The COVID-19 era: the view from Nigeria.

If we were told that one day the entire world would take its guidance for managing a health crisis from empirical thought, nobody would have believed it. However, with the December 2019 arrival of COVID-19 in China, the world subsequently went into a frenzied state that resulted in the widespread adoption of untested strategies or potential cures; circumstantial evidence provided without randomized control trials (RCTs) was published rapidly and widely considered the gold standard in medical research and therapeutics. Nigeria and much of the rest of the world blindly adopted treatments like chloroquine or hydroxychloroquine and various prevention strategies, often without monitoring the efficacy of these treatment and social control strategies. COVID-19 provided Nigeria a critical opportunity to create or strengthen its national laboratory system by building up its Level 3 laboratories in all parts of the country with the capability to perform PCR tests and viral isolation. There was also an opportunity to establish hospitals in every region of a sufficient standard to reduce the numbers of Nigerians travelling abroad to seek medical treatment; to invest in building capacity to develop antiviral medications and vaccines in Nigeria, and to ensure better international health policies. Rather, Nigerian leaders, government and health managers decided (like most other nations of the world) to shut down the society using isolationist policies that were not necessarily tailored to local needs. Despite adopting these methods, COVID-19 cases continued to skyrocket in Nigeria. In the future, before adopting such broad sweeping policies, there should be local tailoring to assess their effectiveness in different communities. Given that the country has much experience in controlling Lassa and Marburg Fever outbreaks, Nigeria should lead by developing new strategies, new protocols and new local guidelines, based on validated and reproducible studies to ensure that the public health authorities are not caught unaware by any new outbreaks of emerging or remerging diseases.

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.

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.

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.

Utility of paired BACTEC MYCO/F LYTIC blood culture vials for detection of bacteremia, mycobacteremia, and fungemia.

In previous bloodstream infection studies in Malawi, we inoculated blood from a single venesection into a single BACTEC MYCO/F LYTIC (MFL) vial. Inoculation of one vial, however, would be expected to reduce the sensitivity of bloodstream pathogen detection with MFL vials. To ascertain the degree of this loss of sensitivity, blood was drawn from each of 228 febrile, adult inpatients in Malawi and 5 ml of each blood sample was inoculated into each of two MFL vials. Of 228 paired vials, 51 (22%) were both positive, 172 (75%) were both negative, and 5 (3%) had discordant results. Bloodstream infection would have been detected in 11 (92%) of 12 patients with mycobacteremia and 38 (92%) of 41 patients with bacteremia had only one MFL vial been inoculated. Our study shows that a second MFL vial does not significantly increase diagnostic sensitivity.

Comparison of BACTEC MYCO/F LYTIC and WAMPOLE ISOLATOR 10 (lysis-centrifugation) systems for detection of bacteremia, mycobacteremia, and fungemia in a developing country.

In less-developed countries, studies of bloodstream infections (BSI) have been hindered because of the difficulty and costs of culturing blood for bacteria, mycobacteria, and fungi. During two study periods (study period I [1997] and study period II [1998]), we cultured blood from patients in Malawi by using the BACTEC MYCO/F LYTIC (MFL), ISOLATOR 10 (Isolator), Septi-Chek AFB (SC-AFB), and Septi-Chek bacterial (SC-B) systems. During study period I, blood was inoculated at 5 ml into an MFL bottle, 10 ml into an Isolator tube for lysis and centrifugation, and 10 ml into an SC-B bottle. Next, 0.5-ml aliquots of Isolator concentrate were inoculated into an SC-AFB bottle and onto Middlebrook 7H11 agar slants, chocolate agar slants, and Inhibitory Mold Agar (IMA) slants. During study period II, the SC-B and chocolate agar cultures were discontinued. MFL growth was detected by fluorescence caused by shining UV light (lambda = 365 nm) onto the indicator on the bottom of the bottle. During study period I, 251 blood cultures yielded 44 bacterial isolates. For bacteremia, the MFL was similar to the Isolator concentrate on chocolate agar (34 of 44 versus 27 of 44; P, not significant [NS]), but more sensitive than the SC-B bottle (34 of 44 versus 24 of 44; P = 0.05). For both study periods combined, 486 blood cultures yielded 37 mycobacterial and 13 fungal isolates. For mycobacteremia, the sensitivities of the MFL and Isolator concentrate in the SC-AFB bottle were similar (30 of 37 versus 29 of 37; P, NS); the MFL bottle was more sensitive than the concentrate on Middlebrook agar (30 of 37 versus 15 of 37; P = 0.002). For fungemia, the MFL bottle was as sensitive as the SC-B bottle or Isolator concentrate on chocolate agar or IMA slants. We conclude that the MFL bottle, inoculated with just 5 ml of blood and examined under UV light, provides a sensitive and uncomplicated method for comprehensive detection of BSI in less-developed countries.

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.

A hospital-based prevalence survey of bloodstream infections in febrile patients in Malawi: implications for diagnosis and therapy.

The etiology of bloodstream infections (BSIs) in febrile (> or =37.5 degrees C) adults (> or =18 years old) in one Malawi hospital were determined during August and September 1997. After clinical evaluation, blood was drawn for comprehensive culture, human immunodeficiency virus (HIV) type 1 testing, and malaria smear. Of 233 patients, 173 (74%) were HIV-1 infected, and 70 (30%) had BSI. BSI pathogens included 25 (33%) Streptococcus pneumoniae and 21 (28%) Mycobacterium tuberculosis. Nine patients (4%) had malaria parasitemia. BSIs were more likely in HIV-1-positive than in -negative patients (62/173 vs. 8/60, P<.01). Clinical predictors of BSI included HIV-1 infection and altered mental status. Mortality among inpatients with BSI was higher than among those without BSI (P<.001). In conclusion, S. pneumoniae and M. tuberculosis are frequent causes of BSI in febrile adults. Similar surveys, performed periodically in developing countries, may assist in the identification of clinical predictors of BSI and in planning appropriate therapy.

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.

Implementing a malaria curtains project in rural Malawi.

This paper describes planning, implementation, monitoring and evaluation activities carried out in support of a malaria control project that used permethrin-impregnated curtains in eight villages in rural Malawi. Findings from formative evaluation and project monitoring aspects of the evaluation are presented. Permethrin-impregnated curtains were introduced to villagers who participated in household self-help projects. To implement the project, village health workers were trained and worked closely with existing project personnel as well as traditional headmen to assure village participation, facilitate health education and coordinate curtain-dipping (impregnation) meetings. A quasi-experimental evaluation design used surveys and observations to measure change in cognitive, behavioural and health outcome indicators. Village adoption rates averaged 50%, with variation between villages. Monitoring data showed a high degree of compliance with curtain re-impregnation initially and high perceived efficacy of curtains. Issues discussed include village readiness for change, trust, acceptability of the innovation, cost, sustainability and leadership.

PIP: Many malaria prevention strategies in sub-Saharan Africa promote household preventive sanitation self-help activities. However, it has been shown to have limited effectiveness, as well as increased parasite resistance to anti-malarial drugs, or unacceptable levels of toxicity in environmental spraying. This paper reports on planning, implementation, monitoring of an impregnated curtain project in rural Malawi. In this intervention, permethrin-impregnated curtains were introduced to villagers who participated in household self-help projects. To implement the project, village health workers were trained and worked closely with existing project personnel, as well as traditional headmen to assure village participation, facilitate health education and coordinate curtain-dipping (impregnation) meetings. A quasi-experimental evaluation design used surveys and observations to measure change in cognitive, behavioral and health outcome indicators. Village adoption rates averaged 50%, with variation between villages. Monitoring data showed a high degree of compliance with curtain re-impregnation initially and high perceived efficacy of curtains. Other issues discussed include village readiness for change, trust, and acceptability of the innovation, cost, sustainability, and leadership.

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.