Journal of Infection最新文献

Background

Upregulation of IL-6 has been associated with worse prognosis in COVID-19 patients. Impact on IL-6 signalling has mostly been limited to clinical outcomes in IL-6 receptor antagonist trials.

Methods

We performed a phase 2, randomised, double-blind, placebo-controlled trial (NCT04380961) of US-based hospitalised adults (<85 years) with laboratory-confirmed SARS-CoV-2 infection and severe (low levels of supplemental oxygen) or critical disease (high levels of oxygen supplementation). Patients received sirukumab 5 mg/kg or placebo single dose IV on Day 1 plus standard of care. The primary endpoint was time to sustained clinical improvement up to Day 28 based on an ordinal scale. Secondary endpoints included clinical improvement, all-cause mortality, and safety. Following an interim analysis, the protocol was amended to only recruit patients with critical COVID-19.

Findings

From May 2020 to March 2021, 209 patients were randomised; 112 had critical disease (72 sirukumab, 40 placebo) at baseline. Median time to sustained clinical improvement in critical patients was 17 and 23 days in the sirukumab and placebo groups (HR, 1∙1; 95% CI, 0∙66–1∙88; p > 0∙05). At Day 28, 59∙4% versus 55∙0% of patients achieved clinical improvement with sirukumab versus placebo and rates of all-cause mortality were 24∙6% versus 30∙0%, respectively. Rates of grade ≥3 adverse events were comparable between the sirukumab and placebo groups (25∙9% vs 32∙9%; all patients).

Interpretation

In critical COVID-19 patients who received sirukumab, there was no statistically significant difference in time to sustained clinical improvement versus placebo despite objective sequestration of circulating IL-6, questioning IL-6 as a key therapeutic target in COVID-19.

Children with hemoglobin AC or AS have decreased susceptibility to clinical malaria. Parasite variant surface antigen (VSA) presentation on the surface of infected erythrocytes is altered in erythrocytes with hemoglobin C (Hb AC) or sickle trait (Hb AS) mutations in vitro. The protective role of incomplete or altered VSA presentation against clinical malaria in individuals with Hb AC or AS is unclear. Using a high-throughput protein microarray, we sought to use serological responses to VSAs as a measure of host exposure to VSAs among Malian children with Hb AC, Hb AS, or wildtype hemoglobin (Hb AA). In uncomplicated malaria, when compared to Hb AA children, Hb AC children had significantly lower serological responses to extracellular Plasmodium falciparum erythrocyte membrane protein-1 (PfEMP1) domains but did not differ in responses to intracellular PfEMP1 domains and other VSAs, including members of the repetitive interspersed family (RIFIN) and subtelomeric variable open reading frame (STEVOR) family. Healthy children with Hb AC and Hb AS genotypes recognized fewer extracellular PfEMP1s compared to children with Hb AA, especially CD36-binding PfEMP1s. These reduced serologic responses may reflect reduced VSA presentation or lower parasite exposure in children with Hb AC or AS and provide insights into mechanisms of protection.

Objectives

To estimate the effectiveness and waning of the bivalent BA.4–5 or BA.1 mRNA booster vaccine against Covid-19-related hospitalization and death in immunocompromised individuals.

Methods

Nationwide analyses across Nordic countries from 1 September 2022 to 31 October 2023 using a matched cohort design. Individuals boosted with a BA.4–5 or BA.1 vaccine were matched 1:1 with unboosted individuals. The outcomes of interest were country-combined vaccine effectiveness (VE) estimates against Covid-19-related hospitalization and death at day 270 of follow-up. Waning was assessed in 45-day intervals.

Results

A total of 352,762 BA.4–5 and 191,070 BA.1 booster vaccine doses were included. At day 270, the comparative VE against Covid-19-related hospitalization was 34.2% (95% CI, 7.1% to 61.3%) for the bivalent BA.4–5 vaccine and 42.6% (95% CI, 31.3% to 53.9%) for the BA.1 vaccine compared with matched unboosted. The comparative VE against Covid-19-related death was 53.9% (95% CI, 38.6% to 69.3%) for the bivalent BA.4–5 vaccine and 57.9% (95% CI, 48.5% to 67.4%) for the BA.1 vaccine.

Conclusions

In immunocompromised individuals, vaccination with bivalent BA.4–5 or BA.1 booster lowered the risk of Covid-19-related hospitalization and death over a follow-up period of 9 months. The effectiveness was highest during the first months since vaccination with subsequent gradual waning.

Background

Though observational evidence supports indirect effects of SARS-CoV-2 vaccines, randomised experiments are lacking. To address this gap, the double-blinded, prospective follow-up of the household contacts (HHCs) of Philippine participants of the individually-randomised, placebo-controlled trial of the adjuvanted-subunit protein COVID-19 vaccine, SCB-2019, (EudraCT, 2020–004272–17; ClinicalTrials.gov, NCT04672395) was analyzed in a cluster-randomised fashion.

Methods

Over an eight-week period, HHCs were followed by rRT-PCR and paired rapid antibody tests (RATs) to detect symptomatic (SCI, primary) and all (ACI, secondary) SARS-CoV-2 infection. A standard analysis estimated the indirect effectiveness of SCB-2019 for each endpoint, excluding HHC RAT-positive at enrollment. A secondary analysis employed enzyme-linked immunosorbent assay (ELISA) results to correct for suspected bias.

Findings

SCB-2019 (N = 3470) and placebo (N = 3225) exposed HHCs contributed to at least one analysis. The standard analysis estimated that SCB-2019 reduced the risk of SCI by 83% (95% confidence/credible interval [CI: 32% to 96%), with no effect against ACI. The bias-corrected relative risk reduction was 97% (95% CI: 74% to 100%) for SCI and 79% (95% CI: 14% to 96%) for ACI, with an estimated one SARS-CoV-2 infection prevented per 4.8 households where one member received SCB-2019.

Interpretation

SCB-2019 demonstrated bias-corrected indirect effectiveness against SARS-CoV-2 infection among HHC, even at a modest coverage level in the household (approximately 25%). Further research into the indirect effects of SARS-CoV-2 vaccines is needed to optimize the impact of limited doses in low and middle-income settings.

Background

Shorter duration therapy for hepatitis C virus (HCV) infection might reduce treatment costs and increase the number of patients treated and cured. We determined factors associated with treatment response after an 8-week sofosbuvir-based therapy and developed a simple model to predict an individual’s likelihood of treatment success.

Methods

Among 2907 patients who received ledipasvir/sofosbuvir for 8 weeks, we determined failure rates by demographic and clinical characteristics, and IFNL4-∆G/TT genotype. We estimated the average IFNL4 genotype-related treatment failure rate in major ancestry groups by applying our IFNL4 genotype results to genotype distributions from reference populations. We created a treatment response model based on three personal characteristics.

Results

Overall, 4.4% of the patients failed treatment. We observed significantly lower failure rates for persons <50 years (1.6%), females (2.6%), those carrying the IFNL4-TT/TT genotype (1.8%), those with HCV RNA <5.8 log₁₀ copies/mL (2.0%) or HCV genotype-1B infection (2.6%). In a model based on ancestry, age and sex, the predicted probability of treatment failure ranged from 0.5% among females of East Asian ancestry <50 years of age to 8.5% among males of African ancestry age ≥65 years.

Conclusion

Applying this algorithm at the point-of-care might facilitate HCV elimination, especially in low- and middle-income countries.

Background

Our aim was to assess the impact of COVID-19 pandemic on mortality in patients hospitalised with Gram-negative bloodstream infections (GNBSIs).

Methods

A retrospective cohort study including cases of Escherichia coli, Klebsiella species and Pseudomonas aeruginosa in England (January 2015–December 2021) reported to UKHSA’s Second Generation Surveillance System. The outcome was 30-day all-cause mortality. Multivariable logistic regression models were built, and adjusted Odds Ratios (ORs) with 95% confidence intervals were reported.

Results

Total E. coli, Klebsiella spp. and P. aeruginosa infections were 206,030, 53,819 and 21,129, respectively. Compared to the pre-pandemic period, odds of death during the pandemic (March 2020 onwards) in E. coli, Klebsiella spp. and P. aeruginosa infections with no COVID-19 infection within 28-days of onset were 1.13 (1.08–1.18), 1.15 (1.07–1.25) and 1.09 (0.97–1.22), while odds in GNBSIs with an associated COVID-19 infection were 2.45 (2.26–2.66), 2.96 (2.62–3.34) and 3.15 (2.61–3.80), respectively. Asian patients with an associated COVID-19 infection were more likely to die during the pandemic compared to White patients (E. coli: OR 1.28 (0.95–1.71); Klebsiella spp. OR 1.59 (1.20–2.11); P. aeruginosa: OR 2.02 (1.23–3.31)).

Conclusions

Patients suffering from a GNBSI had increased risk of death during the pandemic, with the risk higher in patients with an associated COVID-19 infection.

Background

Evidence for the effect of favipiravir treatment of acute COVID-19 on recovery, hospital admissions and longer-term outcomes in community settings is limited.

Methods

In this multicentre. open-label, multi-arm, adaptive platform randomised controlled trial participants aged ≥18 years in the community with a positive test for SARS-CoV-2 and symptoms lasting ≤14 days were randomised to: usual care; usual care plus favipiravir tablets (loading dose of 3600 mg in divided doses on day one, then 800 mg twice a day for four days); or, usual care plus other interventions. Co-primary endpoints were time to first self-reported recovery and hospitalisation/death related to COVID-19, within 28 days, analysed using Bayesian models. Recovery at six months was the primary longer-term outcome. Trial registration: ISRCTN86534580.

Findings

The primary analysis model included 8811 SARS-CoV-2 positive mostly COVID vaccinated participants, randomised to favipiravir (n = 1829), usual care (n = 3256), and other treatments (n = 3726). Time to self-reported recovery was shorter in the favipiravir group than usual care (estimated hazard ratio 1·23 [95% credible interval 1·14 to 1·33]), a reduction of 2·98 days [1·99 to 3·94] from 16 days in median time to self-reported recovery for favipiravir versus usual care alone. COVID-19 related hospitalisations/deaths were similar (estimated odds ratio 0·99 [0·61 to 1·61]; estimated difference 0% [−0·9% to 0·6%]). 14 serious adverse events occurred in the favipiravir group and 4 in usual care. By six months, the proportion feeling fully recovered was 74·9% for favipiravir versus 71·3% for usual care (RR = 1·05, [1·02 to 1·08]).

Interpretation

In this open-label trial in a largely vaccinated population with COVID-19 in the community, favipiravir did not reduce hospital admissions, but shortened time to recovery and had a marginal positive impact on long term outcomes.

Objectives

Blood cultures (BCs) are commonly ordered in emergency departments (EDs), while a minority yields a relevant pathogen. Diagnostic stewardship is needed to safely reduce unnecessary BCs. We aimed to develop and validate a bacteremia prediction model for ED patients, with specific focus on the benefit of incorporating procalcitonin.

Methods

We included adult patients with suspected bacteremia from a Dutch ED for a one-year period. We defined 23 candidate predictors for a “full model”, of which nine were used for an automatable "basic model”. Variations of both models with C-reactive protein and procalcitonin were constructed using LASSO regression, with bootstrapping for internal validation. External validation was done in an independent cohort of patients with confirmed infection from 71 Spanish EDs. We assessed discriminative performance using the C-statistic and calibration with calibration curves. Clinical usefulness was evaluated by sensitivity, specificity, saved BCs, and Net Benefit.

Results

Among 2111 patients in the derivation cohort (mean age 63 years, 46% male), 273 (13%) had bacteremia, versus 896 (20%) in the external cohort (n = 4436). Adding procalcitonin substantially improved performance for all models. The basic model with procalcitonin showed most promise, with a C-statistic of 0.87 (0.86–0.88) upon external validation. At a 5% risk threshold, it showed a sensitivity of 99% and could have saved 29% of BCs while only missing 10 out of 896 (1.1%) bacteremia patients.

Conclusions

Procalcitonin-based bacteremia prediction models can safely reduce unnecessary BCs at the ED. Further validation is needed across a broader range of healthcare settings.