It has been said that the first important American contribution to hematology was that of Thomas B. Cooley and his co-worker Pearl Lee, in 1925. They were studying a group of children suffering from Jaksch's disease, well known to all pediatricians at that time but not mentioned in most pediatrie textbooks today. It was a disease characterized by anemia, splenomegaly, and immaturity of both red and white cells. Some called it a pseudoleukemia.
Cooley and Lee separated five children from this group who had the classic symptoms of Jaksch's disease but who also showed some discoloration of the skin and changes in their body structure. They named the condition erythroblastic anemia, also called Cooley's anemia by many pediatricians of that era.
In the early 1930s, Louis K. Diamond and his associates suggested that the three conditions found among certain newbornsanemia of the newborn, icterus gravis neonatorum, and hydrops fetali s - were all part of a single syndrome, "cause unknown" but felt to be familial and hereditary. The syndrome came to be known as erythroblastosis fetalis. (The Rh factor was not discovered by Philip Levine until 1939.
This resulted in confusion, for erythroblastosis was the term that had been used for Cooley's anemia, and now it was also being used to identify a syndrome of the newborn period. So, subsequently, when Cooley discovered that his anemia was confined largely to children of Mediterranean background, the nomenclature was changed to thalassemia, a word derived from the Greek thalassa, of or pertaining to the sea.
Sickle-cell anemia is another of the "area disease" or ethnic diseases, for its origins were in Africa and it is limited essentially to blacks. The disease as such apparently was recognized for at least 100 years before blood studies demonstrated the fact that persons with the disease had abnormal blood cells. I saw my first case in 1928, at a time when we knew little about the disease; we were mystified that certain people with sickle cells in their blood had marked symptoms, while others, even in the same families, had no symptoms at all. Twenty-one years later, J. V. Neel demonstrated the genetics of the condition, explaining the difference between those who had sickle-cell anemia and those who had sicklecell trait.
There are many interesting features of this painful disease, but one of the strange and unaccountable facts is that its sufferers have protection against malaria. It seems difficult to view sickle-cell anemia as a protective mechanism when dehydration is probably more frequent in the heat of Africa than in most other countries and when hyperosmolarity is one of the added difficulties associated with the disease. Hereditary spherocytosis is another of the genetic "area diseases"; it is found largely among people in northern European countries.
One of the diagnostic advances of the past 10 years has been the development of means to detect thalassemia and sickle-cell anemia prenatally by means of amniocentesis. This gives prospective parents the opportunity to choose to terminate a pregnancy that forebodes a life of pain and serious problems, both physical and emotional.
With this issue of PEDIATRIC ANNALS, Dr. Bertil E. Glader, director of the hematologyoncology program at the Children's Hospital of Stanford, Calif., and his contributors complete the symposium on hematology that began last year. The two previous issues, published in June and July, 1979, covered leukocyte disorders, newborn bleeding disorders, hemophilia, anemia in the newborn period, nutritional anemias, and bone-marrow failure in children. This issue covers each of the diseases we have been discussing above - sickle-cell anemia, thalassemia, and hereditary spherocytosis.
In the opening two articles in this issue, the pathophysiology, diagnosis, prognosis, and treatment of sickle-cell disease are discussed by Drs. William C. Mentzer and Winfred C. Wang. As the authors point out, there are two types of crises - one due to anemia, another caused by vasoocclusion. It is the latter, the painful crisis of vaso-occlusion, that is most likely to be called to the attention of the pediatrician. These crises may result from a lack of adequate oxygen or from infections, dehydration, ingestion of certain drugs, exposure to cold, or - less frequently - other conditions.
Drs. Mentzer and Wang describe the various diagnostic features that occur when vasoocclusion by sickle cells occurs in different areas of the body. The effects of the anemia resulting from homozygous sickle-cell disease are also detailed. An important section of this article deals with infection, for the patient with sickle-cell anemia is especially susceptible to pneumococcus and - to a lesser degree - to Hemophilus influenzae, type B. The authors recommend the use of a recently developed pneumococcus vaccine that gives 80 to 90 percent protection against pneumococcal infections.
In reading through the section on infections, one can hardly help being perplexed by several unusual findings in children with this disease. For example, more than half of the cases of osteomyelitis in sickle-cell patients are due to Salmonella - a microorganism almost never found otherwise in association with osteomyelitis, Another strange occurrence is that when the sickle trait and hemoglobin-C trait are inherited together (SC disease), the result is a milder sickle-cell disease than when the hemoglobin-C trait is not present - all symptoms are less frequent and less severe, with the exception of sickle retinopathy, which is more common in this combination than in sickle-cell anemia. Why?
Drs. Mentzer and Wang present a plan for a sickle-cell screening program that could detect those with the disease before the onset of complications and also those who are carriers of the trait.
Their second article is a complete and up-to-date review of prognosis and treatment of sicklecell disease. This is a comprehensive article that includes treatment for hypoxia, vaso-occlusive crisis, and infections in persons with sickle-cell disease. The authors also discuss the questionable use of splenectomy and review the new antisickling agents. They include a large bibliography reporting on articles up to the present years.
The third article in this symposium covers the thalassemia syndromes and has been contributed by Dr. Richard David Propper, of Children's Hospital Medical Center, Boston. Most pediatricians in this country tend to think of betathalassemia when the term thalassemia is mentioned, for this is by far the most common form of the disease found here. Dr. Propper, however, discusses all forms of the disorder - alpha-, beta-, gamma-, and delta-thalassemia - while devoting his major attention to beta-thalassemia. He points out that the basic pathology is due to an interaction of the anemia, the massive, ineffective erythropoiesis, and the body's attempt to maintain homeostasis. He then discusses all the signs and symptoms of the disease as related to these three body difficulties.
During the past 30 years, methods of therapy for children with thalassemia have depended on the use of intensive transfusions, given in thalassemia clinics throughout the country. The children have been living longer, but one severe problem has been encountered: there has been an accumulation of excess iron within their systems, with the resultant pathologic effects. Deferoxamine, a chelating agent administered to those with acute iron poisoning, has been tried on thalassemia patients during the past 10 years, in a daily intramuscular dose. The results until now have been an inadequate excretion of the excess iron. Dr. Propper, one of the primary investigators in the study of chelation therapy for thalassemia patients, now reports on a method of constant subcutaneous infusion given 10 to 14 hours daily that results in increased iron excretion.
The author also discusses the therapeutic aspects of splenectomy, with emphasis on postoperative drug and vaccine therapy. This article brings us up to date on the control and treatment of betathalassemia.
Dr. Drew W. Sullivan and our guest editor, Dr. Glader, discuss hereditary spherocytosis in children in the final article in this issue. Hereditary spherocytosis is the most common intrinsic redcell-membrane disorder associated with hemolysis and is found primarily in persons of northern European extraction. Red corpuscles of persons with the disease are spherical rather than discoid and rigid rather than being capable of bending. They thus become trapped in the spleen, where they are injured or destroyed. Hemolysis is usually moderate, with only a mild anemia.
The diagnosis of hereditary spherocytosis is usually definite, from symptoms and laboratory findings. There are other medical conditions, however, in which spherocytosis is found, and these are discussed by Drs. Sullivan and Glader. Splenectomy is the treatment they specify for the disease; it is "curative," although spherocytes remain in the bloodstream. As with sickle-cell anemia and thalassemia, the treatment of the postsplenectomy patient is routine, with antibiotics and pneumococcus vaccine.
Space limitations prevent us from publishing in this issue an additional paper on a hereditary blood disorder, Willebrand's disease, that had been planned by Dr. Glader for this issue. It will appear in September.