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American Journal of Respiratory and Critical Care Medicine Vol 169. pp. 543-544, (2004)
© 2004 American Thoracic Society

Correspondence

Acute Respiratory Failure after Interferon-{gamma} Therapy in IPF

To the Editor:

We agree with the hypothesis of Honoré and colleagues (1) that interferon-{gamma} therapy can induce an acute respiratory failure in patients with advanced pulmonary fibrosis. They reported four patients who died of acute respiratory failure. The histopathologic pattern observed was a diffuse alveolar damage associated with preexisting usual interstitial pneumonia (1). Because interferon-{gamma} has demonstrated promising results in a small group of patients with idiopathic pulmonary fibrosis (2), a multicenter clinical trial using this drug is ongoing and it was presented as an alternative treatment in the International Consensus Statement (3). The prevalence and treatment of interferon-{gamma}–induced lung injury is an important and emerging question, so we would like to describe a similar case.

The patient is a 68-year-old exsmoker (7 pack-years) with a 4-year diagnosis of idiopathic pulmonary fibrosis. Initial lung function showed a restrictive pattern (total lung capacity 69% of predicted value) and impaired diffusing capacity (57%), and the high-resolution computed tomography (CT) scan showed diffuse reticular opacities and honeycombing. Between October 1999 and November 2001 he was treated with steroids (methylprednisolone or prednisone), immunosuppressor (cyclophosphamide), and/or antifibrotic agent (colchicine) without improvement. In January 2002, interferon-{gamma} was initiated (200 µg three times per week). The patient reported malaise and fever after the injections and received paracetamol. On April 26 (4 months later), after the 47th injection, he developed fever (38.5°C) and severe respiratory failure (SpO2 83%). The patient was admitted to the intensive care unit and, 5 days later, needed invasive mechanical ventilation. Results of blood, urine, and bronchoalveolar lavage cultures were negative, as well as serology for legionella and mycoplasma. The high-resolution CT scan showed diffuse ground glass opacities superimposed on preexisting honeycombing reticular opacities. We assume that the acute worsening of lung function was caused by interferon-{gamma} lung toxicity. Intravenous methylprednisolone (1 g over 3 days) was prescribed, and recruitment maneuvers and a high positive end-expiratory pressure (PEEP) level (15 cm H2O), according to the pressure volume curve, were applied. The patient presented a progressive functional (PaO2/FIO2 from 90 to 210) and radiologic improvement (Figure 1) . Instead of the respiratory improvement, the patient died 15 days later of abdominal sepsis after intestinal perforation.



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  		Figure 1. Thoracic computed tomography scan of patient with idiopathic pulmonary fibrosis (A) before interferon (IFN)-{gamma} therapy (November 2001), (B) after 47th IFN-{gamma} injection (May 2, 2002), and (C) after pulse therapy with methylprednisolone and positive end-expiratory pressure of 15 cm H2O (May 6, 2002).

 
This case adds information relating interferon-{gamma} and lung toxicity. We believe that besides the drug interruption and treatment with high-dose methylprednisolone, the use of high levels of PEEP after recruiting maneuvers, like in acute respiratory distress syndrome (ARDS) (4), should be beneficial in these cases. The rationale for these therapeutic strategies is the presence of increased endothelial permeability (5) and the histopathologic substrate (i.e., diffuse alveolar damage) similar in ARDS and interferon-{gamma} lung toxicity.

Carlos R. R. Carvalho, Ronaldo A. Kairalla and Guilherme P. P. Schettino

Pulmonary Division Hospital das Clínicas University of São Paulo Intensive Care Unit Hospital Sírio Libanês São Paulo, Brazil

FOOTNOTES

Conflict of Interest Statement: C.R.R.C., R.A.K., and G.P.P.S. have no declared conflict of interest.

Dr. Selman was given an opportunity to respond to this letter, but declined to do so.

REFERENCES

  1. Honoré I, Nunes H, Groussard O, Kambouchner M, Chambellan A, Aubier M, Valeyre D, Crestani B. Acute respiratory failure after interferon-{gamma} therapy of end-stage pulmonary fibrosis. Am J Respir Crit Care Med 2003;167:953–957.[Abstract/Free Full Text]
  2. 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]
  3. International Consensus Statement. Idiopathic pulmonary fibrosis: diagnosis and treatment. Am J Respir Crit Care Med 2000;161:646–664.[Free Full Text]
  4. Amato MBP, Barbas CSV, Medeiros DM, Magaldi RB, Schettino GPP, Lorenzi-Filho G, Kairalla RA, Deheinzelin D, Munoz C, Oliveira R, et al. Effect of a lung protective approach on mortality in the acute respiratory distress syndrome. N Engl J Med 1998;338:347–354.[Abstract/Free Full Text]
  5. Selman M. A dark side of interferon-{gamma} in the treatment of idiopathic pulmonary fibrosis? Am J Respir Crit Care Med 2003;167:945–946.[Free Full Text]
 

From the Authors:

We appreciate the comments of Dr. Carvalho and colleagues on our article (1). The case report described by Dr. Carvalho suggests some further comments.

First, the acute respiratory failure occurred after the 47th injection of interferon-{gamma}. This delay between interferon-{gamma} therapy initiation and the deterioration of respiratory status is longer than what we observed in our four patients (2–35 injections).

Second, if the respiratory deterioration was secondary to interferon-{gamma}, then it demonstrates that interferon-{gamma} may have a deleterious effect even in patients with less deteriorated lung function (namely, total lung capacity [TLC] 69% and carbon monoxide transfer factor [TLco] 57% in this patient), whereas the four patients that we described had a far advanced idiopathic pulmonary fibrosis (IPF) with either TLC less than 45% predicted or TLco less than 30% predicted. This observation could be put in perspective with the increased frequency of nonfatal pneumonias observed in patients treated with interferon-{gamma} in a recently reported trial (2). Interferon-{gamma}–triggered acute respiratory failure may be better tolerated and even resolve in patients with less evolved IPF.

Third, Dr. Carvalho speculates on the beneficial effect of positive end-expiratory pressure and recruiting maneuvers in ventilated patients with acute exacerbation of IPF. It is not clear from the letter whether improvement of respiratory failure was secondary to high-dose corticosteroids or to the maneuvers promoted by Dr. Carvalho and colleagues. Recent articles (3–5) have shown the uniformly poor prognosis of acute respiratory failure in patients with IPF admitted to the intensive care unit, with most patients dying either in hospital or within 2 months after discharge. Optimizing ventilation is certainly desirable in acute exacerbations of IPF, although its efficacy is not demonstrated.

Bruno Crestania and Dominique Valeyreb

a Service de Pneumologie Hôpital Bichat Paris, France
b Service de Pneumologie Hôpital Avicenne Bobigny, France

FOOTNOTES

Conflict of Interest Statement: B.C. and D.V. have no declared conflict of interest.

REFERENCES

  1. Honoré I, Nunes H, Groussard O, Kambouchner M, Chambellan A, Aubier M, Valeyre D, Crestani B. Acute respiratory failure after interferon-{gamma} therapy of end-stage pulmonary fibrosis. Am J Respir Crit Care Med 2003;167:953–957.
  2. Raghu G, Brown KK, Bradford WZ, Starko K, Noble PW, Schwartz DA, King TE Jr. Idiopathic Pulmonary Fibrosis Study Group. A placebo-controlled trial of interferon gamma-1b in patients with idiopathic pulmonary fibrosis. N Engl J Med 2004;350:125–133.[Abstract/Free Full Text]
  3. Saydain G, Islam A, Afessa B, Ryu JH, Scott JP, Peters SG. Outcome of patients with idiopathic pulmonary fibrosis admitted to the intensive care unit. Am J Respir Crit Care Med 2002;166:839–842.[Abstract/Free Full Text]
  4. Stern JB, Mal H, Groussard O, Brugiere O, Marceau A, Jebrak G, Fournier M. Prognosis of patients with advanced idiopathic pulmonary fibrosis requiring mechanical ventilation for acute respiratory failure. Chest 2001;120:213–219.[Abstract/Free Full Text]
  5. Blivet S, Philit F, Sab JM, Langevin B, Paret M, Guerin C, Robert D. Outcome of patients with idiopathic pulmonary fibrosis admitted to the ICU for respiratory failure. Chest 2001;120:209–212.[Abstract/Free Full Text]



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[Abstract] [Full Text] [PDF]

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