Thomas R. Kinney

Prediction of Adverse Outcomes in Children with Sickle Cell Disease

BACKGROUND The ability to identify infants with sickle cell anemia who are likely to have severe complications later in life would permit accurate prognostication and tailoring of therapy to match disease-related risks and facilitate planning of clinical trials. We attempted to define the features of such babies by following the clinical course of 392 children with sickle cell disease from infancy to about the age of 10 years. METHODS We analyzed the records of 392 infants who received the diagnosis of homozygous sickle cell anemia or sickle cell-Beta(0)-thalassemia before the age of six months and for whom comprehensive clinical and laboratory data were recorded prospectively; data were available for a mean (+/-SD) of 10.0+/-4.8 years. Results obtained before the age of two years were evaluated to determine whether they predicted the outcome later in life. RESULTS Of the 392 infants in the cohort, 70 (18 percent) subsequently had an adverse outcome, defined as death (18 patients [26 percent]), stroke (25 [36 percent]) frequent pain (17 [24 percent]), or recurrent acute chest syndrome (10 [14 percent]). Using multivariate analysis, we found three statistically significant predictors of an adverse outcome: an episode of dactylitis before the age of one year (relative risk of an adverse outcome, 2.55; 95 percent confidence interval, 1.39 to 4.67), a hemoglobin level of less than 7 g per deciliter (relative risk, 2.47; 95 percent confidence interval, 1.14 to 5.33), and leukocytosis in the absence of infection (relative risk, 1.80; 95 percent confidence interval, 1.05 to 3.09). CONCLUSIONS Three easily identifiable manifestations of sickle cell disease that may appear in the first two years of life (dactylitis, severe anemia, and leukocytosis) can help to predict the possibility of severe sickle cell disease later in life.

Role of child and maternal processes in the psychological adjustment of children with sickle cell disease

In this study, 64% of children aged 7-12 years with sickle cell disease were found to have a parent-reported behavior problem, and 50% met the criteria for a Diagnostic and Statistical Manual of Mental Disorders (3rd ed.) diagnosis based on a structural clinical interview of the child. Internalizing types of behavior problems and diagnoses were the most frequent. Support was provided for a transactional stress and coping model in delineating the processes associated with child adjustment. In particular, maternal anxiety accounted for 16%-33% of the variance in mother-reported internalizing and externalizing behavior problems, respectively, and child pain-coping strategies accounted for 21% of the variance in child-reported adjustment problems.

Discontinuing penicillin prophylaxis in children with sickle cell anemia

OBJECTIVE To evaluate the consequences of discontinuing penicillin prophylaxis at 5 years of age in children with sickle cell anemia who had received prophylactic penicillin for much of their lives. DESIGN Randomized, double-blind, placebo-controlled trial. SETTING Eighteen teaching hospitals throughout the United States. PATIENTS Children with sickle cell anemia (hemoglobin SS or hemoglobin S beta 0-thalassemia) who had received prophylactic penicillin therapy for at least 2 years immediately before their fifth birthday and had received the 23-valent pneumococcal vaccine between 2 and 3 years of age and again at the time of randomization. Of 599 potential candidates, 400 were randomly selected and followed for an average of 3.2 years. INTERVENTIONS After randomization, patients received the study medication twice daily--either penicillin V potassium, 250 mg, or an identical placebo tablet. Patients were either seen in the clinic or contacted every 3 months thereafter for an interval history and dispensing of the study drug. A physical examination was scheduled every 6 months. MAIN OUTCOME MEASURES The primary end point was a comparison of the incidence of bacteremia or meningitis caused by Streptococcus pneumoniae in children continuing penicillin prophylaxis versus those receiving the placebo. RESULTS Six children had a systemic infection caused by S. pneumoniae, four in the placebo group (2.0%; 95% confidence interval 0.5%, 5.0%) and two in the continued penicillin prophylaxis group (1.0%; 95% confidence interval 0.1%, 3.6%) with a relative risk of 0.5 (95% confidence interval 0.1, 2.7). All invasive isolates were either serotype 6(A or B) or serotype 23F. Four of the isolates were penicillin susceptible, and two (one from each treatment group) were penicillin and multiply antibiotic resistant. Adverse effects of the study drug were reported for three patients (nausea, vomiting, or both), one of whom was in the placebo group. CONCLUSION Children with sickle cell anemia who have not had a prior severe pneumococcal infection or a splenectomy and are receiving comprehensive care may safely stop prophylactic penicillin therapy at 5 years of age. Parents must be aggressively counseled to seek medical attention for all febrile events in children with sickle cell anemia.

Prevelance and clinical correlates of glomerulopathy in children with sickle cell disease

Objectives: Glomerular disease and renal failure cause substantial morbidity for patients with sickle cell disease (SCD). Proteinuria is an early manifestation of sickle nephropathy, but the prevalence of proteinuria and its clinical correlations in children with SCD are unknown. Study design: Data were collected prospectively on children with SCD for 10 years including physical measurements, laboratory test results, and clinical complications. Persistent proteinuria was defined as ≥1 + protein on urinalysis for at least 6 months. The glomerular filtration rate was estimated with serum creatinine concentration and height. Proteinuria was correlated with other variables by χ 2 analysis. Results: Proteinuria occurred in 20 of 442 pediatric patients including 15 (6.2%) with sickle cell anemia. Proteinuria increased with age, affecting 12% of older teenagers with sickle cell anemia. Proteinuria was significantly associated with lower hemoglobin concentration, higher mean corpuscular volume, and higher leukocyte count. For children of some ages, proteinuria was associated with complications including stroke, acute chest syndrome, cholelithiasis, and hospitalizations. Glomerular filtration rate hyperfiltration occurred early in life, followed by normalization. Conclusions: Sickle nephropathy, manifested as persistent proteinuria, begins early in life, occurs in all forms of SCD, and is associated with severity of disease. Early detection of proteinuria may allow therapy to prevent progressive renal insufficiency.

Cooperative Study of Sickle Cell Disease: Demographic and socioeconomic characteristics of patients and families with sickle cell disease.

Socioeconomic data on 3538 black patients enrolled in the Cooperative Study of Sickle Cell Disease (CSSCD) from 1979 to 1981 are summarized and compared with the U.S. black population (USBP) where appropriate. The following contrasts between the patients and families with Sickle Cell Disease (SCD) and the USBP were found: family structure differed, with fewer two-parent families (40 vs 54%) and more single female heads-of-household (53 vs 42%) within the SCD population; of those employed, twice as many of the SCD patients of both sexes worked in white collar positions; a higher percentage of patients were unemployed and disabled; and male SCD patients had a lower median personal income than USBP males. Several similarities were also noted: the percentage of high school graduates was 71% for SCD patients and 75% for the USBP; female heads-of-household employed full time earned approximately the same salary as USBP females. These data will help health professionals who counsel SCD patients and their families.

Elective cholecystectomy in children with sickle hemoglobinopathies. Successful outcome using a preoperative transfusion regimen.

Twenty-seven children with major sickle hemoglobinopathies underwent elective cholecystectomy for cholelithiasis. All were managed with a preoperative transfusion regimen to achieve a hemoglobin concentration of 11-14 g/dl with greater than 65% hemoglobin A. Intraoperative cholangiography revealed common bile duct stones in five patients, although only one case was diagnosed by preoperative ultrasonographic examination. Twenty-four children underwent incidental appendectomy by total intussusception. There were no vaso-occlusive events nor any other perioperative morbidity or mortality. Four months after cholecystectomy, one boy had a small bowel obstruction requiring surgical re-exploration. No patients had transfusion-acquired infection, although one boy had erythrocyte allosensitization to Lewis A antigen. This preoperative transfusion regimen and careful perioperative management permits safe elective cholecystectomy in children with sickle cell disease.

Venous thrombosis in a family with defective release of vascular plasminogen activator and elevated plasma factor VIII/von Willebrand's factor

A family is described in which venous thrombosis developed in five members as early as 14 years of age. Routine coagulation studies, plasma antithrombin III, factor V, plasminogen, beta-thromboglobulin, fibrinopeptide A, prothrombin fragment F1+2, and thrombin-antithrombin III complex were all within normal limits. However, defective release of vascular plasminogen activator was observed on several occasions in all five subjects as compared with a control population of 125 persons (0.04 Committee on Thrombolytic Agents [CTA] units/ml plasma as compared with 0.21 CTS units/ml). In addition, levels of factor VII/von Willebrands factor were significantly elevated above the normal range in this pedigree.

Erythrocytapheresis can reduce iron overload and prevent the need for chelation therapy in chronically transfused pediatric patients

Purpose This research was undertaken to determine the advantages, complications, costs, and efficacy of erythrocytapheresis in young pediatric patients who receive chronic erythrocyte transfusion therapy. Patients and Methods We retrospectively analyzed data for 10 children who received erythrocytapheresis for an average of 16 months. Erythrocytapheresis was compared to simple transfusion therapy with respect to annual blood unit exposure, occurrence of alloimmunization, and costs. Serum ferritin levels were compared before and after the period of erythrocytapheresis. Results Erythrocytapheresis was well tolerated, even in children as young as 5 years or as small as 20 kg. It required a greater annual unit exposure than simple transfusions, but did not increase alloimmunization. Ferritin levels decreased significantly in children receiving concurrent deferoxamine, and decreased or stablized in those not on chelation therapy. Children started on erythrocytapheresis soon after stroke have not developed iron overload. Although the costs of erythorocytapheresis exceed that of simple transfusion, the substantial costs of deferoxamine therapy should be considered; one child on erythrocytapheresis has been able to discontinue chelation therapy following normalization of his ferritin level. Conclusion Erythrocytapheresis is a safe and effective method for young patients receiving chronic erythrocyte transfusions. Erythrocytapheresis can reduce total iron burden and may obviate the need for expensive chelation therapy.

Psychological adjustment of children with sickle cell disease: Stability and change over a 10-month period.

Rates of poor psychological adjustment of children with sickle cell disease remained relatively constant over initial and follow-up assessment points. However, there was relatively little stability in the classification of the adjustment of individuals, low congruence in specific behavior problem patterns and diagnoses in accordance with the Diagnostic and Statistical Manual of Mental Disorders (3rd ed.; American Psychiatric Association, 1980), and less stability in child adjustment by child report than by mother report. With initial levels of adjustment controlled, childrens strategies for coping with pain accounted for a significant increment in child-reported symptoms (19%) and mother-reported internalizing behavior problems (8%) at follow-up beyond the contribution of illness and demographic parameters and follow-up interval. The findings suggest that childrens coping strategies are a salient intervention target for enhancing adjustment.

Coping strategies and laboratory pain in children with sickle cell disease

Studies have found that coping strategies are significant predictors of pain report, health care use, and psychosocial adjustment in children with sickle cell disease (SCD); however, the mechanisms of the relationship are not clear. In this study, 41 children with SCD completed a laboratory pain task to analyze their pain perception under standardized conditions. Sensory decision theory analyses were used to analyze the pain perception data. Children and their parents also completed measures of coping strategies and adjustment. Hierarchical regression analyses controlling for the child’s age indicated that children who reported using active cognitive and behavioral coping strategies had a lower tendency to report pain during the laboratory pain task. Results are discussed in terms of the utility of using laboratory pain models with children and the need for future intervention studies to target coping strategies in children with SCD pain.