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01/09/13

Treatment of idiopathic pulmonary fibrosis

Official reprint from UpToDate www.uptodate.com 2013 UpToDate

Treatment of idiopathic pulmonary fibrosis Author Talmadge E King, Jr, MD Disclosures All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jul 2013. | This topic last updated: ago 9, 2013. INTRODUCTION Idiopathic pulmonary fibrosis (IPF, also called cryptogenic fibrosing alveolitis) is specific form of chronic, progressive, fibrosing interstitial pneumonia of unknown cause, occurring in adults and limited to the lungs. It is associated with the histopathologic and/or radiologic pattern of usual interstitial pneumonia (UIP). In the past, treatment was aimed at minimizing inflammation and slowing the progression from inflammation to fibrosis. However, the underlying lesion in IPF may be more fibrotic than inflammatory, explaining why few patients respond to antiinflammatory therapies and the prognosis remains poor [1-3]. The following questions will be discussed in this topic review, although considerable uncertainty remains about the answers [2,4,5]: Which patients should be treated? When should therapy be started? What is the best therapy? How should the disease course and the response to treatment be monitored? The evaluation, diagnosis, and pathogenesis of IPF are presented separately. (See "Idiopathic interstitial pneumonias: Clinical manifestations and pathology", section on 'Usual interstitial pneumonia' and "Pathogenesis of idiopathic pulmonary fibrosis".) NATURAL HISTORY The following observations about the natural history of IPF may be helpful in guiding therapy. Historically, patients with untreated IPF progress; disease progression is usually insidious, at least initially [6-8]. Data from the placebo arm of clinical trials suggest that the rate of decline in forced vital capacity (FVC) among untreated patients is 150 to 200 mL per year [9]. The course of the disease may be unpredictable, as some patients develop an acute deterioration after a period of apparent stability. Patients in the age group affected by IPF (the majority are >55 years old) may have difficulty discerning whether their functional limitations are the result of disease progression, deconditioning, or simply the aging process. Comorbid conditions (eg, COPD, heart failure) may also contribute to symptoms such as cough and reduced exercise tolerance. GENERAL APPROACH Overview The most important first step is to establish the diagnosis since misdiagnosis can lead to
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Section Editor Kevin R Flaherty, MD, MS

Deputy Editor Helen Hollingsworth, MD

01/09/13

Treatment of idiopathic pulmonary fibrosis

inappropriate initial therapy. High resolution computed tomography (HRCT) may be adequate to establish the diagnosis with a high degree of confidence in a minority of patients with a compatible clinical presentation and no evidence of another contributing process (eg, hypersensitivity pneumonitis, systemic sclerosis, rheumatoid arthritis). (See "Idiopathic interstitial pneumonias: Clinical manifestations and pathology", section on 'Usual interstitial pneumonia'.) When the results of HRCT are not classic for IPF, a video-assisted thoracoscopic or open lung biopsy is often necessary. (See "Idiopathic interstitial pneumonias: Clinical manifestations and pathology", section on 'Usual interstitial pneumonia' and "Role of lung biopsy in the diagnosis of interstitial lung disease".) The next step is to stage the patient's severity of disease as this will help to guide treatment choices. Finally, a disease management plan is tailored to the disease severity and desires of the individual patient. Ongoing assessment is needed to refine these choices as the disease progresses. Assessing disease severity No definitive staging system exists for assessing the severity of IPF, although patients usually progress from mild to moderate to severe respiratory limitation. Disease severity is assessed on the basis of symptoms, HRCT, and pulmonary function testing. Patients with mild or early disease are often asymptomatic or may have a mild, nonproductive cough and dyspnea with substantial exertion. Radiographic changes of reticular opacities and areas of honeycombing are limited to subpleural and basilar areas, involving less than 10 percent of the lung parenchyma. Pulmonary function tests may be normal or may show mild reductions in forced vital capacity (FVC), diffusing capacity (DLCO), and/or distance walked on the six-minute walk test. The alveolar to arterial oxygen gradient (P[A-a]O2) is normal or mildly elevated (<20 mmHg). Moderate disease is characterized by dyspnea on moderate exertion, nonproductive cough, and mild to moderate pulmonary function abnormalities. The latter may include a reduced FVC (eg, 50 to 70 percent of predicted), a reduced DLCO (eg, 45 to 65 percent of predicted) and/or P(A-a)O2 (eg, 21 to 30 mmHg). Discordance in the degree of impairment of FVC and DLCO may be noted. Supplemental oxygen may be needed with exertion. Radiographic changes are more extensive with reticular opacities involving 20 to 30 percent of the lung and honeycombing involving of <5 percent of the parenchyma [10]. One way of assessing the extent of radiographic changes is to quantitate these radiographic abnormalities on HRCT slices taken at three levels (eg, tracheal carina, inferior pulmonary veins, and 1 cm above the dome of the diaphragm) [1]. Advanced disease is characterized clinically by dyspnea on mild exertion (eg, walking <300 feet or climbing <1 flight of stairs) and requirement for supplemental oxygen at rest and/or with exertion. Extensive honeycombing is noted on HRCT (>5 percent of the parenchyma in three or more zones) [10]. Pulmonary function testing typically reveals moderate to severe reductions in the FVC (<50 percent of predicted), DLCO (<50 percent of predicted), and oxygen desaturation (4 percent) during a six-minute walk test [11]. Gas exchange is also impaired with room air oxygen saturation below 88 percent and P(A-a)O2 difference elevated (>30 mmHg). Choosing among therapies As no therapy has been proven to be efficacious in this disease, management generally includes some combination of supportive care (eg, supplemental oxygen, pulmonary rehabilitation), consideration for participation in clinical trials, referral for lung transplant evaluation (when appropriate), and identification and treatment of comorbidities [2,12]. Education and various components of supportive care should be offered to all patients with IPF. Supportive care may be preferred as the sole treatment option for many patients given the lack of proven therapy. (See 'Supportive care' below.) Inclusion and exclusion criteria for clinical trials vary, so we provide all patients with information regarding participation in randomized clinical trials whenever appropriate trials are available. Patients with mild to moderate disease are frequently ideal candidates for clinical trials as many limit participation to patients with early disease. (See 'Clinical trials' below.)
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Treatment of idiopathic pulmonary fibrosis

Agents such as pirfenidone show promise, but there is insufficient evidence to recommend their general use at this time. (See 'Pirfenidone' below.) Prevention of gastroesophageal reflux and recurrent microaspiration may slow disease progression. (See 'Future directions' below.) A number of other agents (eg, colchicine, cyclophosphamide, endothelin receptor antagonists, interferon gamma, methotrexate, cyclosporine, penicillamine) have been used in the past either in case series or clinical trials. The agents of doubtful benefit or intolerable toxicity are described below with the evidence against their routine use. (See 'Other agents' below.) Ongoing monitoring Ongoing monitoring is used to evaluate the clinical course and identify patients who develop accelerated deterioration. The response to therapy is usually assessed at three to six month intervals. We monitor symptoms (eg, dyspnea, exercise tolerance), forced vital capacity (FVC), total lung capacity (TLC), DLCO, and oxygenation at rest and with exercise (eg, oximetry, six-minute walk test) [11,13-16]. (See 'Acute exacerbations' below and "Overview of pulmonary function testing in adults".) In patients with advanced or progressive disease, careful evaluation for the development of hypoxemia, pulmonary hypertension, thromboembolic disease, or other comorbid conditions (eg, COPD, heart failure, obstructive sleep apnea) may yield additional treatment options [2,17]. (See 'Supplemental oxygen' below and "Pulmonary hypertension associated with interstitial lung disease" and "Overview of acute pulmonary embolism" and "Clinical presentation and diagnosis of obstructive sleep apnea in adults" and 'Transplantation' below.) SUPPORTIVE CARE The most important components of supportive care for patients with IPF are provision of supplemental oxygen (when needed), education, pulmonary rehabilitation, and vaccination against Streptococcus pneumoniae and influenza. Supplemental oxygen Virtually all patients with IPF will eventually require supplemental oxygen, initially just with exertion and then continuously. Oxygen therapy should be prescribed to enable maintenance of normal activity and possibly to prevent or delay the onset of secondary pulmonary hypertension in hypoxemic patients. The indications, benefits, and prescription of supplemental oxygen are discussed in detail elsewhere. (See "Long-term supplemental oxygen therapy".) Education Results from a survey regarding patients' experience with IPF suggest that improved education and communication about the diagnosis and management of IPF are needed [18]. For patients with progressive IPF, part of the education should include a discussion of end of life issues and advanced directives. Understanding a patient's individual preferences, beliefs, and values is a key step towards achieving an appropriate management plan [19]. Pulmonary rehabilitation Most of the data that supports the use of pulmonary rehabilitation in the management of patients with chronic respiratory disease comes from the study of COPD. Several studies also support the use of pulmonary rehabilitation in interstitial lung disease [20-25]. As an example, in a series of 113 patients with interstitial lung disease, a significant reduction in dyspnea and improvement in six-minute walk distance were found following participation in a pulmonary rehabilitation program [21]. (See "Pulmonary rehabilitation in COPD".) Vaccination Influenza and pneumococcal polysaccharide vaccine should be offered to patients with IPF, as these infections are poorly tolerated in patients with interstitial lung disease. (See "Seasonal influenza vaccination in adults" and "Pneumococcal vaccination in adults".) CLINICAL TRIALS The best hope for patients with IPF is that carefully performed clinical trials will confirm the efficacy and safety of agents that are identified based on animal models of IPF. We encourage appropriate patients to participate in clinical trials of emerging therapies for IPF. Specific trials and registries are available for patients with a familial history of IPF. Clinical trial information is available at Clinicaltrials.gov
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Treatment of idiopathic pulmonary fibrosis

N-ACETYLCYSTEINE Lung injury from excess production of oxidants is thought to be a contributing factor in IPF [26-32]. This is supported by the observation that bronchoalveolar lavage fluid levels of the antioxidant glutathione are low in patients with IPF [28,29]. N-Acetylcysteine (NAC) is a precursor of the antioxidant glutathione, and has been shown to restore depleted glutathione levels in the lung [28-31]. (See "Pathogenesis of idiopathic pulmonary fibrosis".) Evidence in favor of using NAC to treat IPF comes from the IFIGENIA (Idiopathic Pulmonary Fibrosis International Group Exploring N-Acetylcysteine I Annual) trial [26]. When azathioprine/prednisone plus NAC was compared to azathioprine/prednisone/placebo in the IFIGENIA trial, the rate of deterioration in vital capacity (-60 versus -190 mL) and single-breath carbon monoxide diffusing capacity (DLCO) (-0.11 versus -0.70 mmol/min per kPa) was lower in the NAC arm. Mortality was not significantly changed (9 versus 11 percent). There were no significant differences in the type or severity of adverse effects. The efficacy of monotherapy with NAC is being examined in the NAC and placebo arms of the multicenter PANTHER trial (Prednisone, Azathioprine, and N-acetylcysteine: A Study That Evaluates Response in IPF) [33,34]. Dosage and administration The dose of N-acetylcysteine for the treatment of IPF is 1800 mg orally per day (eg, 900 mg administered as effervescent tablets twice daily, 600 mg noneffervescent tablets three times per day). The effervescent formulation, which was used in the IFIGENIA trial above, is not available in the United States; noneffervescent tablets are available, although the relative efficacy is not known. Oral administration of Nacetylcysteine is generally well tolerated. The most common adverse effects include nausea, vomiting, and other gastrointestinal complaints. Rarely, rash with or without fever may occur. PREDNISONE-AZATHIOPRINE-N-ACETYLCYSTEINE Combination therapy with a systemic glucocorticoid and azathioprine has been used for IPF for many years, although supportive clinical trial data was limited [35,36]. Another combination therapy, systemic glucocorticoid, azathioprine, and the antioxidant N-acetylcysteine (NAC) was assessed in the IFIGENIA (Idiopathic Pulmonary Fibrosis International Group Exploring N-Acetylcysteine I Annual) trial [32,33]. However, the IFIGENIA trial examined the addition of NAC or placebo to a baseline regimen of prednisone and azathioprine, rather than comparing the combination regimen to placebo. (See 'N-Acetylcysteine' above.) The multicenter PANTHER trial (Prednisone, Azathioprine, and N-acetylcysteine: A Study That Evaluates Response in IPF) is a three-armed trial comparing combination therapy (prednisone-azathioprine-NAC), NAC alone, and placebo [37]. In an interim analysis, combination therapy (77 patients) was associated with greater mortality (8 versus 1 deaths), more hospitalizations (23 versus 7), and more serious adverse events (24 versus 8) than placebo (78 patients). Therefore, the combination arm of the trial was stopped; the N-acetylcysteine and placebo arms are ongoing. Based on data from the PANTHER trial, we suggest not initiating combination therapy (azathioprine, prednisone, NAC) in patients with IPF. PIRFENIDONE Antifibrotic agents are an active area of research because the predominant pathological findings in IPF are fibroblast foci, collagen deposition, and minimal inflammatory cell infiltration [38,39]. Pirfenidone (5methyl-1-phenyl-2-(1H)-pyridone) is an example of an anti-fibrotic agent. In vitro, it inhibits transforming growth factor beta (TGF-b)-stimulated collagen synthesis, decreases the extracellular matrix, and blocks fibroblast proliferation. (See "Pathogenesis of idiopathic pulmonary fibrosis".) Most case series and randomized trials have shown a modest beneficial effect of pirfenidone in slowing the progression of IPF [40-44]. As examples: Two concurrent, multicenter trials (Clinical studies Assessing Pirfenidone in idiopathic pulmonary fibrosis, CAPACITY 004 and 006) assessed the change in percentage forced vital capacity (FVC) at week 72 [43]. Patients with mild-to-moderate IPF (ie, FVC 50 percent predicted and diffusing capacity [DLCO] 35 percent predicted) were randomly assigned to oral pirfenidone 2403 mg/day, 1197 mg/day, or placebo in the
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Treatment of idiopathic pulmonary fibrosis

004 trial and oral pirfenidone 2403 mg/day or placebo in the 006 trial. The higher dose of pirfenidone significantly decreased the percent fall in FVC in the 004 trial (difference between groups, 4.4 percent, p=0.001), but not the 006 trial (difference between groups, 0.6 percent, p=0.51). The higher dose of pirfenidone significantly reduced the decline in the 6MWTD, a secondary endpoint, in the 006 (absolute difference 32 meters, p=0.0009), but not the 004 trial. A randomized trial of pirfenidone (1800 mg/day) versus placebo was carried out in 107 patients with IPF [41]. The change in the lowest oxygen saturation by pulse oximetry (SpO2) during a six-minute exercise test, the primary endpoint, was not significantly different between the two groups from baseline to six months (+0.6 versus -0.5 percent) and nine months (+0.5 versus -0.9 percent). In a prespecified subset of patients who maintained the SpO2 >80 percent during a six-minute exercise test at baseline, a significant improvement was noted in the pirfenidone group in the lowest SpO2 that occurred during a six-minute exercise test at six months (+0.5 versus -1.9 percent) and nine months (+0.5 versus -1.6 percent), suggesting there may be greater benefit in patients whose disease is less severe. In the same trial, a positive treatment effect was demonstrated in secondary endpoints including an increase in vital capacity measurements at nine months (-0.03 versus -0.13 liters) and fewer episodes of acute exacerbation of IPF (14 percent versus none). The trial was aborted in favor of pirfenidone treatment due to the decreased number of acute exacerbations in the pirfenidone group. In a separate multicenter trial, 275 patients were randomly assigned to one of three groups: pirfenidone 1800 mg per day, 1200 mg per day, or placebo [42]. The primary endpoint, change in vital capacity (VC), was assessed at 52 weeks; the secondary endpoint was progression free survival. The decline in VC was only slightly less in the high-dose pirfenidone group compared with placebo, but the difference was statistically significant. The progression free survival time was slightly longer in the high dose pirfenidone group compared with placebo. Pirfenidone appears to slow the progression of lung impairment in patients with pulmonary fibrosis due to Hermansky-Pudlak syndrome [45]. Dosage and administration The dose of pirfenidone ranges up to 40 mg/kg per day (to maximum of 2403 mg per day) in three divided doses. This medication is approved for use in patients with mild-to-moderate IPF in Japan, Europe, and Canada, but not in the United States. The most common side effects include rash, photosensitivity, abdominal discomfort, dyspepsia, anorexia, nausea, fatigue, and lethargy. The gastrointestinal side effects may be ameliorated by taking the medication after meals. Other potential side effects include: diarrhea, constipation, itching, dry skin, hyperpigmentation, headache, and weakness. PHOSPHODIESTERASE INHIBITORS As IPF progresses, a substantial portion of patients develop pulmonary hypertension. This has led to the hypothesis that treating IPF-related pulmonary hypertension with a phosphodiesterase inhibitor might improve exercise tolerance, as in idiopathic pulmonary hypertension [46-48]. (See "Treatment of pulmonary hypertension in adults", section on 'PDE5 inhibitors'.) In a randomized trial, 180 patients with advanced IPF (defined as a diffusing capacity less than 35 percent of predicted) were assigned to sildenafil 20 mg three times daily or placebo for 12 weeks [48]. Exclusion criteria included a six-minute walk distance (6MWD) less than 50 m (164 feet), treatment with medications containing nitrates, and presence of aortic stenosis or hypertrophic subaortic stenosis. No difference was found in the primary end-point of at least a 20 percent improvement in the six-minute walk distance compared with baseline. Small differences were noted between the groups in dyspnea and quality of life, favoring sildenafil. In a substudy of this trial that looked at subjects with pretreatment echocardiograms, sildenafil treatment of 22 subjects with right ventricular systolic dysfunction was associated with a smaller decrement in 6MWD and a greater improvement in quality of life measures than placebo [49].
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Treatment of idiopathic pulmonary fibrosis

Two smaller studies found mixed results with sildenafil. An open-label observational study of 14 patients with IPF and PAH found that treatment with the phosphodiesterase inhibitor sildenafil resulted in a modest improvement in six-minute walk with a mean increase in distance walked of 49 meters, which is lower than the usual standard of 54 m for a clinically important increase [46]. However, a subsequent randomized trial of 29 subjects found no significant difference in the six-minute walk with sildenafil compared with placebo [47]. Further trials of longer duration are needed to determine the safety and efficacy of sildenafil in the treatment of IPF. However, given the paucity of treatment options for advanced IPF, a trial of sildenafil may be a reasonable option in patients with a DLCO <35 percent, echocardiographic evidence of right ventricular dysfunction, and no contraindications to sildenafil (eg, unstable angina, use of nitrates). The initial dose of sildenafil (20 mg) is given while monitoring symptoms, blood pressure, and pulse oxygen saturation for 60 minutes. If tolerated, sildenafil is continued at a dose of 20 mg three times daily. ACUTE EXACERBATIONS Patients with IPF may suffer acute deterioration secondary to infections, pulmonary embolism, pneumothorax, or heart failure [12,50]. In addition, the clinical course of IPF is often complicated by "acute exacerbations" or an "accelerated phase of rapid clinical decline" without an identifiable cause [9,50-54]. These processes are associated with a poor prognosis. The incidence of these acute exacerbations ranges from 10 to 57 percent, apparently depending on the length of follow-up [50,54]. The risk factors for acute exacerbations of IPF are unknown. Acute viral infection is unlikely to be a common etiology [55]. When lung biopsies have been performed during an episode, the histopathologic pattern of acute lung injury (diffuse alveolar damage) is often found on the background of UIP. Definition The following criteria for an acute exacerbation of IPF have been proposed [50]: Previous or concurrent diagnosis of idiopathic pulmonary fibrosis Unexplained development or worsening of dyspnea within 30 days High-resolution computed tomography with new bilateral ground-glass abnormality and/or consolidation superimposed on a background reticular or honeycomb pattern consistent with usual interstitial pneumonia No evidence of pulmonary infection by endotracheal aspirate or bronchoalveolar lavage Exclusion of alternative causes, including left heart failure, pulmonary embolism, and other identifiable causes of acute lung injury Patients who do not meet all five criteria should be termed "suspected acute exacerbation." Clinical manifestations The key clinical feature is acute or subacute worsening of dyspnea over days to weeks, but generally in less than 30 days [50,56]. Cough, fever, and flu-like symptoms may also be present. Respiratory insufficiency can be severe and require noninvasive support or mechanical ventilation. The most common criteria for impaired gas exchange are an arterial oxygen tension to fraction of inspired oxygen ratio (PaO2/FIO2) of less than 225 mmHg or a decrease in the PaO2 of 10 mmHg or more from baseline. High resolution CT scans (HRCT) obtained during an acute exacerbation of IPF typically show the underlying fibrotic changes of IPF with new, superimposed alveolar opacities that may be peripheral, multifocal, or diffuse [56-58]. Among these patterns, prognosis appears to vary; the peripheral pattern may have a better prognosis, multifocal an intermediate prognosis, and diffuse a worse outcome. Implications for practice After excluding other potential causes of worsening dyspnea and hypoxemia, we typically treat patients who have an acute exacerbation with broad-spectrum antibiotics and high dose glucocorticoids (eg, prednisone 1 mg/kg per day orally or methylprednisolone 1 to 2 g per day intravenously), although scientific evidence for this is lacking [2,50,59]. Some practitioners add a cytotoxic agent such as azathioprine or, rarely, cyclophosphamide [54,56]. Better understanding and management of these episodes will be
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Treatment of idiopathic pulmonary fibrosis

critical to reducing the death rate in IPF [12]. Mechanical ventilation is often required, but is not usually successful; the hospital mortality rate was 78 percent in one study [60]. In patients who survive, a recurrence of acute exacerbation is common and usually results in death [61]. TRANSPLANTATION IPF is the most common interstitial lung disease among referrals for lung transplantation and the second most frequent disease for which lung transplantation is performed [62,63]. Indications and choice of procedure Patients with IPF have the highest death rate among the diagnostic groups on the transplant waiting list [64]. For this reason, early referral for transplant evaluation should be considered, even before the response to initial medical therapy has been determined [65]. Under the current United Network for Organ Sharing (UNOS) system, priority for transplantation is determined by medical urgency and expected outcome using a lung allocation score (LAS) (table 1). Scores are normalized to a continuous scale from 1 to 100, with higher scores representing higher urgency and greater potential transplant benefit. (See "Lung transplantation: An overview", section on 'Lung allocation' and "Lung transplantation: Disease-based choice of procedure".) General guidelines for transplantation include histologic or radiographic evidence of usual interstitial pneumonia (UIP) and any of the following [66]: A diffusing capacity (DLCO) <39 percent of predicted A decrement in forced vital capacity (FVC) >10 percent during six months of follow up A decrease in pulse oximetry below 88 percent saturation during a six-minute walk test Honeycombing on high resolution chest tomography (HRCT) (fibrosis score >2 [67]) Among 1256 patients transplanted between May 2005 and December 2007, the one year survival rate was 74 percent among those with scores in the highest lung allocation quartile (LAS 52.0 to 94.1) and 84 percent among those in the lowest lung allocation score quartile (LAS 31.1 to 37.8) [68]. Evaluation of the LAS factors predicting mortality revealed that IPF patients being ventilated before transplantation had an increased risk of mortality at one year (HR, 3.78; 95% CI, 2.32 to 6.17) [68]. The five-year survival rate for lung transplantation in IPF is 40 to 50 percent, compared with a five-year survival rate of 52 percent for all lung transplant recipients [63,69-71]. Although single lung transplantation (SLT) has been the standard procedure for IPF, bilateral lung transplant (BLT) may prove to have better long-term survival [69,70,72-77]. Mild to moderate secondary pulmonary hypertension preoperatively increased the risk of reperfusion injury in one study, but did not appear to affect survival in two retrospective studies [78,79]. Following SLT, the low lung compliance and high vascular resistance of the remaining native lung preferentially direct both ventilation and perfusion to the transplanted lung. Cysts, bullae, and bronchiectasis that occasionally develop in the later stages of IPF can act as a nidus for infectious complications after SLT; when these are identified, BLT may be preferred. Early experience suggests that living donor lobar lung transplantation (LDLLT) may be an option for patients with IPF who are likely to die while waiting for SLT. In a report of nine such patients, eight of whom were dependent on systemic glucocorticoids (up to 50 mg/day), only one early death occurred after transplant of two lower lobes donated by two healthy relatives [80]. Eight patients were still alive after 10 to 48 months of follow-up. Physiologic changes After SLT or BLT, spirometric parameters, lung volumes, diffusing capacity, and oxygenation improve significantly, and these improvements have been sustained in long-term follow-up of recipients without complications [72-75]. In a series that compared SLT and BLT recipients with IPF, the mean FEV1 was higher in BLT recipients than SLT recipients one year after transplantation (2.25 versus 2.00 liters) [75].
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Treatment of idiopathic pulmonary fibrosis

After SLT, most lung function is contributed by the allograft. As a result, the vital capacity (VC) of the recipient correlates closely with the predicted vital capacity of the donor organ [81]. Improvements in cardiopulmonary function continue for up to one year following transplantation. As an example, in one study of SLT recipients, the mean VC increased from 43 percent of the predicted normal value preoperatively to 65 percent three months and 69 percent one year after transplantation. None of the eight recipients tested one year after transplantation required supplemental oxygen at rest or during exercise, and their treadmill exercise tolerance was much improved [74]. Prior treatment The effect of prior glucocorticoid therapy on the outcome of lung transplantation is uncertain. Most studies suggest that low-dose glucocorticoid therapy has no adverse effect on outcome [82-84]. However, high-dose glucocorticoid therapy may be associated with decreased survival after lung transplantation [84]. The International Guidelines for the Selection of Lung Transplant Candidates lists prednisone use >20 mg/day as a relative contraindication for lung transplantation [66]. (See "Lung transplantation: General guidelines for recipient selection", section on 'Glucocorticoid use'.) PROGNOSIS The prognosis of IPF is poor, with only 20 to 30 percent of subjects alive five years after diagnosis [4,5,7,85-89]. Several factors have been associated with shortened survival time: older age at presentation, extensive cigarette smoking, lower body mass index (BMI), more severe physiologic impairment, greater radiologic extent of disease, and the development of other complications or conditions, eg, pulmonary hypertension, emphysema, and bronchogenic cancer [13,90-96]. Co-morbid diseases and adverse effects of therapy also contribute (table 2) [92,97]. Clinical deterioration is most frequently due to disease progression. Data from the placebo arms of recent randomized clinical trials show that the mean rate of decline in forced vital capacity (FVC) is approximately 150 to 200 mL/yr [92]. Hospitalizations for respiratory problems are common events and are frequently associated with death [9,98]. Patients with IPF admitted to intensive care units are at greater risk of mortality than expected based on their severity of illness, as assessed by the APACHE score [61,92]. (See "Predictive scoring systems in the intensive care unit", section on 'Acute Physiologic and Chronic Health Evaluation (APACHE)'.) FUTURE DIRECTIONS The agents currently available for the treatment of IPF are clearly inadequate. Therapeutic response is obtained in only a subset of patients, and survival is poor even for those who respond. In addition, these agents all carry significant side effects and toxicity. For these reasons, there is much interest in developing more effective, less toxic pharmacologic therapy [99,100]. Some examples of potential future therapies are provided in the following sections. Thalidomide Thalidomide is an immune modulator and anti-fibrotic agent that ameliorates bleomycin-induced pulmonary fibrosis in mice [101]. The effect of thalidomide on cough, a debilitating symptom in IPF, was assessed in 23 patients with IPF who were randomly assigned to thalidomide or placebo in a 24 week crossover trial [102]. Twenty-two participants completed 12 weeks of the placebo regimen, and 20 completed 12 weeks of thalidomide. The primary endpoint, improvement in the Cough Quality of Life Questionnaire (CQLQ), favored thalidomide (mean difference versus placebo, -11.4 [95% CI, -15.7 to -7.0]). Cough severity measured on a visual analog scale also improved. Adverse events attributed to thalidomide included constipation (36 percent), dizziness (27 percent), malaise 14 percent, anorexia (5 percent) and asymptomatic bradycardia (5 percent). The potential benefit of thalidomide in IPF will need validation in a larger and longer multicenter trial that assesses additional endpoints, such as mortality and lung function. Tyrosine kinase inhibitors Several of the fibrogenic growth factors that appear to participate in IPF (eg, platelet-derived growth factor, vascular endothelial growth factor, fibroblast growth factor) act via tyrosine kinase receptors, raising the possibility that inhibition of these receptors would slow the rate of disease progression. (See "Pathogenesis of idiopathic pulmonary fibrosis", section on 'Cytokines, growth factors, and other molecules'.) The efficacy of the tyrosine kinase inhibitor BIBF 1120 (nintedanib) was assessed as a treatment for IPF in a phase 2 trial (To Improve Pulmonary Fibrosis with BIBF 1120) [103]. A total of 432 patients were randomly assigned to one
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Treatment of idiopathic pulmonary fibrosis

of four oral doses of BIBF 1120 or placebo. The group taking the highest dose of BIBF 1120, 150 mg twice daily, showed a trend towards a slower decline in lung function and fewer exacerbations compared with placebo. However, the methodologic problems related to the multiple doses of study medication may have reduced the likelihood of a positive result; improvements were noted in several of the secondary endpoints. Another tyrosine kinase inhibitor, imatinib, inhibits a narrower spectrum of growth factors and had no effect on survival or lung function in IPF, when compared with placebo. (See 'Imatinib' below.) Immunomodulation Although there is still much to be learned regarding the roles of various cytokines and growth factors in the complex process of pulmonary fibrosis, it is clear that these agents are critical [99,100]. Inhibitors of specific fibrogenic cytokines or growth factors (eg, tumor necrosis factor alpha antagonists, interleukin 1 receptor antagonist [IL-1ra], anti-CD 11 antibody) may help to retard the fibrotic process [104-106]. Although these agents may appear to be effective in animal models of pulmonary fibrosis, it will be important to evaluate them fully in randomized, placebo-controlled trials in humans. Another potential strategy involves interfering with the process of leukocyte retention in the lung [99]. Leukocyte adhesion molecules play an important role in this process, and antibodies to such adhesion molecules have been shown to prevent collagen deposition in an animal model of lung injury [107]. Agents that block the expression or function of adhesion molecules are rapidly becoming available and may someday prove clinically useful [100]. Gastroesophageal reflux and chronic microaspiration Up to 90 percent of patients with IPF have gastroesophageal reflux (GER) [108-110]. It has been hypothesized that GER is an important risk factor for the development and/or progression of IPF [111-115]. In a systematic review, it was noted that 67 to 76 percent of patients with IPF assessed with ambulatory pH probe monitoring had abnormal distal esophageal acid exposure [116]. In addition, classic symptoms of GER (heartburn, acid regurgitation) were poor predictors of increased esophageal acid exposure among patients with moderate to severe IPF. In a separate study, reflux in patients with IPF was associated with a hypotensive lower esophageal sphincter and abnormal esophageal peristalsis, and often extended into the proximal esophagus [117]. The effect of anti-GER treatment on IPF disease progression has also been examined. A retrospective study of 204 patients with IPF found that reported use of anti-GER medications was associated with decreased radiographic fibrosis scores on chest computed tomography and was an independent predictor of longer survival time [118]. An analysis of data from three randomized controlled trials identified patients with IPF assigned to receive placebo and used prospectively obtained data about diagnosis and treatment of abnormal acid gastroesophageal reflux [119]. Of the 242 patients randomly assigned to the placebo groups of the three trials, 124 (51 percent) were taking a protonpump inhibitor (PPI) or H2 blocker at enrollment. After adjustment for sex, baseline FVC as a percentage of predicted, and baseline diffusing capacity for carbon monoxide (DLCO) as a percentage of predicted, patients taking a PPI or H2 blocker at baseline had a smaller decrease in FVC at 30 weeks (-0.06 L, 95% CI -0.11 to -0.01) than did those not taking anti-acid treatment (-0.12 L, -0.17 to -0.08; difference 007 L, 95% CI 0-0.14). These data suggest that anti-GER treatment could be beneficial in patients with IPF and support the previous reports suggesting that abnormal acid gastroesophageal reflux contributes to disease progression. However, controlled clinical trials of acid reflux treatments in IPF are needed. OTHER AGENTS A number of agents have been evaluated for use in IPF, but are not currently used for this indication. The following agents are mentioned here to provide clinicians with an overview of the evidence for and against their use. Anticoagulation It has been proposed that a prothrombotic state exists in patients with IPF that may contribute to mortality [120,121]. The hypothesis that anticoagulation might reduce mortality in IPF was initially tested in a nonblinded trial of 56 IPF patients who were hospitalized due to worsening dyspnea; subjects were randomly assigned to prednisolone PLUS long-term anticoagulation or prednisolone alone [122]. A significant improvement in survival was found at three years in the anticoagulant group (63 versus 35 percent).

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However, due to methodologic concerns with the above study, the Anticoagulant Effectiveness in Idiopathic Pulmonary Fibrosis trial (ACE-IPF; NCT00957242), was performed [12,123,124]. In the ACE-IPF trial, 145 subjects with IPF but without other indications for anticoagulation were randomly assigned to warfarin anticoagulation (to an International Normalized Ratio [INR] of 2.0 to 3.0) or placebo [124]. After a mean follow-up of 28 weeks, the study was stopped due to an increase in mortality in the subjects randomized to warfarin (14 warfarin versus 3 placebo deaths; P = 0.005) and a low probability of benefit. None of the deaths was attributed to bleeding complications. Anticoagulation with warfarin is not indicated in patients with IPF who lack other indications for anticoagulation, due to the increased risk of mortality. However, anticoagulation should not be withheld from patients with IPF who have other indications for anticoagulation based on this trial. Colchicine We suggest not using colchicine in the treatment of IPF because evidence of efficacy is lacking. There have been numerous in vitro and animal model studies suggesting that colchicine may slow the fibrotic process [125-128]. However, several clinical studies, including retrospective studies [90,129], a randomized trial [91], and a nonrandomized prospective study [130], failed to show a significant difference in the rate of decline of lung function when patients were treated with colchicine or glucocorticoids. Cyclophosphamide We rarely use cyclophosphamide (Cytoxan) because of its toxicity and lack of proven benefit. Although several small series suggested that cyclophosphamide (usually given along with low doses of glucocorticoids) might be beneficial in the treatment of IPF [131-133], one of the largest retrospective series found no survival benefit among 82 patients on the combination of prednisone and oral cyclophosphamide compared with 82 on prednisone alone [134]. We suggest that cyclophosphamide only be used to treat IPF when there has been a clinical impression of response to immunosuppressive treatment, but the combination of glucocorticoid, azathioprine, and Nacetylcysteine has not been tolerated. Dosing and treatment considerations for the use of cyclophosphamide are discussed in detail separately. (See "General principles of the use of cyclophosphamide in rheumatic and renal disease" and "General toxicity of cyclophosphamide and chlorambucil in inflammatory diseases".) Endothelin receptor antagonists Several trials examining the efficacy of endothelin receptor antagonists in IPF failed to meet their primary objectives and are not being used in IPF treatment. Bosentan (Tracleer), a nonselective endothelin receptor antagonist, was evaluated as a therapy for IPF because of its antifibrotic properties [135]. In the multicenter trial BUILD 1 (Efficacy and Safety of Oral Bosentan in Patients With Idiopathic Pulmonary Fibrosis), there was no significant difference in the primary endpoint of exercise capacity, as measured by a six-minute walk, or in the secondary endpoints of dyspnea and quality of life [136,137]. A follow-up study, the multinational BUILD 3 trial (Bosentan Use in Interstitial Lung Disease 3), was designed to examine the trend toward delayed time to death or disease progression observed in BUILD 1 [136,138]. However, it did not meet its primary end-point of time to IPF worsening or death. A multinational trial examining the role of macitentan, a highly potent, tissue-targeting endothelin receptor antagonist in early IPF failed to meet the primary endpoint (Macitentan Use in an IPF Clinical Study or MUSIC trial; clinical trials identifier: NCT00903331 at Clinicaltrials.gov). The "ARTEMIS-IPF Trial" (Randomized, Placebo-Controlled Study to Evaluate Safety and Effectiveness of Ambrisentan in IPF; clinical trials identifier: NCT00768300) comparing ambrisentan, a type A endothelin receptor antagonist, was terminated due to lack of efficacy [139]. Of note, ambrisentan may be deleterious in IPF, not just of no benefit. The risks of disease progression and respiratory hospitalization were higher in the ambrisentan-treated group than placebo. A subset analysis of patients with pulmonary hypertension complicating IPF found similar results, including a greater likelihood of disease progression. Imatinib Imatinib mesylate is a tyrosine kinase inhibitor with activity against the platelet-derived growth factor receptors (PDGFRs), c-kit, and c-Abl. As PDGFR has been implicated in the pathogenesis of IPF, imatinib was
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Treatment of idiopathic pulmonary fibrosis

evaluated as a possible therapy. In a 96 week trial, 119 patients with mild to moderate IPF were randomly assigned to receive imatinib or placebo 600 mg once daily [140]. Imatinib had no effect on survival or lung function, when compared with placebo. Interferon gamma-1b The rationale for the use of subcutaneous interferon gamma (interferon gamma-1b) in IPF came, in part, from the hypothesis that an acquired deficiency of interferon gamma exists in IPF and may contribute to the exaggerated wound healing process characteristic of this disease [141-143]. A placebo-controlled, randomized trial suggested a possible mortality benefit [125], but a subsequent large multinational trial was halted when the primary end point of a mortality benefit was not achieved [144]. We recommend not using subcutaneous interferon gamma-1b to treat IPF. Methotrexate Methotrexate, an analogue of the vitamin folic acid, inhibits cellular proliferation by inducing an acute intracellular deficiency of certain folate coenzymes. It has both antineoplastic and immunosuppressive effects. There have been several descriptions of using methotrexate in sarcoidosis, but very little has been written regarding its effectiveness in IPF [145-148]. In general, we do not use methotrexate to treat patients with IPF because of the lack of data demonstrating benefit and concern about methotrexate-induced pneumonitis. In patients with IPF, it may be difficult to distinguish pulmonary drug toxicity from progression of the underlying disease. Interstitial lung disease in the context of autoimmune disease (eg, rheumatoid arthritis) may have a significant component of usual interstitial pneumonitis based on radiographic and histologic assessment. In this situation, methotrexate may be of benefit. As an example, one study described three patients with IPF associated with connective tissue disease who appeared to respond favorably to methotrexate [149]. The use of low dose methotrexate is described separately. (See "Use of methotrexate in the treatment of rheumatoid arthritis" and "Major side effects of low-dose methotrexate" and "Methotrexate-induced lung injury".) Cyclosporine Experience with cyclosporine for the treatment of IPF is limited; we do not prescribe cyclosporine in patients with IPF because of the high toxicity and absence of proven benefit. The few published reports have been anecdotal and less than encouraging [150-153]. Etanercept Animal models of pulmonary fibrosis have suggested that antagonists of tumor necrosis factor (TNF)-alpha might be effective in treating IPF [104]. The efficacy and safety of the TNF-alpha receptor blocker, etanercept, were evaluated in a trial that randomly assigned 88 patients to twice weekly subcutaneous etanercept or placebo [154]. After 48 weeks, no significant difference was seen in the primary endpoints of change in percent predicted FVC or DLCO, or in the arterial-alveolar oxygen gradient. Given the potential side effects and lack of proven efficacy, we recommend that etanercept NOT be used to treat IPF [2]. Penicillamine We suggest not using d-penicillamine as a treatment for IPF because evidence of efficacy is lacking. D-penicillamine is capable of affecting collagen biosynthesis and the immune system. Several animal studies suggested a possible role for penicillamine in the treatment of fibrotic lung disorders [155-158]. In addition, two retrospective studies of patients with fibrosing alveolitis associated with scleroderma reported that penicillamine therapy was associated with an improvement in DLCO (but not in other pulmonary function test parameters) [159,160]. Experience with penicillamine in patients with IPF is limited and not encouraging [130,161,162]. A nonrandomized prospective study in patients with IPF compared colchicine/prednisone (n = 19), D-penicillamine/prednisone (n = 11), D-penicillamine/colchicine/prednisone (n = 11), and prednisone alone (n = 15). No significant differences in survival or in lung function relative to the baseline measurement were found in any group [130]. INFORMATION FOR PATIENTS UpToDate offers two types of patient education materials, The Basics and Beyond the Basics. The Basics patient education pieces are written in plain language, at the 5th to 6th grade
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reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon. Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on patient info and the keyword(s) of interest.) Basics topic (see "Patient information: Idiopathic pulmonary fibrosis (The Basics)") SUMMARY AND RECOMMENDATIONS Sufficient clinical evidence that any treatment improves survival or quality of life for patients with idiopathic pulmonary fibrosis (IPF) is lacking. (See 'General approach' above.) We offer supportive care (eg, supplemental oxygen, pulmonary rehabilitation) and provide information regarding participation in randomized trials to all patients. (See 'General approach' above and 'Supportive care' above and 'Clinical trials' above.) N-Acetylcysteine (NAC) is an antioxidant agent. For patients who desire active therapy rather than supportive care alone and are not interested in participating in a clinical trial, we suggest oral Nacetylcysteine (Grade 2C). The usual dose is 1800 mg orally per day (eg, 900 mg administered as effervescent tablets twice daily, 600 mg noneffervescent tablets three times per day). (See 'N-Acetylcysteine' above.) Alternatively, for patients who desire active therapy rather than supportive care alone, are not interested in participating in a clinical trial, and live in an area where pirfenidone is available, we suggest administering pirfenidone (Grade 2C). The dose ranges up to 40 mg/kg per day (to maximum of 2403 mg per day) in three divided doses. Rash, photosensitivity, dyspepsia, and nausea are common side effects. (See 'Pirfenidone' above.) We suggest NOT using glucocorticoid monotherapy for treatment of IPF (Grade 2B). In addition, we suggest NOT using combination therapy with azathioprine, prednisone, and N-acetylcysteine for routine therapy (Grade 2B). (See 'Prednisone-Azathioprine-N-Acetylcysteine' above.) For advanced IPF, a trial of sildenafil may be a reasonable option in patients with a diffusing capacity (DLCO) <35 percent of predicted, echocardiographic evidence of right ventricular dysfunction, and no contraindications to sildenafil. (See 'Phosphodiesterase inhibitors' above.) Lung transplantation may be an option for patients with progressive disease and minimal comorbidities. For appropriate patients (based on criteria from the United Network for Organ Sharing [UNOS]), we suggest early referral for lung transplantation evaluation rather than waiting until the patient has developed advanced disease (Grade 2C). (See 'Transplantation' above.) In patients with an acute exacerbation of IPF, we typically administer broad-spectrum antibiotics and high dose glucocorticoids in combination with a cytotoxic agent such as azathioprine, although data to support this practice is lacking. (See 'Acute exacerbations' above and 'Prednisone-Azathioprine-N-Acetylcysteine' above.)

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47. Jackson RM, Glassberg MK, Ramos CF, et al. Sildenafil therapy and exercise tolerance in idiopathic pulmonary fibrosis. Lung 2010; 188:115. 48. Idiopathic Pulmonary Fibrosis Clinical Research Network, Zisman DA, Schwarz M, et al. A controlled trial of sildenafil in advanced idiopathic pulmonary fibrosis. N Engl J Med 2010; 363:620. 49. Han MK, Bach DS, Hagan PG, et al. Sildenafil preserves exercise capacity in patients with idiopathic pulmonary fibrosis and right-sided ventricular dysfunction. Chest 2013; 143:1699. 50. Collard HR, Moore BB, Flaherty KR, et al. Acute exacerbations of idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 2007; 176:636. 51. Kondoh Y, Taniguchi H, Kawabata Y, et al. Acute exacerbation in idiopathic pulmonary fibrosis. Analysis of clinical and pathologic findings in three cases. Chest 1993; 103:1808. 52. Ambrosini V, Cancellieri A, Chilosi M, et al. Acute exacerbation of idiopathic pulmonary fibrosis: report of a series. Eur Respir J 2003; 22:821. 53. Churg A, Wright JL, Tazelaar HD. Acute exacerbations of fibrotic interstitial lung disease. Histopathology 2011; 58:525. 54. Song JW, Hong SB, Lim CM, et al. Acute exacerbation of idiopathic pulmonary fibrosis: incidence, risk factors and outcome. Eur Respir J 2011; 37:356. 55. Wootton SC, Kim DS, Kondoh Y, et al. Viral infection in acute exacerbation of idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 2011; 183:1698. 56. Simon-Blancal V, Freynet O, Nunes H, et al. Acute exacerbation of idiopathic pulmonary fibrosis: outcome and prognostic factors. Respiration 2012; 83:28. 57. Akira M, Kozuka T, Yamamoto S, Sakatani M. Computed tomography findings in acute exacerbation of idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 2008; 178:372. 58. Tcherakian C, Cottin V, Brillet PY, et al. Progression of idiopathic pulmonary fibrosis: lessons from asymmetrical disease. Thorax 2011; 66:226. 59. Hyzy R, Huang S, Myers J, et al. Acute exacerbation of idiopathic pulmonary fibrosis. Chest 2007; 132:1652. 60. Kim DS, Park JH, Park BK, et al. Acute exacerbation of idiopathic pulmonary fibrosis: frequency and clinical features. Eur Respir J 2006; 27:143. 61. Saydain G, Islam A, Afessa B, et al. Outcome of patients with idiopathic pulmonary fibrosis admitted to the intensive care unit. Am J Respir Crit Care Med 2002; 166:839. 62. Alalawi R, Whelan T, Bajwa RS, Hodges TN. Lung transplantation and interstitial lung disease. Curr Opin Pulm Med 2005; 11:461. 63. Christie JD, Edwards LB, Kucheryavaya AY, et al. The Registry of the International Society for Heart and Lung Transplantation: Twenty-eighth Adult Lung and Heart-Lung Transplant Report--2011. J Heart Lung Transplant 2011; 30:1104. 64. Thabut G, Mal H, Castier Y, et al. Survival benefit of lung transplantation for patients with idiopathic pulmonary fibrosis. J Thorac Cardiovasc Surg 2003; 126:469. 65. Steinman TI, Becker BN, Frost AE, et al. Guidelines for the referral and management of patients eligible for solid organ transplantation. Transplantation 2001; 71:1189. 66. Orens JB, Estenne M, Arcasoy S, et al. International guidelines for the selection of lung transplant candidates: 2006 update--a consensus report from the Pulmonary Scientific Council of the International Society for Heart and Lung Transplantation. J Heart Lung Transplant 2006; 25:745. 67. Kazerooni EA, Martinez FJ, Flint A, et al. Thin-section CT obtained at 10-mm increments versus limited three-level thin-section CT for idiopathic pulmonary fibrosis: correlation with pathologic scoring. AJR Am J Roentgenol 1997; 169:977. 68. Weiss ES, Allen JG, Merlo CA, et al. Lung allocation score predicts survival in lung transplantation patients with pulmonary fibrosis. Ann Thorac Surg 2009; 88:1757. 69. Christie JD, Edwards LB, Kucheryavaya AY, et al. The Registry of the International Society for Heart and Lung Transplantation: 29th adult lung and heart-lung transplant report-2012. J Heart Lung Transplant 2012;
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idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 2003; 168:538. 94. Alakhras M, Decker PA, Nadrous HF, et al. Body mass index and mortality in patients with idiopathic pulmonary fibrosis. Chest 2007; 131:1448. 95. Nadrous HF, Pellikka PA, Krowka MJ, et al. Pulmonary hypertension in patients with idiopathic pulmonary fibrosis. Chest 2005; 128:2393. 96. du Bois RM, Weycker D, Albera C, et al. Ascertainment of individual risk of mortality for patients with idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 2011; 184:459. 97. Panos RJ, Mortenson RL, Niccoli SA, King TE Jr. Clinical deterioration in patients with idiopathic pulmonary fibrosis: causes and assessment. Am J Med 1990; 88:396. 98. Fernndez Prez ER, Daniels CE, Schroeder DR, et al. Incidence, prevalence, and clinical course of idiopathic pulmonary fibrosis: a population-based study. Chest 2010; 137:129. 99. Davies HR, Richeldi L. Idiopathic pulmonary fibrosis: current and future treatment options. Am J Respir Med 2002; 1:211. 100. Selman M, Thannickal VJ, Pardo A, et al. Idiopathic pulmonary fibrosis: pathogenesis and therapeutic approaches. Drugs 2004; 64:405. 101. Tabata C, Tabata R, Kadokawa Y, et al. Thalidomide prevents bleomycin-induced pulmonary fibrosis in mice. J Immunol 2007; 179:708. 102. Horton MR, Santopietro V, Mathew L, et al. Thalidomide for the treatment of cough in idiopathic pulmonary fibrosis: a randomized trial. Ann Intern Med 2012; 157:398. 103. Richeldi L, Costabel U, Selman M, et al. Efficacy of a tyrosine kinase inhibitor in idiopathic pulmonary fibrosis. N Engl J Med 2011; 365:1079. 104. Piguet PF, Vesin C. Treatment by human recombinant soluble TNF receptor of pulmonary fibrosis induced by bleomycin or silica in mice. Eur Respir J 1994; 7:515. 105. Giri SN, Hyde DM, Hollinger MA. Effect of antibody to transforming growth factor beta on bleomycin induced accumulation of lung collagen in mice. Thorax 1993; 48:959. 106. Piguet PF, Vesin C, Grau GE, Thompson RC. Interleukin 1 receptor antagonist (IL-1ra) prevents or cures pulmonary fibrosis elicited in mice by bleomycin or silica. Cytokine 1993; 5:57. 107. Piguet PF, Rosen H, Vesin C, Grau GE. Effective treatment of the pulmonary fibrosis elicited in mice by bleomycin or silica with anti-CD-11 antibodies. Am Rev Respir Dis 1993; 147:435. 108. Tobin RW, Pope CE 2nd, Pellegrini CA, et al. Increased prevalence of gastroesophageal reflux in patients with idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 1998; 158:1804. 109. Raghu G, Freudenberger TD, Yang S, et al. High prevalence of abnormal acid gastro-oesophageal reflux in idiopathic pulmonary fibrosis. Eur Respir J 2006; 27:136. 110. Sweet MP, Hoopes C, Golden J, et al. Prevalence of delayed gastric emptying and gastroesophageal reflux in patients with end-stage lung disease. Ann Thorac Surg 2006; 82:1570; author reply 1570. 111. Schachter LM, Dixon J, Pierce RJ, O'Brien P. Severe gastroesophageal reflux is associated with reduced carbon monoxide diffusing capacity. Chest 2003; 123:1932. 112. Lee JS, Collard HR, Raghu G, et al. Does chronic microaspiration cause idiopathic pulmonary fibrosis? Am J Med 2010; 123:304. 113. Pashinsky YY, Jaffin BW, Litle VR. Gastroesophageal reflux disease and idiopathic pulmonary fibrosis. Mt Sinai J Med 2009; 76:24. 114. Bandeira CD, Rubin AS, Cardoso PF, et al. Prevalence of gastroesophageal reflux disease in patients with idiopathic pulmonary fibrosis. J Bras Pneumol 2009; 35:1182. 115. Raghu G, Yang ST, Spada C, et al. Sole treatment of acid gastroesophageal reflux in idiopathic pulmonary fibrosis: a case series. Chest 2006; 129:794. 116. Hershcovici T, Jha LK, Johnson T, et al. Systematic review: the relationship between interstitial lung diseases and gastro-oesophageal reflux disease. Aliment Pharmacol Ther 2011; 34:1295. 117. Sweet MP, Patti MG, Leard LE, et al. Gastroesophageal reflux in patients with idiopathic pulmonary fibrosis
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referred for lung transplantation. J Thorac Cardiovasc Surg 2007; 133:1078. 118. Lee JS, Ryu JH, Elicker BM, et al. Gastroesophageal reflux therapy is associated with longer survival in patients with idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 2011; 184:1390. 119. Lee JS, Collard HR, Anstrom KJ. Anti-acid treatment and disease progression in idiopathic pulmonary fibrosis: an analysis of data from three randomised controlled trials. Lancet Respir Med 2013; 1:369. 120. Hubbard RB, Smith C, Le Jeune I, et al. The association between idiopathic pulmonary fibrosis and vascular disease: a population-based study. Am J Respir Crit Care Med 2008; 178:1257. 121. Sode BF, Dahl M, Nielsen SF, Nordestgaard BG. Venous thromboembolism and risk of idiopathic interstitial pneumonia: a nationwide study. Am J Respir Crit Care Med 2010; 181:1085. 122. Kubo H, Nakayama K, Yanai M, et al. Anticoagulant therapy for idiopathic pulmonary fibrosis. Chest 2005; 128:1475. 123. Kinder BW, Collard HR, King TE Jr. Anticoagulant therapy and idiopathic pulmonary fibrosis. Chest 2006; 130:302. 124. Noth I, Anstrom KJ, Calvert SB, et al. A placebo-controlled randomized trial of warfarin in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 2012; 186:88. 125. Raghu G, Brown KK, Bradford WZ, et al. A placebo-controlled trial of interferon gamma-1b in patients with idiopathic pulmonary fibrosis. N Engl J Med 2004; 350:125. 126. Dubrawsky C, Dubravsky NB, Withers HR. The effect of colchicine on the accumulation of hydroxyproline and on lung compliance after irradiation. Radiat Res 1978; 73:111. 127. Zhang L, Zhu Y, Luo W, et al. The protective effect of colchicine on bleomycin-induced pulmonary fibrosis in rats. Chin Med Sci J 1992; 7:58. 128. Rennard SI, Bitterman PB, Ozaki T, et al. Colchicine suppresses the release of fibroblast growth factors from alveolar macrophages in vitro. The basis of a possible therapeutic approach ot the fibrotic disorders. Am Rev Respir Dis 1988; 137:181. 129. Douglas WW, Ryu JH, Schroeder DR. Idiopathic pulmonary fibrosis: Impact of oxygen and colchicine, prednisone, or no therapy on survival. Am J Respir Crit Care Med 2000; 161:1172. 130. Selman M, Carrillo G, Salas J, et al. Colchicine, D-penicillamine, and prednisone in the treatment of idiopathic pulmonary fibrosis: a controlled clinical trial. Chest 1998; 114:507. 131. Kolb M, Kirschner J, Riedel W, et al. Cyclophosphamide pulse therapy in idiopathic pulmonary fibrosis. Eur Respir J 1998; 12:1409. 132. Johnson MA, Kwan S, Snell NJ, et al. Randomised controlled trial comparing prednisolone alone with cyclophosphamide and low dose prednisolone in combination in cryptogenic fibrosing alveolitis. Thorax 1989; 44:280. 133. Baughman RP, Lower EE. Use of intermittent, intravenous cyclophosphamide for idiopathic pulmonary fibrosis. Chest 1992; 102:1090. 134. Collard HR, Ryu JH, Douglas WW, et al. Combined corticosteroid and cyclophosphamide therapy does not alter survival in idiopathic pulmonary fibrosis. Chest 2004; 125:2169. 135. Park SH, Saleh D, Giaid A, Michel RP. Increased endothelin-1 in bleomycin-induced pulmonary fibrosis and the effect of an endothelin receptor antagonist. Am J Respir Crit Care Med 1997; 156:600. 136. King TE Jr, Behr J, Brown KK, et al. BUILD-1: a randomized placebo-controlled trial of bosentan in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 2008; 177:75. 137. Raghu G, King TE Jr, Behr J, et al. Quality of life and dyspnoea in patients treated with bosentan for idiopathic pulmonary fibrosis (BUILD-1). Eur Respir J 2010; 35:118. 138. King TE Jr, Brown KK, Raghu G, et al. BUILD-3: a randomized, controlled trial of bosentan in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 2011; 184:92. 139. Raghu G, Behr J, Brown KK, et al. Treatment of idiopathic pulmonary fibrosis with ambrisentan: a parallel, randomized trial. Ann Intern Med 2013; 158:641. 140. Daniels CE, Lasky JA, Limper AH, et al. Imatinib treatment for idiopathic pulmonary fibrosis: Randomized
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placebo-controlled trial results. Am J Respir Crit Care Med 2010; 181:604. 141. Ziesche, R. Long-term survival in idiopathic pulmonary fibrosis patients treated with interferon gamma-1b (abstract). Chest 2002; 122:75S. 142. Bienkowski RS, Gotkin MG. Control of collagen deposition in mammalian lung. Proc Soc Exp Biol Med 1995; 209:118. 143. Ziesche R, Hofbauer E, Wittmann K, et al. A preliminary study of long-term treatment with interferon gamma1b and low-dose prednisolone in patients with idiopathic pulmonary fibrosis. N Engl J Med 1999; 341:1264. 144. King TE Jr, Albera C, Bradford WZ, et al. Effect of interferon gamma-1b on survival in patients with idiopathic pulmonary fibrosis (INSPIRE): a multicentre, randomised, placebo-controlled trial. Lancet 2009; 374:222. 145. Pesci A, Bertorelli G, Manganelli P, Ambanelli U. Bronchoalveolar lavage analysis of interstitial lung disease in CREST syndrome. Clin Exp Rheumatol 1986; 4:121. 146. Lacher MJ. Spontaneous remission or response to methotrexate in sarcoidosis. Ann Intern Med 1968; 69:1247. 147. Lower EE, Baughman RP. The use of low dose methotrexate in refractory sarcoidosis. Am J Med Sci 1990; 299:153. 148. Lower, EE, Baughman, RP, Winget, D. The long term use of methotrexate in patients with chronic symptomatic sarcoidosis. Sarcoidosis 1992; 9:465S. 149. Scott DG, Bacon PA. Response to methotrexate in fibrosing alveolitis associated with connective tissue disease. Thorax 1980; 35:725. 150. Alton EW, Johnson M, Turner-Warwick M. Advanced cryptogenic fibrosing alveolitis: preliminary report on treatment with cyclosporin A. Respir Med 1989; 83:277. 151. Venuta F, Rendina EA, Ciriaco P, et al. Efficacy of cyclosporine to reduce steroids in patients with idiopathic pulmonary fibrosis before lung transplantation. J Heart Lung Transplant 1993; 12:909. 152. Moolman JA, Bardin PG, Rossouw DJ, Joubert JR. Cyclosporin as a treatment for interstitial lung disease of unknown aetiology. Thorax 1991; 46:592. 153. Grgic A, Lausberg H, Heinrich M, et al. Progression of fibrosis in usual interstitial pneumonia: serial evaluation of the native lung after single lung transplantation. Respiration 2008; 76:139. 154. Raghu G, Brown KK, Costabel U, et al. Treatment of idiopathic pulmonary fibrosis with etanercept: an exploratory, placebo-controlled trial. Am J Respir Crit Care Med 2008; 178:948. 155. Ward WF, Shih-Hoellwarth A, Tuttle RD. Collagen accumulation in irradiated rat lung: modification by Dpenicillamine. Radiology 1983; 146:533. 156. Ekimoto H, Aikawa M, Ohnuki T, et al. Immunological involvement in pulmonary fibrosis induced by peplomycin. J Antibiot (Tokyo) 1985; 38:94. 157. Molteni A, Ward WF, Ts'ao CH, et al. Monocrotaline-induced pulmonary fibrosis in rats: amelioration by captopril and penicillamine. Proc Soc Exp Biol Med 1985; 180:112. 158. Geismar LS, Hennessey S, Reiser KM, Last JA. D-penicillamine prevents collagen accumulation in lungs of rats given bleomycin. Chest 1986; 89:153S. 159. Steen VD, Owens GR, Redmond C, et al. The effect of D-penicillamine on pulmonary findings in systemic sclerosis. Arthritis Rheum 1985; 28:882. 160. de Clerck LS, Dequeker J, Francx L, Demedts M. D-penicillamine therapy and interstitial lung disease in scleroderma. A long-term followup study. Arthritis Rheum 1987; 30:643. 161. Cegla UH. [Treatment of idiopathic fibrosing alveolitis. Therapeutic experiences with azathioprine-prednisolone and D-penicillamine-prednisolone combination therapy]. Schweiz Med Wochenschr 1977; 107:184. 162. Chapela R, Ziga G, Selman M. D-penicillamine in the therapy of fibrotic lung diseases. Int J Clin Pharmacol Ther Toxicol 1986; 24:16. Topic 4328 Version 26.0

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GRAPHICS
Lung allocation score for candidates age 12 and older
Step 1: The transplant center enters the factors in part 1 below on the UNet web site. A Cox proportional hazards model is used to derive an estimate of the number of days a recipient would be expected to live during the first year post transplant. This is the post transplant survival measure. Step 2: The transplant center enters the factors in part 2 below on the UNet web site. A Cox proportional hazards model is used to derive an estimate of the expected number of days a candidate would live without a transplant during an additional year on the waitlist. This is the waitlist survival measure. Step 3: Using the values derived in steps 1 and 2, the transplant benefit measure is calculated: Transplant benefit = post transplant survival (days) - waitlist survival (days). Step 4: The raw allocation score = transplant benefit (days) - waitlist survival (days). Step 5: The lung allocation score is derived by normalizing the raw allocation score to a range of 0 to 100. The higher the score the higher the priority.

Part 1 Post transplant survival measure:


1. FVC (Group B, D) 2. PCW pressure 20 (Group D) 3. Continuous mechanical ventilation 4. Age 5. Serum creatinine 6. Functional Status (NYHA class) 7. Diagnosis

Part 2 Waiting list urgency measure:


1. Forced vital capacity (FVC) 2. Pulmonary artery systolic pressure (Group A, C, D)* 3. Supplemental O2 required at rest (Group A, C, D) * 4. Age 5. Body mass index (BMI) 6. Diabetes 7. Functional status 8. Six-minute walk distance 9. Continuous mechanical ventilation 10. Diagnosis 11. pCO2

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*Group A: COPD, alpha-1-antitrypsin, emphysema, lymphangioleiomyomatosis, bronchiectasis, sarcoidosis with a mean PA pressure 30 mmHg. Group B: Pulmonary hypertension (IPAH, Eisenmenger's syndrome, etc). Group C: Cystic fibrosis, immunodeficiency disorders (eg, Hypogammaglobulinemia). Group D: IPF, other causes of pulmonary fibrosis, sarcoidosis with PA >30 mmHg, obliterative bronchiolitis (non-retransplant). pCO2 may be taken from arterial, capillary or venous measurement. If venous, 6 mmHg will be subtracted to produce an equivalent arterial value. This a adjusted for any change in value over time that is greater than 15 percent. Data from: http://www.unos.org/resources/frm_LAS_Calculator.asp.

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Complications of idiopathic pulmonary fibrosis


Progressive respiratory failure
Mortality - 39 percent Findings suggestive of disease progression are multiple and nonspecific

Bronchogenic carcinoma
Mortality - 10 percent Excess risk of 14:1 compared to general population; same histologic distribution as seen in population

Cardiovascular disease
Mortality - 24 percent Right ventricular hypertrophy, cor pulmonale due to progressive, longstanding pulmonary hypertension and right heart failure Left ventricular heart failure usually due to concurrent ischemic heart disease

Pulmonary infection
Mortality - 2 to 4 percent Increased incidence; glucocorticoid and cytotoxic therapy may further increase risk

Pneumothorax
Occurs less often than in other interstitial lung disease - <10 percent

Pulmonary embolism
Mortality 3 to 7 percent Pulmonary angiography frequently required to make diagnosis

Complications of therapy
See text Adapted from Panos, RJ, Mortenson, RL, Niccoli, SA, King TE Jr, Am J Med 1990; 88:396.

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