Pirfenidone

Pirfenidone is an oral drug that has anti-fibrotic and anti-inflammatory properties . It can reduce the decline of absolute and percent predicted FVC and improve performance in the 6-min walking test (6MWT) with a 43% reduction of IPF progression or death as compared to placebo . Adverse effects are mostly gastrointestinal (nausea, dyspepsia, anorexia, gastroesophageal reflux) Skin-related complications are less frequent (e.g., photosensitivity rash). Alanine or aspartate aminotransferase levels are frequently elevated during treatment with pirfenidone, but this is reversible and has no clinically significant effect .

Nintedanib

Nintedanib is an intracellular triple oral angiokinase inhibitor that targets three receptors: fibroblast, platelet-derived, and vascular endothelial growth factor receptors, which are all involved in IPF pathogenesis . Nintedanib reduced the FVC decline, prevented exacerbations, and maintained the quality of life in Phase II studies including patient with mild to moderate disease; no survival benefit was noted, although the study was not powered to address survival . Common side effects were nausea, vomiting, and diarrhea. Reversible increase of alanine or aspartate aminotransferase levels could be observed during treatment with pirfenidone with no clinically significant effect.

Anti-acids drugs

Gastroesophageal reflux is very common in patients with IPF (88% according to different studies), and it has been hypothesized that chronic micro-aspiration is responsible for triggering the development of the disease . Anti-reflux treatment has been shown to improve survival and performance in IPF patients . Gastroesophageal treatment is advocated even in asymptomatic IPF patients . The best antacid regimens and their drug interaction with anti-fibrotic agents are not well established .

Pulmonary rehabilitation

Pulmonary rehabilitation significantly improves the quality of life, dyspnea, and 6MWT in IPF patients . In the past, rehabilitation was indicated only for end-stage patients with limited daily activities; nowadays, pulmonary rehabilitation is indicated for all IPF patients as soon as diagnosis is established. Pulmonary rehabilitation is important before and after lung transplantation . In fact, the capacity to perform rehabilitation exercises is a key criterion for selecting the transplant candidate. Moreover, pulmonary rehabilitation helps patients to psychologically get ready for the surgery and is associated with weight loss, as well as getting accustomed to certain breathing strategies and exercises .

Oxygen therapy

Long-term oxygen should be provided to IPF patients with hypoxemia while resting and sleeping . However, given the ethical concerns related to withholding oxygen, its efficacy has not been investigated by randomized clinical trials . A retrospective study showed no survival benefit when using oxygen compared to colchicine and corticosteroids , although multiple studies showed that oxygen therapy might allow these patient to remain physically and socially active with a better quality of life. Therefore, oxygen treatment is important in the overall management of IPF patients .

Lung transplantation

Lung transplantation has proven to be an effective treatment for IPF patients , providing an associated 75% reduced death risk after lung transplantation. Timely referral to a transplant center is important. Listed below are the criteria for referral and listing .

Timing of referral :

• •
  

  Diagnosis of usual interstitial pneumonitis or fibrosing non-specific interstitial pneumonitis, regardless of lung function.

  
  
• •
  

  Any dyspnea or functional limitation secondary to IPF

  
  
• •
  

  Any oxygen requirement, even if only during exertion.

  
  
• •
  

  Abnormal lung function: forced vital capacity (FVC) <80% predicted or carbon monoxide diffusion capacity (Dlco) <40% predicted.

  
  
• •
  

  For inflammatory interstitial lung disease, persistent dyspnea, oxygen requirement, and/or lung function after trial of medical therapy.

Timing of listing :

• •
  

  Decline in FVC ≥10% during 6 months of follow-up

  
  
• •
  

  Desaturation to <88% or distance <250 m on 6-MWT or >50 m decline in 6-MWT over a 6-month period.

  
  
• •
  

  Decline in Dlco ≥15% during 6 months of follow-up.

  
  
• •
  

  Diagnosis of secondary pulmonary hypertension.

  
  
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  Hospitalization for acute or chronic respiratory failure or pneumothorax.

LAMA

LAMAs include tiotropium, umeclidium, glycopyrronium, and aclidinium. There are few clinically important differences between the LAMAs . Aclidinium has a shorter duration of action, and therefore, it is prescribed in a twice-daily regimen . These drugs have adverse effects that include urinary retention in patients with prostatic enlargement, worsening of glaucoma, and atrial arrhythmias.

LABA

The choice of a second-line drug depends on the patient’s preference and response. There are significant differences between LABAs that are obvious to patients and are important in affecting their choice . Most importantly, formoterol, indacaterol, and vilanterol have a fast onset of action (5–10 min), while salmeterol has a 30-min onset. These differences may not be important once patients are taking long-acting bronchodilators regularly. Like salmeterol, formoterol, and indacaterol, the newly available LABAs vilanterol and olodaterol have statistically and clinically significant effects on lung function, SABA use, dyspnea, exacerbations, exercise tolerance, and quality of life . LABAs are well tolerated, and there are small differences between them in relation to adverse effects .

Combination therapy

Guidelines recommend inhaled corticosteroids (ICS) in addition to LAMA or LABA when the FEV1 is less than 50% predicted and the patient has had more than one exacerbation during the previous year . In the stepwise management of stable COPD, combination ICS/LABA therapy is recommended for this group of patients. Many patients, at that point, will already have been taking a LAMA, so they will be stepping up from a double long-acting bronchodilator to “triple therapy.” With the availability of double mechanism bronchodilators, there has been a change in COPD management. Indeed, dual bronchodilators have been shown not only to improve lung function, exercise capacity, and dyspnea and reduce the use of short-acting bronchodilators, compared to either LABA or LAMA alone, but also to reduce COPD exacerbations .

The role of ICS is being questioned as their primary use is to reduce exacerbations. Several studies have tested different designs—either withdrawal of ICS or a comparison of LAMA plus LABA versus ICS plus LABA . Of note, ICS has significant adverse effects. In fact, there is substantial evidence from randomized clinical trials that in COPD patients, high dose of inhaled corticosteroids (>500 μg/day fluticasone propionate or equivalent) is associated with an increased risk of pneumonia.

It is essential that clinicians familiarize themselves with the new inhaled medications and administration devices and tailor the treatment to the patient’s needs. Every new treatment should be considered in light of the device in which it is delivered and its suitability for each patient. The patients should be educated on proper use of these devices to ensure appropriate dose delivery.

Oxygen

Oxygen therapy is recommended in COPD patients with hypoxic exacerbations. Patients with reduced FEV1 (<30% of predicted) should be tested for need of oxygen therapy at rest, on exertion, and during sleep. Oxygen therapy for more than 15–18 h is associated with survival benefit.

COPD patients present with increased work of breathing due to increased dead-space ventilation resulting in hypoxemia and hypercapnia .

Non-invasive ventilation

Ventilatory support should be implemented in patients with acute hypercapnia or severe respiratory distress that persists despite administration of bronchodilators and systemic glucocorticoids. For patients with COPD, non-invasive ventilation (NIV) should be considered the first-line therapy for hypercapnic respiratory failure if there are no contraindications as it reduces the risk of endotracheal intubation, treatment failure, and mortality associated with severe exacerbations of COPD . Patients with acute hypercapnia derive the greatest benefit, whereas use of NIV in milder exacerbations has not been associated with improved outcomes and is often poorly tolerated .

Lung volume reduction surgery

Lung volume reduction surgery (LVRS) may improve the quality and quantity of life of severe COPD patients by reducing ventilation–perfusion mismatch and improving respiratory mechanics. The goal of LVRS is to reduce hyperinflation in patients with heterogeneous disease with upper-lobe predominant emphysema and reduced exercise-tolerance. Clinical trials have shown better quality of life and exercise capacity after LVRS in COPD patients with FEV1 <30% of predicted .

Lung transplantation

Lung transplantation is a therapeutic option for end-stage COPD patients capable of undergoing rehabilitation.

Listed below are timing of referral and listing for COPD patients :

Timing of referral :

• •
  

  Progressive disease despite medication, pulmonary rehabilitation, and oxygen therapy.

  
  
• •
  

  Patient not a candidate for LVRS. Referral for both lung transplant and LVRS is advocated.

  
  
• •
  

  BODE (body mass, airflow obstruction, dyspnea, and exercise capacity) index of 5–6.

  
  
• •
  

  PaCO ₂ >50 mmHg and/or PaO ₂ <60 mmHg

  
  
• •
  

  FEV1 <25% predicted.

Timing of listing (presence of one criterion is sufficient) :

• •
  

  BODE index ≥7.

  
  
• •
  

  FEV1 <15%–20% predicted.

  
  
• •
  

  Severe exacerbation with acute hypercapnic respiratory failure. Multiple severe exacerbations during previous 12 months.

  
  
• •
  

  Moderate to severe pulmonary hypertension.

LAMA

LAMAs include tiotropium, umeclidium, glycopyrronium, and aclidinium. There are few clinically important differences between the LAMAs . Aclidinium has a shorter duration of action, and therefore, it is prescribed in a twice-daily regimen . These drugs have adverse effects that include urinary retention in patients with prostatic enlargement, worsening of glaucoma, and atrial arrhythmias.

LABA

The choice of a second-line drug depends on the patient’s preference and response. There are significant differences between LABAs that are obvious to patients and are important in affecting their choice . Most importantly, formoterol, indacaterol, and vilanterol have a fast onset of action (5–10 min), while salmeterol has a 30-min onset. These differences may not be important once patients are taking long-acting bronchodilators regularly. Like salmeterol, formoterol, and indacaterol, the newly available LABAs vilanterol and olodaterol have statistically and clinically significant effects on lung function, SABA use, dyspnea, exacerbations, exercise tolerance, and quality of life . LABAs are well tolerated, and there are small differences between them in relation to adverse effects .

Combination therapy

Guidelines recommend inhaled corticosteroids (ICS) in addition to LAMA or LABA when the FEV1 is less than 50% predicted and the patient has had more than one exacerbation during the previous year . In the stepwise management of stable COPD, combination ICS/LABA therapy is recommended for this group of patients. Many patients, at that point, will already have been taking a LAMA, so they will be stepping up from a double long-acting bronchodilator to “triple therapy.” With the availability of double mechanism bronchodilators, there has been a change in COPD management. Indeed, dual bronchodilators have been shown not only to improve lung function, exercise capacity, and dyspnea and reduce the use of short-acting bronchodilators, compared to either LABA or LAMA alone, but also to reduce COPD exacerbations .

The role of ICS is being questioned as their primary use is to reduce exacerbations. Several studies have tested different designs—either withdrawal of ICS or a comparison of LAMA plus LABA versus ICS plus LABA . Of note, ICS has significant adverse effects. In fact, there is substantial evidence from randomized clinical trials that in COPD patients, high dose of inhaled corticosteroids (>500 μg/day fluticasone propionate or equivalent) is associated with an increased risk of pneumonia.

It is essential that clinicians familiarize themselves with the new inhaled medications and administration devices and tailor the treatment to the patient’s needs. Every new treatment should be considered in light of the device in which it is delivered and its suitability for each patient. The patients should be educated on proper use of these devices to ensure appropriate dose delivery.

Oxygen

Oxygen therapy is recommended in COPD patients with hypoxic exacerbations. Patients with reduced FEV1 (<30% of predicted) should be tested for need of oxygen therapy at rest, on exertion, and during sleep. Oxygen therapy for more than 15–18 h is associated with survival benefit.

COPD patients present with increased work of breathing due to increased dead-space ventilation resulting in hypoxemia and hypercapnia .

Non-invasive ventilation

Ventilatory support should be implemented in patients with acute hypercapnia or severe respiratory distress that persists despite administration of bronchodilators and systemic glucocorticoids. For patients with COPD, non-invasive ventilation (NIV) should be considered the first-line therapy for hypercapnic respiratory failure if there are no contraindications as it reduces the risk of endotracheal intubation, treatment failure, and mortality associated with severe exacerbations of COPD . Patients with acute hypercapnia derive the greatest benefit, whereas use of NIV in milder exacerbations has not been associated with improved outcomes and is often poorly tolerated .

Lung volume reduction surgery

Lung volume reduction surgery (LVRS) may improve the quality and quantity of life of severe COPD patients by reducing ventilation–perfusion mismatch and improving respiratory mechanics. The goal of LVRS is to reduce hyperinflation in patients with heterogeneous disease with upper-lobe predominant emphysema and reduced exercise-tolerance. Clinical trials have shown better quality of life and exercise capacity after LVRS in COPD patients with FEV1 <30% of predicted .

Lung transplantation

Lung transplantation is a therapeutic option for end-stage COPD patients capable of undergoing rehabilitation.

Listed below are timing of referral and listing for COPD patients :

Timing of referral :

• •
  

  Progressive disease despite medication, pulmonary rehabilitation, and oxygen therapy.

  
  
• •
  

  Patient not a candidate for LVRS. Referral for both lung transplant and LVRS is advocated.

  
  
• •
  

  BODE (body mass, airflow obstruction, dyspnea, and exercise capacity) index of 5–6.

  
  
• •
  

  PaCO ₂ >50 mmHg and/or PaO ₂ <60 mmHg

  
  
• •
  

  FEV1 <25% predicted.

Timing of listing (presence of one criterion is sufficient) :

• •
  

  BODE index ≥7.

  
  
• •
  

  FEV1 <15%–20% predicted.

  
  
• •
  

  Severe exacerbation with acute hypercapnic respiratory failure. Multiple severe exacerbations during previous 12 months.

  
  
• •
  

  Moderate to severe pulmonary hypertension.