IPF

Treatment and Management

Prompt recognition of IPF after symptom onset and access to an ILD specialty center could minimize harm, promote early institution of standard therapies such as supplemental oxygen, and allow timely access to clinical trials and lung transplantation evaluation. A longer delay was found to be associated with an increased risk of death independent of age, sex, forced vital capacity, third-party payer, and educational attainment (adjusted HR per doubling of delay was 1.3, 95% CI 1.03 to 1.6)¹. A careful assessment of the goals of care is essential to the comprehensive care of patients with IPF. The goals of care will vary based on the patient’s age, comorbidities, values and preferences, and will likely change as the disease progresses. Therefore, the goals of care should be actively discussed at the time of diagnosis and regularly thereafter².

Three pillars of care for the patient with IPF have been recommended as “disease-centered management”, “symptom-centered management”, and “education and self-management”. These three pillars rest upon a foundation of active engagement and collaboration between the provider and the patient².

Education and self-management

Because the goal of maintaining a maximum level of wellness and quality of life requires the active participation of the patient and because patients affected by IPF will need to make critical life decisions sooner or later, education about the disease and its course is an important component of care in IPF management. Education and self-management strengthen the provider–patient partnership by enabling patients to set realistic goals, make meaningful choices, remain in control of his or her care, enjoy a higher quality of life, and prepare for the future. Education should be initiated as soon as a diagnosis of IPF is established, which can occur in the physician’s office, in an IPF center, as online courses or educational seminars offered in the community. IPF support groups and pulmonary rehabilitation programs are also excellent places for patients to learn about their disease as well as symptom management².

Symptom-centered management

IPF causes a significant symptom burden for patients and profound emotional suffering for patients and their families. The progressive course of IPF makes symptom-centered management an important and necessary treatment priority. Four common symptoms in patients with IPF include dyspnea, cough, fatigue/deconditioning, and depression/anxiety².

Dyspnea

Dyspnea is nearly universal among patients with IPF, contributes to reduced quality of life, and is an important prognostic marker. The cause of dyspnea in IPF is likely multifactorial and includes direct disease processes (e.g. increased ventilatory demand) as well as secondary processes (e.g. muscle weakness, depression, and anxiety). However, there is a surprising paucity of data on the management of dyspnea in IPF. Referral for pulmonary rehabilitation and oxygen therapy is recommended if patients are hypoxemic. Comorbidities that can contribute to dyspnea shall also be evaluated and controlled, such as pulmonary hypertension, sleep-disordered breathing, muscle weakness, psychosocial factors and increased weight. Sildenafil and opioid therapy may be beneficial².

Chronic cough

Chronic cough is a common and difficult to treat symptom in patients with IPF. Cough can be a primary manifestation of IPF, but is frequently due to or exacerbated by more common causes of chronic cough, such as gastroesophageal reflux disease (GERD), asthma, and upper airway cough syndrome. Evaluate and manage above comorbidities that can contribute to cough. Consider antitussives (e.g. benzonatate, codeine) to control cough. In severe cases, oral corticosteroids may be considered².

Fatigue/deconditioning

For some IPF patients, fatigue is a dominant symptom. The development of muscle deconditioning further exacerbates the symptom of fatigue. Fatigue and deconditioning should be recognized and treated early to avoid vicious cycle. Refer patients for pulmonary rehabilitation and provide oxygen therapy if hypoxemic. Evaluate and manage comorbidities that can contribute to fatigue and deconditioning, such as obesity, sleep-disordered breathing, or hypoxemia².

Depression/anxiety

Many IPF patients experience symptoms of depression and anxiety due to chronic and debilitating symptoms, side effects from medications, and fear associated with IPF’s poor prognosis. Refer patients for psychosocial support through counseling or patient support groups. Evaluate and control comorbidities that can contribute to depression and anxiety such as dyspnea, fatigue and deconditioning, or polypharmacy. Consider pulmonary rehabilitation, and pharmacological therapy in patients unresponsive to conservative therapy².

Disease-centered management

No sufficient evidence is available to support the routine use of any specific pharmacological therapy in patients with IPF². The American Thoracic Society, European Respiratory Society, Japanese Respiratory Society and Latin American Thoracic Association has jointly published a guideline on treating IPF in 2011 and revised on 2015. Some therapies are recommended under certain conditions while many therapies are not recommended³.

Anticoagulation 

Oral anticoagulation with warfarin at target international normalized ratio of 2.0 to 3.0 is strongly recommended against as a treatment for IPF. However, patients with other indications such as venous thromboembolic disease or atrial fibrillation should be treated as the treatment guidelines for these conditions independent of their underlying IPF³.

Imatinib (tyrosine kinase inhibitor)

Imatinib is a potent inhibitor of lung fibroblast–myofibroblast differentiation and proliferation, as well as an inhibitor of extracellular matrix production through inhibition of PDGF and TGF-β signaling. However, imatinib failed to demonstrate benefit in preventing mortality or disease progression in the clinical trial of treating patients with IPF. Therefore, imatinib is strongly recommended against as a treatment for IPF³.

The combination of N-acetylcysteine, azathioprine, and prednisone

The combination of N-acetylcysteine, azathioprine, and prednisone was evaluated in a multicenter, randomized placebo-controlled trial to treat patients with IPF. The study was stopped early after a signal of increase in mortality was seen in patients receiving the combination therapy. As a result, the combination therapy of N-acetylcysteine, azathioprine, and prednisone is strongly recommended against as a treatment for IPF³.

Ambrisentan (selective endothelin type A receptor antagonist)

Ambrisentan is a selective endothelin type A (ET-A) receptor antagonist (ERA). ET-A are usually found on vascular smooth muscle cells and can induce vasoconstriction. ET-A receptors have been shown to propagate epithelial-to-mesenchymal transition through intermediary cytokines, leading to a profibrotic state. Ambrisentan did not demonstrate benefit in decreasing mortality for IPF patients in a randomized placebo-controlled trial, and increased disease progression instead. Therefore, ambrisentan is strongly recommended against using in patients with IPF³.

Pirfenidone (oral antifibrotic)

Pirfenidone is an oral antifibrotic drug with pleiotropic effects. Pooled results from the RCTs suggested improved mortality with pirfenidone (RR, 0.70; 95% CI, 0.47–1.02) and reduced the rate of FVC decline (standardized mean difference, 0.23; 95% CI, 0.06–0.41). Due to the potential benefit of pirfenidone on patient-important outcomes such as disease progression as measured by rate of FVC decline and mortality, it is recommended to be used in treating patients with IPF³.

Nintedanib (tyrosine kinase inhibitor)

Nintedanib is an intracellular inhibitor of several tyrosine kinases that targets multiple growth factor receptors, including vascular endothelial growth factor, fibroblast growth factor, and platelet-derived growth factor (PDGF). Nintedanib treatment was evaluated in three randomized controlled studies (RCTs) that enrolled over 1000 patients with IPF. The pooled analysis of these three trials showed a RR of 0.70 (95% CI, 0.47–1.03) for mortality, a HR of 0.47 (95% CI, 0.17–1.29) for acute exacerbation, and significantly fewer patients with > 10% absolute decline in FVC (RR, 1.15; 95% CI, 1.06–1.25)³. In a post hoc analyses of two of the RCTs, both patients with preserved lung volume (baseline FVC > 90% predicted) and those with more impaired lung volume benefited from nintedanib in reduced rate of FVC decline⁴. In another pooled analysis of five clinical trials, the effect of nintedanib on reducing the rate of FVC decline was consistent whether the patients were younger or older than 75-year-old, whether the patients had less or more than 5 comorbidities, or whether the patients had lower or higher comorbidity index scores⁵. Due to the benefit of nintedanib on patient-important outcomes such as disease progression as measured by rate of FVC decline and mortality, it is recommended to be used in treating patients with IPF³.