US Pharm. 2015;40(7):HS12-HS16.

ABSTRACT: Pulmonary fibrosis (PF) is a chronic, progressive, interstitial lung disease in which thickening and scarring of lung tissue eventually leads to death. When an etiology for PF cannot be clearly identified, the condition is termed idiopathic pulmonary fibrosis (IPF). Once thought to be a predominantly proinflammatory disorder, IPF is increasingly understood to be the result of an irreversible fibroproliferative and aberrant wound-healing cascade. Signs and symptoms of IPF become more severe as the disease progresses. Medication and other therapies can usually ease symptoms and improve quality of life, but there is no curative treatment. Two recently approved drugs, pirfenidone and nintedanib, offer promise for patients with IPF.

Pulmonary fibrosis (PF) is a progressive respiratory disorder characterized by a scarring and thickening of the lining of the lungs that causes irreversible loss of ability to transport and exchange oxygen.1,2 As lung tissue scars, it becomes more rigid, making it more difficult for the lungs to inflate and deflate. When this happens, less oxygen is transferred into the bloodstream, making it harder to breathe. As PF worsens, a person becomes progressively weaker and short of breath. Lung tissue damaged by PF cannot be restored to normal function, and this damage eventually results in death.1,2

Idiopathic Pulmonary Fibrosis

PF for which an etiology cannot be clearly identified is termed idiopathic pulmonary fibrosis (IPF).1-3 IPF, a chronic disease that destroys the small interstitial spaces within the lungs, is the most common type of diffuse parenchymal lung disease. IPF was once thought to be a predominantly proinflammatory disorder, but it is increasingly understood to be the result of an irreversible fibroproliferative and aberrant wound-healing cascade.1,2

IPF increases recoil in the lungs; decreases lung volume, making it more difficult to breathe; and leads to moderate-to-severe coughing episodes. Symptoms include fatigue, unexpected weight loss, dry cough for 30 days, chronic shortness of breath, rales or rhonchi, chest pain, palpitations, aching muscles and joints, and clubbing of the fingers and toes.2-4

As IPF progresses, a host of comorbidities, including respiratory failure, heart failure, and pulmonary hypertension (PH), develop. IPF causes inflammation and fibrotic changes in lung parenchyma, which is mechanically linked to pulmonary capillaries in the alveoli. Capillaries in affected alveoli are thus destroyed, and their ability to exchange oxygen and introduce oxygen-rich blood into systemic circulation is lost. A patchy or pied appearance and honeycombing where fibrotic changes have occurred are evident on high-resolution CT and are highly predictive of IPF.5

Epidemiology

The precise prevalence of IPF is unknown, but the American Lung Association estimates that IPF affects about 140,000 Americans yearly, and about 40,000 people die from it each year.1,3,4,6 IPF typically occurs in people aged ≥50 years (range, 40-70 years), and more men than women are affected. Median survival is 2 to 3 years after initial diagnosis. About two-thirds of IPF patients die within 5 years, and the risk of death increases with age.7 Several characteristics associated with increased mortality in IPF patients include older age, male gender, increased severity of dyspnea, diminished pulmonary function, reduced exercise capacity, and radiographic findings showing increased fibrosis.3 Six- and 12-month longitudinal declines in pulmonary function and exercise tests have also been reported to predict mortality.7

Risk Factors

A multitude of chemical and environmental factors can cause scarring of lung tissue associated with IPF (TABLE 1).8,9 Other factors include age (PF is more likely in middle-aged and older adults), long-term exposure to tobacco smoke, viruses, emphysema, chronic lung disease (CLD), and occupation (e.g., mining, farming, construction). Some types of PF appear to have a genetic component. In most cases, the cause is never identified.2-4

Complications

Complications resulting from IPF include a number of medical conditions.3,8,10

PH: This serious disease becomes progressively worse and may eventually prove fatal. It begins when the smallest arteries and capillaries in the lungs are compressed by scar tissue, which results in increased resistance to blood flow in the lungs. This, in turn, raises pulmonary arterial and right ventricular pressure.

Right-sided Heart Failure: Also known as cor pulmonale, this condition can occur when the right ventricle of the heart has to pump harder than normal to move blood through partially blocked pulmonary arteries and into systemic circulation.

Respiratory Failure: Respiratory failure can be the last stage of CLD. It occurs when blood oxygen levels fall dangerously low. Because the lungs are so stiff, it is harder to breathe, which leads to fatigue and loss of appetite.

Lung Cancer: Long-standing PF can increase the risk of lung cancer. Although lung cancer occurs separately from PF, it can also be a product of PF as it progresses.

Emphysema: In chronic smokers, emphysema may be a complication of long-standing PF, although it also can manifest in patients without PF.

Diagnosis

IPF is often a diagnosis of exclusion and requires a multidisciplinary approach, usually involving a pulmonologist, pathologist, and radiologist to rule out other known causes of IPF or similar diseases.3 A thorough patient history and physical examination must be obtained, along with radiologic studies and lung biopsy with or without bronchoalveolar lavage, to rule out alternative diagnoses.3,4

During the physical examination, the physician listens carefully to the lungs to detect and assess any atypical sounds. If there are any unusual lung findings, a number of tests or procedures may be conducted.3,4

• Chest x-ray—This test can reveal lung scar tissue that is typical of PF and may be used as a baseline or for following the disease course and/or treatment progress. If the x-ray is normal, further tests may be needed to explain the presence of IPF signs and symptoms or rule out a respiratory condition.3,4

• CT—Multiple integrated x-ray images are used to produce cross-sectional images of internal structures. High-resolution CT can be particularly helpful in determining the extent of lung damage/scarring caused by PF.3,4

• Echocardiogram—Sound waves are used to visualize the heart and its function. This test can produce real-time still images of the heart’s structures and videos of heart function, including the amount of pressure in the right ventricle.11

• Pulmonary/lung function test—The patient exhales quickly and forcefully through a tube connected to a machine, which measures how much air the lungs can retain and how quickly air moves in and out.3,4

• Oximetry—A sensor is clamped onto one finger to measure blood oxygen saturation. This is an easy and accurate way to monitor the course of disease.3,4

• Exercise stress test—An exercise treadmill or stationary bike may be used to monitor lung function in an active patient.3,4

• Bronchoscopy—This procedure is used to obtain very small lung tissue samples.3,4

• Bronchoalveolar lavage—A salt solution is injected into air sacs in the lung and immediately suctioned out for analysis.3,4

• Surgical biopsy—Surgical instruments and a small camera are inserted through several small incisions between ribs. The surgeon is able to view the lungs on a video monitor while collecting tissue specimens.3,4

IPF Treatment

Typically, treatment strategies for IPF aim to improve quality of life (i.e., relieve disease signs/symptoms) or attempt to limit further inflammation and scarring.12 Anti-inflammatory drugs, including corticosteroids and cytotoxic agents, are used even though there is no evidence of a benefit for long-term survival. Prednisone and similar medications given as monotherapy or in combination with immunosuppressive drugs (e.g., methotrexate, cyclosporine, cyclophosphamide, azathioprine) may be used, along with oxygen and pulmonary rehabilitation, to suppress T- and B-cell and humoral immunity, thereby reducing levels of inflammatory molecules.3,13-17 Adding acetylcysteine to prednisone may help slow the disease.18 Flu and pneumonia vaccines may be helpful. If coughing becomes troublesome, a cough syrup containing codeine may be needed. IPF patients with gastroesophageal reflux (GERD) may need antireflux agents. Since traditional therapy offers only symptomatic benefits, this article will focus on the two drugs holding the most promise for the treatment of IPF: pirfenidone and nintedanib.

Pirfenidone (Esbriet): Pirfenidone is the only drug approved worldwide for clinical use in the treatment of IPF. In October 2014, the FDA granted pirfenidone fast track, priority review, orphan product, and breakthrough designations and approved it to treat IPF. See TABLE 2 for dosing.19-26 Pirfenidone works by multiple mechanisms to mitigate fibrosis and scarring and inhibit transforming growth factor beta, thereby slowing the progression of IPF.3,22,23 In clinical trials, about one-half of patients with mild-to-moderate IPF who were taking pirfenidone had a smaller decrease in forced vital capacity, an indicator of delayed disease progression. Participants in the 52-week trial experienced other benefits, including improved 6-minute walking distances and decreases in mortality. Pirfenidone is not recommended for patients who have severe liver problems or end-stage renal disease or who require dialysis. Before therapy is initiated, baseline kidney and liver-function values should be obtained. Pirfenidone should be taken with food to minimize the potential for nausea and dizziness. Patients should avoid or minimize exposure to sunlight and sunlamps and should wear sunscreen. Common adverse events (AEs) include photosensitivity, nausea, rash, abdominal pain/stomach cramps, upper respiratory tract infection, diarrhea, fatigue, headache, dyspepsia, dizziness, vomiting, decreased/loss of appetite, GERD, sinusitis, insomnia, weight loss, and arthralgia.19-26

Nintedanib (Ofev): In October 2014, the FDA approved nintedanib for the treatment of IPF and granted it fast track, priority review, orphan product, and breakthrough designations.3,27,28 Nintedanib is a tyrosine kinase inhibitor that blocks multiple pathways that may be involved in the scarring of lung tissue. See TABLE 3 for dosing.27,28 Before therapy is initiated, baseline kidney and liver-function values should be obtained. By inhibiting tyrosine, nintedanib limits scarring and fibrotic changes. Its safety and effectiveness were established in three clinical trials involving 1,231 patients with IPF. The decline in forced vital capacity was significantly reduced in patients receiving nintedanib compared with patients receiving placebo. Nintedanib is not recommended for patients with moderate-to-severe liver disease. Nintedanib can cause birth defects or fetal death. Women should not become pregnant while taking nintedanib, and those of childbearing potential should use adequate contraception during use and for 3 months after the last dose of nintedanib. Common AEs include diarrhea, nausea, abdominal pain, vomiting, liver-enzyme elevation, decreased appetite, headache, weight loss, and hypertension.3,27,28

Surgery: The only intervention that improves survival in selected patients is lung transplantation. This may be an option of last resort for younger patients or patients aged <65 years with severe pulmonary fibrosis who have gotten little to no benefit from other treatments. The major complications are infections and lung rejection.3,4

Oxygen Therapy: Supplemental oxygen may be needed during sleep or exercise. Some patients use oxygen around the clock, while others carry a canister of oxygen with them, allowing for more mobility. Using oxygen cannot prevent lung damage, but it can help make breathing and exercise easier; prevent or reduce complications from low blood oxygen levels; reduce blood pressure in the right side of heart; improve sleep; and reduce anxiety. Oxygen should be used with caution, especially near an open flame.3,4

Pulmonary Rehabilitation: The aim of pulmonary rehabilitation is to treat disease and improve daily living functions. To that end, rehabilitation programs focus on physical exercise to strengthen and improve endurance, on breathing techniques to improve lung efficiency, and on helping people live full, satisfying lives.3,4

The Pharmacist’s Role

Pharmacists need to be knowledgeable about IPF to better address patients’ questions about their current health status; possible disease progression; current and future medication treatments; importance of medication compliance and AEs; and use of nonprescription cough and cold medication. Often, patients will need assistance obtaining durable medical equipment and oxygen. If the patient smokes or uses other forms of tobacco, the pharmacist can assist with smoking-cessation programs and education. Patients should be advised to avoid second-hand smoke and toxic air pollutants.

Since IPF is irreversible and only a few drugs are available for treatment, pharmacists can encourage patients to participate in investigational drug trials. Patients may lose weight because eating is uncomfortable and extra energy is needed to breathe while eating. A healthful, nutritionally rich diet with adequate calories is essential for these patients. Patients should be vaccinated for pneumonia and should receive an annual flu shot, since respiratory infections can worsen symptoms of PF. Close family members should be reminded to get these vaccinations also. Patients should avoid crowded places, where the risk of infection is higher. Pharmacists need to be available in emergencies and should recommend that patients seek medical attention immediately when respiratory complications develop.

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