The World Health Organization (WHO) and the International Consensus Classification (ICC) have both granted recognition to primary cold agglutinin disease (CAD) as a new diagnostic entity, based on case study findings from Italy published in the journal Histopathology.

Primary CAD is an autoimmune hemolytic anemia that is associated with monoclonal cold agglutinin autoantibodies that cause red blood cell agglutination at temperatures between 0⁰C and 4⁰C. The disorder is linked to an underlying bone marrow-based clonal B-cell proliferation.

Clinical and laboratory results, including molecular data and bone marrow histology, are needed to confirm a diagnosis of primary CAD. The current case report describes the diagnostic workup of an 84-year-old woman in whom previously well-controlled primary CAD was aggravated by the development of an active SARS-CoV-2 infection.

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The patient presented to the hospital with dyspnea on exertion, moderate asthenia, and numerous purpuric lesions on her trunk and limbs. About 2 weeks before her presentation, she had experienced COVID-19 infection, with mild respiratory symptoms and progressive weakness observed.

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Her blood tests showed moderate macrocytic anemia and mild leukocytosis with lymphopenia. Her serum lactate dehydrogenase and total bilirubin levels were elevated, whereas her haptoglobin level was low. A serum immunoglobulin M kappa paraprotein was identified. Her cold agglutinin titer was 1:4096 (normal range, 0-1:63) at 4⁰C. Based on a peripheral blood smear, red blood cell agglutination and anisocytosis were detected.

Additional findings included a positive direct antiglobulin test result for C3d. A bone marrow biopsy revealed small intertrabecular aggregates of small-sized lymphocytes mixed with rare, polytypic plasma cells. Whole-body computed tomography exhibited no splenomegaly, hepatomegaly, or lymphadenopathy. Her laboratory, pathologic, and clinical findings confirmed a diagnosis of primary CAD.

She underwent steroid treatment for 4 months, with rapid hemolysis control reported. After 2 weeks of steroid withdrawal, her haptoglobin levels were undetectable and her lactate dehydrogenase levels rose. Rituximab monotherapy once weekly for 4 weeks was initiated, with benefits reported.

The patient experienced another SARS-CoV-2 infection, which was followed by a severe decline in her hemoglobin level and signs of hemolysis. Antiviral therapy (nirmatrelvir/ritonavir) plus steroids were given, with little benefit in terms of hemolysis reported. Reintroduction of rituximab failed to control her hemolysis.

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A possible treatment option for the patient at this time was sutimlimab—a new therapeutic option for primary CAD. Because the agent was unavailable in Italy at the time, cyclophosphamide was administered, with significant hemolysis control seen at 2 months from initiation of therapy.

Key criteria for establishing a diagnosis of primary CAD include the following signs of chronic hemolysis:

  • Typical direct antiglobulin test pattern that is strongly positive for C3d
  • Cold agglutinin titer greater than 64 that is typically higher at 4⁰C
  • No overt malignant neoplasm/lymphoma or relevant infection
  • Evidence of a clonal B-cell disorder evaluated by bone marrow biopsy or flow cytometry in bone marrow aspirate

“In the present case, hemolysis signs were present before SARS-Cov-2 infection,” the researchers indicated. “Our patient history suggests that a previously well-controlled autoimmune disease was exacerbated by an active SARS-CoV-2 infection, highlighting the relevance of understanding the mechanisms of the cytokine storm caused by SARS-CoV-2 infection in worsening a previously well-controlled [primary] CAD,” they concluded.


Zanelli M, Nizzoli ME, Sanguedolce F, et al. Primary cold agglutinin disease: a recently recognised diagnostic entity in WHO and ICC. Histopathology. Published online May 17, 2023. doi:10.1111/his.14943