Chest Wall Diseases: Respiratory Pathophysiology.

The chest wall consists of various structures that function in an integrated fashion to ventilate the lungs. Disorders affecting the bony structures or soft tissues of the chest wall may impose elastic loads by stiffening the chest wall and decreasing respiratory system compliance. These alterations increase the work of breathing and lead to hypoventilation and hypercapnia. Respiratory failure may occur acutely or after a variable period of time. This review focuses on the pathophysiology of respiratory function in specific diseases and disorders of the chest wall, and highlights pathogenic mechanisms of respiratory failure.

Complementary Role of CMR to Conventional Screening in the Diagnosis and Prognosis of Cardiac Sarcoidosis.

OBJECTIVES: The goal of this study was to assess the independent and collective diagnostic value of various modalities in cardiac sarcoidosis, delineate the role of cardiac magnetic resonance (CMR), and identify patients at risk. BACKGROUND: Cardiac sarcoidosis is associated with increased morbidity and mortality. CMR is a key modality in the evaluation of patients with cardiac symptoms, but the complementary role of CMR to conventional tests for the diagnosis of cardiac sarcoidosis is not fully defined. METHODS: Patients (N = 321) with biopsy-proven sarcoidosis underwent conventional cardiac testing and CMR with late gadolinium enhancement (LGE) and were followed up for primary (composite of all-cause mortality, sustained ventricular tachycardia [VT] episodes, or hospitalization for heart failure) and secondary (nonsustained VT episodes) endpoints. RESULTS: Cardiac sarcoidosis was diagnosed in 29.9% of patients according to the Heart Rhythm Society consensus criteria. CMR was the most sensitive and specific test (area under the curve: 0.984); it detected 44 patients with cardiac symptoms and/or electrocardiogram (ECG) abnormalities but normal echocardiogram, as well as 15 asymptomatic patients with normal baseline testing. Echocardiography added to cardiac history and ECG did not change sensitivity of the initial screening strategy (68.8% vs. 72.9%). Despite a high positive predictive value (83.9%), echocardiography had a low sensitivity (27.1%). During follow-up, 7.2% of patients reached the primary endpoint and another 3.4% reached the secondary endpoint. LGE was and independent predictor of primary endpoints (hazard ratio: 5.68; 95% CI: 1.74 to 18.49; p = 0.004). LGE, age, and baseline nonsustained VT were independent predictors of all events. In patients with cardiac symptoms and/or an abnormal ECG, CMR increased diagnostic accuracy and independently predicted primary endpoints (hazard ratio: 12.71; 95% confidence interval: 1.48 to 109.35; p = 0.021). CONCLUSIONS: Of all cardiac tests, CMR was the most valuable in the diagnosis and prognosis of cardiac sarcoidosis in a general sarcoidosis population. Echocardiography had an overall limited diagnostic value as a screening test, and an abnormal study, despite a high positive predictive value, may still need confirmation with CMR.

Respiratory dysfunction in multiple sclerosis.

Respiratory dysfunction frequently occurs in patients with advanced multiple sclerosis (MS), and may manifest as acute or chronic respiratory failure, disordered control of breathing, respiratory muscle weakness, sleep disordered breathing, or neurogenic pulmonary edema. The underlying pathophysiology is related to demyelinating plaques involving the brain stem or spinal cord. Respiratory complications such as aspiration, lung infections and respiratory failure are typically seen in patients with long-standing MS. Acute respiratory failure is uncommon and due to newly appearing demyelinating plaques extensively involving areas of the brain stem or spinal cord. Early recognition of MS patients at risk for respiratory complications allows for the timely implementation of care and measures to decrease disease associated morbidity and mortality.

Evolution of cardiac dysfunction in patients with antiphospholipid antibodies and/or antiphospholipid syndrome: a 10-year follow-up study.

OBJECTIVES: To describe the evolution of valve involvement and myocardial dysfunction over time in patients with systemic lupus erythematosus (SLE) with or without antiphospholipid antibodies (aPL) and/or antiphospholipid syndrome (APS). METHODS: From an initial cohort of 150 patients assessed by transthoracic echocardiography 10 years ago, 17 patients with primary APS (PAPS), 23 with SLE-associated APS (SLE/APS), 19 with SLE positive for aPL without APS, and 23 with SLE negative for aPL were re-evaluated in the present echocardiography study. RESULTS: Valvulopathy was detected in 65% of PAPS and 62% of SLE patients with or without aPL. Disease duration [odds ratio (OR), 1.63; 95% confidence interval (CI), 1.13-2.36; p = 0.009 for every 5 years of increase] and presence of SLE/APS (OR, 3.51; 95% CI, 1.27-9.67; p = 0.015) were the only factors associated with the progression of valvular disease in univariate and multivariate analyses. Left ventricular diastolic dysfunction similarly progressed over time, with deceleration time (DT) and isovolumic relaxation time (IVRT) being equally prolonged in each of the four groups (p < 0.05). Right ventricular DT was significantly prolonged in each of the three SLE patient groups (p < 0.001), whereas IVRT increased only in SLE/APS patients (p = 0.040). CONCLUSIONS: Among patients with APS and SLE (with or without aPL), SLE/APS and disease duration were independent factors for valvular disease progression in the present 10-year follow-up echocardiography study. Anticoagulation did not arrest valvular disease progression. Ventricular diastolic dysfunction, primarily of the left ventricle, also progressed over the 10-year period.

Elevated pulmonary arterial systolic pressure in patients with sarcoidosis: prevalence and risk factors.

BACKGROUND: Sarcoidosis-related pulmonary hypertension (SRPH) is an entity associated with significant morbidity and mortality irrespective of disease severity, while the pathogenic mechanisms remain poorly understood. METHODS: This cross-sectional study included consecutive patients with biopsy-proven sarcoidosis (n = 313) who were followed up in an outpatient setting from October 2002 through June 2010. All patients underwent clinical and cardiopulmonary evaluation, including cardiac MRI, to assess prevalence of SRPH and identify possible underlying pathophysiological mechanisms. RESULTS: By Doppler echocardiographic criteria, 37 (11.8 %) patients were found to have pulmonary arterial systolic pressure (PASP) >40 mmHg. Twelve of the 37 patients agreed to undergo right heart catheterization and SRPH was confirmed in nine patients. Compared to patients without SRPH, those with SRPH were significantly older and had greater lung function impairment; disease duration did not differ between patients with and without SRPH. Multiple logistic regression analysis showed that diffusing capacity for carbon monoxide (DLCO) and age were independent determinants of SRPH. Pulmonary fibrosis and left ventricular diastolic dysfunction due to cardiac sarcoidosis or other comorbidities accounted for SRPH in the majority of patients. In the nonpulmonary fibrosis group, DLCO ≤ 50.65 (% predicted) was associated with SRPH (sensitivity = 77.8 %, specificity = 72.2 %; p = 0.031, AUC = 0.759). CONCLUSION: In a large cohort of sarcoidosis patients, this study found a prevalence of SRPH of about 12 %. Pulmonary fibrosis and left ventricular diastolic dysfunction due to cardiac sarcoidosis or other comorbidities are frequent pathogenic mechanisms.

Activin-A overexpression in the murine lung causes pathology that simulates acute respiratory distress syndrome.

RATIONALE: Activin-A is up-regulated in various respiratory disorders. However, its precise role in pulmonary pathophysiology has not been adequately substantiated in vivo. OBJECTIVES: To investigate in vivo the consequences of dysregulated Activin-A expression in the lung and identify key Activin-A-induced processes that contribute to respiratory pathology. METHODS: Activin-A was ectopically expressed in murine lung, and functional, structural, and molecular alterations were extensively analyzed. The validity of Activin-A as a therapeutic target was demonstrated in animals overexpressing Activin-A or treated with intratracheal instillation of LPS. Relevancy to human pathology was substantiated by demonstrating high Activin-A levels in bronchoalveolar lavage (BAL) samples from patients with acute respiratory distress syndrome (ARDS). MEASUREMENTS AND MAIN RESULTS: Overexpression of Activin-A in mouse airways caused pulmonary pathology reminiscent of acute lung injury (ALI)/ARDS. Activin-A triggered a lasting inflammatory response characterized by acute alveolar cell death and hyaline membrane formation, sustained up-regulation of high-mobility group box 1, development of systemic hypercoagulant state, reduction of surfactant proteins SpC, SpB, and SpA, decline of lung compliance, transient fibrosis, and eventually emphysema. Therapeutic neutralization of Activin-A attenuated the ALI/ARDS-like pathology induced either by ectopic expression of Activin-A or by intratracheal instillation of LPS. In line with the similarity of the Activin-A-induced phenotype to human ARDS, selective up-regulation of Activin-A was found in BAL of patients with ARDS. CONCLUSIONS: Our studies demonstrate for the first time in vivo the pathogenic consequences of deregulated Activin-A expression in the lung, document novel aspects of Activin-A biology that provide mechanistic explanation for the observed phenotype, link Activin-A to ALI/ARDS pathophysiology, and provide the rationale for therapeutic targeting of Activin-A in these disorders.

Portopulmonary hypertension and serum endothelin levels in hospitalized patients with cirrhosis.

BACKGROUND: Cirrhosis is associated with several extrahepatic manifestations including portopulmonary hypertension (PPHT). Recent data suggest that endothelins (ETs) are related to the pathophysiology of PPHT. The study aimed to measure serum ET levels in hospitalized cirrhotic patients and to determine their association with PPHT and patient outcome. METHODS: Fifty-seven cirrhotic patients [43 males; median age 58 (28-87) years] underwent Doppler echocardiography. Patients with systolic pulmonary arterial pressure ≥40 mmHg and pulmonary acceleration time <100 ms were deemed to have PPHT. ET-1, 2, and 3 serum levels were measured with an ELISA assay. All-cause mortality was recorded over a median period of 24 months. RESULTS: Nine out of 57 patients (15.8%) had PPHT. Among various clinical variables, only autoimmune hepatitis was associated with PPHT (OR=11.5; 95% CI, 1.58-83.4; P=0.01). ET-1 levels [9.1 (1.6-20.7) vs 2.5 (1.4-9.2) pg/mL, P=0.02] and the ET-1/ET-3 ratio [4.73 (0.9-22.4) vs 1.6 (0.3-10.7), P=0.02] were significantly higher in patients with PPHT than in those without. ET-2 and ET-3 levels did not differ between the two groups. There was no difference in survival between the two groups, although ET-1 levels were associated with an adverse outcome in Cox regression analysis (HR=1.11; 95% CI, 1.02-1.22; P=0.02 per unit increase in ET-1). CONCLUSION: Our data suggest that ET-1 and the ET-1/ET-3 ratio are elevated in patients with PPHT and that ET-1 is associated with a poor outcome irrespective of PPHT.

The many faces of scleroderma sine scleroderma: a literature review focusing on cardiopulmonary complications.

Scleroderma sine scleroderma (ssSSc) is an occult form of systemic sclerosis that may cause diagnostic difficulties due to the absence of skin involvement. Delays in the diagnosis of ssSSc means lost opportunites to address and treat the often lethal involvement of internal organs such as the lungs and heart. In this systemic review we collected all published cases of ssSSc using EMBASE, MEDLINE, PubMed, and Web of Science from 1950 to present. Our purpose was to describe the range and frequency of the clinical manifestations of ssSSc. A total of 108 published cases of ssSSc were analyzed. Lung involvement was present in 66% of cases. Peripheral vascular system involvement was present in all patients whereas gastrointestinal manifestations were present in 82% of the cases. Overall the clinical presentation is subtle and heightened clinical awareness is required to facilitate prompt recognition and treatment.

Association of the shrinking lung syndrome in systemic lupus erythematosus with pleurisy: a systematic review.

OBJECTIVES: To report 2 patients with systemic lupus erythematosus and typical shrinking lung syndrome (SLS) in which pleuritic chest pain was the predominant symptom. In addition, to record the prevalence of pleuritic chest pain in all reported cases of patients with SLS and diaphragmatic dysfunction. METHODS: We conducted a comprehensive search of the English literature to record the association of pleurisy and SLS in all reported cases using the MEDLINE database from 1965 to present. RESULTS: Of the 77 patients with SLS reported in the literature, 50 (65%) patients had pleuritic chest pain at the time of evaluation. Treatment with anti-inflammatory agents improved symptoms in the majority of cases. CONCLUSIONS: Pleuritic inflammation and pain may have an important role in the pathogenesis of SLS. A possible mechanism linking pleural inflammation and diaphragm dysfunction may be via a reflex inhibition of diaphragmatic activation.

Cryptogenic organizing pneumonia associated with primary Sjogren's syndrome.

The association of cryptogenic organizing pneumonia (COP) with primary Sjogren's syndrome (PSS) is extremely rare. We report a case of simultaneous diagnosis of PSS and COP. A 70-year-old female presented with fever, non-productive cough and dyspnea of 2 months' duration. She had experienced sicca symptoms for the past 2 years. The chest radiograph revealed a right lower lobe infiltrate, which was unresponsive to antibiotics. Bronchoscopy, bronchoalveolar lavage and an open lung biopsy established the diagnosis of COP, while a lip biopsy was consistent with PSS. The patient improved on steroids. Organizing pneumonia may be one of the early manifestations of PSS. Exclusion of PSS should be part of a thorough evaluation of the patient with COP.

Chest CT findings in patients with inflammatory myopathy and Jo1 antibodies.

Thoracic high-resolution computed tomography scans (HRCT) of 17 patients with inflammatory muscle disorders (IMD) and positive Jo1 antibodies were retrospectively reviewed regarding presence, extension, and distribution of pathological findings. Abnormal findings were found in 14 (82.3%) patients. The predominant CT abnormality was ground glass attenuation, which was present in seven patients (41.1%), having a bilateral and diffuse distribution. In general, lesions tended to appear in the lower lobes and more specifically in the lung bases. Interlobular septal thickening was found in six patients (35.3%); it was seen in the upper and lower lobes with peripheral distribution and bilateral localization in five out of six patients. Bronchiectases, reticular opacities, and honeycombing were found in six patients (35.3%). Air space consolidation was seen in about 17% of the patients. Lung involvement is a frequent feature of IMD patients with positive Jo1 antibodies and its most common radiological pattern is that of nonspecific interstitial pneumonia.

Relative contributions of the ribcage and abdomen to lung volume displacement during speech production.

We tested the hypothesis that the pattern of chest wall configuration during speech production correlates with the pattern of chest wall motion during resting breathing. Twenty-one men (age 40 +/- 8 years) with ankylosing spondylitis and varied degrees of ribcage involvement participated in the study. None of the patients had an obvious speech abnormality. Ribcage and abdominal displacements during quiet breathing and during reading were measured with a respiratory plethysmograph. Measurements were taken in the sitting and standing body positions. In each body position, ribcage or abdominal displacements during quiet breathing correlated with the corresponding chest wall displacements recorded during reading (P < 0.001). In addition, linear regression analysis showed that the slope of the chest wall motion loop during quiet breathing correlated with the ratio of ribcage to abdomen contribution to lung volume displacement during reading (r = 0.78, P < 0.001 for sitting and r = 0.64, P = 0.002 for standing position). The slopes of the regression lines did not differ between the sitting and standing body position (P > 0.05). We conclude that the relative contribution of the ribcage and abdomen to lung volume displacement during speech production correlates with the relative ribcage and abdomen contribution to tidal volume during quiet breathing; our data support the notion that the pattern of chest wall configuration during quiet breathing largely predicts the pattern of ribcage and abdomen displacement during speech.

Pattern and distribution of myocardial fibrosis in systemic sclerosis: a delayed enhanced magnetic resonance imaging study.

OBJECTIVE: To assess the prevalence and pattern of myocardial fibrosis as detected by delayed enhanced magnetic resonance imaging (DE-MRI) in patients with systemic sclerosis (SSc), and to evaluate a possible association between myocardial fibrosis and cardiac arrhythmias. METHODS: Forty-one patients with SSc underwent 24-hour Holter monitoring, Doppler echocardiography, and DE-MRI following gadolinium administration. RESULTS: Technically acceptable DE-MRIs were obtained in 36 patients with SSc. Enhancement on DE-MRI, consistent with myocardial fibrosis, was observed in 24 of these patients (66%), and it was invariably midwall with a linear pattern, mostly involving basal and midcavity segments of the left ventricle. The volume of enhancement (total volume percentage index [TVPI]) did not differ between patients with diffuse SSc and those with limited SSc (mean +/- SD 1.46 +/- 1.73% versus 1.44 +/- 1.77%; P = 0.98). Patients with a long duration (> or = 15 years) of Raynaud's phenomenon had a greater number of enhancing segments (mean +/- SD 6.55 +/- 4.93 versus 2.96 +/- 3.46; P = 0.017) and a greater TVPI (mean +/- SD 2.44 +/- 1.97% versus 1.02 +/- 1.43%; P = 0.02) than those with a duration of Raynaud's phenomenon <15 years. Nineteen patients with SSc (53%) had abnormal Holter study results. Compared with patients with normal Holter study results, those with abnormal results had a greater number of enhancing segments (mean +/- SD 5.4 +/- 4.8 versus 2.5 +/- 2.9; P < 0.05) and a greater TVPI (mean +/- SD 2.1 +/- 1.9% versus 0.8 +/- 1.2%; P < 0.05). CONCLUSION: DE-MRI can identify myocardial fibrosis in a significant percentage of patients with SSc and may be a useful noninvasive tool for determining cardiac involvement.

Chest wall motion during speech production in patients with advanced ankylosing spondylitis.

PURPOSE: To test the hypothesis that ankylosing spondylitis (AS) alters the pattern of chest wall motion during speech production. METHOD: The pattern of chest wall motion during speech was measured with respiratory inductive plethysmography in 6 participants with advanced AS (5 men, 1 woman, age 45+/-8 years, Schober test 1.45+/-1.5 cm, Bath Ankylosing Spondylitis Functional Index [BASFI] score 6+/-1.7) and 6 healthy volunteers, matched for age and gender. Measurements were made with participants in the upright seated and upright standing body position. RESULTS: During reading in the seated and standing body positions, the rib cage wall volume displacements were smaller and abdominal wall volume displacements were larger in participants with AS than in healthy controls. There were no differences in the overall lung volume displacements recorded during the expiratory limb of reading in either body position. In the participants with AS, the rib cage remained near the end-expiratory level in both the seated and standing body position, differing from that for the control group. CONCLUSION: In individuals with advanced AS, the abdomen is the primary contributor to volume displacement. In the absence of speech impairment in participants with AS, the data show the capacity of the abdomen to compensate for the decreased compliance of the rib cage.

Determinants of pulmonary arterial hypertension in scleroderma.

OBJECTIVE: To define risk factors associated with pulmonary arterial hypertension (PAH) in a large cohort of patients with systemic sclerosis (SSc). METHODS: SSc patients undergoing screening for PAH by means of Doppler echocardiography were identified and their charts were retrospectively reviewed. In all patients, we recorded systolic pulmonary artery pressure along with pulmonary function testing, clinical, and laboratory data. PAH was defined as right ventricular systolic pressure equal or greater than 40 mm Hg. RESULTS: Of 114 SSc patients with echocardiographic measurements, PAH was found in 33 (29%) patients. In a multiple logistic regression analysis, the presence of pulmonary fibrosis on thoracic computed tomography (OR 6.78, CI 1.54 to 29.9), forced vital capacity less than 80% predicted (OR 3.03, CI 1.1 to 8.35), and duration of Raynaud's phenomenon preceding the onset of skin changes for at least 3 years (OR 5.75, CI 1.9 to 17.41) were found to be independent predictors of PAH. Age, disease duration, disease subtype, or autoantibodies were not associated with PAH in our patients. CONCLUSIONS: The present analysis identified pulmonary fibrosis and Raynaud's phenomenon preceding SSc skin manifestations by at least 3 years as risk factors for PAH in our scleroderma cohort. Screening for PAH in these high-risk patients may detect PAH at an earlier stage and guide decisions on therapeutic interventions.