Human vaccine and immunisation research in South Africa: A bibliometric study.

BACKGROUND: Research in human vaccines and immunisation plays a crucial role in shaping national, regional and global health policies aimed at controlling vaccine preventable diseases (VPDs). To our knowledge, the landscape of human vaccine and immunisation research in South Africa (SA) is not well characterised. OBJECTIVES: To characterise research in human vaccines and immunisation in SA. METHODS: We conducted a bibliometric study. Seven electronic databases (PubMed; Scopus; Web of Science; Cochrane; CINAHL; Africa-Wide Information; and MEDLINE (via EBSCOhost)) were searched for eligible studies published in English between 1 January 2007 and 31 March 2020. Selected primary studies needed to be on human vaccine and immunisation research conducted in SA. All types of reviews were excluded. For the included studies, outcomes of interest included publication journals, publication trends, types of studies and VPDs, targeted populations, as well as author affiliations. RESULTS: A total of 9 212 studies was retrieved. After screening for eligibility, 366 studies met the inclusion criteria. The key findings were as follows: (i) a total of 54 (14.8 %) articles on human vaccine and immunisation research in SA appeared in local journals, while 312 (85.2%) were in non-SA (international) journals; (ii) the number of publications on human vaccine and immunisation research in SA increased from 13 in 2007 to 47 in 2015; (iii) there were 189 (51.7%) operational studies and 177 (48.3%) clinical studies, with 88 (49.7%) of the latter being clinical trials; (iv) human vaccine and immunisation research in SA is conducted across all age groups, with a focus on children; and (v) authors of the identified research outputs and those mostly represented were from the universities of Cape Town and the Witwatersrand, Johannesburg. CONCLUSIONS: The landscape of human vaccine and immunisation research in SA is growing and adapting to the emerging trends in vaccinology, with a focus on the duo epidemic of HIV and TB, as well as Expanded Programme on Immunisation (EPI)-related vaccinations. This research contributes to locally relevant evidence that can be used to inform future vaccine and EPI-related research.

Lessons learnt during the national introduction of human papillomavirus (HPV) vaccination programmes in 6 African countries: Stakeholders' perspectives.

BACKGROUND: Infection with human papillomavirus (HPV) significantly increases the risk of developing cervical cancer later in life. Therefore, globally, HPV vaccines targeted to pre-adolescent and adolescent girls have been on the rise since the licensure in 2006. However, the introduction of HPV vaccines has been relatively slow in Africa. At the end of 2016, only 8 of the 54 countries in Africa were reported to have introduced HPV vaccination at a national level. By 2019, the number of countries had grown marginally to 11. OBJECTIVES: To investigate stakeholders' perspectives on the experiences, challenges and lessons learnt during national HPV vaccine introduction in Africa. METHODS: A questionnaire was administered to selected participants from 8 African countries. These countries had successfully introduced HPV vaccination at a national level by the end of 2016. We used in-depth interviews and self-administered online questionnaires for data collection and analysis. Data are presented without naming the country or participants; therefore, readers will not be able to identify the results that are specific to individual countries. Narrative and thematic reporting were used to describe the results. RESULTS: We obtained results from 6 of the 8 targeted countries. The challenges reported during HPV vaccination programmes were: identifying the target population, using a school-based vaccine-delivery strategy, obtaining political support, the need to integrate HPV vaccination with existing school health programmes and engaging multiple stakeholders. These challenges were similar in all 6 countries. The lessons learnt were that a school-based delivery strategy is a successful approach for national HPV vaccination, and that identifying girls for vaccination at schools was less challenging if implemented through a class-based instead of an age-based approach. CONCLUSIONS: Most African countries do not have established platforms to deliver vaccines to pre-adolescent and adolescent populations. The successful introduction of the HPV vaccine through school-based vaccination strategies in African countries may have created a platform to deliver other adolescent vaccines. The similarity of the study findings across the 6 participating countries further strengthens the need to document and disseminate the challenges and lessons learnt during HPV vaccine introduction in Africa. Documentation and dissemination of the challenges and lessons learnt are useful to other countries in Africa that plan to introduce an HPV vaccination programme, and possibly other adolescent vaccines.

Hepatitis A seroprevalence in Western Cape Province, South Africa: Are we in epidemiological transition?

BACKGROUND: Hepatitis A virus (HAV) is the most common cause of viral hepatitis worldwide. Hepatitis A vaccine is not included in the Expanded Programme on Immunisation in South Africa (EPI-SA), as the country is considered to be highly endemic for hepatitis A. OBJECTIVES: To determine the seroprevalence of hepatitis A infection in Western Cape Province (WCP), South Africa. METHODS: We conducted a cross-sectional seroprevalence study in the 1 - 7-year age group in WCP. Our samples (N=482) were blood specimens left over after laboratory testing obtained from referral hospitals between August and October 2015. A Siemens enzyme immunoassay was used to test for total hepatitis A antibodies. We also analysed hepatitis A immunoglobulin G antibody results from the National Health Laboratory Service (NHLS) Disa*Lab database at Groote Schuur Hospital from 2009 to 2014, and included 2009 - 2014 acute hepatitis A (immunoglobulin M-positive) surveillance data from the National Institute for Communicable Diseases to look at trends in notified acute infections over the same period. RESULTS: Our cross-sectional study showed 44.1% seroprevalence in the 1 - 7-year age group. Hepatitis A data from the NHLS database indicated a seroprevalence of <90% up to age 10 years, indicating intermediate endemicity. The surveillance data showed that a substantial number of symptomatic hepatitis A infections occurred in the 7 - 40-year age group, suggesting that an increasing proportion of the population is susceptible to HAV infection. CONCLUSIONS: These results suggest an urgent need for detailed evidence-based considerations to introduce hepatitis A vaccine into the EPI-SA.

Consensus statement on the revised World Health Organization recommendations for BCG vaccination in HIV-infected infants.

This document outlines the consensus agreement from the Union's BCG Working Group regarding BCG vaccination in HIV-infected infants, in response to recently revised World Health Organization (WHO) guidelines, which make HIV infection in infants a full contraindication to bacille Calmette-Guérin (BCG) vaccination. BCG is one of the most widely given vaccines globally and is safe in immunocompetent individuals. Recent evidence shows that HIV-infected infants who were routinely vaccinated with BCG at birth, when asymptomatic, and who later developed AIDS, are at high risk of developing disseminated BCG disease (estimated incidence 407-1300 per 100 000). The document outlines requirements to implement selective BCG vaccination strategies in infants born to HIV-infected women and strategies to reduce the risk of vertical HIV transmission and disseminated BCG disease in infants.

Comparison of mantoux skin test with three generations of a whole blood IFN-gamma assay for tuberculosis infection.

SETTING: A rural town in South Africa. OBJECTIVE: To compare the performance of Quanti-FERON assays with the tuberculin skin test (TST) for identifying latent tuberculosis infection (LTBI) in a high TB burden community. DESIGN: In a cross-sectional study in healthy adults, we applied the TST and took blood for the three generations of QuantiFERON assays. RESULTS: Of 358 participants whose results were analysed, 291 (81%) had a TST result of > or = 10 mm induration, and 187 (52%) > or = 15 mm. QuantiFERON-TB was positive in 215 (60%), QuantiFERON-TB Gold in 137 (38%), and QuantiFERON-TB Gold (In-Tube method) in 201 (56%). There was poor agreement between TST and QuantiFERON tests, and between the different generations of QuantiFERON tests (kappa = 0.12-0.50). Of the subset with TST indurations > or = 15 mm, 30-56% had negative QuantiFERON tests. However, positive Quanti-FERON tests were associated with males, who have a higher incidence of TB in this area. CONCLUSION: We showed poor agreement between TST and the different QuantiFERON tests in diagnosing LTBI. The surprising discordance between the Quanti-FERON TB Gold and QuantiFERON TB Gold (In-Tube method) tests needs to be investigated further.

Twice weekly vs. daily chemotherapy for childhood tuberculosis.

BACKGROUND: Treating childhood tuberculosis places a large burden on health services, and ways of lessening this were sought. METHODS: A randomized controlled trial was conducted to determine the effectiveness of fully intermittent twice weekly treatment for intrathoracic childhood tuberculosis and its effect on adherence to treatment, in comparison with daily (weekday) treatment. The setting was a district of Cape Town, South Africa, an area of high incident tuberculosis. We randomized 206 children with confirmed (4%), probable (94%) and suspected (2%) intrathoracic tuberculosis: 89 (median age, 25 months) received intermittent treatment; and 117 (median age, 28 months) received daily treatment. Intermittent treatment (twice weekly for 6 months) was isoniazid 15 mg/kg/dose, rifampin 15 mg/kg/dose and pyrazinamide 55 mg/kg/dose for 2 months, followed by isoniazid and rifampin only for 4 months. Daily treatment was isoniazid 10 mg/kg/day, rifampin 10 mg/kg/day and pyrazinamide 25 mg/kg/day on weekdays for 6 months. RESULTS: At 6 months 97% of subjects were discharged, with treatment outcomes in the two groups equivalent at that time (P = 0.90) and at the 18- to 30-month follow-up. One relapse occurred in the twice weekly group (P = 0.25). Adherence was equivalent; 70 children (79%) on intermittent and 90 (77%) on daily treatment took 75% or more of the prescribed doses (P = 0.90). Nonadherence over the full course of therapy was significantly associated with nonadherence during the first month of treatment (P = 0.0002) and household crowding (P = 0.002). CONCLUSIONS: Six month fully intermittent antituberculosis treatment is an effective and acceptable alternative to daily treatment.

Duration of illness in ambulatory children diagnosed with bronchiolitis.

OBJECTIVES: To measure the duration of illness in ambulatory children diagnosed with bronchiolitis and to examine clinical predictors of duration of illness. DESIGN: Validation inception cohort study. Duration of follow up was 28 days. SETTING: A primary-level ambulatory department of a public sector children's hospital in Cape Town, South Africa. PATIENTS: One hundred eighty-one children aged 2 to 23 months who went to the hospital as their first contact for that episode of illness, and had a clinical diagnosis of bronchiolitis were enrolled consecutively on weekday mornings if their guardian stated that they were contactable by telephone. MAIN OUTCOME MEASURE: Resolution of symptoms, as judged by the guardian, measured by twice-weekly telephone interviews. RESULTS: Median duration of illness (calculated as the reported duration of symptoms before initial hospital visit plus the time from first consultation to recovery) was 12 days (95% confidence interval, 11-14 days). After 21 days, 18% were still ill and after 28 days, 9% were still ill. Sixty-two patients (34.2%) had unscheduled consultations within 28 days, a median of 13 days after the first consultation. There was no association of duration of illness with age, sex, z score for weight for age, or respiratory rate. CONCLUSIONS: Ambulatory children diagnosed with bronchiolitis recover with few complications, but the resolution of symptoms may take several weeks. Providing parents with this information could help reduce the high rate of unscheduled return visits as observed in this cohort.

Health activism in Cape Town: a case study of the Health Workers Society.

The Health Workers Society (HWS), founded in 1980, was one of several progressive health organisations that fought for a democratic health system in South Africa. We document the sociopolitical context within which it operated and some of its achievements. HWS, many of whose members were staff and students of the University of Cape Town (UCT), provided a forum for debate on health-related issues, politics and society, and worked closely with other organisations to oppose the apartheid state's health policies and practices. They assisted with the formation of the first dedicated trade union for all healthcare workers and were one of the first to pioneer the primary healthcare approach in an informal settlement in Cape Town.

Predictive factors for latent tuberculosis infection among adolescents in a high-burden area in South Africa.

SETTING: A high tuberculosis (TB) burden area in South Africa (notification rate for all TB cases 1400 per 100 000 population). OBJECTIVE: To determine the prevalence of and predictive factors associated with latent TB infection in adolescents. DESIGN: Adolescents aged 12-18 years were recruited from high schools, clinical and demographic data were collected, and a tuberculin skin test (TST) and a QuantiFERON®-TB Gold In-Tube (QFT) assay performed. RESULTS: A total of 6363 (58.2%) of 10 942 adolescents at the schools were enrolled. After exclusions, of 5244 participants, 55.2% (95%CI 53.8-56.5) had TST ≥ 5 mm, while 50.9% (49.5-52.2) were QFT-positive. On multivariate analysis, Black/mixed race racial groups, male sex, older age, household TB contact, low income and low education level were predictive factors for both TST- and QFT-positive results. CONCLUSION: About half of the adolescents were found to be latently infected with TB in a high TB burden area with demographic and poverty-related socio-economic factors predicting the risk of TB infection. Adolescents from deprived communities should be considered an important target group for educational interventions by TB control programmes in high-burden settings.

Are adolescents ready for tuberculosis vaccine trials?

Tuberculosis (TB) vaccine trials are planned in adolescents in a high tuberculosis burden rural area near Cape Town, South Africa. To determine the knowledge and attitudes of adolescents about tuberculosis, vaccines and vaccine trials, a representative sample of adolescent learners was chosen from high schools in the trial area. A questionnaire was administered and focus group discussions held with the group and a sample of their parents. The questionnaire response rate was 65%. Knowledge of tuberculosis was fair 63.7% but knowledge of vaccines poor 41.9% based on a TB and vaccine knowledge score, respectively. Willingness to participate in vaccine trials will be influenced by the type of procedures involved (60% willing to answer questions, 43% willing to be examined, 32% willing to undergo skin tests and 39% willing to undergo blood draw). In general, better knowledge was statistically associated with greater willingness to participate in study procedures except for the blood draw. The focus group discussions showed that adolescents and their parents were positive about participating in vaccine trials but concerns about safety and the provision of adequate information should be considered when planning TB vaccine trials. This study suggests that TB vaccine trials would be acceptable amongst adolescents in this community with certain provisos.

Outcome of HIV infected children with culture confirmed tuberculosis.

BACKGROUND: Tuberculosis (TB) is an important disease in human immunodeficiency virus (HIV) infected children living in regions where TB is endemic. There are limited data on the outcome of culture confirmed TB in HIV infected children. AIMS AND METHODS: To describe the outcome on TB therapy and overall mortality in HIV infected children with culture confirmed TB through a retrospective cohort study. RESULTS: Eighty seven children, median age 24 months, contributed to 93 TB episodes; six children had two confirmed episodes. Pulmonary disease (PTB) was present in 71 episodes (76.3%), extrapulmonary disease (EPTB) in 43 (46.2%), and of these, both PTB and EPTB were present in 21 (22.6%). There was cure based on bacteriological and/or radiological criteria in 54 episodes (58.1%). Eighteen children died during TB therapy and there were a total of 34 deaths (39.1%). In univariate analysis (n = 87 patients), severe malnutrition, age < or =1 year, and a negative tuberculin skin test were significant risk factors for death during TB therapy. In multivariate survival analysis (n = 87 patients), HIV disease category, severe malnutrition at diagnosis, and lack of cure at the end of TB therapy were significantly associated with overall mortality. CONCLUSION: In the absence of antiretroviral therapy, HIV infected children with confirmed TB have poor outcomes on antituberculosis therapy and are at high risk of death during and after completion of antituberculosis therapy, especially due to non-TB related causes. There is an urgent need to optimise and monitor antituberculosis therapy in HIV infected children and to improve access to TB and other preventative therapy.

A randomized, controlled trial of vitamin A in children with severe measles.

BACKGROUND: Measles kills about 2 million children annually, and there is no specific therapy for the disease. It has been suggested that vitamin A may be of benefit in the treatment of measles. METHODS: We conducted a randomized, double-blind trial involving 189 children who were hospitalized at a regional center in South Africa because of measles complicated by pneumonia, diarrhea, or croup. The children (median age, 10 months) were assigned to receive either vitamin A (total dose, 400,000 IU of retinyl palmitate, given orally; n = 92) or placebo (n = 97), beginning within five days of the onset of the rash. At base line, the characteristics of the two groups were similar. RESULTS: Although clinically apparent vitamin A deficiency is rare in this population, the children's serum retinol levels were markedly depressed (mean [+/- SEM], 0.405 +/- 0.021 mumols per liter [11.6 +/- 0.6 micrograms per deciliter]), and 92 percent of them had hyporetinemia (serum retinol level less than 0.7 mumols per liter [20 micrograms per deciliter]). Serum concentrations of retinol-binding protein (mean, 30.1 +/- 2.0 mg per liter) and albumin (mean, 33.4 +/- 0.5 g per liter) were also low. As compared with the placebo group, the children who received vitamin A recovered more rapidly from pneumonia (mean, 6.3 vs. 12.4 days, respectively; P less than 0.001) and diarrhea (mean, 5.6 vs. 8.5 days; P less than 0.001), had less croup (13 vs. 27 cases; P = 0.03), and spent fewer days in the hospital (mean, 10.6 vs. 14.8 days; P = 0.01). Of the 12 children who died, 10 were among those given placebo (P = 0.05). For the group treated with vitamin A, the risk of death or a major complication during the hospital stay was half that of the control group (relative risk, 0.51; 95 percent confidence interval, 0.35 to 0.74). CONCLUSIONS: Treatment with vitamin A reduces morbidity and mortality in measles, and all children with severe measles should be given vitamin A supplements, whether or not they are thought to have a nutritional deficiency.

Routine high-dose vitamin A therapy for children hospitalized with measles.

Measles is without specific therapy and remains important globally as a cause of childhood death. In controlled studies, high-dose vitamin A therapy (Hi-VAT)--with 400,000 IU vitamin A--has been demonstrated to markedly reduce measles-associated morbidity and mortality. We performed a retrospective study of the hospital records of 1720 children < 15 years of age who were hospitalized for measles, to determine the extent to which these findings, in research settings, are applicable to the case management of measles under conditions of routine hospital practice. The outcomes were studied of children hospitalized during two non-consecutive 2 year periods (1985-6 and 1989-90). A policy of Hi-VAT for all children hospitalized with measles was started during the intervening period. As compared with the group of children on standard therapy (n = 1061), children receiving Hi-VAT (n = 651) had a shorter hospital stay (mean 10 versus 13 days; P < 0.001), a lower requirement for intensive care (4.3 versus 10.5 per cent; P < 0.001), and a lower death rate (1.6 versus 5 per cent; P < 0.001). No adverse effects of Hi-VAT therapy were observed. We conclude that a policy of high dose oral vitamin A (400,000 IU) supplementation in measles provides benefits which are equivalent to those previously observed only in controlled research trials, that it is highly cost effective, and that it should form part of the routine case management of all children hospitalized with measles.

Clinical problems in measles case management.

Measles remains one of the leading causes of childhood morbidity and mortality in developing countries. The World Health Organization has identified effective case management as one of the specific strategies to reduce the burden of this disease. The purpose of this article is to review the aetiology, natural history, treatment and outcome of the common clinical problems associated with measles with a view to identifying possible deficiencies in case management. Complications such as pneumonia, diarrhoea, croup and malnutrition have been well defined in terms of their relative contribution to morbidity and mortality. However, there are few published data on the aetiology and natural history of these specific complications. Such data are crucial for rational case management strategies. Data on treatment of measles and its complications are limited and the role of antibiotic prophylaxis and therapy is unclear. The only specific research focus on case management during the last decade has been vitamin A therapy. There is a continuing need for community and hospital-based studies on the natural history of measles and its complications, the aetiology of these complications and intervention strategies that will improve measles case management.

Randomised controlled trial of clinical outcome after chest radiograph in ambulatory acute lower-respiratory infection in children.

BACKGROUND: When available, chest radiographs are used widely in acute lower-respiratory-tract infections in children. Their impact on clinical outcome is unknown. METHODS: 522 children aged 2 to 59 months who met the WHO case definition for pneumonia were randomly allocated to have a chest radiograph or not. The main outcome was time to recovery, measured in a subset of 295 patients contactable by telephone. Subsidiary outcomes included diagnosis, management, and subsequent use of health facilities. FINDINGS: There was a marginal improvement in time to recovery which was not clinically significant. The median time to recovery was 7 days in both groups (95% CI 6-8 days and 6-9 days in the radiograph and control groups respectively, p=0.50, log-rank test) and the hazard ratio for recovery was 1.08 (95% CI 0.85-1.34). This lack of effect was not modified by clinicians' experience and no subgroups were identified in which the chest radiograph had an effect. Pneumonia and upper-respiratory infections were diagnosed more often and bronchiolitis less often in the radiograph group. Antibiotic use was higher in the radiograph group (60.8% vs 52.2%, p=0.05). There was no difference in subsequent use of health facilities. INTERPRETATION: Chest radiograph did not affect clinical outcome in outpatient children with acute lower-respiratory infection. This lack of effect is independent of clinicians' experience. There are no clinically identifiable subgroups of children within the WHO case definition of pneumonia who are likely to benefit from a chest radiograph. We conclude that routine use of chest radiography is not beneficial in ambulatory children aged over 2 months with acute lower-respiratory-tract infection.

PIP: The impact of chest radiographs on the diagnosis, treatment, follow-up, and clinical outcome of children with ambulatory acute lower-respiratory infections was assessed in 518 children 2-59 months old who presented to the Red Cross Hospital in Cape Town, South Africa, with symptoms consistent with the World Health Organization case definition of pneumonia. 257 were randomly assigned to receive a radiograph and 261 were controls (no diagnostic intervention). The median time to recovery, measured in a subset of 295 children whose parents were reachable by telephone, was 7 days for both cases and controls (95% confidence intervals, 6-8 and 6-9 days, respectively). The unadjusted Cox proportional hazards ratio for recovery for the radiograph group compared with controls was 1.08 (95% confidence interval, 0.85-1.34). This rate was unaffected by adjustment for age, weight for age, duration of symptoms before presentation, respiratory rate, clinician's postgraduate pediatric qualifications, and clinician's perception of the need for chest radiograph. More radiograph patients were diagnosed with pneumonia or upper-respiratory infection, while a higher proportion of controls were diagnosed as having bronchiolitis. 149 children in the radiograph group (60.8%) compared with 133 controls (52.2%) received antibiotics. There was no difference in subsequent use of health facilities. These findings indicate that there are no clinically identifiable subgroups of children likely to benefit from routine use of chest radiography.

The costs and benefits of a vaccination programme for Haemophilus influenzae type B disease.

Haemophilus influenzae type b (Hib) infection is a major cause of severe bacterial infection in young children in South Africa and world-wide. These diseases can be prevented by immunisation with conjugate Hib vaccines. In South Africa, unlike some developed countries, Hib vaccines are not part of the routine immunisation schedule. The objective of this study was to measure the expected net benefits from a hypothetical programme of vaccination of the 1992 Cape Town birth cohort (N = 46,537). Costs were calculated by summing the estimated direct medical care costs together with the indirect costs of Hib disease. The latter were calculated by valuing human life using alternative, and conservative human capital and willingness-to-pay measures. The difference between Hib disease costs (i.e. the benefits which would be gained from a successful vaccination programme) and the costs of the vaccination programme itself (HibTITER, Praxis Biologicals) defined the expected net benefits. In the absence of an immunisation programme, the estimated economic costs of Hib disease in the 1992 Cape Town cohort ranged from R10.7 million to R11.8 million. The costs of introducing the vaccine would have amounted to R8.3 million. Had the vaccine been administered to the 1992 birth cohort, benefits would have exceeded costs by between R2.4 million and R3.5 million.

The 1992 measles epidemic in Cape Town--a changing epidemiological pattern.

Over the last 6 years there has been a decline in the incidence of measles in Cape Town. However, during August 1992 an outbreak occurred, with cases reported at many schools in children presumably immunised. The objectives of this study were to characterise the epidemic in Cape Town and to determine possible reasons for the outbreak. The investigation consisted of two components--a description of the epidemic and an investigation of an outbreak at one primary school. Results indicate that during the last 4 months of the year, 757 cases were notified in Cape Town, compared with 144 in the first 8 months. The epidemic affected mainly white and coloured children over 5 years of age (P < 0.001). In contrast, during the period before the epidemic most cases occurred in black children and in those aged less than 1 year (P < 0.001). There was no significant increase in hospitalised cases. Investigation of the outbreak at one school revealed that the attack rate was 7.6% (25/329 children). Immunisation coverage (at least one dose of any measles vaccine) was 91% and vaccine efficacy was estimated to be 79% (95% CI 55-90); it was highest for monovalent measles (100%) and lowest for measles-mumps-rubella (74%). The epidemiology of measles in Cape Town has thus changed as evinced in this epidemic, with an increase in the number of cases occurring in older, previously vaccinated children. The possible reasons for this include both primary and secondary vaccine failure.(ABSTRACT TRUNCATED AT 250 WORDS)

Plasma vitamin A and zinc levels in HIV-infected adults in Cape Town, South Africa.

A cross-sectional study of 132 adults attending an HIV clinic in Cape Town, South Africa, was conducted to determine predictors of low plasma vitamin A and Zn levels. No patients were on antiretroviral therapy. The possible confounding effect of the acute-phase response was controlled by including C-reactive protein levels in multivariate analysis and by excluding active opportunistic infections. Retinol levels were low (<1.05 micromol/l) in 39 % of patients with early disease (WHO clinical stages I and II) compared with 48 and 79 % of patients with WHO stage III and IV respectively (P<0.01). Plasma Zn levels were low (<10.7 micromol/l) in 20 % of patients with early disease v. 36 and 45 % with stage III and IV disease respectively (P<0.05). C-reactive protein levels were normal in 63 % of subjects. Weak, positive associations were found between CD4+ lymphocyte count and plasma levels of retinol (r 0.27; 95 % CI 0.1, 0.43) and Zn (r 0.31; 95 % CI 0.25, 0.46). Multivariate analysis showed the following independent predictors of low retinol levels: WHO stage IV (odds ratio 3.4; 95 % CI 2.1, 5.7) and body weight (odds ratio per 5 kg decrease 1.15; 95 % CI, 1.08, 1.25), while only body weight was significantly associated with low Zn levels (OR per 5 kg decrease 1.19; 95 % CI 1.09, 1.30). CD4+ lymphocyte count <200/microl was not significantly associated with either low retinol or Zn levels. In resource-poor settings, simple clinical features (advanced disease and/or weight loss) are associated with lowered blood concentrations of vitamin A and/or Zn. The clinical significance of low plasma retinol and/or Zn levels is unclear and more research is required to establish the role of multiple micronutrient intervention strategies in HIV disease.

Immunological manifestations of HIV-infected children.

This cross-sectional study of stable HIV-infected children was designed to document the immunological manifestations of paediatric HIV infection and to determine whether inexpensive markers of immunosuppression could be identified. Investigations included lymphocyte count and subset analysis, levels of total protein, albumin, immunoglobulins, beta-2 microglobulin and neopterin. The median age of the 74 children studied was 16.5 months and 76% and 39% had subnormal percentage CD4+ counts and absolute CD4+ counts, respectively. According to the Centers for Disease Control (CDC) guidelines, 85% were moderately or severely immunosuppressed. The majority had elevated neopterin, beta-2 microglobulin, IgG, IgM and IgA concentrations. The IgG concentration correlated positively with total globulin, IgG1 and IgG3 concentrations. On bivariate analysis, the absolute CD4+ count correlated positively with total lymphocyte count (r = 0.28 < 0.48 < 0.64) and negatively with total IgG concentration (r = -0.47 < -0.27 < -0.04), IgG1 concentration (r = -0.51 < -0.31 < -0.08), and neopterin concentration (r = -0.49 < -0.28 < -0.04). There was no correlation between CD4+ count, total globulin or beta-2 microglobulin concentration. On multiple linear regression analysis only the total lymphocyte count correlated with CD4+ count. Furthermore, on bivariate analysis total lymphocyte count correlated positively with absolute CD8+ count (r = 0.82 < 0.88 < 0.92). In conclusion, although there was a positive correlation between absolute CD4+ count and total lymphocyte count, the clinical significance is questionable as the total lymphocyte count correlated more strongly with the absolute CD8+ count.