NORD gratefully acknowledges David A. Schwartz, MD, Department of Medicine and Department of Immunology, University of Colorado School of Medicine, for assistance in the preparation of this report.
Idiopathic pulmonary fibrosis (IPF) is a chronic lung disorder characterized by thickening, stiffening and scarring (fibrosis) of tissue within the lungs. Affected individuals develop shortness of breath and progressive lung disease. Ultimately, IPF results in life-threatening complications such as respiratory failure. The rate of progression can vary greatly from one person to another. Over years, most individuals experience increasing respiratory symptoms, progressive scarring of the lungs and a gradual decline in lung function. Less often, affected individuals have mild scarring within the lungs and little to no change in the disease for many years. In some cases, the disorder can progress rapidly (acutely), causing life-threatening complications within several years of diagnosis. The term ‘idiopathic’ means that the underlying cause of the disorder is unknown or unproven, however, recently genetic susceptibility has been shown to account for 35-40% of the risk of developing this disease. Although there is no cure for IPF, various different treatments are available to manage the disorder and several newer therapeutic options are being studied. Ultimately, some affected individuals will require a lung transplant.
IPF is classified as a form of idiopathic interstitial pneumonia, which is a group of lung diseases that damage the lungs in a similar manner and occur due to unknown causes. This group of disorders is also known as diffuse parenchymal lung diseases. Collectively, these disorders are classified under the broader umbrella term, interstitial lung diseases (ILDs). ILDs a large group of disorders (more than 200) characterized by progressive scarring of the lungs. IPF is the most common form.
In the early stages of IPF no symptoms may be present (asymptomatic). As stated above, the progression of the disorder is highly variable. Some individuals may experience ‘exacerbations’ in which symptoms worsen for a period of time, before improving somewhat. The initial, characteristic symptom is shortness of breath that is particularly noticeable during exertion such as exercise. This is known as breathlessness or dyspnea. Affected individuals may also exhibit a mild, dry cough that produces little to no sputum (nonproductive cough). Sputum is material that is coughed up from the respiratory tract and can include saliva, mucus and phlegm. This persistent, nonproductive cough lasts for more than 30 days.
As the disease progresses, affected individuals develop breathlessness upon moderate exertion or exercise. They may exhibit fast, shallow breathing. The dry, hacking nonproductive cough may also occur. Eventually, breathlessness may develop upon minimal exertion or even at rest. Affected individuals may experience repeated bouts of coughing that cannot be controlled.
Additional symptoms that may occur include abnormal fatigue, discomfort in the chest, gradual, unintended weight loss, and aching joints and muscles. Some individuals develop clubbing of the fingers or toes. Clubbing is when the tissue at the bottom of the fingernails and toenails swells, becoming wider and rounder. Affected individuals have an increased risk of developing repeated chest infections (chronic pneumonia).
Ultimately, respiratory function in individuals with IPF declines to cause severe complications including respiratory failure. Pulmonary fibrosis can lead to other severe medical conditions including pneumonia (lung infection), collapsed lungs (pneumothorax), high blood pressure of the main artery of the lungs (pulmonary hypertension), blood clots in the lungs (pulmonary embolism), and heart failure. Individuals with IPF may be at an increased risk of developing lung cancer.
Some individuals experience an ‘acute exacerbation,’ which describes a rapid progression of the disease and a rapid deterioration of lung function. Acute exacerbations may be associated with a complicating factor such as an infection, pulmonary embolism, pneumothorax or heart failure. However, in many cases, acute exacerbations occur without any identifiable cause.
The exact, underlying cause of IPF is not fully understood. The disorder is occurs in families and also sporadically. Different factors, including immunologic, environmental, and genetic ones, are thought to play a role in the development of the disorder. The strongest risk factor, accounting for 30% of risk of developing IPF, is a variation in the MUC5B gene that results in more mucus production in the smallest airways in the lung (respiratory bronchioles).
For many years, researchers believed that most cases resulted from generalized inflammation in the lungs that progressed to cause excessive scarring in the lungs. However, researchers now believe that most cases result from damage to certain cells that line the small airways and alveoli (epithelial cells). The alveoli are tiny, thin-walled air sacs found in large numbers in the lungs. Alveoli are where oxygen enters the blood and carbon dioxide exits the blood. Alveoli are found at the ends of small, narrow tubes called bronchioles, which branch off from the main airway passages within the lungs. Basically, air is breathed in through the nose and mouth and travels down the throat to the windpipe (trachea). The trachea divides into air passages called bronchial tubes to which the bronchioles are connected. Most likely, as a part of normal wound healing, the body attempts to repair the damaged epithelial cells. This response is abnormal leading to progressive scarring and damage to the alveoli and surrounding lung tissue.
As explained, the underlying reason why the initial damage occurs is not always understood. Such damage may result from chronic exposure to an inciting or ‘triggering’ agent. Cigarette smoking is strongly associated with IPF, particularly in individuals with at least 20 ‘pack’ years of smoking history. Additional triggering agents include chronic breathing into the lungs of foreign material (chronic aspiration) and the chronic breathing in of certain environmental pollutants including various gases and fumes, inorganic dusts (e.g. silica and hard metal dusts), and organic dusts (e.g. bacteria and animal proteins). Viral or bacterial infections, radiation therapies, and certain medications including specific chemotherapeutic drugs, antibiotics and heart medications have also been linked to IPF. Autoimmune diseases such as rheumatoid arthritis, lupus or scleroderma are known to be associated with pulmonary fibrosis. In many cases, no inciting or triggering agent can be identified.
Researchers suspect that certain affected individuals are genetically predisposed (susceptible) to developing IPF following such exposures described above. A person who is genetically predisposed to a disorder carries a gene (or genes) for the disease, but it may not be expressed unless it is triggered or “activated” under certain circumstances, such as due to particular environmental or immunologic factors. A number of genes have implicated in the development of IPF and in aggregate account for 35-40% of the risk of developing IPF. These genes include genes that preserve host defense, cell survival, and cell-cell interactions.
Specific genetic abnormalities that may be associated with IPF in certain cases include mutations of the MUC5B gene, which produces a mucus protein; mutations of the SP-C gene, which encodes surfactant protein C (surfactant is a mixture of fats and proteins that reduces surface tension of fluids that coat the lungs); and mutations of the TERT and TERC genes, which are involved in the health and function of telomeres. Telomeres are structures found at the end of chromosomes that are essential in the replication and stability of chromosomes. Telomeres have been compared to the plastic tips of shoelaces because they prevent chromosomes from sticking together, becoming frayed or damaged and protect the vital genetic information on a chromosome. However, a variant controlling the expression of the MUC5B gene is the most important risk factor for the development of IPF, accounting for 30% of the risk of developing this disease. Most likely, IPF and idiopathic interstitial pneumonias in general, are caused in part by multiple genetic variations acting alone or in some combination. More research is necessary to determine the exact role such genetic mutations play in the development of IPF in specific cases.
In 5-10% of the cases, IPF has occurred in more than one member of the same family unit (i.e. parent, children and siblings). When this occurs, the term familial idiopathic pulmonary fibrosis is used. The symptoms and objective signs of familial IPF are the same as those for sporadic IPF, but the disorder tends to occur at a slightly younger age.
Pulmonary fibrosis can occur as part of a distinct genetic disorder such as Hermansky-Pudlack syndrome. HPS is characterized by albinism, vision abnormalities and platelet dysfunction leading to prolonged bleeding. In specific cases, affected individuals can develop pulmonary fibrosis. Mutations in several different genes are known to cause HPS; pulmonary fibrosis only appears to be associated with two specific mutations, the HPS1 gene and the HPS4 gene. (For more information on this disorder, choose “Hermansky Pudlak” as your search term in the Rare Disease Database.)
Several conditions occur with greater frequency in individuals with IPF than in individuals within the general population including backflow (regurgitation) of the contents of the stomach into the esophagus (gastroesophageal reflux or GERD), obesity, emphysema and obstructive sleep apnea. The connection, if any, between these disorders is not fully understood. Some researchers believe that chronic GERD may be a risk factor for developing IPF because of repeated, unintentional aspiration of very small amounts of reflux material into the lungs.
The exact prevalence and incidence of IPF is unknown. Estimates have ranged from 2-29 people per 100,000 in the general population. This variation may be partially due to the lack of a uniform definition when attempting to identify the disorder. Additionally, many cases of IPF go undiagnosed or misdiagnosed, making it difficult to determine the true frequency in the general population. Familial IPF accounts for approximately 5-10% of all cases of IPF. IPF primarily affects older adults. Males tend to be affected more often than females.
A diagnosis of idiopathic pulmonary fibrosis may be suspected based upon identification of characteristic symptoms, a detailed patient history, and a thorough clinical evaluation. A diagnosis may be confirmed based upon a variety of specialized tests including traditional chest x-rays (radiography), computer tomography (CT) scans, pulmonary function tests, blood tests, and the surgical removal and microscopic examination of lung tissue (lung biopsy).
Detailed diagnostic criteria for IPF have been published by the combined efforts of several groups including the American Thoracic Society, the European Respiratory Society, the Japanese Respiratory Society, and the Latin American Thoracic Association (Wells AU, 2013).
Clinical Testing and Workup
Traditional chest x-rays can demonstrate scarring within the lungs, which is suggestive but not diagnostic of IPF. Some individuals may have normal chest x-rays at the time of diagnosis. A special type of CT scanning known as high resolution computed tomography (HRCT) can be used to diagnose individuals with IPF. During CT scanning, a computer and x-rays are used to create a film showing cross-sectional images of certain tissue structures. HRCT gives sharper, more detailed pictures of the lungs than traditional x-rays or conventional CT scanning. HRCT can reveal the presence of scar tissue and the extent of lung damage and in some cases the presence of specific findings can be adequate to establish a diagnosis. Many cases of IPF are associated with a distinct pattern of lung damage known as usual interstitial pneumonia (UIP). This pattern consists of patches of normal lung tissues that alternate with patches of dense scar tissue (fibrosis).
Pulmonary function tests to measure how well the lungs take in and exhale oxygen and how efficiently they transfer oxygen to the blood may also be helpful. There are no blood tests for IPF, but certain blood tests can help to rule out other conditions. Exercise testing, in which blood pressure, oxygen saturation levels and heart function are monitored, may be recommended. Specific methods vary, but walking on a treadmill or riding a stationary bike are common methods used during exercise testing.
A procedure known as bronchoalveolar lavage (BAL) may be used to help rule out other conditions. During BAL, a narrow tube (bronchoscope) is slid down the windpipe into the lungs and a sterile solution is passed through the tube washing out (lavaging) cells. This fluid is collected and then the tube is removed, allowing the cells to be studied.
If a diagnosis of IPF cannot be confirmed by other tests, a lung biopsy or a video-assisted thoracoscopy may be necessary. A lung biopsy involves removing samples of lung tissue from several places within the lungs. A lung biopsy can rule out specific conditions and confirm a diagnosis of IPF. Video-assisted thoracoscopy involves inserting a narrow tube called an endoscope affixed with a tiny camera through a very small cut (incision) in the chest wall. This allows physicians to examine the lungs or other structures within the chest cavity.
In 2014, the U.S. Food and Drug Administration (FDA) approved two drugs for the treatment of IPF. Ofev (nintedanib), distributed by Boehringer Ingelheim Pharmaceuticals, Inc., is a kinase inhibitor that blocks multiple pathways that may be involved in the scarring of lung tissue.
Esbriet (pirfenidone), manufactured for InterMune, Inc., acts on multiple pathways that may be involved in the scarring of lung tissue.
Various other treatment options are aimed at treating the symptoms of IPF, slowing the progression of the disease, and helping affected individuals remain active and healthy and to maintain their quality of life.
Specific therapeutic procedures and interventions may vary, depending upon numerous factors, such as disease progression; the presence of additional, unrelated illnesses (co-morbidities); the presence or absence of certain symptoms; an individual’s age and general health; and/or other elements. Decisions concerning the use of particular drug regimens and/or other treatments should be made by physicians and other members of the health care team in careful consultation with the patient based upon the specifics of his or her case; a thorough discussion of the potential benefits and risks, including possible side effects and long-term effects; patient preference; and other appropriate factors.
At some point in their lives, most individuals with IPF will require supplemental oxygen (oxygen therapy) to compensate for the inability of the lungs to transfer oxygen into the bloodstream. At first, oxygen therapy may be required only upon exertion, but in some cases may eventually be required continuously. Oxygen therapy can reduce breathlessness and allow individuals to be more active.
Individuals with IPF may benefit from a program known as a pulmonary rehabilitation, a standard treatment option for individuals with chronic lung diseases. Pulmonary rehabilitation usually involves a team of specialists at a clinic experienced in lung disease. Pulmonary rehabilitation teaches individuals about exercise training; specific breathing strategies or techniques; nutritional counseling; and energy-conserving techniques. These specialists can also provide education on lung disease including how to best manage the disease and can provide psychological counseling.
Affected individuals who smoke are strongly encouraged to stop. Influenza and pneumococcal polysaccharide vaccinations are strongly recommended as well because these infections are particularly harmful to individuals with IPF.
Certain other medications have been used to treat individuals with IPF. For many years, corticosteroid medications such as prednisolone often along with an immunosuppressive drug such as azathioprine have been used to treat individuals with IPF. These drugs reduce inflammation and/or suppress the immune system. Another drug known as N-acetylcysteine (a naturally occurring antioxidant) is often added to this drug regimen. These drugs were usually recommended based upon the initial theory that generalized inflammation was a major component of IPF. However, the drugs were often ineffective or provided only minimal relief and there is no evidence that they improve long-term survival. In 2011 (Raghu, et al.), a consensus paper published by the American Thoracic Society stated that combination therapy involving prednisolone, azathioprine, and N-acetylcysteine is recommended only in a minority of patients.
Individuals with IPF may eventually require a lung transplant. Such surgery is more likely in younger patients (under 65 years of age) with severe disease who have not responded to other treatments and who do not have other serious medical complications. Some medical centers consider lung transplantations for individuals over 65 who do not have other serious medical complications. As with any organ transplant, a lung transplant carries a risk of significant complications such as rejection or infection.
Gastroesophageal reflux may be treated with standard medications that reduce or suppress the production of acid in the stomach. GERD treatment may be particularly important in individuals with IPF because some studies have shown longer survival times and lower fibrosis scores in individuals receiving treatment for GERD.
Additional therapies are symptomatic and follow standard guidelines. For example, antibiotics may be prescribed for lung infections and cough medications and oral codeine may provide relief from chronic coughing.
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