eMedicine Specialties > Pulmonology > Interstitial Lung Diseases

Pulmonary Fibrosis, Interstitial (Nonidiopathic)

Author: Eleanor M Summerhill, MD, Assistant Professor of Medicine, Division of Pulmonary and Critical Care Medicine, Warren Alpert Medical School of Brown University; Director of Internal Medicine Residency Program, Memorial Hospital of Rhode Island
Contributor Information and Disclosures

Updated: Jun 20, 2008

Introduction

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. However, a number of common features justify their inclusion in a single disease category.

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 interstitial pneumonitis 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); lymphocytic interstitial pneumonia (LIP) (see Lymphocytic Interstitial Pneumonia); sarcoidosis (see Sarcoidosis); hypersensitivity pneumonia (HSP) (see Hypersensitivity Pneumonitis);pulmonary Langerhans cell histiocytosis (PLCH) (see Eosinophilic Granuloma (Histiocytosis X)); tuberous sclerosis; and lymphangioleiomyomatosis (LAM) (see Lymphangioleiomyomatosis).

Some of these disorders, for example, RBILD, DIP, and PLCH, are clearly associated with smoking. Some forms of DPLD may also be 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). Although the recognized etiologies of these disorders are numerous, several groupings are clinically relevant. This article presents a broad overview, with an emphasis on those etiologies that result in pulmonary fibrosis not discussed elsewhere in this series.

The Medscape CME courses Interstitial Lung Disease and Pulmonary Hypertension and High-Resolution Chest Tomography in Idiopathic Pulmonary Fibrosis and Nonspecific Interstitial Pneumonia: Utility and Challenges may be helpful.

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).

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.

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. 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 BernalilloCounty 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 CzechRepublic 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.

• Some diseases are insidious in onset and gradual but unrelenting in progression (eg, similar to IPF), while other diseases are acute in onset but responsive to therapy (eg, COP).
• Diseases that most closely approximate IPF have a similar mortality rate of approximately 50% at 5 years.
• In the United States, mortality attributed to all types of DPLDs is estimated to be 10-15% of that of chronic obstructive pulmonary disease.

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 white persons.

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 BernalilloCounty study estimated a prevalence of 80.9 cases per 100,000 population in men and 67.2 cases per 100,000 population 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.

Clinical

History

The clinical history offered by patients with a DPLD is variable and related to the underlying disease process.

• In general, all manifest primarily with respiratory symptoms that may be erroneously attributed to aging, obesity, deconditioning, or recent respiratory tract infection.
  • Dyspnea is the most frequent symptom, but chronic cough, wheezing, hemoptysis, and chest pain can occur.
  • Digital clubbing is common with some diagnoses (eg, IPF and asbestosis) and may first be noted by the patient. When it develops in a patient with known interstitial lung disease, it is usually indicative of advanced fibrosis. However, it may also herald an underlying bronchogenic carcinoma.
• Clinical history may include the following:
  • Incidental diagnosis may be made from a chest radiograph or abnormal screening spirometry findings obtained for unrelated reasons.
  • Diagnosis may occur as a result of screening for high-risk occupational exposure, such as asbestos.
  • Medical attention may be sought for other manifestations of systemic illness that also affect the lungs.
• Broadly, the manifestations of fibrotic lung disease can be grouped as follows:
  • They may be chronic, insidious, and slowly progressive.
  • They may be subacute, with a resolving, remitting, relapsing, or progressive course.
  • They may be acute, with a fulminant, progressive, remitting, or resolving course.
• Disorders with chronic, insidious, and slowly progressive courses are those that clinically resemble IPF and usually share a common pathology (ie, UIP).
  • Many of the rheumatologic/connective-tissue diseases (eg, rheumatoid arthritis; calcinosis cutis, Raynaud phenomenon, esophageal motility disorder, sclerodactyly, and telangiectasia (CREST) syndrome/progressive systemic scleroderma; systemic lupus erythematosus; mixed connective-tissue disease; the pneumoconioses (eg, asbestosis, silicosis); chronic hypersensitivity pneumonitis; and drug-related pulmonary fibrosis (eg, due to bleomycin) generally fit into this category.
  • Development of clinically apparent lung diseases related to occupational exposures (eg, pneumoconiosis) generally occurs many years after the exposure. Radiation fibrosis often develops months to years after radiation exposure.
  • A lag time of months or years can occur between the use of pulmonary toxic medications and the development of fibrotic disease. The effect can be dose-dependent (eg, bleomycin), although, in other cases, the relationship is less clear.
  • Pulmonary manifestations of rheumatologic/connective-tissue disease may develop in advance of, coincident with, or many years after the onset of articular disease.
  • Pulmonary sarcoidosis, although sometimes acute or subacute in onset, in some cases may present insidiously over time.
• Subacute presentations with a variable course are typified by COP.
  • COP often develops weeks or months after the onset of a flulike  illness.
  • Patients can present to medical attention with dyspnea or exercise intolerance.
  • The course is variable and may either spontaneously remit or progress.
  • The disorder is thought to be very responsive to steroid therapy, although it may recur when steroids are withdrawn or tapered.
  • In some cases, COP may progress to end-stage fibrotic lung disease.
• Disorders with an acute onset are typified by AIP, which is an idiopathic form of severe lung injury.
  • The histopathology is that of adult respiratory distress syndrome with diffuse alveolar damage.
  • Patients present either with no antecedent history of lung disease or as part of an accelerated phase of underlying interstitial disease.
  • Most patients progress rapidly to respiratory failure.
  • Some patients may improve with steroids or other immunosuppressive therapy.

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.
  • Patients frequently are dyspneic, which may be more pronounced with activity and generally is associated with an accompanying tachypnea.
  • Central cyanosis may be present if significant hypoxemia and arterial oxygen desaturation are present.
  • Lung volumes are usually reduced. Fine end-inspiratory pulmonary rales (Velcro rales) are a common finding and may be difficult to distinguish from those auscultated in patients with congestive heart failure. Pulmonary sarcoidosis and other granulomatous disorders are often an exception.
  • Wheezes may be heard and reflect airway involvement, as in sarcoidosis.
  • A pulmonary squawk has been described with HSP.
  • A right-sided gallop (S₃), an accentuated second heart sound (P₂) with fixed or paradoxic splitting, and a right ventricular lift may be present. These indicate cor pulmonale.
  • Digital clubbing may accompany many of these disorders, as previously discussed.
• Disease-specific findings include the following:
  • Generalized lymphadenopathy often occurs with sarcoidosis.
  • Cutaneous and articular findings are associated with rheumatologic disease.
  • Gastrointestinal manifestations occur with inflammatory bowel disease.

Causes

Numerous causes/diagnoses are included among the DPLDs, many of which can be grouped as follows:

• Those that mimic interstitial lung disease in clinical presentation and chest radiographic findings, including the following:
  • Congestive heart failure
  • Atypical pneumonia (including Pneumocystis species)
  • Lymphangitic spread of cancer
• Those associated with environmental or occupational exposures, including the following:
  • Pneumoconioses (a group of occupational lung diseases related to inhalational exposures to inorganic dusts [eg, silicosis, asbestosis, berylliosis, coal worker's pneumoconiosis {black lung}])
  • HSP caused by exposure to protein antigens (eg, farmer's lung, pigeon-breeder's lung, hot-tub lung)
  • Fibrotic lung disease due to exposure to toxic gases, fumes, aerosols, and vapors (eg, silo-filler's disease)
  • Radiation exposure (ionizing radiation, frequently used in medical therapeutics)
• Those associated with rheumatologic/connective-tissue diseases, such as the following:
  • Scleroderma (CREST syndrome/progressive systemic scleroderma)
  • Rheumatoid arthritis
  • Mixed connective-tissue disease
  • Systemic lupus erythematosus
  • The pulmonary-renal syndromes (ie, Wegner or Goodpasture disease) - Often included with this group; however, predominant manifestation is vasculitis rather than fibrosis
• Those related to drug exposure, including the following:
  • Cytotoxic agents (eg, bleomycin, busulfan, methotrexate)
  • Antibiotics (eg, nitrofurantoin, sulfasalazine)
  • Antiarrhythmics (eg, amiodarone, tocainide)
  • Anti-inflammatory medications (eg, gold, penicillamine)
  • Illicit drugs (eg, crack cocaine, heroin)
• Sarcoidosis and other granulomatous diseases (eg, berylliosis)
• Those related to other systemic illnesses, including the following:
  • Hepatitis C
  • Inflammatory bowel disease
  • Acquired immunodeficiency syndrome
• Idiopathic or rare DPLDs, such as the following:
  • COP (idiopathic)
  • PLCH (rare)
  • Eosinophilic pneumonia
• Inherited DPLDs, including the following:
  • Familial IPF or sarcoidosis
  • Tuberous sclerosis
  • Neurofibromatosis
  • Niemann-Pick disease
  • Gaucher disease
  • Hermansky-Pudlak syndrome
• Certain DPLDs, such as RBILD, DIP, and PLCH, are largely or only seen in current or former smokers.

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