Persons who have undergone splenectomy are at higher risk for severe and relapsing babesiosis and, like other immunocompromised persons, typically receive longer courses of antiparasitic medications than otherwise healthy persons.⁷ Although prolonged antimicrobial treatment may prevent relapsing babesiosis, the cases presented here show a unique syndrome of recrudescent clinical hemolysis 2 to 4 weeks after the initiation of antiparasitic treatment, in the absence of parasitemia on peripheral-blood smear. The post-babesiosis WAHA syndrome occurred in 7% of all the patients with babesiosis during the study period and in one third of asplenic patients. Although four patients required immunosuppressive treatment owing to the severity of their clinical hemolysis, there were no deaths as may occur in severe cases of autoimmune hemolytic anemia, especially when there are delays in the administration of immunosuppressive treatment or the transfusion of blood products.¹⁵
We have described here a clinical syndrome of post-babesiosis WAHA in patients without a history of immune-mediated hemolysis. Although the development of autoimmunity to red cells in asplenic patients with babesiosis has been noted previously in seven cases, there was ongoing parasitemia in five of these cases at the time of positivity on direct antiglobulin tests.¹¹–¹⁴ In one of these cases, immune hemolysis developed in the context of transfusion-related alloantibodies.¹¹ Two of the seven patients had a history of autoimmune hemolytic anemia before acquiring babesiosis and subsequently had the Evans syndrome.¹⁴ The cases in the current report are distinct in that WAHA developed despite the clearance of B. microti parasitemia, and none of the patients had a history of autoimmune hemolytic anemia. An asplenic patient recently received a diagnosis of post-babesiosis WAHA at Nantucket Cottage Hospital, Massachusetts, and has required immunosuppression with glucocorticoids and rituximab (Pearl D: personal communication). The infrequency of asplenia in the general population may explain why post-babesiosis WAHA had not been recognized previously in endemic areas.
We considered alternative explanations for WAHA in our patients, but none seemed plausible. Although Hodgkin’s lymphoma and acute myeloid leukemia are rarely associated with autoimmune hemolytic anemia, our two patients with these cancers were in remission at the time of presentation. The one patient in whom the syndrome developed 3 years after allogeneic stem-cell transplantation had a self-limited course without the need for immunosuppression, making a graft-versus-host disease–like phenomenon unlikely. Only one patient with the syndrome had received a transfusion in the 3 months before presentation, and no alloantibodies were detected. Drug-induced autoimmune hemolytic anemia is unlikely, because only one patient received quinine,¹⁶ and autoimmune hemolytic anemia has not been associated with atovaquone, azithromycin, or clindamycin.¹⁷ Although PCR testing for B. microti remained positive in five of the six cases at the time of the diagnosis of WAHA, there was no evidence of parasitemia on peripheral-blood smears. Microscopic examination of Giemsa-stained thick and thin blood smears has a detection limit of 10 to 100 parasites per microliter (0.0002 to 0.002% parasitemia), whereas PCR testing for B. microti lowers the limit of detection to 5 parasites per microliter (approximately 0.0001% parasitemia).¹⁸ Such a low parasite burden cannot clinically explain the degree of hemolytic anemia that developed in these patients at the time of the diagnosis of WAHA.
A plausible mechanism for post-babesiosis WAHA in asplenic patients is immune-complex–mediated, or type III, hypersensitivity. In type III hypersensitivity, the antibody response to foreign antigens leads to the overproduction of immunoglobulins and increased amounts of insoluble immune complexes. These immune complexes are removed inefficiently by phagocytosis, particularly in asplenic patients, and can trigger the classical complement cascade and intense release of inflammatory mediators and subsequent lysis of red cells.¹⁹ In the absence of a spleen to maintain red-cell surfaces free of immune complexes, accumulation of these complexes may occur to a critical threshold, leading to clinically significant red-cell phagocytic clearance and complement-mediated destruction.¹⁹
An alternative explanation for the development of post-babesiosis WAHA is antibody-mediated, or type II, hypersensitivity, in which cross-reacting antibodies initially elicited against B. microti antigens that have been adsorbed onto red cells are subsequently elicited against similar human antigens. Splenectomy would facilitate the persistence of these erythrocytic surface antigens, which otherwise would be removed rapidly by the spleen, and the subsequent development of autoreactive antibodies. The time needed to stimulate and accumulate autoreactive antibodies may account for the delay of a few weeks that we observed for the development of WAHA after the initial diagnosis of babesiosis. A postinfectious delayed autoimmune hemolytic anemia has also been described with malaria,²⁰ including in a few cases that occurred 1 to 4 weeks after the treatment of severe malaria with parenteral artesunate, by which time the patients had clinical improvement and resolution of parasitemia.²¹ ²²
The pathogenesis of post-babesiosis WAHA seems distinct from that of autoimmune hemolytic anemia in general. Splenectomy is a treatment for autoimmune hemolytic anemia, whereas in this syndrome, asplenia is a risk factor. In addition, in typical autoimmune hemolytic anemia, direct binding of antibody or complement to red-cell membranes leads to clearance by reticuloendothelial system cells rather than immune-complex deposition on the surface of red cells.²³
In summary, the post-babesiosis WAHA syndrome can be a hematologic complication of babesiosis, and asplenic patients appear to be particularly at risk. Immune-mediated hemolysis and screening for WAHA should be considered in patients with worsening or recrudescent hemolytic anemia after treatment of babesiosis, especially in asplenic patients. Post-babesiosis WAHA responds to immunosuppressive treatment rather than antiparasitic treatment. Understanding the activation of the immune response to babesiosis may elucidate the mechanisms of other causes of autoimmune hemolytic anemias.
