Adult paroxysmal cold hemoglobinuria following mRNA COVID‐19 vaccination

Abstract Paroxysmal cold hemoglobinuria (PCH) is an extremely rare subtype of autoimmune hemolytic anemia (AIHA) in adults. PCH is caused by the biphasic Donath–Landsteiner (DL) antibody which fixes complement to red blood cells at low temperatures and dissociates at warmer temperatures, leading to complement‐mediated intravascular hemolysis. Autoimmune hematological disorders including AIHA and immune thrombocytopenia have been reported to develop following the mRNA COVID‐19 vaccination. However, PCH developing subsequent to mRNA vaccination has never been reported. We report a 59‐year‐old male who developed PCH approximately a month after his second mRNA COVID‐19 vaccination.


INTRODUCTION
Autoimmune hemolytic anemia (AIHA) is a rare disorder and can be classified into five subtypes [1]. Three of the AIHA subtypes are coldtypes of AIHA, which are cold agglutinin disease (CAD), secondary cold agglutinin syndrome (CAS), and paroxysmal cold hemoglobinuria (PCH).
PCH is caused by an autoantibody that fixes complement to red blood cells (RBCs) at low temperatures and dissociates at warmer temperatures, leading to complement-mediated intravascular hemolysis.
This biphasic antibody is known as the Donath-Landsteiner (DL) antibody and its presence is essential for the diagnosis of PCH. There are many pediatric cases of PCH, while adult cases are extremely rare [2]. Most adult PCH cases were known to be caused by syphilis in with the decrease of untreated syphilis patients. Reports of PCH are scarce in recent years, and the causes of PCH were reported to be idiopathic or due to hematological malignancies including non-Hodgkin lymphoma (NHL), chronic lymphocytic leukemia, myelofibrosis, and myelodysplastic syndrome (MDS) [3][4][5][6].

CASE REPORT
A 59-year-old Japanese male was admitted to our institution in early December, 2021 due to a two-week history of high fever, fatigue, Thus, COVID-19 vaccination-related PCH was suspected. As for treatment, RBC transfusions and hydration were carried out, and the patient was kept warm. Anemia, LDH levels, and renal failure gradually improved, and the patient was discharged 10 days from admission.
On his first outpatient visit, his general condition was well, and laboratory data showed improved hemoglobin levels and normalization of renal function. Two months after first outpatient visit, hemoglobin levels normalized but the indirect DL test remained positive ( Figure 3).

DISCUSSION
We encountered a case of adult onset PCH with no preceding infections or LPDs. PCH is a rare immunologic disorder often associated with infections and LPDs. Although syphilis and viral infections are known to trigger production of DL antibodies, the underlying mech- Therefore, when PCH is strongly suspected, the indirect DL test should be additionally performed even when the direct DL test is negative.
Another important diagnostic clue is peripheral blood erythrophagocytosis, which is highly specific to PCH. In the presented case, DAT was positive for complement C3b/C3d and negative for IgG, the indirect DL test was positive, erythrophagocytosis was observed in the peripheral blood smear, and thus a firm diagnosis of PCH was rendered.
Management of PCH is fundamentally supportive, constituted by methods such as hydration, RBC transfusions, and avoiding cold exposure. Use of infusion warmers should be considered when blood transfusions and fluid infusions are to be carried out. Although immunesuppressive therapies including corticosteroid, rituximab, intravenous immunoglobulin (IVIG), and azathioprine have been used for severe or chronic hemolysis due to PCH, the true efficacy of these agents are unclear. Eculizumab, a humanized anti-C5 monoclonal antibody which blocks the complement pathway at the C5 stage, has been looked upon as a promising treatment method for PCH [14]. In the presented case, hemolysis promptly improved with warming alone and no recurrence has been seen, and thus additional therapies were not necessary.
In conclusion, we report the first case of PCH developing subsequent to the mRNA COVID-19 vaccination. Several autoimmune hema-tologic disorders have been reported following the mRNA COVID-19 vaccination, and PCH may be an underrecognized adverse event.
Although we could only provide circumstantial evidence and no solid proof that mRNA COVID-19 vaccination contributed to the development of PCH, adult PCH in the current era is extremely rare and the possibility of PCH developing coincidentally following vaccination can be considered highly unlikely. Accumulation of cases and further etiological studies are necessary for understanding the exact relationship between mRNA COVID-19 vaccination and PCH.

ACKNOWLEDGMENTS
We thank the members of Department of Hematology, Juntendo University School of Medicine for encouraging this study.

FUNDING
No funding was provided for this study.

CONFLICT OF INTEREST
The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.

ETHICS STATEMENT
This study was approved by the ethics committee of Juntendo Shizuoka Hospital. Written informed consent for this study was obtained from the patient.

DATA AVAILABILITY STATEMENT
Not applicable as no datasets were generated for this study.