Determinants of Kaposi's sarcoma-associated herpesvirus seropositivity, viral DNA detection and cellular immune responses in Uganda

Kaposi's Sarcoma-associated Herpesvirus (KSHV), is a necessary cause of Kaposi's sarcoma (KS), the risk of which increases among people with immune suppression, such as that caused by infection with HIV. KS incidence varies, being highest in places with a high prevalence of KSHV. Controlling KSHV transmission is key in reducing KS incidence. Documented KSHV prevalence is reported to be higher in rural Uganda than has been found elsewhere. This PhD research focused on investigating environmental and immunological factors associated with KSHV antibody responses and viral detection/shedding in blood and in saliva as well as KSHV specific cell-mediated immune responses in Uganda. ELISA and Luminex were used for antibody measurements, real-time PCR for viral detection and quantification and an ELISPOT assay for cell-mediated IFN-γ response measurement. Infections such as malaria and helminths were the main environmental risk factors analysed. The factors associated with higher KSHV antibody responses included early age of infection, malaria parasitaemia, low haemoglobin levels and Schistosoma mansoni infection. Malaria infection was also associated with higher levels of KSHV DNA in blood while male sex was associated with increased viral shedding in saliva. Children had the highest proportion of individuals with detectable KSHV DNA in blood and in saliva. In relation to IFN- production, individuals responded to a wide variety of KSHV peptides without any immune dominance. In conclusion, KSHV transmission in endemic areas occurs mainly in childhood; this may play a role in the failure to control the virus, leading to increased viral shedding and increased viral transmission. Parasite infections such as malaria and worms may play a significant role in rendering children susceptible to KSHV infection as well as in enhancing reactivation of the virus, increasing lytic replication and, thereby increasing transmission and 3 pathogenesis.The cell-mediated immune response to KSHV is complex due to the lack of immunodominance

Metastatic Breast Cancer and Hormonal Receptor Status among a Group of Women in Sub Saharan Africa

Background: Breast cancer is the third commonest cancer in women in Uganda. The majority of breast cancer patients in Uganda present with advanced disease. Many studies show that metastatic lesions frequently lodge in bones, lung and liver. Tumour hormone receptor status correlates with site of metastatic lesions and survival among breast cancer patients.Objective: To determine the sites of metastatic breast lesions and how they relate to the hormonal receptor status.Methods: In this cross sectional descriptive study, 71 women with histologically confirmed incident breast cancer with metastases were analysed, their hormonal receptor status was determined. All patients underwent a chest X-ray, an abdominopelvic ultrasound scan and a bone scan. The χ² and t tests were used to compare variables for statistical differences.Results: The mean age of participants was 45 years. Most metastases were to bone 56% (40/71), of these 45% (32/71 ) tumours were exclusive to bone and 94% of these (30/32) were ER+ . Of the 13 (18% of all patients) who had metastases to the liver, 7 were exclusive to the liver, and 1 (14.%) was ER positive. Of the 30 (42 %) patients with lung metastases, 23 patients were exclusive to lungs and 9/30 (39%) were ER+. In all 68% (48/71) were ER+, and bone metastases were associated with ER positivity and low grade tumors.Conclusion: Breast metastases had a preponderance to bone in this largely premenopausal group of women and these tumors were mostly ER positive. In the absence of tests to determine ER status, empirical antihormonal therapy may be used.Key words: Metastatic Breast Cancer, Hormonal Receptor Statu

Is sexual risk taking behaviour changing in rural south-west Uganda? Behaviour trends in a rural population cohort 1993–2006

OBJECTIVE: To describe sexual behaviour trends in a rural Ugandan cohort in the context of an evolving HIV epidemic, 1993-2006. METHODS: Sexual behaviour data were collected annually from a population cohort in which HIV serological surveys were also conducted. Behaviour trends were determined using survival analysis and logistic regression. Trends are reported based on the years in which the respective indicators were collected. RESULTS: Between 1993 and 2006, median age at first sex increased from 16.7 years to 18.2 years among 17-20-year-old girls and from 18.5 years to 19.9 years among boys. Both sexes reported a dip in age at sexual debut between 1998 and 2001. One or more casual partners in the past 12 months among men rose from 11.6% in 1997 to 12.7% in 2004 and then declined to 10.2% in 2006. Among women it increased from 1.4% in 1997 to 3.7% in 2004 and then reduced to 1.4% in 2006. The rise in casual partners between 1997 and 2004 was driven mainly by older age groups. Trends in condom use with casual partners varied by age, increasing among those aged 35+ years, declining in the middle age groups and presenting a dip and then a rise in the youngest aged group (13-19 years). CONCLUSION: Among youth, risky behaviour declined but increased in the late 1990s/early 2000s. Among those aged 35+ years, condom use rose but casual partners also rose. Several indicators portrayed a temporary increase in risk taking behaviour from 1998 to 2002

The effect of current Schistosoma mansoni infection on the immunogenicity of a candidate TB vaccine, MVA85A, in BCG-vaccinated adolescents: An open-label trial.

INTRODUCTION: Helminth infection may affect vaccine immunogenicity and efficacy. Adolescents, a target population for tuberculosis booster vaccines, often have a high helminth burden. We investigated effects of Schistosoma mansoni (Sm) on the immunogenicity and safety of MVA85A, a model candidate tuberculosis vaccine, in BCG-vaccinated Ugandan adolescents. METHODS: In this phase II open label trial we enrolled 36 healthy, previously BCG-vaccinated adolescents, 18 with no helminth infection detected, 18 with Sm only. The primary outcome was immunogenicity measured by Ag85A-specific interferon gamma ELISpot assay. Tuberculosis and schistosome-specific responses were also assessed by whole-blood stimulation and multiplex cytokine assay, and by antibody ELISAs. RESULTS: Ag85A-specific cellular responses increased significantly following immunisation but with no differences between the two groups. Sm infection was associated with higher pre-immunisation Ag85A-specific IgG4 but with no change in antibody levels following immunisation. There were no serious adverse events. Most reactogenicity events were of mild or moderate severity and resolved quickly. CONCLUSIONS: The significant Ag85A-specific T cell responses and lack of difference between Sm-infected and uninfected participants is encouraging for tuberculosis vaccine development. The implications of pre-existing Ag85A-specific IgG4 antibodies for protective immunity against tuberculosis among those infected with Sm are not known. MVA85A was safe in this population. TRIAL REGISTRATION: ClinicalTrials.gov NCT02178748

Monitoring changes in malaria epidemiology and effectiveness of interventions in Ethiopia and Uganda: Beyond Garki Project baseline survey.

Published onlineJournal ArticleResearch Support, Non-U.S. Gov'tBACKGROUND: Scale-up of malaria interventions seems to have contributed to a decline in the disease but other factors may also have had some role. Understanding changes in transmission and determinant factors will help to adapt control strategies accordingly. METHODS: Four sites in Ethiopia and Uganda were set up to monitor epidemiological changes and effectiveness of interventions over time. Here, results of a survey during the peak transmission season of 2012 are reported, which will be used as baseline for subsequent surveys and may support adaptation of control strategies. Data on malariometric and entomological variables, socio-economic status (SES) and control coverage were collected. RESULTS: Malaria prevalence varied from 1.4 % in Guba (Ethiopia) to 9.9 % in Butemba (Uganda). The most dominant species was Plasmodium vivax in Ethiopia and Plasmodium falciparum in Uganda. The majority of human-vector contact occurred indoors in Uganda, ranging from 83 % (Anopheles funestus sensu lato) to 93 % (Anopheles gambiae s.l.), which is an important factor for the effectiveness of insecticide-treated nets (ITNs) or indoor residual spraying (IRS). High kdr-L1014S (resistance genotype) frequency was observed in A. gambiae sensu stricto in Uganda. Too few mosquitoes were collected in Ethiopia, so it was not possible to assess vector habits and insecticide resistance levels. ITN ownership did not vary by SES and 56-98 % and 68-78 % of households owned at least one ITN in Ethiopia and Uganda, respectively. In Uganda, 7 % of nets were purchased by households, but the nets were untreated. In three of the four sites, 69-76 % of people with access to ITNs used them. IRS coverage ranged from 84 to 96 % in the three sprayed sites. Half of febrile children in Uganda and three-quarters in Ethiopia for whom treatment was sought received diagnostic tests. High levels of child undernutrition were detected in both countries carrying important implications on child development. In Uganda, 7-8 % of pregnant women took the recommended minimum three doses of intermittent preventive treatment. CONCLUSION: Malaria epidemiology seems to be changing compared to earlier published data, and it is essential to have more data to understand how much of the changes are attributable to interventions and other factors. Regular monitoring will help to better interpret changes, identify determinants, modify strategies and improve targeting to address transmission heterogeneity.UK aid (PPA

Infection-exposure in infancy is associated with reduced allergy-related disease in later childhood in a Ugandan cohort.

Background: Lack of early infection-exposure has been associated with increased allergy-related disease (ARD) susceptibility. In tropical Africa, little is known about which infections contribute to development of ARDs, and at which time. Methods: We used latent class analysis to characterise the early infection-exposure of participants in a Ugandan birth cohort and assessed ARDs in later childhood. Results: Of 2345 live births, 2115 children (90%) had data on infections within the first year of life while 1179 (50%) had outcome data at 9 years. We identified two latent classes of children based on first-year infection-exposure. Class 1 (32% membership), characterised by higher probabilities for malaria (80%), diarrhoea (76%), and lower respiratory tract infections (LRTI) (22%), was associated with lower prevalence of wheeze, eczema, rhinitis, and Dermatophagoides skin prick test (SPT) positivity at 9 years. Based on 5-year cumulative infection experience, class 1 (31% membership), characterised by higher probabilities for helminths (92%), malaria (79%), and LRTI (45%), was associated with lower probabilities of SPT positivity at 9 years. Conclusions: In this Ugandan birth cohort, early childhood infection-exposure, notably to malaria, helminths, LRTI, and diarrhoea, is associated with lower prevalence of atopy and ARDs in later childhood. Funding: This work was supported by several funding sources. The Entebbe Mother and Baby Study (EMaBS) was supported by the Wellcome Trust, UK, senior fellowships for AME (grant numbers 064693, 079110, 95778) with additional support from the UK Medical Research Council. LL is supported by a PhD fellowship through the DELTAS Africa Initiative SSACAB (grant number 107754). ELW received funding from MRC Grant Reference MR/K012126/1. SAL was supported by the PANDORA-ID-NET Consortium (EDCTP Reg/Grant RIA2016E-1609). HM was supported by the Wellcome's Institutional Strategic Support Fund (grant number 204928/Z/16/Z)

Cross-sectional study of IgG antibody levels to invasive nontyphoidal Salmonella LPS O-antigen with age in Uganda.

Invasive nontyphoidal Salmonella (iNTS) disease is a major cause of deaths among children and HIV-infected individuals in sub-Saharan Africa. Acquisition of IgG to iNTS lipopolysaccharide (LPS) O-antigen in Malawi in early childhood corresponds with a fall in cases of iNTS disease suggesting that vaccines able to induce such antibodies could confer protection. To better understand the acquisition of IgG to iNTS in other African settings, we performed a cross-sectional seroepidemiological study using sera from 1090 Ugandan individuals aged from infancy to old age. Sera were analysed for IgG to LPS O-antigen of S. Typhimurium and S. Enteritidis using an in-house ELISA. Below 18 months of age, most children lacked IgG to both serovars. Thereafter, specific IgG levels increased with age, peaking in adulthood, and did not wane noticeably in old age. There was no clear difference in antibody levels between the sexes and the few HIV-infected individuals in the study did not have obviously different levels from uninfected subjects. While IgG to iNTS is acquired at a younger age in Malawian compared with Ugandan children, it is not clear whether this is due to differences in the populations themselves, their exposure to iNTS, or variations between assays used. In conclusion, there is a need to develop a harmonised method and standards for measuring antibodies to iNTS across studies and to investigate acquisition of such antibodies with age across different sites in sub-Saharan Africa

Elevated serum IL-10 is associated with severity of neonatal encephalopathy and adverse early childhood outcomes

BACKGROUND: Neonatal encephalopathy (NE) contributes substantially to child mortality and disability globally. We compared cytokine profiles in term Ugandan neonates with and without NE, with and without perinatal infection or inflammation and identified biomarkers predicting neonatal and early childhood outcomes. METHODS: In this exploratory biomarker study, serum IL-1α, IL-6, IL-8, IL-10, TNFα, and VEGF (<12 h) were compared between NE and non-NE infants with and without perinatal infection/inflammation. Neonatal (severity of NE, mortality) and early childhood (death or neurodevelopmental impairment to 2.5 years) outcomes were assessed. Predictors of outcomes were explored with multivariable linear and logistic regression and receiver-operating characteristic analyses. RESULTS: Cytokine assays on 159 NE and 157 non-NE infants were performed; data on early childhood outcomes were available for 150 and 129, respectively. NE infants had higher IL-10 (p < 0.001), higher IL-6 (p < 0.017), and lower VEGF (p < 0.001) levels. Moderate and severe NE was associated with higher IL-10 levels compared to non-NE infants (p < 0.001). Elevated IL-1α was associated with perinatal infection/inflammation (p = 0.013). Among NE infants, IL-10 predicted neonatal mortality (p = 0.01) and adverse early childhood outcome (adjusted OR 2.28, 95% CI 1.35-3.86, p = 0.002). CONCLUSIONS: Our findings support a potential role for IL-10 as a biomarker for adverse outcomes after neonatal encephalopathy. IMPACT: Neonatal encephalopathy is a common cause of child death and disability globally. Inflammatory cytokines are potential biomarkers of encephalopathy severity and outcome. In this Ugandan health facility-based cohort, neonatal encephalopathy was associated with elevated serum IL-10 and IL-6, and reduced VEGF at birth. Elevated serum IL-10 within 12 h after birth predicted severity of neonatal encephalopathy, neonatal mortality, and adverse early childhood developmental outcomes, independent of perinatal infection or inflammation, and provides evidence to the contribution of the inflammatory processes. Our findings support a role for IL-10 as a biomarker for adverse outcomes after neonatal encephalopathy in a sub-Saharan African cohort