Managing IPF: Taking a hard look at today's choices

March 1, 2007

**IPF is the most common form of idiopathic interstitial lung disease. The recent development of histopathological and clinical criteria that accurately define IPF has resulted in expansion of our scientific knowledge, development of novel therapies, and initiation of high-quality clinical trials.

**IPF is the most common form of idiopathic interstitial lung disease. The recent development of histopathological and clinical criteria that accurately define IPF has resulted in expansion of our scientific knowledge, development of novel therapies, and initiation of high-quality clinical trials.

Despite these recent advances, IPF remains a disease without optimal therapy or consensus regarding treatment. Physicians who care for patients with IPF often feel compelled to offer therapy regardless of a lack of high-quality evidence. In this setting, many pharmacological agents are increasingly marketed and available.

The decision to treat patients with IPF should be based on patient preference and clinical circumstance. All patients should be offered the option of participation in clinical trials and should be educated regarding lung transplantation and observation without therapy.

Before initiating pharmacological therapy for IPF, one must be certain the diagnosis is correct. While this seems obvious, the diagnosis of IPF is often challenging and may require surgical lung biopsy and referral for expert consultation. In addition, nonpharmacological therapy for patients with IPF should include oxygen, pulmonary rehabilitation, vaccinations, and end-of-life counseling when appropriate.

Traditional therapy for IPF has included a trial of corticosteroids in conjunction with azathioprine or cyclophosphamide.1 This approach is often associated with drug-related adverse effects and has never been validated in a prospective clinical trial. There is little evidence to support routine use of immunosuppressive or cytotoxic therapy in carefully diagnosed IPF. However, a time-limited trial of corticosteroids and/or cytotoxic therapy with careful clinical follow-up may be reasonable in select patients in whom the diagnosis of IPF cannot be differentiated from other forms of interstitial lung disease, as when the patient or physician prefers not to pursue surgical lung biopsy.

IFN-g has been enthusiastically promoted as a treatment for IPF since Ziesche and associates2 reported dramatic improvement in 18 patients with IPF who were treated with open-label IFN-g in 1999. The initial enthusiasm was tempered when a randomized, double-blind, placebo-controlled clinical trial of 330 patients with IPF showed no difference between placebo and IFN-g in all-cause mortality (the primary outcome), pulmonary function, or oxygenation.

A retrospective subgroup analysis from this study showed a survival advantage for patients with mild to moderate disease, defined as forced vital capacity (FVC) of at least 62% of predicted and carbon monoxide-diffusing capacity (DlCO) of at least 35% of predicted.3 Another clinical trial is under way to determine whether IFN-g is effective in patients with mild to moderate disease. Clinicians should be aware that while the effect of IFN-g is uncertain in patients with mild to moderate disease, it is unlikely to be beneficial in those with severe disease.

N-acetylcysteine (NAC) is an oral antioxidant available in the United States without a prescription. In a study of IPF patients treated with prednisone and azathioprine, the addition of NAC was associated with a higher FVC and DlCO at 12 months' follow-up, compared with placebo.4 Although the differences in FVC and DlCO were statistically significant, they were small, and the beneficial effect of NAC may be to limit toxicities caused by treatment with prednisone and azathioprine.

Notwithstanding these study limitations, NAC is an attractive therapeutic option because of its low cost and limited side-effect profile. It is reasonable to consider NAC in patients who are treated with prednisone and azathioprine.

Several pharmacological strategies may be considered in specific clinical circumstances. Patients with IPF who have gastroesophageal reflux (GER) should consider acid-suppressive treatment; there is a known association of GER with IPF, but causality is unknown. Patients with pulmonary hypertension (PH) and IPF may benefit symptomatically from treatment of PH. Several drugs that are approved to treat PH, such as sildenafil, bosentan, and epoprostenol, are undergoing study to determine their effect in patients with IPF.

Acute symptomatic worsening of IPF accompanied by new diffuse radiographic infiltrates with no underlying cause may be a distinct clinicopathological event. These acute exacerbations frequently cause death in patients with IPF. Although no therapy is known to alter the course of acute exacerbations of IPF, Kubo and associates5 demonstrated improved survival in hospitalized IPF patients who were treated with long-term anticoagulation therapy.

Not all IPF patients will opt for observation or participation in clinical trials. Some will ask their physician to recommend pharmacological therapy. While many therapies are available for IPF, none are currently supported by enough evidence to warrant their routine clinical use. Physicians should be forthright about the uncertainty of their recommendations and reach a joint decision with an educated patient.

References:

1.

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(2 pt 1):646-664.

2.

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.

3.

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.

4.

Demedts M, Behr J, Buhl R, et al. High-dose acetylcysteine in idiopathic pulmonary fibrosis.

N Engl J Med.

2005;353:2229-2242.

5.

Kubo H, Nakayama K, Yanai M, et al. Anticoagulant therapy for idiopathic pulmonary fibrosis.

Chest

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