The Elusive Goal of Therapy for Usual Interstitial Pneumonia
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《新英格兰医药杂志》
Idiopathic pulmonary fibrosis, defined pathologically as usual interstitial pneumonia, is a fatal disease that occurs most commonly among persons who are 60 years of age or older and in otherwise good health. Usual interstitial pneumonia progressively impairs breathing, but because its onset is insidious, patients are frequently treated for other diseases for many months. By the time the diagnosis is established, pulmonary function has often substantially deteriorated.1
Several entities fall under the wide umbrella of chronic interstitial pneumonias,2 including usual interstitial pneumonia, nonspecific interstitial pneumonitis, desquamative interstitial pneumonia, acute interstitial pneumonia, respiratory bronchiolitis–associated interstitial lung disease, and cryptogenic organizing pneumonia.3 The prognosis and treatment may vary according to the type of pneumonia, which must therefore be established before treatment is initiated. The workup often includes open lung biopsy. For the clinician, there is a clear separation between usual interstitial pneumonia and all the other idiopathic interstitial pneumonias. Although the other types usually respond to corticosteroid therapy, there is no effective treatment for the majority of cases of usual interstitial pneumonia.
Patients present with tachypnea; a nonproductive cough; bilateral inspiratory crackles with a distinctive tone to them, which are often referred to as "cellophane" or "Velcro" rales; restrictive pulmonary dysfunction; and exercise-related hypoxemia. Clubbing is common, and pulmonary hypertension and cor pulmonale may ensue. Signs of airway disease are minimal. Chest radiographs reveal small lung volumes, bibasilar linear reticulations, and honeycombing. High-resolution computed tomography (CT) is excellent for distinguishing usual interstitial pneumonia from other fibrosing entities.4 The clinician must rule out multiorgan connective-tissue diseases in which the lung is one of several fibrotic organs. A thorough occupational history-taking is essential, since pulmonary asbestosis can have a similar clinical presentation.
It is vital to differentiate usual interstitial pneumonia from the other interstitial pneumonias, especially nonspecific interstitial pneumonitis, since the latter disease usually has a better prognosis and response to treatment.5 Fortunately, the diagnosis of usual interstitial pneumonia can generally be confirmed by findings of a heterogeneous distribution of patchy, peripheral reticular densities, broad bands of fibrosis, and honeycombing on high-resolution CT. Some ground-glass opacities may be present. In a patient with an appropriate history, findings on physical examination, and functional abnormalities, the typical pattern on high-resolution CT is diagnostic of usual interstitial pneumonia, and in this circumstance, many clinicians forgo a confirmatory lung biopsy.6 However, when uncertainty exists, lung biopsy is required. If granulomatous or neoplastic disease or infections remain to be ruled out, bronchoscopic biopsy and bronchoalveolar lavage may be diagnostic. However, the definitive diagnostic biopsy for usual interstitial pneumonia is open lung biopsy by means of video-assisted or standard thoracotomy.
Since the cause of usual interstitial pneumonia is unknown, nonspecific antiinflammatory or immunosuppressive therapy has been considered appropriate. Common treatments include prednisone at an initial dose of 1 mg per kilogram of body weight.1 Colchicine, azathioprine, cyclophosphamide, penicillamine, and pirfenidone have been used alone or as corticosteroid-sparing drugs.7,8 No well-controlled, randomized, and blinded studies have shown any of these medications to be efficacious. Since all of these medications are toxic, physicians are reluctant to treat usual interstitial pneumonia until the symptoms become disabling or pulmonary function is severely impaired. Currently, the average life expectancy of patients with usual interstitial pneumonia is between two and five years after diagnosis, regardless of treatment.
Although many of the molecular and biochemical events leading to fibrosis of the lung are now known, one or more unknown agents are thought to initiate a diffuse inflammatory alveolitis, which progresses to fibrosis as a result of fibroblast proliferation, mediated by transforming growth factor 1 (TGF-1). Interferon gamma-1b down-regulates the gene for TGF-1 and inhibits the proliferation of fibroblasts. In 1999, Ziesche et al. reported the results of a one-year study of 18 patients with usual interstitial pneumonia, 9 of whom received interferon gamma-1b and prednisolone, and 9 prednisolone alone.9 Total lung capacity increased, the partial pressure of arterial oxygen improved, and the levels of transcription of the genes for TGF-1 and connective-tissue growth factor decreased markedly in the patients who received interferon gamma-1b and prednisolone but not in those who received only prednisolone.
The study by Ziesche et al. gave impetus to the larger, multicenter trial of interferon gamma-1b for the treatment of usual interstitial pneumonia reported in this issue of the Journal.10 Raghu et al. randomly assigned 330 patients with usual interstitial pneumonia that was unresponsive to corticosteroid therapy to receive interferon gamma-1b or placebo. The study was well conducted: an average of 93 percent of all scheduled doses were received, and 90 percent of the patients largely complied with the protocol. Regrettably, interferon gamma-1b had no effect on the outcome measures of improved pulmonary function, gas exchange, or the quality of life. Adverse events occurred in both groups of patients, with fever, rigors, headache, and myalgia being more common among patients who received interferon gamma-1b. These symptoms usually subsided after the first several weeks of treatment.
An unexpected salutary outcome, not one of the target end points, was increased survival among patients who were compliant with interferon gamma-1b treatment. Sixteen of the 162 patients in the interferon gamma-1b group died, as compared with 28 of the 168 patients in the placebo group. Since there was no measurable improvement in lung disease, this outcome is unexplained. It should be emphasized that survival data based on one year of observation in a disease with an unknown date of onset and a life expectancy of two to five years after diagnosis may be very misleading. The five-year follow-up should prove more informative. It is possible that in the prior, preliminary study, the nine patients with functional improvement after interferon gamma-1b therapy represented a unique subgroup of patients with usual interstitial pneumonia who had reductions in the levels of transcription of the genes for TGF-1 and connective-tissue growth factor. Similar analyses were not performed in the study by Raghu et al.
This negative study will greatly disappoint patients. What should clinicians tell them? Frankly, patients should be told that there are no studies that prove that any medication is efficacious for the treatment of usual interstitial pneumonia. Therefore, what treatment, if any, should be prescribed, and when should treatment begin? The most effective approaches are obvious. Patients should stop smoking, since cigarette smoking increases the risk of superimposed inflammatory bronchial disease and neoplasia and aggravates usual interstitial pneumonia. Influenza and pneumonia vaccine should be administered. Oxygen saturation should be maintained at a level above 90 percent through the use of oxygen therapy. Treatment of pulmonary hypertension with newer agents may be of benefit. Although in some cases improvement has been reported with corticosteroids and immunosuppressive therapies, a Cochrane Review found no data that support the use of immunosuppressive medications.11
The timing of treatment may be important. Since approximately 30 percent of patients treated with prednisone have had objective evidence of improvement,1 prednisone is indicated. Since all therapies have serious side effects, prudent physicians delay treatment until symptoms are severe or physiological measurements are substantially impaired. Although the improved survival among the patients in the interferon gamma-1b group in the study by Raghu et al. remains unexplained, it is noteworthy that this benefit occurred in a subgroup of patients with less impaired function who strictly adhered to the treatment protocol. Thus, early treatment may be more effective. Lung transplantation is the last resort.
Although Raghu et al. did not find interferon gamma-1b to be efficacious, they should be commended for using the first scientifically based agent against usual interstitial pneumonia in a well-conducted, large, controlled trial. Studies of other promising agents that are based on the growing knowledge of the pathogenesis of organ fibrosis are indicated, since interferon gamma-1b has not proved to be the answer.
Source Information
From the Division of Pulmonary and Critical Care Medicine, Mount Sinai Medical Center, New York.
References
American Thoracic Society. Idiopathic pulmonary fibrosis: diagnosis and treatment. International consensus statement. American Thoracic Society (ATS), and the European Respiratory Society (ERS). Am J Respir Crit Care Med 2000;161:646-664.
Liebow AA, Carrington CB. The interstitial pneumonias. In: Simon M, Potchen EJ, LeMay M, eds. Frontiers of pulmonary radiology: pathophysiologic, roentgenographic and radioisotopic considerations; proceedings of the symposium sponsored by Harvard Medical School, April 21-22, 1967. New York: Grune & Stratton, 1969:102-41.
Katzenstein AL, Myers JL. Idiopathic pulmonary fibrosis: clinical relevance of pathologic classification. Am J Respir Crit Care Med 1998;157:1301-1315.
Strollo DC. Imaging of idiopathic interstitial lung diseases: concepts and conundrums. Am J Respir Cell Mol Biol 2003;29:Suppl 3:S10-S18.
Daniil ZD, Gilchrist FC, Nicholson AG, et al. A histologic pattern of nonspecific interstitial pneumonia is associated with a better prognosis than usual interstitial pneumonia in patients with cryptogenic fibrosing alveolitis. Am J Respir Crit Care Med 1999;160:899-905.
Hunninghake GW, Lynch DA, Galvin JR, et al. Radiologic findings are strongly associated with a pathologic diagnosis of usual interstitial pneumonia. Chest 2003;124:1215-1223.
Lynch JP III, McCune WJ. Immunosuppressive and cytotoxic pharmacotherapy for pulmonary disorders. Am J Respir Crit Care Med 1997;155:395-420.
Raghu G, Johnson WC, Lockhart D, Mageto Y. Treatment of idiopathic pulmonary fibrosis with a new antifibrotic agent, pirfenidone: results of a prospective, open-label Phase II study. Am J Respir Crit Care Med 1999;159:1061-1069.
Ziesche R, Hofbauer E, Wittmann K, Petkov V, Block LH. A preliminary study of long-term treatment with interferon gamma-1b and low-dose prednisolone in patients with idiopathic pulmonary fibrosis. N Engl J Med 1999;341:1264-1269.
Raghu G, Brown KK, Bradford WZ, et al. A placebo-controlled trial of interferon gamma-1b in patients with idiopathic pulmonary fibrosis. N Engl J Med 2004;350:125-133.
Davies HR, Richeldi L, Walters EH. Immunomodulatory agents for idiopathic pulmonary fibrosis. Cochrane Database Syst Rev 2003;3:CD003134-CD003134.
Related Letters:
Interferon Gamma-1b for Pulmonary Fibrosis
Hill A. R., Fruchter O., Eisner M. D., Tsoutsou P. G., Gourgoulianis K. I., Vourlekis J. S., Richeldi L., Raghu G., King T. E. Jr., Teirstein A. S.(Alvin S. Teirstein, M.D.)
Several entities fall under the wide umbrella of chronic interstitial pneumonias,2 including usual interstitial pneumonia, nonspecific interstitial pneumonitis, desquamative interstitial pneumonia, acute interstitial pneumonia, respiratory bronchiolitis–associated interstitial lung disease, and cryptogenic organizing pneumonia.3 The prognosis and treatment may vary according to the type of pneumonia, which must therefore be established before treatment is initiated. The workup often includes open lung biopsy. For the clinician, there is a clear separation between usual interstitial pneumonia and all the other idiopathic interstitial pneumonias. Although the other types usually respond to corticosteroid therapy, there is no effective treatment for the majority of cases of usual interstitial pneumonia.
Patients present with tachypnea; a nonproductive cough; bilateral inspiratory crackles with a distinctive tone to them, which are often referred to as "cellophane" or "Velcro" rales; restrictive pulmonary dysfunction; and exercise-related hypoxemia. Clubbing is common, and pulmonary hypertension and cor pulmonale may ensue. Signs of airway disease are minimal. Chest radiographs reveal small lung volumes, bibasilar linear reticulations, and honeycombing. High-resolution computed tomography (CT) is excellent for distinguishing usual interstitial pneumonia from other fibrosing entities.4 The clinician must rule out multiorgan connective-tissue diseases in which the lung is one of several fibrotic organs. A thorough occupational history-taking is essential, since pulmonary asbestosis can have a similar clinical presentation.
It is vital to differentiate usual interstitial pneumonia from the other interstitial pneumonias, especially nonspecific interstitial pneumonitis, since the latter disease usually has a better prognosis and response to treatment.5 Fortunately, the diagnosis of usual interstitial pneumonia can generally be confirmed by findings of a heterogeneous distribution of patchy, peripheral reticular densities, broad bands of fibrosis, and honeycombing on high-resolution CT. Some ground-glass opacities may be present. In a patient with an appropriate history, findings on physical examination, and functional abnormalities, the typical pattern on high-resolution CT is diagnostic of usual interstitial pneumonia, and in this circumstance, many clinicians forgo a confirmatory lung biopsy.6 However, when uncertainty exists, lung biopsy is required. If granulomatous or neoplastic disease or infections remain to be ruled out, bronchoscopic biopsy and bronchoalveolar lavage may be diagnostic. However, the definitive diagnostic biopsy for usual interstitial pneumonia is open lung biopsy by means of video-assisted or standard thoracotomy.
Since the cause of usual interstitial pneumonia is unknown, nonspecific antiinflammatory or immunosuppressive therapy has been considered appropriate. Common treatments include prednisone at an initial dose of 1 mg per kilogram of body weight.1 Colchicine, azathioprine, cyclophosphamide, penicillamine, and pirfenidone have been used alone or as corticosteroid-sparing drugs.7,8 No well-controlled, randomized, and blinded studies have shown any of these medications to be efficacious. Since all of these medications are toxic, physicians are reluctant to treat usual interstitial pneumonia until the symptoms become disabling or pulmonary function is severely impaired. Currently, the average life expectancy of patients with usual interstitial pneumonia is between two and five years after diagnosis, regardless of treatment.
Although many of the molecular and biochemical events leading to fibrosis of the lung are now known, one or more unknown agents are thought to initiate a diffuse inflammatory alveolitis, which progresses to fibrosis as a result of fibroblast proliferation, mediated by transforming growth factor 1 (TGF-1). Interferon gamma-1b down-regulates the gene for TGF-1 and inhibits the proliferation of fibroblasts. In 1999, Ziesche et al. reported the results of a one-year study of 18 patients with usual interstitial pneumonia, 9 of whom received interferon gamma-1b and prednisolone, and 9 prednisolone alone.9 Total lung capacity increased, the partial pressure of arterial oxygen improved, and the levels of transcription of the genes for TGF-1 and connective-tissue growth factor decreased markedly in the patients who received interferon gamma-1b and prednisolone but not in those who received only prednisolone.
The study by Ziesche et al. gave impetus to the larger, multicenter trial of interferon gamma-1b for the treatment of usual interstitial pneumonia reported in this issue of the Journal.10 Raghu et al. randomly assigned 330 patients with usual interstitial pneumonia that was unresponsive to corticosteroid therapy to receive interferon gamma-1b or placebo. The study was well conducted: an average of 93 percent of all scheduled doses were received, and 90 percent of the patients largely complied with the protocol. Regrettably, interferon gamma-1b had no effect on the outcome measures of improved pulmonary function, gas exchange, or the quality of life. Adverse events occurred in both groups of patients, with fever, rigors, headache, and myalgia being more common among patients who received interferon gamma-1b. These symptoms usually subsided after the first several weeks of treatment.
An unexpected salutary outcome, not one of the target end points, was increased survival among patients who were compliant with interferon gamma-1b treatment. Sixteen of the 162 patients in the interferon gamma-1b group died, as compared with 28 of the 168 patients in the placebo group. Since there was no measurable improvement in lung disease, this outcome is unexplained. It should be emphasized that survival data based on one year of observation in a disease with an unknown date of onset and a life expectancy of two to five years after diagnosis may be very misleading. The five-year follow-up should prove more informative. It is possible that in the prior, preliminary study, the nine patients with functional improvement after interferon gamma-1b therapy represented a unique subgroup of patients with usual interstitial pneumonia who had reductions in the levels of transcription of the genes for TGF-1 and connective-tissue growth factor. Similar analyses were not performed in the study by Raghu et al.
This negative study will greatly disappoint patients. What should clinicians tell them? Frankly, patients should be told that there are no studies that prove that any medication is efficacious for the treatment of usual interstitial pneumonia. Therefore, what treatment, if any, should be prescribed, and when should treatment begin? The most effective approaches are obvious. Patients should stop smoking, since cigarette smoking increases the risk of superimposed inflammatory bronchial disease and neoplasia and aggravates usual interstitial pneumonia. Influenza and pneumonia vaccine should be administered. Oxygen saturation should be maintained at a level above 90 percent through the use of oxygen therapy. Treatment of pulmonary hypertension with newer agents may be of benefit. Although in some cases improvement has been reported with corticosteroids and immunosuppressive therapies, a Cochrane Review found no data that support the use of immunosuppressive medications.11
The timing of treatment may be important. Since approximately 30 percent of patients treated with prednisone have had objective evidence of improvement,1 prednisone is indicated. Since all therapies have serious side effects, prudent physicians delay treatment until symptoms are severe or physiological measurements are substantially impaired. Although the improved survival among the patients in the interferon gamma-1b group in the study by Raghu et al. remains unexplained, it is noteworthy that this benefit occurred in a subgroup of patients with less impaired function who strictly adhered to the treatment protocol. Thus, early treatment may be more effective. Lung transplantation is the last resort.
Although Raghu et al. did not find interferon gamma-1b to be efficacious, they should be commended for using the first scientifically based agent against usual interstitial pneumonia in a well-conducted, large, controlled trial. Studies of other promising agents that are based on the growing knowledge of the pathogenesis of organ fibrosis are indicated, since interferon gamma-1b has not proved to be the answer.
Source Information
From the Division of Pulmonary and Critical Care Medicine, Mount Sinai Medical Center, New York.
References
American Thoracic Society. Idiopathic pulmonary fibrosis: diagnosis and treatment. International consensus statement. American Thoracic Society (ATS), and the European Respiratory Society (ERS). Am J Respir Crit Care Med 2000;161:646-664.
Liebow AA, Carrington CB. The interstitial pneumonias. In: Simon M, Potchen EJ, LeMay M, eds. Frontiers of pulmonary radiology: pathophysiologic, roentgenographic and radioisotopic considerations; proceedings of the symposium sponsored by Harvard Medical School, April 21-22, 1967. New York: Grune & Stratton, 1969:102-41.
Katzenstein AL, Myers JL. Idiopathic pulmonary fibrosis: clinical relevance of pathologic classification. Am J Respir Crit Care Med 1998;157:1301-1315.
Strollo DC. Imaging of idiopathic interstitial lung diseases: concepts and conundrums. Am J Respir Cell Mol Biol 2003;29:Suppl 3:S10-S18.
Daniil ZD, Gilchrist FC, Nicholson AG, et al. A histologic pattern of nonspecific interstitial pneumonia is associated with a better prognosis than usual interstitial pneumonia in patients with cryptogenic fibrosing alveolitis. Am J Respir Crit Care Med 1999;160:899-905.
Hunninghake GW, Lynch DA, Galvin JR, et al. Radiologic findings are strongly associated with a pathologic diagnosis of usual interstitial pneumonia. Chest 2003;124:1215-1223.
Lynch JP III, McCune WJ. Immunosuppressive and cytotoxic pharmacotherapy for pulmonary disorders. Am J Respir Crit Care Med 1997;155:395-420.
Raghu G, Johnson WC, Lockhart D, Mageto Y. Treatment of idiopathic pulmonary fibrosis with a new antifibrotic agent, pirfenidone: results of a prospective, open-label Phase II study. Am J Respir Crit Care Med 1999;159:1061-1069.
Ziesche R, Hofbauer E, Wittmann K, Petkov V, Block LH. A preliminary study of long-term treatment with interferon gamma-1b and low-dose prednisolone in patients with idiopathic pulmonary fibrosis. N Engl J Med 1999;341:1264-1269.
Raghu G, Brown KK, Bradford WZ, et al. A placebo-controlled trial of interferon gamma-1b in patients with idiopathic pulmonary fibrosis. N Engl J Med 2004;350:125-133.
Davies HR, Richeldi L, Walters EH. Immunomodulatory agents for idiopathic pulmonary fibrosis. Cochrane Database Syst Rev 2003;3:CD003134-CD003134.
Related Letters:
Interferon Gamma-1b for Pulmonary Fibrosis
Hill A. R., Fruchter O., Eisner M. D., Tsoutsou P. G., Gourgoulianis K. I., Vourlekis J. S., Richeldi L., Raghu G., King T. E. Jr., Teirstein A. S.(Alvin S. Teirstein, M.D.)