key: cord-0945193-miqceb4n authors: Dandu, Himanshu; Yadav, Geeta; Malhotra, Hardeep Singh; Pandey, Saurabh; Sachu, Ruovinuo; Dubey, Kinjalk title: Hemophagocytic histiocytosis in severe SARS‐CoV‐2 infection: A bone marrow study date: 2021-06-04 journal: Int J Lab Hematol DOI: 10.1111/ijlh.13619 sha: 840b3eb75a479d9dd3080c0f7637273e3d8cbd49 doc_id: 945193 cord_uid: miqceb4n INTRODUCTION: The clinical and laboratory features of severe COVID‐19 infection overlap with those of hemophagocytic lymphohistiocytosis (HLH), a hyperinflammatory disorder often associated with several viral infections. The clinical syndrome of HLH encompasses fever, organomegaly, cytopenias, hyperferritinemia, hypertriglyceridemia, raised transaminases, hypofibrinogenemia, absent natural killer (NK) cell activity, increased soluble CD25 and hemophagocytic lymphohistiocytosis in bone marrow, spleen, and lymph nodes. METHODS: We analyzed clinicopathological and laboratory features of thirteen patients with severe COVID‐19 infection suspected to have HLH and found to have hemophagocytic histiocytosis on bone marrow examination (BME). RESULTS: Five of thirteen (38.46%) patients fulfilled five of eight HLH 2004 criteria and/or had a H‐score ≥169. Three (23.08%) satisfied four of eight and remainder five (38.46%) satisfied three of eight HLH 2004 criteria. Fever, raised serum ferritin (13/13, 100%), transaminases (9/13, 69.23%), triglycerides (4/13, 30.76%), cytopenias (5/13, 38.46%), hypofibrinogenemia (2/13, 15.38%), and organomegaly (1/13, 7.69%) were observed in our patients. BME showed hemophagocytic histiocytosis without lymphocytosis in all. Contrary to HLH, lymphocytopenia (11/13, 84.61%), leukocytosis (7/13, 53.84%), neutrophilia (7/13, 53.84%), and hyperfibrinogenemia (7/13, 53.84%) were observed. Serum CRP, LDH, and plasma D‐dimer were elevated in all, while serum albumin was decreased in 12 of 13 (92.3%) patients. Five patients recovered with high‐dose pulsed corticosteroid therapy. CONCLUSION: The immune response associated with severe COVID‐19 infection is similar to HLH with few differences. HLH should be suspected in severe COVID‐19 infection although all patients may not fulfill required HLH diagnostic criteria. BME should be done in suspected cases so that appropriate therapy may be initiated early. Coronavirus disease 2019 (COVID- 19) , a disease caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has become a pandemic with massive disease burden. As of November 10, 2020, COVID-19 has been confirmed in 51.5 million people worldwide, with a mortality rate of approximately 3.4%. In India, 8 .64 million confirmed cases have been recorded with an estimated mortality of 1.6% as of November 10, 2020. 1, 2 It commonly presents with fever, cough, dyspnea, and myalgia. Although the majority of patients with COVID-19 have mild symptoms, some progress to serious outcomes including pneumonia, acute respiratory distress syndrome (ARDS), multiorgan failure and even death. 3 Some of the serious patients admitted in the intensive care unit (ICU) have clinical and laboratory features mimicking hemophagocytic lymphohistiocytosis (HLH) a condition characterized by a cytokine storm with severe life-threatening hyperinflammation. [4] [5] [6] The early identification of this HLH-like picture is crucial for the management of these patients. In this study, we evaluated clinicopathological and laboratory parameters in thirteen patients with serious SARS-CoV-2 infection who underwent bone marrow examination (BME) for suspected HLH based on clinical and laboratory parameters and were found to have hemophagocytic histiocytosis on BME. This study included thirteen SARS-CoV-2 infected patients who turned out negative for SARS-CoV-2 with due course of time but still had severe respiratory distress and were in the ICU. All patients had clinical features and laboratory findings partially overlapping with HLH 2004 diagnostic criteria and/or the H-score which are used for the diagnosis of HLH (Table 1) . 7, 8 All patients underwent BME which included bone marrow aspiration (BMA) and bone marrow biopsy (BMB) and were found to have hemophagocytic histiocytosis on BMA and BMB. The demographic details (age, sex), date of onset of symptoms and date of admission of each patient were recorded. Clinical findings of each patient including fever, sore throat, cough, organomegaly, and respiratory distress were recorded from history obtained from the patient's relatives and from hospital records. Laboratory The study included seven males and six females with age ranging from forty-one to seventy-four years. Fever was present in all thir- The clinical and laboratory manifestations of severe COVID-19 infection are caused by a cytokine storm associated with increased interleukin-6 levels. Increased interleukin-6 levels induce a persistent inflammatory state which is responsible for the increased levels of acute phase reactants including plasma fibrinogen. 20, 21 Increased levels of pro-inflammatory cytokines interleukin-6, inter- and TNFα). [25] [26] [27] NKG2A receptor overexpression in NK cells is also seen in HLH leading to reduced activity of NK cells in HLH. 28 The immune response associated with severe COVID-19 infection is similar to HLH with a few differences. It is associated with lymphopenia in the peripheral blood and hemophagocytic histiocytosis without lymphocytosis in the bone marrow. Cytopenia, organo- The authors have no competing interests. All authors participated substantially so as to be considered au- The data that support the findings of this study are available from the corresponding author upon reasonable request. Geeta Yadav https://orcid.org/0000-0001-8193-8436 Home -Ministry of Health and Family Welfare -GOI" Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study Could hemophagocytic lymphohistiocytosis be the core issue of severe COVID-19 cases Histiocytic hyperplasia with hemophagocytosis and acute alveolar damage in COVID-19 infection typhoon, cyclone or hurricane in patients with COVID-19? 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