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COVID-19-associated secondary hemophagocytic lymphohistiocytosis requiring hematopoietic cell transplant.

ABSTRACT: Coronavirus disease 2019 (COVID-19) infection causes a variety of extrapulmonary complications in pediatric patients. Multisystem inflammatory syndrome and hemophagocytic lymphohistiocytosis (HLH) are related to hypercytokinemia in COVID-19 patients. HLH is a disorder of exaggerated inflammation resulting in a cytokine storm and unrestricted hemophagocytosis. HLH can be primary (familial) or secondary (acquired). Secondary HLH (sHLH) can occur in patients with rheumatologic, oncologic, or infectious diseases. The link between COVID-19 and HLH has been reported in pediatric patients. Here we report a case of a pediatric patient who developed refractory sHLH secondary to COVID-19 infection and required a hematopoietic cell transplant for the cure.

SUBMITTER: Greenmyer JR

PROVIDER: S-EPMC9348183 | biostudies-literature | 2022 May

REPOSITORIES: biostudies-literature

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COVID-19-associated secondary hemophagocytic lymphohistiocytosis requiring hematopoietic cell transplant.

Greenmyer Jacob R JR Wyatt Kirk D KD Milanovich Sam S Kohorst Mira A MA Ferdjallah Asmaa A

EJHaem 20220511 3

Coronavirus disease 2019 (COVID-19) infection causes a variety of extrapulmonary complications in pediatric patients. Multisystem inflammatory syndrome and hemophagocytic lymphohistiocytosis (HLH) are related to hypercytokinemia in COVID-19 patients. HLH is a disorder of exaggerated inflammation resulting in a cytokine storm and unrestricted hemophagocytosis. HLH can be primary (familial) or secondary (acquired). Secondary HLH (sHLH) can occur in patients with rheumatologic, oncologic, or infect ...[more]

PMID: 35941881

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Project description:ContextCOVID-19 has been associated with features of a cytokine storm syndrome with some patients sharing features with the hyperinflammatory disorder, secondary hemophagocytic lymphohistiocytosis (sHLH).HypothesisWe hypothesized that proteins associated with sHLH from other causes will be associated with COVID-sHLH and that subjects with fatal COVID-sHLH would have defects in immune-related pathways.Methods and modelsWe identified two cohorts of adult patients presenting with COVID-19 at two tertiary care hospitals in Seattle, Washington in 2020 and 2021. In this observational study, we assessed clinical laboratory values and plasma proteomics. Subjects identified as having sHLH (ferritin > 1000 plus cytopenias in two or more lineages [WBC < 5000 odds ratio [OR] ANC (absolute neutrophil count) < 1000, hemoglobin < 9 or hematocrit < 27, platelets < 100,000], and elevated transaminases [either AST (aspartate aminotransferase) or ALT (alanine aminotransferase) > 30] OR subjects with a ferritin > 3000) were compared with those with COVID-19 without sHLH. We identified 264 patients with COVID-19 of whom 24 met our sHLH definition. Eight patients who died of COVID-sHLH underwent genomic sequencing to identify variants in immune-related genes.ResultsNine percent of enrolled COVID-19 subjects met our defined criteria for sHLH (n = 24/264). Using broad serum proteomic approaches (O-link and SomaScan), we identified three proteins increased in subjects with COVID-19-associated sHLH (soluble PD-L1 [sPD-L1], tumor necrosis factor-R1, and interleukin [IL]-18BP, p < 0.05 for O-link and false discovery rate < 0.05 for SomaScan), supporting a role for proteins previously associated with other forms of sHLH (IL-18BP and soluble tumor necrosis factor receptor 1). We also identified candidate proteins and pathways associated with COVID-sHLH, including sPD-L1 and the syntaxin pathway. We detected pathogenic variants in DOCK8 and TMPRSS15 in deceased individuals with COVID-sHLH, further suggesting that alterations in immune-related processes may contribute to hyperinflammation and fatal outcomes in COVID-19.Interpretations and conclusionsProteins increased in COVID-19-associated sHLH, such as sPD-L1, and pathways, such as the syntaxin pathway, suggest important roles for the immune response in driving sHLH in the context of COVID-19.

Project description:Hemophagocytic lymphohistiocytosis (HLH) is a fatal systemic inflammatory syndrome. HLH has been reported as a rare immune-related adverse event (irAE) in patients receiving immunotherapy with nivolumab, ipilimumab, and/or pembrolizumab. The data are limited to case reports and case series. The objective of this research is to compile data on this rare but potentially life-threatening adverse event of immune checkpoint inhibitors (ICIs) and identify the common agents that cause this irAE, clinical spectrum, and successful management strategies to assist the treating oncologists. A review was done using PubMed database. Eligible articles included case reports and case series published from January 1, 2015, through February 1, 2021. Reports published in languages other than English were excluded. Data were compiled into a detailed supplementary table and simple descriptive analysis was used to interpret data. A total of 22 cases were included, which constituted 14 individual case reports and two case series. The immunotherapy prescribed consisted of antibodies against and programmed cell death 1 (PD-1) or its ligand, programmed cell death ligand 1 (PD-L1) in all 22 patients. Out of them, immunotherapy consisting of anti-cytotoxic T-lymphocyte antigen 4 (anti-CTLA-4) antibodies was prescribed in nine patients. Fever was the most common symptom at the presentation (90.9%). The most common laboratory findings were anemia (90.9%), thrombocytopenia (90.9%), and elevated ferritin (90.9%). All the patients received steroids (100%). HLH responded to treatment in 19 patients. Three patients died. Three patients were rechallenged with immunotherapy, with no recurrence of HLH. HLH in the setting of ICI therapy is life-threatening, but potentially treatable with early detection. However, diagnosis is often delayed due to difficulty in differentiating the presenting symptoms and laboratory findings from complications of cancer and other therapies. Majority have shown an adequate response to standard HLH treatment; however, some required a longer course of corticosteroids. HLH is not always associated with other irAE. Rechallenging with immunotherapy was successful in some patients after completing treatment for HLH.

Dataset Information

COVID-19-associated secondary hemophagocytic lymphohistiocytosis requiring hematopoietic cell transplant.

Publications

COVID-19-associated secondary hemophagocytic lymphohistiocytosis requiring hematopoietic cell transplant.

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