Effect of Oral Oseltamivir on Virological Outcomes in Low-risk Adults With Influenza: A Randomized Clinical Trial.

BACKGROUND: Duration of viral shedding is a determinant of infectivity and transmissibility, but few data exist about oseltamivir's ability to alter viral shedding. METHODS: From January 2012 through October 2017, a randomized, double-blinded multicenter clinical trial was conducted in adults aged 18-64 years at 42 sites in Thailand, the United States, and Argentina. Participants with influenza A or B and without risk factors for complications of influenza were screened for the study. Eligible participants were randomized to receive oseltamivir 75 mg or placebo twice daily for 5 days. The primary endpoint was the percentage of participants with virus detectable by polymerase chain reaction in nasopharyngeal swab at day 3. RESULTS: Of 716 adults screened for the study, 558 were randomized, and 501 were confirmed to have influenza. Forty-six participants in the pilot study were excluded, and 449 of the 455 participants in the population for the primary analysis had day 3 viral shedding results. Ninety-nine (45.0%) of 220 participants in the oseltamivir arm had virus detected at day 3 compared with 131 (57.2%) of 229 participants in the placebo arm (absolute difference of -12.2% [-21.4%, -3.0%], P =; .010). The median time to alleviation of symptoms was 79.0 hours for the oseltamivir arm and 84.0 hours for the placebo arm (P =; .34) in those with confirmed influenza infection. CONCLUSIONS: Oseltamivir decreased viral shedding in this low-risk population. However, in the population enrolled in this study, it did not significantly decrease the time to resolution of clinical symptoms. CLINICAL TRIALS REGISTRATION: NCT01314911.

Anti-influenza immune plasma for the treatment of patients with severe influenza A: a randomised, double-blind, phase 3 trial.

BACKGROUND: Infection with influenza virus causes substantial morbidity and mortality globally, although antiviral treatments are available. Previous studies have suggested that anti-influenza immune plasma could be beneficial as treatment, but they were not designed as randomised, blinded, placebo-controlled trials. Therefore, we aimed to prospectively evaluate the clinical efficacy of high-titre immune plasma compared with standard low-titre plasma to improve outcomes in patients with severe influenza A infection. METHODS: We did this randomised, double-blind, phase 3 trial at 41 US medical centres to assess the efficacy of high-titre anti-influenza plasma (haemagglutination inhibition antibody titre ≥1:80) compared with low-titre plasma (≤1:10). Children and adults with PCR-confirmed influenza A infection, a National Early Warning score of 3 or greater, and onset of illness within 6 days before randomisation were eligible. Patients were randomly assigned (2:1) using an interactive web response system to receive either two units (or paediatric equivalent) of high-titre plasma (high-titre group) or low-titre plasma (low-titre group), and were followed up for 28 days from randomisation. High-titre and low-titre plasma had the same appearance. Randomisation was stratified by severity (in intensive care unit, not in intensive care but requiring supplemental oxygen, or not in intensive care and not requiring supplemental oxygen) and age (<18 years and ≥18 years). All participants, site staff, and the study team were masked to treatment allocation until after the final database lock. The primary endpoint was clinical status assessed by a six-point ordinal scale on day 7 (death, in intensive care, hospitalised but requiring supplemental oxygen, hospitalised not requiring supplemental oxygen, discharged but unable to resume normal activities, and discharged with full resumption of normal activities) analysed in a proportional odds model (an odds ratio [OR] >1 indicates improvement in clinical status across all categories for the high-titre vs the low-titre group). The primary analysis was done in the intention-to-treat population, excluding two participants who did not receive plasma. This trial is registered with ClinicalTrials.gov, NCT02572817. FINDINGS: Participants were recruited between Jan 26, 2016, and April 19, 2018. Of 200 participants enrolled (177 adults and 23 children), 140 met the criteria for randomisation and were assigned to the high-titre group (n=92) or to the control low-titre group (n=48). One participant from each group did not receive plasma. At baseline, 60 (43%) of 138 participants were in intensive care and 55 (71%) of 78 participants who were not in intensive care required oxygen. 93% of planned plasma infusions were completed. The study was terminated in July, 2018, when independent efficacy analysis showed low conditional power to detect an effect of high-titre plasma even if full accrual (150 participants) was achieved. The proportional OR for improved clinical status on day 7 was 1·22 (95% CI 0·65-2·29, p=0·54). 47 (34%) of 138 participants experienced 88 serious adverse events: 32 (35%) with 60 events in the high-titre group and 15 (32%) with 28 events in the low-titre group. The most common serious adverse events were acute respiratory distress syndrome (ARDS; four [4%] vs two [4%]), allergic transfusion reactions (two [2%] vs two [4%]), and respiratory distress (three [3%] vs none). 65 (47%) participants experienced 183 adverse events: 42 (46%) with 126 events in the high-titre group and 23 (49%) with 57 events in the low-titre group. The most common adverse events were anaemia (four [3%] vs two [4%]) and ARDS (four [3%] vs three [5%]). Ten patients died during the study (six [7%] in the high-titre group vs four [9%] in the low-titre group, p=0·73). The most common cause of death was worsening of acute respiratory distress syndrome (two [2%] vs two [4%] patients). INTERPRETATION: High-titre anti-influenza plasma conferred no significant benefit over non-immune plasma. Although our study did not have the precision to rule out a small, clinically relevant effect, the benefit is insufficient to justify the use of immune plasma for treating patients with severe influenza A. FUNDING: National Institute of Allergy and Infectious Diseases of the National Institutes of Health (Bethesda, MD, USA).

Oseltamivir, amantadine, and ribavirin combination antiviral therapy versus oseltamivir monotherapy for the treatment of influenza: a multicentre, double-blind, randomised phase 2 trial.

BACKGROUND: Influenza continues to have a substantial socioeconomic and health impact despite a long established vaccination programme and approved antivirals. Preclinical data suggest that combining antivirals might be more effective than administering oseltamivir alone in the treatment of influenza. METHODS: We did a randomised, double-blind, multicentre phase 2 trial of a combination of oseltamivir, amantadine, and ribavirin versus oseltamivir monotherapy with matching placebo for the treatment of influenza in 50 sites, consisting of academic medical centre clinics, emergency rooms, and private physician offices in the USA, Thailand, Mexico, Argentina, and Australia. Participants who were aged at least 18 years with influenza and were at increased risk of complications were randomly assigned (1:1) by an online computer-generated randomisation system to receive either oseltamivir (75 mg), amantadine (100 mg), and ribavirin (600 mg) combination therapy or oseltamivir monotherapy twice daily for 5 days, given orally, and participants were followed up for 28 days. Blinded treatment kits were used to achieve masking of patients and staff. The primary endpoint was the percentage of participants with virus detectable by PCR in nasopharyngeal swab at day 3, and was assessed in participants who were randomised, had influenza infection confirmed by the central laboratory on a baseline nasopharyngeal sample, and had received at least one dose of study drug. Safety assessment was done in all patients in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, number NCT01227967. FINDINGS: Between March 1, 2011, and April 29, 2016, 633 participants were randomly assigned to receive combination antiviral therapy (n=316) or monotherapy (n=317). Seven participants were excluded from analysis: three were not properly randomised, three withdrew from the study, and one was lost to follow-up. The primary analysis included 394 participants, excluding 47 in the pilot phase, 172 without confirmed influenza, and 13 without an endpoint sample. 80 (40·0%) of 200 participants in the combination group had detectable virus at day 3 compared with 97 (50·0%) of 194 (mean difference 10·0, 95% CI 0·2-19·8, p=0·046) in the monotherapy group. The most common adverse events were gastrointestinal-related disorders, primarily nausea (65 [12%] of 556 reported adverse events in the combination group vs 63 [11%] of 585 reported adverse events in the monotherapy group), diarrhoea (56 [10%] of 556 vs 64 [11%] of 585), and vomiting (39 [7%] of 556 vs 23 [4%] of 585). There was no benefit in multiple clinical secondary endpoints, such as median duration of symptoms (4·5 days in the combination group vs 4·0 days in the monotherapy group; p=0·21). One death occurred in the study in an elderly participant in the monotherapy group who died of cardiovascular failure 13 days after randomisation, judged by the site investigator as not related to study intervention. INTERPRETATION: Although combination treatment showed a significant decrease in viral shedding at day 3 relative to monotherapy, this difference was not associated with improved clinical benefit. More work is needed to understand why there was no clinical benefit when a difference in virological outcome was identified. FUNDING: National Institute of Allergy and Infectious Diseases, National Institutes of Health, USA.

Comparison of esophageal acid exposure distribution along the esophagus among the different gastroesophageal reflux disease (GERD) groups.

BACKGROUND: Patients with nonerosive reflux disease (NERD) have the lowest esophageal acid exposure profile compared with the other gastroesophageal reflux disease (GERD) groups. AIM: To compare lower esophageal acid exposure recordings 1 cm above the lower esophageal sphincter (LES) with those 6 cm above the LES as well as to determine the characteristics of esophageal acid exposure along the esophagus among the different GERD groups. METHODS: Patients with classic heartburn symptoms were enrolled into the study. Patients were evaluated by a demographics questionnaire and the validated GERD Symptom Checklist. Upper endoscopy was performed to evaluate the presence of esophageal erosions and Barrett's esophagus (BE). Ambulatory pH testing was performed using a commercially available 4-sensor pH probe with sensors located 5 cm apart. The distal sensor was placed 1 cm above the LES. RESULTS: Sixty-four patients completed the study. Of those, 21 patients had NERD, 20 had erosive esophagitis (EE), and 23 had BE. All patient groups demonstrated greater esophageal acid exposure 1 cm above the LES than 6 cm above the LES. In NERD and EE, this phenomenon was primarily a result of a higher mean percentage of upright time with pH <4. Unlike patients with EE and BE, those with NERD had very little variation in esophageal acid exposure throughout the esophagus (total and supine). CONCLUSIONS: ALL GERD groups demonstrated significant greater esophageal acid exposure at the very distal portion of the esophagus, primarily as a result of short upright reflux events. Unlike erosive esophagitis and BE, NERD patients demonstrate a more homogenous acid distribution along the esophagus.

Functional heartburn patients demonstrate traits of functional bowel disorder but lack a uniform increase of chemoreceptor sensitivity to acid.

BACKGROUND: Functional heartburn (FH) patients have a profound impact on the response to anti-reflux therapy of the nonerosive reflux disease (NERD) group as compared to the response of the erosive esophagitis group. Thus far, there is paucity of information about their physiological and clinical characteristics that may separate them from the other NERD patients. AIM: To compare physiological and clinical characteristics of patients with FH to their counterparts within the NERD group (NERD-positive [NERD+]). METHODS: Subjects with typical heartburn symptoms, at least twice a week, were evaluated by an upper endoscopy. Only those with normal esophageal mucosa were recruited into the study and underwent pH testing to assess esophageal acid exposure. The patients were divided into those with normal pH test (FH) and those with abnormal pH test (NERD+). The groups were compared for demographics, gastroesophageal reflux disease symptom characteristics, psychological profile, and reported quality of life. Additionally, the two patient groups were compared for stimulus response functions to acid, autonomic function response, and rate of Helicobacter pylori infection. RESULTS: Fifty-two patients included 30 with FH and the rest with NERD+. There was no statistical difference in demographics, frequency of hiatal hernia and H. pylori infection between the two groups. Patients with FH had a significantly longer history of heartburn and reported more episodes of chest pain than NERD+ patients (M--7.5 yr and M--once a week vs M--3.5 yr and M--once a month, respectively, p < 0.05). Patients with FH scored significantly higher in the somatization domain than patients with NERD+ (M--60 vs 52.5, p < 0.05), but had similar reported quality of life. Patients with NERD+ demonstrated a significantly shorter time to symptom perception and higher intensity rating (p < 0.05). Only patients with FH demonstrated a statistically significant increase in heart rate and skin conductance after acid perfusion, as compared to those with NERD+ (p < 0.05). CONCLUSION: Patients with FH demonstrate increased reports of chest pain and somatization, an alteration in autonomic function but lack a uniform increase in chemoreceptor sensitivity to acid as compared to those with NERD+. This suggests that while FH patients harbor clinical traits of a functional bowel disorder, hypersensitivity to acid is not a general phenomenon.

Attitudes and referral patterns of primary care physicians when evaluating subjects with noncardiac chest pain--a national survey.

Noncardiac chest pain (NCCP) may affect up to 23% of the U.S. population. The clinical approach and referral patterns of primary care physicians (PCPs) when evaluating NCCP subjects are unknown. We aimed to determine the preferences of diagnostic tests, referral patterns, and treatment plans of NCCP patients by PCPs. PCPs were randomly selected from the American Medical Association national membership list. A 24-item questionnaire was mailed, which focused on demographic information, characteristics of practice, preferences of diagnostic tests, referral patterns, and treatment plans. Two hundred five (40%) PCPs returned the questionnaire (mean age, 49; 77% males; practice type--community-based, 40.5%; hospital-based, 10.7%; and combined, 47.3%; physician type--internists, 46.3%; family physicians, 44.4%; general practitioners, 4.9%; and others, 2.9%). The mean number of NCCP patients seen in the past 6 months was 108 (6.4% of total patients) and 79.5% were treated primarily by PCPs. The three most common diagnostic tests used were empirical proton pump inhibitor (PPI) trial (45.6%), chest radiograph (39.9%), and upper endoscopy (18.7%). Most PCPs reported that they are either comfortable (44.6%) or very comfortable (21.2%) in diagnosing NCCP. The three most commonly used therapeutic modalities for NCCP were PPIs (37.8%), lifestyle modification (33.7%), and H2 blockers (12.4%). Of those NCCP patients referred to a subspecialist, most ended up in gastroenterology (75.6%), followed by cardiology (7.8%) and pulmonary (1.6%) clinics. We conclude that most PCP's diagnose and treat NCCP patients without referring them to a gastroenterologist. However, diagnostic and treatment strategies may not follow the current understanding and knowledge of the disorder.

Noncardiac chest pain: the role of the cardiologist--a national survey.

BACKGROUND: The current assumption is that noncardiac chest pain (NCCP) patients diagnosed by a cardiologist are commonly referred to a gastroenterologist for further evaluation. Thus far, there are no studies that assess the clinical approach and referral patterns of cardiologists when evaluating subjects with NCCP. AIM: To determine the extent of involvement of cardiologists in the management of NCCP patients. METHODS: Cardiologists were randomly selected from the American College of Cardiology national membership list and sent a 20-item questionnaire that included demographic information, characteristics of practice, preferences of diagnostic tests, referral patterns, and treatment plans. RESULTS: A total of 246 (33%) cardiologists returned the questionnaire. A mean of 12.6% of patients were diagnosed with NCCP and 45.5% were treated by a cardiologist in the past 6 months. Of the NCCP patients that were referred, most ended up in the primary care physician clinic (45.9%) followed by gastroenterologist clinic (29.3%). Most cardiologists are either comfortable (35%) or very comfortable (43.1%) in diagnosing NCCP. Proton pump inhibitors (44.9%), lifestyle modifications (28.7%), and H2 blockers (11.8%) are the three most commonly used therapeutic modalities for NCCP. CONCLUSION: Cardiologists manage about half of the diagnosed NCCP patients by themselves. Of those NCCP patients that are referred, cardiologists prefer to send them to a primary care physician rather than a gastroenterologist.