Thomas Lahiri

Cystic Fibrosis Foundation Pulmonary Guideline*. Pharmacologic Approaches to Prevention and Eradication of Initial Pseudomonas aeruginosa Infection

DESCRIPTION The Cystic Fibrosis (CF) Foundation developed clinical care guidelines for the prevention of Pseudomonas aeruginosa infection, the treatment of initial P. aeruginosa infection, and the use of bronchoscopy to obtain routine airway cultures in individuals with CF. METHODS A multidisciplinary committee developed questions about the prevention and treatment of initial P. aeruginosa infection and the use of bronchoscopy to obtain routine airway cultures. The outcome measure of interest was cultures without P. aeruginosa growth. Systematic reviews of PubMed, EMBASE, and the Cochrane Central Register of Controlled Trials were conducted in May 2012 and August 2013. Searches combined controlled vocabulary terms and text words for CF and terms relevant to each question. The entire committee reviewed the evidence, and final recommendation statements were graded using the U.S. Preventive Services Task Force system. Recommendation 1: The CF Foundation strongly recommends inhaled antibiotic therapy for the treatment of initial or new growth of P. aeruginosa from an airway culture (certainty of net benefit, high; estimate of net benefit, substantial; grade of recommendation, A). The favored antibiotic regimen is inhaled tobramycin (300 mg twice daily) for 28 days. Recommendation 2: The CF Foundation recommends against the use of prophylactic antipseudomonal antibiotics to prevent the acquisition P. aeruginosa (certainty of net benefit, moderate; estimate of net benefit, zero; grade of recommendation, D). Recommendation 3: The CF Foundation recommends routine oropharyngeal cultures rather than bronchoalveolar lavage cultures obtained by bronchoscopy in individuals with CF who cannot expectorate sputum to determine if they are infected with P. aeruginosa (certainty of net benefit, moderate; estimate of net benefit, moderate; grade of recommendation, B).

Changing epidemiology of life-threatening upper airway infections: the reemergence of bacterial tracheitis.

OBJECTIVE. As a consequence of evolving medical practice, the epidemiology of potentially life-threatening upper airway infections is changing. We report our experience over 9 years with viral croup, epiglottitis, and bacterial tracheitis. PATIENTS AND METHODS. We studied a retrospective case series of patients admitted to Vermont Childrens Hospital with potentially life-threatening upper airway infections viral croup, epiglottitis, or bacterial tracheitis between 1997 and 2006. MEASUREMENT AND MAIN RESULTS. There were 107 patients with viral croup admitted to Vermont Childrens Hospital, with 16 (15%) admitted to the pediatric intensive care unit. Three patients with croup (17% of pediatric intensive care unit admissions, 3% of total admissions) required intubation. There were no serious complications. Eighteen patients were admitted with bacterial tracheitis. Ninety-four percent (n = 17) were admitted to the pediatric intensive care unit. Eighty-three percent (n = 15) were intubated. Twenty-eight percent of patients (n = 5) developed serious complications. Two adolescent patients were admitted with epiglottitis. Both were intubated and recovered without complications. Of 35 patients admitted to the pediatric intensive care unit with these potentially life-threatening upper airway infections, 20 patients (57%) developed respiratory failure. Fifteen patients (75%) had bacterial tracheitis, 3 patients (15%) had viral croup, and 2 patients (10%) had nonclassic epiglottitis. CONCLUSIONS. Immunization against Haemophilus influenza type b and widespread use of corticosteroids for the treatment of viral croup have changed the epidemiology of acute infectious upper airway disease. As potentially life-threatening infections, viral croup and epiglottitis have been eclipsed by bacterial tracheitis. In this series, bacterial tracheitis was 3 times more likely to have caused respiratory failure than viral croup and epiglottitis combined. Bacterial tracheitis should be considered in children who present with acute life-threatening upper airway infection.

Clinical Practice Guidelines From the Cystic Fibrosis Foundation for Preschoolers With Cystic Fibrosis

Cystic fibrosis (CF) clinical care guidelines exist for the care of infants up to age 2 years and for individuals ≥6 years of age. An important gap exists for preschool children between the ages of 2 and 5 years. This period marks a time of growth and development that is critical to achieve optimal nutritional status and maintain lung health. Given that disease often progresses in a clinically silent manner, objective and sensitive tools that detect and track early disease are important in this age group. Several challenges exist that may impede the delivery of care for these children, including adherence to therapies. A multidisciplinary committee was convened by the CF Foundation to develop comprehensive evidence-based and consensus recommendations for the care of preschool children, ages 2 to 5 years, with CF. This document includes recommendations in the following areas: routine surveillance for pulmonary disease, therapeutics, and nutritional and gastrointestinal care.

Baseline Characteristics and Factors Associated With Nutritional and Pulmonary Status at Enrollment in the Cystic Fibrosis EPIC Observational Cohort

The EPIC Observational Study is an ongoing prospective cohort study investigating risk factors for and clinical outcomes associated with early Pseudomonas aeruginosa (Pa) acquisition in young children with cystic fibrosis (CF).

Barriers to adherence to cystic fibrosis infection control guidelines

In 2003, the American Cystic Fibrosis (CF) Foundation published revised, evidence‐based guidelines for infection control. We sought to assess potential barriers to adherence to these guidelines experienced by health care professionals (HCPs) caring for CF patients.

Efficacy and safety of lumacaftor and ivacaftor in patients aged 6–11 years with cystic fibrosis homozygous for F508del-CFTR: a randomised, placebo-controlled phase 3 trial

BACKGROUND Lumacaftor and ivacaftor combination treatment showed efficacy in patients aged 12 years or older with cystic fibrosis homozygous for F508del-cystic fibrosis transmembrane conductance regulator (CFTR) in placebo-controlled studies and patients aged 6-11 years with cystic fibrosis homozygous for F508del-CFTR in an open-label study. We report efficacy and safety of lumacaftor and ivacaftor in patients with cystic fibrosis aged 6-11 years homozygous for F508del-CFTR. METHODS In this phase 3, randomised, double-blind, placebo-controlled, multicentre study, patients were enrolled at 54 hospitals and medical centres in nine countries (the USA, Australia, Belgium, Canada, Denmark, France, Germany, Sweden, and the UK). Eligible patients weighed at least 15 kg, with a confirmed diagnosis of cystic fibrosis, percent predicted forced expiratory volume in 1 s (FEV1) of 70 or more, and lung clearance index2·5 (LCI2·5) of 7·5 or more at screening (values less than these thresholds were permitted at day 1). All patients were tested for CFTR genotype at screening; eligible patients had to have the F508del-CFTR mutation on both alleles. Exclusion criteria included any comorbidity or laboratory abnormality that might confound the study results or pose additional risk to the patient. Patients were stratified by weight (<25 kg vs ≥25 kg) and ppFEV1 severity (<90 vs ≥90) determined at the screening visit, and randomly assigned 1:1 to treatment using an interactive web response system to receive 200 mg lumacaftor and 250 mg ivacaftor every 12 hours or placebo for 24 weeks. Patients, all site personnel including the investigator and the site monitor, and the study team were blinded, with the exception of site personnel needing this information in the event of medical emergency or pregnancy and patient safety and regulatory affairs personnel to meet serious adverse event reporting requirements. The primary endpoint was the mean absolute change in LCI2·5 from all on-treatment study visits up to and including week 24. All randomly assigned patients who were exposed to any amount of study drug, with treatment assignment as assigned were included in primary and other efficacy analyses. All patients who were exposed to any amount of study drug, with treatment assignment as treated, were included in the safety analysis. This study was registered with ClinicalTrials.gov, number NCT02514473. FINDINGS Between July 23, 2015, and Sept 20, 2016, a total of 206 patients were enrolled and randomly assigned to receive lumacaftor and ivacaftor (n=104) or placebo (n=102). Two randomly assigned patients were never dosed with study drug (one in the placebo arm due to ineligibility arising from a streptococcal throat infection and one in the lumacaftor and ivacaftor arm due to withdrawal based on refusal to provide blood tests) and were not included in the analyses. 103 patients received at least one dose of lumacaftor and ivacaftor and 101 patients received at least one dose of placebo. For the primary endpoint, the average absolute change in LCI2·5 from baseline over all study visits up to and including the week 24 visit, least squares mean difference was -1·09 units (95% CI -1·43 to -0·75, p<0·0001) for lumacaftor and ivacaftor versus placebo. For the key secondary endpoint of sweat chloride concentration, the least squares mean difference versus placebo was -20·8 mmol/L (95% CI -23·4 to -18·2, average absolute change at day 15/week 4; p<0·0001). The least squares mean difference compared with placebo in absolute change in ppFEV1 from all on-treatment study visits until week 24 was 2·4 (95% CI 0·4-4·4, p=0·0182). 196 (96%) of 204 patients reported adverse events, most of which were mild (87 [43%]) or moderate (98 [48%]). Treatment was discontinued due to adverse events in three (3%) of 103 patients in the lumacaftor and ivacaftor group and two (2%) of 101 patients in the placebo group. Serious adverse events were reported in 13 (13%) of 103 patients in the lumacaftor and ivacaftor group and 11 (11%) of 101 patients in the placebo group. INTERPRETATION Treatment with lumacaftor and ivacaftor was associated with statistically significant improvements in lung function, as measured by LCI2·5 and ppFEV1, versus placebo in patients aged 6-11 years with cystic fibrosis homozygous for F508del-CFTR. The overall safety profile was consistent with previous phase 3 studies of lumacaftor and ivacaftor. FUNDING Vertex Pharmaceuticals.

A survey of once-daily dosage tobramycin therapy in patients with cystic fibrosis.

The purpose of this study was to quantify the prevalence of once‐daily dosage of tobramycin (ODDT) among Cystic Fibrosis Foundation‐accredited care centers and affiliated programs (CFFACCs) and characterize the ODDT approaches used by these institutions. An anonymous cross‐sectional survey of CFFACCs was performed using an electronic survey tool. This tool was electronically mailed to the program directors. Eighty‐four out of 195 institutions completed the survey (response rate = 43%). Fifty‐one (61%) of 84 centers reported using ODDT. Of those 51 institutions, 34 (67%) use a dosage of 10 mg/kg/dose. Serum creatinine was measured routinely in 51 centers (100%) with weekly monitoring being used in 40 centers (78%). Audiometric evaluation was performed routinely in 22 (43%) centers with annual assessment performed in 14 (64%) of these 22 centers. In conclusion, a majority of responding institutions use ODDT. The most common reported dosage is 10 mg/kg. Serum creatinine was routinely measured in all institutions with weekly assessment being the most common frequency. Audiometic assessment is routinely performed in <50% of centers. Of the institutions performing audiograms routinely, annual assessment is the most common frequency. Pediatr Pulmonol. 2009; 44:325–329.

High-dose ibuprofen is not associated with increased biomarkers of kidney injury in patients with cystic fibrosis.

High‐dose ibuprofen (IBU) may slow the decline of lung function in patients with cystic fibrosis (CF), but its use has been limited due to concerns over renal and gastrointestinal toxicity. In this pilot study, we examined the association of IBU with markers of acute kidney injury (AKI) in patients with CF. The effect of aminoglycoside (AG) exposure on AKI biomarkers was also examined. The AKI markers, kidney injury molecule‐1 (KIM), N‐acetyl‐β‐glucosaminidase (NAG) and urine protein, normalized for creatinine, were chosen as they are more sensitive indicators of kidney injury than changes in serum creatinine. Urine samples from 52 patients, 26 from patients who were treated with IBU, were analyzed. There was no significant association between IBU treatment and KIM‐1, NAG or protein levels, compared to patients never treated with IBU. While there was an association between AG courses and KIM‐1 levels, there were no differences in biomarker levels between IBU and non‐IBU groups with respect to AG courses. These preliminary results suggest that IBU treatment in patients with CF may be safe with respect to renal toxicity. Pediatr Pulmonol. 2014; 49:148–153.

A Breath Biofeedback Computer Game for Children With Cystic Fibrosis

The authors sought to develop and test a breath-controlled video game using a digital spirometer that, by providing visual breath biofeedback, could promote awareness of breathing techniques in children with cystic fibrosis (CF). To assess improvement in game performance during hospitalizations for CF exacerbations, the authors conducted a trial on 10 inpatients. Subjects had at least five 15-minute exposures to a breath biofeedback game that challenged them to track a moving target using their breath. Subjects reacted positively to the breath tracking challenge. Repeated-measures analysis of variance of a tracking fidelity statistic showed improvement in eye—breath coordination over 5 sessions ( P = .026). It was concluded that an electronic breath game is safe and can improve breath awareness among children with CF. This technology could also contribute to awareness of respiratory symptoms and foster social ties among CF patients.

Exhaled nitric oxide decreases in association with attendance at an asthma summer cAMP.

Attendance at a summer asthma camp has been associated with improved outcomes in children with asthma. We hypothesized that one mechanism involved in improved asthma outcomes is reduction in airway inflammation. To investigate this, we measured the fractional concentration of exhaled nitric oxide (FeNO), lung function (forced expiratory volume in 1 sec, FEV1) and asthma control (Juniper Asthma Control Questionnaire, ACQ) from children at the beginning and end of a 1-week asthma summer camp. We also obtained a symptoms-only ACQ at 1 and 6 months after the end of camp. We enrolled 10 girls, 17 boys, mean (± SD) age = 9.6 ± 1.3 years. At baseline, FeNO (ppb), median (25–75 IQR) = 11.4 (7.2–21.3); ACQ = 0.86 (0.43–1.21); FEV1 (%pred, mean ± SD) = 87 ± 10. At the end of camp, FeNO = 6.2 (4.4–8.4), a change of −45%, p < 0.0001; ACQ = 0.71 (0.43–1.14), a fall of 14%, p = 0.72; and mean FEV1% predicted remained unchanged. There were no significant changes in the follow-up symptoms-only ACQ at 1 and 6 months. We conclude that airway inflammation, as measured by FeNO, improved during 1 week of asthma camp, but there were no significant changes in lung function or asthma control. Since no child had a change in anti-inflammatory therapy during camp, these findings suggest that airway inflammation was reduced because of improved adherence to therapy and/or reduced exposure to pro-inflammatory stimuli in the home environment. The finding of reduced inflammation following attendance at an asthma summer camp should motivate the child, the parents and the clinician to focus their efforts on improving adherence to therapy and reducing exposures at home.