SEATTLE--Pulmonologists have always had a much easier time diagnosing idiopathic pulmonary fibrosis (IPF) than treating it. "Any prudent pulmonary physician should be able to diagnose IPF using simple clinical skills," asserted Ganesh Raghu, MD, head of the chest clinic at the University of Washington Medical Center in Seattle and a leading authority on interstitial lung disease (ILD) and IPF.

Nevertheless, said Robert J. Mason, MD, "the standard therapy of glucocorticoids and immunosuppression is basically ineffective." Dr. Mason, a professor of medicine at the National Jewish Medical and Research Center in Denver, led a recent National Heart, Lung, and Blood Institute workshop on IPF treatment.[1] A similar conclusion was reached by a consensus committee convened by the American Thoracic Society and the European Respiratory Society.[2]

A lack of good, solid clinical research has been a major obstacle to the development of effective IPF therapies. "A lot of the dogma about the treatment of this condition is based on word of mouth and individual cases, not prospective, double-blind, controlled clinical trials," Dr. Mason explained. That's surprising, he said, considering that IPF has such high mortality. Death often occurs only four or five years after symptom onset.

MAKING THE DIAGNOSIS

Because of its accuracy, surgical lung biopsy has long been the gold standard for diagnosing IPF. However, improved imaging techniques have made clinical diagnosis a viable alternative. To assess the accuracy of clinical diagnosis, researchers led by Dr. Raghu recently compared it with lung biopsy in a prospective study of 59 consecutive patients with new- or early-onset ILD.[3]

"Even though this was a single-center study, it relates very well to clinical practice," Dr. Raghu told PULMONARY REVIEWS. "That's because it included patients with ILD who had been referred by community pulmonary physicians and then thoroughly evaluated."

Dr. Raghu and colleagues defined clinical diagnosis as:

• Insidious onset of otherwise unexplained exertional dyspnea of six months' duration or longer.
• Bibasilar end-inspiratory "Velcro" crackles.
• A restrictive lung defect without coexisting airflow obstruction, decreased diffusing capacity of carbon monoxide, and increased alveolar-arterial oxygen pressure difference at rest or with exercise.
• Bibasilar reticular opacities on chest films and high-resolution computed tomography (HRCT) scans of the chest (Figure 1).
• Transbronchial lung biopsy or bronchoalveolar lavage results that do not support a specific diagnosis, such as sarcoid, pulmonary histiocytosis X, or alveolar proteinosis.

"The diagnosis doesn't take much expertise, but it does require a pulmonary physician," stressed Dr. Raghu. "These subspecialists are trained to interpret HRCT scans of the chest, as well as other specialized pulmonary studies, whereas internists or general practitioners are not."

It's essential to do these scans early in the disease process. "Diagnosing advanced IPF is relatively straightforward," stated Dr. Raghu. "That's why our study eliminated advanced patients and included only those with ILD of unknown cause and of less than two years' duration." Dr. Raghu added, "Accurate diagnosis of ILD and IPF is particularly important for providing a realistic prognosis and initiating appropriate treatment."

Compared with surgical lung biopsy, clinical diagnosis was 62% sensitive and 97% specific in accurately diagnosing IPF, the researchers reported. They concluded, therefore, that not all patients with new- or early-onset ILD need a surgical lung biopsy.

Yet, despite the availability of state-of-the-art techniques and clinical expertise, an accurate clinical diagnosis was not obtained in about one third of IPF cases. That prompted the researchers to recommend a surgical lung biopsy for patients with new- or early-onset ILD when the diagnosis is unclear. Biopsy specimens from those with IPF must exhibit histologic characteristics of usual interstitial pneumonia, Dr. Raghu emphasized.

NOVEL TREATMENTS SOUGHT

Although good research on IPF treatment is lacking, enough data exist on the standard therapy of glucocorticoids and immunosuppressive agents to know it is usually of no benefit. "That's why we need a national consortium to do multicenter, prospective, long-range clinical trials to find a new regimen," Dr. Mason said.

Two such trials are already in the early stages. One is looking at the anti-inflammatory interferon beta-1a, which is now widely used in the United States to treat multiple sclerosis. Initial results of the trial should be available early in 2001. "But interferon beta probably isn't going to be the miracle IPF cure, though it may be a significant step forward," cautioned Kevin Brown, MD, one of the key players in the clinical trials and director of the clinical ILD program at the National Jewish Medical and Research Center.

The second trial, a phase III multicenter clinical study under the direction of Dr. Raghu, is about to begin. It will examine IPF treatment with the potentially antifibrotic agent interferon gamma. In a small study of 18 patients with IPF, this agent appeared to improve lung function significantly when given in combination with low-dose prednisolone.[4] Dr. Raghu cautioned, however, that "only a multicenter clinical trial with a large, well-defined patient population can prove its efficacy. Until then, clinicians should not use interferon gamma or other experimental agents in routine clinical practice."

"There's also been some interest in pirfenidone," Dr. Mason noted. In some IPF patients, this antifibrotic appears to produce improvement with limited toxicity.

That's what Dr. Raghu found last year when he led a small open-label study of IPF treatment with oral pirfenidone.[5] "The study included 54 patients with well-documented, but very advanced, IPF who were deteriorating despite having received prednisone and/or immunosuppressive agents," he said. "These people basically were dying."

Surprisingly, pirfenidone treatment produced one- and two-year survival rates of 78% and 63%, respectively. Furthermore, it enabled all patients to discontinue immunosuppressive therapy and/or reduce their steroid dosage. Pirfenidone recipients had only minor side effects, such as drowsiness, skin rash, and gastrointestinal upset.

"This was a novel, very provocative, and promising study. When you consider the results of our own lung transplantation program, the results are very encouraging," Dr. Raghu said. The overall cumulative first-year survival in lung transplant recipients with IPF is about 75%--a rate not dissimilar to that found in the pirfenidone study--even though the transplant patients have less-advanced lung disease. Also encouraging is the fact that pirfenidone did not appear to cause the severe side effects and complications associated with presently available therapies for IPF.

Unfortunately, the study findings are currently moot. "Pirfenidone isn't FDA-approved and it's not currently available in the United States," Dr. Brown pointed out. Pirfenidone may prove beneficial, but it probably won't emerge as the major breakthrough in IPF treatment, he predicted.

"But I think we're close to a breakthrough," he continued, "and it will probably lead to a major shift in how we treat lung fibrosis within the next two years. But for somebody starting therapy tomorrow, the best we can offer is still what we've been using for the past 20 years."

Dr. Raghu stressed, "It is high time that community physicians, experienced investigators, funding agencies, pharmaceutical companies, and patients join hands to find a cure for this frustrating problem."

--Timothy Begany

References
1. Mason RJ, Schwartz MI, Hunninghake GW, Musson RA. NHLBI workshop summary: pharmacological therapy for idiopathic pulmonary fibrosis. Past, present, and future. Am J Respir Crit Care Med. 1999;160:1771-1777.
2. American Thoracic Society. Idiopathic pulmonary fibrosis: diagnosis and treatment: international consensus statement. Am J Respir Crit Care Med. 2000;161:646-664.
3. Raghu G, Mageto YN, Lockhart D, et al. The accuracy of the clinical diagnosis of new-onset idiopathic pulmonary fibrosis and other interstitial lung disease: a prospective study. Chest. 1999;116:1168-1174.
4. Ziesche R, Hofbauer E, Wittmann K, et al. 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.
5. 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(4 pt 1):1061-1069.

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