Screening for Latent Tuberculosis Infection in Adults: Updated Evidence Report and Systematic Review for the US Preventive Services Task Force.

Importance: Latent tuberculosis infection (LTBI) can progress to active tuberculosis disease, causing morbidity and mortality. Objective: To review the evidence on benefits and harms of screening for and treatment of LTBI in adults to inform the US Preventive Services Task Force (USPSTF). Data Sources: PubMed/MEDLINE, Cochrane Library, and trial registries through December 3, 2021; references; experts; literature surveillance through January 20, 2023. Study Selection: English-language studies of LTBI screening, LTBI treatment, or accuracy of the tuberculin skin test (TST) or interferon-gamma release assays (IGRAs). Studies of LTBI screening and treatment for public health surveillance or disease management were excluded. Data Extraction and Synthesis: Dual review of abstracts, full-text articles, and study quality; qualitative synthesis of findings; meta-analyses conducted when a sufficient number of similar studies were available. Main Outcomes and Measures: Screening test accuracy; development of active tuberculosis disease, transmission, quality of life, mortality, and harms. Results: A total of 113 publications were included (112 studies; N = 69 009). No studies directly evaluated the benefits and harms of screening. Pooled estimates for sensitivity of the TST were 0.80 (95% CI, 0.74-0.87) at the 5-mm induration threshold, 0.81 (95% CI, 0.76-0.87) at the 10-mm threshold, and 0.60 (95% CI, 0.46-0.74) at the 15-mm threshold. Pooled estimates for sensitivity of IGRA tests ranged from 0.81 (95% CI, 0.79-0.84) to 0.90 (95% CI, 0.87-0.92). Pooled estimates for specificity of screening tests ranged from 0.95 to 0.99. For treatment of LTBI, a large (n = 27 830), good-quality randomized clinical trial found a relative risk (RR) for progression to active tuberculosis at 5 years of 0.35 (95% CI, 0.24-0.52) for 24 weeks of isoniazid compared with placebo (number needed to treat, 112) and an increase in hepatotoxicity (RR, 4.59 [95% CI, 2.03-10.39]; number needed to harm, 279). A previously published meta-analysis reported that multiple regimens were efficacious compared with placebo or no treatment. Meta-analysis found greater risk for hepatotoxicity with isoniazid than with rifampin (pooled RR, 4.22 [95% CI, 2.21-8.06]; n = 7339). Conclusions and Relevance: No studies directly evaluated the benefits and harms of screening for LTBI compared with no screening. TST and IGRAs were moderately sensitive and highly specific. Treatment of LTBI with recommended regimens reduced the risk of progression to active tuberculosis. Isoniazid was associated with higher rates of hepatotoxicity than placebo or rifampin.

Gut microbiome in sudden infant death syndrome (SIDS) differs from that in healthy comparison babies and offers an explanation for the risk factor of prone position.

The role of bacteria in the causation of sudden infant death syndrome (SIDS) is gaining acceptance. Mainstream research favouring respiratory compromise has failed to provide a plausible pathogenetic mechanism despite many years of investigation and thousands of research papers. Bacterial colonisation of the colon of the human infant is influenced by many factors including age, mode of delivery, diet, environment, and antibiotic exposure. The gut microbiome influences development of the immune system. The gut microflora could be important in protection against the bacteria and/or their toxins purportedly involved in SIDS pathogenesis. The aim was to perform a preliminary investigation of the gut microflora in sudden infant death syndrome (SIDS) compared with live comparison babies. The intestinal contents from 52 SIDS, and 102 faecal samples from age-matched live comparison infants were screened by PCR to target 16s RNA genes of Clostridium innocuum, Cl. Perfringens, Cl. difficile, Bacteroides thetaiotaomicron and Staphylococcus aureus. Gut colonisation of the babies with these bacteria was analysed in relation to age, gender and type of feeding; and for SIDS babies sleeping position. Cl. difficile, Cl. innocuum and B. thetaiotaomicron were significantly associated with SIDS with 25%, 46% and 30% of cases PCR positive for these respective bacteria compared with only 6%, 23% and 8.8% respectively in the comparison group. SIDS babies had dual colonisation by both Cl. perfringens and Cl. difficile significantly more often than comparison babies and also with triple colonisation by Cl. perfringens, Cl. difficile and Cl. innocuum. SIDS babies were more often colonised by S. aureus than comparison babies. In addition, SIDS babies found prone were significantly more likely to be colonised by S. aureus than for other positions recorded (OR = ∞; CI = 2·04 - ∞). No significant differences between breast and bottle-fed SIDS babies was observed in regard to each clostridial bacterium, or S. aureus, however Cl. innocuum was found to be significantly associated with formula feeding in the comparison cohort. Comparison of breast and formula feeding of SIDS babies with live comparison babies revealed significant differences with regards to some of the clostridial bacteria. Age-specific differences in gut bacterial microbiome were observed in both SIDS and comparison healthy babies. This study gives an insight into differences in the gut bacterial microbiome of SIDS babies compared with healthy babies. These differences could be important in contributing to a baby's susceptibility to infection and therefore to SIDS. The association of S. aureus colonisation with prone sleep position supports the hypothesis that prone sleep position could increase the risk of ingestion/inhalation of bacteria contaminating the sleeping surface and could account for the increased risk of SIDS in babies who are put to sleep prone. The study provides impetus for broader studies into the gut microbiome of babies and could lead to effective approaches to SIDS prevention.

Distribution of interleukin-1 receptor antagonist genotypes in sudden unexpected death in infancy (SUDI); unexplained SUDI have a higher frequency of allele 2.

AIMS: This investigation was designed to explore the role of IL-1RN genotype in unexplained infant deaths (including sudden infant death syndrome (SIDS)), non-infectious infant deaths, and infectious infant deaths, and to investigate whether IL-1RN genotype is related to the finding of organisms in normally sterile sites in infant deaths. METHODS: IL-1RN 89bp variable number of tandem repeat polymorphism genotype was determined using polymerase chain reaction for 49 cases of unexplained sudden unexpected death in infancy (uSUDI), 13 cases of infectious sudden unexpected death in infancy, 10 cases of non-infectious sudden unexpected death in infancy, and 103 live control infants. IL-1RN genotype was then compared with the presence of bacteria in normally sterile sites in infant deaths. RESULTS: An association was found between the homozygous A2 allele and uSUDI (P = 0.007; 95% confidence interval 1.41-17.67) where carriage of the 2/2 genotype was 4.85 times more likely to increase risk of uSUDI compared with the predominant 1/1 genotype. CONCLUSIONS: The role of infection in uSUDI and SIDS may be via an immune response pathway where IL-1RN A2 affects interleukin (IL)-1 regulation. These results are consistent with previous research where polymorphic genotypes conferring more severe proinflammatory responses are found more frequently in uSUDI/SIDS infants than in controls.

The frequency of molecular detection of virulence genes encoding cytolysin A, high-pathogenicity island and cytolethal distending toxin of Escherichia coli in cases of sudden infant death syndrome does not differ from that in other infant deaths and healthy infants.

Consistent pathological findings in sudden infant death syndrome (SIDS) are seen which display similarities to the pathogenesis of toxaemic shock and/or sepsis. A key candidate infectious agent that is possibly involved is Escherichia coli, given its universal early colonization of the intestinal tract of infants and an increased frequency of toxigenic and mouse-lethal isolates from SIDS compared with comparison infants. An explanation for these findings has yet to be identified. Using PCR, we screened E. coli isolates from 145 SIDS and 101 dead control and healthy infants for three new candidate pathogenicity-related genes: clyA (cytolysin A), irp2 [high-pathogenicity island (HPI)-specific gene] and cdt (cytolethal distending toxin). The results failed to show a positive correlation with SIDS, instead proving that clyA and irp2 genes were common to the infant intestinal E. coli. Interestingly we observed a high rate of carriage of these two potentially pathogenic genes in E. coli from healthy infants in the absence of diarrhoeal disease, and we report that in a number of cases, the detection of HPI-specific genes was predictable by serotype. Despite the lack of associations defined so far, there remains the likelihood that genetic determinants influence the interactions between E. coli and the host, so these factors may be part of the multi-factorial aspect of SIDS.