Hospitalier Universitaire, Amiens, France.;Centre Régional de Pharmacovigilance d'Amiens, Amiens, France.", "authors": "Laschinski|Bérengère|B|;Arnault|Jean-Philippe|JP|;Gras-Champel|Valérie|V|", "chemical_list": "D000903:Antibiotics, Antineoplastic; D001761:Bleomycin", "country": "France", "delete": false, "doi": "10.2515/therapie/2015039", "fulltext": null, "fulltext_license": null, "issn_linking": "0040-5957", "issue": "70(6)", "journal": "Therapie", "keywords": null, "medline_ta": "Therapie", "mesh_terms": "D000368:Aged; D000903:Antibiotics, Antineoplastic; D001761:Bleomycin; D015496:CD4-Positive T-Lymphocytes; D006801:Humans; D007676:Kidney Failure, Chronic; D008231:Lymphopenia; D008297:Male; D012514:Sarcoma, Kaposi; D012878:Skin Neoplasms; D014012:Tinnitus", "nlm_unique_id": "0420544", "other_id": null, "pages": "539-40", "pmc": null, "pmid": "26220920", "pubdate": "2015", "publication_types": "D002363:Case Reports; D004740:English Abstract; D016422:Letter; D016454:Review", "references": null, "title": "Tinnitus in a Patient Treated by Bleomycin for Kaposi's Sarcoma.", "title_normalized": "tinnitus in a patient treated by bleomycin for kaposi s sarcoma" }

[ { "companynumb": "FR-FRESENIUS KABI-FK201504205", "fulfillexpeditecriteria": "1", "occurcountry": "FR", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "BLEOMYCIN SULFATE" }, "drugadditional": null, "drugadministrationroute": "030", "drugauthorizationnumb": "065185", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "INJECTION", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "KAPOSI^S SARCOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "2", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "201406", "drugstartdateformat": "610", "drugstructuredosagenumb": "15", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BLEOMYCIN" } ], "patientagegroup": null, "patientonsetage": "65", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Tinnitus", "reactionmeddraversionpt": "18.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Flagellate dermatitis", "reactionmeddraversionpt": "18.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Nail discolouration", "reactionmeddraversionpt": "18.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "LASCHINSKI B,ARNAULT J,GRAS-CHAMPEL V. TINNITUS IN A PATIENT TREATED BY BLEOMYCIN FOR KAPOSI^S SARCOMA.. THERAPIE. 2015 JUL 28;.", "literaturereference_normalized": "tinnitus in a patient treated by bleomycin for kaposi s sarcoma", "qualification": "3", "reportercountry": "FR" }, "primarysourcecountry": "FR", "receiptdate": "20150903", "receivedate": "20150903", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 11456149, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20151125" } ]

{ "abstract": "Natalizumab (Tysabri) is a monoclonal antibody (α4 integrin antagonist) approved for treatment of multiple sclerosis, both for patients who fail therapy with other disease modifying agents and for patients with aggressive disease. Natalizumab is highly effective, resulting in significant decreases in rates of both relapse and disability accumulation, as well as marked decrease in MRI evidence of disease activity. As such, utilization of natalizumab is increasing, and the presentation of its associated complications is increasing accordingly. This review focuses on the clinical and neuroimaging features of the major complications associated with natalizumab therapy, focusing on the rare but devastating progressive multifocal leukoencephalopathy (PML). Associated entities including PML associated immune reconstitution inflammatory syndrome (PML-IRIS) and the emerging phenomenon of rebound of MS disease activity after natalizumab discontinuation are also discussed. Early recognition of neuroimaging features associated with these processes is critical in order to facilitate prompt diagnosis, treatment, and/or modification of therapies to improve patient outcomes.", "affiliations": "Division of Neuroradiology, University of Colorado School of Medicine, 12700 E 19th Avenue Mail Stop C278, Aurora, CO 80045, USA.;Division of Neuroradiology, University of Colorado School of Medicine, 12700 E 19th Avenue Mail Stop C278, Aurora, CO 80045, USA.;Division of Neuroradiology, University of Colorado School of Medicine, 12700 E 19th Avenue Mail Stop C278, Aurora, CO 80045, USA.", "authors": "Honce|Justin M|JM|;Nagae|Lidia|L|;Nyberg|Eric|E|", "chemical_list": null, "country": "Egypt", "delete": false, "doi": "10.1155/2015/809252", "fulltext": "\n==== Front\nMult Scler IntMult Scler IntMSIMultiple Sclerosis International2090-26542090-2662Hindawi Publishing Corporation 10.1155/2015/809252Review ArticleNeuroimaging of Natalizumab Complications in Multiple Sclerosis: PML and Other Associated Entities Honce Justin M. \n*\nNagae Lidia Nyberg Eric Division of Neuroradiology, University of Colorado School of Medicine, 12700 E 19th Avenue Mail Stop C278, Aurora, CO 80045, USA*Justin M. Honce: justin.honce@ucdenver.eduAcademic Editor: Martin Stangel\n\n2015 21 9 2015 2015 80925212 6 2015 14 8 2015 31 8 2015 Copyright © 2015 Justin M. Honce et al.2015This 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.Natalizumab (Tysabri) is a monoclonal antibody (α4 integrin antagonist) approved for treatment of multiple sclerosis, both for patients who fail therapy with other disease modifying agents and for patients with aggressive disease. Natalizumab is highly effective, resulting in significant decreases in rates of both relapse and disability accumulation, as well as marked decrease in MRI evidence of disease activity. As such, utilization of natalizumab is increasing, and the presentation of its associated complications is increasing accordingly. This review focuses on the clinical and neuroimaging features of the major complications associated with natalizumab therapy, focusing on the rare but devastating progressive multifocal leukoencephalopathy (PML). Associated entities including PML associated immune reconstitution inflammatory syndrome (PML-IRIS) and the emerging phenomenon of rebound of MS disease activity after natalizumab discontinuation are also discussed. Early recognition of neuroimaging features associated with these processes is critical in order to facilitate prompt diagnosis, treatment, and/or modification of therapies to improve patient outcomes.\n==== Body\n1. Introduction\nNatalizumab is a monoclonal antibody directed against the α4β1 and α4β7 integrins, approved for therapy in relapsing remitting multiple sclerosis [1]. The drug prevents inflammatory cells from binding to cerebrovascular endothelial cells, thereby preventing them from crossing the blood brain barrier and entering the brain [1, 2], resulting in profound immunosuppression within the CNS (Figure 1). This blockade is a highly effective therapy for multiple sclerosis, with placebo controlled studies demonstrating up to a 68% reduction in clinical relapse rates, 42% reduced risk of sustained progressive disability, 92% fewer gadolinium enhancing lesions, and an 83% decrease in the accumulation of new or enlarging T2 hyperintense white matter lesions [3–5]. Up to 37% of patients appear completely free of clinical and radiological disease activity while on therapy over 2 years [6]. Given its clinical efficacy, utilization of natalizumab has rapidly increased, with approximately 134,800 MS patients receiving or having received the drug as of March 2015 (https://medinfo.biogen.com/, accessed June 2015). With increasing utilization of natalizumab, radiologists and neurologists are more likely to encounter its complications in clinical practice, and prompt recognition of these complications is critical for optimal management.\n\nThe overall incidence of adverse events associated with natalizumab is low. Infusion and allergic reactions have been reported in small groups of patients but are managed efficiently with corticosteroids [7]. Hepatic injuries have been reported to occur after the first infusion, though they are not common [8, 9]. Several cases of melanoma have been reported in patients on natalizumab [10–12], but incidence appears similar between placebo and natalizumab and there is insufficient evidence to support a definitive link to natalizumab [11, 13, 14]. There have been 6 reported cases of CNS lymphoma in patients treated with natalizumab [15–19]. However, two of these patients may have had preexisting lymphoma and at least one was negative for EBV, suggesting that these lymphomas may not have been caused by natalizumab therapy, though potentiation of progression is not excluded [16, 20].\n\nThe primary complication of natalizumab therapy is progressive multifocal leukoencephalopathy (PML). Rapid drug removal, usually by plasma exchange (PLEX), may contribute to improved patient survival, but early diagnosis is crucial [21–23]. Unfortunately, despite successful management of PML, PML associated immune reconstitution inflammatory syndrome (PML-IRIS) may occur resulting in a paradoxical worsening of symptoms. The IRIS phenomenon is not limited to PML treatment and is emerging in a subset of patients upon cessation of natalizumab therapy for other reasons who experience exuberant rebound of MS disease activity after natalizumab discontinuation. These three phenomena, PML, PML-IRIS, and natalizumab rebound, each have significant negative effects on patient morbidity and mortality and are the main focus of this review. Early recognition of the spectrum of clinical and imaging findings is crucial in order to limit their devastating impact.\n\n2. PML: Background\nPML is an opportunistic infection of the brain caused by the JC virus, affecting severely immunosuppressed patients with impaired T-lymphocyte responses [24]. Early investigations of PML-infected brains demonstrated that the JC virus predominantly infects myelin-producing oligodendrocytes resulting in severe irreversible demyelination [25, 26]. While oligodendrocytes are the primary site of CNS infection, the virus has also been detectable in astrocytes [27] and cell loss in the granule layer of the cerebellum and neuronal infections have been reported [28–30]. JCV viral infection is widespread, with serum antibodies against JC virus detectable in as much as 80% of the population [31]. PML may result from reactivation of latent JC virus infection in the brain [26] or spread from peripheral reservoirs in the kidneys [32] and bone marrow [33] to the brain during immunosuppression.\n\nPML was originally reported in rare association with lymphoma. As HIV emerged, the incidence of PML also increased, with up to 5% of AIDS patients contracting the disease [34]. PML has also been reported in patients with rheumatic diseases such as lupus, those receiving organ transplants and patients taking immunosuppressive therapies such as alkylating agents, purine analogues, and monoclonal antibodies [35]. Besides natalizumab, PML has recently been reported in two MS patients treated with fingolimod [36] and one patient treated with tecfidera [37] without prior exposure to other immunosuppressants. PML has also been reported in 3 patients receiving dimethyl fumarate (DMF), both with and without lymphopenia [38–40]. While these patients were being treated for psoriasis, not MS, DMF is also used in the treatment of MS, necessitating vigilant monitoring for PML in this patient group as well.\n\n3. Natalizumab and PML\nThree cases of PML were reported in patients being treated with natalizumab, soon after introduction of the drug in the US market in 2004. Two of the cases occurred in MS patients and one in a patient being treated for Crohn's disease [41–43]. In February 2005 clinical trials and commercial dosing were voluntarily suspended due to these three cases. In July 2006, however, the drug was reintroduced, with additional precautions, when studies demonstrated no new cases of PML in previously treated patients [44]. These new precautions included mandatory risk mitigation and restriction to RRMS patients with high disease activity. Despite these new precautions, three additional cases of natalizumab associated PML were identified by 2008 and, since then, the number of reported PML cases has steadily risen, with 42 cases by March 2010, 372 cases by June 2013, and 566 confirmed cases as of June 2015 (https://medinfo.biogen.com/, accessed July 2015). The actual number of PML infections may be even higher as PML is frequently underdiagnosed as many PML cases may be missed or misclassified. The global overall risk of PML for patients on natalizumab therapy is estimated to be 3.96 per 1000 patients (95% CI 3.64–4.30) (https://medinfo.biogen.com/, accessed July 2015). The presence of JC virus antibodies in the blood of MS patients is a risk factor for PML development, stratified by the JVC antibody index: an index >0.4 indicates positivity and <0.2 indicates negativity, while an index between 0.2 and 0.4 denotes an indeterminate response [45]. The estimated incidence for MS patients who test negative (index < 0.2) for JC virus antibody is extremely low, less than 0.11 per 1000 (95% CI 0.00–0.59), and reaches 5.55 per 1000 (95% CI 5.34–6.42) in those testing positive (index > 0.4) without other risk factors. The risk of PML increases with longer treatment duration, peaking at 24 months with a risk of 6.11 per 1000 (95% CI 5.35–6.47). A prior history of immunosuppressant use [35] further increases risk, reaching a maximum incidence of 13 per 1000 in JCV-Ab + patients on natalizumab greater than 49 months and with prior immunosuppressive therapy exposure (https://medinfo.biogen.com/, accessed July 2015).\n\n4. Natalizumab and PML: Prognosis\nThe mortality rate in natalizumab associated PML is approximately 22% [46]. This is considerably lower than the more common HIV-AIDS associated form, which has been reported in up to 40–50% in the HAART era [23, 46]. Those who survive, however, usually suffer from significant disability with 90% of patients having moderate or severe disability per Karnofsky Performance Scale (KPS) scores 6 months after diagnosis (https://medinfo.biogen.com/, accessed July 2015). Mortality rates are higher in patients who are older and have poorer baseline function related to the severity of MS and in those in whom diagnosis was delayed [23]. The presence or absence of symptoms at the time of diagnosis appears to be an important prognostic factor. Asymptomatic patients demonstrate significantly lower mean Expanded Disability Status Scale (EDSS) scores, higher mean KPS scores, and improved survival compared with symptomatic patients [47].\n\n5. Natalizumab and PML: Clinical Features\nThe clinical presentation of PML is heterogeneous and may include focal and nonfocal neurologic deficits affecting neurobehavioral, motor, language, and visual functions [21, 48]. Cognitive deficits are not surprisingly the most common, given the widely distributed nature of cognitive function throughout the brain and the already compromised neural condition of MS patients. Although quite rare, brain stem involvement causes the most severe symptoms. While PML can be detected in patients who are asymptomatic [47, 49], the earliest symptoms attributable to PML are usually nonspecific and subtle and may be misinterpreted as exacerbations of multiple sclerosis, related to depression or may be missed entirely [50]. Symptoms in the mid and later stages of the disease can be mistakenly diagnosed as stroke or seizure disorders, and seizures have been reported in up to 20% of patients with PML [51]. Therefore, PML should be considered in the differential diagnosis of any MS patient taking natalizumab presenting with new neurologic symptoms. As the name implies, the disease is progressive and symptoms worsen over time. Moreover, if this entity is not recognized and diagnosis is delayed, symptom progression may accelerate.\n\n6. PML: Surveillance and Diagnosis\nConfident diagnosis of PML is achieved through a combination of clinical features, characteristic imaging findings, laboratory testing, and histopathology as outlined in the recently proposed case definition for natalizumab associated PML and in the AAN consensus statement on PML diagnostic criteria [52, 53]. These guidelines emphasize that the highest level of diagnostic certainty requires histopathologic confirmation but that the presence of clinical and/or imaging findings in combination with JCV DNA in the CSF is also diagnostic. These criteria not only provide some certainty to the diagnosis, but also serve as a guideline on what further testing could be obtained to achieve a more conclusive diagnosis.\n\nCurrently there is no consensus on how frequently surveillance MRI should be performed to monitor for PML, with some suggesting scanning up to every 3-4 months [54]. When PML is suspected clinically, timely MRI imaging and cerebrospinal fluid sampling with polymerase chain reaction (PCR) testing for JC virus DNA should be performed to confirm diagnosis. PCR for JCV DNA in the CSF has a reported sensitivity of 80% and specificity of 90% [55].\n\nNegative CSF PCR for JCV does not exclude PML as viral loads can be very low (<100 copies/mL), and most commercial tests are only able to detect JCV DNA in excess of 200 copies/mL [21, 56]. Patients with repeatedly negative CSF JCV PCR can nevertheless demonstrate MR imaging suggestive of PML [22, 44, 52, 57]. A recently proposed test to help confirm the diagnosis of PML in such cases relies on the elevation of anti-JCV IgG antibodies in the CSF and the calculation of the CSF JCV antibody index: an index of >1.5 was 100% specific and 57% sensitive for the diagnosis of PML in these cases [56]. In difficult cases where the clinical, radiologic, or laboratory findings are inconclusive, brain biopsy can also be performed [53].\n\n7. PML: Imaging Features\nCT imaging abnormalities in patients with PML have been described, generally demonstrating multiple areas of low attenuation with scalloped borders in the peripheral and subcortical white matter, with these areas coalescing as the disease progresses [58].\n\nIn the current era, MRI has supplanted CT as the modality of choice for the diagnosis of PML. PML characteristically presents as one or more areas of T2/FLAIR hyperintensity in the white matter in a peripheral, bilateral, but asymmetric distribution. Lesions vary in shape and size, growing larger and becoming confluent as the disease progresses. Lesions classically involve the subcortical U-fibers in nearly all cases [59]. This subcortical involvement leads to a sharp border between the superficial aspect of the lesion and the overlying cortex, while the deeper border remains ill defined (Figure 2). Involvement of the overlying cortex, while originally thought to be rare, has been increasingly reported [59–63]. As the disease is usually peripheral, the periventricular white matter is typically spared [48]; however, the periventricular location does not preclude the possibility of PML (Figure 3(a)).\n\nOn T1 weighted imaging lesions become increasingly hypointense, as irreversible white matter destruction occurs [44, 48, 59]. T2-weighted imaging may demonstrate a “microcyst” or “granular” pattern, especially in larger lesions [48, 59]. This finding has been suggested to represent small areas of demyelination which occur in the immediate vicinity of infected oligodendrocytes or early immune response within perivascular spaces [59] (Figure 3(b)).\n\nThe regular use of MRI imaging in MS patients may be able to detect the disease very early before the patients become symptomatic [49, 64–67]. Imaging at these stages typically shows hazy, typically hyperintense T2 signal in the juxtacortical white matter and usually involves the U-fibers, most commonly in a single lobe. The lesions may not be as focal as a typical MS relapse and generally do not enhance while the patient is asymptomatic (Figures 4(a) and 4(b)). Gray matter involvement may be present in up to 83%. 60% of asymptomatic patients have lesions which show high signal intensity on DWI [67].\n\nIn the supratentorial brain the parietal, occipital, and frontal lobes are the most frequently involved. Like other aggressive infiltrating lesions, PML can infiltrate the corpus callosum, though isolated corpus callosal involvement is rare (Figures 4(d) and 4(f)). Deep gray matter involvement has been reported in conjunction with white matter lesions in up to 5–31% of patients in some series [48, 68, 69]. The thalami are more commonly involved than the basal ganglia. Cortical involvement is increasingly recognized as well. In the early stages of the disease there is typically no mass effect; however, as lesions progress mild mass effect can develop. The degree of mass effect appears mild compared to the extent of disease (Figures 4(d) and 4(e)).\n\nPosterior fossa involvement is frequently reported, most commonly involving the cerebellum and middle cerebellar peduncles, although the brainstem can also be involved [70]. “Crescent” shaped lesions involving middle cerebellar peduncles and adjacent cerebellar and/or pontine white matter may be specific to PML, rather than MS, as they have so far only been reported in PML patients (Figure 5) [48, 70–73]. The optic nerve and spinal cord are spared. Hemorrhage is a rare finding that has been reported on occasion in the literature for HIV patients taking natalizumab [74] and is rarely seen in PML [41].\n\nThe incidence of contrast enhancement at initial diagnostic imaging in natalizumab associated PML is higher than that in HIV populations, with up to 43% of natalizumab symptomatic PML cases reporting contrast enhancement at diagnosis [21], compared with 15% in HIV populations [25]. The pattern of enhancement is variable and may be patchy, linear, nodular, or peripheral and in some cases demonstrates a perivascular pattern [75]. Enhancement at time of diagnosis is correlated with decreased survival and greater clinical disability than those that do not enhance [76]. Enhancement suggests that in this subset of patients natalizumab associated PML involves an inflammatory response to the JCV infection, despite the immunosuppression provided by the drug. Therefore, new enhancing lesions on MRI in patients on natalizumab should not necessarily be assumed to be MS relapse [21].\n\n8. Diffusion Imaging\nConventional T2-weighted and T2 FLAIR imaging is sensitive to increased water in brain tissue. However, T2 does not differentiate between cytotoxic processes resulting in intracellular edema, for example, in the setting of cell injury or death, and vasogenic interstitial edema. Diffusion weighted MR imaging (DWI), however, is highly sensitive to the restriction of Brownian diffusion of water molecules which occurs in the setting of cellular injury and cytotoxic edema [77]. The DWI appearance of PML lesions varies depending on the stage of the disease. Early in the course of the disease when lesions are relatively small, infected oligodendrocytes swell and die, resulting in high signal on DWI [78]. As the lesions enlarge the signal on DWI remains high within the peripheral as new oligodendrocytes become infected [78–80] (Figure 6). As treatment is initiated and the lesions become quiescent, the rim loses its DWI hyperintensity (Figure 7). Over time, the more typical appearance of low signal on DWI develops due to later phases of tissue destruction and compromise of the blood brain barrier resulting in relatively free diffusion of water within the damaged tissue [81]. Pathologic correlation has suggested that this lesion core corresponds to areas of dead and shrunken oligodendrocytes, bizarre astrocytes, and numerous macrophages and indicates irreversibly destroyed white matter [78]. Since the T1 and T2 signal changes associated with PML are in general irreversible, DWI is an essential tool for monitoring disease progression and treatment response [81–85].\n\nDiffusion tensor imaging (DTI) has emerged as a useful imaging modality for detection of microstructural changes in the white matter, including myelination, and assessing white matter integrity [83]. In PML fractional anisotropy (FA) values are reduced, compatible with myelin injury. These changes occur very early in the disease and may detect PML before conventional imaging shows abnormalities [79]. As white matter injury progresses ADC values rise [81, 86], compatible with more irreversible damage.\n\n9. MR Spectroscopy\nMRS in PML lesions typically demonstrates lower levels of N-acetylaspartate, elevated levels of choline (Cho), and variable myoinositol levels. Spectra differ somewhat between the center and periphery of the lesion and depend on the phase of disease. In general, the periphery of the lesion demonstrates greater increases in Cho and less notable decreases in NAA than in the center of the lesion. This corresponds to more active demyelination peripherally and more advanced neuronal destruction centrally [87–89]. Unfortunately MRS findings in PML are nonspecific, with similar spectra seen in multiple other types of CNS lesions, including malignancies and MS plaques.\n\n10. PML: Differential Diagnoses\nIt is important to consider the differential diagnosis for new MRI findings in MS patients receiving natalizumab as this will affect treatment decisions. JCV infection is the most common opportunistic infection, but other viral CNS infections, including varicella zoster myelitis and herpes simplex encephalitis, have also been reported in natalizumab patients [90]. Varicella-zoster myelitis may demonstrate T2 hyperintense signal and enhancement in the spinal cord [91], differentiating it from PML. Herpes zoster encephalitis presents as rapidly progressive cortical and subcortical T2 hyperintensity, swelling, and occasional enhancement involving the temporal lobes +/− other limbic regions [92]. Various bacterial and fungal infections may also occur.\n\nThe most important differential consideration is whether new lesions are related to multiple sclerosis relapse. New MS lesions tend to be small, focal, and well delineated, favoring the periventricular and juxtacortical white matter and are typically round or ovoid in shape [48, 69]. MS lesions may enhance homogenously or peripherally, whereas PML generally does not. MS lesions generally only restrict diffusion in the hyperacute phase (<1 week) [93].\n\nTumefactive demyelinating can be misinterpreted for PML lesions as they demonstrate large areas of T2 hyperintensity and T1 hypointensity; however, mass effect is usually greater in tumefactive lesions [94], and T1 hypointensity improves over time in tumefactive lesions due to remyelination [94–96], while this does not occur in PML. Acute disseminated encephalomyelitis (ADEM) can appear similar to PML with large areas of T2 signal abnormality in the white matter and deep gray structures with minimal enhancement and variable mass effect [97]. Posterior reversible encephalopathy syndrome (PRES) can appear superficially similar to PML on initial examination, but lesions tend to be more symmetric than those in PML and predominantly involve the posterior aspects of the brain. Finally, PRES lesions typically resolve with treatment of the inciting etiology [98].\n\n11. PML: Treatment\nThe goal of treatment for natalizumab associated PML is the restoration of immune function by expedient removal of the drug. This is typically achieved with plasma exchange (PLEX) or immunoadsorption (IA), which clears natalizumab from the α4β1 receptors. Three to five PLEX sessions may be required over the course of 2 weeks [99]; however, more or fewer sessions may be needed and serum natalizumab level monitoring during PLEX may be of benefit [100].\n\n12. PML-IRIS\nImmune Reconstitution Inflammatory Syndrome (IRIS) is a phenomenon originally reported in AIDS patients who were prescribed highly active antiretroviral therapy and subsequently experienced a paradoxical clinical deterioration [101]. In PML patients treated with PLEX, once clearance of natalizumab has been achieved, many patients will experience rapid worsening of neurologic symptoms. This is thought to be due to an exuberant immune response to viral antigens resulting in inflammation mediated damage to infected and noninfected neuronal and glial tissue. Given the strong association between natalizumab associated PML and IRIS, the combined term PML-IRIS is used to describe this phenomenon (Figure 8) [66].\n\nPML-IRIS may occur following discontinuation of natalizumab in the absence of PLEX; however, it tends to occur later, usually approximately 90 days after last dose, reflecting the longer time necessary to clear the drug [21, 102]. The clinical impact of the PML-IRIS phenomenon should not be understated, as it results in substantially worsened EDSS scores and up to 30% mortality [23]. The most common therapy for PML-IRIS is high dose corticosteroids in an attempt to control the deleterious effects of the exuberant inflammatory cascade [35, 66, 76].\n\n13. PML-IRIS: Imaging Features\nGiven the substantial morbidity and mortality associated with PML-IRIS, prompt recognition of the phenomenon is crucial for rapid initiation of supportive therapies. Progression of the typical imaging findings of PML and evidence of active inflammation following clearance of natalizumab from the patient's system are the hallmarks of PML-IRIS. Existing PML lesions may increase in size and may coalesce as more white matter becomes involved. This is accompanied by increasing edema, cerebral swelling, and mass effect, which are not typical of PML. Contrast enhancement develops or increases and exhibits variable patterns, including patchy, punctate, irregular and hazy, ill-defined enhancement patterns (Figure 9) [59]. These inflammatory MR findings will progress then regress over time. Lesions remain T2/FLAIR hyperintense after cessation of the active inflammatory response. Typically T1 hypointensity increases indicating irreversible white matter damage. Long term retrograde neuronal degeneration results in atrophy of the overlying cortex.\n\n14. Natalizumab Rebound\nPatients may find it necessary to discontinue natalizumab therapy for a variety of reasons including the fear of contracting PML after long term usage, JC virus seroconversion, disease progression despite treatment, pregnancy or the intention to become pregnant, antibodies to natalizumab, or allergy [103]. Multiple small studies have demonstrated an unusually robust inflammatory response greater than a patient's typical relapse severity before starting natalizumab therapy (i.e., rebound) on MR imaging performed within approximately three months following discontinuation of the drug [104–112]. The picture is not definitive, however, as phase III clinical trial data shows renewed disease progression at an expected pre-natalizumab level [113]; however, other trials demonstrate disease severity greater than what had been previously experienced. This is referred to as the “rebound phenomenon” [114, 115] and may occur in 10–40% of patients after discontinuation of natalizumab [108, 109, 116]. Rebound may be more frequent in those patients with a lower pretreatment level of disease activity and in those patients in whom the gap between discontinuation of natalizumab and initiation of another subsequent therapy is delayed [103, 117]. Therefore, clinicians need to be vigilant when monitoring patients after cessation of natalizumab, as the disease may become more aggressive during this period, resulting in a more profound relapse than would otherwise be expected. On MR imaging the appearance of the rebound phenomenon appears as new enhancing and/or nonenhancing lesions. The number of new or enhancing lesions may be greater than in a typical relapse and can be quite severe [108–110] (Figure 10). Development of enhancement at the margins of old lesions has also been reported [109].\n\n15. Conclusion\nGiven the widespread and increasing use of natalizumab for the treatment of RRMS it is crucial for the neurologist and neuroradiologist to understand and recognize the common major complications of this treatment. These primarily include PML, PML-IRIS, and natalizumab rebound. The imaging presentation of PML is typified by bilateral but asymmetric areas of abnormal T2 signal in the peripheral subcortical white matter, with or without enhancement. Diffusion weighted imaging is of particular value in the evaluation of patients suspected of PML, as peripheral hyperintensity and central hypointensity on DWI images are classic. DWI may have utility in differentiating early PML from MS relapse and may be used to monitor patients treated for PML. Although not yet in widespread clinical use, DTI may be able to detect PML earlier than conventional imaging, before it is clinically manifest. PML is treated by rapid clearance of natalizumab from the patient with PLEX. Clearance of natalizumab, with or without PLEX, often results in PML-IRIS, which is typified by progression of the typical imaging findings of PML and evidence of new contrast enhancement and swelling. Finally, the phenomenon of natalizumab rebound after drug discontinuation, while controversial, may be a distinct entity in a subset of patients. This is essentially an aggressive relapse and may demonstrate more numerous enhancing lesions as well as enhancement of the margins of old lesions.\n\nConflict of Interests\nThe authors declare that there is no conflict of interests regarding the publication of this paper.\n\nFigure 1 Pathophysiology of MS and mechanism of action of natalizumab.\n\nFigure 2 25-year-old woman with RRMS who developed worsening symptoms including weakness and inability to ambulate after beginning natalizumab. MRI FLAIR image demonstrates classic appearance of PML including a sharply demarcated peripheral border along the subcortical U-fibers (arrow) and a hazy, ill-defined central border (dashed arrow).\n\nFigure 3 63-year-old woman with MS presenting with profound neurologic deterioration. (a) FLAIR image demonstrates characteristic PML lesions involving the subcortical U-fibers which also extent centrally to the periventricular surface. (b) T2-weighted image on the same patient demonstrates “granular” or “microcystic” foci (arrows).\n\nFigure 4 32-year-old woman with RRMS and no new neurologic symptoms developed MR findings on FLAIR images (a) without enhancement (b) consistent with PML (arrows) after having been on natilizumab for approximately 4.5 years. The drug was discontinued and she received PLEX and steroids. Follow-up imaging was obtained at (c-d) one month, (e-f) three months, and (g-h) four months later demonstrating progressive PML lesions, which corresponded to progressive clinical neurological decline. FLAIR (c) and postcontrast (d) images obtained at one month demonstrate disease progression without enhancement. Images obtained at three months show progressive disease (e-f) without enhancement to suggest active MS or IRIS. Like other aggressive infiltrating white matter lesions PML can cross the corpus callosum (arrows). Note also that there is now involvement of the left caudate (dotted arrow). The final images obtained four months after presentation (g-h) demonstrate swelling and compression of the gyri. There is now marked involvement of the deep gray matter structures (dotted arrows) which occurs in up to one-third of cases. However, note that despite involvement of almost the entire hemisphere, the lateral ventricle remains only mildly compressed and there is no midline shift, as would be expected with other lesions of this size, and no enhancement has developed.\n\nFigure 5 45-year-old woman with a 10-year history of RRMS was started on natalizumab. She did well for six years and then developed gait abnormality and fatigue. MR imaging demonstrates large lesions in the cerebellar peduncles demonstrating a “crescent” shape.\n\nFigure 6 Diffusion weighted images in a patient with large PML lesions demonstrate peripheral restricted diffusion where the lesion is active (arrows) and central facilitated diffusion where the lesion is more quiescent (dotted arrows).\n\nFigure 7 (a) T2 FLAIR and (b) DWI images demonstrate a large PML lesion. (b) DWI demonstrates cytotoxic edema along the advancing edge of the lesion (arrows) surrounding the quiescent center. (c) Repeat MR DWI image following PLEX demonstrates absence of the hyperintense rim suggesting that disease progression has resolved.\n\nFigure 8 Pathophysiology of PML-IRIS: (a) natalizumab blocks the α4β1 integrin, preventing lymphocyte tracking into the CNS. (b) To treat PML natalizumab must be rapidly cleared from the blood, often through PLEX. (c) With natalizumab effectively cleared from α4β1 integrin receptors the lymphocytes reenter the CNS to attack the PML virus. The response is often overwhelming, possibly exacerbating IRIS and leading to further destruction of brain tissue.\n\nFigure 9 39-year-old woman with RRMS treated with natalizumab developed worsening symptoms. (a) MRI was performed at an outside institution demonstrating a new subcortical lesion in the right frontal lobe (arrow). She was treated for MS exacerbation. The patient presented to our institution approximately 3 months later with progressive symptoms and functional decline. (b) Repeat MRI shows increase in size of the right frontal lesion with characteristic bilateral, asymmetric distribution of lesions involving the subcortical U-fibers (arrows). (c) DWI shows a bright rim of signal along the advancing edge of the lesion (dashed arrows) with darker signal more anteriorly where the lesion is no longer active (dotted arrows). At this time there was no contrast enhancement (not shown). The patient was diagnosed with PML and PLEX was performed. Approximately one month later the patient experienced functional decline. Repeat MRI shows expansion of the (d) FLAIR lesions with increased swelling and mass effect and (e) the development of patchy central enhancement consistent with PML-IRIS. Note that the DWI image (f) no longer demonstrates an advancing edge of restricted diffusion.\n\nFigure 10 27-year-old female with a typical relapse severity prior to natalizumab of 0–2 enhancing lesions on MRI. 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Relapse and rebound risks after natalizumab discontinuation in patients with multiple sclerosis. (P3.294) Neurology 2015 84 14 P3.294 \n117 Clares R. H. Torres R. C. Carreon E. Andreu E. La Llana J. M. Fernandez M. Risk of rebound in multiple sclerosis after a switch from natalizumab to fingolimod. Early onset versus delayed onset. (P3.291) Neurology 2015 84 14, supplement P3.291\n\n", "fulltext_license": "CC BY", "issn_linking": "2090-2654", "issue": "2015()", "journal": "Multiple sclerosis international", "keywords": null, "medline_ta": "Mult Scler Int", "mesh_terms": null, "nlm_unique_id": "101566861", "other_id": null, "pages": "809252", "pmc": null, "pmid": "26483978", "pubdate": "2015", "publication_types": "D016428:Journal Article; D016454:Review", "references": "2731089;9109865;20163378;22710964;24642511;25205744;14593446;19201654;18256405;6302172;17438235;15947080;23614603;25078275;16510745;20298967;23616161;22931715;23092189;20019096;10718540;24442606;11942377;23728144;23568998;22302545;21777829;22807558;11596788;22048950;24682966;19557867;17296996;24610329;22914844;20298966;17353479;10680816;6304757;23614604;16510746;11997718;15947079;25273271;23695498;19798646;24720783;7472533;19798645;19433659;20451009;18560918;18324406;17685415;12942223;23035065;14504320;16862584;25877065;22054207;19188571;19609591;24728334;24739400;19513133;23100404;16510744;18474743;21328606;8794345;22154948;25493267;21052756;20937940;22383229;15947078;21576685;10201428;23606731;23100527;21543733;17872364;22576893;22136455;15095552;16434670;21665227;17136224;830323;19798640;21832229;12424695;22076540;25853764;17452584;18657729;18596284;22013244;23280794;16879291;25150761;24373819;18004634;24729444;15623704;17021685;24192217;18485317;22289971;20818793", "title": "Neuroimaging of Natalizumab Complications in Multiple Sclerosis: PML and Other Associated Entities.", "title_normalized": "neuroimaging of natalizumab complications in multiple sclerosis pml and other associated entities" }

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{ "abstract": "We report a case of a 63-year-old-man presenting with chronic diarrhea and weight loss while on olmesartan treatment for hypertension. Investigation showed multiple nutritional deficiencies associated with diffuse intestinal villous atrophy. Serologies for celiac disease were negative and other causes of villous atrophy were excluded. Olmesartan as a precipitant agent was suspected and withdrawn. Clinical improvement occurred in days with no need for other therapeutic measures. Follow-up at three months showed clinical remission and almost complete recovery of intestinal atrophy. Olmesartan is an angiotensin receptor blocker commonly prescribed for the management of hypertension. Spruelike enteropathy associated with this drug is a recently described entity with few cases reported. It presents with chronic diarrhea and intestinal villous atrophy and should be included in its differential diagnosis. This case intends to alert clinicians for the possibility of this event in a patient on treatment with this drug.", "affiliations": "Gastroenterology Departament, Centro Hospitalar do Algarve, EPE, Faro, Portugal.;Gastroenterology Departament, Centro Hospitalar do Algarve, EPE, Faro, Portugal.;Gastroenterology Departament, Centro Hospitalar do Algarve, EPE, Faro, Portugal.;Gastroenterology Departament, Centro Hospitalar do Algarve, EPE, Faro, Portugal.;Gastroenterology Departament, Centro Hospitalar do Algarve, EPE, Faro, Portugal.;Pathology Department, Centro Hospitalar do Algarve, EPE, Faro, Portugal.;Gastroenterology Departament, Centro Hospitalar do Algarve, EPE, Faro, Portugal.", "authors": "Eusébio|Marta|M|;Caldeira|Paulo|P|;Antunes|Artur Gião|AG|;Ramos|André|A|;Velasco|Francisco|F|;Cadillá|Jesús|J|;Guerreiro|Horácio|H|", "chemical_list": null, "country": "Switzerland", "delete": false, "doi": "10.1016/j.jpge.2015.09.005", "fulltext": "\n==== Front\nGE Port J GastroenterolGE Port J GastroenterolGE Portuguese Journal of Gastroenterology2341-45452387-1954Karger Publishers S2341-4545(15)00118-010.1016/j.jpge.2015.09.005Clinical CaseOlmesartan-Induced Enteropathy: An Unusual Cause of Villous Atrophy Enteropatia Induzida pelo Olmesartan: Uma Causa Incomum de Atrofia Vilositária Eusébio Marta martaeusebio@gmail.coma⁎Caldeira Paulo aAntunes Artur Gião aRamos André aVelasco Francisco aCadillá Jesús bGuerreiro Horácio aa Gastroenterology Departament, Centro Hospitalar do Algarve, EPE, Faro, Portugalb Pathology Department, Centro Hospitalar do Algarve, EPE, Faro, Portugal⁎ Corresponding author. martaeusebio@gmail.com20 10 2015 Mar-Apr 2016 20 10 2015 23 2 91 95 29 7 2015 14 9 2015 © 2015 Sociedade Portuguesa de Gastrenterologia. Published by Elsevier España, S.L.U.2015Sociedade Portuguesa de GastrenterologiaThis is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).We report a case of a 63-year-old-man presenting with chronic diarrhea and weight loss while on olmesartan treatment for hypertension. Investigation showed multiple nutritional deficiencies associated with diffuse intestinal villous atrophy. Serologies for celiac disease were negative and other causes of villous atrophy were excluded. Olmesartan as a precipitant agent was suspected and withdrawn. Clinical improvement occurred in days with no need for other therapeutic measures. Follow-up at three months showed clinical remission and almost complete recovery of intestinal atrophy.\n\nOlmesartan is an angiotensin receptor blocker commonly prescribed for the management of hypertension. Spruelike enteropathy associated with this drug is a recently described entity with few cases reported. It presents with chronic diarrhea and intestinal villous atrophy and should be included in its differential diagnosis. This case intends to alert clinicians for the possibility of this event in a patient on treatment with this drug.\n\nResumo\nApresentamos o caso de um homem de 63 anos com diarreia crónica e perda ponderal. Apresentava hipertensão arterial tratada com olmesartan. A investigação complementar mostrou múltiplos défices nutricionais associados a atrofia vilositária intestinal difusa. As serologias de doença celíaca foram negativas e outras causas de atrofia vilositária foram excluídas. Suspeitou-se do olmesartan como agente precipitante, sendo este suspenso. Observou-se melhoria clínica em dias, sem necessidade de outras medidas terapêuticas. No seguimento, aos 3 meses, constatou-se remissão clínica e recuperação quase completa da atrofia intestinal.\n\nO olmesartan é um bloqueador dos recetores da angiotensina, geralmente prescrito no tratamento da hipertensão. A enteropatia “spruelike” associada a este fármaco é uma entidade recentemente descrita, com poucos casos reportados. Manifesta-se por diarreia crónica associada a atrofia vilositária intestinal, devendo ser incluída no seu diagnóstico diferencial. Com este caso pretende-se alertar os clínicos para a possibilidade deste evento em doentes sob tratamento com este fármaco.\n\nKeywords\nAtrophyGastrointestinal DiseasesAngiotensin II Receptor Antagonist/adverse effectsPalavras-chave\nAtrofiaDoenças GastrointestinaisAntanosistas dos Recetores da Angiotensina II/efeitos adversos\n==== Body\n1 Introduction\nThe most common cause of villous atrophy is celiac disease.1, 2 The villous atrophy results from injury to the small intestine and leads to loss of absorptive surface area, reduction of digestive enzymes, and consequential impaired absorption of micronutrients.3 Negative celiac serology or nonresponse to a gluten-free diet implies a broad and challenging differential diagnosis which includes Crohn's disease, enteric infections (e.g. Giardia lamblia), collagenous sprue, tropical sprue, common variable immunodeficiency, autoimmune enteropathy, hematological malignancies and medication-associated enteropathy.2 Regarding the latter, olmesartan medoxomil, an angiotensin receptor blocker for the management of hypertension, has been recently recognized as a cause of “sprue-like enteropathy”.4, 5, 6\n\nWe report a case of severe enteropathy associated with olmesartan use.\n\n2 Clinical case\nA 63-year-old man was admitted to our department complaining of progressive diarrhea and significant weight loss (12 kg) for one year. He reported between 5 and 7 daily episodes of bulky, watery and nonbloody diarrhea. Over the preceding two weeks, it was associated with severe fatigue, anorexia and vomiting. He denied abdominal pain, fever or other symptoms. There was no history of recent travels or sick contacts.\n\nApart from arterial hypertension, treated with olmesartan and hydrochlorothiazide (20/12.5 mg) for two years, his past medical history was unremarkable.\n\nThe patient had already undergone total colonoscopy and abdominal computed tomography with no remarkable findings. A gluten and lactose-free diet were tried without improvement. He also failed initial conservative treatment with a trial of oral antibiotic for possible small bowel bacterial overgrowth.\n\nOn presentation at our department, his body mass index was 20 kg/m2 (normal (N): 18.5–24.99 kg/m2), close to the lower limit of normal. Muscle wasting was also seen without evident weakness. There was no peripheral edema or other relevant findings on physical examination.\n\nLaboratory evaluation revealed: hemoglobin 11.6 g/dL (normal: 13–17) with normal mean corpuscular volume and mean corpuscular hemoglobin; serum potassium 1.8 mmol/L (N: 3.6–5.1), phosphorus 1.7 mg/dL (N: 2.3–4.7), magnesium 1.3 mg/dL (N: 3.6–5.1), corrected calcium 8.6 mg/dL (N: 8.8–10); albumin 2.9 g/dL (N: 3.4–4.8), total protein 4.9 g/dL (N: 6.2–8.5), aspartate aminotransferase 205 UI/L (N: 5–34), alanine aminotransferase 106 UI/L (N < 55) and protein C-reaction 25 mg/L (N: <5 mg/L). The prothrombine time (PT) was increased (26.6 s; N: 9.4–13) as well as activated partial thromboplastin time (aPTT) (50 s; N: 20–40).\n\nOther laboratory work-up was unremarkable including leucogram, serum glucose, B12 vitamin, folic acid, transglutaminase antibodies, serum immunoglobulins, thyroid stimulating hormone and serology for human immunodeficiency virus. Platelets, bleeding time and fibrinogen were also normal.\n\nOther causes for hypertransaminasemia were additionally excluded (no alcohol consumption; bilirubin, alkaline phosphatase, gamma-glutamyl transpeptidase, serum iron, ferritin, transferrin saturation, cholesterol and triglycerides were normal; hepatitis B and C serologies were negative; antinuclear antibodies and smooth muscle antibodies were negative and abdominal ultrasound excluded liver or biliary abnormalities).\n\nStool examination namely cultures, Clostridium difficile toxin assay, ova and parasites was unrevealing.\n\nA colonoscopy was repeated and, despite all efforts, the terminal ileum could not be intubated. Colonic random biopsies excluded microscopic colitis or other abnormalities. Upper endoscopy evidenced a discrete attenuation of duodenal villous pattern without other findings (Fig. 1). Histopathological examination confirmed a partial villous atrophy and chronic lymphocytic infiltration of the lamina propria (Fig. 2). Capsule endoscopy was performed and demonstrated a diffuse flattening of the small bowel villi (Fig. 3).Figure 1 Initial upper endoscopy showing a discrete attenuation of villous pattern of the second portion of the duodenum.\n\nFigure 2 Small intestinal biopsy showing villous atrophy and chronic lymphocytic infiltration of the lamina propria (hematoxylin and eosin, 4×).\n\nFigure 3 Capsule endoscopy showing marked villous atrophy of the small bowel.\n\n\n\nWe suspected of olmesartan-associated sprue-like enteropathy. This drug was therefore withdrawn along with replacement of electrolytes and vitamin K administration. Prompt improvement was achieved within a few days. One week after hospital admission, the patient was discharged without diarrhea or need for nutritional/electrolyte support and began to gain weight. Olmesartan was switched to amlodipine.\n\nThree months later, a complete recovery of weight (12.5 kg) was seen along with full normalization of laboratory tests (hemoglobin, electrolytes, albumin, TP, aPTT, protein-C reaction and aminotransferases). Upper endoscopy and capsule endoscopy (Fig. 4) were, again, performed and showed normal small bowel appearance. Histopathological analysis of duodenal biopsies confirmed an almost complete recovery of duodenal villi and no lymphocyte infiltration (Fig. 5). At sixth month follow-up, the patient remained asymptomatic with no laboratory abnormalities.Figure 4 Follow-up capsule endoscopy showing normal small bowel appearance.\n\nFigure 5 Histopathological image showing almost complete recovery of duodenal villi three months after discontinuing olmesartan (hematoxylin and eosin, 4×).\n\n\n\n3 Discussion\nWe described a case of a patient presenting with chronic diarrhea and malabsorption as evidenced by multiple nutritional deficits including electrolyte imbalance and reduced serum albumin. Prolonged PT and aPTT in a patient not taking vitamin K antagonists, with no evidence of liver disease, biliary obstruction or disseminated intravascular coagulation suggested, in this clinical setting, vitamin K malabsorption. In addition, villous atrophy was present throughout the entire small bowel as demonstrated by capsule endoscopy, which explains the malabsoption.\n\nIn our case, celiac disease, the most common cause of villous atrophy,1, 2 was excluded by serology methods and the lack of clinical response to a gluten-free diet. After excluding other causes of villous atrophy, we considered an olmesartan-associated enteropathy.\n\nOlmesartan medoxomil is an angiotensin II receptor blocker approved for the treatment of hypertension since 2002.7 A sprue-like enteropathy associated with olmesartan was first reported by Rubio-Tapia et al.4 and since then, similar cases have been described, although mainly as case reports or small case series.6, 8, 9, 10, 11, 12, 13, 14, 15 As a result, United States Food and Drug Administration reported this olmesartan associated adverse event via a MedWatch alert in July 2013.\n\nClinical presentation of this entity include chronic diarrhea, vomiting, abdominal pain, bloating, weight loss and fatigue.4, 6, 11 More severe cases with dehydration,4, 9, 13 acute renal failure9 and a case of colonic perforation11 have been reported. According to previous descriptions, the duration of exposure to olmesartan before the onset of diarrhea has varied between several months and years.4, 6 In our case, it took one year to present symptoms, which is in accordance with the timing reported.\n\nLaboratory investigation may show normocytic, normochromic anemia, hypoalbuminemia and one or multiple electrolyte abnormalities,4 as evidenced in our case. Human leukocyte antigen (HLA) assessment, when performed, may reveal a higher prevalence of DQ2 or DQ8 haplotypes than expected for the general population, which suggests a possible role for genetics in this enteropathy.4, 6\n\nUpper endoscopy may be normal, show a nodular appearance of the duodenal mucosa or flattening of villi.6 In our case, only a discrete attenuation of duodenal villous pattern was observed. Capsule endoscopy, however, highlighted a diffuse and obvious flattening of the small bowel villi.\n\nThe most common histopathological finding is intestinal villous atrophy (either total or partial), which may be associated with variable degrees of mucosal inflammation. In contrast to celiac disease, flattening of villi is not always associated with increased intra-epithelial lymphocytes and inflammation.6 In addition, involvement of the stomach and colon with lymphocytic aggregation was also reported by some authors,4, 8, 15 suggesting that this disorder may affect the entire gastrointestinal tract.\n\nRegarding treatment, previous reports have demonstrated clinical remission in all patients after discontinuation of olmesartan.4, 6, 8, 9, 10, 11, 12, 13, 15 Moreover, almost all patients have shown histological recovery of the duodenum after drug withdrawal (although follow-up intestinal biopsies have not been done systematically in all patients).4, 6, 10, 12 In contrast to other enteropathies, such as celiac disease that may take years to achieve histological recovery, despite adequate treatment,16, 17 olmesartan-induced enteropathy is associated with a quick mucosal recovery (median eight months from the suspension of the drug to follow-up biopsies).4\n\nIn our case, the complete resolution of symptoms and malabsorption, the intestinal villous atrophy improvement without any other therapeutic/dietary measures besides discontinuation of the drug and the absence of other causes of enteropathy support this diagnosis. Deliberate rechallenge test with olmesartan was not performed because of the life-threatening nature of the disease and was not clinically pertinent.\n\nOne additional interesting finding, in our case, was the hypertransaminasemia that normalized after the discontinuation of the drug. After excluding other causes for this finding, we believe that this could be linked to the enteropathy, similar to that described for celiac disease. Celiac patients with hypertransaminasemia have an important increase in intestinal permeability compared with those whose liver enzymes are normal.18 One proposed explanation for hepatic involvement in these patients is that the increased intestinal permeability may ease the entry of toxins, antigens, and inflammatory substances (cytokines and/or autoantibodies) to the portal circulation that, subsequently, play a role in liver injury.19 In our case of severe olmesartan-induced enteropathy we speculate that similar mechanisms could be on the basis of hypertransaminasemia. The report of more cases of this drug-induced enteropathy is crucial to clarify these findings.\n\nThe pathogenesis of this entity is still unclear. The long interval between the beginning of olmesartan therapy and the onset of diarrhea suggests a cell-mediated immune mechanism.4, 11 Some reports have indicated a potential inhibitory effect of angiotensin receptor blockers on transforming growth factor, which is responsible for gut immune homeostasis.20, 21 Another proposed theory is related to a pro-apoptotic effect of angiotensin (AT) II on intestinal epithelial cells. Angiotensin II binds to two receptor forms, AT1 and AT2, with different properties and different gastrointestinal distribution. AT1 receptor is expressed throughout the whole alimentary tract, while AT2 receptor is expressed particularly in the duodenum and jejunum.22 Sun et al. suggested that angiotensin II through binding to AT2 receptor up-regulates pro-apoptotic proteins, such as Bax and GATA-6, in association with a down-regulation of Bcl-2, an anti-apoptotic protein.23 Olmesartan shows high affinity for AT1 receptors. In case of saturation of this receptors, circulating angiotensin II could bind to AT2 receptor resulting in a pro-apoptotic effect and, consequently, to villous atrophy.6 Further investigations are needed to elucidate the physiopathological mechanisms underlying this entity.\n\nAnother issue to clarify is if other angiotensin II receptor blockers can have a similar adverse reaction. Recently, valsartan was implicated in a case of “sprue-like” enteropathy.24 Nevertheless, cases of enteropathy related to other angiotensin II receptor inhibitors seem to be much less frequent than olmesartan-induced enteropathy.5 The selective role of olmesartan might be explained by its conversion into the active form in the intestine, its longer half-life and higher efficacy compared to other sartans.25\n\nIn conclusion, this report intends to alert the clinical community for this probably underreported problem,11 since this condition is serious and olmesartan is commonly prescribed for the treatment of hypertension. Negative serology for celiac disease and absence of response to a gluten-free diet on patients taking olmesartan should aware clinicians for the possibility of this condition. We show iconography namely capsule endoscopic images, that document the endoscopic findings associated with this entity and can add information on the hallmarks of this entity. Increasing reports of this drug-induced enteropathy may lead to the identification of more cases, a better characterization of this entity and an earlier diagnosis, with obvious benefits to patients.\n==== Refs\nReferences\n1 Fasano A. Catassi C. Clinical practice. Celiac disease N Engl J Med 367 2012 2419 2426 23252527 \n2 DeGaetani M. Tennyson C.A. Lebwohl B. Lewis S.K. Abu Daya H. Arguelles-Grande C. Villous atrophy and negative celiac serology: a diagnostic and therapeutic dilemma Am J Gastroenterol 108 2013 647 653 23644957 \n3 Reilly N.R. Fasano A. Green P.H.R. Presentation of celiac disease Gastrointest Endosc Clin N Am 22 2012 613 621 23083982 \n4 Rubio-Tapia A. Herman M.L. Ludvigsson J.F. Kelly D.G. Mangan T.F. Wu T-T. Severe spruelike enteropathy associated with olmesartan Mayo Clin Proc 87 2012 732 738 22728033 \n5 Marthey L. Cadiot G. Seksik P. Pouderoux P. Lacroute J. Skinazi F. Olmesartan-associated enteropathy: results of a national survey Aliment Pharmacol Ther 40 2014 1103 1109 25199794 \n6 Laniro G. Bibbò S. Montalto M. Ricci R. Gasbarrini A. Cammarota G. Systematic review: sprue-like enteropathy associated with olmesartan Aliment Pharmacol Ther 40 2014 16 23 24805127 \n7 The seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure 2004 National Institutes of Health, National Heart, Lung, and Blood Institute, US Department of Health and Human Services Bethesda, MD NIH Publication No. 04-5230 \n8 Fiorucci G. Puxeddu E. Colella R. Reboldi G.P. Villanacci V. Bassotti G. Severe spruelike enteropathy due to olmesartan Rev Esp Enferm Dig 106 2014 142 144 24852741 \n9 Dreifuss S.E. Tomizawa Y. Farber N.J. Davison J.M. Sohnen A.E. Spruelike enteropathy associated with olmesartan: an unusual case of severe diarrhea Case Rep Gastrointest Med 2013 618071 23573432 \n10 Halevy D. Teeuwen U. Kohlhof P. Eine neue sprue-ähnliche erkrankung als ursache schwerer diarrhoe Dtsch Med Wochenschr 139 2014 2290 2293 25350242 \n11 Abdelghany M. Iii L.G. Slater J. Begley C. Case report: olmesartan associated sprue-like enteropathy and colon perforation Case Rep Gastrointest Med 2014 3 6 2014 \n12 Heerasing N. Hair C. Wallace S. Olmesartan-induced enteropathy Intern Med J 45 2015 117 118 25582943 \n13 Théophile H. David X-R. Miremont-Salamé G. Haramburu F. Five cases of sprue-like enteropathy in patients treated by olmesartan Dig Liver Dis 46 2014 465 469 24472297 \n14 Bhat N. Anupama N.K. Yelsangikar A. Vizhi K. Olmesartan-related sprue-like enteropathy Indian J Gastroenterol 33 2014 564 567 25303875 \n15 Ould Sidi Mohamed M. Colardelle P. Entéropathie due à l’olmesartan Ann Cardiol Angeiol 2015 (in press) \n16 Wahab P.J. Meijer J.W.R. Mulder C.J.J. Histologic follow-up of people with celiac disease on a gluten-free diet: slow and incomplete recovery Am J Clin Pathol 118 2002 459 463 12219789 \n17 Rubio-Tapia A. Rahim M.W. See J.A. Lahr B.D. Wu T-T. Murray J.A. Mucosal recovery and mortality in adults with celiac disease after treatment with a gluten-free diet Am J Gastroenterol 105 2010 1412 1420 20145607 \n18 Novacek G. Miehsler W. Wrba F. Ferenci P. Penner E. Vogelsang H. Prevalence and clinical importance of hypertransaminasaemia in coeliac disease Eur J Gastroenterol Hepatol 11 1999 283 288 10333201 \n19 Zanini B. Baschè R. Ferraresi A. Pigozzi M.G. Ricci C. Lanzarotto F. Factors that contribute to hypertransaminasemia in patients with celiac disease or functional gastrointestinal syndromes Clin Gastroenterol Hepatol 12 2014 804.e2–810.e2 \n20 Macdonald T.T. Monteleone G. Immunity, inflammation, and allergy in the gut Science 307 2005 1920 1925 15790845 \n21 Matt P. Schoenhoff F. Habashi J. Holm T. Van Erp C. Loch D. Circulating transforming growth factor-beta in Marfan syndrome Circulation 120 2009 526 532 19635970 \n22 Fändriks L. The angiotensin II type 2 receptor and the gastrointestinal tract J Renin Angiotensin Aldosterone Syst 11 2010 43 48 19861352 \n23 Sun L. Wang W. Xiao W. Liang H. Yang Y. Yang H. Angiotensin II induces apoptosis in intestinal epithelial cells through the AT2 receptor, GATA-6 and the Bax pathway Biochem Biophys Res Commun 424 2012 663 668 22776205 \n24 Herman M.L. Rubio-Tapia A. Wu T.-T. Murray J.A. A case of severe sprue-like enteropathy associated with valsartan ACG Case Rep J 2 2015 92 94 26157924 \n25 Scialom S. Malamut G. Meresse B. Guegan N. Brousse N. Verkarre V. Gastrointestinal disorder associated with olmesartan mimics autoimmune enteropathy PLOS ONE 10 2015 e0125024 26101883\n\n", "fulltext_license": "CC BY-NC-ND", "issn_linking": "2387-1954", "issue": "23(2)", "journal": "GE Portuguese journal of gastroenterology", "keywords": "Angiotensin II Receptor Antagonist/adverse effects; Atrophy; Gastrointestinal Diseases", "medline_ta": "GE Port J Gastroenterol", "mesh_terms": null, "nlm_unique_id": "101685861", "other_id": null, "pages": "91-95", "pmc": null, "pmid": "28868439", "pubdate": "2016", "publication_types": "D002363:Case Reports", "references": "24711933;19635970;12219789;25199794;24211290;23644957;25303875;26101883;19861352;15790845;23083982;26157924;10333201;22728033;25582943;23573432;24805127;22776205;20145607;25350242;24472297;24852741;23252527", "title": "Olmesartan-Induced Enteropathy: An Unusual Cause of Villous Atrophy.", "title_normalized": "olmesartan induced enteropathy an unusual cause of villous atrophy" }

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{ "abstract": "Rasmussen encephalitis (RE) is an inflammatory unilateral progressive medically refractory epilepsy associated with hemiparesis, cognitive dysfunction, and hemispheric atrophy. Here, we present 2 cases from our institution that demonstrate the dual nature of RE in 2 similarly aged children. Overall, 2 types of RE have been described: type 1 has a short prodromal phase and more explosive onset and type 2 has a longer prodromal of partial seizures followed by hemiparesis and atrophy. Younger patients are more likely to fit into the type 1 presentation and have been described as more likely to have dual pathology. Perhaps the patients with a more acute onset are more likely to have a dual pathology as is found in our 2 cases. We review the typical findings in RE and discuss current treatment options, highlighting new experimental treatments.", "affiliations": "Department of Neurology, Children's Hospital Colorado, University of Colorado, Anschutz Medical Campus, Aurora, CO.;Department of Neurology, Children's Hospital Colorado, University of Colorado, Anschutz Medical Campus, Aurora, CO.;Department of Neurology, Children's Hospital Colorado, University of Colorado, Anschutz Medical Campus, Aurora, CO. Electronic address: kevin.chapman@childrenscolorado.org.", "authors": "Press|Craig|C|;Wallace|Adam|A|;Chapman|Kevin E|KE|", "chemical_list": null, "country": "United States", "delete": false, "doi": null, "fulltext": null, "fulltext_license": null, "issn_linking": "1071-9091", "issue": "21(2)", "journal": "Seminars in pediatric neurology", "keywords": null, "medline_ta": "Semin Pediatr Neurol", "mesh_terms": "D001921:Brain; D002675:Child, Preschool; D004660:Encephalitis; D005260:Female; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D049268:Positron-Emission Tomography; D012640:Seizures", "nlm_unique_id": "9441351", "other_id": null, "pages": "129-36", "pmc": null, "pmid": "25149947", "pubdate": "2014-06", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "The Janus-faced nature of Rasmussen's encephalitis.", "title_normalized": "the janus faced nature of rasmussen s encephalitis" }

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THE JANUS-FACED NATURE OF RASMUSSEN^S ENCEPHALITIS. SEMIN PEDIATR NEUROL. 2014;21(2):129-36.", "literaturereference_normalized": "the janus faced nature of rasmussen s encephalitis", "qualification": "1", "reportercountry": "COUNTRY NOT SPECIFIED" }, "primarysourcecountry": "US", "receiptdate": "20150226", "receivedate": "20150226", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 10869446, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 2, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20150721" }, { "companynumb": "PHHY2014US117136", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "TOPIRAMATE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TOPIRAMATE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CLOBAZAM" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CLOBAZAM" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "HUMAN IMMUNOGLOBULIN G" }, "drugadditional": null, "drugadministrationroute": "042", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "IMMUNOGLOBULIN I.V" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "VALPROIC ACID" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "078290", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VALPROIC ACID." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "LACOSAMIDE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LACOSAMIDE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "OXCARBAZEPINE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "OXCARBAZEPINE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CLONAZEPAM" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CLONAZEPAM." } ], "patientagegroup": null, "patientonsetage": "4", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Partial seizures with secondary generalisation", "reactionmeddraversionpt": "17.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Gait disturbance", "reactionmeddraversionpt": "17.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Rasmussen encephalitis", "reactionmeddraversionpt": "17.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Asthenia", "reactionmeddraversionpt": "17.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Ataxia", "reactionmeddraversionpt": "17.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "PRESS C, WALLACE A, CHAPMAN K E. THE JANUS-FACED NATURE OF RASMUSSEN?S ENCEPHALITIS. SEMINARS IN PEDIATRIC NEUROLOGY. 2014;21 (2):1129-136", "literaturereference_normalized": "the janus faced nature of rasmussen s encephalitis", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20140916", "receivedate": "20140916", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 10457556, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20150326" }, { "companynumb": "US-UCBSA-2014012776", "fulfillexpeditecriteria": "2", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "LACOSAMIDE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "022253", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "FILM-COATED TABLET", "drugdosagetext": "UNKNOWN DOSE", "drugenddate": null, "drugenddateformat": null, "drugindication": "SEIZURE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VIMPAT" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "OXCARBAZEPINE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNKNOWN DOSE", "drugenddate": null, "drugenddateformat": null, "drugindication": "SEIZURE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "OXCARBAZEPINE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "CLONAZEPAM" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNKNOWN DOSE", "drugenddate": null, "drugenddateformat": null, "drugindication": "SEIZURE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CLONAZEPAM." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "PHENYTOIN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNKNOWN DOSE", "drugenddate": null, "drugenddateformat": null, "drugindication": "SEIZURE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PHENYTOIN." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "LEVETIRACETAM" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNKNOWN DOSE", "drugenddate": null, "drugenddateformat": null, "drugindication": "SEIZURE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LEVETIRACETAM." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "CLOBAZAM" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNKNOWN DOSE", "drugenddate": null, "drugenddateformat": null, "drugindication": "SEIZURE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CLOBAZAM" } ], "patientagegroup": null, "patientonsetage": "3", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug ineffective", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "PRESS C, WALLACE A, CHAPMAN KE. THE JANUS-FACED NATURE OF RASMUSSEN^S ENCEPHALITIS. SEMIN PEDIATR NEUROL. 2014?21:129-36", "literaturereference_normalized": "the janus faced nature of rasmussen s encephalitis", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20151111", "receivedate": "20151111", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 11724585, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 2, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20160304" }, { "companynumb": "US-UCBSA-2014014468", "fulfillexpeditecriteria": "2", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "OXCARBAZEPINE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNKNOWN DOSE", "drugenddate": null, "drugenddateformat": null, "drugindication": "SEIZURE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "OXCARBAZEPINE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "VALPROATE SODIUM" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNKNOWN DOSE", "drugenddate": null, "drugenddateformat": null, "drugindication": "SEIZURE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VALPROATE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "TOPIRAMATE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNKNOWN DOSE", "drugenddate": null, "drugenddateformat": null, "drugindication": "SEIZURE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TOPIRAMATE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "LACOSAMIDE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "022253", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "FILM-COATED TABLET", "drugdosagetext": "UNKNOWN DOSE", "drugenddate": null, "drugenddateformat": null, "drugindication": "SEIZURE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VIMPAT" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CLONAZEPAM" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNKNOWN DOSE", "drugenddate": null, "drugenddateformat": null, "drugindication": "SEIZURE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CLONAZEPAM." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CLOBAZAM" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNKNOWN DOSE", "drugenddate": null, "drugenddateformat": null, "drugindication": "SEIZURE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CLOBAZAM" } ], "patientagegroup": "3", "patientonsetage": null, "patientonsetageunit": null, "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug ineffective", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "PRESS C, WALLACE A, CHAPMAN KE. THE JANUS-FACED NATURE OF RASMUSSEN^S ENCEPHALITIS. SEMINARS IN PEDIATRIC NEUROLOGY. 2014?21:129-36", "literaturereference_normalized": "the janus faced nature of rasmussen s encephalitis", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20151111", "receivedate": "20151111", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 11725001, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 2, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20160304" } ]

{ "abstract": "The antibiotic linezolid is a ribosomal inhibitor with excellent efficacy. Although the administration period has been reduced to 28 days, side effects, usually of hematologic or neuropathic origin, are still reported due to secondary inhibition of mitochondrial protein synthesis. Susceptibility to linezolid toxicity remains unknown. Therefore, the objective of this study was to gain an understanding of clinical heterogeneity in response to identical linezolid exposures through exhaustive examination of the molecular basis of tissue-dependent mitotoxicity, consequent cell dysfunction, and the association of mitochondrial genetics with adverse effects of linezolid administered for the recommended period. Peripheral blood mononuclear cells (PBMC) and skin nerve fibers from 19 and 6 patients, respectively, were evaluated before and after a 28-day linezolid treatment in order to assess toxic effects on mitochondria and cells. Mitochondrial DNA haplotypes and single nucleotide polymorphisms (SNPs) in ribosomal sequences where linezolid binds to mitochondrial ribosomes were also analyzed to investigate their genetic contributions. We found that linezolid reduced mitochondrial protein levels, complex IV activity, and mitochondrial mass in PBMC and was associated with a trend toward an increase in the rate of apoptosis. In skin tissue, mitochondrial mass increased within nerve fibers, accompanied by subclinical axonal swelling. Mitochondrial haplogroup U, mutations in 12S rRNA, and the m.2706A→G, m.3197T→C, and m.3010G→A polymorphisms in 16S rRNA showed a trend toward an association with increased mitochondrial and clinical adverse effects. We conclude that even when linezolid is administered for a shorter time than formerly, adverse effects are reported by 63% of patients. Linezolid exerts tissue-dependent mitotoxicity that is responsible for downstream cellular consequences (blood cell death and nerve fiber swelling), leading to adverse hematologic and peripheral nervous side effects. Multicentric studies should confirm genetic susceptibility in larger cohorts.", "affiliations": "Muscle Research and Mitochondrial Function Laboratory, Cellex-IDIBAPS, Faculty of Medicine and Health Sciences-University of Barcelona, Barcelona, Spain garrabou@clinic.ub.es.;Infectious Diseases Department, Hospital Clinic of Barcelona, Barcelona, Spain.;Centro de Investigación Biomédica en Red en Enfermedades Raras‡.;Neurology Department, Hospital Clinic of Barcelona, Barcelona, Spain.;Centro de Investigación Biomédica en Red en Enfermedades Raras‡.;Muscle Research and Mitochondrial Function Laboratory, Cellex-IDIBAPS, Faculty of Medicine and Health Sciences-University of Barcelona, Barcelona, Spain.;Centro de Investigación Biomédica en Red en Enfermedades Raras‡.;Neurology Department, Hospital Clinic of Barcelona, Barcelona, Spain.;Centro de Investigación Biomédica en Red en Enfermedades Raras‡.;Muscle Research and Mitochondrial Function Laboratory, Cellex-IDIBAPS, Faculty of Medicine and Health Sciences-University of Barcelona, Barcelona, Spain.;Muscle Research and Mitochondrial Function Laboratory, Cellex-IDIBAPS, Faculty of Medicine and Health Sciences-University of Barcelona, Barcelona, Spain.;Muscle Research and Mitochondrial Function Laboratory, Cellex-IDIBAPS, Faculty of Medicine and Health Sciences-University of Barcelona, Barcelona, Spain.;Centro de Investigación Biomédica en Red en Enfermedades Raras‡.;Centro de Investigación Biomédica en Red en Enfermedades Raras‡.;Infectious Diseases Department, Hospital Clinic of Barcelona, Barcelona, Spain.;Muscle Research and Mitochondrial Function Laboratory, Cellex-IDIBAPS, Faculty of Medicine and Health Sciences-University of Barcelona, Barcelona, Spain.", "authors": "Garrabou|G|G|;Soriano|À|À|0000-0002-9374-0811;Pinós|T|T|;Casanova-Mollà|J|J|;Pacheu-Grau|D|D|;Morén|C|C|;García-Arumí|E|E|;Morales|M|M|;Ruiz-Pesini|E|E|;Catalán-Garcia|M|M|;Milisenda|J C|JC|;Lozano|E|E|;Andreu|A L|AL|;Montoya|J|J|;Mensa|J|J|;Cardellach|F|F|", "chemical_list": "D000900:Anti-Bacterial Agents; D024101:Mitochondrial Proteins; D011500:Protein Synthesis Inhibitors; D012335:RNA, Ribosomal; D012336:RNA, Ribosomal, 16S; C075526:RNA, ribosomal, 12S; D050994:Voltage-Dependent Anion Channels; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D003576:Electron Transport Complex IV; D000069349:Linezolid", "country": "United States", "delete": false, "doi": "10.1128/AAC.00542-17", "fulltext": null, "fulltext_license": null, "issn_linking": "0066-4804", "issue": "61(9)", "journal": "Antimicrobial agents and chemotherapy", "keywords": "16S rRNA; genetic polymorphisms; haplogroups; linezolid; mitochondrial genetics; mitochondrial protein synthesis; single nucleotide polymorphisms; toxicity", "medline_ta": "Antimicrob Agents Chemother", "mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000900:Anti-Bacterial Agents; D051546:Cyclooxygenase 2; D003576:Electron Transport Complex IV; D005260:Female; D006801:Humans; D007963:Leukocytes, Mononuclear; D000069349:Linezolid; D008297:Male; D008875:Middle Aged; D008928:Mitochondria; D024101:Mitochondrial Proteins; D009412:Nerve Fibers; D020641:Polymorphism, Single Nucleotide; D011500:Protein Synthesis Inhibitors; D012335:RNA, Ribosomal; D012336:RNA, Ribosomal, 16S; D012867:Skin; D050994:Voltage-Dependent Anion Channels", "nlm_unique_id": "0315061", "other_id": null, "pages": null, "pmc": null, "pmid": "28674062", "pubdate": "2017-09", "publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't", "references": "2461737;21852764;17194826;22251664;7477980;21907311;15909253;1692359;15317746;15288827;14583875;16723564;16575728;16306535;17088489;16180279;19883791;8482979;12659607;18757750;23223015;15117929;2444231;7955428;19707157;7525553;16127068;12115113;12529096;23075177;22734900;12963753;942051;15307017;20554968;18637969;12510056;20626771;22180620;11718489;17461714;20860455;24798272", "title": "Influence of Mitochondrial Genetics on the Mitochondrial Toxicity of Linezolid in Blood Cells and Skin Nerve Fibers.", "title_normalized": "influence of mitochondrial genetics on the mitochondrial toxicity of linezolid in blood cells and skin nerve fibers" }

[ { "companynumb": "JP-ALKEM LABORATORIES LIMITED-JP-ALKEM-2018-06129", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "LINEZOLID" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": "205517", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "10 MG/KG, EVERY 8 HOURS", "drugenddate": null, "drugenddateformat": null, "drugindication": "ENDOCARDITIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "10", "drugstructuredosageunit": "007", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LINEZOLID." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "LINEZOLID" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": "205517", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "30 MG/KG, QD", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "30", "drugstructuredosageunit": "007", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LINEZOLID." } ], "patientagegroup": null, "patientonsetage": "2", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Toxicity to various agents", "reactionmeddraversionpt": "21.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Aplasia pure red cell", "reactionmeddraversionpt": "21.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "GARRABOU G, SORIANO A, PINOS T, CASANOVA?MOLLA J, ET AL.. INFLUENCE OF MITOCHONDRIAL GENETICS ON THE MITOCHONDRIAL TOXICITY OF LINEZOLID IN BLOOD CELLS AND SKIN NERVE FIBERS. ANTIMICROBIAL AGENTS AND CHEMOTHERAPY. 2017?61(9):1?14", "literaturereference_normalized": "influence of mitochondrial genetics on the mitochondrial toxicity of linezolid in blood cells and skin nerve fibers", "qualification": "3", "reportercountry": "ES" }, "primarysourcecountry": "JP", "receiptdate": "20180816", "receivedate": "20180816", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15286980, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20181010" } ]

{ "abstract": "Efficacy and tolerability of telaprevir, pegylated interferon and ribavirin combination was assessed in 32 cirrhotic genotype 1 hepatitis C (HCV)-HIV coinfected patients. Undetectability of HCV-RNA was observed in 23/32 (71.9%) patients after 24 weeks. Treatment failure was observed in 9/32 subjects: four of them (45.5%) failed triple therapy due to virological rebound, while 5 patients (55.5%) experienced drug-related side effects driving to treatment interruption. These data suggest that telaprevir-containing triple therapy should be considered for treatment of genotype 1 HCV in HIV coinfected patients with liver cirrhosis, although a close vigilance is required because of potential drug-related side effects.", "affiliations": "Immunovirology Laboratory, Biomedicine Institute of Seville (IBiS), Infectious Diseases Service, Virgen del Rocío University Hospital, Sevilla, Spain.;Hospital Santa María del Rosell-Santa Lucía, Cartagena, Spain.;Hospital Universitario San Cecilio, Granada, Spain.;Department of Infectious Diseases, Hospital de la Santa Creu i Sant Pau, Universitat Autónoma de Barcelona, Barcelona, Spain.;Department of Infectious Diseases, Hospital de la Santa Creu i Sant Pau, Universitat Autónoma de Barcelona, Barcelona, Spain.;Hospital Santa María del Rosell-Santa Lucía, Cartagena, Spain.;Hospital Santa María del Rosell-Santa Lucía, Cartagena, Spain.;Hospital Perpetuo Socorro, Badajoz, Spain.;Hospital Comarcal de la Merced, Osuna, Sevilla, Spain.;Infectious Diseases Unit, Department of Internal Medicine, University Hospital of Ferrol, Health Area of Ferrol, A Coruña, Spain.;Infectious Diseases Unit, Department of Internal Medicine, University Hospital of Ferrol, Health Area of Ferrol, A Coruña, Spain.;Hospital Dr José Molina Orosa, Lanzarote, Spain.;Hospital Universitario San Cecilio, Granada, Spain.;Hospital Perpetuo Socorro, Badajoz, Spain.;Immunovirology Laboratory, Biomedicine Institute of Seville (IBiS), Infectious Diseases Service, Virgen del Rocío University Hospital, Sevilla, Spain.;Immunovirology Laboratory, Biomedicine Institute of Seville (IBiS), Infectious Diseases Service, Virgen del Rocío University Hospital, Sevilla, Spain. Electronic address: mleal@telefonica.net.", "authors": "Genebat|Miguel|M|;Vera|Francisco|F|;Hernández-Quero|José|J|;Domingo|Pere|P|;Guardiola|José M|JM|;Martínez-Madrid|Onofre|O|;Martínez|Lorena|L|;de la Llana|Francisco García|FG|;Sánchez-Villegas|Jorge|J|;Alvarez|Hortensia|H|;Mariño|Ana|A|;Lluch|José F|JF|;Martínez-Pérez|María A|MA|;Marín|Jorge|J|;Ruiz-Mateos|Ezequiel|E|;Leal|Manuel|M|", "chemical_list": "D000998:Antiviral Agents; D009842:Oligopeptides; D012254:Ribavirin; C486464:telaprevir; D007372:Interferons", "country": "Netherlands", "delete": false, "doi": null, "fulltext": null, "fulltext_license": null, "issn_linking": "0166-3542", "issue": "104()", "journal": "Antiviral research", "keywords": "HIV; Hepatitis C virus; Liver cirrhosis; Telaprevir", "medline_ta": "Antiviral Res", "mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D000998:Antiviral Agents; D060085:Coinfection; D004359:Drug Therapy, Combination; D005260:Female; D015658:HIV Infections; D019698:Hepatitis C, Chronic; D006801:Humans; D007372:Interferons; D008103:Liver Cirrhosis; D008297:Male; D008875:Middle Aged; D009842:Oligopeptides; D012254:Ribavirin; D013997:Time Factors; D016896:Treatment Outcome; D019562:Viral Load; D055815:Young Adult", "nlm_unique_id": "8109699", "other_id": null, "pages": "59-61", "pmc": null, "pmid": "24491797", "pubdate": "2014-04", "publication_types": "D016428:Journal Article; D016448:Multicenter Study; D013485:Research Support, Non-U.S. Gov't", "references": null, "title": "Efficacy and tolerability after 24 weeks of treatment with telaprevir, pegylated interferon and ribavirin in cirrhotic HIV-HCV coinfected subjects.", "title_normalized": "efficacy and tolerability after 24 weeks of treatment with telaprevir pegylated interferon and ribavirin in cirrhotic hiv hcv coinfected subjects" }

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EFFICACY AND TOLERABILITY AFTER 24 WEEKS OF TREATMENT WITH TELAPREVIR, PEGYLATED INTERFERON AND RIBAVIRIN IN CIRRHOTIC HIV-HCV COINFECTED SUBJECTS. ANTIVIRAL RESEARCH 2014?104 (1):59-61.", "literaturereference_normalized": "efficacy and tolerability after 24 weeks of treatment with telaprevir pegylated interferon and ribavirin in cirrhotic hiv hcv coinfected subjects", "qualification": "1", "reportercountry": "ES" }, "primarysourcecountry": "ES", "receiptdate": "20190201", "receivedate": "20190115", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15824310, "safetyreportversion": 3, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": 1, "seriousnessother": null, "transmissiondate": "20190417" }, { "companynumb": "ES-ROCHE-2245281", "fulfillexpeditecriteria": "1", "occurcountry": "ES", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "DARBEPOETIN ALFA" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "DOSAGE FORM: UNSPECIFIED", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "40", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ARANESP" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "RALTEGRAVIR" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "DOSAGE FORM: UNSPECIFIED", "drugenddate": null, "drugenddateformat": null, "drugindication": "HIV INFECTION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RALTEGRAVIR." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "RIBAVIRIN" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": "021511", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": null, "drugenddate": "20130317", "drugenddateformat": "102", "drugindication": "HEPATITIS C", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": "20130206", "drugstartdateformat": "102", "drugstructuredosagenumb": "1000", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RIBAVIRIN." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "INTERFERON ALFA-2A OR INTERFERON ALFA-2B" }, "drugadditional": null, "drugadministrationroute": "058", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "DOSAGE FORM: UNSPECIFIED, 180/SEM", "drugenddate": null, "drugenddateformat": null, "drugindication": "HEPATITIS C", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "INTERFERON ALFA NOS" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "TELAPREVIR" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": null, "drugenddate": "20130317", "drugenddateformat": "102", "drugindication": "HEPATITIS C", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": "20130206", "drugstartdateformat": "102", "drugstructuredosagenumb": "2250", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "INCIVO" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "EMTRICITABINE\\TENOFOVIR DISOPROXIL FUMARATE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "DOSAGE FORM: UNSPECIFIED", "drugenddate": null, "drugenddateformat": null, "drugindication": "HIV INFECTION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TRUVADA" } ], "patientagegroup": null, "patientonsetage": "49", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Septic shock", "reactionmeddraversionpt": "21.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Subarachnoid haemorrhage", "reactionmeddraversionpt": "21.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Pyrexia", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Off label use", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Acute kidney injury", "reactionmeddraversionpt": "21.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Product used for unknown indication", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Urosepsis", "reactionmeddraversionpt": "21.1", "reactionoutcome": "5" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 20130206" } }, "primarysource": { "literaturereference": "GENEBAT M, VERA F, HERNANDEZ- QUERO J, DOMINGO P, GUARDIOLA J, MARTINEZ-MADRID O, ET AL. EFFICACY AND TOLERABILITY AFTER 24 WEEKS OF TREATMENT WITH TELAPREVIR, PEGYLATED INTERFERON AND RIBAVIRIN IN CIRRHOTIC HIV HCV COINFECTED SUBJECTS.. ANTIVIRAL RESEARCH 2014?104:59-61.", "literaturereference_normalized": "efficacy and tolerability after 24 weeks of treatment with telaprevir pegylated interferon and ribavirin in cirrhotic hiv hcv coinfected subjects", "qualification": "1", "reportercountry": "ES" }, "primarysourcecountry": "ES", "receiptdate": "20190129", "receivedate": "20190121", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15847385, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20190417" }, { "companynumb": "ES-VERTEX PHARMACEUTICALS-2014-004739", "fulfillexpeditecriteria": "1", "occurcountry": "ES", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "TELAPREVIR" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": "201917", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": "1125 MG, UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "HIV INFECTION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "1125", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "INCIVO" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "TELAPREVIR" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": "201917", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": "1125 MG, UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "1125", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "INCIVO" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "RIBAVIRIN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "HIV 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"drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PEGYLATED INTERFERON NOS" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "PEGINTERFERON ALFA-2A OR PEGINTERFERON ALFA-2B OR PEGINTERFERON BETA-1A OR PEGINTERFERON LAMBDA-1A" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PEGYLATED INTERFERON NOS" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Pyelonephritis acute", "reactionmeddraversionpt": "18.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Off label use", "reactionmeddraversionpt": "18.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "GENEBAT M, VERA F, HERNANDEZ QUERO J, DOMINGO P, GUARDIOLA J, DOMINGO P, ET AL.. EFFICACY AND TOLERABILITY AFTER 24 WEEKS OF TREATMENT WITH TELAPREVIR, PEGYLATED INTERFERON AND RIBAVIRIN IN CIRRHOTIC HIV-HCV COINFECTED SUBJECTS.. ANTIVIRAL RESEARCH APR. 2014;104:59-61", "literaturereference_normalized": "efficacy and tolerability after 24 weeks of treatment with telaprevir pegylated interferon and ribavirin in cirrhotic hiv hcv coinfected subjects", "qualification": "1", "reportercountry": "ES" }, "primarysourcecountry": "ES", "receiptdate": "20141203", "receivedate": "20141203", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 10622433, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20150529" } ]

{ "abstract": "A case report of a 4-yr-old child who developed an anaphylactic reaction to parenteral nutrition is presented. Dermal allergy tests demonstrated a sensitivity to Travasol solution and Armour multivitamin 2 solution. This is the first reported case known to us of such a response to elemental parenteral nutrition.", "affiliations": null, "authors": "Pomeranz|S|S|;Gimmon|Z|Z|;Ben Zvi|A|A|;Katz|S|S|", "chemical_list": "D000596:Amino Acids; D004573:Electrolytes; D057947:Parenteral Nutrition Solutions; D012996:Solutions; C545824:amino-acid, glucose, and electrolyte solution; D005947:Glucose", "country": "United States", "delete": false, "doi": "10.1177/0148607187011003314", "fulltext": null, "fulltext_license": null, "issn_linking": "0148-6071", "issue": "11(3)", "journal": "JPEN. Journal of parenteral and enteral nutrition", "keywords": null, "medline_ta": "JPEN J Parenter Enteral Nutr", "mesh_terms": "D000596:Amino Acids; D000707:Anaphylaxis; D002675:Child, Preschool; D004342:Drug Hypersensitivity; D004573:Electrolytes; D005947:Glucose; D006801:Humans; D008297:Male; D010288:Parenteral Nutrition; D057947:Parenteral Nutrition Solutions; D012882:Skin Tests; D012996:Solutions", "nlm_unique_id": "7804134", "other_id": null, "pages": "314-5", "pmc": null, "pmid": "3110449", "pubdate": "1987", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Parenteral nutrition-induced anaphylaxis.", "title_normalized": "parenteral nutrition induced anaphylaxis" }

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PARENTERAL NUTRITION-INDUCED ANAPHYLAXIS. JOURNAL OF PARENTERAL AND ENTERAL NUTRITION. 1987;11(3):314-315", "literaturereference_normalized": "parenteral nutrition induced anaphylaxis", "qualification": "1", "reportercountry": "IL" }, "primarysourcecountry": "IL", "receiptdate": "20170414", "receivedate": "20170414", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 13445316, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170830" } ]

{ "abstract": "BACKGROUND\nThis phase I study investigates the feasibility of carboplatin plus dose-dense (q2-week) pemetrexed given concurrently with radiotherapy (XRT) for locally advanced and oligometastatic non-small cell lung cancer (NSCLC).\n\n\nMETHODS\nEligible patients had Stage III or IV (oligometastatic) NSCLC. Patients received XRT to 63 Gy in standard fractionation. Patients received concurrent carboplatin (AUC = 6) during weeks 1 and 5 of XRT, and pemetrexed during weeks 1, 3, 5, and 7 of XRT. The starting dose level (level 1) of pemetrexed was 300 mg/m2. Following the finding of dose limiting toxicity (DLT) in dose level 1, an amended dose level (level 1A) continued pemetrexed at 300 mg/m2, but with involved field radiation instead of extended nodal irradiation. Consolidation consisted of carboplatin (AUC = 6) and pemetrexed (500 mg/m2) q3 weeks × 2 -3 cycles.\n\n\nRESULTS\nEighteen patients were enrolled. Fourteen patients are evaluable for toxicity analysis. Of the initial 6 patients treated on dose level 1, two experienced DLTs (one grade 4 sepsis, one prolonged grade 3 esophagitis). There was one DLT (grade 5 pneumonitis) in the 8 patients treated on dose level 1A. In 16 patients evaluable for response (4 with oligometastatic stage IV disease and 12 with stage III disease), the median follow-up time is 17.8 months. Thirteen of 16 patients had in field local regional response. The actuarial median survival time was 28.6 months in all patients and 34.7 months (estimated) in stage III patients.\n\n\nCONCLUSIONS\nConcurrent carboplatin with dose-dense (q2week) pemetrexed at 300 mg/m2 with involved field XRT is feasible and encouraging in patients with locally advanced and oligometastatic NSCLC.", "affiliations": "Department of Radiation Oncology, Kimmel Cancer Center, Jefferson Medical College of Thomas Jefferson University, Philadelphia, USA.", "authors": "Shen|Xinglei|X|;Denittis|Albert|A|;Werner-Wasik|Maria|M|;Axelrod|Rita|R|;Gilman|Paul|P|;Meyer|Thomas|T|;Treat|Joseph|J|;Curran|Walter J|WJ|;Machtay|Mitchell|M|", "chemical_list": "D005971:Glutamates; D000068437:Pemetrexed; D006147:Guanine; D016190:Carboplatin", "country": "England", "delete": false, "doi": "10.1186/1748-717X-6-17", "fulltext": "\n==== Front\nRadiat OncolRadiation Oncology (London, England)1748-717XBioMed Central 1748-717X-6-172132416010.1186/1748-717X-6-17ResearchPhase i study of 'dose-dense' pemetrexed plus carboplatin/radiotherapy for locally advanced non-small cell lung carcinoma Shen Xinglei 1xinglei.shen@jeffersonhospital.orgDeNittis Albert 2denittisa@mlhs.orgWerner-Wasik Maria 1maria.werner-wasik@jeffersonhospital.orgAxelrod Rita 3rita.axelrod@mail.tju.eduGilman Paul 4gilmanp@mlhs.orgMeyer Thomas 4meyert@mlhs.orgTreat Joseph 5treatjo@lilly.comCurran Walter J 16wcurran@emory.eduMachtay Mitchell 17mitchell.machtay@uhhospitals.org1 Department of Radiation Oncology, Kimmel Cancer Center, Jefferson Medical College of Thomas Jefferson University, Philadelphia, USA2 Department of Radiation Oncology, Lankenau Hospital and Lankenau Institute for Medical Research, Main Line Health System, Pennsylvania, USA3 Department of Medical Oncology, Kimmel Cancer Center, Jefferson Medical College of Thomas Jefferson University, Philadelphia, USA4 Department of Hematology/Oncology, Lankenau Hospital and Lankenau Institute for Medical Research, Main Line Health System, Pennsylvania, USA5 Eli Lilly, Inc., Indianapolis, USA6 Department of Radiation Oncology, Emory University Hospital, Atlanta, USA7 Department of Radiation Oncology, University Hospitals, Case Medical Center, Cleveland, USA2011 16 2 2011 6 17 17 23 9 2010 16 2 2011 Copyright ©2011 Shen et al; licensee BioMed Central Ltd.2011Shen et al; licensee BioMed Central Ltd.This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Background\nThis phase I study investigates the feasibility of carboplatin plus dose-dense (q2-week) pemetrexed given concurrently with radiotherapy (XRT) for locally advanced and oligometastatic non-small cell lung cancer (NSCLC).\n\nMethods\nEligible patients had Stage III or IV (oligometastatic) NSCLC. Patients received XRT to 63 Gy in standard fractionation. Patients received concurrent carboplatin (AUC = 6) during weeks 1 and 5 of XRT, and pemetrexed during weeks 1, 3, 5, and 7 of XRT. The starting dose level (level 1) of pemetrexed was 300 mg/m2. Following the finding of dose limiting toxicity (DLT) in dose level 1, an amended dose level (level 1A) continued pemetrexed at 300 mg/m2, but with involved field radiation instead of extended nodal irradiation. Consolidation consisted of carboplatin (AUC = 6) and pemetrexed (500 mg/m2) q3 weeks × 2 -3 cycles.\n\nResults\nEighteen patients were enrolled. Fourteen patients are evaluable for toxicity analysis. Of the initial 6 patients treated on dose level 1, two experienced DLTs (one grade 4 sepsis, one prolonged grade 3 esophagitis). There was one DLT (grade 5 pneumonitis) in the 8 patients treated on dose level 1A. In 16 patients evaluable for response (4 with oligometastatic stage IV disease and 12 with stage III disease), the median follow-up time is 17.8 months. Thirteen of 16 patients had in field local regional response. The actuarial median survival time was 28.6 months in all patients and 34.7 months (estimated) in stage III patients.\n\nConclusions\nConcurrent carboplatin with dose-dense (q2week) pemetrexed at 300 mg/m2 with involved field XRT is feasible and encouraging in patients with locally advanced and oligometastatic NSCLC.\n\nTrial Registration\nClinicalTrials.gov NCT00330044\n==== Body\nBackground\nConcurrent chemoradiation has been established as the standard of care for non-operable stage III non-small cell lung cancer (NSCLC) [1-4]. With this approach, the median survival time is approximately 17 months and about 15% of patients survive 5+ years. Concurrent combined modality therapy has improved survival over single modality or sequential therapy[1-4], but overall outcomes remain poor.\n\nThe optimal chemotherapy regimen to use with concurrent radiation therapy remains uncertain. Initial studies of concurrent treatment have used cisplatin plus a second drug given at near-systemic doses for two cycles during RT [1-4]. No platinum based doublet has clear proven superiority over other regimens. These combinations have significant toxicity with high rates of esophagitis, nausea/vomiting, and myelosuppression.\n\nAlternative less toxic chemotherapy drugs and schedules, most notably weekly carboplatin/paclitaxel regimens have been extensively studied [5-8]. This regimen has been criticized because safe and feasible \"radiosensitizing\" doses of carboplatin (AUC = 1.5 to 2) and paclitaxel (45-50 mg/m2) are well below the dose intensities considered independently active against NSCLC[9]. Thus, while this regimen may have excellent radiosensitization properties, it likely has little effect on tumor populations outside of the radiation portal. The solution has been to combine concurrent chemoradiotherapy with induction [8,10] or consolidation [4,5] chemotherapy given at systemic doses. This approach necessarily delays the initiation of either local or systemic therapy.\n\nIn contrast, the new cytotoxic drug pemetrexed has independent activity against NSCLC and reduced toxicity [11,12], and may be feasible to deliver at near-systemic doses with concurrent radiotherapy[13]. Pemetrexed belongs to the antimetabolite class of antineoplastic drugs. It targets multiple molecules within the folate metabolism pathway, including thymidylate synthase and dihydrofolate reductase. Preclinical data support the hypothesis that pemetrexed serves as a radiosensitizer in addition to having independent activity against NSCLC in vitro and in vivo [14,15]. A large randomized trial comparing pemetrexed to docetaxel in second line treatment of metastatic NSCLC showed similar response and survival with a more favorable toxicity profile for pemetrexed [16]. In the first line chemotherapy setting for advanced NSCLC, a randomized trial showed that pemetrexed in combination with cisplatin resulted in equivalent survival to gemcitabine with cisplatin [17].\n\nPreliminary results of several studies testing pemetrexed plus radiotherapy have been presented. A phase I trial showed that pemetrexed at a dose of 500 mg/m2 q3weeks (Weeks 1, 4, and 7) could be combined with a full course of standard radiotherapy[13]. Recent update from the CALBG trial #30407 showed that systemic dose pemetrexed may be combined with systemic dose carboplatin (AUC = 6) q3weeks with concurrent radiation to 70 Gy with acceptable toxicities. Efficacy data presented at ASCO 2009 is encouraging, with a median survival time of 22.3 months[18].\n\nThe modest toxicity profile of pemetrexed led us to consider whether further intensification of pemetrexed during chemoradiotherapy could be accomplished, with the long-term goal of improving local and distant control. This strategy has successfully improved outcomes in node-positive breast cancer [19,20], aggressive non-Hodgkin's lymphoma[21], and ovarian cancer[22]. We designed and initiated a pilot (phase I) feasibility trial of dose-dense (q2-week) pemetrexed with systemic dose carboplatin and concurrent radiotherapy in the treatment of locally advanced and oligometastatic NSCLC.\n\nMethods\nThis was a prospective, investigator-initiated clinical trial, approved by the scientific Clinical Research Committee of the Kimmel Cancer Center at Thomas Jefferson University as well as the Internal Review Board (IRB) of Thomas Jefferson University (TJU). The study was also approved by the IRB of the participating medical center, Lankeanu Hospital (Lower Merion, PA), a member of the Jefferson Health System. Eli Lilly Inc. supported the study with a grant to Thomas Jefferson University; however, the study was written, conducted and analyzed by TJU and Lankenau investigators and sponsored by TJU, independently from any corporate entity. The study was monitored by the Kimmel Cancer Center's Data and Safety Monitoring Board in addition to the investigators.\n\nPatients/Eligibility\nThis study was available to patients with locally advanced NSCLC who required definitive full dose radiotherapy as part of their treatment plan. This included stage IIIA, IIIB and oligometastatic stage IV (without diffuse hematogenous metastases) NSCLC. Patients with stage IV NSCLC were only eligible if they had bulky local-regional disease deemed to require high dose local radiotherapy and no symptoms from their extrathoracic disease.\n\nOther eligibility requirements included Zubrod performance status 0-1, absence of severe (>10%) weight loss, FEV1 >1000 cc, serum creatinine < 1.5 mg/dl, serum bilirubin < 1.5 mg/dl, SGOT < 1.5 times institutional upper limits of normal, hemoglobin >8.0 g/dl, ANC >2000 cells/mm3, platelets > 100,000 cells/mm3, and no recent (< 6 months) myocardial infarction, unstable angina, congestive heart failure or uncontrolled arrhythmia. Exclusion criteria also included prior chemotherapy for lung cancer and/or prior thoracic radiotherapy that would result in field overlap.\n\nRadiotherapy\nRadiotherapy (RT) planning via 3-dimensional, CT-scan based planning was required. Intensity modulated radiation therapy (IMRT) was not used. The choice of field arrangements was left to the discretion of the radiation oncologist, and typically consisted of two to four conformally planned, coplanar fields designed to minimize irradiation of the spinal cord and contralateral lung. Respiratory gating was not used. The protocol-specified dose of radiotherapy to tumor as defined by CT (and PET scan where appropriate) was 63 Gy, given in conventional (1.8-2 Gy) once daily fractionation.\n\nThe initial protocol design (Dose Level #1) was to irradiate a large volume to 45 Gy, followed by a cone-down to the gross tumor (plus a small margin) for an 18 Gy boost. This initial volume would include the gross tumor plus a generous margin (at least 2 cm) and the comprehensive bilateral mediastinal nodal space (from the thoracic inlet to at least 5 cm below the carina). In some cases, radiotherapy fields included the inferior mediastinal nodes to the crus of the diaphragm (if subcarinal nodes were involved) and/or contralateral hilar nodes (if bilateral mediastinal nodes were involved), based on the principle of irradiating at least one echelon of lymph nodes beyond that known to be grossly involved.\n\nThe protocol was subsequently amended in response to two DLTs to require the use of involved field irradiation from the start of radiotherapy (Dose Level #1A). Involved field radiotherapy included areas positive by CT scan and/or PET scan, with an option to include areas located geographically between two involved areas (e.g. inclusion of the ipsilateral hilum if the adjacent mediastinal nodes are involved). Contralateral mediastinal, contralateral hilar and supraclavicular nodes were no longer electively irradiated.\n\nChemotherapy/Dose Escalation Plan\nThe study was designed to use a fixed dose of carboplatin (AUC = 6, based upon the Cockroft-Gault formula), during Weeks 1 and 5 of radiotherapy (preferably during Day 1 or 2 of those weeks). There were no plans to alter this dose/schedule.\n\nThe pemetrexed design of the study was to administer this drug on a biweekly basis (Weeks 1, 3, 5, and 7) during radiotherapy; on Weeks 1 and 5 it would be given together on the same day with carboplatin. The starting dose of pemetrexed for the study was 300 mg/m2, with plans to dose escalate to 400 and 500 mg/m2 in subsequent patients based upon analysis of feasibility and toxicity (these dose escalations did not successfully occur).\n\nDose/schedule modifications were allowed for toxicity. If grade 3-4 neutropenia/thrombocytopenia and/or grade 3 non-hematologic toxicity occurred, all agents (RT, carboplatin, radiotherapy, and pemetrexed) were to be held for 1-2 weeks. When toxicity resolved to Grade 0-1, treatment was to be resumed with a reduction in pemetrexed by 50 mg/m2 (i.e. from 300 mg/m2 to 250 mg/m2). If a second episode of Grade 4 hematologic or grade 3 non-hematologic toxicity were to occur, this would be considered a DLT and the patient removed from study.\n\nPatients who successfully completed carboplatin/pemetrexed and concurrent radiotherapy were allowed to continue on to consolidation carboplatin/pemetrexed after recovering from acute effects of chemoradiotherapy. The consolidation regimen consisted of 2-3 cycles of carboplatin (AUC = 6) and pemetrexed (500 mg/m2) q3 weeks. Growth factor (G-CSF or GM-CSF) support was recommended.\n\nPatients were given a subcutaneous injection of B12 (1000 mcg) before starting study treatment and once per month while on study. Folic acid (1000 mcg daily) was also prescribed starting Day 1.\n\nStudy Endpoints/Analysis plan\nThe primary endpoint of the study was dose-limiting toxicity (DLT), defined as any one of the following serious adverse events (SAE's) as determined by the study investigators and medical monitor to be the result of study treatment:\n\n1. Death within 30 days after the completion of radiotherapy or within 90 days of start of radiotherapy.\n\n2. Grade 4 non-hematologic toxicity occurring during or within 30 days after the completion of radiotherapy or within 90 days of start of radiotherapy.\n\n3. Grade 3 pulmonary toxicity within 90 days after the completion of chemoradiotherapy.\n\n4. Prolonged (>14 days) grade 3 esophagitis 30 days after the completion of radiotherapy or within 90 days of start of radiotherapy preventing the patient from being able to proceed with anti-cancer treatment.\n\n5. Inability to complete at least 54 Gy of thoracic radiotherapy due to toxicity\n\nThe Kimmel Cancer Center of Thomas Jefferson University assigned an independent medical monitor to review SAE's with the study investigators and help determine if/when a DLT occurred and if pemetrexed dose may be escalated (or de-escalated) per study protocol.\n\nThe statistical plan called for dose escalation from Dose Level #1 (300 mg/m2) to Dose Level #2 (400 mg/m2) if/when none of the first three or one of the first six patients enrolled and evaluable experienced a DLT. A similar plan was made for further escalation beyond Dose Level #2. If at any given dose level, a second DLT occurred, the study was to be closed to further accrual, discussed with the medical monitor and IRB, and modified in order to assure patient safety.\n\nSecondary endpoints included local tumor response rates, and progression-free and overall survival. Survival times were calculated from date of registration on trial.\n\nResults\nAccrual/Feasibility\nThis study enrolled its first patient in April 2006; the final patient enrolled in April 2008. There were several time periods where the study was closed for safety/toxicity assessment.\n\nOf the 18 patients accrued, two patients were never treated with study chemoradiotherapy and are not evaluable for any study endpoints. Both patients were found to be fully eligible, signed informed consent, and were enrolled using our institution's registration mechanism. One patient withdrew consent and switched to non-protocol chemoradiotherapy; the second developed a GI bleed and severe anemia prior to receiving any study medication.\n\nOf the remaining 16 patients, two patients are not evaluable for the primary study endpoint (determination of DLT). These two patients (Pts 9 and 10) were enrolled onto Dose Level #2 (400 mg/m2 pemetrexed), based upon what initially appeared to be a favorable toxicity profile among the first six evaluable patients in Dose Level #1. However, as patients #9 and 10 were beginning treatment, a delayed DLT in Dose Level #1 occurred (prolonged esophagitis/weight loss requiring feeding tube). After discussions among the investigators and medical monitor, they were offered the option of withdrawing or continuing with a reduced pemetrexed dose of 250 mg/m2 (Dose Level # -1). These patients opted to continue at the reduced pemetrexed dose. Of note, these two patients completed therapy on schedule with no significant non-hematologic toxicities.\n\nPatient characteristics\nPatient characteristics are shown in Table 1. The median patient age was 70. No patient was considered a candidate for surgical resection. The median FEV1 was 2.00 L. Most patients had stage III disease (6 stage IIIA; 6 stage IIIB) and 4 patients had oligometastatic (3 brain, 1 bone) stage IV disease. Histology was squamous in 3 patients, adenocarcinoma in 9 patients, and not-otherwise-specified (NOS) in 4 patients.\n\nTable 1 Patient Characteristics and Treatment Delivery\n\nPatient\tAge\tStage\tHistology\tDose Level\tXRT dose/Tx time (Gy/days)\tConcurrent Pemetrexed Dose Received (mg/m2)\t\n1 TJ\t55\tIIIB\tAd\t1\t63/45\t1150\t\n\t\n2 ST\t72\tIIIB\tSq\t1\t63/48\t900\t\n\t\n3 LM\t64\tIIIA\tAd\t1\t39.6/33*\t900\t\n\t\n4 SR\t45\tIIIB\tAd\t1\t59.4/57\t1200\t\n\t\n5 MW\t54\tIV\tAd\t1\t63/47\t1200\t\n\t\n6 SR\t75\tIIIA\tAd\t1\t63/51\t900\t\n\t\n7 PH\t68\tIIIB\tNOS\t2/-1\t63/55\t1300\t\n\t\n8 JD\t72\tIIIB\tAd\t2/-1\t63/51\t1150\t\n\t\n9 JB\t78\tIIIB\tNOS\t1A\t63/47\t900\t\n\t\n10 BS\t61\tIV\tNOS\t1A\t63/49\t1200\t\n\t\n11 ES\t63\tIV\tAd\t1A\t63/48\t900\t\n\t\n12 JB\t83\tIIIA\tSq\t1A\t63/53\t1200\t\n\t\n13 EH\t73\tIV\tAd\t1A\t63/54\t1200\t\n\t\n14 ML\t74\tIIIA\tAd\t1A\t63/47\t1200\t\n\t\n15 CN\t74\tIIIA\tSq\t1A\t63/49\t1200\t\n\t\n16 UG\t62\tIIIA\tNOS\t1A\t63/48\t1200\t\n*Pt suffered neutropenic fever/sepsis requiring treatment discontinuation.\n\nHistology: Ad = Adenocarcinoma; Sq = Squamous; NOS = Not-otherwise-specified\n\nTreatment compliance\nFourteen patients were evaluable for the study's primary endpoints of feasibility and assessment of DLT; all these patients received both doses of carboplatin (AUC = 6), and 13 of 14 patients completed their full course of radiotherapy. All 14 patients received at least 3 of four planned courses of pemetrexed (7 of 14 received all four courses; the other 7 missed one course due to neutropenia and/or anemia). Of the 13 patients who completed radiotherapy, 8 received at least two cycles of adjuvant chemotherapy and 5 did not (2 developed progressive disease, 2 had dose limiting toxicities precluding further therapy, and 1 developed a pulmonary embolism).\n\nToxicity\nOf the six patients enrolled into Dose Level #1, two patients developed DLT. One DLT was neutropenic fever, sepsis and multi-organ failure, which appeared to arise in the setting of colonic perforation at the site of chronic diverticulitis. The patient recovered after urgent surgery and a prolonged hospital course, but was unable to resume any anti-cancer treatment. The second DLT was a delayed and prolonged grade 3 esophagitis after completion of concurrent chemoradiation requiring feeding tube placement, preventing the patient from receiving any additional anti-cancer treatment. Based on these two DLTs, Dose Level #1 was considered infeasible as originally designed and the study was amended utilizing reduced radiotherapy fields.\n\nDose Level #1A enrolled eight patients evaluable for toxicity. One patient suffered a DLT: an 83 year-old man with significant underlying COPD developed respiratory decompensation one week after completing chemoradiotherapy, and ultimately died. The treating physicians initially determined that this was 'unrelated' to study treatment and primarily related to age and underlying respiratory insufficiency. However, on comprehensive review by the entire study investigation team and independent medical monitors, it was concluded that the patient's death should be considered 'possibly related' to treatment.\n\nThe overall toxicity profile of sixteen evaluable patients is shown in Table 2. The most common toxicity was neutropenia, including 7 cases of grade 3-4 neutropenia. There was one Grade 5 toxicity and one patient with Grade 4 non-hematologic toxicity (neutropenic fever/sepsis). Three patients developed grade 3 esophagitis. One patient developed grade 3-4 fatigue. In Dose Level #1, the rate of any Grade 3 or greater non-hematologic toxicity was 33% (2/6); in Dose Level #1A, the rate of Grade 3 or greater non-hematologic toxicity was 25% (2/8).\n\nTable 2 Acute Toxicity\n\nToxicity\tGrade 1-2\tGrade 3\tGrade 4\tGrade 5\t\nDose Level #1* (N = 6)\t\n\t\nNeutropenia\t1\t2\t1 ††\t---\t\n\t\nThrombocytopenia\t1\t1\t1 ††\t---\t\n\t\nAnemia\t3\t1\t---\t---\t\n\t\nEsophagitis\t3\t1\t---\t---\t\n\t\nPneumonitis\t2\t1\t---\t---\t\n\t\nSepsis\t--\t--\t1 ††\t--\t\n\t\nFatigue\t4\t--\t---\t---\t\n\t\nElevated LFT's\t4\t1 ††\t---\t---\t\n\t\nElevated Creatinine\t1\t--\t---\t---\t\n\t\nWorst Toxicity Overall\t2\t3\t1\t---\t\n\t\nWorst non-heme Toxicity Overall\t4\t1\t1\t---\t\n\t\n\t\t\t\t\t\n\t\nDose Level #1A* (N = 8)\t\n\t\nNeutropenia\t4\t3\t1\t---\t\n\t\nThrombocytopenia\t2\t1\t---\t---\t\n\t\nAnemia\t6\t1\t---\t---\t\n\t\nEsophagitis\t5\t2\t---\t---\t\n\t\nPneumonitis\t3\t---\t---\t1 §\t\n\t\nSepsis\t---\t---\t---\t---\t\n\t\nFatigue\t5\t---\t1 §\t---\t\n\t\nElevated LFT's\t1\t---\t---\t---\t\n\t\nElevated Creatinine\t1\t---\t---\t---\t\n\t\nWorst Toxicity Overall\t3\t3\t---\t1\t\n\t\nWorst non-heme Toxicity Overall\t4\t1\t---\t1\t\n\t\n\t\t\t\t---\t\n\t\nOverall Study Population (N = 16) †\t\n\t\nNeutropenia\t5\t5\t2\t---\t\n\t\nThrombocytopenia\t3\t2\t1 ††\t---\t\n\t\nAnemia\t9\t2\t---\t---\t\n\t\nEsophagitis\t8\t3\t---\t---\t\n\t\nPneumonitis\t5\t1\t---\t1 §\t\n\t\nFatigue\t9\t0\t1\t---\t\n\t\nElevated LFT's\t5\t1\t---\t---\t\n\t\nElevated Creatinine\t2\t---\t---\t---\t\n\t\nWorst Toxicity Overall\t5\t6\t1 ††\t1 §\t\n\t\nWorst non-heme Toxicity Overall\t8\t2\t1 ††\t1 §\t\n* Dose Level #1 and Dose Level #1A used the same doses (pemetrexed 300 mg/m2 q2-week); however Dose Level #1 used extended field RT and Dose Level #1A used involved field RT.\n\n† Overall study population included all of the patients treated in Dose Level #1 and Dose Level #1A, as well as two patients who were re-assigned from Dose Level #2 (400 mg/m2) to Dose Level -I (250 mg/m2) because of safety purposes.\n\n†† Single patient with sepsis and multi-organ failure in the setting of acute diverticulitis.\n\n§ Elderly (83-year old) patient with COPD, died from respiratory failure 30 days post-RT.\n\nResponse/Efficacy\nA total of 15 patients are evaluable for treatment response and patterns of failure (Table 3). In-field local-regional tumor response (partial or complete response) by RECIST criteria was observed in 14, while the other patient demonstrated stable disease without evidence of in-field progression on serial CT and/or PET scans at 40 months. Three patients developed local-regional recurrence as the first site of failure. One progressed just outside of the radiotherapy portal ('marginal miss') and a second patient progressed in an elective nodal region not treated with involved field radiation. These two patients, each with a small focus of intrathoracic progression, were treated with additional radiotherapy. A third patient who progressed within the treatment field at 22 months was treated with salvage brachytherapy. In all, five patients progressed locally at a median time of 10 months.\n\nTable 3 Treatment Response and Outcomes Data\n\nPatient\tDose Level\tInitial Local response \tDistant Metastases\tSurvival Status\t\n1 TJ\t1\tNR/SD\tNone\tAWD @ 40 mo.\t\n\t\n2 ST\t1\tPR\tDiffuse Mets\tDOD @ 34 mo.\t\n\t\n3 LM\t1\tPR\tDiffuse Mets\tDOD @ 15 mo.\t\n\t\n4 SR\t1\tCR\tDiffuse Mets\tDOD @ 29 mo.\t\n\t\n5 MW\t1\tPR\tMets at presentation\tDOD @ 6 mo.\t\n\t\n6 SR\t1\tCR\tNone\tNED @ 26 mo.\t\n\t\n7 PH\t2/-1\tCR\tNone\tAWD @ 26 mo.\t\n\t\n8 JD\t2/-1\tPD*\tNone\tNED @ 27 mo.\t\n\t\n9 JB\t1A\tCR\tNone\tNED @ 24 mo.\t\n\t\n10 BS\t1A\tPR\tMets at presentation\tDOD @ 9 mo.\t\n\t\n11 ES\t1A\tPR\tMets at presentation\tDOD @ 6 mo.\t\n\t\n12 JB\t1A\tNA\tNA\tDID/DOC @ 3 mo.\t\n\t\n13 EH\t1A\tPR\tMets at presentation\tDOD @ 6 mo.\t\n\t\n14 ML\t1A\tPR\tNone\tNCRM @ 9 mo.\t\n\t\n15 CN\t1A\tPR\tNone\tAWD @ 18 mo.\t\n\t\n16 UG\t1A\tCR\tNone\tAWD @ 18 mo.\t\nNR/SD: No Response/Stable Disease\n\nPR: Partial Response\n\nCR: Complete Response\n\nPD*: Progressive Disease (one patient had PD just outside of the radiotherapy field edge)\n\nNA: Not Assessable - one patient is not assessable or evaluable due to early (possibly treatment related) death.\n\nAWD: Alive with Disease\n\nDOD: Died of Disease\n\nNED: No Evidence of (Active) Disease\n\nDID/DOC: Died of intercurrent Disease and/or treatment Complications\n\nNCRM: Non-cancer related mortality (one patient died of a MI while NED)\n\nThree patients (20%) without distant metastases at registration developed distant metastases as the first site of failure at a median time of 5 months. Four additional patients (27%) had oligometastatic disease at presentation, and all four succumbed to progressive systemic metastases at a median time of 6 months.\n\nThere have been nine deaths among the 16 study patients, seven from metastatic NSCLC, one from respiratory failure (due to intercurrent disease and/or treatment complication) and one from an unrelated myocardial infarction. The median follow-up period for all patients is 15.2 months (3 - 40 months) and 24.2 months for surviving patients (12-40 months). The one-year actuarial overall survival rate is 63%, and two-year 56%. Median survival time for all patients was 28.6 months, and among stage III patients it was not reached, but estimated at 34.7 months (Figure 1). Median survival time for oligometastatic patients was 6 months.\n\nFigure 1 Kaplan-Meier survival curve. Median survival time for all patients treated is 28.6 months. For stage III patients, the median survival time was not reached, but estimated at 34.7 months.\n\nDiscussion\nWe demonstrate the feasibility and safety of combining dose-dense (q2-week) pemetrexed and systemic dose carboplatin (AUC = 6) with radiotherapy for NSCLC. All patients were able to receive both doses of carboplatin and at least three (out of four) doses of pemetrexed with concurrent radiation. All but one patient was able to complete radiotherapy. The main toxicity observed in this study was myelosuppression, primarily manifesting as neutropenia.\n\nToxicity was decreased by amending the study to mandate the use of smaller (involved-field) radiotherapy treatment plans. We found that 2 of the first 6 patients enrolled in our study suffered non-hematologic DLT's when treated with comprehensive mediastinal irradiation. After changing the radiotherapy planning portion of our study, non-hematologic DLT's occurred in 1 of 8 patients. This patient was an 83 year-old man with severe COPD who died from respiratory decompensation following completion of chemoradiotherapy. We conservatively report this as a DLT although intercurrent disease played a significant role.\n\nWhen the study was originally designed (in 2005), standard RT consisted of comprehensive mediastinal irradiation to 45-50 Gy followed by a boost to gross tumor to 60-64 Gy, as used in the Radiation Therapy Oncology Group (RTOG) clinical trials [2,23,24]. More recently, data show that outcomes (local control and survival) are not compromised by using involved-field radiotherapy from the start of treatment, and reduced treatment volume may allow the delivery of higher radiotherapy dose [25,26].\n\nIn contrast to previous chemoradiation regimens containing reduced radiosensitizing doses of carboplatin and paclitaxel, this study investigated the used of systemic doses of carboplatin (AUC = 6), which has independent activity in NSCLC. The dose dense pemetrexed at 300 mg/m2 also approaches systemic dose of pemetrexed. Although our study was not powered for assessment of anti-tumor efficacy, the results of our survival data are very promising with a median survival time of 28.6 months in all patients, and estimated 34.7 months in stage III patients.\n\nWe note that almost all evaluable patients had a clinical local response and at least short term in-field local control of their cancer. Although pathologic assessment of local disease was not performed in our study, our data do support the hypothesis that dose-dense carboplatin/pemetrexed is an effective radiosensitization regimen for definitive therapy of locally advanced non-operative NSCLC.\n\nDespite excellent in field control, progression of disease outside the radiation treatment fields remains exceedingly common. Our study included four patients with oligometastatic diease, and each of these patients quickly progressed systemically with a median survival of only 6 months. Three additional patients developed metastatic disease as the first site of recurrence, and two patients recurred locoregionally outside the treatment field. We hypothesize that this reflects chemoresistance in micrometastatic deposits outside of the radiotherapy fields. With improving local control, the ability to control micrometastatic disease has increasing importance in improving overall survival. It is possible that higher dose intensity of platinum, pemetrexed and/or addition of a third cytotoxic drug could be more effective, although at a cost of higher toxicity.\n\nA recent study by Cullen et al. failed to show an advantage to increased dose intensity of pemetrexed in advanced/metastatic (platinum-refractory) NSCLC[27]. This study compared 500 mg/m2 q3week versus 900 mg/m2 q3week. It is unclear whether dose intensification of pemetrexed using a q2week schedule, or in a less heavily pre-treated population such as ours, might yield different results.\n\nAnother strategy might be to add a biologic agent such as a vascular targeting drug or an anti-EGFR agent to our regimen. The Cancer and Leukemia Group B (CALGB) study #30407 investigated in a prospective phase II randomized trial combining carboplatin/radiotherapy and pemetrexed (standard 500 mg/m2 q3-week schedule) with or without cetuximab. Presented in abstract form at the 2009 ASCO national meeting, the carboplatin/pemetrexed/RT arm had a promising median survival time of 22.3 months, but the addition of cetuximab did not result in improved survival with a median survival time of 18.7 months [18].\n\nA complementary strategy may be more careful selection of semi-customized treatments. Randomized studies of single agent pemetrexed in second line chemotherapy treatment of NSCLC and of platinum/pemetrexed in first line treatment of advanced NSCLC demonstrated an improved survival in patients with non-squamous NSCLC, and a worse outcome in patients with squamous histology [16,17]. This difference may be related to increased expression of thymidylate synthase (TS) in squamous cancers or other proteins relevant to the target of pemetrexed[17]. Our study did not collect tissue to perform this analysis, but evaluation of TS will be important to future studies of pemetrexed and radiation in NSCLC.\n\nConclusions\nDose-dense (q-2week) pemetrexed at a dose of 300 mg/m2 and carboplatin (AUC = 6) combined with concurrent involved field radiation is feasible. It was not feasible with extended field radiotherapy. Responses are encouraging and this is a suitable platform for further development of future combined modality trials.\n\nCompeting interests\nXS, AD, MWW, RA, PG, TM, WJC, MM declare that they have no competing interests.\n\nJT is employed by Eli Lilly, Inc.\n\nAuthors' contributions\nMWW, RA, PG, TM, JT, WJC and MM participated in study design. AD, MWW, WJC and MM participated in the radiation therapy of patients. RA, PG, TM participated in the chemotherapy treatment of patients. XS, AD, and MM participated in data collection. XS and MM performed the data analysis analysis.\n\nAll authors read and approved the final manuscript.\n\nAcknowledgements\nThis study was partially supported by a grant from Eli Lilly, Inc.\n==== Refs\nCurran WJ Scott CB Langer CJ Long-term benefit is observed in a phase III comparison of sequential vs concurrent chemo-radiation for patients with urnsected stage III NSCLC: RTOG 9410. 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[Abstract] J Clin Oncol 2009 27 7505 \nCitron ML Berry DA Cirrincione C Randomized trial of dose-dense versus conventionally scheduled and sequential versus concurrent combination chemotherapy as postoperative adjuvant treatment of node-positve primary breast cancer: first report of Intergroup Trial C9741/Cancer and Leukemia Group B Trial 9741 J Clin Oncol 2003 21 1431 9 10.1200/JCO.2003.09.081 12668651 \nKummel S Krocker J Kohls A Randomised trial: survival benefit and safety of adjuvant dose-dense chemotherapy for node-positive breast cancer Br J Cancer 2006 94 1237 44 10.1038/sj.bjc.6603085 16622463 \nPfreundschuh M Trumper L Kloess M Two-weekly or 3-weekly CHOP chemotherapy with or without etoposide for the treatment of young patients with good-prognosis (normal LDH) aggressive lymphomas: results of the NHL-B1 trial of the DSHNHL Blood 2004 104 626 33 10.1182/blood-2003-06-2094 14982884 \nIsonishi S Yasuda M Takahashi F Randomized phase III trial of conventional paclitaxel and carboplatin (c-TC) versus dose-dense weekly paclitaxel and carboplatin (dd-TC) in women with advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer: Japanese Gynecologic Oncology. [Abstract] J Clin Oncol 2008 26s 5506 \nChoy H Swann S Walter C Whipple G Demas W Ettinger D A Phase I trial of Gemcitabine, Carboplatin or Gemcitabine, Paclitaxel and Concurrent Radiation Therapy Followed by Consolidative Gemcitabine and Carboplatin for Inoperable Stage III Non-Small Cell Lung Cancer: An RTOG Study. [Abstract] J Clin Oncol 2005 23s 646s \nWerner-Wasik M Swann S Curran W JrA Phase II Study of Cetuximab (C225) In Combination with Chemoradiation (CRT) in Patients (PTS) with Stage IIIA/B Non-Small Cell Lung Cancer (NSCLC): An Interim Overall Toxicity Report of the RTOG 0324 Trial. [Abstract] J Clin Oncol 2005 23s 654s \nBradley J Graham MV Winter K Toxicity and outcome results of RTOG 9311: a phase I-II dose-escalation study using three-dimensional conformal radiotherapy in patients with inoperable non-small-cell lung carcinoma Int J Radiat Oncol Biol Phys 2005 61 318 28 10.1016/j.ijrobp.2004.06.260 15667949 \nYuan S Sun X Li M A randomized study of involved field irradiation versus elective nodal irradiation in combination with concurrent chemotherapy for inoperable stage III nonsmall cell lung cancer Am J Clin Oncol 2007 30 239 44 10.1097/01.coc.0000256691.27796.24 17551299 \nCullen MH Zatloukal P Sorenson S A randomized phase III trial comparing standard and high-dose pemetrexed as second-line treatment in patients with locally advanced or metastatic non-small-cell lung cancer Ann Oncol 2008 19 939 45 10.1093/annonc/mdm592 18283036\n\n", "fulltext_license": "CC BY", "issn_linking": "1748-717X", "issue": "6()", "journal": "Radiation oncology (London, England)", "keywords": null, "medline_ta": "Radiat Oncol", "mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols; D016190:Carboplatin; D002289:Carcinoma, Non-Small-Cell Lung; D003131:Combined Modality Therapy; D018450:Disease Progression; D004305:Dose-Response Relationship, Drug; D005240:Feasibility Studies; D005971:Glutamates; D006147:Guanine; D006801:Humans; D008175:Lung Neoplasms; D008875:Middle Aged; D000068437:Pemetrexed; D011879:Radiotherapy Dosage; D016019:Survival Analysis; D016896:Treatment Outcome", "nlm_unique_id": "101265111", "other_id": null, "pages": "17", "pmc": null, "pmid": "21324160", "pubdate": "2011-02-16", "publication_types": "D017426:Clinical Trial, Phase I; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't", "references": "18283036;12668651;10561343;15967829;15667949;12885812;17551299;16043262;17026812;15339061;15117980;17404369;16622463;16087956;11955753;18487565;21747084;17255273;14982884;16087941;9438691;18506025;10741729", "title": "Phase i study of 'dose-dense' pemetrexed plus carboplatin/radiotherapy for locally advanced non-small cell lung carcinoma.", "title_normalized": "phase i study of dose dense pemetrexed plus carboplatin radiotherapy for locally advanced non small cell lung carcinoma" }

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"drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "1000", "drugstructuredosageunit": "004", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VITAMIN B12" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Oesophagitis", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "SHEN, X.. PHASE I STUDY OF ^DOSE-DENSE^ PEMETREXED PLUS CARBOPLATIN/RADIOTHERAPY FOR LOCALLY ADVANCED NON-SMALL CELL LUNG CARCINOMA. RADIATION ONCOLOGY. 2011;6:17", "literaturereference_normalized": "phase i study of dose dense pemetrexed plus carboplatin radiotherapy for locally advanced non small cell lung carcinoma", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20170113", "receivedate": "20170106", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 13094779, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170428" }, { "companynumb": "US-MYLANLABS-2017M1010379", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "CARBOPLATIN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "091063", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "FIXED DOSE", "drugenddate": null, "drugenddateformat": null, "drugindication": "NON-SMALL CELL LUNG CANCER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CARBOPLATIN." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "PEMETREXED" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "300 MG/M2", "drugenddate": null, "drugenddateformat": null, "drugindication": "NON-SMALL CELL LUNG CANCER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PEMETREXED" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "FOLIC ACID" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "NON-SMALL CELL LUNG CANCER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FOLIC ACID." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Oesophagitis", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "SHEN X, DENITTIS A, WERNER-WASIK M, AXELROD R, GILMAN P, MEYER T, ET AL. PHASE I STUDY OF ^DOSE-DENSE^ PEMETREXED PLUS CARBOPLATIN/RADIOTHERAPY FOR LOCALLY ADVANCED NON-SMALL CELL LUNG CARCINOMA. RADIAT-ONCOL 2011;6:NO. 17.", "literaturereference_normalized": "phase i study of dose dense pemetrexed plus carboplatin radiotherapy for locally advanced non small cell lung carcinoma", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20170221", "receivedate": "20170221", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 13257135, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170428" }, { "companynumb": "US-PFIZER INC-2017002450", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "CARBOPLATIN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "076517", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK UNK, CYCLIC (AUC = 6) DURING WEEKS 1 AND 5 OF XRT", "drugenddate": null, "drugenddateformat": null, "drugindication": "NON-SMALL CELL LUNG CANCER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CARBOPLATIN." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "FOLIC ACID" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "1000 UG, DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "1000", "drugstructuredosageunit": "004", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FOLIC ACID." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "CYANOCOBALAMIN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "1000 UG, MONTHLY", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": "802", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "1000", "drugstructuredosageunit": "004", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VITAMIN B12" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "CYANOCOBALAMIN" }, "drugadditional": null, "drugadministrationroute": "058", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "1000 UG", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "1000", "drugstructuredosageunit": "004", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VITAMIN B12" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "PEMETREXED" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "300 MG/M2, CYCLIC (DURING WEEKS 1, 3, 5, AND 7 OF XRT)", "drugenddate": null, "drugenddateformat": null, "drugindication": "NON-SMALL CELL LUNG CANCER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "300", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PEMETREXED" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Febrile neutropenia", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Sepsis", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Multiple organ dysfunction syndrome", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Liver function test increased", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Thrombocytopenia", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "SHEN, X.. PHASE I STUDY OF ^DOSE-DENSE^ PEMETREXED PLUS CARBOPLATIN/RADIOTHERAPY FOR LOCALLY ADVANCED NON-SMALL CELL LUNG CARCINOMA. RADIATION ONCOLOGY. 2011;6:17", "literaturereference_normalized": "phase i study of dose dense pemetrexed plus carboplatin radiotherapy for locally advanced non small cell lung carcinoma", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20170113", "receivedate": "20170104", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 13085955, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": 1, "seriousnessother": 1, "transmissiondate": "20170428" } ]

{ "abstract": "A phase I study was conducted in order to determine the maximum tolerated dose (MTD) and dose-limiting toxicities (DLTs) of the combination of vinorelbine and capecitabine in patients affected with metastatic breast cancer. Eighteen patients with histologically confirmed advanced breast cancer, who had failed =1 prior chemotherapy regimen, were enrolled. The median age was 56 years (range, 39-70 years). All but 1 had previously received a combination of anthracyclines and taxanes; performance status (Eastern Cooperative Oncology Group) was 0/1 or 2 in 13 and 5 patients, respectively. Vinorelbine was administered at a fixed dosage of 25 mg/m2 on days 1 and 8 every 3 weeks. Capecitabine was administered orally, at an escalated dose ranging from 1400 mg/m2 to 2250 mg/m2 for 14 consecutive days starting on day 1 of the cycle, divided into 2 daily doses delivered half an hour after eating at 12-hour intervals. Three patients were treated at each dose level: if 1 patient developed a DLT, an additional 3 patients were treated at the same dose level. If 2 additional patients experienced DLT, no further escalation was allowed and the previous dose level was declared MTD. Dose-limiting toxicity was reached at 2250 mg/m2 of capecitabine with 3 out of 3 patients experiencing grade 4 neutropenia plus grade 3 diarrhea and grade 3 oral mucositis in 1 patient). Thus, MTD was defined at 2000 mg/m2 capecitabine. Other observed grade 2 side effects were: 1 patient with neutropenia, 1 with hand-foot syndrome, 2 with mucositis, 1 with cutaneous rash, and 1 with thrombocytopenia. With regard to response rate, we observed 1 complete response (5.5%), 6 partial responses (33%), and 4 disease stabilizations (22%). The median time to progression was 12 weeks and the median survival 41 weeks. The MTD of capecitabine in combination with vinorelbine at 25 mg/m2 dosage on days 1 and 8 of a 3-week schedule is 2000 mg/m2/day for 14 consecutive days. Moreover, this regimen showed interesting activity with 61% overall disease control (complete plus partial response plus disease stabilization) in patients pretreated with anthracyclines and taxanes warranting further investigations in a large, multicenter phase II study.", "affiliations": "Medical Oncology Department, Oncology Institute of Bari, Italy. vitolorusso@inwind.it", "authors": "Lorusso|Vito|V|;Crucitta|Enrico|E|;Silvestris|Nicola|N|;Guida|Michele|M|;Misino|Andrea|A|;Latorre|Agnese|A|;De Lena|Mario|M|", "chemical_list": "D003841:Deoxycytidine; D014747:Vinblastine; D000069287:Capecitabine; D000077235:Vinorelbine; D005472:Fluorouracil", "country": "United States", "delete": false, "doi": "10.3816/cbc.2003.n.019", "fulltext": null, "fulltext_license": null, "issn_linking": "1526-8209", "issue": "4(2)", "journal": "Clinical breast cancer", "keywords": null, "medline_ta": "Clin Breast Cancer", "mesh_terms": "D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D001943:Breast Neoplasms; D000069287:Capecitabine; D003841:Deoxycytidine; D004334:Drug Administration Schedule; D005260:Female; D005472:Fluorouracil; D006801:Humans; D007262:Infusions, Intravenous; D008875:Middle Aged; D016896:Treatment Outcome; D014747:Vinblastine; D000077235:Vinorelbine", "nlm_unique_id": "100898731", "other_id": null, "pages": "138-41", "pmc": null, "pmid": "12864942", "pubdate": "2003-06", "publication_types": "D016430:Clinical Trial; D017426:Clinical Trial, Phase I; D016428:Journal Article", "references": null, "title": "A phase I study of capecitabine in combination with vinorelbine in advanced breast cancer.", "title_normalized": "a phase i study of capecitabine in combination with vinorelbine in advanced breast cancer" }

[ { "companynumb": "IT-ROCHE-1507308", "fulfillexpeditecriteria": "1", "occurcountry": "IT", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "CAPECITABINE" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": "020896", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": "RANGING FROM 1400 MG/M2 TO 2250 MG/M2 FOR 14 CONSECUTIVE DAYS STARTING ON DAY 1 OF THE CYCLE, DIVIDE", "drugenddate": null, "drugenddateformat": null, "drugindication": "BREAST CANCER METASTATIC", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "2", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CAPECITABINE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "VINORELBINE\\VINORELBINE TARTRATE" }, "drugadditional": null, "drugadministrationroute": "042", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "BREAST CANCER METASTATIC", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "25", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VINORELBINE" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "ONDANSETRON" }, "drugadditional": null, "drugadministrationroute": "042", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "16", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ONDANSETRON" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "DEXAMETHASONE" }, "drugadditional": null, "drugadministrationroute": "042", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "8", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DEXAMETHASONE." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Diarrhoea", "reactionmeddraversionpt": "18.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Febrile neutropenia", "reactionmeddraversionpt": "18.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Neutropenia", "reactionmeddraversionpt": "18.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Mucosal inflammation", "reactionmeddraversionpt": "18.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "LORUSSO V, CRUCITTA E, SILVESTRIS N, GUIDA M, MISINO A, LATORRE A, AND LENA M. A PHASE I STUDY OF CAPECITABINE IN COMBINATION WITH VINORELBINE IN ADVANCED BREAST CANCER . CLINICAL BREAST CANCER 2003 JUN 01;4(2):138-141.", "literaturereference_normalized": "a phase i study of capecitabine in combination with vinorelbine in advanced breast cancer", "qualification": "1", "reportercountry": "IT" }, "primarysourcecountry": "IT", "receiptdate": "20141215", "receivedate": "20141215", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 10653404, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20150529" } ]

{ "abstract": "MicroRNAs (miRNAs) may be useful biomarkers of rejection and allograft outcome in kidney transplantation. Elevated urinary CXCL10 levels have been associated with acute rejection (AR) and may predict allograft failure. We examined the correlation of miRNA, CXCL10 levels and immunosuppressive drug exposure with AR and graft function in kidney transplant recipients.\n\n\n\nEighty de novo kidney transplant recipients were recruited from four European centres. All patients received tacrolimus, mycophenolate mofetil, and methylprednisolone. Urinary pellet expression of miR-142-3p, miR-210-3p and miR-155-5p was assessed by quantitative real-time polymerase chain reaction and urinary CXCL10 levels by enzyme-linked immunosorbent assay at the 1st week and the 1st , 2nd , 3rd and 6th months post-transplantation.\n\n\n\nEight patients experienced AR. Before and during AR, patients showed a significant increase of urinary miR-142-3p, miR-155-5p and CXCL10 levels and a decrease of miR-210-3p levels. Receiver operating characteristic curve analysis showed that miR-155-5p (area under the curve = 0.875; P = 0.046) and CXCL10 (area under the curve = 0.865; P = 0.029) had excellent capacity to discriminate between rejectors and nonrejectors. The optimal cut-off values for the prognosis of AR were 0.51, with 85% sensitivity and 86% specificity for miR-155-5p and 84.73 pg ml-1 , with 84% sensitivity and 80% specificity for CXCL10. miR-155-5p and CXCL10 levels correlated with glomerular filtration rate. Levels of both biomarkers normalized after recovery of graft function.\n\n\n\nThe regular early post-transplantation monitoring of urinary miR-155-5p and CXCL10 can help in the prognosis of AR and graft dysfunction. Large prospective randomized multicentre trials are warranted to refine our cut-off values and validate the clinical usefulness of these biomarkers.", "affiliations": "Pharmacology and Toxicology Laboratory, CDB, IDIBAPS, Hospital Clinic of Barcelona, University of Barcelona, Spain.;Medizinische Klinik mit Schwerpunkt Nephrologie, Charité Universitätsmedizin Berlin, Berlin, Germany.;Department of Nephrology, University of Heidelberg, University Hospital of Heidelberg and Mannheim, Heidelberg, Germany.;Pharmacology and Toxicology Laboratory, CDB, IDIBAPS, Hospital Clinic of Barcelona, University of Barcelona, Spain.;Medizinische Klinik mit Schwerpunkt Nephrologie, Charité Universitätsmedizin Berlin, Berlin, Germany.;Renal Transplant Unit, Nephrology Department, Fundació Puigvert, Barcelona, Spain.;Medizinische Klinik mit Schwerpunkt Nephrologie, Charité Universitätsmedizin Berlin, Berlin, Germany.;Department of Nephrology, University of Heidelberg, University Hospital of Heidelberg and Mannheim, Heidelberg, Germany.;Renal Transplant Unit, Nephrology Department, Fundació Puigvert, Barcelona, Spain.;Renal Transplant Unit, Nephrology Department, Fundació Puigvert, Barcelona, Spain.;Pharmacology and Toxicology Laboratory, CDB, IDIBAPS, Hospital Clinic of Barcelona, University of Barcelona, Spain.", "authors": "Millán|Olga|O|0000-0002-6861-5832;Budde|Klemens|K|;Sommerer|Claudia|C|;Aliart|Irene|I|;Rissling|Olesja|O|;Bardaji|Beatriz|B|;Matz|Maaren|M|;Zeier|Martin|M|;Silva|Irene|I|;Guirado|Lluis|L|;Brunet|Mercè|M|", "chemical_list": "D015415:Biomarkers; C114753:CXCL10 protein, human; D054357:Chemokine CXCL10; D007166:Immunosuppressive Agents; C524942:MIRN155 microRNA, human; D035683:MicroRNAs", "country": "England", "delete": false, "doi": "10.1111/bcp.13399", "fulltext": null, "fulltext_license": null, "issn_linking": "0306-5251", "issue": "83(12)", "journal": "British journal of clinical pharmacology", "keywords": "CXCL10; acute rejection; drug exposure; kidney graft function; kidney transplantation; miR-142-3p; miR-155-5p; miR-210-3p; microRNAs", "medline_ta": "Br J Clin Pharmacol", "mesh_terms": "D000328:Adult; D000368:Aged; D019540:Area Under Curve; D015415:Biomarkers; D054357:Chemokine CXCL10; D004359:Drug Therapy, Combination; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005858:Germany; D006084:Graft Rejection; D006085:Graft Survival; D006801:Humans; D007166:Immunosuppressive Agents; D016030:Kidney Transplantation; D008297:Male; D035683:MicroRNAs; D008875:Middle Aged; D011237:Predictive Value of Tests; D011446:Prospective Studies; D012372:ROC Curve; D060888:Real-Time Polymerase Chain Reaction; D015203:Reproducibility of Results; D013030:Spain; D013997:Time Factors; D016896:Treatment Outcome; D016482:Urinalysis", "nlm_unique_id": "7503323", "other_id": null, "pages": "2636-2650", "pmc": null, "pmid": "28880456", "pubdate": "2017-12", "publication_types": "D016428:Journal Article; D016448:Multicenter Study; D064888:Observational Study; D013485:Research Support, Non-U.S. Gov't", "references": "11085753;24316592;25498051;17463289;23511211;10075613;16572110;26114403;19877012;20194716;27676419;26977997;26078872;21812928;26002284;15149352;28880456;24912917;21459143;23577151;17463290;18624759;12183154;9987096;26722652;27165815;21812927;24025639;22152163;18645476;19234151;20888269;19289845;11904577;19357111;26694099;16885212;25197634;12426003;20335831", "title": "Urinary miR-155-5p and CXCL10 as prognostic and predictive biomarkers of rejection, graft outcome and treatment response in kidney transplantation.", "title_normalized": "urinary mir 155 5p and cxcl10 as prognostic and predictive biomarkers of rejection graft outcome and treatment response in kidney transplantation" }

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"METHYLPREDNISOLONE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "METHYLPREDNISOLONE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNK", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "40 MILLIGRAM, QD", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "40", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHYLPREDNISOLONE." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "BASILIXIMAB" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "RENAL TRANSPLANT", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BASILIXIMAB" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "MYCOPHENOLATE MOFETIL" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "RENAL TRANSPLANT", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MYCOPHENOLATE MOFETIL." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Kidney transplant rejection", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "MILLAN O, BUDDE K, SOMMERER C, ALIART I, RISSLING O, BARDAJI B ET AL.. URINARY MIR-155-5P AND CXCL10 AS PROGNOSTIC AND PREDICTIVE BIOMARKERS OF REJECTION, GRAFT OUTCOME AND TREATMENT RESPONSE IN KIDNEY TRANSPLANTATION.. BRITISH JOURNAL OF CLINICAL PHARMACOLOGY.. 2017?83:2636-50", "literaturereference_normalized": "urinary mir 155 5p and cxcl10 as prognostic and predictive biomarkers of rejection graft outcome and treatment response in kidney transplantation", "qualification": "3", "reportercountry": "ES" }, "primarysourcecountry": "ES", "receiptdate": "20190322", "receivedate": "20190322", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16108268, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190418" } ]

{ "abstract": "Crusted scabies is a rare disease variant associated with T-cell dysregulation. Transplant patients are at risk of developing crusted scabies as a consequence of their immunosuppressive regimens. We report a case of crusted scabies presenting with recurrent septicemia in a 65-year-old renal transplant recipient, treated with daily ivermectin for 7 days after initial failure of weekly ivermectin dosing. A literature review of crusted scabies in transplant recipients consisting of 19 cases reports was summarized. Pruritus was common, and initial misdiagnosis was frequent. Most were treated with topical therapy, with one-third receiving ivermectin. Three of seven cases presenting with a concomitant infection died. Crusted scabies is commonly misdiagnosed in transplant recipients owing to its rarity, varied appearance, and different skin distributions. It should be considered in the differential diagnosis of transplant recipients presenting with rash and pruritus, given its association with secondary infection and subsequent mortality.", "affiliations": "Division of General Internal Medicine, Department of Medicine, McMaster University, Hamilton, Ontario, Canada.;Department of Medicine, University of Toronto, Toronto, Ontario, Canada.;Department of Medicine, Queen's University, Kingston, Ontario, Canada.;Division of Infectious Diseases, Department of Medicine, McMaster University, Hamilton, Ontario, Canada.;Division of Infectious Diseases, Department of Medicine, McMaster University, Hamilton, Ontario, Canada.;Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada.;Division of Nephrology, Department of Medicine, McMaster University, Hamilton, Ontario, Canada.;Division of Nephrology, Department of Medicine, McMaster University, Hamilton, Ontario, Canada.", "authors": "Wang|Michael Ke|MK|https://orcid.org/0000-0002-4949-3235;Chin-Yee|Benjamin|B|;Lo|Carson Ka-Lok|CK|;Lee|Stephen|S|;El-Helou|Philippe|P|;Alowami|Salem|S|;Gangji|Azim|A|;Ribic|Christine|C|", "chemical_list": "D014640:Vancomycin; D007559:Ivermectin", "country": "Denmark", "delete": false, "doi": "10.1111/tid.13077", "fulltext": null, "fulltext_license": null, "issn_linking": "1398-2273", "issue": "21(3)", "journal": "Transplant infectious disease : an official journal of the Transplantation Society", "keywords": "crusted scabies; ivermectin; renal transplantation", "medline_ta": "Transpl Infect Dis", "mesh_terms": "D000284:Administration, Oral; D000368:Aged; D000818:Animals; D003937:Diagnosis, Differential; D005076:Exanthema; D006801:Humans; D007165:Immunosuppression Therapy; D007559:Ivermectin; D016030:Kidney Transplantation; D008297:Male; D012008:Recurrence; D012520:Sarcoptes scabiei; D012532:Scabies; D018805:Sepsis; D012867:Skin; D014640:Vancomycin", "nlm_unique_id": "100883688", "other_id": null, "pages": "e13077", "pmc": null, "pmid": "30873722", "pubdate": "2019-06", "publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review", "references": null, "title": "Crusted scabies in a renal transplant recipient treated with daily ivermectin: A case report and literature review.", "title_normalized": "crusted scabies in a renal transplant recipient treated with daily ivermectin a case report and literature review" }

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"reactionmeddraversionpt": "22.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Bacteraemia", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Respiratory failure", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Pleural effusion", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Rash pruritic", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Leukocytosis", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Enterococcal bacteraemia", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Acute respiratory distress syndrome", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Disease recurrence", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Staphylococcal bacteraemia", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Pneumonia", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Pyrexia", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Product use in unapproved indication", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "WANG MK, CHIN-YEE B, KA-LOK LO C, LEE S, EL-HELOU P, ALOWAMI S ET AL.. CRUSTED SCABIES IN A RENAL TRANSPLANT RECIPIENT TREATED WITH DAILY IVERMECTIN: A CASE REPORT AND LITERATURE REVIEW. TRANSPLANT INFECTIOUS DISEASE. 2019?21:1-7", "literaturereference_normalized": "crusted scabies in a renal transplant recipient treated with daily ivermectin a case report and literature review", "qualification": "3", "reportercountry": "CA" }, "primarysourcecountry": "CA", "receiptdate": "20190830", "receivedate": "20190703", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16528908, "safetyreportversion": 4, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": 1, "seriousnessother": null, "transmissiondate": "20191004" }, { "companynumb": "CA-TEVA-2019-CA-1074069", "fulfillexpeditecriteria": "1", "occurcountry": "CA", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "CYCLOSPORINE" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": "65078", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "2", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "75", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYCLOSPORINE." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "AZATHIOPRINE" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "30", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "AZATHIOPRINE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "PREDNISONE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "080356", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "ON ALTERNATING DAYS", "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "5", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISONE." } ], "patientagegroup": null, "patientonsetage": "65", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Acarodermatitis", "reactionmeddraversionpt": "22.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Acute respiratory distress syndrome", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Staphylococcal infection", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Enterococcal infection", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Sepsis", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Pneumonia", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "WANG M. CRUSTED SCABIES IN A RENAL TRANSPLANT RECIPIENT TREATED WITH DAILY IVERMECTIN: A CASE REPORT AND LITERATURE REVIEW. TRANSPL-INFECT-DIS. 2019?21(3):13077.", "literaturereference_normalized": "crusted scabies in a renal transplant recipient treated with daily ivermectin a case report and literature review", "qualification": "3", "reportercountry": "CA" }, "primarysourcecountry": "CA", "receiptdate": "20200210", "receivedate": "20190711", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16562548, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20200409" }, { "companynumb": "CA-SUN PHARMACEUTICAL INDUSTRIES LTD-2019R1-213128", "fulfillexpeditecriteria": "1", "occurcountry": "CA", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "PREDNISONE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "089247", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "5 MILLIGRAM, QOD", "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "2", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "5", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISONE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CEPHALEXIN" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", 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"drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "AZATHIOPRINE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CEFAZOLIN" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "BACTERAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CEFAZOLIN" }, { "actiondrug": "5", "activesubstance": { 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"drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PNEUMONIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MOXIFLOXACIN." } ], "patientagegroup": null, "patientonsetage": "65", "patientonsetageunit": "801", "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Treatment failure", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Condition aggravated", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Respiratory failure", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Acarodermatitis", "reactionmeddraversionpt": "23.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "WANG MK, CHIN?YEE B, LO CK?L, LEE S, EL?HELOU P, ALOWAMI S ET AL. CRUSTED SCABIES IN A RENAL TRANSPLANT RECIPIENT TREATED WITH DAILY IVERMECTIN: A CASE REPORT AND LITERATURE REVIEW. TRANSPL INFECT DIS. 2019?21(3):E13077 (1?7)", "literaturereference_normalized": "crusted scabies in a renal transplant recipient treated with daily ivermectin a case report and literature review", "qualification": "3", "reportercountry": "CA" }, "primarysourcecountry": "CA", "receiptdate": "20200702", "receivedate": "20190709", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16543470, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20201102" } ]

{ "abstract": "Colchicine is a natural pseudo-alkaloid found in plants such as the autumn crocus (Colchicum autumnale) and glory lily (Gloriosa superba), which is used to treat gout and some other rheumatological disease. Colchicine binds to tubuline and prevents its polymerization into microtubules. It is thus able to impair those cellular functions that involve microtubules, eg. it arrests mitosis in metaphase. Tissues with high mitotic activity are preferentially affected. We report suicidal colchicine poisoning leading to death after 61 hours. Clinical course was typical for colchicine action. We observed severe diarrhea, cardiovascular shock, ARDS, multiorgan system failure and DIC. Postmortem toxicological studies confirm colchicine poisoning.", "affiliations": "Instytut Medycyny Pracy i Zdrowia, Srodowiskowego w Sosnowcu, Oddział Toksykologii Klinicznej z Regionalnym, Ośrodkiem Ostrych Zatruć. m.kicka@imp.sosnowiec.pl", "authors": "Kicka|Mariusz|M|;Olszowy|Zofia|Z|;Jankowski|Zbigniew|Z|;Celiński|Rafał|R|;Kłopotowski|Tomasz|T|;Bazylewicz|Anna|A|;Miśkiewicz|Łukasz|Ł|;Picheta|Sebastian|S|", "chemical_list": "D003078:Colchicine", "country": "Poland", "delete": false, "doi": null, "fulltext": null, "fulltext_license": null, "issn_linking": "0033-2240", "issue": "67(8)", "journal": "Przeglad lekarski", "keywords": null, "medline_ta": "Przegl Lek", "mesh_terms": "D003078:Colchicine; D017809:Fatal Outcome; D006801:Humans; D008297:Male; D008875:Middle Aged; D011041:Poisoning; D013405:Suicide", "nlm_unique_id": "19840720R", "other_id": null, "pages": "630-2", "pmc": null, "pmid": "21387793", "pubdate": "2010", "publication_types": "D002363:Case Reports; D004740:English Abstract; D016428:Journal Article; D016454:Review", "references": null, "title": "Fatal colchicine poisoning--case report and review of literature.", "title_normalized": "fatal colchicine poisoning case report and review of literature" }

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FATAL COLCHICINE POISONING - CASE REPORT AND REVIEW OF LITERATURE. PRZEGLAD LEKARSKI. 2010;67(8):630-632", "literaturereference_normalized": "fatal colchicine poisoning case report and review of literature", "qualification": "1", "reportercountry": "PL" }, "primarysourcecountry": "PL", "receiptdate": "20170502", "receivedate": "20170502", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 13503049, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170830" }, { "companynumb": "PL-RANBAXY-2012R1-51736", "fulfillexpeditecriteria": "1", "occurcountry": "PL", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "ENALAPRIL" }, "drugadditional": null, "drugadministrationroute": "065", 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"1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Leukocytosis", "reactionmeddraversionpt": "18.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Toxicity to various agents", "reactionmeddraversionpt": "18.0", "reactionoutcome": "5" }, { "reactionmeddrapt": "Nausea", "reactionmeddraversionpt": "18.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Cardiogenic shock", "reactionmeddraversionpt": "18.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Disseminated intravascular coagulation", "reactionmeddraversionpt": "18.0", "reactionoutcome": "5" }, { "reactionmeddrapt": "Vomiting", "reactionmeddraversionpt": "18.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Diarrhoea", "reactionmeddraversionpt": "18.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Cardiac arrest", "reactionmeddraversionpt": "18.0", "reactionoutcome": "5" }, { "reactionmeddrapt": "Multi-organ failure", "reactionmeddraversionpt": "18.0", "reactionoutcome": "5" }, { "reactionmeddrapt": "Completed suicide", "reactionmeddraversionpt": "18.0", "reactionoutcome": "5" }, { "reactionmeddrapt": "Acute respiratory distress syndrome", "reactionmeddraversionpt": "18.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Overdose", "reactionmeddraversionpt": "18.0", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "KICKA M, OLSZOWY Z, JANKOWSKI Z, CELINSKI R, KLOPOTOWSKI T, BAZYLEWICZ A ET AL. FATAL COLCHICINE POISONING-CASE REPORT AND REVIEW OF LITERATURE. PRZEGL LEK. 2010;67(8):630-632", "literaturereference_normalized": "fatal colchicine poisoning case report and review of literature", "qualification": "3", "reportercountry": "PL" }, "primarysourcecountry": "PL", "receiptdate": "20141016", "receivedate": "20120119", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 8342885, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20150529" } ]

{ "abstract": "Tuberculosis (TB) is a global health problem, in which the majority of cases occur in population-dense developing countries. Despite advances in various diagnostic TB modalities, extrapulmonary TB remains a challenge due to complexities related to its diagnostic approach. Hereby, we present a rare case of endocarditis and spondylodiscitis associated with Mycobacterium tuberculosis (MTB). This case report highlighted the challenges faced in diagnosing blood culture-negative infective endocarditis (BCNIE). We also emphasized the importance of considering MTB as etiology of BCNIE, particularly in endemic TB areas.", "affiliations": "Department of Cardiology and Vascular Medicine, Faculty of Medicine, Universitas Padjadjaran - Hasan Sadikin General Hospital, Bandung, Indonesia.;Department of Cardiology and Vascular Medicine, Faculty of Medicine, Universitas Padjadjaran - Hasan Sadikin General Hospital, Bandung, Indonesia.;Infection and Tropical Medicine Division, Department of Internal Medicine, Faculty of Medicine, Universitas Padjadjaran - Hasan Sadikin General Hospital, Bandung, Indonesia.;Cardiothoracic and Vascular Surgery Division, Department of Surgery, Faculty of Medicine, Universitas Padjadjaran - Hasan Sadikin General Hospital, Bandung, Indonesia.;Department of Orthopedic Surgery, Faculty of Medicine, Universitas Padjadjaran - Hasan Sadikin General Hospital, Bandung, Indonesia.;Cardiovascular and Thoracic Anesthesiology Division, Department of Anesthesiology and Intensive Therapy, Faculty of Medicine, Universitas Padjadjaran - Hasan Sadikin General Hospital, Bandung, Indonesia.;Department of Anatomical Pathology, Faculty of Medicine, Universitas Padjadjaran - Hasan Sadikin General Hospital, Bandung, Indonesia.;Department of Biomedical Sciences, Faculty of Medicine, Universitas Padjadjaran, Bandung, Indonesia.;Department of Radiology, Faculty of Medicine, Universitas Padjadjaran - Hasan Sadikin General Hospital, Bandung, Indonesia.;Department of Cardiology and Vascular Medicine, Faculty of Medicine, Universitas Padjadjaran - Hasan Sadikin General Hospital, Bandung, Indonesia.;Department of Cardiology and Vascular Medicine, Faculty of Medicine, Universitas Padjadjaran - Hasan Sadikin General Hospital, Bandung, Indonesia.;Infection and Tropical Medicine Division, Department of Internal Medicine, Faculty of Medicine, Universitas Padjadjaran - Hasan Sadikin General Hospital, Bandung, Indonesia.;Department of Cardiology and Vascular Medicine, Faculty of Medicine, Universitas Padjadjaran - Hasan Sadikin General Hospital, Bandung, Indonesia.", "authors": "Saboe|Aninka|A|;Sakasasmita|Sylvie|S|;Hartantri|Yovita|Y|;Maryani|Euis|E|;Hadar|Abdul Kadir|AK|;Sudjud|Reza Widianto|RW|;Azis|Afiati|A|;Chaidir|Lidya|L|;Nugraha|Harry Galuh|HG|;Hasan|Melawati|M|;Cool|Charlotte Johanna|CJ|;Alisjahbana|Bachti|B|;Akbar|Mohammad Rizki|MR|", "chemical_list": null, "country": "Netherlands", "delete": false, "doi": "10.1016/j.idcr.2021.e01313", "fulltext": "\n==== Front\nIDCases\nIDCases\nIDCases\n2214-2509\nElsevier\n\nS2214-2509(21)00269-9\n10.1016/j.idcr.2021.e01313\ne01313\nArticle\nA case of endocarditis and spondylodiscitis associated with Mycobacterium tuberculosis\nSaboe Aninka aninka.saboe@unpad.ac.id\na⁎\nSakasasmita Sylvie a\nHartantri Yovita b\nMaryani Euis c\nHadar Abdul Kadir d\nSudjud Reza Widianto e\nAzis Afiati f\nChaidir Lidya g\nNugraha Harry Galuh h\nHasan Melawati a\nCool Charlotte Johanna a\nAlisjahbana Bachti b\nAkbar Mohammad Rizki a\na Department of Cardiology and Vascular Medicine, Faculty of Medicine, Universitas Padjadjaran - Hasan Sadikin General Hospital, Bandung, Indonesia\nb Infection and Tropical Medicine Division, Department of Internal Medicine, Faculty of Medicine, Universitas Padjadjaran - Hasan Sadikin General Hospital, Bandung, Indonesia\nc Cardiothoracic and Vascular Surgery Division, Department of Surgery, Faculty of Medicine, Universitas Padjadjaran - Hasan Sadikin General Hospital, Bandung, Indonesia\nd Department of Orthopedic Surgery, Faculty of Medicine, Universitas Padjadjaran - Hasan Sadikin General Hospital, Bandung, Indonesia\ne Cardiovascular and Thoracic Anesthesiology Division, Department of Anesthesiology and Intensive Therapy, Faculty of Medicine, Universitas Padjadjaran - Hasan Sadikin General Hospital, Bandung, Indonesia\nf Department of Anatomical Pathology, Faculty of Medicine, Universitas Padjadjaran - Hasan Sadikin General Hospital, Bandung, Indonesia\ng Department of Biomedical Sciences, Faculty of Medicine, Universitas Padjadjaran, Bandung, Indonesia\nh Department of Radiology, Faculty of Medicine, Universitas Padjadjaran - Hasan Sadikin General Hospital, Bandung, Indonesia\n⁎ Correspondence to: Department of Cardiology and Vascular Medicine, Universitas Padjadjaran, Jalan Eyckman 38, Bandung 40161, Indonesia. aninka.saboe@unpad.ac.id\n19 10 2021\n2021\n19 10 2021\n26 e013134 9 2021\n18 10 2021\n18 10 2021\n© 2021 The Author(s)\n2021\nhttps://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).\nTuberculosis (TB) is a global health problem, in which the majority of cases occur in population-dense developing countries. Despite advances in various diagnostic TB modalities, extrapulmonary TB remains a challenge due to complexities related to its diagnostic approach. Hereby, we present a rare case of endocarditis and spondylodiscitis associated with Mycobacterium tuberculosis (MTB). This case report highlighted the challenges faced in diagnosing blood culture-negative infective endocarditis (BCNIE). We also emphasized the importance of considering MTB as etiology of BCNIE, particularly in endemic TB areas.\n\nAbbreviations\n\nTB, Tuberculosis\nMTB, Mycobacterium tuberculosis\nEPTB, Extrapulmonary tuberculosis\nTTE, Transthoracic echocardiography\nPML, Posterior mitral leaflet\nIE, Infective endocarditis\nDOI, Day of illness\nCRP, C-reactive protein\nMR, Mitral regurgitation\nMRI, Magnetic resonance imaging\nBCNIE, Blood culture-negative infective endocarditis\nAML, Anterior mitral leaflet\nRT-PCR, Real-time- polymerase chain reaction\nHIV, Human immunodeficiency virus\nDNA, Deoxyribonucleic acid\nKeywords\n\nBlood culture-negative infective endocarditis (BCNIE)\nextrapulmonary tuberculosis\ntuberculous endocarditis\npyrosequencing method\nRT-PCR\n==== Body\npmcIntroduction\n\nTuberculosis (TB) is an infectious disease caused by Mycobacterium tuberculosis (MTB). Today, TB remains one of the leading causes of death globally. Indonesia is one of the most TB prevalent countries globally, second only to India [1]. Extrapulmonary tuberculosis (EPTB) occurs in approximately 15–20% of TB cases. The most common sites of EPTB are lymph nodes, pleura, and the osteoarticular system; although rare, EPTB may involve the endocardial layer of the heart [2]. Hereby, we presented a case of EPTB manifesting as endocarditis and spondylodiscitis. Furthermore, we highlighted the diagnostic challenges in identifying MTB.\n\nCase report\n\nA fifty-seven-year-old male patient without previous history of heart disease presented to the hospital with worsening shortness of breath since one week before admission. He also complained of fever and weight loss for three months. Additionally, he also experienced back pain along with lower limb weakness for a month. The patient was diagnosed with pneumonia and was treated with moxifloxacin. His sputum examinations were sterile and negative for acid-fast bacilli staining and GeneXpert MTB/RIF. After one week of antibiotic therapy, at the day of illness (DOI)−14, there is no noticeably clinical improvement. The patient was then referred to the cardiology department and underwent transthoracic echocardiography (TTE), in which a large oscillating mass at the posterior mitral leaflet (PML) was detected. The patient was diagnosed with infective endocarditis (IE) and given Ampicillin/Sulbactam and Gentamycin. Three consecutive blood cultures were negative. On the third week of hospitalization (DOI-28), the patient's condition did not improve, and he was referred to our hospital.\n\nUpon our hospital admission (DOI-30), the patient looked lethargic; the blood pressure was 100/60 mmHg, with a heart rate of 88 bpm, respiratory rate of 30 times per minute, and the temperature was 36.8 °C. Physical examination showed an enlarged heart with a 3/6 pansystolic murmur at the apex with paraparesis and paresthesia of the lower limb at the level of L3. However, no gibbous was observed on spine examination.\n\nThe laboratory results showed a hemoglobin of 9.2 gr/dl, leukocytes of 15,230/mm3 with increased C-reactive protein (CRP) (6.01 mg/dL), and procalcitonin (10.20 ng/ml) level, and positive rheumatoid factor. The electrocardiogram showed left ventricular hypertrophy with first-degree AV block. The echocardiography evaluation revealed mitral regurgitation (MR) with ruptured chordae tendineae, perforated leaflet, and multiple vegetation attached to both leaflets (Fig. 1). Magnetic resonance imaging (MRI) for the spine revealed multiple small abscesses at L2-3, L5-S1 (Fig. 2). The patient was diagnosed with blood culture-negative infective endocarditis (BCNIE) and spondylodiscitis due to pyogenic infections. We resumed the antibiotic, performed blood culture assessments, and planned for early surgery. However, the subsequent five consecutive blood cultures were negative for aerobic, anaerobic, and fungal blood cultures. A multidisciplinary clinical meeting was performed, and it was decided that the patient would undergo discectomy first, followed by cardiac surgery afterward.Fig. 1 Transthoracic echocardiography in (a) parasternal long-axis view and (b) apical four-chamber view demonstrated severe mitral regurgitation (MR) with large oscillating mass at PML (white arrow).\n\nFig. 1\n\nFig. 2 The vertebrae magnetic resonance imaging. The coronal view with (a) T1 weighted (b) T2 post-contrast showed mild scoliosis with multiple small abscesses indicates spondylodiscitis L2-3, L5-S1 (white arrow) caused spinal canal compression at the level of L2-3. The axial view at the level of L2-3 with (c) T1 weighted (d) T2 post-contrast and at the level L5-S1 with (e) T1 weighted (f) T2 post-contrast also showed abscess (white arrow).\n\nFig. 2\n\nAn open discectomy was performed three weeks after admission to our hospital (DOI-48). Granuloma tissue was found without purulent or abscess tissue. Debridement and irrigation were conducted. The pathologic examination of the spinal tissue showed proliferation of epithelioid cells with multinucleated datia Langhans (Fig. 3a and b). Although these findings suggest tuberculous infection, the GeneXpert MTB/RIF test was negative.Fig. 3 The tissue pathology results of (a and b) the lumbal vertebrae and (c and d) the cardiac mitral valve. Hematoxylin-eosin staining was used with enlargement of (a and c) 40 times and (b and d) 100 times. In (b), the proliferation of epithelioid cells (black arrow) and multinucleated datia Langhans (white arrow) were shown at the lumbar vertebra. In (d), the proliferation of epithelioid cells (black arrow) with caseous necrosis area (white arrow) and multinucleated datia Langhans (blackhead arrow) were also revealed at the mitral valve.\n\nFig. 3\n\nCardiac surgery was performed one week later (DOI-57). The surgery was performed with the left atrial approach. Multiple vegetation in the anterior mitral leaflet (AML) and PML (Fig. 4) were detected. The mitral valve was replaced with a mechanical prosthetic valve. During the postoperative period, rebleeding occurred in the intensive care unit. We planned to perform a redo surgery; however, the patient's family refused, and the patient passed away.Fig. 4 Vegetations appeared in the mitral valve during the surgery (white arrow).\n\nFig. 4\n\nThe pathologic examination of mitral valve tissue showed proliferation of epithelioid cells with caseous necrosis area and multinucleated datia Langhans (Fig. 3c and d). The vegetation was cultured and showed no bacterial, MTB, or fungal growth. The smear for Acid Fast Bacilli and GeneXpert MTB/RIF were also negative. The real-time polymerase chain reaction (RT-PCR) consisted of IS6110, an insertion gene corresponding to the detection of MTB complex, which was performed on the vegetation tissue. The RT-PCR result showed amplification for IS6110 and was confirmed with the pyrosequencing method. The summary of patient history can be seen in Fig. 5.Fig. 5 Timeline of the patient's medical history, present illness, treatment, and outcome.\n\nFig. 5\n\nDiscussion\n\nBlood culture-negative infective endocarditis (BCNIE) poses challenges for physicians despite the advancement of cardiac imaging diagnostic and therapeutic fields. It is associated with higher morbidity and mortality than blood culture-positive endocarditis [3]. Previous studies also described that BCNIE was associated with a higher frequency of heart failure and valve perforation; furthermore, even surgically treated BCNIE is associated with a higher incidence of multiorgan failure, postoperative heart failure, and in-hospital mortality [4], [5].\n\nIn all cases of culture-negative endocarditis, an evaluation of epidemiological factors, history of prior infections, cardiovascular disease, antimicrobial exposure, and extracardiac sites of infection should be performed. Typically, BCNIE can be found in three conditions: previous antibiotic use, fastidious microorganisms that need a more extended growth period or particular culture media, and non-infectious endocarditis [6]. The microorganism which has been known related to BCNIE including Coxiella burnetii, Bartonella spp., Aspergillus spp., Mycoplasma pneumonia, Brucella spp. and Legionella pneumophila, Tropheryma whipplei, Bartonella spp., and fungi (Candida spp., Aspergillus spp.) [7].\n\nThere is still no universal guideline that is uniformly applicable with regards to BCNIE. According to the European Society of Cardiology guidelines, several modalities are needed to identify the causative microorganism in BCNIE, including serology and PCR [7]. The incidence of MTB as a cause of endocarditis is unknown and could be underestimated due to its diagnostic complexities. Furthermore, no consensus nor guideline has included MTB as a cause of BCNIE [7], [8], [9]; hence, it might be missed in TB's endemic country, such as our country. Detecting MTB from the blood is difficult due to its paucibacillary nature with slow-growing - fastidious characteristics [10].\n\nThe pathogenesis for tuberculous endocarditis is not well understood. The mechanism which likely could explain is similar to EPTB pathogenesis. The process begins when MTB is inhaled into the lungs as the primary site of infection. They multiply and induce macrophages and neutrophils to migrate to the infected area. Accumulated macrophages at sites of bacterial implantation further differentiate into epithelioid cells that form tuberculous granuloma. MTB is maintained and persists within the center of the granuloma in a low active and anaerobic state to avoid an encounter with the host's immune defense. Reactivation happens once the balance between bacillary persistence and the immune response gets disturbed due to aging, malnutrition, steroids, or Human Immunodeficiency Virus (HIV) infection. The infection then leads the epithelial layer of alveolar cells to erode and spread through the bloodstream to other organs. Another way for MTB to infect other organs is by using phagocytes as vehicles to approach other organs through lymph nodes and blood [11].\n\nThe role of blood culture in TB has its limitations, especially in an immunocompetent patient, such as our patient. Blood cultures for MTB detection require mycobacteria-specific, radioisotope-labeled systems with specific nutrient growth requirements that are not met by routine culture systems. In studies among HIV patients, MTB can be cultured from 30% to 32% of the blood samples collected, with a sensitivity of only 14.8% in one blood sample, and increased to 27.5% by adding another blood sample [12]. Nevertheless, in one study on clinically diagnosed TB patients, Mycobacteremia was found only in 7.8% of non-HIV patients [13].\n\nIdentification of tuberculosis as a cause of endocarditis could be made by detecting mycobacteria from extrapulmonary sites, using (1) direct method, through detecting the mycobacterium and its product which is difficult due to its nature, inadequate clinical sample sizes, nonuniform bacteria distribution, and difficulty to access the site and (2) indirect method, which depends on the measurement of the host's humoral and cellular response against mycobacterium. Despite the negative results of acid-fast bacilli staining and GeneXpert MTB/RIF tests, due to the high suspicion of TB infection, we examined the RT-PCR with the pyrosequencing method, which revealed MTB deoxyribonucleic acid (DNA) on vegetation tissue. This method has a higher sensitivity than Gene Expert MTB/RIF, which makes the etiology successfully shown in our case [2].\n\nThe percentages of the association between IE and spondylodiscitis vary from 5% to 13%. The spondylodiscitis in IE occurred predominantly through the hematogenous arterial route, allowing the seeding of infection from a distant site into the vertebral column. It is suggested that spondylodiscitis is due to microemboli of immune complexes, with or without bacteria [14]. The locations of infection metastatic typically occur in the lumbar vertebrae site due to the highest density of vascular followed by the thoracal vertebrae [15]. It was almost impossible to determine whether the endocarditis or spondylodiscitis occurred first or whether both occurred simultaneously. Both tuberculosis infection and infective endocarditis are systemic diseases with various systemic manifestations and could mask symptoms of each entity. From the literature, only two old cases of tuberculous endocarditis were reported to have a complication with vertebrae involvement, which are similar to our patient's [16], [17].\n\nThe treatment of tuberculous endocarditis consists of damaged valve replacement, mass evacuation, and aggressive disease eradication with anti-TB chemotherapy. In most reported cases, the anti-TB treatment has a minimum duration of six months and up to twelve months [18]. In this report, the patient underwent surgery due to uncontrolled infection and a high risk of embolization, which was planned to be followed by a minimum of 9 months of antituberculosis drugs per TB treatment guidelines for patients with bone involvement [19].\n\nBefore the 1980s, most of the patients who reported having tuberculous endocarditis cases died and were diagnosed through an autopsy study [16], [20]. The prognosis of patients with tuberculous endocarditis began to improve since the 1980s with the improvement and advancement of cardiac imaging and appropriate treatment [21]. To date, a limited study has described the prognosis among particularly tuberculous endocarditis patients. A study of mycobacterium endocarditis conducted by Yuan SM showed that approximately 50% of the patients with endocarditis were event-free. In contrast, many patients experienced relapses or complications, and 34% died during the follow-up. The cause of death in these patients include multiorgan failure, hospital-acquired pneumonia, stroke, progressive heart failure, and respiratory distress [22].\n\nConclusion\n\nPhysicians should consider Mycobacterium tuberculosis as a cause of BCNIE, particularly in tuberculosis endemic areas and in cases with concomitant spondylodiscitis. The PCR method should be used in highly suspicious tuberculosis cases, regardless of the culture results.\n\nLimitation\n\nIn this case, the patient didn't go through any autopsy due to no obligation for the procedure at our center when the cause of death was inevitable. However, we believe that the data from the autopsy may shed light on the patient's illness. Secondly, we did not perform the pulmonary computed tomography scan, which could more precisely recognize pulmonary tuberculosis. Finally, MTB strain and complete drug sensitivity examination were also not conducted due to limited specimens.\n\nEthics approval and consent to participate\n\nInformed consent was obtained from the participant in this study.\n\nStatement of human rights: This study was conducted following the 1964 Declaration of Helsinki and its subsequent amendments.\n\nStatement of animal welfare: We do not involve animals in our study.\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 on request.\n\nFunding\n\nThis study received no specific grant from any funding agency, commercial or not-for-profit sectors.\n\nCRediT authorship contribution statement\n\nAninka Saboe: Conceptualization, Investigation, Supervision, Writing – review & editing. Sylvie Sakasasmita: Data curation, Investigation, Writing – original draft, Writing – review & editing. Yovita Hartantri, Euis Maryani, Abdul Kadir Hadar, Afiati, Lidya Chaidir, Harry Galuh Nuhraga, Melawati Hasan: Data curation, Investigation, Writing – review & editing. Bachti Alisjahbana: Data curation, Investigation, Writing – review & editing, Supervision. Reza Widianto Sudjud, Charlotte Johanna Cool, Mohammad Rizki Akbar: Writing – review & editing.\n\nCompeting interests\n\nThe authors have no conflicts of interest to declare.\n\nAcknowledgments\n\nWe would like to express our sincere gratitude to Erwinanto, MD, for contributing to case management.\n==== Refs\nReferences\n\n1 World Health Organization. WHO report on TB 2020; 2020.\n2 Ramírez-Lapausa M. Menéndez-Saldaña A. Noguerado-Asensio A. Extrapulmonary tuberculosis Rev Esp Sanid Penit 17 1 2015 3 11 25803112\n3 Katsouli A. Massad M.G. Current issues in the diagnosis and management of blood culture-negative infective and non-infective endocarditis Ann Thorac Surg 95 4 2013 1467 1474 23481702\n4 Zamorano J. Sanz J. Moreno R. Almería C. Rodrigo J.L. Samedi M. Comparison of outcome in patients with culture-negative versus culture-positive active infective endocarditis Am J Cardiol 87 12 2001 1423 1425 11397371\n5 Salsano A. Giacobbe D.R. Del Puente F. Natali R. Miette A. Moscatelli S. Culture-negative infective endocarditis (CNIE): impact on postoperative mortality Open Med 15 1 2020 571 579\n6 Fournier P.E. Gouriet F. Casalta J.P. Lepidi H. Chaudet H. Thuny F. Blood culture-negative endocarditis: improving the diagnostic yield using new diagnostic tools Medicine 96 47 2017 e8392\n7 Habib G. Lancellotti P. Antunes M.J. Bongiorni M.G. Casalta J.P. Del Zotti F. ESC Guidelines for the management of infective endocarditis: the Task Force for the Management of Infective Endocarditis of the European Society of Cardiology (ESC) Eur Heart J 36 44 2015 3075 3128 2015 26320109\n8 Baddour L.M. Wilson W.R. Bayer A.S. Fowler V.G. Tleyjeh I.M. Rybak M.J. Infective endocarditis in adults: diagnosis, antimicrobial therapy, and management of complications Circulation 132 15 2015 1435 1486 26373316\n9 Malaysia MoH. Clinical practice guidelines for the prevention, diagnosis & management of infective endocarditis; 2017.\n10 European Centre for Disease Prevention and Control. Handbook on tuberculosis laboratory diagnostic methods in the European Union. Stockholm: ECDC; 2018.\n11 Yang D. Kong Y. The bacterial and host factors associated with extrapulmonary dissemination of Mycobacterium tuberculosis Front Biol 10 3 2015 252 261\n12 Ceia F. Santos-Silva A. Alves J. Silva-Pinto A. Oliveira O. Cláudia Carvalho A. Mycobacterial blood cultures in the diagnosis of tuberculosis in human immunodeficiency virus-infected patients: are they useful? Clin Microbiol Infect 25 2 2019 264 265 30267928\n13 David S.T. Mukundan U. Brahmadathan K.N. John T.J. Detecting mycobacteraemia for diagnosing tuberculosis Indian J Med Res 119 6 2004 259 266 15243163\n14 Morelli S. Carmenini E. Caporossi A.P. Aguglia G. Bernardo M.L. Gurgo A.M. Spondylodiscitis and infective endocarditis: case studies and review of the literature Spine 26 5 2001 499 500 11242377\n15 Trecarichi E.M. Di Meco E. Mazzotta V. Fantoni M. Tuberculous spondylodiscitis: epidemiology, clinical features, treatment, and outcome Eur Rev Med Pharmacol Sci 16 Suppl 2 2012 58 72\n16 Gilmore H.R. Tuberculosis involving the pulmonary valve Am J Pathol Am J Pathol 16 2 1940 229-232.1\n17 Kannangara D.W. Salem F.A. Rao B.S. Thadepalli H. Cardiac tuberculosis: TB of the endocardium Am J Med Sci 287 3 1984 45 47\n18 Sultan F.A.T. Fatimi S. Jamil B. Moustafa S.E. Mookadam F. Tuberculous endocarditis: valvular and right atrial involvement Eur J Echocardiogr 11 4 2010 E13\n19 World Health Organization Treatment of tuberculosis: guidelines 4th ed 2010 World Health Organization Geneva\n20 Wainwright J. Tuberculous endocarditis: a report of 2 cases S Afr Med J 56 18 1979 731 733 505202\n21 Soyer R. Brunet A. Chevallier B. Leroy J. Morere M. Redonnet M. Tuberculous aortic insufficiency. Report of a case with successful surgical treatment J Thorac Cardiovasc Surg 82 2 1981 254 256 7253687\n22 Yuan S.-M. Mycobacterial endocarditis: a comprehensive review Rev Bras Cir Cardiovasc 30 1 2015 93 103 25859873\n\n", "fulltext_license": "CC BY-NC-ND", "issn_linking": "2214-2509", "issue": "26()", "journal": "IDCases", "keywords": "AML, Anterior mitral leaflet; BCNIE, Blood culture-negative infective endocarditis; Blood culture-negative infective endocarditis (BCNIE); CRP, C-reactive protein; DNA, Deoxyribonucleic acid; DOI, Day of illness; EPTB, Extrapulmonary tuberculosis; HIV, Human immunodeficiency virus; IE, Infective endocarditis; MR, Mitral regurgitation; MRI, Magnetic resonance imaging; MTB, Mycobacterium tuberculosis; PML, Posterior mitral leaflet; RT-PCR; RT-PCR, Real-time- polymerase chain reaction; TB, Tuberculosis; TTE, Transthoracic echocardiography; extrapulmonary tuberculosis; pyrosequencing method; tuberculous endocarditis", "medline_ta": "IDCases", "mesh_terms": null, "nlm_unique_id": "101634540", "other_id": null, "pages": "e01313", "pmc": null, "pmid": "34745887", "pubdate": "2021", "publication_types": "D002363:Case Reports", "references": "15243163;19970497;505202;23481702;25859873;7253687;11397371;26373316;11242377;26557138;29381916;33336013;6731481;30267928;22655484;20007719;25803112;26320109", "title": "A case of endocarditis and spondylodiscitis associated with Mycobacterium tuberculosis.", "title_normalized": "a case of endocarditis and spondylodiscitis associated with mycobacterium tuberculosis" }

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{ "abstract": "OBJECTIVE\nTo report the clinical and genetic features of the first cases of chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature (CANDLE) syndrome in an Arab population and to compare them with patients of C1q deficient systemic lupus erythematosus (SLE).\n\n\nMETHODS\nThis is a retrospective case series of patients with CANDLE syndrome and C1q deficient SLE seen at a single tertiary hospital. Medical records were reviewed for demographic data, clinical and laboratory features, histopathology and imaging findings, and response to therapeutic intervention. Descriptive data were summarized.\n\n\nRESULTS\nThree patients from unrelated families fulfilled the clinical manifestations of CANDLE syndrome. The disease onset was within the first 4 months of age. Two patients had uncommon features including uveitis, pulmonary involvement, aseptic meningitis and global delay. Skin biopsy showed heterogeneous findings. Genomic DNA screening was homozygous for mutation in PSMB8, (NM_004159.4:c.212C>T, p.T71M) in one patient and inconclusive for the other two patients. The comparison group was three patients with familial C1q deficient SLE from three unrelated families, who were born to consanguineous parents with at least one affected sibling. They presented with extensive mucocutaneous lesions, discoid rash and scarring alopecia. They required frequent admissions due to infections.\n\n\nCONCLUSIONS\nThis is the first report of CANDLE syndrome in an Arab population; our patients had heterogeneous phenotypic and genetic features with overlap manifestations with C1q deficient SLE. Both are monogenic interferonopathies. However, C1q deficient SLE had more systemic inflammatory disease.", "affiliations": "Department of Pediatric Rheumatology, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.;Department of Pediatric Rheumatology, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.;Department of Pediatric Rheumatology, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.;Department of Pediatric Rheumatology, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.;Department of Pathology, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.;Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.;Department of Allergy and Immunology, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.", "authors": "Al-Mayouf|Sulaiman M|SM|http://orcid.org/0000-0003-0142-6698;AlSaleem|Alhanouf|A|;AlMutairi|Nora|N|;AlSonbul|Abdullah|A|;Alzaid|Tariq|T|;Alazami|Anas M|AM|;Al-Mousa|Hamoud|H|", "chemical_list": "D015922:Complement C1q", "country": "England", "delete": false, "doi": "10.1111/1756-185X.13228", "fulltext": null, "fulltext_license": null, "issn_linking": "1756-1841", "issue": "21(1)", "journal": "International journal of rheumatic diseases", "keywords": "C1q deficiency; CANDLE syndrome; autoinflammatory; interferonopathies; systemic lupus erythematosus", "medline_ta": "Int J Rheum Dis", "mesh_terms": "D000293:Adolescent; D018912:Arabs; D002648:Child; D002675:Child, Preschool; D015922:Complement C1q; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D008060:Lipodystrophy; D008180:Lupus Erythematosus, Systemic; D008297:Male; D010641:Phenotype; D011379:Prognosis; D012189:Retrospective Studies; D012529:Saudi Arabia; D016463:Sweet Syndrome; D062606:Tertiary Care Centers", "nlm_unique_id": "101474930", "other_id": null, "pages": "208-213", "pmc": null, "pmid": "29115062", "pubdate": "2018-01", "publication_types": "D002363:Case Reports; D003160:Comparative Study; D016428:Journal Article", "references": null, "title": "Monogenic interferonopathies: Phenotypic and genotypic findings of CANDLE syndrome and its overlap with C1q deficient SLE.", "title_normalized": "monogenic interferonopathies phenotypic and genotypic findings of candle syndrome and its overlap with c1q deficient sle" }

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{ "abstract": "BACKGROUND Following acute coronary intervention in cardiology patients, the combined medical therapy with the platelet inhibitory drug ticagrelor and a statin medication (e.g., simvastatin) is recommended according to international guidelines. Yet combined therapeutic regimens have the potential of pharmacological interaction with both ticagrelor and simvastatin being metabolized by CYP3A4. Rhabdomyolysis is a known side-effect of statin therapy and combined therapy increases the susceptibility to this complication. CASE REPORT A 72-year-old patient presented to our Emergency Department with typical signs of rhabdomyolysis consisting of muscular cramps and pain in both legs and a significant elevation of creatinine kinase (CK). Five months prior to this presentation, he had been hospitalized due to acute coronary syndrome followed by a coronary intervention of a high-grade left anterior descending artery stenosis. His long-term medication included simvastatin 20 mg daily, which he had taken for several years, and ticagrelor, which had been added to his medication following coronary intervention. The patient showed fast recovery of symptoms and rapid normalization of CK levels upon treatment change from ticagrelor to clopidogrel with a paused statin administration. CONCLUSIONS The combined use of ticagrelor with low dose simvastatin poses a risk for rhabdomyolysis even in patients with normal kidney function. Patients treated with ticagrelor might require changes in statin therapy and dose adjustments in order to avoid pharmacological interactions and higher risk for adverse effects.", "affiliations": "Department of Cardiology and Vascular Diseases, West German Heart and Vascular Center, University Hospital Essen, Essen, Germany.;Department of Cardiology and Vascular Diseases, West German Heart and Vascular Center, University Hospital Essen, Essen, Germany.;Department of Cardiology and Vascular Diseases, West German Heart and Vascular Center, University Hospital Essen, Essen, Germany.", "authors": "Mrotzek|Simone M|SM|;Rassaf|Tienush|T|;Totzeck|Matthias|M|", "chemical_list": "D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D003402:Creatine Kinase; D000077486:Ticagrelor; D000241:Adenosine", "country": "United States", "delete": false, "doi": "10.12659/ajcr.905974", "fulltext": "\n==== Front\nAm J Case RepAm J Case RepamjcaserepThe American Journal of Case Reports1941-5923International Scientific Literature, Inc. 2916741510.12659/AJCR.905974905974ArticlesTicagrelor Leads to Statin-Induced Rhabdomyolysis: A Case Report Mrotzek Simone M. ABCDERassaf Tienush AEFTotzeck Matthias ABEFDepartment of Cardiology and Vascular Diseases, West German Heart and Vascular Center, University Hospital Essen, Essen, GermanyAuthors’ 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\nCorresponding Author: Matthias Totzeck, e-mail: Matthias.Totzeck@uk-essen.de2017 23 11 2017 18 1238 1241 29 6 2017 20 7 2017 © Am J Case Rep, 20172017This work is licensed under Creative Common Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)Patient: Male, 72\n\nFinal Diagnosis: Rhabdomyolysis\n\nSymptoms: Muscle pain\n\nMedication: Ticagrelor\n\nClinical Procedure: —\n\nSpecialty: Cardiology\n\nObjective:\nUnusual clinical course\n\nBackground:\nFollowing acute coronary intervention in cardiology patients, the combined medical therapy with the platelet inhibitory drug ticagrelor and a statin medication (e.g., simvastatin) is recommended according to international guidelines. Yet combined therapeutic regimens have the potential of pharmacological interaction with both ticagrelor and simvastatin being metabolized by CYP3A4. Rhabdomyolysis is a known side-effect of statin therapy and combined therapy increases the susceptibility to this complication.\n\nCase Report:\nA 72-year-old patient presented to our Emergency Department with typical signs of rhabdomyolysis consisting of muscular cramps and pain in both legs and a significant elevation of creatinine kinase (CK). Five months prior to this presentation, he had been hospitalized due to acute coronary syndrome followed by a coronary intervention of a high-grade left anterior descending artery stenosis. His long-term medication included simvastatin 20 mg daily, which he had taken for several years, and ticagrelor, which had been added to his medication following coronary intervention. The patient showed fast recovery of symptoms and rapid normalization of CK levels upon treatment change from ticagrelor to clopidogrel with a paused statin administration.\n\nConclusions:\nThe combined use of ticagrelor with low dose simvastatin poses a risk for rhabdomyolysis even in patients with normal kidney function. Patients treated with ticagrelor might require changes in statin therapy and dose adjustments in order to avoid pharmacological interactions and higher risk for adverse effects.\n\nMeSH Keywords:\nAcute Coronary SyndromeAngiostatinsRhabdomyolysis\n==== Body\nBackground\nAfter acute coronary syndrome (ACS), dual antiplatelet therapy with aspirin and ticagrelor (or prasugrel) is recommended according to the guidelines of the American Heart Association [1,2] and the European Society of Cardiology [3,4]. A significantly reduced rate of death from vascular causes, myocardial infarction, or stroke was shown in patients who had ACS, with or without ST-segment elevation, who had treatment with ticagrelor compared to clopidogrel [5].\n\nFurthermore, an intensive lipid lowering therapy with statin is recommended in patients with ACS [6,7]. To evaluate the need for drug treatment of hypercholesterolemia, elevation of total cholesterol and low-density lipoprotein-cholesterol (LDL-C) are relevant. Intervention strategies are dependent of the total cardiovascular risk and LDL-C level [8].\n\nA relevant side effect of statin-therapy is myopathies. From 1997 to 2000 more than 600 reported cases of rhabdomyolysis were documented from the Adverse Event Reporting System Database of the Food and Drug Administration [9,10].\n\nTicagrelor is metabolized through the enzymes cytochrome P450 (CYP) 3A4/3A5 and is also a weak inhibitor of CYP3A [11]. Thus, ticagrelor may increase the potency of statins, which require CYP3A4 for their metabolism. Therefore, a concomitant use of ticagrelor with doses of simvastatin or lovastatin greater than 40 mg is not recommended [12,13]. Another frequently used combination with statin therapy is the application of cyclosporine A in renal transplant recipients and post-transplant hyperlipidemia. It has been suggested that a similar problem with an increased rate of rhabdomyolysis occurs due to metabolization by CYP3A4. Therefore, a change from simvastatin to fluvastatin, which is metabolized by P459 CYP2C9, is suggested [14].\n\nCase Report\nA 72-year-old patient presented to our emergency department (ED) with muscle pain in both legs and cramps in his calves. Five months prior to this presentation, he had been hospitalized due to ACS followed by a coronary intervention of a high-grade left anterior descending artery stenosis with percutaneous transluminal coronary angioplasty and drug-eluting stent implantation. His further diagnoses included a coronary three-vessel disease with previous interventions of the right coronary artery, intermediate and first diagonal branch, a few years ago. Echocardiography showed an ejection fraction of 50% with a diastolic dysfunction grade II. Brain natriuretic peptide (BNP) levels were normal (8.5 pg/mL). Furthermore, a mitral valve regurgitation grade I was noted. Additional risk factors were arterial hypertension and chronic obstructive pulmonary disease GOLD grade II. His medication upon his current presentation consisted of acetylsalicylic acid 100 mg 1-0-0, ticagrelor 90 mg 1-0-1, ramipril 2.5 mg 1-0-1, pantoprazole 20 mg 1-0-0, simvastatin 20 mg 0-0-1, tiotropium bromide inhalation 1-0-1, and beclomethasone plus formoterol 100/6 μg inhalation 1-0-1.\n\nHis blood results showed an elevated creatinine kinase (CK) of initially 4,117 U/L (normal 38–174 U/L). Measurement of CK was performed according to the International Federation of Clinical Chemistry modified by Szasz [15]. Myoglobin was also elevated with 426 μg/L (normal <110 μg/L). The muscle-brain type CK was within normal range (42 U/L) with a percentage of 1%.\n\nDue to his clinical presentation, in combination with the observed increased CK blood levels, we diagnosed rhabdomyolysis. His long-term medication included simvastatin in a low dose (20 mg/day), with ticagrelor added to the daily medication five month prior to presentation at our ED. The treatment consisted of an intravenous substitution of liquids. We paused the administration of simvastatin on day one and changed the antiplatelet therapy with ticagrelor to clopidogrel. The patient showed fast recovery of symptoms and normalization of CK levels. Table 1 shows the results of the blood tests. Kidney function was normal at all times represented by CK and urea values. The change of CK levels at different time points are graphically depicted in Figure 1. We released the patient from the hospital on day 3. The patient presented to our outpatient clinic seven days later (day 10) for follow-up, and was free of symptoms with normal blood test results.\n\nDiscussion\nHere we report the first published case of rhabdomyolysis in a patient with normal kidney function and low-dose simvastatin therapy, most likely due to co-medication with ticagrelor.\n\nTwo case reports of rhabdomyolysis due to interactions of ticagrelor with statins were found in our literature search. In the first case report, the patient, in addition to elevated CK and myoglobin values, had acute renal failure and was treated with high-dose atorvastatin (80 mg daily) [9]. In the other case report, statin therapy consisted of 40 mg rosuvastatin, a drug that is not metabolized by CYP3A4. One week after taking ticagrelor, the patient showed an acute renal failure with elevated serum CK resulting in accumulation of rosuvastatin and presumably resulted in rhabdomyolysis [16]. In addition, it has been reported that unrecognized hypothyroidism can be a risk factor for rhabdomyolysis in combination with low dose statin and should be screened before starting statin therapy [17].\n\nIn our patient, TSH (thyroid stimulating hormone) was within normal range (0.86 mU/L [0.3–3.0 mU/L]) indicating an euthyroid metabolic state.\n\nPharmacological interaction due to metabolization of simvastatin and ticagrelor through CYP3A4 has been proven [11]. In a recent randomized controlled study co-administration of ticagrelor or placebo with simvastatin showed an increase of maximum plasma concentration by 81% and increase of area under the plasma concentration-time curve from zero to infinity by 56%. Results for atorvastatin showed a lower effect [18].\n\nProduct information for ticagrelor recommends co-administration with simvastatin at a maximal dose of 40 mg [12,13]. Our case report, together with the aforementioned report of increase of simvastatin-plasma-concentrations when combined with ticagrelor, demands a re-evaluation of this recommendation. Our patient only received 20 mg simvastatin per day and showed no muscular symptoms in the years before starting the medication with ticagrelor.\n\nIn every patient who receives the addition of ticagrelor as a medication, its combination with a CYP3A4-metabolized statin should be avoided. As aforementioned, simvastatin showed a higher increase of plasma levels compared to atorvastatin. This indicates that at least a dose adjustment of simvastatin should be performed; however, the therapy could thus become less effective. A change to other statins, for example rosuvastatin or fluvastatin, which are not metabolized by CYP3A4, should therefore be considered. Further randomized controlled trials are needed to assess safety and interactions in more detail.\n\nMoreover, it is suspected that the benefit of treatment with ticagrelor compared to clopidogrel might also be due to increased statin serum concentrations that have a positive and protective effect in patients with coronary artery disease [12].\n\nConclusions\nThe combination of ticagrelor with simvastatin poses a risk for rhabdomyolysis even with low-dose simvastatin, as shown in this case report. This, individual re-evaluation of statin therapy and doses should be performed when co-prescribed with ticagrelor in order to avoid adverse effects. While our findings are the first to describe rhabdomyolysis due to an interaction of simvastatin with ticagrelor in a patient with normal kidney function, future research is needed to determine dosage and risk profiles in this patient population. Until then, the findings of this study should be taken into account when it comes to guideline-based therapy in patients with acute coronary syndrome.\n\nConflicts of interest\n\nNone.\n\nFigure 1. Changes of creatinine kinase (CK) levels in U/L at different time points. Treatment: day 1: paused administration of simvastatin, substitution of liquids; day 2: conduction and change of antiplatelet therapy from ticagrelor to clopidogrel; day 10: follow up, patient presented without remaining symptoms.\n\nTable 1. Blood test results.\n\n\tStandard value\tDay 1 (11 a.m.)\tDay 1 (8 p.m.)\tDay 2\tDay 3\tDay 10\t\nCreatinine (mg/dl)\t0.9–1.3\t1.09\t1.1\t1.14\t1.1\t1.11\t\nUrea (mg/dl)\t6–19.8\t–\t17\t12\t10\t14\t\nCreatinine kinase (U/l)\t38–174\t4117\t4451\t2439\t1867\t135\t\nMuscle-brain type CK (U/l)\t<25\t42\t52\t31\t31\t0\t\nMyoglobin (μg/l)\t<110\t426\t442\t277\t476\t–\t\nLactate dehydrogenase (U/l)\t100–247\t336\t–\t–\t260\t–\n==== Refs\nReferences:\n1. Amsterdam EA Wenger NK Brindis RG 2014 AHA/ACC Guideline for the Management of Patients with Non-ST-Elevation Acute Coronary Syndromes: A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines J Am Coll Cardiol 2014 64 24 e139 228 25260718 \n2. O’Gara PT Kushner FG Ascheim DD 2013 ACCF/AHA guideline for the management of ST-elevation myocardial infarction: A report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines Circulation 2013 127 4 e362 425 23247304 \n3. Roffi M Patrono C Collet JP 2015 ESC Guidelines for the Management of Acute Coronary Syndromes in Patients Presenting Without Persistent ST-segment Elevation Rev Esp Cardiol (Engl Ed) 2015 68 12 1125 26675199 \n4. Taylor J 2012 ESC Guidelines on acute myocardial infarction (STEMI) Eur Heart J 2012 33 20 2501 2 23065971 \n5. Wallentin L Becker RC Budaj A Ticagrelor versus clopidogrel in patients with acute coronary syndromes N Engl J Med 2009 361 11 1045 57 19717846 \n6. Ray KK Cannon CP McCabe CH Early and late benefits of high-dose atorvastatin in patients with acute coronary syndromes: Results from the PROVE IT-TIMI 22 trial J Am Coll Cardiol 2005 46 8 1405 10 16226162 \n7. Reiner Z Catapano AL De Backer G ESC/EAS Guidelines for the management of dyslipidaemias: The Task Force for the management of dyslipidaemias of the European Society of Cardiology (ESC) and the European Atherosclerosis Society (EAS) Eur Heart J 2011 32 14 1769 818 21712404 \n8. Catapano AL Graham I De Backer G 2016 ESC/EAS Guidelines for the Management of Dyslipidaemias Eur Heart J 2016 37 39 2999 3058 27567407 \n9. Kido K Wheeler MB Seratnahaei A Rhabdomyolysis precipitated by possible interaction of ticagrelor with high-dose atorvastatin J Am Pharm Assoc (2003) 2015 55 3 320 23 26003161 \n10. Omar MA Wilson JP FDA adverse event reports on statin-associated rhabdomyolysis Ann Pharmacother 2002 36 2 288 95 11847951 \n11. Zhou D Andersson TB Grimm SW In vitro evaluation of potential drug-drug interactions with ticagrelor: Cytochrome P450 reaction phenotyping, inhibition, induction, and differential kinetics Drug Metab Dispos 2011 39 4 703 10 21177984 \n12. Dinicolantonio JJ Serebruany VL Exploring the ticagrelor-statin interplay in the PLATO trial Cardiology 2013 124 2 105 7 23407140 \n13. Brilique summary of product characteristics. 2010 [Accessed 18 July 2012]. Available from URL http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/001241/WC500100494.pdf \n14. Gumprecht J Zychma M Grzeszczak W Simvastatin-induced rhabdomyolysis in a CsA-treated renal transplant recipient Med Sci Monit 2003 9 9 CS89 91 12960932 \n15. Horder M Elser RC Gerhardt W International Federation of Clinical Chemistry (IFCC) : Scientific Division, Committee on Enzymes. IFCC methods for the measurement of catalytic concentration of enzymes. Part 7. IFCC method for creatine kinase (ATP: creatine (N-phosphotransferase, EC 2.7.3.2). IFCC Recommendation J Automat Chem 1990 12 1 22 40 18925260 \n16. van Vuren AJ de Jong B Bootsma HP Ticagrelor-induced renal failure leading to statin-induced rhabdomyolysis Neth J Med 2015 73 3 136 38 25852115 \n17. El-Husseini A Chemitiganti R Burks J Hypothyroidism and simvastatin as a combined cause of rhabdomyolysis acute renal failure Am J Case Rep 2010 11 7 9 \n18. Teng R Mitchell PD Butler KA Pharmacokinetic interaction studies of co-administration of ticagrelor and atorvastatin or simvastatin in healthy volunteers Eur J Clin Pharmacol 2013 69 3 477 87 22922682\n\n", "fulltext_license": "CC BY-NC-ND", "issn_linking": "1941-5923", "issue": "18()", "journal": "The American journal of case reports", "keywords": null, "medline_ta": "Am J Case Rep", "mesh_terms": "D000241:Adenosine; D000368:Aged; D003402:Creatine Kinase; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008297:Male; D012206:Rhabdomyolysis; D000077486:Ticagrelor", "nlm_unique_id": "101489566", "other_id": null, "pages": "1238-1241", "pmc": null, "pmid": "29167415", "pubdate": "2017-11-23", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": "25852115;12960932;21712404;18925260;23065971;21177984;26675199;16226162;19717846;11847951;27567407;22922682;26003161;23407140;23247304;25260718", "title": "Ticagrelor Leads to Statin-Induced Rhabdomyolysis: A Case Report.", "title_normalized": "ticagrelor leads to statin induced rhabdomyolysis a case report" }

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{ "abstract": "OBJECTIVE\nTo evaluate outcomes of Descemet membrane endothelial keratoplasty (DMEK) in eyes with previous trabeculectomy or a drainage device.\n\n\nMETHODS\nThis is a retrospective study of 108 consecutive DMEK performed between October 2013 and December 2015. All eyes were divided into 3 groups: surgical treatment (ST) group, medical treatment (MT) group, and control group. Visual improvement, endothelial cell loss, and postoperative complications, including rejection, graft failure, and intraocular pressure elevation (≥25 mm Hg) were evaluated.\n\n\nRESULTS\nThe length of follow-up was 9.7 ± 7.3 months. Best-corrected visual acuity (BCVA) improved postoperatively in 85.3% of the ST group, 100% of the MT group, and 93% of the control (P = 0.24). Significantly more lines of BCVA were gained in the ST and MT groups (8.1 ± 8.1 and 9.2 ± 6.3 lines, respectively) than in the control (4.8 ± 5.6 lines, P < 0.05). The mean time to BCVA was 2.9 ± 2.8 months for the ST group, 4.7 ± 5.3 months for the MT group, and 3.0 ± 3.3 months for the control (P = 0.75). Endothelial cell loss was greater in the ST group (44.6 ± 17.8%) than in the MT group (29.9 ± 12.0%) and the control group (32.7 ± 11.3%, P = 0.001). There was one primary failure and no secondary graft failures. The overall rejection rate was 0.9%. Postoperative intraocular pressure elevation was less common in the ST group (14.7%) and control (23.3%) than in the MT group (50.0%, P = 0.04). There was no difference in the air injection rate among all groups (P = 1.0).\n\n\nCONCLUSIONS\nDMEK in eyes with previous trabeculectomy and drainage device can result in very good short-term outcomes.", "affiliations": "*Cornea Division, Department of Ophthalmology, Stein Eye Institute, David Geffen School of Medicine, University of California, Los Angeles, CA; and †Departamento de Oftalmología, Escuela de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile.", "authors": "Aravena|Carolina|C|;Yu|Fei|F|;Deng|Sophie X|SX|", "chemical_list": null, "country": "United States", "delete": false, "doi": "10.1097/ICO.0000000000001095", "fulltext": null, "fulltext_license": null, "issn_linking": "0277-3740", "issue": "36(3)", "journal": "Cornea", "keywords": null, "medline_ta": "Cornea", "mesh_terms": "D000368:Aged; D002452:Cell Count; D003316:Corneal Diseases; D055954:Corneal Endothelial Cell Loss; D057111:Descemet Stripping Endothelial Keratoplasty; D004728:Endothelium, Corneal; D005260:Female; D005901:Glaucoma; D020327:Glaucoma Drainage Implants; D006085:Graft Survival; D006801:Humans; D007429:Intraocular Pressure; D008297:Male; D008875:Middle Aged; D017063:Outcome Assessment, Health Care; D012189:Retrospective Studies; D014130:Trabeculectomy; D014792:Visual Acuity", "nlm_unique_id": "8216186", "other_id": null, "pages": "284-289", "pmc": null, "pmid": "27893525", "pubdate": "2017-03", "publication_types": "D016428:Journal Article", "references": "9342604;24957432;22146552;25526945;22197439;21872938;21242787;19395036;10458176;25448318;26057326;24322807;26386848;21850163;21963858;26418431;22218143;25439596;26075461;25062336;26382893;25526947;21168120;26271841;22705345;22397955;21746971;23892494;19875170;21955628;26020827", "title": "Outcomes of Descemet Membrane Endothelial Keratoplasty in Patients With Previous Glaucoma Surgery.", "title_normalized": "outcomes of descemet membrane endothelial keratoplasty in patients with previous glaucoma surgery" }

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OUTCOMES OF DESCEMET MEMBRANE ENDOTHELIAL KERATOPLASTY IN PATIENTS WITH PREVIOUS GLAUCOMA SURGERY. CORNEA. 2017;36(3):284-289", "literaturereference_normalized": "outcomes of descemet membrane endothelial keratoplasty in patients with previous glaucoma surgery", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20170313", "receivedate": "20170313", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 13334158, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170428" }, { "companynumb": "US-ALLERGAN-1709270US", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "PREDNISOLONE ACETATE" }, "drugadditional": null, "drugadministrationroute": "047", "drugauthorizationnumb": "017011", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "EYE DROPS, SUSPENSION", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "POSTOPERATIVE CARE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISOLONE ACETATE, 1.0%" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Transplant rejection", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Incorrect drug administration duration", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "ARAVENA C, YU F, DENG SX. OUTCOMES OF DESCEMET MEMBRANE ENDOTHELIAL KERATOPLASTY IN PATIENTS WITH PREVIOUS GLAUCOMA SURGERY. CORNEA. 2017;36(3):284-289", "literaturereference_normalized": "outcomes of descemet membrane endothelial keratoplasty in patients with previous glaucoma surgery", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20170313", "receivedate": "20170313", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 13334176, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170428" }, { "companynumb": "US-ALLERGAN-1709267US", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "PREDNISOLONE ACETATE" }, "drugadditional": "3", "drugadministrationroute": "047", "drugauthorizationnumb": "017011", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "EYE DROPS, SUSPENSION", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "POSTOPERATIVE CARE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISOLONE ACETATE, 1.0%" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Transplant rejection", "reactionmeddraversionpt": "19.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "ARAVENA C, YU F, DENG SX. OUTCOMES OF DESCEMET MEMBRANE ENDOTHELIAL KERATOPLASTY IN PATIENTS WITH PREVIOUS GLAUCOMA SURGERY. CORNEA. 2017;36(3):284-289", "literaturereference_normalized": "outcomes of descemet membrane endothelial keratoplasty in patients with previous glaucoma surgery", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20170313", "receivedate": "20170313", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 13334155, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170428" } ]

{ "abstract": "We report a case of vancomycin-induced thrombocytopenia (VIT) with rapid onset after re-exposure to vancomycin. A 58-year-old man with cellulitis was initiated on vancomycin. Approximately 1 hour into the vancomycin infusion, the patient developed an infusion-related reaction. Vancomycin infusion was stopped. A complete blood count obtained 4 hours after discontinuation of the vancomycin infusion revealed a platelet count of 31 ×10-9/L. Investigations ruled out likely causes of thrombocytopenia. VIT was diagnosed based on clinical symptoms and confirmed with drug-dependent platelet antibody testing. Without complications, platelet counts recovered within 7 days after discontinuation of vancomycin. No correlation between vancomycin level and VIT was observed.", "affiliations": "College of Pharmacy, University of Florida, Gainesville, Florida, USA.;College of Pharmacy, University of Florida, Gainesville, Florida, USA.;Department of Medicine, University of Florida, Gainesville, Florida, USA.;College of Pharmacy, University of Florida, Gainesville, Florida, USA akhoury@cop.ufl.edu.", "authors": "Rattanasuwan|Thakul|T|;Marks|Yael|Y|;Delaune|Jess|J|;Khoury|Adonice P|AP|http://orcid.org/0000-0002-6764-5263", "chemical_list": "D000900:Anti-Bacterial Agents; D014640:Vancomycin", "country": "England", "delete": false, "doi": "10.1136/bcr-2021-243027", "fulltext": null, "fulltext_license": null, "issn_linking": "1757-790X", "issue": "14(7)", "journal": "BMJ case reports", "keywords": "haematology (drugs and medicines); infections", "medline_ta": "BMJ Case Rep", "mesh_terms": "D000900:Anti-Bacterial Agents; D001792:Blood Platelets; D006801:Humans; D008297:Male; D008875:Middle Aged; D010976:Platelet Count; D013921:Thrombocytopenia; D014640:Vancomycin", "nlm_unique_id": "101526291", "other_id": null, "pages": null, "pmc": null, "pmid": "34312134", "pubdate": "2021-07-26", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Rapid onset vancomycin-induced thrombocytopenia confirmed by vancomycin antibody test.", "title_normalized": "rapid onset vancomycin induced thrombocytopenia confirmed by vancomycin antibody test" }

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"reactionmeddraversionpt": "24.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Chest pain", "reactionmeddraversionpt": "24.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Thrombocytopenia", "reactionmeddraversionpt": "24.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Respiratory distress", "reactionmeddraversionpt": "24.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Tachycardia", "reactionmeddraversionpt": "24.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "RATTANASUWAN T, MARKS Y, DELAUNE J, KHOURY AP. RAPID ONSET VANCOMYCIN?INDUCED THROMBOCYTOPENIA CONFIRMED BY VANCOMYCIN ANTIBODY TEST. BMJ CASE REPORTS.2021?14(7)?ARTICLE NUMBER E243027.", "literaturereference_normalized": "rapid onset vancomycin induced thrombocytopenia confirmed by vancomycin antibody test", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210820", "receivedate": "20210811", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 19684924, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20211014" }, { "companynumb": null, "fulfillexpeditecriteria": "2", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "VANCOMYCIN" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "65490", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "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": "VANCOMYCIN" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "VANCOMYCIN" }, "drugadditional": "3", "drugadministrationroute": "042", "drugauthorizationnumb": "65490", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK, APPROXIMATEY 1 HOUR OF INFUSION FOR CELLULITIS OF HIS RIGHT LOWER LEG", "drugenddate": null, "drugenddateformat": null, "drugindication": "Cellulitis", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VANCOMYCIN" } ], "patientagegroup": "5", "patientonsetage": null, "patientonsetageunit": null, "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Thrombocytopenia", "reactionmeddraversionpt": "25.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "Rattanasuwan T, Marks Y, Delaune J, Khoury AP.. Rapid onset vancomycin-induced thrombocytopenia confirmed by vancomycin antibody test.. 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"drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "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": "BUMETANIDE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "NICOTINE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK 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null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FLUOXETINE" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "CEFEPIME HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "042", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "CELLULITIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CEFEPIME" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "INSULIN ASPART" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "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": "INSULIN ASPART" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "LISINOPRIL" }, "drugadditional": null, "drugadministrationroute": null, 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"reactionmeddrapt": "Tachycardia", "reactionmeddraversionpt": "24.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Thrombocytopenia", "reactionmeddraversionpt": "24.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Chills", "reactionmeddraversionpt": "24.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Chest pain", "reactionmeddraversionpt": "24.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "RATTANASUWAN, T.. RAPID ONSET VANCOMYCIN?INDUCED THROMBOCYTOPENIA CONFIRMED BY VANCOMYCIN ANTIBODY TEST. BMJ CASE REPORTS. 2021?14 (7):10.1136/BCR?2021?243027", "literaturereference_normalized": "rapid onset vancomycin induced thrombocytopenia confirmed by vancomycin antibody test", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210825", "receivedate": "20210818", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 19716942, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20211014" }, { "companynumb": "US-HIKMA PHARMACEUTICALS USA INC.-US-H14001-21-55183", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "FLUOXETINE 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"actiondrug": "5", "activesubstance": { "activesubstancename": "BUMETANIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNKNOWN", "drugdosagetext": "UNKNOWN", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BUMETANIDE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ASPIRIN" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNKNOWN", "drugdosagetext": "UNKNOWN", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ACETYLSALICYLIC ACID" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "INSULIN ASPART" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": 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"drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ENOXAPARIN" } ], "patientagegroup": null, "patientonsetage": "58", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Chills", "reactionmeddraversionpt": "24.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Thrombocytopenia", "reactionmeddraversionpt": "24.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Chest pain", "reactionmeddraversionpt": "24.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Tachycardia", "reactionmeddraversionpt": "24.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Respiratory distress", "reactionmeddraversionpt": "24.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Hypoxia", "reactionmeddraversionpt": "24.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Drug hypersensitivity", "reactionmeddraversionpt": "24.0", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "RATTANASUWAN T, MARKS Y, DELAUNE J, KHOURY AP. RAPID ONSET VANCOMYCIN?INDUCED THROMBOCYTOPENIA CONFIRMED BY VANCOMYCIN ANTIBODY TEST. BMJ CASE REPORTS.2021?14(7)?ARTICLE NUMBER E243027. DOI: 10.1136/BCR?2021?243027", "literaturereference_normalized": "rapid onset vancomycin induced thrombocytopenia confirmed by vancomycin antibody test", "qualification": null, "reportercountry": "COUNTRY NOT SPECIFIED" }, "primarysourcecountry": "US", "receiptdate": "20210820", "receivedate": "20210820", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 19723855, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20211014" }, { "companynumb": "US-BAXTER-2021BAX025581", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "TRAZODONE HYDROCHLORIDE" }, "drugadditional": null, 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"patientonsetage": "58", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Thrombocytopenia", "reactionmeddraversionpt": "24.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Tachycardia", "reactionmeddraversionpt": "24.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Chills", "reactionmeddraversionpt": "24.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Chest pain", "reactionmeddraversionpt": "24.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Respiratory distress", "reactionmeddraversionpt": "24.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Hypoxia", "reactionmeddraversionpt": "24.0", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "RATTANASUWAN T, MARKS Y, DELAUNE J, KHOURY A. RAPID ONSET VANCOMYCIN?INDUCED THROMBOCYTOPENIA CONFIRMED BY VANCOMYCIN ANTIBODY TEST. BMJ CASE REPORTS. 2021?14:1?3.", "literaturereference_normalized": "rapid onset vancomycin induced thrombocytopenia confirmed by vancomycin antibody test", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210820", "receivedate": "20210820", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 19727963, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20211014" } ]

{ "abstract": ": Lipemic blood was noted in the surgical field by a neurosurgeon after 12.5 hours of anesthesia consisting of infusions of propofol (total dose, 14,956 mcg) and remifentanil (total dose, 25,091 mcg). For most of that time, the rate of propofol was 120-160 mcg·kg-1·min-1 and never exceeded 160 mcg·kg-1·min-1. Lipemia was confirmed by allowing a sample of the patient's blood to settle in a syringe. The triglyceride concentration was 15.8 mmol/L. There was no metabolic acidosis or other indications of propofol infusion syndrome. Postoperatively, liver enzymes were elevated (peak aspartate aminotransferase, 420 units/L) but returned to nearly normal within 5 days. The patient recovered from surgery uneventfully. Reports of intraoperative lipemia during propofol anesthesia are very rare but raise concerns about the safety of prolonged propofol infusion.", "affiliations": "Departments of *Anesthesiology; and †Neurological Surgery, University of Washington, Seattle.", "authors": "Bowdle|Andrew|A|;Richebe|Philippe|P|;Lee|Lorri|L|;Rostomily|Robert|R|;Gabikian|Patrik|P|", "chemical_list": "D018686:Anesthetics, Intravenous; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D015742:Propofol", "country": "United States", "delete": false, "doi": "10.1097/FTD.0000000000000073", "fulltext": null, "fulltext_license": null, "issn_linking": "0163-4356", "issue": "36(5)", "journal": "Therapeutic drug monitoring", "keywords": null, "medline_ta": "Ther Drug Monit", "mesh_terms": "D000328:Adult; D000410:Alanine Transaminase; D018686:Anesthetics, Intravenous; D001219:Aspartate Aminotransferases; D003399:Craniotomy; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D006949:Hyperlipidemias; D015228:Hypertriglyceridemia; D008099:Liver; D009464:Neuroma, Acoustic; D015742:Propofol", "nlm_unique_id": "7909660", "other_id": null, "pages": "556-9", "pmc": null, "pmid": "25222854", "pubdate": "2014-10", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Hypertriglyceridemia, lipemia, and elevated liver enzymes associated with prolonged propofol anesthesia for craniotomy.", "title_normalized": "hypertriglyceridemia lipemia and elevated liver enzymes associated with prolonged propofol anesthesia for craniotomy" }

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"drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DEXAMETHASONE." } ], "patientagegroup": null, "patientonsetage": "39", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Propofol infusion syndrome", "reactionmeddraversionpt": "18.1", "reactionoutcome": "2" }, { "reactionmeddrapt": "Hepatic enzyme increased", "reactionmeddraversionpt": "18.1", "reactionoutcome": "2" }, { "reactionmeddrapt": "Hypertriglyceridaemia", "reactionmeddraversionpt": "18.1", "reactionoutcome": "2" }, { "reactionmeddrapt": "Hyperlipidaemia", "reactionmeddraversionpt": "18.1", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "BOWDLE A, RICHEBE P, LEE L, ROSTOMILY R, GABIKIAN P. HYPERTRIGLYCERIDEMIA, LIPEMIA, AND ELEVATED LIVER ENZYMES ASSOCIATED WITH PROLONGED PROPOFOL ANESTHESIA FOR CRANIOTOMY. THER-DRUG-MONIT 2014; 36(5):556-9.", "literaturereference_normalized": "hypertriglyceridemia lipemia and elevated liver enzymes associated with prolonged propofol anesthesia for craniotomy", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20150706", "receivedate": "20150706", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 11239343, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20151125" } ]

{ "abstract": "To evaluate the plasma trough concentrations ( C trough ) of dolutegravir and rilpivirine used in combination with simeprevir and sofosbuvir in HIV/hepatitis C virus (HCV)-coinfected patients with liver cirrhosis. Virological efficacy and safety of both ART and anti-HCV therapy were assessed.\n\n\n\nA prospective observational study in HIV/HCV-coinfected patients with liver cirrhosis on ART with dolutegravir plus rilpivirine and treated with simeprevir plus sofosbuvir (±ribavirin) was conducted. Dolutegravir, rilpivirine, GS-331007 (sofosbuvir metabolite) and simeprevir C trough were evaluated with a validated HPLC method at anti-HCV treatment baseline and weeks 2 and 4. Geometric means were calculated to summarize C trough values.\n\n\n\nTwelve patients were evaluated: 75% were males and the median (IQR) age was 53 (53-55) years. All patients were Child-Pugh stage A, except one who was stage B. The geometric mean (95% CI) of C trough of rilpivirine and dolutegravir did not change between baseline and week 4 ( P  =   0.654 and P  =   0.268, respectively), with corresponding overall values of 135 (102-177) and 1357 (970-1897) ng/mL. The overall geometric mean (95% CI) of GS-331007 and simeprevir C trough was 370 (268-512) and 2537 (1569-4101) ng/mL, respectively, without significant variation between weeks 2 and 4 ( P  =   0.643 and P  =   0.179, respectively). All patients completed anti-HCV treatment, achieving sustained virological response. All but two patients maintained undetectable HIV-RNA up to post-treatment week 24.\n\n\n\nDolutegravir and rilpivirine C trough appeared not to be affected by concomitant treatment with simeprevir plus sofosbuvir in these HIV/HCV-coinfected patients with liver cirrhosis, supporting the use of this antiretroviral regimen in this setting.", "affiliations": "Infectious Diseases Clinic, IRCCS San Raffaele Hospital, Milan, Italy.;Infectious Diseases Clinic, IRCCS San Raffaele Hospital, Milan, Italy.;Department of Medical Sciences, University of Turin, Turin, Italy.;Department of Medical Sciences, University of Turin, Turin, Italy.;Infectious Diseases Clinic, IRCCS San Raffaele Hospital, Milan, Italy.;Infectious Diseases Clinic, IRCCS San Raffaele Hospital, Milan, Italy.;Infectious Diseases Clinic, IRCCS San Raffaele Hospital, Milan, Italy.;Department of Medical Sciences, University of Turin, Turin, Italy.;Infectious Diseases Clinic, IRCCS San Raffaele Hospital, Milan, Italy.;Department of Medical Sciences, University of Turin, Turin, Italy.;Infectious Diseases Clinic, IRCCS San Raffaele Hospital, Milan, Italy.", "authors": "Merli|Marco|M|;Galli|Laura|L|;Marinaro|Letizia|L|;Ariaudo|Alessandra|A|;Messina|Emanuela|E|;Uberti-Foppa|Caterina|C|;Castagna|Antonella|A|;D'Avolio|Antonio|A|;Lazzarin|Adriano|A|;Bonora|Stefano|S|;Hasson|Hamid|H|", "chemical_list": "D006575:Heterocyclic Compounds, 3-Ring; D010078:Oxazines; D010879:Piperazines; D011728:Pyridones; D012367:RNA, Viral; D000069616:Simeprevir; C562325:dolutegravir; D000068696:Rilpivirine; D000069474:Sofosbuvir", "country": "England", "delete": false, "doi": "10.1093/jac/dkw492", "fulltext": null, "fulltext_license": null, "issn_linking": "0305-7453", "issue": "72(3)", "journal": "The Journal of antimicrobial chemotherapy", "keywords": null, "medline_ta": "J Antimicrob Chemother", "mesh_terms": "D060085:Coinfection; D004359:Drug Therapy, Combination; D005260:Female; D005838:Genotype; D015658:HIV Infections; D016174:Hepacivirus; D019698:Hepatitis C, Chronic; D006575:Heterocyclic Compounds, 3-Ring; D006801:Humans; D008103:Liver Cirrhosis; D016031:Liver Transplantation; D008297:Male; D008875:Middle Aged; D010078:Oxazines; D010879:Piperazines; D011446:Prospective Studies; D011728:Pyridones; D012367:RNA, Viral; D000068696:Rilpivirine; D000069616:Simeprevir; D000069474:Sofosbuvir; D019562:Viral Load", "nlm_unique_id": "7513617", "other_id": null, "pages": "812-815", "pmc": null, "pmid": "27999010", "pubdate": "2017-03-01", "publication_types": "D016428:Journal Article; D064888:Observational Study", "references": null, "title": "Pharmacokinetics of dolutegravir and rilpivirine in combination with simeprevir and sofosbuvir in HIV/hepatitis C virus-coinfected patients with liver cirrhosis.", "title_normalized": "pharmacokinetics of dolutegravir and rilpivirine in combination with simeprevir and sofosbuvir in hiv hepatitis c virus coinfected patients with liver cirrhosis" }

[ { "companynumb": "IT-VIIV HEALTHCARE LIMITED-IT2021GSK067848", "fulfillexpeditecriteria": "1", "occurcountry": "IT", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "SOFOSBUVIR" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "400 MG, QD (PILLS)", "drugenddate": null, "drugenddateformat": null, "drugindication": "HEPATITIS C", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "400", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "SOFOSBUVIR" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "RILPIVIRINE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "25 MG, QD", "drugenddate": null, "drugenddateformat": null, "drugindication": "HIV INFECTION", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "25", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RILPIVIRINE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "SIMEPREVIR" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "150 MG, QD (PILLS)", "drugenddate": null, "drugenddateformat": null, "drugindication": "HEPATITIS C", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "150", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "SIMEPREVIR" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "DOLUTEGRAVIR" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": "204790", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "50 MG, QD", "drugenddate": null, "drugenddateformat": null, "drugindication": "HIV INFECTION", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "50", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DOLUTEGRAVIR" } ], "patientagegroup": "5", "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Treatment noncompliance", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Virologic failure", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Blood HIV RNA increased", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "MERLI M, GALLI L, MARINARO L, ARIAUDO A, MESSINA E, UBERTI?FOPPA C ET AL.. PHARMACOKINETICS OF DOLUTEGRAVIR AND RILPIVIRINE IN COMBINATION WITH SIMEPREVIR AND SOFOSBUVIR IN HIV/HEPATITIS C VIRUS?COINFECTED PATIENTS WITH LIVER CIRRHOSIS. JOURNAL OF ANTIMICROBIAL CHEMOTHERAPY. 2017?72 (3):812?815", "literaturereference_normalized": "pharmacokinetics of dolutegravir and rilpivirine in combination with simeprevir and sofosbuvir in hiv hepatitis c virus coinfected patients with liver cirrhosis", "qualification": "3", "reportercountry": "IT" }, "primarysourcecountry": "IT", "receiptdate": "20210325", "receivedate": "20210325", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 19060802, "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" }, { "companynumb": "IT-VIIV HEALTHCARE LIMITED-IT2021GSK070341", "fulfillexpeditecriteria": "1", "occurcountry": "IT", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "SOFOSBUVIR" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "400 MG, QD (PILLS)", "drugenddate": null, "drugenddateformat": null, "drugindication": "HEPATITIS C", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "400", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "SOFOSBUVIR" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "RILPIVIRINE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "25 MG, QD", "drugenddate": null, "drugenddateformat": null, "drugindication": "HIV INFECTION", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "25", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RILPIVIRINE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "DOLUTEGRAVIR" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": "204790", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "50 MG, QD", "drugenddate": null, "drugenddateformat": null, "drugindication": "HIV INFECTION", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "50", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DOLUTEGRAVIR" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "SIMEPREVIR" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "150 MG, QD (PILLS)", "drugenddate": null, "drugenddateformat": null, "drugindication": "HEPATITIS C", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "150", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "SIMEPREVIR" } ], "patientagegroup": "5", "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Blood HIV RNA increased", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Virologic failure", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "MERLI M, GALLI L, MARINARO L, ARIAUDO A, MESSINA E, UBERTI?FOPPA C ET AL.. PHARMACOKINETICS OF DOLUTEGRAVIR AND RILPIVIRINE IN COMBINATION WITH SIMEPREVIR AND SOFOSBUVIR IN HIV/HEPATITIS C VIRUS?COINFECTED PATIENTS WITH LIVER CIRRHOSIS. JOURNAL OF ANTIMICROBIAL CHEMOTHERAPY. 2017?72 (3):812?815", "literaturereference_normalized": "pharmacokinetics of dolutegravir and rilpivirine in combination with simeprevir and sofosbuvir in hiv hepatitis c virus coinfected patients with liver cirrhosis", "qualification": "3", "reportercountry": "IT" }, "primarysourcecountry": "IT", "receiptdate": "20210325", "receivedate": "20210325", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 19060803, "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\nParoxysmal ataxia and dysarthria (PAD) is a relatively rare symptom in Multiple Sclerosis patients. PAD involves transient dysfunction in control, coordination and initiation of speech and/or limb movements.\n\n\nOBJECTIVE\nTo describe the successful use of levetiracetam for the treatment of PAD.\n\n\nMETHODS\nCase report.\n\n\nRESULTS\nA 37-year-old woman with MS developed PAD approximately 3 months after a multifocal MS relapse. Brain MRI showed a lesion in the posterior aspect of the midbrain as well as in the right posterior internal capsule, both of which were adjacent to the red nucleus. Attack frequency was reduced after starting levetiracetam at a dose of 500mg twice daily, and attacks stopped completely once the dose was increased to 750mg twice daily.\n\n\nCONCLUSIONS\nGiven its advantages (in terms of side effects, safety profile and ease of use compared to other anticonvulsants), we suggest that levetiracetam be considered for management of PAD, and perhaps for other paroxysmal MS symptoms as well.", "affiliations": "Department of Neurology, University of Minnesota Medical School, Minneapolis, MN, United States; Brain Sciences Center, VA Medical Center, Minneapolis, MN, United States.;Department of Neurology, University of Minnesota Medical School, Minneapolis, MN, United States; Brain Sciences Center, VA Medical Center, Minneapolis, MN, United States. Electronic address: carpe004@umn.edu.", "authors": "Goodwin|Shikha J|SJ|;Carpenter|Adam F|AF|", "chemical_list": "D000927:Anticonvulsants; D000077287:Levetiracetam; D010889:Piracetam", "country": "Netherlands", "delete": false, "doi": "10.1016/j.msard.2016.09.003", "fulltext": null, "fulltext_license": null, "issn_linking": "2211-0348", "issue": "10()", "journal": "Multiple sclerosis and related disorders", "keywords": "Levetiracetam; Multiple sclerosis; Paroxysmal dysarthria", "medline_ta": "Mult Scler Relat Disord", "mesh_terms": "D000328:Adult; D000927:Anticonvulsants; D001921:Brain; D004401:Dysarthria; D005260:Female; D006801:Humans; D000077287:Levetiracetam; D008279:Magnetic Resonance Imaging; D020529:Multiple Sclerosis, Relapsing-Remitting; D010889:Piracetam; D014741:Video Recording", "nlm_unique_id": "101580247", "other_id": null, "pages": "79-81", "pmc": null, "pmid": "27919504", "pubdate": "2016-11", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Successful treatment of paroxysmal ataxia and dysarthria in multiple sclerosis with levetiracetam.", "title_normalized": "successful treatment of paroxysmal ataxia and dysarthria in multiple sclerosis with levetiracetam" }

[ { "companynumb": "US-UCBSA-2016040055", "fulfillexpeditecriteria": "2", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "LEVETIRACETAM" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ATAXIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LEVETIRACETAM." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "GLATIRAMER ACETATE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNKNOWN DOSE", "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": "GLATIRAMER ACETATE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "LEVETIRACETAM" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "500 MG, 2X/DAY (BID)", "drugenddate": null, "drugenddateformat": null, "drugindication": "DYSARTHRIA", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "2", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "500", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LEVETIRACETAM." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "LEVETIRACETAM" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "750 MG, 2X/DAY (BID)", "drugenddate": "201511", "drugenddateformat": "610", "drugindication": "OFF LABEL USE", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "2", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "750", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LEVETIRACETAM." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "NATALIZUMAB" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNKNOWN DOSE", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "201502", "drugstartdateformat": "610", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "NATALIZUMAB" } ], "patientagegroup": null, "patientonsetage": "33", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "No adverse event", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "GOODWIN SJ, CARPENTER AE. SUCCESSFUL TREATMENT OF PAROXYSMAL ATAXIA AND DYSARTHRIA IN MULTIPLE SCLEROSIS WITH LEVETIRACETAM. MULTIPLE SCLEROSIS AND RELATED DISORDERS. 2016?10:79-81", "literaturereference_normalized": "successful treatment of paroxysmal ataxia and dysarthria in multiple sclerosis with levetiracetam", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20191210", "receivedate": "20191210", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17133616, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 2, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20200122" } ]

{ "abstract": "For patients with colorectal liver metastases (CLM) undergoing major hepatectomy, extensive preoperative chemotherapy has been associated with increased morbidity and mortality. The impact of extensive chemotherapy on total liver volume (TLV) change is unclear. The aims of the current study were twofold: (1) to determine the change of TLV following preoperative chemotherapy in patients undergoing resection for CLM and (2) to investigate the correlations among TLV change, postoperative hepatic insufficiency (PHI), and death from liver failure.\n\n\n\nClinicopathological features of patients with CLM who underwent preoperative chemotherapy and curative resection were reviewed (2008-2015). TLV change (degree of atrophy) was defined as the percentage difference of TLV (estimated by manual volumetry)/standardized liver volume (SLV) ratio: ([Pre-chemotherapy TLV]-[Post-chemotherapy TLV])×100÷SLV (%). Receiver operating characteristic (ROC) analysis was performed to decide the accurate cut-off value of degree of atrophy to predict PHI. The Cox proportional hazard model was performed to identify the predictors of severe degree of atrophy and PHI.\n\n\n\nThe study cohort consisted of 459 patients, of which 154 patients (34%) underwent extensive preoperative chemotherapy (≥7 cycles). ROC analysis identified the degree of atrophy ≥10% as an accurate cut-off to predict PHI, which was significantly correlated with ≥7 cycles of preoperative chemotherapy. Four factors independently predicted PHI: standardized future liver remnant ≤30% (odds ratio [OR] 4.03, p=0.019), high aspartate aminotransferase-to-platelet ratio index (OR 5.27, p=0.028), degree of atrophy ≥10% (OR 43.5, p<0.001), and major hepatic resection (OR 5.78, p=0.005). Degree of atrophy ≥10% was associated with increased mortality from liver failure (0% [0/374] vs. 15% [13/85], p<0.001).\n\n\n\nExtensive preoperative chemotherapy induced significant atrophic change of TLV. Degree of atrophy ≥10% is an independent predictor of PHI and death in patients with CLM undergoing preoperative chemotherapy and resection.\n\n\n\nExtensive preoperative chemotherapy for patients with colorectal liver metastases (CLM) could induce hepatic atrophy. A higher degree of atrophy is an independent predictor of postoperative hepatic insufficiency and death in patients with CLM undergoing preoperative chemotherapy and resection.", "affiliations": "Department of Surgical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA.;Department of Surgical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA; Hepatobiliary-Pancreatic, Surgery Division, Department of Digestive Surgery, Toranomon Hospital, Tokyo, Japan.;Department of Surgical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA.;Department of Surgical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA.;Department of Surgical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA.;Department of Surgical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA.;Department of Surgical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA. Electronic address: jvauthey@mdanderson.org.", "authors": "Yamashita|Suguru|S|;Shindoh|Junichi|J|;Mizuno|Takashi|T|;Chun|Yun Shin|YS|;Conrad|Claudius|C|;Aloia|Thomas A|TA|;Vauthey|Jean-Nicolas|JN|", "chemical_list": null, "country": "Netherlands", "delete": false, "doi": "10.1016/j.jhep.2017.01.031", "fulltext": null, "fulltext_license": null, "issn_linking": "0168-8278", "issue": "67(1)", "journal": "Journal of hepatology", "keywords": "Colorectal liver metastases; Postoperative hepatic insufficiency; Preoperative chemotherapy; Total liver volume", "medline_ta": "J Hepatol", "mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001284:Atrophy; D015179:Colorectal Neoplasms; D005260:Female; D006498:Hepatectomy; D048550:Hepatic Insufficiency; D006801:Humans; D008099:Liver; D008113:Liver Neoplasms; D008297:Male; D008875:Middle Aged; D011183:Postoperative Complications; D011446:Prospective Studies; D055815:Young Adult", "nlm_unique_id": "8503886", "other_id": null, "pages": "56-64", "pmc": null, "pmid": "28192187", "pubdate": "2017-07", "publication_types": "D016428:Journal Article; D052061:Research Support, N.I.H., Extramural", "references": null, "title": "Hepatic atrophy following preoperative chemotherapy predicts hepatic insufficiency after resection of colorectal liver metastases.", "title_normalized": "hepatic atrophy following preoperative chemotherapy predicts hepatic insufficiency after resection of colorectal liver metastases" }

[ { "companynumb": "US-PFIZER INC-2017281206", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "LEUCOVORIN CALCIUM" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "008107", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK, CYCLIC, FOR 3 MONTHS", "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": "CALCIUM FOLINATE" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "OXALIPLATIN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "078813", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK, CYCLIC, FOR 5 MONTHS", "drugenddate": null, "drugenddateformat": null, "drugindication": "COLORECTAL CANCER METASTATIC", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "OXALIPLATIN." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "IRINOTECAN HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "020571", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK, CYCLIC, FOR 3 MONTHS", "drugenddate": null, "drugenddateformat": null, "drugindication": "COLORECTAL CANCER METASTATIC", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "IRINOTECAN HCL" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "LEUCOVORIN CALCIUM" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "008107", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK, CYCLIC, FOR 5 MONTHS", "drugenddate": null, "drugenddateformat": null, "drugindication": "COLORECTAL CANCER METASTATIC", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CALCIUM FOLINATE" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "FLUOROURACIL" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK, CYCLIC, FOR 3 MONTHS", "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": "FLUOROURACIL." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "FLUOROURACIL" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK, CYCLIC, FOR 5 MONTHS", "drugenddate": null, "drugenddateformat": null, "drugindication": "COLORECTAL CANCER METASTATIC", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FLUOROURACIL." } ], "patientagegroup": null, "patientonsetage": "62", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Hepatic atrophy", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "YAMASHITA, S.. HEPATIC ATROPHY FOLLOWING PREOPERATIVE CHEMOTHERAPY PREDICTS HEPATIC INSUFFICIENCY AFTER RESECTION OF COLORECTAL LIVER METASTASES. JOURNAL OF HEPATOLOGY. 2017;67 (1):56-64", "literaturereference_normalized": "hepatic atrophy following preoperative chemotherapy predicts hepatic insufficiency after resection of colorectal liver metastases", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20170705", "receivedate": "20170630", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 13705884, "safetyreportversion": 2, "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-PFIZER INC-2017281362", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "OXALIPLATIN" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": "078813", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "COLORECTAL CANCER METASTATIC", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "OXALIPLATIN." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "LEUCOVORIN CALCIUM" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": "008107", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "COLORECTAL CANCER METASTATIC", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CALCIUM FOLINATE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "FLUOROURACIL" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "COLORECTAL CANCER METASTATIC", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FLUOROURACIL." } ], "patientagegroup": null, "patientonsetage": "56", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Hepatic atrophy", "reactionmeddraversionpt": "20.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "YAMASHITA, S.. HEPATIC ATROPHY FOLLOWING PREOPERATIVE CHEMOTHERAPY PREDICTS HEPATIC INSUFFICIENCY AFTER RESECTION OF COLORECTAL LIVER METASTASES. JOURNAL OF HEPATOLOGY. 2017;67 (1):56-64", "literaturereference_normalized": "hepatic atrophy following preoperative chemotherapy predicts hepatic insufficiency after resection of colorectal liver metastases", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20170630", "receivedate": "20170630", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 13706192, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20170830" } ]

{ "abstract": "Mixed infections with seasonal influenza A virus strains are a common occurrence and an important source of genetic diversity. Prolonged viral shedding, as observed in immunocompromised individuals, can lead to mutational accumulation over extended periods. Recently, drug resistance was reported in immunosuppressed patients infected with the 2009 pandemic influenza A (H1N1) virus within a few days after oseltamivir treatment was initiated. To better understand the evolution and emergence of drug resistance in these circumstances, we used a deep sequencing approach to survey the viral population from an immunosuppressed patient infected with H1N1/2009 influenza and treated with neuraminidase inhibitors. This patient harbored 3 genetic variants from 2 phylogenetically distinct viral clades of pandemic H1N1/2009, strongly suggestive of mixed infection. Strikingly, one of these variants also developed drug resistance de novo in response to oseltamivir treatment. Immunocompromised individuals may, therefore, constitute an important source of genetic and phenotypic diversity, both through mixed infection and de novo mutation.", "affiliations": "Center for Vaccine Research, Department of Computational and Systems Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA. elg21@pitt.edu", "authors": "Ghedin|Elodie|E|;Laplante|Jennifer|J|;DePasse|Jay|J|;Wentworth|David E|DE|;Santos|Roberto P|RP|;Lepow|Martha L|ML|;Porter|Joanne|J|;Stellrecht|Kathleen|K|;Lin|Xudong|X|;Operario|Darwin|D|;Griesemer|Sara|S|;Fitch|Adam|A|;Halpin|Rebecca A|RA|;Stockwell|Timothy B|TB|;Spiro|David J|DJ|;Holmes|Edward C|EC|;St George|Kirsten|K|", "chemical_list": "D000998:Antiviral Agents; D012367:RNA, Viral; D053139:Oseltamivir", "country": "United States", "delete": false, "doi": "10.1093/infdis/jiq040", "fulltext": null, "fulltext_license": null, "issn_linking": "0022-1899", "issue": "203(2)", "journal": "The Journal of infectious diseases", "keywords": null, "medline_ta": "J Infect Dis", "mesh_terms": "D000293:Adolescent; D000998:Antiviral Agents; D044822:Biodiversity; D024882:Drug Resistance, Viral; D005838:Genotype; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D016867:Immunocompromised Host; D053118:Influenza A Virus, H1N1 Subtype; D007251:Influenza, Human; D008297:Male; D008969:Molecular Sequence Data; D053139:Oseltamivir; D058873:Pandemics; D010802:Phylogeny; D012367:RNA, Viral; D017385:Sequence Homology", "nlm_unique_id": "0413675", "other_id": null, "pages": "168-74", "pmc": null, "pmid": "21288815", "pubdate": "2011-01-15", "publication_types": "D002363:Case Reports; D016428:Journal Article; D052061:Research Support, N.I.H., Extramural", "references": "16731699;18179705;19961677;19433588;19605485;20029664;20522774;19465683;19745803;19651908;20007549;19553313;19580433;18193056;19696719;14759262;12606750;19407738;19907034;20028826;20394718;14530136;16056220;16208317;19392620;9918945;20218988;9636873;16026181;16371626;7594676;18835410;20345239;11807683;16479508;15034147", "title": "Deep sequencing reveals mixed infection with 2009 pandemic influenza A (H1N1) virus strains and the emergence of oseltamivir resistance.", "title_normalized": "deep sequencing reveals mixed infection with 2009 pandemic influenza a h1n1 virus strains and the emergence of oseltamivir resistance" }

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{ "abstract": "BACKGROUND\nThe role of the microbiome in liver transplantation (LT) outcome has received a growing interest in the past decades. In contrast to bacteria, the role of endogenous viral communities, known as the virome, is poorly described. Here, we applied a viral metagenomic approach to study the dynamic evolution of circulating viruses in the plasma of LT recipients and its effect on the clinical course of patients.\n\n\nMETHODS\nPatients chronically infected with hepatitis B virus (HBV) that received a LT due to endstage liver disease were included in this study. Longitudinal plasma samples were collected pre- and post-LT. Intact viral particles were isolated and sequenced on an Illumina HiSeq 2500 platform. Short read libraries were analysed with an in-house bioinformatics pipeline. Key endpoints were the dynamics of viral families and post-LT complications.\n\n\nRESULTS\nThe initiation of immunosuppression induced a bloom of the Anelloviridae that dominated the post-LT plasma virome. A variety of post-LT complication were observed. Nephrotoxicity was reported in 38% of the patients and was associated with a high abundance of anelloviruses. Besides nephrotoxicity, 16 (67%) patients experienced flares of viral or bacterial infections in post-transplant follow-up. These flares were recognized by an increased burden of anelloviruses (p < 0.05). Interestingly, no mortality was observed in patients infected with human pegivirus.\n\n\nCONCLUSIONS\nThese findings suggest a diagnostic potential for the Anelloviridae family in post-LT complications. Furthermore, the impact of human pegivirus infection on post-transplant survival should be further investigated.\n\n\nBACKGROUND\nThis trial was supported by Gilead Sciences grant number BE-2017-000133.", "affiliations": "KU Leuven, Department of Microbiology, Immunology and Transplantation, Rega Institute, Laboratory for Clinical and Epidemiological Virology, Herestraat 49, Post box 1040, BE-3000 Leuven, Belgium.;Department of Hepatology and Gastroenterology, Charité - Universitätsmedizin Berlin, Campus Charité Mitte and Campus Virchow-Klinikum, Berlin, Germany.;KU Leuven, Department of Microbiology, Immunology and Transplantation, Rega Institute, Laboratory for Clinical and Epidemiological Virology, Herestraat 49, Post box 1040, BE-3000 Leuven, Belgium.;KU Leuven, Department of Microbiology, Immunology and Transplantation, Rega Institute, Laboratory for Clinical and Epidemiological Virology, Herestraat 49, Post box 1040, BE-3000 Leuven, Belgium.;KU Leuven, Department of Microbiology, Immunology and Transplantation, Rega Institute, Laboratory for Clinical and Epidemiological Virology, Herestraat 49, Post box 1040, BE-3000 Leuven, Belgium.;Department of Gastroenterology and Hepatology, University Hospitals Leuven, Leuven, Belgium.;Department of Gastroenterology and Hepatology, University Hospitals Leuven, Leuven, Belgium.;KU Leuven, Department of Microbiology, Immunology and Transplantation, Rega Institute, Laboratory for Clinical and Epidemiological Virology, Herestraat 49, Post box 1040, BE-3000 Leuven, Belgium.;KU Leuven, Department of Microbiology, Immunology and Transplantation, Rega Institute, Laboratory for Clinical and Epidemiological Virology, Herestraat 49, Post box 1040, BE-3000 Leuven, Belgium; Health Policy Research Centre, Institute of Health, Shiraz University of Medical Sciences, Shiraz, Iran; Blood Transfusion Research Centre, High Institute for Research and Education in Transfusion Medicine, Tehran, Iran. Electronic address: Mahmoudreza.pourkarim@kuleuven.be.", "authors": "Thijssen|Marijn|M|;Tacke|Frank|F|;Beller|Leen|L|;Deboutte|Ward|W|;Yinda|Kwe Claude|KC|;Nevens|Frederik|F|;Laleman|Wim|W|;Van Ranst|Marc|M|;Pourkarim|Mahmoud Reza|MR|", "chemical_list": "D000998:Antiviral Agents", "country": "Netherlands", "delete": false, "doi": "10.1016/j.ebiom.2020.103009", "fulltext": "\n==== Front\nEBioMedicine\nEBioMedicine\nEBioMedicine\n2352-3964 Elsevier \n\nS2352-3964(20)30385-6\n10.1016/j.ebiom.2020.103009\n103009\nResearch paper\nClinical relevance of plasma virome dynamics in liver transplant recipients\nThijssen Marijn a Tacke Frank b Beller Leen a Deboutte Ward a Yinda Kwe Claude a Nevens Frederik c Laleman Wim c Van Ranst Marc a Pourkarim Mahmoud Reza Mahmoudreza.pourkarim@kuleuven.beade⁎ a KU Leuven, Department of Microbiology, Immunology and Transplantation, Rega Institute, Laboratory for Clinical and Epidemiological Virology, Herestraat 49, Post box 1040, BE-3000 Leuven, Belgium\nb Department of Hepatology and Gastroenterology, Charité – Universitätsmedizin Berlin, Campus Charité Mitte and Campus Virchow-Klinikum, Berlin, Germany\nc Department of Gastroenterology and Hepatology, University Hospitals Leuven, Leuven, Belgium\nd Health Policy Research Centre, Institute of Health, Shiraz University of Medical Sciences, Shiraz, Iran\ne Blood Transfusion Research Centre, High Institute for Research and Education in Transfusion Medicine, Tehran, Iran\n⁎ Corresponding author. Mahmoudreza.pourkarim@kuleuven.be\n24 9 2020 \n10 2020 \n24 9 2020 \n60 1030093 6 2020 25 8 2020 2 9 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/).Background\nThe role of the microbiome in liver transplantation (LT) outcome has received a growing interest in the past decades. In contrast to bacteria, the role of endogenous viral communities, known as the virome, is poorly described. Here, we applied a viral metagenomic approach to study the dynamic evolution of circulating viruses in the plasma of LT recipients and its effect on the clinical course of patients.\n\nMethods\nPatients chronically infected with hepatitis B virus (HBV) that received a LT due to endstage liver disease were included in this study. Longitudinal plasma samples were collected pre- and post-LT. Intact viral particles were isolated and sequenced on an Illumina HiSeq 2500 platform. Short read libraries were analysed with an in-house bioinformatics pipeline. Key endpoints were the dynamics of viral families and post-LT complications.\n\nFindings\nThe initiation of immunosuppression induced a bloom of the Anelloviridae that dominated the post-LT plasma virome. A variety of post-LT complication were observed. Nephrotoxicity was reported in 38% of the patients and was associated with a high abundance of anelloviruses. Besides nephrotoxicity, 16 (67%) patients experienced flares of viral or bacterial infections in post-transplant follow-up. These flares were recognized by an increased burden of anelloviruses (p < 0.05). Interestingly, no mortality was observed in patients infected with human pegivirus.\n\nInterpretation\nThese findings suggest a diagnostic potential for the Anelloviridae family in post-LT complications. Furthermore, the impact of human pegivirus infection on post-transplant survival should be further investigated.\n\nFunding\nThis trial was supported by Gilead Sciences grant number BE-2017-000133.\n\nKeywords\nViromeLiver transplantationPlasmaTransfusionMetagenomicAnellovirus\n==== Body\nResearch in context\nEvidence before this study\nImmunosuppressive therapies have significantly improved the survival of organ transplant patients. However, these therapies also increase the chance of post-transplant complications including secondary infections and de novo malignancies. Mounting evidence suggest an important role of the microbiome in organ transplant survival and patient longevity. The viral part of the microbiome, called the virome, has been associated with the functioning of the immune system. The crosstalk between the virome and immune system could have important implications in organ transplantation medicine. However, limited information is available concerning the peculiar role of these ‘commensal’ viruses.\n\nAdded value of this study\nPatients that received a liver transplantation due chronic HBV infection were included in the study.\n\nViral metagenomic analyses of longitudinal plasma samples collected before and after liver transplantation revealed the presence of a divergent virus community. The initiation of immunosuppressive therapy induced a bloom of anelloviruses in both absolute abundance and species diversity. A variety of post-transplant complications were observed, including renal failure and infections. Remarkably, patients diagnosed with nephrotoxicity and post-transplant infections had a higher abundance of the Anelloviridae family in the blood samples. Both multi- and univariate analyses implied that the anellovirus abundance could be a proxy for immunosuppression and the possible risk of post-transplant complications. Besides the Anelloviridae, also human pegivirus (Flaviviridae) was observed. Previous studies have subscribed immunomodulatory effects to this virus in different clinical backgrounds. In our study, no mortality was observed in patients that were found positive for pegivirus. These findings clearly demonstrate the potential clinical relevance of the virome in post-liver transplantation complications.\n\nImplications of all the available evidence\nThe virome remains an understudied component of the human microbiome. This study continued to further explore the implications of viruses in human health. Based on our findings, specific members of the human blood virome could be used as a diagnostic marker for post-transplant complications. Little is known about the ‘commensal’ viruses that inhabit the blood stream and their interactions with the immune system. However, based on previous findings and the data presented in this study, these viruses could be attractive for developing innovative biomarkers and support clinicians in developing personalized treatment strategies.\n\nAlt-text: Unlabelled box\n\n\n\n1 Introduction\nIn patients receiving liver transplantation (LT), organ rejection, post-transplant infections and complications related to long-term immunosuppression such as nephrotoxicity and de novo malignancies are the main substantial threats [1]. All these complications are potentially related to viral infections or viral reactivations. Consequently, viral infections impose an adverse impact on the survival rate after LT [2]. For instance, cytomegalovirus (CMV) is the most common infectious pathogen that leads to graft failure in liver transplant recipients [3]. Therefore, liver transplanted patients are regularly monitored for CMV viremia and subjected to preventive antiviral therapy in case of high-risk serological constellations [4,5]. Notably, patients diagnosed with viral hepatitis-related hepatocellular carcinoma (HCC) have a higher risk of adverse post-transplant outcomes compared to the non-viral HCC patients because of possible recurrent infections [6].\n\nOver the past decades, there has been a growing interest in the role of endogenous microbes for the outcome of organ transplantation. Studies of the gut microbiota revealed that dysbiosis following liver transplantation is associated with impaired graft survival [7]. On a functional level, increased intestinal permeability, decreased abundance of beneficial commensal bacteria and an increase in pathogenic species may contribute to post-transplant infections and acute rejection [8]. However, there is still a large gap of information concerning the role of the virome in liver transplantation.\n\nThe virome is the most abundant and genetically diverse fraction of the human microbiome [9]. The virome interacts with host genetic factors and other microbiome components to shape the immunophenotype [9,10]. This phenotype can affect the clinical outcome of infections with pathogens, inflammatory illnesses and interventions like organ transplantation [10]. Viral metagenomic studies in organ transplant settings demonstrated that some plasma virome components take advantage of the reduced immunocompetence imposed by immunosuppressive agents [4]. These findings suggest that the viral abundance of particular viruses could be a marker of immunocompetence in immunosuppressed patients. Besides the potential role as a prognostic biomarker of adverse events, virome components are also related to positive outcomes in specific clinical manifestations. For example, the co-infection of human pegivirus (HPgV) with HIV has a beneficial impact on the survival of HIV infected individuals [11].\n\nWe hypothesized that the plasma virome and its dynamic evolution after transplantation might be associated with the clinical course of liver transplanted patients. To fill the current gap, we evaluated the impact of LT on the virome composition and dynamics before and after transplantation in a cohort of hepatitis B virus (HBV) infected individuals undergoing liver transplantation. HBV-infected patients provide a unique opportunity to study such virome-host interactions. They typically cure their HBV infection due to the liver transplantation that is accompanied by antiviral therapy and HBV hyperimmunoglobulin (HBIG) administration. However, these patients have a higher risk of hepatic malignancies, while the risk for liver transplant-related events (rejection, cirrhosis, re-transplantation) and death after transplantation are similar to non-HBV exposed recipients [12]. By analysing longitudinal plasma samples via next-generation sequencing and corresponding clinical data, we provide a comprehensive analysis of the dynamic evolution of the circulating virome and its associations with the clinical course in LT patients.\n\n2 Methods\n2.1 Study population and ethics statement\nHBV infected patients diagnosed with end-stage liver diseases who received a liver transplantation at UZ Leuven (Belgium) between 2007 and 2014 were consecutively enrolled in this study. These patients are part of the chronic HBV cohort that is followed in UZ Leuven. Indications for liver transplantation other than HBV infection and a history of previous organ transplantations were used as exclusion criteria. This study was performed in accordance with the Declaration of Helsinki and was approved by the Ethics committee research UZ/KU Leuven, Belgium. All participants gave informed consent and were able to withdraw from the study at any moment.\n\nSerial plasma samples were collected from the HBV biobank. In total, six longitudinal samples were collected per patient, two plasma samples before (samples A and B) and four (samples C, D, E and F) after liver transplantation. The two samples (A and B) before transplant were collected at 41 ± 45 (A) and 2 ± 1 (B) months pre-transplant, while four samples (C, D, E and F) after transplant were taken at 0.5 ± 0.2 (C), 5 ± 1 (D), 13 ± 6 (E), and 23 ± 11 (F) months post-transplant. Biochemical, serological, and virologic markers were assayed by the hospital laboratories. Moreover, demographic data including age, sex, country of origin, and medication were obtained from the patient clinical record.\n\n2.2 Post-liver transplant treatment protocol\nAll patients received immunosuppressive therapy that consisted of tacrolimus (e.g. 2 × 1 mg/d), mycophenolate mofetil (e.g. 2 × 250 mg/d) and methylprednisolone. Dosages of immunosuppressive therapies were adapted according to the therapeutic window and clinical signs of side-effects. Initially, methylprednisolone was prescribed in high dose of 2 × 20 mg/d and tapered in the following months until discontinuation after three months, depending on clinical conditions of the patients. Infection prophylaxis included a regimen of antibiotic and antiviral compounds. Prophylactic therapy with Valganciclovir (450 mg/d) was prescribed in case of donor and recipient CMV mismatch. Since all patients received a liver transplantation due HBV related end-stage liver disease, HBV prophylaxis was prescribed post-liver transplantation. Anti-HBV therapy consisted of intravenous injection of HBV antibodies and HBV nucleoside analogues.\n\n2.3 Plasma sample processing and viral nucleic acid extraction\nPlasma samples were treated with an optimized viral enrichment protocol. First, samples were sequentially filtered with 5.0 µm polypropylene (Millipore) and 0.8 µm polyethersulphone (Sartorius) filters. To reduce free-floating nucleic acids, filtrated plasma samples were treated with a cocktail of micrococcal nuclease (New England Biolabs) and benzonase (Millipore) and subsequently extracted with the QIAmp Viral RNA Mini Kit (Qiagen) without carrier RNA. To increase the yield of nucleic acids content, a random amplification step was performed using the Whole Transcriptome Amplification Kit 2 (WTA2, Sigma Aldrich) with an initial denaturation step at 95 °C instead of 70 °C. The extracted nucleic acids were subjected to 20 amplification cycles and purified using the MSB SPIN PCRAPACE kit (Stratec).\n\n2.4 Sequencing library preparation and sequencing\nNGS library preparation was performed using the Nextera XT DNA Library Preparation kit (Illumina) with a decreased tagmentation time to 4 min (input DNA of 1.2 ng/ µl) and halved reagent quantities to increase average DNA fragment sizes. The average fragment sizes of DNA libraries were evaluated using the High Sensitivity DNA Kit (Agilent) on a Bioanalyzer 2100 (Agilent). Libraries were quantified with the KAPA Library Quantification kit (Kapa Biosystems). Finally, sequencing was performed on a HiSeq 2500 platform (Illumina) for 2 × 150 cycles, with a total of 10 million paired end reads per sample.\n\n2.5 Bioinformatic analysis\nNGS reads were analysed with an in-house bioinformatics pipeline. Raw reads were trimmed with Trimmomatic [13]. To remove non-viral sequences, reads were mapped against the human genome and a non-redundant database of contaminating sequences with Bowtie2 [14]. The remaining reads were de novo assembled with metaSPAdes and the assembled contigs were annotated by DIAMOND with the sensitive option using the Genbank's non-redundant database [15,16]. Moreover, an additional annotation was performed using BLASTn against the nucleotide reference database (NCBI database of January 2018). Bacteriophages were annotated using both MetaPhinder2 and VirSorter in ‘virome decontamination’ mode [17,18]. The assembled contigs were clustered to generate genome bins with 95% nucleotide identity and a minimal coverage of 80% using nucmer from the MUMmer package [19]. Finally, reads were mapped back against the clustered genomes with BBMap and genome bins that mapped less than 100 reads were discarded from further analysis [20].\n\n2.6 Anellovirus quantification\nqPCR was carried out on 1:10 diluted extracted DNA/RNA samples. Universal forward (ACWKMCGAATGGCTGAGTTT) and reverse (CCCKWGCCCGARTTGCCCCT) primers were used targeting the UTR of the Anelloviridae. The qPCR-assay was developed for detecting and quantifying anelloviruses with a SYBR-green approach. Oligonucleotides (Eurogentec, Belgium) with known concentration were used for the standard curve to determine the sample concentrations. Per sample, the master mix consisted of 10 µl qPCRBIO SyGreen Blue Mix Lo-ROX (Sopachem, Belgium), 2.5 µl of both primers (10 µM), 4 µl dNTPs, and 1 µl H2O. Samples were analysed on a 7500 Fast real-time PCR system (Applied Biosystems). PCR cycle parameters were as follows: 95°C for 90 seconds, forty cycles at 94°C for 15 seconds, and 68°C for 1 minute.\n\n2.7 Phylogenetic analysis\nThe Anelloviridae family constitutes a highly heterogenous group of viruses that are classified based on the genetic similarity of the open reading frame 1 (ORF1). The current demarcation criterion for Anelloviridae species is set at 35% nucleotide sequence identity of the ORF1 by ICTV taxonomy. We extracted all ORF1 sequences with ORF Finder from the dataset and clustered these at 35% cut-off to generate a non-redundant anellovirus database [21]. Amino acid alignment was performed with MUSCLE in MEGA7.0 [22]. A maximum-likelihood (ML) phylogenetic tree was generated from the extracted ORF1 amino acid sequences in MEGA7.0 with LG + F model. Support for ML trees was assessed by 1000 bootstrap replications.\n\n2.8 Statistics\nAll statistical analyses were performed using R-software [23]. The non-parametric Wilcoxon rank-sum test was used to test statistically significant differences of Anelloviridae abundance and sum of species in patients with or without nephrotoxic side-effects. A similar approach was applied for determining ‘statistical significance between virome data and post-LT complications. Spearman's rank correlation coefficient was calculated to determine the correlation between the qPCR and metagenomic sequencing results. Fisher's exact test was used to determine significant differences in viral presence and absence count data and categorical variables. The Friedman test was used for repeated measures with a post-hoc Dunn's-test analysis with Bonferroni correction for multiple testing. Kaplan-Meier curves were constructed using the survival package and FactoMineR was utilized to perform factor analysis of mixed data [24,25]. The lme4 package was used for logistic regression analysis [26]. Statistical significance was assessed at an alpha level of < 0.05. The ggplot2 package was used for designing figures [27].\n\n2.9 Role of the funding source\nThe funders had no role in the study design, data collection, data analysis, interpretation, and writing of the report.\n\n3 Results\n3.1 Participants\nTwenty-four patients that received a liver transplantation due to HBV related end-stage liver diseases were included in this study and we collected a total number of 142 longitudinal samples. These individuals were part of the chronic HBV cohort that are followed in UZ Leuven, Belgium. Patients were chronically infected with HBV and three were co-infected with hepatitis D virus (HDV) before LT. Both recipient and donor characteristics are summarized in Table 1. The diagnosis for LT in these individuals were either liver cirrhosis (N = 10) or hepatocellular carcinoma (N = 14) due to a chronic HBV infection. The study population consisted of 19 males and 5 females with a median age of 58 (range, 39–70) at the time of liver transplantation (Table 1). The median lab MELD score was 15 and the median donor age 52. Furthermore, we retrieved blood transfusion data from 23/24 patients. In these 23 patients, a variety of blood product were given during the course of surgery, including erythrocyte concentrates, fresh-frozen plasma and platelet concentrates. No differences were observed in demographic data and patients diagnosed with liver cirrhosis or HCC.Table 1 Demographic overview of the study population. The numbers are expressed as absolute values (percentage) or median (range).\n\nTable 1Recipients characteristics\t\nGender\tMale\t19\t(79%)\t\n\tFemale\t5\t(21%)\t\nAge\t\t58\t(39–70)\t\nDisease\tCirrhosis\t10\t(42%)\t\n\tHCC\t14\t(58%)\t\nLabMELD\t\t15\t(7–34)\t\nAntiviral therapy\tHBV-nucleoside analogues\t24\t(100%)\t\n\t Lamivudine\t13\t(54%)\t\n\t Tenofovir\t7\t(29%)\t\n\t Adefovir + Lamivudine\t3\t(13%)\t\n\t Entecavir\t1\t(4%)\t\n\tHBV Immunoglobulins (post-LT)\t24\t(100%)\t\n\tCMV-nucleoside analogues\t5\t(21%)\t\n\t Valganciclovir\t5\t(100%)\t\nHDV coinfection\t\t3\t(13%)\t\nBlood transfusion\t\t23\t(96%)\t\nPre-LT\tAST\t62\t(13–157)\t\n\tALT\t52\t(14–115)\t\nHospital stay (days)\tICU\t5\t(1–23)\t\n\tOff ICU\t16\t(7–43)\t\nIschemic perfusion time (hours)\tCold\t7\t(4–11)\t\n\tWarm\t0.7\t(0.5–1.3)\t\nDonor characteristics\t\t\t\t\nGender\tMale\t18\t(75%)\t\n\tFemale\t6\t(25%)\t\nAge\t\t52\t(16–57)\t\n\n\nThe clinical data revealed that all patients received nucleoside analogues before LT, including lamivudine, tenofovir, entecavir, or adefovir and lamivudine dual treatment. Anti-HBV treatment was complemented with the administration of HBIG for all patients post-LT, which was part of the standard of care protocol for HBV related LT. Furthermore, five patients received valganciclovir as anti-CMV treatment. Patients followed a strict therapeutic protocol including immunosuppressive drugs and anti-inflammatory treatment post-LT. This protocol included a standard initiation therapy with tacrolimus, mycophenolate mofetil and methylprednisolone. In three patients that suffered from liver cirrhosis, tacrolimus was combined with everolimus.\n\n3.2 Sequencing data\nIllumina sequencing generated ∼1.4 billion reads, which was reduced by removing low quality and human genome reads to ∼0.5 billion reads. In total, 65 million reads were annotated as viral and corresponded to 4.7% of all the generated reads. The majority of viral reads were attributed to eukaryotic viruses (70.9%), followed by prokaryotic viruses (28.9%) and unclassified viral reads (0.2%) (Fig. 1). Three known bloodborne viral families that infect humans were detected, including Anelloviridae, Hepadnaviridae, and Flaviviridae, together with HDV (prototype virus of the deltavirus genus). Different genera of the Anelloviridae consisting of alphatorque, betatorque, and gammatorquevirus, as well as a group of unclassified anelloviruses were the most frequently identified viruses and widely present in the blood stream of the study population.Fig. 1 Distribution of the annotated viral reads over different taxonomical ranks.\n\nFig 1\n\nThe virome composition was determined in plasma samples at different time points before and after LT. The relative abundance of eukaryotic viral families before (A and B) and after (C, D, E, and F) LT (Fig. 2(a)) were strikingly different, indicating an impact by the initiation of immunosuppressive therapy post-LT. Before transplant (samples A and B), the eukaryotic viral component is majorly composed of the Hepadnaviridae family (52%). Sample A corresponds to the first sample that was collected in UZ Leuven after which all patients received anti-HBV therapy. The impact of therapy is illustrated by the decline of Hepadnaviridae abundance (24%) seen in sample B, shortly before LT. In total, six and eight patients out of 24 were positive for HBV reads and were detected before transplant in samples A and B respectively. Also, members of the deltavirus genus (HDV in two and three patients in samples A and B respectively) were detected in three patients. Furthermore, infections with Flaviviridae were observed in two patients at timepoint A and one patient in timepoint B, making up 18% and 5% of the relative abundance of all eukaryotic viruses respectively (Fig. 2(b) and (a)).Fig. 2 (a) Relative abundance of the detected viral families in different timepoint before (A and B) and after (C, D, E and F) liver transplant. (b) Number of patients that are positive for the different viral families before (A and B) and after (C, D, E and F) liver transplant. (c) Relative abundance of the detected viral families in CI and HCC patients. CI: cirrhosis, HCC: hepatocellular carcinoma.\n\nFig 2\n\nTowards transplantation, the relative abundance of the Anelloviridae increases. While in sample A, the Anelloviridae family constituted only 19% of the eukaryotic viral reads, in sample B the abundance increased up to 53%. After transplant (samples C, D, E, and F) the virome is dominated by the Anelloviridae (Fig. 2(a) and (b)).\n\nBesides anelloviruses, also Flaviviridae were detected with 4% of the annotated reads in both samples D and E, and 7% in sample F. The Anelloviridae make up the remaining eukaryotic viral reads. After transplant, the number of patients that were found positive for Anelloviridae increased up to 23 out of 24 patients in samples E and F (Fig. 2(b)). Differentiating the study population based on the clinical indication for LT, shows a sustained HBV abundance in HCC patients before transplant while in cirrhotic patients the abundance decreases. However, this trend did not reach statistical significance (Wilcoxon rank-sum: p > 0.05).\n\nTo further explore the viral presence in liver cirrhosis and HCC patients, we generated cross-tables (Table 2) for the different viral families and patient diagnosis. For the Anelloviridae, the patients were categorized based on the tertiles of the average anellovirus abundance in high, intermediate and low burden groups. Although, a Fisher's exact test did not supportdifferences of Flaviviridae presence between cirrhosis and HCC patients (Fisher's exact test: p > 0.05), an increasing trend was observed in cirrhosis patients. Finally, patients diagnosed with HCC had a higher prevalence of the Hepadnaviridae (Fisher's exact test:p < 0.05 ).Table 2 Cross tables for the presence of viral families in patients diagnosed with liver cirrhosis or hepatocellular carcinoma. Numbers are expressed in frequencies and the percentage of patients positive for the virus within the disease group.\n\nTable 2\tAnelloviridae\tHepadnaviridae*\tFlaviviridae\tDeltavirus\t\nN (%)\tHigh\tMedium\tLow\tPresent\tAbsent\tPresent\tAbsent\tPresent\tAbsent\t\nCI\t4 (40)\t3 (30)\t3 (30)\t1 (10)\t9 (90)\t3 (30)\t7 (70)\t1 (10)\t9 (90)\t\nHCC\t4 (28)\t5 (36)\t5 (36)\t8 (57)\t6 (43)\t1 (7)\t13 (93)\t2 (14)\t12 (86)\t\n⁎ Fisher's exact test p < 0.05.\n\n\n\n3.3 Anelloviridae\nDue to the large abundance of Anelloviridae in the transplant patients, we further characterized their genera. The anelloviruses identified in this study were annotated in three genera and an additional group of unclassified anelloviruses. No significant changes were detected in the relative abundance of the three genera (Fig. 3(a)). However, the absolute number of reads of alphatorque, gammatorque and unclassified anelloviruses increased after transplant (Fig. 3(b)). To confirm the NGS results for the anelloviruses, an in-house designed qPCR assay was used on the original samples. A linear correlation was found between the number of reads and the qPCR results (Fig. 3(c), Spearman's rank correlation r= 0.85, p < 0.001).Fig. 3 (a) Relative abundance of the Anelloviridae genera before (A and B) and after (C, D, E and F) liver transplantation. (b) Logarithmic value of the absolute number of reads for the different Anelloviridae genera before and after liver transplantation. Grey dotted line: liver transplantation. (c) Linear model describing the correlation between NGS and qPCR data for Anelloviridae abundance. Red: pre-liver transplantation, blue: post-liver transplantation. Vertical grey dotted line: liver transplantation. Dunn's test: * p < 0.05 ** p < 0.01 *** p < 0.001.\n\nFig 3\n\nAnellovirus ORF1 was extracted from the non-redundant contig dataset to perform phylogenetic analysis. A ML phylogenetic tree was inferred from the aligned amino acid data and shows the clustering of the ORF1 sequences in the three main genera and unclassified Anelloviridae sequences (Fig. 4). To determine the presence or absence of the different ORFs in the samples, a threshold of 100 reads was set. An increasing number of anellovirus species were detected in the samples after transplant, with the majority of species derived from the alphatorque genus.Fig. 4 ML phylogenetic tree of the extracted amino acid ORF1 sequences with a corresponding presence and absence heatmap ranked according to the different timepoints.\n\nFig 4\n\n3.4 The virome and post-transplant complications\nThe clinical data revealed incidences of post-LT side-effects in the study population. Primarily, cases of mortality, post-LT infection, nephrotoxicity and new-onset type II diabetes (NO-TIID) were reported (Table 3). The frequency of post-LT complications was compared between cirrhosis and HCC patients. The highest discrepancy was observed in mortality, with six patients in the HCC group compared to one in the cohort of patients diagnosed with liver cirrhosis (Fig. S1). However, no statistically significant differences were observed across the different post-LT complications (Fisher's exact test: p > 0.05).Table 3 Overview of the post-liver transplant complications.\n\nTable 3Variable\tN\tPercentage\t\nMortality\t7\t(29)\t\n\tRecurrent HCC\t2\t(29)\t\n\tHCC metastasis\t4\t(57)\t\n\tPneumonia\t1\t(14)\t\nInfection\t16\t(67)\t\nViral\tCMV\t2\t(11)\t\n\tEBV\t2\t(11)\t\n\tPolyomavirus\t1\t(5)\t\nBacterial\tUrinary tract\t7\t(37)\t\n\tPositive blood culture\t4\t(21)\t\n\tGastroenteritis\t2\t(11)\t\nNephrotoxicity\t\t9\t(38)\t\nNO-TIID\t\t7\t(29)\t\n\n\n3.5 Nephrotoxicity\nNine patients (38%) were diagnosed with symptoms of nephrotoxic side-effects post-LT. We compared the number of Anelloviridae reads in patients that developed kidney failure to patients that did not report impaired kidney function. The tacrolimus level remained between the reference values (Fig. 5(a)) (5–15 µg/L) and did not differ between both patient groups. However, both the absolute number of Anelloviridae species and the viral abundance indicate a significant increase of this family in patients suffering from nephrotoxic side-effects post-LT (Fig. 5(b) and (c), Dunn's-test). Interestingly, the increase in anellovirus preceded and paralleled increases in serum creatinine concentrations, supporting the association between anellovirus and renal insufficiency (Fig. 5(d)). Besides an increase of the Anelloviridae read abundance on family level, both reads attributed to the alphatorque genus and unclassified anelloviruses were higher for patients with renal complications in post-LT samples (E/F and D/E respecively, Dunn's-test). To evaluate the individual Anelloviridae species in patients with different clinical courses, we compared the OTU presence in both patient groups (Fig. 5(g) and (h)). This analysis indicated that 8/9 (89%) of patients with nephrotoxic symptoms carried the SEN-virus in timepoint D (Fig. 5(e)), compared to 3/15 (20%) non-nephrotoxic patients (Fig. 5(f)) (Fisher's exact test: p < 0.05).Fig. 5 (a) Distribution of the tacrolimus concentration in patients diagnosed with or without nephrotoxic side-effects. (b) Sum of all Anelloviridae species divided in patients with and without nephrotoxic side effects. (c) Differences in the number of Anelloviridae reads (logarithmic) between patients with and without nephrotoxic side effects. (d) Differences in blood creatinine concentrations between patients with and without nephrotoxic side effects. (e) The number of reads attributed (logarithmic) to the alphatorque genus. (f) The number of unclassified Anelloviridae reads (logarithmic). (g) The most abundant viral species in patients with nephrotoxic side-effects. (h) The most abundant viral species in patients without nephrotoxic side-effects. Blue: with nephrotoxic side effects, yellow: without nephrotoxic side effects. Vertical grey dotted line: liver transplantation. Horizontal grey dotted line: reference values. Wilcoxon rank-sum test: * p < 0.05 ** p < 0.01 *** p < 0.001.\n\nFig 5\n\n3.6 Infections\nAnalysis of routine laboratory results and patients’ clinical data revealed a substantial number of infections occuring after LT. A total of 16 (67%) patients experienced flares of infection in post-transplant samples, either bacterial or viral infections (Fig. 6 and Table 3). Infections were documented during regular and emergency consultations in post-transplant care. We analyzed the anellovirus load in samples close to the diagnosis of infection. The data indicates that in both the number of reads as well as the qPCR data, the Anelloviridae abundance is increased during infection compared to non-infection timepoint (Wilcoxon rank-sum: p < 0.05).Fig. 6 (a) The Anelloviridae reads abundance in samples diagnosed with or without infections. (b) qPCR results of the Anelloviridae family in samples diagnosed with or without infections. Only significant p-values are shown (Wilcoxon rank-sum test).\n\nFig 6\n\n3.7 Survival analysis\nA 5-year survival analysis was performed to determine the impact of initial diagnosis on post-LT survival (Fig. S2). No significant difference was found in post-LT survival after five years (log rank test: p > 0.05). In total, three patients died in the cirrhosis group, with pneumonia being the cause of death in two patients and cancer in one patient. In the group of individuals that received an LT because of HBV induced HCC, six patients died of recurrent HCC or HCC metastasis and one individual of intestinal ischemia. Remarkably, post-LT survival for individuals that died during follow-up was lower for patients with HCC (median survival 24.5 months) compared to cirrhosis patients (median survival 98 months).\n\nA more detailed analysis was performed to study the relationship between viral families and 5-year post-LT survival. All patients had post-LT samples that were positive for anelloviruses through the course of follow-up. Therefore, to study the impact of anellovirus burden on patient survival, we classified the population according to the average post-LT presence of anelloviruses (Fig. S2(b)). Between the different groups (high, medium and low Anelloviridae abundance) no difference was found in 5-year post-LT survival (log rank test: p > 0.05). In patients that were tested positive for HBV in pre-LT samples, 56% of the patients were still alive after five years compared to 80% in HBV negative patients (Fig. S2(c)). Furthermore, HDV co-infected patients (N=3) were still alive after five years. Patients that were found positive for HPgV in follow-up samples did not report mortality cases (N=4) post-LT (Fig. S2(d)).\n\n3.8 New-onset type II diabetes\nBesides nephrotoxicity, seven patients (29%) were diagnosed with new-onset tye II diabetes (NO-TIID). Tacrolimus concentration in patients were not different in NO-TIID patients (Fig. S3(a), Wilcoxon rank-sum: p > 0.05). However, there was an increasing trend in the Anelloviridae abundance shortly after LT (Fig. S3(b)). Furthermore, comparing the most abundant OTUs of patients with and without NO-TIID (Figs. S3(c) and (d), repectively) did not show significant changes (Wilcoxon rank-sum: p > 0.05).\n\n3.9 Clinical relevance of the Anelloviridae\nTo study the relationships between individuals and different quantitative and qualitative variables, a factor analysis of mixed data was applied (Fig. 7). In multiple panels, a clustering of patients diagnosed with post-transplant complications were observed. The two dimensions in the analysis account for 28.8 % of the variance of the dataset. Scattering across the second dimension is primarily driven by clinical markers of hepatitis and the logarithm of the Anelloviridae reads in the opposite direction (Fig. 7(a)). Serum AST an ALT (R2: 0.79 and 0.71 respectively, p < 0.05) are positively correlated and the Anelloviridae abundance is negatively correlated (R2: −0.52, p < 0.05) with dimension one. The vertical distribution is mainly related to metastasis and mortality (Fig. 7(d)). Clustering of samples diagnosed with infection and nephrotoxicity along the horizontal axis partially overlap the distribution of the Anelloviridae abundance (Fig. 7(a)–(c)). These findings indicate that the Anelloviridae abundance might have discriminative power to identify nephrotoxicity and infection in clinical samples.Fig. 7 (a) Contribution plot of the quantitative variables across the first two dimensions. (b) Clustering of individual samples of patients diagnosed with nephrotoxicity. (c) Clustering of individual samples of patients diagnosed with post-liver transplantation infections. (d) Clustering of individual samples of patients that died during follow-up.\n\nFig 7\n\nTo further elucidate the diagnostic potential of the Anelloviridae abundance, a univariate logistic regression analysis was applied. The clinical outcome was used as the outcome variable and the logarithm of the Anelloviridae reads as the independent variable with patient ID as random effect. We observed a significant odds ratio (OR) for infection (OR 1.58, 95% CI 1.24–2.15, logistic regression: p < 0.001) and renal failure (OR 1.59, 95% CI 1.21–2.20, logistic regression: p < 0.01) (Table 4). However, no significant OR was observed for mortality (OR 1.04, 95% CI 0.11–11.70, logistic regression: p > 0.05) and NO-TIID (OR 1.63, 95% CI 0.93–3.47, logistic regression: p > 0.05).Table 4 Relationship between Anelloviridae abundance and post-liver transplant complications.\n\nTable 4\tOdds ratio\t95% CI\t\nAnelloviridae\tInfection\t1.58⁎⁎\t1.24–2.15\t\n\tNephrotoxicity\t1.59*\t1.21–2.20\t\n\tMortality\t1.04\t0.11–11.70\t\n\tNO-TIID\t1.63\t0.93–3.47\t\nLogistic regression analysis\n\n⁎ p < 0.01\n\n⁎⁎ p < 0.001\n\n\n\n4 Discussion\nMetagenomic studies have provided a strong link between the clinical status of patients and fluctuation of microorganism populations living and circulating in different biological niches of the human body [4,28]. This research added fundamental knowledge for finding disease aetiology, therapeutic and prophylactic measures. For the first time, we studied the fluctuation of the blood virome in LT recipients before and after surgery in a set of longitudinal samples.\n\n4.1 Viral persistence (HBV)\nThe implemented antiviral strategy to prevent resurgence of HBV infection seemed to be effective considering that no HBV was detected post-LT in the study population. The majority of patients positive for HBV were diagnosed with HCC. Among these individuals, the primary cause of mortality was related to recurrent HCC or HCC metastasis. This supports previous data describing HBV related HCC as a risk factor for post-LT mortality [29,30]. The increased presence of HBV in HCC patients could be explained by the decreased availability of hepatocytes for viral replication in liver cirrhosis patients [31]. Also, highly active tumour cells in HCC conditions could function as a viral replication site and act as a potential reservoir [32]. However, providing HBV prophylaxis reduces the risk of recurrent HBV infection as demonstrated in this study.\n\n4.2 Post-LT complications\nAn increase in the abundance and number of Anelloviridae species was observed post-LT. Furthermore, multivariate and univariate analyses further confirmed the potential clinical relevance of the Anelloviridae abundance in diagnosing post-LT complications. These observations corresponded with the initiation of immunosuppressive therapy. The interaction between immunosuppression and blooming of the anellovirus population in LT recipients approves previous studies in other organ transplantation settings [4,33].\n\nThe Anelloviridae family constitutes a highly heterogeneous group of viruses that are widely distributed in healthy individuals [34]. Anellovirus infection is acquired shortly after birth from which it establishes a possibly lifelong infection. Currently, no pathogenic effects have been subscribed to these viruses, albeit an association with autoimmune diseases and cancers has been implied in the past [35].\n\nPrevious studies demonstrated an association between the anellovirus load and solid organ rejection [4]. Of note, a lower anellovirus abundance corresponded to an increased risk of organ rejections, while a high Anelloviridae load translated in an elevated susceptibility of opportunistic infections and secondary cancers. Although, no cases of liver transplant rejection were observed, 23/24 patients suffered from post-LT complications.\n\n4.3 Post-liver transplantation infections\nIn 16 patients we observed bacterial or viral post-transplant infections. The risk of infection is the result of two factors, the pathogenic exposure and the patient immune status [5]. Bacterial infections that occurred shortly after transplantation were mainly related to surgical procedures and hospital environment exposure, i.e. nosocomial exposure. The reduced immunocompetence after samples C (± 3-6 months post-LT) accommodated the occurrence of opportunistic viral infections, such as CMV and EBV reactivation. Importantly, the samples that were collected during the course of infections, contained a higher Anelloviridae load, both in terms of read number and qPCR value (Wilcoxon rank-sum: p < 0.05). This data suggests that anellovirus kinetics might be indicative for post-transplant infections, which is consistent with previous reports in different types of organ transplantations [4,36,37]. In contrast to previous findings, this study focussed at intact viral particles in an untargeted manner, that allows a broader exploration of the viral landscape in LT patients. Therefore, a more detailed assessment of the wide variety of anelloviruses in immunosuppressed patients was achieved covering multiple genera of the Anelloviridae family. In current clinical practice, the reduced signs of inflammation and possible drug interactions complicate the development of optimized diagnostic and treatment strategies in immunocompromised patients respectively [5]. Our findings support the potential use of anelloviruses as a surrogate marker of the net immune status in immunocompromised patients [4,38]. However, these findings should be interpreted with caution, as not all infectious episodes were accompanied by high Anelloviridae loads and vice versa. A careful longitudinal follow-up of organ transplant patients is required to validate the diagnostic relevance of anelloviruses in post-transplant care.\n\n4.4 Post-liver transplantation nephrotoxicity\nBesides post-LT infections, nine patients suffered from nephrotoxic side-effects after liver transplantation. An impaired renal function was related to a higher anellovirus load after LT compared to non-renal failure patients. Multiple scenarios might explain this clinical observation. The administration of immunosuppressive calcineurin inhibitors (CNIs), like tacrolimus, have significantly improved transplantation success and patient survival. However, nephrotoxicity is a common side-effect of long-term exposure to these compounds [39]. Therefore, the reported increase of Anelloviridae in patients with an impaired kidney function can be a direct consequence from the elevated tacrolimus concentration, which also negatively affects renal function. However, no significant differences were observed in the plasma tacrolimus concentrations in patients with or without renal toxicity. In contrast, the Anelloviridae load corresponded to an increase in the plasma creatinine concentration. Creatinine clearance is a biomarker that indicates kidney functioning [40]. Although, it is not considered a highly sensitive biomarker, our data demonstrates that serum creatinine is elevated in patient with renal failure. Furthermore, the data suggests that the Anelloviridae could be used as a proxy for nephrotoxic side-effects, based on the increased abundance in patients suffering from renal failure. A more detailed analysis of the individual anellovirus species revealed that some species occurred more often in patients suffering from renal failure than others. As such, SEN-virus was detected in 8/9 timepoint D samples for patients with reduced renal function. SEN-virus infection has been related to non-A-E hepatitis, albeit the data is highly inconsistent [41]. Considering the epidemiological pattern of this virus in different populations, it is unlikely that it exerts detrimental consequences for the host. Studies that demonstrated the presence of SEN-virus in healthy blood donors imply that this virus can be transmitted through blood transfusions [42,43]. However, the viral abundance did not correspond to the frequency or type of blood transfusions. Another explanation for the increase of SEN-virus post-LT, could be related to the increased Anelloviridae abundance in immunosuppressed conditions. Therefore, the incremental replication causes the viral load to pass the detection threshold of NGS post-LT. Future studies should focus at characterizing the dynamics and elucidating the role of SEN-virus in post-transplant complications and blood transfusion practice.\n\n4.5 Post-liver transplantation new onset type II diabetes\nBesides the emergence of nephrotoxic side-effects, a substantial number of patients reported post-LT NO-TIID (7/24). Multiple factors are known to contribute to the development of NO-TIID like pre-existing insulin resistance. Furthermore, drugs administered in post-LT standard care regimen negatively affect glucose control of the patient and instigates the progression to NO-TIID [44]. For instance, corticosteroids are widely used in high doses shortly after transplant and are known for causing hyperglycaemia. However, tapering of the drug improves glucose tolerance and restores the normal homeostasis. Besides corticosteroids, CNIs (e.g. tacrolimus) have been associated with the development of NO-TIID. In this study, we analysed Anelloviridae kinetics in patients with or without NO-TIID. We detected an increasing trend in the Anelloviridae abundance in NO-TIID patients, albeit no statistically significant result was found. Also, NO-TIID did not seem to correlate with other post-LT outcomes, in contrast to previous findings [45].\n\nThe plasma concentration of CNIs is an important indicator of immunosuppression and possible risk of side-effects [46]. However, we demonstrated that the level of CNIs did not discriminate between individuals diagnosed with or without post-LT complications. Although, CNIs are considered as the main contributor to post-transplant toxicities, a possible synergistic scenario between immunosuppressive drugs and viral families have not been evaluated. For instance, it has been shown that viruses such as the BK polyomavirus are involved in renal failure of non-renal solid organ transplant recipients who received immunosuppressive agents [47]. Although, we did not report the presence of BK polyomavirus in our samples, the clinical impact of other viral families found in this study should be further explored.\n\n4.6 Anelloviridae\nThe majority of clinical studies have focused on the presence the alphatorquevirus genus of the Anelloviridae family. The alphatorquevirus genus is often targeted by qPCR in different clinical manifestation and is considered a potential marker for immunocompetence in organ transplant patients [48,49]. Although, this approach seems promising, a well-validated anellovirus biomarker is still lacking. Our findings indicate that a single patient can be coinfected with multiple species that belong to different genera of the Anelloviridae family. This complicates the development of a unique biomarker for clinical interpretation. Future studies should regard the high heterogeneity of the Anelloviridae family to validate the clinical importance of these viruses as biomarkers for immunocompetence.\n\n4.7 Human pegivirus\nBesides anelloviruses, we detected human HPgV in samples of four patients (three patients with cirrhosis and one patient with HCC). All patients that were found positive for HPgV were still alive 5-years post-LT, which might indicate a protective role of HPgV in post-LT survival. HPgV infection has received a growing attention by the research community because of its immune modulating potential and positive outcomes in other viral infections. Patients coinfected with HIV and HPgV demonstrated a prolonged survival with decreased HIV viral load and higher CD4+ T-cell counts [50], [51], [52]. Furthermore, HIV infected patients that acquired HPgV through blood transfusion demonstrated an improved survival compared to non-HPgV infected patients [53]. These characteristics have inspired researchers to explore the use of HPgV as a bio vaccine to complement anti-HIV therapy [11,54]. Besides the positive impact on HIV-outcome, HPgV co-infection demonstrated a potential protective role in Ebola virus infected patients [55]. Despite a single study that reported a decreasing trend in HBV DNA in HBV and HIV coinfected individuals with HPgV, the role of HPgV in HBV infected individuals is still unexplored [56]. Furthermore, the impact of HPgV and post-LT mortality should be further investigated in future studies. In contrast to the positive impact on HIV and Ebola patients’ survival, the immune modulating effect of the virus may contribute to the development and progression of non-Hodgkin's lymphoma [57,58]. Therefore, additional research is warranted to study the long-term impact of HPgV infection in healthy, HBV infected and organ transplanted patients in a larger population.\n\nIn this study, the samples were collected in a retrospective manner from the HBV cohort in UZ Leuven with a limited population size. The relatively small number of patients could have underpowered parts of the analysis. Therefore, future research should confirm the observed clinical relevance of the Anelloviridae abundance in a larger population. Furthermore, exploring the virome in different clinical settings is recommended. For instance, studying the virome in other organ transplant or blood transfusion settings will provide a more detailed insight in virome-modulating factors that could attenuate the relationship between these viruses and clinical outcomes.\n\nIn conclusion, in the assessment of longitudinal plasma samples, multiple viral families have been detected in the blood virome of liver transplant recipients. The metagenomic approach provided an unprecedented insight in the viral communities. These findings support that the clinical status and pharmacological perturbation of the immune system can have a profound impact on the presence and abundance of viral populations. The notion of an increased Anelloviridae abundance and diversity in patients suffering from post-LT side-effects calls for a further exploration of the relationship between these viruses and immunocompromised individuals. The identification of HPgV in a subgroup of our study population, highlights the necessity of studying the impact of this virus on the clinical outcome of HBV infected patients.\n\nData sharing statement\nRaw reads were deposited in NCBI's Sequence Read Archive (SRA) database under accession no. PRJNA660895.\n\nDeclaration Competing Interest\nWe declare no competing interests.\n\nAuthor contributions\nMRP and MVR designed the study. MT, MRP, WL and FN recruited the patients, collected the samples and clinical data. MT and CKY did the NGS sequencing. MT, LB and WD analysed the NGS data. MT did the statistical analysis over the clinical data and NGS findings. MT and FT provided the first draft of manuscript and developed it. LB, WD, CKY, FN, MRP and MVR edited the manuscript and improved it. All authors read and approved the final version of the manuscript.\n\nFunding\nMT is a strategic based PhD fellow at the Research Foundation Flanders (FWO, Belgium). MRP is supported by a postdoctoral grant from the FWO. LB was funded by FWO. CKY was funded by the Interfaculty Council for the Development Cooperation (IRO) from the KU Leuven. The funders had no role in the study design, data collection, data analysis, interpretation, and writing of the report.\n\nAppendix Supplementary materials\nSupplementary figure 1. Post-liver transplant complications in patients diagnosed with liver cirrhosis (yellow) and hepatocellular carcinoma (blue). CI: cirrhosis, HCC: hepatocellular carcinoma, NOD: new-onset type II diabetes.\n\nImage, image 1 Supplementary figure 2. Kaplan-Meier plots of 5-year post-liver transplant survival.\n\nImage, image 2 Supplementary figure 3. (a) Distribution of the tacrolimus concentration in patients diagnosed with or without NO-TIID. (b) Differences in the number of Anelloviridae reads (logarithmic) between patients with and without NO-TIID. (c) The most abundant viral species in patients diagnosed with NO-TIID. (d) The most abundant viral species in patients without NO-TIID. Vertical grey dotted line: liver transplantation. Horizontal grey dotted line: reference values. Blue: with NO-TIID, grey: without NO-TIID. Only significant p-values are shown.\n\nImage, image 3 \n\nSupplementary material associated with this article can be found, in the online version, at doi:10.1016/j.ebiom.2020.103009.\n==== Refs\nReferences\n1 Burra P Burroughs A Graziadei I Pirenne J Valdecasas JC Muiesan P EASL clinical practice guidelines: liver transplantation J Hepatol 64 2 2016 433 485 26597456 \n2 Tsai HI Yu HP. 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Open forum infectious diseases 2017 Oxford University Press US \n51 Vahidnia F Petersen M Stapleton JT Rutherford GW Busch M Custer B Acquisition of GB virus type C and lower mortality in patients with advanced HIV disease Clin Infect Dis 55 7 2012 1012 1019 22752515 \n52 Tillmann HL Heiken H Knapik-Botor A Heringlake S Ockenga J Wilber JC Infection with GB virus C and reduced mortality among HIV-infected patients N England J Med 345 10 2001 715 724 11547740 \n53 Lanteri MC Vahidnia F Tan S Stapleton JT Norris PJ Heitman J Downregulation of cytokines and chemokines by GB virus C after transmission via blood transfusion in HIV-positive blood recipients J Infect Dis 211 10 2015 1585 1596 25425697 \n54 Gretch D Editorial commentary: advocating the concept of GB virus c biotherapy against AIDS 2012 Oxford University Press \n55 Lauck M Bailey AL Andersen KG Goldberg TL Sabeti PC O'Connor DH GB virus C coinfections in West African Ebola patients J Virol 89 4 2015 2425 2429 25473056 \n56 N'Guessan KF Boyce C Kwara A Archampong TN Lartey M Sagoe KW Human pegivirus (HPgV) infection in Ghanaians co-infected with human immunodeficiency virus (HIV) and hepatitis B virus (HBV) Virus Genes 54 3 2018 361 367 29551002 \n57 Chang CM Stapleton JT Klinzman D McLinden JH Purdue MP Katki HA GBV-C infection and risk of NHL among US adults Cancer Res 74 19 2014 5553 5560 25115299 \n58 Krajden M Yu A Braybrook H Lai AS Mak A Chow R GBV-C/hepatitis G virus infection and non-Hodgkin lymphoma: a case control study Int J Cancer 126 12 2010 2885 2892 19904755\n\n", "fulltext_license": "CC BY-NC-ND", "issn_linking": "2352-3964", "issue": "60()", "journal": "EBioMedicine", "keywords": "Anellovirus; Liver transplantation; Metagenomic; Plasma; Transfusion; Virome", "medline_ta": "EBioMedicine", "mesh_terms": "D000328:Adult; D000368:Aged; D000998:Antiviral Agents; D060085:Coinfection; D019295:Computational Biology; D005260:Female; D006801:Humans; D016031:Liver Transplantation; D008297:Male; D054892:Metagenome; D056186:Metagenomics; D008875:Middle Aged; D010802:Phylogeny; D066027:Transplant Recipients; D014766:Viremia; D000083422:Virome; D014777:Virus Diseases", "nlm_unique_id": "101647039", "other_id": null, "pages": "103009", "pmc": null, "pmid": "32979836", "pubdate": "2020-10", "publication_types": "D016428:Journal Article", "references": "30375165;23099188;24267896;24767359;29082660;25170223;23703735;31145443;15987351;11547740;27004904;26985385;25115299;26647107;23906500;23778792;22752513;26289820;26038737;30053048;19230553;24695404;22752515;29255726;30468687;29692764;31754812;26913379;25425697;28298430;28117944;27684958;25473056;30403735;22388286;19218475;29904294;19904755;26650437;25402007;27289565;30072250;10868275;30234787;25676209;30341363;24679532;26038873;29551002", "title": "Clinical relevance of plasma virome dynamics in liver transplant recipients.", "title_normalized": "clinical relevance of plasma virome dynamics in liver transplant recipients" }

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{ "abstract": "Invasive pulmonary aspergillosis (IPA) is a severe fungal infection with a high mortality rate. The incidence of IPA is on the rise due to an increase in the number of patients undergoing transplants and receiving chemotherapy and immunosuppressive therapy. Diagnosis is challenging due to the non-specific nature of symptoms. Voriconazole is the mainstay of therapy. We present a case of an elderly woman presenting with acute bronchitis and asthma exacerbation, who succumbed to overwhelming IPA. It is uncommon for IPA to develop in patients on short-term steroid therapy for asthma exacerbation. The possibility of aspergillosis in immunocompetent patients should be considered in those on systemic steroids and deteriorating pulmonary functions.", "affiliations": "Department of Internal Medicine, Montefiore New Rochelle Hospital, Albert Einstein College of Medicine, New Rochelle, NY, USA; anaaraay@montefiore.org.;Department of Internal Medicine, Montefiore New Rochelle Hospital, Albert Einstein College of Medicine, New Rochelle, NY, USA.;Department of Internal Medicine, Montefiore New Rochelle Hospital, Albert Einstein College of Medicine, New Rochelle, NY, USA.;Department of Internal Medicine, Montefiore New Rochelle Hospital, Albert Einstein College of Medicine, New Rochelle, NY, USA.;Department of Internal Medicine, Montefiore New Rochelle Hospital, Albert Einstein College of Medicine, New Rochelle, NY, USA.", "authors": "Naaraayan|Ashutossh|A|;Kavian|Ronak|R|;Lederman|Jeffrey|J|;Basak|Prasanta|P|;Jesmajian|Stephen|S|", "chemical_list": null, "country": "United States", "delete": false, "doi": "10.3402/jchimp.v5.26322", "fulltext": "\n==== Front\nJ Community Hosp Intern Med PerspectJ Community Hosp Intern Med PerspectJCHIMPJournal of Community Hospital Internal Medicine Perspectives2000-9666Co-Action Publishing 2632210.3402/jchimp.v5.26322Review ArticleInvasive pulmonary aspergillosis – case report and review of literature Naaraayan Ashutossh MD*Kavian Ronak MDLederman Jeffrey MD, FACPBasak Prasanta MD, FACPJesmajian Stephen MD, FACPDepartment of Internal Medicine, Montefiore New Rochelle Hospital, Albert Einstein College of Medicine, New Rochelle, NY, USA* Correspondence to: Ashutossh Naaraayan, Department of Internal Medicine, Montefiore New Rochelle Hospital, Albert Einstein College of Medicine, 16 Guion Place, New Rochelle 10801, NY, USA, Email: anaaraay@montefiore.org03 2 2015 2015 5 1 10.3402/jchimp.v5.2632214 10 2014 05 12 2014 12 12 2014 © 2015 Ashutossh Naaraayan et al.2015This is an Open Access article distributed under the terms of the Creative Commons Attribution-Noncommercial 3.0 Unported License, permitting all non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.Invasive pulmonary aspergillosis (IPA) is a severe fungal infection with a high mortality rate. The incidence of IPA is on the rise due to an increase in the number of patients undergoing transplants and receiving chemotherapy and immunosuppressive therapy. Diagnosis is challenging due to the non-specific nature of symptoms. Voriconazole is the mainstay of therapy. We present a case of an elderly woman presenting with acute bronchitis and asthma exacerbation, who succumbed to overwhelming IPA. It is uncommon for IPA to develop in patients on short-term steroid therapy for asthma exacerbation. The possibility of aspergillosis in immunocompetent patients should be considered in those on systemic steroids and deteriorating pulmonary functions.\n\naspergillussteroidsasthma exacerbationvascular invasionground glass opacities\n==== Body\nAspergillus is a fungus which is commonly found in the soil, food, plant debris, and indoor environment. The spores are easily aerosolized and inhaled. In the respiratory mucosa, the spores may germinate into hyphae, which in turn can invade the mucosa leading to invasive pulmonary aspergillosis (IPA) (1). Both innate immune responses and inflammatory cells limit fungal growth and prevent disease in the majority of individuals. Depending on host's immune status and specific immune-deficiencies, Aspergillus may lead to different pulmonary manifestations (Table 1).\n\nTable 1 Clinical course following inhalation of Aspergillus spores\n\nNormal immune competent host: No infection\t\nPrevious cavitary lung disease: Aspergilloma\t\nExcess Th2 response (allergic response): Allergic broncho pulmonary aspergillosis\t\nMild immune compromised state: Chronic necrotizing aspergillosis\t\nSevere immune deficiency: Invasive pulmonary aspergillosis\t\nIPA usually occurs in severely immunocompromised patients. Classic at-risk patients are those with prolonged neutropenia, either due to chemotherapy or immunosuppressive therapy, post hematopoietic stem cell transplant (SCT), or solid organ transplant (1, 2). Risk factors for IPA are summarized in Table 2.\n\nTable 2 Risk factors for developing IPA\n\nStem cell transplant or solid organ (especially lung) transplant\t\nHematologic malignancies\t\nProlonged neutropenia\t\nCritically illness in intensive care unit\t\nSteroid use\t\nHemodialysis\t\nLiver disease\t\nChronic obstructive pulmonary disease (COPD)/chronic lung diseases\t\nChronic granulomatous diseases\t\nIPA has rarely been reported in patients on short-course steroid therapy without chronic lung diseases (3, 4). We describe the case of an elderly woman who was found to have extensive IPA, in the absence of classic risk factors.\n\nCase report\nA 73-year-old woman was admitted to our hospital with complaints of shortness of breath and malaise. Nineteen days prior to admission, she was treated with inhaled steroids and cefpodoxime for acute bronchitis. A week before admission, she complained of fever, chills, wheezing, and cough with yellow sputum. She received oral prednisone and levofloxacin. However her symptoms worsened, and she presented to our emergency department. Her medical history included asthma with infrequent exacerbations (three exacerbations in the previous 3 years), hypertension, hyperlipidemia, diabetes mellitus, hypothyroidism, gout, spinal stenosis, and chronic kidney disease. Her home medications included carvedilol, furosemide, atorvastatin, gemfibrozil, sitagliptin, levothyroxine, allopurinol, erythropoietin, montelukast, fluticasone, and albuterol inhalers. Vital signs in the emergency department were temperature 97°F, blood pressure 144/66 mm Hg, heart rate 80/min, respiratory rate 16/min, and oxygen saturation 99% on room air. Examination revealed bilateral diffuse wheezing and pharyngeal wall erythema. Laboratory data showed white cell count 2.8×103 cells/dl with 72% neutrophils, hemoglobin 8.7 g/dl, hematocrit 27.2%, blood urea nitrogen 67 mg/dl, and serum creatinine 2.73 mg/dl. Liver function tests and electrolytes were normal. Electrocardiogram was normal and chest X-ray was without any infiltrate. Peak expiratory flow rate was 200 L/min. Diagnostic impression was asthma exacerbation secondary to acute bronchitis. Intravenous methylprednisolone 40 mg every 8 hours, bronchodilators, and levofloxacin were given. Serum mycoplasma antibody, urine legionella antigen, nasal swab for respiratory syncytial virus and influenza antigen, and rapid streptococcal throat tests were negative. On day 5 of admission, a high-resolution contrast tomographic (HRCT) scanning of the chest revealed bilateral multifocal ground glass opacities. On day 7 of admission, she complained of chest pain and had oxygen saturation of 80% on room air. Cardiac enzymes were undetectable and echocardiogram was normal. Perfusion lung scan showed perfusion defects highly suspicious for pulmonary embolism, and intravenous heparin was started. On day 10 of admission chest X-ray revealed new multifocal bilateral infiltrates, and ceftazidime and azithromycin were added. She was intubated for respiratory failure. Hemodialysis was done on day 11 of admission. Repeat HRCT showed development of new extensive bilateral pulmonary nodular infiltrates with ground glass opacities (Fig. 1). Antibiotics were switched to ertapenem and azithromycin. On day 13 of admission, sputum cytology showed Aspergillus species, and voriconazole was administered. She was extubated on day 14 of admission per the family's wishes and she died later that day. Autopsy revealed Aspergillus hyphae invading through the bronchial mucosa, almost completely obliterating the lumen of mid- to small-sized bronchi (Fig. 2). Vascular invasion by Aspergillus was also evident with concomitant widespread pulmonary arterial thrombi (Fig. 3). Acute tubular necrosis in the kidneys and centrilobular liver necrosis were also reported.\n\nFig. 1 High-resolution computed tomographic scan of the chest revealing multiple foci of ground glass opacities (blue arrows) and bilateral pulmonary nodular infiltrates (green arrows).\n\nFig. 2 Light microscopic findings of lung specimen (40×) stained with hematoxylin and eosin showing Aspergillus hyphae invading through the bronchial wall. A blood vessel is visible in the lower left field with an occluding thrombus and inflammatory cells in its lumen.\n\nFig. 3 Hematoxylin and eosin stain of the lung specimen under a light microscope at 200× showing typical branching, septate Aspergillus hyphae, invading through the mucosa of a distal bronchi.\n\nDiscussion\nIPA is caused by one of the four species of Aspergillus: A. fumigatus, A. flavus, A. niger, and A. terreus (5). It is increasingly seen due to a rise in the number of patients undergoing SCT and solid organ transplants, and also due to increasing number of patients on chemotherapy (6). Construction work in the vicinity of susceptible patients may increase spore aerosolization and is an independent risk factor (7). Mannose-binding lectin deficiency has also been associated with IPA (8).\n\nLower respiratory tract symptoms such as cough with or without sputum production, respiratory distress, wheezing, and fever are common. Aspergillus has a predilection for invading vasculature, especially in the neutropenic patients, leading to thrombosis, tissue infarction, and necrosis. In such cases pleuritic chest pain and hemoptysis may be present (2).\n\nThe diagnosis of IPA is challenging due to the non-specific nature of the symptoms and is often delayed due to lack of clinical suspicion in patients without classic risk factors. Tissue biopsy with histopathologic demonstration of tissue invasion by fungal hyphae is considered the ‘gold standard’ (9). However, obtaining tissue specimens from critically ill, often intubated, and hemodynamically unstable patients is not always feasible. Identification of Aspergillus species in the sputum could represent colonization, especially in immunocompetent patients (1, 10). On the contrary, isolation of Aspergillus from sputum in patients with leukemia, or in those who have undergone SCT, has a positive predictive value of 80–90% for the presence of IPA (1, 11, 12). With regard to imaging studies, Patterson et al., in their review of 595 cases of IPA, reported that 85% of the cases had computed tomographic (CT) scan findings suggestive of IPA (13). HRCT is recommended in all cases of suspected IPA. Pulmonary nodules are the most commonly seen abnormality whereas the ‘halo sign’ is relatively more specific with a high predictive value for IPA in patients with neutropenic fever after SCT (14). Laboratory tests to detect Aspergillus antigens in body fluids, either serum or bronchoalveolar lavage fluid (BAL), are increasingly helpful in the diagnosis of IPA. Galactomannan (GM) testing or Aspergillus polymerase chain reaction (PCR) assay in BAL has good sensitivity and specificity for IPA (2, 15). Testing for both GM and PCR may increase sensitivity without compromising the specificity (2). BAL GM testing is part of the diagnostic criteria for IPA (16).\n\nDefinitions for proven, probable, and possible IPA for the susceptible population of immunocompromised patients with cancer and recipients of SCT have been stated (16). A criterion has also been suggested for the diagnosis of IPA in chronic obstructive pulmonary disease (COPD) patients (17).\n\nThe mortality rate of IPA continues to be very high, exceeding 50% in neutropenic patients (14), and 90% in SCT recipients (18). Amphotericin used to be the preferred antifungal, until a large randomized clinical trial comparing amphotericin with voriconazole for primary treatment of IPA showed a better response rate and higher survival (71 vs. 58%) at 12 weeks of therapy in the voriconazole group. Voriconazole also has a better side effect profile and is generally better tolerated. Echinocandins, such as caspofungin, are used as salvage therapy in patients not responding to or not tolerating first-line therapy (1). Due to differences in their mechanisms of action, combination therapy with azoles, trienes, and echinocandins could be a strategy to treat IPA (1). At present, voriconazole is considered the therapy of choice (19).\n\nProlonged and high-dose corticosteroid therapy is an established risk factor for the development of IPA (1, 2). Steroids inhibit macrophage killing of Aspergillus by non-oxidative mechanisms (20). Steroids may also promote the growth of Aspergillus (21). Although IPA is seen in patients with chronic lung diseases on long-term steroids, it is rarely seen with short use of corticosteroids (1, 2, 22). To the best of our knowledge, diagnosis of IPA after short-course steroid therapy for asthma in a 31-year-old man is the only other case of IPA in a similar clinical scenario (3). Relatively few cases of IPA are observed in truly immunocompetent patients without classic risk factors (3, 4).\n\nConclusion\nShort duration steroid therapy may be a risk factor for IPA in certain individuals. Classic risk factors for IPA were absent in our patient, and thus IPA was not high on the differential diagnosis. In our patient, hypoxia raised the possibility of pulmonary embolism, and perfusion lung scan further supported this diagnosis. Angioinvasive IPA can lead to thrombosis and create perfusion defects (2, 23). Thus, the diagnosis of pulmonary embolism confounded the clinical picture by giving an alternate explanation for the patient's symptoms, preventing further investigations such as bronchoscopy.\n\nRefractoriness to therapy manifested as worsening clinical symptoms, progressive hypoxia, and increasing pulmonary infiltrates despite aggressive antibiotic therapy should raise suspicion for IPA. In our opinion, bronchoscopy should be considered in such patients along with antigen detection with GM and PCR testing. Early treatment with voriconazole is the only hope, and treatment should be initiated as soon as IPA is suspected. Every effort should be made to taper off steroids in these patients.\n\nAcknowledgements\nDr Giulia Orsatti, MD (Pathology), provided the light microscopic images of lung (Figs. 2 and 3).\n\nConflict of interests and funding\nThe authors have not received any funding or benefits from the industry or elsewhere to conduct this study.\n==== Refs\nReferences\n1 Zmeili OS Soubani AO Pulmonary aspergillosis: A clinical update QJM 2007 100 6 317 34 17525130 \n2 Kosmidis C Denning DW The clinical spectrum of pulmonary aspergillosis Thorax 2014 10 29 pii: thoraxjnl-2014-206291 10.1136/thoraxjnl-2014-206291 \n3 Lake KB Browne PM Van Dyke JJ Ayers L Fatal disseminated aspergillosis in an asthmatic patient treated with corticosteroids Chest 1983 83 1 138 9 6848318 \n4 Choi YR Kim JT Kim JE Jung HW Choe KH Lee KM Invasive aspergillosis involving the lungs and brain after short period of steroid injection: A case report Tuberc Respir Dis (Seoul) 2012 72 5 448 51 23101010 \n5 Steinbach WJ Marr KA Anaissie EJ Azie N Quan SP Meier-Kriesche HU Clinical epidemiology of 960 patients with invasive aspergillosis from the PATH Alliance registry J Infect 2012 65 5 453 64 22898389 \n6 Chandrasekar P Invasive mold infections: Recent advances in management approaches Leuk Lymphoma 2009 50 5 703 15 19337880 \n7 Pini G Faggi E Donato R Sacco C Fanci R Invasive pulmonary aspergillosis in neutropenic patients and the influence of hospital renovation Mycoses 2008 51 2 117 22 18254747 \n8 Lambourne J Agranoff D Herbrecht R Troke PF Buchbinder A Willis F Association of mannose-binding lectin deficiency with acute invasive aspergillosis in immunocompromised patients Clin Infect Dis 2009 49 10 1486 91 19827955 \n9 Shelhamer JH Gill VJ Quinn TC Crawford SW Kovacs JA Masur H The laboratory evaluation of opportunistic pulmonary infections Ann Intern Med 1996 124 6 585 99 8597323 \n10 Soubani AO Khanchandani G Ahmed HP Clinical significance of lower respiratory tract Aspergillus culture in elderly hospitalized patients Eur J Clin Microbiol Infect Dis 2004 23 6 491 4 15141337 \n11 Horvath JA Dummer S The use of respiratory-tract cultures in the diagnosis of invasive pulmonary aspergillosis Am J Med 1996 100 2 171 8 8629651 \n12 Yu VL Muder RR Poorsattar A Significance of isolation of Aspergillus from the respiratory tract in diagnosis of invasive pulmonary aspergillosis. Results from a three-year prospective study Am J Med 1986 81 249 54 3090879 \n13 Patterson TF Kirkpatrick WR White M Hiemenz JW Wingard JR Dupont B Invasive aspergillosis. Disease spectrum, treatment practices, and outcomes. I3 Aspergillus Study Group Medicine (Baltimore) 2000 79 4 250 60 10941354 \n14 Yeghen T Kibbler CC Prentice HG Berger LA Wallesby RK McWhinney PH Management of invasive pulmonary aspergillosis in hematology patients: A review of 87 consecutive cases at a single institution Clin Infect Dis 2000 31 4 859 68 11049762 \n15 Hoenigl M Prattes J Spiess B Wagner J Prueller F Raggam RB Performance of galactomannan, beta-d-glucan, Aspergillus lateral-flow device, conventional culture, and PCR tests with bronchoalveolar lavage fluid for diagnosis of invasive pulmonary aspergillosis J Clin Microbiol 2014 52 6 2039 45 24671798 \n16 De Pauw B Walsh TJ Donnelly JP Stevens DA Edwards JE Calandra T 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 12 1813 21 10.1086/588660 18462102 \n17 Bulpa P Dive A Sibille Y Invasive pulmonary aspergillosis in patients with chronic obstructive pulmonary disease Eur Respir J 2007 30 4 782 800 17906086 \n18 Fukuda T Boeckh M Carter RA Sandmaier BM Maris MB Maloney DG Risks and outcomes of invasive fungal infections in recipients of allogeneic hematopoietic stem cell transplants after nonmyeloablative conditioning Blood 2003 102 3 827 33 12689933 \n19 Herbrecht R Denning DW Patterson TF Bennett JE Greene RE Oestmann JW Invasive Fungal Infections Group of the European Organisation for Research and Treatment of Cancer and the Global Aspergillus Study Group. Voriconazole versus amphotericin B for primary therapy of invasive aspergillosis N Engl J Med 2002 347 6 408 15 12167683 \n20 Schaffner A Schaffner T Glucocorticoid-induced impairment of macrophage antimicrobial activity: Mechanisms and dependence on the state of activation Rev Infect Dis 1987 9 Suppl 5 S620 9 3317755 \n21 Ng TT Robson GD Denning DW Hydrocortisone-enhanced growth of Aspergillus spp.: Implications for pathogenesis Microbiology 1994 140 Pt 9 2475 9 7952197 \n22 Cornet M Mallat H Somme D Guérot E Kac G Mainardi JL Fulminant invasive pulmonary aspergillosis in immunocompetent patients – A two-case report Clin Microbiol Infect 2003 9 12 1224 7 14686988 \n23 Lopes Bezerra LM Filler SG Interactions of Aspergillus fumigatus with endothelial cells: Internalization, injury, and stimulation of tissue factor activity Blood 2004 103 6 2143 9 14630829\n\n", "fulltext_license": "CC BY-NC-ND", "issn_linking": "2000-9666", "issue": "5(1)", "journal": "Journal of community hospital internal medicine perspectives", "keywords": "aspergillus; asthma exacerbation; ground glass opacities; steroids; vascular invasion", "medline_ta": "J Community Hosp Intern Med Perspect", "mesh_terms": null, "nlm_unique_id": "101601396", "other_id": null, "pages": "26322", "pmc": null, "pmid": "25656673", "pubdate": "2015", "publication_types": "D016428:Journal Article", "references": "19337880;3317755;18462102;8629651;22898389;25354514;17906086;12689933;17525130;11049762;24671798;10941354;19827955;7952197;6848318;15141337;8597323;14630829;12167683;18254747;3090879;23101010;14686988", "title": "Invasive pulmonary aspergillosis - case report and review of literature.", "title_normalized": "invasive pulmonary aspergillosis case report and review of literature" }

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INVASIVE PULMONARY ASPERGILLOSIS - CASE REPORT AND REVIEW OF LITERATURE.. JOURNAL OF COMMUNITY HOSPITAL INTERNAL MEDICINE PERSPECTIVES. 2015;5(1):26322", "literaturereference_normalized": "invasive pulmonary aspergillosis case report and review of literature", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20170222", "receivedate": "20170222", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 13260001, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20170428" } ]

{ "abstract": "Parathyroid carcinoma is a rare neuroendocrine tumor. Non-functional parathyroid carcinomas are exceedingly rare neoplasms which generally present at an advanced disease stage, and occasionally can masquerade as medullary thyroid carcinoma.", "affiliations": "Department of Pathology, The University of Texas MD Anderson Cancer, United States of America.;Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer, United States of America.;Department of Radiology, The University of Texas MD Anderson Cancer, United States of America.;Department of Endocrine Neoplasia and Hormonal Disorders, The University of Texas MD Anderson Cancer, United States of America.;Department of Pathology, The University of Texas MD Anderson Cancer, United States of America; Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer, United States of America. Electronic address: diana.bell@mdanderson.org.", "authors": "Khalil|Mohamed|M|;Zafereo|Mark|M|;Gule-Monroe|Maria|M|;Sherman|Steven I|SI|;Bell|Diana|D|", "chemical_list": null, "country": "United States", "delete": false, "doi": "10.1016/j.anndiagpath.2021.151791", "fulltext": null, "fulltext_license": null, "issn_linking": "1092-9134", "issue": "54()", "journal": "Annals of diagnostic pathology", "keywords": "Non functional; Parathyroid carcinoma; Water-clear cell", "medline_ta": "Ann Diagn Pathol", "mesh_terms": null, "nlm_unique_id": "9800503", "other_id": null, "pages": "151791", "pmc": null, "pmid": "34293707", "pubdate": "2021-10", "publication_types": "D016428:Journal Article", "references": null, "title": "Non-functional water clear cell parathyroid carcinoma masquerading as medullary thyroid carcinoma.", "title_normalized": "non functional water clear cell parathyroid carcinoma masquerading as medullary thyroid carcinoma" }

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{ "abstract": "OBJECTIVE\nTo determine the cardiovascular tolerance of clonidine used as a first-line sedative after cardiac surgery in small infants.\n\n\nMETHODS\nRetrospective chart review.\n\n\nMETHODS\nA tertiary and quaternary referral cardiac PICU.\n\n\nMETHODS\nAll infants younger than 2 months who received a clonidine infusion for sedation after cardiac surgery from October 2011 to July 2013.\n\n\nMETHODS\nNone.\n\n\nRESULTS\nHeart rate, blood pressure, central venous and left atrial pressure, vasoactive inotropic score, volume of fluid bolus, and lactate and central mixed venous saturation were assessed. Preinfusion values were compared with postinfusion values. Of 224 potentially eligible patients, only 23 infants met inclusion criteria, as most patients only received high doses of morphine and some received midazolam instead of clonidine. Clonidine administration was started at a median of 12 hours after surgery (Q1-Q3, 5-23), and infusion rate was 0.5-2 μg/kg/hr for a median duration of 30 hours (Q1-Q3, 12-54). Heart rate decreased (maximal mean decrease: 12% [149 beats/min (SD, 17) to 131 beats/min (SD, 17)]; p < 0.0001). Apart from a transient and limited drop in diastolic blood pressure of 13% (maximal mean decrease: from 42.8 mm Hg [SD, 5.9] to 37.1 mm Hg [SD, 4.0]; p = 0.018), all other cardiovascular variables were stable or improved. A contemporaneous cohort of patients who received midazolam, did so sooner after surgery, stayed longer in the PICU and showed less favorable hemodynamics.\n\n\nCONCLUSIONS\nIV clonidine as sedative added to morphine in selected patients seems hemodynamically safe. The observed decrease in heart rate and diastolic blood pressure seems of minimal clinical importance as all other hemodynamic variables remained stable or improved. The safety of clonidine given early after cardiac surgery as alternative to midazolam merits further study.", "affiliations": "1Royal Children's Hospital, Pediatric Intensive Care Unit, Melbourne, Victoria, Australia. 2Intensive Care and Department of Pediatric Surgery, Erasmus MC-Sophia Children's Hospital, Rotterdam, The Netherlands. 3Department of Pediatrics, Medical University of Innsbruck, Innsbruck, Austria. 4Unité de recherche clinique appliquée, Research Center, CHU Sainte-Justine, Université de Montréal, Montréal, Québec, Canada. 5Murdoch Children's Research Institute, Melbourne, Victoria, Australia.", "authors": "Kleiber|Niina|N|;de Wildt|Saskia N|SN|;Cortina|Gérard|G|;Clifford|Michael|M|;Ducruet|Thierry|T|;Tibboel|Dick|D|;Millar|Johnny|J|", "chemical_list": "D000700:Analgesics; D006993:Hypnotics and Sedatives; D009020:Morphine; D003000:Clonidine", "country": "United States", "delete": false, "doi": "10.1097/PCC.0000000000000672", "fulltext": null, "fulltext_license": null, "issn_linking": "1529-7535", "issue": "17(4)", "journal": "Pediatric critical care medicine : a journal of the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies", "keywords": null, "medline_ta": "Pediatr Crit Care Med", "mesh_terms": "D000700:Analgesics; D001794:Blood Pressure; D006348:Cardiac Surgical Procedures; D003000:Clonidine; D004359:Drug Therapy, Combination; D005260:Female; D006339:Heart Rate; D006439:Hemodynamics; D006801:Humans; D006993:Hypnotics and Sedatives; D007223:Infant; D007231:Infant, Newborn; D015278:Intensive Care Units, Pediatric; D008297:Male; D009020:Morphine; D011184:Postoperative Period; D012189:Retrospective Studies", "nlm_unique_id": "100954653", "other_id": null, "pages": "332-41", "pmc": null, "pmid": "26914623", "pubdate": "2016-04", "publication_types": "D016428:Journal Article", "references": null, "title": "Clonidine as a First-Line Sedative Agent After Neonatal Cardiac Surgery: Retrospective Cohort Study.", "title_normalized": "clonidine as a first line sedative agent after neonatal cardiac surgery retrospective cohort study" }

[ { "companynumb": "AU-MYLANLABS-2016M1022092", "fulfillexpeditecriteria": "1", "occurcountry": "AU", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "CLONIDINE" }, "drugadditional": null, "drugadministrationroute": "042", "drugauthorizationnumb": "020615", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": "39.5", "drugcumulativedosageunit": "008", "drugdosageform": "INJECTION", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "SEDATIVE THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CLONIDINE." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Bradycardia neonatal", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "KLEIBER N, DE WILDT SN, CORTINA G, CLIFFORD M, DUCRUET T, TIBBOEL D, ET AL. CLONIDINE AS A FIRST-LINE SEDATIVE AGENT AFTER NEONATAL CARDIAC SURGERY: RETROSPECTIVE COHORT STUDY. PEDIATR-CRIT-CARE-MED 2016;17(4):332-341.", "literaturereference_normalized": "clonidine as a first line sedative agent after neonatal cardiac surgery retrospective cohort study", "qualification": "1", "reportercountry": "AU" }, "primarysourcecountry": "AU", "receiptdate": "20160527", "receivedate": "20160527", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 12411695, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20160815" } ]

{ "abstract": "We report the case of a patient initially diagnosed with a high-grade neuroendocrine carcinoma, which 5 years later was determined to have a low-grade typical carcinoid. The patient received radiotherapy and numerous chemotherapy regimens for treatment of a high-grade metastatic mixed large and small cell neuroendocrine carcinoma, without a significant response to any treatment. Subsequent imaging revealed widely metastatic disease and computed tomography-guided biopsy demonstrated a carcinoid tumor with no necrosis. The patient was started on temozolomide + capecitabine, long-acting octreotide and denosumab, with everolimus planned upon disease progression. Findings from this case study highlight the importance of accurate histopathologic classification of thoracic neuroendocrine tumors at diagnosis, to avoid the unnecessary administration of aggressive chemotherapy to patients with low-grade tumors.", "affiliations": "University of Miami, Jackson Memorial Hospital, 1611 NW 12th Avenue, Miami, FL 33136, USA.;Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, 1192 East Newport Center Drive, Suite 100, Deerfield Beach, FL 33442-7753, USA.", "authors": "Warsch|Sean|S|;Jahanzeb|Mohammad|M|", "chemical_list": null, "country": "England", "delete": false, "doi": "10.2217/lmt-2017-0010", "fulltext": "\n==== Front\nLung Cancer ManagLung Cancer ManagLMTLung Cancer Management1758-19661758-1974Future Medicine Ltd London, UK 10.2217/lmt-2017-0010Case ReportPatient with typical carcinoid initially diagnosed as high-grade neuroendocrine carcinoma Warsch & JahanzebTypical carcinoid diagnosed as a high-grade tumorWarsch Sean *\n1\nJahanzeb Mohammad **\n2\n\n1 University of Miami, Jackson Memorial Hospital, 1611 NW 12th Avenue, Miami, FL 33136, USA\n2 Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, 1192 East Newport Center Drive, Suite 100, Deerfield Beach, FL 33442-7753, USA*Author for correspondence: swarsch@med.miami.edu**Author for correspondence: mjahanzeb@med.miami.edu11 2017 26 10 2017 6 2 41 45 02 6 2017 20 9 2017 26 10 2017 © 2017 Mohammad Jahanzeb2017This work is licensed under the Attribution-NonCommercial-NoDerivatives 4.0 Unported LicenseWe report the case of a patient initially diagnosed with a high-grade neuroendocrine carcinoma, which 5 years later was determined to have a low-grade typical carcinoid. The patient received radiotherapy and numerous chemotherapy regimens for treatment of a high-grade metastatic mixed large and small cell neuroendocrine carcinoma, without a significant response to any treatment. Subsequent imaging revealed widely metastatic disease and computed tomography-guided biopsy demonstrated a carcinoid tumor with no necrosis. The patient was started on temozolomide + capecitabine, long-acting octreotide and denosumab, with everolimus planned upon disease progression. Findings from this case study highlight the importance of accurate histopathologic classification of thoracic neuroendocrine tumors at diagnosis, to avoid the unnecessary administration of aggressive chemotherapy to patients with low-grade tumors.\n\nKeywords: \ncarcinoiddiagnosisneuroendocrine tumorssmall cell carcinomatreatment\n==== Body\nPractice points\nDiagnosis and classification of neuroendocrine tumors (NET) is challenging.\n\nPathologic classification of thoracic NET should involve assessment of both proliferation rate (Ki-67 and mitoses) and cell differentiation (well, moderately or poorly differentiated).\n\nWe describe a case of thoracic NET first misdiagnosed as high-grade neuroendocrine carcinoma, with no Ki-67 performed during classification, leading to the patient being unnecessarily treated with aggressive chemotherapy.\n\nStandard first-line treatment for high-grade neuroendocrine carcinoma consists of chemotherapy.\n\nPoor response to chemotherapies led to rediagnosis of this tumor as a typical carcinoid.\n\nChemotherapy is not recommended for typical carcinoids unless there are no other feasible treatment options.\n\nCurrent treatment guidelines recommend everolimus as a first-line therapy for advanced and progressive thoracic carcinoids.\n\nThis case highlights the importance of accurate initial diagnosis for optimal treatment selection.\n\nNeuroendocrine tumors (NET) are a heterogeneous group of rare malignancies arising from neuroendocrine cells, with approximately 25% of NET originating in the respiratory tract [1]. Lung NET can be classified into four subtypes according to WHO criteria: typical carcinoids (TC); atypical carcinoids (AC); large cell neuroendocrine carcinoma (LCNEC) and small cell lung carcinoma (SCLC), based on histologic diagnostic criteria, including: cell size; cell morphology; mitotic index; architectural growth patterns and necrosis [2].\n\nTwo key characteristics that aid in distinguishing between lung NET subtypes and help guide treatment decisions are the degree of aggressiveness (mitotic rate and Ki-67 proliferation index) and the extent of necrosis [2]. TC and AC are well-differentiated, low- or intermediate-grade lung NET. TC are defined as tumors measuring 0.5 cm or more, with fewer than two mitoses per 2 mm2 of viable tumor area and lacking necrosis, while AC characteristically show 2–10 mitoses per 2 mm2, with focal necrosis [2]. LCNEC and SCLC are poorly differentiated, high-grade lung NET, both demonstrating a high mitotic rate of greater than ten per 2 mm2 and extensive necrosis [3]. LCNEC and SCLC are primarily distinguished from one another on the basis of cell size and other cytologic features [2]. While the utility of Ki-67 in distinguishing TC from AC is not yet established, it is a useful marker to distinguish carcinoids from LCNEC and SCLC, because the proliferation rate in these tumors is very high compared with carcinoids [2].\n\nThe WHO classification system for pulmonary NET subtypes are best applied to correctly handled and optimally fixed surgical specimens [3]. Subtle differences can make histopathologic classification difficult, particularly in small biopsies or fine needle aspiration cytology samples or due to sample handling/procedural errors [3,4]. In addition, NET cell proliferation rates can vary between different regions within the same tumor [4]. The mitotic rate and Ki-67 index may also be discordant; for example, the mitotic rate might indicate a low-grade tumor, while the Ki-67 index indicates a higher grade tumor [4]. Generally, NET grading is based upon the most aggressive (highly proliferative) tumor site or indicator.\n\nCorrect histologic classification of advanced lung NET at diagnosis is critical in guiding treatment decision-making. Standard first-line treatment for SCLC and LCNEC consists of chemotherapy, with cisplatin or carboplatin in combination with etoposide recommended for SCLC [1,5]. However, chemotherapy is not recommended for lung carcinoids unless there are no other feasible treatment options and may only be considered for advanced, aggressive AC (high-proliferating carcinoids) [6,7]. For advanced, progressive carcinoids, everolimus is recommended as first-line therapy, unless somatostatin analogues (octreotide long-acting repeatable [LAR] or lanreotide) may be considered (e.g., in TC with slow growth-expressing somatostatin receptors) [7]. Everolimus is the first agent to receive US regulatory approval for well-differentiated lung NET (TC and AC), based on the RADIANT-4 Phase III trial [8].\n\nDiagnosis of LCNEC or SCLC as a lower-grade carcinoid tumor may constitute a missed opportunity for timely initiation of aggressive cytotoxic therapy. Conversely, diagnosis of a carcinoid tumor as LCNEC or SCLC may expose patients unnecessarily to chemotherapy toxicity, and place them at risk of early disease progression. While overinterpretation of carcinoids as a more aggressive tumor is a rare occurrence, this remains a very real risk in clinical practice [3].\n\nHere, we describe the disease characteristics and management of a patient initially diagnosed with a high-grade neuroendocrine carcinoma, who was subsequently determined to have a low-grade TC.\n\nCase\nIn November 2010, a 78-year-old Haitian male never-smoker presented with right arm pain. Radiographic imaging revealed a humeral mass. A proximal humerus biopsy revealed a high-grade, metastatic, mixed large and small cell neuroendocrine carcinoma, with no Ki-67 performed. The patient underwent surgery and had a rod placed to stabilize the bone; he received no adjuvant chemotherapy or radiation and was subsequently lost to follow-up.\n\nThe patient had no follow-up or surveillance imaging done for 2 years. In December 2012, the patient presented with pain and swelling in his shoulder region. Computed tomography (CT) imaging of the chest and right upper extremity revealed a large lytic lesion in the proximal right humerus, mediastinal mass and pulmonary nodules. In February 2013, chemotherapy with carboplatin + etoposide was initiated for six cycles along with palliative radiotherapy to the shoulder, followed by surveillance. Weekly paclitaxel was initiated in November 2013, followed by vinorelbine as monotherapy in November 2014; however, no significant response to either treatment was observed. In December 2014, a positron emission tomography/CT scan revealed widely metastatic disease. Treatment with carboplatin + etoposide was restarted in January 2015 and the patient completed six cycles of treatment by May 2015, with a best response of stable disease; he was then started on surveillance.\n\nIn January 2016, a chest CT revealed an increase in the large heterogeneous infiltrating mass involving the mediastinum. CT-guided biopsy of the mediastinal mass was performed in February 2016 and showed a carcinoid tumor with no necrosis, <2 mitoses per 10 high-powered fields and a Ki-67 proliferation index <2%. Immunohistochemistry was strongly positive for CgA and synaptophysin and negative for TTF-1, napsin A, prostate-specific antigen, prostate-specific antigen phosphatase and KX3.\n\nThe patient was referred to our institution in March 2016. At this time, urine 5-hydroxyindoleacetic acid was elevated to 10.7 mg/24 h (reference range: 2–8 mg/24 h) [9]. An Octreoscan showed a large infiltrative soft tissue mass in the mediastinum measuring 11.5 × 11.5 cm with diffuse uptake, in addition to active lesions in the lung, liver and bone. Based on the indolent natural course of disease, along with lack of significant response or progression throughout the course of several treatments, we considered the most likely diagnosis to be a low-grade carcinoid tumor (TC). The patient was started on treatment with temozolomide + capecitabine, along with octreotide LAR and denosumab.\n\nIn April 2016, x-ray imaging revealed a large, expansile and destructive lesion within the proximal right humerus (surgical hardware within the humerus appeared well seated and intact; Figure 1). Nodule densities in the lateral right lower lobe corresponded to pulmonary nodules, as observed in the chest CT scan from the previous month. The CT scan identified two adjacent hypermetabolic pulmonary nodules in the left lower lobe measuring 1.5 × 1.2 cm with standard uptake value (SUV) 6.3 and 0.9 × 1.1 cm with SUV 5.7. Additional pulmonary nodules were seen with lower level 18-fluorodeoxyglucose uptake, including a 0.5-cm nodule in the superior segment of the right lower lobe, SUV 1.4 and a 0.9-cm nodule at the right lung base, SUV 2.2 (Figure 2). In August 2016, the patient presented with a mass on his right arm and palliative radiation therapy is planned (Figure 3). If the patient exhibits further evidence of disease progression, a switch to treatment with everolimus is planned.\n\nFigure 1.  \nX-ray revealing a large, expansile and destructive lesion within the proximal right humerus and nodule densities in the lateral right lower lobe.\n\nFigure 2.  \nRecent computed tomography scan identifying two adjacent hypermetabolic pulmonary nodules in the left lower lobe.\n\nFigure 3.  \nMass on the patient's right arm in August 2016.\n\nDiscussion\nThis case highlights the importance of accurate histopathologic classification of thoracic NET at diagnosis to ensure a timely and appropriate treatment approach. With this case, the eventual diagnosis of TC was only reached on the basis of the indolent disease course and lack of response to therapy. The initial diagnosis resulted in several iterations of suboptimal and aggressive systemic therapy, with a substantial delay (≈6 years) in initiating appropriate treatment. While we rely on pathologists to make a histologic diagnosis, we must also include clinical judgment to guide our treatment decisions. The fact that the patient was a nonsmoker, as well as the indolent nature of the disease, were indicators that perhaps the initial biopsy was not providing us with the complete picture.\n\nThis case is similar to those of Pelosi et al. [3], who reported on a series of seven cases of lung carcinoids (two TC and five AC) which were initially diagnosed as SCLC. Crush artifact had occurred in five of the seven cases, which was likely to have contributed to the difficulties in tumor classification. As a result, six of the seven patients received preoperative cytotoxic chemotherapy before receiving a correct lung carcinoid diagnosis [3].\n\nSuch case reports underline the challenges faced by expert pathologists in definitively classifying thoracic NET samples. These difficulties were demonstrated in a study by den Bakkar et al. [10], who collected slides from 170 cases diagnosed as SCLC, LCNEC or general neuroendocrine lung carcinoma. The slides were distributed to nine pathologists with a special interest in pulmonary pathology, who were asked to review and classify the samples using WHO criteria. There was a unanimous diagnosis made in only 20 cases, a majority consensus in 117 cases and no consensus in 33 cases. The number of cases diagnosed as SCLC varied from 49 to 109, while diagnoses of LCNEC varied between 14 and 85 cases [10].\n\nIndicators of tumor aggressiveness are important markers for thoracic NET classification. In an analysis of 200 patients with pulmonary NET, Travis et al. [11] found that mitotic count was the only independent prognostic factor, underscoring the importance of accurate grading in this class of tumors. In addition, Ki-67 can help distinguish between carcinoids and other lung NET subtypes. Ki-67 immunoreactivity tends to be well preserved even in samples with crush artifact [3] and is considered to be the more reliable marker in cases where Ki-67 and the mitotic rate are discordant [4]. Also, in small cytologic samples, a greater number of cells are likely to express Ki-67 than be in active mitosis [4]. The value of Ki-67 as a marker was clearly demonstrated in the aforementioned article by Pelosi et al. [3]; compared with SCLC cases, the seven carcinoid cases had low Ki-67 indices (1–17%), whereas all control cases of SCLC showed Ki-67 >50% (60–96%).\n\nWith regard to other markers of interest, higher levels of CgA and synaptophysin immunoreactivity has been identified among carcinoid cases compared with SCLC [3]. TTF-1 is found infrequently in TC and AC; for example, only one of the seven cases in the report by Pelosi et al. showed focal immunoreactivity to TTF-1, but TTF-1 was consistently expressed among SCLC [3]. These markers, along with mitotic rate and Ki-67, should be considered together when classifying lung NET tissue samples.\n\nConclusion\nFrom our clinical experience, we conclude that diagnosis of TC/AC as high-grade neuroendocrine carcinoma can lead to delays in the initiation of appropriate treatment or the use of ineffective, aggressive treatment approaches without clear benefit. Inappropriate treatment may also expose patients unnecessarily to excessive treatment-related toxicity and reduced quality of life. Improved awareness of the correct sample handling procedures and the nuances of known lung NET markers is expected to improve tumor classification accuracy and thus enhance patient outcomes.\n\n\nAcknowledgements\n\nWe thank LM Balfe, PA-C, at the Sylvester Comprehensive Cancer Center and University of Miami Miller School of Medicine for assistance with preparation of the patient case materials.\n\n\nFinancial & competing interests disclosure\n\n\nM Jahanzeb has received research grants from Lilly, AbbVie, Genentech, Ipsen and Novartis. He has served as a consultant for AbbVie, Genentech, Ipsen and Novartis. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.\n\nMedical writing assistance was provided by ApotheCom and was funded by Novartis Pharmaceuticals Corporation.\n\n\nInformed consent disclosure\n\n\nThe authors state that they have obtained verbal and written informed consent from the patient/patients for the inclusion of their medical and treatment history within this case report.\n\n\nOpen access\n\n\nThis work is licensed under the Attribution-NonCommercial-NoDerivatives 4.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-nd/4.0/\n==== Refs\nReferences\n1 National Comprehensive Cancer Network NCCN Clinical Practice Guidelines in Oncology Small Cell Lung Cancer Version 2 2017 www.nccn.org/professionals/physician_gls/pdf/sclc.pdf \n2 Travis WD Brambilla E Burke AP Marx A Nicholson AG WHO Classification of Tumours of the Lung, Pleura, Thymus and Heart International Agency for Research on Cancer Lyon, France 2015 \n3 Pelosi G Rodriguez J Viale G Rosai J Typical and atypical pulmonary carcinoid tumor overdiagnosed as small cell carcinoma on biopsy specimens: a major pitfall in the management of lung cancer patients Am. J. Surg. Pathol. 29 2 179 187 2005 15644774 \n4 Klimstra DS Pathology reporting of neuroendocrine tumors: essential elements for accurate diagnosis, classification, and staging Semin. Oncol. 40 1 23 36 2013 23391110 \n5 National Comprehensive Cancer Network NCCN Clinical Practice Guidelines in Oncology Non-Small Cell Lung Cancer Version 3 2017 www.nccn.org/professionals/physician_gls/pdf/nscl.pdf \n6 National Comprehensive Cancer Network NCCN Clinical Practice Guidelines in Oncology Neuroendocrine Tumors Version 2 2016 www.nccn.org/professionals/physician_gls/pdf/neuroendocrine.pdf \n7 Pavel M O'Toole D Costa F All other Vienna Consensus Conference participants, ENETS Consensus Guidelines update for the management of distant metastatic disease of intestinal, pancreatic, bronchial neuroendocrine neoplasms (NEN) and NEN of unknown primary site Neuroendocrinology 103 2 172 185 2016 26731013 \n8 Yao JC Fazio N Singh S For the RAD001 in Advanced Neuroendocrine Tumours, Fourth Trial (RADIANT-4) Study Group. Everolimus for the treatment of advanced, non-functional neuroendocrine tumours of the lung or gastrointestinal tract (RADIANT-4): a randomised, placebo-controlled, Phase III study Lancet 387 10022 968 977 2016 26703889 \n9 Vinik A Feliberti E Perry RR Carcinoid Tumors. [Updated 2014 Aug 1] Endotext De Groot LJ Chrousos G Dungan K MDText.com Inc. MA, USA 2000 www.endotext.org/chapter/carcinoid-tumors/ \n10 den Bakker MA Willemsen S Grünberg K Small cell carcinoma of the lung and large cell neuroendocrine carcinoma interobserver variability Histopathology 56 3 356 363 2010 20459535 \n11 Travis WD Rush W Flieder DB Survival analysis of 200 pulmonary neuroendocrine tumors with clarification of criteria for atypical carcinoid and its separation from typical carcinoid Am. J. Surg. Pathol. 22 8 934 944 1998 9706973\n\n", "fulltext_license": "CC BY-NC-ND", "issn_linking": "1758-1966", "issue": "6(2)", "journal": "Lung cancer management", "keywords": "carcinoid; diagnosis; neuroendocrine tumors; small cell carcinoma; treatment", "medline_ta": "Lung Cancer Manag", "mesh_terms": null, "nlm_unique_id": "101588392", "other_id": null, "pages": "41-45", "pmc": null, "pmid": "30643569", "pubdate": "2017-11", "publication_types": "D002363:Case Reports", "references": "15644774;20459535;23391110;26291007;26703889;26731013;28404761;9706973", "title": "Patient with typical carcinoid initially diagnosed as high-grade neuroendocrine carcinoma.", "title_normalized": "patient with typical carcinoid initially diagnosed as high grade neuroendocrine carcinoma" }

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{ "abstract": "Autism Spectrum Disorder (ASD) is characterized by persistent deficits in social communication and restrictive behavior, interests, and activities. Our previous case-control study showed that use of acetaminophen at age 12-18 months is associated with increased likelihood for ASD (OR 8.37, 95% CI 2.08-33.7). In this study, we again show that acetaminophen use is associated with ASD (p = 0.013). Because these children are older than in our first study, the association is reversed; fewer children with ASD vs. non-ASD children use acetaminophen as a \"first choice\" compared to \"never use\" (OR 0.165, 95% CI 0.045, 0.599). We found significantly more children with ASD vs. non- ASD children change to the use of ibuprofen when acetaminophen is not effective at reducing fever (p = 0.033) and theorize this change in use is due to endocannabinoid system dysfunction. We also found that children with ASD vs. non-ASD children are significantly more likely to show an increase in sociability when they have a fever (p = 0.037) and theorize that this increase is due to anandamide activation of the endocannabinoid system in ASD children with low endocannabinoid tone from early acetaminophen use. In light of this we recommend that acetaminophen use be reviewed for safety in children.", "affiliations": "Department of Physiology, School of Medicine, University of Texas Health Science Center San Antonio, 7703 Floyd Curl Drive, San Antonio, TX 78229, USA.;Department of Physiology, School of Medicine, University of Texas Health Science Center San Antonio, 7703 Floyd Curl Drive, San Antonio, TX 78229, USA.", "authors": "Schultz|Stephen T|ST|;Gould|Georgianna G|GG|", "chemical_list": null, "country": "United States", "delete": false, "doi": null, "fulltext": "\n==== Front\n10158568540353Autism Open AccessAutism Open AccessAutism-open access2165-789010.4172/2165-7890.1000170nihpa784085ArticleAcetaminophen Use for Fever in Children Associated with Autism Spectrum Disorder Schultz Stephen T *Gould Georgianna G Department of Physiology, School of Medicine, University of Texas Health Science Center San Antonio, 7703 Floyd Curl Drive, San Antonio, TX 78229, USA* Corresponding author: Schultz ST, Department of Physiology, School of Medicine, University of Texas Health Science Center San Antonio, 7703 Floyd Curl Drive, San Antonio, TX 78229, USA, Tel: 210-567-4114; stevendri@outlook.com6 5 2016 28 3 2016 4 2016 30 9 2016 6 2 170This 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.Autism Spectrum Disorder (ASD) is characterized by persistent deficits in social communication and restrictive behavior, interests, and activities. Our previous case-control study showed that use of acetaminophen at age 12–18 months is associated with increased likelihood for ASD (OR 8.37, 95% CI 2.08–33.7). In this study, we again show that acetaminophen use is associated with ASD (p = 0.013). Because these children are older than in our first study, the association is reversed; fewer children with ASD vs. non-ASD children use acetaminophen as a “first choice” compared to “never use” (OR 0.165, 95% CI 0.045, 0.599). We found significantly more children with ASD vs. non- ASD children change to the use of ibuprofen when acetaminophen is not effective at reducing fever (p = 0.033) and theorize this change in use is due to endocannabinoid system dysfunction. We also found that children with ASD vs. non-ASD children are significantly more likely to show an increase in sociability when they have a fever (p = 0.037) and theorize that this increase is due to anandamide activation of the endocannabinoid system in ASD children with low endocannabinoid tone from early acetaminophen use. In light of this we recommend that acetaminophen use be reviewed for safety in children.\n\nAutismAutism spectrum disorderAcetaminophenAnandamideEndocannabinoidCannabinoidFeverMedication\n==== Body\nIntroduction\nAutism Spectrum Disorder (ASD), as defined by the Diagnostic and Treatment Manual for Mental Disorders, Fifth Edition (DSM-5), is characterized by persistent deficits in social communication and interaction and restricted-repetitive patterns of behavior, interests, or activities. These symptoms manifest in early childhood, and produce clinically significant developmental impairment [1]. Many children with ASD share traits of Attention Deficit/hyperactivity disorder (ADHD) and epilepsy is comorbid with ASD in an estimated 20–25% of cases [1–4]. Some features of ASD, commonly called autism or autistic disorder, are seen in genetic and chromosomal abnormalities such as fragile X syndrome, Down syndrome, and genomic insertions and deletions; however, most cases of ASD have an unknown etiology. Two of the prominent clinical features of ASD are immune system dysregulation and abnormal brain connectivity [5–7]. The US Centers for Disease Control and Prevention (CDC) estimates that ASD occurs in one of every 68 children in the US, while the National Health Interview Survey puts the estimate of ASD higher with one child affected out of every 45 children aged 3–17 years in the US [8,9].\n\nRecently it has been shown that more than half of ASD cases are attributable to environmental factors [10]. A subset of children with ASD undergo a period of apparently normal development followed by a regression in development [11]. Since children with regression in development did not initially manifest ASD features, they may have been more likely influenced by drugs or other environmental exposures. In our own data, regression was featured in 38% of cases, and we were able to show an increased likelihood for ASD from acetaminophen use, which was higher in children with regression [12]. Prenatal and perinatal use of acetaminophen, also known as paracetamol, was linked to ASD in an ecological study [13]. We have theorized that acetaminophen disruption of the endocannabinoid system may underlie some of the increased likelihood for ASD, particularly in children with genetically compromised primary conjugation pathways that normally metabolize this drug [14].\n\nAcetaminophen is one of three analgesics derived from aniline dye; the others, acetanilide and phenacetin, have been discontinued due to side effects [15]. Although acetaminophen has been used as an analgesic for more than a hundred years, its mechanism of action was unclear. It has now been shown that acetaminophen produces analgesia by acting in the brain as an indirect agonist at cannabinoid receptors through conversion of the acetaminophen metabolite p-aminophenol to N-arachidonoylaminophenol (AM404) which inhibits the reuptake of anandamide [15–17]. Blocking cannabinoid receptors completely eliminates the analgesic effect of acetaminophen [15,18].\n\nWe have shown in a case-control study that use of acetaminophen early in life is associated with increased likelihood for ASD [12]. We showed in this study that children who used acetaminophen at age 12 to 18 months vs. those who did not were eight times more likely to have ASD when all children were considered and nearly 21 times more likely to have ASD when limiting cases to children with regression in development. Ibuprofen use at age 12 to 18 months was not significantly associated with ASD for either of these groups.\n\nIn a later report we showed that the events in the history of acetaminophen use were related to the number of children with ASD [19]. In this report, acetaminophen history was linked with the number of eligible persons with autism by birth year from a 1999 report to the legislature by the California Department of Developmental Services. We showed that the number of children with ASD greatly increased after the CDC issued a warning against using aspirin for children’s fever in 1980. We further showed separate decreases in the number of children with ASD born after highly publicized incidents in 1982 and 1986 where acetaminophen capsules were laced with cyanide in the US. These incidents caused precipitous declines in acetaminophen sales.\n\nTo continue investigating whether ASD is associated with acetaminophen use, we searched for available data which described acetaminophen use in older children with and without ASD. In 2015, we discovered data to re-test our ASD-acetaminophen link in children. The current study was undertaken to determine if acetaminophen use for fever in older children was associated with ASD.\n\nMaterials and Methods\nOur data source was the National Database for Autism Research (NDAR) of the National Institute of Mental Health (NIMH) which is one of the institutes in the National Institutes of Health (NIH) in the US. Approval for use of this data was obtained from NIMH and the University of Texas Health Science Center San Antonio. The data we chose to use was from the study entitled “Association between pupillary light reflex and sensory behaviors in children with autism spectrum disorders.” This de-identified data contained information on ASD diagnoses and over-the-counter medications used to treat fever. The selection criteria for these children may be found in the 2013 paper by Daluwatte et al. [20].\n\nThe diagnosis of ASD in our data was listed as confirmed by testing the children with the Autism Diagnostic Observation Schedule (ADOS) or the Autism Diagnostic Interview-Revised (ADI-R). In order to focus on the effect of environmental exposures, only children with ASD and without known genetic disease were included as cases. Genetic diseases linked to ASD which were excluded include fragile X syndrome, Down Syndrome, tuberous sclerosis, Rett Syndrome, and known ASD-linked chromosome insertions and deletions. After these exclusions, we obtained information concerning 155 children with ASD and 154 non-ASD children. We further limited our data analysis to the individuals for whom information regarding acetaminophen use for fevers was available which yielded 118 case children with ASD and 79 control children.\n\nSPSS version 23 for Windows was used for all statistical analyses unless otherwise noted. Chi square tests were used to determine whether fever medication use was associated with ASD. Age at time of interview was tested for association with ASD by ANOVA. Logistic regression modeling was used to produce age-adjusted models for levels of fever medication use in children with ASD compared to children without ASD.\n\nResults\nTable 1 shows the characteristics of children in our study. We limited our dataset to children with information regarding acetaminophen use for fevers. However, some of the other questions analyzed were answered by fewer respondents. Therefore for clarity, the number of cases and controls available for analysis of each question is listed in the table. There was no significant difference in the ages of the children, mean 131 months for cases and 135 months for controls. Acetaminophen use for fevers was significantly different for cases compared to controls (p = 0.013). Ibuprofen use for fevers was not significantly different between cases and controls (p = 0.570). Aspirin use for fevers was extremely low in both cases and controls; a total of four children were reported to ever use aspirin, and no comparative analysis was possible for aspirin use. Compared to control children, the frequency of fevers showed a trend for increasing rate in case children (p = 0.057), and case children were significantly more likely to show better social interaction when experiencing a fever (p = 0.037).\n\nTable 2 shows the results of age-adjusted logistic regression models for three levels of acetaminophen and ibuprofen use compared to never or rarely use in case children with ASD vs. control children without ASD. Using acetaminophen as a first choice was 83% less likely in children with ASD (OR 0.165, 95% CI 0.045, 0.599) while use of acetaminophen if other medication doesn’t bring down fever was 82% less likely in children with ASD (OR 0.183, 95% CI 0.050, 0.675). Using only acetaminophen for fever showed a non-significant negative trend with a p value of 0.065. There was no significant difference in the three levels of ibuprofen use between cases and controls.\n\nTable 3 shows the use of ibuprofen if acetaminophen doesn’t bring down fever vs. rarely or never use ibuprofen for children with ASD vs. non-ASD children while limiting the analysis to children who use acetaminophen as first choice. A significantly higher number of children with ASD vs. non-ASD children used ibuprofen to bring down their fever vs. rarely or never using ibuprofen (p = 0.033). This result indicates that significantly more children with ASD vs non-ASD children switch to the use of ibuprofen if acetaminophen does not bring down their fever.\n\nDiscussion\nAs seen in Table 1, the use of acetaminophen in children with ASD compared to control children was still significantly different in the current study as it was in our 2008 study. However, as seen in Table 2, the association direction seen in our current study for acetaminophen use is opposite to our previous results which asked about acetaminophen use in young children. In our current study, older children with ASD compared to control children were significantly less likely to use acetaminophen for fever; whereas, in our 2008 study, younger children with ASD compared to control children were significantly more likely to use acetaminophen at 12–18 months of age and after the MMR vaccination. If we consider that early use of acetaminophen may be responsible for endocannabinoid system dysfunction, this could result in acetaminophen losing effectiveness. In this case, the results we found in older children are to be expected.\n\nWe have shown that the acetaminophen metabolites AM404 and p-aminophenol are toxic for mouse embryonic cortical neurons [21]. AM404 increases brain endocannabinoid levels by decreasing the re-uptake of anandamide [15]. We have further shown that acetaminophen differentially changes social behavior in adult male black and tan brachury tufted (BTBR) mice, a commonly used mouse model of behavioral traits of autism [22]. Neonatal exposure to acetaminophen affects cognitive function and reduces its analgesic and anxiolytic response in adult male mice and in our lab produced long-lasting immune system changes [23–25].\n\nAs we saw in our 2008 study, the use of ibuprofen in the current study is not significantly different for children with ASD vs. non-ASD children, although the use of ibuprofen has now increased from 56% to 87%. The children in our current study are older on average than our first study, 11 years vs. 7.5 years, and parents would have time to switch to a different anti-pyretic drug for their children if acetaminophen is no longer effective. We have shown in Table 3 that children with ASD vs. non-ASD children are significantly (p = 0.033) more likely to switch to the use of ibuprofen if acetaminophen doesn’t bring down their fever. The reasons for this reversal in analgesic use seen in our current study for children with ASD vs. non-ASD children could be a decrease in acetaminophen effectiveness due to endocannabinoid system dysfunction.\n\nThe endocannabinoid system plays a key role in the development of the central nervous system and its activation can induce long-lasting functional alterations [26]. Use of the exogenous cannabinoid tetrahydrocannabinol in the still-maturing brain may produce persistent alterations in brain structure and cognition [27]. Animal models have revealed the danger of both cannabis abuse and exposure to cannabinoid drugs during brain development [28,29].\n\nDysfunction of the endocannabinoid system can occur through either of the two classic cannabinoid receptors, CB1 or CB2. CB1 receptors are primarily located in the central nervous system (CNS) and are concentrated in the cerebellum, hippocampus, and the basal ganglia which are areas in the brain implicated as dysfunctional in ASD [30,31]. It has been demonstrated that during fetal life, CB1 receptors and their associated endocannabinoids provide axon guidance cues and are responsible for synaptogenesis [32–34]. Children with ASD have been shown to have abnormal brain connectivity which could be due to lack of CB1 axon guidance [7].\n\nCB2 receptors are primarily located on immune system cells and serve a regulatory function. CB2 receptors have been shown to control the movement of inflammatory cells to the site of injury, and CB2 receptors’ reverse agonists may serve as immune system modulators [35]. CB2 receptor agonists reduce transendothelial migration of monocytes by interfering with endothelial adhesion [36]. It has been shown in many studies that children with ASD have immune system dysregulation [37–43]. This dysregulation includes differential monocyte responses, abnormal cytokine levels, decreased T cell mitogen response, decreased numbers of lymphocytes, and abnormal serum immunoglobulin levels. Other studies have shown that children with ASD exhibit abnormal antibodies against brain and central nervous system proteins [44–50] and increased plasma pro-inflammatory cytokine levels [51]. These problems could be due to dysregulation of the immune system through CB2 receptors.\n\nSiniscalco et al. in a 2013 landmark paper were able to confirm endocannabinoid system dysfunction in ASD vs healthy subjects by showing in peripheral blood mononuclear cells that the mRNA and protein for CB2 was significantly increased and mRNA for the gene that synthesizes anandamide, N-acylphosphatidyl-ethanolamine-hydrolyzing phospholipase D (NAPE-PLD), was significantly decreased [52]. This upregulation of CB2 receptors and downregulation of NAPE-PLD in these immune system cells indicates endocannabinoid system dysfunction in children with ASD. This dysfunction could result from insufficient endocannabinoid system tone. Also in 2013, Földy et al. found that neuroligin-3 mutations associated with autism commonly disrupt tonic endocannabinoid signaling, providing further evidence of endocannabinoid system involvement in ASD [53].\n\nThe endocannabinoid system participates in fever generation by increasing anandamide activation of CB1 receptors [54,55]. We have shown in Table 1 that fever is associated with a significant increase in social interaction in children with ASD compared to non-ASD children. The increase in social interaction seen in this study could be due to fever producing a normalization of endocannabinoid tone in a system that has been made dysfunctional by acetaminophen use in children with ASD.\n\nKerr et al. have demonstrated dysfunction in the endocannabinoid system in the rat valproic acid model of autism. Alterations include reduced expression in the frontal cortex of PPARα and GPR55 and in the hippocampus of PPARγ and GPR55, which are additional receptor targets of the endocannabinoids. They found increased tissue levels of anandamide and palmitoylethanolamide (PEA) in the hippocampus after social interaction [56]. PEA is found abundantly in the central nervous system, especially in neurons and glial cells, and is a dietary supplement available without a prescription in Europe [57]. Administration of PEA has been shown to increase tissue levels of anandamide and increase activation of the endocannabinoid system [58]. PEA attenuates seizures in rats through CB1 and CB2 cannabinoid receptors [59]. Antonucci and colleagues in 2015 reported two case studies of boys with ASD in which PEA supplementation reduced inflammatory markers and produced rapid clinically significant improvements. With the success of these cases, they have recommended appropriate double-blind controlled clinical trials to further explore the potential of PEA as a treatment for ASD [60].\n\nThe warning in 1980 by the CDC against aspirin use in children has been very effective. As physicians began recommending acetaminophen as an alternative antipyretic drug, sales of children’s aspirin precipitously declined beginning in 1980 and were replaced with sales of acetaminophen [61]. As seen in our current study only four children were ever given aspirin for fever. However, since the initial CDC warning against the use of aspirin for fever in children, reports have been published casting doubt on the initial studies which associate children’s use of aspirin with Reye Syndrome [62–64]. As reported in an excellent review by Schrör in 2007, the attribution of Reye Syndrome to aspirin use in children was not sufficiently supported by research [65,66]. We have shown that the current rise in cases of autism began in 1980 in the US, which is the same year that the CDC warned against the use of aspirin in US children [19]. There is no good evidence that acetaminophen is superior to aspirin for use in children, and we have shown evidence that acetaminophen use is associated with ASD. We recommend that the use of acetaminophen in children be reviewed for safety. Also, the strong warning against the use of aspirin for fever in children should be reviewed.\n\nConclusion\nIn summary, we have presented evidence for the association of acetaminophen use with ASD. Our theory of how this may occur can be explained in the following illustration. Suppose a susceptible young boy has a fever due to a viral infection or after the MMR vaccination. His parents give him acetaminophen which increases endocannabinoid stimulation in his brain making him feel better and bringing down his fever. But the increased activation of the endocannabinoid system also decreases immune system function which prolongs the illness and leads to even more acetaminophen use. Eventually, the boy recovers but his endocannabinoid system has been dysregulated to a lower level to compensate for the prolonged over-activation. Now the neurons in his brain are not getting the proper guidance for their growth through CB1 receptors and further suffer from increased inflammation due to lack of CB2 regulation in immune system cells. The boy develops ASD. When the boy gets a fever, his parents again give him acetaminophen but it no longer works well since his endocannabinoid tone is at a low level, and his parents switch to ibuprofen. Also, when he gets a fever, the increased anandamide levels briefly increase endocannabinoid tone and improve his sociability. After the fever, the endocannabinoid tone again drops back to low levels and his sociability decreases again. His condition, however, may be reversible with new cannabinoid medications to increase endocannabinoid system activation and allow his brain to slowly recover. Research needs to be conducted to see if PEA, cannabidiol, or other cannabinoids will be effective treatments for ASD.\n\nData and/or research tools used in the preparation of this manuscript were obtained from the NIH-supported National Database for Autism Research (NDAR). NDAR is a collaborative informatics system created by the National Institutes of Health to provide a national resource to support and accelerate research in autism. Dataset identifier: 102336. This manuscript reflects the views of the authors and may not reflect the opinions or views of the NIH or of the Submitters submitting original data to NDAR. As required by NDAR, information regarding this research will be placed in their archive after article publication. We would also like to acknowledge Dr. Gang Yao who provided the data to NDAR and who graciously answered our questions regarding variable interpretation. Research was supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development NICHD081261.\n\nAuthor Disclosure\n\nThe authors declare that there is no conflict of interest regarding the publication of this paper.\n\nTable 1 Characteristics of children in the 2015 ASD -acetaminophen study by case-control status.\n\nVariable\tCases\tControls\tp value*\t\nn = Cases, Controls\tMean (SD)\tMean (SD)\t\t\nAge (months) (n = 118, 79)\t131.3 (43.6)\t134.9 (39.6)\t0.5631\t\n\t% (n)\t% (n)\t\t\nAcetaminophen use for fever (n = 118, 79)\t\t\t0.0132\t\nOnly use this\t15.3 (18)\t12.7 (10)\t\t\nFirst choice\t35.6 (42)\t46.8 (37)\t\t\nUse if other medication doesn’t bring down fever\t31.4 (37)\t36.7 (29)\t\t\nRarely or never use\t17.8 (21)\t3.8 (3)\t\t\nIbuprofen use for fever (n = 110, 73)\t\t\t0.57\t\nOnly use this\t9.1 (10)\t4.1 (3)\t\t\nFirst choice\t44.5 (49)\t50.7 (37)\t\t\nUse if other medication doesn’t bring down fever\t33.6 (37)\t32.8 (24)\t\t\nRarely or never use\t12.7 (14)\t12.3 (9)\t\t\nAspirin use for fever (n = 90, 51)\t\t\t1.0002\t\nOnly use this\t1.1 (1)\t0.0 (0)\t\t\nFirst choice\t0.0 (0)\t0.0 (0)\t\t\nUse if other medication doesn’t bring down fever\t2.2 (2)\t2.0 (1)\t\t\nRarely or never use\t96.7 (87)\t98.0 (50)\t\t\nFrequency of Fevers (n = 117, 78)\t\t\t0.057\t\nRarely (< 4 times / year)\t85.5 (100)\t93.6 (73)\t\t\nSometimes (5–8 times / year)\t10.3 (12)\t6.4 (5)\t\t\nOften (>12 times / year)\t4.3 (5)\t0.0 (0)\t\t\nSocial Interaction Better with Fever (n = 118, 79)\t\t\t0.0372\t\nNo\t81.4 (96)\t92.4 (73)\t\t\nYes\t18.6 (22)\t7.6 (6)\t\t\n* p values by Pearson chi square unless otherwise noted. A p value of less than 0.05 was considered significant and is marked in bold.\n\n1 F test p value.\n\n2 Fisher’s exact test p value, two sided.\n\nTable 2 Age adjusted associations of acetaminophen or ibuprofen use for fever in children with ASD compared to control children by logistic regression.\n\nVariable\tB\tOdds Ratio\t95% Confidence Interval\tp value*\t\nAcetaminophen use for fever compared to rarely or never use:\t\t\t\t\t\nOnly use this\t− 1.352\t0.259\t0.062, 1.088\t0.065\t\nFirst choice\t− 1.804\t0.165\t0.045, 0.599\t0.006\t\nUse if other medication doesn’t bring down fever\t− 1.697\t0.183\t0.050, 0.675\t0.011\t\nIbuprofen use for fever compared to rarely or never use:\t\t\t\t\t\nOnly use this\t0.782\t2.186\t0.467, 10.235\t0.321\t\nFirst choice\t−0.16\t0.852\t0.333, 2.183\t0.739\t\nUse if other medication doesn’t bring down fever\t0.001\t1.001\t0.374, 2.679\t0.998\t\n* p value by logistic regression likelihood ratio with a value less than 0.05 considered significant and listed in bold.\n\nTable 3 Use of ibuprofen if acetaminophen doesn’t bring down fever vs. rarely or never use ibuprofen for children with or without autism spectrum disorder while limiting the analysis to children who use acetaminophen as first choice.\n\n\tFor children who use acetaminophen as first choice:\t\t\n\tUse of ibuprofen if acetaminophen doesn’t bring down fever\tRarely or Never use ibuprofen\tp value* 0.033\t\nChildren with ASD\t33\t0\t\t\nChildren without ASD\t22\t4\t\t\n* p value by mid-P exact test, OpenEpi Open Source Epidemiologic Statistics for Public Health, Version 3.03a\n==== Refs\n1 American Psychiatric Association 2013 Autism Spectrum Disorder, 299.00 (F84.0) Diagnostic and Statistical Manual of Mental Disorders 5 American Psychiatric Publishing 50 59 \n2 Ronald A Simonoff E Kuntsi J Asherson P Plomin R 2008 Evidence for overlapping genetic influences on autistic and ADHD behaviours in a community twin sample J Child Psychol Psychiatry 49 535 542 18221348 \n3 Taurines R Schwenck C Westerwald E Sachse M Siniatchkin M 2012 ADHD and autism: differential diagnosis or overlapping traits? 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Acta Neurobiol Exp (Wars) 70 227 231 20628445 \n15 Bertolini A Ferrari A Ottani A Guerzoni S Tacchi R 2006 Paracetamol: new vistas of an old drug CNS Drug Rev 12 250 275 17227290 \n16 Högestätt ED Jönsson BA Ermund A Andersson DA Björk H 2005 Conversion of acetaminophen to the bioactive N-acylphenolamine AM404 via fatty acid amide hydrolase-dependent arachidonic acid conjugation in the nervous system J Biol Chem 280 31405 31412 15987694 \n17 Mallet C Daulhac L Bonnefont J Ledent C Etienne M 2008 Endocannabinoid and serotonergic systems are needed for acetaminophen-induced analgesia Pain 139 190 200 18485596 \n18 Ottani A Leone S Sandrini M Ferrari A Bertolini A 2006 The analgesic activity of paracetamol is prevented by the blockade of cannabinoid CB1 receptors Eur J Pharmacol 531 280 281 16438952 \n19 Becker KG Schultz ST 2010 Similarities in features of autism and asthma and a possible link to acetaminophen use Med Hypotheses 74 7 11 19748189 \n20 Daluwatte C Miles JH Christ SE 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(acetaminophen) administration during neonatal brain development affects cognitive function and alters its analgesic and anxiolytic response in adult male mice Toxicological Sciences 138 139 147 24361869 \n25 Edwards MT Gould GG Alvarez R Schultz ST 2016 Early Juvenile exposure of mice to high-dose acetaminophen confers elevated serum eotaxin levels and sociability impairments in adulthood The Toxicologist: Supplement to Toxicological Sciences, 55th Annual Meeting of the Society of Toxicology New Orleans, LA 2016 \n26 Campolongo P Trezza V Palmery M Trabace L Cuomo V 2009 Developmental exposure to cannabinoids causes subtle and enduring neurofunctional alterations Int Rev Neurobiol 85 117 133 19607965 \n27 Jager G Ramsey NF 2008 Long-term consequences of adolescent cannabis exposure on the development of cognition, brain structure and function: an overview of animal and human research Curr Drug Abuse Rev 1 114 123 19630711 \n28 Anavi-Goffer S Mulder J 2009 The polarised life of the endocannabinoid system in CNS development Chembiochem 10 1591 1598 19533710 \n29 Drysdale AJ Platt B 2003 Cannabinoids: mechanisms and therapeutic applications in the CNS Curr Med Chem 10 2719 2732 14529462 \n30 Bauman ML Kemper TL 2005 Neuroanatomic observations of the brain in autism: a review and future directions Int J Dev Neurosci 23 183 187 15749244 \n31 Ecker C Bookheimer SY Murphy DG 2015 Neuroimaging in autism spectrum disorder: brain structure and function across the lifespan Lancet Neurol 14 1121 1134 25891007 \n32 Berghuis P Rajnicek AM Morozov YM Ross RA Mulder J 2007 Hardwiring the brain: endocannabinoids shape neuronal connectivity Science 316 1212 1216 17525344 \n33 Harkany T Mackie K Doherty P 2008 Wiring and firing neuronal networks: endocannabinoids take center stage Curr Opin Neurobiol 18 338 345 18801434 \n34 Fride E Gobshtis FE Dahan H Weller A Giuffrida A 2009 The endocannabinoid system during development: emphasis on perinatal events and delayed effects Vitam Horm 81 139 158 19647111 \n35 Lunn CA Reich EP Fine JS Lavey B Kozlowski JA 2008 Biology and therapeutic potential of cannabinoid CB2 receptor inverse agonists Br J Pharmacol 153 226 239 17906679 \n36 Rajesh M Mukhopadhyay P Bátkai S Haskó G Liaudet L 2007 CB2-receptor stimulation attenuates TNF-alpha-induced human endothelial cell activation, transendothelial migration of monocytes, and monocyte endothelial adhesion Am J Physiol Heart Circ Physiol 293 H2210 H2218 17660390 \n37 Enstrom AM Onore CE Van de Water JA Ashwood P 2010 Differential monocyte responses to TLR ligands in children with autism spectrum disorders Brain Behav Immun 24 64 71 19666104 \n38 Ashwood P Wills S Van de Water J 2006 The immune response in autism: a new frontier for autism research J Leukoc Biol 80 1 15 16698940 \n39 Warren RP Singh VK Averett RE Odell JD Maciulis A 1996 Immunogenetic studies in autism and related disorders Mol Chem Neuropathol 28 77 81 8871944 \n40 Jyonouchi H Geng L Ruby A Zimmerman-Bier B 2005 Dysregulated innate immune responses in young children with autism spectrum disorders: their relationship to gastrointestinal symptoms and dietary intervention Neuropsychobiology 51 77 85 15741748 \n41 Molloy CA Morrow AL Meinzen-Derr J Schleifer K Dienger K 2006 Elevated cytokine levels in children with autism spectrum disorder J Neuroimmunol 172 198 205 16360218 \n42 Li X Chauhan A Sheikh AM Patil S Chauhan V 2009 Elevated immune response in the brain of autistic patients J Neuroimmunol 207 111 116 19157572 \n43 Krakowiak P Goines PE Tancredi DJ Ashwood P Hansen RL 2015 Neonatal Cytokine Profiles Associated with Autism Spectrum Disorder Biol Psychiatry \n44 Ashwood P Van de Water J 2004 Is autism an autoimmune disease? Autoimmun Rev 3 557 562 15546805 \n45 Martin LA Ashwood P Braunschweig D Cabanlit M Van de Water J 2008 Stereotypies and hyperactivity in rhesus monkeys exposed to IgG from mothers of children with autism Brain Behav Immun 22 806 816 18262386 \n46 Cohly HH Panja A 2005 Immunological findings in autism Int Rev Neurobiol 71 317 341 16512356 \n47 Connolly AM Chez MG Pestronk A Arnold ST Mehta S 1999 Serum autoantibodies to brain in Landau-Kleffner variant, autism, and other neurologic disorders J Pediatr 134 607 613 10228297 \n48 Singh VK Warren RP Odell JD Warren WL Cole P 1993 Antibodies to myelin basic protein in children with autistic behavior Brain Behav Immun 7 97 103 7682457 \n49 Wills S Cabanlit M Bennett J Ashwood P Amaral D 2007 Autoantibodies in autism spectrum disorders (ASD) Ann N Y Acad Sci 1107 79 91 17804535 \n50 Kawashti MI Amin OR Rowehy NG 2006 Possible immunological disorders in autism: concomitant autoimmunity and immune tolerance Egypt J Immunol 13 99 104 17974154 \n51 Ashwood P Krakowiak P Hertz-Picciotto I Hansen R Pessah I 2011 Elevated plasma cytokines in autism spectrum disorders provide evidence of immune dysfunction and are associated with impaired behavioral outcome Brain Behav Immun 25 40 5 20705131 \n52 Siniscalco D Sapone A Giordano C Cirillo A de Magistris L 2013 Cannabinoid receptor type 1, but not type 2, is up-regulated in peripheral blood mononuclear cells of children affected by autistic disorders J Autism Dev Disord 43 2686 2695 23585028 \n53 Földy C Malenka RC Südhof TC 2013 Autism-associated neuroligin-3 mutations commonly disrupt tonic endocannabinoid signaling Neuron 78 498 509 23583622 \n54 Fraga D Zanoni CI Rae GA Parada CA Souza GE 2009 Endogenous cannabinoids induce fever through the activation of CB1 receptors Br J Pharmacol 157 1494 1501 19681872 \n55 Fraga D Zanoni CI Zampronio AR Parada CA Rae GA 2015 Endocannabinoids, through opioids and prostaglandins, contribute to fever induced by key pyrogenic mediators Brain Behav Immun S0889–1591: 00470–00475 \n56 Kerr DM Downey L Conboy M Finn DP Roche M 2013 Alterations in the endocannabinoid system in the rat valproic acid model of autism Behav Brain Res 249 124 132 23643692 \n57 Mattace Raso G Russo R Calignano A Meli R 2014 Palmitoylethanolamide in CNS health and disease Pharmacol Res 86 32 41 24844438 \n58 Jonsson KO Vandevoorde S Lambert DM Tiger G Fowler CJ 2001 Effects of homologues and analogues of palmitoylethanolamide upon the inactivation of the endocannabinoid anandamide Br J Pharmacol 133 1263 1275 11498512 \n59 Aghaei I Rostampour M Shabani M Naderi N4 Motamedi F 2015 Palmitoylethanolamide attenuates PTZ-induced seizures through CB1 and CB2 receptors Epilepsy Res 117 23 28 26370914 \n60 Antonucci N Cirillo A Siniscalco D 2015 Beneficial Effects of Palmitoylethanolamide on Expressive Language, Cognition, and Behaviors in Autism: A Report of Two Cases Case Rep Psychiatry 2015 325061 26491593 \n61 Arrowsmith JB Kennedy DL Kuritsky JN Faich GA 1987 National patterns of aspirin use and Reye syndrome reporting, United States, 1980 to 1985 Pediatrics 79 858 863 3588140 \n62 Arrowsmith JB Kennedy DL Kuritsky JN Faich GA 1987 National patterns of aspirin use and Reye syndrome reporting, United States, 1980 to 1985 Pediatrics 79 858 863 3588140 \n63 Gauthier M Guay J Lacroix J Lortie A 1989 Reye’s syndrome. A reappraisal of diagnosis in 49 presumptive cases Am J Dis Child 143 1181 1185 2801659 \n64 Casteels-Van Daele M Van Geet C Wouters C Eggermont E 2000 Reye syndrome revisited: a descriptive term covering a group of heterogeneous disorders Eur J Pediatr 159 641 648 11014461 \n65 Orlowski JP Hanhan UA Fiallos MR 2002 Is aspirin a cause of Reye’s syndrome? A case against Drug Saf 25 225 231 11994026 \n66 Schrör K 2007 Aspirin and Reye syndrome: a review of the evidence Paediatr Drugs 9 195 204 17523700\n\n", "fulltext_license": "CC BY", "issn_linking": "2165-7890", "issue": "6(2)", "journal": "Autism-open access", "keywords": "Acetaminophen; Anandamide; Autism; Autism spectrum disorder; Cannabinoid; Endocannabinoid; Fever; Medication", "medline_ta": "Autism Open Access", "mesh_terms": null, "nlm_unique_id": "101585685", "other_id": null, "pages": null, "pmc": null, "pmid": "27695658", "pubdate": "2016-04", "publication_types": "D016428:Journal Article", "references": "20705131;22542870;17525344;25891007;7682457;19607965;16360218;19157572;21727249;8871944;25729218;16932856;19681872;18801434;23583622;20628445;10228297;11498512;22851255;15987694;19666104;15741748;19748189;26291402;26491593;24844438;24670961;24361869;17906679;18221348;23248075;14529462;23656698;17227290;17660390;19630711;16438952;15749244;16698940;26392128;24155705;17974154;19533710;19647111;15225337;18262386;26632847;3588140;11014461;15546805;26370914;21906670;18485596;2801659;18445737;11994026;21771276;16512356;23643692;23585028;17804535;17523700", "title": "Acetaminophen Use for Fever in Children Associated with Autism Spectrum Disorder.", "title_normalized": "acetaminophen use for fever in children associated with autism spectrum disorder" }

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{ "abstract": "Guidelines recommend that patients treated with continuous renal replacement therapy be delivered an effluent dose of 20 to 25 mL/kg/h. There is debate, especially at the extremes of body mass index, as to whether actual or ideal body weight (IBW) should be used in these dose calculations. A middle-aged woman with severe anorexia presented with 48 hours of altered mental status. Laboratory tests showed severe metabolic acidosis necessitating intubation, which was ultimately found to be due to nonprescribed use of metformin for weight loss. The patient became anuric and was initiated on continuous venovenous hemodialysis. Due to refractory acidosis, the modality was converted to continuous venovenous hemodiafiltration by adding postfilter hypertonic bicarbonate solution. Based on changes in sodium and bicarbonate levels over 4 hours with hypertonic bicarbonate solution, we were able to calculate an \"effective\" volume of distribution for this severely underweight patient. Our calculations suggest that IBW gives a better approximation of effective volume of distribution than actual body weight in a severely underweight woman. Inadequate effluent flow rate calculated based on actual rather than IBW may lead to insufficient correction of metabolic derangements in extremely underweight patients.", "affiliations": "Division of Renal Diseases and Hypertension, University of Colorado Denver Anschutz Medical Campus, Aurora, CO.;Division of Renal Diseases and Hypertension, University of Colorado Denver Anschutz Medical Campus, Aurora, CO.;Division of Renal Diseases and Hypertension, University of Colorado Denver Anschutz Medical Campus, Aurora, CO.;Division of Renal Diseases and Hypertension, University of Colorado Denver Anschutz Medical Campus, Aurora, CO.;Division of Renal Diseases and Hypertension, University of Colorado Denver Anschutz Medical Campus, Aurora, CO.;Division of Renal Diseases and Hypertension, University of Colorado Denver Anschutz Medical Campus, Aurora, CO.", "authors": "Griffin|Benjamin R|BR|;Ambruso|Sophia|S|;Jovanovich|Anna|A|;Bansal|Anip|A|;Linas|Stu|S|;Dylewski|James|J|", "chemical_list": null, "country": "United States", "delete": false, "doi": "10.1016/j.xkme.2019.04.007", "fulltext": "\n==== Front\nKidney Med\nKidney Med\nKidney Medicine\n2590-0595 Elsevier \n\nS2590-0595(19)30045-7\n10.1016/j.xkme.2019.04.007\nCase Report\nContinuous Renal Replacement Therapy Dosing in the Severely Underweight: A Case Report\nGriffin Benjamin R. benjamin.griffin@ucdenver.edu1∗ Ambruso Sophia 12 Jovanovich Anna 12 Bansal Anip 1 Linas Stu 13 Dylewski James 13 1 Division of Renal Diseases and Hypertension, University of Colorado Denver Anschutz Medical Campus, Aurora, CO\n2 Renal Section, VA Eastern Colorado Health Care System, Denver, CO\n3 Division of Nephrology, Denver Health Medical Center, Denver, CO\n∗ Address for Correspondence: Benjamin R. Griffin, MD, 12700 E 19th Ave, Research 2, Rm 7018, Aurora, CO 80045. benjamin.griffin@ucdenver.edu\n17 6 2019 \nJul-Aug 2019 \n17 6 2019 \n1 4 217 220\n© 2019 The Authors2019This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Guidelines recommend that patients treated with continuous renal replacement therapy be delivered an effluent dose of 20 to 25 mL/kg/h. There is debate, especially at the extremes of body mass index, as to whether actual or ideal body weight (IBW) should be used in these dose calculations. A middle-aged woman with severe anorexia presented with 48 hours of altered mental status. Laboratory tests showed severe metabolic acidosis necessitating intubation, which was ultimately found to be due to nonprescribed use of metformin for weight loss. The patient became anuric and was initiated on continuous venovenous hemodialysis. Due to refractory acidosis, the modality was converted to continuous venovenous hemodiafiltration by adding postfilter hypertonic bicarbonate solution. Based on changes in sodium and bicarbonate levels over 4 hours with hypertonic bicarbonate solution, we were able to calculate an “effective” volume of distribution for this severely underweight patient. Our calculations suggest that IBW gives a better approximation of effective volume of distribution than actual body weight in a severely underweight woman. Inadequate effluent flow rate calculated based on actual rather than IBW may lead to insufficient correction of metabolic derangements in extremely underweight patients.\n\nIndex Words\nAcute kidney injury (AKI)continuous renal replacement therapy (CRRT)dialysis dosevolume of distribution\n==== Body\nIntroduction\nSevere acute kidney injury requiring dialysis has an in-hospital mortality rate > 50% in critically ill patients,1, 2 making it one of the deadliest conditions commonly encountered in US hospitals. Continuous renal replacement therapy (CRRT) is generally the preferred dialysis option in the intensive care unit because it is associated with less hemodynamic instability than intermittent therapy.3\n\nA major component of the CRRT prescription is dose, which is based on urea clearance. In CRRT, in which dialysate or replacement fluid flow rates are low relative to blood flow, urea clearance is a function of effluent flow rate.4 KDIGO (Kidney Disease: Improving Global Outcomes) recommended in their 2012 clinical practice guideline that patients treated with CRRT receive an effluent flow rate normalized for body weight of 20 to 25 mL/kg/h (a 1A level recommendation).5 However, whether effluent flow rate should be normalized for ideal body weight (IBW) or actual body weight is unknown. Differences in IBW and actual body weight can lead to wide discrepancies in weight-normalized delivered doses at the extremes of body mass index.6, 7 In this case report, we provide evidence for use of IBW rather than actual body weight in a severely underweight woman.\n\nCase Report\nA middle-aged woman with a history of hypothyroidism and severe anorexia was admitted with a 2-day history of altered mental status. She had no other significant medical, surgical, social, or family history. She had no prescribed medications other than levothyroxine, but was later found to be taking nonprescribed metformin for weight loss.\n\nA timeline of events and laboratory flow sheet are given in Figure 1 and Table 1. Initial vital signs were significant for weight of 27 kg, body mass index of 10.1 kg/m2, and blood pressure of 70/34 mm Hg. Her IBW was calculated as 57 kg. Laboratory results were notable for the following values: lactate, 21 mmol/L; bicarbonate, 7 mmol/L; and creatinine, 2.1 mg/dL. An arterial blood gas drawn at arrival to the emergency department showed an initial pH < 6.80, Pco2 of 32 mm Hg, and calculated bicarbonate level of 5 mg/dL. Protocolized sepsis management was initiated, including fluid resuscitation, and she was intubated. She became anuric, and approximately 6 hours after arriving at the hospital was initiated on CRRT using continuous venovenous hemodialysis (CVVHD). The initial dialysate dose, prescribed using actual weight, was 800 mL/h (30 mL/kg/h), with dialysate fluid that had a sodium concentration of 140 mmol/L and bicarbonate concentration of 36 mmol/L.Figure 1 Timeline of events on treatment day 1. Abbreviations: CRRT, continuous renal replacement therapy; CVVHD, continuous venovenous hemodialysis; CVVHDF, continuous venovenous hemodiafiltration.\n\nTable 1 Arterial Blood Gas, Basic Metabolic Panel, and Lactate Values on Day 1\n\nTime Since Admission\t0\t0.5 h\t1.5 h\t6.5 h\t8 h\t12 h\t16 h\t19 h\t\nKey events\tAdmission\tIntubation\t\tCRRT initiated\tCRRT modified\t\tCRRT, hypertonic bicarbonate initiation\tCRRT, post–hypertonic bicarbonate\t\nArterial blood gas\t\t\t\t\t\t\t\t\t\n pH\t<6.80\t6.84\t\t6.83\t\t6.87\t\t7.16\t\n Pco2, mm Hg\t32\t15\t\t10\t\t10\t\t10\t\n Calculated bicarbonate, mmol/L\t5\t3\t\t2\t\t2\t\t5\t\nBasic metabolic panel and lactate\t\t\t\t\t\t\t\t\t\n Sodium, mmol/L\t146\t\t143\t\t143\t145\t143\t147\t\n Potassium, mmol/L\t2.7\t\t2.5\t\t4.2\t4.1\t4.4\t3.9\t\n Chloride, mmol/L\t104\t\t104\t\t106\t107\t107\t103\t\n Bicarbonate, mmol/L\t7\t\t2\t\t3\t3\t3\t5\t\n Creatinine, mg/dL\t2.0\t\t2.1\t\t1.8\t1.6\t1.5\t1.4\t\n Lactate, mmol/L\t21\t\t23\t\t22\t22\t21\t21\t\nAbbreviation: CRRT, continuous renal replacement therapy.\n\n\n\nLaboratory tests 2 hours later showed serum bicarbonate level of 3 mmol/L, prompting an increase in dialysate flow rate to 1,750 mL/h (30 mL/kg/h), which was calculated using IBW of 57 kg. Laboratory tests assessed 12 hours after arrival showed that bicarbonate level was stable at 3 mmol/L, with lactate level of 22 mg/dL and pH 6.87. Given that pH had not improved despite 6 hours of CVVHD, the CRRT modality was converted to continuous venovenous hemodiafiltration, with 1,500 mL/h of dialysate and 250 mL/h of postfilter hypertonic bicarbonate solution, which was composed of 6 ampules of bicarbonate in 1 L of water (300 mmol/L of sodium bicarbonate). Four hours after initiation of hypertonic bicarbonate solution administration, pH increased to 7.16 and bicarbonate level increased to 5 mmol/L.\n\nDiscussion\nThis case describes a severely underweight woman with lactic acidosis due to metformin toxicity who was initiated on CRRT. Because the patient was anuric, changes in sodium and bicarbonate levels were assumed to be due to CRRT alone, allowing for an estimation of the patient’s effective volume of distribution (VD). We found that IBW better estimated VD than actual body weight.\n\nVD Based on Changes in Sodium\nExpected changes in sodium levels while on CRRT can be calculated using the following equation8: (1) [Na+](t)=[Na+]i+([Na+]RF−[Na+]i)×(1−e−DtV) \n\n[Na+]i is sodium concentration at initiation, [Na+]RF is sodium concentration of the replacement fluid (or dialysate), D is effluent flow rate in L/h, and [Na+](t) is sodium concentration after t hours of treatment.\n\nThe patient’s dialysate [Na+] was 140 mmol/L, and postfilter sodium bicarbonate [Na+] was 300 mmol/L. At rates of 1,500 and 250 mL/h, the effective [Na+]RF was 163 mmol/L. (2) Effective[Na+]RF=(140mmolL×1,500mLh+300mmolL×250mLh)1,750mL=163mmolL \n\nGiven that the initial sodium level at the time of hypertonic bicarbonate solution initiation was 143 mmol/L and that 4 hours later sodium level was 147 mmol/L, we can estimate the effective VD as follows: (3) 147=143+(163−143)×(1−e−(1.75)×4V) \n\nSolving for V, “effective” VD is 31 L. If we assume that VD in this patient is similar to that of an elderly woman (55% of body weight), her effective weight is 57 kg, which is identical to IBW and more than double her actual body weight of 27 kg.\n\nVD Based on Changes in Bicarbonate\nWe can similarly use bicarbonate level changes to estimate “effective” volume of distribution using the following equation: (4) ΔHCO3−=TotalHCO3−Given−EndogenousAcidProductionVD \n\nAt bicarbonate levels < 10 mmol/L, VD for bicarbonate approximates body weight,9 so calculated VD was used to find the patient’s effective body weight.\n\nTo calculate total bicarbonate, we add the dialysate contribution to the postfilter replacement fluid bicarbonate contribution. The bicarbonate gradient used was 32 mmol/L, based on a bicarbonate level before starting hypertonic bicarbonate solution administration of 3 mmol/L and 5 mmol/L afterward. The gradient was calculated by subtracting the average serum bicarbonate level (4 mmol/L) from the dialysate concentration (36 mmol/L). Based on dialysate and postfilter bicarbonate flow rates, her bicarbonate load was 123 mmol/h: (5) 1.5L/h×32mmol/L+0.25L/h×300mmol/L=123mmol/h \n\nWe can calculate endogenous acid production based on the fact that serum bicarbonate level did not change after 4 hours of CVVHD at 1.75 L/h with a bicarbonate gradient of 33 mmol/L. (6) 1.75L/h×33mmol/L=57.75mmol/h \n\nEndogenous acid production must be at least this rate to counteract the administered bicarbonate. Acid production may have been higher because buffering from other sources such as bone (phosphate) could not be calculated.\n\nAcid production during administration of hypertonic bicarbonate solution was assumed to be unchanged because lactate level was unchanged following this 4-hour period. If we subtract acid production from the bicarbonate given, we get 65.25 mmol/h net bicarbonate, which over 4 hours is a net gain of 261 mmol of bicarbonate.\n\nOver 4 hours, bicarbonate level increased by 2 mmol/L. The difference in calculated arterial blood gas bicarbonate level was 3 mmol/L. VD calculations are as follows: (7) Increaseof2mmol/L:261mmol÷2mmol/L=130.5L (8) Increaseof3mmol/L:261mmol÷3mmol/L=87L \n\nThese calculated VD values are much higher than IBW or actual body weight, which suggests that there was more endogenous acid production that was buffered by alternative pathways than anticipated, illustrating the possible far-reaching consequences of sustained severe acidosis. These calculations also illustrate that as bicarbonate levels decrease, VD increases.9 It is also notable that at extremely low bicarbonate levels, small changes in bicarbonate levels lead to large differences in calculated VD.\n\nTo further illustrate that IBW better predicted bicarbonate level changes that actual body weight, we can calculate expected increases in bicarbonate levels based on actual versus IBW. (9) Expectedincreasebasedonactualbodyweight:261mmol÷27L=9.7mmol/L (10) ExpectedincreasebasedonIBW:261mmol÷57L=4.6mmol/L \n\nGiven that the actual change was 2 to 3 mmol/L, it is clear that using IBW gave an estimation that was much closer to the observed outcome.\n\nThere are several limitations in this case report. VD was not directly measured. As noted in the discussion, slight changes in values, especially in bicarbonate, would have a marked effect on the calculated VD. The bicarbonate calculations are based on 1 set of laboratory tests following hypertonic bicarbonate solution administration, and the margin of error for bicarbonate can be up to 2 mmol/L. In addition, endogenous acid production did not account for nonbicarbonate sources of buffer. Finally, it is unclear whether IBW better predicts VD in patients with extremely high body mass index, which is the much more common scenario in the United States.\n\nNonetheless, this case report has several strengths; notably, analyses based on clinical data of an anuric patient on CRRT. Because the patient was anuric, all changes during the 4 hours of hypertonic bicarbonate solution therapy could reasonably be attributed to CRRT alone, which allows for calculation of effective body weight. We were also able to show that lactate levels were constant over the course of treatment, making our assumptions of constant acid production plausible.\n\nThis case illustrates that in a severely underweight woman treated with CRRT, IBW rather than actual body weight provides a better approximation of the VD of sodium and bicarbonate. IBW therefore appears to be more appropriate to use when normalizing the effluent flow rate for patient weight when prescribing dialysis therapies.\n\nArticle Information\nAuthors’ Full Names and Academic Degrees\nBenjamin R. Griffin, MD, Sophia Ambruso, DO, Anna Jovanovich, MD, Anip Bansal, MD, Stu Linas, MD, and James Dylewski, MD.\n\nSupport\nDr Griffin is supported by a National Research Service Award Institutional Predoctoral Training Grant (T32), grant number T32 DK 007135. Dr Jovanovich is supported by VA CDA 5IK2CX001030-04.\n\nFinancial Disclosure\nThe authors declare that they have no relevant financial interests.\n\nPeer Review\nReceived January 18, 2019. Evaluated by 1 external peer reviewer, with direct editorial input from an Associate Editor and the Editor-in-Chief. Accepted in revised form April 27, 2019.\n\nComplete author and article information provided before references.\n==== Refs\nReferences\n1 Uchino S. Bellomo R. Morimatsu H. Continuous renal replacement therapy: a worldwide practice survey. The beginning and ending supportive therapy for the kidney (B.E.S.T. kidney) investigators Intensive Care Med 33 9 2007 1563 1570 17594074 \n2 Palevsky P.M. Zhang J.H. O'Connor T.Z. Intensity of renal support in critically ill patients with acute kidney injury N Engl J Med 359 1 2008 7 20 18492867 \n3 Deepa C. Muralidhar K. Renal replacement therapy in ICU J Anaesthesiol Clin Pharmacol 28 3 2012 386 396 22869954 \n4 Claure-Del Granado R. Macedo E. Chertow G.M. Effluent volume in continuous renal replacement therapy overestimates the delivered dose of dialysis Clin J Am Soc Nephrol 6 3 2011 467 475 21115626 \n5 Stevens P.E. Levin A. Evaluation and management of chronic kidney disease: synopsis of the Kidney Disease: Improving Global Outcomes 2012 clinical practice guideline Ann Intern Med 158 11 2013 825 830 23732715 \n6 Lameire N. Van Biesen W. Vanholder R. Dose of dialysis in the intensive care unit: is the venom in the dose or in the clinical experience? Crit Care 13 3 2009 155 19519962 \n7 Prowle J.R. Schneider A. Bellomo R. Clinical review: optimal dose of continuous renal replacement therapy in acute kidney injury Crit Care 15 2 2011 207 21489322 \n8 Yessayan L. Yee J. Frinak S. Szamosfalvi B. Continuous renal replacement therapy for the management of acid-base and electrolyte imbalances in acute kidney injury Adv Chronic Kidney Dis 23 3 2016 203 210 27113697 \n9 Garella S. Dana C.L. Chazan J.A. Severity of metabolic acidosis as a determinant of bicarbonate requirements N Engl J Med 289 3 1973 121 126 4711340\n\n", "fulltext_license": "CC BY-NC-ND", "issn_linking": "2590-0595", "issue": "1(4)", "journal": "Kidney medicine", "keywords": "Acute kidney injury (AKI); continuous renal replacement therapy (CRRT); dialysis dose; volume of distribution", "medline_ta": "Kidney Med", "mesh_terms": null, "nlm_unique_id": "101756300", "other_id": null, "pages": "217-220", "pmc": null, "pmid": "32734202", "pubdate": "2019", "publication_types": "D002363:Case Reports", "references": "22869954;21115626;18492867;17594074;21489322;27113697;23732715;19519962;4711340", "title": "Continuous Renal Replacement Therapy Dosing in the Severely Underweight: A Case Report.", "title_normalized": "continuous renal replacement therapy dosing in the severely underweight a case report" }

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CONTINUOUS RENAL REPLACEMENT THERAPY DOSING IN THE SEVERELY UNDERWEIGHT: A CASE REPORT. KIDNEY-MED 2019?1(4):217-220.", "literaturereference_normalized": "continuous renal replacement therapy dosing in the severely underweight a case report", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20191023", "receivedate": "20191001", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16874719, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": 1, "seriousnessother": null, "transmissiondate": "20200122" }, { "companynumb": "US-BAUSCH-BL-2019-021496", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "LEVOTHYROXINE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "HYPOTHYROIDISM", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LEVOTHYROXINE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "METFORMIN HYDROCHLORIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "021748", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "WEIGHT DECREASED", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METFORMIN" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "METFORMIN HYDROCHLORIDE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": "021748", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USE IN UNAPPROVED INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METFORMIN" } ], "patientagegroup": "5", "patientonsetage": null, "patientonsetageunit": null, "patientsex": "2", "patientweight": "27", "reaction": [ { "reactionmeddrapt": "Toxicity to various agents", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Lactic acidosis", "reactionmeddraversionpt": "23.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Prescription drug used without a prescription", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Product use in unapproved indication", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "GRIFFIN B, AMBRUSO S, JOVANOVICH A, BANSAL A, LINAS S, DYLEWSKI J. CONTINUOUS RENAL REPLACEMENT THERAPY DOSING IN THE SEVERELY UNDERWEIGHT: A CASE REPORT. KIDNEY MEDICINE. 2019?20(20):1?4. DOI:10.1016/J.XKME.2019.04.007", "literaturereference_normalized": "continuous renal replacement therapy dosing in the severely underweight a case report", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210310", "receivedate": "20190731", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16653419, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20210419" }, { "companynumb": "US-MYLANLABS-2019M1088563", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "METFORMIN HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "075973", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "WEIGHT CONTROL", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METFORMIN" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "LEVOTHYROXINE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "HYPOTHYROIDISM", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LEVOTHYROXINE." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": "2", "patientweight": "27", "reaction": [ { "reactionmeddrapt": "Lactic acidosis", "reactionmeddraversionpt": "22.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Anuria", "reactionmeddraversionpt": "22.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Intentional product misuse", "reactionmeddraversionpt": "22.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Mental status changes", "reactionmeddraversionpt": "22.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Product use in unapproved indication", "reactionmeddraversionpt": "22.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Toxicity to various agents", "reactionmeddraversionpt": "22.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Prescription drug used without a prescription", "reactionmeddraversionpt": "22.0", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "GRIFFIN BR, AMBRUSO S, JOVANOVICH A, BANSAL A, LINAS S, DYLEWSKI J. CONTINUOUS RENAL REPLACEMENT THERAPY DOSING IN THE SEVERELY UNDERWEIGHT: A CASE REPORT. KIDNEY-MED 2019?1(4):217-220.", "literaturereference_normalized": "continuous renal replacement therapy dosing in the severely underweight a case report", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20190923", "receivedate": "20190923", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16840420, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": 1, "seriousnessother": null, "transmissiondate": "20191005" }, { "companynumb": "US-GLENMARK PHARMACEUTICALS-2019GMK042367", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "METFORMIN HYDROCHLORIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "78170", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "WEIGHT DECREASED", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METFORMIN HYDROCHLORIDE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "LEVOTHYROXINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "HYPOTHYROIDISM", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LEVOTHYROXINE." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": "2", "patientweight": "27", "reaction": [ { "reactionmeddrapt": "Mental status changes", "reactionmeddraversionpt": "22.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Lactic acidosis", "reactionmeddraversionpt": "22.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Toxicity to various agents", "reactionmeddraversionpt": "22.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Anuria", "reactionmeddraversionpt": "22.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Prescription drug used without a prescription", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "GRIFFIN BR, AMBRUSO S, JOVANOVICH A, BANSAL A, LINAS S, DYLEWSKI J.. CONTINUOUS RENAL REPLACEMENT THERAPY DOSING IN THE SEVERELY UNDERWEIGHT: A CASE REPORT.. KIDNEY MEDICINE.. 2019", "literaturereference_normalized": "continuous renal replacement therapy dosing in the severely underweight a case report", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20190801", "receivedate": "20190801", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16656211, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": 1, "seriousnessother": 1, "transmissiondate": "20191004" }, { "companynumb": "US-SUN PHARMACEUTICAL INDUSTRIES LTD-2019R1-221312", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "METFORMIN HYDROCHLORIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "021591", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "WEIGHT DECREASED", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METFORMIN" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": "2", "patientweight": "27", "reaction": [ { "reactionmeddrapt": "Metabolic acidosis", "reactionmeddraversionpt": "23.1", "reactionoutcome": "2" }, { "reactionmeddrapt": "Mental status changes", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Decreased appetite", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Product use in unapproved indication", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Toxicity to various agents", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "GRIFFIN BR, AMBRUSO S, JOVANOVICH A, BANSAL A, LINAS S, DYLEWSKI J. CONTINUOUS RENAL REPLACEMENT THERAPY DOSING IN THE SEVERELY UNDERWEIGHT: A CASE REPORT. KIDNEY MED. 2019?1(4):217?220", "literaturereference_normalized": "continuous renal replacement therapy dosing in the severely underweight a case report", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20200908", "receivedate": "20200908", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 18241381, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20201103" }, { "companynumb": "US-DRREDDYS-USA/USA/19/0112435", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "METFORMIN HYDROCHLORIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "077787", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNKNOWN", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "WEIGHT DECREASED", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METFORMIN" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "LEVOTHYROXINE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNKNOWN", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "HYPOTHYROIDISM", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LEVOTHYROXINE." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": "2", "patientweight": "27", "reaction": [ { "reactionmeddrapt": "Anuria", "reactionmeddraversionpt": "23.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Mental status changes", "reactionmeddraversionpt": "23.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Toxicity to various agents", "reactionmeddraversionpt": "23.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Lactic acidosis", "reactionmeddraversionpt": "23.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Prescription drug used without a prescription", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "GRIFFIN BR, AMBRUSO S, JOVANOVICH A, BANSAL A, LINAS S, DYLEWSKI J. CONTINUOUS RENAL REPLACEMENT THERAPY DOSING IN THE SEVERELY UNDERWEIGHT: A CASE REPORT. KIDNEY MEDICINE. 2019. DOI: 10.1016/J.XKME.2019.04.007.", "literaturereference_normalized": "continuous renal replacement therapy dosing in the severely underweight a case report", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210312", "receivedate": "20190729", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16641283, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": 1, "seriousnessother": 1, "transmissiondate": "20210419" } ]

{ "abstract": "The objective of the present study was to comprehensively compare the clinical outcomes between abiraterone acetate (AA) and enzalutamide (Enz) in Japanese patients with docetaxel-naive metastatic castration-resistant prostate cancer (mCRPC).\n\n\n\nThe present study retrospectively included 280 consecutive mCRPC patients, consisting of 113 and 167 who had received AA and Enz, respectively, without previous treatment with docetaxel.\n\n\n\nOf the several baseline characteristics examined, some parameters, including performance status (PS), prostate-specific antigen (PSA) value, and incidence of lymph node metastasis, significantly favored the Enz over the AA group. The PSA response rate in the Enz group was significantly greater than that in the AA group, and the PSA progression-free survival in the Enz group was significantly superior to that in the AA group. Multivariate analyses of several parameters identified the following independent predictors of PSA progression-free survival: duration of androgen deprivation therapy and PS for the AA group, age and PS for the Enz group, and PS but not the introduced agent (ie, AA vs. Enz) for the overall patients. The common adverse events observed in the present series were fatigue (19.4%) and liver toxicity (11.5%) in the AA group and fatigue (32.3%) and appetite loss (19.2%) in the Enz group. In addition, the proportion of patients with adverse events grade ≥ 3 in the Enz group (11.4%) was significantly greater than that in the AA group (4.4%).\n\n\n\nBoth AA and Enz were effective and tolerable for patients with docetaxel-naive mCRPC in the routine clinical setting.", "affiliations": "Division of Urology, Kobe University Graduate School of Medicine, Kobe, Japan; Department of Urology, Hamamatsu University School of Medicine, Hamamatsu, Japan. Electronic address: hideakimiyake@hotmail.com.;Division of Urology, Kobe University Graduate School of Medicine, Kobe, Japan.;Division of Urology, Kobe University Graduate School of Medicine, Kobe, Japan.;Department of Urology, Hamamatsu University School of Medicine, Hamamatsu, Japan.;Division of Urology, Kobe University Graduate School of Medicine, Kobe, Japan.", "authors": "Miyake|Hideaki|H|;Hara|Takuto|T|;Terakawa|Tomoaki|T|;Ozono|Seiichiro|S|;Fujisawa|Masato|M|", "chemical_list": "D000970:Antineoplastic Agents; D001549:Benzamides; D009570:Nitriles; D010669:Phenylthiohydantoin; C540278:enzalutamide; D000069501:Abiraterone Acetate", "country": "United States", "delete": false, "doi": "10.1016/j.clgc.2016.06.010", "fulltext": null, "fulltext_license": null, "issn_linking": "1558-7673", "issue": "15(2)", "journal": "Clinical genitourinary cancer", "keywords": "AR axis-targeted agents; Adverse event; Progression-free survival; Response; mCRPC", "medline_ta": "Clin Genitourin Cancer", "mesh_terms": "D000069501:Abiraterone Acetate; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents; D001549:Benzamides; D006801:Humans; D007564:Japan; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D009570:Nitriles; D010669:Phenylthiohydantoin; D011379:Prognosis; D064129:Prostatic Neoplasms, Castration-Resistant; D012189:Retrospective Studies; D016019:Survival Analysis; D016896:Treatment Outcome", "nlm_unique_id": "101260955", "other_id": null, "pages": "313-319", "pmc": null, "pmid": "27424256", "pubdate": "2017-04", "publication_types": "D003160:Comparative Study; D016428:Journal Article", "references": null, "title": "Comparative Assessment of Clinical Outcomes Between Abiraterone Acetate and Enzalutamide in Patients With Docetaxel-Naive Metastatic Castration-Resistant Prostate Cancer: Experience in Real-World Clinical Practice in Japan.", "title_normalized": "comparative assessment of clinical outcomes between abiraterone acetate and enzalutamide in patients with docetaxel naive metastatic castration resistant prostate cancer experience in real world clinical practice in japan" }

[ { "companynumb": "JP-JNJFOC-20180921757", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "ABIRATERONE ACETATE" }, "drugadditional": "3", "drugadministrationroute": "048", "drugauthorizationnumb": "202379", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PROSTATE CANCER METASTATIC", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ABIRATERONE ACETATE." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Decreased appetite", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Nausea", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Hepatotoxicity", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Fatigue", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Asthenia", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Diarrhoea", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Arthralgia", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Anaemia", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Hypertension", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "MIYAKE H, HARA T, TERAKAWA T, OZONO S, FUJISAWA M. COMPARATIVE ASSESSMENT OF CLINICAL OUTCOMES BETWEEN ABIRATERONE ACETATE AND ENZALUTAMIDE IN PATIENTS WITH DOCETAXEL-NAIVE METASTATIC CASTRATION-RESISTANT PROSTATE CANCER: EXPERIENCE IN REAL-WORLD CLINICAL PRACTICE IN JAPAN. CLIN GENITOURIN CANCER 2017?15 (2):313-319.", "literaturereference_normalized": "comparative assessment of clinical outcomes between abiraterone acetate and enzalutamide in patients with docetaxel naive metastatic castration resistant prostate cancer experience in real world clinical practice in japan", "qualification": "1", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20181008", "receivedate": "20181008", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 15473887, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190205" }, { "companynumb": "JP-JNJFOC-20170421288", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "ABIRATERONE ACETATE" }, "drugadditional": "3", "drugadministrationroute": "048", "drugauthorizationnumb": "202379", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PROSTATE CANCER METASTATIC", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ABIRATERONE ACETATE" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Hepatotoxicity", "reactionmeddraversionpt": "20.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Decreased appetite", "reactionmeddraversionpt": "20.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Asthenia", "reactionmeddraversionpt": "20.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Diarrhoea", "reactionmeddraversionpt": "20.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Anaemia", "reactionmeddraversionpt": "20.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Hypertension", "reactionmeddraversionpt": "20.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Nausea", "reactionmeddraversionpt": "20.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Fatigue", "reactionmeddraversionpt": "20.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Arthralgia", "reactionmeddraversionpt": "20.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "MIYAKE H, HARA T, TERAKAWA T, OZONO S, FUJISAWA M. COMPARATIVE ASSESSMENT OF CLINICAL OUTCOMES BETWEEN ABIRATERONE ACETATE AND ENZALUTAMIDE IN PATIENTS WITH DOCETAXEL-NAIVE METASTATIC CASTRATION-RESISTANT PROSTATE CANCER: EXPERIENCE IN REAL-WORLD CLINICAL PRACTICE IN JAPAN. CLIN GENITOURIN CANCER 2017;15 (2):313-319.", "literaturereference_normalized": "comparative assessment of clinical outcomes between abiraterone acetate and enzalutamide in patients with docetaxel naive metastatic castration resistant prostate cancer experience in real world clinical practice in japan", "qualification": "1", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20170426", "receivedate": "20170426", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 13486430, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170830" } ]

{ "abstract": "The role of antiviral prophylaxis before chemotherapy or immunosuppressive therapy to prevent hepatitis B virus (HBV) reactivation in patients with resolved HBV infection [hepatitis B surface antigen (HBsAg) negative, hepatitis B core antibody (anti-HBc) positive] is unclear. This study aimed to evaluate the efficacy of prophylactic antiviral therapy and outcomes of HBsAg-negative, anti-HBc-positive patients who received chemotherapy or immunosuppressive therapy.\n\n\n\nWe retrospectively evaluated the medical records of HBsAg-negative, anti-HBc-positive patients who underwent chemotherapy or immunosuppressive therapy from January 2013 through November 2016 at a single institute in southern Taiwan.\n\n\n\nAmong 1000 included HBsAg-negative, anti-HBc-positive patients, the rate of hepatitis B surface antibody (anti-HBs) seropositivity before chemotherapy or immunosuppressive therapy was 76.6%. Twenty-six patients received a prophylactic oral antiviral agent (one telbuvudine, two lamivudine, 22 entecavir, and one tenofovir). Seven (0.7%) patients were diagnosed with HBV reactivation during or after chemotherapy courses. In multivariate Cox regression analysis, an rituximab-based regimen (hazard ratio: 11.74; 95% confidence interval: 1.62-84.94; P=0.02) and baseline anti-HBs-positive status (hazard ratio: 0.17; 95% confidence interval: 0.04-0.8; P=0.03) were significant predictive factors for HBV reactivation. Among anti-HBs-negative recipients of rituximab-based chemotherapy, HBV reactivation was observed in zero of nine patients who received prophylactic antiviral therapy and three (33.3%) of nine patients who did not.\n\n\n\nNegative anti-HBs status and rituximab-containing regimens are both important factors for predicting chemotherapy or immunosuppressive therapy-related HBV reactivation in patients with resolved HBV infection. Therefore, antiviral prophylaxis should be considered in this patient population.", "affiliations": "Departments of Pharmacy.;Departments of Pharmacy.;Internal Medicine, Division of Gastroenterology.;Surgery, Kaohsiung Veterans General Hospital.", "authors": "Su|Yi-Chia|YC|;Lin|Pei-Chin|PC|;Yu|Hsien-Chung|HC|;Wu|Chih-Chien|CC|", "chemical_list": "D000074322:Antineoplastic Agents, Immunological; D000998:Antiviral Agents; D015415:Biomarkers; D006510:Hepatitis B Antibodies; D006514:Hepatitis B Surface Antigens; D007166:Immunosuppressive Agents; D000069283:Rituximab", "country": "England", "delete": false, "doi": "10.1097/MEG.0000000000001130", "fulltext": null, "fulltext_license": null, "issn_linking": "0954-691X", "issue": "30(8)", "journal": "European journal of gastroenterology & hepatology", "keywords": null, "medline_ta": "Eur J Gastroenterol Hepatol", "mesh_terms": "D000368:Aged; D000074322:Antineoplastic Agents, Immunological; D000998:Antiviral Agents; D015415:Biomarkers; D016009:Chi-Square Distribution; D005260:Female; D016174:Hepacivirus; D006509:Hepatitis B; D006510:Hepatitis B Antibodies; D006514:Hepatitis B Surface Antigens; D006801:Humans; D016867:Immunocompromised Host; D007166:Immunosuppressive Agents; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D016016:Proportional Hazards Models; D012189:Retrospective Studies; D012307:Risk Factors; D000069283:Rituximab; D013624:Taiwan; D014775:Virus Activation", "nlm_unique_id": "9000874", "other_id": null, "pages": "925-929", "pmc": null, "pmid": "29621049", "pubdate": "2018-08", "publication_types": "D003160:Comparative Study; D016428:Journal Article", "references": null, "title": "Hepatitis B virus reactivation in patients with resolved hepatitis B virus infection receiving chemotherapy or immunosuppressive therapy.", "title_normalized": "hepatitis b virus reactivation in patients with resolved hepatitis b virus infection receiving chemotherapy or immunosuppressive therapy" }

[ { "companynumb": "TW-MYLANLABS-2018M1089078", "fulfillexpeditecriteria": "1", "occurcountry": "TW", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "RITUXIMAB" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNK", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "SIX CYCLES OF TREATMENT [R-CEOP REGIMEN]", "drugenddate": null, "drugenddateformat": null, "drugindication": "CHEMOTHERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RITUXIMAB." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "EPIRUBICIN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "065371", "drugbatchnumb": "UNK", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "SIX CYCLES OF TREATMENT [R-CEOP REGIMEN]", "drugenddate": null, "drugenddateformat": null, "drugindication": "CHEMOTHERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "EPIRUBICIN" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "PREDNISOLONE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNK", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "SIX CYCLES OF TREATMENT [R-CEOP REGIMEN]", "drugenddate": null, "drugenddateformat": null, "drugindication": "CHEMOTHERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISOLONE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "VINCRISTINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNK", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "SIX CYCLES OF TREATMENT [R-CEOP REGIMEN]", "drugenddate": null, "drugenddateformat": null, "drugindication": "CHEMOTHERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VINCRISTINE" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "CYCLOPHOSPHAMIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNK", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "SIX CYCLES OF TREATMENT [R-CEOP REGIMEN]", "drugenddate": null, "drugenddateformat": null, "drugindication": "CHEMOTHERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYCLOPHOSPHAMIDE." } ], "patientagegroup": null, "patientonsetage": "66", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Hepatitis B reactivation", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Hepatitis", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "SU YC, LIN PC, YU HC, WU CC. HEPATITIS B VIRUS REACTIVATION IN PATIENTS WITH RESOLVED HEPATITIS B VIRUS INFECTION RECEIVING CHEMOTHERAPY OR IMMUNOSUPPRESSIVE THERAPY. EUR-J-GASTROENTEROL-HEPATOL 2018?30(8):925-929.", "literaturereference_normalized": "hepatitis b virus reactivation in patients with resolved hepatitis b virus infection receiving chemotherapy or immunosuppressive therapy", "qualification": "1", "reportercountry": "TW" }, "primarysourcecountry": "TW", "receiptdate": "20181204", "receivedate": "20181204", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 15685244, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190205" }, { "companynumb": "TW-MYLANLABS-2018M1089083", "fulfillexpeditecriteria": "1", "occurcountry": "TW", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "CYCLOPHOSPHAMIDE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYCLOPHOSPHAMIDE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "VINCRISTINE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VINCRISTINE" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "MITOXANTRONE HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "TWO CYCLES OF TREATMENT [CNOP REGIMEN]", "drugenddate": null, "drugenddateformat": null, "drugindication": "CHEMOTHERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MITOXANTRONE" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "CYCLOPHOSPHAMIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "TWO CYCLES OF TREATMENT [CNOP REGIMEN]", "drugenddate": null, "drugenddateformat": null, "drugindication": "CHEMOTHERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYCLOPHOSPHAMIDE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "PREDNISOLONE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "202179", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "TWO CYCLES OF TREATMENT [CNOP REGIMEN]", "drugenddate": null, "drugenddateformat": null, "drugindication": "CHEMOTHERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISOLONE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "VINCRISTINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "TWO CYCLES OF TREATMENT [CNOP REGIMEN]", "drugenddate": null, "drugenddateformat": null, "drugindication": "CHEMOTHERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VINCRISTINE" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "PREDNISOLONE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "202179", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISOLONE." } ], "patientagegroup": null, "patientonsetage": "56", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Hepatitis", "reactionmeddraversionpt": "21.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Hepatitis B reactivation", "reactionmeddraversionpt": "21.1", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "SU YC, LIN PC, YU HC, WU CC. HEPATITIS B VIRUS REACTIVATION IN PATIENTS WITH RESOLVED HEPATITIS B VIRUS INFECTION RECEIVING CHEMOTHERAPY OR IMMUNOSUPPRESSIVE THERAPY. EUR-J-GASTROENTEROL-HEPATOL 2018?30(8):925-929.", "literaturereference_normalized": "hepatitis b virus reactivation in patients with resolved hepatitis b virus infection receiving chemotherapy or immunosuppressive therapy", "qualification": "1", "reportercountry": "TW" }, "primarysourcecountry": "TW", "receiptdate": "20181203", "receivedate": "20181203", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 15682707, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20190205" }, { "companynumb": "TW-MYLANLABS-2018M1089089", "fulfillexpeditecriteria": "1", "occurcountry": "TW", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "VINCRISTINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "SIX CYCLES OF TREATMENT [R-CEOP REGIMEN]", "drugenddate": null, "drugenddateformat": null, "drugindication": "CHEMOTHERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VINCRISTINE" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "PREDNISOLONE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "202179", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISOLONE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "CYCLOPHOSPHAMIDE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYCLOPHOSPHAMIDE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "RITUXIMAB" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "SIX CYCLES OF TREATMENT [R-CEOP REGIMEN]", "drugenddate": null, "drugenddateformat": null, "drugindication": "CHEMOTHERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RITUXIMAB." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "VINCRISTINE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VINCRISTINE" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "EPIRUBICIN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "SIX CYCLES OF TREATMENT [R-CEOP REGIMEN]", "drugenddate": null, "drugenddateformat": null, "drugindication": "CHEMOTHERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "EPIRUBICIN" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "PREDNISOLONE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "202179", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "SIX CYCLES OF TREATMENT [R-CEOP REGIMEN]", "drugenddate": null, "drugenddateformat": null, "drugindication": "CHEMOTHERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISOLONE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "CYCLOPHOSPHAMIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "SIX CYCLES OF TREATMENT [R-CEOP REGIMEN]", "drugenddate": null, "drugenddateformat": null, "drugindication": "CHEMOTHERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYCLOPHOSPHAMIDE." } ], "patientagegroup": null, "patientonsetage": "68", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Hepatitis B reactivation", "reactionmeddraversionpt": "21.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Hepatitis", "reactionmeddraversionpt": "21.1", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "SU YC, LIN PC, YU HC, WU CC. HEPATITIS B VIRUS REACTIVATION IN PATIENTS WITH RESOLVED HEPATITIS B VIRUS INFECTION RECEIVING CHEMOTHERAPY OR IMMUNOSUPPRESSIVE THERAPY. EUR-J-GASTROENTEROL-HEPATOL 2018?30(8):925-929.", "literaturereference_normalized": "hepatitis b virus reactivation in patients with resolved hepatitis b virus infection receiving chemotherapy or immunosuppressive therapy", "qualification": "1", "reportercountry": "TW" }, "primarysourcecountry": "TW", "receiptdate": "20181204", "receivedate": "20181204", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 15684519, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20190205" }, { "companynumb": "TW-MYLANLABS-2018M1089084", "fulfillexpeditecriteria": "1", "occurcountry": "TW", "patient": { "drug": [ { "actiondrug": "4", "activesubstance": { "activesubstancename": "CYCLOPHOSPHAMIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "CHEMOTHERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYCLOPHOSPHAMIDE." }, { "actiondrug": "4", "activesubstance": { "activesubstancename": "EPIRUBICIN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "065371", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "CHEMOTHERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "EPIRUBICIN" }, { "actiondrug": "4", "activesubstance": { "activesubstancename": "PREDNISOLONE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISOLONE." }, { "actiondrug": "4", "activesubstance": { "activesubstancename": "VINCRISTINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "CHEMOTHERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VINCRISTINE" }, { "actiondrug": "4", "activesubstance": { "activesubstancename": "PREDNISOLONE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "CHEMOTHERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISOLONE." }, { "actiondrug": "4", "activesubstance": { "activesubstancename": "RITUXIMAB" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "CHEMOTHERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RITUXIMAB." }, { "actiondrug": "4", "activesubstance": { "activesubstancename": "VINCRISTINE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VINCRISTINE" }, { "actiondrug": "4", "activesubstance": { "activesubstancename": "CYCLOPHOSPHAMIDE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYCLOPHOSPHAMIDE." } ], "patientagegroup": null, "patientonsetage": "70", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Hepatitis", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Hepatitis B reactivation", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "SU YC, LIN PC, YU HC, WU CC. HEPATITIS B VIRUS REACTIVATION IN PATIENTS WITH RESOLVED HEPATITIS B VIRUS INFECTION RECEIVING CHEMOTHERAPY OR IMMUNOSUPPRESSIVE THERAPY. EUR-J-GASTROENTEROL-HEPATOL 2018?30(8):925-929.", "literaturereference_normalized": "hepatitis b virus reactivation in patients with resolved hepatitis b virus infection receiving chemotherapy or immunosuppressive therapy", "qualification": "1", "reportercountry": "TW" }, "primarysourcecountry": "TW", "receiptdate": "20181203", "receivedate": "20181203", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 15681709, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190205" }, { "companynumb": "TW-MYLANLABS-2018M1089090", "fulfillexpeditecriteria": "1", "occurcountry": "TW", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "PREDNISOLONE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISOLONE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "VINCRISTINE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VINCRISTINE" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "EPIRUBICIN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "065371", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "SIX CYCLES OF TREATMENT [R-CEOP REGIMEN]", "drugenddate": null, "drugenddateformat": null, "drugindication": "CHEMOTHERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "EPIRUBICIN" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "RITUXIMAB" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "SIX CYCLES OF TREATMENT [R-CEOP REGIMEN]", "drugenddate": null, "drugenddateformat": null, "drugindication": "CHEMOTHERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RITUXIMAB." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "CYCLOPHOSPHAMIDE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYCLOPHOSPHAMIDE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "VINCRISTINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "SIX CYCLES OF TREATMENT [R-CEOP REGIMEN]", "drugenddate": null, "drugenddateformat": null, "drugindication": "CHEMOTHERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VINCRISTINE" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "PREDNISOLONE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "SIX CYCLES OF TREATMENT [R-CEOP REGIMEN]", "drugenddate": null, "drugenddateformat": null, "drugindication": "CHEMOTHERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISOLONE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "CYCLOPHOSPHAMIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "SIX CYCLES OF TREATMENT [R-CEOP REGIMEN]", "drugenddate": null, "drugenddateformat": null, "drugindication": "CHEMOTHERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYCLOPHOSPHAMIDE." } ], "patientagegroup": null, "patientonsetage": "54", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Hepatitis B reactivation", "reactionmeddraversionpt": "21.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Hepatitis", "reactionmeddraversionpt": "21.1", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "SU YC, LIN PC, YU HC, WU CC. HEPATITIS B VIRUS REACTIVATION IN PATIENTS WITH RESOLVED HEPATITIS B VIRUS INFECTION RECEIVING CHEMOTHERAPY OR IMMUNOSUPPRESSIVE THERAPY. EUR-J-GASTROENTEROL-HEPATOL 2018?30(8):925-929.", "literaturereference_normalized": "hepatitis b virus reactivation in patients with resolved hepatitis b virus infection receiving chemotherapy or immunosuppressive therapy", "qualification": "1", "reportercountry": "TW" }, "primarysourcecountry": "TW", "receiptdate": "20181203", "receivedate": "20181203", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 15682171, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20190205" } ]

{ "abstract": "BACKGROUND\nMiller Fisher syndrome is usually a monophasic disorder. Recurrent Miller Fisher syndrome is extremely rare, and all patients with recurrences have been adults. Although the optimal treatment for Miller Fisher syndrome has yet to be established, the typical therapy includes intravenous immunoglobulin or plasma exchange. The efficacy of steroids is still debated.\n\n\nMETHODS\nWe describe two children with recurrent Miller Fisher syndrome. Episodes occurred at the age of 11.5 and 13 years in patient 1 and at the age of 8 and 13 years in patient 2.\n\n\nRESULTS\nClinical patterns of the first and recurrent episodes of Miller Fisher syndrome were overlapping. In both patients, steroids were effective in controlling clinical deterioration of Miller Fisher syndrome recurrences.\n\n\nCONCLUSIONS\nRecurrent Miller Fisher syndrome is a rare disorder that may occur in children. Our observations and a review of the literature suggest that there may be a small group of patients in whom steroids may be a therapeutic option when intravenous immunoglobulin fails to control clinical symptoms.", "affiliations": "Neurology-Immunology and Pediatric Endocrinology Unit, Department of Pediatrics, University of Siena, Siena, Italy; Department of Pediatrics, University of Siena, Siena, Italy. Electronic address: salvatore.grosso@unisi.it.;Department of Pediatrics, University of Perugia, Perugia, Italy.;Department of Pediatrics, University of Siena, Siena, Italy.;Department of Pediatrics, University of Siena, Siena, Italy.;Department of Neurological, Neurosurgical and Behavioral Sciences, University of Siena, Siena, Italy.;Department of Pediatrics, University of Siena, Siena, Italy.", "authors": "Grosso|Salvatore|S|;Verrotti|Alberto|A|;Tei|Monica|M|;Cornacchione|Sara|S|;Giannini|Fabio|F|;Balestri|Paolo|P|", "chemical_list": "D016756:Immunoglobulins, Intravenous; D007155:Immunologic Factors; D013256:Steroids", "country": "United States", "delete": false, "doi": null, "fulltext": null, "fulltext_license": null, "issn_linking": "0887-8994", "issue": "50(3)", "journal": "Pediatric neurology", "keywords": "Guillaine-Barrè syndrome; demyelination; neuroimmunology; pediatrics; steroids", "medline_ta": "Pediatr Neurol", "mesh_terms": "D000293:Adolescent; D002648:Child; D006801:Humans; D016756:Immunoglobulins, Intravenous; D007155:Immunologic Factors; D008297:Male; D019846:Miller Fisher Syndrome; D012008:Recurrence; D013256:Steroids; D016896:Treatment Outcome", "nlm_unique_id": "8508183", "other_id": null, "pages": "269-71", "pmc": null, "pmid": "24321544", "pubdate": "2014-03", "publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review", "references": null, "title": "Recurrent Miller Fisher syndrome in children.", "title_normalized": "recurrent miller fisher syndrome in children" }

[ { "companynumb": "IT-TAKEDA-2020TUS054598", "fulfillexpeditecriteria": "1", "occurcountry": "IT", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "HUMAN IMMUNOGLOBULIN G" }, "drugadditional": "3", "drugadministrationroute": "042", "drugauthorizationnumb": "125105", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNK", "drugdosagetext": "400 MILLIGRAM/KILOGRAM, QD", "drugenddate": null, "drugenddateformat": null, "drugindication": "MILLER FISHER SYNDROME", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "400", "drugstructuredosageunit": "007", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "HUMAN NORMAL IMMUNOGLOBULIN" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "HUMAN IMMUNOGLOBULIN G" }, "drugadditional": "3", "drugadministrationroute": "042", "drugauthorizationnumb": "125105", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNK", "drugdosagetext": "1 GRAM PER KILOGRAM, QD", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "HUMAN NORMAL IMMUNOGLOBULIN" } ], "patientagegroup": null, "patientonsetage": "13", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug ineffective", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Off label use", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "GROSSO S, VERROTTI A, TEI M, CORNACCHIONE S, GIANNINI F, BALESTRI P. RECURRENT MILLER FISHER SYNDROME IN CHILDREN. PEDIATRIC NEUROLOGY. 2014?50(3):269-271", "literaturereference_normalized": "recurrent miller fisher syndrome in children", "qualification": "3", "reportercountry": "IT" }, "primarysourcecountry": "IT", "receiptdate": "20201216", "receivedate": "20201216", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 18625207, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210114" } ]

{ "abstract": "We describe the characteristics of the 15 patients with fingolimod-associated progressive multifocal leukoencephalopathy (PML) identified from the Novartis data safety base and provide risk estimates for the disorder.\n\n\n\nThe Novartis safety database was searched for PML cases with a data lock point of August 31, 2017. PML classification was based on previously published criteria. The risk and incidence were estimated using the 15 patients with confirmed PML and the overall population of patients treated with fingolimod.\n\n\n\nAs of August 31, 2017, 15 fingolimod-treated patients had developed PML in the absence of natalizumab treatment in the preceding 6 months. Eleven (73%) were women and the mean age was 53 years (median: 53 years). Fourteen of the 15 patients were treated with fingolimod for >2 years. Two patients had confounding medical conditions. Two patients had natalizumab treatment. This included one patient whose last dose of natalizumab was 3 years and 9 months before the diagnosis of PML. The second patient was receiving fingolimod for 4 years and 6 months, which was discontinued to start natalizumab and was diagnosed with PML 3 months after starting natalizumab. Absolute lymphocyte counts were available for 14 of the 15 patients and none exhibited a sustained grade 4 lymphopenia (≤200 cells/μL).\n\n\n\nThe risk of PML with fingolimod in the absence of prior natalizumab treatment is low. The estimated risk was 0.069 per 1,000 patients (95% confidence interval: 0.039-0.114), and the estimated incidence rate was 3.12 per 100,000 patient-years (95% confidence interval: 1.75-5.15). Neither clinical manifestations nor radiographic features suggested any unique features of fingolimod-associated PML.", "affiliations": "From the Department of Neurology (J.R.B.), Perelman School of Medicine, University of Pennsylvania, Philadelphia; Multiple Sclerosis Centre (B.A.C.), University of California, San Francisco; University of Texas Southwestern Medical Center (B.G.), Multiple Sclerosis Program, Dallas, TX; Department of Neurology (B.H.), Klinikum Rechts der Isar, Technical University of Munich; Munich Cluster for Systems Neurology (SyNergy) (B.H.), Munich, Germany; Infectious Diseases Division (B.J.W.), Research Institute of the McGill University Health Centre, Montreal, Canada; Novartis Pharmaceuticals Corporation (V.M.D.), East Hanover, NJ; and Novartis Pharma AG (M.M.), Basel, Switzerland. joseph.berger@uphs.upenn.edu.;From the Department of Neurology (J.R.B.), Perelman School of Medicine, University of Pennsylvania, Philadelphia; Multiple Sclerosis Centre (B.A.C.), University of California, San Francisco; University of Texas Southwestern Medical Center (B.G.), Multiple Sclerosis Program, Dallas, TX; Department of Neurology (B.H.), Klinikum Rechts der Isar, Technical University of Munich; Munich Cluster for Systems Neurology (SyNergy) (B.H.), Munich, Germany; Infectious Diseases Division (B.J.W.), Research Institute of the McGill University Health Centre, Montreal, Canada; Novartis Pharmaceuticals Corporation (V.M.D.), East Hanover, NJ; and Novartis Pharma AG (M.M.), Basel, Switzerland.;From the Department of Neurology (J.R.B.), Perelman School of Medicine, University of Pennsylvania, Philadelphia; Multiple Sclerosis Centre (B.A.C.), University of California, San Francisco; University of Texas Southwestern Medical Center (B.G.), Multiple Sclerosis Program, Dallas, TX; Department of Neurology (B.H.), Klinikum Rechts der Isar, Technical University of Munich; Munich Cluster for Systems Neurology (SyNergy) (B.H.), Munich, Germany; Infectious Diseases Division (B.J.W.), Research Institute of the McGill University Health Centre, Montreal, Canada; Novartis Pharmaceuticals Corporation (V.M.D.), East Hanover, NJ; and Novartis Pharma AG (M.M.), Basel, Switzerland.;From the Department of Neurology (J.R.B.), Perelman School of Medicine, University of Pennsylvania, Philadelphia; Multiple Sclerosis Centre (B.A.C.), University of California, San Francisco; University of Texas Southwestern Medical Center (B.G.), Multiple Sclerosis Program, Dallas, TX; Department of Neurology (B.H.), Klinikum Rechts der Isar, Technical University of Munich; Munich Cluster for Systems Neurology (SyNergy) (B.H.), Munich, Germany; Infectious Diseases Division (B.J.W.), Research Institute of the McGill University Health Centre, Montreal, Canada; Novartis Pharmaceuticals Corporation (V.M.D.), East Hanover, NJ; and Novartis Pharma AG (M.M.), Basel, Switzerland.;From the Department of Neurology (J.R.B.), Perelman School of Medicine, University of Pennsylvania, Philadelphia; Multiple Sclerosis Centre (B.A.C.), University of California, San Francisco; University of Texas Southwestern Medical Center (B.G.), Multiple Sclerosis Program, Dallas, TX; Department of Neurology (B.H.), Klinikum Rechts der Isar, Technical University of Munich; Munich Cluster for Systems Neurology (SyNergy) (B.H.), Munich, Germany; Infectious Diseases Division (B.J.W.), Research Institute of the McGill University Health Centre, Montreal, Canada; Novartis Pharmaceuticals Corporation (V.M.D.), East Hanover, NJ; and Novartis Pharma AG (M.M.), Basel, Switzerland.;From the Department of Neurology (J.R.B.), Perelman School of Medicine, University of Pennsylvania, Philadelphia; Multiple Sclerosis Centre (B.A.C.), University of California, San Francisco; University of Texas Southwestern Medical Center (B.G.), Multiple Sclerosis Program, Dallas, TX; Department of Neurology (B.H.), Klinikum Rechts der Isar, Technical University of Munich; Munich Cluster for Systems Neurology (SyNergy) (B.H.), Munich, Germany; Infectious Diseases Division (B.J.W.), Research Institute of the McGill University Health Centre, Montreal, Canada; Novartis Pharmaceuticals Corporation (V.M.D.), East Hanover, NJ; and Novartis Pharma AG (M.M.), Basel, Switzerland.;From the Department of Neurology (J.R.B.), Perelman School of Medicine, University of Pennsylvania, Philadelphia; Multiple Sclerosis Centre (B.A.C.), University of California, San Francisco; University of Texas Southwestern Medical Center (B.G.), Multiple Sclerosis Program, Dallas, TX; Department of Neurology (B.H.), Klinikum Rechts der Isar, Technical University of Munich; Munich Cluster for Systems Neurology (SyNergy) (B.H.), Munich, Germany; Infectious Diseases Division (B.J.W.), Research Institute of the McGill University Health Centre, Montreal, Canada; Novartis Pharmaceuticals Corporation (V.M.D.), East Hanover, NJ; and Novartis Pharma AG (M.M.), Basel, Switzerland.", "authors": "Berger|Joseph R|JR|;Cree|Bruce A|BA|;Greenberg|Benjamin|B|;Hemmer|Bernhard|B|;Ward|Brian J|BJ|;Dong|Victor M|VM|;Merschhemke|Martin|M|", "chemical_list": "D007166:Immunosuppressive Agents; D000068876:Fingolimod Hydrochloride", "country": "United States", "delete": false, "doi": "10.1212/WNL.0000000000005529", "fulltext": "\n==== Front\nNeurology\nNeurology\nneurology\nneur\nneurology\nNEUROLOGY\nNeurology\n0028-3878\n1526-632X\nLippincott Williams & Wilkins Hagerstown, MD\n\n29669908\nNEUROLOGY2017862540\n10.1212/WNL.0000000000005529\n41\n142\nArticle\nProgressive multifocal leukoencephalopathy after fingolimod treatment\nBerger Joseph R. MD Scientific Advisory Boards:\n\nDr. Berger has served as a consultant and/or on the PML adjudication committees of Novartis, and Takeda. He also serves on the Scientific Advisory Board of NeuVir, ExcisionBio, and Inhibikase.\n\nGifts:\n\nNONE\n\nFunding for travel or speaker honoraria:\n\nDr. Berger has received honoraria from Prime Education, AcademicCME, Arcus Medica, Eisenhower Medical Center, River West Meetings, and the MS Foundation for lectures.\n\nEditorial Boards:\n\nDr. Berger serves as an editorial board member of Neurology Reviews and MS and Related Disorders\n\nPatents:\n\nNONE\n\nPublishing Royalties:\n\nPortegies P, Berger JR (Editors): HIV/AIDS and the Nervous System. In Vinken PJ, Bruyn G (Editors): Handbook of Clinical Neurology, Volume 85; Elsevier, Amsterdam, 2007.\n\nEmployment, Commercial Entity:\n\nNONE\n\nConsultancies:\n\nDr. Berger has served on a consultant to AlcimedAlcimed, Alkermes, Bayer, Biogen, EMD Serono, Genentech, Inhibikase, Novartis, and Takeda.\n\nSpeakers' Bureaus:\n\nNONE\n\nOther Activities:\n\nNONE\n\nClinical Procedures or Imaging Studies:\n\nNONE\n\nResearch Support, Commercial Entities:\n\nBiogen Teva\n\nResearch Support, Government Entities:\n\nNONE\n\nResearch Support, Academic Entities:\n\nNONE\n\nResearch Support, Foundations and Societies:\n\nNONE\n\nStock/Stock Options/Board of Directors Compensation:\n\nNONE\n\nLicense Fee Payments, Technology or Inventions:\n\nNONE\n\nRoyalty Payments, Technology or Inventions:\n\nNONE\n\nStock/Stock Options, Research Sponsor:\n\nNONE\n\nStock/Stock Options, Medical Equipment & Materials:\n\nNONE\n\nLegal Proceedings:\n\nNONE\n\nCree Bruce A. MD, PhD Scientific Advisory Boards:\n\nNONE\n\nGifts:\n\nNONE\n\nFunding for Travel or Speaker Honoraria:\n\nNONE\n\nEditorial Boards:\n\nAnnals of Neurology, editor, service concluded in 2016.\n\nPatents:\n\nNONE\n\nPublishing Royalties:\n\nNONE\n\nEmployment, Commercial Entity:\n\nNONE\n\nConsultancies:\n\nAbbvie, Biogen, EMD Serono, GeNeuro, Novartis, Sanofi Genzyme.\n\nSpeakers' Bureaus:\n\nNONE\n\nOther Activities:\n\nNONE\n\nClinical Procedures or Imaging Studies:\n\nNONE\n\nResearch Support, Commercial Entities:\n\nContracted research support (clinical trials) from Acorda, Celgene, Hoffman La Roche, MedImmune, Novartis and Teva\n\nResearch Support, Government Entities:\n\nNONE\n\nResearch Support, Academic Entities:\n\nNONE\n\nResearch Support, Foundations and Societies:\n\nNONE\n\nStock/Stock Options/Board of Directors Compensation:\n\nNONE\n\nLicense Fee Payments, Technology or Inventions:\n\nNONE\n\nRoyalty Payments, Technology or Inventions:\n\nNONE\n\nStock/Stock Options, Research Sponsor:\n\nNONE\n\nStock/Stock Options, Medical Equipment & Materials:\n\nNONE\n\nLegal Proceedings:\n\nNONE\n\nGreenberg Benjamin MD Scientific Advisory Boards:\n\nNONE\n\nGifts:\n\nNONE\n\nFunding for travel or speaker honoraria:\n\nTransverse Myelitis Association, funding for travel\n\nEditorial Boards:\n\nNONE\n\nPatents:\n\nDr. Greenberg has filed patents on the use of antibody suppression in multiple sclerosis\n\nPublishing Royalties:\n\nNONE\n\nEmployment, Commercial Entity:\n\nNONE\n\nConsultancies:\n\nNovartis, Alexion, EMD Serono\n\nSpeakers' Bureaus:\n\nNONE\n\nOther Activities:\n\nNONE\n\nClinical Procedures or Imaging Studies:\n\nNONE\n\nResearch Support, Commercial Entities:\n\nAcorda, Medimmune, Chugai, Medday\n\nResearch Support, Government Entities:\n\nNIH RO1 NS071463, Co-investigator 2012-14\n\nResearch Support, Academic Entities:\n\nUnviersity of Texas Southwestern\n\nResearch Support, Foundations and Societies:\n\nGuthy Jackson Foundation, PCORI\n\nStock/Stock Options/Board of Directors Compensation:\n\nNONE\n\nLicense Fee Payments, Technology or Inventions:\n\nNONE\n\nRoyalty Payments, Technology or Inventions:\n\nNONE\n\nStock/Stock Options, Research Sponsor:\n\nNONE\n\nStock/Stock Options, Medical Equipment & Materials:\n\nNONE\n\nLegal Proceedings:\n\nNONE\n\nHemmer Bernhard MD Scientific Advisory Boards:\n\nAdvisory Boards for F. Hoffmann-La Roche Ltd, Novartis, Bayer AG, and Genentech; he has served as DMSC member for AllergyCare\n\nGifts:\n\nMe or my institution have received speaker honoraria from Biogen Idec, Teva Neuroscience, Merck Serono, Medimmune, Novartis, Desitin, Hoffman-LaRoche\n\nFunding for travel or speaker honoraria:\n\nExcemed\n\nEditorial Boards:\n\nEditorial board member of Jama Neurology and MS Journal\n\nPatents:\n\nI hold part of two patents; one for the detection of antibodies a n d T c e l l s a g a i n s t K I R 4 . 1 i n a s u b p o p u l a t i o n o f M S p a t i e n t s a n d o n e f o r g e n e t i c d e t e r m i n a n t s o f neutralizing antibodies to interferon β\n\nPublishing Royalties:\n\nNONE\n\nEmployment, Commercial Entity:\n\nNONE\n\nConsultancies:\n\nNONE\n\nSpeakers' Bureaus:\n\nNONE\n\nOther Activities:\n\nNONE\n\nClinical Procedures or Imaging Studies:\n\nNONE\n\nResearch Support, Commercial Entities:\n\nChugai Pharmaceuticals\n\nResearch Support, Government Entities:\n\nGerman Research foundation, German Ministry of Education and Research, EU Horizon 2020, EU IMI\n\nResearch Support, Academic Entities:\n\nNONE\n\nResearch Support, Foundations and Societies:\n\nNONE\n\nStock/Stock Options/Board of Directors Compensation:\n\nNONE\n\nLicense Fee Payments, Technology or Inventions:\n\nNONE\n\nRoyalty Payments, Technology or Inventions:\n\nNONE\n\nStock/Stock Options, Research Sponsor:\n\nNONE\n\nStock/Stock Options, Medical Equipment & Materials:\n\nNONE\n\nLegal Proceedings:\n\nNONE\n\nWard Brian J. MDCM Scientific Advisory Boards:\n\nServe on expert committee for Novartis to review infectious disease complications of disease-modifying therapies\n\nGifts:\n\nNONE\n\nFunding for travel or speaker honoraria:\n\nOccasional speaker fees for talks related to infectious diseases and vaccine use in people taking of disease-modifying therapies and vaccine use\n\nEditorial Boards:\n\nNONE\n\nPatents:\n\nNONE\n\nPublishing Royalties:\n\nNONE\n\nEmployment, Commercial Entity:\n\nServe as medical officer for Medicago Inc since 2009, a biotechnology company making vaccines and monoclonal antibodies in plants (no commercial products)\n\nConsultancies:\n\nServe as an ad hoc consultant for Novartis to address questions from practitioners related to infectious disease complications of disease-modifying therapies\n\nSpeakers' Bureaus:\n\nNONE\n\nOther Activities:\n\nNONE\n\nClinical Procedures or Imaging Studies:\n\nNONE\n\nResearch Support, Commercial Entities:\n\nNONE\n\nResearch Support, Government Entities:\n\nNONE\n\nResearch Support, Academic Entities:\n\nNONE\n\nResearch Support, Foundations and Societies:\n\nNONE\n\nStock/Stock Options/Board of Directors Compensation:\n\nNONE\n\nLicense Fee Payments, Technology or Inventions:\n\nNONE\n\nRoyalty Payments, Technology or Inventions:\n\nNONE\n\nStock/Stock Options, Research Sponsor:\n\nNONE\n\nStock/Stock Options, Medical Equipment & Materials:\n\nNONE\n\nLegal Proceedings:\n\nNONE\n\nDong Victor M. MD Scientific Advisory Boards:\n\nNONE\n\nGifts:\n\nNONE\n\nFunding for Travel or Speaker Honoraria:\n\nNONE\n\nEditorial Boards:\n\nNONE\n\nPatents:\n\nNONE\n\nPublishing Royalties:\n\nNONE\n\nEmployment, Commercial Entity:\n\nNovartis Pharmaceuticals Corporation, Sr. Brand Safety Leader, 7 years\n\nConsultancies:\n\nNONE\n\nSpeakers' Bureaus:\n\nNONE\n\nOther Activities:\n\nNONE\n\nClinical Procedures or Imaging Studies:\n\nNONE\n\nResearch Support, Commercial Entities:\n\nNONE\n\nResearch Support, Government Entities:\n\nNONE\n\nResearch Support, Academic Entities:\n\nNONE\n\nResearch Support, Foundations and Societies:\n\nNONE\n\nStock/Stock Options/Board of Directors Compensation:\n\nNONE\n\nLicense Fee Payments, Technology or Inventions:\n\nNONE\n\nRoyalty Payments, Technology or Inventions:\n\nNONE\n\nStock/Stock Options, Research Sponsor:\n\nNONE\n\nStock/Stock Options, Medical Equipment & Materials:\n\nNONE\n\nLegal Proceedings:\n\nNONE\n\nMerschhemke Martin MD Scientific Advisory Boards:\n\nNONE\n\nGifts:\n\nNONE\n\nFunding for Travel or Speaker Honoraria:\n\nNONE\n\nEditorial Boards:\n\nNONE\n\nPatents:\n\nNONE\n\nPublishing Royalties:\n\nNONE\n\nEmployment, Commercial Entity:\n\nEmployee of Novartis Pharma AG, Global Program Clinical Head, 7 years. As an employee of Novartis Pharma AG, I also hold stock and stock options from Novartis Pharma AG\n\nConsultancies:\n\nNONE\n\nSpeakers' Bureaus:\n\nNONE\n\nOther Activities:\n\nNONE\n\nClinical Procedures or Imaging Studies:\n\nNONE\n\nResearch Support, Commercial Entities:\n\nNONE\n\nResearch Support, Government Entities:\n\nNONE\n\nResearch Support, Academic Entities:\n\nNONE\n\nResearch Support, Foundations and Societies:\n\nNONE\n\nStock/Stock Options/Board of Directors Compensation:\n\nNONE\n\nLicense Fee Payments, Technology or Inventions:\n\nNONE\n\nRoyalty Payments, Technology or Inventions:\n\nNONE\n\nStock/Stock Options, Research Sponsor:\n\nNONE\n\nStock/Stock Options, Medical Equipment & Materials:\n\nNONE\n\nLegal Proceedings:\n\nNONE\n\nFrom the Department of Neurology (J.R.B.), Perelman School of Medicine, University of Pennsylvania, Philadelphia; Multiple Sclerosis Centre (B.A.C.), University of California, San Francisco; University of Texas Southwestern Medical Center (B.G.), Multiple Sclerosis Program, Dallas, TX; Department of Neurology (B.H.), Klinikum Rechts der Isar, Technical University of Munich; Munich Cluster for Systems Neurology (SyNergy) (B.H.), Munich, Germany; Infectious Diseases Division (B.J.W.), Research Institute of the McGill University Health Centre, Montreal, Canada; Novartis Pharmaceuticals Corporation (V.M.D.), East Hanover, NJ; and Novartis Pharma AG (M.M.), Basel, Switzerland.\nCorrespondence Dr. Berger joseph.berger@uphs.upenn.edu\nThe Article Processing Charge was funded by Novartis Pharmaceuticals Corporation.\n\nGo to Neurology.org/N for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article.\n\n15 5 2018\n15 5 2018\n90 20 e1815e1821\n13 11 2017\n27 2 2018\nCopyright © 2018 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.\n2018\nAmerican Academy of Neurology\nThis is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND), which permits downloading and sharing the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.\n\nObjective\n\nWe describe the characteristics of the 15 patients with fingolimod-associated progressive multifocal leukoencephalopathy (PML) identified from the Novartis data safety base and provide risk estimates for the disorder.\n\nMethods\n\nThe Novartis safety database was searched for PML cases with a data lock point of August 31, 2017. PML classification was based on previously published criteria. The risk and incidence were estimated using the 15 patients with confirmed PML and the overall population of patients treated with fingolimod.\n\nResults\n\nAs of August 31, 2017, 15 fingolimod-treated patients had developed PML in the absence of natalizumab treatment in the preceding 6 months. Eleven (73%) were women and the mean age was 53 years (median: 53 years). Fourteen of the 15 patients were treated with fingolimod for >2 years. Two patients had confounding medical conditions. Two patients had natalizumab treatment. This included one patient whose last dose of natalizumab was 3 years and 9 months before the diagnosis of PML. The second patient was receiving fingolimod for 4 years and 6 months, which was discontinued to start natalizumab and was diagnosed with PML 3 months after starting natalizumab. Absolute lymphocyte counts were available for 14 of the 15 patients and none exhibited a sustained grade 4 lymphopenia (≤200 cells/μL).\n\nConclusions\n\nThe risk of PML with fingolimod in the absence of prior natalizumab treatment is low. The estimated risk was 0.069 per 1,000 patients (95% confidence interval: 0.039–0.114), and the estimated incidence rate was 3.12 per 100,000 patient-years (95% confidence interval: 1.75–5.15). Neither clinical manifestations nor radiographic features suggested any unique features of fingolimod-associated PML.\n\nSTATUSONLINE-ONLY\nOPEN-ACCESSTRUE\n==== Body\nProgressive multifocal leukoencephalopathy (PML) is a rare opportunistic infection of the CNS caused by reactivation of a latent John Cunningham virus (JCV), with a prevalence of 0.2 cases per 100,000 persons in the general population.1 In 2005, PML was confirmed in 3 patients participating in natalizumab clinical trials of multiple sclerosis (MS)2,3 and Crohn disease,4 disorders that were not previously associated with PML. As of August 2017, 749 confirmed cases of PML associated with natalizumab have been reported5 and, further, in 5 dimethyl fumarate–treated patients with MS.6 This has raised the possibility that there has been an increased risk of PML in patients with MS treated with immunosuppressive or immunomodulatory agents.\n\nFingolimod is a sphingosine 1-phosphate receptor modulator approved for the treatment of relapsing forms of MS. Fingolimod prevents the egress of T and B lymphocytes from lymph nodes and reduces the infiltration of autoaggressive cells into the CNS.7,8\n\nAlthough peripheral blood lymphocyte counts declined by 73% from baseline values within 1 month of drug initiation,9,10 consistent with the pharmacodynamic action of fingolimod, serious or opportunistic infections have only been infrequently observed in the postmarketing setting. To date, no correlation has been shown between absolute lymphocyte counts and the incidence of serious or opportunistic infections. Since 2015, PML cases not attributed to prior exposure to immunosuppressants have been reported in fingolimod-treated patients. The US prescribing information was subsequently updated to include opportunistic infections including PML.11 Herein, we describe the characteristics of 15 PML cases reported in fingolimod-treated patients with MS.\n\nMethods\n\nThe Novartis safety database was searched for PML cases using the following search terms (MedDRA [Medical Dictionary for Regulatory Activities], version 19.1) with a data lock point of August 31, 2017: progressive multifocal leukoencephalopathy, leukoencephalopathy, leukoencephalomyelitis, and JC virus granule cell neuronopathy. The PML cases were classified as “definite,” “probable,” “possible,” or “not PML” based on the criteria presented by Berger et al. in 2014,12 by an adjudication committee comprising experts in MS and PML. This classification is based on JCV DNA PCR status of CSF, MRI findings, and clinical presentation.\n\nOverall patient exposure estimates were determined based on a combination of patient exposure to fingolimod in clinical trials together with an estimate of postmarketing patient exposure (which is calculated based on worldwide sales volume in kilograms of active substance sold during the period and the defined daily dose of 0.5 mg).\n\nThe incidence of PML in patients treated with fingolimod was estimated using the 15 confirmed PML cases and an overall population of patients treated with fingolimod. Patient characteristics were compiled based on the pharmacovigilance reports from the treating physicians held in the Novartis safety database, and patient identifiers are not revealed.\n\nData availability\n\nThese data are not from a clinical trial or specific study setup. It is rather based on postmarketing spontaneous reports made to Novartis in the context of routine pharmacovigilance. This reporting comes from various regions/countries with their respective data privacy laws. Data available in the Novartis safety database have been used to describe the carefully deidentified individual cases, and as such, no further data will be shared in either a repository or on request.\n\nResults\n\nIn total, 15 confirmed PML cases—12 “definite” and 3 “probable”—for which prior immunotherapy is not implicated, were identified in the real-world setting. Based on data from 15 confirmed PML cases associated with fingolimod treatment alone, the estimated risk is 0.069 per 1,000 patients (95% confidence interval [CI]: 0.039–0.114) and the estimated incidence rate is 3.12 per 100,000 patient-years (95% CI: 1.75–5.15). Details of the clinical features of the 15 PML cases are shown in the table.\n\nTable Case details of patients with MS who developed PML after fingolimod treatment\n\nDemographics and baseline characteristics\n\nThe patients were geographically dispersed across Europe (n = 6), North America (n = 5), and Asia (n = 4). Of the 15 patients, 11 were women. The mean patient age was 53 years (median: 53 years) and 5 patients were younger than 50 years. The duration of MS in these patients ranged from 4 to 35 years (considering those with known year of MS onset). Of the 15 patients with PML, 2 presented with confounding medical conditions (one with previous cancer and one patient with ulcerative colitis with prior immunosuppressive therapy). In addition, there were 2 patients who had received therapy with natalizumab; however, the contributory role of fingolimod in the occurrence of PML could not be excluded in these cases. The first patient had previous natalizumab exposure for 10 months, which was discontinued for 7 months, and then the patient received fingolimod treatment for 38 months before PML diagnosis. The second patient was receiving fingolimod for 4 years, 6 months, which was discontinued to start natalizumab and was diagnosed with PML 3 months later. Fourteen of the 15 patients were exposed to fingolimod for >2 years. Based on the available reported absolute lymphocyte counts in 14 of 15 patients, 4 of the patients exhibited grade 4 lymphopenia (≤200 cells/μL). Previous MS treatments included natalizumab, interferons, corticosteroids, and glatiramer acetate, with no clinically identifiable patterns.\n\nVirologic characteristics\n\nTo date, there is only limited sequence information on the JCVs associated with PML in fingolimod-treated patients with MS who developed PML.\n\nPML clinical features and diagnosis\n\nHeralding manifestations of PML at the time of clinical presentations included walking instability, weakness, memory problems, confusion, dysarthria, visual hallucinations, cognitive impairment, speech disturbances, concentration deficits, and visual impairment. One patient was clinically asymptomatic at presentation, and the disorder was diagnosed radiographically. No identifiable pattern was observed in clinical symptoms at presentation.\n\nBrain MRIs were consistent with PML in 13 of the 15 cases and showed varying presentations, ranging from few but extending lesions to multiple lesions extending into adjacent lobes, cortical, subcortical, and juxtacortical regions, and sometimes ill-defined lesions, described with and without microcysts. Some images showed strong hyperintense diffusion-weighted imaging signals, whereas others were without clear diffusion signals.\n\nPCR results for JCV DNA in the CSF were positive in all 15 patients when tested at local laboratories and/or at the NIH reference laboratory (Bethesda, MD). Serology for serum JCV antibodies was reported for 8 of the 15 patients and was positive in all.\n\nTreatment and clinical outcome\n\nTreatment with fingolimod was discontinued in all patients, and subsequent therapies for PML included mefloquine, mirtazapine, and cidofovir in varying combinations. Three of the PML cases were fatal. Most patients were reported to be clinically stable or with slightly improving neurologic functions or with deficits including aphasia, mobility, and cognition.\n\nDiscussion\n\nIn total, 15 patients with PML occurring in association with fingolimod administration alone were identified in the Novartis safety database, including 12 “definite” and 3 “probable” cases, by August 2017. This included 6 cases that have been published in the literature.13–18 The overall rate of PML with fingolimod treatment is estimated to be <1:10,000 patients, which was considered low risk in a recent article that classified the risk of PML with current disease-modifying therapies.19 The current estimated risk of PML with fingolimod treatment is 0.069 (95% CI: 0.039–0.114) per 1,000 patients and the incidence rate is 3.12/100,000 patient-years.\n\nThere are limitations for these risk estimates in that they are solely based on the PML cases spontaneously reported to Novartis from the postmarketing setting. Another potential limitation is the estimate of patient exposure data, which are derived from sales data. PML is a rare, serious opportunistic infection with high awareness in the MS community; thus, the probability of physicians reporting these cases is good. The reporting rate over time has remained constant, thus suggesting that cases of PML are being reported.\n\nIn a recent review,19 the risk of PML stratified by various disease-modifying therapies used in patients with MS suggested that natalizumab is associated with a significantly higher risk of PML. Fingolimod and dimethyl fumarate are associated with significantly lower risks. Alemtuzumab, mitoxantrone, rituximab, and teriflunomide have a potential risk of PML because all of these agents are associated with the risk of PML when used in treatment regimens/indications other than MS or have a related compound with which PML has been observed. For newer compounds, such as daclizumab and ocrelizumab, clinical experience is very limited and the associated PML risk is unknown. The current risk of PML with fingolimod is very low; to date, only 15 cases have been reported. Moreover, the few cases observed and evaluated so far do not allow the identification of any evidence-based specific guidance to form monitoring and risk-mitigation strategies for fingolimod. However, certain risk mitigation strategies have been proposed for other drugs with a larger number of such cases or a potentially clearer correlation with their mode of action, such as routine JCV antibody testing or specific lymphocyte cutoffs. However, the value of such guidance systems and their ability to prevent additional PML cases is yet to be proven. So far, the risk stratification algorithm has not led to any marked reduction in the incidence of PML in natalizumab-treated patients.20 Another previous report suggested that, although a decrease in the incidence of PML has not been noted, the rate of incidence increase has certainly reduced significantly between 2013 and 2016, after the introduction of the Stratify JCV assay.21 Nevertheless, JCV antibody status should be retested regularly considering the false-negative rates and the potential for seroconversion.22,23\n\nThe number of PML cases reported so far with fingolimod is too low to trigger any specific interventions at this point in time. Guidelines that are not evidence-based may result in an additional burden for patients with uncertain benefits, including the risk of inappropriate modification of an effective MS therapy, which in itself carries the risk of increasing morbidity in such patients. At present, no PML risk stratification methodology has been identified for patients treated with fingolimod. However, risk mitigation is focused on increased awareness and education of patients and prescribers regarding such cases because, in most instances, early diagnosis and appropriate management are key to improved therapeutic outcomes.\n\nThe clinical signs and symptoms of PML often resemble those observed with an MS relapse; however, in contrast to an MS relapse, these tend to be slowly and persistently progressive in nature. Physicians should keep this in mind when investigating patients for PML and must look for features that distinguish PML from other differential diagnoses including MS. In a PML case series consisting of 28 patients,24 typical clinical presentation included neurobehavioral, motor, language, and visual symptoms, with cognitive changes being more prominent. Acute or subacute cognitive changes, language disturbances, and seizures should serve as “red flags” for the possibility of PML. Optic neuritis and myelopathy would not be anticipated as clinical manifestations of PML.\n\nMRI scans offer a sensitive tool in the diagnosis of PML. Typical PML lesions are diffuse, subcortical, and located exclusively in the white matter. These lesions appear as single or multiple hyperintense areas in T2-weighted images, which become confluent and large with disease progression. MRI contrast enhancement is believed to be minimal or absent in PML25; however, in AIDS-associated PML, 10% of patients exhibited contrast enhancement on CT scans and 15% on MRI with gadolinium.26 In natalizumab-associated PML, 43% of cases showed gadolinium contrast enhancement at the time of diagnosis.24 Although contrast enhancement alone cannot be used as a feature to distinguish an MS relapse from PML, patterns of contrast enhancement, the nature and location of the lesions, and the presence of a dark rim around the lesions on susceptibility weighted imaging or gradient echo imaging may be helpful in distinguishing the demyelinating lesions of PML from those of MS.27,28\n\nAs of August 2017, approximately 217,000 patients have been treated with fingolimod in both clinical trials and postmarketing settings, and the total patient exposure exceeds 480,000 patient-years. Although the risk of PML with fingolimod treatment is considered very low, vigilance toward PML is required for all patients irrespective of the low risk. The current understanding of the mechanism of action of fingolimod does not provide a convincing causal link between fingolimod treatment and the incidence of PML. Fingolimod has been shown to prevent the egress of CCR7+ve naive T cells and central memory T cells from lymph nodes, sparing CCR7−ve effector memory T cells.29 The redistribution of CD4+ central memory T cells from circulation to lymphatic organs may contribute to the development of PML. In some cases, because of its partial sequestration of effector memory T cells, fingolimod may have a contributory role to other factors in reducing immune response to JCV reactivation. Isolating and fully characterizing the viruses in cases of fingolimod-associated PML may assist in understanding the disease pathogenesis with fingolimod.\n\nBased on available data, there appear to be no clinically or radiographically unique features of fingolimod-associated PML. The sex distribution is concordant with the overall fingolimod-treated population. Ten of the 15 patients were older than 50 years at the time of PML diagnosis. Although an exact relationship with fingolimod treatment duration cannot be elucidated, all 15 cases occurred after 18 months or more of treatment. There appears to be no correlation with profound lymphopenia and lymphocyte subsets (CD4, CD8, and CD4/8 ratios) in fingolimod-treated patients, and this is not believed to be informative of PML risk. Treating physicians should be vigilant for signs and symptoms suggestive of PML in all patients who are being treated with fingolimod. As soon as PML is suspected, the drug should be discontinued until it has been ruled out. Early diagnosis is critical for better clinical outcomes. Unfortunately, there is no established treatment for PML,30 and at this point of time, no treatment recommendations can be made based on the limited number of cases seen.\n\nAcknowledgment\n\nThe authors thank Sreelatha Komatireddy (Novartis Healthcare Pvt. Ltd., Hyderabad, India) for assistance with formatting the manuscript.\n\nAuthor contributions\n\nAll authors contributed to the design, data collection, data analysis, and interpretation, and provided critical review during the preparation of the manuscript. All authors edited the manuscript for intellectual content, provided guidance during manuscript development, and approved the final version submitted for publication. The final responsibility for the content lies with the authors.\n\nStudy funding\n\nNo targeted funding reported.\n\nDisclosure\n\nJ. Berger reports grants from Biogen and TEVA; personal fees from Biogen, Genentech/Roche, Genzyme, Millennium/Takeda, Novartis, Inhibikase, Excision Bio, Roche, Amgen, AstraZeneca, Alkermes, and Bayer. B. Cree reports personal fees from Biogen, EMD Serono, GeNeuro, Novartis, and Sanofi Genzyme. B. Greenberg reports personal fees from Novartis, Alexion; grants from MedImmune, Chugai, and Genentech. B. Hemmer reports grants from Chugai, Roche, and MedImmune; personal fees from Roche and Allergy Therapeutica; personal fees and nonfinancial support from Biogen, Merck, Bayer, and Teva. He was funded by the German MS Competence Network, the Transregional Research Center TR118, and the EU project Multiple MS. B. Ward reports personal fees from Novartis. V. Dong is an employee of Novartis. M. Merschhemke is an employee of Novartis. Go to Neurology.org/N for full disclosures.\n\nGlossary\n\nCI confidence interval\n\nJCV John Cunningham virus\n\nMS multiple sclerosis\n\nPML progressive multifocal leukoencephalopathy\n==== Refs\nReferences\n\n1. Palazzo E , Yahia SA Progressive multifocal leukoencephalopathy in autoimmune diseases. Joint Bone Spine 2012;79 :351–355.22281228\n2. Kleinschmidt-DeMasters BK , Tyler KL Progressive multifocal leukoencephalopathy complicating treatment with natalizumab and interferon beta-1a for multiple sclerosis. N Engl J Med 2005;353 :369–374.15947079\n3. Langer-Gould A , Atlas SW , Green AJ , Bollen AW , Pelletier D Progressive multifocal leukoencephalopathy in a patient treated with natalizumab. N Engl J Med 2005;353 :375–381.15947078\n4. Van Assche G , Van Ranst M , Sciot R , et al Progressive multifocal leukoencephalopathy after natalizumab therapy for Crohn's disease. N Engl J Med 2005;353 :362–368.15947080\n5. Tysabri Safety Update [online]. Available at: medinfo.biogen.com/secure/download?doc=workspace%3A%2F%2FSpacesStore%2Fa22baae1-7220-416c-8c2c-28c42cdacff8&type=pmldoc&path=null&dpath=null&mimeType=null&Continue=Continue. Accessed July 21, 2017.\n6. Biogen. Tecfidera (Dimethyl Fumarate): PML Case Reports. Available at: medinfo.biogen.com. Accessed January 9, 2017.\n7. Brinkmann V , Davis MD , Heise CE , et al The immune modulator FTY720 targets sphingosine 1-phosphate receptors. J Biol Chem 2002;277 :21453–21457.11967257\n8. Mandala S , Hajdu R , Bergstrom J , et al Alteration of lymphocyte trafficking by sphingosine-1-phosphate receptor agonists. Science 2002;296 :346–349.11923495\n9. Cohen JA , Barkhof F , Comi G , et al Oral fingolimod or intramuscular interferon for relapsing multiple sclerosis. N Engl J Med 2010;362 :402–415.20089954\n10. Kappos L , Radue EW , O'Connor P , et al A placebo-controlled trial of oral fingolimod in relapsing multiple sclerosis. N Engl J Med 2010;362 :387–401.20089952\n11. GILENYA [prescribing information]. Available at: www.pharma.us.novartis.com/product/pi/pdf/gilenya.pdf. Accessed May 18, 2017.\n12. Berger JB Progressive multifocal leukoencephalopathy. In: Tselis AC ,Booss J , editors. Handbook of Clinical Neurology. Amsterdam: Elsevier B.V.; 2014:357–376.\n13. Gyang TV , Hamel J , Goodman AD , Gross RA , Samkoff L Fingolimod-associated PML in a patient with prior immunosuppression. Neurology 2016;86 :1843–1845.27164718\n14. Calzado G , Virgós T , Bullejos M , et al Progressive multifocal leukoencephalopathy associated with fingolimob use in a patient with multiple sclerosis without previous exposure to immunosuppressant drugs. Eur J Hosp Pharm 2016;23 :A156.\n15. Kume K , Takada T , Kawakita R , et al A case of progressive multifocal leukoencephalopathy in a patient who was receiving fingolimod. Neurol Ther 2016;33 :S253.\n16. Nakahara J , Kufukihara K , Tanikawa M , et al Third Japanese case of fingolimod-associated PML in natalizumab-naive MS: coincidence or alarm bell? (P762). Mult Scler J 2017;23 (Suppl 3 ):382–3.\n17. Nishiyama S , Misu T , Shishido-Hara Y , et al Fingolimod-associated PML with mild IRIS in MS. Neurol Neuroimmunol Neuroinflamm 2018;5 :e415.29725611\n18. Rossi F , Turazzini M , Ricci S , et al Progressive multifocal leucoencephalopathy in patient with fingolimod treatment: one-year follow-up. Mult Scler J 2017;23 :680–975.\n19. Berger JR Classifying PML risk with disease modifying therapies. Mult Scler Relat Disord 2017;12 :59–63.28283109\n20. Cutter GR , Stuve O Does risk stratification decrease the risk of natalizumab-associated PML? Where is the evidence? Mult Scler 2014;20 :1304–1305.24812045\n21. Campagnolo D , Dong Q , Lee L , Ho PR , Amarante D , Koendgen H Statistical analysis of PML incidences of natalizumab-treated patients from 2009 to 2016: outcomes after introduction of the Stratify JCV® DxSelect™ antibody assay. J Neurovirol 2016;22 :880–881.27730447\n22. Gorelik L , Lerner M , Bixler S , et al Anti-JC virus antibodies: implications for PML risk stratification. Ann Neurol 2010;68 :295–303.20737510\n23. Outteryck O , Zephir H , Salleron J , et al JC-virus seroconversion in multiple sclerosis patients receiving natalizumab. Mult Scler 2014;20 :822–829.24072722\n24. Clifford DB , De Luca A , Simpson DM , Arendt G , Giovannoni G , Nath A Natalizumab-associated progressive multifocal leukoencephalopathy in patients with multiple sclerosis: lessons from 28 cases. Lancet Neurol 2010;9 :438–446.20298967\n25. Sahraian MA , Radue EW , Eshaghi A , Besliu S , Minagar A Progressive multifocal leukoencephalopathy: a review of the neuroimaging features and differential diagnosis. Eur J Neurol 2012;19 :1060–1069.22136455\n26. Berger JR , Pall L , Lanska D , Whiteman M Progressive multifocal leukoencephalopathy in patients with HIV infection. J Neurovirol 1998;4 :59–68.9531012\n27. Yousry TA , Pelletier D , Cadavid D , et al Magnetic resonance imaging pattern in natalizumab-associated progressive multifocal leukoencephalopathy. Ann Neurol 2012;72 :779–787.23280794\n28. Hodel J , Outteryck O , Verclytte S , et al Brain magnetic susceptibility changes in patients with natalizumab-associated progressive multifocal leukoencephalopathy. AJNR Am J Neuroradiol 2015;36 :2296–2302.26316568\n29. Mehling M , Brinkmann V , Antel J , et al FTY720 therapy exerts differential effects on T cell subsets in multiple sclerosis. Neurology 2008;71 :1261–1267.18852441\n30. Williamson EML , Berger JR Diagnosis and treatment of progressive multifocal leukoencephalopathy associated with multiple sclerosis therapies. Neurotherapeutics 2017;14 :961–973.28913726\n\n", "fulltext_license": "CC BY-NC-ND", "issn_linking": "0028-3878", "issue": "90(20)", "journal": "Neurology", "keywords": null, "medline_ta": "Neurology", "mesh_terms": "D000368:Aged; D001921:Brain; D004185:Disability Evaluation; D005260:Female; D000068876:Fingolimod Hydrochloride; D005500:Follow-Up Studies; D006801:Humans; D007166:Immunosuppressive Agents; D007968:Leukoencephalopathy, Progressive Multifocal; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D016896:Treatment Outcome", "nlm_unique_id": "0401060", "other_id": null, "pages": "e1815-e1821", "pmc": null, "pmid": "29669908", "pubdate": "2018-05-15", "publication_types": "D016428:Journal Article", "references": "11923495;15947080;28913726;24072722;25015495;20298967;22281228;20089952;26316568;9531012;27164718;28283109;15947079;27730447;24812045;20737510;15947078;22136455;20089954;23280794;29725611;18852441;11967257", "title": "Progressive multifocal leukoencephalopathy after fingolimod treatment.", "title_normalized": "progressive multifocal leukoencephalopathy after fingolimod treatment" }

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Progressive multifocal leukoencephalopathy after fingolimod treatment.. 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Progressive multifocal leukoencephalopathy after fingolimod treatment.. 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Progressive multifocal leukoencephalopathy after fingolimod treatment.. 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Progressive multifocal leukoencephalopathy after fingolimod treatment.. 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Progressive multifocal leukoencephalopathy after fingolimod treatment.. 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Progressive multifocal leukoencephalopathy after fingolimod treatment.. 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Progressive multifocal leukoencephalopathy after fingolimod treatment.. 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{ "abstract": "Mycosis fungoides is the most common subtype of primary cutaneous lymphoma and has several clinical variants. We report a 74-year-old man presenting with an acquired palmoplantar keratoderma initially diagnosed and treated as psoriasis with suboptimal improvement. Several months later the patient developed patches and plaques that were histologically consistent with mycosis fungoides. These lesions were ameliorated with the treatment of the underlying mycosis fungoides and the palmoplantar keratoderma resolved promptly with radiotherapy. This case highlights the importance of considering mycosis fungoides as an infrequent but serious cause of acquired palmoplantar keratoderma.", "affiliations": "Department of Dermatology, Royal Perth Hospital, Perth, Western Australia, Australia.", "authors": "Kim|Janet|J|;Foster|Rachael|R|;Lam|Minh|M|;Kumarasinghe|Sujith Prasad|SP|", "chemical_list": null, "country": "Australia", "delete": false, "doi": "10.1111/ajd.12155", "fulltext": null, "fulltext_license": null, "issn_linking": "0004-8380", "issue": "56(1)", "journal": "The Australasian journal of dermatology", "keywords": "T-cell lymphoma; cutaneous lymphoma; mycosis fungoides; palmoplantar hyperkeratosis; palmoplantar keratoderma", "medline_ta": "Australas J Dermatol", "mesh_terms": "D000368:Aged; D003937:Diagnosis, Differential; D006801:Humans; D007645:Keratoderma, Palmoplantar; D008297:Male; D009182:Mycosis Fungoides; D011565:Psoriasis", "nlm_unique_id": "0135232", "other_id": null, "pages": "49-51", "pmc": null, "pmid": "24575903", "pubdate": "2015-02", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Mycosis fungoides: an important differential diagnosis for acquired palmoplantar keratoderma.", "title_normalized": "mycosis fungoides an important differential diagnosis for acquired palmoplantar keratoderma" }

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"literaturereference": "KIM J, FOSTER R, LAM M, KUMARASINGHE SP. MYCOSIS FUNGOIDES: AN IMPORTANT DIFFERENTIAL DIAGNOSIS FOR ACQUIRED PALMOPLANTAR KERATODERMA. AUSTRALASIAN JOURNAL OF DERMATOLOGY 2015;56(1):49-51. DOI: 10.1111/AJD.12155", "literaturereference_normalized": "mycosis fungoides an important differential diagnosis for acquired palmoplantar keratoderma", "qualification": "3", "reportercountry": "AU" }, "primarysourcecountry": "AU", "receiptdate": "20150325", "receivedate": "20150325", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 10953718, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20150721" } ]

{ "abstract": "OBJECTIVE\nTo investigate the impact of intravitreal chemotherapy on intraocular pressure (IOP) in children with retinoblastoma.\n\n\nMETHODS\nThis was a retrospective study of 10 eyes of 10 patients with retinoblastoma (7 males, 3 females, mean age: 33.6 ± 9.4 months) with vitreous seeding injected with intravitreal melphalan and topotecan. IOP was measured with Tonopen (Reichert, Inc., Buffalo, NY) at baseline prior to injecting and then repeatedly following each intravitreal injection.\n\n\nRESULTS\nMean pre-injection IOP was 8.2 ± 2.3 mm Hg (range: 4 to 12 mm Hg). Mean IOP 1 to 30 seconds after intravitreal melphalan (first injection) was 45.4 ± 14.3 mm Hg. The IOP of 89.5% of patients declined to 29 mm Hg or less in a mean 153.3 ± 97.5 seconds. Mean IOP 1 to 30 seconds after intravitreal topotecan (second injection) was 44.5 ± 11.0 mm Hg, which decreased to 31.0 ± 5.0 mm Hg by 150 seconds after injection. No significant relationship was found between age and post-injection IOP elevation. IOP exceeded the calculated mean arterial perfusion pressure in four encounters.\n\n\nCONCLUSIONS\nIntravitreal chemotherapy caused a transient rise in IOP. Post-injection IOP elevations can reach levels that may exceed mean arterial pressure. [J Pediatr Ophthalmol Strabismus. 2017;54(3):185-190.].", "affiliations": null, "authors": "Karl|Matthew D|MD|;Francis|Jasmine H|JH|;Iyer|Saipriya|S|;Marr|Brian|B|;Abramson|David H|DH|", "chemical_list": "D018906:Antineoplastic Agents, Alkylating; D059004:Topoisomerase I Inhibitors; D019772:Topotecan; D008558:Melphalan", "country": "United States", "delete": false, "doi": "10.3928/01913913-20161116-01", "fulltext": null, "fulltext_license": null, "issn_linking": "0191-3913", "issue": "54(3)", "journal": "Journal of pediatric ophthalmology and strabismus", "keywords": null, "medline_ta": "J Pediatr Ophthalmol Strabismus", "mesh_terms": "D000293:Adolescent; D000328:Adult; D018906:Antineoplastic Agents, Alkylating; D004305:Dose-Response Relationship, Drug; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D007429:Intraocular Pressure; D058449:Intravitreal Injections; D008297:Male; D008558:Melphalan; D009366:Neoplasm Seeding; D019572:Retinal Neoplasms; D012175:Retinoblastoma; D012189:Retrospective Studies; D059004:Topoisomerase I Inhibitors; D019772:Topotecan; D016896:Treatment Outcome; D014822:Vitreous Body; D055815:Young Adult", "nlm_unique_id": "7901143", "other_id": null, "pages": "185-190", "pmc": null, "pmid": "28092395", "pubdate": "2017-05-01", "publication_types": "D016428:Journal Article", "references": "25616769;24731161;18775528;8976706;18026202;22459105;24407202;16647122;16258092;24819859;10926989;22694968;17057819;21620994;20010243;4004614;25650712;21277463;17573861;13890561;9479511;4088631;22858038;25092962;24043335;3369998;21150677;24187047;26378741;18040242;68942;23044940;25791262;25808017;25795478;11318296;23093311;23740960", "title": "Intraocular Pressure Changes Following Intravitreal Melphalan and Topotecan for the Treatment of Retinoblastoma With Vitreous Seeding.", "title_normalized": "intraocular pressure changes following intravitreal melphalan and topotecan for the treatment of retinoblastoma with vitreous seeding" }

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INTRAOCULAR PRESSURE CHANGES FOLLOWING INTRAVITREAL MELPHALAN AND TOPOTECAN FOR THE TREATMENT OF RETINOBLASTOMA WITH VITREOUS SEEDING. 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INTRAOCULAR PRESSURE CHANGES FOLLOWING INTRAVITREAL MELPHALAN AND TOPOTECAN FOR THE TREATMENT OF RETINOBLASTOMA WITH VITREOUS SEEDING. 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"primarysource": { "literaturereference": "KARL MD, FRANCIS JH, IYER S, MARR B, ABRAMSON DH.. INTRAOCULAR PRESSURE CHANGES FOLLOWING INTRAVITREAL MELPHALAN AND TOPOTECAN FOR THE TREATMENT OF RETINOBLASTOMA WITH VITREOUS SEEDING. 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{ "abstract": "This work aims to facilitate diagnosing Aspergillus appendicitis, which can be missed clinically due to its rarity, by proposing a clinical pentad for Aspergillus appendicitis based on literature review and one new case. The currently reported case of pathologically-proven Aspergillus appendicitis was identified by computerized search of pathology database at William Beaumont Hospital, 1999-2014. Prior cases were identified by computerized literature search. Among 10980 pathology reports of pathologically-proven appendicitis, one case of Aspergillus appendicitis was identified (rate = 0.01%). A young boy with profound neutropenia, recent chemotherapy, and acute myelogenous leukemia presented with right lower quadrant pain, pyrexia, and generalized malaise. Abdominal computed tomography scan showed a thickened appendiceal wall and periappendiceal inflammation, suggesting appendicitis. Emergent laparotomy showed an inflamed, thickened appendix, which was resected. The patient did poorly postoperatively with low-grade-fevers while receiving antibacterial therapy, but rapidly improved after initiating amphotericin therapy. Microscopic examination of a silver stain of the appendectomy specimen revealed fungi with characteristic Aspergillus morphology, findings confirmed by immunohistochemistry. Primary Aspergillus appendicitis is exceptionally rare, with only 3 previously reported cases. All three cases presented with (1)-neutropenia, (2)-recent chemotherapy, (3)-acute leukemia, and (4)-suspected appendicitis; (5)-the two prior cases initially treated with antibacterial therapy, fared poorly before instituting anti-Aspergillus therapy. The current patient satisfied all these five criteria. Based on these four cases, a clinical pentad is proposed for Aspergillus appendicitis: clinically-suspected appendicitis, neutropenia, recent chemotherapy, acute leukemia, and poor clinical response if treated solely by antibacterial/anti-candidial therapy. Patients presenting with this proposed pentad may benefit from testing for Aspergillus infection by silver-stains/immunohistochemistry and considering empirical anti-Aspergillus therapy pending a tissue diagnosis.", "affiliations": "Mihajlo Gjeorgjievski, Mitchell S Cappell, Division of Gastroenterology and Hepatology, William Beaumont Hospital, Royal Oak, MI 48073, United States.;Mihajlo Gjeorgjievski, Mitchell S Cappell, Division of Gastroenterology and Hepatology, William Beaumont Hospital, Royal Oak, MI 48073, United States.;Mihajlo Gjeorgjievski, Mitchell S Cappell, Division of Gastroenterology and Hepatology, William Beaumont Hospital, Royal Oak, MI 48073, United States.", "authors": "Gjeorgjievski|Mihajlo|M|;Amin|Mitual B|MB|;Cappell|Mitchell S|MS|", "chemical_list": "D000935:Antifungal Agents", "country": "United States", "delete": false, "doi": "10.3748/wjg.v21.i44.12713", "fulltext": null, "fulltext_license": null, "issn_linking": "1007-9327", "issue": "21(44)", "journal": "World journal of gastroenterology", "keywords": "Acute myelocytic leukemia; Appendicitis; Aspergillosis; Aspergillus appendicitis; Chemotherapy; Fungal appendicitis; Neutropenia", "medline_ta": "World J Gastroenterol", "mesh_terms": "D000935:Antifungal Agents; D001062:Appendectomy; D001064:Appendicitis; D001228:Aspergillosis; D001230:Aspergillus; D001431:Bacteriological Techniques; D002648:Child; D006801:Humans; D008297:Male; D012307:Risk Factors; D014057:Tomography, X-Ray Computed; D016896:Treatment Outcome", "nlm_unique_id": "100883448", "other_id": null, "pages": "12713-21", "pmc": null, "pmid": "26640349", "pubdate": "2015-11-28", "publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review", "references": "13630116;24767095;16504141;16758192;17180588;19597008;19850903;20618330;21095116;20636423;21985304;22622518;23109838;23196957;3277825;2299371;2218411;2267490;2081387;1396907;1401213;8072452;7756482;8879787;9631905;10631859;10941357;11886192;12852516;709532;7259499;6948978;6696356;3966697;22864935;24050103;24034232;24758620;15576478;16206084", "title": "Characteristic clinical features of Aspergillus appendicitis: Case report and literature review.", "title_normalized": "characteristic clinical features of aspergillus appendicitis case report and literature review" }

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CHARACTERISTIC CLINICAL FEATURES OF ASPERGILLUS APPENDICITIS: CASE REPORT AND LITERATURE REVIEW. 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CHARACTERISTIC CLINICAL FEATURES OF ASPERGILLUS APPENDICITIS: CASE REPORT AND LITERATURE REVIEW. 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CHARACTERISTIC CLINICAL FEATURES OF ASPERGILLUS APPENDICITIS: CASE REPORT AND LITERATURE REVIEW. 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"primarysource": { "literaturereference": "GJEORGJIEVSKI M, AMIN MB, CAPPELL MS.. CHARACTERISTIC CLINICAL FEATURES OF ASPERGILLUS APPENDICITIS: CASE REPORT AND LITERATURE REVIEW.. 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CHARACTERISTIC CLINICAL FEATURES OF ASPERGILLUS APPENDICITIS: CASE REPORT AND LITERATURE REVIEW. 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CHARACTERISTIC CLINICAL FEATURES OF ASPERGILLUS APPENDICITIS CASE REPORT AND LITERATURE REVIEW.. WORLD JOURNAL OF GASTROENTEROLOGY. 2015?21(44):12713-12721.", "literaturereference_normalized": "characteristic clinical features of aspergillus appendicitis case report and literature review", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20151217", "receivedate": "20151217", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 11848105, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20160305" } ]

{ "abstract": "Patients undergoing multivisceral transplantation are particularly susceptible to post-operative infections due to immunosuppression and the inclusion of bowel in the transplanted graft. These patients typically receive broad-spectrum antimicrobial and antifungal agents as prophylaxis and treatment. However, evidence for this is limited due to the small number of patients undergoing the procedure. We present a case of occult disseminated invasive aspergillosis infection in a patient who underwent multivisceral transplantation.", "affiliations": "Department of Gastroenterology, Addenbrooke's Hospital, Cambridge University Hospitals NHS Foundation Trust, Hills Road, Cambridge CB2 0QQ, UK.;Department of Gastroenterology, Addenbrooke's Hospital, Cambridge University Hospitals NHS Foundation Trust, Hills Road, Cambridge CB2 0QQ, UK.;Department of Gastroenterology, Addenbrooke's Hospital, Cambridge University Hospitals NHS Foundation Trust, Hills Road, Cambridge CB2 0QQ, UK.;Department of Gastroenterology, Addenbrooke's Hospital, Cambridge University Hospitals NHS Foundation Trust, Hills Road, Cambridge CB2 0QQ, UK.;Department of Histopathology and Cytology, Addenbrooke's Hospital, Cambridge University Hospitals NHS Foundation Trust, Hills Road, Cambridge CB2 0QQ, UK.;Clinical Microbiology and Public Health Laboratory (Public Health England), Addenbrooke's Hospital, Cambridge University Hospitals NHS Foundation Trust, Hills Road, Cambridge CB2 0QQ, UK.;Department of Transplant Surgery, Addenbrooke's Hospital, Cambridge University Hospitals NHS Foundation Trust, Hills Road, Cambridge CB2 0QQ, UK.;Department of Gastroenterology, Addenbrooke's Hospital, Cambridge University Hospitals NHS Foundation Trust, Hills Road, Cambridge CB2 0QQ, UK.", "authors": "Rutter|C S|CS|;Sharkey|L M|LM|;Gao|R|R|;Pither|C|C|;Ibrahim|A|A|;Enoch|D A|DA|;Butler|A J|AJ|;Middleton|S J|SJ|", "chemical_list": null, "country": "Netherlands", "delete": false, "doi": "10.1016/j.idcr.2014.06.005", "fulltext": "\n==== Front\nIDCasesIDCasesIDCases2214-2509Elsevier S2214-2509(14)00018-310.1016/j.idcr.2014.06.005Case ReportOccult invasive aspergillosis infection following multivisceral transplantation Rutter C.S. crutter@nhs.neta⁎Sharkey L.M. aGao R. aPither C. aIbrahim A. bEnoch D.A. cButler A.J. dMiddleton S.J. aa Department of Gastroenterology, Addenbrooke's Hospital, Cambridge University Hospitals NHS Foundation Trust, Hills Road, Cambridge CB2 0QQ, UKb Department of Histopathology and Cytology, Addenbrooke's Hospital, Cambridge University Hospitals NHS Foundation Trust, Hills Road, Cambridge CB2 0QQ, UKc Clinical Microbiology and Public Health Laboratory (Public Health England), Addenbrooke's Hospital, Cambridge University Hospitals NHS Foundation Trust, Hills Road, Cambridge CB2 0QQ, UKd Department of Transplant Surgery, Addenbrooke's Hospital, Cambridge University Hospitals NHS Foundation Trust, Hills Road, Cambridge CB2 0QQ, UK⁎ Corresponding author at: Department of Gastroenterology Box 133, Addenbrooke's Hospital, Cambridge University Hospitals NHS Foundation Trust, Hills Road, Cambridge, CB2 0QQ, UK. Tel.: +44 1223 216226. crutter@nhs.net10 7 2014 2014 10 7 2014 1 3 53 54 3 6 2014 28 6 2014 28 6 2014 © 2014 The Authors2014This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/3.0/).Patients undergoing multivisceral transplantation are particularly susceptible to post-operative infections due to immunosuppression and the inclusion of bowel in the transplanted graft. These patients typically receive broad-spectrum antimicrobial and antifungal agents as prophylaxis and treatment. However, evidence for this is limited due to the small number of patients undergoing the procedure. We present a case of occult disseminated invasive aspergillosis infection in a patient who underwent multivisceral transplantation.\n\nKeywords\nInvasive aspergillosisMultivisceral transplantMouldsGalactomannan\n==== Body\nCase\nA 53-year-old female, diagnosed with Crohn's disease in 1979, had a colonic perforation with peritonitis and was left with short bowel syndrome following surgery in 1989. She was dependent on parenteral nutrition but developed intestinal failure associated liver disease and underwent a multivisceral transplant (stomach, liver, pancreas, small bowel and colon) in December 2011. She was discharged home after 5 months.\n\nFifteen months post-transplantation she was readmitted with diarrhoea and nausea due to small and large bowel rejection. She failed to respond to increasing immunosuppression (methylprednisolone, tacrolimus, mycophenolate mofetil and infliximab) and so her transplanted colon was resected to facilitate reduction in her immunosuppression. She developed sepsis and was temporarily neutropenic, so received broad-spectrum antibacterial agents and fluconazole (due to an anaphylactic reaction to liposomal amphotericin B).\n\nShe developed multiorgan failure including a microangiopathic haemolytic anaemia requiring plasma exchange. Magnetic resonance imaging of her brain showed multiple small ischaemic lesions in the cortex and white matter bilaterally and a larger lesion in the right cerebellum, which was either haemorrhagic or an abscess (Fig. 1). A transthoracic echocardiogram showed no vegetations.\n\nTwo days later a serum galactomannan was performed which was positive (1.18 [normal range < 0.5], and sputum grew Aspergillus fumigatus; fluconazole was changed to posaconazole. Despite this the patient continued to deteriorate and died. Post mortem confirmed aspergillosis involving the brain, lungs and myocardium (Fig. 2).\n\nDiscussion\nInvasive aspergillosis occurs in 1–15% of solid organ transplant recipients [1]. There are three case reports of invasive aspergillosis infection following multivisceral transplantation [2], [3], [4]. It should be considered in profoundly immunosuppressed individuals even after a significant time post-transplant.\n\nWe believe that mould-active prophylaxis should be considered in this group of patients as studies of the use of antigen tests (e.g. galactomannan) and nucleic acid amplification tests in solid organ transplant recipients are limited [5] and have not been described in this population. In haematology patients, studies suggest normal neutrophil counts [6] and mould-active prophylaxis can reduce the sensitivity of this test [6], [7]. It has been reported that they are less sensitive in other solid organ transplant recipients than in the stem cell transplant population [1]. The choice of antifungal can be difficult as some patients are intolerant to amphotericin B (including lipid formulations) and triazoles interact with many other agents.\n\nOur patient demonstrated disseminated invasive aspergillosis infection more than 18 months post transplantation. This is later than has previously been reported in this patient group [2], [3], [4]. In addition, it was difficult to diagnose despite using galactomannan testing, imaging and a low threshold for therapy.\n\nTransplant teams (including microbiology, infectious diseases and radiology) must be aware of the risk of mould infections in all patients undergoing multivisceral transplant and ensure adequate therapy is administered. Early diagnosis is also essential to improve prognosis.\n\nAuthor contributions\nCharlotte Rutter (first author, literature review,); Lisa Sharkey (reviewing author), Rui Gao (reviewing author), Charlotte Pither (reviewing author), Ashraf Ibrahim (reviewing author, provided histopathology image), David Enoch (reviewing author, literature review), Andrew Butler (reviewing author), Stephen Middleton (reviewing author). All authors have approved the final article.\n\nConflict of interests\nThe authors declare no conflict of interest.\n\nFunding source\nNone.\n\nEthics approval\nNot required.\n\nConsent\nWritten informed consent was obtained from the patient's next of kin 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 on request.\n\nFig. 1 MRI brain showing lesion in right cerebellum suggestive of haemorrhage or an abscess.\n\nFig. 2 Cardiac myocardium specimen showing fungal hyphae.\n==== Refs\nReferences\n1 Singh N.M. Hussain S. AST Infectious Diseases Community of Practice Aspergillosis in solid organ transplantation Am J Transplant 13 2013 228 241 23465016 \n2 Viana R. Misra V. Fridell J.A. Goldman M. Mangus R.S. Tector J. Survival after disseminated invasive aspergillosis in a multivisceral transplant recipient Transplantt Proc 39 2007 306 307 \n3 Kohler S. Gerlach U. Guckelberger O. Sauer I.M. Jorres D. Neuhaus P. Successful treatment of invasive spenoidal, pulmonary and intracerebral aspergillosis after multivisceral transplantation Transplant Int 22 5 2009 589 591 \n4 Gerlach U.A. Kohler S. Sauer I.M. Joerres D. Kandziora F. Neuhaus P. Aspergillosis spondylodiscitis after multivisceral transplantation Ann Transplant 14 4 2009 52 57 20009156 \n5 Tabarsi P. Soraghi A. Mariani M. Zandian P. Baghaei P. Najafizadeh K. Comparison of serum and bronchoalveolar lavage galactomannan in diagnosing invasive aspergillosis in solid-organ transplant recipients Exp Clin Transplant 10 2012 278 281 22631066 \n6 Barton R.C. Laboratory diagnosis of invasive aspergillosis: from diagnosis to prediction of outcome Scientifica (Cairo) 2013 459405 24278780 \n7 Leeflang M.M. Debets-Ossenkopp Y.J. Visser C.E. Scholten R.J. Hooft L. Bijlmer H.A. Galactomannan detection for invasive aspergillosis in immunocompromized patients Cochrane Database Syst Rev October (4) 2008 CD007394 18843747\n\n", "fulltext_license": "CC BY-NC-ND", "issn_linking": "2214-2509", "issue": "1(3)", "journal": "IDCases", "keywords": "Galactomannan; Invasive aspergillosis; Moulds; Multivisceral transplant", "medline_ta": "IDCases", "mesh_terms": null, "nlm_unique_id": "101634540", "other_id": null, "pages": "53-4", "pmc": null, "pmid": "26955527", "pubdate": "2014", "publication_types": "D016428:Journal Article; D002363:Case Reports", "references": "18843747;19175558;24278780;20009156;23465016;22631066;17275530", "title": "Occult invasive aspergillosis infection following multivisceral transplantation.", "title_normalized": "occult invasive aspergillosis infection following multivisceral transplantation" }

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OCCULT INVASIVE ASPERGILLOSIS INFECTION FOLLOWING MULTIVISCERAL TRANSPLANTATION. IDCASES 1 2014:53-54.", "literaturereference_normalized": "occult invasive aspergillosis infection following multivisceral transplantation", "qualification": "3", "reportercountry": "GB" }, "primarysourcecountry": "GB", "receiptdate": "20150319", "receivedate": "20150319", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 10928542, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20150721" } ]

{ "abstract": "Inhaled corticosteroids are generally considered safe and do not usually lead to systemic adverse events since their plasma concentrations are low due to hepatic metabolism by the cytochrome P450 3A4. However, when associated with inhibitors of this cytochrome, such as ritonavir, they may lead to iatrogenic Cushing syndrome by the systemic accumulation of corticosteroids and consequent suppression of the hypothalamic-pituitary-adrenal axis. We present a case of iatrogenic Cushing syndrome complicated by multifocal osteonecrosis in a patient with HIV infection on antiretroviral therapy with protease inhibitors boosted with ritonavir, after the association of inhaled fluticasone. This clinical case highlights a relevant interaction between corticosteroids and inhibitors of the cytochrome P450 and the severe consequences that may occur.", "affiliations": "Serviço de Endocrinologia, Universidade de Lisboa Faculdade de Medicina, Lisboa, Portugal.;Hospital de Santa Maria, Serviço de Doenças Infecciosas, Centro Hospitalar Lisboa Norte EPE, Lisboa, Portugal.;Hospital de Santa Maria, Serviço de Reumatologia e Doenças Ósseas Metabólicas, Centro Hospitalar Lisboa Norte EPE, Lisboa, Portugal.;Serviço de Endocrinologia, Universidade de Lisboa Faculdade de Medicina, Lisboa, Portugal sonia.vale@chln.min-saude.pt.", "authors": "Figueiredo|Joana|J|;Serrado|Margarida|M|;Khmelinskii|Nikita|N|;do Vale|Sónia|S|http://orcid.org/0000-0001-9287-4095", "chemical_list": "D001993:Bronchodilator Agents; D017320:HIV Protease Inhibitors; D000068298:Fluticasone; D019438:Ritonavir", "country": "England", "delete": false, "doi": "10.1136/bcr-2019-233712", "fulltext": "\n==== Front\nBMJ Case Rep\nBMJ Case Rep\nbmjcr\nbmjcasereports\nBMJ Case Reports\n1757-790X BMJ Publishing Group BMA House, Tavistock Square, London, WC1H 9JR \n\nbcr-2019-233712\n10.1136/bcr-2019-233712\nReminder of Important Clinical Lesson\n1506\n1524\n1560\n1322 1338\n1325\n75\n1330\n1865\n187 558\n1561\n382\n532\n539\nCase reportIatrogenic Cushing syndrome and multifocal osteonecrosis caused by the interaction between inhaled fluticasone and ritonavir\nFigueiredo Joana 1 Serrado Margarida 2 Khmelinskii Nikita 34 http://orcid.org/0000-0001-9287-4095do Vale Sónia 15 1 Serviço de Endocrinologia, Universidade de Lisboa Faculdade de Medicina, Lisboa, Portugal\n2 Hospital de Santa Maria, Serviço de Doenças Infecciosas, Centro Hospitalar Lisboa Norte EPE, Lisboa, Portugal\n3 Hospital de Santa Maria, Serviço de Reumatologia e Doenças Ósseas Metabólicas, Centro Hospitalar Lisboa Norte EPE, Lisboa, Portugal\n4 Unidade de Investigação em Reumatologia, Instituto de Medicina Molecular, Lisboa, Portugal\n5 Hospital de Santa Maria, Serviço de Endocrinologia, Centro Hospitalar Lisboa Norte EPE, Lisboa, Portugal\nCorrespondence to Professor Sónia do Vale; sonia.vale@chln.min-saude.pt\n2020 \n27 5 2020 \n27 5 2020 \n13 5 e23371223 4 2020 © BMJ Publishing Group Limited 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.2020http://creativecommons.org/licenses/by-nc/4.0/This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.Inhaled corticosteroids are generally considered safe and do not usually lead to systemic adverse events since their plasma concentrations are low due to hepatic metabolism by the cytochrome P450 3A4. However, when associated with inhibitors of this cytochrome, such as ritonavir, they may lead to iatrogenic Cushing syndrome by the systemic accumulation of corticosteroids and consequent suppression of the hypothalamic-pituitary-adrenal axis. We present a case of iatrogenic Cushing syndrome complicated by multifocal osteonecrosis in a patient with HIV infection on antiretroviral therapy with protease inhibitors boosted with ritonavir, after the association of inhaled fluticasone. This clinical case highlights a relevant interaction between corticosteroids and inhibitors of the cytochrome P450 and the severe consequences that may occur.\n\ndrug interactionsadrenal disordersHIV / AIDSunwanted effects / adverse reactionsdrugs: musculoskeletal and joint diseasesspecial-featureunlocked\n==== Body\nBackground\nRitonavir is a protease inhibitor that is often used in combination with other antiretrovirals in the treatment of HIV infection. It is a potent inhibitor of the hepatic cytochrome P450 3A4 (CYP3A4) acting as a booster and allowing other antiretroviral agents metabolised by this cytochrome to reach higher plasma concentrations. This enables a decrease in pill burden and an increase of the dosing intervals, improving patient adherence and decreasing treatment failure.1\n\nInhaled corticosteroids are drugs widely used in the treatment of asthma, allergic rhinitis and chronic obstructive pulmonary disease (COPD). They are considered safe due to the low plasma concentrations they reach after metabolism by the CYP3A4. When combined with potent inhibitors of this cytochrome, there may be a significant increase in plasma corticosteroid levels.1 This may cause iatrogenic Cushing syndrome, suppression of the hypothalamic–pituitary–adrenal (HPA) axis, acute adrenal insufficiency in case of abrupt corticosteroid withdrawal, as well as hypertension, osteoporosis and avascular necrosis.1–5\n\nWe report a case of iatrogenic Cushing syndrome and multifocal osteonecrosis in a patient with HIV1 infection on a ritonavir-boosted antiretroviral therapy (ART) and COPD treated with fluticasone. It is intended to emphasise the importance of the interaction between inhaled corticosteroids and cytochrome P450 (CYP450) inhibitors and its potential severe consequences.\n\nCase presentation\nA 40-year-old man with well-controlled HIV1 infection (CD4+ T cell count of 518 cells/mm3 and undetectable HIV1 RNA) presented to the Endocrinology Department due to weight gain and abdominal and limb striae. His medical background included COPD and alcohol, tobacco and past intravenous heroin abuse. HIV1 infection was diagnosed when he was 25 years old and treatment with lopinavir/ritonavir 400 mg/100 mg two times per day, saquinavir 1000 mg two times per day and tenofovir 300 mg one time a day was started at the age of 33 years (CD4+ T cell count of 78 cells/mm3 and HIV1 RNA viral load of 2300 copies, log10 3.38, before ART). At 35 years of age inhaled therapy with fluticasone/salmeterol 250 µg/50 µg two times per day and tiotropium bromide 18 µg one time a day was added for COPD. One year later, he developed avascular necrosis of the right femoral head and underwent total hip arthroplasty.\n\nThe patient was first observed in January 2013, 5 years after the initiation of inhaled corticosteroid therapy. He reported a gradual increase in abdominal and cervical volume, 15 kg weight gain over the previous 6 months, appearance of abdominal and limb striae, gynecomastia, ankle oedema, erectile dysfunction and humoral lability. On physical examination he was noted to have a plethoric ‘full moon’ facies, centripetal obesity (body mass index (BMI) of 35 kg/m2), dorsocervical fat pads, proximal muscular atrophy, wide and divergent purpuric striae in the abdomen, arms and thighs (figure 1) and high blood pressure.\n\nFigure 1 Centripetal obesity and wide and divergent purpuric striae.\n\nInvestigations\nLaboratory evaluation revealed low serum and urinary cortisol with low serum adrenocorticotrophic hormone (ACTH) concentrations, indicating suppression of the HPA axis. Furthermore, dyslipidaemia and hypergonadotropic hypogonadism were detected (table 1). A bone density scan (BDS) revealed low bone mineral density (Z-score of the lumbar spine of −3.6), compatible with osteoporosis.\n\nTable 1 Laboratory findings evolution\n\n\tNormal range\tWith corticosteroids\tWithout corticosteroids (since Jul 2013)\t\nJanuary 2013,\n40 years old*\tMay 2013\tSeptember 2013\tFebruary 2014,\n41 years old\tSeptember 2014\tMarch 2015,\n42 years old\tDecember 2015\tApril 2017,\n44 years old\t\nACTH\n(pg/mL)\t0–46\t<5\t<5\t10.5\t21.4\t16\t17.9\t26.4\t\t\nSerum cortisol\n(μg/dL)\t4.3–23\t0.4\t0.4\t2.6\t12.2\t9.1\t10.4\t20.5\t\t\nUrinary cortisol\n(μg/24 hours)\t55.5–286\t10\t9\t13\t84\t\t194\t\t\t\nFSH (U/L)\t1.4–18.1\t\t36.6\t26.3\t25.0\t\t27.2\t\t30.0\t\nLH (U/L)\t1.5–9.3\t\t12.7\t12.7\t13.7\t\t15.9\t\t13.0\t\nTotal testosterone\n(ng/dL)\t240–830\t\t\t465\t309\t\t290\t\t337\t\nFree testosterone\n(pg/mL)\t6.6–23\t\t2.0\t5.4\t5.1\t\t5.6\t\t9.3\t\nSHBG\n(nmol/L)\t10–57\t\t\t64.2\t67.6\t\t54.9\t\t69.0\t\n*At this time the diagnosis of exogenous Cushing syndrome was made, and the patient started reducing the dose of corticosteroids.\n\nACTH, adrenocorticotropic hormone; FSH, follicle-stimulating hormone; LH, luteinising hormone; SHBG, sexhormone-binding globulin.\n\nDifferential diagnosis\nPresented with these findings, a diagnosis of exogenous/iatrogenic Cushing syndrome secondary to inhaled fluticasone was made.\n\nRegarding the differential diagnosis of Cushing syndrome in patients undergoing ART, it is important to consider ART-related lipodystrophy. In lipodystrophy, there is a metabolic dysregulation that leads to weight gain, central fat distribution and dorsocervical fat pads. In the case at hand, the presence of rapid weight gain, purpuric abdominal striae and facial plethora all point to the Cushing syndrome. In contrast, HIV-associated lipodystrophy is associated with more evident peripheral muscular atrophy than Cushing syndrome.1–3 Laboratory evaluation clarifies the diagnosis since there are abnormal concentrations of cortisol and ACTH in the Cushing syndrome.\n\nWe must also distinguish between iatrogenic and endogenous Cushing syndrome. When Cushing syndrome is iatrogenic, the endogenous synthesis of cortisol is supressed due to the negative feedback exerted by the excess of exogenous corticosteroids on the hypothalamus and the pituitary gland. Suppressed ACTH and cortisol concentrations mean that the source of corticosteroids is exogenous, representing therefore an iatrogenic Cushing syndrome. However, if the patient is taking hydrocortisone, the cortisol measurements do not distinguish whether the source of cortisol is endogenous or administered. Other corticosteroids may also interfere with these measurements.\n\nTreatment\nAfter the diagnosis, the dose of fluticasone was progressively reduced. The patient also started antihypertensive and statin therapy.\n\nOutcome and follow-up\nAfter 4 months of corticosteroids at a halved dose, the patient continued to demonstrate HPA axis suppression and the decision was made to continue weaning fluticasone. Eventually the fluticasone/salmeterol was totally ceased and replaced by indacaterol 150 µg one time a day in July 2013.\n\nIn September 2013, after 3 months without corticosteroids, the patient had a less ‘full moon’ facies, no oedema, less purpuric striae and a 6 kg weight loss over a 9 month period (BMI of 33 kg/m2). He reported an improvement of erectile dysfunction. From the respiratory point of view, the patient remained stable without the need of steroid therapy. Serum and urinary cortisol were closer to reference values and ACTH was not suppressed (table 1).\n\nApproximately 1 year after corticosteroid cessation, the patient complained of left knee pain and claudication. Plain radiography of the knees revealed bilateral sclerotic lesions in a serpiginous pattern and the diagnosis of aseptic necrosis with subchondral bone collapse of the medial left femoral condyle was confirmed by magnetic resonance imaging (figure 2). Conservative treatment that included protected weightbearing with crutches, non-steroidal anti-inflammatory drugs and alendronate 70 mg weekly for 2 years ensured full symptomatic relief and no radiographic progression on long-term follow-up.\n\nFigure 2 Resonance imaging of the left knee demonstrating aseptic necrosis with subchondral bone collapse of the medial left femoral condyle.\n\nThere was a gradual improvement of the Cushing syndrome signs as well as laboratory abnormalities, with normalisation of the HPA axis function. Reassessment BDS revealed improvement of the bone mineral density. Laboratory tests performed at the same time revealed total testosterone and free testosterone levels within normal range, while maintaining high follicle-stimulating hormone and luteinising hormone(table 1).\n\nDiscussion\nThe presented clinical case describes an iatrogenic Cushing syndrome complicated by multifocal osteonecrosis resulting from a drug interaction between ritonavir and fluticasone. There are already a number of published articles describing the consequences of the interaction between these two drugs.3In 2013, a Review article found 51 published case reports regarding adverse effects with the use of inhaled or/and intranasal corticosteroids and protease inhibitors, most of which (approximately 86%) were related to the association between fluticasone and ritonavir.3 The most common reported symptoms were ‘full moon’ facies, facial hirsutism, central obesity and weight gain, dorsocervical fat pads, striae and easy bruising.3 There were five cases of osteoporosis and one case of osteonecrosis of both hips.3 5 However, despite the presence of these well-documented cases of iatrogenic Cushing syndrome, similar reports continue to emerge.2 6 7\n\nRitonavir, being a potent inhibitor of the hepatic CYP3A4, increases the concentration of other protease inhibitors included in the combined ART and enhances HIV treatment success. However, ritonavir can also increase corticosteroids concentrations, as they are substrates of the CYP3A4. Therefore, this interaction can result in impaired metabolism and systemic corticosteroid accumulation, adrenal suppression and Cushing syndrome.1 2\n\nCompared with other inhaled corticosteroids, fluticasone exhibits the most suppressive impact on the HPA axis. This is due to its pharmacokinetic properties, such as higher glucocorticoid receptor binding affinity, longer half-life and higher lipophilicity, allowing a greater volume of distribution. These characteristics facilitate the systemic accumulation of fluticasone and make it more susceptible to drug interactions.1–3\n\nThe most common clinical feature of the Cushing syndrome is weight gain with central fat distribution. Other typical manifestations include, ‘full moon’ facies, facial plethora, dorsocervical fat pads (‘buffalo hump’), skin atrophy, acne, easy bruising and purple striae. Hirsutism (in women), proximal myopathy, insulin resistance, dyslipidaemia, hypertension, immunosuppression, psychiatric disorders and osteopenia or osteoporosis are also common.2 8 9 Given the reported clinical case, it is also important to note that hypogonadism, HIV infection, ART and tobacco and alcohol abuse may also contribute to a decrease in bone mineral density.10 11\n\nThere are other important consequences of hypercortisolism, namely gonadal dysfunction and aseptic osteonecrosis. Gonadal dysfunction occurs in more than 75% of patients with Cushing syndrome and is usually hypogonadotropic.9 11 However, the patient presented with hypergonadotropic hypogonadism and several contributing factors transpire: chronic alcoholism, the use of certain illicit drugs and HIV infection.11 12\n\nAs mentioned, the patient developed avascular necrosis of the right femoral head and, approximately 5 years after, of both knees. Although infrequent, avascular necrosis may have been the first manifestation of the Cushing syndrome.13 Multiple other risk factors for avascular necrosis were also present: alcoholism, hypertriglyceridemia, HIV infection and smoking.4 5 13 Therefore, we cannot conclude that hypercortisolism was an isolated cause of multifocal osteonecrosis, but it probably was a significant contributing factor. To our knowledge, only two other cases of avascular necrosis have been reported as being attributed to the interaction between fluticasone and ritonavir.4 5\n\nAfter the diagnosis of iatrogenic Cushing syndrome due to the interaction between inhaled corticosteroids and ritonavir, treatment involves either replacing ritonavir with another antiretroviral that does not inhibit the CYP3A4 or changing fluticasone while maintaining ritonavir. Fluticasone can be substituted for another less potent inhaled corticosteroid and less dependent on CYP450 metabolism (eg, beclomethasone), a leukotriene antagonist (eg, montelukast) or an anticholinergic agent (eg, tiotropium). It is unclear if significant dose reductions of the intranasal/inhaled corticosteroid will result in the complete resolution of the clinical picture since accounts of this interaction have been reported at low doses.2 3\n\nIf treatment with another inhaled corticosteroid is started, the lowest possible dose should always be administered and the clinical course should be closely monitored considering case reports of iatrogenic Cushing syndrome due to other inhaled corticosteroids.1 3\n\nIf corticosteroid therapy is to be suspended, this should always be done progressively because of the risk of acute adrenal insufficiency. The exogenous corticosteroids supress the HPA axis. With an abrupt cessation of exogenous corticosteroids, the HPA axis is incapable of rapidly producing endogenous cortisol, which results in acute adrenal insufficiency.6\n\nIn conclusion, corticosteroid therapy even in ‘non-systemic’ formulations, namely intranasal or inhaled, should be avoided in patients receiving ritonavir (or another CYP3A4 inhibitor). If treatment with an inhaled corticosteroid is imperative, fluticasone should not be the first therapeutic option.\n\nLearning points\nRitonavir is a potent cytochrome P450 3A4 inhibitor acting as a booster of other drugs metabolised via this cytochrome, such as corticosteroids.\n\nCo-administration of ritonavir (or other potent cytochrome P450 (CYP450) inhibitors) with corticosteroids, including intranasal or inhaled formulations, may induce systemic corticosteroid accumulation, Cushing syndrome, adrenal insufficiency, hypertension, osteoporosis and avascular necrosis.\n\nCompared with other inhaled corticosteroids, fluticasone is the most susceptible to drug interactions with CYP450 inhibitors while beclomethasone is probably the safest option.\n\nTreatment options for the iatrogenic Cushing syndrome induced by this interaction include replacing ritonavir with another antiretroviral or slow tapering of fluticasone and replacing it with beclomethasone, a leukotriene antagonist or an anticholinergic agent.\n\nContributors: MS, NK and SdV were involved in the treament of the presented patient. JF wrote the manuscript with the help from SdV, NK and MS. All authors contributed to the final version of the manuscript.\n\nFunding: The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.\n\nCompeting interests: None declared.\n\nPatient consent for publication: Obtained.\n\nProvenance and peer review: Not commissioned; externally peer reviewed.\n==== Refs\nReferences\n1 Mahlab-Guri K , Asher I , Gradstein S , et al \nInhaled fluticasone causes iatrogenic Cushing's syndrome in patients treated with ritonavir\n. J Asthma \n2011 ;48 :860 –3\n. 10.3109/02770903.2011.606580 21854345 \n2 Epperla N , McKiernan F \nIatrogenic Cushing syndrome and adrenal insufficiency during concomitant therapy with ritonavir and fluticasone\n. Springerplus \n2015 ;4 :455. 10.1186/s40064-015-1218-x 26322261 \n3 Saberi P , Phengrasamy T , Nguyen DP \nInhaled corticosteroid use in HIV-positive individuals taking protease inhibitors: a review of pharmacokinetics, case reports and clinical management\n. HIV Med \n2013 ;14 :519 –29\n. 10.1111/hiv.12039 23590676 \n4 Pollett S , Graves B , Richards B , et al \nAvascular necrosis in a HIV patient receiving ritonavir and inhaled fluticasone\n. Int J STD AIDS \n2014 ;25 :458 –60\n. 10.1177/0956462413513747 24287027 \n5 Kaviani N , Bukberg P , Manessis A , et al \nIatrogenic osteoporosis, bilateral hip osteonecrosis, and secondary adrenal suppression in an HIV-infected man receiving inhaled corticosteroids and ritonavir-boosted highly active antiretroviral therapy\n. Endocr Pract \n2011 ;17 :74 –8\n. 10.4158/EP09288.CR 20713349 \n6 Wood BR , Lacy JM , Johnston C , et al \nAdrenal insufficiency as a result of ritonavir and exogenous steroid exposure: report of 6 cases and recommendation for management\n. J Int Assoc Provid AIDS Care \n2015 ;14 :300 –5\n. 10.1177/2325957414567681 25589302 \n7 Azevedo L , Pêgo H , Souto Moura T , et al \nIatrogenic Cushing's syndrome and osteoporosis due to an interaction between fluticasone and ritonavir\n. BMJ Case Rep \n2015 ;2015 :bcr2015211080. 10.1136/bcr-2015-211080 \n8 Ntali G , Grossman A , Karavitaki N \nClinical and biochemical manifestations of Cushing's\n. Pituitary \n2015 ;18 :181 –7\n. 10.1007/s11102-014-0631-4 25571880 \n9 Alves M , Neves C , Medina JL \nDiagnóstico Laboratorial de Síndrome de Cushing\n. Acta Médica Portuguesa \n2008 ;23 :063 –76\n.\n10 Ashby J , Goldmeier D , Sadeghi-Nejad H \nHypogonadism in human immunodeficiency virus-positive men\n. Korean J Urol \n2014 ;55 :9 –16\n. 10.4111/kju.2014.55.1.9 24466391 \n11 Darby E , Anawalt BD \nMale hypogonadism : an update on diagnosis and treatment\n. Treat Endocrinol \n2005 ;4 :293 –309\n. 10.2165/00024677-200504050-00003 16185098 \n12 Ponte CMM , Gurgel MHC , Montenegro RM \nDisfunção do eixo gonadotrófico em homens com infecção pelo HIV/AIDS\n. Arq Bras Endocrinol Metab \n2009 ;53 :983 –8\n. 10.1590/S0004-27302009000800012 \n13 Koch CA , Tsigos C , Patronas NJ , et al \nCushing's disease presenting with avascular necrosis of the hip: an orthopedic emergency\n. J Clin Endocrinol Metab \n1999 ;84 :3010 –2\n. 10.1210/jcem.84.9.5992 10487656\n\n", "fulltext_license": "CC BY-NC", "issn_linking": "1757-790X", "issue": "13(5)", "journal": "BMJ case reports", "keywords": "HIV / AIDS; adrenal disorders; drug interactions; drugs: musculoskeletal and joint diseases; unwanted effects / adverse reactions", "medline_ta": "BMJ Case Rep", "mesh_terms": "D000280:Administration, Inhalation; D000328:Adult; D001993:Bronchodilator Agents; D003480:Cushing Syndrome; D004347:Drug Interactions; D000068298:Fluticasone; D015658:HIV Infections; D017320:HIV Protease Inhibitors; D006801:Humans; D007049:Iatrogenic Disease; D008297:Male; D010020:Osteonecrosis; D029424:Pulmonary Disease, Chronic Obstructive; D019438:Ritonavir", "nlm_unique_id": "101526291", "other_id": null, "pages": null, "pmc": null, "pmid": "32467117", "pubdate": "2020-05-27", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": "26322261;25571880;23590676;20126851;20713349;16185098;10487656;21854345;24466391;25589302;26516245;20353708;24287027", "title": "Iatrogenic Cushing syndrome and multifocal osteonecrosis caused by the interaction between inhaled fluticasone and ritonavir.", "title_normalized": "iatrogenic cushing syndrome and multifocal osteonecrosis caused by the interaction between inhaled fluticasone and ritonavir" }

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"reactionmeddrapt": "Osteonecrosis", "reactionmeddraversionpt": "23.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Osteoporosis", "reactionmeddraversionpt": "23.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Cushing^s syndrome", "reactionmeddraversionpt": "23.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Arthritis", "reactionmeddraversionpt": "23.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Osteonecrosis", "reactionmeddraversionpt": "23.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "DO VALE S, FIGUEIREDO J, SERRADO M, KHMELINSKII N. IATROGENIC CUSHING SYNDROME AND MULTIFOCAL OSTEONECROSIS CAUSED BY THE INTERACTION BETWEEN INHALED FLUTICASONE AND RITONAVIR. BMJ CASE REP. 2020?13:E233712.", "literaturereference_normalized": "iatrogenic cushing syndrome and multifocal osteonecrosis caused by the interaction between inhaled fluticasone and ritonavir", "qualification": "1", "reportercountry": "COUNTRY NOT SPECIFIED" }, "primarysourcecountry": "PT", "receiptdate": "20200617", "receivedate": "20150715", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 11273909, "safetyreportversion": 3, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20200713" } ]

{ "abstract": "OBJECTIVE\nDenosumab is a biologic agent used to treat osteoporosis. Its safety profile given concurrently with biologic drugs for rheumatoid arthritis (RA) has not been well studied. We evaluated hospitalized infections among patients treated with biologic agents for RA who initiated denosumab or zoledronic acid (ZA), a parenteral bisphosphonate without known associations with infection. We hypothesized that the rate of hospitalized infection with denosumab would be noninferior to ZA.\n\n\nMETHODS\nWe identified RA patients enrolled in Medicare in 2006-2012 treated with biologic agents who initiated denosumab or ZA. Cox proportional hazards models compared the risk for hospitalized infection, comparing denosumab users to ZA users and adjusting for potentially confounding factors. A noninferiority margin was specified a priori to demonstrate that denosumab had no greater infection risk than ZA if the upper bound of the 95% confidence interval (95% CI) of the hazard ratio (HR) was <1.5.\n\n\nRESULTS\nEligible RA patients receiving biologic agents initiated denosumab (n = 1,354) or ZA (n = 4,460). Characteristics of the denosumab users were as follows: mean ± SD age 73.0 ± 8.9, 98.2% women, with a majority receiving infliximab (35.7%) or abatacept (18.6%). Denosumab users had a higher prevalence of prior infections (11.5% hospitalized and 48.3% outpatient) and infection-related risk factors. The crude rate of hospitalized infections for denosumab (14.9/100 person-years [95% CI 12.2-18.1]) was comparable to that for ZA (13.9/100 person-years [95% CI 12.5-15.4]). After adjustment, the HR of hospitalized infection for denosumab users was noninferior to that for ZA users (HR 0.89 [95% CI 0.69-1.15]).\n\n\nCONCLUSIONS\nThe rate of hospitalized infection among RA patients receiving denosumab concurrently with biologic agents for RA was not increased compared to those receiving zoledronate.", "affiliations": "University of Alabama at Birmingham.;University of Alabama at Birmingham.;University of Alabama at Birmingham.;University of Alabama at Birmingham.;University of Alabama at Birmingham.;University of Alabama at Birmingham.", "authors": "Curtis|Jeffrey R|JR|;Xie|Fenglong|F|;Yun|Huifeng|H|;Saag|Kenneth G|KG|;Chen|Lang|L|;Delzell|Elizabeth|E|", "chemical_list": "D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D018501:Antirheumatic Agents; D001685:Biological Factors; D050071:Bone Density Conservation Agents; D004164:Diphosphonates; D007093:Imidazoles; D018796:Immunoconjugates; D000069448:Denosumab; D000077211:Zoledronic Acid; D000069594:Abatacept; D000069285:Infliximab; D000068879:Adalimumab", "country": "United States", "delete": false, "doi": "10.1002/art.39075", "fulltext": null, "fulltext_license": null, "issn_linking": "2326-5191", "issue": "67(6)", "journal": "Arthritis & rheumatology (Hoboken, N.J.)", "keywords": null, "medline_ta": "Arthritis Rheumatol", "mesh_terms": "D000069594:Abatacept; D000068879:Adalimumab; D000368:Aged; D000369:Aged, 80 and over; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D018501:Antirheumatic Agents; D001172:Arthritis, Rheumatoid; D001685:Biological Factors; D050071:Bone Density Conservation Agents; D000069448:Denosumab; D004164:Diphosphonates; D005260:Female; D006760:Hospitalization; D006801:Humans; D007093:Imidazoles; D018796:Immunoconjugates; D007239:Infections; D000069285:Infliximab; D008297:Male; D006278:Medicare; D008875:Middle Aged; D010024:Osteoporosis; D016016:Proportional Hazards Models; D012307:Risk Factors; D014481:United States; D000077211:Zoledronic Acid", "nlm_unique_id": "101623795", "other_id": null, "pages": "1456-64", "pmc": null, "pmid": "25708920", "pubdate": "2015-06", "publication_types": "D016428:Journal Article; D013487:Research Support, U.S. Gov't, P.H.S.", "references": null, "title": "Risk of hospitalized infection among rheumatoid arthritis patients concurrently treated with a biologic agent and denosumab.", "title_normalized": "risk of hospitalized infection among rheumatoid arthritis patients concurrently treated with a biologic agent and denosumab" }

[ { "companynumb": "US-JNJFOC-20150603470", "fulfillexpeditecriteria": "2", "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": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "RHEUMATOID ARTHRITIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "INFLIXIMAB, RECOMBINANT" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Infection", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "CURTIS JR, XIE F, YUN H, SAAG KG, CHEN L, DELZELL E. RISK OF HOSPITALIZED INFECTION AMONG RHEUMATOID ARTHRITIS PATIENTS CONCURRENTLY TREATED WITH A BIOLOGIC AGENT AND DENOSUMAB.. ARTHRITIS + RHEUMATOLOGY 2015;67 (6):1456-64.", "literaturereference_normalized": "risk of hospitalized infection among rheumatoid arthritis patients concurrently treated with a biologic agent and denosumab", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20150814", "receivedate": "20150814", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 11381237, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20151125" } ]

{ "abstract": "The authors report a case of treatment-resistant schizophrenia in a 22-year-old woman, who, despite multiple trials of antipsychotics, did not respond to treatment. Clozapine treatment was initiated, but the patient's symptoms did not remit until after she had a clozapine-induced seizure. The authors discuss the importance in considering that electroconvulsive therapy may be effective in reducing positive and negative symptoms in patients suffering from treatment-resistant schizophrenia.", "affiliations": "All are with the Department of Psychiatry, Aga Khan University Karachi, Pakistan.;All are with the Department of Psychiatry, Aga Khan University Karachi, Pakistan.;All are with the Department of Psychiatry, Aga Khan University Karachi, Pakistan.", "authors": "Jawaid|Hena|H|;Younus|Sana|S|;Mesiya|Hanif|H|", "chemical_list": null, "country": "United States", "delete": false, "doi": null, "fulltext": null, "fulltext_license": null, "issn_linking": "2158-8333", "issue": "13(5-6)", "journal": "Innovations in clinical neuroscience", "keywords": "Treatment-resistant schizophrenia (TRS); clozapine; electroconvulsive therapy (ECT); seizure", "medline_ta": "Innov Clin Neurosci", "mesh_terms": null, "nlm_unique_id": "101549695", "other_id": null, "pages": "78-80", "pmc": null, "pmid": "27800285", "pubdate": "2016", "publication_types": "D002363:Case Reports", "references": "14969782;25537107;25377372;23499244;9718630;9871852;3566457;19086588", "title": "Remission of Psychosis in Treatment-resistant Schizophrenia Following a Seizure: A Case Report.", "title_normalized": "remission of psychosis in treatment resistant schizophrenia following a seizure a case report" }

[ { "companynumb": "PK-ACCORD-045568", "fulfillexpeditecriteria": "1", "occurcountry": "PK", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "CLOZAPINE" }, "drugadditional": "1", "drugadministrationroute": null, "drugauthorizationnumb": "202873", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "DOSE WAS TITRATED UP?ON 14TH DAY:175MG DIVIDED INTO 75 MG IN MORNING AND 100 MG IN EVENING", "drugenddate": null, "drugenddateformat": null, "drugindication": "SCHIZOPHRENIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": [ { "drugrecuraction": "Generalised tonic-clonic seizure" } ], "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CLOZAPINE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "RISPERIDONE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "SCHIZOPHRENIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "25", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RISPERIDONE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "OLANZAPINE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "DOSE WAS TITRATED UP TO 20MG", "drugenddate": null, "drugenddateformat": null, "drugindication": "SCHIZOPHRENIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "5", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "OLANZAPINE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "TRIHEXYPHENIDYL" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "SALIVARY HYPERSECRETION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "2", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TRIHEXYPHENIDYL" } ], "patientagegroup": null, "patientonsetage": "22", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Weight increased", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Head injury", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Fall", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Salivary hypersecretion", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Increased appetite", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Generalised tonic-clonic seizure", "reactionmeddraversionpt": "19.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Sedation", "reactionmeddraversionpt": "19.1", "reactionoutcome": "3" }, { "reactionmeddrapt": "Alopecia", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "JAWAID H, YOUNUS S, MESIYA H. REMISSION OF PSYCHOSIS IN TREATMENT-RESISTANT SCHIZOPHRENIA FOLLOWING A SEIZURE: A CASE REPORT. INNOV CLIN NEUROSCI. 2016 JUN 1;13(5-6):78-80.", "literaturereference_normalized": "remission of psychosis in treatment resistant schizophrenia following a seizure a case report", "qualification": "1", "reportercountry": "PK" }, "primarysourcecountry": "PK", "receiptdate": "20161117", "receivedate": "20161117", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 12948537, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170207" } ]