Abstract: The idiopathic interstitial pneumonias (IIPs) are the most commonly diagnosed forms of interstitial lung disease. These diseases represent specific clinicopathologic entities characterized by varying degrees of lung parenchymal inflammation and fibrosis. While most patients present with chronic dyspnea and have evidence of restriction on pulmonary function testing, certain findings can help differentiate among the IIPs. For example, patients with idiopathic pulmonary fibrosis (IPF)--the most common IIP--commonly present in the sixth or seventh decade of life, while those with desquamative interstitial pneumonia or respiratory bronchiolitis with interstitial lung disease typically present in the third or fourth decade of life and have a history of smoking. IPF is characterized by usual interstitial pneumonia (UIP) on lung biopsy; a UIP pattern can also be identified by high-resolution CT. (J Respir Dis. 2005;26(9):372-378)
Interstitial lung disease (ILD) is a diverse group of infiltrative pulmonary disorders that cause disruption of the architecture and function of the lung parenchyma. Because ILD encompasses many diseases that involve pulmonary compartments other than the lung interstitium, the term is a misnomer. Although the term "diffuse infiltrative lung disease" may be more accurate, we will follow convention and use the term "ILD."
The common features of this large, heterogeneous group of disorders include exertional dyspnea; restrictive changes on pulmonary function testing, with loss of gas exchange surface area; diffuse radiographic changes; and histopathologic changes that generally show inflammatory cell infiltration and altered lung architecture. Major categories of ILD include the various forms of idiopathic intersti- tial pneumonia (IIP), rheumatologic lung diseases, occupational lung diseases, hereditary disorders, drug-induced ILD, and granulomatous lung disease.
ILD was recognized as early as in the 19th century, when autopsy examination revealed severely fibrosed lungs in patients who had had dyspnea. The observation of such stiff, severely scarred lung tissue led to descriptions such as "cirrhosis of the lung" by Corrigan in the 1860s and, later, "lung as hard as cartilage" by Osler.1 Over the next century, tremendous progress was made in the histopathologic characterization and radiologic differentiation of the different forms of ILD, which number well over 100 (see "ILD: The basic terms").
Clinicians can now obtain high-resolution CT (HRCT) scans of the chest, perform flexible bronchoscopy with bronchoalveolar lavage (BAL), and sample lung tissue by transbronchial or surgical lung biopsy to diagnose specific ILDs. As was the case in Osler's time, however, recognition of the possibility of an ILD diagnosis and a comprehensive and carefully obtained history and physical examination remain important keys to making an accurate diagnosis.
Thus, unlike other fields of medicine in which the history and physical examination have taken a back seat to expensive tests, the diagnosis of ILD rests to a large degree on the clinician's ability to elicit crucial clinical and historical clues. The correct diagnosis of a specific ILD remains almost as much an art as a science.
In this article, the first of a 3-part series, we will give a general overview of ILD. In coming issues of The Journal of Respiratory Diseases, we will continue our review of the clinical presentation of specific ILDs and provide an integrative diagnostic algorithm.
The epidemiology of ILD is difficult to assess because of the heterogeneous clinical presentation, lack of population-based screening, and lack of uniform diagnostic criteria. Despite these limitations, estimates have been made regarding the incidence of ILD. Coultas and associates2 conducted a population-based assessment in New Mexico and found that over 2 years, the incidence of ILD was 31.5 per 100,000/year in men and 26.1 per 100,000/year in women. Nearly half of these cases were idiopathic pulmonary fibrosis (IPF). Interestingly, the prevalence of undiagnosed cases at autopsy was only 1.8%, and the prevalence in older persons was quite high.
In contrast, a study in Spain that involved 23 centers over 1 year found an incidence of 7.6 cases per 100,000/year; IPF was the most common diagnosis.3 This study was limited by the use of a standardized questionnaire to identify new cases of ILD at each center. Nevertheless, an incidence range of 7.6 to 31 cases per 100,000/year is not trivial. In comparison, the incidence of colorectal cancer is about 15 to 18 cases per 100,000/year.4 These data suggest that most cases of ILD are diagnosed before death and that ILD is more common in the general population than previously thought.
The ILDs can be placed in broad categories, such as occupational/ toxin-related; familial; iatrogenic/ drug-related; IIP; connective tissue disease-related; granulomatous lung disease; and other, less common entities (Table 1). This classification system is widely used and is clinically useful. However, many ILDs share overlapping clinical, radiographic, and histopathologic features. For example, chronic aluminum inhalation may lead to granulomatous lung disease, and beryllium exposure can lead to a presentation indistinguishable from that of sarcoidosis.
Nevertheless, the structured approach to differential diagnosis provided by this classification scheme is invaluable. An exposure that can cause ILD may be detected only by asking patients the right questions.
IDIOPATHIC INTERSTITIAL PNEUMONIAS
The IIPs are the most commonly diagnosed forms of ILD. These diseases represent specific clinicopathologicentities characterized by varying degrees of lung parenchymal inflammation and fibrosis. The IIPs include IPF, nonspecific interstitial pneumonia (NSIP), desquamative interstitial pneumonia (DIP), respiratory bronchiolitis with interstitial lung disease (RB-ILD), cryptogenic organizing pneumonia (COP), acute interstitial pneumonia (AIP), and lymphoid interstitial pneumonia (LIP).
IPF is the most frequently diagnosed IIP. However, considerable confusion persisted until the mid-1990s regarding the terminology of the various forms of IIP. Some of the different forms have been categorized as variations of IPF, and the Europeans have used the term "cryptogenic fibrosing alveolitis" instead of IPF.
To better define these clinicopathologic entities, the American Thoracic Society (ATS) and the European Respiratory Society (ERS) issued a joint consensus statement, which has helped standardize the nomenclature and establish different IIPs as specific entities.5 The statement emphasizes that the diagnosis of a specific IIP depends on the integration of clinical, radiographic, and pathologic findings.
A multidisciplinary approach involving the clinician, radiologist, and pathologist is advised, because it facilitates establishing the diagnosis while minimizing the risks of invasive diagnostic testing. Each of the IIPs has a histopathologic name and a clinical name, and certain characteristics on HRCT can help differentiate these entities (Table 2).
The term "IPF" is now used specifically for patients with usual interstitial pneumonia (UIP) on lung biopsy without evidence of connective tissue disease.UIP describes the histopathology of IPF, not the clinical syndrome. Most patients who have lung biopsy evidence of UIP have IPF, but this histopathologic pattern may be present in a rheumatologic disorder, such as rheumatoid arthritis or scleroderma.
Idiopathic pulmonary fibrosis
IPF is almost exclusively a disease of older persons.6 Patients commonly present in the sixth or seventh decade of life with chronic and progressive dyspnea and chest radiographs that demonstrate progressive architectural distortion. Severe hypoxemia occurs during the later stages of disease, invariably followed by death.
The pathogenesis of IPF is not clear, but one hypothesis suggests that lung inflammation and injury occur as a result of a persistent unknown antigen. Eventually, there is polarization of the repair mechanisms away from the normal re-epithelialization response to fibrosis.7
The differentiation of IPF from the other IIPs is critical given IPF's relatively poor prognosis and unresponsiveness to corticosteroids. The 5-year survival for patients with IPF--estimated at approximately 20%--stands in stark contrast to that for patients with NSIP (60% to 70%) and DIP or RB-ILD (80%).8 The diagnosis of IPF is generally a devastating one, because this entity is typically unresponsive to anti-inflammatory and immunosuppressive therapies, and antifibrotic therapies have not yet been shown to have a significant impact.
Over the past decade, prednisone,9 prednisone plus cyclophosphamide,10 colchicine (anti-fibrotic),11 and most recently, interferon gamma-1b12 have not prevented disease progression or reduced the mortality of IPF. Currently, there are no FDA-approved therapies for IPF. Thus, it is important for the patient and the family to have a clear diagnosis established for future planning, such as consideration of lung transplantation and counseling to avoid futile interventions (such as mechanical ventilation) if the disease progresses to ventilatory failure without identification of a reversible cause.
The ATS/ERS joint statement recognized the importance of making a precise diagnosis of IPF and recommended that evidence of a UIP pattern on surgical lung biopsy be required for a definitive diagnosis (Table 3).5 The UIP pattern is characterized by temporal heterogeneity of fibrosis with areas of active and old fibrosis and interspersed areas of normal or relatively normal lung tissue (Figure 1). The active areas reveal nests of fibroblasts (fibroblastic foci), and the location is predominantly subpleural; honeycombing is often present.
However, surgical lung biopsy is not without risk, particularly in patients with IPF, who are often older and have other comorbidities. A retrospective review of the Mayo Clinic experience with IPF revealed a 17% 30-day mortality after surgical lung biopsy.13 Fortunately, within the past decade, HRCT of the chest has made it possible to identify IPF accurately without the need for open lung biopsy if a radiographic UIP pattern is present.
A definite UIP pattern on HRCT consists of involvement that is predominantly bibasilar with a subpleural, heterogeneous distribution of honeycombing, reticular opacities, and traction bronchiectasis with minimal to no ground-glass opacities (Figure 2). When this pattern is present, a diagnostic specificity of greater than 95% is achieved.14
An ATS/ERS expert panel15 has recommended major and minor criteria for diagnosis if a surgical lung biopsy is not obtained (Ta- ble 4). Findings such as lymphadenopathy and pleural effusions are notably absent; their presence suggests an alternative diagnosis.
DIP and RB-ILD
Both DIP and RB-ILD are smoking-related IIPs that are thought to represent diseases along a spectrum. RB-ILD is characterized by a cellular bronchiolitis with pigmented alveolar macrophages ("smoker's macrophages") with more bronchiolar than alveolar involvement. DIP is also characterized by pigmented macrophages and has more alveolar than bronchiolar involvement.14Histopathologically, both diseases are characterized by temporal homogeneity and the absence of fibroblastic foci, in contrast to UIP.
Patients who have RB-ILD typically present in the third or fourth decade of life with chronic dyspnea and cough. HRCT shows centrilobular nodules with patchy ground-glass attenuation and peribronchial thickening.Patients who have DIP present in the same age group and have chronic dyspnea. However, in contrast to those with RB-ILD, nearly 50% of patients with DIP have clubbing.
In patients who have DIP, HRCT shows diffuse ground-glass opacities in a lower lung zone distribution. Since both disorders are associated with smoking, coexistent centrilobular emphysema is often present on HRCT.
DIP and RB-ILD are characterized by a much more favorable clinical course than is IPF/UIP. Patients are often asymptomatic or mildly symptomatic over many years. Respiratory symptoms often respond to corticosteroid therapy and smoking cessation; the latter is thought to be essential for clinical improvement to occur. However, some patients with DIP can have progression to end-stage fibrotic lung disease.
Nonspecific interstitial pneumonia
NSIP is a histopathologic entity that shares many clinical and radiographic features with the other IIPs.16 As with UIP, patients with NSIP often present with chronic dyspnea, basilar crackles, basilar infiltrates on the chest radiograph, and restrictive physiology on pulmonary function testing. NSIP can be caused by hypersensitivity, certain drugs, or collagen vascular disease, or it can be idiopathic.
Patients with NSIP are often younger (the median age at onset is 40 to 50 years)17 than patients with UIP and are less likely to have digital clubbing. HRCT also reveals important differences: in patients with NSIP, the bibasilar changes are mainly ground-glass opacities rather than honeycombing.18
In contrast to UIP, histopathologic findings associated with NSIP reveal temporal homogeneity, lack of fibroblastic foci, and absent or minimal honeycombing. When fibrosis is present (NSIP-fibrotic), the connective tissue reveals homogeneous fibrosis. When a prominent inflammatory cellular infiltrate is present (NSIP-cellular), homogeneous infiltration with lymphocytes is found.
NSIP has a better long-term prognosis than UIP, especially if fibrosis is absent.19 It also responds better to corticosteroid therapy. However, NSIP frequently coexists with UIP on the same lung biopsy specimen. Patients with this finding have a natural course of disease that is similar to that of UIP alone; therefore, the presence of UIP on biopsy "trumps" all other histopathologic subtypes.20
Cryptogenic organizing pneumonia
This entity is also known as idiopathic bronchiolitis obliterans with organizing pneumonia (BOOP). Histopathology shows intraluminal organizing fibrosis in the bronchioles, alveolar ducts, and alveoli. COP is generally a patchy process that is temporally homogeneous and usually does not destroy lung architecture.It has been associated with infections, drugs, radiation, collagen vascular disease, and inflammatory bowel disease. When there is no such disease association, the lesion of organizing pneumonia is clinically called COP or idiopathic BOOP.
In one series, the mean age at onset was 55 years.21 Patients often have an acute or subacute onset, with cough and dyspnea for a median duration of 3 months.21 Many patients present with constitutional signs and symptoms, such as fever and weight loss. An elevated erythrocyte sedimentation rate is common.22 A restrictive ventilatory defect with diffusion impairment is usually present, although a mixed obstructive/restrictive defect may also occur.
CT demonstrates subpleural or peribronchial distribution of ground-glass opacities or consolidation.23 A similar pattern can be seen in chronic eosinophilic pneumonia. A history of asthma, peripheral eosinophilia, and BAL fluid eosinophilia can help differentiate chronic eosinophilic pneumonia from COP. Occasionally, COP presents with multiple large nodules, and the presence of irregular margins and air bronchograms within the nodules helps identify the lesion as organizing pneumonia.23 Overall, COP has a very good prognosis and responds well to corticosteroid therapy.
Acute interstitial pneumonia
AIP has an acute onset and rapid clinical course. Histopathologic examination shows organizing diffuse alveolar damage, which consists of hyaline membranes that are diffuse and temporally homogeneous and are not unique for AIP. Diffuse alveolar damage can be seen in many other conditions, such as acute respiratory distress syndrome (ARDS), Pneumocystis jiroveci pneumonia, and connective tissue disease. The diagnosis of AIP is made when there is no disease association and the clinical course is rapid.
Patients often present with severe hypoxemia within days to weeks of the onset of dyspnea. The PaO2/fraction of inspired oxygen ratio is often less than 200, and CT shows diffuse ground-glass opacities and/or consolidation. In contrast to ARDS, the diffuse opacities are more symmetric and have a greater lower lung zone predominance.24 CT can demonstrate lung cysts, traction bronchiectasis, and honeycombing during the proliferative or fibrotic phase of resolution.
Overall mortality is high (50%), with most deaths occurring within the first 1 to 2 months of the illness.25 Treatment with corticosteroids is not clearly beneficial.
Lymphoid interstitial pneumonia
Although LIP has been classified as a form of IIP, it is recognized as a rare, benign lymphoproliferative disorder that is characterized by the diffuse infiltration of lung interstitium with lymphocytes and plasma cells. It usually occurs in patients who have an underlying disorder, such as Sjögren syndrome, and it usually does not cause extensive lung remodeling and fibrosis. HRCT typically shows bilateral areas of ground-glass attenuation and cysts.
1. Sharma OP, Chan K. Idiopathic interstitial pneumonitis/fibrosis: a historical note.
Curr Opin Pulm Med.
2. Coultas DB, Zumwalt RE, Black WC, Sobonya RE. The epidemiology of interstitial lung diseases.
Am J Respir Crit Care Med.
1994; 150: 967-972.
3. Xaubet A, Ancochea J, Morell F, et al. Report on the incidence of interstitial lung diseases in Spain.
Sarcoidosis Vasc Diffuse Lung Dis.
4. Jermal A, Murray T, Samuels A, et al. Cancer statistics 2003.
CA Cancer J Clin.
5. American Thoracic Society; European Respiratory Society. American Thoracic Society/European Respiratory Society International Multidisciplinary Consensus Classification of the Idiopathic Interstitial Pneumonias.
Am J Respir Crit Care Med.
6. Collard HR, King TE Jr. Demystifying idiopathic interstitial pneumonia.
Arch Intern Med.
7. Streiter R, Kaminski N, Belperio JA, et al. Idiopathic pulmonary fibrosis.
Am J Respir Cell Mol Biol.
8. Bjoraker JA, Ryu JH, Edwin MK, et al. Prognostic significance of histopathologic subsets in idiopathic pulmonary fibrosis.
Am J Respir Crit Care Med.
9. Flaherty KR, Toews GB, Lynch JP III, et al. Steroids in IPF: a prospective assessment of adverse reactions, response to therapy and survival.
Am J Med.
10. Nicholson AG, Colby TV, DuBois RM, et al. The prognostic significance of the histologic pattern of interstitial pneumonia in patients presenting with the clinical entity of cryptogenic fibrosing alveolitis.
Am J Respir Crit Care Med.
11. Douglas WW, Ryu JH, Swensen SJ, et al. Colchicine versus prednisone in the treatment of IPF. A randomized prospective study. Members of the Lung Study Group.
Am J Respir Crit Care Med.
12. 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.
13. Utz JP, Ryu JH, Douglas WW, et al. High short-term mortality following lung biopsy for usual interstitial pneumonia.
Eur Respir J.
14. Johkoh T, Muller N, Cartier Y, et al. Idiopathic interstitial pneumonias: diagnostic accuracy of thin-section CT in 129 patients.
. 1999;211: 555-560.
15. Joint Statement of the American Thoracic Society (ATS) and the European Respiratory Society (ERS). Idiopathic pulmonary fibrosis: diagnosis and treatment: international consensus statement.
Am J Respir Crit Care Med.
16. Katzenstein A, Fiorelli R. Nonspecfic interstitial pneumonia/fibrosis. Histologic features and clinical significance.
Am J Surg Pathol.
17. Flaherty KR, Toews GB, Travis WD, et al. Clinical significance of histological classification of idiopathic interstitial pneumonia.
Eur Respir J.
18. MacDonald SL, Rubens MB, Hansell DM, et al. Nonspecific interstitial pneumonia: comparative appearances at and diagnostic accuracy of thin-section CT.
19. Flaherty KR, Martinez F, Travis WD, et al. Nonspecific interstitial pneumonia.
Semin Respir Crit Care Med.
20. Monaghan H, Wells AU, Colby TV, et al. Prognostic implications of histologic patterns in multiple surgical lung biopsies from patients with idiopathic interstitial pneumonias.
21. King TE, Mortenson RL. Cryptogenic organizing pneumonitis. The North American experience.
22. Epler GR. Bronchiolitis obliterans organizing pneumonia: definition and clinical features.
23. Akira M, Yamamoto S, Sakatani M. BOOP manifesting as multiple large nodules or masses.
24. Tomiyama N, Muller NL, Johkoh T, et al. Acute respiratory distress syndrome and acute interstitial pneumonia: comparison of thin-section CT findinvvvvvvvvvvvvvvvvvvvvvvvvvvgs.
J Comput Assist Tomogr.
25. Katzenstein AL, Myers JL, Mazur MT. Acute interstitial pneumonia. A clinicopathologic, ultrastructural, and cell kinetic study.
Am J Surg Pathol.