Community-based distribution of sulfadoxine-pyrimethamine for intermittent preventive treatment of malaria during pregnancy improved coverage but reduced antenatal attendance in southern Malawi.

OBJECTIVE: To evaluate the impact of a 2-year programme for community-based delivery of sulfadoxine-pyrimethamine (SP) on intermittent preventive treatment during pregnancy coverage, antenatal clinic attendance and pregnancy outcome. METHODS: Fourteen intervention and 12 control villages in the catchment areas of Chikwawa and Ngabu Government Hospitals, southern Malawi, were selected. Village-based community health workers were trained in information, education and counselling on malaria control in pregnancy and the importance of attending antenatal clinics and promoted these messages to pregnant women. In the intervention group community health workers also distributed SP to pregnant women. RESULTS: In the control area, coverage of intermittent preventive treatment during pregnancy (>2 doses) was low before (44.1%) and during the intervention (46.1%). In the intervention area, coverage increased from 41.5% to 82.9% (P < 0.01). Antenatal clinic attendance (>2 visits) was maintained in control villages at above 90%, but fell in intervention villages from 87.3% to 51.5% (P < 0.01). Post-natal malaria parasitaemia prevalence fell in women from both study areas during the intervention phase (P < 0.05). Increasing the coverage of intermittent preventive treatment during pregnancy to >40% did not significantly improve maternal haemoglobin or reduce low birthweight prevalence. CONCLUSIONS: Better coverage of community-based intermittent preventive treatment during pregnancy can lower attendance at antenatal clinics; thus its effect on pregnancy outcome and antenatal attendance need to be monitored.

The Tingathe Surge: a multi-strategy approach to accelerate HIV case finding in Malawi.

SETTING: Nineteen health facilities in rural, southeastern Malawi. OBJECTIVE: To describe the implementation and results of a 6-week intervention to accelerate human immunodeficiency virus (HIV) case finding. DESIGN: Six HIV testing strategies were simultaneously implemented. Routinely collected data from Ministry of Health registers were used to determine the number of HIV tests performed and of new cases identified. The weekly averages of the total number of tests and new cases before and during the intervention were compared. Testing by age group and sex was described. The percentage yield of new cases was compared by testing strategy. RESULTS: Of 29 703 HIV tests conducted, 1106 (3.7%) were positive. Of the total number of persons tested, 69.5% were women and 75.5% were aged >15 years. The yield of positive test results was 3.5% among women, 4.3% among men, 4.4% among those aged >15 years and 1.5% among those aged ⩽15 years. The average weekly number of tests increased 106.7% from 3337 to 6896 (P = 0.002). The average weekly number of positive cases identified increased 51.9% from 158 to 240 (P = 0.017). The testing strategy with the highest yield resulted in a 6.0% yield; the lowest was 1.3%. The yield for all strategies, except one, was highest in adult men. CONCLUSION: A multi-strategy approach to HIV testing and counseling can be an effective means of accelerating HIV case finding.

Burden of disease and risk factors for death among children treated for tuberculosis in Malawi.

SETTING: Tuberculosis (TB) is a leading cause of childhood death. Patient-level data on pediatric TB in Malawi that can be used to guide programmatic interventions are limited. OBJECTIVE: To describe pediatric TB case burden, disease patterns, treatment outcomes, and risk factors for death and poor outcome. DESIGN: We conducted a retrospective cohort study utilizing routine data. Odds ratios (ORs) for factors associated with poor outcome and death were calculated using generalized estimating equations. RESULTS: Children represented 8% (371/4642) of TB diagnoses. The median age was 7 years (interquartile range 2.8-11); 32.8% (113/345) were human immunodeficiency virus (HIV) infected. Of these, 54.0% were on antiretroviral therapy (ART) at the time of anti-tuberculosis treatment (ATT) initiation, 21.2% started ART during ATT, and 24.8% had no documented ART. The treatment success rate was 77.3% (11.2% cured, 66.1% completed treatment), with 22.7% experiencing poor outcomes (9.5% died, 13.2% were lost to follow-up). Being on ART at the time of ATT initiation was associated with increased odds of death compared to beginning ART during treatment (adjusted OR 2.75, 95%CI 1.27-5.96). CONCLUSION: Children represent a small proportion of diagnosed TB cases and experience poor outcomes. Higher odds of death among children already on ART raises concerns over the management of these children. Further discussion of and research into pediatric-specific strategies is required to improve case finding and outcomes.

Genotypic analysis of the protease and reverse transcriptase of HIV type 1 subtype C isolates from antiretroviral drug-naive adults in Malawi.

The protease (PR) and reverse transcriptase (RT) regions of HIV-1 isolates from 21 antiretroviral (ARV)-naive Malawian adults were sequenced and analyzed to determine the prevalence of drug resistance-associated mutations in this population. Phylogenetic analysis confirmed that all isolates grouped with HIV-1 subtype C, the predominant subtype in Malawi. No major mutations associated with resistance to PR inhibitors (PIs), nucleoside RT inhibitors (NRTIs), or nonnucleoside RT inhibitors (NNRTIs) were found. In contrast, accessory mutations were found in the protease region at positions 10, 20, 36, 63, 77, and 93, and in the RT region at positions 118, 211, and 214. Further studies will be needed to determine the clinical impact of these polymorphisms on viral susceptibility to existing antiretroviral drugs.

Efficacy of mefloquine and sulfadoxine-pyrimethamine for the treatment of uncomplicated Plasmodium falciparum infection in Machinga District, Malawi, 1998.

In response to the spread of chloroquine-resistant Plasmodium falciparum, Malawi changed its first-line antimalarial drug in 1993 from chloroquine to sulfadoxine-pyrimethamine (SP). Surveillance data has suggested that resistance to SP may be increasing. We compared the efficacy of SP with a potential successor, mefloquine (MQ). By use of a modified World Health Organization in vivo protocol, children infected with P. falciparum were randomized to receive SP (sulfadoxine 25 mg/kg) or MQ (15 mg/kg). We observed combined RII and RIII parasitologic failures of 20.0 and 22.0% in the SP and MQ arms, respectively. Among those in the MQ arm, the relative hazard of failing with a Day 2 drug level < 500 ng/mL was 10.6 times higher than those with levels > or = 500 ng/mL. Given the decreased efficacy of the first-line antimalarial drug and the high failure rates of MQ at this lower dosage, Malawi should consider assessing the efficacy and feasibility of alternative drugs to treat uncomplicated falciparum malaria.

Detection of bloodstream pathogens in a bacille Calmette-Guérin (BCG)-vaccinated pediatric population in Malawi: a pilot study.

Children in Malawi receive bacille Calmette-Guérin (BCG) vaccination within the first 3 days of life. Thus, we hypothesized that Malawian children infected with the human immunodeficiency type 1 virus (HIV-1) might be particularly vulnerable to dissemination of the BCG Mycobacterium bovis strain with which they were vaccinated. Following informed consent by parents, we studied children admitted to a Malawi general hospital during the 1998 wet and dry seasons. Blood from cohorts of acutely ill children was cultured for bacteria, including mycobacteria, and fungi, and tested for anti-HIV-1 antibodies. It was shown that non-typhi Salmonella and Escherichia coli were the predominant bloodstream pathogens during the wet and dry seasons, and that bloodstream dissemination of the BCG M. bovis strain is uncommon in HIV-1-infected children who receive the BCG vaccine.

Malaria and human immunodeficiency virus infection among male employees of a sugar estate in Malawi.

In sub-saharan Africa, where malaria is endemic and diagnostic and laboratory services are limited, fever is generally presumed to be due to malaria; however, the proportion of fevers actually related to malaria is unknown in most places. This study was conducted to determine the relationship between fever, malaria parasitaemia and human immunodeficiency virus (HIV) infection. Between February and April 1994, 643 consenting adult male workers of the Sugar Corporation of Malawi (SUCOMA) in Nchalo, Chikwawa District, Malawi were enrolled in a cross-sectional study. Participants underwent routine physical examinations and data were collected on age, axillary temperature, and history of fever or other illness in the 2 weeks before enrollment. Patients with axillary temperature > or = 37.5 degrees C were considered to be febrile. Blood was collected and thick blood films were prepared and examined for the presence of malaria parasites. HIV testing was done using the Wellcozyme enzyme-linked immunosorbent assay. Complete information was obtained from 605 subjects (94%), of whom 248 (41%) reported a history of fever (only 15% of the fever reporters were parasitaemic), 139 (23%) were HIV positive, and 131 (22%) received an antimalarial drug. HIV infection was significantly associated with fever but not with parasitaemia. Fever reporters and non-fever reporters were of similar age (means 32.8 and 33.1 years, respectively). These data suggest that in this population there was both high HIV seroprevalence and gross overestimation of fever as malaria. High HIV prevalence makes it necessary to re-examine the common practice in Malawi of treating all fever among adults as malaria.

PIP: 643 adult male employees of the Sugar Corporation of Malawi in Nchalo, Chikwawa District, participated in a cross-sectional study during February-April 1994 to determine the relationship between fever, malaria parasitemia, and HIV infection. Participants underwent routine physical examinations and data were collected on their ages, axillary temperatures, and histories of fever or other illnesses in the 2 weeks before enrollment in the study. Blood was collected and thick blood films prepared and examined for the presence of malaria parasites. Complete information was obtained from 605 subjects, of whom 248 (41%) reported a history of fever, 139 (23%) were HIV positive, and 131 (22%) received an antimalarial drug. Only 15% of fever reporters were parasitemic. HIV infection was significantly associated with fever, but not with parasitemia. Fever reporters and non-fever reporters were of mean ages 32.8 and 33.1 years, respectively. These data suggest that there was both high HIV seroprevalence and considerable overestimation of fever as malaria in this population. This high prevalence of HIV demands the reconsideration of the common practice in Malawi of treating all fever among adults as malaria.

Seasonal variation in the etiology of bloodstream infections in a febrile inpatient population in a developing country.

OBJECTIVES: Published data suggest that Streptococcus pneumoniae, non-typhi Salmonella species, and Mycobacterium tuberculosis are the predominant causes of bloodstream infection (BSI) in hospitalized populations in sub-Saharan Africa. This study was conducted during the wet season to ascertain the etiology and prevalence of BSI among febrile inpatients in a hospital where the dry season BSI profile in a similar study population had already been documented. METHODS: In the period from March to May 1998, consecutive febrile (> or = 37.5 degrees C) adult (> or = 14 y) patients presenting to a Malawi hospital were enrolled after providing informed consent. Following clinical evaluation, blood was drawn for culture (bacteria, mycobacteria, and fungi), human immunodeficiency virus (HIV) testing, and malaria smears. RESULTS: Of 238 enrolled patients, 173 (73%) were HIV-positive and 67 (28%) had BSI. The predominant wet season BSI pathogens were non-typhi Salmonella species (41%), M. tuberculosis (19%), and Cryptococcus neoformans (9%) (cf. the predominant dry season pathogen was S. pneumoniae). Mycobacteremia was more likely in HIV-positive than in HIV-negative patients (13/173 vs. 0/65; P < 0.05). A logistic regression model yielded clinical predictors of BSI that included chronic fever, oral candidiasis, or acute diarrhea. CONCLUSION: Pathogens causing BSI in febrile inpatients in a Malawi teaching hospital vary by season. Season- and country-specific studies, such as this one, provide data that may facilitate empirical therapy of febrile illnesses whose etiologies vary by season.

Risk factors for mortality in Malawian children with human immunodeficiency virus and tuberculosis co-infection.

SETTING: A large urban pediatric human immunodeficiency virus (HIV) clinic in Lilongwe, Malawi. OBJECTIVE: To identify demographic and clinical risk factors for mortality in children co-infected with HIV and tuberculosis (TB). DESIGN: A retrospective cohort study of HIV-infected children (aged <18 years) enrolled between October 2004 and October 2010 with at least one current or historical TB diagnosis. Descriptive statistics and logistic regression analyses were performed to determine factors associated with mortality. RESULTS: A total of 1561 patients met the inclusion criteria, representing 32% of patients ever enrolled. Median age at TB diagnosis was 3.8 years (interquartile range 1.5-7.4); 60.9% had severe immune suppression and 47.6% of those with available data had some degree of acute malnutrition at TB diagnosis. Of the 1113 patients with known outcomes, 225 (20.2%) died. Children with TB-HIV co-infection not initiated on antiretroviral therapy (ART) at any time were 8.8 times more likely to die compared to those initiated on ART 0-2 months after initiation of anti-tuberculosis treatment (adjusted OR 8.83, 95%CI 4.42-17.63). Severe immunosuppression and World Health Organization Stage IV were also associated with mortality. CONCLUSIONS: Pediatric TB-HIV co-infection is common and mortality is high in this cohort of Malawian children. Prompt initiation of ART should be emphasized in this high-risk patient population.

Sexually Transmitted Infection (STI) screening, case and contact treatment, and condom promotion resulting in STI reduction two years later in rural Malawi.

As part of a longitudinal cohort study in rural Malawi in 2000, 469 men and 758 women were asked to respond to a series of surveys, were tested for gonorrhea and chlamydia, and received their results and treatment, if applicable, for themselves and up to 2 partners if positive for either sexually transmitted infection (STI). Two years later, in 2002, 328 men and 525 women were again asked to respond to survey questions, tested again for gonorrhea and chlamydia, and were also tested for HIV--of these, 247 men and 453 women had also given urine samples in 2000. In 2000, the gonorrhea and chlamydia prevalence was 6.2% and 5.8% among men, and 3.6% and 4.9% among women. Two years later, prevalence of gonorrhea and chlamydia was 0.7% and 1.4% among men, and 1.3% and 1.1% among women. Although we did not test for HIV in the first round, the HIV prevalence in 2002 was 19.2%. The implications of the findings are discussed in the context of interventions for STI prevention and to reduce HIV transmission in sub-Saharan Africa.

Childhood tuberculosis in Malawi: caseload, diagnostic practices and treatment outcomes.

There were 22,982 cases of TB registered in Malawi in 1998, of which 2739 (11.9%) were children. Children accounted for 11.3% of all case notifications with smear-positive pulmonary TB (PTB), 21.3% with smear-negative PTB and 15.9% with extrapulmonary TB (EPTB). A significantly higher proportion of TB cases were diagnosed in central hospitals. Only 45% of children completed treatment. There were high rates of death (17%), default (13%) and unknown treatment outcomes (21%). Treatment outcomes were worse in younger children and in children with smear-negative PTB. In 2001, all 44 non-private hospitals in Malawi that register and treat children with tuberculosis (TB) were surveyed to determine actual diagnostic practice. This cross sectional study identified 150 children aged 14 years or below in hospital receiving anti-TB treatment, 98 with pulmonary TB (PTB) and 52 with extrapulmonary TB (EPTB). Median duration of illness was 8 weeks. Most patients had fever, no response to anti-malarial treatment and antibiotics, and 40% had a positive family history of TB. Nearly 45% had weight for age < 60%. Diagnosis was mainly based on clinical features and radiography, with less than 10% having tuberculin skin tests or HIV serology, and very few having other sophisticated investigations. Diagnostic difficulties make it difficult to accurately define the actual burden of childhood TB in Malawi. Diagnostic practices are poor and treatment outcomes unsatisfactory.

Usefulness of clinical case-definitions in guiding therapy for African children with malaria or pneumonia.

The World Health Organisation has developed disease-specific clinical case-definitions to guide management of children with fever or cough, the cardinal signs of malaria and pneumonia. To assess the usefulness of the case-definitions and to investigate their interaction, we studied children with fever or cough brought to a hospital in Lilongwe, Malawi. For all children, a thick blood smear was examined for Plasmodium falciparum parasites. Chest radiography was done only for children with parasitaemia and those who satisfied the clinical case-definition for pneumonia; others were assumed to have normal chest radiographs. Of 1599 enrolled children, 566 (35%) had parasitaemia and 116 had radiographic evidence of pneumonia; 43 had both pneumonia and parasitaemia. Of the 471 children who met the clinical definition for pneumonia, 449 (95%) also met the malaria clinical definition. Among children with radiographic evidence of pneumonia, the clinical definition for malaria was not predictive of parasitaemia (sensitivity 93%, specificity 5%). Whether malaria parasitaemia was present or absent, the pneumonia clinical definition distinguished children with and without radiographic evidence of pneumonia (sensitivity and specificity > 60%). Children who satisfied the pneumonia clinical definition were more likely to have radiographic evidence of pneumonia (odds ratio 10.4, 95% confidence interval 5.2-20.7), parasitaemia (1.6, 1.2-2.2), or both at the same time (4.2, 2.1-8.4) than were children who did not meet the definition. Children who satisfy the malaria and pneumonia clinical definitions need treatment for both disorders. Scarce diagnostic methods, especially microscopy, are needed for more specific treatment of children with fever and cough.

PIP: The WHO has developed disease-specific clinical case definitions to guide the management of children with fever and cough, the cardinal signs of malaria and pneumonia. To assess the usefulness of these case definitions and to investigate their interaction, the authors studied children with fever or cough who were brought to Lilongwe, Malawi. For all children, a thick blood smear was examined for Plasmodium falciparum parasites. Chest radiography was done only for children with parasitemia and those who satisfied the clinical case definition for pneumonia; others were assumed to have normal chest radiographs. Of 1599 enrolled children, 566 (35%) had parasitemia; 43 had both parasitemia and pneumonia. Of the 471 children who met the clinical definition for pneumonia, 449 (95%) also met the clinical definition for malaria. Among children with radiographic evidence of pneumonia, the clinical definition for malaria was not predictive of parasitemia (sensitivity 93%, specificity 5%. Whether malaria parasitemia was present or not, the pneumonia clinical definition distinguished children with and without radiographic evidence of pneumonia (sensitivity and specificity 60%). Children who satisfied the pneumonia clinical definition were more likely to have radiographic evidence of pneumonia (odds ration 10.4, 95% confidence interval 5.2-20.7), parasitemia (1.6, 1.2-2.2), or both at the same time (4.2, 2.1-8.4) than were children who did not meet the definition. Children who satisfy both clinical definitions need treatment for both disorders. Scarce diagnostic methods, especially microscopy, are necessary for more specific treatment of children with fever and cough.

The effect of oral iron therapy during treatment for Plasmodium falciparum malaria with sulphadoxine-pyrimethamine on Malawian children under 5 years of age.

In sub-Saharan countries, although malaria and malaria-associated anaemia are major public health problems, the usefulness of supplementary iron treatment for children with malaria-associated anaemia is unknown. In a 6-week period during the 1995 rainy season, 222 Malawian children aged < 5 years, who sought treatment for malaria, had > or = 500 parasites/microliter blood and at least 5 g haemoglobin (HB)/dl blood and whose parents gave consent, were randomized into a prospective study comparing the efficacy of sulphadoxine- pyrimethamine only (SP), SP plus daily iron (SPD) and SP plus weekly iron (SPW) as treatment for malaria-associated anaemia. The patients had their HB concentrations measured on enrollment (day 0), just before antimalarial treatment, and on days 3, 7, 14, 21 and 28; 215 (96.8%) completed the 28-day study. Among the children with 5-8 g HB/dl on enrolment, HB gain by the end of the study was significantly greater than in the children with > 8 g HB/dl initially (4.1 v. 2.2 g/dl; P < 0.05), and those in the SPD group gained significantly more HB by days 21 and 28 (3.6 and 4.9 g/dl, respectively) than those in either the SPW (2.7 and 3.7 g/dl, respectively) or the S2 groups (2.6 and 3.5 g/dl, respectively); there was no difference in HB gain between the SP and SPW groups. Type of treatment had no apparent effect, at any time during the study, on HB gains in those patients who had > 8 g HB/dl on enrolment. Thus the children with 5-8 g HB/dl on enrolment benefited from daily iron therapy whereas those with > 8 g HB/dl derived no significant benefit; improvement in HB depended most on whether enrolment HB was < or = 8.0 g/dl. As treatment with an effective antimalarial drug resulted in HB gains, irrespective of treatment group or HB concentration at enrolment, the anaemia observed may be mostly related to malaria. However, as a larger proportion of the iron-treated patients failed to clear their parasitaemias than of those given SP alone, oral iron may inhibit SP action. It is therefore recommended that, for children with both malaria and malaria-associated anaemia, the malaria should first be cleared with an effective antimalarial drug, such as SP, before the anaemia, if it still persists, is treated with iron.

Malarone-donation programme in Africa.

PIP: Glaxo Wellcome announced in November 1996 its intent to donate up to 1 million treatment courses per year of its new antimalarial drug, Malarone, to countries in Africa, Southeast Asia, and South America, where malaria is endemic. Because the effectiveness of the small number of available antimalarial drugs is threatened by the emergence of drug resistance, the advantages of introduction of this new drug to a given area should be given careful consideration. Chloroquine, for example, is nearing the end of its effectiveness as a first-line drug for the treatment of uncomplicated falciparum malaria in many areas of East and Central Africa. The lifespan of its replacement, sulfadoxine-pyrimethamine, is likely to be even shorter given its long half-life and the ease with which resistance-conferring mutations occur. In Southeast Asia and the Amazon basin of South America, where multidrug-resistant Plasmodium falciparum malaria is a serious problem, the advantages of Malarone introduction clearly outweigh any disadvantages. In sub-Saharan Africa, the premature distribution and increasing use of artemisinins may jeopardize their long-term effectiveness, however. Another factor complicating decisions to introduce Malarone is its required 3-day course of treatment, necessitating hospitalization if compliance is to be ensured. The donation project gives patients in developing countries access to an expensive drug that would otherwise be unavailable. Time must be taken, however, to fully debate the project's pros and cons, resolve inherent logistic problems, and establish guidelines for Malarone use in sub-Saharan Africa.^ieng

Chloroquine in Africa: critical assessment and recommendations for monitoring and evaluating chloroquine therapy efficacy in sub-Saharan Africa.

Chloroquine-resistant malaria is a major public health threat in sub-Saharan Africa. While a few countries have already replaced chloroquine as the first-line therapy for uncomplicated malaria or are in the process of doing so, other countries are faced with the complicated task of assessing the current status of drug resistance, making national policy-level decisions about whether to replace chloroquine or not, and initiating a monitoring system to track changes in the efficacy of malaria therapy. There is currently no standardized approach for collecting and interpreting data on therapy efficacy. There is also no agreement as to how much chloroquine resistance or treatment failure is acceptable and how much warrants a change in treatment policy. Using data collected in 10 sites in eastern and southern Africa between 1990 and 1996, we have assessed the therapeutic response to chloroquine and investigated predictors of clinical success or failure. Based on these experiences and analyses, a standardized protocol for in vivo studies of the efficacy of malaria therapy and for approaches to designing monitoring systems are proposed. The process of making policy-level decisions based on data collected by these systems is also discussed.

Beyond chloroquine: implications of drug resistance for evaluating malaria therapy efficacy and treatment policy in Africa.

Emphasis on retaining chloroquine as the first-line therapy for Plasmodium falciparum infections in most of sub-Saharan Africa for as long as it remains effective has resulted in widespread reliance on chloroquine in areas where it can have little effect on P. falciparum parasitemia. To address this issue, clinical, parasitologic, and hematologic responses to chloroquine or pyrimethamine/sulfadoxine treatment were assessed among very young children in Malawi (n = 153) and Kenya (n = 73). The median time to resumption of clinical symptoms in chloroquine-treated children was 13.5 days in Malawi and 9.5 days in Kenya. Children treated with pyrimethamine/sulfadoxine maintained clinical improvement and had greater increases in their hemoglobin concentration during the follow-up period than did children treated with chloroquine. Treatment with chloroquine failed to produce either a durable clinical improvement or optimal hematologic recovery. Consequently, chloroquine can no longer be considered adequately effective therapy of clinical P. falciparum malaria in very young children in these areas of Africa.

Age-related differences in cell-specific cytokine production by acutely ill Malawian patients.

Age-related changes in human cell-specific cytokine responses to acute illness have not been well examined. We therefore evaluated age-related differences in T, B and natural killer (NK) peripheral blood lymphocyte cytokine responses of 309 acutely ill hospitalized people in Malawi, Africa, < 1 month-61 years of age. We used four-colour flow cytometry and performed Wilcoxon rank sum and Kruskal-Wallis tests, Pearson (rp) and Spearman (rs) correlations, and linear and logistic regression analyses to control for human immunodeficiency virus infection (HIV) status, the percentages of lymphocytes expressing CD4, and the nature of the acute infection. The percentages of CD8- and CD8+ T cells producing induced IL-8 decreased with age (rs = -0.44 and -0.53). The percentages of T cells producing TNF-alpha were higher, and the percentages producing IL-10 were lower, in those > or =13 than those < 13 years old (medians: 17.7 versus 10.5 and 1.4 versus 3.0, respectively). The percentages of CD8- T cells producing IFN-gamma were higher and stable in those > or =1 year old compared to infants (medians: 23.5 versus 10.4); the percentages of NK producing IFN-gamma were higher post-infancy and then declined to relatively low levels with increasing age. The percentages of T cells producing IL-2 were highest in those 5- <31 years old (median 5.6) and lowest in those > or =31 years old (median 1.9). The ratios of the percentages of T cells producing IL-4 to those producing IL-8 and to those producing IL-10 both increased with age. These data suggest that innate immunity, represented by NK IFN-gamma production, dominates in early life. A number of shifts occur after infancy and before adolescence, including a proinflammatory shift from IL-8 to TNF-gamma and a type 2 shift from IL-10 to IL-4 dominance. These findings suggest distinct age-related differences in the human response to acute illness and may be useful in directing future efforts at immunomodulatory therapies.

Comparison of serum and cell-specific cytokines in humans.

Cytokines function at the cellular, microenvironmental level, but human cytokine assessment is most commonly done at the macro level, by measuring serum cytokines. The relationships between serum and cellular cytokines, if there are any, are undefined. In a study of hospitalized patients in Malawi, we compared cytometrically assessed, cell-specific cytokine data to serum interleukin 2 (IL-2), IL-4, IL-6, IL-8, IL-10, gamma interferon (IFN-gamma), and tumor necrosis factor alpha (TNF-alpha) levels in 16 children and 71 (IL-2, -4, -6, -10) or 159 (IL-8, IFN-gamma, and TNF-alpha) adults, using Wilcoxon rank sum tests and Pearson's (r(p)) and Spearman's (r(s)) rank correlations. For the entire study group, correlations between identical serum and cellular cytokines mainly involved IL-8 and IFN-gamma, were few, and were weakly positive (r < 0.40). Blood culture-positive persons had the most and strongest correlations, including those between serum IL-2 levels and the percentages of lymphocytes spontaneously making IL-2 (r(s) = +0.74), serum IL-8 levels and the percentages of lymphocytes spontaneously making IL-8 (r(p) = +0.66), and serum IL-10 levels and the percentages of CD8(+) T cells making TNF-alpha (r(p) = +0.89). Human immunodeficiency virus (HIV)-positive persons had the next largest number of correlations, including several serum IL-8 level correlations, correlation of serum IL-10 levels with the percentages of lymphocytes producing induced IL-10 (r(s) = +0.36), and correlation of serum IFN-gamma levels and the percentages of lymphocytes spontaneously making both IL-6 and IFN-gamma in the same cell (r(p) = +0.59). HIV-negative, malaria smear-positive, and pediatric patients had few significant correlations; for the second and third of these subgroups, serum IL-8 level was correlated with the percentage of CD8(-) T cells producing induced IL-8 (r(s) = +0.40 and r(s) = +0.56, respectively). Thus, the strength of associations between serum and cellular cytokines varied with the presence or absence of bloodstream infection, HIV status, and perhaps other factors we did not assess. These results strongly suggest that serum cytokines at best only weakly reflect peripheral blood cell cytokine production and balances.

Clinical algorithm for treatment of Plasmodium falciparum malaria in children.

BACKGROUND: Identification of children who need antimalarial treatment is difficult in settings where confirmatory laboratory testing is not available, as in much of sub-Saharan Africa. The current national policy in Malawi is to treat all children with fever, usually defined as the mother's report of fever in the child, for presumed malaria. To assess this policy and to find out whether a better clinical case definition could be devised, we studied acutely ill children presenting to two hospital outpatient departments in Malawi. METHODS: The parent or guardian of each enrolled child (n = 1124) was asked a standard series of questions about the symptoms and duration of the child's illness. Each child was examined, axillary and rectal temperatures and blood haemoglobin concentrations were measured, and a giemsastained thick smear was examined for malaria parasites. Logistic regression procedures were used to identify clinical predictors of parasitaemia. FINDINGS: High temperature (37.7 degrees C or above), nailbed pallor, enlarged spleen, and being seen at one of the clinics rather than the other were associated with an increased risk of malaria parasitaemia in univariate analyses. A revised malaria case definition of rectal temperature of 37.7 degrees C or higher, splenomegaly, or nailbed pallor was 85% sensitive in identifying parasitaemic children and 41% specific; the corresponding sensitivity and specificity for the nationally recommended definition that equates mother's history of fever with malaria were 93% and 21%. The revised case definition had 89% sensitivity in identifying parasitaemic children with haemoglobin concentration below 80 g/L and 89% sensitivity in identifying children with parasite density greater than 10,000/microL, characteristics that indicate a clear need for antimalarial treatment. INTERPRETATION: These results suggest that better clinical definitions are feasible, that splenomegaly and pallor are helpful in identifying children with malaria, and that much overtreatment of children without parasitaemia could be avoided.