The HLA Class II Allele Allele DRB1*15 is over-represented in patients with Idiopathic Pulmonary Fibrosis

Idiopathic pulmonary fibrosis (IPF) is a progressive and medically refractory lung disease with a grim prognosis. Although the etiology of IPF remains perplexing, abnormal adaptive immune responses are evident in many afflicted patients. We hypothesized that perturbations of human leukocyte antigen (HLA) allele frequencies, which are often seen among patients with immunologic diseases, may also be present in IPF patients. METHODS/PRINCIPAL FINDINGS:
HLA alleles were determined in subpopulations of IPF and normal subjects using molecular typing methods. HLA-DRB1*15 was over-represented in a discovery cohort of 79 Caucasian IPF subjects who had lung transplantations at the University of Pittsburgh (36.7%) compared to normal reference populations. These findings were prospectively replicated in a validation cohort of 196 additional IPF subjects from four other U.S. medical centers that included both ambulatory patients and lung transplantation recipients. High-resolution typing was used to further define specific HLA-DRB1*15 alleles. DRB1*1501 prevalence in IPF subjects was similar among the 143 ambulatory patients and 132 transplant recipients (31.5% and 34.8%, respectively, p = 0.55). The aggregate prevalence of DRB1*1501 in IPF patients was significantly greater than among 285 healthy controls (33.1% vs. 20.0%, respectively, OR 2.0; 95%CI 1.3-2.9, p = 0.0004). IPF patients with DRB1*1501 (n = 91) tended to have decreased diffusing capacities for carbon monoxide (DL(CO)) compared to the 184 disease subjects who lacked this allele (37.8±1.7% vs. 42.8±1.4%, p = 0.036). CONCLUSIONS/SIGNIFICANCE:
DRB1*1501 is more prevalent among IPF patients than normal subjects, and may be associated with greater impairment of gas exchange. These data are novel evidence that immunogenetic processes can play a role in…

Long-term Course and Prognosis of Idiopathic Pulmonary Fibrosis in the Modern Era

The American Thoracic Society and European Respiratory Society guidelines for the diagnosis and treatment of idiopathic pulmonary fibrosis (IPF) have been published recently. However, the influence, practical application, and utility of the prior consensus statement for IPF have never been evaluated. Demographics, diagnostic criteria, pulmonary function data, and disposition of patients with IPF evaluated at an interstitial lung disease center between 2000 and 2009 were analyzed. Enrollment in clinical drug trials, lung transplantation, and mortality also were assessed. A total of 521 patients with IPF were evaluated, with pulmonary function testing available in 446. In the 64% of patients without surgical lung biopsy, the most common major criterion not fulfilled was bronchoscopy. Lung transplantation was performed in 16.1% of patients, whereas 27.4% of prescreened patients were enrolled in a prospective drug study. Patients with mild, moderate, and severe disease categorized by FVC % predicted had median survivals of 55.6, 38.7, and 27.4 months, respectively. The attrition rate of patients who survived beyond 5 years was attenuated in subsequent years. IPF remains a deadly disease with a poor prognosis. Bronchoscopy does not appear to be required for an accurate diagnosis. A minority of patients were accommodated within a clinical trial or with transplantation. Categorization by baseline FVC % predicted effectively discriminates groups with different long-term outcomes. Our analysis supports the view that the value of statements also can be realized in the subsequent demonstration of their impact on patient management, which might enable further refinements in a continuous, iterative rediscovery process….

Parameters of donor-recipient mismatch and survival after bilateral lung transplantation

The purpose of this study was to investigate the relationship between donor-recipient height, gender and predicted estimates of total lung capacity (pTLC) mismatches and post-transplant survival. METHODS:
The lung transplant databases at three programs were reviewed. The pTLC ratios (donor pTLC/recipient pTLC) and height ratios (donor height/recipient height) were calculated retrospectively. Patients were grouped according to pTLC ratio ≤1.0 or >1.0 and height ratio ≤1.0 or >1.0, and according to gender (mis-)matching. A time-to-event analysis was performed for risk of death after transplantation conditional on 30-day survival using Kaplan-Meier survival and Cox proportional hazard models. RESULTS:
There were 211 adult bilateral lung transplant recipients who qualified for the analysis. Mean follow-up was comparable for all cohorts (range 2.21 to 3.85 years). In the univariate Cox proportional hazard models, a pTLC ratio >1.0 (HR 0.43, p = 0.002) and a height ratio >1.0 (HR 0.61, p = 0.03) were associated with better survival, and a female-donor-to-male-recipient gender mismatch (F-to-M) was associated with worse survival (HR 2.35, p = 0.01). In the multivariate Cox proportional hazard model accounting for F-to-M gender mismatch and height ratio >1.0, a pTLC ratio >1.0 remained associated with survival (HR 0.38, p = 0.015). However, accounting for a pTLC ratio >1.0, a height ratio of >1.0 and F-to-M mismatch were not associated with survival. CONCLUSIONS:
A pTLC ratio >1.0 is associated with improved survival after bilateral lung transplantation. The pTLC ratio might better reflect allograft-thorax mismatch than the height ratio, as it also accounts for effects of gender on lung…

Lung Size Mismatch in Bilateral Lung Transplantation Is Associated With Allograft Function and Bronchiolitis Obliterans Syndrome

Size mismatch between donor lungs and a recipient thorax could affect the major determinants of maximal expiratory airflow: airway resistance, propensity of airways to collapse, and lung elastic recoil. METHODS:
A retrospective review of 159 adults who received bilateral lung transplants was performed. The predicted total lung capacity (pTLC) for donors and recipients was calculated based on sex and height. Size matching was represented using the following formula: pTLC ratio = donor pTLC / recipient pTLC. Patients were grouped according to those with a pTLC ratio > 1.0 (oversized) or those with a pTLC ratio ≤ 1.0 (undersized). Allograft function was analyzed in relation to the pTLC ratio and to recipient and donor predicted function. RESULTS:
The 96 patients in the oversized cohort had a mean pTLC ratio of 1.16 ± 0.13 vs 0.89 ± 0.09 in the 63 patients of the undersized group. At 1 to 6 months posttransplant, the patients in the oversized cohort had higher FEV(1)/FVC ratios (0.895 ± 0.13 vs 0.821 ± 0.13, P < .01) and lower time constant estimates of lung emptying (0.38 ± 0.2 vs 0.64 ± 0.4, P < .01) than patients in the undersized cohort. Although the FVCs expressed as % predicted for the recipient were not different between cohorts, the FVCs expressed as % predicted for the donor organ were lower in the oversized cohort compared with the undersized cohort (at 1-6 months, 52.4% ± 17.1% vs 65.3% ± 18.3%, P < .001). Kaplan-Meier estimates for the occurrence of bronchiolitis obliterans syndrome...

Pulmonary Complications of Lung Transplantation

Lung transplantation is an effective treatment option for select patients with a variety of end-stage lung diseases. Although transplant can significantly improve the quality of life and prolong survival, a myriad of pulmonary complications may result in significant morbidity and limit long-term survival. The recognition and early treatment of these complications is important for optimizing outcomes. This article provides an overview and update of the pulmonary complications that may be commonly encountered by pulmonologists caring for these patients. …

Parenchymal trafficking of pleural mesothelial cells in idiopathic pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is characterised by myofibroblast proliferation leading to architectural destruction. Neither the origin nor the continued proliferation of myofibroblasts is well understood. Explanted human IPF lungs were stained by immunohistochemistry for calretinin, a marker of pleural mesothelial cells (PMCs). Chronic obstructive pulmonary disease (COPD) and cystic fibrosis (CF) lungs acted as controls. The number of PMCs per 100 nucleated cells and per photomicrograph was estimated along with the Ashcroft score of fibrosis. Mouse PMCs expressing green fluorescent protein (GFP) or labelled with nanoparticles were injected into the pleural space of mice given intranasal transforming growth factor (TGF)-β1. Mouse lungs were lavaged and examined for the presence of GFP, smooth muscle α-actin (α-SMA) and calretinin. Calretinin-positive PMCs were found throughout IPF lungs, but not in COPD or CF lungs. The number of PMCs correlated with the Ashcroft score. In mice, nanoparticle-laden PMCs were recoverable by bronchoalveolar lavage, depending on the TGF-β1 dose. Fluorescent staining showed α-SMA expression in GFP-expressing PMCs, with co-localisation of GFP and α-SMA. PMCs can traffic through the lung and show myofibroblast phenotypic markers. PMCs are present in IPF lungs, and their number correlates with IPF severity. Since IPF presumably begins subpleurally, PMCs could play a pathogenetic role via mesothelial-mesenchymal transition …

Exercise Prescription for Patients With Chronic Lung Disease

Chronic lung disease (CLD) and any consequent disease-related muscle myopathy along with deconditioning can cause both dyspnea and/or leg discomfort during exertion. These unpleasant experiences frequently lead an individual to reduce or even eliminate daily tasks which adversely impacts quality of life for the individual. The primary goal of exercise training is to restore the individual patient to the highest possible level of independent function. Improvements in exertional breathlessness observed following an exercise training program may be due to a physiologic training effect, enhanced mechanical efficiency, and/or psychologic desensitization. Any symptomatic patient with CLD who is motivated to participate should be referred to a pulmonary rehabilitation program. Exercise prescription is based on the principle of “overload” training. Although there is no optimal or best training regimen established for patients with CLD, we provide general guidelines for the mode, frequency, intensity, and duration of exercise training. The recommended minimal intensity of exercise training is 50% of peak work rate, although exercise at “maximal limits tolerated by symptoms” may also be prescribed. The recommended minimal duration of training is 20 to 30 minutes of continuous exertion. Resistance training should be incorporated into a comprehensive exercise program. One approach for patients with CLD to monitor their training intensity is to use a “dyspnea target” as a guide for intensity of training effort. …

Acquired Methemoglobinemia: A Case Report of Benzocaine-Induced Methemoglobinemia and a Review of the Literature

Benzocaine is widely used as a topical anesthetic and is also present in a number of over-the-counter preparations. Methemoglobinemia is a rare, but potentially serious, complication of its use; a fact that is not well documented in the Physician’s Desk Reference or product inserts. Unfamiliarity with this complication may delay diagnosis and appropriate therapy. A case of methemoglobinemia occurring as a complication of using benzocaine during bronchoscopy is presented and is followed by a review of the literature and discussion of the pathophysiology, clinical presentation, diagnosis, and treatment of acquired methemoglobinemia. Methemoglobin is incapable of carrying oxygen and is formed when the ferrous iron in the heme molecule is oxidized to the ferric state. The normal mechanisms that convert methemoglobin back to hemoglobin can be overwhelmed by many oxidant drugs, resulting in toxic methemoglobinemia. The diagnosis should be entertained when cyanosis, unresponsive to 100% oxygen therapy, appears suddenly, especially when exposure to an oxidant drug is established. Diagnosis is confirmed by multiple-wavelength cooximetry. Most cases require only decontamination and supportive care. Methylene blue is the specific antidote, but should be reserved for more severe cases or if comorbid conditions make mild hypoxia unadvisable. Exchange transfusion or hemodialysis may be indicated in patients who fail to respond to methylene blue. …

The Fibrinolytic Defect in Adult Respiratory Distress Syndrome: A New Therapeutic Opportunity?

Prominent alveolar fibrin deposition characterizes the adult respiratory distress syndrome (ARDS). Increased local expression of procoagulant activity and concurrently decreased fibrinolytic activity promote alveolar fibrin deposition in the lungs in ARDS. Thrombi in the lung vasculature and disseminated intravascular coagulation also occur in association with ARDS, further suggesting that disordered fibrin turnover may contribute to the pathogenesis of the syndrome. The fibrinolytic defect in ARDS potentiates alveolar fibrin deposition and organization of the fibrinous neomatrix, resulting in lung dysfunction and fibrotic repair. Similar disorders of pathways of fibrin turnover occur in systemic sepsis and these have recently been exploited to clinical advantage. Anticoagulant strategies have successfully been used in recent interventional trials in septic patients. The results of these trials suggest the possibility that this approach could be extrapolated to protect the lung in ARDS. Recent preclinical trials demonstrate that that similar anticoagulant strategies are feasible and effective in primates with evolving ARDS. Additional preclinical studies are now being performed to determine if fibrinolytic interventions likewise protect against lung injury in ARDS. Small clinical trials and case reports suggest that fibrinolysins can be of clinical benefit in selected patients with ARDS and support this approach. However, these agents increase the risk of bleeding. At this time, the use of fibrinolysins in ARDS patients is not routine and their place in the therapy of ARDS remains to be established. …

Negative-Pressure Ventilation: Who, When, How?

A resurgence of interest in noninvasive mechanical ventilation to treat patients with acute or chronic respiratory failure is mainly an attempt to avoid complications commonly associated with the presence of an artificial airway when providing conventional positive-pressure ventilation. Although noninvasive ventilation via noninvasive positive-pressure ventilation has largely supplanted negative ventilation as a form of noninvasive ventilation, negative-pressure ventilation still has an active role in patients who require ventilatory assistance but who cannot tolerate noninvasive positive-pressure ventilation. In some centers throughout Europe, negative-pressure ventilation is used to treat acute respiratory decompensation due to chronic obstructive pulmonary disease, neurologic disorders, or neonates suffering with respiratory distress syndrome. In this review, we discuss the details of applying negative-pressure ventilation and explore the physiologic effects of negative-pressure ventilation on gas exchange, upper airway function, cardiovascular performance, and lower esophageal sphincter tone. Finally, we discuss the application of negative-pressure ventilation in specific disease states including neonatal respiratory distress syndrome, a variety of neuromuscular diseases, and in patients with chronic obstructive pulmonary disease. …