Interstitial (Nonidiopathic) Pulmonary Fibrosis 

Updated: Oct 16, 2018
Author: Eleanor M Summerhill, MD, FACP, FCCP; Chief Editor: Zab Mosenifar, MD, FACP, FCCP 

Overview

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.

Frontal chest radiograph demonstrating bilateral r 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 Idiopathic Pulmonary Fibrosis). 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 Imaging in 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 Interstitial Lung Disease Associated With Collagen-Vascular 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.

Etiology

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:

  • Congestive heart failure

  • Atypical pneumonia (including Pneumocystis species)

  • Lymphangitic spread of cancer

DPLDs associated with environmental or occupational exposures include 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)

DPLDs associated with rheumatologic/connective-tissue diseases include 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

DPLDs related to drug exposure include 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)

DPLDs related to other systemic illnesses include the following:

  • Hepatitis C

  • Inflammatory bowel disease

  • Acquired immunodeficiency syndrome

Idiopathic or rare DPLDs include the following:

  • COP (idiopathic)

  • PLCH (rare)

  • Eosinophilic pneumonia

Inherited DPLDs include 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.

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.

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.

Prognosis

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 (COPD).

Patient Education

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

 

Presentation

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. 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.

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:

  • Chronic, insidious, and slowly progressive

  • Subacute, with a resolving, remitting, relapsing, or progressive course

  • 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 Examination

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. 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 the presence of 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.

Complications

Potential complications of DPLDs include the following:

  • Progressive respiratory failure
  • Cor pulmonale
  • Pulmonary embolism
  • Pneumothorax
  • Pneumonia
  • Bronchogenic carcinoma
 

DDx

 

Workup

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. Reticular and/or nodular opacities are the hallmark (see image below).

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

Honeycombing is a late finding and correlates with severe histopathologic findings.[3]  Findings may be normal in 10% of patients with histologically proven disease. Therefore, a complete evaluation including pulmonary function testing and, in some cases, pulmonary exercise testing, should be undertaken in all patients clinically suspected to have underlying interstitial lung disease.

Certain patterns and distributions of abnormality seen on chest radiographs are suggestive of particular diseases. Sarcoid-associated interstitial disease often demonstrates symmetric hilar adenopathy. IPF, asbestosis, and connective-tissue disease–related changes are most often basilar and peripheral in distribution. Radiation fibrosis is restricted to the previous radiation port but also may have upper lung zone predominance, as may sarcoidosis, PLCH, HSP, pneumoconioses, and drug-related DPLD due to gold or nitrofurantoin therapy. Some patterns of abnormality, such as reverse congestive heart failure or a bat-wing pattern, are described with eosinophilic pneumonia.

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]

High-resolution chest CT scan of patient with bila 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:

  • Linear reticular opacities are the most common findings.

  • A ground-glass pattern is less common. It is an opacification that does not obscure underlying lung markings and is thought to be a favorable prognostic finding.

  • Airspace consolidation may be present in eosinophilic pneumonia and COP.

  • The presence of nodules suggests HSP, granulomatous disease (eg, sarcoidosis), PLCH, and RBILD.

  • Large cystic spaces may be seen in PLCH and LAM.

  • Honeycombing is indicative of end-stage disease and carries a poor prognosis.

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. The ratio of forced expiratory volume in 1 second to forced vital capacity is usually normal or increased. Diffusing capacity for carbon monoxide (DLCO) is generally reduced. Static pulmonary compliance is reduced. The restrictive defect may be absent in patients with significant smoking history due to coexistent chronic obstructive pulmonary disease. An obstructive defect may be present in patients with coexistent chronic obstructive pulmonary disease, sarcoidosis, LAM, and eosinophilic granuloma.

Arterial blood gas analysis often reveals an increased alveolar-arterial partial pressure of oxygen gradient and a reduced partial pressure of oxygen. Oxygen desaturation is common. All of these findings may be worsened with exercise.

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.

 

Treatment

Medical Care

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

  • Smoking cessation should be counseled.

  • Good pulmonary hygiene is important.

  • Supplemental oxygen therapy may be useful for any patients who demonstrate significant hypoxemia (oxygen saturation [SaO2] less than or equal to 88% or PaO2< 55 mm Hg while breathing room air either at rest or upon exertion).

  • If inhalational exposures are thought to be the etiology, as in HP and occupational forms of interstitial lung disease, removal from exposure is mandatory.

  • If a toxic medication is suspected, its discontinuation is mandated.

  • Respiratory infections should be promptly treated.

  • Pulmonary rehabilitation may improve exercise tolerance and quality of life (see Pulmonary Rehabilitation).

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.

Pirfenidone and nintedanib are approved by the US Food and Drug Administration for IPF treatment.[15, 16, 17]

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.[18] 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.[19]

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.[20] It is the only interventional modality that has been shown to increase survival time in patients with UIP/IPF.[21, 22] Survival rates worldwide after single lung transplantation are approximately 74% at 1 year, 58% at 3 years, 47% at 5 years, and 24% at 10 years. Survival rates are lower for bilateral lung transplantation. Following transplantation, patients overall report improved quality of life with better physical, social, and general health functioning.

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.

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.[23]

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

 

Medication

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.[24]

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).

Pirfenidone and nintedanib are approved by the US Food and Drug Administration for IPF treatment.[15, 16, 17]

Corticosteroids

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.

Prednisone (Rayos, Deltasone)

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)

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

Immunosuppressants

Class Summary

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

Cyclophosphamide

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)

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)

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

Methotrexate (Otrexup, Rasuvo, Rheumatrex, Trexall)

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.

Anti-inflammatories

Class Summary

Immunosuppressive effects may inhibit cellular division and fibrosis.

Colchicine (Colcrys, Mitigare)

Decreases leukocyte motility and phagocytosis observed in inflammatory responses.

Pulmonary, Tyrosine Kinase Inhibitors

Class Summary

Inhibition of various tyrosine kinases decreases the proliferative activities that lead to fibrosis.

Nintedanib (Ofev)

Nintedanib inhibits multiple tyrosine kinases and targets growth factors, which have been shown to be potentially involved in pulmonary fibrosis (eg, vascular endothelial growth factor receptor [VEGFR], fibroblast growth factor receptor [FGFR], platelet-derived growth factor receptor [PDGF]. It binds competitively to the adenosine triphosphate (ATP)-binding pocket of these receptors and blocks the intracellular signaling, which is crucial for the proliferation, migration, and transformation of fibroblasts, representing essential mechanisms of the idiopathic pulmonary fibrosis pathology.

Transforming Growth Factor Inhibitors

Class Summary

Reduction of fibroblast proliferation may decrease the formation and/or accumulation of fibrotic materials within the lungs.

Pirfenidone (Esbriet)

The precise mechanism by which pirfenidone may work in pulmonary fibrosis has not been established. It inhibits transforming growth factor (TGF)-beta, a chemical mediator that controls many cell functions including proliferation and differentiation. It also inhibits the synthesis of TNF-alpha, a cytokine that is known to have an active role in inflammation.

 

Questions & Answers

Overview

What are diffuse parenchymal lung diseases (DPLDs)?

What is the pathophysiology of diffuse parenchymal lung diseases (DPLDs)?

Which diffuse parenchymal lung diseases (DPLDs) are associated with rheumatologic/connective-tissue diseases?

Which diffuse parenchymal lung diseases (DPLDs) are associated with drug exposure?

Which diffuse parenchymal lung diseases (DPLDs) mimic interstitial lung disease?

Which diffuse parenchymal lung diseases (DPLDs) are associated with environmental or occupational exposures?

Which diffuse parenchymal lung diseases (DPLDs) are associated with systemic illnesses?

What is the incidence of diffuse parenchymal lung diseases (DPLDs) in the US?

What is the global incidence of diffuse parenchymal lung diseases (DPLDs)?

What are the racial predilections of diffuse parenchymal lung diseases (DPLDs)?

How does the incidence of diffuse parenchymal lung diseases (DPLDs) vary by sex?

How does the incidence of diffuse parenchymal lung diseases (DPLDs) vary by age?

What is the prognosis of diffuse parenchymal lung diseases (DPLDs)?

What information about diffuse parenchymal lung diseases (DPLDs) should patients be given?

Presentation

Which clinical history findings are characteristic of diffuse parenchymal lung diseases (DPLDs)?

How are diffuse parenchymal lung diseases (DPLDs) diagnosed?

How are manifestations of diffuse parenchymal lung diseases (DPLDs) categorized?

Which diffuse parenchymal lung diseases (DPLDs) are characterized as chronic, insidious, and slowly progressive?

Which diffuse parenchymal lung diseases (DPLDs) are characterized as subacute?

Which diffuse parenchymal lung diseases (DPLDs) are characterized as acute onset?

Which physical findings are characteristic of diffuse parenchymal lung diseases (DPLDs)?

What are the disease-specific findings of diffuse parenchymal lung diseases (DPLDs)?

What are the potential complications of diffuse parenchymal lung diseases (DPLDs)?

DDX

What are the differential diagnoses for Interstitial (Nonidiopathic) Pulmonary Fibrosis?

Workup

What is the role of lab studies in the diagnosis of diffuse parenchymal lung diseases (DPLDs)?

What is the role of imaging studies in the diagnosis of diffuse parenchymal lung diseases (DPLDs)?

Which findings seen on high-resolution chest CT scanning suggest diffuse parenchymal lung diseases (DPLDs)?

What is the role of pulmonary function testing in the diagnosis of diffuse parenchymal lung diseases (DPLDs)?

What is the role of arterial blood gas analysis in the diagnosis of diffuse parenchymal lung diseases (DPLDs)?

What is the role of pulmonary exercise testing in the diagnosis of diffuse parenchymal lung diseases (DPLDs)?

Which procedures are performed in the diagnosis of diffuse parenchymal lung diseases (DPLDs)?

Which histologic findings are characteristic of diffuse parenchymal lung diseases (DPLDs)?

What are prognostic indicators for diffuse parenchymal lung diseases (DPLDs) staged?

Treatment

What is included in general supportive care for diffuse parenchymal lung diseases (DPLDs)?

What is the role of pharmacologic therapy in the treatment of diffuse parenchymal lung diseases (DPLDs)?

What is the role of surgery in the treatment of diffuse parenchymal lung diseases (DPLDs)?

Which specialist consultations are beneficial for patients with diffuse parenchymal lung diseases (DPLDs)?

Which dietary modifications are beneficial in the treatment of diffuse parenchymal lung diseases (DPLDs)?

Which activity modifications are beneficial in the treatment of diffuse parenchymal lung diseases (DPLDs)?

What should be included in the long-term monitoring of diffuse parenchymal lung diseases (DPLDs)?

Medications

Which medications are used in the treatment of diffuse parenchymal lung diseases (DPLDs)?

Which medications in the drug class Transforming Growth Factor Inhibitors are used in the treatment of Interstitial (Nonidiopathic) Pulmonary Fibrosis?

Which medications in the drug class Pulmonary, Tyrosine Kinase Inhibitors are used in the treatment of Interstitial (Nonidiopathic) Pulmonary Fibrosis?

Which medications in the drug class Anti-inflammatories are used in the treatment of Interstitial (Nonidiopathic) Pulmonary Fibrosis?

Which medications in the drug class Immunosuppressants are used in the treatment of Interstitial (Nonidiopathic) Pulmonary Fibrosis?

Which medications in the drug class Corticosteroids are used in the treatment of Interstitial (Nonidiopathic) Pulmonary Fibrosis?