Physical Activity in Patients with Sarcoidosis: The Role of Cardiac and Musculoskeletal Involvement

A Cast of the Left Bronchial Tree

Unfolded Protein Response in Acute Respiratory Distress Syndrome

Deletion of LysM in LysMCre Recombinase Homozygous Mice is Non-contributory in LPS-Induced Acute Lung Injury Abstract Lysozyme is an important component of the innate immune system and has roles in peptidoglycan cleavage of gram-positive organisms. Myeloid cells highly express the isoform, lysozyme M, and its promoter has been used to direct Cre recombinase expression to target deletion of floxed genes in myeloid cells. However, generation of the LysMCre mouse effectively disrupts the LysM gene, and mice homozygous for the Cre allele lack the LysM gene product. To test the contribution of LysM in sterile acute lung injury, we generated LysMCre mice homozygous for the Cre allele (+/+) or wild-type allele (−/−). These mice were challenged with LPS delivered via oropharygneal aspiration. Mice were monitored and weighed daily, and BAL cell counts, differential, protein, and cytokine levels were assessed at days 2 and 4. LysMCre+/+ and LysMCre−/− had similar weight loss and recovery, and similar inflammatory responses to LPS at days 2 and 4. These findings indicate that loss of LysM and expression of Cre recombinase are non-contributory in sterile acute lung injury.

Management of Australian Adults with Bronchiectasis in Tertiary Care: Evidence-Based or Access-Driven? Abstract Purpose Australian data regarding the management of patients with bronchiectasis is scarce. We sought to compare the management of adults with bronchiectasis attending tertiary Australian centres with recent national and international guidelines. Methods The Australian Bronchiectasis Registry is a centralised database of patients with radiologically confirmed bronchiectasis unrelated to cystic fibrosis recruited from 14 tertiary Australian hospitals. We excluded children (<18 years) and those with incomplete data, leaving 589 adults for cross-sectional analyses. We compared the proportion of patients receiving certain therapies, as compared to the proportion eligible for those treatments according to the current guidelines and baseline clinical information available from the registry. Results Pulmonary rehabilitation was attended by 22%, although it was indicated in 67% of the cohort. Airway clearance was undertaken in 52% of patients, although 71% reported chronic productive cough. Sputum bacterial culture results were available for 59%, and mycobacterial culture results were available for 29% of the cohort. Inhaled antibiotics were used in half of potentially eligible patients. Despite guideline recommendations against routine use, inhaled corticosteroids were used in 48% of patients. Long-term macrolides were used in 28% of participants. Conclusions Discrepancies exist between guideline recommendations and real-world treatment of bronchiectasis in Australia, even in tertiary centres. These findings suggest the need for increased patient referral to pulmonary rehabilitation, increased attention to airway clearance, increased collection of sputum samples (especially for mycobacterial culture) and rationalisation of inhaled corticosteroid use. These findings encourage a review of treatment access and will inform ongoing education to promote evidence-based care for people living with bronchiectasis.

Development of Chronic Pseudomonas aeruginosa- Positive Respiratory Cultures in Children with Tracheostomy Abstract Background Up to 90% of children develop Pseudomonas aeruginosa (Pa)-positive respiratory cultures after tracheotomy. Objective To identify the factors associated with chronic Pa-positive respiratory cultures in the first 2 years after tracheotomy. Methods We conducted a retrospective cohort study of 210 children ≤ 18 years old who underwent tracheotomy at a single freestanding children’s hospital that had two or more years of respiratory cultures post-tracheotomy available for analysis. We conducted multivariable logistic regression to test the association between demographic and clinical factors to our primary outcome of chronic Pa infection, defined as > 75% of respiratory cultures positive for Pa in the first 2 years after tracheotomy. Results Of the primarily male (61%), Hispanic (68%), and publicly insured (88%) cohort, 18% (n = 37) developed chronic Pa-positive respiratory cultures in the first 2 years. On multivariable logistic regression, pre-tracheotomy Pa-positive respiratory culture (aOR 11.3; 95% CI 4–1.5) and discharge on beta agonist (aOR 6.3; 95% CI 1.1–36.8) were independently associated with chronic Pa-positive respiratory cultures, while discharge on chronic mechanical ventilation was associated with decreased odds (aOR 0.3; 95% CI 0.1–0.7). On sensitivity analysis examining those without a pre-tracheotomy Pa-positive respiratory culture, discharge on MV continued to be associated with decreased odds of chronic Pa (aOR 0.1; 95% CI 0.02–0.4) and three other variables (male gender, chronic lung disease, and discharge on inhaled corticosteroids) were associated with increased odds of chronic Pa. Conclusion Because pre-tracheotomy Pa growth on respiratory culture is associated with post-tracheotomy chronic Pa-positive respiratory cultures, future research should examine pre-tracheotomy Pa eradication or suppression protocols.

Characterisation of a New Human Alveolar Macrophage-Like Cell Line (Daisy) Abstract Purpose There is currently no true macrophage cell line and in vitro experiments requiring these cells currently require mitogenic stimulation of a macrophage precursor cell line (THP-1) or ex vivo maturation of circulating primary monocytes. In this study, we characterise a human macrophage cell line, derived from THP-1 cells, and compare its phenotype to the THP-1 cells. Methods THP-1 cells with and without mitogenic stimulation were compared to the newly derived macrophage-like cell line (Daisy) using microscopy, flow cytometry, phagocytosis assays, antigen binding assays and gene microarrays. Results We show that the cell line grows predominantly in an adherent monolayer. A panel of antibodies were chosen to investigate the cell surface phenotype of these cells using flow cytometry. Daisy cells expressed more CD11c, CD80, CD163, CD169 and CD206, but less CD14 and CD11b compared with mitogen-stimulated THP-1 cells. Unlike stimulated THP-1 cells which were barely able to bind immune complexes, Daisy cells showed large amounts of immune complex binding. Finally, although not statistically significant, the phagocytic ability of Daisy cells was greater than mitogen-stimulated THP-1 cells, suggesting that the cell line is more similar to mature macrophages. Conclusions The observed phenotype suggests that Daisy cells are a good model of human macrophages with a phenotype similar to human alveolar macrophages.

Association Between Diaphragmatic Paralysis and Ipsilateral Cervical Spondylosis on MRI Abstract Purpose Diaphragmatic paralysis (DP) is an important cause of dyspnea with many underlying etiologies; however, frequently no cause is identified despite extensive investigation. We hypothesized that cervical spondylosis (CS), as manifest by cervical neuroforaminal stenosis on magnetic resonance imaging (MRI), is an underrecognized cause of unilateral DP. Methods A retrospective study was performed assessing cervical spine imaging utilization in the investigation of unilateral DP, and the contribution of CS to its pathogenesis. To assess the relationship between CS and DP, comparison was made between severity of ipsilateral and contralateral foraminal stenosis on cervical spine MRI in individuals with idiopathic DP, and to controls with DP of known etiology. Results Record searches identified 334 individuals with DP who were classified as idiopathic (n = 101) or DP of known etiology (n = 233). Of those with idiopathic DP, only 37% had undergone cervical spine imaging. Cervical spine MRIs, available for 32 individuals from the total cohort identified (n = 15 idiopathic DP, n = 17 DP of known etiology), were reviewed and severity of CS graded (0–2). In idiopathic DP, CS was significantly more severe (grade 2 stenosis) on the side of DP at C3–C4 (73% affected vs 13% unaffected side; p = 0.031) and C4–C5 (60% affected vs 20% unaffected side; p = 0.0039), while no difference was observed in DP of known etiology. Overall severity of CS across all cervical spine levels was significantly worse in idiopathic DP versus those with DP of known etiology. Conclusions In unilateral idiopathic DP, severity of CS is associated with DP laterality and is an underrecognized cause of diaphragmatic dysfunction. We propose that evaluation of ‘idiopathic’ DP should routinely include cervical spine imaging, preferably by MRI.

Clinical Characteristics and Natural History of Autoimmune Forms of Interstitial Lung Disease: A Single-Center Experience Abstract Objective To describe the phenotypic characteristics and natural history of patients with autoimmune forms of interstitial lung disease (ILD). Methods Retrospective, descriptive, single-center study of patients with autoimmune forms of ILD evaluated between February 2008 and August 2014. All data were extracted from the electronic medical record. Longitudinal changes in forced vital capacity (FVC%) and diffusion capacity for carbon monoxide (DLco%) in percent predicted were analyzed and time-to-event analyses for death were performed using Cox regression. Results Of the entire cohort (n = 243), systemic sclerosis (SSc)-associated ILD (n = 88, 36%), interstitial pneumonia with autoimmune features (IPAF, n = 56, 23%), rheumatoid arthritis (RA)-associated ILD (n = 42, 17%), and idiopathic inflammatory myopathy (IIM)-associated ILD (n = 26, 11%) were the most common phenotypes. The SSc-ILD, IIM-ILD, and IPAF groups had similar features: average age in the mid-50s, strongly female predominant and more likely to have nonspecific interstitial pneumonia (NSIP). In contrast, RA-ILD patients were older, gender balanced, more likely to be past smokers and were UIP predominant. Adjusted longitudinal lung function was stable during a median follow-up period of nearly 4 years and the independent predictors for death were older age (p = 0.003), male sex (p = 0.019), and lower FVC (p =  < 0.001). Conclusions The predominant phenotypes of autoimmune ILD were SSc-ILD, IPAF, RA-ILD, and IIM-ILD. In contrast to the other subsets, those with RA-ILD may be older, gender balanced, with more smoking history, and higher proportion of UIP. Longitudinal lung function was stable among the groups and younger age, female gender, and better lung function were associated with improved survival.

Thyroid Dysfunction in Patients with Pulmonary Artery Hypertension (PAH): The Effect of Therapies Affecting the Prostanoid Pathway Abstract Introduction Epoprostenol, a synthetic prostaglandin I2 (PGI2) analog, has been the mainstay of treatment for severe pulmonary arterial hypertension (PAH) for the last two decades. Treprostinil, another synthetic prostaglandin analog, and selexipag, an oral selective Inositol Phosphate (IP) prostacyclin receptor agonist, have also been approved for treatment of PAH. Prostacyclin and its analogs cause a variety of side effects in patients with PAH; however, thyroid dysfunction is rarely reported. Methods After treating an index case of thyroid dysfunction occurring after initiation of epoprostenol, we reviewed our databases of PAH patients treated with epoprostenol, treprostinil or selexipag to identify the occurrence of this association. Results We identified six cases of thyroid dysfunction in our cohort: five after initiation of an intravenous prostacyclin (epoprostenol) and one after initiation of an oral prostacyclin receptor agonist (selexipag). Four of the patients presented with hyperthyroidism and two with a large autoimmune goiter. Graves’ disease was seen in three patients, Hashimoto’s disease in two patients and thyrotoxicosis in one patient. Conclusion Therapy with medications targeting the prostacyclin pathway is a potential risk factor for the development of symptomatic thyroid disease.