MILITARY MEDICINE, 169, 11:920, 2004

Vitamin C Supplementation and Respiratory Infections: a Systematic Review Guarantor: Harri Hemila, MD PhD Contributor: Harri Hemila, MD PhD In this review, the vitamin C trials with military personnel and with other subjects living under conditions comparable to those of military recruits are analyzed to find out whether vitamin C supplementation affects respiratory infections. For this systematic review, we identified seven trials with military personnel, three trials with students in crowded lodgings, and two trials with marathon runners. Eight of these trials were double blind and placebo controlled and seven were randomized. Five small trials found a statistically significant 45 to 91% reduction in common cold incidence in the vitamin C group. These trials were short and the participants were under heavy exertion during the trial. Furthermore, three other trials found a statistically significant 80 to 100% reduction in the incidence of pneumonia in the vitamin C group. The large number of positive findings seems to warrant further consideration of the role of vitamin C in respiratory infections, particularly in military recruits.

with the original reports, overlooked several highly relevant findings, and analyzed data inappropriately.^'" The purpose of the present review was to analyze the findings of vitamin C trials with military personnel and of trials with participants under conditions similar to those of military recruits to find out whether vitamin C affects the incidence or severity of respiratory infections. Methods

Selection of the Trials I previously searched the literature on \1tamin C and respiratory infections using various MEDLINE, EMBASE, and SCISEARCH database searches, and I inspected the reference lists of reviews and original reports.''" '^ One other author independently searched for trials on vitamin C and the common cold and published the identified bibliography,''' For this systematic review, further MEDLINE searches covering the years Introduction 1999-2002 were carried out. high incidence of pneumonia and other respiratory infecThe present review covers only controlled trials in which tions is a common problem among military recruits, possi- vitamin C was administered to one study group: the control bly caused hy the crovi'ding together of young adults from widely group may or may not have received a placebo. This analysis dispersed geographic areas,' "* Naw and Marine recruits were at focused on trials reporting respiratory tract infection out30 times higher risk of hospital admission for pneumonia than comes. Two groups of trials were selected on the basis of were nonrecruits,' and Navy and Marine personnel with less subjects used in the trials; military personnel (seven trials: than 1 year of service were at five times higher risk of pneumo- Table I) and students accommodated in crowded lodgings and nia than their peers with 4 or more years of service.'' Conse- marathon runners (five trials: Table II). Except for one trial,'^ quently, factors affecting susceptibility to respiratory infections the trials in the tables are prophylactic such that participants in military recruits are of considerable practical importance, were healthy at the trial's outset and supplementation conThe notion that Wtaniin C affects susceptibility to various tinued over the occurring respiratory infection episodes. Alinfections—and respiratory infections in particular—is an old though one trial examined patients hospitalized for influenza one/'*^ but the topic came to wider popularity only in the 1970s. A. it was nevertheless prophylactic with respect to the occurwhen Pauling^'^ suggested that vitamin C supplementation rence of pneumonia after the initiation of vitamin C supplewould reduce the incidence and severity of colds. Trials carried mentation. "*

A

out since then have consistently found that vitamin C alleviates common cold symptoms, but yields only modest benefit.^''^ Vitamin C had no effect on the incidence of the common cold in the largest trials.^'^'^ but trials with British men'^ and with subjects under heavy, acute physical stress'"^ found reduction in common cold incidence, suggesting that vitamin C affects susceptibility to respiratory infections in restricted groups of people. Although Pauling was considerably overoptimistic about the potential benefits of vitamin C,''*^''"'^ another problem in this area of interest has been the negative bias against vitamin C, Three iniluential reviews concluded that vitamin C is ineffective against colds: however, the reviews presented data inconsistent Department of Public Health. University of Helsinki. Helsinki, Finland, This manuscript was received for reiiew in April 2003. The reiised manuscript was accepted for publication in January' 2004. Reprint & Copyright © by Association of Militarv' Surgeons of U.S.. 2004.

Military Medicine, Vol, 169, November 2004

Statistical Methods Tables 1 and II show the p values calculated by the current author for the differences in the outcome values between the two groups. For dichotomous data, the mid-p modification^** of the Fisher's exact test^^ was used to calculate p. For continuous variables, the exact p value was calculated using the t test.^^ when mean and SD were reported in the original articles. The x^ test^*^ was used to test whether the distribution of participants with correct and incorrect answers in the Pitt and Costrlni trial'^ is explained by random variation. Assuming pure guessing, the expected number of correct and wrong answers is equal: both are one-half of all of the answers. Consequently, with 316 answers in the Pitt and Costrini trial, the expected number of correct and wrong answers is 158.

920

Vitamin C Supplementation and Respiratory Infections

921 TABLE I

VITAMIN C AND RESPIRATORY INFECTIONS IN MILITARY PERSONNEL Treatment Trial-

Variable

Vitamin C

331 600

Control 343 619 1.97 11.5 7

Difference in Outcome (%)

p (onetaUed)"

Pitt and Costrini"^ United States 2 g/day 2 months

Subjects Common cold episodes Severity of colds'' Duration of colds (days) Pneumonia cases

Dahlbergetal.'^ Sweden 0.5 g/day 3 months

Subjects Subjects with the common cold Subjects with more severe respiratory infections'*

Kimbarowskl and Mokrow'" Soviet Union 0,3 g/day Therapeutic trial

Patients with influenza A Pneumonia rases Stay at hospital, all subjects (average, days)

Sabiston and Radomskl'^ Canada 1 g/day 1-2 week

Subjects Subjects with the common cold Constitutional symptoms (mean ± SD, days)'' Throat/chest symptoms (mean ± SD. days) Nasal symptoms (mean ± SD. days)

Elliott 20 United States 2 g/day 2.5 months

Subjects Number of common cold episodes Sore throat (days/group) Hoarseness (days/groupl Productive cough (days/group) Nonproductive cough (days/group)

37

Liljefors^' Sweden 2 g/day 2 weeks

Subjects Subjects with the common cold

33 10

33

9

+ 11

0,6

Niemi^'^ Finland 0.1 g/day 2-3 months

Subjects Subjects with the common cold

147 24

152 18

+33

0.8

1.87

1L2 i

!,266 130 10

1.259

126 5 114 2

0 -5 -3 -85

0.11

-80

0.009

0,027 0,045 0.13 0.2

9

56

56

6

14 2.4 ± 2.1 6.0 ± 3.0 5.6 ± 2.8

-57 -67 -28 -25

33 — 107 36 72 42

0 -72 -63 -69 -60

a

— _ — —

0,022

-2 -50

112 10 12

0.8 ± 0,8 4.3 ± 3.0 4.2 ± 3,8

0,012'

0,016" 0,033"

" Reflects country, dose of vitamin C, and duration, respectively. "The p values were calculated by this aiilhor, e.xcept for the Elliott data, Elliott used the Wilcoxon test to calculate p. —, Data not published, '• Difference between the treatment groups: p was calculated from x^ (15 d/] = 27,8 reported by Pitt and Costrini,'** Severity scale is from 1 to 4, '' Pneumonia, bronchitis, sinusitis, tonsilitis, and otitis media. *' Genera! malaise, headache, chilis and fever, and vomiting.

The one-tailed p values are used in the tables and text because the explicit question in the present analysis is whether vitamin C supplementation decreases the incidence and severity of respiratory infections. There is no experimental or theoretical reason to expect that vitamin C supplementation would increase morbidity from respiratory infections. Confidence intervals are not calculated because the primary purpose of this review was to test the hypothesis that vitamin C affects respiratory infections. Trial settings and outcome definitions vary substantially, which limits the possibility to generalize the point estimates: therefore, no pooled estimates were calculated. Trials with Military Personnel Seven trials examined the effect of vitamin C supplementation on respiratory infections in military personnel. Table I shows the number of participants, the duration of the trial,

the dosage of vitamin C, and the outcome values, There is substantial variation in the common cold incidence in the control groups. Pitt and Costrini"^ observed 11 colds per person-year, whereas Dahlberg et al.''' observed only 0,4 colds per person-year, although both of these large trials examined military recruits. Pitt and Costrini'*" carried out a large-scale, randomized, double-blind, placebo-controlled trial with Marine recruits in a training camp in South Carolina in the wintertime. The participants were vaccinated against adenovirus and inlluenza. and they received penicillin or crythromycin as streptococcai prophylaxis. The study groups showed no difference in common cold incidence. Vitamin C caused a statistically significant, although clinically minor, reduction in common cold severity. Of the eight pneumonia cases observed, five were caused by pneumococcus but two of them had a coinfection with parainfluenza virus. The incidence of pneumonia was significantly tower in the vitamin C group.

MilitaiT Medicine, Vol. 169, November 2004

Vitamin C Supplementation and Respiratory Infections

922 TABLEn

VITAMIN C AND RESPIRATORY INFECTIONS IN STUDENTS ACCOMMODATED IN CLOSED QUARTERS AND IN MARATHON RUNNERS Treatment Trial"

Variable

Glazebrook and Thomson^^ United Kinfidom Boarding school 0,05-0.1 g/day 6 months

Subjects Subjects with the common cold Admitted to hospital Stay al hospital (mean, days) Streptococcal infections'' Admitted to hospital Stay at hospital (mean + SD. days) Pneumonia cases Rlieumatic fever cases Slay at hospital, all subjects (mean, days)

Ritzel'i^'' Switzerland Skiing camp 1 g/day 1 week

Subjects Subjects with the common cold Duration of colds (days) Constitulional symptoms'' Cases Days/group

Bessell-Lorck'^^ West Oeramny Skiiing camp 1 g/day I week

Subjects Subjects with the common rold

Peters et al.^'^ South Africa Marathon runners 0.5 g/day 2 weeks

Subjects Subjects with the common ro!d Duration of colds (mean ± SD, days)

Peters et al.^^ South Atrica Marathon runners 0.5 g/day 2 weeks

Subjects Subjects with the common cold Duration ot colds (mean, days)

Vitamin C

335 72

59 6.3 29 18 10,1 ± 7.0 0 0 2.5

Control

1.100 286 253 6.4 94 83 16.7 ± H.9 17 16 5.0

Diiference in Outcome (%)

p (onetailed)''

-17

0,047 0.017

-23

0 0 -29 -40 -100 -iOO -50

0.09 0.012 0.006 0.007

139 17 1.8

140 31 2.6

-45 -3t

0.015