The Emily Cooley Lecture. Etiology and Pathogenesis of Acquired Hemolytic Anemia

The demonstration of recurrent lymphadenitis attributable to CMV during periods of hemolysis in a patient with chronic acquired hemolytic anemia of autoimmune type, led to the investigation of the possible etiologic relationship between this virus and acquired hemolytic anemia. In children a frequent association was demonstrated. Previously unrecognized clinical manifestations attributable to CMV were frequently observed. In this age group lymphadenopathy was a prominent finding in the majority of the cases and appeared to correspond to periods of rapid virus multiplication. It was noted that the predominant cellular lesion was not the well known pathognomonic large inclusion‐bearing cell which is a comparatively rare end state in the cellular response to the virus but less fully developed cellular lesions representing early and intermediate states. Recognition of these lesions permitted a rough appraisal of the extent of viral activity and showed that the latter generally correlated well with the hemolytic process. A basis for active infection by an ordinarily occult virus was sought and frequently found in an apparent impairment of the normal immune mechanism expressed clinically by extreme susceptibility to intercurrent infections and frequently associated with organic defects conducive to such a state. In young infants age‐determined susceptibility alone seemed to explain the lack of resistance to the occult viral agent. The findings led to the following interrelated hypotheses: 1. The presence of CMV in AHA is not fortuitous or coincidental but reflects a (not necessarily exclusive) etiologic relationship. 2. Acute, intermittent, or chronic hemolysis in AHA is related to primary or reactivated latent infection with CMV or other occult viruses in individuals susceptible by virtue of physiologically or pathologically impaired immunity, the cause of which is apparent in symptomatic forms but not as yet in the idiopathic type. 3. The pathogenesis of AHA involves viremia or the presence of noninfective viral particles or products in the circulation. Infection within the RE system as opposed to sites less accessible to the circulation, such as epithelium, permits their discharge into the blood stream and determines hemolysis. 4. The demonstration of the same agent in autoimmune and non‐autoantibody AHA suggests a unified concept of pathogenesis in which erythrocyte autoantibodies represent a variable secondary response to heterogenetic stimuli of viral origin. 5. In the light of this theory the role of autoantibodies in autoimmune AHA is likely to be at most contributory, as also indicated by the frequent dissociation of hemolysis and antiglobulin reaction, and earlier data bearing on this question need to be reevaluated.