Joanne Billings

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.

Phase II studies of nebulised Arikace in CF patients with Pseudomonas aeruginosa infection

Rationale Arikace is a liposomal amikacin preparation for aerosol delivery with potent Pseudomonas aeruginosa killing and prolonged lung deposition. Objectives To examine the safety and efficacy of 28 days of once-daily Arikace in cystic fibrosis (CF) patients chronically infected with P aeruginosa. Methods 105 subjects were evaluated in double-blind, placebo-controlled studies. Subjects were randomised to once-daily Arikace (70, 140, 280 and 560 mg; n=7, 5, 21 and 36 subjects) or placebo (n=36) for 28 days. Primary outcomes included safety and tolerability. Secondary outcomes included lung function (forced expiratory volume at one second (FEV1)), P aeruginosa density in sputum, and the Cystic Fibrosis Quality of Life Questionnaire—Revised (CFQ-R). Results The adverse event profile was similar among Arikace and placebo subjects. The relative change in FEV1 was higher in the 560 mg dose group at day 28 (p=0.033) and at day 56 (28 days post-treatment, 0.093L±0.203 vs −0.032L±0.119; p=0.003) versus placebo. Sputum P aeruginosa density decreased >1 log in the 560 mg group versus placebo (days 14, 28 and 35; p=0.021). The Respiratory Domain of the CFQ-R increased by the Minimal Clinically Important Difference (MCID) in 67% of Arikace subjects (560 mg) versus 36% of placebo (p=0.006), and correlated with FEV1 improvements at days 14, 28 and 42 (p<0.05). An open-label extension (560 mg Arikace) for 28 days followed by 56 days off over six cycles confirmed durable improvements in lung function and sputum P aeruginosa density (n=49). Conclusions Once-daily Arikace demonstrated acute tolerability, safety, biologic activity and efficacy in patients with CF with P aeruginosa infection.

Insulin Secretion Improves in Cystic Fibrosis Following Ivacaftor Correction of CFTR: A Small Pilot Study

To determine whether the cystic fibrosis (CF) transmembrane conductance regulator (CFTR) is involved in human insulin secretion by assessing the metabolic impact of the new CFTR corrector—ivacaftor.

Community respiratory virus infections following lung transplantation

Abstract: Respiratory infections remain a significant cause of morbidity and mortality after lung transplantation. In addition to cytomegalovirus, the community respiratory viruses such as respiratory syncytial virus (RSV), parainfluenza virus (PIV), influenza virus, and adenovirus, are important causes of infection in transplant recipients, often involve the lower respiratory tract, and may be associated with significant morbidity and mortality. In this review, we summarize the current state of knowledge regarding the epidemiology, clinical manifestations, diagnosis, treatment and outcomes associated with RSV, PIV, influenza virus, and adenovirus infections in lung transplant recipients.

Insulin secretion improves in cystic fibrosis following ivacaftor correction of CFTR

To determine whether the cystic fibrosis (CF) transmembrane conductance regulator (CFTR) is involved in human insulin secretion by assessing the metabolic impact of the new CFTR corrector—ivacaftor.

An International Randomized Multicenter Comparison of Nasal Potential Difference Techniques

BACKGROUND The transepithelial nasal potential difference (NPD) is used to assess cystic fibrosis transmembrane conductance regulator (CFTR) activity. Unreliability, excessive artifacts, and lack of standardization of current testing systems can compromise its use as a diagnostic test and outcome measure for clinical trials. METHODS To determine whether a nonperfusing (agar gel) nasal catheter for NPD measurement is more reliable and less susceptible to artifacts than a continuously perfusing nasal catheter, we performed a multicenter, randomized, crossover trial comparing a standardized NPD protocol using an agar nasal catheter with the same protocol using a continuously perfusing catheter. The data capture technique was identical in both protocols. A total of 26 normal adult subjects underwent NPD testing at six different centers. RESULTS Artifact frequency was reduced by 75% (P < .001), and duration was less pronounced using the agar catheter. The measurement of sodium conductance was similar between the two catheter methods, but the agar catheter demonstrated significantly greater CFTR-dependent hyperpolarization, because Δ zero Cl- + isoproterenol measurements were significantly more hyperpolarized with the agar catheter (224.2 ± 12.9 mV with agar vs 18.2 ± 9.1 mV with perfusion, P < .05). CONCLUSIONS The agar nasal catheter approach demonstrates superior reliability compared with the perfusion nasal catheter method for measurement of NPD. This nonperfusion catheter method should be considered for adoption as a standardized protocol to monitor CFTR activity in clinical trials.

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.

A pre-post retrospective study of patients with cystic fibrosis and gastrostomy tubes.

Objectives: The aim of the study was to assess the efficacy of gastrostomy tube (GT) placement on improving nutritional status and pulmonary function in patients with cystic fibrosis (CF). Patients and Methods: Data were collected from the Minnesota Cystic Fibrosis Database. Subjects with at least 5 percent-predicted forced expiratory volume in 1 second (ppFEV1) and 1 BMI percentile (pBMI) measurements before and after GT placement were included. Median pBMI values were compared 2 years before and 1, 2, and 4 years after GT placement using a signed rank test. Longitudinal mixed model analysis was used to assess the effect of GT placement on ppFEV1. To assess the effect of ppFEV1 at GT placement on efficacy, the estimated ppFEV1 change was regressed against the ppFEV1 level at placement. Results: Forty-six subjects with CF who met entry criteria were identified. Mean estimated step changes in ppFEV1 at placement for men, women, boys, and girls were 2.16% (P = 0.52), 0.43% (P = 0.92), 0.99% (P = 0.65), and −0.91% (P = 0.74), respectively. Mean estimated slope changes of ppFEV1 after GT placement were 5.01% (P = 0.02), 4.48% (P = 0.07), 1.49% (P = 0.23), and 4.02% (P = 0.01) per year for men, women, boys, and girls, respectively. Median change in pBMI in the second year after GT placement was 13.3% (P ⩽ 0.0001). Estimated coefficients for the effect of ppFEV1 level at placement on the ppFEV1 step and slope change were −0.041 (P = 0.28) and −0.005 (P = 0.84), respectively. Conclusions: GT placement in patients with CF results in significant improvement in both pBMI and ppFEV1, except in women. The change in lung function after GT placement is not dependent on the level of lung function at placement.

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.

Respiratory Failure due to Possible Donor-Derived Sporothrix schenckii Infection in a Lung Transplant Recipient

Background. De novo and donor-derived invasive fungal infections (IFIs) contribute to morbidity and mortality in solid organ transplant (SOT) recipients. Reporting of donor-derived IFIs (DDIFIs) to the Organ Procurement Transplant Network has been mandated since 2005. Prior to that time no systematic monitoring of DDIFIs occurred in the United States. Case Presentation. We report a case of primary graft dysfunction in a 49-year-old male lung transplant recipient with diffuse patchy bilateral infiltrates likely related to pulmonary Sporothrix schenckii infection. The organism was isolated from a bronchoalveolar lavage on the second day after transplantation. Clinical and radiographic responses occurred after initiation of amphotericin B lipid formulation. Conclusion. We believe that this was likely a donor-derived infection given the early timing of the Sporothrix isolation after transplant in a bilateral single lung transplant recipient. This is the first case report of sporotrichosis in a lung transplant recipient. Our patient responded well to amphotericin induction therapy followed by maintenance therapy with itraconazole. The implications of donor-derived fungal infections and Sporothrix in transplant recipients are reviewed. Early recognition and management of these fungi are essential in improving outcomes.