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Foreword: Highlights of Progress in Pediatric Hematology
SYMPOSIUM
ON
PEDIATRIC
HEMATOLOGY
FOREWORD
Highlights of Progress in Pediatric Hematology CARL H. SMITII, M.D.
Editor
The search for understanding is an adventure, or more commonly a series of adventures. _.. Now that geographical boundaries in our own and in other civilized lands have been determined, the pioneering spirit finds in scientific research enticing vistas for adventure.-Walter B. Cannon: The Way of an Investigator.
The subject matter comprising this issue of the Pediatric Clinics reflects indeed the enormous achievements resulting from scientific curiosity and the spirit of adventure in a recently developed specialty. The extraordinary growth of pediatric hematology is a reflection of these explorations. The expansion of knowledge has been largely accomplished by the application of disciplines, techniques and orientation common to all fields of medicine at present. It is axiomatic that in this period of intense activity in a single specialty there would be concomitant growth in all fields, so that specialties are no longer isolated, but are interdependent and flow over one on to the other. The fabric of the newer knowledge represented in these papers is interwoven with data obtained from studies in genetics, metabolic aberrations, enzymology, virology, immunology, in the precise delineation of intestinal absorption and malabsorption and in the blood proteins, i.e. haptoglobins, transferrins, those involved in coagulation, and in the transport of essential minerals and vitamins. One of the inherent difficulties in identifying a specific blood dis521
522
FOREWORD
order in infancy and childhood is that the diagnostic features are obscured by certain inherent physiologic and anatomic changes which originate within and outside the hematopoietic system. These influences, many dating from fetal life, operate with diminishing force from birth to adolescence. The accuracy of diagnosis in the congenital and acquired hemolytic anemias, iron deficiency, white blood cell disorders and those of blood coagulation in early life is predicated upon the appraisal of this shifting background. Throughout the papers in this volume an attempt has been made to stress the normal background against which abnormalities are appraised. The present symposium represents in effect the continuing story of the many subjects reviewed in the previous symposium of 1957. Many of the problems posed at that time have been elucidated, others have remained unsolved. Clarification has often generated new complexities. For example, one of the topics under current scrutiny is the so-called physiologic jaundice. Perhaps it was the preoccupation with neurologic abnormalities incident to hyperbilirubinemia in erythroblastosis fetalis that provoked a hard look at the heretofore "benign or physiologic" jaundice of the newborn. It may have been the discovery of kernicterus in autopsies of premature infants or the increased incidence of hyperbilirubinemia after excessive vitamin K dosage or with the use of sulfisoxazole (Gantrisin) in premature infants or other complicating factors that led to a reinvestigation of physiologic jaundice. Although hyperbilirubinemia of nonhemolytic and that of hemolytic origin have in common increased concentrations of indirect bilirubin, the attitude towards treatment is by no means uniform in each type. In a recent canvass of opinions from several large clinics in this country, the lack of a uniform policy in the management of nonhemolytic hyperbilirubinemia was striking. Although the majority of workers agreed that kernicterus was a threat, opinion was divided whether the critical 20-mg. yardstick should be adhered to as rigidly as in the hemolytic disease, whether a more relaxed attitude should be followed until levels of 25 mg. per 100 mI., or higher, were reached, or whether any treatment need be given in the uncomplicated case. Of importance in the problem of managing hemolytic and nonhemolytic hyperbilirubinemia is the possibility that posticteric sequelae may develop which are not flagrant, but are nevertheless manifested as minor symptoms.6 Some degree of hyperactivity, awkwardness, delayed speech acquisition, may represent belated manifestations of increased concentrations of pigment in the neonatal period. The papers dealing with this subject in this symposium will therefore be read with great interest, since newly developed diagnostic guides and treatment are presented. It is gratifying that since the last symposium, aplastic anemia, heretofore regarded as almost uniformly fatal in children despite trans-
CARL H. SMITH
523
fusions and steroids, has been found to respond in many cases to testosterone. It is unfortunate that many of the· acquired cases have once more been precipitated by the promiscuous use of chloramphenicol when other antibiotics could readily have been substituted or when no specific therapy was necessary. The continued interest in the intriguing possibility of transplanting human bone marrow prompted the inclusion of a paper on this subject. Periodically much interest is aroused by the reports of successful marrow "grafting." Unfortunately, the complete story is not always available, nor is it always possible to appraise the full therapeutic effect of the graft without considering the benefits from the modalities used to reduce the normal resistance of the host to the graft, or of supportive therapy. Nevertheless bone marrow transplantation in the human being may ultimately duplicate the success of animal experimentation and provide an important means of treating aplastic anemia, acute leukemia and other malignant diseases. Investigations of the carbohydrate metabolism of red cells constitute an integral part of the recent explosive interest in the enzymes of the blood. The hematologist has, therefore, had to acquire a knowledge of glycolytic pathways and of the enzymes with which they are associated. Specific enzymes have been described which maintain the integrity of the red cell, or playa role in the synthesis of the porphyrins and of heme, or which are deficient in iron deficiency anemia. Emphasis has centered on the fluctuations of one of these enzymes, glucose-6phosphate dehydrogenase. This enzyme is increased in the erythrocytes of newborn infants, decreased as a hereditary defect in certain druginduced hemolytic anemias and, depending on its concentration, serves as a means of classifying congenital nonspherocytic hemolytic anemia. Thus the revolution in thinking about inborn errors of metabolism as enzymatic defects has spread with equal force to hematologic syndromes. Among the white blood cell disorders, the leukemias and lymphomas are constantly perplexing problems to the pediatrician. There is no question that the course of acute leukemia has been greatly modified by advances in chemotherapy. Although survival rates are being prolonged, alertness is constantly needed in introducing "the new drug" and reassessing the value of the older compound. The present status of chemotherapy has been well summarized by Welch: 7 "The only accurate prediction which can now be made is that in almost any patient in whom a favorable response to a chemotherapeutic agent is obtained, there will eventually develop a state of refractoriness which is usually referred to as drug resistance. The basic problem is the emergence of mutant cells which serve as the progenitors of a new population of drug resistant cells." The papers dealing with the leukemias and lymphomas in this symposium are of especial value,
524
FOREWORD
since they not only list the available therapeutic agents, but also review the remarkable strides made with their use based on a knowledge of the biochemical changes they are expected to produce, rather than on the empiricism of the past. Since the etiology of leukemia is under constant scrutiny, much might be said about a current theory which implicates the fetus as an intermediary. Gross 5 demonstrated a viral etiology for lymphoid leukemias in mice which is noncontagious, but is communicated to offspring during embryonal life through either the male or female parent. Leukemia results after a period of latency of one third to one half of the life span of the animal. The virus exists in inactive form, disclosing its malignant capabilities only when challenged by stimuli such as radiation exposure. The virus would not necessarily become activated during the life span of the carrier, but might be transmitted through scveral generations before becoming clinically manifest. Although the leukemogenic effects of x-ray exposure have been well documented, there is no information as yet on a threshold dose for the induction of leukemia. 3 It is of interest that more extensive investigation now questions previous statements that acute leukemia in childhood is disproportionately increased if the mother had been subjected to x-ray exposure during pregnancy. It should be emphasized, however, that the x-ray dose from pelvimetry may be considerably higher than the customary diagnostic x-rays, and biologic sensitivity of fetal tissues may be of far-reaching significance, especially since the fetus receives total body radiation. 3 Comment should also be made of two additional subjects of intensive scrutiny at present, namely, the genetic transmission of disease and autoimmunization. The gene and the specific protein for which it is responsible are elements in a dynamic biochemical relationship. The concept of a genetic code involves primarily the deoxyribonucleic acid (DNA) in the molecules of the chromosomes which carries the information to ribonucleic acid (RNA) in cytoplasm for the synthesis of specific polypeptide chains from amino acids. In the case of hemoglobin, this sequence finds ultimate expression in the formation of the polypeptide chains of the globin portion, namely, the two alpha and two beta chains. In the hemoglobinopathies the heterozygotes and homozygotes owe their differences to their content of normal and abnormal hemoglobins, more specifically in the alpha and beta chains or their derivatives, each under the control of a specific gene. The differentiation of normal hemoglobin and many of its variants by finger-printing, defining specific amino-acid substitutions, constitutes a major break-through in hematologic research. Of interest also in the hemoglobinopathies has been the discovery of the high fetal hemoglobin gene which is responsible for the persistence of a high concentration of alkali-resistant hemoglobin in erythro-
ill!
CARL H. SMITH
525
cytes in the absence of evidence of disease or other abnormalities.l This benign inherited anomaly of hemoglobin synthesis has a particular bearing when combined with sickle hemoglobin. The absence of hemolytic disease in persons heterozygous for the fetal anomaly and hemoglobin S has been ascribed to the uniform distribution of fetal hemoglobin among the red cells, thus preventing sickling. On the other hand, in homozygous sickle cell disease, the fetal hemoglobin is distributed heterogeneously. In the absence of sufficient hemoglobin F in the latter, red cells are not protected from sickling, and cell destruction ensues. l The revolutionary concept of autoimmune disease postulated by Burnet2 has far-reaching implications. According to this theory, autoimmune disease results from a breakdown of "immunologic hemostasis" presumably acquired in fetal life. It is in fetal life that the physiologic state is established in which immunologic tolerance for all normal body constituents develops. Ehrlich applied the term "horror autotoxicus" to such dire circumstances in which a living organism becomes capable of producing antibodies against its own body constituents. According to Burnet, when the inhibitions controlling "immunologic hemostasis" disappear because of infections or radiation exposure, for example, immunologically competent cells previously sequestered emerge in the form of "forbidden clones." These emerging cells are capable of producing abnormal antibodies against the patient's own normal tissue and blood cells. Erythrocyte, leukocyte and platelet destruction in which antibodies have been demonstrated, and the whole array of antibodies encountered in such a complex disease as systemic lupus erythematosus may originate from such an autoimmune mechanism. 4 This theory of "clonal selection," attractive as it appears, awaits experimental confirmation. The list of titles in this symposium bespeaks the remarkable growth of pediatric hematology. Within a brief space of years a younger generation of pediatricians has assumed leadership in hematology, each making notable contributions in this rapidly growing field of medicine. The contributors selected for this symposium do not by any means exhaust the large number of active and outstanding workers in pediatric hematology. Invitations were extended to those who from their previous publications evinced a central interest in certain areas that appeared of current concern. Although diagnosis and therapy are emphasized, each paper includes pertinent background information. In a field known for the complexity of nomenclature and the controversial nature of the subject matter, the simplicity with which these data have been assembled and appraised is a notable achievement in itself. As Editor of this volume, I wish to express my deep gratitude to the participants for the time and effort
526
FOREWORD
expended in the preparation of their manuscripts and for the excellence of the finished products. Finally, it should be emphasized that regardless of the complexity of hematology, the detection of the common blood disorders is still within the grasp of every medical practitioner by careful history and physical examination with the use of simple instruments and techniques. It is hoped that the information obtained from the papers In this symposium will contribute towards this goal. REFERENCES
1. Bradley, T. B., Brawner, J. N., III, and Conley, C. L.: Further Observations on an Inherited Anomaly Characterized by Persistence of Fetal Hemoglobin. Bull. Johns Hopkins Hosp., 108:242, 1961. 2. Burnet, F. M.: The New Approach to Immunology. New England]. Med., 264:24, 1961. 3. Cronkite, E. P., Moloney, W., and Bond, V. P.: Radiation Leukemogenesis. An Analysis of the Problem. Am. J. Med., 28:673, 1960. 4. Dameshek, W., Schwartz, R., and Oliver, H.: Current Concepts of Autoimmuniza· tion: An Interpretive Review. Blood, 17:775, 1961. 5. Gross, L.: Is Leukemia Caused by a Transmissible Virus? A Working Hypothesis. Blood, 9:557,1954. 6. Perlstein, M. A.: The Late Clinical Syndrome of Posticteric Encephalopathy. PEDIAT. CLIN. N.AMER., 7:665, 1960. 7. Welch, A. D.: The Problem of Drug Resistance in Cancer Chemotherapy. Cancer Research, 19:359, 1959. 525 E. 68th St. New York 21, N.Y.
ON
PEDIATRIC
HEMATOLOGY
FOREWORD
Highlights of Progress in Pediatric Hematology CARL H. SMITII, M.D.
Editor
The search for understanding is an adventure, or more commonly a series of adventures. _.. Now that geographical boundaries in our own and in other civilized lands have been determined, the pioneering spirit finds in scientific research enticing vistas for adventure.-Walter B. Cannon: The Way of an Investigator.
The subject matter comprising this issue of the Pediatric Clinics reflects indeed the enormous achievements resulting from scientific curiosity and the spirit of adventure in a recently developed specialty. The extraordinary growth of pediatric hematology is a reflection of these explorations. The expansion of knowledge has been largely accomplished by the application of disciplines, techniques and orientation common to all fields of medicine at present. It is axiomatic that in this period of intense activity in a single specialty there would be concomitant growth in all fields, so that specialties are no longer isolated, but are interdependent and flow over one on to the other. The fabric of the newer knowledge represented in these papers is interwoven with data obtained from studies in genetics, metabolic aberrations, enzymology, virology, immunology, in the precise delineation of intestinal absorption and malabsorption and in the blood proteins, i.e. haptoglobins, transferrins, those involved in coagulation, and in the transport of essential minerals and vitamins. One of the inherent difficulties in identifying a specific blood dis521
522
FOREWORD
order in infancy and childhood is that the diagnostic features are obscured by certain inherent physiologic and anatomic changes which originate within and outside the hematopoietic system. These influences, many dating from fetal life, operate with diminishing force from birth to adolescence. The accuracy of diagnosis in the congenital and acquired hemolytic anemias, iron deficiency, white blood cell disorders and those of blood coagulation in early life is predicated upon the appraisal of this shifting background. Throughout the papers in this volume an attempt has been made to stress the normal background against which abnormalities are appraised. The present symposium represents in effect the continuing story of the many subjects reviewed in the previous symposium of 1957. Many of the problems posed at that time have been elucidated, others have remained unsolved. Clarification has often generated new complexities. For example, one of the topics under current scrutiny is the so-called physiologic jaundice. Perhaps it was the preoccupation with neurologic abnormalities incident to hyperbilirubinemia in erythroblastosis fetalis that provoked a hard look at the heretofore "benign or physiologic" jaundice of the newborn. It may have been the discovery of kernicterus in autopsies of premature infants or the increased incidence of hyperbilirubinemia after excessive vitamin K dosage or with the use of sulfisoxazole (Gantrisin) in premature infants or other complicating factors that led to a reinvestigation of physiologic jaundice. Although hyperbilirubinemia of nonhemolytic and that of hemolytic origin have in common increased concentrations of indirect bilirubin, the attitude towards treatment is by no means uniform in each type. In a recent canvass of opinions from several large clinics in this country, the lack of a uniform policy in the management of nonhemolytic hyperbilirubinemia was striking. Although the majority of workers agreed that kernicterus was a threat, opinion was divided whether the critical 20-mg. yardstick should be adhered to as rigidly as in the hemolytic disease, whether a more relaxed attitude should be followed until levels of 25 mg. per 100 mI., or higher, were reached, or whether any treatment need be given in the uncomplicated case. Of importance in the problem of managing hemolytic and nonhemolytic hyperbilirubinemia is the possibility that posticteric sequelae may develop which are not flagrant, but are nevertheless manifested as minor symptoms.6 Some degree of hyperactivity, awkwardness, delayed speech acquisition, may represent belated manifestations of increased concentrations of pigment in the neonatal period. The papers dealing with this subject in this symposium will therefore be read with great interest, since newly developed diagnostic guides and treatment are presented. It is gratifying that since the last symposium, aplastic anemia, heretofore regarded as almost uniformly fatal in children despite trans-
CARL H. SMITH
523
fusions and steroids, has been found to respond in many cases to testosterone. It is unfortunate that many of the· acquired cases have once more been precipitated by the promiscuous use of chloramphenicol when other antibiotics could readily have been substituted or when no specific therapy was necessary. The continued interest in the intriguing possibility of transplanting human bone marrow prompted the inclusion of a paper on this subject. Periodically much interest is aroused by the reports of successful marrow "grafting." Unfortunately, the complete story is not always available, nor is it always possible to appraise the full therapeutic effect of the graft without considering the benefits from the modalities used to reduce the normal resistance of the host to the graft, or of supportive therapy. Nevertheless bone marrow transplantation in the human being may ultimately duplicate the success of animal experimentation and provide an important means of treating aplastic anemia, acute leukemia and other malignant diseases. Investigations of the carbohydrate metabolism of red cells constitute an integral part of the recent explosive interest in the enzymes of the blood. The hematologist has, therefore, had to acquire a knowledge of glycolytic pathways and of the enzymes with which they are associated. Specific enzymes have been described which maintain the integrity of the red cell, or playa role in the synthesis of the porphyrins and of heme, or which are deficient in iron deficiency anemia. Emphasis has centered on the fluctuations of one of these enzymes, glucose-6phosphate dehydrogenase. This enzyme is increased in the erythrocytes of newborn infants, decreased as a hereditary defect in certain druginduced hemolytic anemias and, depending on its concentration, serves as a means of classifying congenital nonspherocytic hemolytic anemia. Thus the revolution in thinking about inborn errors of metabolism as enzymatic defects has spread with equal force to hematologic syndromes. Among the white blood cell disorders, the leukemias and lymphomas are constantly perplexing problems to the pediatrician. There is no question that the course of acute leukemia has been greatly modified by advances in chemotherapy. Although survival rates are being prolonged, alertness is constantly needed in introducing "the new drug" and reassessing the value of the older compound. The present status of chemotherapy has been well summarized by Welch: 7 "The only accurate prediction which can now be made is that in almost any patient in whom a favorable response to a chemotherapeutic agent is obtained, there will eventually develop a state of refractoriness which is usually referred to as drug resistance. The basic problem is the emergence of mutant cells which serve as the progenitors of a new population of drug resistant cells." The papers dealing with the leukemias and lymphomas in this symposium are of especial value,
524
FOREWORD
since they not only list the available therapeutic agents, but also review the remarkable strides made with their use based on a knowledge of the biochemical changes they are expected to produce, rather than on the empiricism of the past. Since the etiology of leukemia is under constant scrutiny, much might be said about a current theory which implicates the fetus as an intermediary. Gross 5 demonstrated a viral etiology for lymphoid leukemias in mice which is noncontagious, but is communicated to offspring during embryonal life through either the male or female parent. Leukemia results after a period of latency of one third to one half of the life span of the animal. The virus exists in inactive form, disclosing its malignant capabilities only when challenged by stimuli such as radiation exposure. The virus would not necessarily become activated during the life span of the carrier, but might be transmitted through scveral generations before becoming clinically manifest. Although the leukemogenic effects of x-ray exposure have been well documented, there is no information as yet on a threshold dose for the induction of leukemia. 3 It is of interest that more extensive investigation now questions previous statements that acute leukemia in childhood is disproportionately increased if the mother had been subjected to x-ray exposure during pregnancy. It should be emphasized, however, that the x-ray dose from pelvimetry may be considerably higher than the customary diagnostic x-rays, and biologic sensitivity of fetal tissues may be of far-reaching significance, especially since the fetus receives total body radiation. 3 Comment should also be made of two additional subjects of intensive scrutiny at present, namely, the genetic transmission of disease and autoimmunization. The gene and the specific protein for which it is responsible are elements in a dynamic biochemical relationship. The concept of a genetic code involves primarily the deoxyribonucleic acid (DNA) in the molecules of the chromosomes which carries the information to ribonucleic acid (RNA) in cytoplasm for the synthesis of specific polypeptide chains from amino acids. In the case of hemoglobin, this sequence finds ultimate expression in the formation of the polypeptide chains of the globin portion, namely, the two alpha and two beta chains. In the hemoglobinopathies the heterozygotes and homozygotes owe their differences to their content of normal and abnormal hemoglobins, more specifically in the alpha and beta chains or their derivatives, each under the control of a specific gene. The differentiation of normal hemoglobin and many of its variants by finger-printing, defining specific amino-acid substitutions, constitutes a major break-through in hematologic research. Of interest also in the hemoglobinopathies has been the discovery of the high fetal hemoglobin gene which is responsible for the persistence of a high concentration of alkali-resistant hemoglobin in erythro-
ill!
CARL H. SMITH
525
cytes in the absence of evidence of disease or other abnormalities.l This benign inherited anomaly of hemoglobin synthesis has a particular bearing when combined with sickle hemoglobin. The absence of hemolytic disease in persons heterozygous for the fetal anomaly and hemoglobin S has been ascribed to the uniform distribution of fetal hemoglobin among the red cells, thus preventing sickling. On the other hand, in homozygous sickle cell disease, the fetal hemoglobin is distributed heterogeneously. In the absence of sufficient hemoglobin F in the latter, red cells are not protected from sickling, and cell destruction ensues. l The revolutionary concept of autoimmune disease postulated by Burnet2 has far-reaching implications. According to this theory, autoimmune disease results from a breakdown of "immunologic hemostasis" presumably acquired in fetal life. It is in fetal life that the physiologic state is established in which immunologic tolerance for all normal body constituents develops. Ehrlich applied the term "horror autotoxicus" to such dire circumstances in which a living organism becomes capable of producing antibodies against its own body constituents. According to Burnet, when the inhibitions controlling "immunologic hemostasis" disappear because of infections or radiation exposure, for example, immunologically competent cells previously sequestered emerge in the form of "forbidden clones." These emerging cells are capable of producing abnormal antibodies against the patient's own normal tissue and blood cells. Erythrocyte, leukocyte and platelet destruction in which antibodies have been demonstrated, and the whole array of antibodies encountered in such a complex disease as systemic lupus erythematosus may originate from such an autoimmune mechanism. 4 This theory of "clonal selection," attractive as it appears, awaits experimental confirmation. The list of titles in this symposium bespeaks the remarkable growth of pediatric hematology. Within a brief space of years a younger generation of pediatricians has assumed leadership in hematology, each making notable contributions in this rapidly growing field of medicine. The contributors selected for this symposium do not by any means exhaust the large number of active and outstanding workers in pediatric hematology. Invitations were extended to those who from their previous publications evinced a central interest in certain areas that appeared of current concern. Although diagnosis and therapy are emphasized, each paper includes pertinent background information. In a field known for the complexity of nomenclature and the controversial nature of the subject matter, the simplicity with which these data have been assembled and appraised is a notable achievement in itself. As Editor of this volume, I wish to express my deep gratitude to the participants for the time and effort
526
FOREWORD
expended in the preparation of their manuscripts and for the excellence of the finished products. Finally, it should be emphasized that regardless of the complexity of hematology, the detection of the common blood disorders is still within the grasp of every medical practitioner by careful history and physical examination with the use of simple instruments and techniques. It is hoped that the information obtained from the papers In this symposium will contribute towards this goal. REFERENCES
1. Bradley, T. B., Brawner, J. N., III, and Conley, C. L.: Further Observations on an Inherited Anomaly Characterized by Persistence of Fetal Hemoglobin. Bull. Johns Hopkins Hosp., 108:242, 1961. 2. Burnet, F. M.: The New Approach to Immunology. New England]. Med., 264:24, 1961. 3. Cronkite, E. P., Moloney, W., and Bond, V. P.: Radiation Leukemogenesis. An Analysis of the Problem. Am. J. Med., 28:673, 1960. 4. Dameshek, W., Schwartz, R., and Oliver, H.: Current Concepts of Autoimmuniza· tion: An Interpretive Review. Blood, 17:775, 1961. 5. Gross, L.: Is Leukemia Caused by a Transmissible Virus? A Working Hypothesis. Blood, 9:557,1954. 6. Perlstein, M. A.: The Late Clinical Syndrome of Posticteric Encephalopathy. PEDIAT. CLIN. N.AMER., 7:665, 1960. 7. Welch, A. D.: The Problem of Drug Resistance in Cancer Chemotherapy. Cancer Research, 19:359, 1959. 525 E. 68th St. New York 21, N.Y.