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The global burden of sepsis is concentrated in sub-Saharan Africa (SSA), where epidemic HIV and unique pathogen diversity challenge the effective management of severe infections. In this context, patient stratification based on biomarkers of a dysregulated host response may identify subgroups more likely to respond to targeted immunomodulatory therapeutics. In a prospective cohort of adults hospitalized with suspected sepsis in Uganda, we applied machine learning methods to develop a prediction model for 30-day mortality that integrates physiology-based risk scores with soluble biomarkers reflective of key domains of sepsis immunopathology. After model evaluation and internal validation, whole-blood RNA sequencing data were analyzed to compare biological pathway enrichment and inferred immune cell profiles between patients assigned differential model-based risks of mortality. Of 260 eligible adults (median age, 32 years; interquartile range, 26–43 years; 59.2% female, 53.9% living with HIV), 62 (23.8%) died by 30 days after hospital discharge. Among 14 biomarkers, soluble tumor necrosis factor receptor 1 (sTNFR1) and angiopoietin 2 (Ang-2) demonstrated the greatest importance for mortality prediction in machine learning models. A clinicomolecular model integrating sTNFR1 and Ang-2 with the Universal Vital Assessment (UVA) risk score optimized 30-day mortality prediction across multiple performance metrics. Patients assigned to the high-risk, UVA-based clinicomolecular subgroup exhibited a transcriptional profile defined by proinflammatory innate immune and necroptotic pathway activation, T-cell exhaustion, and expansion of key immune cell subsets including regulatory and gamma-delta T cells. Clinicomolecular stratification of adults with suspected sepsis in Uganda enhanced 30-day mortality prediction and identified a high-risk subgroup with a therapeutically targetable immunological profile. Further studies are needed to advance pathobiologically informed sepsis management in SSA.

The global burden of sepsis is concentrated in sub-Saharan Africa, where extensive pathogen diversity and limited laboratory capacity challenge targeted antimicrobial management of life-threatening infections. In this context, established and emerging rapid pathogen diagnostics may stratify sepsis patients into subgroups with prognostic and therapeutic relevance. In a prospective cohort of adults (age ≥18 years) hospitalized with suspected sepsis in Uganda, we stratified patients using rapid diagnostics for HIV, tuberculosis (TB), malaria, and influenza, and compared clinical characteristics and 30-day outcomes across these pathogen-driven subgroups. From April 2017 to August 2019, 301 adults were enrolled (median age, 32 years [interquartile range, 26–42 years]; female, n = 178 [59%]). A total of 157 patients (53%) were HIV infected. Sixty-one patients (20%) tested positive for malaria, 52 (17%), for TB (including 49 of 157 [31%] HIV-infected patients), and 17 (6%), for influenza. Co-infection was identified in 33 (11%) patients. The frequency of multi-organ failure, including shock and acute respiratory failure, was greatest among patients with HIV-associated TB. Mortality at 30 days was 19% among patients with malaria, 40% among patients with HIV-associated TB, 32% among HIV-infected patients without microbiological evidence of TB, 6% among patients with influenza, and 11% among patients without a pathogen identified. Despite improvements in anti-retroviral delivery, the burden of sepsis in Uganda remains concentrated among young, HIV-infected adults, with a high incidence of severe HIV-associated TB. In parallel with improvements in acute-care capacity, use of rapid pathogen diagnostics may enhance triage and antimicrobial management during emergency care for sepsis in sub-Saharan Africa, and could be used to enrich study populations when trialing pathogen-specific treatment strategies in the region.

Among a prospective cohort of children and adults admitted to a national COVID-19 treatment unit in Uganda from March to December 2020, we characterized the epidemiology of and risk factors for severe illness. Across two epidemic phases differentiated by varying levels of community transmission, the proportion of patients admitted with WHO-defined severe COVID-19 ranged from 5% (7/146; 95% CI: 2–10) to 33% (41/124; 95% CI: 25–42); 21% (26/124; 95% CI: 14–29%) of patients admitted during the peak phase received oxygen therapy. Severe COVID-19 was associated with older age, male sex, and longer duration of illness before admission. Coinfection with HIV was not associated with illness severity; malaria or tuberculosis coinfection was rare. No patients died during admission. Despite low mortality, hospital incidence of severe COVID-19 during the first epidemic peak in Uganda was substantial. Improvements in vaccine deployment and acute care capacity, including oxygen delivery, are urgently needed to prevent and manage severe COVID-19 in sub-Saharan Africa.

Introduction Drivers of lower vaccine efficacy and impaired vaccine-specific immune responses in low-income versus high-income countries, and in rural compared with urban settings, are not fully elucidated. Repeated exposure to and immunomodulation by parasite infections may be important. We focus on Plasmodium falciparum malaria, aiming to determine whether there are reversible effects of malaria infection on vaccine responses. Methods and analysis We have designed a randomised, double-blind, placebo-controlled, parallel group trial of intermittent preventive malaria treatment versus placebo, to determine effects on vaccine response outcomes among school-going adolescents (9 to 17 years) from malaria-endemic rural areas of Jinja district (Uganda). Vaccines to be studied comprise BCG vaccine on day ‘zero’; yellow fever, oral typhoid and human papilloma virus vaccines at week 4; and tetanus/diphtheria booster vaccine at week 28. Participants in the intermittent preventive malaria treatment arm will receive dihydroartemisinin/piperaquine (DP) dosed by weight, 1 month apart, prior to the first immunisation, followed by monthly treatment thereafter. We expect to enrol 640 adolescents. Primary outcomes are BCG-specific interferon-γ ELISpot responses 8 weeks after BCG immunisation and for other vaccines, antibody responses to key vaccine antigens at 4 weeks after immunisation. In secondary analyses, we will determine effects of monthly DP treatment (versus placebo) on correlates of protective immunity, on vaccine response waning, on whether there are differential effects on priming versus boosting immunisations, and on malaria infection prevalence. We will also conduct exploratory immunology assays among subsets of participants to further characterise effects of the intervention on vaccine responses. Ethics and dissemination Ethics approval has been obtained from relevant Ugandan and UK ethics committees. Results will be shared with Uganda Ministry of Health, relevant district councils, community leaders and study participants. Further dissemination will be done through conference proceedings and publications. Trial registration number Current Controlled Trials identifier: ISRCTN62041885.

There are no reports of severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) and HIV co‐infection from sub‐Saharan Africa where 70% of people living with HIV are found. We report a case of HIV/SARS‐CoV‐2 co‐infection from Uganda. A 34 year old HIV‐positive female on antiretroviral therapy (tenofovir disoproxil fumarate, lamivudine and efavirenz) for 5 years, tested positive for SARS‐CoV‐2, the causative agent for coronavirus disease 19 (COVID‐19). She was asymptomatic at presentation but subsequently developed headache, chest pain, diarrhoea, anorexia and fatigue on day 3 of isolation without cough, fever or shortness of breath. Her CD4 count was 965 cells/mm3, the HIV viral load was undetectable (

Background The foreskin is the main site of HIV acquisition in a heterosexual uncircumcised man, but many men in endemic countries are reluctant to undergo penile circumcision (PC). Observational studies suggest that proinflammatory anaerobic bacteria are enriched on the uncircumcised penis, where they may enhance HIV susceptibility through increased foreskin inflammatory cytokines and the recruitment of HIV-susceptible CD4+ target cells. This trial will examine the impact of systemic and topical antimicrobials on ex vivo foreskin HIV susceptibility. Methods/design This randomized, open-label clinical trial will randomize 125 HIV-negative Ugandan men requesting voluntary PC to one of five arms (n = 25 each). The control group will receive immediate PC, while the four intervention groups will defer PC for 1 month and be provided in the interim with either oral tinidazole, penile topical metronidazole, topical clindamycin, or topical hydrogen peroxide. The impact of these interventions on HIV entry into foreskin-derived CD4+ T cells will be quantified ex vivo at the time of PC using a clade A, R5 tropic HIV pseudovirus assay (primary endpoint); secondary endpoints include the impact of antimicrobials on immune parameters and the microbiota of the participant’s penis and of the vagina of their female partner (if applicable), assessed by multiplex enzyme-linked immunosorbent assay and 16S rRNA sequencing. Discussion There is a critical need to develop acceptable, simple, and effective means of HIV prevention in men unwilling to undergo PC. This trial will provide insight into the causative role of the foreskin microbiota on HIV susceptibility, and the impact of simple microbiota-focused clinical interventions. This may pave the way for future clinical trials using low-cost, nonsurgical intervention(s) to reduce HIV risk in uncircumcised heterosexual men. Trial registration ClinicalTrials.gov, NCT03412071. Retrospectively registered on 26 January 2018. Electronic supplementary material The online version of this article (10.1186/s13063-019-3545-7) contains supplementary material, which is available to authorized users.

Background Helminth infections, common in low‐income countries, may protect against allergy‐related disease. Early exposure may be a key. In the Entebbe Mother and Baby Study, treating helminths during pregnancy resulted in increased eczema rates in early childhood. We followed the cohort to determine whether this translated to increased asthma rates at school age. Methods This randomized, double‐blind, placebo‐controlled trial, conducted in Entebbe, Uganda, had three interventions. During pregnancy, women were randomized, simultaneously, to albendazole vs placebo and to praziquantel vs placebo. Their children were independently randomized to quarterly albendazole vs placebo from age 15 months to 5 years. We here report follow‐up to age 9 years. Primary outcomes at 9 years were recent reported wheeze, skin prick test positivity (SPT) to common allergens and allergen‐specific IgE positivity to dust mite or cockroach. Secondary outcomes were doctor‐diagnosed asthma and eczema rates between 5 and 9 years, recent eczema, rhinitis and urticaria at 9 years, and SPT and IgE responses to individual allergens. Results 2507 pregnant women were enrolled; 1215 children were seen at age nine, of whom 1188 are included in this analysis. Reported wheeze was rare at 9 years (3.7%) while SPT positivity (25.0%) and IgE positivity (44.1%) were common. There was no evidence of a treatment effect for any of the three interventions on any of the primary outcomes. Conclusions Prenatal and early‐life treatment of helminths, in the absence of change in other exposures, is unlikely to increase the risk of atopic diseases later in childhood in this tropical, low‐income setting.

Background The malaria burden in sub-Saharan Africa (SSA) has fallen substantially. Nevertheless, malaria remains a serious health concern, and Uganda ranks third in SSA in total malaria burden. Epidemiological studies of adult malaria in Uganda are scarce and little is known about rates of malaria in non-pregnant adult women. This pilot study assessed malaria prevalence among adult women from Wakiso district, historically a highly malaria endemic region. Methods Adult women using public health services were screened for malaria, HIV and pregnancy. A physician-selected subset of women presenting to the Outpatient Department of Entebbe General Hospital (EGH) with current fever (axillary temperature ≥37.5 °C) or self-reporting fever during the previous 24 h, and a positive thick smear for malaria in the EGH laboratory were enrolled (n = 86). Women who self-identified as pregnant or HIV-positive were excluded from screening. Malaria infection was then assessed using HRP2/pLDH rapid diagnostic tests (RDTs) in all participants. Repeat microscopy and PCR were performed at a research laboratory for a subset of participants. In addition, 104 women without a history of fever were assessed for asymptomatic parasitaemia using RDT, and a subset of these women screened for parasitaemia using microscopy (40 women) and PCR (40 women). Results Of 86 women diagnosed with malaria by EGH, only two (2.3%) had malaria confirmed using RDT, subsequently identified as a Plasmodium falciparum infection by research microscopy and PCR. Subset analysis of hospital diagnosed RDT-negative participants detected one sub-microscopic infection with Plasmodium ovale. Compared to RDT, sensitivity, specificity and PPV of hospital microscopy were 100% (CI 19.8–100), 0% (CI 0–5.32) and 2.33% (CI 0.403–8.94) respectively. Compared to PCR, sensitivity, specificity and PPV of hospital microscopy were 100% (CI 31.0–100), 0% (CI 0–34.5) and 23.1% (CI 6.16–54.0), respectively. No malaria was detected among asymptomatic women using RDT, research microscopy or PCR. Conclusions Malaria prevalence among adult women appears to be low in Wakiso, but is masked by high rates of malaria overdiagnosis. More accurate malaria testing is urgently needed in public hospitals in this region to identify true causes of febrile illness and reduce unnecessary provision of anti-malarial therapy.

BACKGROUND: To investigate the effect of helminth infections and their treatment during pregnancy on HIV load, we conducted a 2 × 2 factorial randomized controlled trial of albendazole versus placebo and praziquantel versus placebo in pregnant women in Entebbe, Uganda. METHODS: Two hundred sixty-four HIV-infected pregnant women from the Entebbe Mother and Baby Study (ISRCTN 32849447) were included in this analysis. Women were tested for helminth infections at enrollment, and mean HIV load was compared between infected and uninfected groups. The effect of anthelmintic treatment on HIV load was evaluated at 6 weeks after treatment and at delivery using linear regression and adjusting for enrollment viral load. RESULTS: Hookworm and Trichuris infections were associated with higher mean viral load at enrollment [adjusted mean difference 0.24 log10 copies/mL, 95% confidence interval (CI): 0.01 to 0.47, P = 0.03, and 0.37 log(10) copies/mL, 95% CI: 0.00 to 0.74, P = 0.05, respectively]. There were no associations between viral load and other helminth species. There was some evidence that albendazole reduced viral load at 6 weeks after treatment (adjusted mean difference -0.17, 95% CI: -0.36 to 0.01, P = 0.07); however, this effect did not differ according to mother's hookworm infection status and had diminished at delivery (adjusted mean difference -0.11, 95% CI: -0.28 to 0.07, P = 0.23). There was no effect of praziquantel treatment on HIV load at any time point. CONCLUSIONS: Infection with some soil-transmitted helminth species is associated with increased HIV load in pregnancy. Treatment with albendazole causes a small decrease in HIV load; however, this may not represent a direct effect of worm removal.

SUMMARYIn 1994 and 2002, respectively, the World Health Organisation proposed that treatment for hookworm and schistosomiasis could be provided during pregnancy. It was hoped that this might have benefits for maternal anaemia, fetal growth and perinatal mortality; a beneficial effect on the infant response to immunisation was also hypothesised. Three trials have now been conducted. Two have examined the effects of benzimidazoles; one (the Entebbe Mother and Baby Study) the effects of albendazole and praziquantel. All three were conducted in settings of high prevalence but low intensity helminth infection. Results suggest that, in such settings and given adequate provision of haematinics, the benefit of routine anthelminthics during pregnancy for maternal anaemia may be small; none of the other expected benefits has yet been demonstrated. The Entebbe Mother and Baby Study found a significant adverse effect of albendazole on the incidence of infantile eczema in the whole study population, and of praziquantel on the incidence of eczema among infants of mothers with Schistosoma mansoni. Further studies are required in settings that differ in helminth species and infection intensities. Further research is required to determine whether increased rates of infantile eczema translate to long-term susceptibility to allergy, and to explore the underlying mechanisms of these effects. The risks and benefits of routine anthelminthic treatment in antenatal clinics may need to be reconsidered.

Background: Allergy is commoner in developed than in developing countries. Chronic worm infections show inverse associations with allergy, and prenatal exposures may be critical to allergy risk. Objective: To determine whether anthelminthic treatment during pregnancy increases the risk of allergy in infancy. Methods: A randomised, double-blind, placebo-controlled trial on treatment in pregnancy with albendazole versus placebo and praziquantel versus placebo was conducted in Uganda, with a 2 · 2 factorial design; 2507 women were enrolled; infants’ allergy events were recorded prospectively. The main outcome was doctor-diagnosed infantile eczema. Results: Worms were detected in 68% of women before treatment. Doctor-diagnosed infantile eczema incidence was 10.4/100 infant years. Maternal albendazole treatment was associated with a significantly increased risk of eczema [Cox HR (95% CI), p: 1.82 (1.26–2.64), 0.002]; this effect was slightly stronger among infants whose mothers had no albendazole-susceptible worms than among infants whose mothers had such worms, although this difference was not statistically significant. Praziquantel showed no effect overall but was associated with increased risk among infants of mothers with Schistosoma mansoni [2.65 (1.16–6.08), interaction p = 0.02]. In a sample of infants, skin prick test reactivity and allergen-specific IgE were both associated with doctor-diagnosed eczema, indicating atopic aetiology. Albendazole was also strongly associated with reported recurrent wheeze [1.58 (1.13–2.22), 0.008]; praziquantel showed no effect. Conclusions: The detrimental effects of treatment suggest that exposure to maternal worm infections in utero may protect against eczema and wheeze in infancy. The results for albendazole are also consistent with a direct drug effect. Further studies are required to investigate mechanisms of these effects, possible benefits of worms or worm products in primary prevention of allergy, and the possibility that routine deworming during pregnancy may promote allergic disease in the offspring.

Summary Background Helminth infections affect the human immune response. We investigated whether prenatal exposure to and treatment of maternal helminth infections affects development of an infant's immune response to immunisations and unrelated infections. Methods In this randomised, double-blind, placebo-controlled trial, we enrolled 2507 women in the second or third trimester of pregnancy who were planning to deliver in Entebbe General Hospital, Entebbe, Uganda. With a computer-generated random number sequence in blocks of 100, we assigned patients to 440 mg albendazole and 40 mg/kg praziquantel (n=628), 440 mg albendazole and a praziquantel-matching placebo (n=625), 40 mg/kg praziquantel and an albendazole-matching placebo (n=626), or an albendazole-matching placebo and praziquantel-matching placebo (n=628). All participants and hospital staff were masked to allocation. Primary outcomes were immune response at age 1 year to BCG, tetanus, and measles immunisation; incidence of infectious diseases during infancy; and vertical HIV transmission. Analysis was by intention-to-treat. This trial is registered, number ISRCTN32849447. Findings Data were available at delivery for 2356 women, with 2345 livebirths; 2115 (90%) of liveborn infants remained in follow-up at 1 year of age. Neither albendazole nor praziquantel treatments affected infant response to BCG, tetanus, or measles immunisation. However, in infants of mothers with hookworm infection, albendazole treatment reduced interleukin-5 (geometric mean ratio 0·50, 95% CI 0·30–0·81, interaction p=0·02) and interleukin-13 (0·52, 0·34–0·82, 0·0005) response to tetanus toxoid. The rate per 100 person-years of malaria was 40·9 (95% CI 38·3–43·7), of diarrhoea was 134·1 (129·2–139·2), and of pneumonia was 22·3 (20·4–24·4). We noted no effect on infectious disease incidence for albendazole treatment (malaria [hazard ratio 0·95, 95% CI 0·79–1.14], diarrhoea [1·06, 0·96–1·16], pneumonia [1·11, 0·90–1·38]) or praziquantel treatment (malaria [1·00, 0·84–1·20], diarrhoea [1·07, 0·98–1·18], pneumonia [1·00, 0·80–1·24]). In HIV-exposed infants, 39 (18%) were infected at 6 weeks; vertical transmission was not associated with albendazole (odds ratio 0·70, 95% CI 0·35–1·42) or praziquantel (0·60, 0·29–1·23) treatment. Interpretation These results do not accord with the recently advocated policy of routine antenatal anthelmintic treatment, and the value of such a policy may need to be reviewed. Funding Wellcome Trust.

Some vaccines show poor efficacy in tropical countries. Within a birth cohort in Uganda, we investigated factors that might influence responses to BCG and tetanus immunisation. Whole blood assay responses to crude culture filtrate proteins of Mycobacterium tuberculosis (cCFP)) and tetanus toxoid (TT) were examined among 1506 and 1433 one-year-olds, respectively. Maternal Mansonella perstans infection was associated with higher interleukin (IL)-10 responses to both immunogens but no reduction in gamma interferon (IFN-γ), IL-5 and IL-13 responses; other maternal helminth infections showed little effect. Tetanus immunisation during pregnancy was associated with higher infant responses to TT; maternal BCG scar (from past immunisation) with lower infant IL-5 and IL-13 responses to cCFP. IFN-γ, IL-5 and IL-13 to TT were reduced in HIV-exposed-uninfected infants; infant malaria and HIV were associated with lower IFN-γ, IL-5 and IL-13 responses to both immunogens. We conclude that maternal helminth infections are unlikely to explain poor vaccine efficacy in the tropics. Effects of maternal immunisation on infant responses to vaccines should be explored. Prevention of infant malaria and HIV could contribute to effectiveness of immunisation programmes.

Helminth infections and malaria are widespread in the tropics. Recent studies suggest helminth infections may increase susceptibility to Plasmodium falciparum infection. If confirmed, this increased susceptibility could be particularly important during pregnancy-induced immunosuppression.To evaluate the geographical distribution of P. falciparum-helminth coinfection and the associations between P. falciparum infection and infection with various parasite species in pregnant women in Entebbe, Uganda.A cross-sectional study was conducted at baseline during a trial of antihelminthic drugs during pregnancy. Helminth and P. falciparum infections were quantified in 2,507 asymptomatic women. Subjects' socioeconomic and demographic characteristics and geographical details were recorded.Hookworm and Mansonella perstans infections were associated with P. falciparum infection, but the effect of hookworm infection was seen only in the absence of M. perstans infection. The odds ratio [OR] for P. falciparum infection, adjusted for age, tribe, socioeconomic status, HIV infection status, and location was as follows: for individuals infected with hookworm but not M. perstans, 1.53 (95% confidence interval [CI], 1.09-2.14); for individuals infected with M. perstans but not hookworm, 2.33 (95% CI, 1.47-3.69); for individuals infected with both hookworm and M. perstans, 1.85 (CI, 1.24-2.76). No association was observed between infection with Schistosoma mansoni, Trichuris, or Strongyloides species and P. falciparum infection.Hookworm-P. falciparum coinfection and M. perstans-P. falciparum coinfection among pregnant women in Entebbe is more common than would be expected by chance. Further studies are needed to elucidate the mechanism of this association. A helminth-induced increase in susceptibility to P. falciparum could have important consequences for pregnancy outcome and responses to P. falciparum infection in infancy.

Background Helminths have profound effects on the immune response, allowing long-term survival of parasites with minimal damage to the host. Some of these effects “spill-over”, altering responses to non-helminth antigens or allergens. It is suggested that this may lead to impaired responses to immunizations and infections, while conferring benefits against inflammatory responses in allergic and autoimmune disease. These effects might develop in utero, through exposure to maternal helminth infections, or through direct exposure in later life. Purpose To determine the effects of helminths and their treatment in pregnancy and in young children on immunological and disease outcomes in childhood. Methods The trial has three randomized, double-blind, placebo-controlled interventions at two times, in two people: a pregnant woman and her child. Pregnant women are randomized to albendazole or placebo and praziquantel or placebo. At age 15 months their children are randomized to three-monthly albendazole or placebo, to continue to age five years. The proposed designation for this sequence of interventions is a 2 × 2(×2) factorial design. Children are immunized with BCG and against polio, Diphtheria, tetanus, Pertussis, Haemophilus, hepatitis B and measles. Primary immunological outcomes are responses to BCG antigens and tetanus toxoid in whole blood cytokine assays and antibody assays at one, three and five years of age. Primary disease outcomes are incidence of malaria, pneumonia, diarrhoea, tuberculosis, measles, vertical HIV transmission, and atopic disease episodes, measured at clinic visits and twice-monthly home visits. Effects on anaemia, growth and intellectual development are also assessed. Conclusion This trial, with a novel design comprising related interventions in pregnant women and their offspring, is the first to examine effects of helminths and their treatment in pregnancy and early childhood on immunological, infectious disease and allergic disease outcomes. The results will enhance understanding of both detrimental and beneficial effects of helminth infection and inform policy.

Bacille Calmette-Guérin (BCG) immunization provides variable protection against tuberculosis. Prenatal antigen exposure may have lifelong effects on responses to related antigens and pathogens. We therefore hypothesized that maternal latent Mycobacterium tuberculosis infection (LTBI) influences infant responses to BCG immunization at birth. We measured antibody (n = 53) and cellular (n = 31) responses to M. tuberculosis purified protein derivative (PPD) in infants of mothers with and without LTBI, in cord blood and at one and six weeks after BCG. The concentrations of PPD-specific antibodies declined between birth (median [interquartile range (IQR)]) 5600 ng ml(-1) [3300-11 050] in cord blood) and six weeks (0.00 ng ml(-1) [0-288]). Frequencies of PPD-specific IFN-γ-expressing CD4(+)T cells increased at one week and declined between one and six weeks (p = 0.031). Frequencies of IL-2- and TNF-α-expressing PPD-specific CD4(+)T cells increased between one and six weeks (p = 0.019, p = 0.009, respectively). At one week, the frequency of PPD-specific CD4(+)T cells expressing any of the three cytokines, combined, was lower among infants of mothers with LTBI, in crude analyses (p = 0.002) and after adjusting for confounders (mean difference, 95% CI -0.041% (-0.082, -0.001)). In conclusion, maternal LTBI was associated with lower infant anti-mycobacterial T-cell responses immediately following BCG immunization. These findings are being explored further in a larger study.

Objectives: To measure the prevalence of reproductive tract infections (RTIs) during pregnancy in Entebbe, Uganda, and to evaluate the current syndromic diagnosis and management approach in effectively targeting infections, such as bacterial vaginosis (BV) and trichomoniasis, that are associated with low birth weight and prematurity among newborns. Methods: We enrolled 250 antenatal clinic attenders. Vaginal swabs and diagnostic tests were performed for BV, Trichomonas vaginalis (TV), candida, Neisseria gonorrhoeae, Chlamydia trachomatis and for HIV-1 and active (TPHA+/RPR+) syphilis infection. Same day treatment was offered for symptoms according to syndromic management guidelines. The treatment actually provided by healthcare workers was documented. Sensitivity, specificity, positive and negative predictive values were used to assess the effectiveness of syndromic management guidelines and practice. Results: The prevalence of infections were: BV 47.7%, TV 17.3%, candida 60.6%, gonorrhoea 4.3%, chlamydia 5.9%, syphilis 1.6%, and HIV 13.1%. In total, 39.7% of women with BV and 30.2% of those with TV were asymptomatic. The sensitivity of syndromic management as applied by health workers in targeting BV and TV was 50.0% and 66.7%, respectively. This would have increased to 60.3% (BV) and 69.8% (TV) had the algorithm been followed exactly. Conclusions: The prevalence of BV and TV seen in this and other African populations is high. High rates of asymptomatic infection and a tendency of healthcare workers to deviate from management guidelines by following their own personal clinical judgment imply that many vaginal infections remain untreated. Alternative strategies, such as presumptive treatment of BV and TV in pregnancy, should be considered.

Background Worms may protect against allergy. Early-life worm exposure may be critical, but this has not been fully investigated. Objectives To investigate whether worms in pregnancy and in early childhood are associated with childhood eczema incidence. Methods The Entebbe Mother and Baby Study, an anthelminthic treatment trial, enrolled pregnant women between 2003 and 2005 in Uganda. Mothers were investigated for worms during pregnancy and children annually. Eczema was doctor-diagnosed from birth to age five years. A planned observational analysis was conducted within the trial cohort to investigate associations between worms and eczema. Results Data for 2345 live-born children were analysed. Hookworm was the most prevalent maternal worm (45%). Childhood worms were less prevalent. Eczema incidence was 4.68/100 person-years. Maternal hookworm was associated with reduced eczema incidence [adjusted hazard ratio (95% confidence interval), p-value: 0.71(0.51–0.99), 0.04] and modified effects of known risk factors for eczema: Dermatophagoides-specific IgE in children was positively associated with eczema incidence if the mother had no hookworm [2.72(1.11–6.63), 0.03], but not if the mother had hookworm [0.41(0.10–1.69), 0.22], interaction p-value = 0.03. Similar interactions were seen for maternal history of eczema {[2.87(1.31–6.27, 0.008) vs. [0.73(0.23–2.30), 0.60], interaction p-value = 0.05}, female gender {[1.82(1.22–2.73), 0.004 vs. [0.96(0.60–1.53), 0.87], interaction p-value = 0.04} and allergen-specific IgE. ChildhoodTrichuris trichiura and hookworm were inversely associated with eczema. Conclusions Maternal hookworm modifies effects of known risk factors for eczema. Mechanisms by which early-life worm exposures influence allergy need investigation. Worms or worm products, and intervention during pregnancy have potential for primary prevention of allergy.

Summary objective To describe uptake of HIV and syphilis testing in a prevention of mother-to-child HIV transmission programme in Uganda. methods Analysis of data from routine HIV and syphilis testing at Entebbe Hospital antenatal services. results A total of 20 738 women attended antenatal services. Exactly 62.8% of women, but only 1.8% of their male partners, accepted testing for HIV; 82.2% of women, but only 1.1% of their male partners accepted syphilis testing. Partners of women with positive HIV results were more likely to come for subsequent testing. Of 200 couples whose partners accepted HIV-testing within 30 days of one another, 19 (9.5%) were HIV-discordant, representing 65.5% of couples with at least one partner HIVpositive. HIV prevalence was 12.6% for women and 10.8% for men; syphilis prevalence was 4.0% for women and 6.2% for men. conclusion Uptake of HIV and syphilis testing was fairly good among pregnant women attending antenatal clinics at Entebbe Hospital, but very low among their male partners. The level of HIVdiscordant couples was high. These clinics should be made more couples-friendly to identify both HIVpositive men for treatment and discordant couples for HIV prevention.

Background Allergy is commoner in developed than in developing countries. Chronic worm infections show inverse associations with allergy, and prenatal exposures may be critical to allergy risk. Objective To determine whether anthelminthic treatment during pregnancy increases the risk of allergy in infancy. Methods A randomised, double-blind, placebo-controlled trial on treatment in pregnancy with albendazole versus placebo and praziquantel versus placebo was conducted in Uganda, with a 2 × 2 factorial design; 2507 women were enrolled; infants’ allergy events were recorded prospectively. The main outcome was doctor-diagnosed infantile eczema. Results Worms were detected in 68% of women before treatment. Doctor-diagnosed infantile eczema incidence was 10.4/100 infant years. Maternal albendazole treatment was associated with a significantly increased risk of eczema [Cox HR (95% CI), p: 1.82 (1.26–2.64), 0.002]; this effect was slightly stronger among infants whose mothers had no albendazole-susceptible worms than among infants whose mothers had such worms, although this difference was not statistically significant. Praziquantel showed no effect overall but was associated with increased risk among infants of mothers with Schistosoma mansoni [2.65 (1.16–6.08), interaction p = 0.02]. In a sample of infants, skin prick test reactivity and allergen-specific IgE were both associated with doctor-diagnosed eczema, indicating atopic aetiology. Albendazole was also strongly associated with reported recurrent wheeze [1.58 (1.13–2.22), 0.008]; praziquantel showed no effect. Conclusions The detrimental effects of treatment suggest that exposure to maternal worm infections in utero may protect against eczema and wheeze in infancy. The results for albendazole are also consistent with a direct drug effect. Further studies are required to investigate mechanisms of these effects, possible benefits of worms or worm products in primary prevention of allergy, and the possibility that routine deworming during pregnancy may promote allergic disease in the offspring.

Although infections with multiple human papillomavirus (HPV) types have been reported widely, more information is needed on the occurrence of the different types. We determined the distribution of seroprevalences to multiple HPV types in Finland and Uganda to compare the epidemiology of the different HPV types in the 2 populations. Serum samples were obtained from 2784 Finnish and 1964 Ugandan women (mean ages 22 y and 25 y, respectively) of whom 44% and 57%, respectively, had antibodies to at least 1 of the 7 HPV types (6, 11, 16, 18, 31, 33, 45) tested (p < 0.001). Multiple HPV antibody positivity was common. HPV45-seropositive Finns had a higher risk of having antibodies to other high-risk HPV types: HPV18 (odds ratio (OR) = 10.9), HPV31 (OR 6.1), HPV33 (OR 12.2), than their Ugandan counterparts: HPV18 (OR 3.4), HPV31 (OR 2.2), HPV33 (OR 3.3). Increased estimates for being double antibody-positive were also noted among HPV18- and HPV16-seropositive women, but there were no major differences between HPV16-seropositive Finns and Ugandans. In addition to biological and behavioural factors, iatrogenic and societal factors (screening vs no screening) may also result in the different occurrence of infections with the high-risk HPV types in Finland and Uganda.

Two billion people are estimated to be infected with schistosomes and geohelminths, and mass deworming programs are widely advocated [1]. Previously, de-worming has been avoided during pregnancy and lactation because of safety concerns; however, in areas where women are pregnant or lactating for over half of their reproductive lives, this may result in treatment delays and morbidity [2]. Moreover, detrimental effects of helminths on maternal anemia, fetal growth, and infant mortality have been suggested [2-4]. Therefore, in 1994, the World Health Organization recommended the treatment of hookworm during pregnancy in [2] areas where hookworm is endemic, and in 2002, it recommended the use of praziquantel during pregnancy in areas where schistosomiasis is endemic, in addition to evaluation of birth outcomes [5]. Recommendations of benzimidazoles during pregnancy are supported by a small number of studies [6], and the results reported are inconclusive. A benefit of albendazole for maternal anemia in a small study in Sierra Leone where albendazole and iron-folate supplementation were examined in a factorial design [7] was not confirmed by a larger trial of mebendazole in Peru, in which all women received iron supplements [8]. Observational studies of mebendazole during pregnancy in Sri Lanka [9] and albendazole in Nepal [3] suggested a benefit for birth weight and for infant survival, but the Peru trial showed no effect of mebendazole on these outcomes, except for the rare outcome of very low birth weight [8]. There is even less data for praziquantel and, in 2005, a World Health Organization working group called for placebo-controlled trials of praziquantel during pregnancy [10]. Therefore, in a large placebo-controlled trial of albendazole and praziquantel during pregnancy in Uganda (ISRCTN32849447; designed to address effects on immune responses and disease susceptibility in offspring [11]), we examined important additional outcomes: maternal anemia, birth weight, perinatal death, and congenital anomalies.

Summary The objectives of this study were to estimate the prevalence of atopic sensitization, and to identify common aeroallergens associated with atopic sensitization among women in Entebbe, Uganda, and to determine risk factors for atopic sensitization among those with and without a history of asthma or eczema. A case–control study was conducted within a trial of deworming in pregnancy, approximately 2 years after the intervention. Skin prick test reactivity was assessed among 20 women with a history of asthma, 25 with history of eczema and 95 controls. Overall prevalence of reactivity was estimated by adjusting for the prevalence of asthma in the whole cohort. Overall skin prick test prevalence was: any allergen 30.7%, Blomia tropicalis 10.9%, Dermatophagoides mix 16.8%, cockroach 15.8%. The prevalence of a positive skin prick test was significantly associated with a history of asthma (70% to any allergen vs. 32%, P = 0.002) but not with a history of eczema (44% vs. 36%, P = 0.49). Women with Mansonella perstans had significantly reduced odds for atopic sensitization (adjusted odds ratio 0.14, 95% CI 0.03–0.69); women with a history of asthma were less likely to have hookworm (adjusted odds ratio 0.24, 95% CI 0.07–0.81) but this association was weaker for women with a history of eczema. [Clinical Trial No. ISRCTN32849447]

BackgroundMaternal schistosomiasis and filariasis have been shown to influence infant responses to neonatal bacille Calmette-Guérin (BCG) immunisation but the effects of maternal hookworm, and of de-worming in pregnancy, are unknown.MethodsIn Entebbe, Uganda, we conducted a randomised, double-blind, placebo-controlled trial of a single dose of 400 mg of albendazole in the second trimester of pregnancy. Neonates received BCG. Interferon-gamma (IFN-γ) and interleukin (IL)-5 responses to a mycobacterial antigen (crude culture filtrate proteins (CFP) ofMycobacterium tuberculosis) were measured in a whole blood assay. We analysed results for binary variables using χ2tests and logistic regression. We analysed continuous variables using Wilcoxon's tests.ResultsMaternal hookworm was associated with reduced maternal IFN-γ responses to CFP (adjusted odds ratio for IFN-γ > median response: 0.14 (95% confidence interval 0.02–0.83, p = 0.021). Conversely, maternal hookworm was associated with subsequent increased IFN-γ responses in their one-year-old infants (adjusted OR 17.65 (1.20–258.66; p = 0.013)). Maternal albendazole tended to reduce these effects.ConclusionUntreated hookworm infection in pregnancy was associated with reduced maternal IFN-γ responses to mycobacterial antigens, but increased responses in their infants one year after BCG immunisation. The mechanisms of these effects, and their implications for protective immunity remain, to be determined.

1 London School of Hygiene and Tropical Medicine, London, UK 2 Uganda Virus Research Institute, Entebbe, Uganda 3 Department for International Development, Kampala, Uganda 4 The AIDS Support Organisation, Kampala, Uganda 5 Wakiso District Council, Entebbe, Uganda 6 HIV Division, World Health Organisation, Geneva, Switzerland 7 Centre for Sexual Health & HIV Research, University College London, London, UK

Background Low avidity of antibodies against viral, bacterial and parasitic agents has been used for differential diagnosis of acute versus recent/past infections. The low-avidity antibodies may however, persist for a longer period in some individuals. Findings We studied the association of human papillomavirus (HPV) type 16 antibody avidity with seroprevalence to HPV types 6/11/18/31/33/45. Antibody avidity was analysed for 365 HPV16 seropositive pregnant Finnish and Ugandan women using a modified ELISA. Low avidity of HPV16 antibodies was found in 15% of Finnish and 26% of Ugandan women. Ugandan women with low-avidity HPV16 antibodies had an increased risk estimate for HPV6/11 (odds ratio, OR 2.9; 95%CI 1.01-8.4) seropositivity but not to high-risk HPV types 18/31/33/45. Conclusion Association of the low avidity HPV16 antibody "phenotype" with possible susceptibility to infections with other HPV types warrants investigation.

Background Disparities in perinatal health care occur worldwide. If the UN Millennium Development Goals in maternal and child health are to be met, this needs to be addressed. This study was conducted to facilitate our understanding of the changing use of maternity care services in a semi-urban community in Entebbe Uganda and to examine the range of antenatal and delivery services received in health care facilities and at home. Methods We conducted a retrospective community survey among women using structured questionnaires to describe the use of antenatal services and delivery care. Results In total 413 women reported on their most recent pregnancy. Antenatal care attendance was high with 96% attending once, and 69% the recommended four times. Blood pressure monitoring (95%) and tetanus vaccination (91%) were the services most frequently reported and HIV testing (47%), haematinics (58%) and presumptive treatment for malaria (66%) least frequently. Hospital clinics significantly outperformed public clinics in the quality of antenatal service. A significant improvement in the reported quality of antenatal services received was observed by year (p < 0.001). Improvement in the range and consistency of services at Entebbe Hospital over time was associated with an increase in the numbers who sought care there (p = 0.038). Although 63% delivered their newborn at a local hospital, 11% still delivered at home with no skilled assistance and just under half of these women reported financial/transportation difficulties as the primary reason. Less educated, poorer mothers were more likely to have unskilled/no assistance. Simple newborn care practices were commonly neglected. Only 35% of newborns were breastfed within the first hour and delayed wrapping of newborn infants occurred after 27% of deliveries. Conclusion Although antenatal services were well utilised, the quality of services varied. Women were able and willing to travel to a facility providing a good service. Access to essential skilled birth attendants remains difficult especially for less educated, poorer women, commonly mediated by financial and transport difficulties and several simple post delivery practices were commonly neglected. These factors need to be addressed to ensure that high quality care reaches the most vulnerable women and infants.