Infections are often overlooked in autoimmune hemolytic anemia (AIHA), although they represent a considerable risk factor for morbidity and mortality of patients. On one hand, infectious agents may trigger AIHA onset and relapse; on the other hand, AIHA patients may suffer from infectious complications due to the administration of immunosuppressive treatments.

Cold agglutinin disease (CAD), a type of AIHA, can be classified into primary and secondary. Among other causes, secondary CAD can be triggered by viral and mycobacterial infections. Moreover, cases of pathogen reactivations have been described in response to treatment with specific medications. Here we will discuss the evidence for the infectious burden in patients with CAD.

CAD Secondary to Infections

An increasing number of publications have reported an association between infections and CAD. Among the most common reported infectious causes of CAD are Mycoplasma pneumonia and the Epstein–Barr virus (EBV). In some cases, patients who develop CAD as a complication of infections experience unusual clinical presentations. For instance, a team from India reported the case of an 8-year-old boy who developed CAD with peripheral gangrene following Mycoplasma infection. A case of an 18-year-old male patient who developed CAD and biliary stasis secondary to EBV was also presented, in the journal Case Reports.

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In addition, several cases have suggested that infection by the novel coronavirus, SARS-CoV-2, could trigger CAD.

Two teams from the US reported the cases of 2 female patients who developed CAD as a complication of acute SARS-CoV-2 infection. One of the patients, a 69‐year‐old woman, presented with both CAD and myositis, while the other, a 51-year-old woman, had cooccurring CAD and pulmonary embolism.

Cold Agglutinin Disease in the Context of the COVID-19 Pandemic

The 69‐year‐old patient, whose case was described in the journal Clinical Case Reports, was readmitted to the hospital about 2 weeks after testing positive for SARS‐CoV‐2, due to severe intractable pain in the bilateral lower extremities with subjective pelvic girdle weakness. “Peripheral blood smear revealed marked agglutination of red blood cells and a cold agglutinin with thermal amplitude of 30°C was identified with complement C3B and C4 identified on red blood cells,” the authors explained. Upon the diagnosis of CAD, she initiated rituximab (375 mg/m2, weekly, 4 doses).

The 51-year-old patient’s case was reported by Patil and colleagues, researchers from Wayne State University in Detroit, Michigan, in the journal Hematology/Oncology and Stem Cell Therapy. The patient was diagnosed with severe coronavirus disease 2019 (COVID-19) infection and started on hydroxychloroquine. Her peripheral blood smear showed red blood cell agglutination and her cold agglutinin titer was elevated at 80, which was consistent with CAD and cold AIHA. Therefore, she was initiated on folic acid and recommended to use warm intravenous fluids and blood products.

Physicians: SARS-CoV-2 Could Trigger Pediatric Cold Agglutinin Disease

“Cold AIHA secondary to viral infections usually occurs within 2 weeks of the onset of primary infection and improves by the time of infection resolution,” Patil et al explained. They added that patients with CAD secondary to infections usually have polyclonal cold agglutinin, in contrast to patients with chronic CAD, who usually have a monoclonal cold agglutinin.

The therapeutic approach in infection-associated CAD aims to reduce antibody production. Severely ill hospitalized patients may also benefit from plasmapheresis or intravenous immunoglobulin as temporary treatment in addition to blood transfusion. On the other hand, steroids are generally ineffective.

Risk of Infection Related to Treatment

As explained by Giannotta et al in the Journal of Clinical Medicine, “The risk and type of infections associated with AIHA treatments differ according to the dose, the time of exposure and the depth of immunosuppression induced by each therapy.”

Rituximab, an anti-CD20 monoclonal antibody targeting B lymphocytes, is recommended as first-line treatment for patients with CAD. It can be used as a standalone therapy or in combination with the chemotherapeutic drug bendamustine (Treanda®). Due to its effects on reducing the number of B cells, it has been associated with increased infection risk.

Hence, the administration of rituximab to treat CAD in hospitalized patients with COVID-19 should be considered with caution, according to Patil et al. Rituximab causes lymphopenia in nearly half of patients at a median of 14 days, a condition already observed in most hospitalized patients with COVID-19. Hence, Patil et al. explained that “Administering rituximab to patients with COVID-19 may be risky because it can cause further B-cell depletion and can increase their risk for acquiring other infections.”

Additionally, treatment with rituximab has been associated with the development of progressive multifocal leukoencephalopathy, a demyelinating disease of the central nervous system caused by the reactivation of the John Cunningham virus. Less common infections associated with rituximab are Pneumocystis jirovecii pneumonia, enterovirus encephalitis, parvovirus B19, cytomegalovirus, West Nile virus, and babesiosis.

Overall, the occurrence of infections or pathogen reactivations after rituximab administration in patients with AIHA is rare and, therefore, its use is generally considered safe. A team from the Chinese Academy of Medical Sciences and Peking Union Medical College, China, showed that out of 16 patients with CAD, 3 presented with grade 3–4 neutropenia but only one developed infection. However, some therapeutic combinations garner additional attention and prophylaxis should be considered accordingly.


Giannotta JA, Fattizzo B, Cavallaro F, Barcellini W. Infectious complications in autoimmune hemolytic anemia. J Clin Med. 2021;10(1):164. doi:10.3390/jcm10010164

Aldaghlawi F, Shammah A, Kio E. SARS-CoV-2 infection complicated with cold agglutinin disease and myositis. Clin Cas Rep. 2021;9(4):2196-2199. doi:10.1002/ccr3.3981

Patil NR, Herc ES, Girgis M. Cold agglutinin disease and autoimmune hemolytic anemia with pulmonary embolism as a presentation of COVID-19 infection. Hematol Oncol Stem Cell Ther. Published online July 6, 2020. doi:10.1016/j.hemonc.2020.06.005

Jia M-N, Qiu Y, Wu Y-Y, et al. Rituximab-containing therapy for cold agglutinin disease: a retrospective study of 16 patients. Sci Rep. 2020;10(1):12694. doi:10.1038/s41598-020-69465-2

Sudhakar M, Mohandoss V, Chaudhary H, Ahluwalia J, Bhattarai D, Jindal AK. Multifocal thrombosis with peripheral gangrene in a young boy: Mycoplasma infection triggered cold agglutinin disease. Immunobiology. 2021;226(3):152075. doi:10.1016/j.imbio.2021.152075

Teijido J, Tillotson K, Liu JM. A rare presentation of Epstein-Barr virus infection. J Emerg Med. 2020;58(2):e71-e73. doi:10.1016/j.jemermed.2019.11.043