Prognostic indicators of early and late death in children admitted to district hospital in Kenya: cohort study.

OBJECTIVES: To identify clinical indicators of immediate, early, and late mortality in children at admission to a sub-Saharan district hospital and to develop prognostic scores. DESIGN: Prospective cohort study. SETTING: One district hospital in Kenya. PARTICIPANTS: Children aged over 90 days admitted to hospital from 1 July 1998 to 30 June 2001. MAIN OUTCOME MEASURES: Prognostic indicators of mortality. RESULTS: Of 8091 children admitted up to 1 June 2000, 436 (5%) died. Sixty (14%) died within four hours after admission (immediate), 193 (44%) after 4-48 hours (early), and 183 (42%) after 48 hours (late). There were marked differences in the clinical features associated with immediate, early, and late death. Seven indicators (neurological status, respiratory distress (subcostal indrawing or deep breathing), nutritional status (wasting or kwashiorkor), severe anaemia, jaundice, axillary temperature, and length of history) were included in simplified prognostic scores. Data from 4802 children admitted from 1 July 2000 to 30 June 2001 were used to validate the scores. For simplified prognostic scores the areas under the receiver operating characteristic curves were 0.93 (95% confidence interval 0.92 to 0.94), 0.82 (0.80 to 0.83), and 0.82 (0.81 to 0.84) for immediate, early, and late death, respectively. CONCLUSION: In children admitted to a sub-Saharan hospital, the prognostic indicators of early and late deaths differ but a small number of simple clinical signs predict outcome well.

Diagnosis of acute bacterial meningitis in children at a district hospital in sub-Saharan Africa.

BACKGROUND: The diagnosis of acute bacterial meningitis in children is difficult in sub-Saharan Africa, because the clinical features overlap with those of other common diseases, and laboratory facilities are inadequate in many areas. We have assessed the value of non-laboratory tests and incomplete laboratory data in diagnosing childhood acute bacterial meningitis in this setting. METHODS: We prospectively studied 905 children undergoing lumbar puncture at a rural district hospital in Kenya over 1 year. We related microbiological findings and cerebrospinal-fluid (CSF) laboratory measurements to tests that would typically be available at such a hospital. FINDINGS: Acute bacterial meningitis was proven in 45 children (5.0% [95% CI 3.7-6.6]) and probable in 26 (2.9% [1.9-4.2]). 21 of the 71 cases of proven or probable acute bacterial meningitis had neither neck stiffness nor turbid CSF. In eight of 45 children with proven disease the CSF leucocyte count was less than 10x10(6)/L or leucocyte counting was not possible because of blood-staining. The presence of either a leucocyte count of 50x10(6)/L or more or a CSF/blood glucose ratio of 0.10 or less detected all but two of the 45 children with proven acute bacterial meningitis; these two samples were grossly blood-stained. INTERPRETATION: The diagnosis of childhood acute bacterial meningitis is likely to be missed in a third of cases at district hospitals in sub-Saharan Africa without adequate and reliable laboratory resources. CSF culture facilities are expensive and difficult to maintain, and greater gains could be achieved with facilities for accurate leucocyte counting and glucose measurement.

Antibiotic susceptibility and genotypes of non-typhi Salmonella isolates from children in Kilifi on the Kenya coast.

A 4-year retrospective study was undertaken at the Kilifi District Hospital on the coast of Kenya to determine the antibiotic-susceptibility patterns and genotypes of non-typhi Salmonella (NTS) isolates from children. Overall, during the period 1994-97, positive cultures were obtained from 543 (14%) of 3885 blood samples, 364 (30%) of 1210 stool samples and 143 (11%) of 1283 cerebrospinal fluid (CSF) samples. NTS were isolated from 151 (27.8%), 72 (19.8%), and 11 (7.7%) of these positive cultures, respectively. The total 234 NTS isolates were serotyped: the most frequent were Salmonella enterica serotype Enteritidis (41%) and S. enterica serotype Typhimurium (38%). Antibiotic sensitivity testing was done using ampicillin (amp), chloramphenicol (chl), gentamicin (cn), co-trimoxazole (s-t), cefuroxime (cxm), ciprofloxacin (cip), cefotaxime (ctx), amoxicillin-clavulanic acid 20 micrograms-10 micrograms (amc), and tobramycin (tob). Of the 234 isolates, 43 were sensitive to all antibiotics tested and 133 were multiple drug resistant (MDR). The most common resistance type seen was amp, cn, cxm, s-t, ctx, amc, tob (36/234). Our results indicate a high proportion of MDR amongst the isolates from Kilifi. We conclude that 2 major serotypes of salmonella, i.e., S. enterica serotype Typhimurium and S. enterica serotype Enteritidis, of micro-epidemic nature that have been previously unrecognized in Kilifi are responsible for infection in Kilifi district on the coast of Kenya and that over half (56.8%) of total NTS isolates are MDR.

Plasmodium falciparum-infected erythrocytes: agglutination by diverse Kenyan plasma is associated with severe disease and young host age.

The variant surface antigens (VSAs) of Plasmodium falciparum-infected red blood cells are potentially important targets of naturally acquired immunity to malaria. Natural infections induce agglutinating antibodies specific to the VSA variants expressed by the infecting parasites. Previously, when different parasite isolates were tested against a panel of heterologous plasma from Kenyan children, the proportion of plasma that agglutinated the parasites (the agglutination frequency [AF]) was highly variable among isolates, suggesting the existence of rare and prevalent variants. Here, the AF of 115 isolates from Kenyan children were compared. The results show that the AF of isolates causing severe malaria were significantly higher than those of isolates causing mild malaria; and AF decreased significantly with the increasing age of the infected child. We propose that parasites causing severe disease tend to express a subset of VSA variants that are preferentially associated with infections of children with low immunity.

Antibody recognition of Plasmodium falciparum erythrocyte surface antigens in Kenya: evidence for rare and prevalent variants.

Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) is the name given to a family of parasite proteins that are inserted into the infected erythrocyte surface. Studies using agglutination assays have shown previously that PfEMP1 epitopes are extremely diverse. In a study in Kenya, 21 parasite isolates, including nine from children with severe malaria, were tested for agglutination by 33 pairs of plasma, 21 of which were from the corresponding children. Each plasma pair consisted of a sample taken at the time of disease (acute) and one taken 3 weeks later (convalescent). In agreement with previous studies, infection was generally followed by the induction of antibodies specific to the homologous parasite isolate. In addition however, the results show that (i) some isolates were agglutinated very frequently by heterologous plasma; (ii) unexpectedly, these frequently agglutinated isolates tended to be from individuals with severe malaria; (iii) an inverse relationship existed between the agglutination frequency of each parasite isolate in heterologous plasma and the agglutinating antibody repertoire of the homologous child at the time of disease; and (iv) A 3-month-old child apparently still carrying maternal antibodies was infected by a rarely agglutinated isolate. This child's plasma agglutinated all isolates at the time of disease, apart from the homologous isolate. These results support the idea that preexisting anti-PfEMP1 antibodies can select the variants that are expressed during a new infection and may suggest the existence of a dominant subset of PfEMP1 variants.

A community randomized controlled trial of insecticide-treated bednets for the prevention of malaria and anaemia among primigravid women on the Kenyan coast.

The effectiveness of insecticide-treated bednets (ITBN) in preventing malaria and anaemia among primigravidae living in Kilifi District, Kenya, was assessed by a randomized controlled trial between September 1994 and November 1995. All residents within 28 community clusters received ITBN in July 1993, whilst residents of another 28 clusters served as contemporaneous controls. All resident primigravid women with singleton pregnancies attending antenatal care at Kilifi District Hospital were eligible for recruitment. 503 primigravidae were recruited. 91.4% were anaemic antenatally (Hb < 11 g/dl): 91.0% from the intervention arm and 92.0% from the control arm. Severe anaemia (Hb < 7 g/dl) was found among 15.1% of intervention women and 20.1% of control women (P = 0.28). No significant differences were observed in reports of febrile illness or the presence of chloroquine in the serum or peripheral parasitaemia during the third trimester between the two groups. In the women delivering in hospital (n = 130), there was no association between placental malaria infection and the intervention: 77.4% of placentas from control women had evidence of past or active infection, compared with 72.0% of placentas from intervention women (P = 0.76). Similarly, in the women delivering in hospital, ITBN did not improve birth weight, and there were no differences in perinatal mortality between the two study groups. Despite ITBN having a great impact on paediatric severe malaria and mortality in this transmission setting, there was very little impact of ITBN on the morbidity associated with malaria infection in primigravidae. Alternative strategies are required to tackle this continued public health problem for pregnant women living in endemic areas similar to the Kenyan Coast.

Parasite antigens on the infected red cell surface are targets for naturally acquired immunity to malaria.

The feasibility of a malaria vaccine is supported by the fact that children in endemic areas develop naturally acquired immunity to disease. Development of disease immunity is characterized by a decrease in the frequency and severity of disease episodes over several years despite almost continuous infection, suggesting that immunity may develop through the acquisition of a repertoire of specific, protective antibodies directed against polymorphic target antigens. Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) is a potentially important family of target antigens, because these proteins are inserted into the red cell surface and are prominently exposed and because they are highly polymorphic and undergo clonal antigenic variation, a mechanism of immune evasion maintained by a large family of var genes. In a large prospective study of Kenyan children, we have used the fact that anti-PfEMP1 antibodies agglutinate infected erythrocytes in a variant-specific manner, to show that the PfEMP1 variants expressed during episodes of clinical malaria were less likely to be recognized by the corresponding child's own preexisting antibody response than by that of children of the same age from the same community. In contrast, a heterologous parasite isolate was just as likely to be recognized. The apparent selective pressure exerted by established anti-PfEMP1 antibodies on infecting parasites supports the idea that such responses provide variant-specific protection against disease.

Malaria is an important cause of anaemia in primigravidae: evidence from a district hospital in coastal Kenya.

A study was undertaken in order to determine the prevalence and aetiology of anaemia in pregnancy in coastal Kenya, so as to establish locally important causes and enable the development of appropriate intervention strategies. 275 women attending the antenatal clinic at Kilifi district hospital, Kenya, were recruited in November 1993. The prevalence of anaemia (haemoglobin [Hb] < 11 g/dL) was 75.6%, and the prevalence of severe anaemia (Hb < 7g/dL) was 9.8% among all parities; 15.3% of 73 primigravidae were severely anaemic, compared with 7.9% of 202 multigravidae (P = 0.07). In primigravidae, malaria infection (Plasmodium falciparum) was strongly associated with moderate and severe anaemia (chi 2 test for trend, P = 0.003). Severe anaemia was more than twice as common in women with peripheral parasitaemia as in those who were aparasitaemic, and parasitaemia was associated with a 2.2g/dL decrease in mean haemoglobin level (P < 0.001). In multigravidae, iron deficiency and hookworm infection were the dominant risk factors for anaemia. Folate deficiency and human immunodeficiency virus infection were not strongly associated with anaemia. It is suggested that an intervention that can effectively reduce malaria infection in primigravidae could have a major impact on the health of these women and their infants.

Acridine orange fluorescence techniques as alternatives to traditional Giemsa staining for the diagnosis of malaria in developing countries.

Traditional Giemsa-stained thick blood films were compared with 2 fluorescence microscopy techniques, acridine orange (AO) staining of thin blood films and the quantitative buffy coat (QBC) method, for the microscopical diagnosis of malaria. Of 200 samples examined, 141 were positive by Giemsa staining, 146 by AO and 137 by QBC. Overall sensitivities for the 2 fluorescence techniques compared to Giemsa staining were good: AO 97.9% and QBC 93.6%. However, with parasitaemias < 100/microL the QBC sensitivity fell to 41.7% whereas that of AO was 83.3%. Both AO and QBC were unable to differentiate accurately between individual malaria species. We conclude that the QBC technique alone cannot replace Giemsa-stained thick blood films for most purposes in an African setting. However, apart from species differentiation, the AO method is an appropriate technique for the laboratory diagnosis of malaria in developing countries.

Severe childhood malaria in two areas of markedly different falciparum transmission in east Africa.

Malaria remains a major public health challenge in sub-Saharan Africa, yet our knowledge of the epidemiology of malaria in terms of patterns of mortality and morbidity is limited. We have examined the presentation of severe, potentially life-threatening malaria to district hospitals in two very different transmission settings: Kilifi, Kenya with low seasonal transmission and Ifakara, Tanzania with high seasonal transmission. The minimum annual rates of severe disease in children below five years in both populations were similar (46 per 1000 children in Kilifi and 51 per 1000 children in Ifakara). However, there were important differences in the age and clinical patterns of severe disease; twice as many patients were under one year of age in Ifakara compared with Kilifi and there was a four fold higher rate of cerebral malaria and three fold lower rate of malaria anaemia among malaria patients at Kilifi compared with Ifakara. Reducing malaria transmission in Ifakara by 95%, for example with insecticide-treated bed nets, would result in a transmission setting comparable to that of Kilifi and although this reduction may yield early successes in reducing severe malaria morbidity and mortality in young, immunologically naive children, place these same children at increased risk at older ages of developing severe and potentially different manifestations of malaria infection hence producing no net cohort gain in survivorship from potentially fatal malaria.

Mechanisms of exercise-induced pulmonary hemorrhage in the equine athlete.

This article discusses exercise-induced pulmonary hemorrhage (EIPH), a pathophysiological syndrome which occurs worldwide in the equine athlete. It reviews the history of EIPH, the incidence in performance horses, the etiology, studies performed on the treadmill to determine the mechanisms of EIPH, and the most likely causes of stress failure of the pulmonary capillaries.

Influence of cyclooxygenase inhibitors on furosemide-induced hemodynamic effects during exercise in horses.

Furosemide, which commonly is used as a prophylactic treatment for exercise-induced pulmonary hemorrhage in horses, may mediate hemodynamic changes during exercise by altering prostaglandin metabolism. To determine if furosemide's hemodynamic effects during exercise in horses could be reversed, cyclooxygenase inhibitors were administered with furosemide. Four treatments were administered 4 hours prior to treadmill exercise at 9 and 13 m/s. They included a control treatment (10 ml of 0.9% NaCl solution, IV), furosemide (1 mg/kg of body weight, IV) administered alone, and furosemide in combination with phenylbutazone (4 mg/kg, IV, q 12 h for 2 days) or with flunixin meglumine (1.1 mg/kg, IV, on the day of experiment). Five horses were randomly assigned to complete all treatments. Physiologic variables at rest prior to exercise were not influenced by treatments. Furosemide, administered alone, reduced mean right atrial pressure and mean pulmonary artery pressure during exercise. The combinations of furosemide and flunixin meglumine or furosemide and phenylbutazone, at both levels of exercise intensity, returned mean right atrial pressure and mean pulmonary artery pressure to the value of the control treatment. During rest and exercise, plasma lactate concentration, PCV, heart rate, mean carotid artery pressure, oxygen consumption, carbon dioxide elimination, and cardiac output were not altered by any of the treatments. At 5 minutes after exercise, the administration of furosemide, alone or with phenylbutazone, reduced mean right atrial pressure. Other measured variables were not significantly influenced by treatments during recovery from exercise. These results suggested that cyclooxygenase inhibition partially reverses the decrease in mean right atrial pressure or pulmonary artery pressure induced by furosemide during exercise.(ABSTRACT TRUNCATED AT 250 WORDS)

Influence of furosemide on hemodynamic responses during exercise in horses.

Four hours prior to exercise on a high-speed treadmill, 4 dosages of furosemide (0.25, 0.50, 1.0, and 2.0 mg/kg of body weight) and a control treatment (10 ml of 0.9% NaCl) were administered IV to 6 horses. Carotid arterial pressure (CAP), pulmonary arterial pressure (PAP), and heart rate were not different in resting horses before and 4 hours after furosemide administration. Furosemide at dosage of 2 mg/kg reduced resting right atrial pressure (RAP) 4 hours after furosemide injection. During exercise, increases in treadmill speed were associated with increases in RAP, CAP, PAP, and heart rate. Furosemide (0.25 to 2 mg/kg), administered 4 hours before exercise, reduced RAP and PAP during exercise in dose-dependent manner, but did not influence heart rate. Mean CAP was reduced by the 2-mg/kg furosemide dosage during exercise at 9 and 11 m/s, but not at 13 m/s. During recovery, only RAP was decreased by furosemide administration. Plasma lactate concentration was not significantly influenced by furosemide administration. Furosemide did not influence PCV or hemoglobin concentration at rest prior to exercise, but did increase both variables in dose-dependent manner during exercise and recovery. However, the magnitude of the changes in PCV and hemoglobin concentration were small in comparison with changes in RAP and PAP, and indicate that furosemide has other properties in addition to its diuretic activities. Furosemide may mediate some of its cardiopulmonary effects by vasodilatory activities that directly lower pulmonary arterial pressure, but also increase venous capacitance, thereby reducing venous return to the atria and cardiac filling.

Further observations on self-catheterization.

A non-sterile technique of intermittent self-catheterization was used for 218 patients with an inability to void in a normal fashion because of obstructive uropathy, decompensated detrusor or neurogenic bladder. Marked improvement was noted in urinary continence, urinary infection, renal function, bladder emptying and, perhaps most important, the mental and emotional status of the patient and/or parents. The extremely low incidence of complications and its therapeutic efficacy clearly make clean, intermittent self-catheterization an outstanding weapon in the urological armamentarium and a most persuasive reminder that host resistance is still the primary factor in the occurrence of infection.

Further observations on self-catheterization.

A non-sterile technique of intermittent self-catheterization was used for 218 patients with an inability to void in a normal fashion because of obstructive uropathy, decompensated detrusor or neurogenic bladder. Marked improvement was not in urinary continence, urinary infection, renal function, bladder emptying and, perhaps most important, the mental and emotional status of the patient and/or parents. The extremely low incidence of complications and its therapeutic efficacy clearly make clean, intermittent self-catheterization an outstanding weapon in the urological armamentarium and a most persuasive reminder that host resistance is still the primary factor in the occurrence of infection.