Project description:Drug-resistant tuberculosis (TB) remains a formidable global health challenge. Host-directed therapies (HDTs) offer the potential to mitigate tissue damage, reduce treatment duration, and improve clinical outcomes by modulating immune responses. We assessed the safety and potential efficacy of adjunctive ibuprofen—an inexpensive, well‐tolerated non-steroidal anti-inflammatory drug—in patients with pre-extensively drug-resistant (pre-XDR) and extensively drug-resistant (XDR) TB. In this prospective, open-label, randomized pilot study (NCT02781909) conducted in Georgia, 28 adults with bacteriologically confirmed pulmonary pre-XDR or XDR-TB were randomized 1:1 to receive either standard-of-care (SoC) TB treatment alone (n=14) or SoC plus 400 mg ibuprofen daily during the first 2 months (n=14). Participants were followed for 6 months. The primary endpoints were early sputum culture conversion and radiological improvement. Secondary endpoints included WHO-defined final treatment outcomes, safety, health-related quality of life (HQoL), and changes in inflammatory markers. By week 2, culture negativity was achieved in 27% of control participants versus 9% in the ibuprofen group (risk difference 18%, 95% CI −13 to 50). The median time to culture conversion was 4 months in both groups. At month 2, favourable X-ray evolution was observed in 64% of controls compared with 54% of the ibuprofen group (risk difference 9%, 95% CI −32 to 50), with 90% of participants in each group showing improvement by month 6. Final treatment outcomes were comparable (≈71% cured) and the incidence of safety-related events did not differ significantly. Notably, the ibuprofen group exhibited greater proportional reductions in inflammatory markers—including a statistically significant decrease in the monocyte-to-lymphocyte ratio at months 2 and 5, along with reductions in interferon gamma levels and the enrichment score for Thompson_FAIL_13 gene signature at month 6. Although adjunctive ibuprofen did not improve primary microbiological or radiological endpoints, its excellent safety profile and significant anti-inflammatory effects support its potential role as an immune-modulating adjunct in the treatment of drug-resistant TB. These findings warrant further investigation in larger studies to optimize dosing and evaluate clinical benefits.
Project description:Streptococcus pneumoniae is a frequent coloniser of the human nasopharynx and a major cause of life-threating invasive infections such as pneumonia, meningitis and sepsis. Over 1 million people die every year due to invasive pneumococcal disease (IPD), mainly in developing countries. Serotype 1 is a common cause of IPD; however, unlike other serotypes, it is rarely found in the carrier state in the nasopharynx, which is often considered a prerequisite for disease. The aim of this study was to understand this dichotomy. We used murine models of carriage and IPD to characterise the pathogenesis of African serotype 1 (Sequence Type 217) pneumococcal strains obtained from the Queen Elizabeth Central Hospital in Blantyre, Malawi. We found that ST217 pneumococcal strains were highly virulent in a mouse model of invasive pneumonia, but in contrast to the generally accepted assumption, can also successfully establish nasopharyngeal carriage. Interestingly, we found that co-colonising serotypes may proliferate in the presence of serotype 1, suggesting that acquisition of serotype 1 carriage could increase the risk of developing IPD by other serotypes. RNAseq analysis confirmed that key virulence genes associated with inflammation and tissue invasiveness were upregulated in serotype 1. These data reveal important new insights into serotype 1 pathogenesis, with implications for carriage potential and risk of invasive disease through interactions with other co-colonising serotypes; an often overlooked factor in transmission and disease progression.