key: cord-0924857-gxqryn1v
authors: Yamazaki, Susumu; Naito, Erika; Sekiya, Ryu; Yogi, Sanehiro; Komiyama, Kenichiro; Miyakawa, Yoshitaka; Nagata, Makoto
title: Pure red cell aplasia accompanied by COVID-19 successfully treated using cyclosporine
date: 2021-10-25
journal: J Infect Chemother
DOI: 10.1016/j.jiac.2021.10.018
sha: aaab7963ee82fe15b464c72afab34d21e892f6b7
doc_id: 924857
cord_uid: gxqryn1v

A 67-year-old Japanese man was admitted to our hospital with severe coronavirus disease 2019 (COVID-19) in March 2020. Mechanical ventilation was initiated 8 days after admission, due to severe respiratory failure. Multiple severe complications such as liver dysfunction, arrhythmia, brain infarction, and venous thromboembolism were also observed. We initially diagnosed Coombs test-positive warm autoimmune hemolytic anemia. Corticosteroids proved ineffective and anemia worsened with severe erythroid hypoplasia (0.5% erythroblasts in bone marrow), so we diagnosed pure red cell aplasia (PRCA). We also identified massive infiltration of cytotoxic T-lymphocytes expressing CD8, granzyme B, and perforin in bone marrow. Systemic cyclosporine was started, with full resolution of anemia and no need for blood transfusions after 4 weeks. We believe that this represents the first report of COVID-19-associated PRCA successfully treated using cyclosporine.

Coronaviruses are well-known respiratory pathogens in humans and other animals. A novel coronavirus was identified as the cause of an outbreak of fatal pneumonia in Wuhan, Hubei, China at the end of 2019. That infection spread rapidly, resulting in a global pandemic. The resulting pathology was termed coronavirus disease 2019 (COVID-19) by the World Health Organization [1] , and the causative coronavirus was named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) by the International Committee on Taxonomy of Viruses [2] . COVID-19 causes fatal severe respiratory failure or acute respiratory distress syndrome, in addition to complications such as arrhythmia, acute heart failure, acute renal failure, and thromboembolism. Here we report a case of pure red cell aplasia (PRCA) following an initial presentation with warm auto immune hemolytic anemia (AIHA) during the course of treatment for severe COVID-19.

A 67-year-old male Japanese office worker traveled in northern Africa in February 2020.

After returning to Japan, he experienced high fever, headache and loose stools, and subsequent polymerase chain reaction (PCR) testing for SARS-CoV-2 yielded positive J o u r n a l P r e -p r o o f results. On admission, the patient showed high fever (40.2°C) and needed supplemental oxygen at 2 L/min via nasal cannula because of hypoxia. Chest computed tomography (CT) (Figure 1 ) showed patchy ground glass opacities and consolidations in both lungs.

Blood testing on admission revealed inflammation, mild liver dysfunction and elevated levels of D-dimer ( Table 1) . As ciclesonide, lopinavir-ritonavir, levofloxacin, and meropenem all proved ineffective, respiratory failure progressed and the patient was intubated on day 8. On day 38, we diagnosed venous thromboembolism from contrast-enhanced CT and started the anti-Xa inhibitor edoxaban.

The patient was extubated on day 24, but became dependent on red blood cell (RBC) transfusion. Hemoglobin was 7.4 g/dL with low haptoglobin (3 mg/dL) and increases in both serum lactate dehydrogenase (327 U/L) and reticulocytes (27.1‰) on day 26, while total bilirubin was 2.6 mg/dL and indirect bilirubin was 0.6 mg/dL. As the direct Coombs test (immunoglobulin [Ig]G) yielded positive results, we diagnosed warm autoimmune hemolytic anemia (AIHA) and started prednisolone at 60 mg/day (1 mg/kg/day) on day 52. However, prednisolone proved ineffective and was tapered after and hemoglobin recovered to 11.0 g/dL on day 373 ( Figure 3 ).

The patient in this case was diagnosed with AIHA and PRCA during the clinical course of severe COVID-19. We believed that this represents the first description of PRCA associated with COVID-19. Previous reports have described COVID-19 accompanied by several autoimmune diseases and inflammatory disorders, such as Guillan-Barré syndrome, immune thrombocytopenia, AIHA, antiphospholipid syndrome and Kawasaki disease. Aberrant activation and dysregulation of CD8+ T cells have been described in patients with severe COVID-19, following cytokine storm involving inflammatory cytokines such as interleukin-1, interleukin-6, tumor necrosis factor-alpha, interferon gamma-inducible protein 10 and monocyte chemoattractant protein 1.

PRCA is an intractable anemia characterized by selective reduction of erythropoiesis in the bone marrow and consequent marked depletion of reticulocytes (<1%) and development of normocytic anemia [3] . PRCA is a rare benign blood disorder. The annual incidence of PRCA in Japan has been estimated as 0.3 per million population.

No sex predominance is considered present. The pathogenesis of PRCA is idiopathic in 39% of cases, thymoma in 23%, and lymphoproliferative disorder in 14% [4] . In this J o u r n a l P r e -p r o o f case, we excluded infections with B19 parvovirus [5] , acute hepatitis A [6] , human immunodeficiency virus, human T-cell leukemia virus type 1, and Epstein-Barr virus based on serological tests and PCR. As the p-antigen on RBC progenitors is known to act as the receptor for B19 parvovirus, we speculate that cytotoxic T cells might destroy erythroid progenitors in the bone marrow [7] .

PRCA is classified into acute or chronic forms based on the pathogenesis, but criteria for categorizing the duration into acute or chronic forms have yet to be established. In the present case, the patient was initially diagnosed with warm AIHA based on positive test results from the direct Coombs test [9] [10] [11] . Given the clinical resistance to systemic corticosteroids, bone marrow biopsy was performed and led to the diagnosis of PRCA, and the patient was successfully treated using immunosuppressive therapy with cyclosporine. At the time this case was diagnosed and treated, systemic corticosteroids had not been approved for use against COVID-19, as their clinical efficacy was not established and approved for coverage by public health insurance until spring 2020. In J o u r n a l P r e -p r o o f this case, a more up-to-date treatment strategy centered on anti-inflammatory treatment might thus have prevented the onset of AIHA or PRCA in the first place.

Several reports have described PRCA after AIHA, and we speculate that this case was caused by similar mechanisms [12] [13] [14] [15] [16] .

In this case, angiotensin-converting enzyme 2 receptors on endothelial cells may have contributed to the entry of SARS-CoV-2, followed by severe inflammation, acute respiratory failure, and coagulation disorders [17] . Although we confirmed massive infiltration of cytotoxic T cells into bone marrow and PRCA in this case, the mechanisms by which those T cells were induced by SARS-CoV-2 infection remain uncertain. In this case, the onset of anemia was slower than in previously reported cases.

As the amount of RBC transfusion was initially not high, the diagnosis of PRCA was delayed. The exact mechanisms involved in this case remain uncertain, but we speculate that individual differences, magnitude of viral load, and/or strength of cytokine storms might have been contributing factors. Compared to idiopathic PRCA, little is known regarding the prognosis or optimal treatment for COVID-19-associated PRCA. We therefore expect this case report will provide helpful information in understanding secondary blood disorders caused by SARS-CoV-2.

We encountered a case of PRCA complicated by COVID-19, accompanied by massive prothrombin time international normalized ratio, FIB: fibrinogen, FDP: fibrin and fibrinogen degradation products, TP: total protein, CK: creatine kinase, AST: aspartate aminotransferase, ALT: alanine aminotransferase, LDH: lactate dehydrogenase, ALP: alkaline phosphatase, γ-GTP: γ-glutamyl transpeptidase, BUN: blood urea nitrogen, T-Bil: total bilirubin, CRP: C-reactive protein, HbA1c: Hemoglobin A1c, KL-6: sialylated carbohydrate antigen, Krebs von den Lungen-6, BNP: brain natriuretic peptide.

WHO Director-General's remarks at the media briefing on

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Severe acute anemia attributable to concomitant occurrence of AIHA with PRCA induced by parvovirus B19 infection

Pure red-cell aplasia and autoimmune hemolytic anemia in a patient with acute hepatitis A

Erythrocyte P antigen: cellular receptor for B19 parvovirus

Pure red cell aplasia

Autoimmune haemolytic anaemia associated with COVID-19 infection

Simultaneous onset of COVID-19 and autoimmune haemolytic anaemia

COVID-19 infection associated with autoimmune hemolytic anemia

Pure red cell aplasia following autoimmune hemolytic anemia: an enigma

Pure red cell aplasia accompanied by autoimmune hemolytic anemia in a patient with type A viral hepatitis

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Simultaneous occurrence of autoimmune hemolytic anemia and pure red cell aplasia

Structure of the SARS-CoV-2 spike receptor-binding domain bound to the ACE2 receptor