Age: 23.0
Sex: F
Vaccine: COVID19
Symptoms: Flow cytometry, Fungal test, HLA-B*5801 assay, Haemoglobin, Haemophagocytic lymphohistiocytosis
Clinical narrative: Macrophage activation syndrome; adult-onset Still's disease; Toxic epidermal necrosis; This literature-non-study case was reported in a literature article and describes the occurrence of HAEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS (Macrophage activation syndrome), STILL'S DISEASE (adult-onset Still's disease) and TOXIC EPIDERMAL NECROLYSIS (Toxic epidermal necrosis) in a 23-year-old female patient who received mRNA-1273 (Spikevax) for COVID-19 prophylaxis.       No Medical History information was reported.    On an unknown date, the patient received second dose of mRNA-1273 (Spikevax) (unknown route) 1 dosage form. On an unknown date, the patient experienced HAEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS (Macrophage activation syndrome) (seriousness criteria hospitalization prolonged and medically significant), STILL'S DISEASE (adult-onset Still's disease) (seriousness criteria hospitalization prolonged and medically significant) and TOXIC EPIDERMAL NECROLYSIS (Toxic epidermal necrosis) (seriousness criteria hospitalization prolonged and medically significant). The patient was treated with AZITHROMYCIN for Upper respiratory infection, at an unspecified dose and frequency; DEXAMETHASONE for Adult onset Still's disease and Macrophage activation syndrome, at an unspecified dose and frequency; ANAKINRA for Adult onset Still's disease, Macrophage activation syndrome and Epidermal necrosis, at a dose of 100 milligram once a day; ATOVAQUONE for Prophylactic, at an unspecified dose and frequency; PANTOPRAZOLE for Prophylactic, at an unspecified dose and frequency; CYCLOSPORINE for Epidermal necrosis, at a dose of 150 milligram twice a day; IMMUNOGLOBULINS NOS (IMMUNOGLOBULIN I.V) (intravenous) for Epidermal necrosis, at a dose of 500 milligram/kilogram; PREDNISONE at an unspecified dose and frequency; CANAKINUMAB at a dose of 300 milligram; CEPHALOSPORIN NOS at an unspecified dose and frequency; ALLOPURINOL for Lymphoma, at an unspecified dose and frequency; Wound care (rehabilitation) for Haemophagocytic lymphohistiocytosis and Wound care (rehabilitation) for Toxic epidermal necrolysis. At the time of the report, HAEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS (Macrophage activation syndrome), STILL'S DISEASE (adult-onset Still's disease) and TOXIC EPIDERMAL NECROLYSIS (Toxic epidermal necrosis) had resolved.      DIAGNOSTIC RESULTS (normal ranges are provided in parenthesis if available): On an unknown date, Antinuclear antibody: Negative. On an unknown date, Aspartate aminotransferase (10-50): 130 U/L. On an unknown date, Bacterial test: Negative. On an unknown date, Biopsy: Biopsies showed no hemophagocytosis. On an unknown date, Biopsy bone marrow: unrevealing. On an unknown date, Biopsy lymph gland: unrevealing. On an unknown date, Biopsy skin: Skin biopsy later confirmed subepidermal vesicular dermatitis with full-thickness epidermal necrosis.. On an unknown date, Blood culture: Negative. On an unknown date, Blood immunoglobulin G: Negative. On an unknown date, Blood immunoglobulin M: Negative. On an unknown date, Blood pressure measurement: 88/66 mmHg Hypotension. On an unknown date, Blood triglycerides: 811 mg/dl elevated (Reference value<150 mg/dL). On an unknown date, Body surface area: 70 %. On an unknown date, Body temperature: 39.1 degree Celsius On admission (18 days after vaccination).. On an unknown date, C-reactive protein: 186.1 mg/dl (Reference value = 5  mg/L). On an unknown date, Chemokine test: Remained elevated. Total IL-18 greater than 24,000 pg/mL differentiates MAS from other types of familial and secondary HLH (sensitivity, 83%; specificity, 94%). Although IL-18 alone cannot differentiate between AOSD and MAS, it tends to be an order of magnitude higher in MAS. and 548075 pg/ml Reference value less than 647 (<647). On an unknown date, Computerised tomogram abdomen: Revealed splenomegaly and diffuse lymphadenopathy.. On an unknown date, Computerised tomogram pelvis: Revealed splenomegaly and diffuse lymphadenopathy.. On an unknown date, Computerised tomogram thorax: Revealed splenomegaly and diffuse lymphadenopathy.. On an unknown date, Epstein-Barr virus antibody: Negative. On an unknown date, Flow cytometry: Did not show signs of monoclonal expansion/proliferation, therefore ruling out hematolymphoid malignancy.. On an unknown date, Fungal test: Negative. On an unknown date, HLA-B*5801 assay: (Negative) Associated with allopurinol-related Steven Johnson syndrome (SJS)-TEN, was negative.. On an unknown date, Haemoglobin (12-15): 11.4 g/dL. On an unknown date, Hepatic enzyme: elevated and Elevated liver enzymes. On an unknown date, IL-2 receptor assay (175.3-858.2): 6158.5 pg/ml elevated 2-receptor. On an unknown date, Interferon gamma level (89-540): 181803 pg/ml Markedly elevated (181,803 pg/mL) supporting the diagnosis of adult-onset Still's disease with MAS. MAS was diagnosed based on markedly elevated IL-18 and fulfillment of criteria for AOSD.. On an unknown date, Mycobacterium test: Negative. On an unknown date, Natural killer cell activity test: normal. On an unknown date, Pathology test: Did not show signs of monoclonal expansion/proliferation, therefore ruling out hematolymphoid malignancy.. On an unknown date, Physical examination: On admission (18 days after vaccination), sinus tachycardia was 140 bpm, enlarged cervical lymph nodes, and a faint blanchable morbilliform eruption on all extremities. On an unknown date, Platelet count (150-450): 93 10^9/L. On an unknown date, SARS-CoV-2 test: Negative. On an unknown date, Serology test: Autoimmune serologies were all within normal limits.. On an unknown date, Serum ferritin (5-204): 56131 ng/dL elevated. On an unknown date, Transaminases (10-35): 43 U/L. On an unknown date, White blood cell count: Initial evaluation demonstrated leukocytosis (18.19 × 109 /L [411 × 109 /L]) with 93% neutrophils..     For mRNA-1273 (Spikevax) (Unknown), the reporter considered HAEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS (Macrophage activation syndrome) and STILL'S DISEASE (adult-onset Still's disease) to be related. No further causality assessment was provided for TOXIC EPIDERMAL NECROLYSIS (Toxic epidermal necrosis).    Previously healthy patient was admitted multiple times over 4 weeks for spiking fevers, cervical lymphadenopathy, and macular rash. Symptoms began one week after her second SARS-CoV-2 mRNA vaccine and did not respond to outpatient treatment with azithromycin and corticosteroids for presumed upper respiratory infection. Extensive infectious evaluation was unrevealing. It was reported that due to concern for infection, blood cultures were obtained, and broad-spectrum antibiotics were initiated. She was presented to the emergency department with rash, nausea, vomiting, and abdominal pain. Patient had elevated liver enzymes, cytopenias, lymphadenopathy, and splenomegaly. Allopurinol was started and later discontinued. Dexamethasone and anakinra were initiated on day 36 with prophylactic atovaquone and pantoprazole. Patient symptoms and labs improved until day 57 of illness, following hospital discharge, until day 64 after vaccination when patient developed a diffuse, painful, blistering (desquamating) maculopapular rash, and dusky Nikolsky positive eruption consistent with toxic epidermal necrosis despite a brief lapse in anakinra. Although she no longer had symptoms fulfilling criteria for AOSD, her IL-18 remained elevated and, therefore, anakinra was restarted. Steroids were continued to address her underlying MAS. Her rash quickly stopped progressing, and her inflammatory markers trended down. She required prolonged hospitalization for wound care and rehabilitation. Following discharge, she transitioned from anakinra to canakinumab every 28 days, and prednisone was tapered off. She had continued to do well on canakinumab every 4 weeks, without recurrence of MAS or TEN symptoms. It was reported that the patient without history of autoimmune disease developed AOSD with MAS in close to SARS-CoV-2 vaccination. The patient had avoided additional SARS CoV-2 boosters and, instead, was given tixagevimab and cilgavimab for COVID prophylaxis.  Company Comment: This is a literature non-study case concerning a 23 year-old, female patient reported as healthy and without history of autoimmune disease, who experienced the serious (due to medically significant and hospitalization) unexpected, events of Haemophagocytic lymphohistiocytosis (reported as Macrophage activation syndrome, MAS), Still's disease (AESI, reported as Adult onset Still's disease, AOSD) and Toxic epidermal necrolysis (AESI). The events MAS and AOSD occurred approximately 7 days after the second dose of mRNA-1273 vaccine and the event Toxic epidermal necrolysis (TEN), 64 days after vaccination. Patient developed daily fevers and cervical lymphadenopathy 1 week after vaccination, she was initially seen at an urgent care center and prescribed azithromycin and corticosteroids. Her symptoms continued, and, over the next 10 days, she developed rash, nausea, vomiting, and abdominal pain, leading her to present to the emergency department. On admission (18 days after vaccination), patient was febrile, had sinus tachycardia, hypotension, enlarged cervical lymph nodes, and a faint blanchable morbilliform eruption on all extremities. Initial evaluation demonstrated leukocytosis; hemoglobin, 11.4 g/dL (1215 g/dL); platelets, 93 × 109/L (150450 × 109/L), elevated liver enzymes; and elevated CRP. Computed tomography revealed splenomegaly and diffuse lymphadenopathy. Blood cultures were obtained, and broad-spectrum antibiotics were initiated. Her negative cultures and a lack of improvement raised concern for malignancy or autoimmune disease. She underwent excisional lymph node biopsy as well as bone marrow biopsy. Allopurinol was started and later discontinued when biopsy and flow cytometry ruled out hematolymphoid malignancy. Her biopsies showed no hemophagocytosis and negative bacterial, fungal, and mycobacterial staining and cultures. EBV PCR, IgM, and IgG as well as SARS-CoV-2 PCR and nuclear capsid IgG testing were also negative, arguing against prior infection. Autoimmune serologies were all within normal limits. She met 5 of 8 diagnostic criteria for hemophagocytic lymphohistiocytosis (HLH), with fevers; splenomegaly; ferritin, 56,131 ng/mL (5204 ng/mL); triglycerides, 811 mg/dL (< 150 mg/dL); and elevated soluble interleukin (IL) 2-receptor, 6158.5 pg/mL (175.3858.2 pg/mL). Patient also met Yamaguchi criteria for AOSD and had marked elevations in both IL-18 (181,803 pg/mL [89540 pg/mL]) and CXCL9 (548,075 pg/mL [< 647 pg/mL]), supporting the diagnosis of MAS. Dexamethasone and anakinra were initiated along with prophylactic atovaquone and pantoprazole. Her symptoms and labs improved despite a brief lapse in anakinra, following hospital discharge, until day 64 after vaccination, when she developed a painful, desquamating, and dusky Nikolsky positive eruption, involving 70% of her total body surface area and mucosae consistent with TEN. Skin biopsy confirmed subepidermal vesicular dermatitis with full-thickness epidermal necrosis. Potential culprit drugs were suspended (pantoprazole, atovaquone, and cephalosporins), and she received intravenous immunoglobulin and cyclosporine. Anakinra was restarted since IL-18 remained elevated, and steroids were continued due to underlying MAS. Rash stopped progressing, and the inflammatory markers trended down. Patient required prolonged hospitalization for wound care and rehabilitation. Following discharge, anakinra was switched to canakinumab, and prednisone was tapered off, without recurrence of MAS or TEN symptoms. Testing for HLA-B*5801, which is associated with allopurinol-related Steven Johnson syndrome (SJS)-TEN, was negative. The benefit-risk relationship of mRNA-1273 vaccine is not affected by this report.   Most recent FOLLOW-UP information incorporated above includes: On 05-Dec-2022: Follow-up received by safety on 05-Dec-22 has email and contains significant information: Author and citation details were added. On 06-Dec-2022: Live follow up received by safety on 08-Dec-2022 has Email with Agency and contains significant information: Reporter information, new literature citation details, lab data, suspect product coding, treatment medications and event information were updated.; Sender's Comments: Company Comment: This is a literature non-study case concerning a 23 year-old, female patient reported as healthy and without history of autoimmune disease, who experienced the serious (due to medically significant and hospitalization) unexpected, events of Haemophagocytic lymphohistiocytosis (reported as Macrophage activation syndrome, MAS), Still's disease (AESI, reported as Adult onset Still's disease, AOSD) and Toxic epidermal necrolysis (AESI). The events MAS and AOSD occurred approximately 7 days after the second dose of mRNA-1273 vaccine and the event Toxic epidermal necrolysis (TEN), 64 days after vaccination. Patient developed daily fevers and cervical lymphadenopathy 1 week after vaccination, she was initially seen at an urgent care center and prescribed azithromycin and corticosteroids. Her symptoms continued, and, over the next 10 days, she developed rash, nausea, vomiting, and abdominal pain, leading her to present to the emergency department. On admission (18 days after vaccination), patient was febrile, had sinus tachycardia, hypotension, enlarged cervical lymph nodes, and a faint blanchable morbilliform eruption on all extremities. Initial evaluation demonstrated leukocytosis; hemoglobin, 11.4 g/dL (1215 g/dL); platelets, 93 × 109/L (150450 × 109/L), elevated liver enzymes; and elevated CRP. Computed tomography revealed splenomegaly and diffuse lymphadenopathy. Blood cultures were obtained, and broad-spectrum antibiotics were initiated. Her negative cultures and a lack of improvement raised concern for malignancy or autoimmune disease. She underwent excisional lymph node biopsy as well as bone marrow biopsy. Allopurinol was started and later discontinued when biopsy and flow cytometry ruled out hematolymphoid malignancy. Her biopsies showed no hemophagocytosis and negative bacterial, fungal, and mycobacterial staining and cultures. EBV PCR, IgM, and IgG as well as SARS-CoV-2 PCR and nuclear capsid IgG testing were also negative, arguing against prior infection. Autoimmune serologies were all within normal limits. She met 5 of 8 diagnostic criteria for hemophagocytic lymphohistiocytosis (HLH), with fevers; splenomegaly; ferritin, 56,131 ng/mL (5204 ng/mL); triglycerides, 811 mg/dL (< 150 mg/dL); and elevated soluble interleukin (IL) 2-receptor, 6158.5 pg/mL (175.3858.2 pg/mL). Patient also met Yamaguchi criteria for AOSD and had marked elevations in both IL-18 (181,803 pg/mL [89540 pg/mL]) and CXCL9 (548,075 pg/mL [< 647 pg/mL]), supporting the diagnosis of MAS. Dexamethasone and anakinra were initiated along with prophylactic atovaquone and pantoprazole. Her symptoms and labs improved despite a brief lapse in anakinra, following hospital discharge, until day 64 after vaccination, when she developed a painful, desquamating, and dusky Nikolsky positive eruption, involving 70% of her total body surface area and mucosae consistent with TEN. Skin biopsy confirmed subepidermal vesicular dermatitis with full-thickness epidermal necrosis. Potential culprit drugs were suspended (pantoprazole, atovaquone, and cephalosporins), and she received intravenous immunoglobulin and cyclosporine. Anakinra was restarted since IL-18 remained elevated, and steroids were continued due to underlying MAS. Rash stopped progressing, and the inflammatory markers trended down. Patient required prolonged hospitalization for wound care and rehabilitation. Following discharge, anakinra was switched to canakinumab, and prednisone was tapered off, without recurrence of MAS or TEN symptoms. Testing for HLA-B*5801, which is associated with allopurinol-related Steven Johnson syndrome (SJS)-TEN, was negative. The benefit-risk relationship of mRNA-1273 vaccine is not affected by this report.