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.

The effects of iron deficiency on lymphocyte cytokine production and activation: preservation of hepatic iron but not at all cost.

Worldwide, over 40% of children have iron deficiency anaemia, frequently associated with infections. Certain cytokines are involved in both immune activation/response to infection and iron transport/metabolism. We therefore assessed the relations among iron deficiency, cytokine production and lymphocyte activation markers in 142 hospitalized Malawian children. We examined peripheral blood lymphocyte antigens/cytokine production using four- colour flow cytometry and serum transferrin receptor (TfR) levels, an inverse measure of iron status unaffected by acute illness or infection, with an enzyme-linked immunosorbent assay. Wilcoxon rank sum tests and logistic regression analyses (LRA) were performed. Iron deficiency (TfR > or = 10 microg/ml) versus TfR < 10 microg/ml, was associated with higher percentages of lymphocytes producing: (a) induced or spontaneous IL-6 (medians: induced, 15.9% for iron-deficient children versus 8.8% for iron-replete children, P = 0.002; spontaneous, 24.4% versus 13.0%, P < 0.001) and (b) induced IFN-gamma (medians:18.4% versus 12.4%, P = 0.006). The percentages of CD8(+) T cells spontaneously producing IL-6 and of all lymphocytes producing induced TNF-alpha and IFN-gamma in the same cell had the strongest relationships to iron deficiency (b = + 0.0211, P = 0.005 and b = + 0.1158, P = 0.012, respectively, LRA) and were also positively related to the co-expression of the T cell activation markers HLA DR and CD38. Severe iron deficiency (TfR > or = 30 microg/ml) was associated with the percentage of lymphocytes producing induced IL-4 (medians: 0.5% versus 1.6%, P < 0.010). The cytokine patterns associated with iron deficiency in our study would preserve iron stores but also preferentially retain the activation capabilities of T cells, albeit not necessarily other immune cells, until a critical level of iron depletion is reached.

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.

Cytokines and malaria parasitemia.

The balance between pro- and antiinflammatory cytokines may be important in malaria presentation and outcome. Malaria tends to be more severe in children than in adults, presumably because partial immunity develops with age. However, the full nature of, and age-related differences in, anti-malarial immunity are unknown. We compared: (1) serum and cell-specific cytokines of patients with acute malaria to those of patients with other acute illnesses and to those of healthy adults and (2) the cytokine responses of parasitemic children and parasitemic adults. Flow cytometry was done on the peripheral blood mononuclear cells of 148 hospitalized children, 161 febrile hospitalized adults, and 20 healthy adults in Malawi, Africa, a malaria-endemic country. Serum cytokines were also assessed for 80 of these patients. Thirty-eight participants were parasitemic with Plasmodium falciparum. Serum interleukin (IL)-10 (an antiinflammatory, immunoregulatory, and type 2 cytokine) levels were higher in malaria patients than in other patients (medians 502 pg/mL vs 16 pg/mL, P = 0.002), and the percentages of various lymphocyte populations making IL-6 (a proinflammatory, type 2 cytokine regulating iron distribution) were lower in malaria patients than in other patients (e.g., for spontaneous production by children's CD8(+) T cells: medians 1.4% vs 33.1%, P = 0.004). For adult patients, the percentages of lymphocytes spontaneously making IL-4 (a type 2 cytokine) were significantly lower in those with malaria than in those without malaria (medians 0.9% vs 2.1%, P = 0.005). The percentages of monocytes spontaneously making IL-8 (a chemotactic, proinflammatory chemokine) were higher in parasitemic children than in parasitemic adults (medians 5.8% vs 1.7%, P = 0.003). A number of cellular proinflammatory, type 1 parameters were significantly higher in all children (with or without malaria) than in all adults; these included the percentages of various lymphocyte populations making IL-6, both IL-6 and interferon-gamma, or IL-8. These data support the importance of IL-10 in malaria parasitemia. Given the lack of an IL-4 (type 2) response, IL-10's primary role may be immunoregulatory rather than type 2 in nature. In this study, the immune response to malaria was more proinflammatory in children than in adults. This difference, if corroborated by other studies, could be related to malaria's greater severity in children.

Efficacy of sulphadoxine-pyrimethamine for acute uncomplicated malaria due to Plasmodium falciparum in Malawian children under five years old.

In 1993, Malawi replaced chloroquine (CQ) with sulphadoxine-pyrimethamine (SP) as its first-line treatment for uncomplicated malaria in children < 5 years of age. To assess the efficacy of SP after 5 years of widespread use, we undertook this study at 7 sites in 6 districts of Malawi. Febrile children < 5 years attending the outpatient clinics of selected hospitals whose parents consented were enrolled in the study if they had an axillary temperature of > or = 37.5 degrees C and pure Plasmodium falciparum parasitaemia of >or =2000 asexual parasites/mm3. They were then followed for 14 days or until clinical failure. Parasitological resistance rates (RII and RIII) ranged from 7% to 19%. Resistance was higher in the north than in the central and southern regions, although this difference was not statistically significant. Resistance rates were a mean 19% during the rainy season vs. 12% in the dry season (P > 0.05). 80% of parasitological resistance was at the RII level. Of all children who failed parasitologically (90/641), 84 (93%) had no fever on day 7 and their mothers did not report them as being ill; only 6 of 641 (0.9%) patients met the WHO criteria for clinical treatment failure. Regardless of study site, 75% of mothers reported their children as having improved by day 3; 90% reported improvement by day 7, and all reported improvement by day 14. None of the children experienced any serious adverse reactions and none died. We found that after more than 5 years of widespread use of SP in Malawi, its efficacy remains acceptable for treatment of uncomplicated malaria, and it should therefore be retained as first-line treatment.

Natural T, gammadelta, and NK cells in mycobacterial, Salmonella, and human immunodeficiency virus infections.

NK cells, gammadelta T cell antigen receptor chain-positive cells, and CD3(+)CD16/56(+) (natural T [NT]) cells are involved in innate immunity and immunoregulation; however, their role in clinical infection is not well defined. Cytofluorometric analysis was used to examine peripheral blood from bacteremic, nonbacteremic, and healthy human immunodeficiency virus (HIV)-positive and -negative persons in Malawi, Africa. Mycobacteremia was associated with a higher proportion of CD3(+)CD8(-) gammadelta cells (median, 16.6% vs. 0.7% for all other cells; P<.001), and Salmonella bacteremia was associated with a higher proportion of NT cells (4.3% vs. 2.2%; P=. 002). HIV plasma RNA levels were weakly positively correlated with NT cells (rs=.39; P=.002), NK cells (rs=.38; P=.003), and gammadelta cells (rs=.43; P<.001). Compared with patients who survived, patients who died had a higher percentage of NT cells (3.7% vs. 1. 9%; P=.017) and a higher percentage of NT cells that spontaneously produced interferon-gamma (2.4% vs. 1.2%; P=.035). The data support the clinical relevance of gammadelta and NT cells in mycobacterial, Salmonella, and HIV infections and of NT cells in mortality.

Increased carriage of trimethoprim/sulfamethoxazole-resistant Streptococcus pneumoniae in Malawian children after treatment for malaria with sulfadoxine/pyrimethamine.

Treatment of malaria with sulfadoxine/pyrimethamine and of presumed bacterial infections with trimethoprim/sulfamethoxazole (cotrimoxazole) was assessed to see if either increases the carriage of cotrimoxazole-resistant Streptococcus pneumoniae in Malawian children. Children <5 years old treated with sulfadoxine/pyrimethamine, cotrimoxazole, or no antimicrobial agent were enrolled in a prospective observational study. Nasopharyngeal swabs were taken before treatment and 1 and 4 weeks later. Pneumococci were tested for antibiotic susceptibility by broth microdilution. In sulfadoxine/pyrimethamine-treated children, the proportion colonized with cotrimoxazole-nonsusceptible pneumococci increased from 38.1% at the initial visit to 44.1% at the 4-week follow-up visit (P=.048). For cotrimoxazole-treated children, the proportion colonized with cotrimoxazole-nonsusceptible pneumococci increased from 41.5% at the initial visit to 52% at the 1-week follow-up visit (P=.0017) and returned to 41.7% at the 4-week follow-up. Expanding use of sulfadoxine/pyrimethamine to treat chloroquine-resistant malaria may have implications for national pneumonia programs in developing countries where cotrimoxazole is widely used.

Cerebral malaria in Malawian children hospitalized with Plasmodium falciparum infection.

A hospital-based, prospective study was undertaken at Mangochi District Hospital (MDH) and Kamuzu Central Hospital (KCH) in Malawi. The malaria-transmission patterns in the catchment areas of these two hospitals are very different, transmission being continuous around MDH and seasonal, occurring mostly during the rainy season, around KCH. The main purpose of the study was to determine and compare the prevalences of cerebral malaria (CM) among young, hospitalized children (aged < 5 years) at both sites. Among 8600 of such children admitted to the two hospitals, the overall prevalence of CM was 2.3% (2.2% at KCH and 2.5% at MDH). The prevalences of CM on admission were similar at the two sites during the rainy season (at 3.2%), but the prevalence at MDH during the dry season was statistically higher than that at KCH over the same period (2.1% v. 1.0%; P = 0.0078). A nearly significant difference was noted between the two sites in the prevalences of parasitaemia on admission (11.9% at KCH v. 9.2% at MDH; P = 0.07), and of severe malarial anaemia (SMA) on admission (5.4% at KCH v. 4.2% at MDH; P = 0.06). No inter-site differences were noted in the prevalences of CM or SMA when analysed by mean age, weight, haemoglobin, body temperature, weight-for-age Z-scores, duration of hospitalization, or proportion with high parasite score on admission. These findings differ from those by researchers in other parts of sub-Saharan Africa, where the prevalence of CM has been found to be higher in areas with seasonal transmission patterns. It appears that the epidemiology of CM can differ within the same country, with location and season. Whenever possible, therefore, plans to control CM in any sub-Saharan country should be based on locally generated data.

Mutations in Plasmodium falciparum dihydrofolate reductase and dihydropteroate synthase and epidemiologic patterns of pyrimethamine-sulfadoxine use and resistance.

To assess the relationship between mutations in Plasmodium falciparum dihydrofolate reductase (DHFR) and dihydropteroate synthase (DHPS) and clinical pyrimethamine-sulfadoxine resistance, polymerase chain reaction surveys and analyses for new mutations were conducted in four countries with increasing levels of pyrimethamine-sulfadoxine resistance: Mali, Kenya, Malawi, and Bolivia. Prevalence of mutations at DHFR codon 108 and a new mutation at DHPS 540 correlated with increased pyrimethamine-sulfadoxine resistance (P < .05). Mutations at DHFR 51, DHFR 59, and DHPS 437 correlated with resistance without achieving statistical significance. Mutations at DHFR 164 and DHPS 581 were common in Bolivia, where pyrimethamine-sulfadoxine resistance is widespread, but absent in African sites. Two new DHFR mutations, a point mutation at codon 50 and an insert at codon 30, were found only in Bolivia. DHFR and DHPS mutations occur in a progressive, stepwise fashion. Identification of specific sets of mutations causing in vivo drug failure may lead to the development of molecular surveillance methods for pyrimethamine-sulfadoxine resistance.

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

Palpation as a method of fever determination in Malawian children who are less than 5 years old: how reliable is it?

Fever is a common occurrence in children who are < 5 years old and palpation of the forehead may or may not be a reliable method for determining fever in such children. In a study of 1120 Malawian children of this age attending outpatient's clinics, each child's mother and a clinical officer (CO) were asked to palpate the child's forehead and decide whether the child was febrile (felt warm or very warm) or afebrile (felt normal). The rectal temperature of each child was then taken using a thermometer and the child considered febrile if this temperature was > or = 38 degrees C. Using palpation, mothers judged 973 (86.9%) of 1120 children to be febrile and CO judged 565 (50.4%) of 1118 to be febrile, whereas thermometer readings indicated 410 (36.7%) to be truly febrile. False-positives (i.e. afebrile children judged to be febrile by palpation) accounted for 574 (59.0%) of the 973 children who were considered febrile by their mothers and 228 (40.4%) of the 565 children so considered by CO; mothers reported significantly more false-positives than CO (P < 0.05). False-negatives (i.e. febrile children judged to be afebrile by palpation) accounted for 11 (7.5%) of the 147 children who were considered afebrile by their mothers and 73 (13.2%) of the 553 children so considered by CO; CO reported significantly more false-negatives than mothers (P < 0.05). Overall, mothers were as likely as CO to misjudge a child (721/1120 v. 781/1118; P > 0.05). Although the sensitivity of mothers and CO in determining fever was similar (97.3% v. 82.2%; P > 0.05), CO gave a higher degree of specificity than the mothers (67.8% v. 19.2%; P < 0.000001). Although the present results indicate that palpation is not a reliable method of determining fever in children who are < 5 years old, caregivers should continue to use palpation as a useful first step in deciding when a child needs to be referred.

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.

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.

Efficacy of sulphadoxine/pyrimethamine for Plasmodium falciparum malaria in Malawian children under five years of age.

In March 1993, sulphadoxine/pyrimethamine (SP) replaced chloroquine as the first line drug for malaria treatment in Malawi. Since then, the Ministry of Health has been receiving anecdotal and written reports of SP treatment failures in children. To determine whether treatment failure with SP was a widespread problem, children < 5 years of age with axillary temperature > 38.0 degrees C and parasite density > 2000/mm3 attending the outpatient clinics of the Mangochi and Karonga District Hospitals were enrolled in the study with parental consent. These were then followed for 28 days or until they failed clinically. Of 159 patients enrolled, 145 (91.2%) were followed for 28 days or until clinical failure. Of these, none had RII resistance and 3 (1.9%) had RIII resistance: 2/69 (2.9%) in Mangochi and 1/76 (1.3%) in Karonga; 142/145 (97.9%) exhibited RI/sensitive patterns. Of those followed to day 28 or to clinical failure, 77.1% had parasite clearance by day 3 and 98.6% had parasite clearance by day 7. Of those with temperature readings (n = 140), 129 (92.1%) clinically improved on day 3 and 98.6% improved by day 7. Other indicators of clinical improvement (from day 0 to day 3) included, reported increased level of activity in 136 (97.1%) of the children, and mother's impression of child's improvement in 113 (80.7%). Of the 14 patients not followed to day 28 or to clinical failure, 11 were lost to follow-up by day 7. No allergic skin reactions were noted, and no deaths were observed. These data show that after one year of widespread use of SP in Malawi, Plasmodium falciparum parasite resistance remains very low, and therefore contradicts reports of widespread parasite resistance to SP.

Validity of mother's history regarding antimalarial drug use in Malawian children under five years old.

History obtained from parents and carers is an important, and often the only, source of information for health workers treating children for malaria, but its validity has not been well evaluated. At 2 hospitals in Malawi, we obtained malaria treatment histories from mothers of 973 ill children reported to have had fever as part of the illness. Urine samples were collected from 755 of the 973 children (78%). Of the 755, 457 (61%) were reported to have received some kind of treatment. Among those who reportedly received treatment, 79 (17%) were said to have received chloroquine and 23 (5%) a sulphonamide-containing medicine; however, when urine specimens were tested for antimalarial drugs, chloroquine was found in 182 specimens (40%) and a sulphonamide in 148 (32%). Among urine specimens collected from 291 children who were reported to have received no treatment (no report was recorded for 7 children), chloroquine was detected in 56 (19%) and a sulphonamide in 44 (15%). Although not statistically significant, mothers often reported a child as not having received an antimalarial drug if the child was younger than 12 months or had been sick for more than 3 d. The mothers' information regarding home treatment of fever in children was highly inaccurate. Malaria treatment histories, whether collected at health facilities or in surveys of knowledge, attitudes, and practices, must be interpreted with caution.

Using clinical signs to diagnose anaemia in African children.

Anaemia is a serious and common problem among young children in sub-Saharan Africa. As a first step towards developing guidelines for its recognition and treatment, we conducted a study to evaluate the ability of health workers to use clinical findings to identify children with anaemia. Health care workers examined a total of 1104 children under 5 years of age at two hospital-based outpatient clinics in rural Malawi. Blood samples were taken to determine haemoglobin concentrations. Pallor of the conjunctiva, tongue, palm or nail beds was 66% sensitive and 68% specific in distinguishing children with moderate a anaemia (haemoglobin concentration, 5-8 g/dl) and 93% sensitive and 57% specific in distinguishing those with severe anaemia (haemoglobin concentration, < 5 g/dl). Even without laboratory support, which is often unavailable in rural Africa, clinical findings can identify the majority of children with anaemia.

PIP: Anemia is a serious and common problem among young children in Sub-Saharan Africa. As a first step towards developing guidelines for its recognition and treatment, a study was conducted to evaluate the ability of health workers to use clinical findings to identify children with anemia. The study was conducted in the outpatient departments of Mangochi District Hospital and Nkhoma Hospital, serving predominately rural areas. A systematic sample was recruited by approaching the parent of every 4th sick child brought to the clinic for under-5-year-olds in Mangochi between April 17 and May 28, 1993, and every 2nd and 3rd sick child brought to the pediatric clinic in Nkhoma between April 28 and June 5, 1993. Of these, 1104 (97%) underwent a physical examination of the conjunctiva, tongue, palm, and nail bed, and a blood test was taken to determine haemoglobin concentration. The median age of the enrolled children was 13 months (range, 1 month to 60 months); 580 (53%) were boys, and 590 (53%) were seen at Mangochi District Hospital. The mean hemoglobin concentration of enrolled patients was 8.8 g/dl (range, 2.1-17.1 g/dl). 82% were anemic according to the World Health Organization definition; 35% had moderate anemia; and 5% had severe anemia. Pallor of the conjunctiva, tongue, palm, or nail beds was 66% sensitive and 68% specific in distinguishing children with moderate anemia (hemoglobin concentration, 5-8 g/dl) and 93% sensitive and 57% specific in distinguishing those with severe anemia (hemoglobin concentration, 5 g/dl). Probable pallor at any anatomical site was 70% sensitive, 68% specific, and had a 54% positive predictive value in diagnosing a hemoglobin concentration of 8 g/dl. Multiple linear regression models predicting haemoglobin levels showed that children with definite pallor had significantly lower hemoglobin concentrations than children with probable pallor, and those with probable pallor had significantly lower concentrations than those without pallor (p 0.05 for each comparison). Laboratory support is often unavailable in rural Africa, thus clinical findings can identify the majority of children with anemia.

A nation-wide malaria knowledge, attitudes and practices survey in Malawi: objectives and methodology.

A malaria knowledge, attitudes and practices survey was conducted in Malawi during April and May, 1992, to provide policy makers and program managers with information needed to design or improve malaria control programs, to establish epidemiologic and behavioral baselines, and to identify indicators for monitoring program effectiveness. Using cluster-sample survey methodology, 1531 households, in 30 clusters of 51-52 households each, were identified and members interviewed. Interviews were conducted by trained survey teams composed of young Malawian women with secondary level education. Heads of households were asked about malaria prevention methods used and about household economics; caretakers of children were asked about treatment and health seeking behavior in a recent malaria episode in a child; and women who had been pregnant in the past 5 years were asked about their antenatal clinic utilization and malaria during pregnancy. Survey results will be used to make programmatic decisions, including developing health education messages and establishing monitoring and evaluation of malaria control activities and outcomes in Malawi.

PIP: A malaria knowledge, attitudes and practices survey was conducted in Malawi in the late rainy season, April 1-May 16, 1992, corresponding to the season of peak malaria transmission to provide policy makers and program managers with information needed to design or improve malaria control programs, to establish epidemiologic and behavioral baselines, and to identify indicators for monitoring program effectiveness. A cluster-sample survey methodology, modified from the Expanded Program for Immunization cluster-sampling methodology was used to identify and interview members of a total sample of 1531 households, in 30 clusters of 51 to 52 households each. Heads of households were asked about malaria prevention methods used and about household economic; caretakers of children were asked about treatment and health seeking behavior in a recent malaria episode in a child; and women who had been pregnant in the past 5 years were asked about their antenatal clinic utilization and malaria during pregnancy. A total of 7025 persons in 1531 households were included in the survey: 1178 adults with recent fever illness and caretakers of 724 children with recent fever illness were interviewed; 1395 households included at least one woman who had ever been pregnant, with 809 women having completed a pregnancy within the last 5 years. Preventive measures used in the households and household income were ascertained for 1531 households. In several articles, detailed results will be described for each part of the survey. These results will be used to be guide policy makers and program managers in making decisions based on current data in designing and improving malaria control programs and health education messages. Baseline epidemiologic and behavioral indicators will be identified for monitoring program impact to help focus intervention efforts on high risk groups, through channels that will most effectively reach the greatest number of people.