Intravenous immunoglobulin for cystic fibrosis lung disease: commentary on the paper by Balfour-Lynn et al.(Commentary)

In a retrospective review published in this issue, (1) Balfour-Lynn and colleagues describe 16 children with cystic fibrosis (CF) who appeared to show clinical improvement following regular infusions of intravenous immunoglobulin (IVIG). They have not described any criteria for the commencement of treatment, but the majority of children had previously been diagnosed with allergic bronchopulmonary aspergillosis (ABPA). An analysis of efficacy compared lung function and other concomitant treatments before starting therapy and after courses of therapy, the number of which varied considerably between patients. This treatment was associated with a reduction in the doses of oral and inhaled steroids. There was some improvement in forced vital capacity, but no difference in forced expiratory volume in one second.

Clinical practice has been likened to an experiment, where a patient presents with a problem, treatment is initiated, and the results of treatment are later assessed and conclusions drawn about whether or not the treatment is effective. There are a number of factors which may act to bias these conclusions. (2) Firstly the patient may have improved anyway. Secondly, new treatments are more likely to be initiated at a time when, as part of the normal fluctuation in the illness, symptoms, signs, and other measures have reached temporary extreme values which, will "regress towards the mean" when next measured. Any treatment started between the time points will appear to be effective. Thirdly, there is a well described placebo effect and finally, in the absence of blinding, the expectations of the patients and/or clinicians may bias the assessment of whether or not the treatment has been effective. This is particularly the case when outcome measures are based on clinical decisions, such as use of other concomitant therapies.

The n of 1 trial, in which randomised, double blind, multiple crossover comparisons of active and placebo treatments are conducted in an individual patient, (2) has been developed to limit the biases inherent in uncontrolled therapeutic trials. There are a number of situations in which n of 1 trials may be considered. For example, as proposed by these authors, there are situations where clinical trials have not been conducted or may not be feasible. (2) It has also been suggested that they can be used in the early phases of drug development, to assist in the planning of subsequent large clinical trials. (3) Finally, where a treatment has been shown in clinical trials to have an overall benefit, but there is considerable individual variation in response, n of 1 trials can identify which patients are likely to derive benefit. To address the last of these questions, n of 1 trials of recombinant DNase have been successfully performed in CF patients. (4 5) Prerequisites for conducting n of 1 trials are that the underlying condition should be stable over time, the treatment should exert its effect over a short time, and this effect should stop quickly once the treatment is withdrawn. (6)

Uncontrolled clinical trials, such as those described in the paper by Balfour-Lynn and colleagues, (1) have important limitations. Is the alternative, suggested by these authors, of undertaking n of 1 trials of intravenous immunoglobulin in "carefully selected patients" with CF, appropriate? It is not clear from this report whether the patients with severe CF lung disease, who were included, represent a group whose lung disease would be stable, at least over the duration of an n of 1 trial. It is implied in the report, that the response to treatment may be cumulative and therefore multiple crossovers of one month's active treatment and one month's placebo treatment may not enable an adequate assessment. Similarly the observation that improvement was maintained after stopping treatment or indeed that the illness was "switched off" completely suggest that this therapy is not amenable to assessment by n ...