Accurate classification of interstitial lung disease (ILD) requires a multidisciplinary approach that incorporates input from an experienced respirologist, chest radiologist and lung pathologist. Despite a thorough multidisciplinary evaluation, up to 15% of ILD patients have unclassifiable ILD and cannot be given a specific diagnosis. The objectives of this review are to discuss the definition and features of unclassifiable ILD, identify the barriers to ILD classification and outline an approach to management of unclassifiable ILD. Several recent studies have described the characteristics of these patients; however, there are inconsistencies in the definition and terminology of unclassifiable ILD due to limited research in this population. Additional studies are required to determine the appropriate evaluation and management of patients with unclassifiable ILD.

Several placebo-controlled trials have been recently published evaluating novel therapies targeting the defective CFTR protein. This systematic review examines the clinical efficacy and safety of CFTR modulators in individuals with cystic fibrosis (CF) with specific genetic mutations. Online sources were searched for placebo-controlled, parallel-design clinical trials investigating CFTR modulators from January 1, 2005 to March 31, 2018. The primary outcome of interest was FEV 1 % predicted (ppFEV 1 ). Fourteen RCTs met our eligibility criteria. The largest improvement in ppFEV 1 favouring treatment was observed for ivacaftor (IVA) in G551D individuals (≥6 years old). Both tezacaftor-ivacaftor (TEZ-IVA) and lumacaftor-ivacaftor (LUM-IVA) also improved ppFEV 1 in F508del homozygous individuals but there was increased reporting of respiratory adverse events with LUM-IVA compared to placebo. IVA also significantly improved ppFEV 1 in a sub-group of individuals ≥18 years old with an R117H mutation. No significant improvements in ppFEV 1 were observed for IVA, LUM, or TEZ in F508del homozygous individuals, LUM or LUM-IVA in F508del heterozygous individuals, or ataluren in individuals with a nonsense mutation. Significant improvements in ppFEV 1 and other clinical outcomes were observed for IVA in G551D individuals, TEV-IVA and LUM-IVA in F508del homozygous individuals, and IVA in adults with a R117H mutation.

Opinion statementNontuberculous mycobacteria (NTM) are found in approximately 10 % of cystic fibrosis (CF) patients, but only a portion will develop NTM disease. The management of CF lung disease should be optimized, including antibiotic therapy targeted to the individual’s usual airway bacteria, prior to considering treatment for NTM lung disease. Those who meet criteria for NTM lung disease may not necessarily require treatment and could be monitored expectantly if symptoms and radiographic findings are minimal. However, the presence of Mycobacterium abscessus complex (MABSC), severe lung disease, and/or anticipated lung transplant should prompt NTM therapy initiation. For CF patients with Mycobacterium avium complex (MAC), recommended treatment includes triple antibiotic therapy with a macrolide, rifampin, and ethambutol. Azithromycin is generally our preferred macrolide in CF as it is better tolerated and has fewer drug-drug interactions. MABSC treatment is more complex and requires an induction phase (oral macrolide and two IV agents including amikacin) as well as a maintenance phase (nebulized amikacin and two to three oral antibiotics including a macrolide). The induction phase may range from one to three months (depending on infection severity, treatment response, and medication tolerability). For both MAC and MABSC, treatment duration is extended 1-year post-culture conversion. However, in patients who do not achieve culture negative status but tolerate therapy, we consider ongoing treatment for mycobacterial suppression and prevention of disease progression.

BackgroundBirt-Hogg-Dubé (BHD) syndrome is an autosomal dominant condition characterized by dermatologic lesions, pulmonary manifestations, and renal tumors. The syndrome arises from germline mutations in the folliculin (FLCN) gene. We present findings from the single largest family BHD cohort described to date. Primary objectives were to characterize cystic lung changes on computed tomography (CT) chest scanning and identify features that stratify patients at higher risk of pneumothorax. Secondary objectives entailed description of the following: type and natural history of BHD-associated pneumothorax, pulmonary function characteristics, and relationship between cystic lung changes and pulmonary function.MethodsThe study was a retrospective chart review for a case series of a single family. Over 70 family members of a proband with documented BHD were identified, 68 of which consented to genetic testing. All those with confirmed BHD were offered a clinical assessment by the Medical Genetics and Pulmonary services which included a history, physical exam, complete pulmonary function tests, and computed tomography (CT) scan of the chest and abdomen.ResultsThirty-six individuals had a heterozygous mutation in the FLCN gene (c.59delT). Of these, 100 % (28/28) had pulmonary cysts, 41 % (13/32) had spontaneous pneumothoraces, 26 % (8/31) had kidney cysts, 3 % (1/31) had renal tumors, and 53 % (18/34) had dermatologic manifestations. Recurrent pneumothoraces were common (40 %). Cyst size (OR 3.23, 95 % CI 1.35–7.73) and extent of lower lung zone disease (OR 6.43, 95 % CI 1.41–29.2) were the only findings associated with pneumothorax. The size or extent of cystic disease did not correlate with lung function results.ConclusionsThis is the largest single family cohort of patients with BHD syndrome documented to date. We found that all individuals had pulmonary cysts, pneumothoraces were common, and cyst size and lower lobe predominant disease were associated with pneumothorax. Lung function was generally preserved and not affected by a high cyst burden.

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