Interstitial (Nonidiopathic) Pulmonary Fibrosis

Practice Essentials

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 pulmonary fibrosis (IPF) (see Idiopathic Pulmonary Fibrosis). DPLDs can be described by histopathologic features and include the following: usual interstitial pneumonitis (UIP), desquamative interstitial pneumonia (DIP), respiratory bronchiolitis interstitial lung disease (RB-ILD), smoking-related interstitial fibrosis (SRIF), acute interstitial pneumonitis (AIP) (also known as Hamman-Rich syndrome), nonspecific interstitial pneumonia (NSIP), organizing pneumonia (OP) (see Imaging in Bronchiolitis Obliterans Organizing Pneumonia), and lymphocytic interstitial pneumonia (LIP) (see Lymphocytic Interstitial Pneumonia). 

DPLDs can also be grouped based on etiology, which can include occupational/environmental (see Hypersensitivity Pneumonitis), drug, and/or radiation exposure, as well as systemic illness such as connective tissue disease (also known as collagen vascular disease) (see Interstitial Lung Disease Associated With Collagen-Vascular Disease). Other categories of DPLDs includes granulomatous forms, such as sarcoidosis (see Sarcoidosis). Finally, several rare forms of DPLDs exist, including pulmonary Langerhans cell histiocytosis (PLCH) (see Eosinophilic Granuloma (Histiocytosis X)), lymphangioleiomyomatosis (LAM) (which can be sporadic or associated with tuberous sclerosis) (see Lymphangioleiomyomatosis), and pulmonary fibrosis associated with Hermansky-Pudlak syndrome. Some of these disorders are categorized as smoking-related lung diseases, including DIP, RB-ILD, SRIF, and PLCH.

This article presents a broad overview on non-IPF DPLDs with an emphasis on those etiologies that result in pulmonary fibrosis not discussed elsewhere in this series. 

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Pathophysiology

A common pathophysiology has been postulated for these disorders. Although the initial insult or trigger varies among different etiologies, it is thought that later phases share a similar pathophysiology, with an exaggerated inflammatory response, leading to fibroblast proliferation and fibrotic tissue remodeling.^[1]  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).^[2]

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, RB-ILD, AIP, NSIP, HP, and OP are most common and are focused in the alveolar, lobular, and lobar septa, impacting alveoli, small airways, and pulmonary vasculature. 

Genetics

There is published evidence for a genetic basis for a number of DPLDs, including IPF, connective tissue disease (CTD)-associated ILD and HP.  The most studied genetic variant associated with DPLDs is a mutated MUC5B, which encodes mucin 5B. It has been associated with the development of both familial pulmonary fibrosis, IPF, and patients with rheumatoid arthritis-associated ILD.^[3]  The MUC5B mutation appears to be more associated with the development of UIP pattern than others and also is present more frequently in patients that develop HP than in the general population.^{[4]  [5]}

In addition, several mutations of genes associated with telomerase have been implicated, including TERT, TERC, and RTEL1. It is proposed that pulmonary fibrosis in patients with short telomeres is provoked by a loss of alveolar epithelial cells, resulting in aberrant epithelial cell repair.^[6]  Mutations of surfactant protein C (SPC) have also been associated with ILD in both adults and children. Although this gene mutation is thought to be familial, de novo mutations are frequent in children.^[5]

Investigation of these and other genetic contributors to the pathogenesis of DPLDs is ongoing and in particular may provide further insight into prognosis and therapeutic targets. 

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Etiology

The causes of DPLDs are varied and numerous, many of which can be grouped as shown below.

DPLDs associated with environmental, occupational, or iatrogenic causes include the following:

• ​Pneumoconioses - a group of occupational lung diseases related to inhalational exposures to inorganic dusts (e.g., silicosis, asbestosis, berylliosis, coal worker's pneumoconiosis (black lung disease)) 
• HP caused by exposure to protein antigens (e.g., farmer's lung, pigeon-breeder's lung, hot-tub lung) 
• Interstitial lung disease due to exposure to toxic gases, fumes, aerosols, and vapors (e.g., silo-filler's disease) 
• Radiation exposure (ionizing radiation, frequently used in medical therapeutics) 
• Sarcoidosis and other granulomatous diseases (e.g., berylliosis) 

DPLDs associated with rheumatologic/connective-tissue diseases are found in the following diseases: 

• Systemic sclerosis (SSc) 
• Rheumatoid arthritis (RA)  
• Mixed connective-tissue disease (MCTD) 
• Systemic lupus erythematosus (SLE) 
• Myositis (dermatomyositis, polymyositis, anti-synthetase syndrome) 
• Interstitial pneumonia with autoimmune features (IPAF) - a research definition of ILD among patients who exhibit features of autoimmune or rheumatologic disease but do not meet specific criteria 
• Pulmonary-renal syndromes and vasculitides (i.e. Granulomatosis with polyangiitis (GPA, also known as Wegener’s Granulomatosis), Eosinophilic granulomatosis with polyangiitis (EGPA, also known as Churg-Strauss syndrome), or Goodpasture disease) - often included with this group; the predominant manifestation is inflammatory lesiosn of vasculitis (e.g. alveolar hemorrhage, nodules, cavitary lesions), although case series of fibrotic ILD associated with ANCA-associated vasculitis are increasingly reported. 

DPLDs related to drug exposure can be caused by: 

• Cytotoxic agents (e.g., bleomycin, busulfan, methotrexate) 
• Antibiotics (e.g., nitrofurantoin, sulfasalazine) 
• Antiarrhythmics (e.g.,, amiodarone, tocainide) 
• Anti-inflammatory medications (e.g., gold, penicillamine) 
• Illicit drugs (e.g., crack cocaine, heroin) 
• Immunotherapy (e.g. checkpoint inhibitors such as nivolumab, pembrolizumab)
• Other immunosuppresants (e.g. infliximab, leflunomide)

DPLDs related to other systemic illnesses can occur with: 

• Hepatitis C 
• Inflammatory bowel disease 
• Human immunodeficiency virus (HIV)/Acquired immunodeficiency syndrome 

Other rare DPLDs include the following: 

• Cryptogenic organizing pneumonia (COP)
• Pulmonary Langerhans cell histiocytosis (PLCH) (rare) 
• Eosinophilic pneumonia 
• Sporadic lymphangioleiomyomatosis (LAM) 

Inherited diseases that can present with DPLDs include the following: 

• Familial pulmonary fibrosis
• Tuberous sclerosis complex-associated LAM
• Birt-Hogg-Dube syndrome 
• Neurofibromatosis 
• Niemann-Pick disease 
• Gaucher disease 
• Hermansky-Pudlak syndrome 
• Dyskeratosis congenita 

Certain DPLDs, such as RB-ILD, DIP, SRIF, and PLCH are considered smoking-related.

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Epidemiology

Frequency

As a group, diffuse interstitial diseases of the lung are uncommon. Of patients referred to a pulmonary disease specialist, an estimated 10-15% have a DPLD. 

In the United States, the 2021 Global Burden of Disease (GBD) study estimated over 650,000 cases, with an age-standardized prevalence varying from 101 to 156 cases per 100,000 people among states. ^[7]

Race

One multicenter study that included 5275 ILD patients in the United States showed a racial and ethnic group breakdown of 83.2% White, 10.2% Black, and 6.7% Hispanic patients.  The etiology of ILD varied among racial and ethnic groups, with IPF having the highest prevalence in White patients, HP having the highest prevalence in Hispanic patients, and CTD-ILD having the highest prevalence in Black patients.  Black patients were more likely than Hispanic and White patients to be hospitalized, undergo lung transplant, and die at a younger age. ^[8]

Sex

Evaluation of data from the GBD study showed a higher prevalence of ILD among females, with age-adjusted prevalance of 131.4 per 100,000, compared to 121.3 per 100,000 in males in the United States. ^[7]

Several DPLDs show sex-related differences in frequency. In general, IPF affects men more than women (at a ratio of 1.5:1), while LAM and pulmonary tuberous sclerosis almost exclusively affect women. Women are much more likely to develop CTD-ILD than men and thus are more likely to experience pulmonary manifestations of those diseases. However, when affected, men with certain rheumatologic diseases (e.g. RA) are more likely to develop pulmonary manifestations than women. The pneumoconioses (e.g., silicosis) are much more common in men than in women, which may be due to 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. 

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Prognosis

The natural history of DPLD varies based on etiology and histologic and imaging pattern, and among individuals with the same diagnosis. Some diseases are insidious in onset and gradual but unrelenting in progression, while other diseases are acute in onset but responsive to therapy. 

A typical UIP pattern on imaging or histology is associated with progressive disease and poor prognosis (such as in IPF, which has a mean survival of 2-5 years from diagnosis).  Even among different etiologies of ILD that show a typical UIP pattern, there is prognostic value of this pattern compared with other histologic or radiographic patterns.  

CTD-ILD has a significantly higher mortality than CTD without ILD.  Among different CTDs, mortality is similar, with the exception of SSc-ILD, which has poorer long-term outcomes. ^[9]  The progression of CTD-ILD can vary widely among patients, with some showing stabilization of disease with treatment, while others can have continually progressive disease.  

Post-viral fibrotic disease, including disease caused by SARS-CoV-2, has an unclear long-term prognosis, but disease seems to stabilize with resolution of the virus.^[10]

In HP, elimination of the causative antigen and systemic steroids can typically stop progression of disease, and sometimes reverse disease process.  The causative antigen is often not identified in HP, but when it is identified and removed, patients have better outcomes. ^[11]

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Patient Education

Educate patients about the nature of the specific diagnosis and about potential toxicities of prescribed medications.  In addition, many organizations, such as the Pulmonary Fibrosis Foundation, have patient-centered resources to educate patients and caregivers on their diagnosis. 

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History

The clinical history offered by patients with  DPLD is variable and related to the underlying disease process. Many patients with DPLD may experience acute exacerbations of the disease with subsequent decline in lung function. 

In general, all patients manifest primarily with worsening respiratory symptoms. Initially, these symptoms that may mistakenly be 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, an indicator of longstanding chronic hypoxemia, may first be noted by the patient. When it develops in a patient with known interstitial lung disease, it can be indicative of advanced fibrosis or chronically untreated hypoxemia.  

Incidental diagnosis may be made from a chest radiograph or abnormal screening spirometry . 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 courses 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, UIP. Many of the rheumatologic/connective-tissue diseases (e.g., RA, SSc, myositis, SLE, MCTD), pneumoconioses (e.g., asbestosis, silicosis), chronic hypersensitivity pneumonitis, and drug-related pulmonary fibrosis (e.g., bleomycin) may fit into this category as well.  

Development of clinically apparent lung diseases related to occupational exposures 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, such as in bleomycin toxicity, 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 OP or other DPLDs with variable progression, such as CTD-ILDs. COP often develops weeks or months after the onset of a flu-like 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, OP may progress to end-stage fibrotic lung disease. CTD-ILDs, themselves a broad category of DPLDs, will present with variable courses depending on the activity and control of the associated underlying 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. Acute eosinophilic pneumonia (AEP) also presents abruptly. Rapidly-progressive ILD can also be seen in association with certain CTD-ILDs, such as with anti-melanoma differentiation-associated gene 5 (MDA5) positivity^[12] . Most patients progress rapidly to respiratory failure. Some patients may improve with steroids or other immunosuppressive therapy. 

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Physical Examination

Varied etiologies make generalization of physical examination findings difficult for patients with DPLD.  

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, depending on their degree of fibrotic sequelae, are often an exception and may not manifest these rales.) Wheezes may be heard and reflect small airway involvement, as in sarcoidosis, HP, or small-airways disease seen in CTD-ILDs. A pulmonary squawk has been described with HP. If cor pulmonale or pulmonary hypertension is also present, a right-sided gallop (S3), an accentuated second heart sound (P2) with fixed or paradoxic splitting, and a right ventricular lift may be present. Digital clubbing may accompany many of these disorders, as previously discussed. 

Disease-specific findings include the following: 

• Generalized lymphadenopathy may occur with sarcoidosis. 
• Cutaneous and articular findings are associated with rheumatologic disease (e.g., Gottron’s papules or heliotrope rash with dermatomyositis, Raynaud phenomenon seen in SSc) 
• Erythema nodosum or lupus pernio seen in sarcoidosis.
• Proximal muscle weakness or myalgias and mechanic’s hands can be associated with myositis 
• Gastrointestinal manifestations occur with inflammatory bowel disease. 
• Fibrofolliculomas can be seen in Birt-Hogg-Dubé syndrome 

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Complications

Potential complications of DPLDs include the following: 

• Progressive respiratory failure, which may warrant hospitalization, supplemental oxygen, and/or mechanical ventilation 
• Pulmonary hypertension, right heart failure, and cor pulmonale 
• Pulmonary embolism 
• Pneumothorax, particularly among cystic lung diseases and more peripherally distributed DPLDs 
• Pneumonia and/or atypical infections due to abnormal lung architecture 
• Malignant neoplasms

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Approach Considerations

Consultation with Rheumatology, Dermatology, Nephrology, and Neurology may often be indicated depending on the presence of concomitant extrapulmonary manifestations of systemic disease.

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Laboratory Studies

Routine blood analysis and serum chemistries may be supportive of an underlying etiology, though findings generally are nonspecific. Lymphopenia may be seen in autoimmune disorders, sarcoidosis, and HIV-associated ILD. Elevated liver biochemical testing may be seen among patients with myositis or hepatic sarcoidosis. Acute kidney injury or unexplained chronic kidney disease may be seen in ANCA vasculitis, along with hematuria. 

Serologic testing for rheumatologic disease or vasculitis (eg, antinuclear antibodies, rheumatoid factor, erythrocyte sedimentation rate, C-reactive protein, anti-cyclic citrullinated peptide antibody (anti-CCP), anti-topoisomerase I (Scl 70) antibody, RNA polymerase III antibody, antineutrophil cytoplasmic antibodies (ANCA), anti-glomerular basement membrane (anti-GBM)) may be appropriate in specific cases, as may serologic testing for autoantibodies associated with myositis (e.g. SSA-kD, U1, RNP, Smith) or specific for myositis (e.g. TIF-1, NXP-2, Jo-1, EJ/OJ, MDA5). Serum precipitins for common hypersensitivity antigens maybe also be appropriate. ACE testing is not very specific or sensitive but may offer a confirmatory clue to the diagnosis of sarcoidosis, while soluble interleukin-2 receptor, chitotriosidase, and lysozyme may be used as a marker of disease activity and response to therapy. 

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Imaging Studies

Chest radiography findings are frequently abnormal in patients with more advanced fibrotic lung disease. Reticular and/or nodular opacities are the hallmark (see image below).

High-resolution chest computed tomography (CT) scanning is more sensitive than chest radiography is arguably essential to the diagnosis and management of DPLDs. ^{[13, 14]}

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

Honeycombing is a late finding indicating fibrosis and correlates with severe histopathologic findings. ^[15]  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 CTD-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, HP, 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.

Prone and expiratory imaging techniques are also helpful for diagnosis ILD.  Prone imaging can aid in excluding dependent changes, and expiratory imaging can distinguish air trapping from other causes of mosaic attenuation. ^[16]  

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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 scan may be characterized into specific patterns: 

UIP  

• Traction bronchiectasis/bronchiolectasis, honeycombing 
• Subpleural and basilar prednominance;  
• Can be further characterized as definite, probable, or indeterminate UIP ^[17]
• Most associated with IPF, but can be seen in CTD-ILD

​

NSIP  

• Ground glass opacities, often as predominant finding 
• Subpleural sparing may be present and is specific for NSIP
• Reticular and linear opacities 
• Bilateral lower lobe predominance and symmetrical
• Can be associated with CTD-ILD, drug-induced ILD, HP 
• Traction bronchiectasis and coarse reticulation can be associated with fibrotic NSIP 

​

HP 

• Centrilobular nodularity 
• Air trapping on exhalation sequences, mosaic attenuation on inspiratory sequences
• Diffuse or upper lobe distribution
• Further characterized as typical, compatible with, or indeterminate for HP ^[18]  
• Three-density sign, traction bronchiectasis, and coarse reticulation can be associated with fibrotic HP

​

Combined pulmonary fibrosis and emphysema (CPFE) 

• Often presents as emphysema occurring with a UIP pattern, though other ILD patterns may be present
• Emphysema can complicate fibrosis diagnosis, particularly in differentiation between honeycombing and emphysema

Other features that can aid with diagnosis and management include the following: 

• Airspace consolidation may be present in eosinophilic pneumonia and COP. 
• The presence of nodules, depending on distribution pattern, can suggest HP, granulomatous disease (eg, sarcoidosis), PLCH, and RBILD. 
• Large cystic spaces may be seen in PLCH, BHD, LAM, and LIP. 
• Honeycombing is indicative of advanced fibrosis and carries a poor prognosis. 

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Other Tests

Pulmonary function testing (PFT) may demonstrate reduced lung volumes with testing of total lung capacity (TLC), forced expiratory volume in 1 second (FEV1), and forced vital capacity (FVC). The FEV1 to FVC ratio 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 (COPD). An obstructive defect may be present in patients with coexistent COPD, sarcoidosis, LAM, and PLCH. 

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. 

PFT and the 6-minute walk test (6MWT) have demonstrated prognostic utility in ILD.  In one study of 73 patients with ILD ^[19] , change in SpO2, Borg dyspnea score, and 6-minute walk distance (6MWD) correlated with PFT measures, including forced expiratory volume in one second (FEV1), diffusion capacity for carbon monoxide (DLCO), and total lung capacity (TLC). In addition, the Borg dyspnea score and change in SpO2 were correlated with the amount of normal lung as measured by quantitative CT scan. 

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Procedures

The role of lung biopsy remains controversial, with expert opinion weighing in on both sides. ^{[13, 14, 20]}  Consensus appears to be building on the side of forgoing biopsy when the typical clinical and high-resolution CT scan features of a specific disease process are present. 

A multidisciplinary discussion is an essential part of diagnosis of ILD and deciding whether biopsy is necessary.  This discussion often includes pulmonologists, radiologists, pathologists, thoracic surgeons, and rheumatologists.  Multidisciplinary discussions can improve diagnosis by involving more specialties in the discussion, minimizing the effects of interobserver variability, and potentially avoiding invasive procedures. ^[21]

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

Surgical lung biopsy is regarded as the gold standard diagnostic test, however the most recent guidelines suggest that transbronchial cryobiopsy may be an acceptable alternative, in centers with sufficient experience performing the procedure. A balance of risks of these procedures must be weighed with the likelihood of obtaining a diagnostic result. ^[22]

Bronchiolar lavage (BAL) may be helpful in differentiating some types of DPLD from others. Bronchiolar lavage is useful in evaluating the possibility of infection or malignancy. Cell count and differential analysis can differentiate DPLDs that have particular associations with lymphocyte-, neutrophilic-, eosinophilic predominance. For example, IPF is associated with neutrophil predominance, while HP is associated with lymphocyte predominance. ^{[23, 24]} Special stains can provide diagnostic value, as in the case of Periodic acid Schiff stain positivity for pulmonary alveolar proteinosis (PAP). 

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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 ^[25]  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.  In addition, other pathologic patterns may be found, such as those consistent with OP, granulomatous lung disease, HP, giant cell pneumonitis (hard-metal pneumoconiosis), eosinophilic pneumonia, and LIP. 

Interpretation of histopathologic findings may be difficult, even in experienced hands, and disagreement may occur even among expert pathologists. ^[26]  In 2005, a 52% rate of disagreement between local general pathologists and "expert" pathologists was documented in a retrospective analysis. ^[27]  This highlights the value of a multidisciplinary approach to the classification and diagnosis of DPLDs.

Among smoking related lung diseases, definition and classification present ongoing challenges, particularly the variation in histopathologic definition of desquamative interstitial pneumonia (DIP). This is due discrepancies in the pathological concepts underlying smoking related lung diseases and their nomenclature. For example, DIP describes a desquamating process, though contemporary understanding of the disease is not one of desquamation but rather intraalveolar aggregation of macrophages.^[28]

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Medical Care

General supportive measures include the following: 

• Smoking cessation 
• Airway clearance measures and pulmonary hygiene can provide symptomatic relief, particularly when concomitant chronic productive cough is present.
• Supplemental oxygen may improve exercise tolerance in patients with dyspnea.  However, there is very limited data supporting improved outcomes and mortality in patients with DPLD.^[29]
• Avoidance or removal of offending agents, drugs, or exposures may bring improvement or resolution of symptoms. Feasible maintenance of good air quality can be advised (e.g. air purifiers, avoidance of harmful air pollution). 
• Prevention of respiratory infections with regular updating of immunizations
• Prompt treatment of acute pulmonary infections
• Pulmonary rehabilitation may improve exercise tolerance and quality of life (see Pulmonary Rehabilitation). 

The choice of pharmacologic therapy is guided by the underlying etiology of DPLD.

DPLDs such as most CTDs-ILD HP, COP, sarcoidosis, and eosinophilic pneumonia are often steroid-responsive and initially treated with steroids. Transition to steroid-sparing agents can be initiated after evidence of steroid-responsiveness.  One exception is SSc-ILD, for which steroids are not recommended due to the risk of scleroderma renal crisis.  Because scleroderma renal crisis can sometimes occur in MCTD-ILD, steroids are often avoided in these patients as well.^[30]  

For patients with CTD-ILD aside from SSc-ILD, a recent ACR/CHEST guideline recommends azathioprine, mycophenolate, rituximab, and cyclophosphamide as initial steroid-sparing treatments, with consideration of tocilizumab in select conditions (e.g. MCTD) if progression is seen despite initial therapies. ^[30] Cyclophosphamide, once a first-line therapy, is now usually reserved for refractory or rapidly progressive disease due to higher rates of intolerance and adverse effects and current familiarity with similarly efficacious and more tolerable agents. 

For SSc-ILD specifically, tocilizumab has been shown to slow progress of disease and can be considered as a first-line agent.  A decreased rate of decline of FVC compared to placebo was seen in both the faSSCinate and focuSSed trials.^[30]  

Pirfenidone and nintedanib are FDA-approved antifibrotic agents for the treatment of IPF; both have been shown to slow the rate of FVC decline in patients with IPF. In patients who develop a progressive fibrosing phenotype, termed progressive pulmonary fibrosis (PPF), nintedanib has been FDA-approved and shown to reduce the rate of FVC decline among these patients. PPF is defined as an ILD of any etiology other than IPF that displays two of the three following characteristics:  (1) worsening respiratory symptoms; (2) decline in FVC of ≥5% or DLCO of ≥10% over 1 year; (3) radiographic evidence of disease progression.^[31]  In the RELIEF trial^[32] , pirfenidone was shown to decrease the rate of FVC decline, but due to premature study termination, the results should be interpreted with caution. Current ATS guidelines ^[22] cite insufficient evidence to make a recommendation on the use of pirfenidone in PPF. 

One important consideration in treatment of IPF is to avoid the use of systemic steroids.  In the PANTHER trial^[33] , the combination of prednisone, azathioprine, and N-acetylcysteine in patients with IPF led to higher rates in hospitalization and death in patient compared with placebo. 

The FIBRONEER-ILD and FIBRONEER-IPF trials are two studies currently in progress to evaluate the use of nerandomilast, a phosphodiesterase 4B (PDE-4B) inhibitor, to slow the progress of fibrosis in PPF and IPF, respectively.  This drug is being evaluated in phase III currently, and has not been approved by the FDA, as of 11/2024. 

The TETON and TETON-PPF trials are also ongoing to evaluate treatment with inhaled trepostinil, a prostacyclin, to slow progression in IPF and PPF, respectively.  These studies are ongoing, and inhaled prostacyclin for the treatment of IPF or PPF has not been approved by the FDA, as of 11/2024.  

Many patients with DPLD may be treated in community settings by pulmonologists with experience managing these conditions. Transfer to a tertiary care center is indicated when disease is progressive or refractory to treatment or there is uncertainty regarding the diagnosis or management.

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Surgical Care

Lung transplantation is a treatment option for selected patients with advanced or progressive disease refractory to medical therapy who may be expected to have increased post-transplant survival compared to supportive therapy without transplant.^[34]  It is the only interventional modality that has been shown to improve survival in patients with UIP/IPF.^{[35, 36]}   Double lung transplantations are associated with an improved survival in patients with IPF with a mean survival of 65.2 months compared to 50.4 months in IPF patients receiving single lung transplantations.^[37] However, it should be noted that patients receiving double lung transplants were noted in one study to have longer hospitalizations post-transplant, higher reintubation rates, and more postoperative dialysis than patients receiving single lung transplantation.^[38] Following transplantation, patients overall report improved quality of life with better physical, social, and general health functioning. 

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Consultations

Consider consultation with a pulmonary or occupational disease specialist for patients with suspected DPLD. In particular, classification of ILD within a multidisciplinary discussion that includes pulmonologists, radiologists, and potentially pathologists and rheumatologists, is currently considered the gold standard.^[21]

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Activity

Exercise and pulmonary rehabilitation may confer benefits on functional status. However, these activities generally have no effect on disease progression. 

High altitude activities, such as travel by air or mountain hiking, may carry higher risk of hypoxemia. Anticipatory guidance and testing for oxygen needs (such as ambulatory oximetry or high altitude testing where available) can be helpful. 

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Complications

Patients with ILD can have hypoxic respiratory failure, either in the acute setting due to an exacerbation, or more chronically, requiring supplemental oxygen. This can also lead to the need for mechanical ventilation. In addition, WHO Group 3 pulmonary hypertension due to lung parenchymal disease can occur, leading to right heart dysfunction and failure.  Pneumothorax can occur, particularly in patients with cystic or peripherally distributed disease.  Atypical infections can also complicate the course of ILD and occur due to distorted lung architecture.  Finally, there is a higher risk of malignancy in patients with some types of DPLD due to the underlying disease or exposure (e.g. LIP, dermatomyositis, asbestosis, smoking-related lung diseases).

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Prevention

Some types of ILD can be prevented or mitigated. This includes smoking-related ILD.  In addition, HP and occupational lung diseases, including pneumoconioses, can be prevented by adhering to workplace respiratory precautions or avoiding the offending agent. Finally, timely diagnosis and treatment of diseases that put patients at risk for ILD, such as CTD, can help to slow or prevent disease progression.

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Long-Term Monitoring

Patients with DPLD should be evaluated initially 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 arguably essential to making the initial diagnosis and subsequent assessments of disease progression and/or response to therapy. 

The most recent guidelines for patients with CTD-ILD recommend monitoring with HRCT, PFTs, and ambulatory pulse oximetry. 6MWT has not been shown to be an effective test to monitor disease in these patients due to confounding disease processes that can affect the results.^[39]

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, and close monitoring of lung parenchymal or airway abnormalities can be crucial to early detection.^[40]

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

Patients who demonstrate more stable disease over time can increase the intervals between visits. Patients on active therapy or with evolving disease generally should be followed closely, every 3 months.

• References

Medication Summary

Medications are best used for specific diagnoses. However, corticosteroids, cytotoxic agents, and antifibrotics have been used with varying success in some forms of DPLD.^[41]

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.  Smoking-related lung diseases generally respond to smoking cessation. 

Pirfenidone and nintedanib are approved by the US Food and Drug Administration for IPF treatment.^{[42, 43, 44]}

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

Treatment guidelines exist for specific types of DPLD, including IPF, CTD-ILD, and HP. 

• References

Prednisone (Rayos, Deltasone)

• Dosing, Interactions, etc.

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.

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Prednisolone (FloPred, Millipred, Millipred DP, Prelone)

• Dosing, Interactions, etc.

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

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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.

• References

Azathioprine (Imuran, Azasan)

• Dosing, Interactions, etc.

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.

• References

Mycophenolate (CellCept, MMF, Myfortic)

• Dosing, Interactions, etc.

Clinical Context:  Inosine-5'-monophosphate dehydrogenarse inhibitor; halts proliferation of T and B lymphocytes. 

• References

Rituximab (Rituxan, Riabni, Rituximab-abbs)

• Dosing, Interactions, etc.

Clinical Context:  Anti-CD-20 monoclonal antibody, depletes B lymphocytes.

• References

Tocilizumab (Actemra, Tocilizumab-aazg, Tocilizumab-bavi)

• Dosing, Interactions, etc.

Clinical Context:  Anti-IL-6 monoclonal antibody. 

• References

Cyclophosphamide

• Dosing, Interactions, etc.

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.

• References

Cyclosporine (Gengraf, Neoral, Sandimmune)

• Dosing, Interactions, etc.

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

• References

Methotrexate (Otrexup, Rasuvo, Rheumatrex, Trexall)

• Dosing, Interactions, etc.

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.

• References

Class Summary

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

• References

Nintedanib (Ofev)

• Dosing, Interactions, etc.

Clinical Context:  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.

• References

Pirfenidone (Esbriet)

• Dosing, Interactions, etc.

Clinical Context:  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.

• References

Colchicine (Colcrys, Mitigare)

• Dosing, Interactions, etc.

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

• References

Class Summary

Immunosuppressive effects may inhibit cellular division and fibrosis.

• References