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.

The Special Pathogens Research Network: Enabling Research Readiness.

The 2013-2016 epidemic of Ebola virus disease (EVD) that originated in West Africa underscored many of the challenges to conducting clinical research during an ongoing infectious disease epidemic, both in the most affected countries of Guinea, Liberia, and Sierra Leone, as well as in the United States and Europe, where a total of 27 patients with EVD received care in biocontainment units. The Special Pathogens Research Network (SPRN) was established in the United States in November 2016 to provide an organizational structure to leverage the expertise of the 10 Regional Ebola and Other Special Pathogen Treatment Centers (RESPTCs); it was intended to develop and support infrastructure to improve readiness to conduct clinical research in the United States. The network enables the rapid activation and coordination of clinical research in the event of an epidemic and facilitates opportunities for multicenter research when the RESPTCs are actively caring for patients requiring a biocontainment unit. Here we provide an overview of opportunities identified in the clinical research infrastructure during the West Africa EVD epidemic and the SPRN activities to meet the ongoing challenges in the context of Ebola virus and other special pathogens.

Safety and immunogenicity of influenza A(H5N1) vaccine stored up to twelve years in the National Pre-Pandemic Influenza Vaccine Stockpile (NPIVS).

BACKGROUND: As part of the U.S. Department of Health and Human Services (HHS) Pandemic Influenza Plan preparedness and response strategy, the National Pre-Pandemic Influenza Vaccine Stockpile (NPIVS) program was established by the Biomedical Advanced Research and Development Authority (BARDA) in 2005 with the goal of building and maintaining a stockpile of vaccines for influenza viruses with pandemic potential to vaccinate 20 million people in the critical workforce in the event of a pandemic. The NPIVS program continuously monitors the integrity of influenza vaccine antigens and adjuvants stored within the stockpile. In addition to monitoring physical and chemical properties in stability studies, it is important to regularly assess the safety and immunogenicity of stockpiled vaccines and adjuvants to maintain preparedness for use in the event of an influenza pandemic. METHODS: BARDA conducted a randomized, double-blinded Phase 2 clinical study with the oldest stockpiled influenza A(H5N1) antigen, stored over the previous 10-12 years administered with or without MF59® adjuvant, stored over the previous 2-7 years at the time of vaccination. RESULTS: Stockpiled vaccines were well-tolerated, adverse events were generally mild, and there was no drop in immunogenicity to the oldest stockpiled A(H5N1) vaccine. Compared to unadjuvanted vaccine, greater peak antibody responses were observed in subjects who were vaccinated with MF59-adjuvanted vaccines, regardless of antigen dose. Vaccination with the A(H5N1) vaccine antigen also results in cross-reactive antibody responses to contemporary circulating strains of A(H5) influenza viruses. CONCLUSIONS: The frequency, type, and severity of AEs observed during this study are similar to historical clinical study data with A(H5N1) vaccines and MF59 adjuvant indicating that a stockpiled A(H5N1) vaccine appears to remain safe and tolerable. The vaccines were immunogenic when administered as a two-dose vaccine regimen in healthy adults, despite extended storage of HA antigen or MF59 adjuvant within the NPIVS. TRIAL REGISTRATION: ClinicalTrials.gov: NCT02680002.

Randomized controlled noninferiority trial to compare extended release acetaminophen and ibuprofen for the treatment of ankle sprains.

STUDY OBJECTIVE: To compare acetaminophen extended release 1,300 mg 3 times daily and ibuprofen 400 mg 3 times daily for treatment of signs and symptoms of grade I or II lateral ankle sprains. METHODS: Patients (N=260) 18 years or older and with grade I or II lateral ankle sprains were randomized to receive acetaminophen extended release 1,300 mg 3 times daily or ibuprofen 400 mg 3 times daily for 9 days. Primary endpoint was change from baseline at day 4 in pain on walking. Other endpoints included change from baseline at day 9 in pain on walking; change from baseline at days 4 and 9 in ability to walk and ankle swelling, bruising, and range of motion; satisfaction with treatment on days 4 and 9; percentage of patients with positive anterior drawer test on day 4; and time to resume normal activity. Safety assessments consisted of reported adverse events. This study had a noninferiority design in which the hypothesis was that acetaminophen extended release was not inferior to ibuprofen for treatment of signs and symptoms of grade I or II lateral ankle sprains. RESULTS: The difference in least squares means (acetaminophen extended release, ibuprofen) with respect to the primary endpoint within the per-protocol population was -0.88; acetaminophen extended release was comparable to ibuprofen for the primary endpoint because the upper limit (3.26) of the 1-sided 95% confidence interval (CI) for the difference in least squares means did not exceed the noninferiority limit of 6.90. The intention-to-treat population was used to test the second step of the 2-step testing process because the null hypothesis was rejected in the noninferiority test. For this analysis, the difference between acetaminophen extended release and ibuprofen in the least squares mean change from baseline for the primary endpoint was -1.63 (not significant). Results showed that acetaminophen extended release was noninferior to ibuprofen with respect to the secondary endpoints. No serious drug-related adverse events were reported. The most common adverse events, reported by 6.5% of patients, were in the gastrointestinal system (mainly nausea and upper abdominal pain). CONCLUSION: Acetaminophen extended release 3,900 mg daily was comparable to ibuprofen 1,200 mg daily for treatment of grade I or II lateral ankle sprains. Both treatments were well tolerated.

Multicenter, randomized, double-blind, active-controlled, parallel-group trial of the long-term (6-12 months) safety of acetaminophen in adult patients with osteoarthritis.

OBJECTIVE: This study evaluated the safety of acetaminophen 4 g/d administered for up to 12 months to adult patients with osteoarthritis pain, using naproxen 750 mg/d as an active comparator. METHODS: This multicenter, multidose, single-dummy, randomized, double-blind, active-controlled, parallel-group study enrolled patients with mild to moderate osteoarthritis pain of the hip or knee. Patients received acetaminophen 4 g/d or naproxen 750 mg/d for 12 months (group 1) or 6 months (group 2). Patients in both groups had follow-up visits at months 1, 3, and 6 of treatment (or at the time of study withdrawal). Patients in group 1 also had follow-up visits at months 9 and 12 (or at the time of study withdrawal). Tolerability evaluations consisted of determinations of hepatic (aminotransferase activities) and renal (serum creatinine) function, adverse events, and physical examinations. Adverse events reported by the patient or observed by the investigator during clinical evaluation were recorded. In addition, patients were questioned at each visit regarding the occurrence of adverse events using a nonspecific question. Investigators rated the intensity of adverse events and their subjective assessment of the relationship to study medication while blinded to the treatment group. At all visits, patients completed the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), in visual analog scale format, to assess pain, stiffness, and physical function over the previous 2 weeks. The primary efficacy end point was the mean change from baseline in the WOMAC pain subscale score at 6 months. Data from the 6- and 12-month groups were combined for analysis. RESULTS: Of 581 randomized patients, the safety population included 571 patients who received > or = 1 dose of study medication. The 571 patients had a mean (SD) age of 59.3 (8.6) years, 395 (69.2%) were female, and 480 (84.1%) were white. Of 290 patients randomized to receive acetaminophen, 134 completed 3 months of treatment, 96 completed 6 months, 60 completed 9 months, and 55 completed a full 12 months. The median dose adherence ranged from 95.5% to 98.6% during the trial. The completion and adherence patterns were similar for patients receiving naproxen. Of 291 patients randomized to receive naproxen, 151 completed 3 months, 124 completed 6 months, 85 completed 9 months, and 80 completed 12 months. The median dose adherence ranged from 96.4% to 98.4% during the trial. No patient in either treatment group experienced hepatic failure, hepatic dysfunction, aminotransferase levels > or = 2x the upper limit of the reference range, renal failure, or serum creatinine levels > or = 1.5x the upper limit of the reference range. No statistically significant differences were observed between the 2 treatment groups in the proportion of patients who reported > or = 1 adverse event (206 [71.8%] acetaminophen, 209 [73.6%] naproxen) or in the proportion of patients who discontinued treatment because of adverse events (71 [24.7%] acetaminophen, 63 [22.2%] naproxen). Among adverse events considered to be drug related and reported by > or = 1% of patients, constipation and peripheral edema were reported more frequently in the naproxen group than in the acetaminophen group (9.9% vs 3.1% [P<0.002] and 3.9% vs 1.0% [P<0.033], respectively). No adverse event reported in the acetaminophen group was considered both serious and related to study medication. One subject in the naproxen group had an event that was considered serious and related to study drug: gastrointestinal bleeding. No statistically significant differences were observed between the 2 treatment groups for the primary efficacy end point. CONCLUSION: With physician supervision, acetaminophen was found to be generally well tolerated in these patients for the treatment of osteoarthritis pain of the hip or knee for periods of up to 12 months.