Pulmonary rehabilitation in lymphangioleiomyomatosis: a controlled clinical trial.

Lymphangioleiomyomatosis (LAM) is a cystic lung disease frequently associated with reduced exercise capacity. The aim of this study was to assess safety and efficacy of pulmonary rehabilitation in LAM.This controlled clinical trial included 40 patients with LAM and a low physical activity level. The pulmonary rehabilitation programme comprised 24 aerobic and muscle strength training sessions and education. The primary outcome was exercise capacity (endurance time during a constant work rate exercise test). Secondary outcomes included health-related quality of life (St George's Respiratory Questionnaire (SGRQ)), 6-min walking distance (6MWD), dyspnoea, peak oxygen consumption (V'O2 ), daily physical activity (pedometer), symptoms of anxiety and depression, lung function and peripheral muscle strength (one-repetition maximum).The baseline characteristics were well balanced between the groups. The pulmonary rehabilitation group exhibited improvements in the following outcomes versus controls: endurance time (median (interquartile range) 169 (2-303) s versus -33 (-129-39) s; p=0.001), SGRQ (median (interquartile range) -8 (-16-2) versus 2 (-4-5); p=0.002) and 6MWD (median (interquartile range) 59 (13-81) m versus 20 (-12-30) m; p=0.002). Dyspnoea, peak V'O2 , daily physical activity and muscle strength also improved significantly. No serious adverse events were observed.Pulmonary rehabilitation is a safe intervention and improves exercise capacity, dyspnoea, daily physical activity, quality of life and muscle strength in LAM.

Pulmonary involvement in long-term mixed connective tissue disease: functional trends and image findings after 10 years.

OBJECTIVES: Interstitial lung disease (ILD) is highly prevalent in patients with mixed connective tissue disease (MCTD). However, little is known about the long-term progression of ILD in MCTD. The aims of this study were to describe pulmonary function test (PFT) and high-resolution computed tomography (HRCT) results in long-term MCTD patients, to measure changes in PFT and HRCT results over a 10-year period, and to ascertain correlations in functional and imaging data. METHODS: In this retrospective cohort study, comparison between baseline and follow-up PFT and HRCT data was performed for 39 unselected consecutive MCTD patients. RESULTS: At baseline, 51% of the patients had abnormal PFTs. Forced vital capacity (FVC) was slightly reduced at baseline (77% of predicted), but remained stable after 10 years. A relative decrease of 15% in the diffusion capacity for carbon monoxide (DLCO) was detected (from 84% to 71% of predicted, p<0.001). The median lower lobes ILD-HRCT score progressed from 7.5% at baseline to 11.2% at follow-up (p=0.02), and findings of traction bronchiolectasis and honeycombing increased (p<0.05). A moderate negative correlation was observed between functional parameters and quantification of image findings. CONCLUSIONS: Functional and radiologic alterations suggestive of ILD in long-term MCTD patients are prevalent, mild, and progressed slightly over time. The most sensitive parameters for detecting subtle progression of ILD in MCTD patients are trends in DLCO, quantification of lower-lobes disease by HRCT (lower-lobes %ILD-HRCT score), and qualitative analysis of HRCT imaging.

Environmental triggers of autoimmunity in anti-synthetase syndrome: the lungs under the spot light.

The prevalence of interstitial lung involvement in anti-synthetase syndrome (anti-SS) may be as high as 70% and is a major contributor to morbidity and mortality. Histidyl-tRNA synthetase (Jo-1) is the most common autoantigenic target among the aminoacyl-tRNA synthetases. We report two well documented anti-SS cases where it was observed significant exposure to a known inhaled offending antigen, development of a lymphocytic interstitial lung disease (ILD) and negative auto-antibodies, interpreted at first as hypersensitivity pneumonitis. Only after 14 and 30 months, respectively, the development of systemic symptoms compatible with anti-SS and anti-Jo-1 was observed. A growing body of evidence suggests that the lungs are the environment in which Jo-1 autoimmunity may be initiated and propagated. The description of the clinical and laboratorial evolution of these patients together with accumulated evidence of biological plausibility support the hypothesis that anti-SS can follow an episode of lung inflammation secondary to inhaled antigen exposure.

Exercise performance and dynamic hyperinflation in lymphangioleiomyomatosis.

RATIONALE: Lymphangioleiomyomatosis (LAM) is characterized by exercise performance impairment. Although airflow limitation is common, no previous studies have evaluated the prevalence and impact of dynamic hyperinflation (DH) in LAM. OBJECTIVES: To investigate the dynamic responses during maximal exercise and the prevalence, predictors, and repercussions of DH in LAM. METHODS: Forty-two patients with LAM performed symptom-limited incremental cycle exercise and pulmonary functions tests (PFTs) and were compared with 10 age-matched healthy women. Dyspnea intensity, inspiratory capacity, oxygen saturation, and cardiac, metabolic, and respiratory variables were assessed during exercise. Patients with LAM also performed a 6-minute walk test (6MWT). MEASUREMENTS AND MAIN RESULTS: Patients with LAM had higher baseline dyspnea, poorer quality of life, obstructive pattern, air trapping, and reduced diffusing capacity of carbon monoxide in PFTs. Although they had the same level of regular physical activity, their maximal exercise performance was reduced and was associated with ventilatory limitation, greater desaturation, and dyspnea. The prevalence of DH was high in LAM (55%), even in patients with mild spirometric abnormalities, and was correlated with airflow obstruction, air trapping, and diffusing capacity of carbon monoxide. Compared with the non-DH subgroup, the patients who developed DH had a ventilatory limitation contributing to exercise cessation on cycling and higher desaturation and dyspnea intensity during the 6MWT. CONCLUSIONS: Ventilatory limitation and gas exchange impairment are important causes of exercise limitation in LAM. DH is frequent in LAM, even in patients with mild spirometric abnormalities. DH was associated with the severity of disease, higher dyspnea, and lower oxygen saturation. In the 6MWT, desaturation and dyspnea were greater in patients with DH.

Baseline Characteristics and Progression of a Spectrum of Interstitial Lung Abnormalities and Disease in Rheumatoid Arthritis.

BACKGROUND: Interstitial lung abnormalities (ILA) and interstitial lung disease (ILD) are seen in up to 60% of individuals with rheumatoid arthritis (RA), some of which will progress to have a significant impact on morbidity and mortality rates. Better characterization of progressive interstitial changes and identification of risk factors that are associated with progression may enable earlier intervention and improved outcomes. RESEARCH QUESTION: What are baseline characteristics associated with RA-ILD progression? STUDY DESIGN AND METHODS: We performed a retrospective study in which all clinically indicated CT chest scans in adult individuals with RA from 2014 to 2016 were evaluated for interstitial changes, and the data were further subdivided into ILA and ILD based on clinical record review. Progression was determined visually and subsequently semiquantified. RESULTS: Those individuals with a spectrum of interstitial changes (64 of 293) were older male smokers and less likely to be receiving biologics/small molecule disease-modifying antirheumatic drugs. Of 44% of the individuals with ILA, 46% had had chest CT scans performed for nonpulmonary indications. Of the 56 individuals with ILA/ILD with sequential CT scans, 38% had evidence of radiologic progression over 4.4 years; 29% of of individuals with ILA progressed. Risk factors for progressive ILA/ILD included a subpleural distribution and higher baseline involvement. INTERPRETATION: Of 293 individuals with RA with clinically indicated CT scans, interstitial changes were observed in 22%, one-half of whom had had a respiratory complaint at the time of imaging; radiologic progression was seen in 38%. Of individuals with progressive ILA, one-half had had baseline CT scans performed for nonpulmonary indications. Subpleural distribution and higher baseline ILA/ILD extent were risk factors associated with progression. Prospective longitudinal studies of RA-ILA are necessary.

Lung cyst: an unusual manifestation of Niemann-Pick disease.

Niemann-Pick disease is a rare inherited autosomal recessive disorder, currently classified into six subtypes and characterized by the intracellular accumulation of sphingomyelin in the liver, spleen, lungs, bone marrow or brain. The main pulmonary abnormalities described in high-resolution computed tomography (HRCT) of the chest consist of thickening of the interlobular septa and ground-glass opacities. This case report describes a patient with subtype B Niemann-Pick disease characterized by cysts and ground-glass opacities that were detected on HRCT of the chest.

Centrilobular fibrosis: an underrecognized pattern in systemic sclerosis.

BACKGROUND: The impressive association of lung involvement and gastroesophageal reflux in scleroderma raises the possibility of a cause-effect relationship. OBJECTIVES: To determine clinical, radiological and histopathological features of systemic sclerosis (SSc) patients according the presence or absence of centrilobular fibrosis (CLF). METHODS: Twenty-eight SSc patients with lung involvement were submitted to open lung biopsy and the specimens classified for the presence of CLF (bronchocentric distribution of the lesions and intraluminal matter according to the classification of idiopathic interstitial pneumonia). HRCT, pulmonary function tests and esophageal analysis were also performed. Subsequently, cyclophosphamide was introduced for the nonspecific interstitial pneumonia subgroup and antireflux treatment was intensified for isolated CLF patients. RESULTS: Isolated CLF was found in 21% of the biopsies and also found associated to nonspecific interstitial pneumonia in 84% of these patients. The other 3 cases had usual interstitial pneumonia, pulmonary hypertension and respiratory bronchiolitis-associated interstitial lung disease. The histopathological analysis revealed that all 6 patients with isolated CLF had the bronchocentric distribution and intraluminal basophilic content, with foreign bodies detected in one third of them. The central distribution of lung involvement on HRCT was found in 67% of these patients with a consistent patchy distribution (100%). Ground glass (67%) and consolidation (33%) were the predominant patterns found. The constant clinical finding in all isolated CLF cases was dyspnea, esophageal abnormalities and a moderate lung impairment (FVC: 63.83 +/- 16.31%; DLCO: 61.66 +/- 18.84%). Lung function parameters in isolated CLF patients remained stable after 1 year of exclusively intensive antireflux treatment (FVC, p = 0.23; DLCO, p = 0.59). CONCLUSIONS: The novel description of CLF pattern in SSc lung disease with peculiar histological, tomographic and clinical features will certainly contribute to a more appropriate therapeutic approach.

Pulmonary hypertension in lymphangioleiomyomatosis: prevalence, severity and the role of carbon monoxide diffusion capacity as a screening method.

BACKGROUND: Lymphangioleiomyomatosis (LAM) is included within group 5 of the current PH classification (unclear multifactorial mechanisms). However, data regarding the occurrence of PH in LAM are scarce. The aims of the study were to describe the prevalence and characteristics of PH in a large cohort of LAM patients with different levels of severity, and to evaluate the role of echocardiography and carbon monoxide diffusion capacity (DLCO) as screening methods for PH in LAM. METHODS: One hundred five LAM patients underwent transthoracic echocardiography, pulmonary function tests (PFTs) and 6-min walk test (6MWT). Patients with a suspicion of PH on echocardiography, defined by the presence of estimated systolic pulmonary artery pressure (PAP) over 35 mmHg or PFT showing DLco below 40% of the predicted value, underwent right heart catheterisation to confirm the diagnosis of PH. RESULTS: Eight patients (7.6%) had PH confirmed on right heart catheterisation, six patients (5.7%) had a pre-capillary pattern and two patients (1.9%) had a post-capillary profile. Only one patient (1%) had mean PAP over 35 mmHg. Patients with PH had lower FEV1 and DLCO in PFTs and greater oxygen desaturation and dyspnea intensity during 6MWT compared with those without PH. In 63% of the patients with confirmed PH, the right heart catheterisation was performed based only on DLCO result. CONCLUSIONS: The prevalence of PH is low in LAM patients. Pulmonary hypertension in LAM is typically mild and significantly associated with pulmonary parenchymal involvement. Carbon monoxide diffusion capacity significantly improved the identification of PH in LAM patients.

miR-155 in the progression of lung fibrosis in systemic sclerosis.

BACKGROUND: MicroRNA (miRNA) control key elements of mRNA stability and likely contribute to the dysregulated lung gene expression observed in systemic sclerosis associated interstitial lung disease (SSc-ILD). We analyzed the miRNA gene expression of tissue and cells from patients with SSc-ILD. A chronic lung fibrotic murine model was used. METHODS: RNA was isolated from lung tissue of 12 patients with SSc-ILD and 5 controls. High-resolution computed tomography (HRCT) was performed at baseline and 2-3 years after treatment. Lung fibroblasts and peripheral blood mononuclear cells (PBMC) were isolated from healthy controls and patients with SSc-ILD. miRNA and mRNA were analyzed by microarray, quantitative polymerase chain reaction, and/or Nanostring; pathway analysis was performed by DNA Intelligent Analysis (DIANA)-miRPath v2.0 software. Wild-type and miR-155 deficient (miR-155ko) mice were exposed to bleomycin. RESULTS: Lung miRNA microarray data distinguished patients with SSc-ILD from healthy controls with 185 miRNA differentially expressed (q < 0.25). DIANA-miRPath revealed 57 Kyoto Encyclopedia of Genes and Genomes pathways related to the most dysregulated miRNA. miR-155 and miR-143 were strongly correlated with progression of the HRCT score. Lung fibroblasts only mildly expressed miR-155/miR-21 after several stimuli. miR-155 PBMC expression strongly correlated with lung function tests in SSc-ILD. miR-155ko mice developed milder lung fibrosis, survived longer, and weaker lung induction of several genes after bleomycin exposure compared to wild-type mice. CONCLUSIONS: miRNA are dysregulated in the lungs and PBMC of patients with SSc-ILD. Based on mRNA-miRNA interaction analysis and pathway tools, miRNA may play a role in the progression of the disease. Our findings suggest that targeting miR-155 might provide a novel therapeutic strategy for SSc-ILD.

Accuracy of high resolution CT in assessing idiopathic pulmonary fibrosis histology by objective morphometric index.

To determine the accuracy of HRCT in assessing histology by objective morphometric index, twenty-five biopsy specimen-proved UIP were correlated with high-resolution CT (HRCT) by morphometric analysis. The scans were evaluated for the presence and extent of normal parenchyma, ground-glass attenuation, linear opacities, consolidation, honeycombing, vessels and bronchiectasis, and overall extent of histology involvement for normal parenchyma, honeycombing, alveolar septal inflammation, fibrosis, vessels, and bronchiectasis/bronchiolectasis. The comparison between morphometric measurements showed a strong correlation between HRCT and histologic parameters for extension (%) of normal tissue (p = 5 x 10(-5)), honeycombing (p = 6 x 10(-5)), and vessels (p = 0.0047). HRCT consolidation strongly correlated with alveolar septal inflammation (p = 0.015), whereas HRCT linear opacities had the highest correlation with histology for bronchiectasis or bronchiolectasis (p = 0.03). These associations also demonstrated that there was considerable residual scatter about the linear relationships found. By contrast, neither the ground glass patterns nor the bronchioectatic patterns determined by CT were associated with any histologic observation (p < 0.1). There was a borderline negative relationship between vessels determined by CT and histologic fibrosis (p = 0.069), i.e., the percentage of vessel patterns determined by CT was found to be lower when fibrosis was prominent histologically. Our results showed that HRCT patterns, usually employed to provide information about activity (ground glass) and fibrosis (consolidation) in IPF, failed to correlate with histology. On the other hand, chronic cystic lesions had a good correlation with histology. This finding suggests that in patients without a diffuse honeycomb pattern on HRCT, a lung biopsy may provide additional information. The more important limitation of our study was the lack of correlation related to the proximity of the biopsy site to the HRCT location evaluated by morphometry.

Sleep desaturation and its relationship to lung function, exercise and quality of life in LAM.

BACKGROUND: Lymphangioleiomyomatosis (LAM) is characterised by progressive airway obstruction and hypoxaemia in young women. Although sleep may trigger hypoxaemia in patients with airway obstruction, it has not been previously investigated in patients with LAM. METHODS: Consecutive women with lung biopsy proven LAM and absence of hypoxaemia while awake were evaluated with pulmonary function test, echocardiography, 6-min walk test, overnight full polysomnography, and Short Form 36 health-related quality-of-life questionnaire. RESULTS: Twenty-five patients with (mean±SD) age 45±10 years, SpO(2) awake 95%±2, forced expiratory volume in the first second (median-interquartile) FEV(1)(% predicted) 77 (47-90) and carbonic monoxide diffusion capacity, DL(CO) (%) 55 (34-74) were evaluated. Six-minute walk test distance and minimum SpO(2) (median-interquartile) were, respectively, 447m (411-503) and 90% (82-94). Median-interquartile apnoea-hypopnoea index was in the normal range 2 (1-5). Fourteen patients (56%) had nocturnal hypoxaemia (10% total sleep time with SpO(2) <90%), and the median sleep time spent with SpO(2) <90% was 136 (13-201)min. Sleep time spent with SpO(2) <90% correlated with the residual volume/total lung capacity ratio (r(s)=0.5, p: 0.02), DL(CO) (r(s)=-0.7, p: 0.001), FEV(1) (r(s)=-0.6, p: 0.002). Multivariate linear regression model showed that RV/TLC ratio was the most important functional variable related to sleep hypoxaemia. CONCLUSION: Significant hypoxaemia during sleep is common in LAM patients with normal SpO(2) while awake, especially among those with some degree of hyperinflation in lung function tests.

A long-term prospective randomized controlled study of non-specific interstitial pneumonia (NSIP) treatment in scleroderma.

UNLABELLED: The association of cyclophosphamide (CYC) and prednisone (PRED) for the treatment of lung fibrosis in systemic sclerosis (SSc) was only evaluated in uncontrolled studies, although in idiopathic interstitial lung disease (ILD) this association seems to be beneficial in patients with non-specific interstitial pneumonia (NSIP). OBJECTIVES: To treat SSc-ILD in a prospective open-label controlled study based on lung pattern during 12 months of treatment. METHODS: A 3-year analysis was also performed. Twenty-four consecutive patients with SSc and ILD were submitted to an open lung biopsy. Eighteen patients (NSIP) were randomized in two groups: CYC versus CYC + PRED during 12 months. Lung function tests (diffusion lung capacity of monoxide carbone corrected for hemoglobin concentration (DLCO-Hb), forced vital capacity (FVC), total lung capacity) and Modified Rodnan Skin Score (MRSS) were performed before, after one of treatment and after 3 years from the end of the treatment. RESULTS: Pulmonary function tests were similar in both groups on baseline. After 1 year of treatment, FVC% was comparable between CYC groups (p = 0.72) and in CYC + PRED (p = 0.40). Three years after the end of treatment, FVC% values (p = 0.39 in group CYC and p = 0.61 in CYC + PRED and p = 0.22 in CYC + PRED) and DLCO-Hb (p = 0.54 in CYC and p = 0.28 in CYC + PRED) were similar compared to 1 year of treatment. We observed a reduction of the MRSS in the CYC + PRED group after 1 year of treatment (p = 0.02); although after 3 years, MRSS values remained stable in both groups. CONCLUSIONS: CYC was effective to stabilize lung function parameters in NSIP lung pattern of SSc disease for 3 years after the end of a 1-year therapy.

A sigmoidal fit for pressure-volume curves of idiopathic pulmonary fibrosis patients on mechanical ventilation: clinical implications.

OBJECTIVE: Respiratory pressure-volume curves fitted to exponential equations have been used to assess disease severity and prognosis in spontaneously breathing patients with idiopathic pulmonary fibrosis. Sigmoidal equations have been used to fit pressure-volume curves for mechanically ventilated patients but not for idiopathic pulmonary fibrosis patients. We compared a sigmoidal model and an exponential model to fit pressure-volume curves from mechanically ventilated patients with idiopathic pulmonary fibrosis. METHODS: Six idiopathic pulmonary fibrosis patients and five controls underwent inflation pressure-volume curves using the constant-flow technique during general anesthesia prior to open lung biopsy or thymectomy. We identified the lower and upper inflection points and fit the curves with an exponential equation, V = A-B.e-k.P, and a sigmoid equation, V = a+b/(1+e-(P-c)/d). RESULTS: The mean lower inflection point for idiopathic pulmonary fibrosis patients was significantly higher (10.5 ± 5.7 cm H2O) than that of controls (3.6 ± 2.4 cm H2O). The sigmoidal equation fit the pressure-volume curves of the fibrotic and control patients well, but the exponential equation fit the data well only when points below 50% of the inspiratory capacity were excluded. CONCLUSION: The elevated lower inflection point and the sigmoidal shape of the pressure-volume curves suggest that respiratory system compliance is decreased close to end-expiratory lung volume in idiopathic pulmonary fibrosis patients under general anesthesia and mechanical ventilation. The sigmoidal fit was superior to the exponential fit for inflation pressure-volume curves of anesthetized patients with idiopathic pulmonary fibrosis and could be useful for guiding mechanical ventilation during general anesthesia in this condition.

Cognition and chronic hypoxia in pulmonary diseases.

Lung disease with chronic hypoxia has been associated with cognitive impairment of the subcortical type. OBJECTIVES: To review the cognitive effects of chronic hypoxia in patients with lung disease and its pathophysiology in brain metabolism. METHODS: A literature search of Pubmed data was performed. The words and expressions from the text subitems including "pathophysiology of brain hypoxia", "neuropsychology and hypoxia", "white matter injury and chronic hypoxia", for instance, were key words in a search of reports spanning from 1957 to 2009. Original articles were included. RESULTS: According to national and international literature, patients with chronic obstructive pulmonary disease and sleep obstructive apnea syndrome perform worse on tests of attention, executive functions and mental speed. The severity of pulmonary disease correlates with degree of cognitive impairment. These findings support the diagnosis of subcortical type encephalopathy. CONCLUSION: Cognitive effects of clinical diseases are given limited importance in congresses and symposia about cognitive impairment and its etiology. Professionals that deal with patients presenting cognitive loss should be aware of the etiologies outlined above as a major cause or potential contributory factors, and of their implications for treatment adherence and quality of life.

As doenças pulmonares que cursam com hipóxia crônica tem sido associadas à alteração cognitiva do tipo subcortical. OBJETIVO: Revisar os efeitos cognitivos da hipóxia crônica em pacientes com doenças pulmonar e sua fisiopatologia. MÉTODOS: Foi utilizado o banco de dados do Pubmed. As palavras e expressões foram os temas dos subitens da revisão como, por exemplo, "fisiopatologia e hipóxia cerebral", "neuropsicologia e hipoxia", "lesões de substância branca e hipóxia crônica", variando de 1957 to 2009. Artigos originais foram incluídos. RESULTADOS: De acordo com a literatura nacional e internacional, pacientes com doença pulmonar obstrutiva crônica e síndrome da apnéia obstrutiva do sono apresentam desempenho pior em testes neuropsicológicos que avaliam atenção, funções executivas e velocidade de processamento mental. Esses achados configuram uma encefalopatia do tipo subcortical. CONCLUSION: É dada importância limitada às conseqüências cognitivas das doenças clínicas em congressos e simpósios sobre cognição e suas etiologias. Profissionais que lidam com pacientes que apresentam perda cognitiva devem suspeitar das etiologias mencionadas acima com causa principal ou como co-fatores, assim com suas implicações na aderência ao tratamento e qualidade de vida.

Fibrose pulmonar idiopática: uma atualização / Idiopathic pulmonary fibrosis: an update

A fibrose pulmonar idiopática (FPI) é uma das doenças pulmonares intersticiais mais comuns. Tem caráter crônico, progressivo, restringe-se ao pulmão e é de causa desconhecida, acometendo preferencialmente adultos a partir da meia idade. A FPI é uma entidade nosológica distinta; histologicamente, se manifesta no padrão de pneumonia intersticial usual (PIU). Na presença de achados típicos do padrão PIU tomográfico, a TCAR de tórax tem elevada acurácia em predizer o achado histológico de PIU e, nesses casos, o achado tomográfico típico é suficiente para o diagnóstico de FPI dentro de um contexto clínico adequado. Em relação ao tratamento, a necessidade de diferenciação da FPI dentre as outras doenças intersticiais pulmonares vem crescendo devido ao fato de recentes evidências mostrarem um aumento de mortalidade e hospitalizações naqueles pacientes com FPI tratados com azatioprina e prednisona. Além disso, novas drogas antifibróticas de uso restrito na FPI estão surgindo.