American Pediatric Society John Howland Award 2002: Acceptance

0031-3998/03/5303-0529 PEDIATRIC RESEARCH Copyright © 2003 International Pediatric Research Foundation, Inc. Vol. 53, No. 3, 2003 Printed in U.S.A. American Pediatric Society John Howland Award 2002: Acceptance HOWARD A. PEARSON Yale University School of Medicine, New Haven, CT 06520-9064, U.S.A. Thank you, Dr. Siegel, for your guided tour through my life. And thank you for being my friend since you arrived in New Haven as an intern 30 years ago and for being my strong right arm during my years as chairman at Yale. When I wrote the Centennial History of the American Pediatric Society in 1988, I said that the Howland Awardees occupied a pantheon of American pediatrics. Joining this illustrious group is somewhat intimidating, but I accept the honor with gratitude. The Howland Medal is especially meaningful to me because it is awarded by pediatric colleagues and peers for what they consider to be distinguished service to pediatrics as a whole. Following the example of other Howland Awardees, I’d like to acknowledge some mentors who shaped my career. The first of these was my 10th-grade Biology teacher, Mr. Guy Tucker. Guy Tucker was an extraordinary and charismatic teacher who engendered in me a love and wonder of science which has lasted to this day. Dr. Thomas E. Cone, Jr., was a wise and gentle physician (Fig. 1). He was my role model for choosing pediatrics. Dr. Cone, who wrote the definitive text on the history of American pediatrics, inculcated in me a life-long appreciation of medical history. Dr. Louis K. Diamond was the father of pediatric hematology (Fig. 2). Under Dr. Diamond, I learned about blood diseases and mastered blood morphology. He was a quintessential clinical investigator, and with him I first experienced the excitement of clinical research. Early in my academic career, Dr. Waldo “Bill” Nelson invited me to become a contributing editor in hematology to the Journal of Pediatrics. On many later occasions, Dr. Nelson reminded me that he had “discovered” me, and it is certainly true that he gave me my first opportunity on the national scene. Albert Szent-Gyorgyi once wrote, “Discovery consists of seeing what everybody has seen and thinking what nobody has thought.” In 1968, shortly after I came to New Haven, a previously well, 7-mo-old girl was brought to our emergency room, in extremis. She had been perfectly well until 8 h earlier, when Received June 17, 2002; accepted July 24, 2002. Correspondence: Howard A. Pearson, M.D., Yale University School of Medicine, P.O. Box 208064, 333 Cedar Street, New Haven, CT 06520-9064, U.S.A.; e-mail: Accepted at the 2002 Pediatric Academic Societies Annual Meeting, Baltimore, Maryland, U.S.A. DOI: 10.1203/01.PDR.0000052082.62196.55 Figure 1. Dr. Thomas E. Cone, Jr., 1915–1998. she developed progressive fever and then had a seizure. On admission to the emergency room, she was hyperpyrectic with a temperature of 105.8°F and was comatose. Her spleen was greatly enlarged. Despite valiant resuscitative efforts, she died. Type 14 pneumococci grew abundantly from her blood culture. Postmortem Hb electrophoresis showed that she had sickle cell anemia. The first clinical manifestation of sickle cell anemia in this child was death from an overwhelming infection. Only a few months later, a 4-year-old boy with sickle cell anemia was brought to our hospital with severe pneumococcal sepsis, disseminated intravascular coagulation, shock, and a very enlarged spleen. Fortunately, he survived. 529 530 JOHN HOWLAND AWARD 2002 Figure 2. Dr. Louis K. Diamond, 1902–1996. Patients with sickle cell anemia often develop fulminant pneumococcal infections in the first 6 years of life. The same clinical features of severe infections—young age, caused by encapsulated bacteria, chiefly pneumococci, clinically fulminant course with DIC and high mortality—are also seen in young children who have undergone surgical splenectomy. The patient’s blood smear showed the expected morphology of sickle cell anemia with target cells and irreversibly sickled cells, but in addition, many of his red blood cells contained Howell-Jolly bodies. Howell-Jolly bodies are nuclear remnants that are selectively and uniquely plucked from the red cells by the spleen, and their presence on the blood smear usually indicate asplenia. However, this child’s spleen was greatly enlarged, and, in fact, splenomegaly is usually found in children with sickle cell anemia in their first few years of life. We resolved the apparent paradoxes of severe, postsplenectomy-like infection and circulating Howell-Jolly bodies in this patient with an enlarged spleen by performing a technetium 99-sulfur colloid scan. This radiocolloid is taken up by reticuloendothelial organs, permitting their imaging. The radiocolloid scan of the patient showed normal hepatic uptake of the radiocolloid, but there was no splenic uptake. We coined the term functional hyposplenia to describe defective reticuloendothelial function of the clinically enlarged spleens of young children with sickle cell anemia and contrasted this with the anatomic asplenia that occurs in the second decade of life because of autoinfarction. We postulated that functional hyposplenism was an important reason for their early susceptibility to overwhelming pneumococcal infections. We showed that functional hyposplenia was not congenital but rather an acquired defect that develops in early life as the level of fetal Hb (Hb F) decreases. We also showed that functional hyposplenia could be temporarily reversed by blood transfusions during the first five years of life— but not thereafter. To avoid repeated radionuclide scans, we began to use a more simple diagnostic test. As red blood cells age in the circulation, they develop membrane vesicles. Using interference phase contrast microscopy, these vesicles appear as craters, “pits,” or “pocks.” Like Howell-Jolly bodies, the spleen removes these pocks. Patients with normal splenic function have fewer than 3.5% pocked RBC, while asplenic patients have more than 12%. Using this technique, we studied the splenic function of more than 3,000 patients enrolled in the national Cooperative Study of Sickle Cell Diseases. There were characteristic developmental patterns of splenic dysfunction in the various sickle hemoglobinopathies. In Hb SS disease and Hb S␤° thalassemia, functional hyposplenia usually developed in the first year or two of life. In Hb S-␤⫹ thalassemia, functional hyposplenia did not occur. In Hb S-C disease, an intermediate pattern was seen and functional hyposplenia did not usually occur in the first 5 years. These patterns correlated very well with the known clinical and hematological severity as well as the relative risk of infection in these sickle hemoglobinopathies. In the 1960s, as many as 30% of children with sickle cell anemia died from overwhelming infections in the first 5 years of life. We wanted to find a way to try to reduce this inordinate mortality. We reasoned (...truncated)