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A Dark Side of Interferon- in the Treatment of Idiopathic Pulmonary Fibrosis?

Instituto Nacional de Enfermedades Respiratorias, México DF, México

Idiopathic pulmonary fibrosis (IPF) is the most common of the interstitial pneumonias of unknown etiology and the most aggressive interstitial lung disease (1). In this context, it is important to emphasize that this disorder is largely unresponsive to corticosteroid and immunosuppressive therapy and relentlessly follows a progressive and lethal course (2, 3). Therefore, there is a great need for novel therapies to reverse or at least limit the lung fibroblast proliferation/activation and the aberrant connective tissue remodeling that characterize this devastating disease. Unfortunately, new therapeutic approaches for fibrotic lung disorders, including IPF, are scanty.

A promising new therapy is interferon--1b, a multifunctional cytokine that inhibits fibroblast proliferation and collagen synthesis and antagonizes the effects of transforming growth factor-ß (4, 5). In an exciting, albeit very preliminary study, Ziesche and coworkers (6) suggested that this drug could be useful in this disease. In a randomized trial of 18 highly selected patients with IPF, they showed that patients receiving interferon--1b plus low doses of prednisolone exhibited a significant improvement in lung physiology with a concomitant decrease in the tissue expression of several profibrotic molecules. Preliminary data from this group also suggest that the therapy improves survival (7).

A large multicenter, randomized, double-blind, placebo-controlled, phase III study of the safety and efficacy of interferon--1b has recently completed enrollment. Preliminary analysis of the data suggests that although interferon- produced no differences in the observed rate of progression-free survival, it did appear to decrease mortality primarily in patients with mild to moderate disease (T.E. King, Jr., personal communication). We await the final publication to know the details that will give us a better insight into the presumed efficacy of this drug in the treatment of IPF.

One important concern with any drug is related to potentially serious side effects. Adverse effects are common with interferon- but are generally mild and usually reversible at current dosages. These side effects include headache, fatigue, rigors, influenza-like symptoms, depression, myalgia, and granulocytopenia (8, 9). Of note, significant adverse effects have not been reported with interferon--1b.

In this issue of AJRCCM (pp. 953–957), however, Honoré and colleagues (10) give out a warning of a new and allegedly severe adverse effect that is associated with interferon-. The authors describe four patients with IPF from a cohort of 10 patients who developed acute respiratory distress syndrome in an explosive manner and who eventually died from irreversible respiratory failure. Importantly, these acute events were temporally related to interferon--1b therapy. Moreover, the complication occurred shortly after the initiation of the drug in three patients. The clinical behavior was similar in all four patients, with increasing dyspnea, fever, the emergence of large new radiologic areas of ground-glass opacities and rapidly progressive hypoxemia requiring mechanical ventilation and high oxygen concentrations. In two patients, lung histology after the acute event was available, and it demonstrated extensive diffuse alveolar damage with pre-existing usual interstitial pneumonia.

The main questions that this report raises are as follows: Was the acute event caused by interferon--1b therapy? Do these episodes represent the spontaneous acute exacerbation known to occur in some patients with IPF? Were the episodes triggered by an intercurrent condition, such as pulmonary infection or embolism?

As often occurs with studies alleging drug toxicity, it is very difficult to determine whether other processes could have provoked the damage attributed to the drug. A number of studies performed by Honoré and coworkers, however, seem to exclude the possibilities of an associated pathologic situation, and empiric treatment with broad-spectrum antibiotics and intravenous anticoagulation was unsuccessful.

Regarding spontaneous acute exacerbation, the reported incidence, 40%, is too high according to our knowledge so far. In the largest randomized study performed to date, deaths secondary to respiratory failure appeared to occur more acutely in the placebo group. Interferon- was generally well tolerated, with few withdrawals consequent to adverse events, although there was an unexplained excess of nonfatal pneumonias (T.E. King, personal communication).

Were there some peculiar putative risk factors that might explain the development of acute lung damage in the patients of Honoré and colleagues? A clinical/functional comparison with the other six patients in this study and with patients reported in other series (6) shows that the patients who developed the acute event displayed a more advanced disease. Perhaps more important, two out of the four patients had familial pulmonary fibrosis, and another patient had a history of aortocoronary bypass surgery and mild liver fibrosis secondary to hepatitis C. Presently, we do not know whether these conditions have some unusual features that may play a role in the development of acute lung damage, for example, enhancing capillary permeability as described for liver fibrosis (11).

In this context, another question comes to mind. If interferon- triggers a diffuse alveolar damage in pre-existing usual interstitial pneumonia, as observed by Honoré and colleagues, what molecular mechanisms would be implicated? Several recent articles support the notion that interferon- regulates epithelial and endothelial junction integrity and barrier function. Thus, interferon- appears to reduce the expression of epithelial tight junction-associated proteins zonula occludens-1 and occludin, as well as transepithelial resistance, inducing a pronounced increase in transepithelial cell permeability (12, 13). Likewise, this drug significantly increases endothelial permeability in vitro (14, 15). Whether these effects contributed to the development of diffuse alveolar damage in the patients of Honoré and coworkers is unknown.

Finally, although not conclusive, this case series raises concerns that need to be addressed by further studies examining the potential role of interferon--1b in the management of IPF. It is possible that a subset of patients may be at risk of an acute, and rapidly lethal, lung exacerbation, and we need to identify them before instituting therapy. The preliminary findings from this report and the experience of others suggest that patients with endogenous interferon- production or with advanced disease (FVC of less than 50% of predicted; diffusing capacity of less than 40% of predicted), as well as those with some associated diseases or familial IPF, may have an increased risk of adverse outcome when treated with interferon--1b.

REFERENCES

1. Katzenstein ALA, Myers JL. Idiopathic pulmonary fibrosis: clinical relevance of pathologic classification. Am J Respir Crit Care Med 1998;157:1301–1315.[Free Full Text]
2. Selman M, King TE, Pardo A. Idiopathic pulmonary fibrosis: prevailing and evolving hypotheses about its pathogenesis and implications for therapy. Ann Intern Med 2001;134:136–151.[Abstract/Free Full Text]
3. Gross TJ, Hunninghake GW. Idiopathic pulmonary fibrosis. N Engl J Med 2001;345:517–525.[Free Full Text]
4. Gurujeyalakshmi G, Giri SN. Molecular mechanisms of antifibrotic effect of interferon gamma in bleomycin-mouse model of lung fibrosis: downregulation of TGF-beta and procollagen I and III gene expression. Exp Lung Res 1995;21:791–808.[Medline]
5. Eickelberg O, Pansky A, Koehler E, Bihl M, Tamm M, Hildebrand P, Perruchoud AP, Kashgarian M, Roth M. Molecular mechanisms of TGF-(beta) antagonism by interferon (gamma) and cyclosporine A in lung fibroblasts. FASEB J 2001;15:797–806.[Abstract/Free Full Text]
6. 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.[Abstract/Free Full Text]
7. Ziesche R, Bradford WZ, Crager M, Block LH. Long-term survival in idiopathic pulmonary fibrosis patients treated with interferon gamma-1b [abstract]. Chest 2002; 122:74S–75S.
8. Riddell LA, Pinching AJ, Hill S, Ng TT, Arbe E, Lapham GP, Ash S, Hillman R, Tchamouroff S, Denning DW, et al. A phase III study of recombinant human interferon gamma to prevent opportunistic infections in advanced HIV disease. AIDS Res Hum Retroviruses 2001;17:789–797.[CrossRef][Medline]
9. Arnaud P. The interferons: pharmacology, mechanism of action, tolerance and side effects. Rev Med Interne 2002;23:449–458.
10. Honoré I, Nunes H, Groussard O, Kambouchner M, Chambellan A, Aubier M, Valeyre D, Crestani B. Acute respiratory failure after interferon- therapy of end-stage pulmonary fibrosis. Am J Respir Crit Care Med 2003;167:953–957.[Abstract/Free Full Text]
11. Huglo D, De Botton S, Canva-Delcambre V, Colombel JF, Wallaert B, Steinling M, Marchandise X. Simultaneous determination of pulmonary and intestinal permeability in patients with alcoholic liver cirrhosis. Eur J Nucl Med 2001;28:1505–1511.[CrossRef][Medline]
12. Ahdieh M, Vandenbos T, Youakim A. Lung epithelial barrier function and wound healing are decreased by IL-4 and IL-13 and enhanced by IFN-gamma. Am J Physiol Cell Physiol 2001;281:C2029–C2038.[Abstract/Free Full Text]
13. Coyne CB, Vanhook MK, Gambling TM, Carson JL, Boucher RC, Johnson LG. Regulation of airway tight junctions by proinflammatory cytokines. Mol Biol Cell 2002;13:3218–3234.[Abstract/Free Full Text]
14. Oshima T, Laroux FS, Coe LL, Morise Z, Kawachi S, Bauer P, Grisham MB, Specian RD, Carter P, Jennings S, et al. Interferon-gamma and interleukin-10 reciprocally regulate endothelial junction integrity and barrier function. Microvasc Res 2001;61:130–143.[CrossRef][Medline]
15. Shaw SK, Perkins BN, Lim YC, Liu Y, Nusrat A, Schnell FJ, Parkos CA, Luscinskas FW. Reduced expression of junctional adhesion molecule and platelet/endothelial cell adhesion molecule-1 (CD31) at human vascular endothelial junctions by cytokines tumor necrosis factor-alpha plus interferon-gamma does not reduce leukocyte transmigration under flow. Am J Pathol 2001;159:2281–2291.[Abstract/Free Full Text]

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