DISCUSSION
Autoimmune hemolytic anemia is a heterogeneous disease due to autoantibodies directed against red blood cells, with or without complement activation (8). Warm AIHA, the most common type, is typically DAT positive for anti-IgG, or IgG plus complement (C), while cold forms cold agglutinin disease (CAD), are due to IgM, and the DAT is positive for C3d. Among cold AIHAs, it is worth considering paroxysmal cold hemoglobinuria (PCH), usually observed in children. Cold agglutinin AIHA occurs in up to 3% of patients with infectious mononucleosis and Mycoplasma pneumonia infection (8). Cytomegalovirus, Epstein-Barr, influenza, varicella-zoster, and human immunodeficiency viruses may also be the agents accused in etiology (8). Association with underlying systemic illness, most commonly immunodeficiencies and autoimmune disorders, is also reported (7, 8).
In severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, clinical manifestations may directly relate to viral tissue damage or indirectly induced by the antiviral immune response that developed unwanted autoimmune disorders. Hyperactivation of the immune system in an attempt to eradicate the infection may trigger autoimmunity. In these patients, anemia is mainly associated with inflammation or microangiopathic hemolytic anemia due to disseminated intravascular coagulation (9, 10). Recently, adult reports suggest that SARS CoV-2 could have triggered AIHA (11). Agglutinated erythrocytes with microspherocytes indicating immune-mediated hemolysis are visualized on the peripheral blood smear, and AIHA, including cold agglutinin disease, should be considered.
Suspicion of primary immune deficiency and IFN admission was confusing about our patient. Interferon is precisely used in the treatment of hepatitis B and C infection and related warm-agglutinin-mediated hemolytic anemia (12-14). Therefore, we did not consider IFN for the etiology of CM-AIHA. After ruling out the other autoimmune disorders, or other viral infections and underlying hematologic malignancy, the cause of our patient’s cold agglutinins were thought to be COVID-19, being the first pediatric case reported so far.
There are no systematic studies to determine the optimal treatment for CM-AIHA due to its rarity. Treating the underlying etiology is always the primary goal. Corticosteroid treatment is one of the choices to treat M. pneumonia associated AIHA. However, to treat patients with severe, life-threatening hemolytic anemia with cold agglutinins, plasmapheresis, and intravenous immunoglobulin can be used (15). Our patient had a mild, self-limited hemolytic anemia that needs a single unit erythrocyte transfusion.
In conclusion, CM-AIHA is one of the complications of COVID-19 in pediatric patients, and DAT should be kept in mind in anemic COVID-19 patients.
References
1. Dong Y, Mo X, Hu Y, Qi X, Jiang F, Jiang Z, et al. Epidemiology of COVID-19 Among Children in China. Pediatrics. 2020;145(6).
2. Rodriguez Y, Novelli L, Rojas M, De Santis M, Acosta-Ampudia Y, Monsalve DM, et al. Autoinflammatory and autoimmune conditions at the crossroad of COVID-19. J Autoimmun . 2020:102506.
3. Shah S, Danda D, Kavadichanda C, Das S, Adarsh MB, Negi VS. Autoimmune and rheumatic musculoskeletal diseases as a consequence of SARS-CoV-2 infection and its treatment. Rheumatol Int . 2020;40(10):1539-54.
4. Wang D, Hu B, Hu C, Zhu F, Liu X, Zhang J, et al. Clinical Characteristics of 138 Hospitalized Patients With 2019 Novel Coronavirus-Infected Pneumonia in Wuhan, China. JAMA . 2020;323(11):1061-9.
5. Huang C, Wang Y, Li X, Ren L, Zhao J, Hu Y, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China.Lancet. 2020;395(10223):497-506.
6. Fan BE, Chong VCL, Chan SSW, Lim GH, Lim KGE, Tan GB, et al. Hematologic parameters in patients with COVID-19 infection. Am J Hematol . 2020;95(6):E131-E4.
7. Liebman HA WI. Autoimmune hemolytic anemia. . Med Clin North Am 2017;101:351–9.
8. Gehrs BC, Friedberg RC. Autoimmune hemolytic anemia. Am J Hematol . 2002;69(4):258-71.
9. Li Y HY, Yu J, Ma T. . Retrospective analysis of laboratory testing in 54 patients with severe- or critical-type 2019 novel coronavirus pneumonia. . Lab Invest 2020;100(6):794-800.
10. McGonagle D ODJ, Sharif K, Emery P, Bridgewood C. Immune mechanisms of pulmonary intravascular coagulopathy in COVID-19 pneumonia.Lancet Rheumatol 2020;;2(7):e437-e45.
11. Capes A, Bailly S, Hantson P, Gerard L, Laterre PF. COVID-19 infection associated with autoimmune hemolytic anemia. Ann Hematol . 2020;99(7):1679-80.
12. Gentile I, Viola C, Reynaud L, Borrelli F, Cerini R, Ciampi R, et al. Hemolytic anemia during pegylated IFN-alpha2b plus ribavirin treatment for chronic hepatitis C: ribavirin is not always the culprit.J Interferon Cytokine Res . 2005;25(5):283-5.
13. Barbolla L, Paniagua C, Outeirino J, Prieto E, Sanchez Fayos J. Haemolytic anaemia to the alpha-interferon treatment: a proposed mechanism. Vox Sang . 1993;65(2):156-7.
14. Baier JE, Poehlau D. Is alpha-methyldopa-type autoimmune hemolytic anemia mediated by interferon-gamma? Ann Hematol . 1994;69(5):249-51.
15. Chu CS BS, Yarbro JW, Hayden MR. . Corticosteroid treatment of hemolytic anemia associated with Mycoplasma pneumoniae. South Med J 1990;83(09):1106–8.