Pneumococcal nasopharyngeal colonisation in adults

Background: Pneumococcal colonisation, although usually asymptomatic, is key to the pathogenesis of invasive disease. Colonisation is infrequently detected in older adults, despite their high rates of pneumococcal disease; this may relate to sampling from the wrong site or reliance on culture-based rather than molecular diagnostic methods. Anti-pneumococcal immunity (including responses to vaccination) declines with age, but the immunogenicity of colonisation in older adults has not been studied. Alongside innate immunity, three specific defence mechanisms exist against pneumococcal disease: herd immunity, adaptive immunity (conferred by natural or vaccine-induced antibodies) and antibiotics. Current pneumococcal vaccines confer incomplete protection against pneumococcal disease in older adults. Research Questions: 1. Can experimental human pneumococcal colonisation be safely established in older adults? 2. What is the rate of experimental colonisation in older adults? 3. Do anti-pneumococcal antibodies (natural or post-vaccination) prevent experimental colonisation in older adults? 4. Is experimental colonisation immunogenic in older adults? 5. What is the optimal sampling site and diagnostic methodology for detecting colonisation in older adults? 6. What do colonisation studies of the general adult population reveal about herd immunity and pneumococcal antimicrobial resistance in the community? Findings: Experimental colonisation was established in 39% of volunteers (n = 25/64) with no adverse events. Experimental colonisation was unaffected by previous pneumococcal polysaccharide vaccination or baseline anti-capsular antibody levels. Although the rate of experimental colonisation was similar to that of younger volunteers in previous studies, the immune responses were markedly different: older adults did not demonstrate serotype-specific immune boosting following pneumococcal colonisation. Furthermore, pneumococcal challenge without colonisation led to a drop in specific antibody levels. Nasal wash culture appeared to be the optimal detection strategy compared with molecular testing of nasal wash, oropharyngeal swab or saliva. In a review of all prospective experimental human pneumococcal colonisation volunteers between 2010 and 2017, community-acquired colonisation was identified at baseline in 6.5% (n = 52/795) using nasal wash culture. The commonest serotype was 3 (a vaccine serotype), but otherwise non-vaccine serotypes predominated. There were no changes in serotype distribution over time. 15% of isolates (n = 8/52, all identified in 2015 or later) were resistant to at least one of the antibiotics tested. Conclusions: Experimental pneumococcal colonisation is feasible and safe in older people. However, the immunological effects are different to those identified in younger adults in previous studies. We found no evidence that the niche of colonisation changes with age. Nasal wash culture detected higher-than-expected rates of community-acquired colonisation in young adults, with the dominance of non-vaccine serotypes suggesting that the limits of herd immunity have been reached. New pneumococcal vaccines are needed for older adults, and the experimental colonisation model could be used in early phase testing of candidate vaccines. If such vaccines continue to rely on serotype-specific protection, then community colonisation studies could inform the serotype composition

Tuberculosis in HIV-infected South African children with complicated severe acute malnutrition.

Academic tertiary referral hospital in Durban, South Africa. To describe the incidence and diagnostic challenges of tuberculosis (TB) in human immunodeficiency virus (HIV) infected children with severe acute malnutrition (SAM). Post-hoc analysis of a randomised controlled trial that enrolled antiretroviral therapy naïve, HIV-infected children with SAM. Trial records and hospital laboratory results were explored for clinical diagnoses and bacteriologically confirmed cases of TB. Negative binomial regression was used to explore associations with confirmed cases of TB, excluding cases where the clinical diagnosis was not supported by microbiological confirmation. Of 82 children enrolled in the study, 21 (25.6%) were diagnosed with TB, with bacteriological confirmation in 8 cases. Sputum sampling (as opposed to gastric washings) was associated with an increased risk of subsequent diagnosis of TB (adjusted relative risk [aRR] 1.134, 95%CI 1.02-1.26). Culture-proven bacterial infection during admission was associated with a reduced risk of TB (aRR 0.856, 95%CI 0.748-0.979), which may reflect false-negative microbiological tests secondary to empiric broad-spectrum antibiotics. TB is common in HIV-infected children with SAM. While microbiological confirmation of the diagnosis is feasible, empiric treatment remains common, possibly influenced by suboptimal testing and false-negative TB diagnostics. Rigorous microbiological TB investigation should be integrated into the programmatic management of HIV and SAM

Low rate of bacterial co-infection in patients with COVID-19

We agree with Michael J Cox and colleagues1 that clinical management of COVID-19 would be enhanced by further characterisation of bacterial co-infections. A few case reports have described examples of such co-infections.2, 3, 4 However, national5 and international6 guidelines recommend empirical antibiotics for all patients who are severely ill with suspected COVID-19, and that cessation of therapy is left to the clinicians' discretion. Pending the widespread availability of metagenomic sequencing as envisaged by Cox and colleagues,1 we argue that traditional diagnostics still have a role

Insights Into the Effects of Mucosal Epithelial and Innate Immune Dysfunction in Older People on Host Interactions With Streptococcus pneumoniae

In humans, nasopharyngeal carriage of Streptococcus pneumoniae is common and although primarily asymptomatic, is a pre-requisite for pneumonia and invasive pneumococcal disease (IPD). Together, these kill over 500,000 people over the age of 70 years worldwide every year. Pneumococcal conjugate vaccines have been largely successful in reducing IPD in young children and have had considerable indirect impact in protection of older people in industrialized country settings (herd immunity). However, serotype replacement continues to threaten vulnerable populations, particularly older people in whom direct vaccine efficacy is reduced. The early control of pneumococcal colonization at the mucosal surface is mediated through a complex array of epithelial and innate immune cell interactions. Older people often display a state of chronic inflammation, which is associated with an increased mortality risk and has been termed ‘Inflammageing’. In this review, we discuss the contribution of an altered microbiome, the impact of inflammageing on human epithelial and innate immunity to S. pneumoniae, and how the resulting dysregulation may affect the outcome of pneumococcal infection in older individuals. We describe the impact of the pneumococcal vaccine and highlight potential research approaches which may improve our understanding of respiratory mucosal immunity during pneumococcal colonization in older individuals

Symptoms associated with influenza vaccination and experimental human pneumococcal colonisation of the nasopharynx

Background Nasopharyngeal colonisation by S. pneumoniae is a prerequisite for invasive pneumococcal infections. Influenza co-infection leads to increased susceptibility to secondary pneumonia and mortality during influenza epidemics. Increased bacterial load and impaired immune responses to pneumococcus caused by influenza play a role in this increased susceptibility. Using an Experimental Human Challenge Model and influenza vaccines, we examined symptoms experienced by healthy adults during nasal co-infection with S. pneumoniae and live attenuated influenza virus. Methods Randomised, blinded administration of Live Attenuated Influenza Vaccine (LAIV) or Tetravalent Inactivated Influenza Vaccine (TIV) either preceded bacterial inoculation or followed it, separated by a 3-day interval. The presence and density of S. pneumoniae was determined from nasal washes. Participants completed a symptom questionnaire from the first intervention until 6 days post second intervention. Results The timing and type of influenza vaccination and presence of S. pneumoniae in the nasopharynx significantly affected symptom reporting. In the study where influenza vaccination preceded bacterial inoculation: nasal symptoms were less common in the LAIV group than the TIV group (OR 0.57, p < 0.01); with colonisation status only affecting the TIV group where more symptoms were reported by colonised participants compared to non-colonised participants following inoculation (n = 12/23 [52.17%] vs n = 13/38 [34.21%], respectively; p < 0.05). In the study where influenza vaccination followed bacterial inoculation: no difference was seen in the symptoms reported between the LAIV and TIV groups following inoculation and subsequent vaccination; and symptoms were unaffected by colonisation status. Conclusion Symptoms experienced during live viral vaccination and bacterial co-infection in the nasopharynx are directly affected by the precedence of the pathogen acquisition. Symptoms were directly affected by nasal pneumococcal colonisation but only when TIV was given prior to bacterial exposure

Serum levels of anti-PspA and anti-PspC IgG decrease with age and do not correlate with susceptibility to experimental human pneumococcal colonization.

Older adults are at increased risk of pneumococcal disease. This work aims to evaluate whether there is any decrease in serum IgG against variants of the antigens Pneumococcal surface protein A (PspA) and Pneumococcal surface protein C (PspC) in healthy adults with increasing age. Levels of IgG against PspA and PspC variants were determined by ELISA in serum samples comparing volunteers 18-30 years of age with volunteers who were 50-70+ before and after an experimental pneumococcal colonization challenge. The serotype 6B strain used in the challenge belongs to a minor group of pneumococcal isolates expressing two PspC variants. There was a decrease in levels of IgG with increasing age for the most common PspA variants and for all PspC variants analyzed. No correlation was found between basal levels of IgG against these antigens and protection against colonization. There was an increase in levels of IgG against PspA variants that are more cross-reactive with the variant expressed by the challenge strain post challenge in younger individuals who became colonized. Since the challenge strain used in our study expresses two different PspC variants, an increase in serum IgG against all PspC variants tested was observed in younger individuals who became colonized. For some of the antigen variants tested, a decrease in serum IgG was observed in young volunteers who were challenged but did not become colonized. Serum IgG antibodies against PspA and PspC variants thus decrease with age in healthy adults, but there is no correlation between levels of IgG against these antigens and protection against human experimental colonization. Though no correlation between naturally induced serum IgG antibodies against PspA and PspC and protection against colonization was observed, these results do not rule out the protective potential of these antigens as vaccines against pneumococcal infections

Research Priorities for Achieving Healthy Marine Ecosystems and Human Communities in a Changing Climate

ABSTRACT: The health of coastal human communities and marine ecosystems are at risk from a host of anthropogenic stressors, in particular, climate change. Because ecological health and human well-being are inextricably connected, effective and positive responses to current risks require multidisciplinary solutions. Yet, the complexity of coupled social-ecological systems has left many potential solutions unidentified or insufficiently explored. The urgent need to achieve positive social and ecological outcomes across local and global scales necessitates rapid and targeted multidisciplinary research to identify solutions that have the greatest chance of promoting benefits for both people and nature. To address these challenges, we conducted a forecasting exercise with a diverse, multidisciplinary team to identify priority research questions needed to promote sustainable and just marine social-ecological systems now and into the future, within the context of climate change and population growth. In contrast to the traditional reactive cycle of science and management, we aimed to generate questions that focus on what we need to know, before we need to know it. Participants were presented with the question, "If we were managing oceans in 2050 and looking back, what research, primary or synthetic, would wish we had invested in today?" We first identified major social and ecological events over the past 60 years that shaped current human relationships with coasts and oceans. We then used a modified Delphi approach to identify nine priority research areas and 46 questions focused on increasing sustainability and well-being in marine social-ecological systems. The research areas we identified include relationships between ecological and human health, access to resources, equity, governance, economics, resilience, and technology. Most questions require increased collaboration across traditionally distinct disciplines and sectors for successful study and implementation. By identifying these questions, we hope to facilitate the discourse, research, and policies needed to rapidly promote healthy marine ecosystems and the human communities that depend upon them