A battery of diagnostic and treatment tools probably will be needed to reduce the morbidity and mortality of this devastating lung disease.

William C. Pruitt, MBA, RRT, CPFT, AE-C

Pulmonary fibrosis is a component of 200 interstitial lung diseases, many of which have no known cause.1 The overall prognosis for patients with pulmonary fibrosis is very dismal, with a 5-year survival rate of 30%, despite aggressive treatment.2 Interstitial lung diseases can be separated into three groups: those with known causes, including occupational and environmental factors (for example, asbestosis, drug toxicity, hypersensitivity reactions, and infection); those caused by systemic disorders such as sarcoidosis or collagen vascular diseases; and those with unknown causes such as idiopathic interstitial pneumonia. Idiopathic pulmonary fibrosis (IPF) makes up a large subset of idiopathic interstitial pneumonia that has been the focus of much research.

The incidence of IPF has been estimated at 10.7 cases per 100,000 for males and 7.4 per 100,000 for females.3 There is evidence1 that IPF is increasing in many Western nations. Of all men having a diagnosis of idiopathic interstitial pneumonia, 46.2% had IPF, while 44.2% of women with idiopathic interstitial pneumonia had IPF.1 Researchers are looking into the many complexities of pulmonary fibrosis, but it is likely that a battery of diagnostic and treatment tools will be needed to reduce the morbidity and mortality of this devastating lung disease.

Symptoms and Diagnosis

Interstitial lung diseases in which fibrosis is present have several common clinical features. These include dyspnea on exertion that gets progressively worse, nonproductive cough, abnormal breath sounds, abnormal chest radiographs, abnormal high-resolution CT (HRCT) scans, a restrictive pattern seen in pulmonary function testing (PFT) results, and decreased diffusing capacity.1 Chest x-ray results in IPF usually show bibasilar peripheral reticular opacities, which are asymmetrical and often associated with decreased lung volumes.5

HRCT scanning is a key diagnostic technology for diffuse interstitial lung disease due to its accuracy in distinguishing between airspace disease and interstitial lung disease and in detecting coexisting disease (such as carcinoma or emphysema). HRCT also helps diagnosticians avoid some typical problems of conventional radiography, which superimposes structures and is exposure dependent.4

IPF is distinguished from other fibrotic interstitial lung diseases using four primary criteria. First, surgical biopsy reveals usual interstitial pneumonia, which shows a specific histological pattern of normal lung tissue alternating with areas of interstitial inflammation, fibrosis, and honeycombing. Second, other causes such as drug toxicity, environmental exposures, or collagen vascular diseases are excluded. Third, abnormal PFT results include reduction in vital capacity, impaired gas exchange (seen as an increased alveolar-arterial difference in PO2), and decreased diffusing capacity of the lung for carbon monoxide (DLCO). If chronic obstructive pulmonary disease is also present, however, lung-volume measurements may appear normal early in the course of disease. Fourth, bibasilar reticular abnormalities with minimal ground glass opacities are seen in HRCT images.

If a surgical biopsy has not been performed, other diagnoses should be ruled out using either transbronchial lung biopsy or bronchoalveolar lavage. Other supportive criteria include an age of more than 50 years (since IPF incidence increases with age), symptoms lasting longer than 3 months, and bibasilar inspiratory crackles described as sounding like the two sides of hook-and-loop fastener tape being parted. As IPF progresses, the lungs become increasingly stiff and noncompliant. Tachypnea is common, and rapid, shallow breathing increases, bringing on increased work of breathing. Exercise testing is a sensitive means of monitoring the progression of the disease.5

Risk Factors and Disease Mechanisms

Even though the cause(s) of IPF are unknown, six potential risk factors have been identified through research.5 Four of these are cigarette smoking, use of antidepressants, chronic aspiration secondary to gastroesophageal reflux, and genetic predisposition. Exposure to metal dust and wood dust and exposure to solvents are part of the fifth category of environmental risk factors. Various infectious agents constitute the sixth group. The pathogens involved include Epstein-Barr virus, influenza, cytomegalovirus, hepatitis C virus, parainfluenza and parainfluenza 3 viruses, HIV-1, measles virus, herpesvirus 6, Mycoplasma, and Legionella.

Normally, injury to lung tissue triggers a rapid response, with repair of the injured lung and restoration of its normal architecture and function. This response consists of a complex, stepwise process with components that often overlap, starting with coagulation followed by inflammation and then by the formation of granulation tissue by myofibroblasts (which appear and then disappear as the normal lung structure and function are restored). These steps are initiated and mediated by certain cytokines and chemokines, which are messengers and controllers in the ordered process. Many of the cytokines and chemokines are paired, with one acting to start a process or activate a system and the other acting to stop or deactivate the process or system.

Apparently, when IPF occurs, the normal process is disrupted, and several detrimental changes occur in the lung. Some agents, such as the cytokine interleukin 1, act both to promote and to inhibit fibrosis. Tumor necrosis factor can also promote and inhibit fibrosis. Researchers are looking for ways to block the fibrotic effects and/or encourage the antifibrotic actions of these agents.

As IPF develops, normal steps in the coagulation process appear to go awry, and fibrin deposits begin to build up in the lung. Chronic inflammation is another problem, with inflammatory response cells such as neutrophils remaining in the area instead of undergoing apoptosis and normal removal by macrophages. These cells remaining in the area may be linked to release of inflammatory and fibrotic genes.2 In the normal process of lung repair, myofibroblasts appear and form scar tissue, then undergo programmed cell death as the interstitial cells develop and mature. In IPF, myofibroblasts do not die; instead, they begin the formation of an abnormal extracellular matrix that wipes out the normal lung tissue. Some researchers are looking into ways to restart the process of apoptosis in the myofibro-

blasts. These cells also appear to contribute to the recruitment of more inflammatory cells. Moreover, myofibroblasts have contractile properties that change the mechanical characteristics of the fibrotic lung and decrease lung compliance. Collagen deposits also add to the buildup of the extracellular matrix and cause the lung to stiffen. As these fibers and cells persist and accumulate, the abnormalities of lung architecture advance and remodeling continues.6

The concept of multiple hits may explain some of the causes for the spiraling deterioration in the lung parenchyma and continuing buildup of a fibrous, stiff extracellular matrix. This idea is linked to recurring exposure to injury and/or repeated infection and chronic inflammation, with only partial remission. During the formation of the extracellular matrix, a new vascular bed is formed; this appears to be another malfunction that takes place as the pulmonary circulation is remodeled. Without the support of a new vascular bed, it appears that the fibrotic process would be inhibited.2 As fibrosis and the buildup of the abnormal extracellular matrix continue, exercise tolerance decreases, the lungs become less compliant, gas exchange is hampered, respiration becomes more labored, and the other body systems are stressed. Eventually, death occurs.

Current and Future Treatment

Spontaneous remission of IPF does not occur. Despite efforts to treat this disease, the mean survival time ranges from 2 to 4 years after diagnosis. Current treatment involves anti-inflammatory medications, immunosuppressive or cytotoxic medications, antifibrotic agents, and lung transplantation. Transplantation brings about an immediate improvement in pulmonary function and, for a short time, daily activities and quality of life return to almost normal levels. Unfortunately, this is not a lasting solution, and lung rejection often brings the end of life after another 3 to 4 years. Researchers7 in France studied 46 patients referred to a transplantation center with a diagnosis of IPF over a 12-year period. Of these, 27 patients received single-lung transplants, one received a double-lung transplant, 16 died while waiting for a transplant, and two remained on the waiting list at the end of the study. Survival rates were 79.4% 1 year after transplantation, 63.5% after 2 years, and 39% after 5 years.

Graft failure, infection, and heart failure have been listed as causes of early death after transplantation, while bronchiolitis obliterans, infection, and cancer are the main causes of later death after transplantation.5 The international consensus statement published in 2000 recommends that patients with IPF be enrolled in a pulmonary rehabilitation program. By improving exercise tolerance and quality of life, and decreasing feelings of breathlessness, the panel suggests there will be a decreased need for health care services. Oxygen therapy to treat hypoxemia is also included in the panel recommendations.5

Possible future therapeutic strategies include agents that inhibit the negative (fibrotic) effects of cytokines, proteases, or fibroblast growth factors. Dietary modifications may have a beneficial effect. Antioxidants and gene therapy are also being investigated for treatment.5 One form of interferon has been shown to induce apoptosis in myofibroblasts, and research is ongoing into agents to oppose the fibrotic effects of connective tissue growth factor and transforming growth factor beta-1.3


IPF is a heartbreaking disease, and there are very few options to offer a patient for effective treatment to slow its progress. Many researchers are calling for a multicenter, international consortium to bring together a large number of patients for study.5 In the meantime, IPF rates are increasing. Compassion, understanding, and diligence in providing the best care are needed from the health care community while research goes forward in the hope that the outcome of this diagnosis can be changed significantly. In the meantime, use of anti-inflammatory medications, immunosuppressive or cytotoxic medications, antifibrotic agents, lung transplantation, pulmonary rehabilitation, and oxygen therapy may help to improve the quality of life and extend time for patients with IPF.


William C. Pruitt, MBA, RRT, CPFT, AE-C, is an instructor, Department of Cardiorespiratory Care, University of South Alabama, Mobile.


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