Effects of cannabis smoking on the respiratory system: A state-of-the-art review.

The diminished perception of the health risks associated with the consumption of cannabis (marijuana) lead to a progressive increase in its inhalational use in many countries. Cannabis can be smoked through the use of joints, spliffs and blunts, and it can be vaporised with the use of hookah or e-cigarettes. Delta-9 tetrahydrocannabinol (THC) is the main psychoactive component of cannabis smoke but contains numerous other substances. While the recreational use of cannabis smoking has been legalised in several countries, its health consequences have been underestimated and undervalued. The purpose of this review is to critically review the impact of cannabis smoke on the respiratory system. Cannabis smoke irritates the bronchial tree and is strongly associated with symptoms of chronic bronchitis, with histological signs of airway inflammation and remodelling. Altered fungicidal and antibacterial activity of alveolar macrophages, with greater susceptibility to respiratory infections, is also reported. The association with invasive pulmonary aspergillosis in immunocompromised subjects is particularly concerning. Although cannabis has been shown to produce a rapid bronchodilator effect, its chronic use is associated with poor control of asthma by numerous studies. Cannabis smoking also represents a risk factor for the development of bullous lung disease, spontaneous pneumothorax and hypersensitivity pneumonitis. On the other hand, no association with the development of chronic obstructive pulmonary disease was found. Finally, a growing number of studies report an independent association of cannabis smoking with the development of lung cancer. In conclusion, unequivocal evidence established that cannabis smoking is harmful to the respiratory system. Cannabis smoking has a wide range of negative effects on respiratory symptoms in both healthy subjects and patients with chronic lung disease. Given that the most common and cheapest way of assumption of cannabis is by smoking, healthcare providers should be prepared to provide counselling on cannabis smoking cessation and inform the public and decision-makers.

Validation of the risk stratification score in idiopathic pulmonary fibrosis: study protocol of a prospective, multi-centre, observational, 3-year clinical trial.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is characterized by a poor prognosis, with a progressive decline in lung function and considerable variability in the disease's natural history. Besides lung transplantation (LTx), the only available treatments are anti-fibrosing drugs, which have shown to slow down the disease course. Therefore, predicting the prognosis is of pivotal importance to avoid treatment delays, which may be fatal for patients with a high risk of progression. Previous studies showed that a multi-dimensional approach is practical and effective in the development of a reliable prognostic score for IPF. In the RIsk Stratification scorE (RISE), physiological parameters, an objective measure of patient-reported dyspnea and exercise capacity are combined to capture different domains of the complex pathophysiology of IPF. METHODS: This is an observational, multi-centre, prospective cohort study, designed to reflect common clinical practice in IPF. A development cohort and a validation cohort will be included. Patients newly diagnosed with IPF based on the ATS/ERS criteria and multi-disciplinary discussion will be included in the study. A panel of chest radiologists and lung pathologists will further assess eligibility. At the first visit (time of diagnosis), and every 4-months, MRC dyspnea score, pulmonary function tests (FEV1, FVC and DLCO), and 6-min walking distance will be recorded. Patients will be prospectively followed for 3 years. Comorbidities will be considered. The radiographic extent of fibrosis on HRCT will be recalculated at a 2-year interval. RISE, Gender-Age-Physiology, CPI and Mortality Risk Scoring System will be calculated at 4-month intervals. Longitudinal changes of each variable considered will be assessed. The primary endpoint is 3-year LTx-free survival from the time of diagnosis. Secondary endpoints include several, clinically-relevant information to ensure reproducibility of results across a wide range of disease severity and in concomitance of associated pulmonary hypertension or emphysema. DISCUSSION: The objective of this study is to validate RISE as a simple, straightforward, inexpensive and reproducible tool to guide clinical decision making in IPF, and potentially as an endpoint for future clinical trials. TRIAL REGISTRATION: U.S National Library of Medicine Clinicaltrials.gov, trial n. NCT02632123 "Validation of the risk stratification score in idiopathic pulmonary fibrosis". Date of registration: December 16th, 2015.

TPMT and HLA-DQA1-HLA-DRB genetic profiling to guide the use of azathioprine in the treatment of interstitial lung disease: First experience.

BACKGROUND: The choice of immunosuppressive therapy in interstitial lung disease (ILD) other than idiopathic pulmonary fibrosis (IPF) is based on safety profile and expected efficacy. Azathioprine is one of the most commonly used agents to treat ILD. The immunosuppressive effect and pancreatitis risk of azathioprine are influenced by the activity of the enzyme thiopurine methyltransferase (TPMT) and by the genetic mutations in HLA-DQA1-HLA-DRB locus, respectively. We hypothesized that systematic genotyping prior to starting azathioprine improves the rate of discontinuation of immunosuppressive therapy and the total incidence of adverse drug reactions (ADRs). METHODS: Eighty-two patients with ILD other than IPF were included in the study. The rate of immunosuppressive therapy discontinuation due to major ADRs and the total incidence of ADRs were compared between a cohort of genotyped patients (n = 49) and an untested cohort of patients (n = 33). RESULTS: Thirty-seven out of 49 patients in the genotyped cohort and 27 out of 33 patients in the untested cohort were started on azathioprine. The rate of immunosuppressive therapy discontinuation due to major ADRs was significantly lower (6/49) in the genotyped cohort compared to the untested cohort (11/33; p = 0.0276). All but one discontinuation due to severe ADRs occurred within a month of therapy. However, the total incidence rate of ADRs was very similar in the 2 cohorts (0.025 in the genotyped cohort vs. 0.023 in the untested cohort). CONCLUSION: In patients with ILD other than IPF, genotyping for azathioprine metabolism prior to starting therapy is associated with a significantly reduced rate of immunosuppressive therapy discontinuation due to major ADRs, with prevention of bone marrow suppression and pancreatitis, but without a reduction of the total incidence of ADRs. While these data support the use of genetic profiling prior to starting azathioprine to treat ILD, its cost effectiveness remains to be established.

Longitudinal functional changes with clinically significant radiographic progression in idiopathic pulmonary fibrosis: are we following the right parameters?

BACKGROUND: Progression of the disease in idiopathic pulmonary fibrosis (IPF) is difficult to predict, due to its variable and heterogenous course. The relationship between radiographic progression and functional decline in IPF is unclear. We sought to confirm that a simple HRCT fibrosis visual score is a reliable predictor of mortality in IPF, when longitudinally followed; and to ascertain which pulmonary functional variables best reflect clinically significant radiographic progression. METHODS: One-hundred-twenty-three consecutive patients with IPF from 2 centers were followed for an average of 3 years. Longitudinal changes of HRCT fibrosis scores, forced vital capacity (FVC), total lung capacity and diffusing lung capacity for carbon monoxide were considered. HRCTs were scored by 2 chest radiologists. The primary outcome was lung transplant (LTx)-free survival after the follow-up HRCT. RESULTS: During the follow-up period, 43 deaths and 11 LTx occurred. On average, the HRCT fibrosis score increased significantly, and a longitudinal increase > 7% predicted LTx-free survival significantly, with good specificity, but limited sensitivity. The correlation between radiographic and functional progression was moderately significant. HRCT progression and FVC decline predicted LTx-free survival independently and significantly, with better sensitivity, but worse specificity for a ≥ 5% decline of FVC. However, the area under the curve towards LTx-survival were only 0.61 and 0.62, respectively. CONCLUSIONS: The HRCT fibrosis visual score is a reliable and responsive tool to detect clinically meaningful disease progression. Although no individual pulmonary function test closely reflects radiographic progression, a longitudinal FVC decline improves sensitivity in the detection of clinically significant disease progression. However, the accuracy of these methods remains limited, and better prognostication models need to be found.

The CALIPER-Revised Version of the Composite Physiologic Index is a Better Predictor of Survival in IPF than the Original Version.

CALIPER is a computer-based quantitative algorithm to accurately characterize and quantify pulmonary fibrosis, and a revised version of composite physiologic index (CPI) has been developed against this new algorithm. The prognostic capabilities of the original and CALIPER-revised versions of CPI were compared in a cohort of 185 patients with IPF prospectively followed in 2 centers. CALIPER-revised CPI was a significant risk factor towards lung transplant (LTx)-free survival, with enhanced hazard ratio (5.68) compared to the original CPI (5.36). Accuracy of LTx-free survival was substantially improved with CALIPER-revised CPI (area under the curve [AUC] 0.75 vs. 0.66), with much better specificity (83% vs. 55%). Six-month changes of CALIPER-revised CPI predicted survival significantly (AUC 0.65). CALIPER-revised CPI is a better predictor of LTx-free survival in patients with IPF. Since CALIPER technology is not available to all centers, this simple and easy to obtain tool may be used to guide management decisions in IPF.

Sequential Introduction of Exercise First Followed by Nutrition Improves Program Adherence During Pregnancy: a Randomized Controlled Trial.

BACKGROUND: Adhering to nutrition and exercise recommendations simultaneously during pregnancy may be challenging. The purpose was to examine adherence to the sequential introduction of nutrition and exercise behaviors during pregnancy in comparison with a simultaneous approach. METHOD: A randomized controlled trial including nutrition and exercise was executed. Using a stratified body mass index (BMI) randomization, participants (n = 88) were allocated to one of three groups at 12-18 weeks gestation. Group A received nutrition and exercise simultaneously. Group B received nutrition first and Group C received exercise first, and the second behavior was added at 25 weeks gestation for both groups. The program included weekly weighing, supervised walking sessions, and/or nutrition counseling. Adherence (primary outcome) was measured by scoring women on meeting the intervention goals (3 nutrition and 3 exercise goals) and converted to a percentage. Secondary health outcomes were gestational weight gain (GWG) and excessive GWG on the program, birthweight, macrosomia (birthweight > 4000 g), and low birthweight (birthweight < 2500 g). RESULTS: Group C (n = 23) had the highest adherence to the program (80.2 ± 14.7%) compared with Groups A (n = 17; 60.9 ± 17.9%) and B (n = 20; 66.8 ± 16.7%; p < 0.05, ηp2 = 0.26). There was a significant effect for gestational weight gain (p < 0.05; ηp2 = 0.10) as Group C gained less weight (7.7 ± 2.2 kg) over Group B (9.8 ± 2.8 kg; p = 0.04), however, not Group A (9.1 ± 3.5, p = 0.35). Non-significant small effects favored Group C for the prevention of EGWG (Cramer's V = 0.13). CONCLUSION: Introducing exercise first followed by nutrition at 25 weeks gestation can improve adherence to multiple behavior change programs and thus have a positive effect on health outcomes. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02804061.

Implementing an interstitial lung disease clinic improves survival without increasing health care resource utilization.

BACKGROUND: Multidisciplinary collaboration is the cornerstone of interstitial lung disease (ILD) care. Delayed access to specialized care is associated with worse outcome. At the same time, the economic burden of ILD is high. We hypothesized that the establishment of a regional, dedicated ILD clinic would improve survival, but without necessarily causing an increase of health care resource utilization (HRU). METHODS: A historic cohort (January 2000-June 2013, n = 127) and a specialized care cohort followed by a dedicated ILD clinic (July 2013-June 2016, n = 144) were compared. Patients with idiopathic pulmonary fibrosis were excluded, due to the impact of new anti-fibrotic agents. Patients' data were linked to multiple provincial health administrative datasets. HRU included hospitalizations, doctor and emergency visits, pulmonary (including chest x-ray, chest CT scans, pulmonary function tests, bronchoscopies), cardio-vascular investigations, and specific ILD therapies. HRU was calculated as annual rate by domain. Three-year survival from initial assessment was the secondary outcome. RESULTS: The 2 cohorts were closely comparable in terms of specific ILD diagnosis, baseline lung function, comorbidities, neighbourhood income. There were overall no significant differences in terms of HRU. In the specialized care cohort, the use of non-steroid immunosuppressive therapies increased and survival significantly improved, despite significantly older age of patients at the time of initial assessment. Specialized ILD care was independently protective towards survival. CONCLUSIONS: Specialized, multi-disciplinary ILD care in a dedicated regional clinic is associated with improved survival and does not cause an increase of HRU, supporting the institution of potentially more cost-effective care with specialized ILD clinics.

Comprehensive gene expression profiling identifies distinct and overlapping transcriptional profiles in non-specific interstitial pneumonia and idiopathic pulmonary fibrosis.

BACKGROUND: The clinical-radiographic distinction between idiopathic pulmonary fibrosis (IPF) and non-specific interstitial pneumonia (NSIP) is challenging. We sought to investigate the gene expression profiles of IPF and NSIP vs. normal controls. METHODS: Gene expression from explanted lungs of patients with IPF (n = 22), NSIP (n = 10) and from normal controls (n = 11) was assessed. Microarray analysis included Significance Analysis of Microarray (SAM), Ingenuity Pathway, Gene-Set Enrichment and unsupervised hierarchical clustering analyses. Immunohistochemistry and serology of proteins of interest were conducted. RESULTS: NSIP cases were significantly enriched for genes related to mechanisms of immune reaction, such as T-cell response and recruitment of leukocytes into the lung compartment. In IPF, in contrast, these involved senescence, epithelial-to-mesenchymal transition, myofibroblast differentiation and collagen deposition. Unlike the IPF group, NSIP cases exhibited a strikingly homogenous gene signature. Clustering analysis identified a subgroup of IPF patients with intermediate and ambiguous expression of SAM-selected genes, with the interesting upregulation of both NSIP-specific and senescence-related genes. Immunohistochemistry for p16, a senescence marker, on fibroblasts differentiated most IPF cases from NSIP. Serial serum levels of periostin, a senescence effector, predicted clinical progression in a cohort of patients with IPF. CONCLUSIONS: Comprehensive gene expression profiling in explanted lungs identifies distinct transcriptional profiles and differentially expressed genes in IPF and NSIP, supporting the notion of NSIP as a standalone condition. Potential gene and protein markers to discriminate IPF from NSIP were identified, with a prominent role of senescence in IPF. The finding of a subgroup of IPF patients with transcriptional features of both NSIP and senescence raises the hypothesis that "senescent" NSIP may represent a risk factor to develop superimposed IPF.

Assessing the Therapeutic Response to Pirfenidone in Idiopathic Pulmonary Fibrosis: Can We Do Better than with Forced Vital Capacity Alone?

ABSTARCT: New anti-fibrotic agents for idiopathic pulmonary fibrosis (IPF) were approved based on the results of forced vital capacity (FVC) trends, although concerns were raised about the reliability of FVC as the only endpoint parameter. We hypothesized that IPF-specific multi-dimensional scores (Composite Physiologic Index-CPI; gender-age-physiology-GAP; risk stratification score-RISE) would better capture response to therapy. In this pilot study, treated and untreated cohorts of IPF patients, matched for demographic and functional characteristics were prospectively followed for 1 year, at 4-month intervals. Progression-free survival was significantly improved in treated patients (p = 0.0093). While no difference in FVC longitudinal trends was observed, MRC dyspnea score (p = 0.0347), diffusing lung capacity (p = 0.0015), 6-min walk distance (p = 0.0007), CPI (p = 0.0457) and RISE (p = 0.0005) were significantly stabilized in treated patients, compared to steady worsening in untreated subjects. Multi-dimensional scores provide broader spectrum of prognostic information and may facilitate the assessment of efficacy of new drugs for IPF.