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BAL cellular analysis is often recommended during the initial diagnostic evaluation of fibrotic interstitial lung disease (ILD). Despite recommendation for its use, between-center heterogeneity exists and supportive data concerning the clinical utility and correlation of BAL findings with radiologic features or patterns remain sparse.

Previous studies have shown the importance of frailty in patients with fibrotic interstitial lung disease (ILD).

RationaleThe European Quality of Life 5-Dimensions 5-Levels questionnaire (EQ-5D-5L) is a multidimensional patient-reported questionnaire that supports calculation of quality-adjusted life-years. Our objectives were to demonstrate feasibility of use and to calculate the minimum important difference (MID) of the EQ-5D-5L and its associated visual analogue scale (EQ-VAS) in patients with fibrotic interstitial lung disease (ILD).MethodsPatients who completed the EQ-5D-5L were identified from the prospective multicentre CAnadian REgistry for Pulmonary Fibrosis. Validity, internal consistency and responsiveness of the EQ-5D-5L were assessed, followed by calculation of the MID for the EQ-5D-5L and EQ-VAS. Anchor-based methods used an unadjusted linear regression against pulmonary function tests (PFTs) and dyspnoea and other quality of life questionnaires. Distribution-based method used one-half SD and SE measurement (SEM) calculations.Results1816 patients were analysed, including 472 (26%) with idiopathic pulmonary fibrosis. EQ-5D-5L scores were strongly correlated with the dyspnoea and other quality of life questionnaires and weakly associated with PFTs. The estimated MID for EQ-5D-5L ranged from 0.0050 to 0.054 and from 0.078 to 0.095 for the anchor-based and distribution-based methods, respectively. The MID for EQ-VAS ranged from 0.5 to 5.0 and from 8.0 to 9.7 for the anchor-based and distribution-based methods. Findings were similar across ILD subtypes, sex and age.ConclusionWe used a large and diverse cohort of patients with a variety of fibrotic ILD subtypes to suggest validity and MID of both the EQ-5D-5L and EQ-VAS. These findings will assist in designing future clinical trials and supporting cost-effectiveness analyses of potential treatments for patients with fibrotic ILD.

AbstractRATIONALE: INSPIRATION PLUS (NCT02552849) was a prospective, observational registry of Canadian patients with idiopathic pulmonary fibrosis (IPF) treated with the oral antifibrotic agent pirfenidone. As an exploratory analysis of the registry, pirfenidone usage and safety were examined in patients with incident pirfenidone use.OBJECTIVE: To describe pirfenidone usage and tolerability in Canadian patients with IPF.METHODS: Patients with IPF who received pirfenidone were monitored prospectively beginning in April 2013. Planned outcomes included change in percent predicted forced vital capacity and the proportion of patients receiving a full pirfenidone dose (2403 mg/day). Data were collected during routine clinical visits. Pirfenidone usage and safety were analyzed in patients who initiated pirfenidone within 3 months of enrollment.RESULTS: A total of 297 patients enrolled; 125 patients with incident pirfenidone use; 98 patients with both baseline data and ≥ 1 follow-up visit comprised the analysis population. Median (range) duration of follow-up and number of follow-up visits were 10 (0.9–34.4) months and 3 (1–9) visits, respectively. Dose modifications occurred more frequently during the first 6 months of treatment than in the subsequent 6 months (23% vs 8% of patients). The incidence of adverse drug reactions was consistent with the known safety profile for pirfenidone; gastrointestinal-related events were most frequent. Increased age or a history of smoking was associated with an increased risk of discontinuing pirfenidone in the first 12 months of treatment.CONCLUSIONS: Canadian patients with IPF receiving pirfenidone had a similar safety profile compared with clinical trial data.

Fibrotic interstitial lung diseases (ILDs) are highly morbid chronic disorders that frequently occur in working age individuals. The goal of this study was to determine workplace productivity loss, its determinants, and its estimated costs in patients with fibrotic ILD.

AbstractRATIONALE: There is considerable variability in patient outcomes following bronchial thermoplasty (BT), an adjunct therapy for patients with severe asthma. It is unclear if the presence of airway inflammation is important to consider prior to BT.OBJECTIVE: The objective of the article was to ascertain if optimizing airway inflammation guided by sputum cell counts prior to BT, as compared to guideline-based-care, results in better patient outcomes and improved airway hyperresponsiveness.METHODS: We retrospectively evaluated asthmatics who underwent BT at our institution (Firestone Institute for Respiratory Health, St. Joseph’s Healthcare Hamilton, Canada) and compared clinical outcomes (asthma-quality-of-life-questionnaire [AQLQ], asthma-control-questionnaire [ACQ] and provocative concentration of methacholine required to decrease the forced expiratory volume in one second by 20% [PC20]) in those patients managed using guideline-based-care (n = 7) versus a protocol that involved optimizing airway inflammation using quantitative sputum cell counts (n = 7).MEASUREMENTS AND MAIN RESULTS: Following BT, there were greater improvements in the inflammation-optimized group than in the guideline-based-care group for the asthma-quality-of-life-questionnaire (ΔAQLQ: 2.2 ± 1.2 vs 0.8 ± 0.9, p = 0.04), asthma-control-questionnaire (ΔACQ: −2.3 ± 1.3 vs −0.5 ± 1.1, p = 0.02) and airway hyperresponsiveness (ΔPC20: 3.9 ± 1.2 vs. 0.6 ± 0.8 doubling-doses, p = 0.008).CONCLUSION: This is the first study to provide preliminary evidence that BT, when performed after normalizing sputum cell counts, significantly improves patient reported outcomes and airway hyperresponsiveness, compared to current guidelines that presume airway inflammation is controlled.

AbstractStridor is an uncommon presentation for Parkinson’s disease dystonia. We report a case of a 68-year-old female with poorly controlled Parkinson’s disease who presented to the hospital with recurrent episodes of respiratory distress and stridor. Aggressive management of her Parkinson’s disease, including the insertion of a deep brain stimulator, led to resolution of these episodes.

Clinical practice guidelines separately describe radiologic patterns of usual interstitial pneumonia (UIP) and fibrotic hypersensitivity pneumonitis (fHP), without direction on whether or how to apply these approaches concurrently within a single patient.

Interstitial lung diseases (ILD), including those related to connective tissue disease (CTD), and idiopathic pulmonary fibrosis (IPF) carry high morbidity and mortality. Great efforts are under way to develop and investigate meaningful treatments in the context of clinical trials. However, efforts have been challenged by a lack of validated outcome measures and by inconsistent use of measures in clinical trials. Lack of consensus has fragmented effective use of strategies in CTD-ILD and IPF, with a history of resultant difficulties in obtaining agency approval of treatment interventions. Until recently, the patient perspective to determine domains and outcome measures in CTD-ILD and IPF had never been applied. Efforts described here demonstrate unequivocally the value and influence of patient involvement on core set development. Regarding CTD-ILD, this is the first OMERACT working group to directly address a manifestation/comorbidity of a rheumatic disease (ILD) as well as a disease not considered rheumatic (IPF). The OMERACT 11 proceedings of the CTD-ILD Working Group describe the forward and lateral process to include both the medical and patient perspectives in the urgently needed identification of a core set of preliminary domains and outcome measures in CTD-ILD and IPF.

Bronchial thermoplasty (BT) has been demonstrated to be safe and effective in the treatment of severe persistent asthma out to at least 1 year. Preclinical studies have demonstrated that the reduction in airway smooth muscle after bronchial thermoplasty persists out to at least 3 years.

The present article will address the potential for bronchial thermoplasty to be used in addition to conventional medications to help us treat our patients with severe asthma.

Mortality risk assessment in interstitial lung disease (ILD) is challenging. Our objective was to determine the prognostic significance of BMI and change in weight in the most common fibrotic ILD subtypes.

The airway response to deep inspirations (DIs) in asthmatics has been shown to be ineffective in producing bronchodilation and can even cause bronchoconstriction. However, the manner by which a DI is able to cause bronchoconstriction remains ambiguous. We sought to investigate the pathway involved in this stretch-activated contraction and whether this contraction is intrinsic to airway smooth muscle (ASM). In brief, intact bovine bronchial segments were dissected, and side branches were ligated and then mounted horizontally in an organ bath. Intraluminal pressure was measured under isovolumic conditions. Instantaneously opening and then closing the tap on a column of fluid 5 to 30 cm high evoked a sudden increase in intraluminal pressure (equivalent to the height of the column of fluid) followed by a stress relaxation response of the ASM. When tissues were stimulated with carbachol (10-8M) or serotonin (10-7M) for 10 min, and the consequent agonist-evoked pressure response was dissipated manually, the response to the same transmural stretch was accompanied by a slowly developing and prolonged increase in intraluminal pressure. This stretch-activated response was significantly diminished by the stretch-activated cation channel blocker gadolinium (10-3M), the L-type Ca2+channel blockers nifedipine (2 × 10-6M), diltiazem (10-5M), and verapamil (10-5M), the sensory neurotoxin capsaicin (10-5M), and the neurokinin (NK)2receptor antagonists MEN 10376 ([TyrI,d-Trp6,8,9,Lys10]-NKA(4–10)) (10-5M) and SR48968 (N-[(2 S)-4-(4-acetamido-4-phenylpiperidin-1-yl)-2-(3,4-dichlorophenyl)butyl]-N-methylbenzamide) (3 × 10-6M). These results show the ability of isolated airways to exhibit stretch-activated contractions and suggest a role for stretch-activated cation channels, sensory afferent neurons, the neurotransmitter NKA, and L-type Ca2+channels in these isolated airway responses.

This article focuses on two novel asthma therapies – antibiotics and a procedure, bronchial thermoplasty. The challenges of identifying which treatment would best help an individual patient can be addressed by use of noninvasive measurements to define their asthma.

Bronchial thermoplasty is a novel procedure being developed as a potential treatment for asthma. Experience with animal studies has enabled development of appropriate reliable equipment, definition of therapeutic parameters, and descriptions of tissue effects of treatment.

To systematically review the evidence of randomized trials evaluating the effects of residential air filtration systems on patients with asthma.

Background:IL-5 measurement in the fluid phase of induced sputum is considered to be important in the assessment of asthma, but the validity of these measurements is uncertain. Objective:We investigated the validity of sputum IL-5 measurements through a series of spiking experiments and examined the effect of dithiothreitol (DTT) on these measurements. Methods:Induced sputum from 26 asthmatic subjects was spiked with IL-5 and processed, and the percentage of recovery was measured by means of immunoassay. In 6 of the 26 samples the effect of adding albumin to the processing fluids was studied. In 3 separate samples radiolabeled IL-5 was added, and the recovery measured by means of gamma counting and immunoassay were compared. In addition, the effect of DTT on the immunoassay was examined. Results:The mean ± SD recovery of spiked IL-5 was 26.1% ± 14.6% measured by means of immunoassay; adding albumin increased the recovery to 47.7% ± 8.0% (P< .001). The mean recovery measured by means of gamma counting was 84.8% ± 5.7% (P< .001); adding albumin had no effect on recovery. DTT had no significant effect on IL-5 measurement. Conclusion:The validity of IL-5 measurement by means of current methods is poor. The discrepancy in recovery as measured by gamma counting compared with immunoassay suggests that there is a problem with the recognition of IL-5 epitopes by immunoassay in induced sputum. This cannot be attributed to DTT but may be due to other interfering substances present in sputum, such as sputum proteases, soluble receptors, or autoantibodies. (J Allergy Clin Immunol 2000;105:1162-8.)

We have observed clinically relevant increases and fluctuations in metachromatic cell and eosinophil progenitors in response to antigenic challenge in patients with upper and lower respiratory tract disease. Based on this we have developed in vitro models to assess cytokine and microenvironmental influences on nasal mucosal inflammation. Purified structural cells (nasal epithelial cells or fibroblasts) grown from nasal polyps and atopic or nonatopic inferior turbinate secrete known (GM-CSF, G-CSF, and IL-6) and possibly novel (basophil differentiation factor) hemopoietic cytokines capable of inducing neutrophil, monocyte-macrophage, eosinophil, and metachromatic cell differentiation, as well as influencing their activation and survival. Nasal polyp structural cells are phenotypically different from those derived from allergic rhinitis or normal control subjects, having increased proliferative potential and constitutively producing higher levels of cytokines and extracellular matrices capable of supporting cell growth. These studies emphasize the importance of microenvironmental influences on allergic and nonallergic airway inflammation, and point out potentially new approaches to the diagnosis and therapy of nasal polyposis, allergic rhinitis, and asthma.

Secretory leukocyte proteinase inhibitor (SLPI) is the main neutrophil elastase (HLE) inhibitor found in the upper airways during pulmonary inflammation. It has been shown to be synthesized and secreted in vitro by epithelial cells and has been localized in tracheal glands and bronchiolar epithelial cells by immunocytochemistry. In this study, using immunodetection and immunopurification techniques with specific anti‐SLPI immunoglobulin G (IgG), we show that SLPI is present as a native 14‐kDa molecule in neutrophil cytosol. In addition, we demonstrate that SLPI is the major inhibitor of HLE present in neutrophil cytosol because pre‐incubation with specific anti‐SLPI IgG was able to inhibit completely the anti‐HLE activity of the cytosol. SLPI can be secreted (probably in an inactive form) by neutrophils and its secretion is enhanced when the cells are stimulated with phorbol myristate acetate (PMA). Elafin, an elastase‐specific inhibitor, is also present in minute amounts in neutrophil cytosol and its secretion can be upregulated. The presence of SLPI in the cytosol of neutrophils may serve as a protective screen against proteinases spilling from azurophilic granules. An alternative or supplementary role may be the maintenance of a differentiated phenotype. J. Leukoc. Biol. 61: 695–702; 1997.

We examined the mechanisms of corticosteroid inhibition of cell death by apoptosis in human neutrophils. Suppression of apoptosis by dexameth‐asone was abolished by co‐treatment with the protein synthesis inhibitor cycloheximide. At doses of 1 μg/mL cycloheximide did not reduce basal survival of neutrophils but effectively inhibited dexamethasone‐induced increases in 24‐h survival (24.4 ± 8.7 vs. 49.6 ± 10%, P< 0.01). Similar results were obtained with actinomycin D, an inhibitor of mRNA synthesis. The factor(s) responsible for mediating increased survival following dexamethasone treatment is not active extracellularly because dexamethasone‐treated neutrophil‐conditioned medium (CM) had no effect on the survival of naive neutrophils when the direct effects of dexamethasone were neutralized with the steroid antagonist RU‐486. In contrast, LPS‐treated neutrophil CM significantly increased neutrophil survival even after addition of polymyxin b. The survival effect of dexamethasone required the continuous presence of the agonist because addition of RU‐486 caused prompt development of apoptosis in dexamethasone‐treated cells. When naive and dexamethasone‐treated cells were examined by mRNA differential display, a limited number of cDNA bands were consistently and reproducibly detected that were increased in intensity, indicating up‐regulation by dexamethasone. Thus, corticosteroid regulation of neutrophil apoptosis is a specific effect that depends on continuous stimulation of synthesis of a (protein) survival factor. J. Leukoc. Biol. 61: 224–230; 1997.

The excitatory innervation of the airway smooth muscle is primarily cholinergic in nature. However, the potential neural mechanism(s) underlying airway hyperresponsiveness, one of the hallmarks of asthma, is not fully understood. In this study, cholinergic hyperresponsive Flinders sensitive line (FSL) rats and their control counterparts, Flinders resistant line (FRL) rats, were repeatedly challenged with different doses of nebulized methacholine (0, 4, 16, 64, and 256 mg/ml) for 5 min. Airway responsiveness was assessed in spontaneously breathing, unrestrained animals by means of whole body plethysmography. Increased airway responsiveness of FSL rats was evidenced as a more pronounced increase in Penh value (enhanced pause, an index of bronchoconstriction) across different concentrations of methacholine. In subsequent experiments, FSL and FRL rats were sensitized to ovalbumin and challenged with nebulized antigen. Our results indicate that the genetically transmitted cholinergic hyperresponsiveness of the FSL rat is paralleled by an increased susceptibility to allergen-induced bronchoconstriction and inflammation of the airways. This study provides further evidence that neural factors can play an important role in determining airway responsiveness and thus may be relevant for the expression of asthma. In addition, the FSL rat may be a useful model for studies of airway hyperresponsiveness.

SOME months ago Dr. Harry A. Bray, director of the Ray Brook Sanatorium, asked me to make a survey of the upper air tracts of the patients under his care. While engaged in this task, certain observations were made on the larynx which seemed of sufficient importance to be included in a separate report.In this study 236 patients suffering from pulmonary tuberculosis and 40 healthy adults were examined. It is important to note that I first examined all the men in one group. After finishing with the male patients, all the women were examined. This gave me an opportunity such as I never had before to compare the appearance of the larynx in a fairly large number of men, taken consecutively, with its appearance in a similar group of women.The group of males consisted of 119 patients with pulmonary tuberculosis, whose ages varied from 18 to 74. The

Tuberculosis of the middle ear was known and described as a definite clinical entity before the discovery of the tubercle bacillus by Koch in 1882. There are articles on this disease by Wilde1 (1853), Schwartze2 (1878), Toynbee and others.Aural tuberculosis was not sufficiently recognized in the past, owing partly to the belief that it was a rare disease and partly to the difficulties involved in making a positive diagnosis with the older laboratory methods.In a former communication,3 we reported the results of an investigation of a series of children examined at the Manhattan Eye and Ear Hospital and the New York Eye and Ear Infirmary. The aural discharge from these patients with chronic purulent otitis media was cultivated for tubercle bacilli, regardless of the clinical picture presented. As a routine, cultures were taken from the ears of all children with a chronic discharge when they

Background. St. Joseph’s Health System has implemented an integrated comprehensive care bundle care (ICC) program with the hopes that it would improve patients’ care while reducing overall costs. The aim of this analysis was to evaluate the performance of the ICC program within patients admitted with chronic pulmonary obstructive disease (COPD). Methods. We conducted a retrospective observational cohort study comparing ICC patients to non-ICC patients admitted to St. Joseph’s Healthcare Hamilton for COPD being discharged with support services between June 2012 and March 2015, using administrative data. Confounding adjustment was achieved through the use of propensity score matching. Medical resource utilizations during the initial hospitalization and within the 60 days following discharge were compared using regression models. Results. All 76 patients who entered the ICC program (100.0%) were matched 1 : 1 to 76 eligible non-ICC patients (28.4%). Length of stay (6.47 [7.29] versus 9.55 [10.21] days) and resource intensity weights (1.16 [0.80] versus 1.64 [1.69]) were lower in the ICC group within the initial hospitalization but, while favoring the ICC program, healthcare resource use tended not to differ statistically following discharge. Interpretation. The ICC program was able to reduce initial medical resource utilization without increasing subsequent medical resource use.