Unforgettable patients Howard A. Pearson, MD
Perhaps because of a somewhat warped sense of humor, I have always been fascinated by improbable clinical combinations, the concomitant occurrence of conditions that presumably are mutually exclusive or totally incompatible. Several patients in particular come to mind. PATIENT
1
When erythrocytes containing sickle hemoglobin (HbS) are exposed to low oxygen tension, elongated intracellular hemoglobin crystals form that result in the elongated, distorted sickle cell. A straightforward relationship between oxygen tension and sickling forms the basis of most theories about the pathogenesis of sickle cell anemia. A still unique patient seemed to defy this relationship, l A 4-year-old black male patient had a diagnosis of tetralogy of Fallot made in infancy on the basis of physical examination (cyanosis, typical heart murmur) and characteristic roentgenographic and electrocardiographic findings. At 9 months of age he appeared pale, and anemia was documented. Hemoglobin electrophoresis showed a hemoglobin sickle-fetal (HbSF) pattern consistent with sickle cell anemia. Both parents had sickle cell trait. During the first 4 years of the boy's life, he had few symptoms. The only clinical manifestations of sickle cell disease were dactylitis (hand-foot syndrome) on several occasions. At 4 years of age the patient was admitted to the University of Florida Teaching Hospital for cardiac catheterization. His hemoglobin level was 77 gm/L (7.7 gm/dl) and the reticulocyte count was 17.6%, values that are typical of ordinary cases of sickle cell anemia. Cardiac catheterization confirmed the diagnosis of tetralogy of Fallot. His arterial oxygen saturation was 73%, and arterial oxygen tension was 52 mm Hg. We went through considerable soul-searching about the Dr. Pearson is Professor of Pediatrics at Yale University School of Medicine, New Haven, Conn. He was a feUowin pediatric hematology at the Boston Children's Hospital, and was on the faculty of the University of Florida College, Gainesville,f~ofia 1962 to 1968. From 1974 through 1987, he was Chairman of the Department of Pediatrics at Yale University School of Medicine. He will serve as President of the American Academy of Pediatrics from 1992 to 1993. 9/32/35574
154
proper management of this patient but ultimately decided to recommend total surgical correction. In addition to purely cardiologic indications, our reasoning, as i remember, was that the child's sickle cell disease was mild with such a degree of desaturation, and might be even better when this improved. We also were Concerned that because cyanosis requires 5 gm/dl of desaturated hemoglobin, his "working" hemoglobin concentration was only 2 gm/dl. The child had total corrective surgery, which unfortunately was complicated by the development of severe tricuspid insufficiency. He was no longer cyanotic; arterial saturation was now 9 t %, and arterial oxygen tension was 76 mm Hg. However, chronic congestive heart failure requiring digitalis and diuretics developed postoperatively. Five months after surgery, the child's anemia was more severe (hemoglobin level, 50 gm/L; reticulocyte count 22%). The percentage of irreversibly sickled cells in his circulation was significantly increased from that present preoperatively. Painful sickling symptoms became an almost continuous problem. The boy died 1 year later. This case proved to me that more than just HbS and oxygen are involved in the pathogenesis of sickle cell anemia. Other factors, such as circulation time, pH, and tissue stasis, are obviously also critical. Caring for this patient caused great deal of anguish in all of the care givers. Although our intentions and reasoning were sound, even retrospectively, the outcome was disas.tfous. P r i m u m n o n nocere! PATIENT
2
The symptoms and complications of hypogammaglobulinemia syndromes are usually ascribed to deficiency of antibodies. The development of an aggressive immune disease caused by autoantibodies in one of these patients remains a nearly unique occurrence. 2 This boy hhd been studied at 2 years of age because of recurrent bacterial infections; these had included otitis media requiring 20 myringotomies, and several bouts of bacterial pneumonia. A male sibling, born earlier, had died of infection in infancy; abnormal lymph node histologic findings consistent with hypogammaglobulinemiawere noted at autopsy. Serum electrophoresis revealed "hypogammaglobulinemia." A diagnosis of congenital hypogammaglobuline-
Volume 121 Number l
mia was made, and the patient was treated with monthly intramuscular injections of immune globulin, with only slight clinical improvement, At 6 years of age the patient was examined at the University of Florida Teaching Hospital. A complete blood cell count showed normal hemoglobin concentration, hematocrit, and leukocyte and platelet counts. Laboratory findings were as follows: IgG 210 mg/L, IgM undetected and IgA 480 rag/L; these values are consistent with severe hypogammaglobulinemia. Peripheral lymphocytes showed a normal mitotic index after phytohemagglutinin stimulation. The diagnosis of congenital (probably X-linked) hypogammaglobulinemia was reconfirmed. The patient was treated with larger monthly doses of intramuscularly administered immune globulin, with marked clinical improvement. One year later the child became acutely pale and weak. Generalized lymphadenopathy and splenomegaly were present. The hematocrit was now 0.17, hemoglobin concentration 50 gm/L, and reticulocyte count 60%. The erythrocytes showed marked polychromasia and intense spherocytosis. Results of the direct Coombs test were strongly positive: Serum immunoglobulin values were essentially unchanged from the earlier values. Study of erythrocytic eluates showed IgG antibodies with very broad reactivity (anti-LW). The immune globulin preparation that he had previously received showed no anti-LW activity. The patient was treated with prednisone. There was a prompt rise in the hemoglobin level and fall in the reticulocyte count. During the next 2 years, whenever the steroid therapy was discontinued, severe hemolysis recurred. A 3-month course of azathioprine was given. The hematologic picture stabilized into chronic, well-compensated hemolytic anemia. Results of the Coombs test remained strongly positive. At 9 years of age the boy had a normal hemoglobin concentration and reticulocyte count; the Coombs test showed only weakly positive results. At 12 years of age he was hematologically normal and was still receiving monthly doses of intramuscularly administered immune globulin. When last seen, in his thirties, he had had no recurrence of hemolytic anemia. The reason that an aggressive autoantibody developed in this boy with severe hypogammaglobulinemia, and the mechanism at work, remain elusive 30 years later.
Unforgettable patients
PATIENT
155
3
The antibiotic chloramphenicol has been associated with the development of acute anemia and chronic aplastic anemia. Because it is regarded as a bone marrow suppressant, it is usually avoided in patients with blood disorders. A boy had had documented severe neutropenia and recurrent severe bacterial infections since infancy. 3 Despite many infections and a variety of therapies, his absolute neutrophil count (ANC) never exceeded 200 cells/ram 3, and was usually 1500 cells/ ram3). At 8 years of age he was admitted to Yale-New Haven Hospital with progressive pneumonia and was treated with several antibiotics, including chloramphenicol. On admission, his A N C was 40 cells/ram 3. Ten days later there was a sharp increase in A N C to 20,000 cells/ram 3, and he made a rapid recovery. Two weeks after discontinuation of the antibiotics, the A N C was again 20 cells/ram 3. During the next 3 years, neutropenia was repeatedly documented, but on three separate occasions after treatment, by the child's pediatrician, with chloramphenicol for pyoderma, normal numbers of neutrophils were serendipitously noted. He was then reexamined at Yale-New Haven Hospital. A series of studies showed that 10 days after oral chlorampbenicol therapy was begun, a sharp increase in the A N C predictably occurred. Two weeks after the drug therapy was discontinued, neutropenia recurred. A dose-response relationship between chloramphenicol and A N C was documented. Today the patient remains dependent on this drug to keep him free of infection and to maintain normal numbers of neutrophils. He has received 2.0 gm of chloramphenicol per day continuously for more than a decade. Whenever it is discontinued, neutropenia recurs. I have learned of at least five other instances of this relationship, but pediatric hematologists in general remain reluctant to use chloramphenicol in chronic neutropenia syndromes. REFERENCES
1. Pearson HA, Schiebler GL, Krovitz LJ, Bartley TD, David JK. Sickle cell anemia associated with tetralogy of Fallot. N Engl J Med 1965;273:1079-83. 2. Robbins JB, Skinner RS, Pearson HA. Autoimmune hemolytic anemia in a child with congenital X-linked hypogammaglobulinemia. N Engl J Med 1969;288:75-9. 3. Adams GR, Pearson HA. Chloramphenicol-responsive chronic neutropenia. N Engl J Med 1983;309:1039-41.
Perhaps because of a somewhat warped sense of humor, I have always been fascinated by improbable clinical combinations, the concomitant occurrence of conditions that presumably are mutually exclusive or totally incompatible. Several patients in particular come to mind. PATIENT
1
When erythrocytes containing sickle hemoglobin (HbS) are exposed to low oxygen tension, elongated intracellular hemoglobin crystals form that result in the elongated, distorted sickle cell. A straightforward relationship between oxygen tension and sickling forms the basis of most theories about the pathogenesis of sickle cell anemia. A still unique patient seemed to defy this relationship, l A 4-year-old black male patient had a diagnosis of tetralogy of Fallot made in infancy on the basis of physical examination (cyanosis, typical heart murmur) and characteristic roentgenographic and electrocardiographic findings. At 9 months of age he appeared pale, and anemia was documented. Hemoglobin electrophoresis showed a hemoglobin sickle-fetal (HbSF) pattern consistent with sickle cell anemia. Both parents had sickle cell trait. During the first 4 years of the boy's life, he had few symptoms. The only clinical manifestations of sickle cell disease were dactylitis (hand-foot syndrome) on several occasions. At 4 years of age the patient was admitted to the University of Florida Teaching Hospital for cardiac catheterization. His hemoglobin level was 77 gm/L (7.7 gm/dl) and the reticulocyte count was 17.6%, values that are typical of ordinary cases of sickle cell anemia. Cardiac catheterization confirmed the diagnosis of tetralogy of Fallot. His arterial oxygen saturation was 73%, and arterial oxygen tension was 52 mm Hg. We went through considerable soul-searching about the Dr. Pearson is Professor of Pediatrics at Yale University School of Medicine, New Haven, Conn. He was a feUowin pediatric hematology at the Boston Children's Hospital, and was on the faculty of the University of Florida College, Gainesville,f~ofia 1962 to 1968. From 1974 through 1987, he was Chairman of the Department of Pediatrics at Yale University School of Medicine. He will serve as President of the American Academy of Pediatrics from 1992 to 1993. 9/32/35574
154
proper management of this patient but ultimately decided to recommend total surgical correction. In addition to purely cardiologic indications, our reasoning, as i remember, was that the child's sickle cell disease was mild with such a degree of desaturation, and might be even better when this improved. We also were Concerned that because cyanosis requires 5 gm/dl of desaturated hemoglobin, his "working" hemoglobin concentration was only 2 gm/dl. The child had total corrective surgery, which unfortunately was complicated by the development of severe tricuspid insufficiency. He was no longer cyanotic; arterial saturation was now 9 t %, and arterial oxygen tension was 76 mm Hg. However, chronic congestive heart failure requiring digitalis and diuretics developed postoperatively. Five months after surgery, the child's anemia was more severe (hemoglobin level, 50 gm/L; reticulocyte count 22%). The percentage of irreversibly sickled cells in his circulation was significantly increased from that present preoperatively. Painful sickling symptoms became an almost continuous problem. The boy died 1 year later. This case proved to me that more than just HbS and oxygen are involved in the pathogenesis of sickle cell anemia. Other factors, such as circulation time, pH, and tissue stasis, are obviously also critical. Caring for this patient caused great deal of anguish in all of the care givers. Although our intentions and reasoning were sound, even retrospectively, the outcome was disas.tfous. P r i m u m n o n nocere! PATIENT
2
The symptoms and complications of hypogammaglobulinemia syndromes are usually ascribed to deficiency of antibodies. The development of an aggressive immune disease caused by autoantibodies in one of these patients remains a nearly unique occurrence. 2 This boy hhd been studied at 2 years of age because of recurrent bacterial infections; these had included otitis media requiring 20 myringotomies, and several bouts of bacterial pneumonia. A male sibling, born earlier, had died of infection in infancy; abnormal lymph node histologic findings consistent with hypogammaglobulinemiawere noted at autopsy. Serum electrophoresis revealed "hypogammaglobulinemia." A diagnosis of congenital hypogammaglobuline-
Volume 121 Number l
mia was made, and the patient was treated with monthly intramuscular injections of immune globulin, with only slight clinical improvement, At 6 years of age the patient was examined at the University of Florida Teaching Hospital. A complete blood cell count showed normal hemoglobin concentration, hematocrit, and leukocyte and platelet counts. Laboratory findings were as follows: IgG 210 mg/L, IgM undetected and IgA 480 rag/L; these values are consistent with severe hypogammaglobulinemia. Peripheral lymphocytes showed a normal mitotic index after phytohemagglutinin stimulation. The diagnosis of congenital (probably X-linked) hypogammaglobulinemia was reconfirmed. The patient was treated with larger monthly doses of intramuscularly administered immune globulin, with marked clinical improvement. One year later the child became acutely pale and weak. Generalized lymphadenopathy and splenomegaly were present. The hematocrit was now 0.17, hemoglobin concentration 50 gm/L, and reticulocyte count 60%. The erythrocytes showed marked polychromasia and intense spherocytosis. Results of the direct Coombs test were strongly positive: Serum immunoglobulin values were essentially unchanged from the earlier values. Study of erythrocytic eluates showed IgG antibodies with very broad reactivity (anti-LW). The immune globulin preparation that he had previously received showed no anti-LW activity. The patient was treated with prednisone. There was a prompt rise in the hemoglobin level and fall in the reticulocyte count. During the next 2 years, whenever the steroid therapy was discontinued, severe hemolysis recurred. A 3-month course of azathioprine was given. The hematologic picture stabilized into chronic, well-compensated hemolytic anemia. Results of the Coombs test remained strongly positive. At 9 years of age the boy had a normal hemoglobin concentration and reticulocyte count; the Coombs test showed only weakly positive results. At 12 years of age he was hematologically normal and was still receiving monthly doses of intramuscularly administered immune globulin. When last seen, in his thirties, he had had no recurrence of hemolytic anemia. The reason that an aggressive autoantibody developed in this boy with severe hypogammaglobulinemia, and the mechanism at work, remain elusive 30 years later.
Unforgettable patients
PATIENT
155
3
The antibiotic chloramphenicol has been associated with the development of acute anemia and chronic aplastic anemia. Because it is regarded as a bone marrow suppressant, it is usually avoided in patients with blood disorders. A boy had had documented severe neutropenia and recurrent severe bacterial infections since infancy. 3 Despite many infections and a variety of therapies, his absolute neutrophil count (ANC) never exceeded 200 cells/ram 3, and was usually 1500 cells/ ram3). At 8 years of age he was admitted to Yale-New Haven Hospital with progressive pneumonia and was treated with several antibiotics, including chloramphenicol. On admission, his A N C was 40 cells/ram 3. Ten days later there was a sharp increase in A N C to 20,000 cells/ram 3, and he made a rapid recovery. Two weeks after discontinuation of the antibiotics, the A N C was again 20 cells/ram 3. During the next 3 years, neutropenia was repeatedly documented, but on three separate occasions after treatment, by the child's pediatrician, with chloramphenicol for pyoderma, normal numbers of neutrophils were serendipitously noted. He was then reexamined at Yale-New Haven Hospital. A series of studies showed that 10 days after oral chlorampbenicol therapy was begun, a sharp increase in the A N C predictably occurred. Two weeks after the drug therapy was discontinued, neutropenia recurred. A dose-response relationship between chloramphenicol and A N C was documented. Today the patient remains dependent on this drug to keep him free of infection and to maintain normal numbers of neutrophils. He has received 2.0 gm of chloramphenicol per day continuously for more than a decade. Whenever it is discontinued, neutropenia recurs. I have learned of at least five other instances of this relationship, but pediatric hematologists in general remain reluctant to use chloramphenicol in chronic neutropenia syndromes. REFERENCES
1. Pearson HA, Schiebler GL, Krovitz LJ, Bartley TD, David JK. Sickle cell anemia associated with tetralogy of Fallot. N Engl J Med 1965;273:1079-83. 2. Robbins JB, Skinner RS, Pearson HA. Autoimmune hemolytic anemia in a child with congenital X-linked hypogammaglobulinemia. N Engl J Med 1969;288:75-9. 3. Adams GR, Pearson HA. Chloramphenicol-responsive chronic neutropenia. N Engl J Med 1983;309:1039-41.
