Guideline sources The following summarized guidelines for the evaluation and management of idiopathic pulmonary fibrosis (IPF) are prepared by our editorial team based on guidelines from the Latin American Thoracic Association (ALAT/ERS/JRS/ATS 2022; 2018; 2015; 2011), the European Respiratory Society (ERS 2022), the European Society of Cardiology (ESC/ERS 2022), the Japanese Respiratory Society (JRS 2018), the American College of Chest Physicians (ACCP 2018), the French Society of Pulmonology (SPLF 2017), the International Society for Heart and Lung Transplantation (ISHLT 2015), and the British Thoracic Society (BTS/TSANZ/ITS 2008). 1 2 2 2 3 4 5 6 7 8 9 10 11 12 13 14 14 14 Definition IPF is a chronic, progressive fibrosing interstitial pneumonia of idiopathic origin, occurring primarily in older adults, limited to the lungs, and associated with the histopathologic and/or radiologic pattern https://web.pathway.md/diseases/recM02f25EOzK8gCc 1/12 6/24/23, 2:28 PM Idiopathic pulmonary fibrosis Pathway of usual interstitial pneumonia. 2 Epidemiology IPF is a disease of unknown cause. Cigarette smoking, older age, male sex, air pollution, occupational exposures, viral infection, obstructive sleep apnea, gastroesophageal reflux, and genetic polymorphisms are potential risk factors. 2 14 Pathophysiology The incidence of IPF is estimated at 5.8 cases per 100,000 person-years in the United States. 13 Disease course In patients with IPF, secretion of profibrotic mediators lead to matrix deposition by myofibroblasts, with a progressive decline in pulmonary function, respiratory failure, and eventual death. 14 Prognosis and risk of recurrence The prognosis for IPF is poor, with a median survival of 3.8 years in adults 65 years of age in the United States. 14 CalculatorGAP index for idiopathic pulmon Guidelines 1. Screening and diagnosis Diagnosis: As per SPLF 2017 guidelines: Consider establishing the diagnosis of IPF based on a HRCT pattern of definite usual interstitial pneumonia, including honeycombing, after ruling out other causes of usual interstitial pneumonia (secondary forms). E Integrate all the data available for the definitive diagnosis of IPF during a multidisciplinary discussion involving pulmonologists, radiologists and pathologists experienced in the field of ILD. E As per ATS 2011 guidelines, recognize that IPF is defined as a specific form of chronic, progressive fibrosing interstitial pneumonia of unknown cause occurring primarily in older adults, limited to the lungs, and associated with the histopathologic and/or radiologic pattern of usual interstitial pneumonia. E Show 3 more https://web.pathway.md/diseases/recM02f25EOzK8gCc 2/12 6/24/23, 2:28 PM Idiopathic pulmonary fibrosis Pathway 2. Classification and risk stratification Prognosis: As per SPLF 2017 guidelines, consider assessing the prognosis in patients with IPF: at the time of diagnosis, depending on the severity of dyspnea pulmonary function test (FVC and CO diffusing capacity), percutaneous oxygen saturation at the end of a 6-minute walk test, the extent of honeycombing on high-resolution chest CT, the existence of signs of pulmonary hypertension on echocardiography, and using a score such as the GAP score during the follow-up, depending on the evolution of symptoms, FVC and CO diffusing capacity, and possibly the existence of signs of pulmonary hypertension on echocardiography and fibrosis on chest CT. E As per ATS 2011 guidelines, recognize that IPF is a fatal lung disease and the natural history is variable and unpredictable: most patients with IPF demonstrate a gradual worsening of lung function over years and a minority of patients remains stable or declines rapidly some patients may experience episodes of acute respiratory worsening despite previous stability. E Show 2 more 3. Diagnostic investigations History and physical examination: As per ATS 2018 guidelines, elicit a detailed history of both medication use and environmental exposures at home, work, and other places the patient frequently visits to exclude potential causes of ILD. B As per SPLF 2017 guidelines: Assess for evidence supporting a specific cause of ILD, particularly an exposure to drugs, inhaled antigen, mineral particles or a connective tissue disease, in patients with suspected IPF. E Assess for biological features of connective tissue disease in patients with suspected IPF. E Laboratory testing: As per ATS 2018 guidelines: Obtain serological testing to exclude connective tissue disease as a potential cause of the ILD. B Do not obtain serum matrix metalloproteinase-7, surfactant protein D, chemokine ligand-18, or Krebs von den Lungen-6 for the purpose of distinguishing IPF from other ILDs. D As per SPLF 2017 guidelines: Consider obtaining biological tests in patients with suspected IPF, including: CBC, CRP creatinine https://web.pathway.md/diseases/recM02f25EOzK8gCc 3/12 6/24/23, 2:28 PM Idiopathic pulmonary fibrosis Pathway LFTs, gamma-glutamyltransferase, ALPs creatine phosphokinase blood protein electrophoresis ant-nuclear antibodies, anti-cyclic citrullinated peptide, RF, and anti-neutrophil cytoplasmic antibodies. E Consider obtaining antibodies specific for Sj gren syndrome (anti-SSA, anti-SSB), systemic scleroderma (anti-centromere, anti-topoisomerase-1, anti-U3RNP), anti-synthetase antibodies and rare antibodies associated with myositis and a test for precipitins if clinically oriented and according to the clinical orientation or in case of detection of antinuclear antibodies. E As per BTS 2008 guidelines, obtain the following initial tests (with additional tests depending upon clinical context) in all cases of suspected ILD: urine dipstick CBC with differential serum urea creatinine electrolytes LFTs. B Pulmonary function testing: As per SPLF 2017 guidelines: Assess the FVC and the CO diffusing capacity at the time of diagnosis in patients with IPF. E Consider assessing the total lung capacity, arterial blood gas at rest and a 6-minute walk test (distance and percutaneous oxygen saturation). E As per BTS 2008 guidelines, obtain resting spirometric and gas transfer measurement at presentation in all patients with ILD. B Show 2 more Exercise testing: Recognize that desaturation during the 6-minute-walk test at presentation is a stronger prognostic determinant than resting lung function in patients with IPF. B Recognize that maximal exercise data probably add little to resting lung function in assessing the severity of ILD but are sometimes useful, when normal, in excluding clinically significant diffuse lung disease. B Computed tomography: As per ATS 2018 guidelines, obtain HRCT of the chest for evaluation of patients with IPF. As per SPLF 2017 guidelines: Obtain chest CT in patients with acute IPF exacerbation, unexplained change in clinical status, suspicion of lung cancer and for assessment for lung transplantation. E Pay particular attention to the detection of lung cancer when a chest CT is obtained. E https://web.pathway.md/diseases/recM02f25EOzK8gCc 4/12 6/24/23, 2:28 PM Idiopathic pulmonary fibrosis Pathway As per BTS 2008 guidelines, obtain HRCT if the diagnosis of ILD is uncertain after CXR and clinical assessment. B Recognize that HRCT is valuable in detecting ILD in patients with a normal CXR. Recognize that appearances on the HRCT in the appropriate clinical setting may be sufficiently characteristic to preclude the need for BAL or lung biopsy and histopathological confirmation. B Show 2 more Evaluation for pulmonary hypertension: As per ESC 2022 guidelines: Obtain echocardiography when pulmonary hypertension is suspected in patients with lung disease, and interpret results in conjunction with arterial blood gas analysis, pulmonary function tests (including lung diffusion capacity for CO), and CT. B Perform right heart catheterization if the results are expected to aid management decisions in patients with lung disease and suspected pulmonary hypertension. B As per BTS 2008 guidelines: Suspect pulmonary hypertension in patients with ILD having either breathlessness or lung dysfunction (reduced transfer factor for CO or desaturation on exercise) disproportionate to the extent of parenchymal lung disease. B Obtain TTE as a screening tool for the detection of pulmonary hypertension in patients with ILD. B Genetic testing: As per ATS 2022 guidelines, insufficient evidence to recommend for or against the addition of genomic classifier testing for the purpose of diagnosing usual interstitial pneumonia in patients with ILD of undetermined type undergoing transbronchial forceps biopsy. I As per SPLF 2017 guidelines: Elicit family history of ILD in patients with suspected IPF and evaluate for the presence of clinical and biological evidence supporting a genetic cause (age < 50 years, hematological, hepatic or mucocutaneous abnormalities). E Consider making a family tree in patients with IPF in a family context or if there is clinical or biological evidence suggesting a genetic cause, and obtaining molecular genetic analysis of the telomerase complex genes and the genes encoding surfactant proteins and referring to specialized genetic counseling. E 4. Diagnostic procedures BAL fluid analysis: As per ATS 2018 guidelines: Avoid performing cellular analysis of BAL fluid in patients with definite usual interstitial pneumonia on HRCT. D Consider performing cellular analysis of BAL fluid in patients probable usual interstitial pneumonia, indeterminate usual interstitial pneumonia, or alternative diagnosis on HRCT. C https://web.pathway.md/diseases/recM02f25EOzK8gCc 5/12 6/24/23, 2:28 PM Idiopathic pulmonary fibrosis Pathway As per SPLF 2017 guidelines, consider performing BAL in patients with chronic ILD. Consider performing BAL in patients with suspected IPF especially when the radiological pattern is not that of interstitial pneumonia. E As per BTS 2008 guidelines, consider performing BAL in all patients with suspected infection, malignancy and some rare ILDs. C Show 5 more Lung biopsy: As per ATS 2022 guidelines, consider performing transbronchial lung cryobiopsy as an acceptable alternative to surgical lung biopsy for establishing a histopathological diagnosis in patients with IPF of undetermined type in medical centers with experience performing and interpreting transbronchial lung cryobiopsy. C As per ERS 2022 guidelines: Consider performing transbronchial lung cryobiopsy in patients with undiagnosed ILD, whether deemed eligible or ineligible for surgical lung biopsy, if obtaining histopathological data is indicated. C Consider performing step-up surgical lung biopsy in patients with undiagnosed ILD and a non- informative transbronchial lung cryobiopsy, if obtaining histopathological data is indicated. C As per ATS 2018 guidelines, do not perform surgical or transbronchial lung biopsy in patients with definite usual interstitial pneumonia on HRCT. D Show 2 more As per SPLF 2017 guidelines, consider performing lung biopsy in patients with suspected IPF in the absence of a confirmed pattern of usual interstitial pneumonia on chest imaging. Decide on performing biopsy in the context of a multidisciplinary discussion after assessment of the operative risk, in particular according to the age, the functional impact of the disease, the existence of comorbidities and the evolution of interstitial pneumonia. E Show 2 more As per BTS 2008 guidelines, establish a confident pathological diagnosis of IPF only with a surgical lung biopsy. B Show 7 more 5. Respiratory support Supplemental oxygen: As per JRS 2018 guidelines, administer oxygen in patients with IPF in the chronic phase with hypoxemia. B As per ATS 2011 guidelines, initiate long-term oxygen therapy in patients with IPF and clinically significant resting hypoxemia. B As per BTS 2008 guidelines, initiate long-term oxygen therapy in patients with ILD, chronic hypoxia (< 8 kPa) and cor pulmonale. B https://web.pathway.md/diseases/recM02f25EOzK8gCc 6/12 6/24/23, 2:28 PM Idiopathic pulmonary fibrosis Pathway Mechanical ventilation: as per ATS 2011 guidelines, avoid performing mechanical ventilation in the majority of patients with respiratory failure due to IPF. D 6. Medical management General principles: As per ATS 2018 guidelines, consider ensuring a multidisciplinary discussion for diagnostic decision-making in patients with IPF. C As per SPLF 2017 guidelines, refer difficult cases to a reference center or a regional expertise center depending on their proximity. E As per BTS 2008 guidelines, ensure that all patients with ILD have access to a multidisciplinary team based in a regional center with expertise in ILD. B Show 3 more Pirfenidone: As per JRS 2018 guidelines, consider initiating pirfenidone in patients with IPF in the chronic phase. C Show 2 more As per ATS 2015 guidelines, initiate pirfenidone for pharmacologic treatment of IPF. B Landmark trials: ASCEND (pirfenidone) In patients with idiopathic pulmonary fibrosis, pirfenidone was superior to placebo with respect to death or a 10% decline in FVC at 52 weeks. King TE Jr et al. N Engl J Med. 2014 May 29. Nintedanib: As per ATS 2022 guidelines, consider initiating nintedanib for the treatment of patients with progressive pulmonary fibrosis failed standard management for fibrotic ILD, other than IPF. C As per JRS 2018 guidelines, consider initiating nintedanib in patients with IPF in the chronic phase. C As per ATS 2015 guidelines, consider initiating nintedanib (a TKI targeting multiple tyrosine kinases) for pharmacologic treatment of IPF. C Landmark trials: INPULSIS In patients with idiopathic pulmonary fibrosis, nintedanib was superior to placebo with respect to the incidence of decline in FVC, in INPULSIS-1. Richeldi L et al. N Engl J Med. 2014 May 29. https://web.pathway.md/diseases/recM02f25EOzK8gCc 7/12 6/24/23, 2:28 PM Idiopathic pulmonary fibrosis Pathway Interferon gamma-1 beta: do not use interferon-gamma in patients with IPF. D Corticosteroids: As per JRS 2018 guidelines, do not use corticosteroid monotherapy in patients with IPF in the chronic phase. D Show 2 more As per ATS 2011 guidelines, consider initiating corticosteroids in patients with acute exacerbation of IPF. C Show 3 more As per BTS 2008 guidelines, do not use high-dose corticosteroid monotherapy (0.5-1 mg/kg) in patients with IPF as it does not improve survival or otherwise modify the clinical course of the disease and is associated with significant morbidity. D Show 2 more Immunosuppressive agents: As per JRS 2018 guidelines, consider initiating immunosuppressant agents in patients with acute exacerbation of IPF. C As per ATS 2015 guidelines, do not use combination therapy with prednisone, azathioprine, and N-acetylcysteine for pharmacologic treatment of IPF. D As per ATS 2011 guidelines, do not use colchicine, cyclosporine A and etanercept in patients with IPF. D N-acetylcysteine: As per JRS 2018 guidelines, avoid using inhaled N-acetylcysteine monotherapy in the majority of patients with IPF in the chronic phase. D As per ATS 2011 guidelines, do not use N-acetylcysteine monotherapy in the majority of patients with IPF. D As per BTS 2008 guidelines, consider initiating pednisolone (tapering from 0.5 mg/day to 10-20 mg/day) with azathioprine (2 mg/kg, maximum 150 mg/day) and N-acetylcysteine (600 mg TID) over prednisolone and azathioprine alone in patients with IPF. C Phosphodiesterase-5 inhibitors: do not use PDE5 inhibitor (sildenafil) therapy for pharmacologic treatment of IPF. D Endothelin receptor antagonists: As per ATS 2015 guidelines: Do not use selective endothelin receptor antagonists (such as ambrisentan) for pharmacologic treatment of IPF. D Avoid using dual endothelin receptor antagonists (macitentan, bosentan) for pharmacologic treatment of IPF. D Tyrosine kinase inhibitors: do not use imatinib (a selective TKI against platelet-derived growth factor receptors) for pharmacological treatment of IPF. D https://web.pathway.md/diseases/recM02f25EOzK8gCc 8/12 6/24/23, 2:28 PM Idiopathic pulmonary fibrosis Pathway Landmark trials: Imatinib-IPF In patients with idiopathic pulmonary fibrosis, imatinib was not superior to placebo with respect to change in diffusing capacity of CO at 96 weeks. Daniels CE et al. Am J Respir Crit Care Med. 2010 Mar 15. Anticoagulation therapy: as per ATS 2015 guidelines, do not use anticoagulation (warfarin) for pharmacologic treatment of IPF. D Acid-reducing therapy: As per ATS 2022 guidelines, avoid using antacids for the purpose of improving respiratory outcomes in patients with IPF. D As per ACCP 2018 guidelines, avoid using PPIs in patients with IPF, chronic cough and a negative work-up for gastroesophageal reflux. D As per ATS 2011 guidelines, consider initiating treatment for asymptomatic gastroesophageal reflux in the majority of patients with IPF. C Recombinant thrombomodulin: avoid using recombinant thrombomodulin in patients with acute exacerbation of IPF. D Neutrophil elastase inhibitors: avoid using neutrophil elastase inhibitors in patients with acute exacerbation of IPF. D Polymyxin B-immobilized fiber column: avoid using polymyxin-B-immobilized fiber column therapy in patients with acute exacerbation of IPF. D Management of pulmonary hypertension: As per ESC 2022 guidelines, optimize treatment of IPF and, where indicated, hypoxemia, sleep- disordered breathing, and/or alveolar hypoventilation in patients with suspected pulmonary hypertension. B Show 9 more As per ATS 2011 guidelines, avoid initiating treatment for pulmonary hypertension associated with IPF in the majority of patients. D As per BTS 2008 guidelines, consider referring patients with ILD and pulmonary hypertension judged to be contributing to symptoms and disproportionate to the extent of ILD or severe pulmonary hypertension (systolic pulmonary artery pressure > 50 mmHg) to a regional specialist pulmonary hypertension center for assessment and recruitment to high quality clinical trials. C 7. Nonpharmacologic interventions Smoking cessation: offer opportunistic smoking cessation advice from healthcare professionals, recorded in the clinical notes, in current smoker patients with ILD. Offer specialist support and nicotine replacement therapy or bupropion. B https://web.pathway.md/diseases/recM02f25EOzK8gCc 9/12 6/24/23, 2:28 PM Idiopathic pulmonary fibrosis Pathway Pulmonary rehabilitation: As per JRS 2018 guidelines, consider offering pulmonary rehabilitation in patients with IPF in the chronic phase. C As per ATS 2011 guidelines, consider offering pulmonary rehabilitation in the majority of patients with IPF. C As per BTS 2008 guidelines, ensure that patients with ILD have access to a local pulmonary rehabilitation program. B 8. Surgical interventions Lung transplantation: As per ISHLT 2015 guidelines: Refer patients meeting any of the following criteria for the evaluation of lung transplantation: histopathologic or radiographic evidence of usual interstitial pneumonitis or fibrosing non- specific interstitial pneumonitis, regardless of lung function FVC < 80% of predicted or DLCO < 40% of predicted any dyspnea or functional limitation attributable to lung disease any oxygen requirement, even if only during exertion failure to improve dyspnea, oxygen requirement, and/or lung function after a clinically indicated trial of medical therapy (in patients with inflammatory lung diseases). List patients for lung transplantation if any of the following criteria is met: decline in FVC 10% during 6 months of follow-up (recognize that a 5% decline is associated with a poorer prognosis and may warrant listing) decline in DLCO 15% during 6 months of follow-up desaturation to < 88% or distance < 250 m on 6-minute-walk test or > 50 m decline in 6- minute-walk distance over a 6-month period pulmonary hypertension on right heart catheterization or 2D echocardiography hospitalization because of respiratory decline, pneumothorax, or acute exacerbation. As per ATS 2011 guidelines, perform lung transplantation in appropriate patients with IPF. B As per BTS 2008 guidelines, refer to a transplant center if the disease is advanced (transfer factor for CO < 40% of predicted) or progressive ( 10% decline in FVC or 15% decline in FVC during 6 months of follow-up). B Antireflux surgery: do not refer patients with IPF for antireflux surgery for the purpose of improving respiratory outcomes. D 9. Specific circumstances Patients with lung cancer: consider performing surgery in patients with lung cancer with comorbid IPF or other interstitial pneumonias. C https://web.pathway.md/diseases/recM02f25EOzK8gCc 10/12 6/24/23, 2:28 PM Idiopathic pulmonary fibrosis Pathway Show 2 more 10. Follow-up and surveillance Follow-up: Perform clinical examination and obtain pulmonary function testing with FVC measurement every 3-6 months in patients with a confirmed diagnosis of IPF. E Consider obtaining diffusing capacity of CO measurement every 3-6 months in patients with a confirmed diagnosis of IPF. E Likelihood Ratios Pertinent positives The following findings increase the probability of idiopathic pulmonary fibrosis in adults. 1 1 Finding LR+ Value Presence of clinical impression of idiopathic pulmonary fibrosis 20.7 Presence of findings of idiopathic pulmonary fibrosis 7.9 Pertinent negatives The following findings decrease the probability of idiopathic pulmonary fibrosis in adults. 1 1 Finding LR- Value Absence of findings of idiopathic pulmonary fibrosis 0.2 Absence of clinical impression of idiopathic pulmonary fibrosis 0.4 References 1. B Bradley, H M Branley, J J Egan Irish Thoracic Society) et al. Interstitial lung disease guideline: the British Thoracic Society in collaboration with the Thoracic Society of Australia and New Zealand and the Irish Thoracic Society. Thorax. 2008 Sep;63 Suppl 5:v1 58. Open 2. Ganesh Raghu, Harold R Collard, Jim J Egan et al. An official ATS/ERS/JRS/ALAT statement: idiopathic pulmonary fibrosis: evidence-based guidelines for diagnosis and management. Am J Respir Crit Care Med. 2011 Mar 15;183 6 788 824. Open 3. Sakae Homma, Masashi Bando, Arata Azuma et al. Japanese guideline for the treatment of idiopathic pulmonary fibrosis. Respir Investig. 2018 Jul;56 4 268 291. Open 4. Raghu G, Remy-Jardin M, Myers JL et al. Diagnosis of Idiopathic Pulmonary Fibrosis. An Official ATS/ERS/JRS/ALAT Clinical Practice Guideline. Am J Respir Crit Care Med. 2018 Sep 1;198 5):e44-e68. https://web.pathway.md/diseases/recM02f25EOzK8gCc 11/12 6/24/23, 2:28 PM Idiopathic pulmonary fibrosis Pathway Open 5. Ganesh Raghu, Martine Remy-Jardin, Luca Richeldi et al. Idiopathic Pulmonary Fibrosis (an Update) and Progressive Pulmonary Fibrosis in Adults: An Official ATS/ERS/JRS/ALAT Clinical Practice Guideline. Am J Respir Crit Care Med. 2022 May 1;205 9):e18-e47. Open 6. Raghu G, Remy-Jardin M, Myers JL et al. Diagnosis of Idiopathic Pulmonary Fibrosis. An Official ATS/ERS/JRS/ALAT Clinical Practice Guideline. Am J Respir Crit Care Med. 2018 Sep 1;198 5):e44-e68. Open 7. V Cottin, B Crestani, J Cadranel et al. French practical guidelines for the diagnosis and management of idiopathic pulmonary fibrosis 2017 update. Full-length version. Rev Mal Respir. 2017 Oct;34 8 900 968. Open 8. Weill D, Benden C, Corris PA et al. A consensus document for the selection of lung transplant candidates: 2014 an update from the Pulmonary Transplantation Council of the International Society for Heart and Lung Transplantation. J Heart Lung Transplant. 2015 Jan;34 1 1 15. Open 9. Dani l A Korevaar, Sara Colella, Markus Fally et al. European Respiratory Society guidelines on transbronchial lung cryobiopsy in the diagnosis of interstitial lung diseases. Eur Respir J. 2022 Nov 10;60 5 2200425. Open 10. Raghu G, Rochwerg B, Zhang Y et al. An Official ATS/ERS/JRS/ALAT Clinical Practice Guideline: Treatment of Idiopathic Pulmonary Fibrosis. An Update of the 2011 Clinical Practice Guideline. Am J Respir Crit Care Med. 2015 Jul 15;192 2):e3 19. Open 11. Marc Humbert, Gabor Kovacs, Marius M Hoeper et al. 2022 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension. Eur Heart J. 2022 Oct 11;43 38 3618 3731. Open 12. Surinder S Birring, Joanne E Kavanagh, Richard S Irwin et al. Treatment of Interstitial Lung Disease Associated Cough: CHEST Guideline and Expert Panel Report. Chest. 2018 Oct;154 4 904 917. Open 13. Raghu G, Chen SY, Hou Q et al. Incidence and prevalence of idiopathic pulmonary fibrosis in US adults 18 64 years old. Eur Respir J. 2016 Jul;48 1 179 86. Open 14. Lederer DJ, Martinez FJ. Idiopathic Pulmonary Fibrosis. N Engl J Med. 2018 May 10;378 19 1811 1823. Open 15. Roland M du Bois, Derek Weycker, Carlo Albera et al. Ascertainment of individual risk of mortality for patients with idiopathic pulmonary fibrosis. Am J Respir Crit Care Med. 2011 Aug 15;184 4 459 66. Open https://web.pathway.md/diseases/recM02f25EOzK8gCc 12/12