Reply by Ronald B. Turner to Dr. Yiu
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Reply
Ronald B. Turner
Department of Pediatrics, University of Virginia, Charlottesville
Reprints or correspondence: Dr. Ronald B. Turner, Dept. of Pediatrics, University of Virginia Health Care System, PO Box 800386, Charlottesville, VA 22908 (rbt2n@virginia.edu).
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SIRThank you for the opportunity to respond to Dr. Yiu's comments [1] concerning my article on the ineffectiveness of intranasal zinc gluconate for the prevention of experimentally induced rhinovirus colds [2]. I am pleased that he finds the experimental rhinovirus challenge model to be an acceptable method for the evaluation of treatments for the common cold. This model has been used for the study of the pathogenesis and treatment of the common cold for >30 years. When treatments have been studied in both the model and the natural setting, the model has generally been a reliable predictor of treatment efficacy for naturally occurring colds.
The first concern raised by Dr. Yiu relates to the experimental power of the study. As noted in the first paragraph of the Discussion section of the article [2], the experimental power of the study was 80% for detection of a 52% reduction in clinical colds. Treatment effects of at least this magnitude have been consistently observed when agents with well-documented antiviral activity are used as prophylaxis in the experimental challenge model reviewed in a series of studies mentioned elsewhere [3] and in a single study reported in a separate article [4]. In light of this experience, I believe it is unlikely that our study missed clinically important effects of intranasal zinc on rhinovirus colds.
Dr. Yiu also questions the decision to combine data from volunteers challenged with 2 different rhinovirus serotypes in the analysis. The 2 rhinovirus serotypes used in our study are representative of the major group of rhinoviruses that bind to cells via intercellular adhesion molecule 1 (ICAM-1). None of the variety of mechanisms that have been suggested as explanations for the potential effects of zinc on rhinovirus colds, with the exception of inhibition of ICAM binding, would be serotype specific. From a practical perspective, it is difficult to imagine that a treatment that is effective against only a fraction of rhinovirus serotypes would be clinically useful. For these reasons, an analysis that examines the effect of treatment on rhinovirus infection and illness, regardless of serotype, seems appropriate.
Adequate blinding has been particularly difficult to achieve in studies of zinc therapies. In this study, we evaluated and reported (1) whether the volunteers could taste the study medication; (2) if the volunteers could taste the medication, their perception of the quality of taste; and (3) the volunteers' belief regarding whether they were receiving active medication or placebo. We also evaluated whether a difference in the rate of occurrence of side effects in the 2 treatment groups might have biased the study. Dr. Yiu correctly notes that the volunteers who received active medication were significantly more likely to report that they could taste the medication. No differences between the placebo and active treatment groups were found for any of the other measures of blinding in the study. It also seems likely that, had the study been inadequately blinded, this would have favored the active treatment rather than placebo.
The observation of a significant reduction in the virus titers of the nasal lavage samples obtained from volunteers treated with zinc is discussed in some detail in the second paragraph of the Discussion section. Although this antiviral effect is of some modest interest from a biological perspective, the practical significance of an antiviral effect that is not associated with a reduction in either the infection rate or clinical illness is not clear.
Finally, I am not aware of having received previous communication from Dr. Yiu. The article was not publicly made available until it was electronically published in Clinical Infectious Diseases on 25 October 2001. Under the conditions of the study agreement, a draft of the article was provided to the sponsor of the study for comment before it was submitted to Clinical Infectious Diseases. The comments I received from the sponsor, some of which were similar to those of Dr. Yiu, were considered, and changes to the manuscript were made at my discretion. I was not asked to respond to the sponsor's comments, nor do I believe that a response was expected. I am sorry if Dr. Yiu misunderstood this arrangement.
References
1. Yiu SC. Evaluation of the efficacy of intranasal zinc gluconate [letter]. Clin Infect Dis 2002; 34:1657 (in this issue). First citation in article | Full Text | PubMed
2. Turner RB. Ineffectiveness of intranasal zinc gluconate for prevention of experimental rhinovirus colds. Clin Infect Dis 2001; 33:186570. First citation in article | Full Text | PubMed
3. Arruda E, Hayden FG. Clinical studies of antiviral agents for picornavirus infections. In: Jeffries DJ, De Clercq E, eds. Antiviral chemotherapy. Chichester, UK: John Wiley & Sons, 1995:32155. First citation in article
4. Schiff GM, Sherwood JR. Clinical activity of pleconaril in an experimentally induced coxsackievirus A21 respiratory infection. J Infect Dis 2000; 181:206. First citation in article | Full Text | PubMed
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