This guideline is a collaborative effort between the ATS, ERS, Japanese Respiratory Society (JRS), and Latin American Thoracic Association (ALAT). The project chair (G.R.) nominated two co-chairs (J.J.E. and F.J.M.) and a group of experts in IPF and/or evidence-based methodology from North America, Europe, Asia, and South America. This group consisted of clinicians with recognized expertise in IPF and interstitial lung diseases (24 pulmonologists, 4 radiologists, and 4 pathologists), 4 methodologist (also a general pulmonologist), and 1 chief librarian, assisted by 2 librarians experienced with literature searches for pulmonary diseases. This group was approved by and represented the membership of the four sponsoring societies.

Panel members disclosed all potential conflicts of interest. The chair discussed and resolved all potential conflicts of interest with committee members. All potential conflicts of interest (including those of the chair and co-chairs) were discussed with the chair of the Ethics and Conflict of Interest Committee of the ATS.

During all deliberations, members with perceived conflicts of interest abstained from voting on specific recommendations related to the conflict of interest. Furthermore, members were reminded to consider their own and other members' potential conflicts of interest when discussing and voting on recommendations. In addition, other potential conflict of interest, if any (e.g., academic conflicts of interest), that were not apparent in the formal disclosures were left to be resolved by individual committee members based on their own conscience, judgment, and discretion in making recommendations (i.e., voting). The reference librarians did not participate in voting for any of the recommendations.

The committee was divided into subgroups, and each subgroup was provided with articles relevant to their respective sections and/or questions. The subgroups were tasked with reviewing the literature, developing relevant questions, and developing preliminary section drafts. Four face-to-face meetings were held in which the subgroup drafts were reviewed. For certain sections, evidence-based recommendations were discussed, voted on, and finalized by the entire committee.

The chair and a member of the committee (H.R.C.) integrated the draft sections and voting results into a preliminary document that was circulated among the committee members for further input. Input from the committee members was incorporated into the document which was read and edited further by an editing committee (G.R., H.R.C., J.H.R., J.B., M.E., K.R.F., and H.J.S.) via live webinar-teleconference. A final draft document was reviewed by the full committee, finalized, approved, and submitted to the ATS and ERS for peer review. The document was revised to incorporate the pertinent comments suggested by the external reviewers and the input provided by the editor of the ATS documentation and implementation committee. The drafted revised document was read and edited via webinar-teleconference (G.R., J.J.E., F.J.M., H.R.C., and H.J.S.) and circulated to the entire committee for further input. A pre-final draft of the revised document was subsequently finalized via webinar-teleconference (G.R., J.J.E., F.J.M., H.R.C., and H.J.S.). Concerns raised by some committee members regarding the choice of most appropriate words to convey the significance of recommendations were resolved by consensus reached by all concerned, which included the chair (G.R.), co-chairs (F.J.M. and J.J.E.), and committee members (H.J.S., H.R.C., A.U.W., U.C., and J.B.), and incorporated in the document. One committee member (R.D.B.) requested not to be a co-author of the final document due to his concerns regarding the methodology used for the treatment section. Since he participated in voting and document preparation, he is listed as a committee member. The revised document was reviewed by the authors, finalized, approved, and submitted to the editor of the ATS documentation and implementation committee.

This document is structured to provide an evidence-based review of the current state of knowledge regarding IPF, and contains guidelines for the management of IPF that include definition and epidemiology; risk factors; natural history; staging and prognosis; monitoring disease course; future directions. For the diagnosis and treatment sections, pragmatic GRADE evidence-based methodology was applied (2, 3). These sections were organized around specific questions as described below. The committee performed a complete systematic review of the literature for the questions focused on treatment. The literature searches and assessment of the evidence followed the GRADE approach to rate the quality of evidence and strength of the recommendations for all questions in the diagnosis and treatment sections. The remaining sections were written after a thorough review of the available literature in a narrative review format.

Relevant section topics and questions were identified by committee members. Additional input was sought from general pulmonologists in the community and at academic centers.

An evidence profile was created for each question using the GRADE methodology (2, 3). A MEDLINE search from 1996 to December 2006 was performed at the beginning of the committee's work, with periodic updates during document development and finalization through May 31, 2010. Searching the literature before 1996 was not done systematically, since it had been searched extensively for the 2000 Consensus Statement (1). The current search was augmented by searches of EMBASE and committee member files. The literature search was limited to manuscripts published in the English language and English abstracts available from articles published in other languages. For the section on IPF treatment, we utilized the methodology of systematic review, which included meta-analysis of studies where appropriate (4–7). This review examined all relevant studies including randomized controlled trials, cohort studies, case-control studies, and cross-sectional studies. A few studies were not included in this question-based document due to the preliminary nature of their observations (8–11). For details of the literature search methodology and results, please see the online supplement.

The quality of evidence was determined according to the ATS GRADE criteria (3) (Tables 1 and 2). The GRADE approach identifies all outcomes that are of importance to patients and differentiates the critical outcomes from the important but not critical ones. Recommendations depend on the evidence for all patient-important outcomes and the quality of evidence for each of those outcomes. GRADE evidence profiles are tabulated in this document for randomized controlled trials (see Treatment below). For each question, the committee graded the quality of the evidence available (high, moderate, low, or very low), and made a recommendation for or against. Recommendations were decided on the basis of majority vote. There were 31 voting members of the committee (the reference librarians were not voting members). The number of votes for, against, abstaining, and absent are reported for all treatment votes. Recommendations were either “strong” or “weak.” The strength of a recommendation reflects the extent to which one can, across the range of patients for whom the recommendation is intended, be confident that desirable effects outweigh undesirable effects (3).

All recommendations were made after face-to-face, detailed discussions of the evidence profile and quality by committee members present at the face-to-face discussions. While the recommendation on the use of pirfenidone had been made by the committee members during the face-to-face discussions, the question was revisited because of the subsequent release of substantial additional scientific evidence. The ATS and ERS also recommended including the additional scientific data from just-completed clinical trials of pirfenidone that had been released to the scientific and public domain in the committee's recommendation. This new evidence, including a meta-analysis of the available pirfenidone data, was sent to all members of the committee electronically, and the final voting for pirfenidone was made by e-mail. Thus, the total number of votes for the pirfenidone question reflects all the voting members of the committee; that is, it included the votes of the members who were not present during the prior face-to-face discussions of pirfenidone and other topics.

Newer data published subsequent to the final formal face-to-face voting was not considered for evidence-based recommendations because there was not sufficient time for a thorough review and consideration of the data by the committee members. These newer data that were not subjected to formal face-to-face discussion are provided as a summarized narrative in the text of the document. These and all other new pertinent published data will be considered for formal evidence-based recommendations in future updates of this document.

This document was subjected to review by the ATS Board of Directors and ERS Science Committee as well as external peer review. The final document met the approval of the governing bodies of the ATS, ERS, JRS, and ALAT.

1. IPF is defined as a specific form of chronic, progressive fibrosing interstitial pneumonia of unknown cause, occurring primarily in older adults, limited to the lungs, and associated with the histopathologic and/or radiologic pattern of UIP.

2. The diagnosis of IPF requires:

   1. Exclusion of other known causes of interstitial lung disease (ILD) (e.g., domestic and occupational environmental exposures, connective tissue disease, and drug toxicity).

   2. The presence of a UIP pattern on high-resolution computed tomography (HRCT) in patients not subjected to surgical lung biopsy.

   3. Specific combinations of HRCT and surgical lung biopsy pattern in patients subjected to surgical lung biopsy.

      The major and minor criteria proposed in the 2000 ATS/ERS Consensus Statement have been eliminated.

3. The accuracy of the diagnosis of IPF increases with multidisciplinary discussion between pulmonologists, radiologists, and pathologists experienced in the diagnosis of ILD.

4. IPF is a fatal lung disease; the natural history is variable and unpredictable:

   1. Most patients with IPF demonstrate a gradual worsening of lung function over years; a minority of patients remains stable or declines rapidly.

   2. Some patients may experience episodes of acute respiratory worsening despite previous stability.

5. Disease progression is manifested by increasing respiratory symptoms, worsening pulmonary function test results, progressive fibrosis on HRCT, acute respiratory decline, or death.

6. Patients with IPF may have sub-clinical or overt co-morbid conditions including pulmonary hypertension, gastroesophageal reflux, obstructive sleep apnea, obesity, and emphysema. The impact of these conditions on the outcome of patients with IPF is unclear.

The recommendations detailed below are based on the GRADE approach outlined in the introductory section (3). The committee felt the preponderance of evidence to date suggests that pharmacologic therapy for IPF is without definitive, proven benefit. For this reason, the committee has chosen to make recommendations of varying strength against most therapies.

Treatment recommendations for specific therapies are the following (the quality of evidence is in parenthesis, presented as one to four plus signs, with zeroes as place holders where there are fewer than four plus signs):

1. The recommendation against the use of the following agents for the treatment of IPF is strong:

   1. Corticosteroid monotherapy (⊕○○○)

   2. Colchicine (⊕○○○)

   3. Cyclosporine A (⊕○○○)

   4. Combined corticosteroid and immune-modulator therapy (⊕⊕○○)

   5. Interferon γ 1b (⊕⊕⊕⊕)

   6. Bosentan (⊕⊕⊕○)

   7. Etanercept (⊕⊕⊕○)

2. The recommendation against the use of the following agents for the treatment of IPF is weak; that is, these therapies should not be used in the majority of patients with IPF, but may be a reasonable choice in a minority:

   1. Combined acetylcysteine and azathioprine and prednisone (⊕⊕○○)

   2. Acetylcysteine monotherapy (⊕⊕○○)

   3. Anticoagulation (⊕○○○)

   4. Pirfenidone (⊕⊕○○)

3. The recommendation for long-term oxygen therapy in patients with IPF and clinically significant resting hypoxemia is strong (⊕○○○).

4. The recommendation for lung transplantation in appropriate patients with IPF is strong (⊕○○○).

5. The recommendation against mechanical ventilation in patients with respiratory failure due to IPF is weak; that is, mechanical ventilation should not be used in the majority of patients with IPF, but may be a reasonable choice in a minority (⊕⊕○○).

6. The recommendation for pulmonary rehabilitation in patients with IPF is weak; that is, pulmonary rehabilitation should be used in the majority of patients with IPF, but not using pulmonary rehabilitation may be a reasonable choice in a minority (⊕⊕○○).

7. The recommendation for corticosteroids in patients with acute exacerbation of IPF is weak; that is, corticosteroids should be used in the majority of patients with acute exacerbation of IPF, but not using corticosteroids may be a reasonable choice in a minority (⊕○○○).

8. The recommendation against the treatment of pulmonary hypertension associated with IPF is weak; that is, pulmonary hypertension should not be treated in the majority of patients with IPF, but treatment may be a reasonable choice in a minority (⊕○○○).

9. The recommendation for the treatment of asymptomatic gastroesophageal reflux in patients with IPF is weak; that is, asymptomatic gastroesophageal reflux should be treated in the majority of patients with IPF, but not treating asymptomatic gastroesophageal reflux may be a reasonable choice in a minority (⊕○○○).

Based on the evidence published to date, there is no proven pharmacological therapy for IPF. While a few studies have suggested potential benefits from some pharmacologic agents, the recommendations made by the committee for these agents were “weak no.” For the well-informed patient who strongly desires pharmacologic treatment, it is suggested that the choice of agent may be made from therapies that received a weak recommendation against their use (“weak no”).

Continued, concerted efforts should be made by physicians, patients, and sponsors to pursue well-designed clinical trials aimed at improving outcomes, including quality of life, in patients with IPF. The committee recognizes the need to update treatment recommendation when new and pertinent high-quality evidence regarding the use of other treatment becomes available for scientific review.

IPF is defined as a specific form of chronic, progressive fibrosing interstitial pneumonia of unknown cause, occurring primarily in older adults, limited to the lungs, and associated with the histopathologic and/or radiologic pattern of UIP defined below (1, 12, 13). The definition of IPF requires the exclusion of other forms of interstitial pneumonia including other idiopathic interstitial pneumonias and ILD associated with environmental exposure, medication, or systemic disease (1, 12).

IPF should be considered in all adult patients with unexplained chronic exertional dyspnea, and commonly presents with cough, bibasilar inspiratory crackles, and finger clubbing (14–16). The incidence of the disease increases with older age, with presentation typically occurring in the sixth and seventh decades (16–19). Patients with IPF aged less than 50 years are rare; such patients may subsequently manifest overt features of an underlying connective tissue disease that was subclinical at the time IPF was diagnosed (20, 21). More men have been reported with IPF than women, and the majority of patients have a history of cigarette smoking (14–17, 22, 23).

There are no large-scale studies of the incidence or prevalence of IPF on which to base formal estimates. The incidence of IPF was estimated at 10.7 cases per 100,000 per year for men and 7.4 cases per 100,000 per year for women in a population-based study from the county of Bernalillo, New Mexico (23). A study from the United Kingdom reported an overall incidence rate of only 4.6 per 100,000 person-years, but estimated that the incidence of IPF increased by 11% annually between 1991 and 2003 (16). This increase was not felt to be attributable to the aging of the population or increased ascertainment of milder cases. A third study from the United States estimated the incidence of IPF to be between 6.8 and 16.3 per 100,000 persons using a large database of healthcare claims in a health plan (20).

Prevalence estimates for IPF have varied from 2 to 29 cases per 100,000 in the general population (17, 22–25). The wide range in these numbers is likely explained by the previous lack of uniform definition used in identifying cases of IPF, as well as by differences in study designs and populations. A recent analysis based on healthcare claims data of a large health plan in the United States yielded a prevalence estimate of between 14.0 and 42.7 per 100,000 persons depending on the case definition used (20). It is unknown if the incidence and prevalence of IPF are influenced by geographic, ethnic, cultural, or racial factors.

Although idiopathic pulmonary fibrosis is, by definition, a disease of unknown etiology, a number of potential risk factors have been described.

HRCT is an essential component of the diagnostic pathway in IPF (Table 4, Figure 1). The optimal HRCT technique for evaluation of ILD is provided in the online supplement (see Table E6). UIP is characterized on HRCT by the presence of reticular opacities, often associated with traction bronchiectasis (98, 99). Honeycombing is common, and is critical for making a definite diagnosis. Honeycombing is manifested on HRCT as clustered cystic airspaces, typically of comparable diameters on the order of 3–10 mm but occasionally as large as 2.5 cm. It is usually subpleural and is characterized by well-defined walls (100). Ground glass opacities are common, but usually less extensive than the reticulation. The distribution of UIP on HRCT is characteristically basal and peripheral, though often patchy. The presence of coexistent pleural abnormalities (e.g., pleural plaques, calcifications, significant pleural effusion) suggests an alternative etiology for UIP pattern. Micronodules, air trapping, nonhoneycomb cysts, extensive ground glass opacities, consolidation, or a peribronchovascular-predominant distribution should lead to consideration of an alternative diagnosis. Mild mediastinal lymph node enlargement (usually < 1.5 cm in short axis) can be seen (101, 102). The chest radiograph is less useful than HRCT in evaluating patients with suspected IPF (103).

Figure 1. High-resolution computed tomography (HRCT) images demonstrating usual interstitial pneumonia (UIP) pattern and possible UIP pattern. (A and B) UIP pattern, with extensive honeycombing: axial and coronal HRCT images show basal predominant, peripheral predominant reticular abnormality with multiple layers of honeycombing (arrows). (C and D) UIP pattern, with less severe honeycombing: axial and coronal CT images show basal predominant, peripheral predominant reticular abnormality with subpleural honeycombing (arrows). (E and F) Possible UP pattern: axial and coronal images show peripheral predominant, basal predominant reticular abnormality with a moderate amount of ground glass abnormality, but without honeycombing.

Download Figure | Download Powerpoint

[More] [Minimize]

Several studies have documented that the positive predictive value of a HRCT diagnosis of UIP is 90 to 100% (103–108). These studies are affected by selection bias because they only included patients with biopsy-proven diagnoses. Nonetheless, a UIP pattern on HRCT is highly accurate for the presence of UIP pattern on surgical lung biopsy. If honeycombing is absent, but the imaging features otherwise meet criteria for UIP, the imaging features are regarded as representing possible UIP, and surgical lung biopsy is necessary to make a definitive diagnosis. In patients whose HRCT does not demonstrate a UIP pattern, the surgical lung biopsy may still demonstrate UIP pattern on histopathology.

The histopathologic hallmark and chief diagnostic criterion is a heterogeneous appearance at low magnification in which areas of fibrosis with scarring and honeycomb change alternate with areas of less affected or normal parenchyma (1, 12) (Table 5, Figure 2). These histopathologic changes often affect the subpleural and paraseptal parenchyma most severely. Inflammation is usually mild and consists of a patchy interstitial infiltrate of lymphocytes and plasma cells associated with hyperplasia of type 2 pneumocytes and bronchiolar epithelium. The fibrotic zones are composed mainly of dense collagen, although scattered convex subepithelial foci of proliferating fibroblasts and myofibroblasts (so-called fibroblast foci) are a consistent finding. Areas of honeycomb change are composed of cystic fibrotic airspaces that are frequently lined by bronchiolar epithelium and filled with mucus and inflammatory cells. Smooth muscle metaplasia in the interstitium is commonly seen in areas of fibrosis and honeycomb change.

Figure 2. Surgical lung biopsy specimens demonstrating UIP pattern. (A) Scanning power microscopy showing a patchy process with honeycomb spaces (thick arrow), some preserved lung tissue regions (thin arrow), and fibrosis extending into the lung from the subpleural regions. (B) Adjacent to the regions of more chronic fibrosis (thick arrow) is a fibroblast focus (asterisk), recognized by its convex shape and composition of edematous fibroblastic tissue, suggestive of recent lung injury.

Download Figure | Download Powerpoint

[More] [Minimize]

The differential diagnosis for UIP pattern on pathology is relatively short, especially when strict criteria for UIP are maintained. The major differential diagnostic considerations include UIP in other clinical settings such as connective tissue diseases, chronic hypersensitivity pneumonitis (extrinsic allergic alveolitis), and pneumoconioses (especially asbestosis).

Some biopsies may reveal a pattern of fibrosis that does not meet the above criteria for UIP pattern (1). These biopsies may be termed “nonclassifiable fibrosis.” In the absence of histologic features diagnostic of an alternative condition (e.g., hypersensitivity pneumonitis, sarcoidosis, etc.), such biopsies may be consistent with the diagnosis of IPF (Tables 5 and 6) in the appropriate clinical and radiologic setting and after careful multidisciplinary discussion.

TABLE 6. COMBINATION OF HIGH-RESOLUTION COMPUTED TOMOGRAPHY AND SURGICAL LUNG BIOPSY FOR THE DIAGNOSIS OF IPF (REQUIRES MULTIDISCIPLINARY DISCUSSION)

The diagnosis of IPF requires the following:

1. Exclusion of other known causes of ILD (e.g., domestic and occupational environmental exposures, connective tissue disease, and drug toxicity).

2. The presence of a UIP pattern on HRCT in patients not subjected to surgical lung biopsy (see Table 4).

3. Specific combinations of HRCT and surgical lung biopsy pattern in patients subjected to surgical lung biopsy (see Tables 5 and 6).

Thus, the accuracy of diagnosis of IPF increases with clinical, radiologic, and histopathologic correlation and can be accomplished with a multidisciplinary discussion among experienced clinical experts in the field of ILDs (111). This is particularly relevant in cases in which the radiologic and histopathologic patterns are discordant (e.g., HRCT is inconsistent with UIP and histopathology is UIP). An HRCT or pathologic UIP pattern is not 100% specific to IPF (1, 12, 112–114). Discordant histologic patterns on surgical lung biopsy specimens obtained from different segments have been described. Cases with coexisting UIP pattern and fibrotic NSIP pattern (discordant UIP) appear to behave similarly to those with UIP pattern in all lobes (concordant UIP) (115, 116). This supports the obtainment of surgical lung biopsies from multiple lobes in patients with suspected IPF.

Several studies have compared VATS to open thoracotomy (117–120). The diagnostic yield from surgical lung biopsies obtained from VATS and open thoracotomy are similar. While VATS may be associated with lower morbidity and length of stay than open thoracotomy, the decision on which procedure to perform should be based on individual patient characteristics and surgical expertise. In patients with severe physiologic impairment or substantial comorbidity, the risks of surgical lung biopsy may outweigh the benefits of establishing a secure diagnosis of IPF. The final decision regarding whether or not to pursue a surgical lung biopsy must be tailored to the clinical situation of the individual patient.

The exclusion of other known causes of ILD is a broad and inherently subjective criterion, but several specific points should be made. A careful history and physical examination focusing on comorbidities, medication use, environmental exposures, and family history is essential, and physicians should utilize a standardized approach. While there are no validated tools for this, a template, such as the one available through the American College of Chest Physicians (http://www.chestnet.org/memberResources/downloads/networks/IDLDquestionnaire.pdf), may be of use. It is of particular importance to evaluate patients thoroughly for possible chronic hypersensitivity pneumonitis, since such patients may mimic IPF. The inciting antigen may not be identifiable in some patients despite a thorough search (121); bronchoalveolar lavage (BAL) showing a lymphocytosis of 40% or greater may suggest occult hypersensitivity pneumonitis in this setting, prompting further investigations for environmental exposures, and possibly a surgical lung biopsy. Patients who meet established criteria for connective tissue disease do not have IPF. Younger patients, especially women, without clinical or serologic features at presentation may subsequently manifest clinical features of connective tissue disease. Therefore, the index of suspicion for connective tissue disease in younger patients (under the age of 50 yr) should be high.

• Question: Should BAL cellular analysis be performed in the diagnostic evaluation of suspected IPF?

  • Cellular analyses of BAL can be useful in the diagnosis of certain forms of ILD. In the evaluation of patients with suspected IPF, the most important application of BAL is in the exclusion of chronic hypersensitivity pneumonitis; prominent lymphocytosis (> 40%) should suggest the diagnosis. Recent retrospective data suggest that 8% of patients with an HRCT UIP pattern may have BAL findings suggestive of an alternative diagnosis (122). It is unclear whether BAL adds significant diagnostic specificity to a careful exposure history and clinical evaluation.

  • Recommendation: BAL cellular analysis should not be performed in the diagnostic evaluation of IPF in the majority of patients, but may be appropriate in a minority (weak recommendation, low-quality evidence).

  • Values: This recommendation places a high value on the additional risk and cost of BAL in patients with IPF and a low value on possible improved specificity of diagnosis.

  • Remarks: This recommendation is only for BAL differential cell count (“cellular analysis”). It does not refer to the use of BAL in the evaluation of infection, malignancy, etc. At present, BAL cellular analysis should be considered in the evaluation of patients with IPF at the discretion of the treating physician based on availability and experience at their institution/regional laboratory. (Vote: 4 for the use of BAL, 18 against the use of BAL, 1 abstention, 8 absent.)

• Question: Should transbronchial lung biopsy be used in the evaluation of suspected IPF?

  • Transbronchial lung biopsy is useful in the evaluation of selected conditions (e.g., granulomatous disorders such as sarcoidosis). A UIP pattern on HRCT makes these conditions unlikely (104, 105, 109). In cases requiring histopathology, the specificity and positive predictive value of UIP pattern identified by transbronchial biopsy has not been rigorously studied. While transbronchial biopsy specimens may show all the histologic features of UIP (123), the sensitivity and specificity of this approach for the diagnosis for UIP pattern is unknown. It is also unknown how many and from where transbronchial biopsies should be obtained.

  • Recommendation: Transbronchial biopsy should not be used in the evaluation of IPF in the majority of patients, but may be appropriate in a minority (weak recommendation, low-quality evidence).

  • Values: This recommendation places a high value on the additional morbidity of transbronchial lung biopsy in patients with IPF who will subsequently undergo surgical lung biopsy and low value on possible diagnostic specificity.

  • Remarks: (Vote: none for the use of transbronchial biopsy, 23 against the use of transbronchial biopsy, no abstentions, 8 absent.)

• Question: Should serologic testing for connective tissues disease be used in the evaluation of suspected IPF?

  • There are no reliable data on the role of screening serologies in patients with suspected IPF. Connective tissue disease can present with a UIP pattern (124), and ILD has been described as the sole clinical manifestation of these conditions and can precede the overt manifestation of a specific connective tissue disease (125).

  • Recommendation: Serologic testing for connective tissue disease should be performed in the evaluation of IPF in the majority of patients, but may not be appropriate in a minority (weak recommendation, very low-quality evidence).

  • Values: This recommendation places a high value on distinguishing connective tissue disease from IPF and low value on cost.

  • Remarks: Serologic evaluation should be performed even in the absence of signs or symptoms of connective tissue disease, and should include rheumatoid factor, anti-cyclic citrullinated peptide, and anti-nuclear antibody titer and pattern. The routine use of other serological tests such as antisynthetase antibodies (e.g., Jo-1), creatine kinase and aldolase, Sjogren's antibodies (SS-A, SS-B), and scleroderma antibodies (scl-70, PM-1) is of unclear benefit, but may be helpful in selected cases. Patients with IPF may have a mildly positive antinuclear antibody titer and/or rheumatoid factor level without any other clinical features of connective tissue. Such patients should be carefully screened for signs and symptoms of connective tissues disease (e.g., arthritis, Raynaud's phenomenon, skin changes, abnormal esophageal motility). In the absence of additional serologic or clinical evidence to support a connective tissues diagnosis, the diagnosis of IPF is appropriate. Repeat serologic and clinical evaluation during follow up may subsequently confirm the development of a connective tissue disease; in such cases, the diagnosis should be revised. (Vote: 23 for the use of serologic testing, none against the use of serologic testing, no abstentions, 8 absent.)

• Question: Should a multi-disciplinary discussion be used in the evaluation of suspected IPF?

  • The diagnosis of IPF is, by definition, multidisciplinary, drawing on the expertise of experienced clinicians, radiologists, and pathologists. Proper communication between the various disciplines involved in the diagnosis of IPF (pulmonary, radiology, pathology) has been shown to improve inter-observer agreement among experienced clinical experts as to the ultimate diagnosis (111, 126).

  • Recommendation: We recommend that a multi-disciplinary discussion should be used in the evaluation of IPF (strong recommendation, low-quality evidence).

  • Values: This recommendation places a high value on the accurate diagnosis of IPF and a low value on the access to and availability of experts for multidisciplinary discussion.

  • Remarks: It is recognized that a formal multidisciplinary discussion (MDD) between the treating pulmonologist, radiologist, and pathologist is not possible for many practitioners. Effort should be made, however, to promote verbal communication between specialties during the evaluation of the case. There are data to suggest that the accuracy of diagnosis is improved through MDD among ILD experts compared with MDD among specialists in the community setting (126); timely referral to ILD experts is encouraged. (Vote: 23 for the use of multidisciplinary discussion, none against the use of multidisciplinary discussion, no abstentions, 8 absent.)

Recent observations have suggested that acute respiratory worsening occurs in a small minority of patients with IPF annually (approximately 5–10%) (137, 143, 144). These episodes may occur secondary to common conditions such as pneumonia, pulmonary embolism, pneumothorax, or cardiac failure (145, 146). When a cause cannot be identified for the acute respiratory decline, the term acute exacerbation of IPF has been used (144, 145, 147–157). It is presently unclear if acute exacerbation of IPF is simply a manifestation of an unidentified respiratory complication (such as pulmonary emboli, infection) contributing to an acute worsening in a patient with IPF or represents an inherent acceleration in the pathobiological processes involved in IPF. Recent data from gene expression profiling of patients with acute exacerbation of IPF do not suggest an infectious etiology (158).

Historically, criteria for acute exacerbation of IPF have included an unexplained worsening of dyspnea within 1 month, evidence of hypoxemia as defined by worsened or severely impaired gas exchange, new radiographic alveolar infiltrates, and an absence of an alternative explanation such as infection, pulmonary embolism, pneumothorax, or heart failure (143). Acute exacerbation can occur at any point in the course of IPF and occasionally can be its presenting manifestation (149, 153, 159, 160). Worsened cough, fever, and/or increased sputum have been observed (148, 149, 153). While there are no known risk factors for acute exacerbation of IPF, there have been reports of acute respiratory decompensation after thoracic surgery (161–165) and bronchoalveolar lavage (149, 166). It is unclear whether or not these events represent true acute exacerbations or complications of the respective procedures.

Acute exacerbation of IPF histologically manifests as acute or organizing diffuse alveolar damage (DAD), or, less commonly, organizing pneumonia in zones of relatively preserved lung tissue away from the most fibrotic regions (143). Anecdotal experience indicates that sampling issues in some patients may result in specimens demonstrating only uncomplicated UIP or the organizing phase of DAD without histologic evidence of underlying UIP in the sample evaluated (153).

Deaths from pulmonary fibrosis increase with increasing age (18, 167). In addition, there is evidence to suggest increasing mortality from pulmonary fibrosis over the past two decades (18, 167). A recent analysis of the death certificate data in the United States noted a significant increase in mortality from pulmonary fibrosis from 1992 to 2003 (167). When the most rigorous definition of IPF was applied, the mortality rate in the United States in 2003 was 61.2 deaths per 1,000,000 in men and 54.5 per 1,000,000 in women (167). In Japan, the mortality rate for IPF was estimated to be 33 per 1,000,000 in men and 24 per 1,000,000 in women (22). The mortality burden attributable to IPF is higher than that of some cancers (168). Recent evidence suggests that mortality from IPF in the United States is greater in the winter months (169). The most common cause of death is progressive lung disease (60% of deaths) (146, 167). Additional causes of morbidity and mortality in patients with IPF include coronary artery disease (170), pulmonary embolism, and lung cancer.

Patients that are older and male have been reported as having worse prognosis in some but not all studies (15, 131, 171–177). The effect of smoking has been shown to be associated with both increased (134, 178) and decreased (131) risk of subsequent mortality. The prognostic value of geographic, ethnic, cultural, and racial factors is unknown.

Baseline dyspnea has been shown to correlate with quality of life and survival in several studies (15, 179–182). A variety of different metrics for dyspnea have been used, including the medical research council scale, baseline dyspnea index, quality of life (QoL) measurement tools with respiratory questionnaires, Borg scale, University of California San Diego shortness of breath questionnaire, and the clinical-radiological-physiological dyspnea score (183–185). It remains unclear which dyspnea metric is most predictive of outcome in patients with IPF. Change in dyspnea over time has also been shown to predict survival (186).

Baseline pulmonary function test values have shown mixed associations with survival in IPF. This may be due, in part, to comorbid conditions such as emphysema, pulmonary vascular disease, and obesity, or technical differences in testing. Baseline FVC is of unclear predictive value (15, 173, 175, 177, 180, 186–189). Diffusing capacity for carbon monoxide (Dl_CO, single breath, hemoglobin corrected) is more reliably predictive of survival at baseline, and a threshold of approximately 40 percent predicted has been associated with an increased risk of mortality (186, 187, 190, 191). Limited data suggest that baseline total lung capacity (TLC) and alveolar-arterial oxygen difference in partial pressures (P(A-a)O₂) may be predictive of survival, but no clear threshold exists (186). Baseline cardiopulmonary exercise testing (maximal oxygen uptake) has been suggested to predict survival (192).

Longitudinal change in physiology is clearly an important predictor of mortality in IPF. A decline in FVC over 6 or 12 months has been reliably associated with decreased survival (177, 186, 187, 191, 193). Recent data indicate that in IPF, declines in FVC of 5–10% may be predictive of mortality. A decline in Dl_CO has also been associated with decreased survival, although less consistently (186, 187, 191, 193). Greater than 15 mm Hg change in P(A-a)O₂ after 12 months has been shown to be predictive of survival (187). Six-month change in TLC and P(A-a)O₂ may also be predictive of survival (186).

HRCT features of fibrosis and honeycombing are strongly correlated with FVC and Dl_CO measurements (194). Several groups have demonstrated that the extent of fibrosis and honeycombing on HRCT are predictive of survival in IPF (109, 195–198).

Composite scoring systems have been developed utilizing physiological and radiographic variables in an attempt to provide more accurate prognostic information. A composite physiologic index (CPI) has been developed that uses values from FEV₁, FVC, and Dl_CO to predict the extent of disease on HRCT (141, 191). This CPI was a stronger predictor of mortality than individual measures of lung function such as FEV₁, FVC, Dl_CO, TLC, Pa_O2, the clinical-radiographic-physiological scoring system (CRP) (183) or new CRP scoring systems (15). However, this composite approach has not been tested in any prospective clinical trials to date and its clinical utility is unknown.

Although the 6-minute-walk test (6MWT) is widely used in clinical practice, its prognostic value is limited due to lack of standardization of the procedure in patients with IPF. Some studies have suggested that desaturation (i.e., a decline in oxygen saturation to below 88%) during 6MWT is a marker for increased risk of mortality (188, 199, 200). Shorter walk distance and delayed heart-rate recovery after walk testing have been associated with an increased risk of subsequent mortality (188, 201–203). However, it is unclear if desaturation, distance walked, and other variables measured during 6MWT in this population are reproducible (204). A steady-state 6-minute exercise test using a walking treadmill has been used in patients with IPF in a recent clinical trial in Japan, but the clinical utility of this unvalidated test is unclear (144).

Varied histopathologic patterns can be found within individual patients when multiple biopsies are obtained. A pattern of UIP and NSIP has been identified in 12 to 26% of patients with multiple lobe biopsies (115, 116), highlighting the importance of obtaining biopsies from multiple lobes. The prognosis for patients with discordant UIP (pattern of UIP and NSIP within the same patient) appears to be similar to that of patients with concordant UIP (UIP in all lobes biopsied) (115, 116).

An increased number of fibroblast foci has been associated with an increased risk of mortality in some studies (134, 175, 205–207). A higher profusion of fibroblast foci has also been associated with a decline in FVC and Dl_CO over 6 and 12 months of follow-up (205). The utility of detailed histopathologic scoring systems in the day-to-day clinical management of patients with IPF has not been evaluated.

The majority of data regarding the presence and significance of pulmonary hypertension come from patients with IPF undergoing evaluation for lung transplantation. The presence of pulmonary hypertension (defined as a mean pulmonary artery pressure of > 25 mm Hg at rest) has been associated with increased risk of mortality for patients with IPF (140, 142, 176). In a separate series of 70 patients with IPF, receiver operator characteristic (ROC) analysis suggested a mean pulmonary artery pressure of 17 mm Hg as the best discriminator of mortality (189). These data need to be validated. Echocardiographic estimation of pulmonary artery systolic pressures does not correlate well with right heart catheterization (208–210). Increased pulmonary vascular resistance has also been linked to worse survival (211). It is not clear if IPF with pulmonary hypertension represents a distinct clinical phenotype (IPF–PH).

Recent retrospective data suggest that patients with IPF and coexisting emphysema have a poorer outcome than those without emphysema (140, 212). Patients with coexisting IPF and emphysema may require treatment for both conditions. Limited data suggest that patients with IPF and emphysema are likely to require long-term oxygen therapy and may have significant pulmonary hypertension. When controlling for these differences, the presence of emphysema was not significantly predictive of survival (140). Thus, it is not clear if IPF with coexisting emphysema represents a distinct clinical phenotype (combined pulmonary fibrosis and emphysema) with a distinct prognosis or whether emphysema in these cases is simply a comorbidity.

There are limited retrospective data on the predictive value of serum and BAL biomarkers in IPF. However, these are largely unavailable for routine clinical use. Krebs von den Lungen-6 (KL-6) is a high-molecular-weight glycoprotein, classified as human MUC1 mucin, that is produced by regenerating type II pneumocytes (213). Serum levels of KL-6 have been shown to be elevated in patients with IPF, and these levels may correlate with increased risk of subsequent mortality (214, 215). Serum levels of surfactant protein A and D are also elevated in patients with IPF and are predictive of survival (216–218). Recent data demonstrate a relationship between serum CCL18, other chemokines, and serum brain natiuretic peptide levels and mortality (219–223). Studies of plasma and BAL matrix metalloproteinase (MMP) levels suggest that MMP1 and MMP7 are increased in patients with IPF, and MMP7 levels may correlate with disease severity (224). BAL levels of SP-A appear predictive of survival (225, 226). Cellular analysis of BAL is of unclear predictive value in IPF (226, 227). Preliminary evidence suggests that the presence of circulating fibrocytes (mesenchymal progenitor cells) is associated with worse short-term survival (228).

The committee did not find sufficient evidence to support the use of any specific pharmacologic therapy for patients with IPF. However, clinical trials of some agents have suggested a possible benefit. The recommendations detailed below are based on the evidence-based approach outlined in the introductory section; these recommendations may change if additional and/or new data become available in publications subjected to peer review. The number of votes for, against, abstaining, and absent are reported for all treatment votes. Most abstentions were a result of panel members withholding from voting on questions with which they felt they had a potential conflict of interest.

Figure 5. Schematic pathway for clinical management of patients with IPF. Clinicians are required to spend adequate time with patients to discuss patients' values, preferences, and prognosis. All patients should be made aware of available clinical trials for possible enrollment. Patient at increased risk of mortality should be considered for lung transplantation. Pharmacologic treatment should be limited to a carefully selected minority of patients who are willing to accept possible adverse consequences even if expected benefits are small. See text for specific recommendations of pharmacological therapies. Oxygen supplementation (if hypoxemic) and pulmonary rehabilitation are recommended treatments (strong yes and weak yes, respectively). All patients should be monitored for disease progression and identification of complications at 4 to 6 months or sooner as clinically indicated. Corticosteroids are an appropriate treatment option for acute exacerbation (weak yes). Mechanical ventilation is not recommended for the majority of patients with respiratory failure due to progression of their disease (weak no). Symptom control (palliative care) focuses on reducing symptoms (e.g., cough and dyspnea) and providing comfort to patients, rather than treating patients' disease. Advanced directives must be discussed in the ambulatory setting. See text for additional details.

Download Figure | Download Powerpoint

[More] [Minimize]

The strength of a recommendation reflects the extent to which the committee was confident that desirable effects of a therapy outweighed its undesirable effects (3). The recommendations against most treatment therapies are strong; there is insufficient evidence to support the routine use of these therapies. Other treatment recommendations were weak, reflecting the need for better quality data and uncertainty regarding the benefits and risks of therapy. The strength of a recommendation has important implications for patients, clinicians, and policy makers (Table 3).

The committee recommends the use of several nonpharmacologic therapies in appropriate patients with IPF.

• Question: Should patients with IPF and resting hypoxemia receive long-term oxygen therapy?

  • There are no data that directly inform the use of long-term oxygen therapy in patients with IPF. One study has retrospectively compared survival in a cohort of patients with IPF, many of whom (27%) received oxygen therapy (14). In multivariate analysis, no survival benefit was demonstrated with oxygen use. This study was limited by its retrospective design. There is limited evidence demonstrating improvement in exercise capacity in patients with resting hypoxemia using oxygen (275). Indirect evidence from two large randomized trials in obstructive lung disease has demonstrated a clear survival benefit with long-term oxygen therapy (276, 277). Variable definitions of hypoxemia were used in these studies (Pa_O2 of 55–65 mm Hg).

  • Recommendation: We recommend that patients with IPF and clinically significant resting hypoxemia should be treated with long-term oxygen therapy (strong recommendation, very low-quality evidence).

  • Values: This recommendation places a high value on evidence from other chronic lung diseases and a low value on inconvenience to patients and cost.

  • Remarks: The committee was divided over the strength of this recommendation. There was a degree of uncertainty about the balance of benefits and inconvenience to patients/cost. The strong recommendation was driven by physiological rationale, ethical concern over withholding supplemental oxygen in a patient demonstrating clinically significant resting hypoxemia (commonly defined by a resting Sp_O2 of < 88%), and extrapolation from data in COPD. The committee is not able to specify a Pa_O2 cutoff for use of supplemental oxygen; for now this must be determined at the discretion of the treating physician. It is unknown if supplemental long-term oxygen therapy in patients who demonstrate only exertional hypoxemia improves survival. However, limited data suggest improved walk distance with supplemental oxygen in these patients (188). (Vote: 18 for use, none against use, 4 abstentions, 9 absent.)

• Question: Should appropriate patients with IPF undergo lung transplantation?

  • Five-year survival rates after lung transplantation in IPF are estimated at 50 to 56% (278, 279). A single-center study of 46 patients referred for lung transplantation with IPF demonstrated a reduced risk of death at 5 years in patients receiving lung transplantation (280). Additional evidence suggests that patients with pulmonary fibrosis undergoing lung transplantation have favorable long-term survival compared with other disease indications (279). There are no clear data to guide precise timing of transplantation, although criteria have been proposed based on diffusion capacity and or the presence of progressive disease (190). It is unclear if the survival benefit is different in single- versus double-lung transplant recipients (281).

  • Recommendation: We recommend that appropriate patients with IPF should undergo lung transplantation (strong recommendation, low-quality evidence).

  • Values: This recommendation places a high value on low-quality evidence showing a survival benefit and lower value on cost and procedural risk.

  • Remarks. The committee recognizes that there is variability among lung transplantation programs regarding eligibility and timing of listing for transplantation. There are major limitations to the published retrospective studies of lung transplantation for IPF. Most importantly, the patient populations in these studies include patients with other forms of fibrotic lung disease. Discussion of lung transplantation is encouraged in appropriate patients at the time of diagnosis, and detailed evaluation for lung transplantation should occur in a timely manner at the first sign of objective deterioration. (Vote: 21 for use, none against use, 1 abstention, 9 absent.)

• Question: Should patients with respiratory failure due to IPF receive mechanical ventilation?

  • There are several small studies of mechanical ventilation in patients with IPF and respiratory failure, all of which show a high hospital mortality rate (149, 282–291). The inclusion criteria varied among studies, with some only including patients with respiratory failure of unknown etiology (149, 287). A representative study of 23 patients with IPF and respiratory failure who required mechanical ventilation reported a hospital mortality rate of 96% (286). The only survivor underwent lung transplantation 6 hours after intubation. A systematic review of mechanical ventilation in patients with IPF and respiratory failure reports a similarly poor hospital mortality of 87% among the 135 reported cases (292).

  • Recommendation: The majority of patients with respiratory failure due to IPF should not receive mechanical ventilation, but mechanical ventilation may be a reasonable intervention in a minority (weak recommendation, low-quality evidence).

  • Values: This recommendation places a high value on the high mortality observed in this patient population and on reducing unnecessary suffering.

  • Remarks: Clinicians need to evaluate each patient carefully before making the decision to not pursue mechanical ventilation. Given the high mortality associated with mechanical ventilation in IPF, this therapy should only be used after discussion with patients and their caregivers regarding goals of care. Whether or not to receive mechanical ventilation in this situation is a value-laden decision that is best made by the patient, clinician, and family ahead of time (ideally during a previous clinic visit). Noninvasive positive pressure ventilation may be appropriate in some patients. In rare circumstances, mechanical ventilation may be appropriate as a bridge to lung transplantation. (Vote: 2 for use, 19 against use, 2 abstentions, 8 absent.)

• Question: Should patients with IPF receive pulmonary rehabilitation?

  • Pulmonary rehabilitation programs involve aerobic conditioning, strength and flexibility training, educational lectures, nutritional interventions, and psychosocial support. Pulmonary rehabilitation has recently been studied in patients with ILD. Two controlled trials of pulmonary rehabilitation in IPF have demonstrated an improvement in walk distance and symptoms or quality of life (293, 294). Other uncontrolled studies have found similar findings (295–298). The beneficial effects of pulmonary rehabilitation may be more pronounced in patients with worse baseline functional status (295).

  • Recommendation: The majority of patients with IPF should be treated with pulmonary rehabilitation, but pulmonary rehabilitation may not be reasonable in a minority (weak recommendation, low-quality evidence).

  • Values: This recommendation places a high value on moderate-quality data demonstrating improvement in functional status and patient-centered outcomes and a low value on cost and uncertainty regarding duration of benefit.

  • Remarks: The long-term benefit of pulmonary rehabilitation remains unclear. The committee recognizes that the components of pulmonary rehabilitation may need to be tailored to this patient population. (Vote: 19 for use, none against use, 3 abstentions, 9 absent.)

Disease progression may be manifested by increasing respiratory symptoms, worsening pulmonary function test results, progressive fibrosis on HRCT, or acute respiratory decline.

In the absence of another identifiable cause, the presence of any of the following changes is consistent with progressive disease:

• Progressive dyspnea (objectively assessed)

• Progressive, sustained decrease from baseline in absolute FVC

• Progressive, sustained decrease from baseline in absolute Dl_CO (corrected for hemoglobin)

• Progression of fibrosis from baseline on HRCT

• Acute exacerbation

• Death from respiratory failure

These parameters were developed based on data from clinical trials (see Staging and Prognosis). While progressive dyspnea is an important subjective variable, objective assessment of dyspnea is encouraged (e.g., with dysnpea scores, assessment of dyspnea by validated tools such as University of California San Diego shortness of breath questionnaire). Further studies are needed to validate the inclusion of dyspnea assessment and other variables. Evidence from several clinical cohorts to date confirms that a change in absolute FVC of 10% (with or without a concomitant change in Dl_CO) or a change in absolute Dl_CO of 15% (with or without a concomitant change in FVC) is a surrogate marker of mortality and is evidence of, in the absence of an alternative explanation, disease progression (177, 186, 187, 191, 193). Smaller (5–10%) but progressive, sustained changes in FVC may also represent progression of disease (311). The committee was unable to specify the absolute minimum magnitude of FVC and Dl_CO change required for determination of disease progression, but isolated changes of less than 5% in FVC and less than 10% in Dl_CO should be interpreted with caution. Changes in this range are more likely to overlap with the intrinsic variability of the test (312–316). On average, progression of disease is monitored over periods of 3 to 6 months, but sustained changes in symptoms, physiology, and radiology over shorter periods of time may also identify disease progression.

Of the above parameters, pulmonary function testing provides the most standardized approach to objective monitoring and quantification of disease progression. Evidence suggests that progressive fibrosis leads to gradual decline in pulmonary function and worsening symptoms (317). The placebo arms of several large, randomized controlled treatment trials in IPF have suggested an average annual decline in FVC of approximately 0.2 liters in the overall population of patients with IPF with mild to moderate pulmonary function abnormalities at the time of enrollment (135, 137, 144, 260). The rate of decline in individual patients is widely variable.

A decline in absolute Dl_CO in the absence of an alternative explanation is consistent with progressive disease, although such a decline may also reflect changes in the pulmonary vasculature and coexistent pulmonary hypertension. Using our current techniques, longitudinal measurement of other clinical and physiological variables (e.g., TLC, P(A-a)O₂) and 6-MWT variables have significant limitations and are not recommended for routine use in monitoring for disease progression at this time. Monitoring for desaturation during 6MWT is useful, however, in patients with significant exercise intolerance to assess the need for supplemental oxygen.

The physiological effect of comorbidities such as coexisting emphysema on the predictive values of serial changes in pulmonary function is unclear, but is likely to be a confounding factor (318). The committee recognizes that the presence of significant emphysema impacts FVC measurement, and thus changes in FVC alone may not be as reliable an indicator of disease progression in these circumstances (319–321). Under these circumstances, a combination of FVC and Dl_CO may be useful in assessing progression of disease.

The committee recommends that FVC and Dl_CO measurements be performed during routine monitoring in accordance with ATS/ERS standards to follow trends (312–316). While it is appropriate to routinely monitor disease course with FVC and Dl_CO measurements at 3- to 6-month intervals, a subset of patients with rapid progression or acute worsening may not have demonstrated progression during the preceding interval (145). The optimal time interval for repetition of FVC and Dl_CO has not been formally investigated. A flexible approach to monitoring for disease progression is required with a lower threshold for earlier repetition of FVC and Dl_CO in the presence of progressive dyspnea or other features of a more rapidly progressive course.

Identifying patients with worsening respiratory symptoms (e.g., dyspnea) has important management implications. Patients experiencing worsening respiratory symptoms require evaluation for progressive disease, assessment of oxygenation at rest and with exertion, and prompt detection of secondary complications (e.g., development of deep venous thrombosis and pulmonary embolus). In addition, some patients may benefit from symptom-based therapies. There are several research tools available for the quantification of dyspnea. It is unclear if any of these tools have clinical utility.

Oxygen saturation by pulse oximetry should be measured at rest and with exertion in all patients regardless of symptoms to assure adequacy of oxygenation and identify the need for supplemental oxygen at baseline and during follow-up evaluation. Careful attention to the pulse oximetry tracing and signal is required to overcome potential problems related to poor circulation and inadequate signal quality. Generally, desaturation below 88% during a formal 6MWT or equivalent has been used to prescribe supplemental oxygen (322). Such measurements should be performed at baseline and during follow up at 3- to 6-month intervals. Formal cardiopulmonary exercise testing does not have a defined role and is not recommended for routine monitoring.

Comorbidities including pulmonary hypertension, pulmonary embolism, lung cancer, and coronary artery disease are known to occur in IPF. While the development of these comorbidities may influence survival, the role of routine screening to identify such complications in patients with IPF (e.g., annual HRCT for lung cancer surveillance) is unknown. Thus, a recommendation for routine screening cannot be made. In patients demonstrating progressive disease, the identification of pulmonary hypertension may impact consideration for lung transplantation in eligible patients, and evaluation is indicated. Echocardiography is inaccurate in estimating pulmonary hemodynamics in patients with fibrotic lung disease and should not be relied upon to assess the presence and severity of pulmonary hypertension (208, 210, 271). Brain natiuretic peptide levels have been shown to correlate with the presence of moderate to severe pulmonary hypertension, but have not been thoroughly validated as a screening tool (220, 221). A clinical prediction model has also been proposed but requires independent validation (323). At the present time, right heart catheterization is required to confirm the presence of pulmonary hypertension.

Since some patients with connective tissue disease (e.g., younger women) may present with isolated pulmonary abnormalities characteristic of IPF prior to overt manifestations of systemic disease, appropriate serological monitoring for connective tissue disease should be considered in such patients when symptoms arise.

For patients manifesting acute respiratory worsening, the possibility of acute exacerbation of IPF should be entertained, and prompt evaluation for alternative etiologies of acute worsening such as pulmonary embolus, pneumothorax, respiratory infection, or aspiration should be undertaken.

Monitoring for complications associated with pharmacologic therapy will need to be tailored to the known side effect profiles of the specific treatment regimen.

The committee has integrated its recommendations into a schematic pathway for clinical management based on these considerations (Figure 5).