Cold hemolytic anemia: a rare complication of influenza A

Discussion

The incidence of cold AIHA or cold agglutinin disease (CAD) occurs about 4 per 1 million people and commonly affects women more often than men.² The cause of CAD can be subdivided into primary, idiopathic, or secondary causes, which can include infections, malignancies, or benign diseases.^3,4 Primary CAD is a chronic disorder that is generally seen in older women. Secondary CAD can be associated with B-cell lymphoproliferative disorders, such as Waldenstrom macroglobulinemia or chronic lymphocytic leukemia, and infectious agents such as Mycoplasma pneumoniae and mononucleosis caused by Epstein-Barr virus.

Mild hemolysis or acrocyanosis may occur with exposure to cold. The blood smear in CAD demonstrates red blood cell agglutination or clumping, polychromasia, and an absence of spherocytosis. In general, most cases require no treatment, but cytotoxic agents or rituximab can be used to treat more severe cases. Appropriate treatment for infectious causes of CAD includes supportive care aimed at the underlying disease process. In addition, it is helpful to keep the patient warm. There is no role for steroid therapy in CAD unlike in warm AIHA. However, our patient was symptomatic from her pneumonia, so we added steroids to help with her pulmonary insult.

The patient had a cold agglutinin titer of 1:256. Titers of 1:32 or higher are considered elevated by this technique. Elevated titers are generally rarely seen except in primary atypical pneumonia due to either M. pneumoniae, influenza A, influenza B, parainfluenza, and adenovirus, and in certain hemolytic anemias. Low titers of cold agglutinins have been demonstrated in malaria, peripheral vascular disease, and common respiratory diseases.

Warm AIHA is caused by IgG antibody activities at body temperature or at 98.6°F. They may or may not bind complement and are removed from circulation by the spleen. Cold AIHA is due to IgM antibodies coating red cells at lower temperatures. They bind complement and lead to red blood cell destruction of agglutinated cells. If the antibody is active at temperatures approaching 98.6°F, clinically significant intravascular and sometimes extravascular complement-mediated hemolysis occur in the liver.⁵

The incidence of warm AIHA occurs about 10 per 1 million people and affects women twice often as men.² It can be primary or idiopathic, or associated with various underlying conditions, including autoimmune disorders, immunodeficiency syndromes, lymphoproliferative disorders, other malignancies, and certain drugs. In more severe cases, jaundice and splenomegaly may occur. The blood smear in warm AIHA demonstrates variable spherocytosis, polychromasia, and rare erythrophagocytosis. Treatment usually includes steroids, cytotoxic agents, and splenectomy in severe cases.

There have been few case reports describing influenza as a cause of cold agglutinin hemolytic anemia. Chen and colleagues reported a case of influenza A infection in a 22-month-old boy.⁶Schoindre and colleagues reported the case of a 60-year-old woman infected with influenza A H1N1 virus who died from CAD.⁷ Shizuma reported the case of a 67-year-old man with alcoholic cirrhosis who developed a mixed hemolytic anemia and was positive for influenza A.⁸Our patient presented with influenza A, which had been diagnosed by respiratory virus panel at a different hospital, and she was anemic at the time of presentation to the outside hospital, with a positive DAT test. She was treated for influenza A with a full course of osltamivir and then returned with complaints of worsening fatigue and was again noted to be anemic with the development of patchy opacities on chest X-ray. The patient was subsequently transferred to our hospital and remained anemic during the course of her treatment. She received supportive care for her underlying influenza A and had symptomatic improvement. She ultimately decided the she would like to pursue further treatment in her native country and was discharged.

In conclusion, this case represents a rare complication of a common illness. Few cases of influenza causing hemolytic anemia have been reported in the literature. There have been reports of oseltamivir causing hemolytic anemia, but our patient presented with evidence of hemolytic anemia before initiation of the medication. In all the aforementioned cases, the patients died as a result of comorbid conditions. Our patient was stable enough to be discharged from the hospital after treatment of her comorbid conditions.

Acknowledgment
The authors thank David Henry, MD, at Pennsylvania Hospital, Philadelphia, for sharing this case and for his guidance during this patient’s treatment.