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 Table of Contents  
CASE REPORT
Year : 2021  |  Volume : 12  |  Issue : 4  |  Page : 227-231

Hemophagocytic lymphohistiocytosis trigged by COVID-19 infection: Case report and review of the literature


1 Department of Infectious Diseases, Hedi Chaker University Hospital, University of Sfax, Tunisia
2 Hematology Laboratory, Hedi Chaker University Hospital, University of Sfax, Sfax, Tunisia

Date of Submission13-Aug-2021
Date of Acceptance22-Sep-2021
Date of Web Publication18-Jan-2022

Correspondence Address:
Dr. Fatma Hammami
Department of Infectious Diseases, Hedi Chaker University Hospital, University of Sfax, Sfax
Tunisia
Makram Koubaa
Department of Infectious Diseases, Hedi Chaker University Hospital, University of Sfax, Sfax
Tunisia
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/joah.joah_116_21

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  Abstract 


The outbreak of the novel coronavirus-19 (COVID-19) rapidly grew into a worldwide pandemic. The link between the disease severity and higher levels of inflammatory markers was reported including cases of hemophagocytic lymphohistiocytosis (HLH), a potentially life-threatening disorder. We report herein a case of HLH trigged by COVID-19 infection and we review all reported cases of HLH secondary to COVID-19 among immunocompromised patients by searching PubMed publications till July 2021. A 69-year-old woman with a previous medical history of diabetes mellitus and rheumatoid arthritis treated with oral steroids presented for a 5-day history of fever, persistent cough, anorexia, and dyspnea. The diagnosis of COVID-19 was confirmed. She received empiric antibiotic therapy, oxygen supply, and corticosteroids. On day 17, laboratory investigations revealed bicytopenia with a platelets rate of 31,000/mm3 and an hemoglobin rate of 8.2 g/dL. Hyperferritinemia, hypertriglyceridemia, and hypofibrinogenemia were noted. Bone marrow aspiration and biopsy revealed images of hemophagocytosis. The HScore yielded 200 points, representing 80%–88% probability of HLH. We continued corticosteroids and treatment. The disease evolution was favorable. The diagnosis of HLH secondary to COVID-19 shoud be considered in front of cytopenia, hyperinflammatory state, and a worsening clinical condition. Prompt diagnosis and treatment improve the prognosis.

Keywords: Coronavirus-19, hemophagocytic lymphohistiocytosis, immunosuppression


How to cite this article:
Hammami F, Koubaa M, Rekik K, Chaabouni H, Chaari M, Smaoui F, Jemaa MB. Hemophagocytic lymphohistiocytosis trigged by COVID-19 infection: Case report and review of the literature. J Appl Hematol 2021;12:227-31

How to cite this URL:
Hammami F, Koubaa M, Rekik K, Chaabouni H, Chaari M, Smaoui F, Jemaa MB. Hemophagocytic lymphohistiocytosis trigged by COVID-19 infection: Case report and review of the literature. J Appl Hematol [serial online] 2021 [cited 2022 Sep 25];12:227-31. Available from: https://www.jahjournal.org/text.asp?2021/12/4/227/335937




  Introduction Top


The outbreak of the novel coronavirus-19 (COVID-19), which was first reported in Wuhan, China, rapidly grew into a worldwide pandemic. Severe forms of the disease were reported with an acute severe respiratory syndrome.[1] Previous study reported the link between the disease severity and higher levels of inflammatory markers, cytokines, and chemokines,[2] which was identified as a cytokine storm syndrome.[3] This is not a new phenomenon. In fact, cytokine storm syndrome was known since the pre-COVID-19 era. It was known as hemophagocytic lymphohistiocytosis (HLH) or macrophage activation syndrome.[4] In fact, HLH is a potentially life-threatening disorder due to the hypersecretion of cytokines and immune-mediated organ damage, which is the result of the uncontrolled activation of cytotoxic T cells, natural killer cells, and macrophages.[5] The underlying etiology might be an infection, including viral, bacterial, parasitic or fungal infections, malignancy, or rheumatologic disorders.[6] Previous studies reported cases of HLH trigged by COVID-19 among both survivers[7] and deceased patients.[8] We report herein a case of HLH trigged by COVID-19 infection in a 69-year-old immunocompromised patient and we review all reported cases of HLH secondary to COVID-19 among immunocompromised patients by searching PubMed publications till July 2021. Cases with HScore >169, corresponding to a sensitivity of 93% and a specificity of 86% for HLH, were included.[9]


  Case Report Top


A 69-year-old woman with a previous medical history of non-insulin-dependent diabetes mellitus and rheumatoid arthritis treated with oral steroids (prednisone 10 mg/day) presented for a 5-day history of fever, persistent cough, anorexia, and dyspnea. On admission, she was febrile with a blood pressure of 90/50 mmHg and heart rates of 97 beats/min. Her oxygen saturation was 83% in room air and her respiratory rate of 23 breaths/min. She had neither hepatomegaly nor splenomegaly. Laboratory investigations revealed elevated C-reactive protin levels at 142 mg/L, a white blood cells count at 4450/mm3, a lymphopenia at 620/mm3, an hemoglobin level at 11.6 g/dL, and platelets count at 173,000/mm3. Renal and hepatic functions were normal. She was started empiric antibiotic therapy based on intravenous third-generation cephalosporin (cefotaxime at a dose of 1 g every 8 h) for suspected bacterial superinfection, oxygen supply via nasal prongs (4L 99% oxygen), and corticosteroids (dexamethasone at a dose of 4 mg twice daily). COVID-19 polymerase chain reaction test from a nasal swab was positive. Chest computed tomography scan showed COVID-19 typical infiltrates with an estimated 50% involvement. On day 5, she suddenly developed markedly increased tachypnea with a respiratory rate of 38 breaths/min and rapidly decreasing oxyhemoglobin saturations, thus requiring oxygen enrichment (14L flow of 100% oxygen). On day 8, the patient presented watery diarrhea, nausea, and vomiting associated with the fever at 39.6°C. Blood, urine, and stool cultures were negative. Abdominal computed tomography scan revealed fatty infiltration of the mesentery associated with peritoneal effusion localized in the paracolic gutters and in the pelvis without peritoneal collection. On day 17, laboratory investigations revealed bicytopenia with a platelets rate of 31,000/mm3 and an hemoglobin rate of 8.2 g/dL. The white blood cell count was 7350/mm3 with a neutrophil rate of 5390/mm3 and a lymphocyte rate of 1510/mm3. C-reactive protein level decreased to 50 mg/L. Heparin-induced thrombocytopenia was suspected, that's why discontinuation of heparin was immediately indicated. The next day, the disease evolution was marked by the appearance of low abundance rectorrhagia. Worsening thrombocytopenia at 25,000/mm3 and anemia at 7.1 g/dL were noted. The patients received continuous intravenous omeprazole and red blood cell and platelet transfusions. Ferritin level was elevated 951 μg/L and triglyceride rate was high at 2.1 mmol/L. Blood tests also showed a fibrinogen level of 1.21 g/L and a serum lactate dehydrogenase level at 298 UI/L. Bone marrow aspiration and biopsy revealed images of hemophagocytosis. There was no evidence of bacterial infection or hematological malignancy. The HScore yielded 200 points, representing 80%–88% probability of HLH. The patient fulfilled five of the eight HLH-2004 diagnostic criteria including fever, cytopenias, hypofibrinogenemia, hyperferritinemia, and images of hemophagocytosis. The diagnosis of HLH trigged by COVID-19 infection was confirmed. The decision made was to continue corticosteroids based on dexamethasone associated with antipyretic treatment. The disease evolution was favorable with a resolution of fever, rectorrhagia, and progressive improvement of thrombocytopenia and anemia. Platelets rate was 50,000/mm3 than 106,000/mm3, and hemoglobin rate was 8.2 g/dl than 8.8 g/dl, 2 and 4 days later, respectively. The C-reactive protein level was 11 mg/L. The patient's general condition improved and exhibited a slowly decreasing oxygen demand. On day 24, laboratory investigations revealed a platelets rate of 185,000/mm3, an hemoglobin rate of 9.8 g/dL, and a C-reactive protein level of 5 mg/L. The patient was discharged on day 26.


  Discussion Top


The literature search yielded 13 cases of HLH secondary to COVID-19 infection among immunocompromised patients[7],[8],[10],[11],[12],[13],[14],[15],[16] [Table 1]. A male predominance was noted. In fact, similar numbers of cases of COVID-19 were demonstrated in women and men worldwide, with differences between the countries, among which higher incidence in men in the older age groups was reported.[17] As for the diagnosis confirmation, hemophagocytosis in bone marrow was only reported among 5 cases.[7],[10],[12],[15],[16] Using the HScore facilitated the diagnosis of HLH. In fact, bone marrow biopsy, an invasive procedure, wasn't even required in most cases. Specific treatments for HLH including intravenous immunoglobulin,[7],[14],[15] tocilizumab,[13],[15] ruxolitinib,[13] and anakinra[11] were prescribed. Our patient was treated with corticosteroids which were first indicated for the COVID-19 infection, then maintained to treat HLH. The disease evolution was favorable in most cases. Death was noted among four cases.[7],[10],[11],[12] In fact, HLH secondary to COVID-19 among immunocompromised patients is a rare disease. A previous study included 206 cancer patients diagnosed with COVID-19 infection and found that HLH was a rare occurrence based on the HScore (1%).[7] HLH, an acute and rapidly progressive systemic inflammatory disorder, is classified into two subgroups. Primary, also called familial HLH, is an hereditary immune disorder, while acquired HLH, is secondary to infection, malignancy, autoimmune disease or drug hypersensitivity.[18],[19] The most common infectious etiologies associated with HLH include viral infections, such as Epstein–Barr virus, Cytomegalovirus, Parvovirus, and Herpes simplex virus.[20] Since the COVID-19 pandemic, cases of HLH secondary to this virus were reported, while other studies suggest that the cytokine storm caused by the virus has significant similarities with the clinical and laboratory findings of HLH.[18] HScore was developed to estimate the individual's risk of HLH. A cutoff of 169 was associated with 93% sensitivity and 86% specificity for HLH.[9] A previous study reported a trend for a higher HScore among patients with severe COVID-19 with unfavorable courses.[21] However, only 32% of patients included in the study reached the cutoff of 169 for suspicion of HLH.[21] In fact, France et al. concluded that HScore was more useful than the HLH-2004 criteria for children. As for adults, the score was most useful only at the patient's initial presentation, while it is performance dropped to levels similar to the HLH-2004 criteria, once the patient's clinical condition worsens.[22] For our patient, the diagnosis of HLH was confirmed based on both HScore and HLH-2004 criteria after detoriation of her condition. The appearance of bicytopenia was an alarming sign that motivated us to look for the diagnosis of HLH. As for its management, along with appropriate resuscitation and supportive care, specific treatment might be indicated starting with corticosteroids, which are effective in almost half of the cases. Otherwise, cyclosporin, intravenous immunoglobulin, or etoposide might be considered to target the hyperinflammatory state.[23] The prognosis of HLH is closely related to the underlying etiology. The 5-year survival rate in patients with HLH trigged by infections ranged between 83% and 90%.[24]
Table 1: Clinical and laboratory data of haemophagocytic lymphohistiocytosis cases secondary to coronavirus-19 among immunocompromised patients reported in the literature

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HLH trigged by COVID-19 infection among immunocompromised patients was a rare disease. The diagnosis should be considered in front of cytopenia, hyperinflammatory state, and a worsening clinical condition. Prompt diagnosis and treatment improve the prognosis.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Brikman S, Bieber A, Dori G. The hyper-inflammatory response in adults with severe COVID-19 pneumonia differs from the cytokine storm of hemophagocytic syndrome. Isr Med Assoc J 2020;22:505-13.  Back to cited text no. 1
    
2.
Merad M, Martin JC. Pathological inflammation in patients with COVID-19: A key role for monocytes and macrophages. Nat Rev Immunol 2020;20:1.  Back to cited text no. 2
    
3.
Mehta P, McAuley DF, Brown M, Sanchez E, Tattersall RS, Manson JJ, et al. COVID-19: Consider cytokine storm syndromes and immunosuppression. Lancet 2020;395:1033-4.  Back to cited text no. 3
    
4.
Yongzhi X. COVID-19-associated cytokine storm syndrome and diagnostic principles: An old and new Issue. Emerg Microbes Infect 2021;10:266-76.  Back to cited text no. 4
    
5.
Chu R, van Eeden C, Suresh S, Sligl WI, Osman M, Cohen Tervaert JW. Do COVID-19 infections result in a different form of secondary hemophagocytic Lymphohistiocytosis. Int J Mol Sci 2021;22:2967.  Back to cited text no. 5
    
6.
Jordan MB, Allen CE, Greenberg J, Henry M, Hermiston ML, Kumar A, et al. Challenges in the diagnosis of hemophagocytic lymphohistiocytosis: Recommendations from the north American consortium for histiocytosis (NACHO). Pediatr Blood Cancer 2019;66:e27929.  Back to cited text no. 6
    
7.
Hueso T, Bouchez C, Salviat F, Foulon S, Albiges L, Bayle A, et al. Secondary haemophagocytic lymphohistiocytosis is a rare occurrence amongst cancer patients with COVID-19. Br J Haematol 2021;192:e87-90.  Back to cited text no. 7
    
8.
Yang K, Xing MY, Jiang LY, Cai YP, Yang LL, Xie NN, et al. Infection-associated hemophagocytic syndrome in critically ill patients with COVID-19. Curr Med Sci 2021;41:39-45.  Back to cited text no. 8
    
9.
Fardet L, Galicier L, Lambotte O, Marzac C, Aumont C, Chahwan D, et al. Development and validation of the HScore, a score for the diagnosis of reactive hemophagocytic syndrome. Arthritis Rheumatol 2014;66:2613-20.  Back to cited text no. 9
    
10.
Harris CK, Hung YP, Nielsen GP, Stone JR, Ferry JA. Bone marrow and peripheral blood findings in patients infected by SARS-CoV-2. Am J Clin Pathol 2021;155:627-37.  Back to cited text no. 10
    
11.
Dimopoulos G, de Mast Q, Markou N, Theodorakopoulou M, Komnos A, Mouktaroudi M, et al. Favorable anakinra responses in severe COVID-19 patients with secondary hemophagocytic lymphohistiocytosis. Cell Host Microbe 2020;28:117-23.e1.  Back to cited text no. 11
    
12.
von der Thüsen JH, van Bommel J, Kros JM, Verdijk RM, Lopuhaä B, Lam KH, et al. Case report: A fatal combination of hemophagocytic lymphohistiocytosis with extensive pulmonary microvascular damage in COVID-19 pneumonia. J Hematop 2020;14:79-83.  Back to cited text no. 12
    
13.
Portsmore S, Tran Nguyen TN, Beacham E, Neelakantan P. Combined IL-6 and JAK/STAT inhibition therapy in COVID-19-related sHLH, potential game changer. Br J Haematol 2020;190:525-8.  Back to cited text no. 13
    
14.
Ramos-Ruperto L, Busca-Arenzana C, Valdivieso J, López-Granados E, Robles-Marhuenda Á. COVID-19 and pembrolizumab-induced secondary hemophagocytic lymphohistiocytosis: A case report. SN Compr Clin Med 2021;3:1412-5.  Back to cited text no. 14
    
15.
Tholin B, Hauge MT, Aukrust P, Fehrle L, Tvedt TH. Hemophagocytic lymphohistiocytosis in a patient with COVID-19 treated with tocilizumab: A case report. J Med Case Rep 2020;14:1-5.  Back to cited text no. 15
    
16.
Faguer S, Del Bello A, Abravanel F, Nicolau-Travers ML, Kamar N. Tocilizumab for hemophagocytic syndrome in a kidney transplant recipient with COVID-19. Ann Intern Med 2020;173:501-3.  Back to cited text no. 16
    
17.
Gebhard C, Regitz-Zagrosek V, Neuhauser HK, Morgan R, Klein SL. Impact of sex and gender on COVID-19 outcomes in Europe. Biol Sex Differ 2020;11:29.  Back to cited text no. 17
    
18.
Soy M, Atagündüz P, Atagündüz I, Sucak GT. Hemophagocytic lymphohistiocytosis: A review inspired by the COVID-19 pandemic. Rheumatol Int 2021;41:1.  Back to cited text no. 18
    
19.
Morimoto A, Nakazawa Y, Ishii E. Hemophagocytic lymphohistiocytosis: Pathogenesis, diagnosis, and management. Pediatr Int 2016;58:817-25.  Back to cited text no. 19
    
20.
Tothova Z, Berliner N. Hemophagocytic syndrome and critical illness: New insights into diagnosis and management. J Intensive Care Med 2015;30:401-12.  Back to cited text no. 20
    
21.
Lorenz G, Moog P, Bachmann Q, Rosée PL, Heike Schneider MS. Cytokine release syndrome is not usually caused by secondary hemophagocytic lymphohistiocytosis in a cohort of 19 critically ill COVID-19 patients. Sci Rep 2020;10:18277.  Back to cited text no. 21
    
22.
Debaugnies F, Mahadeb B, Ferster A, Meuleman N, Rozen L, Demulder A, et al. Performances of the H-score for diagnosis of hemophagocytic lymphohistiocytosis in adult and pediatric patients. Am J Clin Pathol 2016;145:862-70.  Back to cited text no. 22
    
23.
Sen ES, Clarke SL, Ramanan AV. Macrophage activation syndrome. Indian J Pediatr 2016;83:248-53.  Back to cited text no. 23
    
24.
Malinowska I, Machaczka M, Popko K, Siwicka A, Salamonowicz M, Nasiłowska-Adamska B. Hemophagocytic syndrome in children and adults. Arch Immunol Ther Exp (Warsz) 2014;62:385-94.  Back to cited text no. 24
    



 
 
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