Ward Round - Recurrent anemia and infection in an HIVpositive woman

A 22 year old woman presented to Queen Elizabeth Central Hospital with a three days history of fever, headache and vomiting, with progressive difficulty in swallowin

Early Interferon-γ Production in Human Lymphocyte Subsets in Response to Nontyphoidal Salmonella Demonstrates Inherent Capacity in Innate Cells

Background Nontyphoidal Salmonellae frequently cause life-threatening bacteremia in sub-Saharan Africa. Young children and HIV-infected adults are particularly susceptible. High case-fatality rates and increasing antibiotic resistance require new approaches to the management of this disease. Impaired cellular immunity caused by defects in the T helper 1 pathway lead to intracellular disease with Salmonella that can be countered by IFNγ administration. This report identifies the lymphocyte subsets that produce IFNγ early in Salmonella infection. Methodology Intracellular cytokine staining was used to identify IFNγ production in blood lymphocyte subsets of ten healthy adults with antibodies to Salmonella (as evidence of immunity to Salmonella), in response to stimulation with live and heat-killed preparations of the D23580 invasive African isolate of Salmonella Typhimurium. The absolute number of IFNγ-producing cells in innate, innate-like and adaptive lymphocyte subpopulations was determined. Principal Findings Early IFNγ production was found in the innate/innate-like lymphocyte subsets: γδ-T cells, NK cells and NK-like T cells. Significantly higher percentages of such cells produced IFNγ compared to adaptive αβ-T cells (Student's t test, P<0.001 and ≤0.02 for each innate subset compared, respectively, with CD4+- and CD8+-T cells). The absolute numbers of IFNγ-producing cells showed similar differences. The proportion of IFNγ-producing γδ-T cells, but not other lymphocytes, was significantly higher when stimulated with live compared with heat-killed bacteria (P<0.0001). Conclusion/Significance Our findings indicate an inherent capacity of innate/innate-like lymphocyte subsets to produce IFNγ early in the response to Salmonella infection. This may serve to control intracellular infection and reduce the threat of extracellular spread of disease with bacteremia which becomes life-threatening in the absence of protective antibody. These innate cells may also help mitigate against the effect on IFNγ production of depletion of Salmonella-specific CD4+-T lymphocytes in HIV infection

Correspondence: Strengthening capacity, collaboration and quality of clinical research in Africa: EDCTP Networks of Excellence

Developing countries bear 90% of the global disease burden, but only access about 10% of globally available health research funding. Weak south–south networking hampers effective use of limited resources,production of critical mass of quality scientists, career opportunities and incentives to retain the few available scientists. The south must urgently act strategically to accelerate generation of talented scientists, createenabling environment and incentives to retain scientists and attract back those in diaspora. The creation of strong networks of excellence for clinical research among southern academic and research institutions is a novelstrategic approach championed by European and Developing Countries Clinical Trials Partnership to achieve the aforementioned goals and mitigate the high disease burden. It will promote strong collaboration, resource sharing and cross-mentorship allowing each partner to grow with complementary capacities that support each other rather than compete negatively. It will enable the south and Africa in particular to participate actively and own the means for solving its own health problems and raise the professional quality and capacity of southern institutions to forge better and equal partnership with northern institutions

Case Report-Right iliac fossa mass in an HIV-positive woman

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Loss of Humoral and Cellular Immunity to Invasive Nontyphoidal Salmonella During Current or Convalescent Plasmodium falciparum Infection in Malawian Children.

Invasive nontyphoidal Salmonella (iNTS) infections are commonly associated with Plasmodium falciparum infections, but the immunologic basis for this linkage is poorly understood. We hypothesized that P. falciparum infection compromises the hosts' humoral and cellular immunity to NTS which increases their susceptibility to iNTS infection. We prospectively recruited children aged between 6 and 60 months at a Community Health Centre in Blantyre, Malawi and allocated them to the following groups; febrile with uncomplicated malaria, febrile malaria-negative, non-febrile malaria-negative. S Typhimurium (STm)-specific; serum bactericidal activity (SBA) and blood bactericidal activity (WBBA), complement C3 deposition and neutrophil respiratory burst activity (NRBA) were measured. SBA to STm was reduced in febrile P. falciparum infected (Median -0.201og10, IQR [-1.85, 0.32]) compared to non-febrile malaria-negative (Median -1.42log10, IQR [-2.0, -0.47], p=0.052). In relation to SBA, C3 deposition on STm was significantly reduced in febrile P. falciparum infected (Median 7.5%, IQR [4.1, 15.0]) compared to non-febrile malaria-negative (Median 29%, IQR [11.8, 48.0], p=0.048). WBBA to STm was significantly reduced in febrile P. falciparum infected (Median 0.25log10, IQR [-0.73, 1.13], p=0.0001) compared to non-febrile malaria-negative (Median -1.0log10, IQR [-1.68, -0.16]). In relation to WBBA, STm-specific NRBA was reduced in febrile P. falciparum infected (Median 8.8% IQR [3.7, 20], p=0.0001) compared to non-febrile malaria-negative (Median 40.5% IQR [33, 65.8]). P. falciparum infection impairs humoral and cellular immunity to STm in children during malaria episodes, which may explain the increased risk of iNTS observed in children from malaria endemic settings. The mechanisms underlying humoral immunity impairment are incompletely understood and should be explored further

Sequential Acquisition of T Cells and Antibodies to Nontyphoidal Salmonella in Malawian Children

Background Salmonella Typhimurium (STm) remain a prominent cause of bacteremia in sub-Saharan Africa. Complement-fixing antibodies to STm develop by 2 years of age. We hypothesized that STm-specific CD4+ T cells develop alongside this process. Methods Eighty healthy Malawian children aged 0–60 months were recruited. STm-specific CD4+ T cells producing interferon γ, tumor necrosis factor α, and interleukin 2 were quantified using intracellular cytokine staining. Antibodies to STm were measured by serum bactericidal activity (SBA) assay, and anti-STm immunoglobulin G antibodies by enzyme-linked immunosorbent assay. Results Between 2006 and 2011, STm bacteremias were detected in 449 children <5 years old. STm-specific CD4+ T cells were acquired in infancy, peaked at 14 months, and then declined. STm-specific SBA was detectable in newborns, declined in the first 8 months, and then increased to a peak at age 35 months. Acquisition of SBA correlated with acquisition of anti–STm–lipopolysaccharide (LPS) immunoglobulin G (r = 0.329 [95% confidence interval, .552–.062]; P = .01) but not anti–STm–outer membrane protein or anti–STm-flagellar protein (FliC). Conclusions Acquisition of STm-specific CD4+ T cells in early childhood is consistent with early exposure to STm or cross-reactive protein antigens priming this T-cell development. STm-specific CD4+ T cells seem insufficient to protect against invasive nontyphoidal Salmonella disease, but sequential acquisition of SBA to STm LPS is associated with a decline in its incidence

Caregiver perceptions and experiences of paediatric emergency department attendance during the COVID-19 pandemic: a mixed-methods study

BACKGROUND: During the early stages of the COVID-19 pandemic, concerns were raised about reduced attendance at hospitals, particularly in paediatric emergency departments, which could result in preventable poorer outcomes and late presentations among children requiring emergency care. We aimed to investigate the impact of COVID-19 on health-seeking behaviour and decision-making processes of caregivers presenting to paediatric emergency services at a National Health Service (NHS) Trust in London. MATERIALS AND METHODS: We conducted a mixed-methods study (survey and semi-structured interviews) across two hospital sites between November-December 2020. Data from each study were collected concurrently followed by data comparison. RESULTS: Overall, 100 caregivers participated in our study; 80 completed the survey only, two completed the interview only and 18 completed both. Our quantitative study found that almost two-thirds (63%, n = 62) of caregivers attended the department within two days of their child becoming ill. Our qualitative study identified three major themes which were underpinned by concepts of trust, safety and uncertainty and were assessed in relation to the temporal nature of the pandemic and the caregivers' journey to care. We found most caregivers balanced their concerns of COVID-19 and a perceived "overwhelmed" NHS by speaking to trusted sources, predominantly general practitioners (GPs). CONCLUSION: Caregivers have adapted their health-seeking behaviour throughout the pandemic as new information and guidance have been released. We identified several factors affecting decisions to attend; some existed before the pandemic (e.g., concerns for child's health) whilst others were due to the pandemic (e.g., perceived risks of transmission when accessing healthcare services). We recommend trusted medical professionals, particularly GPs, continue to provide reassurance to caregivers to seek emergency paediatric care when required. Communicating the hospital safety procedures and the importance of early intervention to caregivers could additionally provide reassurance to those concerned about the risks of accessing the hospital environment

First social impact bond for the SAMRC: A novel financing strategy to address the health and social challenges facing adolescent girls and young women in South Africa

A social impact bond (SIB) is an innovative financing mechanism to attract investors to social programmes traditionally funded by governments. In this article, in celebration of the 50th anniversary of the South African Medical Research Council (SAMRC), the authors describe the SAMRC’s first foray into this new world of financing through a SIB to improve the health and quality of life of adolescent girls and young women (AGYW). The AGYW SIB is in its preparatory phase and is scheduled for implementation in 2020. The authors describe the mechanism, including financial flows and the process of customising the SIB to meet the needs of AGYW, focusing on HIV prevention and treatment and the prevention and management of unintended pregnancies in schoolgoing AGYW. The authors outline an approach to designing the package of interventions, the metrics associated with such a programme and the business model. It is hypothesised that the proposed approach will lead to an improvement in programmatic outcomes, monitoring and evaluation tools and cost-effectiveness, and will develop key learning data for the future use of SIBs in health service delivery

Intracellular survival of Streptococcus pneumoniae in human alveolar macrophages is augmented with HIV infection

People Living with HIV (PLHIV) are at an increased risk of pneumococcal pneumonia than HIV-uninfected adults, but the reasons for this are still not well understood. We investigated whether alveolar macrophages (AM) mediated control of pneumococcal infection is impaired in PLHIV compared to HIV-uninfected adults. We assessed anti-bactericidal activity against Streptococcus pneumoniae of primary human AM obtained from PLHIV and HIV-uninfected adults. We found that pneumococcus survived intracellularly in AMs at least 24 hours post ex vivo infection, and this was more frequent in PLHIV than HIV-uninfected adults. Corroborating these findings, in vivo evidence showed that PLHIV had a higher propensity for harboring S. pneumoniae within their AMs than HIV-uninfected adults. Moreover, bacterial intracellular survival in AMs was associated with extracellular propagation of pneumococcal infection. Our data suggest that failure of AMs to eliminate S. pneumoniae intracellularly could contribute to the increased risk of pneumococcal pneumonia in PLHIV