The Journal of Pediatrics
Volume 151, Issue 3 , Pages 228-230, September 2007

Non! to Non-Steroidal Anti-Inflammatory Therapy for Inflammatory Lung Disease in Cystic Fibrosis (at Least at the Moment)

  • Andrew Bush, MB, BS (Hons), MA, MD, FRCP, FRCPCH

      Affiliations

    • Professor of Paediatric Respirology, Imperial School of Medicine at National Heart and Lung Institute, Honorary Consultant Paediatric Chest Physician, Royal Brompton Hospital, London, United Kingdom
    • Corresponding Author InformationReprint requests: Andrew Bush, Department of Paediatric Respiratory Medicine, Royal Brompton Hospital, Sydney Street, London SW3 6NP, UK.
    • ,
  • Jane Davies, MB, ChB, MRCP, MRCPCH, MD

      Affiliations

    • Senior Lecturer in Gene Therapy, Imperial College, Honorary Consultant Paediatric Chest Physician, Royal Brompton Hospital, London, United Kingdom

Article Outline

Abbreviations: CF, Cystic fibrosis, FEV1, Forced expired volume, FVC, Forced vital capacity

 

There is generally a “love-hate” relationship between the inflammatory response and the human organism. On one hand, a major congenital or acquired defect in the recognition of, or response to, an environmental pathogen leads to recurrent severe infections and often rapid death. Conversely, failure to control the inflammatory response can lead to death and destruction from “friendly fire,” the most clear-cut examples being the formation of tissue-specific antibodies such as the anti-glomerular basement membrane antibody in Goodpasture’s syndrome.1

See related article, p 249

In the case of cystic fibrosis (CF), the relationship has been perceived as being more one of “hate-hate” rather then “love-hate.” The dogma has been that chronic airway infection has resulted in an over-exuberant inflammatory response, with the recruitment of excessive amounts of neutrophils, failure of clearance of the micro-organisms, neutrophil necrosis instead of apoptosis, and the release of tissue-damaging enzymes, with resultant tissue destruction disproportionate to the actual burden of infection.2 This idea led to the seemingly paradoxical concept that immunosuppression might be beneficial in the setting of chronic airway infection. The initial choice was prednisone, with the first study, using a huge dose (2 mg/kg on alternate days) reporting benefits, but apparently no adverse effects.3 This was not confirmed in the first of the great series of multicenter CF trials emanating from North America.4 In this study, 2 mg/kg of prednisone on alternate days was compared with 1 mg/kg on alternate days and with placebo. The well-known findings were that the benefit of prednisone was confirmed, but the adverse effects necessitated discontinuing the high- and low-dose prednisone arms after 2 and 4 years, respectively. An important clue, the significance of which has been under-appreciated, was that the benefits of prednisone were confined to those patients chronically infected with Pseudomonas aeruginosa. The subsequent history of steroids, in brief, is that after a number of contradictory studies of inhaled steroids,5 a trial of withdrawal of inhaled steroids (CF WISE study) showed that they are largely ineffective in CF.6 Furthermore, the appreciation has grown of the importance of systemic complications of CF, such as diabetes mellitus7 and bone disease,8 which may be worsened by steroids, and so enthusiasm for steroids in CF (other than when mandated by, for example, allergic bronchopulmonary aspergillosis9) has waned.

However, 2 important lessons can be drawn from the history of steroids in CF. The first is the credulity of physicians who treat CF in their willingness to prescribe treatments of no value; CF WISE had to study withdrawal of inhaled steroids, not prescription of them, because so few patients could be found who were not already taking these medications. Second, from the multicenter prednisone study4 is that the stage of the disease may determine the response to anti-inflammatory therapy. This makes biological sense; the child with CF at birth almost certainly has a sterile and normal airway and initially probably meets and repels pathogens, until eventually the defences are overwhelmed, and chronic infection supervenes. Thus it is likely, but unproven, that very early immunosuppression actually might accelerate the onset of chronic infection. The concept that immunosuppression may cause harm, not good, was further strengthened by the large multicenter study of the leukotriene (LT) B4 receptor antagonist B11L 284 BS.10 The trial was stopped by the data-monitoring committee because of an increase in serious adverse events (infective exacerbations) in the treatment limb.

What then are the lessons for those wishing to study anti-inflammatory medications in CF? Key (and most difficult) must be to have a focussed hypothesis about the type of patient with CF who may benefit from the intervention, rather than trying it out on all comers. This is doubly difficult; we are as yet struggling to generate these hypotheses, and, even when we do so, finding enough patients to do an adequately powered study becomes even more problematic.

In this context, how do we interpret the results of the use of ibuprofen as an anti-inflammatory medication in CF, in particular in the light of the study by Lands et al in this issue of The Journal?11 The logic for the studies is impeccable; if steroids are effective but have adverse effects, why not use non-steroidal anti-inflammatory medications? The initial carefully controlled study showed that ibuprofen slowed the rate of deterioration of first second forced expired volume (FEV1).12 The placebo group had an annual decline of −3.60% ± 0.55% against −2.17% ± 0.57% in the active group. The results were more dramatic in the group that was compliant with medication, and in those who were <13 years old at the start of the trial. Despite this study, ibuprofen has only enjoyed patchy use in the clinic13; whether this is because of worries of albeit rare, but not trivial, adverse effects such as gastrointestinal haemorrhage and acute renal failure,14, 15 the narrow therapeutic window necessitating monitoring of levels,16 or more cynically, because big pharmaceutical companies were not promoting it lavishly and assiduously, is unclear. However, 12 years later, one could be forgiven for questioning the relevance of the study because the rate of decline in lung function in the placebo group is much higher than would be acceptable now,17, 18, 19 and the intervention group results are inferior to those currently seen in some clinics that do not use much ibuprofen. This study11 recruited more patients (n = 142), but studied them during a shorter period (2 years). Patients with relatively mild impairment of lung function (FEV1 >60% predicted) were recruited, but children who were >13-year age cutoff of the earlier study were included. Their power calculation was based on a high expected rate of decline in the placebo group (ΔFEV1 4%/year, higher than was actually seen), set the bar low at 80% power, and concluded that substantially more patients were needed than were recruited, despite a monumental effort by the investigators. They found no change in either their primary end point (rate of change of FEV1) or of another variable that one would expect to be affected by obstructive lung disease, mid-expiratory flow (FEF25-75). However, what they did find was a beneficial effect on forced vital capacity (FVC). In the ibuprofen group, FVC actually did not change in 2 years. After a prolonged post hoc pas de deux with the data, the authors also managed to torture out a small, statistically significant benefit for the patients who were treated in days spent in hospital.

How then should ibuprofen be positioned in the therapeutic armamentarium? Lands et al11 have put in a tremendous effort to make an impeccably designed study work, for which unreserved congratulations are due. However, they fail to convince us that they have shown a biologically likely benefit. Their study was under-powered and failed to show an effect in their primary end point or a biologically plausible secondary end point. Are the changes in FVC biologically plausible in an obstructive lung disease or an artefact of a relatively small study? We do not believe that the case for widespread use of ibuprofen can be made on these data alone.

What of the future? One lesson from this study is that the better we get at conventional treatment, the harder it will be to show an improvement in outcome with a novel therapy. The relative insensitivity of lung function, or rather, the huge numbers of patients needed if spirometry is to be an outcome, has been highlighted20, 21; reliable surrogates, changes in which truly reflect the course of the disease, need to be found. In manipulating CF inflammation, we need to know at what time in the disease we should be repressing instead of boosting the host defenses; we need to know what part of the inflammatory cascade is responsible for the host damage; and we need to be able to measure it easily, repeatedly, and non-invasively. Only at that point will we be able to design rational studies of anti-inflammatory therapies with appropriate end points; after all, the asthma doctors have eventually realized that anti-inflammatory therapy is most effective when the therapeutic target, inflammation, is measured.22, 23, 24, 25, 26 Until that time, trials are likely to include patients who have no chance of benefiting from the proffered treatment, thus diluting any effect, and continue to be under-powered anyway, because lung function and inflammation may be only very loosely related. The concept of treating a genetic defect (premature stop codon) rather than a disease has recently gained practical currency27; we need almost certainly to move to treating specific pathways, not a global mish-mash of “inflammation.”

However, it must be stressed that the absence of evidence of benefit is not the same as evidence of non-benefit. It may be that ibuprofen is the answer for some patients with CF, but we do not yet have the data. Although we disagree with their conclusions, we most readily acknowledge that Lands et al11 have done a signal service by keeping ibuprofen at the forefront of the debate about optimal treatment in CF, by conducting an impressively designed study, and above all, by reminding us of the importance of clinical trial work in children, who may gain from therapies that are useless in adults. If pediatric trial work like this is not done, then substantial therapeutic benefits in the fight against CF may be frittered away.

Back to Article Outline

References 

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PII: S0022-3476(07)00589-6

doi:10.1016/j.jpeds.2007.06.019

Refers to article:

  • High-Dose Ibuprofen in Cystic Fibrosis: Canadian Safety and Effectiveness Trial , 28 June 2007

    Larry C. Lands, Ruth Milner, André M. Cantin, David Manson, Mary Corey
    The Journal of Pediatrics September 2007 (Vol. 151, Issue 3, Pages 249-254)

The Journal of Pediatrics
Volume 151, Issue 3 , Pages 228-230, September 2007

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