X-ray diagnosable pneumonia in children with severe malnutrition at Kenyatta National Hospital.

OBJECTIVES: To estimate the prevalence of radiologically evident pneumonia among children with severe malnutrition and to evaluate the diagnostic utility of commonly used clinical indicators of pneumonia among children with severe malnutrition. METHODS: All children with severe malnutrition and admitted at the then Paediatric Observation Ward without congestive cardiac failure, severe anaemia, or severe dehydration, were clinically evaluated and a posteroanterior chest X-ray taken for each child. Pneumonia was diagnosed on the basis of radiological changes consistent with pneumonia as reported by an experienced radiologist. The performance of the various clinical parameters as diagnostic tests for pneumonia were also evaluated. SETTING: Kenyatta National Hospital, a tertiary level teaching institution for the University of Nairobi. RESULTS: One hundred and seven children comprising 68 males and 39 females were recruited into the study. Of these children, 38 had kwashiorkor, 40 had marasmus, while 29 had marasmic kwashiorkor. Radiological evidence of pneumonia was found in 58% of children with kwashiorkor, 75% with marasmic kwashiorkor, and 82% with marasmus. All the commonly used clinical parameters performed poorly as diagnostic tests for pneumonia among children with severe malnutrition. CONCLUSION: Prevalence of pneumonia was very high among children with severe malnutrition. Available clinical parameters, singly or in combination, are poor diagnostic tools for pneumonia in children with severe malnutrition. It is advisable to treat children with severe malnutrition as if they had pneumonia, even in the absence of suggestive clinical signs.

Risk factors for diarrheal duration.

To identify child feeding behavior and household hygiene practices that are risk factors for prolonged diarrheal illness, a longitudinal community study was conducted over a 14-month period among 920 children aged 3-37 months who lived in an urban slum settlement in Nairobi, Kenya. Morbidity surveillance was done by home visits every third day in the absence of diarrhea and daily during diarrheal illness until termination of the episode. In-home observations were made to characterize maternal hygiene, cooking, and child feeding practices. Overall, 1,496 episodes of diarrhea were detected. The average diarrheal incidence was 3.5 episodes/child-year, and the incidence of diarrhea > 14 days was 3 episodes/100 child-years. Cox regression was used to examine the independent effects of covariates on time to recovery from a diarrheal episode. Adjusted behavioral factors that were observed to influence recovery from diarrhea included: uncovered water containers (rate ratio (RR) = 0.77, 95% confidence interval (CI) 0.64-0.94); giving no fluids (as opposed to oral rehydration solutions (ORS)/sugar salt solutions (SSS)) (RR = 1.42, 95% CI 1.14-1.77); and administration of diluted cow's milk during the first 3 days of an episode (RR = 1.23, 95% CI 1.00-1.52). These associations remained significant after adjusting for diarrheal severity. The authors recommend, among other measures, improvement of water storage and promotion of continued feeding with cereal-milk mix during diarrhea.

Localization and treatment of an oxidation-sensitive defect within the TCR-coupled signalling pathway that is associated with normal and premature immunologic aging.

The age-dependent decline in the ability of T-cells to mount a proliferative response both to mitogens and to receptor ligation is due to an age-related defect in signal transduction, since functional expression of receptors displayed by aged T-cells is not reduced. We show here that, although turnover of phosphatidylinositol is not diminished, total inositol-trisphosphate generation decreases after T-cell receptor (TCR) ligation, resulting in reduced flux of calcium. Defective inositol-trisphosphate generation may result from impaired activation of phospholipase C due to decreased tyrosine phosphorylation of this enzyme after ligation of CD3 in aged cells. Proliferation of aged T-cells, which is normally 10-30% of the level of young controls, was enhanced almost tenfold by glutathione or its precursor N-acetyl L-cysteine (NAC), reached levels of young controls and was accompanied by restoration of normal inositol-trisphosphate generation and calcium flux. These findings suggest that the T-cell antigen receptor is associated with at least two types of signal transduction modules. The first depends on synthesis and phosphorylation of phosphatidylinositol that is independent of sulphydryl groups and is not affected by senescence. The second transduction module includes tyrosine phosphorylation and activation of phospholipase C. This module is regulated by glutathione levels and is diminished in aged T-cells, that are deficient in reducing equivalents which support the PLC gamma-dependent generation of inositol-trisphosphate from phosphatidylinositol derivatives. This underlying biochemical defect also occurs earlier in strains which display premature aging due to differences in the H-2 region of MHC I.

Polymorphic Hh genes in the HLA-B(C) region control natural killer cell frequency and activity.

We demonstrated earlier that individuals homozygous for conserved major histocompatibility complex (MHC)-extended haplotypes have low natural killer (NK) activity as measured by cytolysis of the K562 tumor cell lines. In the present study, we investigated the segregation and MHC linkage of NK activity in families in which MHC haplotypes of human histocompatibility leukocyte antigens (HLA)-A, -C, and -B, complotype, and DR specificities are known. In two informative families, low activity was inherited as a recessive trait linked to the MHC. By using individuals homozygous for specific fragments of extended haplotypes or for HLA-B alleles, we found that the HLA-C and -B and not the complotype or HLA-DR region contains genes controlling NK activity. The majority of the unrelated individuals with low NK activity were homozygous or doubly heterozygous for HLA-B7 (Cw7), B8 (Cw7), B44 (Cw5), B18, or B57 (Cw6). Thus, these alleles form one complementation group designated NKB1. Another less frequent group, NKB2, was also identified, and consisted of individuals homozygous for B35 (Cw4). NK activity was correlated with the number of circulating NK (CD16+ CD56+) cells. Individuals homozygous for the NKB complementation groups have fewer circulating NK cells than individuals heterozygous for these alleles and alleles of other complementation groups, possibly explaining the low activity of cells in these subjects. These findings suggest that during the maturation of NK cells there is NK cellular deletion in donors homozygous for NKB genes resulting in low NK cell numbers and activity.

Genetic control of the decline of natural killer cell activity in aging mice.

NK cell activity declines with age and is strain dependent. We investigated the age associated decline of NK cell activity in the HW26C strain of mice. The bilineal congenic strain HW26C which contains a segment of chromosome 4 of BALB/cBy introduced onto the C57BL/6By (B6) background was used to investigate the decline of NK cell activity with age. Our experiments showed that there is a significant decline of NK cell activity in old (18-26 months) HW26C mice as compared to the B6. By contrast, the NK cell frequency determined using a surface marker for NK cells, NK1.1, did not show any significant difference with age. It appears therefore, that the decline in NK activity during aging is a reflection of loss of lytic activity rather than an actual decline in the number of NK cells and the responsible gene(s) resides in chromosome 4.

Role of a genetic region on chromosome 4 in the regulation of natural killer cell activity in mice.

Natural killer cell (NK) activity is regulated by both the H-2 and non-H-2 genes. Using bilineal congenic HW26C and HW13 mice which differ from the background strain C57BL/6By (B6) in a region of chromosome 4, we investigated the role played by a gene/genes in a segment of chromosome 4 of BALB/cBy on NK cell activity. Percoll separated low density spleen cells from young HW26C and HW13 mice showed a 3.5 fold higher NK activity than the B6. We also observed that the increase in NK activity of HW26C was not due to an increase in the number of NK cells. Using five other bilineal congenics containing different regions of chromosome 4 of BALB/cBy, we observed that the putative gene(s) regulating NK activity may be located between b and IFN-alpha/beta genes of chromosome 4. The level of NK activity of (B6xHW26C)F1 ranked between the HW26C and B6 suggesting that the gene product described is inherited in an incompletely dominant fashion.

Defective signal transduction via T-cell receptor-CD3 structure in T cells from rheumatoid arthritis patients.

T cells from patients with active RA are known to produce low levels of IL-2 and proliferate poorly in response to various mitogenic stimuli. The present work shows that cross-linking of CD3 antigen on patients' T-cell surface induces two- to threefold lower Ca2+ response than in T cells from age-matched controls. Immunofluorescence studies indicate that the attenuated signal may be due to the suppressed expression of CD3 and/or CD45 molecules on patients' T cells. In the majority of the patients, the level of CD45 expression is reduced by 60%-70% as compared with that in the control T cells. Therefore, the poor mitogenic response of patient cells is apparently due to a defect in early stages of signal transduction through the T-cell receptor (TCR-CD3).

Linkage of pemphigus vulgaris antibody to the major histocompatibility complex in healthy relatives of patients.

Pemphigus vulgaris (PV) is an autoimmune disease caused by high concentrations of antibody to an epidermal cadherin. The disease is associated with two kinds of HLA-DR4, DQ8 haplotypes dominantly distributed among Jewish patients, and these plus DR6, DQ5 haplotypes in non-Jewish patients. Low levels of the PV antibody were found in 48% of a total of 120 asymptomatic parents, children, and siblings of 31 patients, thus exhibiting dominant inheritance. The inheritance of these low levels of antibody in asymptomatic relatives was linked to the major histocompatibility complex with a highly significant logarithm of the odds score of 9.07, almost always to a DR4 or DR6 haplotype of the patient. Disease appears to occur in susceptible individuals with low levels of antibody when a second factor, either environmental or genetic, induces high levels, sufficient to produce blisters.

Childhood asthma at Kenyatta National Hospital, Nairobi.

Between January 1986 and July 1988, 356 children with bronchial asthma below 14 years of age were evaluated at the Kenyatta National Hospital. 21.3% experienced initial asthmatic attacks before the age of six months and 55.1% before 2 years. Only 8% of the study patients were below the age of 2 years at recruitment. The male:female ratio was 1:1. Physical exercise led to precipitation or worsening of attacks in 43.4% while 71.6% of the patients experienced attacks in the evening or at night. 18.5% and 42.9% had personal history of atopic dermatitis and allergic rhinitis respectively. The study shows that a substantial number of patients experience initial asthmatic attacks before the age of 6 months contrary to what has been previously believed.

Mortality patterns in a rural Kenyan community.

Causes of death of 239 children below the age of 5 years in a rural community were determined using structured questionnaires. It was found that mortality was highest in infancy, accounting for 63% of all deaths with a trend of decreasing mortality with increasing age. The commonest cause of death was ARI (pneumonia and measles) accounting for 49% of the deaths, followed by diarrhoeal illnesses (8.8%). Only half of the deaths (51.5%) occurred at some health facility, though 77% of all children had been taken to a health facility for treatment during the fatal illness.

Verbal autopsy: a tool for determining cause of death in a community.

Verbal autopsy was used to determine causes of death in 239 children under the age of 5 years. The diagnosis derived from verbal autopsy was corroborated with hospital diagnosis in 39 cases. There was concurrence of diagnosis in 72% of the cases. Using the diagnosis of bronchopneumonia to validate the method, verbal autopsy was found to have a sensitivity of 71%, specificity of 92%, a positive predictive value of 85%. Reliability index of agreement was 0.654. Recall period up to 29 months after death was found to be reliable.