Version May 2024
INTRODUCTION — Idiopathic pulmonary fibrosis (IPF; also called cryptogenic fibrosing alveolitis) is specific form of chronic, progressive, fibrosing interstitial pneumonia of unknown cause, occurring in adults and limited to the lungs. It is associated with the histopathologic and/or radiologic pattern of usual interstitial pneumonia (UIP). In the past, treatment was aimed at minimizing inflammation and slowing the progression from inflammation to fibrosis. However, the underlying lesion in IPF may be more fibrotic than inflammatory, explaining why few patients respond to anti-inflammatory therapies and the prognosis remains poor [1-4].
The following questions will be discussed in this topic review, although considerable uncertainty remains about the answers [2,4]:
●Which patients should be treated?
●When should therapy be started?
●What is the best therapy?
The pathogenesis, evaluation, diagnosis, monitoring, and prognosis of IPF are presented separately. (See "Pathogenesis of idiopathic pulmonary fibrosis" and "Idiopathic interstitial pneumonias: Classification and pathology", section on 'Usual interstitial pneumonia' and "Clinical manifestations and diagnosis of idiopathic pulmonary fibrosis" and "Prognosis and monitoring of idiopathic pulmonary fibrosis" and "Acute exacerbations of idiopathic pulmonary fibrosis".)
NATURAL HISTORY — The following observations about the natural history of IPF may be helpful in guiding therapy.
●Historically, untreated IPF progresses, although disease progression is usually insidious, at least initially [5-7]. Data from the placebo arm of clinical trials suggest that the rate of decline in forced vital capacity (FVC) among untreated patients is 150 to 200 mL per year [8].
●The course of the disease may be unpredictable as some patients develop an acute deterioration after a period of apparent stability.
●Patients in the age group affected by IPF (the majority are >55 years old) may have difficulty discerning whether their functional limitations are the result of disease progression, deconditioning, or simply the aging process.
●Comorbid conditions (eg, chronic obstructive pulmonary disease [COPD], heart failure) may also contribute to symptoms such as cough and reduced exercise tolerance.
GENERAL APPROACH
Overview — The most important first step is to establish the diagnosis since misdiagnosis can lead to inappropriate initial therapy (algorithm 1). The diagnosis of IPF may be established with a high degree of confidence in patients with a compatible clinical presentation, typical high-resolution computed tomography (HRCT) findings (eg, subpleural, bibasilar predominance of reticular markings, honeycombing, and the absence of features inconsistent with usual interstitial pneumonia [UIP] pattern, eg, ground glass opacities, micronodules, cysts, or mosaic attenuation), and no evidence of another contributing process (eg, asbestos exposure, hypersensitivity pneumonitis, systemic sclerosis, rheumatoid arthritis) [2]. Family history may identify cohorts at risk for familial UIP or other fibrosing lung diseases. The diagnosis of IPF is discussed separately. (See "Approach to the adult with interstitial lung disease: Diagnostic testing" and "Clinical manifestations and diagnosis of idiopathic pulmonary fibrosis".)
When the results of HRCT are not classic for IPF, a video-assisted thoracoscopic or surgical lung biopsy is often necessary. (See "Idiopathic interstitial pneumonias: Classification and pathology", section on 'Usual interstitial pneumonia' and "Role of lung biopsy in the diagnosis of interstitial lung disease".)
The next step is to stage the patient's severity of disease as this will help to guide treatment choices. Finally, a disease management plan is tailored to the disease severity and desires of the individual patient. Management generally includes a combination of supportive care, use of selected medications (eg, pirfenidone, nintedanib), consideration for participation in clinical trials, referral for lung transplant evaluation (when appropriate), and identification and treatment of comorbidities [2,4]. (See 'Medical therapies' below.)
Education and various components of supportive care (eg, supplemental oxygen, pulmonary rehabilitation, preventive measures against lung injury, palliative care) should be offered to all patients with IPF. (See 'Supportive care' below.)
Multiple therapies (eg, anticoagulation, azathioprine-prednisone-[N] acetylcysteine combination therapy, colchicine, cyclophosphamide, cyclosporine, endothelin receptor antagonists, interferon gamma, methotrexate, [N] acetylcysteine, penicillamine) have been used in the past either in case series or clinical trials. The agents of doubtful benefit or intolerable toxicity are described below with the evidence against their routine use. (See 'Therapies without clear benefit' below.)
Ongoing assessment is needed to refine these choices as the disease progresses. (See "Prognosis and monitoring of idiopathic pulmonary fibrosis".)
Assessing disease severity and prognosis — Disease severity in IPF is assessed based on symptoms, HRCT, and pulmonary function testing. Patients usually progress from mild to moderate to severe respiratory limitation, although the rate of progression can vary over the course of the disease. The factors that influence prognosis are discussed separately. (See "Prognosis and monitoring of idiopathic pulmonary fibrosis", section on 'Prognosis'.)
●Patients with mild or early disease are often asymptomatic or may have a mild, nonproductive cough and dyspnea with substantial exertion. Radiographic changes of reticular opacities and areas of honeycombing are limited to subpleural and basilar areas, involving less than 10 percent of the lung parenchyma. Pulmonary function tests may be normal or may show mild reductions in forced vital capacity (FVC), diffusing capacity (DLCO), and/or distance walked on the six-minute walk test. The alveolar to arterial oxygen gradient (P[A-a]O2) is normal or mildly elevated (<20 mmHg).
●Moderate disease is characterized by dyspnea on moderate exertion, nonproductive cough, and mild-to-moderate pulmonary function abnormalities. The last may include a reduced FVC (eg, 50 to 70 percent of predicted), a reduced DLCO (eg, 45 to 65 percent of predicted), and/or increased P(A-a)O2 (eg, 21 to 30 mmHg). Discordance in the degree of impairment of FVC and DLCO may be noted. Supplemental oxygen may be needed with exertion. Radiographic changes are more extensive with reticular opacities involving 20 to 30 percent of the lung and honeycombing involving <5 percent of the parenchyma [9]. One way of assessing the extent of radiographic changes is to quantitate these radiographic abnormalities on HRCT slices taken at three levels (eg, tracheal carina, inferior pulmonary veins, and 1 cm above the dome of the diaphragm) [1].
●Advanced disease is characterized clinically by dyspnea on mild exertion (eg, walking <300 feet or climbing more than one flight of stairs) and requirement for supplemental oxygen at rest and/or with exertion. Extensive honeycombing is noted on HRCT (>5 percent of the parenchyma in three or more zones) [9]. Pulmonary function testing typically reveals moderate to severe reductions in the FVC (<50 percent of predicted), DLCO (<50 percent of predicted), and oxygen desaturation (≥4 percent) during a six-minute walk test [10]. Gas exchange is also impaired with room-air oxygen saturation below 88 percent and elevated P(A-a)O2 difference (>30 mmHg).
Gender-Age-Physiology (GAP) model — When developing a treatment plan for each patient, it is helpful to have an estimate of prognosis. The most widely validated clinical prediction model is the GAP model, which incorporates age, gender, FVC, and DLCO into a simple point-score index and staging system predictive of one, two, and three-year mortality [11]. The GAP index and staging system, combined with clinical impression, can be used to guide initial patient discussions regarding prognosis, therapeutic options, urgency of lung transplantation, and timeline of palliative approaches. The GAP system is described in greater detail separately. (See "Prognosis and monitoring of idiopathic pulmonary fibrosis", section on 'Predictors of mortality'.)
Ongoing monitoring — Ongoing monitoring is used to evaluate the clinical course and identify patients with accelerated deterioration. The response to therapy is usually assessed at three- to six-month intervals. We monitor a combination of symptoms, pulmonary function, and exercise capacity as described separately. (See "Prognosis and monitoring of idiopathic pulmonary fibrosis".)
In patients with advanced or progressive disease, careful evaluation for the development of hypoxemia, pulmonary hypertension, thromboembolic disease, or other comorbid conditions (eg, chronic obstructive pulmonary disease [COPD], heart failure, obstructive sleep apnea, depression) may yield additional treatment options [2,12,13]. (See 'Supplemental oxygen' below and "Pulmonary hypertension due to lung disease and/or hypoxemia (group 3 pulmonary hypertension): Treatment and prognosis" and "Epidemiology and pathogenesis of acute pulmonary embolism in adults" and "Clinical presentation and diagnosis of obstructive sleep apnea in adults" and 'Lung transplantation' below.)
SUPPORTIVE CARE — The most important components of supportive care for patients with IPF are provision of supplemental oxygen (when needed), education (including advice about smoking cessation), pulmonary rehabilitation, and vaccination against Streptococcus pneumoniae and influenza [2,14]. Affective disorders are common during the course of IPF and may need attention [15,16]. (See "Comorbid anxiety and depression in adults: Epidemiology, clinical manifestations, and diagnosis".)
Supplemental oxygen — Virtually all patients with IPF will eventually require supplemental oxygen initially just with exertion and then continuously. Oxygen therapy should be prescribed to enable maintenance of normal activity and possibly to prevent or delay the onset of secondary pulmonary hypertension in hypoxemic patients. The indications, benefits, and prescription of supplemental oxygen are discussed in detail elsewhere. (See "Long-term supplemental oxygen therapy".)
Education — Results from a survey regarding patients' experience with IPF suggest that improved education and communication about the diagnosis and management of IPF are needed [17]. For patients with progressive IPF, 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 [18]. Introduction of principles of palliative care for patients with IPF should be undertaken in patients with progressive IPF. (See "Benefits, services, and models of subspecialty palliative care" and "Assessment and management of dyspnea in palliative care" and "Hospice: Philosophy of care and appropriate utilization in the United States".)
Pulmonary rehabilitation — Most of the data that support the use of pulmonary rehabilitation in the management of patients with chronic respiratory disease come from the study of chronic obstructive pulmonary disease (COPD). Several studies also support the use of pulmonary rehabilitation in interstitial lung disease [19-28]. As an example, in a series of 113 patients with interstitial lung disease, a significant reduction in dyspnea and improvement in six-minute walk distance were found following participation in a pulmonary rehabilitation program [20]. (See "Pulmonary rehabilitation".)
Prevention of pulmonary infections and acute exacerbations — Pulmonary infections are poorly tolerated in patients with IPF [29,30]. In addition to the acute effect on lung function, pulmonary infection may result in an acute exacerbation of IPF (AE-IPF), which is defined as "an acute, clinically significant respiratory deterioration characterized by evidence of new widespread alveolar abnormality" [31]. AE-IPF may result from direct lung injury due to chemical, mechanical, or autoimmune etiologies. Further details of risk factors, evaluation, diagnosis, and management of AE-IPF are discussed elsewhere. (See "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 1)
•Respiratory syncytial virus, for those age ≥60 years [32]
There have been several reports of AE-IPF following COVID-19 mRNA vaccine administration [33-36]. However, both case reports [37-39] and clinical experience inform us that infection with COVID-19 poses a larger risk for respiratory failure than vaccination in patients with IPF. 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".)
●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 IPF are designated by the CDC as persons at risk for severe COVID-19 (table 2) 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 IPF should be screened clinically for oropharyngeal dysphagia with a low threshold for formal evaluation [40]. 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, with consideration of surgical options in patients with severe disease. Empiric treatment of reflux in asymptomatic patients is not recommended. (See 'Empiric treatment for asymptomatic gastroesophageal reflux' below.)
●Avoidance of mechanical ventilation – 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.
●Avoidance of harmful therapies – Several pharmacologic interventions have been found to be harmful to patients with IPF in large clinical trials. These include the combination of prednisone, azathioprine, and N-acetyl cysteine [41], warfarin in patients without an additional indication for anticoagulation [42], and ambrisentan [43]. In general, we avoid broadly immunosuppressive therapies unless the patient has a strong alternative indication. (See 'Therapies without clear benefit' below.)
Palliative care — Palliative care aims to relieve suffering at all stages of disease and is not limited to end-of-life care [44-46]. Palliative measures (eg, facial cooling with a fan, opioids, anxiolytics) may be helpful for patients with refractory dyspnea or cough. Patients with advanced IPF may benefit from hospice care (table 3 and table 4). (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".)
MEDICAL THERAPIES — No medication has been found to cure IPF, but two antifibrotic medications, nintedanib and pirfenidone, appear to slow disease progression and reduce the frequency of acute exacerbations [2,4,47,48]. In addition, these agents appear to have a mortality benefit [48,49]. A meta-analysis of trials and cohorts that included 12,956 patients with IPF showed that antifibrotic treatment (nintedanib or pirfenidone) was associated with a decreased risk of all-cause mortality (pooled risk ratio [RR] 0.55, 95% CI 0.45-0.66) and a decreased risk of acute exacerbations (RR 0.63, 95% CI 0.53-0.76) [48]. A large cohort analysis of nearly 50,000 patients with IPF in the United States (24 percent had received antifibrotic treatment) found a significantly improved estimated all-cause mortality (HR 0.69, 95% CI 0.66-0.72) after adjustment for covariates [50]. In the United States, racial disparities in antifibrotic treatments may adversely impact Black patients [51]; we strongly urge physicians to closely examine their prescribing patterns to ensure equitable care for all racial and ethnic groups.
Our approach — For patients with mild or moderate IPF based on pulmonary function tests who do not have underlying liver disease, we recommend initiating therapy with either nintedanib or pirfenidone [4]. Current data are insufficient to direct a firm choice between pirfenidone and nintedanib, and the choice sometimes must be made based on availability. When there is a choice of agent, patient preference and tolerances should be considered, particularly regarding potential adverse effects, such as diarrhea with nintedanib versus nausea and rash with pirfenidone. (See 'Nintedanib' below and 'Pirfenidone' below.)
In addition, for patients with more advanced IPF (forced vital capacity [FVC] <50 percent predicted and/or diffusing capacity [DLCO] <35 percent predicted), we suggest using one of these two agents. The decision is less clear, as these patients were excluded from the major clinical trials. Observational studies suggest that both agents slow disease progression in patients with more advanced disease to a similar extent as that seen in treated patients with less advanced disease [52,53].
Studies examining the combination of nintedanib and pirfenidone are discussed below. As none of these agents are curative, we also provide patients with information about clinical trials. (See 'Combination nintedanib plus pirfenidone' below and 'Clinical trials' below.)
Patients with severe pulmonary hypertension (eg, echocardiographic estimated systolic pulmonary artery pressure ≥60 mmHg) due to advanced IPF should be referred to a specialized pulmonary hypertension center for management. Use of inhaled treprostinil may be beneficial in this population. Other advanced therapies for pulmonary arterial hypertension (eg, systemic prostanoids, sildenafil) may be helpful in select patients with IPF, although trials of oral pulmonary vasodilators have not demonstrated benefit in clinical trials. The use of systemic pulmonary vasodilators risks worsening ventilation-perfusion matching and increasing hypoxemia and should be performed with caution in advanced centers. (See 'Therapies without clear benefit' below and "Pulmonary hypertension due to lung disease and/or hypoxemia (group 3 pulmonary hypertension): Treatment and prognosis".)
Nintedanib — Nintedanib, a receptor blocker for multiple tyrosine kinases that mediate elaboration of fibrogenic growth factors (eg, platelet-derived growth factor, vascular endothelial growth factor (VEGF), fibroblast growth factor), slows the rate of disease progression in IPF [54,55]. Nintedanib has been approved by the US Food and Drug Administration, the European Medicines Agency, and a number of other countries [56].
Dose and administration — The standard dose of nintedanib is 150 mg twice daily, approximately 12 hours apart. Liver function tests (LFTs; alanine aminotransferase [ALT], aspartate aminotransferase [AST], bilirubin) should be assessed prior to initiation of nintedanib; patients with moderate or severe hepatic impairment (Child Pugh B or C) should not take nintedanib [57]. After initiation, LFTs should be repeated monthly for three months, every three months thereafter, and as clinically indicated. Dose modification or interruption may be necessary for liver enzyme elevations. A pregnancy test should be performed prior to initiation of therapy in women of child-bearing age, and conception avoided until at least three months after the last dose [57]. Nintedanib has not been studied in patients with creatinine clearance <30 mL/min. It should be used with caution in patients with kidney impairment given reports of proteinuria and other kidney toxicity with use of nintedanib and other VEGF inhibitors [58]. (See "Non-cardiovascular toxicities of molecularly targeted antiangiogenic agents", section on 'Class side effects of VEGF inhibitors'.)
Nintedanib interacts with P-glycoprotein and CYP3A4 inhibitors and inducers and may also increase the risk of bleeding among patients on full anticoagulation.
The most frequent adverse effects associated with nintedanib are diarrhea (62 percent), nausea (24 percent), vomiting (12 percent), and elevation in LFTs (14 percent), which were greater than five times normal in 6 percent [55,57]. In clinical trials, diarrhea was treated with hydration, antidiarrheal medication (eg, loperamide), and sometimes reduction in the dose to 100 mg twice daily. If the lower dose was not tolerated, treatment was interrupted. Diarrhea led to permanent dose reduction in 11 percent of patients and to discontinuation in 5 percent. Observational studies in real-world settings suggest higher rates of dose reduction (20 to 30 percent) and variable rates of drug discontinuation (5 percent to 25 percent) due to gastrointestinal side effects [59-62].
Efficacy — In clinical trials, the main benefits of nintedanib are a reduction in the rate of decline in lung function and a longer time to first exacerbation [52,55,63-66].
●Nintedanib (BIBF 1120) showed promising results in a phase 2 trial (To Improve Pulmonary Fibrosis with BIBF 1120, TOMORROW) [63]. A total of 432 patients were randomly assigned to one of four oral doses of BIBF 1120 or placebo. The group taking the highest dose of BIBF 1120, 150 mg twice daily, showed a trend toward a slower decline in lung function and fewer exacerbations compared with placebo.
In a two-year extension of the TOMORROW trial, FVC decline was significantly less in patients taking nintedanib 150 mg twice a day compared with placebo or a lower dose of nintedanib (125.4 mL/year versus 189.7 mL/year) [65].
●In two subsequent trials (INPULSIS-1 and INPULSIS-2), a total of 1066 patients with IPF were randomly assigned to nintedanib 150 mg or placebo twice daily for 52 weeks [55]. In INPULSIS-1, the annual rate of decline in FVC was lower in the nintedanib group than the placebo group with a difference of 125.3 mL/year (95% CI 77.7-172.8). The results were similar in INPULSIS-2 where the difference in FVC decline was 93.7 mL/year (95% CI 44.8-142.7). In INPULSIS-1, no difference between nintedanib and placebo was noted in the time to first exacerbation, but in INPULSIS-2, an increase in the time to first exacerbation was noted (hazard ratio [HR] 0.38, 95% CI 0.19-0.77).
Additional subgroup analysis of data from this trial showed that the treatment effects appeared more pronounced in subjects with baseline FVC ≤70 percent predicted [64]. A separate post-hoc analysis (1061 participants) examined the annual rate of decline in FVC over the 52 weeks of INPULSIS; among patients taking nintedanib, 25 percent had improvement or lack of decline in FVC, compared with 9 percent of those taking placebo [67].
●In a combined analysis of data from the TOMORROW trial and the two INPULSIS trials [55,63], nintedanib significantly reduced the risk of acute exacerbation (HR 0.53, 95% CI 0.34-0.83) [66].
The tyrosine kinase inhibitor, imatinib, inhibits a narrower spectrum of growth factors than nintedanib and had no effect on survival or lung function in IPF when compared with placebo [68].
Role in more advanced disease — Based on observational data, nintedanib appears to have a similar effect in slowing decline in pulmonary function tests among patients with more advanced disease, compared with patients with less advanced disease [53,69,70]. However, studies have not demonstrated a benefit in activities of daily living or survival, and adverse effects are frequent, leading to high treatment discontinuation.
In a prospective study, nintedanib was administered to 108 patients with IPF, of whom 51 (47 percent) had advanced disease (FVC <50 percent predicted or DLCO <30 percent predicted) [70]. The rate of disease progression (≥10 percent absolute decline in FVC over 12 months) in the advanced disease group decreased in the 12 months after treatment initiation, compared with the 12 months before (9 versus 79 percent, p<0.001). Declines in FVC and DLCO in the advanced group paralleled those in the nonadvanced disease group. Adverse events were common, including diarrhea (50 percent) and anorexia (45 percent). While similar in occurrence between the two groups, they are more likely to lead to treatment discontinuation in the advanced group.
A separate observational study of 41 patients with advanced IPF (FVC ≤50 percent of predicted and/or DLCO ≤35 percent predicted) compared lung function decline during nintedanib treatment with the six months prior to initiation [53]. The decline in DLCO (both absolute and percent predicted) was lower during nintedanib treatment than in the pretreatment period, but no difference was noted in FVC decline.
Pirfenidone — The predominant pathological findings in IPF are fibroblast foci, collagen deposition, and minimal inflammatory cell infiltration, raising the possibility that antifibrotic agents might slow the rate of disease progression [71,72]. Pirfenidone is an antifibrotic agent that inhibits transforming growth factor beta (TGF-b)-stimulated collagen synthesis, decreases the extracellular matrix, and blocks fibroblast proliferation in vitro. (See "Pathogenesis of idiopathic pulmonary fibrosis".)
Pirfenidone is approved for marketing in a number of countries, including (among others) Germany, France, the United Kingdom, Canada, Japan, and the United States.
Dose and administration — The dose of pirfenidone ranges up to 40 mg/kg per day (to maximum of 2403 mg per day) in three divided doses. Pirfenidone is initiated at a dose of 267 mg (1 capsule) three times a day. After one week, the dose is increased to 534 mg (two capsules) three times a day, and after the second week to the full dose of 801 mg (three capsules) three times a day. Pirfenidone should always be taken with food.
The most common side effects include rash (30 percent), photosensitivity (9 percent), nausea (36 percent), diarrhea (26 percent), abdominal discomfort (24 percent), dyspepsia (19 percent), anorexia (13 percent), and fatigue (26 percent) [73]. Other potential side effects include diarrhea, constipation, itching, dry skin, hyperpigmentation, headache, and weakness. Although most rashes are minor, severe cutaneous adverse reactions, including Stevens-Johnson syndrome, toxic epidermal necrolysis, and drug reaction with eosinophilia and systemic symptoms (DRESS) have been reported. Confirmation of any of these reactions precludes further treatment with pirfenidone.
In the CAPACITY trials (described further below), dose reduction or interruption for gastrointestinal events was required in 18 percent of patients in the 2403 mg/day group, and 2 percent discontinued study medication. In a separate study, pirfenidone-associated gastrointestinal side effects occurred less frequently in those eating a diet high in mono-unsaturated fatty acids compared with those with diets high in saturated fatty acids (27 versus 65 percent) [74]. Taking the medication after meals may improve the gastrointestinal side effects [75]. Diet adjustments have not been well studied, but a trial of a Mediterranean-style diet may also be reasonable based on these data.
Drug-induced liver disease can occur and ranges from mild elevations in LFTs to serious or fatal liver injury [76]. Elevations in LFTs three times the upper limit of normal or higher occurred in 4 percent of patients in phase 3 trials [73]. All LFT elevations resolved with dose modification or treatment discontinuation. LFTs (eg, ALT, AST, bilirubin) should be obtained prior to initiation of therapy and at regular intervals during therapy (eg, approximately monthly for the first six months and at three month intervals thereafter and as clinically indicated) [73]. Elevations in the ALT and/or AST may require a reduction or interruption in dose.
In kidney impairment, there is an accumulation of potentially active metabolites [77]. Based on this data, European regulators do not recommend use of pirfenidone in patients with CrCl <30 mL/min; United States prescribing information suggests close monitoring and possible need for dose adjustment. In small open-label trials including patients with eGFR 15 to 30 mL/min/1.73m2, side effect profiles were similar to those of patients without impaired kidney function, but drop-out rates were high (35 to 45 percent), even after dose reduction [78,79]. A slower titration (dose increases every two to three weeks) is indicated in the setting of CrCl <30 mL/min and pirfenidone should not be given to patients with CrCl <15 mL/min or patients on dialysis.
The dose of pirfenidone should be reduced in the presence of strong or moderate CYP1A2 inhibitors (eg, fluvoxamine, ciprofloxacin) [73].
Efficacy — For patients with mild-to-moderate disease based on pulmonary function tests who are not interested in participating in a clinical trial and live in an area where pirfenidone is available, we recommend initiation of pirfenidone [4]. This recommendation is based upon data from randomized trials and case series that have shown a beneficial effect of pirfenidone in slowing the progression of IPF when administered to patients with mild-to-moderate disease and a possible mortality benefit in a pooled analysis [80-87]. As examples:
●In the ASsessment of pirfenidone to Confirm Efficacy aND safety in idiopathic pulmonary fibrosis (ASCEND) trial, 555 patients with IPF were randomly assigned to receive oral pirfenidone (2403 mg per day) or placebo for 52 weeks [88]. Pirfenidone resulted in a significant reduction in the one-year rate of decline in FVC; the proportion of patients in the pirfenidone group who had a decline of 10 percentage points or more in the percent of predicted FVC or died was reduced by 48 percent compared with the placebo group (46 patients [16.5 percent] versus 88 patients [31.8 percent]), respectively. Nearly 23 percent of the pirfenidone group had no decline in percent of predicted FVC at week 52, compared with 10 percent of the placebo group, representing a more than 133 percent increase in the proportion of patients with no evidence of FVC decline. As secondary end-points, pirfenidone reduced the rate of decline in the six-minute walk difference and improved progression-free survival compared with placebo but did not reduce dyspnea. In a prespecified analysis that pooled results of the ASCEND trial with two prior trials (CAPACITY 004 and 006; 1247 total patients) [83], pirfenidone decreased death from any cause relative to placebo (22 [3.5 percent] in the pirfenidone group as compared with 42 [6.7 percent] in the placebo group; HR 0.52, 95% CI 0.31-0.87). As the ASCEND trial was 52 weeks in duration, the pooled survival analysis only considered data from the first 52 weeks of the CAPACITY trials (which were 72 weeks in duration). A separate pooled analysis considering all available data on all-cause mortality showed a trend favoring pirfenidone but was not statistically significant (Kaplan-Meier estimate 0.75, 95% CI 0.51-1.11).
●Two concurrent, multicenter trials (Clinical studies Assessing Pirfenidone in idiopathic pulmonary fibrosis, CAPACITY 004 and 006) assessed the change in percentage FVC at week 72 [83]. Patients with mild-to-moderate IPF (ie, FVC ≥50 percent predicted and DLCO ≥35 percent predicted) were randomly assigned to oral pirfenidone 2403 mg/day, 1197 mg/day, or placebo in the 004 trial and oral pirfenidone 2403 mg/day or placebo in the 006 trial. The higher dose of pirfenidone significantly decreased the percent fall in FVC in the 004 trial (difference between groups 4.4 percent, p = 0.001) but not the 006 trial (difference between groups 0.6 percent, p = 0.51). The higher dose of pirfenidone significantly reduced the decline in the six-minute walk test, a secondary endpoint, in the 006 (absolute difference 32 meters, p = 0.0009), but not the 004 trial.
●A randomized trial of pirfenidone (1800 mg/day) versus placebo was carried out in 107 patients with IPF [81]. The change in the lowest oxygen saturation by pulse oximetry (SpO2) during a six-minute exercise test, the primary endpoint, was not significantly different between the two groups from baseline to six months (+0.6 versus -0.5 percent) and nine months (+0.5 versus -0.9 percent). In a prespecified subset of patients who maintained the SpO2 >80 percent during a six-minute exercise test at baseline, a significant improvement was noted in the pirfenidone group in the lowest SpO2 that occurred during a six-minute exercise test at six months (+0.5 versus -1.9 percent) and nine months (+0.5 versus -1.6 percent), suggesting there may be greater benefit in patients whose disease is less severe.
In the same trial, a positive treatment effect was demonstrated in secondary endpoints including an increase in vital capacity (VC) measurements at nine months (-0.03 versus -0.13 liters) and fewer episodes of acute exacerbation of IPF (14 percent versus none). The trial was aborted in favor of pirfenidone treatment due to the decreased number of acute exacerbations in the pirfenidone group.
●In a separate multicenter trial, 275 patients were randomly assigned to one of three groups: pirfenidone 1800 mg per day, 1200 mg per day, or placebo [82]. The primary endpoint, change in VC, was assessed at 52 weeks; the secondary endpoint was progression-free survival. The decline in VC was only slightly less in the high-dose pirfenidone group compared with placebo, but the difference was statistically significant. The progression-free survival time was slightly longer in the high-dose pirfenidone group compared with placebo.
●A pooled analysis of ASCEND and CAPACITY 004 and 006 study data demonstrated that patients treated with pirfenidone for one year were >40 percent less likely to reach the threshold of a 10 percent fall in FVC or death and 38 percent less likely to progress at all, compared with those on placebo [87].
●In a follow-up to the original ASCEND and CAPACITY trials, 34 subjects on pirfenidone and 68 subjects on placebo who experienced a ≥10 percent decline in FVC in the first three or six months were assessed again six months later [89]. Fewer subjects in the pirfenidone group experienced a further ≥10 percent decline in FVC or death in the following six months compared with the placebo group (2 of 34 versus 19 of 68, respectively, p<0.009). While the numbers are small, this study suggests that continued pirfenidone treatment may be of benefit in patients despite initial evidence of disease progression.
●A pooled analysis of the combined patient populations of the three global randomized phase 3 trials of pirfenidone versus placebo (CAPACITY 004 and 006 and ASCEND) and a meta-analyses of two Japanese trials showed a reduction in treatment-emergent all-cause mortality, idiopathic-pulmonary-fibrosis-related mortality, and treatment-emergent idiopathic-pulmonary-fibrosis-related mortality for pirfenidone therapy compared with placebo [90].
Pirfenidone appears to slow the progression of lung impairment in patients with pulmonary fibrosis due to Hermansky-Pudlak syndrome [91]. (See "Hermansky-Pudlak syndrome".)
Role in more advanced disease — Studies of pirfenidone in patients with more advanced disease are limited, as these patients were excluded in the pivotal trials described above (see 'Efficacy' above). However, subsequent data suggest that the efficacy of pirfenidone in slowing decline in FVC is similar across the range of disease severity [92-95]. Further study is needed to determine whether pirfenidone has a benefit in terms of quality of life and/or survival.
A post-hoc analysis of the open-label extension study RECAP included 187 patients with more advanced IPF (FVC <50 percent predicted and/or DLCO <35 percent predicted), while 409 patients had less advanced disease (FVC ≥50 percent predicted and/or DLCO ≥35 percent predicted) [93]. Of the patients with more advanced disease, 100 had received pirfenidone during the CAPACITY trial and 87 received placebo; all of the patients transitioned to pirfenidone at the start of RECAP. During the 180 weeks of RECAP, the decline in mean percent-predicted FVC in the group with more advanced disease paralleled that of the group with less advanced disease. Adverse events related to IPF progression (eg, dyspnea, worsening of IPF) were more common among those with more advanced than less advanced disease, as was discontinuation of study drug (72 versus 43 percent).
Clinical trials — The best hope for patients with IPF is that carefully performed clinical trials will confirm the efficacy and safety of agents that are identified based on animal models of IPF. We encourage appropriate patients to participate in clinical trials of emerging therapies for IPF. Specific trials and registries are available for patients with a familial history of IPF. 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. Patients with mild-to-moderate disease are frequently ideal candidates for clinical trials as many trials limit participation to patients with early disease.
Clinical trial information is available at ClinicalTrials.gov. Information about research into the genetic factors that may contribute to the development of familial IPF is available at ClinicalTrials.gov: Genetics of IPF.
LUNG TRANSPLANTATION — IPF is the most common interstitial lung disease among referrals for lung transplantation and the second most frequent disease for which lung transplantation is performed [96]. The median survival following lung transplantation for IPF is estimated to be 5.2 years (figure 2) [96].
Indications and choice of procedure — Patients with IPF have the highest death rate among the diagnostic groups on the transplant waiting list [97]. For this reason, early referral for transplant evaluation should be considered, even before the response to initial medical therapy has been determined [98-100]. Under the current United Network for Organ Sharing (UNOS) system, priority for transplantation is determined by medical urgency and expected outcome using a lung composite allocation score (CAS) (table 5). Scores are normalized to a continuous scale from 0 to 100, with higher scores representing higher priority, in part based on higher expected waiting list mortality and greater potential transplant benefit. (See "Lung transplantation: An overview", section on 'Lung allocation' and "Lung transplantation: Disease-based choice of procedure".)
General guidelines for timing of referral for transplantation include histologic or radiographic evidence of usual interstitial pneumonia (UIP) and the following [101]:
●A diffusing capacity (DLCO) <40 percent of predicted
●A forced vital capacity (FVC) <80 percent of predicted
●Any dyspnea or functional limitation attributable to lung disease
●A decrease in pulse oximetry below 89 percent saturation, even if only during exertion
Criteria for placing on transplant list include the following [101]:
●Decline in FVC ≥10 percent during six months of follow-up (a decline ≥5 percent may also warrant listing)
●Decline in DLCO ≥15 percent during six months of follow-up
●On six-minute walk test: oxygen desaturation to <88 percent or distance walked <250 meters or >50 meter decline in distance walked over six months
●Pulmonary hypertension on right heart catheterization or transthoracic echocardiogram
●Hospitalization because of respiratory decline, pneumothorax, or acute exacerbation
Although single lung transplantation (SLT) has been the standard procedure for IPF, bilateral lung transplant (BLT) may prove to have better long-term survival [96,102-105]. Mild-to-moderate secondary pulmonary hypertension preoperatively increased the risk of reperfusion injury in one study but did not appear to affect survival in two retrospective studies [106,107].
Following SLT, the low lung compliance and high vascular resistance of the remaining native lung preferentially direct both ventilation and perfusion to the transplanted lung. Cysts, bullae, and bronchiectasis that occasionally develop in the later stages of IPF can act as a nidus for infectious complications after SLT; when these are identified, BLT may be preferred.
Early experience suggests that living donor lobar lung transplantation (LDLLT) may be an option for patients with IPF who are likely to die while waiting for SLT. In a report of nine such patients, eight of whom were dependent on systemic glucocorticoids (up to 50 mg/day), only one early death occurred after transplant of two lower lobes donated by two healthy relatives [108]. Eight patients were still alive after 10 to 48 months of follow-up.
Physiologic changes — After SLT or BLT, spirometric parameters, lung volumes, diffusing capacity, and oxygenation improve significantly and these improvements have been sustained in long-term follow-up of recipients without complications [109-112]. In a series that compared SLT and BLT recipients with IPF, the mean forced expiratory volume in one second (FEV1) was higher in BLT recipients than SLT recipients one year after transplantation (2.25 versus 2.00 liters) [112].
After SLT, most lung function is contributed by the allograft. As a result, the vital capacity (VC) of the recipient correlates closely with the predicted VC of the donor organ [113]. Improvements in cardiopulmonary function continue for up to one year following transplantation. As an example, in one study of SLT recipients, the mean VC increased from 43 percent of the predicted normal value preoperatively to 65 percent three months and 69 percent one year after transplantation. None of the eight recipients tested one year after transplantation required supplemental oxygen at rest or during exercise, and their treadmill exercise tolerance was much improved [111].
Factors that may increase the risk of transplantation — Mutations in the genes that contribute to maintenance of telomere length and pretransplant systemic glucocorticoid use may increase the risk of adverse outcomes following lung transplantation.
Telomerase complex mutations — Mutations in the telomerase complex (eg, TERT and TR) are associated with IPF and also with hematologic manifestations such as myelodysplasia, which may place patients undergoing lung transplantation at risk for adverse hematologic outcomes [114-118]. Among nine patients with TERT or TR mutations who underwent lung transplantation for IPF, six developed bone marrow failure and/or myelodysplasia, which contributed to death in four patients [114]. Thrombocytopenia was present in seven patients prior to surgery. Postoperatively, anemia developed in all of the patients, and neutropenia developed in three. In a separate series, eight patients with telomerase mutations received lung allografts and were noted to have a greater need for platelet transfusion and adjustment of the immunosuppressive regimen compared with historic controls. However, seven patients were alive after a median follow-up of 1.9 years (range six months to nine years) [115]. While long-term survival following lung transplant appears feasible, careful assessment of hematologic status is appropriate prior to lung transplantation [116,118]. (See "Dyskeratosis congenita and other telomere biology disorders".)
Glucocorticoid therapy — The effect of prior glucocorticoid therapy on the outcome of lung transplantation is uncertain. Most studies suggest that low-dose glucocorticoid therapy has no adverse effect on outcome [119-121]. However, high-dose glucocorticoid therapy may be associated with decreased survival after lung transplantation [121]. (See "Lung transplantation: General guidelines for recipient selection".)
THERAPIES WITHOUT CLEAR BENEFIT — Several agents have been evaluated for use in IPF but are not currently used for this indication. The following agents are mentioned here to provide clinicians with an overview of the evidence for and against their use.
Empiric treatment for asymptomatic gastroesophageal reflux — Although observational and genetic data indicate a possible role for gastroesophageal reflux (GER) in IPF pathogenesis and progression [122-129], we suggest not treating patients who have IPF with empiric pharmacologic or surgical treatment of GER. However, use of these therapies for symptomatic relief or esophageal disease in patients with confirmed GER may be appropriate. Our approach is consistent with guidelines from major expert panels [130].
GER is common among patients with IPF [131-133]. In a systematic review, it was noted that 67 to 76 percent of patients with IPF assessed with ambulatory pH probe monitoring had abnormal distal esophageal acid exposure [134].
However, a pooled analysis of post-hoc data from randomized trials found that antacid medications led to a small and statistically insignificant benefit on disease progression, as defined by 10 percent decline in forced vital capacity (FVC), 50 m decline in six-minute walk test, or death (risk ratio [RR] 0.88, 95% CI 0.76-1.03) [135]. Additional observational data pointed to a lack of effect on mortality, hospitalization, or lung function outcomes.
One small unblinded trial of 58 patients compared antireflux surgery to no intervention [136]. There was a trend toward reduced overall mortality at 48 weeks in those receiving antireflux surgery (3 versus 14 percent, RR 0.25, 95% CI 0.03-2.10). Similar findings were seen for adjudicated exacerbation rates. A separate observational study reported a smaller trend toward improved mortality at 48 weeks (hazard ratio [HR] 0.74, 95% CI 0.21-2.59) [137]. No differences were seen in hospitalizations or lung function parameters in either of these studies. Severe surgical complications are common (9 percent in one systematic review) [135]. These complications included gastric perforation, severe intraoperative bleeding, rehospitalization for nausea or dysphagia, or need for esophageal dilation.
Anticoagulation — Therapeutic anticoagulation of patients with IPF using warfarin was investigated due to observational evidence of a possible IPF-mediated prothrombotic state [138,139], but this strategy is not recommended due to evidence of increased mortality.
After a small unblinded trial showed possible benefit from warfarin anticoagulation [140], the Anticoagulant Effectiveness in Idiopathic Pulmonary Fibrosis trial (ACE-IPF) was performed [42,141,142]. In ACE-IPF, 145 patients with IPF but without other indications for anticoagulation were randomly assigned to therapeutic warfarin or placebo [42]. The study was stopped at 28 weeks due to an increase in mortality in the patients assigned warfarin (14 versus 3 deaths). None of the deaths were attributed to bleeding complications.
Anticoagulation may still be appropriate in patients with IPF if there are other indications (eg, pulmonary embolism).
Maintenance antibiotic therapy — Alteration of the lung microbiome occurs in patients with IPF [143,144] and may influence disease progression and exacerbations [145]. However, randomized trials of maintenance trimethoprim-sulfamethoxazole or doxycycline failed to show an effect on time to nonelective hospitalization, mortality, or other secondary clinical outcomes compared with usual care [146,147].
Azathioprine, prednisone, and (N) acetylcysteine — The historical strategy of treating patients with IPF using azathioprine, prednisone, and (N) acetylcysteine (NAC) is harmful and should not be used. The multicenter PANTHER trial (Prednisone, Azathioprine, and NAC: A Study That Evaluates Response in IPF) found that, compared with placebo, combination therapy (prednisone-azathioprine-NAC) was associated with greater mortality (8 versus 1 deaths), more hospitalizations (23 versus 7), and more serious adverse events (24 versus 8) [41].
(N) acetylcysteine — Although lung injury from excess production of oxidants is thought to be a contributing factor in IPF [148-154], the potent antioxidant NAC does not ameliorate the course of IPF [150-153,155] and should not be used as monotherapy [4]. (See "Pathogenesis of idiopathic pulmonary fibrosis".)
The PANTHER trial, also mentioned above, showed that NAC alone (1800 mg orally per day) did not slow the decline in FVC over 60 weeks compared with placebo [41,156]. (See 'Azathioprine, prednisone, and (N) acetylcysteine' above.)
Furthermore, NAC did not reduce deaths or acute exacerbations but appeared to increase the rate of serious adverse cardiac events (6.8 versus 1.5 percent).
Other immunosuppressants — After the results of the PANTHER trial, which demonstrated harm from prednisone-azathioprine-NAC, we do not believe there is a role for broadly targeted immunosuppressants in the treatment of IPF. (See 'Azathioprine, prednisone, and (N) acetylcysteine' above and '(N) acetylcysteine' above.)
Based in part on the harms seen in PANTHER, we no longer use systemic glucocorticoid monotherapy in IPF treatment. Multiple studies have found lack of benefit for cyclophosphamide and etanercept in IPF [157,158], and there have been no data to suggest a benefit of other broadly immunosuppressive agents such as cyclosporine or methotrexate. Colchicine and interferon gamma-1b were similarly without benefit in clinical trials [159-163].
Endothelin receptor antagonists — Several trials examining the efficacy of endothelin receptor antagonists in IPF found that these agents were not beneficial and possibly harmful [43,164-167]. This class of drugs is not being used in IPF treatment [4].
Phosphodiesterase-5 inhibitors — A substantial portion of advanced IPF patients develop pulmonary hypertension (PH). However, trials of sildenafil in patients with advanced IPF have failed to show significant benefit [4,168-172]. Sildenafil is therefore not routinely used in this setting. The use of phosphodiesterase inhibitors in PH is discussed separately. (See "Pulmonary hypertension due to lung disease and/or hypoxemia (group 3 pulmonary hypertension): Treatment and prognosis".)
Collagen-modifying agents — Despite the plausible mechanism of impairing collagen deposition, there was no benefit from penicillamine in multiple observational studies [162,173,174]. An investigational molecule targeting the collagen cross-linking enzyme lysyl-oxidase 2 (simtuzumab) was also shown to be ineffective [175].
FUTURE DIRECTIONS — None of the agents currently available for the treatment of IPF are curative. Therapeutic response is obtained in only a subset of patients, and survival is poor even for those who respond. In addition, these agents all carry significant side effects and toxicity. For these reasons, there is much interest in developing more effective, less toxic pharmacologic therapy [176,177]. Some examples of potential future strategies are described below.
Combination nintedanib plus pirfenidone — Nintedanib and pirfenidone slow but do not halt IPF progression (see 'Medical therapies' above). The potential benefit of combined therapy with these two agents is unclear. The safety and tolerability of this combination therapy has been evaluated, and fewer than 25 percent of patients on this combination need to stop therapy due to adverse events [178-181].
As an example, an open-label, phase 4 study assessed the safety and tolerability of treatment with pirfenidone (1602 to 2403 mg/day) plus nintedanib (200 to 300 mg/day) in patients with IPF [180]. The primary endpoint was safety and tolerability of this regimen. Combined pirfenidone and nintedanib use for 24 weeks was tolerated by the majority (78 percent) of patients and associated with a similar pattern of treatment-emergent adverse events as expected for either treatment alone.
Phosphodiesterase 4B inhibitor (BI 1015550) — Phosphodiesterase 4 (PDE4) blockade, which prevents the degradation of cyclic adenosine monophosphate, has antifibrotic and immunomodulatory effects [182]. The selective inhibition of the 4B isoform is expected to improve tolerability by reducing off-target side effects, particularly nausea, emesis, and diarrhea.
In a phase 2 trial, 97 patients with IPF were randomly assigned to receive 18 mg of the PDE4 inhibitor BI 1015550 or placebo twice daily for 12 weeks. The group receiving BI 1015550 was compared with patients receiving placebo in this trial and in previous trials. In patients not taking antifibrotics, forced vital capacity (FVC) increased at 12 weeks with BI 1015550 and decreased with placebo (+5.7 versus -81.7 mL) [183]. In patients receiving background antifibrotics, the benefit was smaller but still significant (+2.7 versus -59.2 mL). Ten patients on background antifibrotics and three patients not on background therapy stopped the drug for adverse events.
Pentraxin 2 — Pentraxin 2 (serum amyloid P) inhibits monocyte differentiation into profibrotic fibrocytes or proinflammatory macrophages, as well as reduces the production of transforming growth factor (TGF)-beta1, a potent regulator of connective tissue synthesis. Pentraxin 2 concentrations are lower in plasma from patients with IPF than in healthy individuals [184]. (See "Pathogenesis of idiopathic pulmonary fibrosis".)
In a phase 2 trial, 111 patients with IPF, most of whom were treated with an antifibrotic agent, received recombinant human pentraxin 2 (10 mg/kg) or placebo intravenously every four weeks for 24 weeks. Patients in the pentraxin 2 group experienced slower decline in FVC (-2.5 versus -4.8 percent) [185]. The most common adverse events were cough and fatigue. In a 76-week open-label extension, the patients who crossed over from placebo to pentraxin 2 showed slowed deterioration of lung function and six-minute walk distance similar to that seen in the initial study [186]. Findings were consistent at 128 weeks [187]. Pentraxin 2 was generally well-tolerated.
A phase 3 placebo-controlled trial (STARSCAPE) evaluating the efficacy and safety of recombinant human pentraxin-2 (rhptx-2; prm-151) in patients with IPF was discontinued because of failure to meet the primary endpoint.
Pamrevlumab (FG-3019) — Pamrevlumab (FG-3019) is a fully humanized, monoclonal antibody specifically designed to target connective tissue growth factor, a central mediator in the pathogenesis of fibrosis [188]. (See "Pathogenesis of idiopathic pulmonary fibrosis", section on 'Cytokines, growth factors, and other molecules'.)
In a phase 2 trial of 103 patients with IPF, patients receiving intravenous pamrevlumab (30 mg/kg every three weeks) had a smaller decline in FVC at 48 weeks compared with patients receiving placebo (-2.9 versus -7.2 percent) [189]. A decline of greater than 10 percent in FVC or death was less frequent in the pamrevlumab group (10 versus 31 percent).
The phase 3 ZEPHYRUS-1 and ZEPHYRUS-2 trials evaluating the safety and efficacy of pamrevlumab in patients with IPF were discontinued because of failure to meet both the primary endpoint of change from baseline in FVC at week 48 and the secondary endpoint of time to disease progression (FVC decline of ≥10 percent predicted or death).
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: Pulmonary rehabilitation".)
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 5th to 6th 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 10th to 12th 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 topic (see "Patient education: Idiopathic pulmonary fibrosis (The Basics)" and "Patient education: Pulmonary rehabilitation (The Basics)")
SUMMARY AND RECOMMENDATIONS
●Overview – Management of IPF generally includes a combination of supportive care, use of selected medications (eg, pirfenidone, nintedanib), consideration for participation in clinical trials, referral for lung transplant evaluation (when appropriate), and identification and treatment of comorbidities. (See 'Our approach' above.)
●Supportive care – We offer supportive care (eg, supplemental oxygen, pulmonary rehabilitation, and COVID-19, pneumococcal, and seasonal influenza vaccination) and provide information about end-of-life issues and advanced directives to all patients. (See 'General approach' above and 'Supportive care' above.)
We use several preventive measures to reduce the risk of lung injury and consequent acute exacerbations of IPF. These include vaccination against respiratory viruses and infections, early treatment of bacterial or viral pulmonary infection, screening for and treatment of dysphagia and reflux aspiration, and avoidance of mechanical ventilation in elective procedures. (See 'Prevention of pulmonary infections and acute exacerbations' above.)
Palliative measures (eg, facial cooling with a fan, opioids, anxiolytics) may be helpful for patients with refractory dyspnea or cough. Patients with advanced IPF may benefit from palliative care (table 3 and table 4). (See 'Palliative care' above.)
●Antifibrotic therapy – For patients with mild-to-moderate IPF based on pulmonary function tests who live in an area where either pirfenidone or nintedanib is available, we recommend initiating therapy with the available agent (Grade 1B). Current data are insufficient to direct a firm choice between nintedanib and pirfenidone. Patient preference and tolerances should be considered, particularly regarding potential adverse effects. (See 'Our approach' above and 'Assessing disease severity and prognosis' above.)
•The dose of nintedanib is 150 mg by mouth twice daily. Patients with known liver disease (Pugh B or worse) or full anticoagulation are not candidates for nintedanib. Diarrhea, nausea, vomiting, and liver function test elevation are common side effects of nintedanib. (See 'Nintedanib' above.)
•The dose of pirfenidone ranges up to 40 mg/kg per day (to maximum of 2403 mg per day) in three divided oral doses. Rash, photosensitivity, nausea, and abdominal discomfort are common side effects of pirfenidone. (See 'Pirfenidone' above.)
•In patients with more severe IPF, we also suggest therapy with either nintedanib or pirfenidone (Grade 2C). Based on observational data, nintedanib and pirfenidone appear to reduce lung function decline in patients with more advanced disease, like the effect in less advanced disease. The decision to try one of these medications depends on the values and preferences of the patient regarding a choice of active therapy with substantial adverse effects versus supportive care alone. (See 'Role in more advanced disease' above and 'Role in more advanced disease' above.)
●Agents without benefit
•Adjunctive therapies – Use of empiric antireflux medications, anticoagulants, or antibiotics for the improvement of pulmonary outcomes in patients with IPF is unlikely to be beneficial based on negative results from clinical trials. (See 'Empiric treatment for asymptomatic gastroesophageal reflux' above and 'Anticoagulation' above and 'Maintenance antibiotic therapy' above.)
•Immunosuppressants – Systemic glucocorticoid monotherapy, combination therapy with azathioprine, prednisone, and (N) acetylcysteine (NAC), monotherapy with NAC, and other broadly targeted immunosuppressants are no longer part of the routine maintenance care for patients with IPF, as there is no demonstrated efficacy, and they may be harmful. (See 'Azathioprine, prednisone, and (N) acetylcysteine' above and '(N) acetylcysteine' above and 'Other immunosuppressants' above.)
•Oral pulmonary vasodilators – Trials of endothelin receptor antagonists and phosphodiesterase-5 inhibitors failed to show an improvement in dyspnea or quality of life in multiple clinical trials. Although occasionally used for select patients with pulmonary hypertension otherwise out of proportion to the severity of their disease, these agents are not likely to benefit most patients with IPF. (See 'Endothelin receptor antagonists' above and 'Phosphodiesterase-5 inhibitors' above.)
●Lung transplantation – Lung transplantation may be an option for patients with progressive disease and minimal comorbidities. For appropriate patients (based on criteria from the United Network for Organ Sharing [UNOS]), we suggest early referral for lung transplantation evaluation rather than waiting until the patient has developed advanced disease (Grade 2C). (See 'Lung transplantation' above.)
●Participation in clinical trials – While antifibrotic agents slow disease progression, a therapeutic response is obtained in only a portion of patients, and survival is poor even for those who respond. A number of potential therapies are in various stages of development. Participation in clinical trials is an important way to improve the therapeutic options available for IPF. (See 'Future directions' above and 'Clinical trials' above.)
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