CROSS-SECTIONAL STUDY OF RECURRENT HERPES LABIALIS

AMERICAN JOURNAL OF EPIDEMIOLOGY

Copyright © 1988 by The Johns Hopkins University School of Hygiene and Public HealthAll rights reserved

Vol. 127, No. 3Printed in U.S.A.

CROSS-SECTIONAL STUDY OF RECURRENT HERPES LABIALIS

PREVALENCE AND RISK FACTORS

THERESA B. YOUNG,1 ERIC B. RIMM,1 AND DONN J. D'ALESSIO5

Young, T. B. (Dept of Preventive Medicine, U. of Wisconsin-Madison, Madison,Wl 53705), E. B. Rimm, and D. J. D'Alessio. Cross-sectional study of recurrentherpes Iabiaiis: prevalence and risk factors. Am J Epfcfem/o/1988; 127:612-25.

Consecutive blood donors at 25 sites in southern Wisconsin were interviewedin 1985 to ascertain recurrent herpes Iabiaiis histories, other periorai conditions,and status on possible predisposing factors and correlates of lesion recurrence.The prevalence of recurrent herpes Iabiaiis was 32.9%. Of the cases, 51.3%reported at least two recurrences per year, 8.6% characterized their condition assevere, and 10% sought medical care. Relations were examined between recur-rent herpes Iabiaiis and family history of the disease, ethnicity, complexion, hairand eye color, other chronic periorai conditions, solar radiation, exposure todental procedures, and smoking. The risk of recurrent herpes Iabiaiis associatedwith disease in various first-degree family members, estimated by age-adjustedodds ratios (nominal 95% confidence intervals) were: mother, 3.30 (1.86-5.84);father, 3.80 (1.80-8.12); sister(s), 3.93 (2.25-6.89); and brothers), 6.81 (3.14-15.04). Ethnicity and phenotypes were not related to disease status. Cases hada higher prevalence of recurrent aphthous ulcers (odds ratio = 3.00, 95% confi-dence interval = 1.79-5.02) and reported more exposure to solar radiation andmore extensive dental histories.

dental care; herpes Iabiaiis; herpes simplex; serology; ulcer, aphthous; ultra-violet rays

It has been estimated (1, 2) that thelifetime prevalence of recurrent herpes Ia-biaiis is between 20 and 40 per cent andthat 100 million episodes of lesions, ranging

Received for publication August 18, 1986, and infinal form May 26, 1987.

1 University of Wisconsin, Department of Preven-tive Medicine, Madison, WI.

1 Harvard School of Public Health, Department ofEpidemiology, Boston, MA.

1 University of Wisconsin, Departments of Preven-tive Medicine and Medicine, Madison, WI.

Reprint requests to Dr. Theresa B. Young, Depart-ment of Preventive Medicine, University of Wiscon-sin-Madiaon, 504 Walnut St., Madison, WI 53705.

This work was supported by a grant from the Uni-versity of Wisconsin Graduate School.

The authors are grateful to Dr. Gary A. Becker,Donna Baltas, and the Badger Regional Red Crossstaff for their support and help. They also thank Dr.David Arch for help in developing data collectioninstruments, and Donald Nelson and Todd Mc-Pherson for laboratory analyses.

from mild to severe and disfiguring, occuryearly in the United States. The need formore research on several aspects of thedisease has been recognized (3-7), but, todate, only a limited number of epidemio-logic studies have been published. Althoughseveral factors have been assumed to berelated to lesion recurrences, few hypothe-sis-testing studies on adequate sampleshave been conducted and little is knownabout risk factors associated with preva-lence of the disease. The goals of the cross-sectional study presented here were to de-scribe the prevalence and selected aspectsof the natural history of recurrent herpesIabiaiis, to determine the role of familyhistory of the disease, ethnicity, complex-ion, and hair and eye phenotypes as predis-posing factors, and to investigate the rela-

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CROSS-SECTIONAL STUDY OF RECURRENT HERPES LABIALIS 613

tions of other perioral conditions, solar ra-diation, dental trauma, and smoking withthe disease.

Based on limited data, it appears thatrecurrent herpes labialis develops in lessthan 50 per cent of individuals who havehad a primary infection with herpes sim-plex virus (1, 4, 8). Primary infection withserotype 1 of herpes simplex virus, the typemost often associated with lip and orallesions, is considered to be common world-wide, with as much as 90 per cent of somepopulations showing seropositivity (9).While often mild or asymptomatic, primaryinfection can involve fever, pharyngitis,gingivitis, and malaise, and is followed bya residual titer of antibodies (4, 7). In new-borns or compromised hosts, potentiallyfatal disease can result (7).

The mechanism underlying the develop-ment of recurrent herpes labialis from theprimary infection is unknown, and the ini-tiating factors for recurrent episodes arepoorly understood. It is generally thoughtthat, following the primary infection, her-pes simplex virus resides in latent form inneural ganglia and that some activatingstimulus triggers intracellular migration ofthe virus to oral epithelium, resulting inone or more lesions (4). Clinical studies ofpatients have indicated that illness, nerveand oral tissue trauma due to dental pro-cedures, and dental decay are associatedwith viral shedding in the oral cavity (10,11).

Recent experiments (10, 12) have dem-onstrated that considerable viral sheddingoccurs without causing oral or labial le-sions. A modification of the "ganglion trig-ger" hypothesis that is compatible with thisclinical research is that local perturbationsprepare the labial skin for viral replicationand, in concert with viral shedding, resultin overt lesions (4). The "skin trigger" the-ory of Hill and Blyth (13) hypothesizes thefollowing chain of events: virus is regularlyproduced in the ganglion, is shed, andreaches epidermal cells every few days,where microfocal labial infections develop;then, as a result of some stimulus, changes

in the skin occur that allow the microfocito develop into overt lesions, either by stim-ulating viral replication or suppression ofdefenses. Hill and Blyth suggest that pros-taglandins, released as a result of manytypes of tissue damage, may be intermedi-ates in the causal scheme.

There is some experimental evidence tosupport an association between lesion re-currence and fever, ultraviolet radiation ex-posure, and nerve trauma (14-17), all ofwhich are conditions known to be corre-lated with prostaglandin release (13). It hasbeen assumed that psychological stress,menstruation, and sun exposure are relatedto recurrences, but the limited researchthat has been conducted has not substan-tiated these hypotheses (18-20).

MATERIALS AND METHODS

A cross-sectional study design was used.The source of the study sample was a setof 25 Red Cross blood donation sites, cov-ering a nine-county area in southern Wis-consin, which represented blood drives overa 10-week period. Three project nurses werestationed at each donation center to enlistand interview individuals immediately aftertheir blood donation. After an interviewwas completed, the next available donorwas approached. Of 452 donors asked toparticipate, 446 (98.7 per cent) agreed to a20-minute interview and serologic analysesof a previously-drawn blood sample.

We used a structured interview schedule,to collect information on recurrent herpeslabialis history (referred to as "cold soresor fever busters"), history of the diseaseamong other family members, other peri-oral conditions, sun exposures, history ofdental work, complexion, occupation,smoking, sociodemographics, and other fac-tors. Prior to questions on recurrent herpeslabialis and other perioral conditions, par-ticipants were read descriptions of the dis-ease, aphthous ulcers (termed "cankersores"), and chapped lips, and were shownphotographs of both mild and severe le-sions. Participants who affirmed that theyhad ever had a cold sore or fever blister


614 YOUNG ET AL.

were asked about their most recent experi-ence and about the period of time whentheir experience was most severe. Theseparticipants were asked to indicate themost commonly affected area on a diagramand to characterize the prodromes, symp-toms, duration, severity, frequency, and du-ration of lesions, whether medical care wassought, and what treatment, if any, wasever used.

Serum samples from the blood donationprocedure were collected for each study par-ticipant and stored at a temperature of -28C. For this report, tests for herpes simplexcomplement-fixing antibody were done pri-marily to verify self-reported positive re-current herpes labialis histories. Sera fromall subjects with histories of two or moreoccasions of labial herpes lesions weretested (n = 159). Negative histories couldnot be validated by serology, since subjectswith true negative histories would be sero-positive if they previously had a primaryherpes simplex infection. As part of anotherstudy, however, a random subsample ofslightly more than half of the history-neg-ative controls (n = 147) were tested for thepresence of herpes simplex antibodies. Se-rology was done by the Virus Section, Wis-consin State Laboratory of Hygiene, usingCasey's micro adaptation of the LaboratoryBranch Complement Fixation method (21).The herpes simplex complement fixation(group) antigen was obtained from FlowLaboratories, McLean, VA.

Recurrent herpes labialis was defined ashaving a history of more than one cold soreand having a herpes simplex virus antibodytiter >8. Persons who met these criteriawere considered cases (n = 139). The con-trol group {n = 283) comprised persons whoreported that they had never had a coldsore. From this group of controls, the sub-sample of 147 controls on whom serologicresults were available could be classifiedfurther into two subgroups: herpes simplexvirus antibody-positive (n = 69) and herpessimplex virus antibody-negative (n = 78).Persons who reported a herpes labialis his-tory of one lesion only (n = 4) or a history

of recurrent lesions, but with herpes sim-plex virus antibody titers <8 (n = 20) didnot fit the definition for either case orcontrol and were excluded from analyses.

Associations between recurrent herpeslabialis and potential risk factors or co-variates were estimated by age-adjustedodds ratios. Subjects without the opportu-nity for a particular exposure were excludedfrom the corresponding analysis. Subjectswith no sisters, for example, were excludedfrom determination of the odds ratios forhaving a sister with the disease. One sub-ject, aged 17 years, was excluded from anal-yses of "adult" exposures (age 18 years andolder). Explanatory models of recurrentherpes labialis and herpes labialis recur-rence rate were constructed with a forwardstepwise logistic regression procedure. Allstatistical analyses were performed usingBMDP computer programs (22). Nominalp values and 95 per cent confidence inter-vals are presented without adjustment formultiple comparisons.

RESULTS

Descriptive features

The prevalence of recurrent herpes labi-alis was 32.9 per cent. Of the cases, 48.6 percent reported a recurrence rate of once ayear or less, 35.1 per cent had a rate of 2-3recurrences/year, and 16.2 per cent had arate of four or more recurrences/year.Based on a severity scale for lesion discom-fort and appearance, 9.4 per cent reportedthat they were "not bothered" by the le-sions, 48.9 per cent were "mildly bothered,"33.1 per cent were "moderately bothered,"and 8.6 per cent were "greatly bothered."

A recurrence within the six-month periodprevious to the interview was reported by52.7 per cent of the cases; 11.6 per cent hadbeen free of recurrences for five years ormore. For 52 per cent of the cases, recur-rences began at age 10 years or younger;only 8 per cent were over age 18 years atdisease onset. Current lesion recurrencerate was not significantly related to currentage. Cases who were 10 years of age or less



at onset tended to report less frequent re-currence rates, but the trend was not sta-tistically significant. The average durationof the most recent disease episode and ofthe worst episodes were 7.3 and 7.6 days,respectively. Ten per cent of the casessought medical care specifically for recur-rent herpes labialis, and 84.9 per centattempted one or more forms of hometreatment.

There were surprisingly few self-reportedcorrelates of lesion occurrence. Partici-pants were read a list of 14 factors with anopen-ended "other" category and asked ifany of the listed factors or any other factorsseemed to be related to recurrences. Psy-chologic stress and wind were mentionedby 6.5 per cent, sun exposure by 4.3 percent, licking or peeling lips by 3.6 jjer cent,illness by 2.9 per cent, and fever by 2.2 percent. Other individual factors were indi-cated by less than 2 per cent.

A description of the sample of cases andcontrols is given in table 1. The distribu-tions according to sex, urban character ofbirthplace, number of siblings, marital sta-tus, number of children, and education weresimilar for the cases and the controls. Al-though the majority of both cases and con-trols were between 26 and 50 years of age,there was a higher proportion of cases overage 50 years (p = 0.01). A lower proportionof cases reported that they were former orcurrent smokers. Among the subset of con-trols tested for herpes simplex virus anti-bodies, 69 (46.9 per cent) had titers indic-ative of having had a primary infection.The mean antibody titer of cases was notsignificantly higher than the mean titer ofthe subsample of seropositive controls.

Family herpes labialis history

Cases were more likely to have a first-degree relative in their childhood householdwith recurrent herpes labialis. As shown intable 2, nominally significant odds ratios of3.30 or greater were found for persons whohad either a sibling or parent with historyof the disease. The odds ratio for having achild with the disease was of similar mag-

nitude; the odds ratio for a spouse withrecurrent herpes labialis was lower. Sinceprimary infection with serotype 1 of herpessimplex virus can be acquired from closecontact with infected family members, anassociation between disease status andfamily history was not surprising. However,under this rationale, seropositive controlsshould also tend to have childhood familymembers with the disease. As shown intable 3, the herpes simplex virus antibody-positive controls were no more likely thancontrols without herpes simplex virusantibodies to have first-degree familymembers with recurrent herpes labialis.Antibody-positive controls, however, weremore likely to have a spouse and otherfamily members in their adult householdwith history of recurrent herpes labialis.

Ethnicity and phenotypes

Due to the lack of racial heterogeneity inthe sampling frame, the sample was com-prised solely of whites. No differences werefound between cases and controls by eth-nicity, measured by grandparents' nation-ality, and by primary heritage identity.Skin type (four categories of dry to oily),tendency to get freckles, complexion (sixcategories of skin coloration), eye color, andnatural hair color were not related to dis-ease status. Compared with controls, casestended to rate their unprotected skin asless vulnerable to sunburn; 53 per cent ofcases and 47 per cent of controls stated thatthey tanned readily.

Other chronic perioral conditions

Odds ratios which estimate recurrentherpes labialis risk associated with otherchronic perioral conditions are shown intable 4. The case group had a higher prev-alence of aphthous ulcers (odds ratio =3.00), but did not differ from controls onindicators of the prevalence of severechapped lips (defined as "chapped lips withcracking and bleeding"), or chronicchapped lips (persistence of chapped lipsover two or more seasons).


616 YOUNG ET AL.

TABLE 1

Description of cross-sectional sample of blood donors selected for study of recurrent herpes labialis,southern Wisconsin, 1985

Variable

SexMaleFemale

Age group (years)17-2526-3536-50>50

Place of birth*CityTown or villageFarm

No. of siblings01

Highest educational attainmentfHigh school or lessCollegeProfessional degree

Married

No. of children01-3£ 4

Tobacco useCurrent smokerEver regular smoker

Herpes simplex virus antibody titerMeanSD*Geometric mean

No. of recurrent herpeslabialis cases

(n = 139)

No.

6970

15365236

722635

516

118

5770

9

110

307930

1846

%

49.650.4

10.825.937.425.9

54.119.526.3

3.617.779.2

41.951.5

6.6

79.1

21.756.521.7

13.233.8

53.3036.2854.61

No(

No.

137146

5487

10042

1494980

950

224

104147

30

197

9114745

47107

. of controlsn-283)

%

48.451.6

19.130.735.314.8

53.617.628.8

3.611.584.9

37.052.310.7

69.6

32.351.816.2

16.838.2

27.10§53.0941.14

Chi-square

0.06

10.95

0.38

2.69

2.20

3.80

5.69

0.700.88

p value

0.81

0.01

0.83

0.26

0.33

0.05

0.06

0.400.35

* Place type unknown for six cases and five controls.t Three cases and two controls were still enrolled in high school.t SD, standard deviation.§ Based on subsample of 147 controls (69 seropositives and 78 seronegatives).

Ultraviolet radiation exposure

Participants were asked to estimate theamount of time spent outdoors (summer,winter) during childhood and as an adult,

and to describe all jobs that entailed out-door work. They were also asked if theyhad ever had a severe sunburn on their facethat caused blisters and lesions, and if theyhad ever used a sunlamp. Participants were



TABLE 2

Comparison of recurrent herpes labiaiis cases and controls on family history of the disease: cross-sectionalsample of blood donors, southern Wisconsin, 1985

Variable % Cases % Controls Oddsratio*

95%confidence

interval

History of recurrent herpes labiaiis among family members in childhood household

All household members (ra •» 139)All negative 44.5a l positive 55.5

Mother (n = 139)Negative 72.3Positive 27.7

Father (n = 139)Negative 83.2Positive 16.8

Sister(s) (n = 117)All negative 63.2a l positive 36.8

Brother(s) (n = 112)All negative 73.2£1 positive 26.8

(n=283)76.623.4

(n = 283)89.610.4

(n = 283)95.05.0

(n - 216)86.613.4

(ra = 233)95.3

4.7

4.16

3.30

3.80

3.93

6.81

2.56-6.67

1.86-5.84

1.80-8.12

2.26-6.89

3.14-15.04

History of recurrent herpes labiaiis among family members in adult household

All household members (n = 139)All negative 69.4>l positive 40.6

Spouse (n = 110)Negative 66.4Positive 33.6

Child(ren) (n = 109)All negative 73.4£ l positive 26.6

(n = 283)77.023.0

(n = 197)77.722.3

(n = 192)88.012.0

2.28

1.98

3.00

1.43-3.57

1.17-3.36

1.60-5.64

* Adjusted for age.

shown photographs of males and femaleswith three grades of suntan and asked torate the degree of suntan they usually de-veloped during childhood (up to age 18years) and as an adult (age 18 years topresent). As shown in table 5, the casesappeared to have more exposure to solarradiation than the controls. Odds ratios,adjusted for age, showed a risk to be asso-ciated with having history of one or moresevere sunburns on the face, sunlamp use,getting deep suntans, and having an out-

door job during childhood. Cases did notdiffer from controls on estimates of theamount of outdoor recreational time, orhaving outdoor jobs as an adult.

Dental history

Dental history variables are presented intable 6. Participants were asked about thenumber of teeth they had with restorationsand crowns, the number of teeth extracted,any root canal procedures, and the type ofdental appliances they had, if any. They


618 YOUNG ET AL.

TABLE 3

Comparison of seropositive controls with seronegative controls on family history of recurrent herpes labialis:cross-sectional sample of blood donors, southern Wisconsin, 1985

Variable % Seropositivecontrols

% Seronegativecontrols

Oddsratio*

95%confidence

interval

History of recurrent herpes labialis among family members in childhood household

All household members (n = 69)All negative 73.5£1 positive 26.5

Mother (n = 69)Negative 85.3Positive 14.7

Father (n = 69)Negative 96.6Positive 4.4

Sister(s) (n = 53)All negative 88.72:1 positive 11.3

Brother(s) (n •= 57)All negative 96.5£1 positive 3.6

(n - 78)69.330.7

(n = 78)86.713.3

(n - 78)92.08.0

(n = 60)81.718.3

(n = 64)93.7

3.3

0.81

1.12

0.53

0.56

1.10

0.37-1.78

0.40-3.17

0.10-2.53

0.17-1.78

0.11-11.38

History of recurrent herpes labialis among family members in adult household

All household members (n = 69)All negative 66.2£1 positive 33.8

Spouse (ra = 48)Negative 67.0Positive 33.0

Child(ren) (n - 47)All negative 89.4£1 positive 10.6

(n = 78)83.416.6

(n = 54)88.911.1

(n = 53)90.69.4

2.56

2.28

1.16

1.10-5.88

0.79-6.87

0.28-4.89

* Adjusted for age.

were also asked to estimate the number oftimes they had dental work done underlocal anesthetic during the two age periods(childhood, adult). Based on all variablesexamined, cases appear to have had moreextensive dental work and were subjectedto more local anesthetic than were the con-trols. Elevated odds ratios, adjusted for age,were found for local anesthetic exposureduring childhood and having one or moreteeth with crowns.

Multivariate models

A stepwise logistic regression program,BMDP-LR (22), was used to construct anexplanatory model, with case status as thedependent variable. Variables for childhoodsolar radiation, dental history, recurrentaphthous ulcers, and family history of thedisease were submitted for consideration asindependent variables, and age was in-cluded as a control variable. The best-



TABLE 4

Association of recurrent herpes labialis with other chronic perioral conditions: cross-sectional sample of blooddonors, southern Wisconsin, 1985

Variable% Cases

(n •= 139)% Controls(n-283)

Oddsratio*

95%confidence

interval

History of aphthous ulcersNegativePositive

Chronic chapped lipsDuring childhood

NoYes

As an adultNoYes

Severe chapped lipsDuring childhood

NoYes

As an adultNoYes

* Adjusted for age.

15.884.2

91.28.8

90.99.1

51.848.2

69.830.2

36.064.0

93.46.6

88.211.8

55.844.2

68.631.4

3.00

1.39

0.72

1.14

0.94

1.79-5.02

0.61-3.15

0.33-1.57

0.75-1.75

0.59-1.50

TABLB 5

Association of recurrent herpes labialis with exposure to solar or ultraviolet radiation: cross-sectional sample ofblood donors, southern Wisconsin, 1985

Variable% Cases

(n - 139)% Controls(n -283)

Oddsratio*

96%confidence

interval

Severe facial sunburnOnce or lessMore than once

Degree of tanDuring childhood

LightDark

As adultLightDark

Sun lamp useNeverEver

Outdoor jobDuring childhood

NoYes

As adultNoYes

* Adjusted for age.

84.815.2

61.738.3

69.530.5

89.110.9

44.655.4

62.237.8

91.18.9

71.328.7

78.921.1

93.36.7

57.642.4

64.235.8

1.67

1.61

1.72

2.02

1.77

1.03

0.89-3.19

1.03-2.53

1.06-2.81

0.94-4.27

1.14-2.70

0.67-1.60


620 YOUNG ET AL.

TABLE 6

Assocation of recurrent herpes labialis with dental history: cross-sectional sample of blood donors,southern Wisconsin, 1985

Variable % Cases(n - 139)

32.467.6

53.746.3

55.644.4

37.862.2

83.017.0

57.442.6

72.127.9

82.417.6

% Controls(n = 283)

44.955.1

63.236.8

59.440.6

50.749.3

91.28.8

70.929.1

76.723.3

90.79.3

Oddsratio*

1.70

1.25

1.12

1.49

1.59

1.66

1.36

1.73

95%confidence

interval

Local anestheticDuring childhood

0-3 times£4 times

As adult0-6 timesa 7 times

Any extractionsDuring childhood

NoYes

As adultNoYes

No. of teeth with restorations<202:20

Any teeth with crownsNoYes

Had root canalNoYes

Any dental applianceNoYes

1.08-2.67

0.79-1.98

0.73-1.73

0.95-2.33

0.83-3.05

1.07-2.60

0.50-3.85

0.92-3.26

* Adjusted for age.

fitting model is presented in table 7. Recur-rent herpes labialis history of childhoodfamily members (parents and/or siblings)was the most significant correlate of thedisease, followed by history of aphthousulcers, tendency for dark suntans as a child,occurrence of more than one severe facialsunburn, and childhood exposure to localanesthesia for dental procedures on four ormore occasions. There was no evidence ofinteractive effects of dental and sun expo-sure variables. Based on three goodness offit tests, the data are adequately describedby this model.

Correlates of lesion recurrence rate werealso examined by multivariate modeling.

Recurrence rate, based on lesion frequencyover the previous five years, was trichotom-ized into no disease (controls), low-rate dis-ease (one recurrence or less per year) andhigh-rate disease (two or more recurrencesper year) and modeled as a function ofvariables that were potential triggers ordeterminants of lesion recurrence. All vari-ables for adult sun and dental exposures,family history of the disease, recurrentaphthous ulcer history, smoking, and agewere submitted for possible inclusion in themodel. The resulting odds ratios for highand low recurrence rates are given in table8. Relative risks for parents/siblings withrecurrent herpes labialis, history of



TABLE 7

Explanatory model of recurrent herpes labialis: cross-sectional sample of blood donors, southern Wisconsin, 1985

VariableOddsratio

95%confidence

interval

Parents/siblings with disease (yes vs. no)

History of recurrent aphthous ulcers (yes VB. no)

Usual suntan as child (dark vs. light)

Severefacial sunburns (£2 vs. <2)

Dental local anesthesia as child (2:4 vs. <4)

Age group (years)>50 vs. <2636-50 vs. <2626-35 vs. <26

0.932

0.501

0.313

0.493

0.208

1.2000.009

-0.308

2.54

1.65

1.37

1.64

1.23

3.381.010.73

1.93-3.33

1.22-2.24

1.05-1.78

1.11-2.41

0.95-1.59

2.13-5.160.64-1.500.43-1.25

Goodness of fit chi-square (2 • log-likelihood ratio) = 122.49, df = 118, p - 0.370.

. TABLE 8

Explanatory models of herpes labialis recurrence rate*: cross-sectional sample of blood donors,southern Wisconsin, 1985

Variable

Parents/siblings with disease(yes vs. no)

Children with disease(yes vs. no)

History of aphthous ulcers(yes vs. no)

Usual suntan as adult(dark vs. light)

Severe facial sunburns(2:2 vs. <2)

Dental local anesthesia as adult(2:7 vs. <7 times)

Age group (years)>50 vs. <2636-50 vs. <2626-35 vs. <26

/S

0.701

0.451

0.457

0.141

0.338

0.132

1.080-0.168-0.186

Low-rate modelt

Oddsratio

2.02

1.57

1.58

1.15

1.40

1.14

2.940.8460.830

96%confidence

interval

1.46-2.79

1.10-2.24

1.11-2.25

0.80-1.66

0.91-2.16

0.85-1.56

1.66-3.940.52-1.380.48-1.42

0.879

0.357

0.737

0.524

0.436

0.337

0.8310.151

-0.120

High-rate

Oddaratio

2.41

1.43

2.09

1.69

1.55

1.40

2.301.160.89

modelt

95%confidence

interval

1.71-3.39

0.96-2.13

1.34-3.25

1.19-2.40

0.97-2.50

1.01-1.95

1.17-4.490.70-1.650.51-1.55

* High rate: 2:2 recurrences per year; low rate: £1 recurrence per year.t Goodness of fit chi-square (2 * log-likelihood ratio) = 139, degrees of freedom (df) = 133, p = 0.336.X Goodness of fit chi-square (2 * log-likelihood ratio) = 131, df = 134, p = 0.540.


622 YOUNG ET AL.

aphthous ulcers, and adult exposure to den-tal local anesthetic exposure and dark sun-tans were stronger for high-rate disease.Other variables showed little or no indica-tion of trend.

Disease severity, based on self-rated dis-comfort and appearance, was not related tofamily history of the disease, aphthous ul-cers, dental history, or sun exposure. Therewas, however, a strong relation (p = 0.01)between sex and severity; over 54 per centof female cases and 30 per cent of malecases reported their lesions as "severe" or"very severe."

Comparisons were made between thecontrol subgroups (herpes antibody-positive and antibody-negative) to deter-mine if the correlates identified in thisstudy were associated primarily with herpessimplex virus infection, rather than specif-ically with recurrent herpes labialis. Con-trols with evidence of seropositivity did notdiffer from antibody-negative controls withrespect to any of the risk factors, with theexception of having a member of their adulthousehold with the disease (table 3).

DISCUSSION

The prevalence of recurrent herpes labi-alis (32.9 per cent) in this sample of 446blood donors is similar to previously re-ported rates of 31.5-38.2 per cent for gen-eral population samples (8,19, 23). Severityratings, recurrence rates, and lesion dura-tion were also similar to findings frominvestigations of the natural history ofrecurrent herpes labialis (2, 8, 9). It is note-worthy that 3 per cent of our total studysample, representing a cross-section of thehealthy, general population, experience"very severe" recurrent herpes labialis(highest rank on a scale of 0-4) and havesought medical care for the disease. Basedon this finding and the finding that over 5per cent of the total sample experience fouror more recurrences per year, this diseaserepresents significant morbidity.

The major rinding of this study is that,relative to controls, cases were more likelyto have first-degree relatives with histories

of the disease. Controls with serologic evi-dence of having had a primary herpes sim-plex virus infection were no more likelythan seronegative controls to have first-degree relatives with the disease. Theseresults suggest that the nature of the pri-mary herpes simplex virus infection may bedifferent for those who develop recurrentdisease compared with the majority of per-sons who never experience a recurrencefollowing the primary infection.

These data are compatible with the pos-sibility that genetic factors influence thehost reaction to primary infection (recur-rent vs. nonrecurrent). We know of oneother study (24) which has reported a fa-milial association for the disease. Based ona sample of 38 matched pairs of cases andcontrols, Schmidt et al. (24) found 74 percent and 14 per cent of cases and controls,respectively, had one or more first-degreerelatives with history of the disease (p <0.001). Preliminary studies of human lym-phocyte antigen (HLA) typing suggest ge-netic segregation of recurrent herpes labi-alis cases, but specific haplotypes have notbeen identified consistently (25).

Alternatively, there may be strain differ-ences among herpes simplex viruses thatdetermine whether recurrent disease willoccur or not. Under this explanation, par-ents, siblings, or any persons within thesame household with the recurrent type ofherpes simplex virus would increase thelikelihood of other household membersbeing infected with the "recurrent" strain.

It is possible that the observed relationsfor family history are a result of selectiverecall among cases. Although all subjectsstated that they were familiar with the de-scription of cold sores or fever blisters, it ispossible that family history of the diseasewas more memorable for persons with thedisease. Due to the magnitude of the oddsratios for the family histories, it would takesubstantial systematic misclassification tospuriously produce the relations. As nofamily histories were verified, however, thedegree of bias present cannot be estimated.

An age-adjusted odds ratio of 3.00 (p <



0.01) was found for recurrent herpes labi-alis and recurrent aphthous ulcers. In themultivariate models of recurrence rates,aphthous ulcers were associated with boththe low and high-rate disease, but theodds ratio was slightly higher for high-ratedisease. A correlation between the two re-current diseases has been clinically well-established in studies based on examina-tions, rather than self-report (19, 26). Al-though the etiology of recurrent aphthousulcers is unknown, the lesions are notthought to be caused by herpes simplexvirus (8) and the association between thetwo recurrent conditions remains unex-plained. It is possible that recurrentaphthous ulcers cause oral tissue traumathat in turn facilitates some step in thecausal chain of events leading to herpesrecurrence.

Cases were not more likely than controlsto have chronic or severe chapped lips.These conditions represent significant tis-sue trauma and thus were potential riskfactors that would be compatible with the"skin trigger" hypothesis. The lack of as-sociation with chapped lips, however, indi-cates that cases do not selectively recallmore perioral conditions and it strengthensthe belief that the association betweenrecurrent herpes labialis and recurrentaphthous ulcers is not due to recall bias.

Elevated odds ratios were found for anumber of indicators of solar radiation anddental procedures. Overall, cases tended toaccumulate more solar radiation and ex-posure to dental procedures compared withcontrols. Due to the early age of diseaseonset for the majority of cases, the "child-hood" and "adult" sun and dental variablescan be considered only as crude indicatorsof the relevant exposures. If these variablesare surrogates for exposures which occurprevious to onset, the associations could betaken as support for a role of nerve or othertissue trauma in initiating the disease. Incomparing these variables in multivariatemodels of low- and high-rate recurrence,however, it appears that the sun and dentalexposures are primarily related to high-rate

disease. This result indicates that exposureto solar radiation and dental trauma ismore likely to be relevant to triggering ofrecurrences, rather than the initiation ofrecurrent lesions following the primary in-fection.

A strong dose-response relation betweenthe variables for oral and labial trauma(aphthous ulcers, and sun and dental ex-posures) and recurrence rates or severitywould support the "skin trigger" hypothesisof lesion recurrence. It is likely that, due tothe small magnitudes of risks, these vari-ables, based on retrospective data, areinadequate for the purpose of investiga-tion of the role of acute events in lesionrecurrence.

Alternatively, the sun and dental vari-ables used may be crude indicators ofchronically abnormal oral mucosa and la-bial skin which indirectly relate to recur-rence. Labial skin lacks the pigment todevelop a protective tan and, in responseto solar radiation, burns more easily thanother skin (27). Changes that result fromsun exposure include loss of elastic fiber,atrophy of fat, and glandular elements,actinic cheilitis and hyperkeratosis (27).Thus, persons who developed deep suntansfrom childhood on are likely to have hadthe most solar exposure and to have thesechronic labial skin conditions. More exten-sive dental histories may reflect cariousteeth that represent irritation to the oralcavity or overall poor oral health. The labialskin with actinic damage and/or the oralmilieu, under conditions of dental decay,may chronically favor activity of virus thathas been released in response to otherstimuli.

Although the magnitudes of differencesbetween cases and controls on the sun anddental variables are not large, the differ-ences are consistent across various mea-sures and over the two age periods consid-ered. Based on comparisons with thesubgroup of seropositive controls, these fac-tors appear to specifically relate to the re-current disease and are not related merelyto herpes simplex virus seropositivity. The


624 YOUNG ET AL.

findings do support the theory that sunexposure and oral trauma play a role inlesion recurrence, but shed little light onthe mechanisms involved.

In the past, recurrent herpes labialis gen-erated little public health concern. Vir-tually no attention was given to preventionand no treatment was available. Within thelast 20 years, a number of factors havestimulated research interest in recurrentherpetic diseases. The dramatic increase inthe incidence of herpes genitalis has hadan impact on the formerly benign status ofrecurrent herpes labialis (28). Althoughgenital herpes is usually caused by herpessimplex virus type 2, there is evidence thatboth serotypes 1 and 2 can infect either oralor genital areas, and can be transmittedfrom either site to the other by oral-genitalcontact (1). As a public health problem,herpes genitalis has had widespread mediacoverage and the general population hasbeen made aware of preventive measures toavoid the inter- and intra-personal spreadof virus from lip lesions as well as fromgenital lesions. By association with genitalherpes, recurrent herpes labialis has be-come a more significant chronic diseasewith some degree of social stigma.

Recent clinical research on the diseasehas been stimulated by the prospect ofeffective therapy for herpetic diseases.Investigators have stressed the need to un-derstand underlying mechanisms of herpeslabialis recurrence in order for antiviraltherapy to be useful. The results of ourstudy suggest that at least 3-5 per cent ofthe healthy, general population would ben-efit from treatment for their severe recur-rent disease. More extensive descriptiveand etiologic studies of recurrent herpeslabialis, to identify persons at risk and cor-relates of lesion recurrences and to assessperceived treatment needs and expectedbenefits, would be of great value in thedevelopment of a therapeutic plan.

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CROSS-SECTIONAL STUDY OF RECURRENT HERPES LABIALIS