Approach

Idiopathic pulmonary fibrosis (IPF) is a progressive, ultimately fatal, disorder that has a variable clinical course. Progression may be rapid, slow, or only occur during acute exacerbations.

ATS/ERS/JRS/ALAT guidelines conditionally recommend using nintedanib or pirfenidone as initial therapy.[Evidence A][Evidence B]​​

Familial pulmonary fibrosis is managed in the same way as IPF.[5][16]​​

Supportive measures are necessary to improve quality of life and mitigate factors that contribute to disease progression (e.g., smoking cessation). Some patients may require lung transplantation.[5]

Acute exacerbations

Acute exacerbations are defined as acute, clinically significant, respiratory deteriorations associated with new widespread alveolar abnormality and no identifiable cause (see Diagnostic criteria).[15] A subset of patients has a disease course characterised by intermittent acute exacerbations followed by an abrupt and often permanent decline in pulmonary function.[15] Short-term mortality rates, including inpatient mortality, are high in these patients.[63][64]

There is no standard of care for acute exacerbation of IPF.[65] Patients receive supportive care with (or without) unproven therapies.[15]

  • Supportive care: focuses on symptom palliation and the correction of hypoxaemia with supplemental oxygen

    • 2011 ATS/ERS/JRS/ALAT guidelines weakly recommend against using mechanical ventilation to treat respiratory failure in most patients with IPF because the in-hospital mortality reaches 90%.[5]

  • High-dose corticosteroids: used in the management of acute exacerbations, despite a lack of supporting evidence

    • 2022 update to the ATS/ERS/JRS/ALAT guidelines weakly recommend the use of corticosteroids in acute exacerbations.[3][4][5]​​

  • Cytotoxic agents: short-term mortality rates, including inpatient mortality, are high.[63][64]​​ One phase 3 placebo-controlled trial concluded that adding intravenous cyclophosphamide to glucocorticoids increased mortality at 3 months.[66]

    • The ATS/ERS/JRS/ALAT guidelines make no recommendation regarding the use of cytotoxic agents.[3][4][5]​​

  • Antifibrotic preventive treatment appears to reduce the risk of acute exacerbations and all-cause mortality.[67][68] 

    • Neither pirfenidone nor nintedanib is recommended for the treatment of acute exacerbations.

Patients not currently experiencing acute exacerbations: pirfenidone and nintedanib

Initial therapy is with pirfenidone or nintedanib.

Pirfenidone and nintedanib have not been compared directly and have not been studied in combination; combination therapy is not recommended.[69] The decision to prescribe is based on availability, patient preference, and adverse effects (when present, these are usually addressed by dose adjustment, temporary cessation, or changing therapy).[70][71]​​​​

Pirfenidone

  • Pirfenidone is an oral agent that has both anti-inflammatory and antifibrotic properties. The ATS/ERS/JRS/ALAT treatment guidelines conditionally recommend the use of pirfenidone to treat IPF.[4][5]​​[Evidence B]

  • Only one of two large phase 3 randomised placebo-controlled trials (CAPACITY 004 and 006) reported a significantly reduced decline in forced vital capacity (at 72 weeks) among patients assigned to pirfenidone.[72][73]​​

  • A subsequent multi-centre, multinational trial (ASCEND) demonstrated a statistically significant decrease in change in the predicted forced vital capacity (FVC) in the pirfenidone group compared with placebo.[74] There were also differences in secondary outcomes, including change in 6-minute walk distance and progression-free survival. There was no statistically significant difference in mortality in the ASCEND trial.

  • A pre-specified pooled analysis of mortality from all 3 trials (ASCEND and both CAPACITY trials) demonstrated a significant reduction in all-cause mortality and death from IPF in the pirfenidone group.

Nintedanib

  • The ATS/ERS/JRS/ALAT treatment guidelines conditionally recommend the use of nintedanib, a tyrosine kinase inhibitor, to treat IPF.[4][5]​​[Evidence A]​​

  • Two concurrent multinational, randomised, placebo-controlled, double-blind trials (INPULSIS-1 and INPULSIS-2) demonstrated a statistically significant difference in the primary outcome of annual rate of change of FVC between the nintedanib and placebo groups.[75] INPULSIS-2 found a significant difference in favour of nintedanib in time to first acute exacerbation, but the difference was not significant in INPULSIS-1. There was no difference in mortality between nintedanib and placebo groups.

  • Analysis of pre-specified subgroups found no difference in the primary endpoint (annual rate of decline in FVC) or key secondary endpoints among different groups.[76]

  • Data describing the experiences of study participants who opted to stay on therapy after the 52-week treatment period in the INPULSIS trials suggest a manageable safety and tolerability profile with long-term use.[77] 

Network meta-analyses conclude that pirfenidone and nintedanib probably reduce mortality in patients with IPF.[68][78]​​[79]

Other pharmacological therapies

Several therapies target the inflammation responsible for lung injury and fibrosis (e.g., corticosteroids, interferon gamma-1b, imatinib, etanercept, bosentan, ambrisentan, and macitentan). Most have failed to demonstrate efficacy in clinical trials.[80][81][82][83][84][85]

The ATS/ERS/JRS/ALAT guidelines make the following recommendations against these options, noting only that they may be appropriate for some patients.

  • Strongly recommend against the use of ambrisentan (an endothelin receptor antagonist) and imatinib (a tyrosine kinase inhibitor).[4][Evidence B]

  • Conditionally recommend against the use of macitentan and bosentan (endothelin receptor antagonists).[4][Evidence B]

  • Strongly recommend against combined therapy with prednisolone, azathioprine, and acetylcysteine.[4][Evidence B]​​ This approach has been associated with increased deaths, hospitalisations, acute exacerbations, and serious adverse events compared with placebo.[86]

  • Conditionally recommend against acetylcysteine monotherapy. In one double-blind randomised trial of patients with IPF, there were no significant differences between acetylcysteine monotherapy and placebo with respect to FVC, acute exacerbations, and mortality.[87]

  • Strongly recommend against the use of warfarin.[4][Evidence C] Warfarin use in the absence of other specific indications for anticoagulation has been associated with an increased rate of all-cause mortality.[88][89][90]

  • Conditionally recommend against the use of sildenafil (a phosphodiesterase-5 inhibitor) for the treatment of IPF.[4][Evidence B]

Supportive measures

  • Educate patients about the progressive nature of IPF and the risks and benefits of any therapy being considered. British Lung Foundation: idiopathic pulmonary fibrosis (IPF) Opens in new window

  • Patients who continue to smoke cigarettes should be advised to quit (see Smoking cessation). 

  • Avoid or withdraw inhalational agents or toxic medications (e.g., bleomycin, amiodarone, acetylsalicylic acid, methotrexate, busulfan, mitomycin) that may cause additional irreversible lung injury.[91]

  • Pulmonary rehabilitation programmes typically include assessment, participation in a regular exercise‐training programme (aerobic and resistance), education, and behavioural change.[92][93]​​​​[94]​ They are safe, improve exercise capacity, and may improve both dyspnoea and health-related quality of life in patients with IPF.[5][93]​​[94][95]​ These changes are probably clinically meaningful for patients and appear to persist over 6-12 months.[93][95]

  • Monitor all patients for the development of hypoxaemia. Severe hypoxaemia (PaO₂ 55 mmHg or lower, or oxygen saturation 89% or lower) at rest or with exertion should be managed by supplemental oxygen, and is strongly recommended by the ATS/ERS/JRS/ALAT guidelines and by the 2020 ATS guideline on home oxygen therapy for adults with chronic lung disease.[5][94][96]​​​​[Evidence C]​​​​ Oxygen therapy may improve exercise tolerance and reduce the risk of developing pulmonary hypertension and cor pulmonale.[97]​ Not all patients will benefit from oxygen therapy, so careful patient selection is important.[94]

  • Symptomatic reflux should be treated as usual (see Gastro-oesophageal reflux disease). ATS/ERS/JRS/ALAT 2022 guidelines conditionally recommended against the medical or surgical treatment of asymptomatic gastro-oesophageal reflux for the purpose of improving respiratory outcomes.[5][98]​​​​[Evidence C]

Palliative care

Palliative measures should be considered whenever physical, psychological, social, or existential needs are identified. Unmet needs can arise at any point along the disease trajectory; therefore, palliative care should be integrated early and within routine care.[99] Needs assessment tools can help with both the early identification and monitoring of people who can benefit from palliative care or other symptom-directed treatment.[94]

Barriers to palliative care, such as fear of talking about the future, diagnostic uncertainty, and confusion about the roles of palliative care should be tackled to avoid unnecessary delays in referral.[100]

Follow a holistic and multi-disciplinary person-centred approach to control core symptoms (i.e., shortness of breath, cough, and fatigue) and improve quality of life for people with serious health-related suffering. The needs of informal carer should also be considered.

Generalists should address palliative care needs in the first instance and provide access to specialist palliative care as needed. Suggested triggers for palliative care referral include starting oxygen therapy or ventilatory support, the persistence of uncontrolled symptoms, functional decline, and when considering opioids.[99]

Palliative care options are available for uncontrolled symptoms of cough and dyspnoea.[5]Oral or parenteral opioids may have a role in the palliation of dyspnoea.[101] [ Cochrane Clinical Answers logo ] [Evidence C]​ ​Low-dose, controlled-release morphine may help to reduce awake cough frequency and can improve quality of life when significant IPF-related cough is present.[102]

​Limited evidence suggests that a comprehensive, home-based, palliative care intervention may improve quality of life and decrease anxiety and depression in patients with interstitial lung disease.[103]

Discuss advance care planning in accordance with patient preferences and revisit decisions periodically.[99]​ Initiating such discussions is challenging, but necessary. Ensuring patient comfort is central to compassionate end of life care for the terminally ill. Hospice admission may need to be considered for patients with very advanced disease.

Lung transplantation

The assessment and care of lung-transplant recipients requires a team approach with a holistic focus.[104]

Lung transplantation should be considered for patients with progressive physiological deterioration despite optimal medical management, contraindications to pharmacological treatment, severe functional impairment, oxygen dependency, and/or a deteriorating course.

A consensus statement by the International Society for Heart and Lung Transplantation (ISHLT) recommends lung transplantation as an option for adults with chronic, end-stage lung disease if they are at high (>50%) risk of death from lung disease within 2 years if lung transplantation is not performed and if they have a high (>80%) likelihood of 5-year post-transplant survival if graft function is adequate.[105] Referral is made at time of diagnosis to avoid missing potentially eligible patients (i.e., those who meet the minimal clinical criteria), especially if familial pulmonary fibrosis is present. Patients treated with antifibrotic therapy are eligible for referral.[105]

The timing of listing for transplant (which necessitates thorough evaluation and careful risk-to-benefit assessment) should consider the rate of progression, expected prognosis, age, comorbidities, and transplant risks.[105] Relevant contraindications include significant extrapulmonary disorders (e.g., liver, renal, or cardiac dysfunction) and an unstable or inadequate psychosocial profile that may negatively influence survival.

Patients are at risk of primary graft dysfunction, opportunistic infections, cancer, and chronic immunosuppression-related health issues following lung transplantation. Nonetheless, chronic lung allograft dysfunction remains the main impediment to long-term survival.[104]​​

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