Summary: Dysregulation of the host immune response has a central role in the pathophysiology of sepsis. There has been much interest in immunomodulatory drugs as potential therapeutic adjuncts in sepsis. We conducted a systematic review and meta‐analysis of randomised controlled trials evaluating the safety and clinical effectiveness of immunomodulatory drugs as adjuncts to standard care in the treatment of adults with sepsis. Our primary outcomes were serious adverse events and all‐cause mortality. Fifty‐six unique, eligible randomised controlled trials were identified, assessing a range of interventions including cytokine inhibitors; anti‐inflammatories; immune cell stimulators; platelet pathway inhibitors; and complement inhibitors. At 1‐month follow‐up, the use of cytokine inhibitors was associated with a decreased risk of serious adverse events, based on 11 studies involving 7138 patients (RR (95%CI) 0.95 (0.90–1.00), I ² = 0%). The only immunomodulatory drugs associated with an increased risk of serious adverse events were toll‐like receptor 4 antagonists (RR (95%CI) 1.18 (1.04–1.34), I ² = 0% (two trials, 567 patients)). Based on 18 randomised controlled trials, involving 11,075 patients, cytokine inhibitors reduced 1‐month mortality (RR (95%CI) 0.88 (0.78–0.98), I ² = 57%). Mortality reduction was also shown in the subgroup of 13 randomised controlled trials that evaluated anti‐tumour necrosis factor α interventions (RR (95%CI) 0.93 (0.87–0.99), I ² = 0%). Anti‐inflammatory drugs had the largest apparent effect on mortality at 2 months at any dose (two trials, 228 patients, RR (95%CI) 0.64 (0.51–0.80), I ² = 0%) and at 3 months at any dose (three trials involving 277 patients, RR (95%CI) 0.67 (0.55–0.81), I ² = 0%). These data indicate that, except for toll‐like receptor 4 antagonists, there is no evidence of safety concerns for the use of immunomodulatory drugs in sepsis, and they may show some short‐term mortality benefit for selected drugs.

Introduction At the end of the first year of the COVID-19 pandemic, more than 78 million known survivors were recorded. The long-term pulmonary sequelae of COVID-19 remain unknown. Methods We performed a retrospective analysis of a post-COVID follow-up service to estimate the burden of persistent pulmonary morbidity in hospitalised COVID survivors. Results A total of 221 patients were followed-up: 44 intensive care unit (ICU) and 177 ward patients. Further investigations were planned as per British Thoracic Society Guidelines: For all ICU patients (n = 44) and for 38 of 177 (21%) ward-based patients who had persistent symptoms and/or persistent radiographic changes on CXR at their initial 8-week follow-up visit. In the ward-based cohort, statistically significant associations with persistent symptoms were being an ex- or current smoker, having pre-existing diabetes, and having a longer length of stay. In patients requiring further investigations, pulmonary function tests (PFTs; n = 67) at an average of 15 weeks post-discharge showed abnormalities in at least one PFT parameter in 79% (equating to 24% of the entire cohort). The most common abnormality was an abnormal diffusion capacity of carbon monoxide (TLCO), highest in the ICU cohort (64% ICU vs. 38% non-ICU). TLCO correlated negatively with length of stay and with maximum inspired FiO₂ in the patient group as a whole. In ICU patients, TLCO correlated negatively with maximum inspired positive airway pressure. Computed tomography scans (n = 72) at an average of 18 weeks post-discharge showed evidence of persistent ground glass opacities in 44% and fibrosis in 21% (equating to 7% of the entire cohort). Conclusion Our data add to the growing evidence that there will be pulmonary sequelae in a proportion of COVID survivors, providing some insight into what may become a significant chronic global health problem.

Population pharmacokinetic studies of β-lactam antimicrobials in critically ill patients derive models that inform their dosing. In non-linear mixed-effects modelling, covariates are often used to improve model fit and explain variability. We aimed to investigate which covariates are most commonly assessed and which are found to be significant, along with global patterns of publication. We conducted a systematic review, searching MEDLINE, Embase, CENTRAL and Web of Science on 01 March 2023, including studies of critically ill adults receiving β-lactam antimicrobials who underwent blood sampling for population pharmacokinetic studies. We extracted and categorized all reported covariates and assessed reporting quality using the ClinPK checklist. Our search identified 151 studies with 6018 participants. Most studies reported observational cohorts (120 studies, 80%), with the majority conducted in high-income settings (136 studies, 90%). Of the 1083 identified covariate instances, 237 were unique; the most common categories were patient characteristics (n = 404), biomarkers (n = 206) and physiological parameters (n = 163). Only seven distinct commonly reported covariates (CL_CR, weight, glomerular filtration rate, diuresis, need for renal replacement, serum albumin and C-reactive protein) were significant more than 20% of the time. Covariates are most commonly chosen based on biological plausibility, with patient characteristics and biomarkers the most frequently investigated. We developed an openly accessible database of reported covariates to aid investigators with covariate selection when designing population pharmacokinetic studies. Novel covariates, such as sepsis subphenotypes, have not been explored yet, leaving a research gap for future work.