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Interstitial Lung Disease

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Interstitial lung disease is a term that broadly describes a diverse collection of more than 200 lung disorders. These diseases are classified together because they all affect the tissue and space around the alveoli (air sacs), called the inter-stitium. Depending on the specific disease, other compartments of the lung, including the alveoli themselves, the airways (trachea, bronchi, and bronchi-oles), the blood vessels, and the pleura (outside lining of the lung), may also be affected. In general, most interstitial lung disease is characterized by four mani-festations: 1) respiratory symptoms such as shortness of breath and cough, 2) specific chest radiographic abnormalities, 3) typical changes on pulmonary function tests in which the lung volume is decreased, and 4) characteristic micro-scopic patterns of inflammation and fibrosis.

Whom does it affect?

Epidemiology, prevalence, economic burden, vulnerable populations

The lungs of patients with interstitial disease show varying degrees of fibrosis and inflammation. Fibrosis is characterized by an increased amount and abnormal structure of the connective tissue; inflammation is characterized by

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excessive inflammatory cells. Lung biopsies with a predominance of fibrosis typically indicate advanced disease and poor prognosis; whereas patients with a predominance of inflammation have a better prognosis and often respond to treatment.

Although interstitial lung disease was once considered rare, epidemiologic investigations have found these diseases to be more common than previously recognized. One study reported that 80.9 per 100,000 men and 67.2 per 100,000 women suffer from interstitial disease in the United States, with 31.5 new cases diagnosed per 100,000 men per year and 26.1 new cases diagnosed per 100,000 women per year (1). In this study, the most prevalent interstitial diseases included pulmonary fibrosis, occupational- and environmental-associated disease, con-nective tissue diseaseassociated interstitial disease, and sarcoidosis.

Interstitial lung disease is predominantly a disease of adults, although it also occurs in children. Certain interstitial diseases such as sarcoidosis, pulmo-nary Langerhans cell histiocytosis, and autoimmune-associated lung diseases, tend to develop in young adults, whereas idiopathic pulmonary fibrosis (IPF) most often occurs between the ages of 40 and 70. In those with familial IPF

Prevalence of specific interstitial lung diseases in Bernalillo County, New Mexico, 19881990 (1)

Interstitial lung disease diagnosisMen

(per 100,000)Women

(per 100,000)

Idiopathic pulmonary fibrosis 20.2 13.2

Pulmonary fibrosis 10.1 14.3

Interstitial pneumonitis 1.8 2.8

Occupational/environmental 20.8 0.6

Sarcoidosis 8.3 8.8

Connective tissue diseases 7.1 11.6

Drug/radiation 1.2 2.2

Pulmonary hemorrhage 0.6 2.2

Other 10.7 11.6

Total 80.9 67.2

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(defined by its presence in two or more first-degree relatives), the onset of fibro-sis appears to be earlier. Both incidence and mortality of interstitial disease increase with age (2,3).

IPF has been reported to occur throughout the world in many different racial and ethnic groups. Studies in the United States have suggested that Cauca-sians are more likely to be diagnosed with IPF and have higher mortality rates from IPF than African Americans (3,4). It is unclear if these findings are due to real differences in racial characteristics or to an under-diagnosis of this condition in minority populations.

The causes of interstitial lung disease can be classified into one of the fol-lowing four categories: 1) diseases associated with a condition that affects other parts of the body (for example, autoimmune or collagen vascular disease), 2) diseases associated with a specific exposure to an agent known to damage the lungs (for example, medications such as bleomycin, occupational exposures such as asbestos, tobacco smoke, or agents in the environment that cause an immune reaction called hypersensitivity pneumonitis), 3) diseases associated with known genetic abnormalities (for example, HermanskyPudlak syndrome), and 4) idiopathic diseases (diseases of an unknown cause). The most common interstitial lung diseases are idiopathic (5).

Two recent studies found that both the number of new cases diagnosed per year and the mortality rates for idiopathic pulmonary fibrosis are rising in the United States (3,6). Investigators from the United Kingdom have reported simi-lar trends: from 1990 to 2003, the incidence of this disease more than doubled (7). Of even greater concern, mortality rates from idiopathic pulmonary fibrosis are expected to increase because there is no established treatment that prolongs life for patients with these diseases (3).

Persons with exposure to environmental hazards (for example, asbestos) have a higher incidence of interstitial lung disease, although less is known about most of the other forms of interstitial disease. Although not all patients who develop IPF have a history of cigarette smoking, smoking has been associated with the development of disease. Exposure to metal and wood dusts has also been associated with an increased likelihood of developing IPF. Although data are limited, other possible risk factors include exposure to certain prescription drugs and chronic gastroesophageal reflux disease. Genetics play a role in the development of the familial cases of IPF. About 8 percent of familial cases can be attributed to a single set of genes (8).

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What are we learning about this disease?

Pathophysiology, causes, genetic, environment, microbes

Inflammation is a characteristic cellular and molecular response to injury, nox-ious exposure, or infectious agents. Fibrosis, or scarring, can be part of the healing response to injury, but fibrosis as a disease process occurs when resto-ration to normal tissue does not occur. Many of the cells and chemical mediators involved in inflammation are also involved in fibrosis. Fibrosis occurs when the laying down of collagen and other connective tissue does not stop and allow a return to the normal structure. This activity could result from ongoing inflammation,

CASE STUDY

An otherwise healthy 59-year-old physical therapist sought medical attention for increasing shortness of breath and a dry cough over a year. He had no other symptom, no exposure to an environmental cause of interstitial lung disease, no medication associated with interstitial lung disease, no family history of lung disease, and no history of smoking. The physical examination revealed abnormal breath sounds at the bases of his lungs (crackles), but was otherwise normal. Crackles are subtle sounds made by the opening of the smallest air spaces with inspiration, which indicate that they close on expiration, an abnormality. Pulmonary function tests showed decreased lung volume (a restrictive pattern) and low blood oxygenation (hypoxemia) on exertion. A computed tomography scan showed the characteristic pattern of IPF. As there was no proven effective medical therapy for IPF, the patient elected to participate in a clinical trial. He was referred for lung transplant evaluation, started on supplemental oxygen, and enrolled in a pulmonary physical rehabilitation program.

Comment

As in this case, IPF typically develops insidiously, with a gradual onset of shortness of breath and a nonproductive cough. The symptoms often progress to become debilitating and all consuming. Although not necessary in this patient, a tissue biopsy is often needed to reach a conclusive diagnosis. Interstitial diseases are generally difficult to treat because established fibrosis causes permanent structural changes of the lungs.

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possibly because the injurious events continue, or because of defects in the inflammatory or repair processes. When the injurious agent is known, the extent of the injury and time of exposure to the injurious agent are important determi-nants in disease outcome.

More is known about the interstitial diseases with known causes, such as the occupational exposures. For example, it appears that minerals (for example, asbestos and silica) that cause interstitial lung disease directly injure the lung and cannot be easily eliminated. Thus, ongoing inflammatory and fibrotic reac-tions occur. In patients with farmers lung, recurrent exposure to the offending particles (antigens) stimulates the immune system recurrently, which results in fibrosis. A similar recurrent immune stimulation probably occurs with the autoim-mune diseases, such as rheumatoid arthritis. For most of the interstitial lung diseases of unknown cause, the mechanisms of lung injury and fibrosis are also unknown. In several interstitial diseases, viral infection has been postulated to be the inciting cause, but this association has not yet been proven.

how is it prevented, treated, and managed?

Prevention, treatment, staying healthy, prognosis

When the cause of the disease is known, the injurious agent should be avoided. For example, with hypersensitivity pneumonitis, one should avoid dust and mold. With idiopathic disorders, because the cause is unknown, there is no known way to prevent them. However, a number of possible risk factors for disease have be