Translating global health research aims into action: the example of the ALPHA network.

There is increasing consensus on the importance of strengthening global health research to meet health and development goals. Three key global health research aims are to ensure that research (i) addresses priority health needs, (ii) contributes to policy development, and (iii) adds value to investments in developing countries through South-South collaboration and capacity-strengthening in the South. The ALPHA network (Analysing Longitudinal Population-based HIV/AIDS data on Africa) is an illustrative example of how these global health research aims can be translated into action. The network facilitates additional collaborative HIV epidemiological research among six independent research projects in Africa studying population-based cohorts. Under the first of the earlier mentioned aims, the network addresses key epidemiology research issues in HIV/AIDS which are crucial to making progress and monitoring progress in the response against HIV/AIDS. Under the second aim, the network's scientific programme of research has contributed to strengthening the evidence base on HIV epidemiology in Africa and has informed policy development in areas such as targeted HIV prevention, social support, monitoring epidemic response and epidemic forecasting. Under the third aim, investment in the network has added value to the research investment in the individual projects through capacity development among African researchers as well as through the collaborative research outputs of the individual projects. Lessons from the network are relevant to collaborations facing similar challenges in other areas of global health research. These include the importance of establishing transparent and efficient governance for research collaborations, developing advance consensus on data sharing, ensuring effective communication for networking and demonstrating the added value of research investment in South-South collaborations.

Herpes simplex virus type 2 trends in relation to the HIV epidemic in northern Malawi.

OBJECTIVES: It is unclear whether the high prevalence of herpes simplex virus type 2 (HSV-2) found in much of Africa predates the HIV epidemic or is, to some extent, a consequence of it. HSV-2 prevalence trends in a rural African community were assessed over a period in which HIV prevalence rose sharply, and antenatal clinic (ANC) surveillance was explored as a method of estimating community HSV-2 prevalence. METHODS: HSV-2 seroprevalence was determined among community controls seen for case-control studies of mycobacterial disease in Karonga district, Malawi, in 1988-90, 1998-2001 and 2002-5, and in women attending ANC as part of surveillance for HIV in 1999-2000. Over this period HIV prevalence rose from 4% to 12%. RESULTS: HSV-2 prevalence in all periods increased sharply with age and was higher in women than in men. After excluding migrants, there was no evidence of change in HSV-2 prevalence in the different periods. Women in the ANC group had lower HSV-2 prevalence than those in the community, but the ANC prevalence was a good approximation to the combined male and female prevalence for the same age group. CONCLUSIONS: This study suggests that HSV-2 was already widespread before the HIV epidemic and has not been greatly influenced by it. It also demonstrates that ANC surveillance may be useful for estimating community HSV-2 prevalence.

Assessment and evaluation of contact as a risk factor for tuberculosis in rural Africa.

SETTING: A rural district in Malawi. OBJECTIVE: To determine the effect of inaccurate recall on estimates of the proportion of tuberculosis (TB) cases attributable to contact with identifiable prior cases. DESIGN: Case-control study of laboratory-confirmed TB cases and community controls, comparing family, household and area contacts identified from a database of TB cases with those named at interview. Estimation of prior contact as a risk factor for TB and identified factors associated with being a named contact. RESULTS: Ninety-five per cent of named contacts were known TB cases. The proportion of total identified contacts who were named at interview was 75%, and was similar for cases and controls. Cases were twice as likely as controls to identify prior contacts. Adding database information did not affect odds ratios, but increased the proportion of TB cases attributable to prior contact. Smear-positive, male and human immunodeficiency virus (HIV) negative TB patients were more likely to be named by subsequent cases. Identifiable recent contact with known smear-positive cases accounted for 12.5% of the TB burden. CONCLUSIONS: Reporting of putative source contacts showed little evidence of recall bias and gave estimates of the relative risk of TB associated with identifiable contact. The lower likelihood of HIV-positive cases being named as contacts may reflect reduced infectiousness.

Population differences in death rates in HIV-positive patients with tuberculosis.

SETTING: Randomised controlled clinical trial of Mycobacterium vaccae vaccination as an adjunct to anti-tuberculosis treatment in human immunodeficiency virus (HIV) positive patients with smear-positive tuberculosis (TB) in Lusaka, Zambia, and Karonga, Malawi. OBJECTIVE: To explain the difference in mortality between the two trial sites and to identify risk factors for death among HIV-positive patients with TB. DESIGN: Information on demographic, clinical, laboratory and radiographic characteristics was collected. Patients in Lusaka (667) and in Karonga (84) were followed up for an average of 1.56 years. Cox proportional hazard analyses were used to assess differences in survival between the two sites and to determine risk factors associated with mortality during and after anti-tuberculosis treatment. RESULTS: The case fatality rate was 14.7% in Lusaka and 21.4% in Karonga. The hazard ratio for death comparing Karonga to Lusaka was 1.47 (95% confidence interval [CI] 0.9-2.4) during treatment and 1.76 (95%CI 1.0-3.0) after treatment. This difference could be almost entirely explained by age and more advanced HIV disease among patients in Karonga. CONCLUSION: It is important to understand the reasons for population differences in mortality among patients with TB and HIV and to maximise efforts to reduce mortality.

The social and economic impact of parental HIV on children in northern Malawi: retrospective population-based cohort study.

From population-based surveys in the 1980s in Karonga district, northern Malawi, 197 'index individuals' were identified as HIV-positive. 396 HIV-negative 'index individuals' were selected as a comparison group. These individuals, and their spouses and children, were followed up in 1998-2000. 582 of 593 index individuals were traced. 487 children of HIV-positive, and 1493 children of HIV-negative, parents were included in analyses. Rates of paternal, maternal, and double orphanhood among children with one or both parents HIV-positive were respectively 6, 8, and 17 times higher than for children with HIV-negative parents. Around 50% of children living apart from both parents had a grandparent as their guardian; for most of the rest the guardian was an aunt, uncle, or sibling. There were no child-headed households. Almost all children aged 6-14 were attending primary school. There was no evidence that parental HIV affected primary school attainment among children <15 years old. Children of HIV-positive parents were less likely to have attended secondary school than those of HIV-negative parents. The extended family has mitigated the impact of orphanhood on children, but interventions to reduce the incidence of orphanhood, and/or which strengthen society's ability to support orphans, are essential, especially as the HIV epidemic matures and its full impact is felt.

Effect of Mycobacterium vaccae (SRL172) immunotherapy on radiographic healing in tuberculosis.

OBJECTIVE: Controlled trials have failed to show an effect of Mycobacterium vaccae immunotherapy on treatment outcome and mortality in patients with tuberculosis (TB); however, several studies have suggested improvement in radiographic clearing and resolution of cavitary disease. METHODS: To assess the effect of M. vaccae immunotherapy on radiographic healing in pulmonary TB, chest X-rays from three randomized placebo-controlled trials of M. vaccae given as a single injection during the first 2 weeks of treatment were interpreted by a single, masked assessor using a standard scheme. Endpoints were the overall degree of radiographic improvement or deterioration and changes in cavitary disease at the end of antituberculosis treatment and follow-up. RESULTS: Of 1018 patients (478 HIV-infected; 540 HIV-uninfected) with an end of treatment or end of follow-up X-ray analyzed, 496 received M. vaccae and 522 received placebo. There was no difference in radiographic improvement or deterioration or cavitary disease at the end of treatment or follow-up comparing the M. vaccae and placebo groups. Results were similar comparing HIV-infected and HIV-uninfected patients. CONCLUSION: Adjunctive immunotherapy of drug-susceptible pulmonary TB with M. vaccae during the first 2 weeks of treatment did not improve radiographic responses to treatment or resolution of cavitary disease.

Tuberculosis and gender: exploring the patterns in a case control study in Malawi.

BACKGROUND: In many populations there is an excess of tuberculosis in young women and older men. We explored possible explanations for these patterns, concentrating on human immunodeficiency virus (HIV) status, pregnancy, smoking, cooking smoke exposure, contact with tuberculosis cases within the household or outside, and gender differences in health service usage and diagnostic delay. DESIGN: Case control study in Karonga District, Malawi. METHODS: Cases were new tuberculosis patients with bacteriological or histological evidence of tuberculosis. Controls were selected in the community using field-based random sampling. RESULTS: The study included 598 tuberculosis cases and 992 controls, with an excess of tuberculosis in young females and older males. This was more marked in HIV-positive individuals. HIV infection was a similarly strong risk factor for tuberculosis in both men and women. Tuberculosis was associated with having a family or household contact with tuberculosis for both men and women. For women, but not men, contacts outside the close family and household were also a risk factor for tuberculosis. Tuberculosis was not associated with current or recent pregnancy, or with smoking or smoke exposure. There were no differences between men and women in health service usage or delay. CONCLUSIONS: In this population, HIV infection and contacts with known tuberculosis patients are important determinants of the gender distribution of cases.

Haematological profiles of the people of rural southern Malawi: an overview.

An integrative review of the results of two published and two unpublished studies of anaemia in children, adolescent females, pregnant women and adults living in southern Malawi is presented. Anaemia was universally present in all age-groups, with the higher prevalences in infants (100%) and adolescent primigravidae (93.8%). Nutritional deficits of iron and vitamin A were major contributory factors but chronic malarial haemolysis also significantly contributed to the anaemia. Among boys, anaemia was more common among those with glucose-6-phosphate-dehydrogenase (G6PD) deficiency than in those without this deficiency (P<0.002). This enzymopathy, which occurred in 23.5% [95% confidence interval (CI)=16.7%-30.1%] of the male and 30% (CI=17.3%-42.7%) of the female infants examined, was also associated with neonatal jaundice. The overall prevalences of the-alpha(3.7)/alphaalpha and -alpha(3.7)/-alpha(3.7) thalassaemia genotypes were estimated at 41.0% (CI=28.3%-53.7%) and 8.7% (CI=1.5%-15.9%), respectively. Haemoglobin AS was present in 18.1% (CI=12.8%-23.4%) of the infants and haemoglobin SS in 2.5% (CI=1.4%-3.6%). As the prevalence of infection with Plasmodium falciparum was significantly higher in infants with haemoglobin AS than in those with AA (21.4% v. 6.7%; P<0.001), an increased risk of early-onset moderate parasitaemias in young infants probably stimulates the development of immunity, protecting older heterozygotes from severe malarial infection. Innovative community approaches are required to break the cycle of ill health that anaemia supports in those living in rural areas of southern Malawi. Interventions in adolescent girls could be of particular importance, as they could break the cycle in both pregnant women and their infants.

Identification of the vectors of lymphatic filariasis in the Lower Shire Valley, southern Malawi.

An investigation of lymphatic filariasis vectors in Malawi is reported. Anopheles funestus, A. arabiensis, and A. gambiae sensu stricto had high rates of filarial infection (2.2-3.1%) and carried infective larvae. Anopheles funestus was the predominant species collected (77.6%) and was the primary vector during the study period of April to May 2002.

Lymphatic filariasis in the Karonga district of northern Malawi: a prevalence survey.

In Malawi, two main foci of lymphatic filariasis (LF) are known to exist: one in the south, in the Shire valley, and the other in the north, along the Songwe River, on the border with Tanzania. There have been no formal surveys in the Songwe area since the 1960s but an opportunity arose in 2000-2001 to map LF in this area, in the context of a leprosy survey that formed part of the follow-up of a large leprosy and tuberculosis vaccine trial. Overall 687 immunochromatographic (ICT) tests were carried out. Wuchereria bancrofti antigenaemia was found in > 25% of adults in each of the 12 villages sampled (four in the Songwe area and eight in the rest of the Karonga district), with village prevalences varying from 28%-58%. Of the 685 adult male residents of the Songwe area who were each given full-body clinical examinations, 80 (11.7%) were identified as cases of hydrocele. Lymphoedema was found in seven (1.0%) of these adult males and in 29 (3.7%) of the 769 adult female residents of the Songwe area who were also examined. Microfilariae were detected in 33 (30.8%) of the 107 thick smears of night-blood samples that were made from individuals with positive ICT cards. The W. bancrofti infection focus in Karonga district is therefore wider than was previously known. This has important implications for the implementation and eventual impact of LF-control activities in this area.

Patterns of helminth infection and relationship to BCG vaccination in Karonga District, northern Malawi.

Surveys of enteric and urinary helminth infections were carried out in 1999 among 501 schoolchildren and among 320 adolescents and young adults participating in a study of immune responses to BCG vaccine in Karonga District, northern Malawi. Hookworm, Schistosoma mansoni and S. haematobium infections were detected in 64%, 27% and 20% of schoolchildren and in 55%, 40% and 25% of the immunology study subjects, respectively. Other helminths were appreciably less common. The prevalence of 'at least one' helminth infection was 76% among schoolchildren, ranging from 60% to 92% in the 4 schools, and was 79% in the immunology study participants. There was no evidence for an association between the presence of a BCG scar and presence or intensity of infection with worms in the schoolchildren, nor evidence that BCG vaccination of adolescents and young adults had any effect on the prevalence of helminth infections 1 year later.

Relationship between IFN-gamma and skin test responsiveness to Mycobacterium tuberculosis PPD in healthy, non-BCG-vaccinated young adults in Northern Malawi.

SETTING: Rural northern Malawi, where vaccination with BCG Glaxo (1077) provides protection against leprosy but not against pulmonary tuberculosis. OBJECTIVE: To evaluate the patterns of responsiveness to purified protein derivative of Mycobacterium tuberculosis (PPD) in terms of delayed type hypersensitivity (DTH) and interferon-gamma (IFN-gamma) production. DESIGN: IFN-gamma was measured in 6 day whole blood cultures diluted 1 in 10, stimulated with PPD RT48, and the results compared to the DTH response to PPD RT23. A total of 633 individuals aged 12 to 28 years, without prior BCG vaccination, were recruited. RESULTS: Overall, 63% of subjects made a positive IFN-gamma response (defined as >62 pg/ml), and 37% gave a DTH induration of >5 mm. A strong correlation between skin test and IFN-gamma responses was observed, although with interesting exceptions: 13/270 individuals with zero DTH showed IFN-gamma responses >500 pg/ml, and 7/53 individuals with >10 mm induration showed IFN-gamma responses < or = 62 pg/ml. The prevalence of skin test responsiveness increased with age, and was higher among older males than females; age-sex patterns were less clear for IFN-gamma production. CONCLUSION: The 6 day IFN-gamma response to PPD correlates well with Mantoux skin test induration. The discordant individuals may represent important subsets in terms of protective immunity and risk of clinical tuberculosis.

Patterns and implications of naturally acquired immune responses to environmental and tuberculous mycobacterial antigens in northern Malawi.

Interferon (IFN)-gamma responsiveness to 12 purified protein derivative (PPD) and new tuberculin antigens from 9 species of mycobacteria was assessed, using a whole blood assay, in 616 young adults living in northern Malawi, where Mycobacterium bovis bacille Calmette-Guérin (BCG) vaccination provides no protection against pulmonary tuberculosis. The prevalence of IFN-gamma responsiveness was highest for PPDs of M. avium, M. intracellulare, and M. scrofulaceum (the MAIS complex). Correlations between responsiveness paralleled genetic relatedness of the mycobacterial species. A randomized, controlled trial was carried out, to assess the increase in IFN-gamma responsiveness to M. tuberculosis PPD that can be attributed to M. bovis BCG vaccination. The BCG-attributable increase in IFN-gamma response to M. tuberculosis PPD was greater for individuals with low initial responsiveness to MAIS antigens than for those with high initial responsiveness. Although not statistically significant, the trend is consistent with the hypothesis that prior exposure to environmental mycobacteria interferes with immune responses to BCG vaccination.

Trends in antituberculosis drug resistance in Karonga District, Malawi, 1986-1998.

SETTING: Karonga District, Malawi. OBJECTIVES: To examine long term trends in initial and acquired resistance to antituberculosis drugs in a rural area of Africa. DESIGN: Monitoring of all patients with culture-confirmed tuberculosis 1986-1998. RESULTS: Initial drug resistance results were available for 1121 patients. The proportion resistant to any of the first line drugs (streptomycin, isoniazid, rifampicin or ethambutol) was 9.6%, and to isoniazid 7.2%. Initial resistance to at least isoniazid and rifampicin (multidrug resistance) was seen in only six patients. No initial resistance to ethambutol was found. There was no significant change in initial drug resistance over time. Overall, 22/120 (18%) patients with previous treatment were resistant to at least one drug; only one had multidrug resistance. Acquired resistance decreased over the period of the study. There were no associations between age, sex or human immunodeficiency virus (HIV) status and initial or acquired drug resistance. CONCLUSIONS: Changes in acquired resistance may reflect the recent performance of a control programme more quickly than those in initial resistance. It is encouraging that acquired resistance decreased and levels of multidrug resistance were low despite more than a decade of use of rifampicin. The lack of association between HIV and drug resistance confirms findings elsewhere in Africa.

Tuberculous lymphadenitis, a diagnostic problem in areas of high prevalence of HIV and tuberculosis.

The human immunodeficiency virus (HIV) epidemic is associated with a marked increase of tuberculosis cases. The influence of HIV on diagnostic methods for tuberculous lymphadenitis is less clear. In an environment of high HIV and tuberculosis prevalence in Blantyre, Malawi, a prospective study compared results of basic procedures diagnosing tuberculous lymphadenitis with the outcome of histology and/or culture. One hundred out-patients, aged 15-55 years, with extra-inguinal lymphadenopathy not responding to general antibiotics, entered the study. Among 52 cases, with whom all procedures were carried out in accordance with the protocol, 38 (73%) were diagnosed as tuberculous lymphadenitis; 84% of the latter (32/38) were seropositive for HIV. Needle aspirate and biopsy smears stained by the Ziehl-Neelsen technique contributed little to detecting tuberculosis, 8% and 11% respectively. In contrast, macroscopic caseation of excised lymph nodes showed a high yield of 82%, which was similar to histology, and higher than that of Löwenstein-Jensen culture (61%). The study suggested that HIV positivity of tuberculous lymphadenitis patients decreased the possibility of histology and culture both being indicative of tuberculosis (odds ratio 0.10; P = 0.06). Consequently histology results, often used as the single definitive method, failed to diagnose 18% (7/38) of tuberculosis cases. However, it was reassuring that 4 simple methods, which can safely be carried out at district level, could be expected to diagnose 80-95% of tuberculous lymphadenitis cases in a timely and cost-effective manner.

PIP: A prospective study conducted in 1994-95 in Blantyre, Malawi, investigated the influence of HIV on diagnostic methods for tuberculous lymphadenitis in 100 outpatients 15-55 years old with extra-inguinal lymphadenopathy not responsive to general antibiotics. For the 52 cases for which all diagnostic procedures were carried out, 38 (73%) were diagnosed as tuberculous lymphadenitis; 32 (84%) of these patients were HIV-positive. Needle aspirate and biopsy smears stained by the Ziehl-Neelsen technique contributed only 8% and 11%, respectively, to detecting tuberculosis. In contrast, macroscopic caseation of excised lymph nodes, histology, and Lowenstein-Jensen culture had yields of 82%, 82%, and 61%, respectively. These findings indicate that, in tuberculous lymphadenitis patients, HIV infection decreases the diagnostic power of culture and histology. However, use of the other methods can diagnose 80-95% of tuberculous lymphadenitis cases in a cost-effective manner in areas with high prevalences of both HIV and tuberculosis.

Finger clubbing and HIV infection in Malawian children.

PIP: While it is unusual for children to present with finger clubbing, the authors began to frequently see such cases in the University of Malawi's Department of Pediatrics, College of Medicine. Clubbing was recognized in 52 children during February-May 1996. An 8-year-old boy died with a diagnosis of endomyocardial fibroelastosis. The remaining 51 children were aged 4 months to 12 years of mean age 37 months. 26 of the 31 children tested for infection with HIV were HIV-ELISA seropositive. A clinical diagnosis of pediatric AIDS according to the World Health Organization criteria was made in 35 cases. A provisional diagnosis of pulmonary tuberculosis was made in 29. Two of the older children had acid-fast bacilli in sputum; one was HIV-positive. Digital clubbing in Malawian children may be associated with chronic lung disease and HIV infection, presenting as early as infancy. In regions where childhood HIV infection is common and resources are scarce, clinical findings which improve diagnostic specificity could prove useful.^ieng