Overview of the management of adults with interstitial lung disease

INTRODUCTION — The diffuse parenchymal lung diseases, often collectively referred to as interstitial lung diseases (ILDs), are a heterogeneous group of disorders that are classified together because of similar clinical, radiologic, physiologic, or pathologic manifestations (algorithm 1) [1-5]. The descriptive term "interstitial" reflects the pathologic appearance that the abnormality begins in the interstitium; however, most of these disorders are also associated with extensive alteration of alveolar and airway architecture.

Although individual treatment regimens vary across these diseases, there are common approaches to many aspects of care, including disease monitoring, evaluation of worsening pulmonary symptoms and comorbidities, and referral for clinical trial participation, lung transplantation, and hospice. These common aspects of care have led to the development of ILD specialty clinics in many tertiary care centers. An overview of shared management strategies for patients with ILD will be reviewed here.

The approach to clinical evaluation and diagnostic work-up of ILD may be found elsewhere:

●(See "Approach to the adult with interstitial lung disease: Clinical evaluation".)

●(See "Approach to the adult with interstitial lung disease: Diagnostic testing".)

●(See "Role of bronchoalveolar lavage in diagnosis of interstitial lung disease".)

●(See "Role of lung biopsy in the diagnosis of interstitial lung disease".)

●(See "Interpretation of lung biopsy results in interstitial lung disease".)

Details regarding specific treatment of individual ILDs are likewise described separately:

●(See "Treatment of idiopathic pulmonary fibrosis".)

●(See "Treatment and prognosis of nonspecific interstitial pneumonia".)

●(See "Hypersensitivity pneumonitis (extrinsic allergic alveolitis): Treatment, prognosis, and prevention".)

●(See "Cryptogenic organizing pneumonia".)

●(See "Respiratory bronchiolitis-associated interstitial lung disease".)

●(See "Acute interstitial pneumonia (Hamman-Rich syndrome)".)

●(See "Treatment of pulmonary sarcoidosis: Initial approach".)

●(See "Interstitial lung disease in rheumatoid arthritis".)

●(See "Treatment and prognosis of interstitial lung disease in systemic sclerosis (scleroderma)".)

●(See "Interstitial lung disease associated with Sjögren's disease: Management and prognosis".)

●(See "Treatment and prognosis of interstitial lung disease in systemic sclerosis (scleroderma)".)

●(See "Interstitial lung disease in dermatomyositis and polymyositis: Treatment".)

●(See "Sporadic lymphangioleiomyomatosis: Treatment and prognosis".)

●(See "Pulmonary Langerhans cell histiocytosis".)

ONGOING MONITORING OF PATIENTS WITH ILD — Following diagnosis, clinical follow-up of patients with ILD involves reassessment of pulmonary symptoms, evaluation of extrapulmonary manifestations of disease, assessment of common comorbidities, and managing complications and toxicities of pharmacologic treatments. Based on this information, further evaluation with pulmonary function testing, chest imaging, and other work-up are appropriate.

History and physical examination

●Pulmonary symptoms and signs – We ask patients about common symptoms in ILD, including dyspnea, cough, sputum production, hemoptysis, and exertional tolerance. The optimal method of assessment has not been determined, but in clinical practice dyspnea is typically assessed by a qualitative history or simple measurements, such as the modified Medical Research Council breathlessness scale (calculator 1) [6]. Frequent reassessment of physical activity limitation can prevent underdiagnosis of occult disease progression. On examination, assessment of respiratory rate, pulmonary adventitious sounds, and oxygenation (resting and exertional) may be helpful.

●Recent ILD exacerbation or other hospitalization – ILD patients are at risk of acute exacerbations of their underlying ILD. ILD patients often fare poorly after hospitalization and may require pulmonary rehabilitation to regain stamina. Hospitalizations in ILD patients for respiratory failure are associated with one-year mortality of more than 50 percent [7,8]. Additionally, exacerbations of ILD or other serious disease frequently result in the initiation of supplemental oxygen therapy and consideration for new therapies or alteration of chronic therapies, including dosing of anti-inflammatory medications for which short-interval follow-up is essential. (See 'Patients with new ground-glass changes' below and "Acute exacerbations of idiopathic pulmonary fibrosis".)

●Nonpulmonary symptoms – Systemic and nonpulmonary symptoms may indicate disease activity that is otherwise clinically silent. Patients with ILD who develop fevers, chills, or weight loss may have developed an underlying infection or may have an exacerbation of their underlying ILD. We also surveil for extrapulmonary manifestations of connective tissue diseases or sarcoidosis in all patients with ILD, as ILD may predate the development of extrapulmonary disease in a significant minority of patients (table 1). (See 'Other testing' below and "Overview of extrapulmonary manifestations of sarcoidosis" and "Clinical manifestations and diagnosis of sarcoidosis", section on 'Typical presentations' and "Approach to the adult with interstitial lung disease: Clinical evaluation", section on 'Extrapulmonary findings of systemic disease' and "Causes, clinical manifestations, evaluation, and diagnosis of nonspecific interstitial pneumonia", section on 'Interstitial pneumonia with autoimmune features'.)

Patients with ILD also tolerate both reflux aspiration and dysphagia poorly. Poor sleep quality and daytime sleepiness may be evidence of obstructive sleep apnea, which can worsen nocturnal hypoxemia, pulmonary hypertension (PH), and reflux aspiration. Clinical evaluation for symptoms and signs of these disorders is appropriate. (See 'Comorbidity identification and management' below.)

●Drug side effects and toxicities – Many patients with ILD require ongoing therapy with systemic glucocorticoids, alternative immunosuppressants, and/or antifibrotic medications. While effective in the treatment of certain ILDs, these therapies carry significant risks of side effects and toxicities that require monitoring.

•Systemic glucocorticoids – Numerous adverse effects are associated with chronic systemic glucocorticoid therapy, including increased risk of diabetes mellitus, skin thinning, weight gain, adrenal suppression, glaucoma, osteoporosis, insomnia, other neuropsychiatric effects, and increased risk of infections (table 2). Patients on more than 20 mg of prednisone or the equivalent should receive prophylaxis for the prevention of Pneumocystis jiroveci pneumonia. Additional information regarding the identification and prevention of glucocorticoid adverse effects can be found elsewhere. (See "Major adverse effects of systemic glucocorticoids" and "Treatment and prevention of Pneumocystis pneumonia in patients without HIV", section on 'Prophylaxis'.)

•Other immunosuppressants – Other immunosuppressant medications commonly used in the treatment of ILD patients include azathioprine, mycophenolate, rituximab, and tocilizumab. Azathioprine requires careful monitoring and dosing to watch for cytopenia and nephrotoxicity. Mycophenolate is teratogenic and may lead to cytopenia and gastrointestinal side effects. Rituximab dramatically reduces antibody levels, which can interfere with routine vaccination efforts against respiratory diseases. Cyclophosphamide use is rare due to its toxicity and is mainly reserved for severe or refractory cases. It also carries a significant risk of teratogenicity, increases the likelihood of developing malignancies, and can lead to cytopenia and nephrotoxicity. It is important to note that all of these medications increase the risk of both opportunistic and common respiratory infections. (See "General toxicity of cyclophosphamide in rheumatic diseases" and "Pharmacology and side effects of azathioprine when used in rheumatic diseases" and "Mycophenolate: Overview of use and adverse effects in the treatment of rheumatic diseases" and "Rituximab: Principles of use and adverse effects in rheumatoid arthritis".)

•Antifibrotics – For patients being considered for or who are currently using antifibrotic therapy, monitoring of liver and kidney function is appropriate.

-Nintedanib – For those receiving nintedanib, liver function test (LFT) monitoring is required before initiation, monthly for three months after initiation, and every three months thereafter. Nintedanib has not been explicitly studied in those with a creatinine clearance (CrCl) <30 mL/min; we use it in patients with kidney impairment, but there have been reports of proteinuria and other kidney toxicity with nintedanib and other vascular endothelial growth factor inhibitors [9]. We also monitor drug side effects (most frequently diarrhea, nausea, and vomiting), which may require dose reduction, temporary dose interruption, or discontinuation. Antidiarrheal medications may be helpful in some cases. (See "Treatment of idiopathic pulmonary fibrosis", section on 'Dose and administration'.)

-Pirfenidone – For those receiving pirfenidone, LFTs should be monitored monthly for the first six months after initiation, and then every three months. Severe drug-induced liver disease has been reported, but LFT elevations are usually reversible with dose modification or drug discontinuation. Kidney impairment should be assessed prior to initiation of pirfenidone, and dose reduction or slower escalation should be performed in the setting of moderately impaired function (estimated glomerular filtration rate (eGFR) 15 to 30 mL/min/1.73 m²). Pirfenidone cannot be used in those with severe renal impairment (CrCl <15 mL/min). Like nintedanib, pirfenidone causes gastrointestinal side effects, but it may also cause rash, photosensitivity, and, rarely, more severe cutaneous adverse reactions (Stevens-Johnson syndrome, toxic epidermal necrolysis, and drug reaction with eosinophilia and systemic symptoms). Pirfenidone clearance may be increased and systemic exposure decreased in cigarette smokers due to hepatic enzyme (ie, CYP1A2) induction. Patients should be instructed to quit smoking prior to initiation of therapy and cigarette smoking should be avoided during therapy. (See "Treatment of idiopathic pulmonary fibrosis", section on 'Dose and administration'.)

Pulmonary function testing — There are no good data to guide the frequency of pulmonary function testing in the absence of clinical worsening; however, it is not uncommon to observe decline in lung function prior to worsening symptoms, particularly in those with mild disease. Assessment of pulse oxygen saturation (SpO₂) at rest or with exertion can be used to identify a gas exchange defect. For most patients, we obtain spirometry, diffusing capacity, and resting SpO₂ every three to six months after initial evaluation or initiation of therapy, until serial testing demonstrates stability. Thereafter, monitoring of pulmonary function may be spaced out to every 6 to 12 months in the absence of clinical change, depending on the clinical scenario. For patients with frailty, comorbidities, or more moderate to severe ILD (moderately reduced diffusing capacity or forced vital capacity [FVC]), we suggest a formal six-minute walk test with oxygen titration, along with other pulmonary function testing to assess for resting, exertional hypoxemia, and overall conditioning.

Chest imaging — The chest radiograph is useful in suggesting the presence of ILD, however, the diagnostic approach to ILD relies on high-resolution computed tomography (HRCT). Outside of the initial evaluation of the patient with ILD, we do not routinely perform chest radiograph imaging in the absence of a salutary or deleterious change in either symptoms or pulmonary function. One exception is in patients with asymptomatic (stage I-II) sarcoidosis, where monitoring chest radiograph every 6 to 12 months for the first two to three years is reasonable to assess for disease remission. For individuals with progressive or active ILD, serial HRCT imaging is recommended at regular intervals (eg, every 6 to 12 months) to monitor disease progression, response to treatment, or to detect complications or comorbidities associated with ILD (such as infections or malignancies). (See "Treatment of pulmonary sarcoidosis: Initial approach", section on 'Approach to asymptomatic patients'.)

Many patients with ILD may qualify for lung cancer screening evaluations due to smoking history; concomitant ILD typically increases the risk of lung cancer, although this has not been well studied in all varieties of ILD. Screening for lung cancer should be considered in the context of the patient's disease severity and other comorbidities using a shared decision-making process. (See "Screening for lung cancer" and "Evaluation and management of lung cancer in patients with interstitial lung disease".)

Other testing

●Surveillance and monitoring of autoantibodies – Monitoring of autoantibodies in patients with systemic lupus erythematosus- and anti-neutrophil cytoplasmic antibody-associated ILD can sometimes be helpful in assessing overall disease quiescence. Additionally, some patients with idiopathic ILD may develop positive autoantibodies suggestive of an evolving connective tissue disease. It is unclear if autoantibodies should be monitored over time and at what frequency. It is our practice to recheck appropriate autoantibody panels in patients with ILD who develop new or worsening signs or symptoms that suggest an evolving connective tissue disease.

●Surveillance for pulmonary hypertension (PH) – We routinely assess for PH with echocardiography in cases where the diffusion capacity for carbon monoxide (DLCO) is disproportionately reduced compared with FVC, in cases where there is symptom progression without clear progression of the underlying ILD, and in patients at elevated risk for PH (eg, patients with systemic sclerosis). Additional testing may be required in patients during evaluation for lung transplantation listing.

Re-evaluating diagnosis or management options — Occasionally, new information during clinical monitoring necessitates revisiting the initial diagnosis or changing the management strategy. Multidisciplinary discussion between clinicians, radiologists, and pathologists has been championed by international guidelines as the gold standard for improving diagnostic certainty [10,11] and can guide management strategy towards anti-inflammatory, antifibrotic, or combination therapies. Also, multidisciplinary discussion can be helpful in determining who should undergo lung biopsy for additional diagnostic information and which method of biopsy may be most appropriate. (See "Role of lung biopsy in the diagnosis of interstitial lung disease".)

GENERAL CARE MEASURES FOR PATIENTS WITH ILD

Comorbidity identification and management — The care of ILD patients requires careful attention to comorbid diseases that can contribute to worsening respiratory quality of life. These include reflux disease, dysphagia, obstructive sleep apnea, systolic or diastolic heart failure, coronary artery disease, pulmonary hypertension (PH), chronic obstructive pulmonary disease (COPD), and lung cancer. We have a low threshold for work-up of these diseases in symptomatic patients with suspicious features on clinical evaluation, pulmonary function testing, or imaging.

Tobacco cessation — Tobacco use is a risk factor for most ILDs, and it is a causative factor for a subset of them (eg, pulmonary Langerhans cell histiocytosis, respiratory bronchiolitis-associated ILD, desquamative interstitial pneumonitis). For those patients who are continuing to use tobacco, we counsel smoking cessation and offer referral to behavioral counseling and prescriptions for pharmacotherapy. ILD clinics should have close affiliations with local resources for smoking cessation to provide a full range of assistance for this group of patients. (See "Overview of smoking cessation management in adults" and "Behavioral approaches to smoking cessation" and "Pharmacotherapy for smoking cessation in adults".)

Oxygen — Patients with progressive ILD will usually develop hypoxemia requiring supplemental oxygen, initially just with exertion and then continuously. Oxygen therapy should be prescribed to enable maintenance of normal activity. Prompt provision of supplemental oxygen may also prevent or delay the onset of secondary PH in hypoxemic patients. The indications, benefits, and prescription of supplemental oxygen are discussed in detail elsewhere. (See "Long-term supplemental oxygen therapy".)

Education and support group participation — Results from a survey regarding patients' experience with idiopathic pulmonary fibrosis (IPF) suggest that improved education and communication about the diagnosis and management of ILD are needed [12]. For patients with progressive disease, part of the education should include a discussion of end-of-life issues and advanced directives. Understanding a patient's individual preferences, beliefs, and values is a key step toward achieving an appropriate management plan [13]. Patient support groups can be strong sources of practical advice and emotional bolstering for patients and their caregivers, and we actively encourage their participation.

Pulmonary rehabilitation — Although much of the data supporting pulmonary rehabilitation come from study of patients with COPD, the American Thoracic Society also recommends pulmonary rehabilitation for patients with ILDs based on demonstrated improvements in exercise capacity and likely improvement in dyspnea and quality of life [14]. Several studies support the use of pulmonary rehabilitation in patients with ILD [15-24]. As an example, in a series of 113 patients with ILD, a significant reduction in dyspnea and improvement in six-minute walk distance were found following participation in a pulmonary rehabilitation program [16]. (See "Pulmonary rehabilitation", section on 'Pulmonary rehabilitation in conditions other than COPD'.)

Prevention of pulmonary infections and acute exacerbations of ILD — Pulmonary infections are poorly tolerated in patients with more advanced or fibrotic ILD [25,26]. In addition to the acute effect on lung function, pulmonary infection may result in an acute exacerbation of ILD (AE-ILD), which is defined as "an acute, clinically significant respiratory deterioration characterized by evidence of new widespread alveolar abnormalities" [27]. (See 'Patients with new ground-glass changes' below and "Acute exacerbations of idiopathic pulmonary fibrosis".)

Given our limited understanding of the pathophysiology of acute exacerbations, the primary focus of prevention is avoidance of respiratory infections and other lung injury. In our practice, this typically includes:

●Vaccination against respiratory infections, including:

•Streptococcus pneumoniae, regardless of age, according to United States Centers for Disease Control and Prevention (CDC) guidelines

•Influenza (yearly, as per the standard adult vaccination schedule) (figure 1)

•Bordetella pertussis (every 10 years, according to the standard adult vaccination schedule) (figure 1)

•COVID-19 (coronavirus disease 2019), according to the age-based schedule (table 3)

•Respiratory Syncytial Virus, in individuals 60 years of age and older

There have been several reports of acute exacerbations in patients with fibrotic ILD following COVID-19 mRNA vaccine administration [28-31]. However, both case reports [32-34] and clinical experience inform us that infection with COVID-19 poses a larger risk for respiratory failure than vaccination in these patients. Until further data are available on the relative risks of acute exacerbations with different vaccine formulations, we continue to recommend vaccination with any approved vaccine against COVID-19. (See "Seasonal influenza vaccination in adults" and "COVID-19: Vaccines" and "Pneumococcal vaccination in adults" and "Respiratory syncytial virus infection in adults", section on 'Vaccination'.)

●Early outpatient treatment of respiratory infection – Treatment includes antibiotics for possible or verified bacterial pneumonia and oseltamivir in the setting of influenza A infection. Patients with ILD are designated by the CDC as persons at risk for severe COVID-19 (table 4) and therefore qualify for prioritized access to antiviral therapies, including nirmatrelvir/ritonavir and remdesivir. (See "Seasonal influenza in nonpregnant adults: Treatment", section on 'Patients at risk for complications or severe illness' and "COVID-19: Management of adults with acute illness in the outpatient setting", section on 'Treatment with COVID-19-specific therapies'.)

●Evaluation and treatment of recurrent aspiration – Patients with ILD should be screened clinically for gastroesophageal reflux or oropharyngeal dysphagia, with a low threshold for formal evaluation [35]. Speech therapy to improve swallow function and appropriate dietary interventions should be strongly encouraged. Pharmacologic treatment of reflux disease is reasonable in patients with symptomatic gastroesophageal reflux. Empiric treatment of reflux in asymptomatic patients is not recommended. (See "Treatment of idiopathic pulmonary fibrosis", section on 'Empiric treatment for asymptomatic gastroesophageal reflux'.)

●Risks of general anesthesia and mechanical ventilation – Mechanical ventilation may worsen lung injury in patients with ILD by causing ventilator-induced lung injury; however, aspiration into an unprotected airway also leads to airway injury and ensuing complications. Elective procedures should be performed under local and regional anesthesia with spontaneous ventilation rather than with mechanical ventilation, when possible. Use of noninvasive ventilation via face mask, nasal device, or laryngeal mask airway is not protective against lung injury and may worsen aspiration risk. If mechanical ventilation is required, it is our practice to recommend lung protective ventilation with use of lower tidal volume ventilation. (See "Anesthesia for patients with interstitial lung disease or other restrictive disorders".)

Palliation of dyspnea and cough — Palliative care aims to relieve suffering at all stages of disease and is not limited to end-of-life care [36-38]. Palliative measures (eg, facial cooling with a fan, opioids, anxiolytics) may be helpful for patients with refractory dyspnea or cough. Introduction of principles of palliative care for patients should be undertaken in patients with progressive ILD, and those with advanced disease may benefit from hospice care (table 5 and table 6). (See "Assessment and management of dyspnea in palliative care" and "Palliative care: Overview of cough, stridor, and hemoptysis in adults" and "Palliative care for adults with nonmalignant chronic lung disease" and 'Referral for end-of-life care' below.)

Nutrition — Although much less well studied than in COPD, weight loss and malnutrition are also common in the setting of advanced ILD. Energy imbalance is likely due to a combination of decreased caloric intake, deconditioning, disuse atrophy, tissue hypoxia, inflammation, and medication effects. Based on experience with improvement in clinical outcomes in COPD, we recommend referring ILD patients with cachexia and/or weight loss for nutritional support. (See "Malnutrition in advanced lung disease".)

Clinical trials and research — For many patients with progressive or fibrotic ILD, future therapies offer a larger chance of benefit than the modest impact of current management. We encourage interested patients with these diseases to participate in clinical trials of emerging therapies. Specific trials and registries are also available for patients with a familial history of ILD. Inclusion and exclusion criteria for clinical trials vary, so we provide all patients with information regarding participation in randomized clinical trials whenever appropriate trials are available.

Clinical trial information is available at ClinicalTrials.gov.

GENERAL TREATMENT PRINCIPLES — The pharmacologic treatment of ILD typically varies based on diagnosis, predominant imaging pattern, and pathologic features. However, we can offer a few general statements regarding treatment of ILDs that may be useful:

●Exposure-associated ILDs – ILDs arising acutely or subacutely after an environmental or drug exposure (drug-induced pneumonitis, acute hypersensitivity pneumonitis) are often successfully treated primarily by removal of the exposure. As adjunctive therapy, a limited course of anti-inflammatory treatment (typically systemic glucocorticoids) may also be used based on the severity of disease. Despite antigen avoidance and anti-inflammatory treatment, a proportion of patients with exposure-associated ILDs (such as hypersensitivity pneumonitis) may develop progressive pulmonary fibrosis [39,40]. (See "Hypersensitivity pneumonitis (extrinsic allergic alveolitis): Treatment, prognosis, and prevention", section on 'Treatment' and "Bleomycin-induced lung injury", section on 'Treatment' and "Amiodarone pulmonary toxicity", section on 'Treatment' and "Toxicities associated with immune checkpoint inhibitors", section on 'Pneumonitis' and "Pulmonary toxicity associated with systemic antineoplastic therapy: Clinical presentation, diagnosis, and treatment", section on 'Treatment'.)

●Smoking-related ILDs – For patients with ILDs that are strongly associated with active tobacco use (eg, pulmonary Langerhans cell histiocytosis, respiratory bronchiolitis-associated ILD, or desquamative interstitial pneumonitis), every effort should be made to achieve smoking cessation. While some lung damage is often irreversible, these conditions frequently improve if smoking cessation can be achieved. (See "Pulmonary Langerhans cell histiocytosis", section on 'Treatment' and "Respiratory bronchiolitis-associated interstitial lung disease", section on 'Initial therapy'.)

●ILDs characterized by glucocorticoid responsiveness – Cryptogenic organizing pneumonia, acute and chronic eosinophilic pneumonia, hypersensitivity pneumonitis, drug-induced ILD, and pulmonary sarcoidosis (with the exception of stage IV disease (table 7)) are characterized by excellent initial response to systemic glucocorticoid therapy and a chance of remission after systemic glucocorticoid treatment. In the absence of contraindications to glucocorticoid therapy or extrapulmonary disease requiring alternative treatments, this is the typical initial approach to patients with these disorders. (See "Treatment of pulmonary sarcoidosis: Initial approach" and "Cryptogenic organizing pneumonia", section on 'Treatment' and "Idiopathic acute eosinophilic pneumonia", section on 'Treatment' and "Chronic eosinophilic pneumonia", section on 'Treatment'.)

●ILDs with accompanying extrapulmonary manifestations – For ILDs associated with connective tissue diseases or with extrapulmonary manifestations (eg, sarcoidosis, rheumatoid arthritis, and scleroderma), ILD management may be only a component of maintaining overall disease control. Because of this, worsening extrapulmonary symptoms should be carefully assessed, and may necessitate changes in therapy despite stable pulmonary function.

APPROACH TO THE ILD PATIENT WITH WORSENING PULMONARY SYMPTOMS

General approach and differential diagnosis — For many types of ILD, especially fibrotic ILDs, disease progression is expected despite optimal medical management. The symptoms of disease progression, such as cough, dyspnea, or hypoxemia, commonly overlap with other conditions such as respiratory infection, acute decompensated heart failure, pulmonary hypertension (PH), pulmonary embolism, or pneumothorax. Additionally, worsening pulmonary symptoms can be triggered by acute exacerbation of the underlying disease, drug toxicity, malignancy, anemia, coronary artery disease, and deconditioning, among others.

For patients with worsening pulmonary symptoms, initial diagnostic steps usually include pulmonary function testing and imaging such as a chest radiograph or computed tomography (CT), tailored based on the presenting symptoms. Additional evaluation and treatment are based on the results of this initial work-up, as outlined below.

Patients with progressive fibrotic changes or worsening restriction — The development of progressive fibrosis and worsening restriction is expected in the patient with idiopathic pulmonary fibrosis (IPF) and may lead to initiation or adjustment in treatment. (See "Treatment of idiopathic pulmonary fibrosis", section on 'Medical therapies'.)

However, patients with non-IPF ILDs can also develop a progressive fibrosing phenotype with a prognosis approaching that of patients with IPF [41]. Those with more extensive fibrosis (≥20 percent of total lung volume) or usual interstitial pneumonia CT imaging pattern are more likely to progress than patients without these features [40,42].

Attempts to collectively study this group of patients at high risk for poor prognosis led to clinical trials with overlapping but different definitions [43-45]. In 2022, a diagnostic guideline published by the American Thoracic Society, European Respiratory Society, Japanese Respiratory Society, and Latin American Thoracic Society coined the term "progressive pulmonary fibrosis" (PPF) and laid out diagnostic criteria for this phenotype [39]. These criteria are as follows:

●Presence of ILD other than IPF with radiologic evidence of lung fibrosis

●Two of the following three signs of fibrotic disease progression within the past year without alternative explanation:

•1) Worsening restrictive physiology (absolute decline in forced vital capacity [FVC] ≥5 percent predicted or absolute decline in diffusing capacity for carbon monoxide [DLCO] ≥10 percent predicted),

•2) Worsening respiratory symptoms, or

•3) Progression of radiologic fibrosis (increased extent or severity of reticular changes, lobar volume loss, or traction bronchiectasis/bronchiolectasis, new ground-glass opacities with traction bronchiectasis, or new/worsening honeycombing)

Notably, these criteria were not based on clear data, and will likely require additional refinement over time. Like many experts in the field, we believe that progression should be judged independent of timeline (ie, progression should be established based on clinical, physiologic, or radiographic evidence regardless of the timeframe over which the change occurred) [46,47]. It is also unlikely that all patients meeting PPF criteria have similar risks of poor outcomes regardless of their underlying disease or which criteria they meet. For example, one study of several cohorts showed that for most criteria, rate of lung function decline after demonstrating progressive fibrosis was much lower for patients with ILD associated with connective tissue disease than for those with chronic hypersensitivity pneumonitis or a non-IPF idiopathic interstitial pneumonia [48]. Similarly, while some criteria, such as relative FVC decline ≥10 percent, appear to identify cohorts of patients with prognosis similar to that of patients with IPF, other criteria were not consistent across cohorts or disease subtypes [41].

While awaiting further refinements, we use the 2022 PPF criteria above as evidence of worsening fibrosis in patients with known fibrotic ILDs, including connective tissue disease-associated ILDs, chronic hypersensitivity pneumonitis, and idiopathic interstitial pneumonias (other than IPF).

●Nintedanib – For patients with non-IPF ILD who develop PPF despite optimal initial ILD management (eg, antigen avoidance or immunosuppressive treatment, depending on ILD subtype), we suggest treatment with nintedanib to reduce the rate of lung function decline. The primary evidence for this approach is based on a placebo-controlled trial that enrolled 663 patients with fibrotic ILD and either a ≥10 percent relative decline in FVC or more than a 5 percent relative decline in FVC accompanied by worsening respiratory symptoms or fibrotic changes over the past 24 months [43]. Treatment with nintedanib (150 mg orally twice daily) resulted in a reduced adjusted decline in FVC at 52 weeks (-80.8 ml with nintedanib and -187.8 ml with placebo; difference +107 mL, 95% CI 65.4 to 148.5). The effect on FVC decline was similar in patients that had a usual interstitial pneumonia pattern (-82.9 ml with nintedanib and -211.1 ml with placebo; difference +128 mL, 95% CI 70.8 to 185.6). There were no clinically significant changes in ILD symptom scores. Diarrhea occurred more commonly with nintedanib treatment compared with placebo (66.9 percent versus 23.9 percent) and led to dose reduction or discontinuation of nintedanib in 33 and 20 percent of patients, respectively.

●Pirfenidone – Two trials have examined pirfenidone in patients with progression of fibrotic ILD. In one placebo-controlled trial of 253 patients with worsening unclassifiable fibrotic ILD, patients receiving pirfenidone (2403 mg orally daily) demonstrated reduced decline in FVC over 24 weeks (-18 versus -113 mL, difference +95 mL, 95% CI 36 to 155 mL) [45]. There were no meaningful differences in patient-reported outcomes or six-minute walk distance. A second trial that included patients with specific ILD diagnoses was stopped early for poor recruitment and required statistically modeling due to missing data; some models suggested a similar effect size to that seen in the other trial [44]. Based on these limited data, we only offer pirfenidone (off-label) to patients with PPF who are unable to take nintedanib. Availability and insurance coverage may be barriers to pirfenidone use.

For patients initiated on antifibrotic therapy for PPF, the continuation of prior anti-inflammatory therapies should be tailored to the individual patient and the underlying cause of ILD. In general, for patients who have progressed despite standard of care (including immunosuppression), we attempt add-on antifibrotic therapy. Depending on patient tolerance, anti-inflammatory therapy may be maintained, dose-reduced, or discontinued. For those with connective tissue disease-associated ILD, anti-inflammatory agents are commonly needed to control extrapulmonary manifestations of their disease. Additional observational and clinical trial data are needed to help inform best practices regarding concomitant antifibrotic and anti-inflammatory therapy. (See "Interstitial lung disease in rheumatoid arthritis", section on 'Antifibrotic therapy, for progressive fibrosis' and "Treatment and prognosis of interstitial lung disease in systemic sclerosis (scleroderma)", section on 'Progressive disease' and "Treatment and prognosis of nonspecific interstitial pneumonia", section on 'Nintedanib'.)

Because progressive fibrotic changes are rarely reversible, patients with PPF should also be re-evaluated for optimal general care measures, including oxygen, pulmonary rehabilitation, and palliative therapies for refractory symptoms. (See 'General care measures for patients with ILD' above.)

Patients with new ground-glass changes — The differential diagnosis of new ground-glass opacities on CT includes respiratory infection, acute decompensated heart failure, aspiration, and acute exacerbation of the underlying ILD. Differentiating between these entities confers both prognostic and therapeutic implications.

●Respiratory infection – Evaluation for respiratory infection commonly includes sputum sampling and respiratory viral panels. In cases where the ILD patient is receiving systemic glucocorticoids or other immunosuppressive therapies, atypical infections, such as pneumocystis jirovecii pneumonia, aspergillosis, and endemic fungal pneumonia, should also be considered. In certain cases, particularly in the absence of sputum production, bronchoscopy with bronchoalveolar lavage may be necessary for further evaluation. (See "Epidemiology of pulmonary infections in immunocompromised patients" and "Approach to the immunocompromised patient with fever and pulmonary infiltrates".)

●Decompensated heart failure – Weight gain, orthopnea, vascular distribution of ground-glass opacities, presence of pleural effusions, and lower extremity edema suggest acute decompensated heart failure. Obtaining a brain natriuretic peptide or N-terminal probrain natriuretic peptide level can be helpful in determining volume status. If cardiac dysfunction is new, an electrocardiogram and echocardiography should be obtained. The mainstay of treatment for pulmonary symptoms is typically initiating or increasing diuretic therapy. The diagnosis and management of heart failure are discussed separately. (See "Approach to diagnosis and evaluation of acute decompensated heart failure in adults" and "Treatment of acute decompensated heart failure: General considerations".)

●Aspiration – Acute or recurrent aspiration are common causes of worsening pulmonary inflammation. In addition to historical evidence of aspiration (eg, choking episodes, vomiting, taste of bile in the throat), CT imaging demonstrating lower lobe predominance of ground-glass opacities and/or consolidation (particularly on the right side), airway-centric inflammatory changes, tree-in-bud opacities, or a patulous esophagus are suggestive of possible aspiration. Aspiration pneumonitis in the setting of ILD may spontaneously resolve, evolve into an aspiration pneumonia, or result in an acute exacerbation of ILD (AE-ILD; see below). From a management standpoint, further evaluation and prevention of recurrent aspiration may help prevent recurrent episodes. We typically obtain a swallowing evaluation and/or esophageal imaging and manometry for further evaluation, depending on the patient's symptoms. (See "Approach to the evaluation of dysphagia in adults".)

●Iatrogenic lung toxicity – Patients with ILD are more symptomatic and likely more susceptible to drug-induced or radiation-induced lung injury. Diffuse ground-glass changes in temporal association with high-risk agents (eg, bleomycin, nitrofurantoin, or immune checkpoint inhibitors (table 8)) should prompt discontinuation of the potentially inciting drug pending further work-up. If no other cause is found, we generally avoid resuming the offending agent. In the case of radiation-induced lung injury, the inflammation is frequently present in the radiation field, but radiation injury can also lead to an acute exacerbation of fibrotic ILD (below) that demonstrates a more diffuse injury pattern. The inflammation generally occurs 3 to 12 weeks after injury. Most symptomatic drug-induced or radiation-induced lung injury is treated with a course of moderate-dose systemic glucocorticoids tapered over several weeks based on patient response. (See "Radiation-induced lung injury" and "Pulmonary toxicity associated with systemic antineoplastic therapy: Clinical presentation, diagnosis, and treatment" and "Pulmonary toxicity of molecularly targeted agents for cancer therapy" and "Nitrofurantoin-induced pulmonary injury".)

●Acute exacerbation of ILD (AE-ILD) – While acute exacerbations are well-described in IPF, acute exacerbations can also occur in other ILDs associated with lung fibrosis, including other idiopathic interstitial pneumonias, chronic hypersensitivity pneumonitis, and connective tissue disease-associated ILDs [49-51]. The key diagnostic feature of an acute exacerbation is the presence of new bilateral ground-glass opacities or consolidation (on a background of underlying pulmonary fibrosis) that occurs over a subacute time frame (<1 month duration) and is not fully explained by heart failure [27]. Other causes of lung injury (eg, infection, aspiration, and iatrogenic injury [above]) may "trigger" an acute exacerbation in susceptible patients; for some patients, no trigger can be identified. There are minimal prospective data to guide treatment of patients with AE-ILD. We suggest attempted treatment with systemic glucocorticoids (1 mg/kg up to 1,000 mg of methylprednisolone [or equivalent], depending on severity of the exacerbation) and use concomitant antibiotic therapy empirically or pending an infectious work-up. Glucocorticoids are tapered slowly based on response in those who improve; we typically do not continue them in patients who do not respond to high doses over the first three to five days. Acute exacerbations portend a very poor prognosis in those with IPF; limited data suggest a substantial short-term mortality, but slightly better prognosis, in patients with AE-ILD from other fibrotic lung diseases [49]. (See "Acute exacerbations of idiopathic pulmonary fibrosis" and "Acute interstitial pneumonia (Hamman-Rich syndrome)".)

As an exception to this approach, cyclophosphamide, rather than high-dose glucocorticoids, may be used for AE-ILD associated with scleroderma to avoid the risk of precipitating scleroderma renal crisis. (See "Kidney disease in systemic sclerosis (scleroderma), including scleroderma renal crisis", section on 'Prevention'.)

Patients with fulminant or rapidly progressive ILD associated with dermatomyositis or polymyositis (typically those with melanoma differentiation-associated gene 5 [MDA5] antibodies) have diseases that mimic AE-ILD, but they are typically treated both with high-dose glucocorticoids and concomitant additional immunosuppressants, including cyclophosphamide. (See "Interstitial lung disease in dermatomyositis and polymyositis: Treatment", section on 'ILD associated with MDA5 antibody'.)

Patients with other ILDs, such as sarcoidosis, hypersensitivity pneumonitis, or cryptogenic organizing pneumonia, may present with new ground-glass inflammatory changes due to increased underlying disease activity in the absence of underlying fibrosis. These episodes are usually called "flares" or "relapses," rather than acute exacerbations. They are most commonly associated with tapering or cessation of anti-inflammatory therapies or (in the case of hypersensitivity pneumonitis) new or worsening antigen exposure. Anti-inflammatory therapies are typically very effective in this setting, and significantly lower doses (eg, ≤60 mg of prednisone orally daily) are typically used. (See "Treatment of pulmonary sarcoidosis: Initial approach", section on 'Relapses and acute bronchitic symptoms' and "Cryptogenic organizing pneumonia", section on 'Treatment of relapses during glucocorticoid taper' and "Hypersensitivity pneumonitis (extrinsic allergic alveolitis): Treatment, prognosis, and prevention", section on 'Acute or subacute HP with persistent symptoms'.)

In those with severe AE-ILD requiring hospitalization, shared decision-making around end-of-life care is of critical importance. Although frequently offered, invasive mechanical ventilation is typically of limited utility in this setting. For example, in one study of 94 patients with AE-ILD, only 5 percent of those with IPF and 14 percent of those with connective tissue disease-associated ILD survived their index hospitalization following invasive mechanical ventilation [52]. Rarely, in patients who have already been listed for transplantation and are hospitalized at a transplant center, a time-limited trial of mechanical ventilation or extracorporeal membrane oxygenation can be used as a bridge to transplant [53].

Worsening air-trapping or obstruction — Patients with ILD can develop worsening obstruction and air-trapping due to comorbid asthma or chronic obstruction pulmonary disease (COPD), development of obstructive bronchiolitis (in patients with certain connective tissue diseases), or due to progression of airway pathology associated with ILD (eg, hypersensitivity pneumonitis or sarcoidosis). It is important to differentiate worsening obstruction from progressive restrictive changes, as treatment may be different depending on the underlying cause. (See "Overview of bronchiolar disorders in adults" and "Treatment of pulmonary sarcoidosis: Initial approach", section on 'Relapses and acute bronchitic symptoms'.)

Isolated worsening diffusing capacity — An isolated worsening diffusing capacity or a diffusing capacity that worsens out of proportion to a decline in FVC should prompt evaluation for PH via transthoracic echocardiogram and, in some cases, right heart catheterization.

Patients with advanced ILD are at increased risk of developing PH associated with alveolar destruction and hypoxemia (group three PH). Certain systemic diseases associated with ILD also increase the risk for PH even in the absence of advanced interstitial disease; these include sarcoidosis, scleroderma, mixed connective tissue disease, and rheumatoid arthritis. (See "Pulmonary hypertension due to lung disease and/or hypoxemia (group 3 pulmonary hypertension): Epidemiology, pathogenesis, and diagnostic evaluation in adults" and "Sarcoidosis-associated pulmonary hypertension: Diagnostic evaluation in adults" and "Pulmonary arterial hypertension in systemic sclerosis (scleroderma): Treatment and prognosis" and "Overview of pleuropulmonary diseases associated with rheumatoid arthritis", section on 'Pulmonary hypertension'.)

Because both PH and ILD cause dyspnea and hypoxemia, it can be difficult to differentiate worsening ILD versus the development of PH based on symptoms or clinical examination alone; isolated changes in DLCO or changes in DLCO out of proportion to changes in vital capacity increase suspicion for PH. Acute decompensated heart failure can also negatively impact DLCO due to poor cardiac output and pulmonary edema, but can often be determined clinically or by imaging (above). Chronic heart failure may itself contribute to the development of PH. Anemia is also a common cause of isolated reduced diffusing capacity. The pulmonary function test (PFT) laboratory will typically obtain a hemoglobin and report a corrected value, but patients without corrected values should be tested for anemia prior to additional evaluation. (See "Diffusing capacity for carbon monoxide", section on 'Adjustments'.)

After transthoracic echocardiogram evaluation, patients at moderate or high suspicion for PH often require cardiac catheterization for diagnosis and categorization. Postdiagnostic testing may include further work-up for additional potential contributory causes, including sleep apnea, chronic thromboembolic disease, and connective tissue diseases, particularly when the PH is more severe than expected for the extent of ILD. (See "Clinical features and diagnosis of pulmonary hypertension of unclear etiology in adults".)

No change in PFTs or chest imaging — Common causes of worsening pulmonary symptoms without changes in imaging or pulmonary function include pulmonary embolism, cardiac disease, thyroid dysfunction, medication side effects, and deconditioning.

●Venous thromboembolism – There is some evidence to suggest that patients with ILD are at increased risk for developing venous thromboembolism [54]. Whether this risk is limited to certain types of ILD (such as IPF) or affects all patients with ILD is not well understood. Patients with advanced ILD may be at increased risk due to limited mobility arising from symptom severity and hypoxemia. Worsening tachypnea, tachycardia, and breathlessness, especially those of acute onset, without changes on chest radiograph, noncontrast CT, or PFTs should prompt evaluation for venous thromboembolism. (See "Clinical presentation, evaluation, and diagnosis of the nonpregnant adult with suspected acute pulmonary embolism".)

●Coronary artery disease – Coronary artery disease is a common comorbidity in patients with ILD, especially those of advanced age [55]. Progressive dyspnea, primarily with exertion, in a patient with risk factors should prompt evaluation for possible coronary ischemia. Paroxysmal episodes of dyspnea and palpitations may also arise from supraventricular tachycardias, which are more common in patients with advanced lung disease [56]. Clinical evaluation, including electrocardiogram and referral to a cardiologist, may be appropriate. (See "Approach to the patient with suspected angina pectoris" and "Narrow QRS complex tachycardias: Clinical manifestations, diagnosis, and evaluation".)

●Fatigue – Fatigue, dyspnea, and exhaustion have overlapping features that are difficult for patients to differentiate. Worsening dyspnea in the absence of change in imaging or PFTs frequently arises from fatigue or deconditioning rather than from a pulmonary etiology. When evaluating possible fatigue, we consider assessment of thyroid function, changes in medications (fatigue is a frequent side effect of many pharmaceuticals), and underlying disease. Fatigue is a major, difficult-to-treat feature of sarcoidosis and many connective tissue diseases; fatigue severity in these conditions is typically not related to the severity of the ILD. Deconditioning is also very common in patients with ILD and is to be expected after acute illnesses or other reasons for relative immobility. Deconditioning in the setting of ILD may improve with pulmonary rehabilitation. (See 'Pulmonary rehabilitation' above.)

●Occult disease progression – As a diagnosis of exclusion, some individuals may experience worsening pulmonary symptoms from ILD progression prior to changes in imaging or PFTs. For those whom another cause is not found or highly uncertain, we typically monitor more closely over the next several months for objective evidence of worsening ILD. (See 'Ongoing monitoring of patients with ILD' above.)

REFERRAL FOR LUNG TRANSPLANTATION EVALUATION — Patients with advanced ILD without other contraindications should undergo evaluation for and counseling about lung transplantation at a lung transplant center. For those with fibrotic ILDs, the poor prognosis after progression and risk of decompensation in the setting of acute exacerbation merits early referral. Our practice is consistent with the International Society of Heart and Lung Transplantation guidelines, which suggest relatively early referral for these patients, with listing of appropriate candidates after evidence of disease progression [57]. (See "Lung transplantation: An overview" and "Lung transplantation: Disease-based choice of procedure".)

Most patients with fibrotic-appearing features of ILD on imaging or pathology are appropriate for initial referral to a transplant center to begin evaluation and counseling. Exceptions include:

●Patients who have evident disease but no symptoms and minimal lung function abnormalities. We often defer transplant evaluation until there is some progression of disease.

●Patients with treatment plans that include anti-inflammatory therapy. In these patients, we usually defer referral or listing until we can assess response to initial anti-inflammatory treatments, unless their disease presentation is rapid or severe. Patients with disease progression despite anti-inflammatory therapy and without other contraindications are appropriate for lung transplant referral.

For patients with ILD referred to transplant for any of the above indications, criteria for placing appropriate candidates on the transplant list include the following [57]:

●Decline in FVC ≥10 percent predicted during six months of follow-up (a decline ≥5 percent predicted with radiographic progression also warrants listing)

●Decline in DLCO ≥10 percent predicted during six months of follow-up

●On six-minute walk test: oxygen desaturation to <88 percent, distance walked <250 meters, or >50 meter decline in distance walked over six months

●Pulmonary hypertension (PH) on right heart catheterization or transthoracic echocardiogram

●Hospitalization because of respiratory decline, pneumothorax, or acute exacerbation

REFERRAL FOR END-OF-LIFE CARE — In the absence of lung transplantation, advanced progressive ILDs have a terminal prognosis. Where available, hospice care is appropriate for patients with end-stage pulmonary disease with life expectancy of six months or less. Hospice criteria for end-stage pulmonary disease include [58]:

●Disabling dyspnea at rest, poorly responsive or unresponsive to bronchodilators, resulting in decreased functional capacity (eg, bed to chair existence, fatigue, and cough)

●Progression of end-stage pulmonary disease, as evidenced by increasing visits to the emergency department or hospitalizations for pulmonary infections and/or respiratory failure

●Hypoxemia (as evidenced by pO₂ ≤55 mmHg, or oxygen saturation ≤88 percent) or hypercapnia (as evidenced by pCO₂ ≥50 mmHg) at rest on room air

Other common features of end-stage ILD include worsening pulmonary hypertension (PH) and cor pulmonale, unintentional progressive weight loss (especially greater than 10 percent), and resting tachycardia.

Additional information regarding palliative care at the end of life and hospice care is discussed elsewhere. (See "Palliative care for adults with nonmalignant chronic lung disease" and "Hospice: Philosophy of care and appropriate utilization in the United States" and "Palliative care and hospice outside of the United States".)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Interstitial lung disease" and "Society guideline links: Sarcoidosis" and "Society guideline links: Palliative care" and "Society guideline links: Pulmonary rehabilitation" and "Society guideline links: Supplemental oxygen".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, “The Basics” and “Beyond the Basics.” The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on “patient info” and the keyword(s) of interest.)

●Basics topics (See "Patient education: Interstitial lung disease (The Basics)" and "Patient education: Idiopathic pulmonary fibrosis (The Basics)" and "Patient education: Sarcoidosis (The Basics)" and "Patient education: Pulmonary rehabilitation (The Basics)".)

SUMMARY AND RECOMMENDATIONS

●Routine monitoring – Clinical follow-up of patients with interstitial lung disease (ILD) involves reassessment of pulmonary symptoms, evaluation of extrapulmonary manifestations of disease, assessment of common comorbidities, and managing complications and toxicities of pharmacologic treatments. We typically perform surveillance of pulmonary function using spirometry and diffusing capacity at regular intervals depending on disease stability and changes in symptoms. (See 'Ongoing monitoring of patients with ILD' above.)

●General care measures – For all patients with ILD, we encourage tobacco cessation and support group participation. We also evaluate the need for oxygen therapy, pulmonary rehabilitation, nutritional support, and palliative treatments of refractory cough and dyspnea. (See 'General care measures for patients with ILD' above.)

To prevent pulmonary infection and lung injury, our typical practice also includes:

•Vaccination against respiratory infections, including streptococcus pneumoniae, influenza, Bordetella pertussis, SARS-CoV-2, and respiratory syncytial virus (for those over age 60)

•Evaluation and treatment of symptomatic gastroesophageal reflux and oropharyngeal dysphagia

•Avoidance of mechanical ventilation or general anesthesia when possible, and otherwise use of lung-protective ventilation strategies

●Treatment principles – The pharmacologic treatment of ILD varies based on diagnosis, predominant imaging pattern, and pathologic features. Diseases associated with environmental or drug exposures (including smoking) benefit most from avoidance of the antigen, toxin, or exposure. Multidisciplinary discussion of clinical factors, imaging, and pathology (when available) can help guide management strategy towards anti-inflammatory, antifibrotic, or combination therapies. (See 'General treatment principles' above.)

●Approach to the patient with worsening symptoms – For patients with worsening pulmonary symptoms, initial diagnostic steps usually include pulmonary function testing and imaging such as a chest radiograph or CT, tailored based on the presenting symptoms. Additional evaluation and treatment are based on the results of this initial work-up. (See 'General approach and differential diagnosis' above.)

•Progressive fibrotic changes and/or worsening restriction – The development of progressive fibrosis and worsening restriction is expected in the patient with idiopathic pulmonary fibrosis (IPF), and may lead to initiation or adjustment in treatment (see "Treatment of idiopathic pulmonary fibrosis", section on 'Medical therapies'). For patients with non-IPF fibrotic ILDs, progressive pulmonary fibrosis is currently defined by two of the following three characteristics: worsening restrictive physiology, increased respiratory symptoms, and progression of radiologic fibrosis. These criteria likely need further refinement, and patients within this group do not have homogeneous risk of further progression. (See 'Patients with progressive fibrotic changes or worsening restriction' above.)

For patients with non-IPF ILD who develop progressive pulmonary fibrosis despite optimal initial ILD management, we suggest treatment with nintedanib (Grade 2C) based on data demonstrating reductions in the rate of lung function decline. For patients with progressive pulmonary fibrosis who cannot use nintedanib, off-label treatment with pirfenidone is a reasonable alternative.

•New ground-glass changes – The differential diagnosis of new ground-glass opacities on computed tomography includes respiratory infection, acute decompensated heart failure, aspiration, and acute exacerbation of the underlying ILD.

For patients without IPF and a suspected acute exacerbation of ILD, we suggest a trial of systemic glucocorticoids rather than supportive care (Grade 2C), although there are minimal prospective data to guide treatment. We typically use 1 mg/kg up to 1,000 mg of methylprednisolone daily or the equivalent, depending on the severity of the exacerbation. Glucocorticoids are tapered slowly over days to weeks based on response in those who improve; we typically do not continue them in patients who do not respond to high doses over the first three to five days. (See 'Patients with new ground-glass changes' above.)

Treatment of acute exacerbations of IPF is discussed separately. (See "Acute exacerbations of idiopathic pulmonary fibrosis", section on 'Treatment'.)

•Isolated worsening diffusing capacity – Symptomatic ILD accompanied by an isolated worsening diffusing capacity or a diffusing capacity that worsens out of proportion to a decline in forced vital capacity (FVC) should prompt evaluation for pulmonary hypertension (PH) via transthoracic echocardiogram. (See 'Isolated worsening diffusing capacity' above.)

•No change in pulmonary function tests (PFTs) or imaging – Common causes of worsening pulmonary symptoms without changes in imaging or pulmonary function include pulmonary embolism, cardiac disease, thyroid dysfunction, medication side effects, and deconditioning.

●Referral for lung transplant evaluation – Patients with advanced ILD without other contraindications should undergo evaluation for and counseling about lung transplantation at a lung transplant center. For those with fibrotic ILDs, the poor prognosis after progression and risk of decompensation in the setting of acute exacerbation merits early referral. (See 'Referral for lung transplantation evaluation' above.)

●Referral for end-of-life care – Patients with disabling dyspnea or functional capacity at rest, escalating hospitalizations, severe hypoxemia, cor pulmonale due to ILD, or unintentional progressive weight loss are appropriate for end-of-life palliative interventions, including hospice referral. (See 'Referral for end-of-life care' above.)