Testing the effects of combining azithromycin with inhaled tobramycin for P. aeruginosa in cystic fibrosis: a randomised, controlled clinical trial.

RATIONALE: Inhaled tobramycin and oral azithromycin are common chronic therapies in people with cystic fibrosis and Pseudomonas aeruginosa airway infection. Some studies have shown that azithromycin can reduce the ability of tobramycin to kill P. aeruginosa. This trial was done to test the effects of combining azithromycin with inhaled tobramycin on clinical and microbiological outcomes in people already using inhaled tobramycin. We theorised that those randomised to placebo (no azithromycin) would have greater improvement in forced expiratory volume in one second (FEV1) and greater reduction in P. aeruginosa sputum in response to tobramycin. METHODS: A 6-week prospective, randomised, placebo-controlled, double-blind trial testing oral azithromycin versus placebo combined with clinically prescribed inhaled tobramycin in individuals with cystic fibrosis and P. aeruginosa airway infection. RESULTS: Over a 6-week period, including 4 weeks of inhaled tobramycin, the relative change in FEV1 did not statistically significantly differ between groups (azithromycin (n=56) minus placebo (n=52) difference: 3.44%; 95% CI: -0.48 to 7.35; p=0.085). Differences in secondary clinical outcomes, including patient-reported symptom scores, weight and need for additional antibiotics, did not significantly differ. Among the 29 azithromycin and 35 placebo participants providing paired sputum samples, the 6-week change in P. aeruginosa density differed in favour of the placebo group (difference: 0.75 log10 CFU/mL; 95% CI: 0.03 to 1.47; p=0.043). CONCLUSIONS: Despite having greater reduction in P. aeruginosa density in participants able to provide sputum samples, participants randomised to placebo with inhaled tobramycin did not experience significantly greater improvements in lung function or other clinical outcomes compared with those randomised to azithromycin with tobramycin.

Immune Profiling to Determine Early Disease Trajectories Associated With Coronavirus Disease 2019 Mortality Rate: A Substudy from the ACTT-1 Trial.

Coronavirus disease 2019 (COVID-19) outcomes are linked to host immune responses and may be affected by antiviral therapy. We investigated antibody and cytokine responses in ACTT-1 study participants enrolled at our center. We studied serum specimens from 19 hospitalized adults with COVID-19 randomized to treatment with remdesivir or placebo. We assessed severe acute respiratory syndrome coronavirus 2 antibody responses and identified cytokine signatures, using hierarchical clustering. We identified no clear immunologic trends attributable to remdesivir treatment. Seven participants were initially seronegative at study enrollment, and all 4 deaths occurred in this group with more recent symptom onset. We identified 3 dominant cytokine signatures, demonstrating different disease trajectories.

Colonoscopic screening shows increased early incidence and progression of adenomas in cystic fibrosis.

BACKGROUND: Colorectal cancer is an emerging problem in cystic fibrosis (CF). The goal of this study was to evaluate adenoma detection by systematic colonoscopic screening and surveillance. METHODS: We analyzed prospectively collected results of colonoscopies initiated at age 40years from 88 CF patients at a single Cystic Fibrosis Center. We also reviewed results of diagnostic colonoscopies from 27 patients aged 30-39years performed during the same time period at the Center. RESULTS: The incidence of polyp detection increased markedly after age 40 in CF patients. Greater than 50% were found to have adenomatous polyps; approximately 25% had advanced adenomas as defined by size and/or histopathology; 3% were found to have colon cancer. Multivariate analysis demonstrated specific risk factors for adenoma formation and progression. CONCLUSIONS: Early screening and more frequent surveillance should be considered in patients with CF due to early incidence and progression of adenomas in this patient population.

Early colon screening of adult patients with cystic fibrosis reveals high incidence of adenomatous colon polyps.

BACKGROUND AND GOALS: Cystic fibrosis (CF) is associated with increased incidence of gastrointestinal cancer. Increasing overall life expectancy of CF patients predicts emergence of colon cancer as a significant clinical problem in the adult CF population. The primary aim of this study was to estimate the incidence of adenomatous colon polyps in patients with CF during systematic screening by colonoscopy. STUDY: This is a single-center series of 45 CF patients aged 40 years and above (mean age, 47 y) undergoing colonoscopic screening. A fraction of these patients (9/45) had history of organ transplantation. Results from transplant and nontransplant patients were analyzed separately. RESULTS: Adult CF patients have a high incidence of adenomatous polyps identified by colonoscopy. In addition, positive examinations are characterized by multiple polyps and common features of advanced pathology. The incidence of adenomatous colon polyps is greater in male patients, although the 1 patient in this cohort found to have colorectal cancer was female. CONCLUSIONS: CF has features of a hereditary colon cancer syndrome. Increasing life expectancy of CF patients suggests that earlier colon screening in this population may be warranted. Optimal criteria for initiation of screening and frequency of surveillance should be subject of further studies.

Comparison of settings used for high-frequency chest-wall compression in cystic fibrosis.

BACKGROUND: Cystic fibrosis (CF) patients commonly use a high-frequency chest-wall compression (HFCWC) device for airway clearance that generates oscillatory flow with a sine-wave configuration. Typical HFCWC settings combine a lower Vest inflation pressure setting (eg, 5 on the Vest's arbitrary 1-10 scale for the setting that controls the background pressure of the inflatable vest) with mid-range frequency (14-16 Hz) (lower-pressure/mid-frequency HFCWC). OBJECTIVE: To determine whether HFCWC with higher pressure settings (6-10 on the Hill-Rom Vest's arbitrary 1-10 scale) combined with variable mid-frequencies (8, 9, and 10 Hz, plus 18, 19, and 20 Hz) (higher-pressure/variable-frequency HFCWC) results in greater sputum expectoration than lower-pressure/mid-frequency HFCWC. METHODS: This was a controlled randomized crossover study. Sixteen clinically stable, adult CF patients participated. Patients performed airway clearance with HFCWC, once each with lower-pressure/mid-frequency HFCWC and higher-pressure/variable-frequency HFCWC, on separate occasions. All sputum produced during each session was collected. Patients completed pulmonary function tests before and after each session. RESULTS: Median sputum wet weight was greater with higher-pressure/variable-frequency HFCWC than with lower-pressure/mid-frequency HFCWC (6.4 g, range 0.49-22.0 g, versus 4.8 g, range 0.24-15.0 g, P = .02). Dry sputum weight differences did not reach statistical significance (higher-pressure/variable-frequency HFCWC 0.20 g, range 0.009-0.62 g, lower-pressure/mid-frequency HFCWC 0.12 g, range 0.0001-1.0 g, P = .23). Higher-pressure/variable-frequency HFCWC and lower-pressure/mid-frequency HFCWC resulted in similar increases in FEV(1) (70 mL vs 90 mL, P = .21) and forced vital capacity (80 mL vs 80 mL, P = .94). Post-therapy sputum viscoelastic properties did not differ. Patients perceived the 2 regimens as equally comfortable and effective (P = .35 and P = .35, respectively). CONCLUSIONS: In adult CF patients, single-session higher-pressure/variable-frequency HFCWC resulted in greater sputum expectoration by wet weight, but not other differences, compared to the commonly used lower-pressure/mid-frequency settings. Longer-term comparisons are needed in a larger, more diverse population to determine whether sustained use of the higher-pressure/variable-frequency settings results in clinically important differences in outcomes.

High prevalence of proximal and distal gastroesophageal reflux disease in advanced COPD.

BACKGROUND: Gastroesophageal reflux disease (GERD) is common in a variety of chronic respiratory diseases, but little is known about GERD in the setting of COPD. The aims of this study were to determine the prevalence, presentation, and predictors of GERD based on proximal and distal esophageal pH monitoring in patients with severe COPD. METHODS: Forty-one COPD patients with a mean FEV1 of 24% of predicted underwent dual-probe 24-h esophageal pH monitoring, and 1 patient underwent esophagogastroduodenoscopy. RESULTS: The prevalence of GERD was 57%. Elevated distal and proximal reflux were present in 41% and 46% of patients undergoing esophageal pH studies, respectively. Fifteen percent of these patients had abnormal proximal reflux despite having normal distal probe results. Most patients with GERD were not receiving acid blockers at the time of their referral, and only one third reported heartburn and/or acid regurgitation during the pH study. Only higher body mass index was predictive of reflux on regression analysis (odds ratio, 1.2; 95% confidence interval, 1.0 to 1.5; p = 0.05). CONCLUSIONS: GERD is common in advanced COPD. Patients are often asymptomatic and have a relatively high prevalence of isolated abnormal proximal reflux. Dual-probe monitoring is therefore well suited for detecting GERD in patients with advanced COPD.

Lung function and ischemic stroke incidence: the Atherosclerosis Risk in Communities study.

BACKGROUND: Few studies have examined the relation between lung function and ischemic stroke incidence; none have studied African Americans. METHODS: We followed 13,842 middle-aged adults initially free of stroke and coronary heart disease and observed 472 incident ischemic strokes over 13 years. Quartiles of FEV(1) as a percentage of predicted value (FEV(1)PP) and FVC as a percentage of a predicted value (FVCPP) were used as the indicators of lung function. RESULTS: In the age-, race-, gender-, and education-adjusted models, both lung function measures were significantly inversely related to ischemic stroke incidence (linear trend for FEV(1)PP, p < 0.01; linear trend for FVCPP, p < 0.01), but adjustment for possible confounders attenuated these relations. For white subjects, a significant inverse relation remained even after full adjustment (relative hazards [RH] across FEV(1)PP quartiles (lowest to highest) were 1.59, 1.52, 1.26, and 1.00; and for FVCPP quartiles were 1.56, 1.80, 1.09, and 1.00 [trend for both, p < 0.05]). There was no association for African Americans (RH across FEV(1)PP and FVCPP quartiles were 0.74, 0.89, 0.73, 1.00 [linear trend, p = 0.27] and 0.81, 1.07, 0.61, 1.00 [linear trend, p = 0.75], respectively). An inverse relation between lung function and ischemic stroke was also observed among white subjects who never smoked (FEV(1)PP) or had no respiratory symptoms (both FEV(1)PP and FVCPP) but not among their African-American counterparts. CONCLUSIONS: Among white subjects, participants with impaired lung function have a modestly higher risk of ischemic stroke even if they have never smoked nor had respiratory symptoms.

Respiratory viruses and chronic rejection in lung transplant recipients.

UNLABELLED: BACKGROUND; Chronic rejection manifested as obliterative bronchiolitis (OB) and bronchiolitis obliterans syndrome (BOS) continue to be major causes of morbidity and mortality after lung transplantation. Community respiratory virus (CRV) infection, including respiratory syncytial virus, parainfluenza virus, and influenza virus, can infect and also cause morbidity in lung transplant recipients. Because CRV and OB/BOS affect the small airways, we sought to determine whether CRV infections predisposed patients to OB/BOS. METHODS: To determine whether CRV predisposed to OB/BOS, a proportional hazards regression analysis of time to OB/BOS was performed with CRV as a time-dependent covariate. To determine the influence of OB/BOS on the subsequent development of CRV infection, we reversed the outcome and time-dependent covariate. To illustrate the effect of CRV on OB/BOS and the effect of OB/BOS on CRV, landmark plots were generated at specific time points. Time to development of OB/BOS was then compared using the Kaplan-Meier method. RESULTS: In our institution, we documented 40 infections caused by CRV in 33 lung transplant recipients during an 11-year period. Community respiratory virus infections occurred predominantly during seasonal community outbreaks, except for parainfluenza infections, which occurred throughout the year. The diagnosis of OB/BOS occurred throughout the year and was not associated with seasonal outbreaks of CRV. Community respiratory virus infection involving both upper and lower respiratory tracts did not predispose to OB or BOS (relative risk [RR], 1.1; 95% confidence interval [CI], 0.52-2.3; p = 0.81). However, patients with documented CRV infection of the lower respiratory tract were predisposed to high-grade BOS development (RR, 2.3; 95% CI, 1.1-4.9; p = 0.04). In addition, a patient with pre-existing OB or BOS was predisposed to developing both upper and lower respiratory tract infection with CRV (RR, 4.2; 95% CI, 1.9-9.4; p < 0.001). CONCLUSIONS: Patients with CRV infection of the lower respiratory tract were predisposed to high-grade BOS development, and patients with OB and BOS were predisposed to CRV infections.