Pulmonary microbiome and transcriptome signatures reveal distinct pathobiologic states associated with mortality in two cohorts of pediatric stem cell transplant patients.

Lung injury is a major determinant of survival after pediatric hematopoietic cell transplantation (HCT). A deeper understanding of the relationship between pulmonary microbes, immunity, and the lung epithelium is needed to improve outcomes. In this multicenter study, we collected 278 bronchoalveolar lavage (BAL) samples from 229 patients treated at 32 children's hospitals between 2014-2022. Using paired metatranscriptomes and human gene expression data, we identified 4 patient clusters with varying BAL composition. Among those requiring respiratory support prior to sampling, in-hospital mortality varied from 22-60% depending on the cluster (p=0.007). The most common patient subtype, Cluster 1, showed a moderate quantity and high diversity of commensal microbes with robust metabolic activity, low rates of infection, gene expression indicating alveolar macrophage predominance, and low mortality. The second most common cluster showed a very high burden of airway microbes, gene expression enriched for neutrophil signaling, frequent bacterial infections, and moderate mortality. Cluster 3 showed significant depletion of commensal microbes, a loss of biodiversity, gene expression indicative of fibroproliferative pathways, increased viral and fungal pathogens, and high mortality. Finally, Cluster 4 showed profound microbiome depletion with enrichment of Staphylococci and viruses, gene expression driven by lymphocyte activation and cellular injury, and the highest mortality. BAL clusters were modeled with a random forest classifier and reproduced in a geographically distinct validation cohort of 57 patients from The Netherlands, recapitulating similar cluster-based mortality differences (p=0.022). Degree of antibiotic exposure was strongly associated with depletion of BAL microbes and enrichment of fungi. Potential pathogens were parsed from all detected microbes by analyzing each BAL microbe relative to the overall microbiome composition, which yielded increased sensitivity for numerous previously occult pathogens. These findings support personalized interpretation of the pulmonary microenvironment in pediatric HCT, which may facilitate biology-targeted interventions to improve outcomes.

Maintained partial protection against Streptococcus pneumoniae despite B-cell depletion in mice vaccinated with a pneumococcal glycoconjugate vaccine.

OBJECTIVES: Anti-CD20 monoclonal antibody therapy rapidly depletes > 95% of CD20+ B cells from the circulation. B-cell depletion is an effective treatment for autoimmune disease and B-cell malignancies but also increases the risk of respiratory tract infections. This effect on adaptive immunity could be countered by vaccination. We have used mouse models to investigate the effects of B-cell depletion on pneumococcal vaccination, including protection against infection and timing of vaccination in relation to B-cell depletion. METHODS: C57BL/6 female mice were B-cell depleted using anti-CD20 antibody and immunized with two doses of Prevnar-13 vaccine either before or after anti-CD20 treatment. B-cell repertoire and Streptococcus pneumoniae-specific IgG levels were measured using whole-cell ELISA and flow cytometry antibody-binding assay. Protection induced by vaccination was assessed by challenging the mice using a S. pneumoniae pneumonia model. RESULTS: Antibody responses to S. pneumoniae were largely preserved in mice B-cell depleted after vaccination resulting in full protection against pneumococcal infections. In contrast, mice vaccinated with Prevnar-13 while B cells were depleted (with > 90% reduction in B-cell numbers) had decreased circulating anti-S. pneumoniae IgG and IgM levels (measured using ELISA and flow cytometry antibody binding assays). However, some antibody responses were maintained, and, although vaccine-induced protection against S. pneumoniae infection was impaired, septicaemia was still prevented in 50% of challenged mice. CONCLUSIONS: This study showed that although vaccine efficacy during periods of profound B-cell depletion was impaired some protective efficacy was preserved, suggesting that vaccination remains beneficial.

What is the effectiveness of community-based health promotion campaigns on chlamydia screening uptake in young people and what barriers and facilitators have been identified? A mixed-methods systematic review.

BACKGROUND: The UK National Chlamydia Screening Programme uses an opportunistic approach. Many programmes use campaigns to raise awareness of chlamydia screening in young people. This review aimed to assess the effectiveness of campaigns on uptake of chlamydia screening in young people. METHODS: We conducted a mixed-methods systematic review of articles assessing the outcomes of community-based health-promotion campaigns to increase chlamydia screening in young people, their experiences of the campaigns and other facilitators and barriers to the conduct of the campaigns. We searched four databases for quantitative and qualitative studies with no language restrictions. MAIN RESULTS: From 10 329 records identified, 19 studies (20 articles) were included in the review: 14 quantitative, 2 qualitative and 3 mixed methods. All studies with quantitative outcomes were before-after study designs or interrupted time series. The prediction interval for relative change (RC) in test counts ranged from 0.95 to 1.56, with a summary pooled estimate of RC 1.22 (95% CI 1.14 to 1.30, 13 studies, I2=97%). For test positivity rate, 95% prediction interval was 0.59 to 1.48, with a summary pooled estimate of RC 0.93 (95% CI 0.81 to 1.07, 8 studies, I2=91.8%). Large variation in characteristics between studies precluded exploring outcomes by type of campaign components. Seven major qualitative themes to improve screening were identified: targeting of campaigns; quality of materials and message; language; anonymity; use of technology; relevance; and variety of testing options. CONCLUSIONS: Health promotion campaigns aiming to increase chlamydia testing in those aged 15-24 years may show some effectiveness in increasing overall numbers of tests, however numbers of positive tests do not follow the same trend. Qualitative findings indicate that campaigns require clear, relevant messaging that displays the full range of testing options and assures anonymity in order to be effective.

Interchangeability of meningococcal group C conjugate vaccines with different carrier proteins in the United Kingdom infant immunisation schedule.

An open, non-randomised study was undertaken in England during 2011-12 to evaluate vaccine antibody responses in infants after completion of the routine primary infant immunisation schedule, which included two doses of meningococcal group C (MenC) conjugate (MCC) vaccine at 3 and 4 months. Any of the three licensed MCC vaccines could be used for either dose, depending on local availability. Healthy term infants registered at participating general practices (GPs) in Hertfordshire and Gloucestershire, UK, were recruited prospectively to provide a single blood sample four weeks after primary immunisation, which was administered by the GP surgery. Vaccination history was obtained at blood sampling. MenC serum bactericidal antibody (SBA) and IgG antibodies against Haemophilus influenzae b (Hib), pertussis toxin (PT), diphtheria toxoid (DT), tetanus toxoid (TT) and thirteen pneumococcal serotypes were analysed according to MCC vaccines received. MenC SBA responses differed significantly (P<0.001) according to MCC vaccine schedule as follows: MenC SBA geometric mean titres (GMTs) were significantly lower in infants receiving a diphtheria cross-reacting material-conjugated MCC (MCC-CRM) vaccine followed by TT-conjugated MCC (MCC-TT) vaccine (82.0; 95% CI, 39-173; n=14) compared to those receiving two MCC-CRM (418; 95% CI, 325-537; n=82), two MCC-TT (277; 95% CI, 223-344; n=79) or MCC-TT followed by MCC-CRM (553; 95% CI, 322-949; n=18). The same group also had the lowest Hib geometric mean concentrations (0.60 µg/mL, 0.27-1.34) compared to 1.85 µg/mL (1.23-2.78), 2.86 µg/mL (2.02-4.05) and 4.26 µg/mL (1.94-9.36), respectively. Our results indicate that MCC vaccines with different carrier proteins are not interchangeable. When several MCC vaccines are available, children requiring more than one dose should receive MCC vaccines with the same carrier protein or, alternatively, receive MCC-TT first wherever possible.