Paul W Noble Department of Medicine, Division of Pulmonary, Allergy and Critical Care, Duke University Medical Center, Durham, North Carolina 27710, USA , Eric B Meltzer Department of Medicine, Division of Pulmonary, Allergy and Critical Care, Duke University Medical Center, Durham, North Carolina 27710, USA.

Findings of bronchoscopy and surgical lung biopsy
The role of bronchoalveolar lavage (BAL) in the diagnosis of IPF remains limited. While the cell count of BAL fluid from patients with IPF has an expected differential distribution (increased numbers of neutrophils and/or eosinophils), the diagnosis of IPF can not made solely on the basis of BAL fluid analysis. Though much effort has been invested in evaluating the clinical utility of BAL, the results of many studies are contradictory ^{[70, 71]}. Still, BAL fluid analysis, and sometimes transbronchial biopsy (TBB), can be helpful in excluding alternative diagnoses. Bronchoscopic exam may demonstrate tumor, infection, Langerhans’ cells or occupational dust exposures.

A surgical lung biopsy is close to the “gold standard” for diagnosis and is recommended to confirm all suspected cases of IPF. Biopsy from two sites is recommended based on data indicating a substantial risk of sampling era unless specific effort is made to reflect the gamut of gross disease ^[72].

In cases presenting with a “confident” HRCT pattern, biopsy can be avoided because the results of biopsy can be predicted ^{[68, 69]}. A sizable tissue specimen is required in order to distinguish patterns of IIP, one from the other. Therefore, surgical biopsy is needed and transbronchial biopsy is inadequate. A surgical lung biopsy can be performed by either open thoracotomy or a video-assisted thoracoscopy (VATS) approach. VATS is preferred since this procedure is associated with lower morbidity and shorter hospital stay as compared with open thoracotomy ^[73].

The decision to perform surgical lung biopsy must be carefully considered. Advanced lung disease, poor functional status and older age are relative contraindications to surgery. The absolute risk associated with biopsy is controversial and all of the evidence related to this issue is derived from retrospective data, thus colored by inherent selection bias. While some studies have noted a high short-term mortality, other studies have demonstrated that surgical lung biopsy can be performed safely ^{[74, 75]}. VATS is usually well tolerated and can provide useful information concerning the diagnosis, prognosis and treatment options.

The gross pathology of IPF may be normal, but often a distinctive nodular appearance of the pleural surface is found. This has been likened to cirrhosis of the liver. The histopathological lesion associated with IPF is known as usual interstitial pneumonia (UIP). This lesion is defined by a distinctly variegated pattern. UIP features normal lung architecture alternating with patchy areas of histologically apparent pulmonary parenchymal fibrosis (Figures 4 and 5). Fibrosis takes the form of alveolar septal thickening with marked involvement of the subpleural regions. The most severely involved areas of the lung demonstrate complete distortion of normal architecture, with sheets of dense collagen replacing normal lung tissue and occasional cystic structures known as microscopic honeycombs. When examined carefully under the microscope, the region of scarred lung tissue appears to encroach upon areas of preserved, normal lung tissue. This has been termed the “leading edge” of fibrosis and contains specialized structures known as fibroblast foci. Fibroblast foci are pale-staining whirls of loose extracellular matrix molecules, interspersed with numerous cells of the fibroblast type (Figures 4 and 5). Inflammation is mostly absent from the UIP pathologic pattern except for occasional lymphoid follicles that are confined to regions of end-stage fibrosis. UIP contains no hyaline membranes, granulomas or organized alveolar exudates. Sometimes emphysema or respiratory bronchiolitis is superimposed upon the UIP pattern when the patient is a former or active smoker. These pathological changes can complicate diagnostic interpretation.

It is important to note that the UIP pattern is found in several diseases and is not limited to IPF. UIP can be associated with connective tissue disease, asbestosis, hypersensitivity pneumonitis, the Hermansky-Pudlak syndrome and drug toxicities (e.g.: bleomycin, amiodarone and nitrofurantoin toxicity). Distinguishing IPF from other disorders that contain UIP requires correlation with the clinical history.

It is also important to realize that honeycomb change of itself is a non-specific manifestation of end-stage fibrosis. Microscopic honeycombs do not equate with the UIP pattern nor do they connote a diagnosis of IPF. Only the full spectrum of UIP is diagnostic for IPF (in the correct clinical setting, as noted above).

Diagnostic criteria
The actual “gold standard” diagnosis of IPF consists of clinical-radiological-pathological correlation and was defined by consensus conference in the year 2000 and adopted by the American Thoracic and European Respiratory Societies (ATS/ERS) in a statement of guidelines published in the same year ^[1]. According to guidelines, the diagnosis of IPF can be considered definitive only in the presence of a surgical (not transbronchial) lung biopsy. The definite diagnosis of IPF requires all of the following: ^[1]

• Surgical lung biopsy revealing a histologic pattern consistent with UIP
• Exclusion of other known causes of interstitial lung disease (e.g.: connective tissue disease, environmental exposure, etc.)
• Abnormal pulmonary physiology with evidence of restriction and/or impaired gas exchange (can exist during exercise alone)
• HRCT demonstrating a pattern of “confident” or “possible” IPF.

In the absence of a surgical biopsy, the diagnosis of IPF remains uncertain. Yet, a set of reproducible clinical criteria were developed to define the probable diagnosis of IPF in cases in which a surgical biopsy is not possible. These clinical criteria were endorsed by the ATS/ERS consensus statement on IPF ^[1]. By consensus opinion, IPF can be reasonably diagnosed if all four major criteria and three-out-of-four minor criteria are satisfied. They are as follows:

Major criteria (Must fulfill all four requirements)
Exclusion of other known causes for interstitial lung disease (such as drug toxicity, environmental exposure and connective tissue disease)
Abnormal pulmonary function testing that includes evidence of restriction (reduced VC often with an increased FEV₁/FVC ratio) and/or impaired gas exchange (increased A-a gradient or decreased diffusion capacity)
Bibasilar reticular abnormalities with minimal ground glass opacities on HRCT scans (a “confident” HRCT is preferred)
Transbronchial lung biopsy or bronchoalveolar lavage (BAL) does not support an alternative diagnosis

Minor criteria (Must fulfill at least three; in addition to major criteria)
Age > 50 yr
Insidious onset of otherwise unexplained dyspnea on exertion
Duration of illness 3 months
Bibasilar, inspiratory crackles (dry or "Velcro" type in quality)
These criteria have never been subjected to a prospective analysis and, over time, diagnostic algorithms have continued to evolve. As HRCT technology has improved and the utility of this modality has been consistently demonstrated in clinical trials, HRCT has become a more important tool in diagnostic algorithms. Meanwhile, transbronchial biopsy and BAL have fallen from favor, mostly due to low diagnostic yield. A new ATS/ERS-sponsored consensus statement should address these issues and publication of such is expected in 2008.

Controversies regarding the diagnosis of IPF
The clinical-radiological-pathological “gold standard” diagnosis of IPF is flawed due to several issues, such as: 1) lack of standardized tests to exclude known causes of interstitial lung disease; 2) poor interobserver agreement regarding the interpretation of radiographic images; and, 3) poor interobserver agreement as regards the recognition of histological patterns. Interobserver agreement amongst radiologists reading HRCT has been reported to be no better than 80% ^[76]. Agreement amongst pathologists has been shown to depend upon experience and training and can be as low as 50% ^{[77, 78]}.

Since the mid-1990s, attention has focused on the division of idiopathic pulmonary fibrosis into histologically-defined subgroups. This practice stems from the description of NSIP in 1994 ^[79]. NSIP pathology consists of homogeneously thickened interstitial spaces that contain accumulated fibrosis and inflammation. In NSIP, fibroblastic foci are scarce and focal areas of organizing pneumonia can be found but remain inconspicuous. It has been suggested that patients with NSIP live longer than patients whose biopsy contains UIP ^[9]. However, a clinical description of NSIP-associated symptoms, along with vital statistics and risk factors for NSIP, have never been systematically recorded. By default, NSIP has come to represent a disease that exists in parallel to IPF. Whether NSIP truly represents a separate disease from IPF remains to be shown. Patients with NSIP are usually ten years younger than those with UIP. NSIP is also reported to be more sensitive to corticosteroids ^[2]. Some authors suggest that NSIP represents an early stage of IPF but this issue is highly controversial ^{[54, 80]}.

Three lines of evidence suggest that NSIP and UIP are different ends of a spectrum resulting from the same disease. The first piece of evidence is found in the examination of patients undergoing multiple surgical lung biopsies. One such study found that 26% of patients with IPF have NSIP pathology in one lobe while simultaneously displaying UIP in a sample from another lobe ^[72]. The second piece of evidence is provided by a study that examined survival, histopathology and pulmonary functions trends ^[5]. This study compared a cohort with 12-month interval physiologic stability to a cohort with declining 12-month physiology. It was found that physiology predicts mortality more strongly than any other measurable parameter, including histopathological distinction (i.e.: UIP vs. NSIP); in fact, pathological pattern conferred no independent prognostic value. The last bit of evidence comes from a cohort of families affected by familial pulmonary fibrosis where both NSIP and UIP were often found within a single family ^[16].

Differential diagnosis
The differential diagnosis of IPF includes other idiopathic interstitial pneumonias. HRCT is useful for excluding disease with predominantly ground glass opacity or nodular patterns. Nonspecific interstitial pneumonia (NSIP) will always remain in the differential and, in some cases, can only be excluded by biopsy.

Connective tissue diseases such as systemic sclerosis, polymyositis or rheumatoid arthritis can mimic IPF, both clinically and radiographically. The great majority of patients with systemic sclerosis will present with HRCT scan features more closely resembling NSIP ^[81]. Yet, remember that such an “atypical” HRCT pattern does not exclude IPF (see the discussion of HRCT patterns above). Elicitation of specific symptoms and the measurement of autoantibodies can distinguish these entities from IPF.

There are also forme fruste autoimmune disorders which can be difficult to recognize. These entities comprise autoimmune-mediated lung disease without a constellation of signs and symptoms to fulfill diagnostic criteria for defined rheumatologic illness. The presence of one or more symptoms, such as Raynaud’s phenomenon, proximal muscle weakness or sicca features, coupled with laboratory features of systemic inflammation (antinuclear and other specific autoantibodies) define the syndrome of undifferentiated connective tissue disease that can accompany pulmonary fibrosis and resemble IPF ^[82].

Chronic hypersensitivity pneumonitis and other environmental (sometimes occupational) exposures can also be difficult to differentiate. The clinical history can serve to discriminate this condition but is oftentimes equivocal. Nonetheless, a history of exposure to asbestos, grain dust and mold should be sought during the initial evaluation of IPF. Radiation pneumonitis, end-stage sarcoidosis, certain drug toxicities (e.g.: bleomycin, nitrofurantoin, amiodarone, carmustine and methotrexate) and several congenital disorders (e.g.: Hermansky-Pudlak, Gaucher’s disease, Niemann-Pick disease and dyskeratosis congenital) are also in the differential.

Management
Current medical therapy for IPF is poorly effective, at best. However, IPF is a progressive, ultimately fatal disorder for which substantive medical therapy is desperately needed. This has led to a history of undue excitement over novel treatment modalities and, sometimes, new medications have been adopted prematurely only to loose credibility with further study. At present, expectant management is the most reasonable approach to IPF care along with supportive measures instituted as necessary. Patients who satisfy enrollment criteria can be enlisted in clinical trials to test novel medications that may prove useful in the future. In addition, patients with IPF can be offered lung transplantation if they are below the age of 70 years. The timing for lung transplantation depends upon an accurate assessment of risks and benefits. This begins with an assessment of disease activity and prognosis in IPF.