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Time to consign cromoglycate to history?
  1. G LASZLO, Consultant Physician Emeritus
  1. Bristol Royal Infirmary
  2. Bristol BS2 8HW, UK
  3. GLaszlo11{at}aol.com
    1. P J HELMS
    1. Department of Child Health
    2. University of Aberdeen
    3. Foresterhill
    4. Aberdeen AB25 2ZD, UK
    5. p.j.helms{at}abdn.ac.uk
      1. M J A TASCHE,
      2. J H J M UIJEN,
      3. R M D BERNSEN,
      4. J C DE JONGSTE,
      5. J C VAN DER WOUDEN
      1. Department of General Practice and Division of Pediatric/Respiratory Medicine
      2. Erasmus University and University Hospital/Sophia Children's Hospital
      3. Rotterdam
      4. The Netherlands
      5. vanderwouden{at}hag.fgg.eur.nl

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        Sodium cromoglycate (SCG) has become a minority option for the treatment of childhood asthma,1 and even positive trials show only marginally relevant differences in the outcomes measured.2 It is therefore interesting to recall that in 1967 the majority of asthmatic subjects were exposed to cigarette smoke and many had deformed chests. Children were not allowed to self-medicate or to receive their treatment at ordinary schools; the most affected were sent to special schools and camps. Oral ephedrine and short acting theophylline preparations were standard treatment, but their effectiveness was limited by tachyphylaxis.

        The children who were treated with SCG when it was introduced experienced less the currently available alternative—dry powder inhalers—are perceived to be more costly. exercise induced asthma and were able to participate in playground games, often for the first time. In addition, fewer colds resulted in wheezing and exacerbations were shorter. The parents and physicians of these children were delighted with this safe remedy which was effective for all but the most severe forms of the condition. The most popular formulation was a mixture of SCG with isoprenaline (Intal compound). This combined the immediate bronchodilator effect of a rapidly acting β adrenergic drug of extremely short duration with protection from antigen challenges and exercise induced asthma which lasted for about 6 hours.

        Salbutamol was introduced in 1969, only 2 years after SCG, and had the same effect in providing both relief and protection. As soon as salbutamol, permitted 6-hourly, became the rescue bronchodilator of choice, it became difficult to demonstrate any clinically relevant benefit attributable solely to SCG in patients who were not dependent on oral steroids. Inhaled beclomethasone was introduced soon afterwards and this enabled even more asthmatics who were dependent on oral steroids to discontinue them. Beclomethasone does not have the unpleasant taste that makes SCG disagreeable to use, and suppresses more components of inflammation than SCG. Furthermore, beclomethasone rapidly reduces symptoms more effectively for the same effect on daytime FEV1 and morning peak flow, possibly by reducing the sensation of inflammation in the airways.3 By the time it was recognised that long term administration of higher doses of inhaled steroids produced significant side effects in children and adults, long acting bronchodilators had been developed and proved to be useful in combination with medium doses of inhaled steroids. The possible use of cromoglycate, with its proven safety record, was not investigated in this context. There are no long term studies which show whether SCG played any part in the improved outcomes in childhood asthma between 1970 and 1980, or whether these are entirely the consequence of inhaled steroid use.

        In a lucid contemporary account, one of the first investigators to test SCG described how he and his colleagues were disappointed to be unable to show any major effect of SCG on FEV1 in spite of a dramatic symptomatic and steroid sparing effect.4 At this time asthma was defined as variable or reversible airflow obstruction, and it was recognised that patients would judge the control of their condition by the frequency of regular, unexpected, or nocturnal attacks rather than by their best lung function. The value of frequent observation during the day was demonstrated by Chaiet al 5 in 1968 and accepted in the late 1970s even by physicians who had previously regarded paroxysmal nocturnal dyspnoea as synonymous with pulmonary oedema.

        Helms1 points out that regulators and authors of meta-analyses have a duty to examine appropriate outcomes. To promote informed discussion, they also need to beaware of the changing therapeutic options that were available when the studies under scrutiny were carried out.

        References

        authors' reply Lazlo provides an historical perspective on the passing cromoglycate era in which he describes the dire state of asthma management, particularly in children, at the time that sodium cromoglycate (SCG) was introduced. He also points out that, soon after SCG was introduced, inhaled isoprenaline became available followed by the selective β2 agonist salbutamol. Although isoprenaline in combination with SCG was common in adult practice, it was used much less frequently in children. There are a number of other child/adult differences in practice and effectiveness that underline the insecurities of extrapolation and inference.1-1 The protective effects of cromones on exercise induced bronchoconstriction are established, but are of relatively short duration1-2 and are therefore unlikely to provide reliable and sustained protection against this troublesome symptom in active children. Whereas long acting β agonists have proved to be useful in combination with moderate doses of inhaled steroids in adults,1-3 the effects in young children have been disappointing1-4 and have been the subject of a narrative review.1-5 Extrapolation of experience from predominantly adult studies into the paediatric age range has been a feature of asthma management but is increasingly being shown to be insecure, again emphasising the need for studies in children, particularly in those in younger age groups where the disease is most prevalent.1-1 There is at least one long term study which attempted to assess the effectiveness of SCG and which concluded that 60–70% of children with persistent symptoms improved over a 3–5 year period.1-6 However, this study, which was an open extension to a formal double blind placebo controlled trial, could not take into account the natural rates of resolution and recurrence of the disease over this prolonged period.1-7

        Despite the popularity of SCG in the 1970s and early 1980s, it could be argued that its marginal effectiveness, masked by its combined use with effective bronchodilator agents, together with concerns about possible systemic effects of steroids prolonged its appearance in the therapeutic armamentarium. The passing cromoglycate era certainly contains many lessons for the prescribing community, and among these must be an awareness of the natural history of the disease in childhood and the potential pitfalls of extrapolating lessons learnt in more severely affected and older age groups into younger age groups.

        References

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        authors' reply We appreciate Dr Laszlo's eloquent historic overview of asthma treatment and agree that a therapy should be considered within the range of available options. This range of options may change over time. However, our systematic review addressed the effectiveness of sodium cromoglycate compared with placebo, not with other active treatments. As a consequence, our findings may be a guidance not only to today's physicians but also to future generations with other therapeutic alternatives.

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