Factors associated with progression to death in patients with Lassa fever in Nigeria: an observational study.

BACKGROUND: Lassa fever is endemic in several west African countries. Case-fatality rates ranging from 21% to 69% have been reported. The pathophysiology of the disease in humans and determinants of mortality remain poorly understood. We aimed to determine host protein biomarkers capable of determining disease outcome. METHODS: In this observational study, we analysed left-over blood samples from patients who tested positive for Lassa fever at Irrua Specialist Teaching Hospital, Nigeria, between January, 2014, and April, 2017. We measured viral load, concentrations of clinical chemistry parameters, and levels of 62 circulating proteins involved in inflammation, immune response, and haemostasis. Patients with a known outcome (survival or death) and at least 200 µL of good-quality diagnostic sample were included in logistic regression modelling to assess the correlation of parameters with Lassa fever outcome. Individuals who gave consent could further be enrolled into a longitudinal analysis to assess the association of parameters with Lassa fever outcome over time. Participants were divided into two datasets for the statistical analysis: a primary dataset (samples taken between Jan 1, 2014, and April 1, 2016), and a secondary dataset (samples taken between April 1, 2016, and April 1, 2017). Biomarkers were ranked by area under the receiver operating characteristic curve (AUC) from highest (most predictive) to lowest (least predictive). FINDINGS: Of 554 patients who tested positive for Lassa fever during the study period, 201 (131 in the primary dataset and 70 in the secondary dataset) were included in the biomarker analysis, of whom 74 (49 in the primary dataset and 25 in the secondary dataset) had died and 127 (82 in the primary dataset and 45 in the secondary dataset) had survived. Cycle threshold values (indicating viral load) and levels of 18 host proteins at the time of admission to hospital were significantly correlated with fatal outcome. The best predictors of outcome in both datasets were plasminogen activator inhibitor-1 (PAI-1; AUC 0·878 in the primary dataset and 0·876 in the secondary dataset), soluble thrombomodulin (TM; 0·839 in the primary dataset and 0·875 in the secondary dataset), and soluble tumour necrosis factor receptor superfamily member 1A (TNF-R1; 0·807 in the primary dataset and 0·851 in the secondary dataset), all of which had higher prediction accuracy than viral load (0·774 in the primary dataset and 0·837 in the secondary dataset). Longitudinal analysis (150 patients, of whom 36 died) showed that of the biomarkers that were predictive at admission, PAI-1 levels consistently decreased to normal levels in survivors but not in those who died. INTERPRETATION: The identification of PAI-1 and soluble TM as markers of fatal Lassa fever at admission, and of PAI-1 as a marker of fatal Lassa fever over time, suggests that dysregulated coagulation and fibrinolysis and endothelial damage have roles in the pathophysiology of Lassa fever, providing a mechanistic explanation for the association of Lassa fever with oedema and bleeding. These novel markers might aid in clinical risk stratification and disease monitoring. FUNDING: German Research Foundation, Leibniz Association, and US National Institutes of Health.

Early administration of interleukin-6 inhibitors for patients with severe COVID-19 disease is associated with decreased intubation, reduced mortality, and increased discharge.

OBJECTIVE: The aim of this observational study was to determine the optimal timing of interleukin-6 receptor inhibitor (IL6ri) administration for coronavirus disease 2019 (COVID-19). METHODS: Patients with COVID-19 were given an IL6ri (sarilumab or tocilizumab) based on iteratively reviewed guidelines. IL6ri were initially reserved for critically ill patients, but after review, treatment was liberalized to patients with lower oxygen requirements. Patients were divided into two groups: those requiring ≤45% fraction of inspired oxygen (FiO2) (termed stage IIB) and those requiring >45% FiO2 (termed stage III) at the time of IL6ri administration. The main outcomes were all-cause mortality, discharge alive from hospital, and extubation. RESULTS: A total of 255 COVID-19 patients were treated with IL6ri (149 stage IIB and 106 stage III). Patients treated in stage IIB had lower mortality than those treated in stage III (adjusted hazard ratio (aHR) 0.24, 95% confidence interval (CI) 0.08-0.74). Overall, 218 (85.5%) patients were discharged alive. Patients treated in stage IIB were more likely to be discharged (aHR 1.43, 95% CI 1.06-1.93) and were less likely to be intubated (aHR 0.43, 95% CI 0.24-0.79). CONCLUSIONS: IL6ri administration prior to >45% FiO2 requirement was associated with improved COVID-19 outcomes. This can guide clinical management pending results from randomized controlled trials.

Management of urinary tract infections from multidrug-resistant organisms.

Antibiotic resistance worsens clinical outcomes and, in some cases, significantly impacts the clinical management of urinary tract infections in the outpatient setting. This article presents the prevalence and mechanism of relevant antimicrobial resistance patterns encountered among uropathogens, and discusses the efficacy of antibiotic regimens and novel therapies in treating commonly encountered multidrug-resistant organisms.

Cost-effectiveness of QuantiFERON testing before initiation of biological therapy in inflammatory bowel disease.

BACKGROUND: Anti-tumor necrosis factor α drugs are known to reactivate latent tuberculosis (TB). Current guidelines recommend screening for latent tuberculosis infection, with either tuberculin skin test (TST) or interferon gamma release assays such as QuantiFERON-TB Gold (QFT-G). Given the high rates of anergy to TST among immunosuppressed inflammatory bowel disease (IBD) patients, there is considerable interest in evaluating the superiority of interferon gamma release assays over TST in this patient population to diagnose latent tuberculosis infection. We compared the performance of TST and QFT-G for screening latent TB among immunosuppressed IBD patients based on prevalence, mortality risk from reactivation TB, and costs. METHODS: A decision analytical model was constructed to compare 1-year outcomes and costs of using TST or interferon gamma release assay in an immunosuppressed IBD population. RESULTS: Under the base case scenario, for every 1000 patients screened, the QFT-G strategy resulted in 0.53 deaths from reactivation TB compared with 1.92 deaths using TST. The QFT-G strategy results in 1.85 reactivation TB versus 6.7 reactivation TB using TST. The model was not sensitive to background prevalence of latent TB. The cost of QFT-G would have to be more than double for the TST strategy to become more cost effective. QFT-G also remains the cost-effective option unless the sensitivity of the TST improves by 400%. CONCLUSIONS: Under a broad range of parameter values, the QFT-G strategy dominates the TST strategy in cost-effectiveness. Consideration should be given to QFT-G as the preferred method of identifying latent TB in all immunosuppressed IBD patients.