Caregivers and community perceptions of blood transfusion for children with severe anaemia in Uganda.

OBJECTIVE: To describe local perceptions of blood transfusion for children with severe anaemia in Uganda. BACKGROUND: Blood transfusion is a common emergency treatment for children with severe anaemia and saves millions of lives of African children. However, the perceptions of transfusion recipients have not been well studied. A better understanding of the perceived risk may improve transfusion care. METHODS: A qualitative study based on 16 in-depth interviews of caregivers of transfused children, and six focus group discussions with community members was conducted in three regions of Uganda between October and November 2017. RESULTS: Caregivers of children and community members held blood transfusion in high regard and valued it as life-saving. However, there were widespread perceived transfusion risks, including: Human immunodeficiency virus (HIV) transmission, too rapid blood infusion and blood incompatibility. Other concerns were: fatality, changes in behaviour, donor blood being 'too strong' and use of animal blood. In contrast, recent transfusion, older age, knowledge of HIV screening of blood for transfusion, faith in God and having a critically ill child were associated with less fear about transfusion. Respondents also emphasised challenges to transfusion services access including distance to hospitals, scarcity of blood and health workers' attitudes. CONCLUSION: Perceptions of the community and caregivers of transfused children in Uganda about blood transfusion were complex: transfusion is considered life-saving but there were strong perceived transfusion risks of HIV transmission and blood incompatibility. Addressing community perceptions and facilitating access to blood transfusion represent important strategies to improve paediatric transfusion care.

Variability in distribution and use of tuberculosis diagnostic tests in Kenya: a cross-sectional survey.

BACKGROUND: Globally, 40% of all tuberculosis (TB) cases, 65% paediatric cases and 75% multi-drug resistant TB (MDR-TB) cases are missed due to underreporting and/or under diagnosis. A recent Kenyan TB prevalence survey found that a significant number of TB cases are being missed here. Understanding spatial distribution and patterns of use of TB diagnostic tests as per the guidelines could potentially help improve TB case detection by identifying diagnostic gaps. METHODS: We used 2015 Kenya National TB programme data to map TB case notification rates (CNR) in different counties, linked with their capacity to perform diagnostic tests (chest x-rays, smear microscopy, Xpert MTB/RIF®, culture and line probe assay). We then ran hierarchical regression models for adults and children to specifically establish determinants of use of Xpert® (as per Kenyan guidelines) with county and facility as random effects. RESULTS: In 2015, 82,313 TB cases were notified and 7.8% were children. The median CNR/100,000 amongst 0-14yr olds was 37.2 (IQR 20.6, 41.0) and 267.4 (IQR 202.6, 338.1) for ≥15yr olds respectively. 4.8% of child TB cases and 12.2% of adult TB cases had an Xpert® test done, with gaps in guideline adherence. There were 2,072 microscopy sites (mean microscopy density 4.46/100,000); 129 Xpert® sites (mean 0.31/100,000); two TB culture laboratories and 304 chest X-ray facilities (mean 0.74/100,000) with variability in spatial distribution across the 47 counties. Retreatment cases (i.e. failures, relapses/recurrences, defaulters) had the highest odds of getting an Xpert® test compared to new/transfer-in patients (AOR 7.81, 95% CI 7.33-8.33). Children had reduced odds of getting an Xpert® (AOR 0.41, CI 0.36-0.47). HIV-positive individuals had nearly twice the odds of getting an Xpert® test (AOR 1.82, CI 1.73-1.92). Private sector and higher-level hospitals had a tendency towards lower odds of use of Xpert®. CONCLUSIONS: We noted under-use and gaps in guideline adherence for Xpert® especially in children. The under-use despite considerable investment undermines cost-effectiveness of Xpert®. Further research is needed to develop strategies enhancing use of diagnostics, including innovations to improve access (e.g. specimen referral) and overcoming local barriers to adoption of guidelines and technologies.

Renal involvement in Gambian children with cerebral or mild malaria.

Kidney function was studied in 80 Gambian children with cerebral malaria, 73 children with mild malaria, and in 19 children with other febrile illnesses. Serum creatinine was measured, and the excretion in urine of immunoglobulin G, transferrin, albumin and alpha 1 microglobulin was determined. Twenty-five percent of children with cerebral malaria, and 4% of children with mild malaria had an elevated serum creatinine above 62 mumol/l. Increased urinary protein excretion was frequent: 53% of children with cerebral malaria had a glomerulo-tubular pattern of protein excretion, and 46% a tubular pattern. Median albuminuria was 68 mg/l in children with cerebral malaria, 18 mg/l in children with mild malaria, and 9 mg/l in febrile children with other diseases (P < 0.0001). There was no significant association between the proteinuria and height of fever or the degree of parasitaemia, and there was no significant association between death and signs of renal impairment. Renal involvement is common in children with malaria in The Gambia, with prerenal, glomerular, and tubulo-interstitial factors contributing. It is more pronounced in children with cerebral malaria than in those with mild malaria. However, renal dysfunction is relatively mild and does not indicate a worse prognosis.

Biochemical and haematological variables in Gambian children with cerebral malaria.

Biochemical and haematological measurements were made in Gambian children who satisfied the criteria for the diagnosis of cerebral malaria over a 3-year period. Biochemical and haematological values were available for 388 and 624 children, respectively. Biochemical signs of renal and hepatic dysfunction were found and these may have contributed in a cumulative way to the high mortality seen in the study children. Cerebral involvement in children with cerebral malaria is only one, though the most important, manifestation of a multi-organ disease.

Estimating sequestered parasite population dynamics in cerebral malaria.

Clinical investigation of malaria is hampered by the lack of a method for estimating the number of parasites that are sequestered in the tissues, for it is these parasites that are thought to be crucial to the pathogenesis of life-threatening complications such as cerebral malaria. We present a method of estimating this hidden population by using clinical observations of peripheral parasitemia combined with an age-structured mathematical model of the parasite erythrocyte cycle. Applying the model to data from 217 Gambian children undergoing treatment for cerebral malaria we conclude that although artemether clears parasitemia more rapidly than quinine, the clearance of sequestered parasites is similar for the two drugs. The estimated sequestered mass was found to be a more direct predictor of fatal outcome than clinically observed parasitemia. This method allows a sequential analysis of sequestered parasite population dynamics in children suffering from cerebral malaria, and the results offer a possible explanation for why artemether provides less advantage than might have been expected over quinine in reducing mortality despite its rapid effect on circulating parasites.

Bacteraemia in cerebral malaria.

As part of a treatment trial of cerebral malaria, blood cultures were done in 276 Gambian children, aged between 1 and 9 years, with cerebral malaria. Fourteen (5%) of these were positive. The organisms isolated were Staphylococcus aureus (6), coliforms (4), Pseudomonas spp. (2), Salmonella spp. (1) and Streptococcus spp. (1). Thirteen of these children survived, most without appropriate antibiotic treatment. Most of the retrieved organisms were therefore suspected to be contaminants. Bacteraemia complicating cerebral malaria is not common in The Gambia, and routine antibiotic treatment of children with cerebral malaria is not warranted.

Predictors of a fatal outcome following childhood cerebral malaria.

Despite prompt treatment with an effective anti-malarial drug, cerebral malaria still has a mortality of 20-30%. To identify factors that may contribute to this high fatality rate, we have studied the relationship between clinical and laboratory features and a fatal outcome in 624 Gambian children with strictly defined cerebral malaria. One hundred twenty-four children (21.5%) died. Three-quarters of the deaths occurred within 24 hr of admission. Multiple logistic regression analysis showed that a cold periphery (odds ratio [OR] = 2.7), a deep coma (OR = 2.0), and hypoglycemia (OR = 4.1) were the clinical signs and laboratory parameters that predicted death most strongly. More than 90% of the children who died had at least one of these conditions. Also, children with elevated urea levels on admission or those who experienced multiple episodes of hypoglycemia or multiple convulsions subsequently were more likely to die. A combination of clinical and laboratory abnormalities can identify a group of children with cerebral malaria who are most at risk of dying, who require intensive care and who are candidates for new forms of therapy.

Residual neurologic sequelae after childhood cerebral malaria.

BACKGROUND: Cerebral malaria is an important cause of pediatric hospital admissions in the tropics. It commonly leads to neurologic sequelae, but the risk factors for this remain unclear and the long-term outcome unknown. OBJECTIVE: The purpose of this study was to identify the common forms of neurologic sequelae that occur after cerebral malaria, their evolution over time, and the major clinical risk factors for residual disability. STUDY DESIGN: Prospective study in 624 children admitted with cerebral malaria to two hospitals in The Gambia, West Africa. RESULTS: We found that 23.3% of survivors had neurologic sequelae on discharge from the hospital. By 1 month the proportion had decreased to 8.6%, and at 6 months only 4.4% of survivors were found to have residual neurologic sequelae. The most common forms of neurologic sequelae were paresis and ataxia, often found in combination with other neurologic abnormalities. In a multiple logistic regression analysis, depth of coma on admission, multiple convulsions, and duration of unconsciousness were the only three independent risk factors. Hypoglycemia and lactate acidosis were not predictive of sequelae, although they are important risk factors for fatality. CONCLUSION: This finding raises the possibility that fatal outcome and neurologic sequelae arise from separate pathologic processes.

Predictors of mortality in Gambian children with severe malaria anaemia.

Severe malaria anaemia is a frequent cause of admission to hospital in tropical Africa and about 10% of children with this condition die. To determine ways in which mortality might be reduced we have studied risk factors for a fatal outcome in 173 children with severe malaria anaemia who were assigned to receive blood transfusion because they had a packed cell volume of less than 12% and/or signs of respiratory distress. Twenty-three children died (13%); in 15 cases (65%) death occurred before blood transfusion was given. The presence of respiratory distress was found to be the most important predictor of death. Children with severe malaria anaemia and signs of respiratory distress must therefore be transfused as soon as possible.

PIP: Severe anemia is a major cause of morbidity and mortality among children in Africa. In areas of moderate seasonal transmission, cerebral malaria is the dominant form of severe malaria. Severe malaria anemia is a frequent cause of admission to hospital in tropical Africa, and results in the death of about 10% of children with the condition. While children with severe malaria anemia can often be saved from death by blood transfusion, deaths from the condition continue to occur even in centers in which transfusion is available. Findings are presented from a study conducted at Royal Victoria Hospital, Banjul, the main referral hospital in The Gambia, to determine how such mortality may be reduced. The authors studied risk factors for a fatal outcome in 173 children of mean age 25.3 months with severe malaria anemia who were assigned to undergo blood transfusion because they had a packed cell volume of less than 12% and/or signs of respiratory distress. 15 of the 23 children who died did so before receiving transfused blood. The presence of respiratory distress was found to be the most important predictor of death. These findings suggest that children with severe malaria anemia and signs of respiratory distress should be transfused as soon as possible.

The effect of a monoclonal antibody to tumor necrosis factor on survival from childhood cerebral malaria.

Tumor necrosis factor (TNF) is thought to play a key role in the pathogenesis of cerebral malaria. A double-blind, placebo-controlled trial of an anti-TNF monoclonal antibody (B-C7) comprised 610 Gambian children with cerebral malaria, with mortality and residual neurologic sequelae as primary study end points. Sixty (19.9%) of 302 children who received B-C7 died compared with 64 (20.8%) of 308 children who received placebo (adjusted odds ratio [OR], 0.90; 95% confidence interval [CI], 0.57-1.42). Residual neurologic sequelae were detected in 15 (6.8%) of 221 survivors from the B-C7 group and in 5 (2.2%) of 225 survivors of the placebo group (adjusted OR, 3.35; 95% CI, 1.08-10.4). The monoclonal antibody used in this study did not improve survival in cerebral malaria and was associated with a significant increase in neurologic sequelae. A possible explanation of the latter observation is that the antibody acts to retain TNF within the circulation and thereby prolongs its effects on vascular endothelium.

Absence of neuropsychological sequelae following cerebral malaria in Gambian children.

Cerebral malaria causes major neurological sequelae in a proportion of survivors and may lead to neuropsychological sequelae in children who seem to have made a good recovery. If this is the case, cerebral malaria could have a dramatic impact on the development of thousands of African children. The present study was carried out to provide information on the incidence and type of neuropsychological sequelae in children who survive the disease without major neurological sequelae. A matched case-control study design was used in which 36 pairs of children were assessed. The cases had been treated for cerebral malaria a mean of 3.4 years before testing. No evidence of a serious long-term impact on most assessed neuropsychological functions was found in these children. Only in the balance test did cases perform less well than their matched controls, but the difference between the 2 groups was only of borderline significance. These findings suggest that the long-term impact of cerebral malaria on the development of children who recover without major neurological sequelae is not as serious as had been feared.

A trial of artemether or quinine in children with cerebral malaria.

BACKGROUND: Cerebral malaria has a mortality rate of 10 to 30 percent despite treatment with parenteral quinine, a situation that may worsen with the spread of quinine resistance. Artemether is a new antimalarial agent that clears parasites from the circulation more rapidly than quinine, but its effect on mortality is unclear. METHODS: We conducted a randomized, unblinded comparison of intramuscular artemether and intramuscular quinine in 576 Gambian children with cerebral malaria. The primary end points of the study were mortality and residual neurologic sequelae. RESULTS: Fifty-nine of the 288 children treated with artemether died in the hospital (20.5 percent), as compared with 62 of the 288 treated with quinine (21.5 percent). Among the 418 children analyzed at approximately five months for neurologic disease, residual neurologic sequelae were detected in 7 of 209 survivors treated with artemether (3.3 percent) and 11 of 209 survivors treated with quinine (5.3 percent, P = 0.5). After adjustment for potential confounders, the odds ratio for death was 0.84 (95 percent confidence interval, 0.53 to 1.32) in the artemether group, and for residual neurologic sequelae, 0.51 (95 percent confidence interval, 0.17 to 1.47). There were fewer local reactions at the injection site with artemether than with quinine (0.7 percent vs. 5.9 percent, P = 0.001). CONCLUSIONS: Artemether is as effective as quinine in the treatment of cerebral malaria in children.

A comparative study of parenteral chloroquine, quinine and pyrimethamine-sulfadoxine in the treatment of Gambian children with complicated, non-cerebral malaria.

Ninety-two children with complicated, but not cerebral, Plasmodium falciparum malaria, aged 1-9 years, were recruited between August 1992 and December 1994 to an open, randomized trial of parenteral chloroquine (28), pyrimethamine-sulfadoxine (P-S) (36) and quinine (28). The median fever clearance time was shorter for chloroquine (27 hours) than for quinine (42 hours) or for P-S (36 hours) (P = 0.02 and P = 0.06, respectively). The parasite clearance times were similar for chloroquine and P-S, but significantly shorter for chloroquine compared with quinine (54 hours vs 66 hours) (P = 0.007) and for P-S compared with quinine (42 hours vs 66 hours) (P < 0.001). However, three children who received chloroquine and three who received P-S required a change to treatment with quinine because of a clinical failure of their initial treatment. Four children died, one in the chloroquine group, one in the quinine group and two in the P-S group. Despite a high level of chloroquine resistance in the community, the majority of Gambian children with complicated malaria responded satisfactorily to parenteral chloroquine given under supervision. The clinical failure rates of chloroquine and P-S were similar. Parenteral chloroquine and P-S remain adequate treatments for complicated, non-cerebral malaria in Gambian children, provided children can be kept under close clinical observation so as to detect early any treatment failures. Parenteral P-S has the advantage that only one dose is required.

Quinine pharmacokinetics in young children with severe malaria.

Children less than two years of age represent a substantial proportion of severe malaria cases in Africa. The standard treatment is parenteral quinine, but little is known about the pharmacokinetics and toxicity of quinine in this age group. We have studied the pharmacokinetics of quinine after intravenous (iv) and intramuscular (im) administration in a group of 20 children less then two years of age with severe malaria. A loading dose of 20 mg/kg of quinine dihydrochloride was followed by 10 mg/kg at 12-hr intervals. The im quinine was very rapidly absorbed, reaching high peak concentrations of 16.4 +/- 3.7 mg/L (mean +/- SD) in 1.1 +/- 0.4 hr. Mean peak levels after iv administration were also high (17.5 +/- 2.4 mg/L). Free quinine levels at 4 hr postadministration ranged from 0.27 to 1.89 mg/L (0.87 +/- 0.53 mg/L). At 2 hr and 4 hr after commencing treatment, an electrocardiogram showed a significant lengthening of the QRS interval compared with baseline (15.6 +/- 21.4%; P = 0.007 and 17.3 +/- 21.9%; P = 0.006 at 2 hr and 4 hr, respectively), whereas this was not observed in a control group of nine older children (age range = 24 months to 10 years) receiving the same im dosage regimen. Free and total quinine levels were not significantly correlated with changes in the QRS interval. Levels of alpha1-acid glycoprotein, which binds quinine within the circulation, did not differ between the younger and the older children. These findings raise the possibility that young children are more susceptible to quinine toxicity than older children, and indicate the need for further evaluation of quinine dosage regimens in this age group.

A randomized trial of chloroquine, amodiaquine and pyrimethamine-sulphadoxine in Gambian children with uncomplicated malaria.

The increasing occurrence of chloroquine-resistant Plasmodium falciparum in sub-Saharan Africa makes it essential to reconsider current recommendations for the treatment of uncomplicated P.falciparum malaria. In an open, randomized trial, we have compared chloroquine (CQ), amodiaquine (AQ), and pyrimethamine-sulphadoxine (PS) in rural Gambian children with uncomplicated P.falciparum malaria. Three hundred children were randomly assigned at the time of consultation (Do) to oral treatment with 25 mg/kg CQ, 25 mg/kg AQ (both given over 3 days), or 1.25/25 mg/kg PS. They were reviewed on day 7 (D7) and day 28 (D28) for symptoms, malaria parasitaemia, and packed cell volume (PCV). Significantly more children treated with PS compared to CQ (17 vs 7%, P = 0.03) or AQ (17 vs 3%, P = 0.001) returned with clinical complaints during the first 3 days after treatment. Five of these patients had a generalized convulsion (1 from the AQ group, 4 from the PS group), of whom 4 developed cerebral malaria. At D7, significantly more patients treated with CQ compared to AQ (25 vs 7%, P = 0.0009) or PS (25 vs 4%, P = 0.0001) were parasitaemic. By D28, the cumulative number of parasitological failures was significantly higher in the CQ group compared to the AQ group (65 vs 35%, P = 0.0001), and significantly higher in the AQ group compared to the PS group (35 vs 14%, P = 0.001). Overall, 91% of parasitological failures observed during the study period were symptomatic and were consequently treated with an alternative antimalarial drug. Over the 28-day study period the mean PCV increased significantly less in the CQ group than in the PS group (1.2 vs 3.8%, P = 0.016) and was lower in the CQ group than in the AQ group (1.2 vs 2.7%, P = 0.12, not significant). These results suggest that PS acts more slowly than 4-aminoquinolines in controlling the clinical features of malaria, and that AQ can be considered as an interim alternative to CQ in the first-line therapy of uncomplicated malaria in African areas of high CQ resistance.

Iron, but not folic acid, combined with effective antimalarial therapy promotes haematological recovery in African children after acute falciparum malaria.

Whether children with malarial anaemia should receive supplementation with iron or folic acid is uncertain. Therefore, the effects of supplementary treatment with iron or folic acid, given together with chloroquine or pyrimethamine-sulfadoxine (Fansidar), has been assessed in 600 Gambian children with uncomplicated falciparum malaria. After one month, haematological recovery was significantly better in the group treated with Fansidar than in the chloroquine-treated group (difference in mean haemoglobin level = 0.54 g/dL, P = 0.01). Children who received iron had a significantly better response than those given placebo (differences in mean haemoglobin level after one month and at dry season follow-up = 0.70 g/dL, P = 0.006, and 0.81 g/dL, P = 0.001, respectively). Iron supplementation was not associated with increased prevalence of malaria. Supplementation with folic acid did not improve the haematological response but, among children who received Fansidar, the treatment failure rate was significantly higher among those given folic acid than among those given placebo. Thus, supplementation with iron, but not folic acid, improves haematological recovery without increasing susceptibility to malaria.

Strain variation in tumor necrosis factor induction by parasites from children with acute falciparum malaria.

A small proportion of individuals infected with Plasmodium falciparum develop cerebral malaria. Why it affects some infected individuals but not others is poorly understood. Since tumor necrosis factor (TNF) has been implicated strongly in the pathogenesis of cerebral malaria, here we have compared different parasite isolates for their ability to induce TNF production by human mononuclear cells in vitro. Wild isolates were collected from 34 Gambian children with cerebral malaria and 66 children with uncomplicated malaria fever. Cerebral malaria isolates tended to stimulate more TNF production than mild malaria isolates, but there was considerable overlap between the two groups, and the present data provide only limited support for the hypothesis that cerebral malaria is caused by strains of P. falciparum inducing high levels of TNF. However, it is notable that the amounts of TNF induced by different wild isolates from a single locality differed by over 100-fold. The biological significance of this polymorphism deserves further scrutiny in view of the central role that TNF is believed to play in host defense and in the clinical symptomatology of human malaria.

Increased concentrations of interleukin-6 and interleukin-1 receptor antagonist and decreased concentrations of beta-2-glycoprotein I in Gambian children with cerebral malaria.

To investigate the pathogenic versus the protective role of cytokines and toxin-binding factors in Plasmodium falciparum infections, we measured the concentrations of tumor necrosis factor alpha, interleukin-1 alpha (IL-1 alpha), IL-1 beta, IL-1 receptor antagonist, and IL-6, as well as soluble receptors of tumor necrosis factor and IL-6 (sIL-6R) in serum of Gambian children with cerebral malaria, mild or asymptomatic malaria, or other illnesses unrelated to malaria. Because cytokine secretion may be triggered by toxic structures containing phosphatidylinositol (PI), we also measured concentrations of anti-PI antibodies and the PI-binding serum protein beta-2-glycoprotein I. We found increased concentrations of IL-6, sIL-6R, IL-1ra, and some immunoglobulin M antibodies against PI in children with cerebral malaria, but those who died had decreased concentrations of beta-2-glycoprotein I. We conclude that increased concentrations of cytokines and soluble cytokine receptors represent a normal host response to P. falciparum infections but that excessive secretion of cytokines like IL-6 may predispose to cerebral malaria and a fatal outcome while beta-2-glycoprotein I may protect against a fatal outcome of cerebral malaria.

Unsuspected Chlamydia trachomatis infection in heterosexual men attending a sexually transmitted diseases clinic: evaluation of risk factors and screening methods.

To characterize the problem of unsuspected Chlamydia trachomatis infection in heterosexual men attending a sexually transmitted diseases (STD) clinic, the authors assessed risk factors for infection and the value of screening for infection by gram-stained smears and urinalysis in 438 men who did not have conventional clinical indications for chlamydial treatment at their initial visit. Evaluations included urethral swabs for gram-stained smears and Neisseria gonorrhoeae and C. trachomatis cultures and microscopy of first-catch urine sediment. C. trachomatis was isolated from 29 subjects (6.6%) and N. gonorrhoeae from 6 subjects (1.3%), (P less than .05). The only demographic or clinical factors that were associated with C. trachomatis were age younger than 21 years and five or more lifetime sexual partners. Screening for C. trachomatis with urethral gram stain and urine sediment examination had sensitivities of only 23% and 35%, respectively. Risk factor assessment and screening with standard microscopic procedures do not adequately predict infection in this group, which accounts for almost 25% of the C. trachomatis burden in heterosexual men who visit an STD clinic. More specific chlamydia detection methods are needed for effective control programs.