One of the unresolved aspects of COVID-19 is its documented association with autoimmune diseases. Saad and colleagues, in their systematic review of reported cases of COVID-19 and autoimmune diseases, wrote, “COVID-19 has been implicated in the development of a range of autoimmune diseases, which may shed light on the association between autoimmune diseases and infections.” 

The review found “one case of subacute thyroiditis (3%), two cases of Kawasaki Disease (6.1%), three cases of coagulopathy and antiphospholipid syndrome (9.1%), three cases of immune thrombocytopenic purpura (9.1%), eight cases of autoimmune hemolytic anemia (24.2%), and sixteen cases of Guillain-Barré syndrome (48.5%),” the researchers wrote. 

In this article, we will focus solely on autoimmune hemolytic anemia (AIHA), particularly cold agglutinin disease (CAD). Reports have emerged of patients being diagnosed with COVID-19 and AIHA at the same time. We will examine 2 such case reports. 


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A Complicated Case 

The following case report was laid out in a paper by Jacobs and Eichbaum on COVID-19 associated with AIHA.

A 33-year-old woman presented with a headache for 2 days. Head CT was normal. Blood count demonstrated extremely low hemoglobin of 1.3 g/dL and hematocrit of 6%, and high total bilirubin at 2.4 mg/dL. Her blood type could not be determined because of an ABO discrepancy, so she received type O D-negative red blood cells (RBCs) for symptomatic anemia and was transferred to a different facility for further care. 

Upon arrival, the patient was confused, tachycardic, and tachypneic. The patient tested positive for SARS-CoV-2, with a chest x-ray showing patchy opacities. Further serological testing was performed.

“The diagnostic evaluation for the underlying cause of the hemolysis in this patient was complicated, as there was evidence of a cold agglutinin, with RBC agglutination on peripheral smear, a positive room temperature antibody screen, and a negative antibody screen when a prewarmed sample at 37°C was used,” Jacobs and Eichbaum wrote. 

Read more about CAD etiology

Throughout her hospital stay, she received 10 units of RBCs via a blood warmer. However, her hemoglobin levels did not improve consistently. She was started on prednisone 1 mg/kg daily. She was administered a single dose of tocilizumab 4mg/kg on day 6, and a single dose of rituximab 600 mg on day 10. Following rituximab therapy, her hemoglobin levels began to stabilize. She continued to improve clinically and was discharged on day 13. 

Co-occurring Warm and Cold AIHA 

This case report was presented in a paper by Brazel et al on warm and cold AIHA in the setting of COVID-19.

A 51-year-old man presented with weakness and jaundice. He had a one-week history of intermittent fever and confusion, and 2 days before presentation he developed jaundice, dark urine, and fatigue. Initial workup revealed: 

  • White blood cells: 41.4 thousand cells/MCL
  • Hemoglobin: 3.1 g/dL
  • Mean corpuscular volume: 124.1 FL
  • Platelets: 343 thousand cells/mL
  • Creatinine: 1.4 mg/dL 
  • Total bilirubin: 5.3 mg/dL 
  • Direct bilirubin: 1.6 mg/dL 

The patient tested positive for COVID-19. EKG revealed supraventricular tachycardia with nonspecific ST segment and T wave changes. CT abdomen and pelvis showed hepatic steatosis and mild splenomegaly. Four units of packed RBCs were transfused. 

“Direct antiglobulin test (DAT) was positive for [immunoglobulin G (IgG)] and C3 complement antibodies, consistent with warm AIHA. Hematopathologist review also revealed agglutination on immediate spin reactivity consistent with cold AIHA,” Brazel and colleagues wrote. 

Read more about CAD treatment 

The patient was started on prednisolone 1 mg/kg daily for empirical treatment of AIHA. Repeat chest x-ray revealed bibasilar opacities. His platelet count decreased to a low of 65 during his hospital stay, but tests were negative for heparin-induced thrombocytopenia. On day 3, a CT chest scan revealed multiple segmental and subsegmental pulmonary emboli in all lobes. The patient was started on apixaban. 

On day 8, the patient was discharged with prednisolone 100 mg/daily. “Repeat flow cytometry performed two weeks after discharge was normal. His hemolysis labs including hemoglobin, bilirubin, haptoglobin, and LDH normalized by his two-week follow-up appointment,” Brazel et al wrote. 

Prednisolone was tapered down to 60 mg daily at 2 months after discharge. His most recent follow-up, at 70 days post-admission, revealed that DAT for IgG and anti-complement remained positive. Prednisolone was further decreased to 50 mg daily. 

A Rare Phenomenon 

“There is scant evidence in the literature of patients presenting with COVID-19 and AIHA; thus, the association between these diseases is unknown,” Jacobs and Eichbaum wrote. 

Brazel and colleagues have a similar conclusion. They wrote, “To date, only a few case reports and one case series describe patients presenting with COVID-19 and AIHA simultaneously. Although the association between COVID-19 and coagulopathies has been well described, future studies are needed to determine whether a causal relationship exists between COVID-19 and AIHA.” 

Studies have previously shown that both warm and cold autoantibodies can develop secondary to a number of medical conditions, including infection. Is SARS-Cov-2 such an infection? Is it able to induce severe AIHA on its own? That is the question that physicians are asking and researchers are attempting to answer. 

Given that there is still much we do not understand about COVID-19, caution is key. Brazel et al concluded, “Clinicians should use caution in patients with declining hemoglobin levels knowing that hemolysis may be masked in COVID-19 infection by frequently elevated LDH and elevated acute phase haptoglobin.” 

References

Saad MA, Alfishawy M, Nassar M, Mohamed M, Esene IN, Elbendary A. COVID-19 and autoimmune diseases: a systematic review of reported cases. Curr Rheumatol Rev. 2021;17(2):193-204. doi:10.2174/1573397116666201029155856

Jacobs J, Eichbaum Q. COVID-19 associated with severe autoimmune hemolytic anemia. Transfusion. 2021;61(2):635-640. doi:10.1111/trf.16226

Brazel D, Eid T, Harding C. Warm and cold autoimmune hemolytic anemia in the setting of COVID-19 disease. Cureus. Published online September 20, 2021. doi:10.7759/cureus.18127