Severe Illnesses Associated With Outbreaks of Respiratory Syncytial Virus and Influenza in Adults.

BACKGROUND: Recent reports have described the contribution of adult respiratory syncytial virus (RSV) infections to the use of advanced healthcare resources and death. METHODS: Data regarding patients aged ≥18 years admitted to any of Maryland's 50 acute-care hospitals were evaluated over 12 consecutive years (2001-2013). We examined RSV and influenza (flu) surveillance data from the US National Respiratory and Enteric Virus Surveillance System and the Centers for Disease Control and Prevention and used this information to define RSV and flu outbreak periods in the Maryland area. Outbreak periods consisted of consecutive individual weeks during which at least 10% of RSV and/or flu diagnostic tests were positive. We examined relationships of RSV and flu outbreaks to occurrence of 4 advanced medical outcomes (hospitalization, intensive care unit admission, intubated mechanical ventilation, and death) due to medically attended acute respiratory illness (MAARI). RESULTS: Occurrences of all 4 MAARI-related hospital advanced medical outcomes were consistently greater for all adult ages during RSV, flu, and combined RSV-flu outbreak periods compared to nonoutbreak periods and tended to be greatest in adults aged ≥65 years during combined RSV-flu outbreak periods. Rate ratios for all 4 MAARI-related advanced medical outcomes ranged from 1.04 to 1.38 during the RSV, flu, or combined RSV-flu outbreaks compared to the nonoutbreak periods, with all 95% lower confidence limits >1. CONCLUSIONS: Both RSV and flu outbreaks were associated with surges in MAARI-related advanced medical outcomes (hospitalization, intensive care unit admission, intubated mechanical ventilation, and death) for adults of all ages.

Clinical Development of Therapeutic Agents for Hospitalized Patients With Influenza: Challenges and Innovations.

BACKGROUND: Since 1999, the US Food and Drug Administration approved neuraminidase and endonuclease inhibitors to treat uncomplicated outpatient influenza but not severe hospitalized influenza. After the 2009 pandemic, several influenza hospital-based clinical therapeutic trials were unsuccessful, possibly due to certain study factors. Therefore, in 2014, the US Health and Human Services agencies formed a Working Group (WG) to address related clinical challenges. METHODS: Starting in 2014, the WG obtained retrospective data from failed hospital-based influenza therapeutic trials and nontherapeutic hospital-based influenza studies. These data allowed the WG to identify factors that might improve hospital-based therapeutic trials. These included primary clinical endpoints, increased clinical site enrollment, and appropriate baseline enrollment criteria. RESULTS: During 2018, the WG received retrospective data from a National Institutes of Health hospital-based influenza therapeutic trial that demonstrated time to resolution of respiratory status, which was not a satisfactory primary endpoint. The WG statisticians examined these data and believed that ordinal outcomes might be a more powerful primary endpoint. Johns Hopkins' researchers provided WG data from an emergency-department (ED) triage study to identify patients with confirmed influenza using molecular testing. During the 2013-2014 influenza season, 4 EDs identified 1074 influenza-patients, which suggested that triage testing should increase enrollment by hospital-based clinical trial sites. In 2017, the WG received data from Northwestern Memorial Hospital researchers regarding 703 influenza inpatients over 5 seasons. The WG applied National Early Warning Score (NEWS) at patient baseline to identify appropriate criteria to enroll patients into hospital-based therapeutic trials. CONCLUSIONS: Data received by the WG indicated that hospital-based influenza therapeutic trials could use ordinal outcome analyses, ED triage to identify influenza patients, and NEWS for enrollment criteria.

Association of influenza outbreaks with advanced pediatric medical support.

Retrospective data evaluated increases in advanced medical support for children with medically attended acute respiratory illness (MAARI) during influenza outbreak periods (IOP). Advanced support included hospitalisation, intensive care unit admission, or mechanical ventilation, for children aged 0-17 years hospitalised in Maryland's 50 acute-care hospitals over 12 influenza seasons. Weekly numbers of positive influenza tests in the Maryland area defined IOP for each season as the fewest consecutive weeks, including the peak week containing at least 85% of positive tests with a 2-week buffer on either side of the IOP. Peak IOP (PIOP) was defined as four consecutive weeks containing the peak week with the most number of positive influenza tests. Off-PIOP was defined as the 'shoulder' weeks during each IOP. Non-influenza season (NIS) was the remaining weeks of that study season. Rate ratios of mean daily MAARI-related admissions resulting in advanced medical support outcomes during PIOP or Off-PIOP were compared with the NIS and were significantly elevated for all 12 study seasons combined. The results suggest that influenza outbreaks are associated with increased advanced medical support utilisation by children with MAARI. We feel that this data may help preparedness for severe influenza epidemics or pandemic.

Placebo response in relation to clinical trial design: a systematic review and meta-analysis of randomized controlled trials for determining biologic efficacy in psoriasis treatment.

There is a need to better define how the efficacy of investigational drugs is affected by study design, implementation, and placebo responses in randomized controlled trials. The improvements observed in placebo groups within trials examining psoriasis treatments may be partially due to study design and implementation. We conducted a systematic review of randomized placebo-controlled trials assessing the efficacy of biologics in the treatment of psoriasis and psoriatic arthritis to evaluate rates of placebo and active drug responders to determine specific factors within study design that may contribute to placebo responses. We included randomized, placebo-controlled trials of etanercept, infliximab, adalimumab, golimumab, ustekinumab, alefacept, and efalizumab that utilized Psoriasis Area Severity Index as an outcomes measure. We compared the rates of the placebo treatment arm versus the active drug arm achieving 75 % improvement of Psoriasis Area Severity Index. 31 trials involving 8285 active treatment and 3999 placebo patients were included. Rates of placebo responders (4.14 %) were significantly lower than active drug responders (48.4 %). The overall odds ratio calculated was 23.94 (p < 0.0001, 95 % CI 16.02-35.76). Binomial regression models showed that treatment indication, randomization fraction, a PASI inclusion requirement, and the time period of outcomes measure documentation affect placebo responses. Placebo responses seen in randomized controlled trials evaluating biologics in the treatment of psoriasis are not likely due to a physiologic mechanism, but may be secondary to chronic disease course and factors of clinical trial design and implementation.

Elevated levels of soluble TNF receptors 1 and 2 correlate with Plasmodium falciparum parasitemia in pregnant women: potential markers for malaria-associated inflammation.

Plasmodium falciparum-infected erythrocytes (IEs) sequester in the intervillous space (IVS) of the placenta causing placental malaria (PM), a condition that increases a woman's chances of having a low-birth-weight baby. Because IEs sequester, they frequently are not observed in peripheral blood smears, resulting in women with PM being misdiagnosed and thus not treated. Because sequestered IEs induce inflammation in the IVS, detection of inflammatory mediators in the peripheral blood may provide an approach for diagnosing PM. Two counterregulatory molecules, TNF-αR (TNFR) 1 and TNFR2, modulate the pathological effects of TNF-α. Levels of these soluble TNFRs (sTNFRs) are reported to be elevated in children with severe malaria, but it is unclear if they are increased in the peripheral blood of PM-positive women with asymptomatic infections. In this study, sTNFR levels were measured throughout the course of pregnancy, as well as at delivery, in women with asymptomatic infections and those who remained uninfected. Results showed that both sTNFRs were significantly increased in the peripheral blood of women with asymptomatic malaria (p < 0.0001) and were positively correlated with parasitemia (p < 0.0001 for sTNFR1 and p = 0.0046 for sTNFR2). Importantly, levels of sTNFR2 were elevated in the peripheral blood of women who were PM-positive but peripheral blood-smear negative (p = 0.0017). Additionally, sTNFR2 levels were elevated in the blood of malaria-positive women who delivered low-birth-weight babies. In vitro studies demonstrated that syncytiotrophoblasts were not a major source of sTNFR. These data suggest that sTNFR2 may be a valuable biomarker for detection of malaria-associated inflammation.

Genetic polymorphisms of mannose-binding lectin do not influence placental malaria but are associated with preterm deliveries.

During pregnancy, Plasmodium falciparum-infected erythrocytes (IE) sequester in the placenta where they induce pathology and increase the risk of low-birth-weight (LBW) babies. The innate immune mediator, mannose-binding lectin (MBL), enhances phagocytosis of pathogens. Since MBL is reported to bind to IE, we hypothesized that it might aid in clearance of IE from the placenta, thereby reducing the risk of LBW babies. To test this hypothesis, molecular genotyping was used to detect polymorphisms at codon 57 (A/C) in exon 1 of MBL2 in 401 pregnant Cameroonian women, with or without placental malaria, who had LBW and normal-weight babies. Polymorphisms in the promoter region at positions -550 (H/L), -221 (X/Y), and +4 (P/Q) were also determined, and plasma MBL levels were measured during pregnancy and at delivery. The expected correlation between genotype and plasma MBL levels was confirmed. However, asymptomatic infections were not associated with an increase in MBL levels in the peripheral blood, and MBL levels were similar in the placental and cord blood of women with or without placental malaria at delivery. There was no evidence that MBL levels at delivery were associated with malaria-related poor pregnancy outcomes. Women with the LXPA haplotype, however, were more likely to have LBW babies, but the risk was not related to malaria. These results do not support the hypothesis that MBL aids in the clearance of parasites from the placenta but suggest that Cameroonian women with LXPA are at risk of having LBW babies due to other causes.