Vitamin D deficiency, impaired lung function and total and respiratory mortality in a cohort of older men: cross-sectional and prospective findings from The British Regional Heart Study

ObjectivesVitamin D deficiency is associated with chronic obstructive pulmonary disease (COPD). We examined the cross-sectional association between 25-hydroxyvitamin D (25(OH)D) and lung function impairment and assessed whether vitamin D deficiency is related to long-term mortality in those with impaired lung function.DesignProspective studySettingGeneral practices in the UK.Participants3575 men aged 60–79 years with no prevalent heart failure.Outcome measuresAirway obstruction and mortality. The Global Initiative on Obstructive Lung diseases (GOLD) spirometry criteria was used to define airway obstruction.ResultsDuring the follow-up period of 20 years, there were 2327 deaths (114 COPD deaths). Vitamin D deficiency was defined as serum 25(OH)D levels<10 ng/mL; insufficiency as 25(OH)D 10–19 ng/mL; sufficient as 25(OH)D>20 ng/mL. In cross-sectional analysis, vitamin D deficiency was more prevalent in those with moderate COPD (FEV/FVC <70% and FEV1 50 to <80%; FEV1, forced expiratory volume in 1 s and FVC, forced vital capacity) and severe COPD (FEV/FVC <70% and FEV1 <50%) but not in those with mild COPD (FEV/FVC <70% and FEV1>80%) or restrictive lung disease (FEV1/FVC >70% and FVC <80%) compared with men with normal lung function . Vitamin D deficiency was associated with increased risk of total and respiratory mortality in both men with COPD and men with restrictive lung disease after adjustment for confounders and inflammation. The adjusted HRs (95% CI) for total mortality comparing levels of 25(OH)D<10 ng/mL to 25(OH)D>=20 ng/mL were 1.39 (1.10 to 1.75), 1.52 (1.17 to 1.98), 1.58 (1.17 to 2.14) and 1.39 (0.83 to 2.33) for those with no lung impairment, restrictive lung function, mild/moderate COPD and severe COPD, respectively.ConclusionMen with COPD were more likely to be vitamin D deficient than those with normal lung function. Vitamin D deficiency is associated with increased all-cause mortality in older men with no lung impairment as well as in those with restrictive or obstructive lung impairment.

Recent Advances in Chronotherapy Targeting Respiratory Diseases

Respiratory diseases contribute to a significant percentage of mortality and morbidity worldwide. The circadian rhythm is a natural biological process where our bodily functions align with the 24 h oscillation (sleep–wake cycle) process and are controlled by the circadian clock protein/gene. Disruption of the circadian rhythm could alter normal lung function. Chronotherapy is a type of therapy provided at specific time intervals based on an individual’s circadian rhythm. This would allow the drug to show optimum action, and thereby modulate its pharmacokinetics to lessen unwanted or unintended effects. In this review, we deliberated on the recent advances employed in chrono-targeted therapeutics for chronic respiratory diseases.

Increased myofibroblasts in the small airways and relation to remodelling and functional changes in smokers and COPD patients: potential role of epithelial-mesenchymal transition (EMT)

IntroductionPrevious reports showed epithelial mesenchymal transition (EMT) as an active process that contributes to small airway (SA) fibrotic pathology. Myofibroblasts are highly active pro-fibrotic cells that secrete excessive and altered extracellular matrix (ECM). Here we relate SA myofibroblast presence with airway remodelling, physiology and EMT activity in smokers and COPD patients.MethodsLung resections from non-smoker controls (NC), normal lung function smokers (NLFS), COPD current (CS) and ex-smokers (ES) were stained with anti-human αSMA, collagen 1, and fibronectin. αSMA+ive cells were computed in reticular basement membrane (Rbm), lamina propria (LP), and adventitia and presented per mm of Rbm and mm2 of LP. Collagen-1 and fibronectin are presented as a percentage change from normal. All analysis including airway thickness were measured using Image-pro-plus 7.0.ResultsWe found an increase in sub-epithelial LP (especially) and adventitia thickness in all pathological groups compared to NC. Increases in αSMA+ive myofibroblasts were observed in sub-epithelial Rbm, LP, and adventitia in both the smoker and COPD groups compared to NCs. Further, the increase in the myofibroblast population in the LP was strongly associated with decrease in lung function, LP thickening, increase in ECM protein deposition, and finally EMT activity in epithelial cells.ConclusionsThis is the first systematic characterisation of small airway myofibroblasts in COPD based on their localisation, with statistically significant correlations between them and other pan-airway structural, lung function, and ECM protein changes. Finally, we suggest that EMT may be involved in such changes.

Increased serum SP-D in identification of high-risk smokers at high risk of COPD

Pulmonary surfactant protein D (SP-D) is an important component of the pulmonary innate immune system with the ability to dampen cigarette smoke-induced lung inflammation. However, cigarette smoking mediates translocation of SP-D from the lung to the blood, and serum SP-D (sSP-D) has therefore previously been suggested as marker for smoke-induced lung injury. In support of this notion, associations between high sSP-D and low lung function measurements have previously been demonstrated in smokers and in COPD. The present investigations employ a 12-year longitudinal Danish twin study to test the hypothesis that baseline sSP-D variation has the capacity to identify smokers with normal baseline lung function who are in high risk of significant future smoke-induced lung function decline. We find that sSP-D is significantly increased in those with normal lung function at baseline that develop lung function decline during follow up compared to those who stay lung healthy. Moreover, we demonstrate that it is the smoke-induced baseline sSP-D level, and not the constitutional level, which has capacity as biomarker, and which is linearly increased with the decline in lung function during follow up. In conclusion, we here present first observation of increased sSP-D for identification of high-risk smokers.

Poor Cognitive Function Is Associated with Obstructive Lung Diseases in Taiwanese Adults

Previous studies have reported an association between the impairment of cognitive performance and lung diseases. However, whether obstructive or restrictive lung diseases have an impact on cognitive function is still inconclusive. We aimed to investigate the association between cognitive function and obstructive or restrictive lung diseases in Taiwanese adults using the Mini-Mental State Examination (MMSE). In this study, we used data from the Taiwan Biobank. Cognitive function was evaluated using the MMSE. Spirometry measurements of forced expiratory volume in 1 s (FEV1) and forced vital capacity (FVC) were obtained to assess lung function. Participants were classified into three groups according to lung function, namely, normal, restrictive, and obstructive lung function. In total, 683 patients enrolled, of whom 357 participants had normal lung function (52.3%), 95 had restrictive lung function (13.9%), and 231 had obstructive lung function (33.8%). Compared to the normal lung function group, the obstructive lung function group was associated with a higher percentage of cognitive impairment (MMSE < 24). In multivariable analysis, a low MMSE score was significantly associated with low FVC, low FEV1, and low FEV1/FVC. Furthermore, a low MMSE score was significantly associated with low FEV1 in the participants with FEV1/FVC < 70%, whereas MMSE was not significantly associated with FVC in the participants with FEV1/FVC ≥ 70%. Our results showed that a low MMSE score was associated with low FEV1, low FVC and low FEV1/FVC. Furthermore, a low MMSE score was associated with obstructive lung diseases but not with restrictive lung diseases.

Shrinking lung syndrome treated with rituximab in pediatric systemic lupus erythematosus: a case report and review of the literature

Background Shrinking lung syndrome (SLS), a rare complication of systemic lupus erythematosus (SLE) characterized by dyspnea, low lung volumes, and a restrictive pattern on pulmonary function tests (PFTs), has only been reported in a few children. Given the rarity of SLS there is a paucity of literature regarding its optimal treatment. Outcomes are variable, with case reports documenting some improvement in most patients treated with corticosteroids, with or without additional immunosuppressive agents. However, most reported patients did not recover normal lung function. We report full recovery of a child with SLE and SLS following treatment with rituximab and review the current literature. Case presentation An 11-year-old boy presented with a malar rash, myositis, arthritis, oral ulcers, leukopenia, anemia, positive lupus autoantibodies and Class II nephritis. He was diagnosed with SLE and treated with corticosteroids, hydroxychloroquine, azathioprine, and subsequently mycophenolate with symptom resolution. At age 14, his SLE flared coincident with a viral chest infection. He presented with a malar rash, polyarthritis, increased proteinuria and pleuritis which all improved with corticosteroids and ongoing treatment with mycophenolate. Six weeks later he presented with severe dyspnea, markedly decreased lung volumes, but otherwise normal chest X-ray (CXR) and high-resolution chest computed tomography (HRCT). He was found to have severely restricted PFTs (FEV1 27%, FVC 29%; TLC 43%). After additional investigations including echocardiography, pulmonary CT angiography, and diaphragmatic fluoroscopy, he was diagnosed with SLS and treated with rituximab and methylprednisolone. At 1 month his symptoms had improved, but he still had dyspnea with exertion and severely restricted PFTs. At 6 months his FVC and TLC had improved to 51 and 57% respectively, and were 83 and 94% respectively at 4 years. He had returned to all baseline activities, including competitive hockey. Conclusions Although extremely rare, it is important to recognize SLS as a possible cause of dyspnea and chest pain in a child with SLE. Optimal treatment strategies are unknown. This is the second reported case of a child treated with rituximab for SLS who recovered normal lung function. International lupus registries should carefully document the occurrence, treatment and outcome of patients with SLS to help determine the optimal treatment for this rare complication.

Airway regulatory T cells are decreased in COPD with a rapid decline in lung function

Background Differences in the expression of regulatory T cells (Tregs) have been suggested to explain why some smokers develop COPD and some do not. Upregulation of Tregs in response to smoking would restrain airway inflammation and thus the development of COPD; while the absense of such upregulation would over time lead to chronic inflammation and COPD. We hypothesized that—among COPD patients—the same mechanism would affect rate of decline in lung function; specifically, that a decreased expression of Tregs would be associated with a more rapid decline in FEV1. Methods Bronchoscopy with BAL was performed in 52 subjects recruited from the longitudinal OLIN COPD study; 12 with COPD and a rapid decline in lung function (loss of FEV1 ≥ 60 ml/year), 10 with COPD and a non-rapid decline in lung function (loss of FEV1 ≤ 30 ml/year), 15 current and ex-smokers and 15 non-smokers with normal lung function. BAL lymphocyte subsets were determined using flow cytometry. Results The proportions of Tregs with regulatory function (FoxP3+/CD4+CD25bright) were significantly lower in COPD subjects with a rapid decline in lung function compared to those with a non-rapid decline (p = 0.019). This result was confirmed in a mixed model regression analysis in which adjustments for inhaled corticosteroid usage, smoking, sex and age were evaluated. No significant difference was found between COPD subjects and smokers or non-smokers with normal lung function. Conclusions COPD subjects with a rapid decline in lung function had lower proportions of T cells with regulatory function in BAL fluid, suggesting that an inability to suppress the inflammatory response following smoking might lead to a more rapid decline in FEV1. Trial registration Clinicaltrials.gov identifier NCT02729220

Forced Expiratory Time: A Composite of Airway Narrowing and Airway Closure

Forced expiratory time (FET) is a spirometrically-derived variable thought to reflect lung function, but its physiologic basis remains poorly understood. We developed a mathematical theory of FET assuming a linear forced expiratory flow-volume profile that terminates when expiratory flow falls below a defined detection threshold. FET is predicted to correlate negatively with both FEV1 and FVC if variations in the rate of lung emptying (relative to normal) among individuals in a population exceed variations in the amount of lung emptying. We retrospectively determined FET pre- and post-methacholine challenge in 1241 patients (818 had normal lung function, 137 were obstructed, and 229 were restricted) and examined its relationships to spirometric and demographic variables in both hyperresponsive and normoresponsive individuals. Mean FET was 9.6 ± 2.2 s in the normal group, 12.3 ± 3.0 s in those with obstruction, and 8.8 ± 1.9 s in those with restriction. FET was inversely related to FEV1/FVC in all groups, negatively related to FEV1 in the obstructed patients, and positively related to FVC in both the normal and restricted patients. There was no relationship with methacholine responsiveness. Overall, our theory of the relationship between FET to the spirometric indices is supported by these findings, and in addition potentially explains how FET is affected by gender, age, smoking status, and possibly body mass index.