Virginia Research Day 2021

Hyerperhemolysis in the setting of Mixed-Autoimmune Hemolytic Anemia: a rare complication of COVID-19 Narula, S MD, Winkle, S MD, Truitt, T MD, Brand, K MD, Shah, F MD, Khan, S MD, Helsley D, DO, Fujikawa, P DO, and Currie, MMD

Discussion (Continued)

Case Report (Continued)

Background

AIHA following SARS-CoV-2 infection with either warm or cold autoantibodies has previously been documented in the literature 1 . The majority of the cases described in the literature were associated with warm autoimmune hemolytic anemia. To our knowledge, this has been the first case in which a patient had tested positive for both warm and cold antibodies. Three reported cases of SARS-CoV-2 associated AIHA also had a history of a prior hematological disorder (ITP). This suggests that preexisting hematological abnormalities may be a risk factor in the development of AIHA 1 . These patients were treated with steroids and/or IVIG, as was our patient with the addition of rituximab in refractory cases. 1 This patient presented with an unusual complication known as hyperhemolysis. Hyperhemolysis is a type of delayed hemolytic transfusion reaction in which there is both hemolysis of transfused red blood cells as well as the recipient’s red blood cells. Though originally described in AIHA, it has most commonly been observed in sickle-cell disease patients who have required multiple transfusions. Since hyperhemolysis is typically seen with complement activation of the membrane attack complex, which is uncommon in IgG predominant AIHA, it is likely that the patient’s presentation with mixed warm-cold antibodies triggered his pathology. Further research needs to be conducted to determine the mechanism between SARS-CoV-2 infections and AIHA. Some have posited that systemic hyperinflammation leading to a cytokine storm is the underlying mechanism behind the mortality of SARS-CoV-2. Specifically, serum cytokine levels that have been found to elevated in patients suffering from a Covid-19 – associated cytokine storm include interleukin- 1β, interleukin -6, IP-10, TNF, interferon- γ, macrophage inflammatory protein 1α and 1β, and VEGF; with an increased frequency of CD4+ and CD8+ T cells seen as well. 4 Also, increased interleukin-6 levels have been strongly associated with a shorter survival amongst patients suffering from Covid-19. 4 On arrival at the outside facility, he was febrile to 39.1C, blood pressure was 134/74, heart rate 74, and respiratory rate of 35. His hemoglobin was 3.0 g/dL, WBC 74 x 10 3 /ul, and platelets were 363 x 10 3 /ul without evidence of overt bleeding. His chest x-ray showed bilateral lung ground glass airspace disease. He tested positive for SARS-CoV-2 via PCR. His DAT IgG and C3 were warm-predominant without cold antibody presence, and the patient was started on rituximab in addition to IVIG and methylprednisone. He received 1U PRBC, but he rapidly deteriorated over the next 2 days. developing multi-organ failure and coagulopathy with DIC. However, he ultimately died from shock secondary to a hyperhemolytic state in the setting of SARS-CoV-2 infection. Discussion

Use of IL-6 inhibitors like tocilizumab has been considered since researchers have noted high concentrations of proinflammatory cytokines, such as IL-6 in severe SARS-CoV-2 infections. It has also been shown to be effective in patients who develop hyperhemolysis in the setting of sickle cell disease. 5 In our patient, the levels of IL-6 were unable to be measured due to the icteric nature of the drawn sample. This patient ultimately died following multiple cardiac arrests, which was related to his severe anemia from his hyperhemolytic state. Of the 15 total cases of autoimmune hemolytic anemia described in the literature, this case is the first of a patient who developed hyperhemolysis in the setting of mixed autoimmune hemolytic anemia secondary to SARS-CoV-2.

SARS-CoV-2 is an emerging human pathogen that is a known cause of pneumonia, respiratory failure, and acute respiratory distress syndrome. While predominantly known for disease and complications involving the respiratory system, the pathology of the virus may extend beyond the lungs, causing sequelae to multiple organ systems. To the author’s knowledge there have been 15 cases of SARS-CoV-2-associated autoimmune hemolytic anemia (AIHA). Herein we report a unique case of hyperhemolysis in the setting of the virus.

Case Report

Conclusion

This case highlights the importance of further monitoring of SARS-CoV- 2 infections and study of the pathology associated with extrapulmonary manifestations of the virus. As a better understanding of associated systemic disease is reported, practitioners will be more prepared to anticipate poor outcomes and treat patients accordingly.

A 33 year-old male with a past medical history of resolved immune thrombocytopenic purpura (ITP) and alcoholism presented to the hospital with acute onset “yellow eyes” and “orange urine” associated with a week of fevers, chills, and night sweats. This was associated with two weeks of malaise, loss of taste and smell, cough, and shortness of breath that had resolved seven days after onset. He had a close contact who had tested positive for SARS-CoV-2 but had not been tested himself. On initial presentation the patient’s vital signs were stable. Labs were significant for a bilirubin of 10 mg/dl while other liver enzymes were unremarkable. He had leukocytosis with a WBC of 15 x 10 3 /ul however hemoglobin (Hgb) and platelet count were within normal limits. PCR for SARS-CoV-2 was negative. The only significant physical exam finding was scleral icterus. Organomegaly and abdominal tenderness were not appreciated. Overnight, the patient reported night sweats, nausea and non-bloody, non-bilious emesis. His RBC count fell from 12.5 to 8.7 g/dL. He was started on IV Dexamethasone 4mg daily. A bone marrow biopsy was done due to concern for hemophagocytic lymphohistiocytosis, showing mild hemophagocytosis. Abdominal CT scan was negative for acute pathology. Hemolysis labs results showed LDH at 759 U/L, Haptoglobin <10 g/L, ferritin 4903 ng/mL, and the percent reticulocyte count was 2.33%. DAT, C3, IgG, anti-E assays were positive in addition to both warm and cold autoantibodies. Type and screen returned positive for all antibodies including the control and it was determined the patient had a complement activating IgM, causing RBC lysis. A total of seven units of PRBC was required to achieve a Hgb of 6 in 48 hours. Transfer to an outside facility was required to provide plasmapheresis.

Referances

1. Lazarian G, Quinquenel A, Bellal M, et al. Autoimmune haemolytic anaemia associated with COVID-19 infection. Br J Haematol . 2020;190(1):29-31. doi:10.1111/bjh.16794 2. Angileri F, Légaré S, Marino Gammazza A, Conway de Macario E, Macario AJL, Cappello F. Is molecular mimicry the culprit in the autoimmune haemolytic anaemia affecting patients with COVID-19?. Br J Haematol . 2020;190(2):e92-e93. doi:10.1111/bjh.16883 3. Alessandra Berzuini, Cristiana Bianco, Cinzia Paccapelo, Francesco Bertolini, Giuliana Gregato, Alessandra Cattaneo, Elisa Erba, Alessandra Bandera, Andrea Gori, Giuseppe Lamorte, Maria Manunta, Laura Porretti, Nicoletta Revelli, Francesca Truglio, Giacomo Grasselli, Alberto Zanella, Stefania Villa, Luca Valenti, Daniele Prati; Red cell – bound antibodies and transfusion requirements in hospitalized patients with COVID-19. Blood 2020; 136 (6): 766 – 768. doi: https://doi.org/10.1182/blood.2020006695 4. Fajgenbaum DC, June CH. Cytokine Storm. N Engl J Med . 2020;383(23):2255-2273. doi:10.1056/NEJMra2026131 5. Sivapalaratnam S, Linpower L, Sirigireddy B, Agapidou A, Jain S, Win N, Tsitsikas DA. Treatment of post-transfusion hyperhemolysis syndrome in Sickle Cell Disease with the anti-IL6R humanised monoclonal antibody Tocilizumab. Br J Haematol. 2019 Sep;186(6):e212-e214. doi: 10.1111/bjh.16103. Epub 2019 Aug 1. PMID: 31368112

This research was supported (in whole or in part) by HCA Healthcare and/or an HCA Healthcare affiliated entity. The views expressed in this publication represent those of the author(s) and do not necessarily represent the official views of HCA or any of its affiliated entities.

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