Interstitial (Nonidiopathic) Pulmonary Fibrosis

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Background

Diffuse parenchymal lung diseases (DPLDs) comprise a heterogenous group of disorders. Clinical, physiologic, radiographic, and pathologic presentations of patients with these disorders are varied (an example is shown in the image below). However, a number of common features justify their inclusion in a single disease category.



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Frontal chest radiograph demonstrating bilateral reticular and nodular interstitial infiltrates with upper zone predominance.

DPLD may be idiopathic, a classic illustration of which is idiopathic interstitial fibrosis (IPF), which is discussed in another article (see Pulmonary Fibrosis, Idiopathic). The underlying histopathology of IPF is usual interstitial pneumonitis (UIP). Other major histopathologic forms of idiopathic interstitial pneumonias include the following: desquamative interstitial pneumonia (DIP), respiratory bronchiolitis interstitial lung disease (RBILD), acute interstitial pneumonitis (AIP), also known as Hamman-Rich syndrome, nonspecific interstitial pneumonia (NSIP), cryptogenic organizing pneumonia (COP) (see Bronchiolitis Obliterans Organizing Pneumonia), and lymphocytic interstitial pneumonia (LIP) (see Lymphocytic Interstitial Pneumonia).

Some forms of DPLD are related to occupational, environmental, drug, and/or radiation exposure, as well as systemic illness such as collagen-vascular disease (see Collagen-Vascular Disease Associated With Interstitial Lung Disease). Another category of DPLDs includes granulomatous forms, such as sarcoidosis (see Sarcoidosis), and hypersensitivity pneumonia (HSP) (see Hypersensitivity Pneumonitis). Finally, a number of very rare forms of DPLDs exist, including pulmonary Langerhans cell histiocytosis (PLCH) (see Eosinophilic Granuloma (Histiocytosis X)), tuberous sclerosis, lymphangioleiomyomatosis (LAM) (see Lymphangioleiomyomatosis), and Hermansky-Pudlak syndrome.

Some of these disorders, for example, RBILD, DIP, and PLCH, are clearly associated with smoking. Some forms of DPLD, as noted above, may also be related to occupational, environmental, drug, radiation exposure, or systemic illness such as collagen-vascular disease. This article presents a broad overview, with an emphasis on those etiologies that result in pulmonary fibrosis not discussed elsewhere in this series.

Pathophysiology

A common pathophysiology has been postulated for these disorders. It is thought to begin with acute injury to the pulmonary parenchyma, leading to chronic interstitial inflammation, then to fibroblast activation and proliferation, and finally progressing to the common endpoint of pulmonary fibrosis and tissue destruction. Current research indicates that inflammation is less important in IPF, which appears to be primarily a disorder of fibroblast activation and proliferation in response to some as yet unknown trigger(s).[1]

The DPLDs typically manifest with the insidious onset of respiratory symptomatology, although onset can be acute and rapidly progressive, as in COP or AIP.

Pathologically, all DPLDs manifest histologically with disease largely within the interstitial compartment of the lung. However, alveolar and airway architecture also may be disrupted to varying degrees. The histologic patterns of UIP, DIP, nonspecific interstitial pneumonitis (NSIP), HSP, LIP, COP, giant cell pneumonitis, and granulomatous pneumonitis are most common and are focused in the alveolar, lobular, and lobar septa, impacting alveoli, small airways, and pulmonary vasculature.

Epidemiology

Frequency

United States

As a group, diffuse interstitial diseases of the lung are uncommon. Based on the Bernalillo County, NM, USA registry data published in 1994, the overall estimated incidence is approximately 30 cases per 100,000 persons per year.[2]  Rates of interstitial lung disease are somewhat higher in men than in women, and the epidemiology is markedly affected by age and occupational exposures. Of patients referred to a pulmonary disease specialist, an estimated 10-15% have a DPLD.

International

Although little published data exist comparing worldwide prevalence, significant differences are apparent. The Bernalillo County study estimated a prevalence of 80.9 cases per 100,000 population in men and 67.2 cases per 100,000 population in women. In comparison, a Japanese study estimated a prevalence of 4.1 cases per 100,000 population; a study in the Czech Republic reported 7-12 cases per 100,000 population; and data from a Finnish registry indicated 16-18 cases per 100,000 population.

Mortality/Morbidity

The natural history of diffuse interstitial lung diseases varies among different diagnostic entities and among individuals with the same diagnosis. Note the following:

Race

Diffuse interstitial diseases of the lung sometimes show racial predilections. Examples include sarcoidosis, which is more common in those of African ancestry in the United States. In contrast, PLCH, also known as histiocytosis X, primarily affects Caucasians.

Sex

Several diffuse interstitial diseases of the lung show sexual predilections. IPF affects men more than women (at a ratio of 1.5:1), while LAM and pulmonary tuberous sclerosis exclusively affect women.

The Bernalillo County study estimated an incidence of 31.5 cases per 100,000/year in men and 26.1 cases per 100,000/year in women.

Women are much more likely to develop rheumatologic/connective-tissue disease than men and thus are more likely to experience pulmonary manifestations of those diseases. However, when affected, men with certain rheumatologic diseases (eg, rheumatoid arthritis) are more likely to develop pulmonary manifestations than women.

The pneumoconioses (eg, silicosis) are much more common in men than in women, probably because of higher rates of occupational exposure.

Age

Many of the DPLDs develop over many years and therefore are more prevalent in older adults. For example, most patients with IPF present in the sixth or greater decade of life. Others forms of interstitial lung disease, such as sarcoidosis, LAM, connective-tissue disease–associated lung disease, and inherited forms of lung disease primarily present in younger adults.

Patient Education

Educate patients about the nature of the specific diagnosis and about potential toxicities of prescribed medications.

History

The clinical history offered by patients with a DPLD is variable and related to the underlying disease process. Many patients with DPLD, particularly IPF/UIP, may experience acute exacerbations of the disease with subsequent persistent decrement in lung function, which has become increasingly recognized.

In general, all manifest primarily with respiratory symptoms that may be erroneously attributed to aging, obesity, deconditioning, or recent respiratory tract infection. Note the following:

Clinical history may include the following:

Broadly, the manifestations of fibrotic lung disease can be grouped as follows:

Disorders with chronic, insidious, and slowly progressive courses are those that clinically resemble IPF and usually share a common pathology (ie, UIP). Note the following:

Subacute presentations with a variable course are typified by COP. Note the following:

Disorders with an acute onset are typified by AIP, which is an idiopathic form of severe lung injury. Note the following:

Physical

Varied etiologies make generalization of physical examination findings difficult for patients with DPLD. However, clinical examination findings noted in patients with idiopathic pulmonary fibrosis are frequently noted in patients with other DPLDs. Note the following:

Disease-specific findings include the following:

Causes

Numerous causes/diagnoses are included among the DPLDs, many of which can be grouped as shown below.

DPLDs that mimic interstitial lung disease in clinical presentation and chest radiographic findings include the following:

DPLDs associated with environmental or occupational exposures include the following:

DPLDs associated with rheumatologic/connective-tissue diseases include the following:

DPLDs related to drug exposure include the following:

DPLDs related to other systemic illnesses include the following:

Idiopathic or rare DPLDs include the following:

Inherited DPLDs include the following:

Certain DPLDs, such as RBILD, DIP, and PLCH, are largely or only seen in current or former smokers.

Laboratory Studies

Routine blood analysis and serum chemistries are of limited value, and findings generally are nonspecific.

Serologic testing for rheumatologic disease or vasculitis (eg, antinuclear antibodies, rheumatoid factor, erythrocyte sedimentation rate, C-reactive protein, anticitrulline antibody, antineutrophil cytoplasmic antibodies, antiglomerular basement membrane) may be appropriate in specific cases, as may serum precipitins for common hypersensitivity antigens. ACE testing is not very specific or sensitive but may offer a confirmatory clue to the diagnosis of sarcoidosis.

Imaging Studies

Chest radiography findings are frequently abnormal in patients with fibrotic lung disease. Note the following:

Certain patterns and distributions of abnormality seen on chest radiographs are suggestive of particular diseases, as follows:

High-resolution chest computed tomography (CT) scanning is more sensitive than chest radiography and may reveal characteristic, if not diagnostic, findings (see image below).[4, 5]



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High-resolution chest CT scan of patient with bilateral reticular and nodular interstitial infiltrates with upper zone predominance.

Findings seen on high-resolution chest CT scanning are as follows:

Other Tests

Pulmonary function testing may demonstrate reduced lung volumes with testing of total lung capacity, forced expiratory volume in 1 second, and forced vital capacity. Note the following:

Arterial blood gas analysis often reveals an increased alveolar-arterial partial pressure of oxygen gradient and a reduced partial pressure of oxygen. Note the following:

Pulmonary exercise testing may demonstrate decreased exercise capacity with exercise-limiting impairments in ventilation and gas exchange.

Procedures

Bronchiolar lavage findings are frequently abnormal although generally not diagnostic. Bronchiolar lavage is useful in evaluating the possibility of infection or malignancy. It can also be diagnostic for eosinophilic pneumonia.[6]

Transbronchial and endobronchial lung biopsies may be diagnostic, particularly for sarcoidosis or lymphangitic spread of carcinoma but frequently are not useful for other diagnoses. This is due to the patchy distribution of the majority of these diseases.

Many patients require open or thoracoscopic lung biopsy to establish a definitive diagnosis. Currently, video-assisted thoracoscopic lung biopsy is the preferred method.

The role of lung biopsy in the setting of high-resolution CT scan findings characteristic of specific disease entities remains controversial, with expert opinion weighing in on both sides.[4, 5, 7] Consensus appears to be building on the side of forgoing biopsy when the typical clinical and high-resolution CT scan features of UIP/IPF are present.

Histologic Findings

The histopathology observed in diffuse interstitial diseases of the lung is varied. The histopathologic classification of idiopathic interstitial pneumonias were updated by Katzenstein and Myers[8] in 1998 to include the following 4 subgroups: UIP, AIP (diffuse alveolar damage), DIP/RBILD, and NSIP. Different histopathologic patterns may also be found in biopsy samples from different regions of the lung in these patients, particularly those with NSIP. Sometimes interstitial lung diseases with known etiologies may manifest one of the preceding histopathologic patterns. In addition, other pathologic patterns may be found. These may be consistent with COP, granulomatous lung disease, HSP, giant cell pneumonitis (hard-metal pneumoconiosis), eosinophilic pneumonia, and LIP (lymphoproliferative disorder).

Interpretation of histopathologic findings may be difficult, even in experienced hands, and disagreement may occur even among expert pathologists.[9] In 2005, a 52% rate of disagreement between local general pathologists and "expert" pathologists was documented in a retrospective analysis.[10]

Staging

Pulmonary function studies and the 6-minute walk study have demonstrated prognostic utility in IPF with histopathologic findings of UIP and NSIP. A diminished diffusion capacity (DLCO) on initial evaluation is a poor prognostic indicator, regardless of histologic type. Egan et al[11] have proposed a classification scheme of advanced versus limited disease based on a cutoff value of DLCO greater or less than 40%. Similarly, a trough saturation of less than 88% during a 6-minute walk study has been shown to confer a worse prognosis. Serial decrements in functional vital capacity and DLCO over time are also associated with increased mortality.

Medical Care

Treatment is best determined by the specific diagnosis. Unfortunately, a specific etiology often is not determined. General supportive measures include the following:

Pharmacologic therapy with corticosteroids (eg, prednisone) and/or cytotoxic agents for their potential steroid-sparing effect (eg, cyclophosphamide, azathioprine, methotrexate) may be indicated for specific diagnoses.

Other immunosuppressive or antifibrotic agents such as colchicine, cyclosporine, and D-penicillamine may have a role in specific cases. Empiric use of these medications without a specific diagnosis should be discouraged because they have significant toxicities.

Interferon-gamma-1b,[12] pirfenidone,[13] and N-acetylcysteine[14] have been studied for the treatment of IPF. Interferon-gamma-1b initially appeared to have a favorable effect. This, however, was not supported in a larger follow-up study. Some evidence suggests that pirfenidone and acetylcysteine may have some benefit in IPF. Further investigation is still needed, particularly in other forms of DPLD. As much remains unknown regarding the optimal therapy for DPLD, eligible patients may benefit from enrollment in an experimental trial.

A 2008 multisystem, randomized, controlled study of bosentan, an endothelin-1 receptor antagonist, and potentially anti-fibrotic agent, did not show superiority over placebo. However, a trend toward delay in progression of disease and improvement in mortality was noted, which was more pronounced in patients with UIP documented by surgical biopsy.[15] Additional phase III trials are ongoing.

Other novel potential therapeutic agents, such as recombinant TNF-alpha antagonists and tyrosine kinase inhibitors, are currently under investigation. These agents are further described in a recently published comprehensive review.[16]

Most patients with DPLD can be treated in community settings. Transfer to a tertiary care center is indicated when the diagnosis is in doubt or when treatment is ineffective.

Surgical Care

Surgery in the form of either thoracoscopic (preferred) or open lung biopsy is often indicated to obtain tissue specimens for definitive diagnosis.

More recently, lung transplantation has become a treatment option for selected patients with advanced disease refractory to medical therapy.[17] It is the only interventional modality that has been shown to increase survival time in patients with UIP/IPF.[18, 19] Note the following:

Consultations

Consider consultation with a pulmonary or occupational disease specialist for patients with suspected DPLD.

Diet

No specific dietary restrictions are warranted for affected patients.

Some suggest that antioxidants have a therapeutic benefit.

Activity

Encourage exercise and pulmonary rehabilitation because they may improve a patient's functional status. However, these activities generally have no effect on disease progression.

Complications

Potential complications of DPLDs include the following:

Long-Term Monitoring

See patients with diffuse interstitial lung disease every 3-6 months. Order pulmonary function testing every 3-6 months to assess disease progression and response to therapy. High-resolution CT scanning is becoming an increasingly important tool in making the initial diagnosis and subsequent assessments of disease progression and/or responses to therapy.

Patients with interstitial lung disease generally are treated in an outpatient setting. With advancing disease, progressive respiratory failure, pneumonia, pulmonary embolism, and cor pulmonale may all occur and require hospital admission. Bronchogenic cancer occurs with increased frequency.[21]

The prognosis is variable and depends on the specific diagnosis and clinical, physiologic, and pathologic severity.

Medication Summary

Medications are best used for specific diagnoses. However, corticosteroids, cytotoxic agents, and, more recently, antifibrotics, antioxidants, and other immunosuppressive agents have been used with varying success in some forms of DPLD.[20]

In general, NSIP, DIP, and COP have been found to be more responsive to corticosteroids and immunosuppressive therapies. UIP is generally thought to be unresponsive to these modalities, and thus, additional research in the form of clinical trials evaluating potentially promising agents continues. RBILD responds to smoking cessation.

Immunosuppressive and antifibrotic medications and supplemental oxygen may be indicated for some patients.

Prompt treatment is necessary for complicating pulmonary disease such as cor pulmonale (oxygen, diuretics), pulmonary embolism (anticoagulants), and infection (antibiotics).

Prednisone (Rayos, Deltasone)

Clinical Context:  Used as immunosuppressant in treatment of autoimmune disorders. By reversing increased capillary permeability and suppressing PMN activity, may decrease inflammation. Oral corticosteroid with relatively less mineralocorticoid activity.

Best prescribed in consultation with a pulmonary disease specialist.

Prednisolone (FloPred, Millipred, Millipred DP, Prelone)

Clinical Context:  Elicits mild mineralocorticoid activity and moderate anti-inflammatory effects; controls or prevents inflammation by controlling rate of protein synthesis, suppressing migration of polymorphonuclear leukocytes (PMNs) and fibroblasts, reversing capillary permeability, and stabilizing lysosomes at cellular level

Class Summary

These agents have anti-inflammatory properties and cause profound and varied metabolic effects. In addition, corticosteroids modify body's immune response to diverse stimuli.

Cyclophosphamide

Clinical Context:  Chemically related to nitrogen mustards. As an alkylating agent, mechanism of action of active metabolites may involve cross-linking of DNA, which may interfere with growth of normal and neoplastic cells of immune system. Possibly a steroid-sparing medication.

Azathioprine (Imuran, Azasan)

Clinical Context:  Inhibits mitosis and cellular metabolism by antagonizing purine metabolism and inhibiting synthesis of DNA, RNA, and proteins. These effects may decrease proliferation of immune cells and result in lower autoimmune activity. Possibly a steroid-sparing medication.

Cyclosporine (Gengraf, Neoral, Sandimmune)

Clinical Context:  Cyclosporine is a cyclic polypeptide that suppresses some humoral immunity and, to a greater extent, cell-mediated immune reactions.

Methotrexate (Otrexup, Rasuvo, Rheumatrex, Trexall)

Clinical Context:  Used for managing constitutional symptoms. It blocks purine synthesis and 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR), thus increasing anti-inflammatory adenosine concentration at sites of inflammation. Methotrexate ameliorates symptoms of inflammation.

Class Summary

These agents may inhibit key factors in involved in immune reactions.

Colchicine (Colcrys, Mitigare)

Clinical Context:  Decreases leukocyte motility and phagocytosis observed in inflammatory responses.

Class Summary

Immunosuppressive effects may inhibit cellular division and fibrosis.

Author

Eleanor M Summerhill, MD, FACP, FCCP, Associate Professor of Medicine, Division of Pulmonary and Critical Care Medicine, Warren Alpert Medical School of Brown University; Director, Internal Medicine Residency Program, Memorial Hospital of Rhode Island

Disclosure: Nothing to disclose.

Specialty Editors

Francisco Talavera, PharmD, PhD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Received salary from Medscape for employment. for: Medscape.

Daniel R Ouellette, MD, FCCP, Associate Professor of Medicine, Wayne State University School of Medicine; Chair of the Clinical Competency Committee, Pulmonary and Critical Care Fellowship Program, Senior Staff and Attending Physician, Division of Pulmonary and Critical Care Medicine, Henry Ford Health System; Chair, Guideline Oversight Committee, American College of Chest Physicians

Disclosure: Nothing to disclose.

Chief Editor

Zab Mosenifar, MD, FACP, FCCP, Geri and Richard Brawerman Chair in Pulmonary and Critical Care Medicine, Professor and Executive Vice Chairman, Department of Medicine, Medical Director, Women's Guild Lung Institute, Cedars Sinai Medical Center, University of California, Los Angeles, David Geffen School of Medicine

Disclosure: Nothing to disclose.

Additional Contributors

Stephen P Peters, MD, PhD, FACP, FAAAAI, FCCP, FCPP, Thomas H Davis Chair in Pulmonary Medicine, Chief, Section on Pulmonary, Critical Care, Allergy and Immunologic Diseases, Professor of Internal Medicine, Pediatrics, and Translational Science, Associate Director, Center for Genomics and Personalized Medicine Research, Wake Forest University School of Medicine; Executive Director of the Respiratory Service Line, Wake Forest Baptist Medical Center

Disclosure: Serve(d) as a speaker or a member of a speakers bureau for: Integrity CE, Merck<br/>Received income in an amount equal to or greater than $250 from: – Array Biopharma, AstraZeneca, Aerocrine, Airsonett AB, Boehringer-Ingelheim, Experts in Asthma, Gilead, GlaxoSmithKline, Merck, Novartis, Ono Pharmaceuticals, Pfizer, PPD Development, Quintiles, Sunovion, Saatchi & Saatichi, Targacept, TEVA, Theron.

Acknowledgements

The authors and editors of eMedicine gratefully acknowledge the contributions of previous author Robert S. Crausman, MD, MMS, to the development and writing of this article.

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Frontal chest radiograph demonstrating bilateral reticular and nodular interstitial infiltrates with upper zone predominance.

Frontal chest radiograph demonstrating bilateral reticular and nodular interstitial infiltrates with upper zone predominance.

High-resolution chest CT scan of patient with bilateral reticular and nodular interstitial infiltrates with upper zone predominance.

Frontal chest radiograph demonstrating bilateral reticular and nodular interstitial infiltrates with upper zone predominance.

High-resolution chest CT scan of patient with bilateral reticular and nodular interstitial infiltrates with upper zone predominance.