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Summary: Rationale: Pulmonary hypertension (PH) commonly complicates the course of patients with idiopathic pulmonary fibrosis (IPF). It has a significant impact on outcomes and is, therefore, important to detect. Objectives: We sought to characterize the accuracy and performance characteristics of the right ventricular systolic pressure (RVSP) as estimated by echocardiography (ECHO) alone and in conjunction with physiologic indices in predicting the presence of PH in IPF patients. Methods: Cross-sectional study of IPF patients from two large tertiary centers in whom both ECHO and right-heart catheterization (RHC) were available. Measurements and main results: There were 110 patients with available ECHOs and RHCs. Estimates of RVSP were reported in 60 of these patients (54.5%) of whom 22 (36.6%) had PH, while 16 of the 50 patients without RVSP estimate (32%) had PH. Twenty-four of 60 (40%) ECHOs accurately reflected the pulmonary arterial systolic pressure as measured by RHC. An optimal RVSP threshold for the screening of PH could not be detected. When assessed in combination with various thresholds of PFT and 6-minute walk test (6MWT) parameters, the performance characteristics of the RVSP were slightly improved. Conclusion: The RVSP is not an accurate test for the assessment of PH in IPF patients. Awareness of the various combinations of threshold values for RVSP with and without PFT and 6MWT might nonetheless assist clinicians in risk stratifying IPF patients for the presence of PH. [Copyright &y& Elsevier]

Summary: Background: Reliable, noninvasive approaches to the diagnosis of pulmonary hypertension in idiopathic pulmonary fibrosis are needed. We tested the hypothesis that the forced vital capacity to diffusing capacity ratio and room air resting pulse oximetry may be combined to predict mean pulmonary artery pressure (MPAP) in idiopathic pulmonary fibrosis. Methods: Sixty-one idiopathic pulmonary fibrosis patients with available right-heart catheterization were studied. We regressed measured MPAP as a continuous variable on pulse oximetry (SpO2) and percent predicted forced vital capacity (FVC) to percent-predicted diffusing capacity ratio (% FVC/% DLco) in a multivariable linear regression model. Results: Linear regression generated the following equation: MPAP=−11.9+0.272×SpO2+0.0659×(100−SpO2)2+3.06×(% FVC/% DLco); adjusted R 2=0.55, p<0.0001. The sensitivity, specificity, positive predictive and negative predictive value of model-predicted pulmonary hypertension were 71% (95% confidence interval (CI): 50–89%), 81% (95% CI: 68–92%), 71% (95% CI: 51–87%) and 81% (95% CI: 68–94%). Conclusions: A pulmonary hypertension predictor based on room air resting pulse oximetry and FVC to diffusing capacity ratio has a relatively high negative predictive value. However, this model will require external validation before it can be used in clinical practice. [Copyright &y& Elsevier]

The prolonged and excessive consumption of alcohol has been shown to predispose the host to a variety of infectious complications, which may be due, in part, to the inability to produce important activating cytokines. In this study, we assessed the effect of chronic alcohol ingestion on bacterial clearance, survival, and cytokine mRNA and protein expression in mice with Klebsiella pneumonia. Two-week ethanol feeding resulted in substantial impairment in the clearance of K. pneumoniae and decreased survival, compared with CD-1 mice receiving an isocaloric diet without ethanol. No differences were noted between control and ethanol groups in the total numbers or percent of bronchoalveolar lavage fluid neutrophils or macrophages at 24 and 48 hr post-intratracheal K. pneumoniae. Importantly, the lungs of alcohol-fed mice with Klebsiella pneumonia displayed a decrease or delay in the expression of interleukin (IL)-12 p35 and p40 mRNA and interferon-γ mRNA, respectively, as well as reduced IL-12 and interferon-γ protein levels, compared with controls. Conversely, a time-dependent increase in lung IL-10 mRNA and protein was noted in ethanol-fed animals, compared with control animals challenged with K. pneumoniae. In summary, our studies indicate that ethanol ingestion results in a profound suppression of lung bacterial clearance and decreased survival in Klebsiella pneumonia, which occurs in association with a shift in the balance of lung cytokine mRNA and protein expression favoring Th2- rather than Th1-phenotype cytokines. [ABSTRACT FROM AUTHOR]

A response by David A. Zisman to a letter to the editor about the article "Transbronchial biopsy in usual interstitial pneumonia" is presented.

Abstract: Fibrotic interstitial lung diseases are illnesses of unknown cause characterized by progressive decline in lung function. Fibrocytes are bone marrow-derived, circulating progenitor cells capable of differentiating into diverse mesenchymal cell types. Prior work has shown fibrocytes to traffic to the lung via the CXCL12–CXCR4 chemokine axis in an animal model of pulmonary fibrosis. We therefore assessed the relevance of fibrocytes in patients with fibrotic interstitial lung disease. We found enhanced expression of CXCL12 in both the lungs and plasma of patients with lung fibrosis. CXCL12 levels were associated with an order of magnitude higher number of circulating fibrocytes in the peripheral blood of these patients. Most of the circulating fibrocytes in patients with interstitial lung diseases were negative for the myofibroblast marker α-smooth muscle actin, suggesting a relatively undifferentiated phenotype. Taken together, these data suggest that fibrocytes are involved in the pathogenesis of human lung fibrosis. [Copyright &y& Elsevier]

The available therapies and prognosis of idiopathic pulmonary fibrosis remain relatively poor, and concurrent pulmonary hypertension further increases the risk of death and complications after lung transplantation. Limited data exist for the treatment of pulmonary hypertension associated with idiopathic pulmonary fibrosis. We describe a case where intravenous treprostinil was used to bridge an elderly patient with idiopathic pulmonary fibrosis with severe pulmonary hypertension to successful single-lung transplantation. [Copyright &y& Elsevier]

Background: Sildenafil, a phosphodiesterase-5 inhibitor, may preferentially improve blood flow to well-ventilated regions of the lung in patients with advanced idiopathic pulmonary fibrosis, which could result in improvements in gas exchange. We tested the hypothesis that treatment with sildenafil would improve walk distance, dyspnea, and quality of life in patients with advanced idiopathic pulmonary fibrosis, defined as a carbon monoxide diffusion capacity of less than 35% of the predicted value., Methods: We conducted a double-blind, randomized, placebo-controlled trial of sildenafil in two periods. The first period consisted of 12 weeks of a double-blind comparison between sildenafil and a placebo control. The primary outcome was the proportion of patients with an increase in the 6-minute walk distance of 20% or more. Key secondary outcomes included changes in oxygenation, degree of dyspnea, and quality of life. The second period was a 12-week open-label evaluation involving all patients receiving sildenafil., Results: A total of 180 patients were enrolled in the study. The difference in the primary outcome was not significant, with 9 of 89 patients (10%) in the sildenafil group and 6 of 91 (7%) in the placebo group having an improvement of 20% or more in the 6-minute walk distance (P=0.39). There were small but significant differences in arterial oxygenation, carbon monoxide diffusion capacity, degree of dyspnea, and quality of life favoring the sildenafil group. Serious adverse events were similar in the two study groups., Conclusions: This study did not show a benefit for sildenafil for the primary outcome. The presence of some positive secondary outcomes creates clinical equipoise for further research. (Funded by the National Heart, Lung, and Blood Institute and others; ClinicalTrials.gov number, NCT00517933.)

Idiopathic pulmonary fibrosis (IPF; also known as cryptogenic fibrosing alveolitis) is a distinctive type of chronic fibrosing interstitial pneumonia of unknown cause associated with the histological pattern usual interstitial pneumonia (UIP). UIP is a distinct histological pattern observed in IPF but may also be found in other etiologies. The diagnosis of UIP can be established by surgical lung biopsy or by high-resolution thin-section CT scans (provided the radiographic features are classical). Historically, patients labeled as 'IPF' encompassed a group of disorders, including UIP, as well as other idiopathic interstitial pneumonias, which differ from UIP in prognosis and responsiveness to therapy. The term IPF should be restricted to patients with idiopathic UIP. The inciting cause(s) and pathogenesis of IPF have not been elucidated but alveolar epithelial cell injury and dysregulation or altered phenotypic expression of fibroblasts are key elements. Inflammatory cells may play minor roles in initiating or propagating the fibrotic process. The prognosis of idiopathic UIP is poor. Mean survival following diagnosis approximates at 3 years. Current medical therapies are of unproven value. Lung transplantation is a viable option for patients failing medical therapy.

Acute allograft rejection is considered to be a predominately type 1 immune mediated response to the donor alloantigen. However, the type 2 immune mediated response has been implicated in multiple fibroproliferative diseases. Based on the fibro-obliterative lesion found during bronchiolitis obliterans syndrome (BOS), we hypothesized that the type 2 immune mediated response is involved in chronic lung allograft rejection. Specifically, whereas acute rejection is, in part, a type 1 immune response, chronic rejection is, in part, a type 2 immune response. We found the type 2 cytokine, IL-13, to be elevated and biologically active in human bronchoalveolar lavage fluid during BOS. Translational studies using a murine model of BOS demonstrated increased expression of IL-13 and its receptors that paralleled fibro-obliteration. In addition, in vivo neutralization of IL-13 reduced airway allograft matrix deposition and murine BOS, by a mechanism that was independent of IL-4. Furthermore, using IL-13Ralpha2(-/-) mice, we found increased fibro-obliteration. Moreover, anti-IL-13 therapy in combination with cyclosporin A had profound effects on reducing murine BOS. This supports the notion that IL-13 biological axis plays an important role during the pathogenesis of BOS independent of the IL-4 biological axis.

Idiopathic pulmonary fibrosis (IPF) is a chronic fibrosing lung disease limited to the lungs and associated with the histologic appearance of usual interstitial pneumonia (UIP) on surgical lung biopsy. The estimated prevalence in the United States is between 35,000 and 55,000 cases,and evidence suggests that the prevalence is increasing for IPF. Risk factors associated with pulmonary fibrosis include smoking, environmental exposures, gastroesophageal reflux dis-ease, commonly prescribed drugs, diabetes mellitus, infectious agents, and genetic factors. The diagnosis requires a careful history and physical examination, characteristic physiological and radiological studies, and, in some cases, a surgical lung biopsy. The natural history of IPF is not known, but evidence supports the concept of a continuum of idiopathic interstitial pneumonias that may overlap in time. Most patients with IPF succumb to respiratory failure, cardiovascular disease, lung cancer, pulmonary embolism, infection, and other health problems. The median survival time for patients with IPF is less than 3 yr. Factors that predict poor outcome include older age, male gender, severe dyspnea, history of cigarette smoking, severe loss of lung function, appearance and severity of fibrosis on radiological studies, lack of response to therapy,and prominent fibroblastic foci on histopathologic evaluation. Conventional therapy (corticosteroids, azathioprine, cyclophosphamide) provides only marginal benefit. Lung transplantation should be considered for patients with IPF refractory to medical therapy. In light of the poor prognosis and lack of response to available anti-inflammatory therapy, alternative approaches to therapy are being pursued. Emerging strategies to treat patients with IPF include agents that inhibit epithelial injury or enhance repair, anti-cytokine approaches, agents that inhibit fibroblast proliferation or induce fibroblast apoptosis, and other novel approaches.

Acute allograft rejection is a major complication postlung transplantation and is the main risk factor for the development of bronchiolitis obliterans syndrome. Acute rejection is characterized by intragraft infiltration of activated mononuclear cells. The ELR-negative CXC chemokines CXCL9, CXCL10, and CXCL11) are potent chemoattractants for mononuclear cells and act through their shared receptor, CXCR3. Elevated levels of these chemokines in bronchoalveolar lavage fluid have been associated with human acute lung allograft rejection. This led to the hypothesis that the expression of these chemokines during an allogeneic response promotes the recruitment of mononuclear cells, leading to acute lung allograft rejection. We performed studies in a rat orthotopic lung transplantation model of acute rejection, and demonstrated increased expression of CXCL9 and CXCL10 paralleling the recruitment of mononuclear cells and cells expressing CXCR3 to the allograft. However, CXCL9 levels were 15-fold greater than CXCL10 during maximal rejection. Inhibition of CXCL9 decreased intragraft recruitment of mononuclear cells and cellular expression of CXCR3, resulting in lower acute lung allograft rejection scores. Furthermore, the combination of low dose cyclosporin A with anti-CXCL9 therapy had more profound effects on intragraft leukocyte infiltration and in reducing acute allograft rejection scores. This supports the notion that CXCL9 interaction with cells expressing CXCR3 has an important role in the recruitment of mononuclear cells, a pivotal event in the pathogenesis of acute lung allograft rejection.

The pathologic findings in biopsy and subsequent explant specimens from 20 patients with usual interstitial pneumonia (UIP) were reviewed to refine histologic criteria for diagnosis, to identify factors that may confound diagnosis, and to assess the relationship of UIP and nonspecific interstitial pneumonia (NSIP). One case of NSIP was also identified and included for comparison. Surgical biopsies from 15 of the 20 UIP cases were diagnosed as UIP, whereas 5 showed only nondiagnostic changes. An important new observation is that areas resembling nonspecific interstitial pneumonia (NSIP-like areas) are present in the majority of UIP cases in both biopsy and explant specimens, and they are extensive in some. Ten of the 15 UIP biopsies were considered straightforward, with typical patchy interstitial fibrosis, honeycomb change, and fibroblast foci. Five cases were considered difficult because of prominent NSIP-like areas in two, extensive honeycomb change in one, superimposed diffuse alveolar damage in one, and superimposed bronchiolitis obliterans-organizing pneumonia in one. The most helpful feature for diagnosing UIP in difficult cases was the presence of a distinct patchwork appearance to the characteristic uneven or variegated parenchymal involvement along with evidence of architectural derangement. No explant showing UIP was preceded by biopsy findings of NSIP, and the one NSIP case appeared similar at biopsy and explant. NSIP or NSIP-like areas and UIP may reflect different mechanisms of fibrosis related either to different severity of injury or to different injuries.