Clinical Update: Idiopathic pulmonary fibrosis: Highlights from the recent literature

December 1, 2006

Idiopathic pulmonary fibrosis (IPF) is a chronic progressive lung disease with unknown etiology and a grim prognosis.1,2 The median survival is about 3 years after diagnosis or 5 years from the onset of symptoms. Its pathologic findings are those of usual interstitial pneumonia.2 Surgical lung biopsy is needed for diagnosis when these findings are not present. Usual interstitial pneumonia is the histopathologic pattern that characterizes IPF (Figure).

Idiopathic pulmonary fibrosis (IPF) is a chronic progressive lung disease with unknown etiology and a grim prognosis.1,2 The median survival is about 3 years after diagnosis or 5 years from the onset of symptoms. Its pathologic findings are those of usual interstitial pneumonia.2 Surgical lung biopsy is needed for diagnosis when these findings are not present. Usual interstitial pneumonia is the histopathologic pattern that characterizes IPF (Figure).

Estimates of the prevalence of IPF are being revised as knowledge of the disease"s clinicopathologic features continues to improve. New research suggests that IPF is much more common in the United States than previously supposed. The poor prognosis for IPF is even worse in patients who have acute exacerbations. Patients with advanced IPF who have pulmonary arterial hypertension (PAH) are significantly less likely to survive.

Unfortunately, the standard treatment for IPF--corticosteroids plus a cytotoxic agent--has proved to be largely ineffective. However, recent studies suggest a potentially promising role for both anticoagulant and antioxidant therapies in treating patients with IPF.

This Clinical Update presents highlights from the recent literature on the epidemiology, prognosis, complications, and treatment of this significant lung disease.

How common is IPF?

Raghu and colleagues3 sought to determine the prevalence and annual incidence of IPF in the United States. Previous prevalence estimates ranged from 3 to 6 cases per 100,000 persons4 to 17 cases per 100,0005; while the previous estimate of IPF incidence pegged it at 9 cases per 100,000 persons per year.5

Retrospective data from a large, geographically diverse health care claims database in the United States were used to estimate the epidemiology of IPF. Persons 18 years or older with IPF were identified based on diagnosis and procedure codes for the disease. To increase the likelihood of diagnostic accuracy, the authors used a narrow case definition for IPF in addition to a broad case definition (Table 1).

Based on the broad criteria, IPF prevalence and annual incidence were estimated to be 42.7 and 16.3 per 100,000, respectively. Based on the narrow definition, overall IPF prevalence and incidence were estimated to be 14.0 and 6.8 per 100,000, respectively.

The authors of this study concluded that IPF is more common--perhaps significantly more common--in the United States than previously reported.

Prevalence and impact of PAH in advanced IPF

The development of PAH can complicate many interstitial lung diseases, including IPF. Lettieri and colleagues6 found that PAH is common in advanced IPF and significantly affects patient survival. Their retrospective study included 79 patients with IPF. The authors compared spirometric results, 6-minute walk test (6MWT) results, and survival for patients with PAH (defined as a mean pulmonary artery pressure of greater than 25 mm Hg) with those for patients without PAH.

PAH was present in 32% of the patients. Those with PAH had a lower mean carbon monoxide-diffusing capacity (DlCO) and were significantly more likely to require supplemental oxygen. They also had a shorter mean distance walked and lower mean oxygen saturation nadir (measured by pulse oximetry) during the 6MWT.

The risk of death during the study was twice as great for patients with PAH (60%) as for those with-out PAH (30%). One-year mortality rates were more than 5 times higher in patients with PAH (29%) than in patients without PAH (5.5%).

The study findings substantiated the prevalence of PAH in patients with advanced IPF and its significant impact on survival. The authors noted that reduced DlCO, supplemental oxygen requirement, and poor 6MWT performance suggest the presence of PAH.

Acute exacerbation in IPF

IPF typically follows an insidious, slowly progressive clinical course. Parambil and colleagues,7 however, found that acute exacerbation can be the initial clinical presentation in some patients. They described the clinical, radiologic, and histopathologic findings associated with acute exacerbation in patients with IPF (Table 2).

The retrospective study included 7 patients (median age, 70 years) with acute exacerbation of IPF who underwent surgical lung biopsy. In 3 patients, acute deterioration was the presenting feature of IPF. A diagnosis of IPF had been previously established in the other 4 patients. All 7 patients required invasive mechanical ventilation and received systemic corticosteroid therapy.

Despite lung-protective ventilation strategies and treatment with high-dose corticosteroids, 6 patients (86%) died during hospitalization. The study showed that the initial clinical manifestation of IPF could be acute exacerbation without an identifiable cause. High-dose corticosteroid therapy was ineffective for acute exacerbations in patients who had surgical lung biopsy. The prognosis for these patients was poor. The authors suggest that a better understanding of the pathogenesis of acute exacerbation is needed to formulate a more effective treatment approach.

Do changes in 6MWT add prognostic value?

Flaherty and colleagues8 hypothesized that changes in distance walked and quantity of desaturation during a 6MWT would add prognostic value to changes in DlCO and forced vital capacity (FVC). The authors retrospectively studied 179 patients. Baseline and serial changes in 6MWT in relation to changes in DlCO and FVC were examined. The study demonstrated that:

• Desaturation at baseline increased the mortality risk even if oxygen saturation remained above 88%.

• Baseline walk distance predicted subsequent walk distance but did not reliably predict mortality.

• The predictive ability of serial changes in physiology varied when patients were stratified by the presence or absence of desaturation greater than 88% during a baseline 6MWT.

The authors concluded that stratifying patients with IPF by degree of desaturation during a 6MHT is important before attributing prognostic value to serial changes in other physiologic variables. Their findings suggested that even mild desaturation is a risk factor for mortality.

Anticoagulant therapy

Kubo and colleagues9 evaluated the effect of anticoagulant therapy on survival of patients with IPF. Their prospective study included 56 patients (mean age, 70 years) who received prednisolone alone or prednisolone plus anticoagulant therapy (oral warfarin and low molecular weight heparin). Baseline characteristics (age, sex, pulmonary function, and plasma d-dimer level) were no different between the groups who received and those who did not receive anticoagulant therapy.

The respective 1-year survival rates for the corticosteroid group versus the corticosteroid plus anticoagulant group were 58% and 87%. The 3-year survival rates for the groups were 35% and 63%, respectively. The major cause of death was acute exacerbation, in which the plasma d-dimer level was significantly elevated.

The outcomes suggested that combined anticoagulant and corticosteroid therapy extends the survival of patients with IPF. The likelihood of survival with corticosteroid monotherapy was poorer. Lack of a patient group treated with anticoagulant therapy alone prevented a clear determination of whether improved prognosis resulted from anticoagulation alone or the combined effect of anticoagulation and corticosteroids. The authors nonetheless concluded that their data support the use of anticoagulant therapy as a new treatment strategy in IPF.

In response to the published findings, Kinder and colleagues10 cautioned against adopting anticoagulant therapy as a new standard of care and noted 3 methodologic limitations in the Kubo study:

• A cohort unrepresentative of the general IPF population.

• A possible disease misclassification bias.

• A compromised randomization benefit because of many patient withdrawals from the anticoagulant group after randomization.

Antioxidant therapy

Demedts and colleagues11 found that high-dose acetylcysteine combined with standard therapy yielded greater treatment benefit in patients with IPF than did standard therapy alone. The double-blind, randomized, placebo-controlled IFIGENIA (Idiopathic Pulmonary Fibrosis International Group Exploring N-Acetylcysteine I Annual) study assessed the effectiveness over 1 year of acetylcysteine 600 mg tid added to standard therapy (prednisolone plus azathioprine) in preserving vital capacity and DlCO. The antioxidant acetylcysteine had previously been shown to restore depleted pul- monary glutathione levels, which occur in patients with IPF, and thereby significantly improve lung function.

High-dose acetylcysteine added to standard therapy significantly slowed the deterioration of vital capacity and DlCO. The relative differences from baseline versus placebo were 9% for vital capacity (P = .02) and 24% for DlCO (P = .003). The authors concluded that acetylcysteine added to prednisolone plus azathioprine preserves pulmonary function in patients with IPF better than does standard therapy alone. A beneficial impact of acetylcysteine on survival was not established.

The authors suggest that acetylcysteine-related preservation of vital capacity and DlCO may slow IPF progression. They also speculate that repeated lung injury in IPF may explain why treatment with corticosteroids and immunosuppressive agents results in only slight therapeutic benefit.

An editorial by Hunninghake12 asserts that the Demedts study does not clearly establish whether acetylcysteine has direct therapeutic benefits for IPF. The findings, Hunninghake observes, might indicate only that acetylcysteine prevents possible toxic effects of standard therapy. He urges new studies to evaluate the toxicity of prednisolone and azathioprine in patients with IPF and to assess whether acetylcysteine directly benefits patients with this lung disease.



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