A Systematic Review

COVID-19 and Immune-Mediated RBC Destruction

Jeremy W. Jacobs, MD; Garrett S. Booth, MD


Am J Clin Pathol. 2022;157(6):844-851. 

In This Article

Abstract and Introduction


Objectives: To summarize the epidemiologic, clinical, and laboratory characteristics of autoimmune hemolytic anemia (AIHA) secondary to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection or vaccination.

Methods: We conducted a systematic review using standardized keyword search to identify all reports of SARS-CoV-2 infection or vaccination and AIHA across , Web of Science, Scopus, and through September 24, 2021.

Results: Fifty patients (mean SD age, 50.8 [21.6] years) diagnosed with coronavirus disease 2019 (COVID-19) and AIHA were identified. AIHA subtypes and number of patients were as follows: cold AIHA (n = 18), warm AIHA (n = 14), mixed-type AIHA (n = 3), direct antiglobulin test (DAT)–negative AIHA (n = 1), DAT-negative Evans syndrome (n = 1), Evans syndrome (n = 3), and subtype not reported (n = 10). Mean (SD) hemoglobin at AIHA diagnosis was 6.5 [2.8] g/dL (95% confidence interval, 5.7–7.3 g/dL). Median time from COVID-19 symptom onset to AIHA diagnosis was 7 days. In total, 19% (8/42) of patients with COVID-19–associated AIHA with reported outcomes were deceased. Four patients (mean SD age, 73.5 [16.9] years) developed AIHA following SARS-CoV-2 vaccination: Pfizer-BioNTech BNT162b2 vaccine (n = 2); Moderna mRNA-1273 vaccine (n = 1); undisclosed mRNA vaccine (n = 1). AIHA occurred after 1 dose in 3 patients (median, 5 days).

Conclusions: SARS-CoV-2 infection and vaccination are associated with multiple AIHA subtypes, beginning approximately 7 days after infectious symptoms and 5 days after vaccination.


The manifestations of symptomatic coronavirus disease 2019 (COVID-19) are heterogenous, with a broad spectrum of systemic complications described. Evidence is mounting that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the viral agent responsible for COVID-19, can induce a multitude of hematologic abnormalities, with an accumulation of case reports and small case series suggesting that autoimmune hemolytic anemia (AIHA) may be associated with COVID-19.[1–10]

AIHA is a rare disorder, with an estimated incidence of 1 to 3 per 100,000 people annually. Approximately half of all AIHA cases are idiopathic, while secondary cases are often associated with underlying autoimmune or lymphoproliferative diseases.[11] Reports of AIHA occurring in the context of several infectious diseases have been described, but a few pathogens have a well-described association with AIHA, including human immunodeficiency virus (HIV), Mycoplasma pneumoniae, and Epstein-Barr virus (EBV).[11,12] Although, a definitive link between COVID-19 and AIHA has not been established, nor has an exact mechanism underlying this potential association been elucidated, several hypotheses have emerged, including immunologic hyperstimulation and molecular mimicry.[13,14]

Most of the evidence proposing an association between COVID-19 and AIHA is based on single case report data, much of which are limited in scope, design, and analysis. Given this overall paucity of data, this systematic review aimed to analyze the epidemiology, laboratory and blood bank parameters, therapeutic interventions, outcome, and AIHA subtype in patients with SARS-CoV-2 infection or vaccination.