Lack of influence of fetal hemoglobin levels or erythrocyte indices on the severity of sickle cell anemia.

Persons with sickle cell anemia who have elevated fetal hemoglobin or lowered erythrocyte mean corpuscular volume are reputed to have less severe clinical manifestations and a greater probability of survival. This study examines the relationship between seven clinical indicators of morbidity in sickle cell anemia and seven hematological parameters that were collected from 214 patients. Risks of sickle cell crisis, acute chest syndrome, hospital admissions, cerebrovascular accident, aseptic necrosis, meningitis/septicemia, and death were used as indicators of morbidity. The hematological parameters included percent fetal hemoglobin, absolute fetal hemoglobin, percent hemoglobin A2, hemoglobin concentration, packed cell volume, mean corpuscular volume, and mean corpuscular hemoglobin concentration. Statistical analyses of the data showed no relationship between the hematological parameters and six of the seven clinical indicators of the severity of sickle cell anemia. The only significant finding was an increased risk of stroke in those patients with lower levels of fetal hemoglobin. Therefore, with this exception, there is no predictable relationship between morbidity and mortality in sickle cell anemia and levels of fetal hemoglobin or erythrocyte indices. Thus, the general belief that there is an association between severity of sickle cell anemia and the levels of fetal hemoglobin has not been established.

Sickle cell anemia: beta s-gene-cluster haplotypes as prognostic indicators of vital organ failure.

Identification of the beta s-gene-cluster haplotype and alpha-gene status provide a useful tool to improve the possibility for early detection in high-risk SS patients. The DNA polymorphisms of the beta s-gene-cluster modify the clinical course in sickle cell anemia especially as it involves the risk of end-stage organ failure of the kidney, lung, and brain. In both Africa and America, the CAR beta s haplotype increases the risk of developing irreversible complications at an early age. The degree of anemia, the Hb F concentration, and the preservation (or lack thereof) of G gamma Hb F is haplotype dependent and correlates with the overall clinical course of the patient. Further modulation of the clinical course by the coinheritance of alpha-thalassemia-2 tends to decrease the risk of soft tissue organ failure but increases the risk of osteonecrosis. A single individual can be expected to fit into the overall pattern. Some sickle related illness will eventually occur in all patients. In the presence of a Senegal haplotype, the patient's health is better, with the CAR haplotype it is always worse; severity is intermediate in the Benin. These genetic markers can be used to identify the endangered patient before the onset of irreversible major organ failure. The high risk SS patient with a CAR chromosome or one who is homozygous Ben without alpha-thalassemia-2 should be monitored closely for evidence of vasculopathy-induced microinfarction of the brain, kidneys, or lungs. Such a patient needs preventive therapy before suffering a major hemisphere stroke, losing kidney function, or developing cor pulmonale secondary to restrictive lung disease.(ABSTRACT TRUNCATED AT 250 WORDS)

Sickle cell chronic lung disease: prior morbidity and the risk of pulmonary failure.

Sickle cell chronic lung disease (SCLD) is a prime contributor to mortality in young adult patients with sickle cell disease, especially those with sickle cell anemia (SS). Both perfusion and diffusion defects have been demonstrated, with generalized pulmonary fibrosis and disabling restrictive lung failure. We report 28 cases (25 SS, 1 S beta(0) thalassemia, 1 S beta(+) thalassemia and 1 SO-Arab) which began during the second decade of life and which ended in death by the fourth decade, after an ordered progression to pulmonary failure and cor pulmonale. Myocardial hypoxia with multifocal fibrosis and segmental infarction occurred in more than one-third of the cases and sudden death was a frequent final event. We define 4 stages of SCLD, based on pulmonary function tests, chest roentgenograms, blood gases, and noninvasive cardiac studies; each stage is 2 or 3 years in length, until death ensues in Stage 4. Case-control analysis showed that the significant risk factors associated with SCLD are 1) the total number of acute chest syndrome events in an individual before the onset of SCLD, (p = 0.0001), 2) sickle cell crisis marked by chest pain (p = 0.03) and 3) aseptic necrosis (p = 0.005). Temporal clustering of acute chest syndrome episodes frequently heralds the onset of SCLD. The pulmonary arterial bed, which has low oxygen tension and low pressure in a slow-flow system, is ideally suited to facilitate the polymerization of sickle hemoglobin, causing endothelial damage and culminating in an obstructive arteriolar vasculopathy. Identification of the significant risk factors predictive of SCLD can lead to early diagnosis of the disease; this is the only hope for effective intervention therapy.

Multisystem damage associated with tricorporal priapism in sickle cell disease.

PURPOSE: Priapism is an uncommon but debilitating complication of sickle cell disease (SCD). Recent observations among adult males regarding the abysmal failure of medical and surgical therapy encouraged us to review our 25-year experience identifying the prognostic features that might determine outcome. PATIENTS AND METHODS: As part of a prospective 25-year longitudinal demographic and clinical cohort study, a subset of 38 (8.2%) patients with priapism were identified among a cohort of 461 men with SCD. The patients with priapism were compared with the nonaffected men with respect to severity of disease expression, hematologic status, beta s globin gene haplotype, and the incidence of sickle-related major organ failure. The influence of the treatment modalities on outcome was also evaluated. RESULTS: Priapism occurred as a single episode in 24 patients, and in 14 as temporally clustered repeat episodes. Eighty-seven percent of those with priapism had sickle cell anemia (SS), an increased risk as compared with other variants of SCD (p = < 0.05). There were two distinct age-related patterns of disease expression. Eight patients were prepubertal; they experienced shorter episodes, involvement of the corpora cavernosa only, few recurrent episodes, and a good prognosis for future erectile function. Non-surgical therapy in children was associated with excellent results. In contrast, the 29 postpubertal adults often had involvement of the corpora cavernosa and corpus spongiosa (tricorporal disease) and half had prolonged episodes that lasted longer than 8 days. One pubescent patient had repeated episodes and became impotent. Prolonged or repeated episodes eventuated in impotence in 56%. Surgical intervention was not beneficial. Sickle cell-related organ failure such as stroke, chronic restrictive lung disease, chronic renal failure, and nonhealing leg ulcers was observed more frequently in men who had priapism. Death occurred in nine adult patients (25%) within 5 years of the first episode of priapism. CONCLUSION: Priapism in adult males identifies those at high risk for other sickle cell-related organ failure syndromes and, as such, is another complication indicative of severe disease. The dismal prognosis in SS adults requires better understanding of the precise pathophysiology of low-flow tricorporal priapism. Clarification of the mechanisms inducing the priapic state should lead to specific therapeutic maneuvers and an improved prognosis for this disabling condition.

Is there an increased risk of Haemophilus influenzae septicemia in children with sickle cell anemia?

The risk of Haemophilus influenzae septicemia/meningitis to children who have sickle cell anemia (SS) has been determined to be greater than that seen among normal infants. Of ten bacteriologically proven cases, eight episodes of infection were observed among 234 children with sickle cell anemia (645 person-years), who were less than 5 years of age. There was one case per 69 infants with sickle cell anemia who were less than 18 months old and one case per 36 children with sickle cell anemia between 19 and 59 months of age. Unexpectedly, two infections occurred among 224 children (824 person-years), aged 5 to 9 years; both died. Contrary to the rapid clinical course of pneumococcal infections in children with sickle cell anemia H influenzae septicemia was regularly heralded by a greater than 24-hour prodrome of upper respiratory tract infection, low-grade fever, and otitis media. Three (30%) preventable deaths occurred. Antibiotic therapy for the febrile child with sickle cell anemia must be predicated on the known 400-fold increased risk of pneumococcal septicemia in those less than 5 years old and the fourfold risk of H influenzae septicemia in those less than 9 years of age.

Rapid diagnosis of sickle cell disease at birth by microcolumn chromatography.

Accurate specific diagnosis of sickle cell disease can now be made at birth on routinely obtained cord blood samples by microcolumn chromatography. The method uses a small column of a cation ion exchange resin, CM-Sephadex, and a single developer that allows definitive rapid distinction of hemoglobin SS, AS, AC, SC, and CC, within two hours. Seventy-five samples or more per day have been analyzed by one technician in a laboratory without special precautions or equipment. In a program which has been initiated on a large, totally unpredictable obstetrical service in Los Angeles, 10,401 consecutively born infants have been studied for hemoglobin type without regard to racial origin. Three SS infants, 1 SC, 143 AS infants, and 37 AC infants as well as several with other abnormal hemoglobins have been identified without interfering with the routine operation of the delivery rooms of the obstetrical service. The diagnosis of sickle cell disease has been confirmed on subsequent examinations of the infants. The feasibility of using microcolumn chromatography as a rapid, accurate, inexpensive, and easy method for the rapid diagnosis of sickle cell disease in newborns has now been established.

Congenital malaria: a rare cause of splenomegaly and anemia in an American infant.

A 38-day-old infant had fever, jaundice, hepatosplenomegaly, and a hemolytic anemia. A peripheral blood smear demonstrated intraerythrocytic malarial parasites identified as Plasmodium vivax. Maternal and infant sera contained antibodies to this species. A directed history revealed the mother had suffered several febrile illnesses in Mexico during her pregnancy. Malaria had not been diagnosed nor was it considered at the time of her delivery at this hospital. Review of this and six other cases of congenital malaria reported in this country since 1950 indicates clinical manifestations seldom appear before 3 weeks of age. Although these signs are more frequently associated with other transplacental infections, their occurrence in an infant whose mother is from or who has traveled in an endemic area should prompt consideration of the diagnosis of congenital malaria.

Combined pressure control/high frequency ventilation in adult respiratory distress syndrome and sickle cell anemia.

Acute chest syndrome complicating sickle cell anemia may progress to adult respiratory distress syndrome despite appropriate therapy. Extra-alveolar air leaks may complicate the care of these patients as conventional mechanical ventilation becomes increasingly difficult. We successfully treated a child with sickle cell anemia, acute chest syndrome, adult respiratory distress syndrome, and severe extra-alveolar air leaks using a new combined mode ventilatory approach: pressure control with high-frequency ventilation.

The influence of fetal hemoglobin on the clinical expression of sickle cell anemia.

The variable levels of HbF in sickle cell anemia reflect the heterogeneous genetic mix of the beta s-gene-cluster haplotypes and coinheritance of alpha-thalassemia-2 in American SS patients. Clinical severity is less when the level of HbF reaches 20% or 1.2 g/dl or more. The coinheritance of alpha-thalassemia-2 not only increases the intracellular red cell water but modifies the HbF level in accordance with the beta-cluster haplotype. In general, the SS patient with at least one Senegalese haplotype who does not have a CAR haplotype in trans, has a significantly greater probability of maintaining HbF above 20%. This is in part related to the genetic control of the G gamma HbF locus. Such a patient is protected from arteriolar vasculopathy and subsequent major organ destruction. Much of this but perhaps not all of the better health of patients with a Senegalese haplotype can be attributed to the elevation of G gamma HbF. The coinheritance of alpha-thalassemia-2 further decreases the risk of major morbidity of the soft tissues but increases the risk of avascular necrosis of the bony skeleton. Although these heterozygous Senegal patients are healthier, eventually most, in time, will show the deleterious effect of HbS as retinopathy and avascular necrosis usually beginning after age 30 and sickle nephropathy after age 40. Because of the age-specific effect, the onset of the sickle vasculopathy is delayed by nearly 20 years in the Sen/Ben patient with increased G gamma HbF as compared to those with a CAR haplotype or the homozygous Benin. Lifetime elevation of HbF above 20% modifies the severity of disease expression and provides relative protection to the patient with sickle cell anemia.

Adenocarcinoma of the colon and rectum in the adolescent.

Between 1969 and 1982, seven adolescents (six girls and one boy) with rectal bleeding and other nonspecific intestinal symptoms were diagnosed with biopsy to have colonic or rectal carcinoma. All came from an impoverished urban environment, and two patients were members of a family with a cancer diathesis (Turcot's syndrome). Surgery provided the only successful curative or palliative treatment. Chemotherapy and radiation therapy were unsuccessful in preventing the progression of disease in far-advanced, nonresectable cases. Prompt attention to lower gastrointestinal bleeding and nonspecific abdominal symptoms in adolescents may result in the earlier diagnosis of colorectal malignancy and improved opportunity for definitive surgical cure.

Pregnancy in sickle cell disease.

Risks associated with pregnancy for mothers with sickle cell disease and their infants have decreased markedly during the last decade. Among 79 women with sickle cell anemia (156 pregnancies), maternal death decreased from 4.1% before 1972 to 1.7% after 1972; their infants' fetal and perinatal death rates decreased from 52.7 to 22.7% (P less than .05), and from 33.3 to 27.3% among infants of women with sickle hemoglobin C disease. There has been a significant improvement in birth weight specific mortality and an increase in number of weeks' gestation from 34.7 to 37.4 (P less than .05). A higher percentage of sickle hemoglobin C disease mothers completed their pregnancies with no complications (43%) when compared with sickle cell anemia mothers (21%), thus identifying a subset of women for whom pregnancy does not represent an increased risk. These results are attributed to improvements in state-of-the-art medical, obstetric, and perinatal care.

Staging laparotomy for Hodgkin's disease in children. Evaluation of the technique.

The evaluation of a technique of laparotomy for the staging of Hodgkin's disease in childhood, including 52 operative procedures, is reviewed. A standard protocol, including splenectomy, multiple hepatic and bone marrow biopsies, and the routine sampling of at least six designated lymph node groups, was employed. It was demonstrated that the surgeon is unable to identify Hodgkin's disease by gross inspection and that the biopsy of node groups previously not included in routine laparotomy studies, ie, mesenteric and porta hepatis nodes is essential to staging in childhood. Stage was altered from stages I and II to stages III and IV in 35% of the patients. The incidence of abdominal recurrence following a negative laparotomy was 7%, and the incidence of post-splenectomy hyperacute infection was 4.5%. This study included minimal use of the lymphangiogram (33%), which accounted for the relatively larger group of patients in clinical stages I and II.

Beta s-gene-cluster haplotypes in sickle cell anemia. Clinical and hematologic features.

Identification of the beta s-gene-cluster haplotype and alpha-gene status provides a useful tool for the detection of the high-risk SS patient. The DNA polymorphisms of the beta s-gene-cluster modulate the clinical course in sickle cell anemia, especially as it involves the risk of end stage organ failure of the kidney, lung, brain, eyes, bones, and leg ulcers. This is schematically represented in Figure 4. The disease severity is modified according to the beta s-gene-cluster haplotypes and the co-inheritance of alpha-thalassemia-2. In both Africa and America, the CAR beta s haplotype increases the risk of developing an irreversible complication at an early age. The rate of progression of organ damage is regulated by the beta s-cluster haplotype from birth. The preservation of G gamma Hb F is haplotype dependent and correlates with the overall clinical course of the patient. Further modulation of the clinical course with the co-inheritance of alpha-thalassemia-2 tends to decrease the risk of soft-tissue organ failure and increase the risk of osteonecrosis. Epidemiologic studies in Africa together with clinical correlative analysis in Southern California show that SS patients with a Ben haplotype have a less severe illness than those with a CAR and a more severe illness than those with a Sen. A single individual can be expected to fit into the overall pattern. Some sickle related illness will eventually occur in all. The variable clinical manifestations in sickle cell anemia are modified according to the interaction of alpha gene deletions and the beta s-gene-cluster haplotype, are distinct for each organ, and markedly influence the age of onset of end stage major organ failure. In the presence of a Senegal haplotype, the patient's health is better; with the CAR haplotype, it is always worse; severity is intermediate in the Benin haplotype.

Priapism.

Priapism in adult patients with sickle cell disease is a devastating complication for which there is no consensus regarding management. Innumerable attempts at pharmacologic and surgical intervention have been employed. Distinction between infarctive low-flow priapism with hypoxia and acidosis and normal-flow priapism without acidosis can be obtained using currently available imaging techniques. Cavernosonography and radionuclide scanning to assess penile hemodynamics are useful in determining whether priapism is of the low-flow type. Advances in our understanding of the physiology of erection have prompted a more physiologic approach to the assessment and management of priapism. Based on this technology, it would be possible to develop a prospective multiinstitutional study, thereby providing sufficient numbers of patients to better evaluate therapy. After the episode of priapism has abated and detumescence has occurred, we recommend that the patient be given the option of beginning a trial of hydroxyurea or another antisickling agent.

Renal failure in sickle cell anemia.

ESRD is a major complication in young adults with sickle cell anemia. As more patients with sickle cell anemia reach the third and fourth decades of life, the incidence of clinically apparent renal insufficiency will increase. As we understand the pathophysiology of renal damage and the effects of various therapies on the sickle renal vasculature, we can tailor specific management without further compromising already impaired renal function. Diagnostic clues must be recognized prior to the onset of irreversible damage, with appropriate intervention initiated at each age group. Bone marrow transplantation (BMT) is the only available cure for SCA at the present time. The demonstration that several distinct haplotypes of the beta s gene cluster on chromosome 11 influence the clinical expression of sickle cell anemia may be useful in delineating children who are at high risk for severe disease, and hence candidates for such hazardous therapeutic interventions as BMT prior to onset of clinically discernable disease. Current BMT preparative regimens can produce renal cortical and pulmonary toxicity, posing a patient selection problem in those cases in which the vasculopathy of the major organs is at an early stage and might be potentially repairable. Gene therapy without toxic preparative regimens is the ultimate answer. The challenge for the near future is the development of effective early therapeutic intervention during childhood and young adulthood.

Staging laparotomy and splenectomy for Hodgkin's disease.

The major objective of diagnostic laparotomy in Hodgkin's disease is to define the extent of involvement not detectable by nonoperative means. Fifty patients in this institution had operative staging procedures; six for recurrent disease three to 11 years after initial therapy. Twenty-four patients had nodular sclerosis, 23 mixed cellularity, and three had other types. The clinical stages were advanced in 13 patients and decreased in seven patients. Two patients (both had mixed cellularity and systemic symptoms) had positive wedge biopsy of the liver, whereas direct needle biopsy was negative. Nineteen spleens contained Hodgkin's disease but only three could be palpated on physical examination. About half the patients with abnormal lymphangiograms had positive periaortic nodes; lymphangiogram had a false negative rate of 12%. Additional procedures performed included appendectomy, oophoropexy, and resection of Meckel's diverticulum. There was no mortality and only one case had severe postoperative Salmonella septicemia. Our findings are comparable with those reported in the literature.

The selective suppression of immunogenicity by hyaluronic acid.

A hyaluronidase-sensitive component of human peritoneal fluid from a patient with Wilms' tumor when injected into rabbits has been shown to suppress the formation of humoral precipitating antibodies to certain major classes of proteins present in the fluid. Furthermore, it has been found that hyaluronic acid, when included with certain test antigens (serum albumin, fetuin) or antigen mixtures (tumor isolates or mixtures of albumin, immunoglobulin G and immunoglobulin M), produces a marked distortion or complete blockage of immunoelectrophoresis precipitin arcs, as well as altered gel chromatography elution profiles. These findings that hyaluronic acid can interfere profoundly with both the elicitation of a complete antibody response and the formation of "normal" patterns of antigen-antibody precipitates in laboratory tests supports the possibility that this polysaccharide may play an immuno-regulatory role by masking potential immunogens. Consideration of the mechanisms for these in vivo and in vitro effects suggests that there may be some common basis in an "excluded volume" property of the hyaluronate, but this does not appear sufficient to explain the complexity and selectivity of the observed phenomena.

Evaluation of the surgical aspects of staging laparotomy for Hodgkin's disease in children.

Experience with 72 children in which the type of staging laparotomy recommended by the Intergroup Hodgkin's Disease in Childhood Study (IHDCS) was employed (1967-1981) is reviewed. Laparotomy altered the stage in 35% of these patients including advance in stage (I-II to III-IV) in 24 patients, and reduction in stage (III to II) in one patient. In adults, Stage III disease is divided into III1 and III2 on the basis of the presence or absence of lower abdominal node involvement; and prognosis is significantly better in III1. Nine patients from two additional institutions were included in a special study of Stage III disease. This included 22 children in III1 and 11 children in III2. Although the children with Stage B (systemic symptoms) disease were concentrated in III2, none of the measured difference between these two groups were significant. No fatal postsplenectomy sepsis has been noted since the use of pneumococcal vaccine and prophylactic penicillin became standard.

Frequency analysis of the EEG in children with sickle cell disease.

An automated technique for EEG frequency analysis was employed in the study of nine children with sickle cell disease. Quotients, Q(1) (delta+theta/alpha+beta) and Q(2) (theta/alpha+8), were calculated from the computed power in each frequency range. Recordings from occipital-parietal and temporal-frontal areas resulted in a higher Q(1) for sickle cell disease patients than for reported normals (p<.002 and p<.05 respectively). Q(2) value from the occipital-parietal sites were also higher for the sickle cell group (p<.05).The technique reported here lends itself to serial studies in appropriate patient groups and suggests the possibility of an organic basis for some of the results found.

The pediatrician and the dying child. "Physician, know thyself".

To deal with problems aroused in professional medical staff working with fatally ill children, a team of psychiatrics and oncologists not only deals with the problems of the children and their families, but also with problems of the medical staff themselves. Psychotherapy to the medical staff is offered only indirectly. The overriding difficulty which prevents the medical staff from maintaining role-appearance behavior is dealing with the theme of death. Often this is the hidden agenda behind a facade of other presenting problems. At times, the medical staff may be unable to deal with their own anger when conforted by demanding patients or hostile parents. At other times, medical staff will overidentify with the patient resulting in inappropriate role behavior. When medical results are poor despite good medical care, staff may feel inappropriately guilty. These issues can be dealt with means of a weekly mental health conference with the focus on the patient.