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.
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