Stephen K. Frankel

Mycophenolate Mofetil Improves Lung Function in Connective Tissue Disease-associated Interstitial Lung Disease

Objective. Small series suggest mycophenolate mofetil (MMF) is well tolerated and may be an effective therapy for connective tissue disease-associated interstitial lung disease (CTD-ILD). We examined the tolerability and longitudinal changes in pulmonary physiology in a large and diverse cohort of patients with CTD-ILD treated with MMF. Methods. We identified consecutive patients evaluated at our center between January 2008 and January 2011 and prescribed MMF for CTD-ILD. We assessed safety and tolerability of MMF and used longitudinal data analyses to examine changes in pulmonary physiology over time, before and after initiation of MMF. Results. We identified 125 subjects treated with MMF for a median 897 days. MMF was discontinued in 13 subjects. MMF was associated with significant improvements in estimated percentage of predicted forced vital capacity (FVC%) from MMF initiation to 52, 104, and 156 weeks (4.9% ± 1.9%, p = 0.01; 6.1% ± 1.8%, p = 0.0008; and 7.3% ± 2.6%, p = 0.004, respectively); and in estimated percentage predicted diffusing capacity (DLCO%) from MMF initiation to 52 and 104 weeks (6.3% ± 2.8%, p = 0.02; 7.1% ± 2.8%, p = 0.01). In the subgroup without usual interstitial pneumonia (UIP)-pattern injury, MMF significantly improved FVC% and DLCO%, and in the subgroup with UIP-pattern injury, MMF was associated with stability in FVC% and DLCO%. Conclusion. In a large diverse cohort of CTD-ILD, MMF was well tolerated and had a low rate of discontinuation. Treatment with MMF was associated with either stable or improved pulmonary physiology over a median 2.5 years of followup. MMF appears to be a promising therapy for the spectrum of CTD-ILD.

Heart Rate Recovery After 6-Min Walk Test Predicts Survival in Patients With Idiopathic Pulmonary Fibrosis

BACKGROUND In patients with idiopathic pulmonary fibrosis (IPF), our objectives were to identify predictors of abnormal heart rate recovery (HRR) at 1 min after completion of a 6-min walk test (6MWT) [HRR1] and 2 min after completion of a 6MWT (HRR2), and to determine whether abnormal HRR predicts mortality. METHODS From 2003 to 2008, we identified IPF patients who had been evaluated at our center (n = 76) with a pulmonary physiologic examination and the 6MWT. We used logistic regression to identify predictors of abnormal HRR, the product-limit method to compare survival in the sample stratified on HRR, and Cox proportional hazards analysis to estimate the prognostic capability of abnormal HRR. RESULTS Cutoff values were 13 beats for abnormal HRR1 and 22 beats for HRR2. In a multivariable model, predictors of abnormal HRR1 were diffusing capacity of the lung for carbon monoxide (odds ratio [OR], 0.4 per 10% predicted; 95% confidence interval [CI], 0.2 to 0.7; p = 0.003), change in heart rate from baseline to maximum (OR, 0.9; 95% CI, 0.8 to 0.97; p = 0.01), and having a right ventricular systolic pressure > 35 mm Hg as determined by transthoracic echocardiogram (OR, 12.7; 95% CI, 2.0 to 79.7; p = 0.01). Subjects with an abnormal HRR had significantly worse survival than subjects with a normal HRR (for HRR1, p = 0.0007 [log-rank test]; for HRR2, p = 0.03 [log-rank test]); these results held for the subgroup of 30 subjects without resting pulmonary hypertension (HRR1, p = 0.04 [log-rank test]). Among several candidate variables, abnormal HRR1 appeared to be the most potent predictor of mortality (hazard ratio, 5.2; 95% CI, 1.8 to 15.2; p = 0.004). CONCLUSION Abnormal HRR after 6MWT predicts mortality in IPF patients. Research is needed to confirm these findings prospectively and to examine the mechanisms of HRR in IPF patients.

IL-4-induced macrophage-derived IGF-I protects myofibroblasts from apoptosis following growth factor withdrawal.

The development of idiopathic pulmonary fibrosis (IPF) is associated with myofibroblast accumulation and collagen deposition in the lung parenchyma. Recent studies have suggested that the fibroproliferative response is associated with immune deviation toward a T helper cell type 2 (Th2) cytokine profile. In addition, myofibroblast accumulation may be the result of resistance to physiologic apoptosis. If and how these events are linked remain largely unknown. Insulin‐like growth factor‐I (IGF‐I) is a fibroblast growth and survival factor that has long been implicated in the pathogenesis of IPF. We have previously shown that interstitial macrophage‐derived IGF‐I correlates with disease severity in IPF, and the Th2 cytokines interleukin (IL)‐4 and IL‐13 stimulate the expression and secretion of IGF‐I by macrophages. In the present study, we tested the hypothesis that IL‐4‐induced, macrophage‐derived IGF‐I protects myofibroblasts from apoptosis. Using a growth factor withdrawal model of apoptosis in the myofibroblast cell line, CCL39, we demonstrate that conditioned media from IL‐4‐stimulated macrophages protect myofibroblasts from apoptosis. The survival effect is lost when IGF‐I is immunodepleted from macrophage‐conditioned media with IGF‐I‐specific antibodies. We also show that the protection of myofibroblasts by macrophage‐derived IGF‐I correlates with and is dependent on the activation of the prosurvival kinases Akt and extracellular signal‐regulated kinase. These findings support the view that IL‐4‐stimulated, macrophage‐derived IGF‐I may contribute to the persistence of myofibroblasts in pulmonary fibrosis in the Th2‐deviated environment of the fibrotic lung.

Compartmentalized Expression of c-FLIP in Lung Tissues of Patients with Idiopathic Pulmonary Fibrosis

Increased apoptosis of alveolar epithelial cells and impaired apoptosis of myofibroblasts have been linked to the pathogenesis of idiopathic pulmonary fibrosis/usual interstitial pneumonia (IPF/UIP). Fas, a death receptor of the TNF-receptor superfamily, has been implicated in apoptosis of both cell types, though the mechanisms are poorly understood. The goals of this study were: (1) to examine the localization of Fas-associated death-domain-like IL-1beta-converting enzyme inhibitory protein (c-FLIP), an NF-kappaB-dependent regulator of Fas-signaling, in lung tissues from IPF/UIP patients and control subjects; and (2) to compare c-FLIP expression with epithelial cell and myofibroblast apoptosis, proliferation, and NF-kappaB activation. c-FLIP expression was restricted to airway epithelial cells in control lung tissues. In contrast, in patients with IPF/UIP, c-FLIP was also expressed by alveolar epithelial cells in areas of injury and fibrosis, but was absent from myofibroblasts in fibroblastic foci and from alveolar epithelial cells in uninvolved areas of lung tissue. Quantification of apoptosis and proliferation revealed an absence of apoptotic or proliferating cells in fibroblastic foci and low levels of apoptosis and proliferation by alveolar epithelial cells. Quantification of NF-kappaB expression and nuclear translocation revealed strong staining and translocation in alveolar epithelial cells and weak staining and minimal nuclear translocation in myofibroblasts. These findings suggest that: (1) c-FLIP expression is induced in the abnormal alveolar epithelium of patients with IPF/UIP, (2) the resistance of myofibroblasts to apoptosis in patients with IPF/UIP occurs independently of c-FLIP expression, and (3) increased NF-kappaB activation and c-FLIP expression by the alveolar epithelium may be linked.

Vasculitis: Wegener granulomatosis, Churg-Strauss syndrome, microscopic polyangiitis, polyarteritis nodosa, and Takayasu arteritis

Identification, diagnosis, and management of the primary vasculitides and their attendant complications is a challenging task for the critical care physician. However, with appropriate therapy, the morbidity and mortality of these diseases can be markedly improved and allow the individual patient to return to their previous functional state.

Pulmonary function and survival in idiopathic vs secondary usual interstitial pneumonia.

BACKGROUND The usual interstitial pneumonia (UIP) pattern of lung injury may occur in the setting of connective tissue disease (CTD), but it is most commonly found in the absence of a known cause, in the clinical context of idiopathic pulmonary fibrosis (IPF). Our objective was to observe and compare longitudinal changes in pulmonary function and survival between patients with biopsy-proven UIP found in the clinical context of either CTD or IPF. METHODS We used longitudinal data analytic models to compare groups (IPF [n = 321] and CTD-UIP [n = 56]) on % predicted FVC (FVC %) or % predicted diffusing capacity of the lung for carbon monoxide (Dlco %), and we used both unadjusted and multivariable techniques to compare survival between these groups. RESULTS There were no significant differences between groups in longitudinal changes in FVC % or Dlco % up to diagnosis, or from diagnosis to 10 years beyond (over which time, the mean decrease in FVC % per year [95% CI] was 4.1 [3.4, 4.9] for IPF and 3.5 [1.8, 5.1] for CTD-UIP, P = .49 for difference; and the mean decrease in Dlco % per year was 4.7 [4.0, 5.3] for IPF and 4.3 [3.0, 5.6] for CTD-UIP, P = .60 for difference). Despite the lack of differences in pulmonary function, subjects with IPF had worse survival in unadjusted (log-rank P = .003) and certain multivariable analyses. CONCLUSIONS Despite no significant differences in changes in pulmonary function over time, patients with CTD-UIP (at least those with certain classifiable CTDs) live longer than patients with IPF--an observation that we suspect is due to an increased rate of mortal acute exacerbations in patients with IPF.

Challenges in pulmonary fibrosis · 3: Cystic lung disease

Cystic lung disease is a frequently encountered problem caused by a diverse group of diseases. Distinguishing true cystic lung disease from other entities, such as cavitary lung disease and emphysema, is important given the differing prognostic implications. In this paper the features of the cystic lung diseases are reviewed and contrasted with their mimics, and the clinical and radiographic features of both diffuse (pulmonary Langerhans’ cell histiocytosis and lymphangioleiomyomatosis) and focal or multifocal cystic lung disease are discussed.

Exercise peripheral oxygen saturation (Spo2) accurately reflects arterial oxygen saturation (Sao2) and predicts mortality in systemic sclerosis

Background: Measures of oxygenation have not been assessed for prognostic significance in systemic sclerosis-related interstitial lung disease (SSc-ILD). Methods: 83 subjects with SSc-ILD performed a maximal cardiopulmonary exercise test with an arterial line. The agreement between peripheral oxygen saturation (Spo2) and arterial oxygen saturation (Sao2) was examined and survival differences between subgroups of subjects stratified on Spo2 were analysed. Cox proportional hazards analyses were used to examine the prognostic capabilities of Spo2. Results: At maximal exercise the mean (SD) difference between Spo2 and Sao2 was 2.98 (2.98) and only 15 subjects had a difference of >4 points. The survival of subjects with SSc-ILD whose maximum exercise Spo2 (Spo2max) fell below 89% or whose Spo2max fell >4 points from baseline was worse than subjects in comparator groups (log rank p = 0.01 and 0.01, respectively). The hazard of death during the median 7.1 years of follow-up was 2.4 times greater for subjects whose Spo2max fell below 89% (hazard ratio 2.4, 95% CI 1.1 to 4.9, p = 0.02) or whose Spo2max fell >4 points from baseline (hazard ratio 2.4, 95% CI 1.1 to 5.0, p = 0.02). Conclusion: In patients with SSc-ILD, Spo2 is an adequate reflection of Sao2 and radial arterial lines need not be inserted during cardiopulmonary exercise tests in these patients. Given the ease of measurement and its prognostic value, Spo2 should be considered as a meaningful clinical and research outcome in patients with SSc-ILD.

Collagen Vascular Diseases of the Lung

The collagen vascular diseases are a diverse group of systemic autoimmune disorders that are frequently complicated by clinically significant lung disease. The development of respiratory symptoms in an otherwise healthy patient may be the presenting feature of an autoimmune disorder, whereas their development in a patient with a characterized autoimmune disease is always of concern because it may herald the development of a disease-related pulmonary complication or may be the result of a direct or indirect (such as infection) complication of its therapy. Inflammatory and/or fibrosing large and small airways disease, interstitial lung disease, pulmonary vascular disease, or pleural disease may occur separately or in combination depending on the underlying collagen vascular disease and the specific clinical circumstances. Although particular complications are more likely to occur with specific characterized entities such as rheumatoid arthritis, progressive systemic sclerosis, systemic lupus erythematosus, polymyositis/dermatomyositis, Sjögren syndrome, and mixed connective tissue disease, considerable overlap exists and one may see virtually any of the known pulmonary disorders in each of these collagen vascular diseases. This article reviews the varied presentations, characterized clinical syndromes, and an approach to the investigation of these disorders.

Eosinophilic Lung Disease

Eosinophilic lung disease broadly describes a diverse group of diffuse parenchymal lung diseases and airway disorders unified by the presence of marked pulmonary eosinophila and/or peripheral blood eosinophilia, and varying patterns of physiological, gas exchange, or radiographic abnormalities. Depending on the specific cause, other compartments of the lung including the blood vessels and/or pleura may also be affected. These disorders may be idiopathic and restricted to the lung or part of a systemic eosinophilic syndrome. Diagnosis remains challenging given the diverse clinicoradiologic patterns that may be seen, as well as the potential for overlapping clinical manifestations among the competing diagnostic considerations. Although corticosteroids represent first-line therapy in many of these disorders, important advances in the understanding of the eosinophil biology and specific disease pathogenesis, such as those with hypereosinophilic syndromes, have led to the development of novel targeted therapies. This clinical review focuses on the most current diagnostic and management strategies of the patient with eosinophilic lung disease.