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)

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.

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.

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.

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.

Sickle cell disease. Summer camp. Experience of a 22-year community-supported program.

A summer camp for children with sickle cell disease (SCD) and other hemoglobinopathies has been in operation for 22 consecutive years (1,556 camper weeks). Two thirds of the campers had sickle cell anemia (SS). With the exception of 1 year, SCD-related medical problems occurred in 10 percent of the children. Episodes of illness were increased during the year when the camp was held at a site 2,200 feet above sea level. Children with SCD can enjoy a remote, physically challenging, and emotionally enriching program. Success requires an experienced and prepared medical staff who leave the organization and "on site" management of camp activities to expert recreational professionals.

Sickle cell anemia and major organ failure.

Major organ failure in sickle cell anemia is the direct consequence of the sickle cell evoked vasculopathy. Major organ failure is first clinically apparent as autosplenectomy, then during childhood presents as cerebral infarction and atrophy, and finally culminates in young adulthood as end stage renal failure (glomerulosclerosis), sickle chronic lung disease, intracranial hemorrhage, retinopathy, disabling leg ulcers, and generalized osteonecrosis. The vascular damage begins years before the overt clinical symptoms are apparent with no pain to act as a signal. Organ damage is progressive and irreversible. The rate of progression is genetically controlled from birth. Except for the management of life-threatening infections that are associated with the non-functioning spleen, disease expression has not been altered by therapy. The focus of future clinical investigations must be the prevention of the vasculopathy and tissue damage which is induced by the sickle red cell.

Is sickle cell crisis a valid measure of clinical severity in sickle cell anemia?

We studied the conditional probability of developing a sickle cell crisis in 509 patients with sickle cell anemia (SS), with variable number of prior crises. These SS patients were followed during different calendar eras, having diverse complications, and had entered and/or lost to follow-up at different ages. The probability of having a sickle cell crisis during the first three decades of life increases significantly with the number of prior crises episodes (p less than 0.001). After more than five cryptogenic crises, the patient has developed a patterned response to stress that overshadows other influences, such as the effects of therapeutic agents, thus lessening the 'power' of sickle crisis as a measure of morbidity.

Infection caused by Streptococcus pneumoniae in children with sickle cell disease: epidemiology, immunologic mechanisms, prophylaxis, and vaccination.

The incidence of invasive infection due to Streptococcus pneumoniae is 6.9 infections per 100 patient-years among children with sickle cell anemia (SS genotype) who are less than 5 years of age; this rate is 30-100 times that which would be expected in a healthy population of this age. Splenic dysfunction is the major contributor to the increased risk. Postulated abnormalities of immunologic defense mechanisms, including synthesis of polyclonal IgG and IgM, the alternative complement pathway, opsonic activity, and T and B cell interaction, may also enhance risk. Preceding or concomitant viral infection is suspected of predisposing to pneumococcal infection, but no definitive data are available. The most prevalent pneumococcal serotypes causing disease in this setting include types 6, 14, 18, 19, and 23; these same serotypes are most frequently involved in "vaccine failure." Current evidence demonstrates only modest protective efficacy for contemporary pneumococcal vaccines in young patients with sickle cell anemia; thus alternative vaccines are required. Convincing evidence for a protective effect of antibiotic prophylaxis has been obtained in limited time trials. However, presently used prophylactic regimens pose problems related to compliance and provide imperfect protection; moreover, their optimal duration remains unknown.

Acquired methemoglobinemia.

Cases of acquired methemoglobinemia have been identified with increasing frequency in Los Angeles during the last several years. Among 18 patients, both infants and adults, the most commonly incriminated agent was silver nitrate used for topical antibacterial prophylaxis of burn wounds. One burned child died from overwhelming septicemia complicated by hypoxia with a methemoglobin level of 5.4 grams per dl. Other causative factors included nitrate-rich vegetables used in early infancy, additives in ethnic foods, and prescribed and overdosed drugs. Discontinuation of the precipitating agent and methylene blue therapy were usually followed by prompt improvement. In burned patients treated with silver nitrate, careful regular monitoring of serum methemoglobin levels and early initiation of specific therapy are mandatory.

Beta S-gene-cluster haplotypes in sickle cell anemia: clinical implications.

Restriction endonuclease analysis was used to detect alpha-gene deletions and to determine the haplotypes in the DNA of the beta S-gene-cluster [Benin, Central African Republic (CAR), and Senegal] in 221 patients with sickle cell anemia (SS). The clinical expression of SS was modified by the beta S-gene-cluster polymorphisms and the alpha-gene status (alpha-thalassemia-2). The overall risk of soft tissue organ failure caused by the obliterative sickle vasculopathy (including stroke, renal failure, chronic lung disease with cor pulmonale, leg ulcers, and young adult death) was increased threefold in those with a CAR haplotype and was decreased in those with a Senegalese chromosome (p = 0.003). In the presence of a Senegalese haplotype, the patient's health is better, and with the CAR haplotype it is always worse. With the Benin, it is intermediate. Acute recurrent clinical events including hospitalized sickle cell crisis, bone infarction, and infection are decreased in frequency in those with a Senegalese haplotype. The risk of most acute events including acute chest syndrome is equivalent in those with Benin or CAR haplotypes. In the United States, alpha-thalassemia-2 is co-inherited randomly among the beta S-gene-cluster haplotypes. Acute events occurring during childhood are minimally effected by this co-inheritance. The risk of soft tissue organ failure is decreased. After the age of 20 years, painful episodes of the lumbar dorsal area are increased in patients who had alpha-thalassemia-2 in association with degenerative bone disease.(ABSTRACT TRUNCATED AT 250 WORDS)