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*
Department of Medicine–Educational Programs, Bethesda, MD 20814,
Department of Primary Care, Internal Medicine Service, U.S. Army Medical Activity, Heidelberg, Germany and
Department of Medicine, Madigan Army Medical Center, Tacoma, WA 98431
2To whom correspondence and reprint request should be addressed.
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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KEY WORDS: • common cold • zinc • meta-analysis • humans
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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,
Gwalthey et al. 1966
, Schappert 1992
).
The cost of this common affliction has been calculated to be $3.5
billion in 1984 dollars, with an inestimable price in human misery
(Couch 1984
). Zinc salts have been found to inhibit
rhinovirus replication in vitro at concentrations of 
0.1
mmol/L (Korant et al. 1974
), possibly by interfering
with rhinovirus protein cleavage (Korant and Butterworth 1976
). Alternatively, it has been suggested that zinc salts may
protect plasma membranes against lysis by cytotoxic agents, such as
microbial toxins and complement (Kelly and Abel, 1983
).
The proposed protective mechanism is either via immunomodulation
(Geist et al. 1987
, Novick et al. 1996
)
or via the binding of zinc ions to rhinovirus surface canyons, thus
inhibiting viral interaction with intercellular adhesion molecule-1
(ICAM-1)3
, the site of rhinovirus binding to cells (Novick et al. 1996
). Because ICAM-1 is also the binding site for leukocyte
function associated antigen-1 (LFA-1), the block of LFA-1/ICAM-1
binding has been postulated to possibly suppress inflammation
(Petrus et al. 1998
). It has also been suggested that
the cold symptoms, sneezing and nasal congestion, might be reduced by
elevations in intranasal zinc salts, producing a "chemical clamp"
on trigeminal and facial nerve endings (Novick et al. 1996
). Alternatively, it has been suggested that the effects
may be due to correction of a subclinical zinc deficiency
(Prasad 1996
). The biological plausibility for many of
these explanations has been questioned because the in vitro inhibitory
effect has been found to be weak (Pasternack 1987
), and
zinc salts lozenges dissolved in oral saliva do not reach the area
infected by the rhinovirus: the nasal mucosa. As one author pointed
out, "The lack of a specific theoretical framework for a zinc effect
is troublesome and reminiscent of prior attempts to cure the common
cold with other immunologically active micronutrients, such as vitamin
C and vitamin A" (Gadomski, 1998
).
We previously published a meta-analysis of eight double-blinded
placebo-controlled trials (Jackson et al. 1997
) in which
we found significant heterogeneity and a summary odds ratio (OR) for
the presence of "any" cold symptoms at 7 d to be 0.50 with a
95% confidence interval that crossed 1 (0.19–1.29). We concluded that
the overall evidence of benefit for zinc was lacking. However,
questions of methodological flaws among the different trials made
definitive conclusions difficult. Since this meta-analysis, an
additional two double-blinded placebo-controlled randomized
clinical trials have been published. Here, we update our previous
analysis and include these additional trials.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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).
Inter-rater agreement was assessed using the kappa statistic. Data
extraction was performed by committee consensus in an unblinded manner.
Because of inconsistent reporting between studies, the data point
selected for analysis was the presence of "any" cold symptom at
7 d. Additional data that were extracted included country of
origin, funding sources, study population, disease characteristics,
nature and dose of intervention, duration and success of followup.
Study directors were contacted for data that were either ambiguous or
not directly retrievable from the text. Unweighted data were tested for
homogeneity using the methods of (Mantel-Haenszel
(Petitti 1994
) and were found to be inhomogeneous
(Q = 47.9, df = 7, P < 0.00001),
as reflected visually with the Galbraith plot (Fig. 1
), so analysis was conducted using the random effects model of
DerSimonian and Laird (Fleiss 1993
). The possibility of
publication bias was assessed and rejected (P = 0.09) using the methods of Egger et al. (1997
).
|
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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). The remaining 10 trials could be divided into
two markedly different study designs (Porter and Hart 1993
): eight studies investigated the effect of zinc salts on
patients in whom colds were developing de novo in the community
(Douglas et al. 1987
, Eby et al. 1984
,
Godfrey 1992
, Macknin 1998
, Mossad et al. 1996
, Smith et al. 1989
, Weismann et al. 1990
), and in two studies, volunteers were inoculated
with rhinovirus 13 or 39 (Farr et al. 1987
) or
rhinovirus 2 (Al-Nakib et al. 1987
). Because of concern
about combining data from studies with markedly different designs
(Potter and Hart 1993
) and because neither of these
studies provided data on the presence of symptoms at d 7, both were
excluded. The director of one of these studies (Farr et al. 1987
) declined to release the data. These two studies reported
opposite findings: one found no effect (Farr et al. 1987
), and one found a small improvement in symptoms among the
12 patients studied (Al-Nakib et al. 1987
).
The comparability of these differing study designs was questioned for
several reasons. First, is it possible that experimentally-induced
colds do not have the same natural history as those attained de novo
(Jackson et al. 1958
)? Second, although rhinovirus is
the most common cause of colds, it has > 100 serotypes and as a
group is responsible for 30–50% of community-acquired colds,
raising issues of generalizability (Jackson et al. 1958
,
Jennings and Dick 1987
).
The final pool of eight placebo-controlled randomized clinical
trials and the excluded trials are shown in Table 1
. The trials had consistent, moderate-quality scores, and there was
good inter-rater agreement on study quality (
= 0.73).
Particular problems included a lack of information provided on the
method of randomization (Douglas et al. 1987
, Eby et al. 1984
, Macknin 1998
, Weismann et al. 1990
), lack of testing of blinding effectiveness
(Al-Nakib et al. 1987
, Macknin 1998
),
evidence that blinding was ineffective (Douglas et al. 1987
, Eby et al. 1984
, Mossad et al. 1996
), small sample sizes (Al-Nakib et al. 1987
,
Smith et al. 1989
), failure to use an intention-to-treat
analysis (Eby et al. 1984
, Godfrey 1992
,
Smith et al. 1989
), significant losses to followup
(Eby et al. 1984
, Godfrey 1992
), lack of
information on losses to follow-up (Weismann et al. 1990
) and lack of power calculations in negative studies
(Douglas et al. 1987
, Smith et al. 1989
,
Weismann et al. 1990
).
|
.
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|
DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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) of no effect was not included
in the analysis. Among studies reporting a benefit from zinc therapy,
many have been criticized for poor blinding of study subjects. One used
an unflavored placebo with a high dropout rate in the zinc gluconate
group due to unpleasant side effects (Eby et al. 1984
),
and another found a higher rate of side effects with the zinc gluconate
lozenge than with the calcium lactate pentahydrate placebo
(Mossad et al. 1996
). Lack of adequate blinding was
eventually believed to have produced misleading results for benefit in
treating colds with ascorbic acid (Chalmers 1973
).
The biologic plausibility of the effectiveness of zinc salts in
treating colds has also been questioned. Both trials that measured
viral shedding found no effect on duration or magnitude of viral
shedding (Al-Nakib et al. 1987
, Farr et al. 1987
). Serum zinc concentrations are well below those required
for a direct viral effect (Farr et al. 1987
), and
although concentrations in oral saliva reach sufficient levels
(Godfrey 1988
), there is no evidence that this
zinc-saliva mixture reaches the nasal mucosa, the site of viral
infection.
The most scientifically rigorous trials of zinc and its effects on cold
symptoms were the two inoculation studies (Al-Nakib et al. 1987
, Farr 1987
). Under close supervision,
patient compliance, cold symptoms and side effects were carefully
monitored. Neither trial found a direct effect on viral shedding, in
either magnitude or duration. In a trial involving only 12 subjects,
Al-Nakib et al. (1987
) found a small improvement in some
cold symptoms on some days, whereas Farr et al. (1987
found no differences in any of the measures. Unfortunately, these were
excluded from this meta-analysis, but it is hard to understand how
some trials can find such a dramatic reduction (Eby et al. 1984
, Godfrey 1992
, Mossad et al. 1996
, Petrus et al. 1998
) in all cold symptoms,
whereas others found little or no benefit (Douglas et al. 1987
, Farr et al. 1987
, Macknin et al. 1998
, Smith et al. 1990, Weismann et al. 1990
).
Critics of trials finding no benefit from zinc have suggested one of
two possibilities for zinc failure in those studies. One has been
criticized for using potentially inadequate doses (Weismann et al. 1990
), whereas three (Douglas et al. 1987
,
Weismann et al. 1990
, Farr 1987
) were
criticized for using preparations that could chelate zinc (Eby 1988
, Zarembo et al. 1992
). The concern about
the inactivation of zinc by other substances is controversial, with
data from Bristol-Myers chemists suggesting that this does not
occur (Lewis 1998
). Moreover, if zinc does not directly
reach the nasopharynx, and it is postulated that serum levels of zinc
are responsible for the beneficial effects, the acidity in the stomach
would render problems of oral chelation meaningless.
This analysis has several important limitations. First, the validity of any meta-analysis is dependent on the validity of the studies analyzed. Some questions of methodology, such as the adequacy of randomization or use of an intention-to-treat analysis, can be used to stratify studies into those of higher and lower quality. However, a meta-analysis has no ability to differentiate truth in the face of conflicting claims of fundamental methodological flaws, as is the case in this analysis. Second, this meta-analysis was limited to a single variable, the presence of "any" cold symptom at 7 d. Other variables, such as the severity of cold symptoms or amount of nasal discharge, which is important in the patient determination of the severity of colds, were not extractable and therefore not analyzable. However, these symptoms paralleled symptom duration, with the studies split on zinc effectiveness on these variables as well. Finally, one of the studies involved pediatric patients, whereas the remaining trials involved adults. If colds or zinc effects are different in children than in adults, then the inclusion of those results is inappropriate. However, there is little evidence to suggest that this is the case, although children have been shown to have more frequent colds than adults.
For clinicians advising patients on the use of zinc lozenges, it is
difficult to know who is correct. Although one report of an acute zinc
overdose found no significant patient harm (Lewis 1998
),
potential adverse effects from excess intake of zinc includes a
reduction in serum copper (Prasad et al. 1978
) and
lymphocyte stimulation as well as a significant reduction in HDL with a
slight increase in LDL (Chandra 1984
). As one author put
it, "The ingestion of gram quantities of zinc by many millions of
persons as therapy for the common cold would represent a kind of
uncontrolled nutritional experiment that is cause for concern. At the
very least, therefore, surveillance for potential toxicity will be
needed for a good many years if zinc therapy becomes widely adopted for
one of mankind’s most common and seemingly most intractable
maladies" (Prasad 1996
). Interestingly, a recent
review of cold treatment by the author of one of the trials concluded
that "a safe effective dose is not yet established" (Chandra 1984
). Our meta-analysis suggests that the evidence of zinc
effectiveness is still lacking.
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FOOTNOTES |
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3 Abbreviations used: ICAM-1, intercellular adhesion molecule-1; LFA, leukocyte function associated antigen-1; OR, odds ratio.
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REFERENCES |
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