The association between stress and episodes of symptom manifestation of genital herpes: a

systematic review of the literature

Eamann BreenThe Mortimer Market Centre

"No article that succeeds in being published isaccompanied by a guarantee of excellence"(Meltzoff).

“It is more important to know what kind of person has the disease than what kind of disease the person has”. (Hippocrates)

Background

Objectives

Search strategy

Selection criteria

Data collection and analysis

Main results

Limitations of review

Conclusions

Genital Herpes

Pathology

Burden of Disease

What is stress?

Definitions

Measurements of stress

Causes and triggers

Stress and the immune system

The effect of stress on the PNI system

Cause Increase in stress

Immunesystem/endocrinesystem Psychological wellbeing

Effect Virus reactivation

Aims and ObjectivesThe aim of this study is to investigate systematically the

hypothesis that there is a relationship between an increase in stress and recurrent genital herpes, specifically where stress

acts as a predictor for repeat episodes of the virus.

Whether there is an association between patient psychological stress and recurrent episodes of genital herpes?

How reliable are the existing studies?

Where is the potential for further research?

DefinitionA Systematic review “is a review of a clearly formulated

question that uses systematic and explicit methods to identify, select and critically appraise relevant research, and to collect and analyse data from studies that are included in

the review."

Why undertake a systematic review?

Research into what is perceived by patients as stressful and what leads to recurrence has already been undertaken.

Additional primary research was rejected with a view to review the work already available.

The purpose of this research is to identify information that may not be apparent from individual studies where the effects under investigation may be small, or where there are conflicting findings from different studies.

Sources of published and ongoing systematic reviews

Databases The Cochrane Database of Systematic Reviews (CDSR) Database of Abstracts of Reviews of Effectiveness(DARE) Health Technology Assessment (HTA) Database NHS Economic Evaluation Database NHSEED

Internet Sites TRIP - http://www.tripdatabase.com Health services/technology assessment text (HSTAT) -http://text.nim.nih.gov/ National Coordinating Centre for Health TechnologyAssessment - http://www.hta.nhsweb.nhs.uk/ NICE appraisals - http://nice.org.uk/nice-web/cat.asp?c=153

Research in progress National Research Register (NRR) - http://www.update-software.com/national/nrr-frame.html Adapted from (Glanville and Sowden 2001)

Guidelines for establishing causation

Temporal Relation Does cause precede the effect Plausibility Is the association consistent with other knowledge Consistency Have similar results been shown in other studies Strength What is the strength of the association Dose-responserelationship

Is variance associated with cause and effect

Reversibility Does removal of possible cause lead to reductionof disease risk

Study Design Is the evidence based on strong study design Judging the evidence How many lines of evidence lead to that

conclusionAdapted from (Beaglehole, Bonita et al. 1993)

Study Selection adapted from (Khan and Kleijnen 2001)

Review Question Is there a relationship between stress and recurrent genital herpes?

Selection Criteria Inclusion Criteria Exclusion Criteria Population Patients diagnosed with No proven diagnosis recurrent herpes Other conditions

Measures Specific measures of stress Other psychological conditions

Study Design Cohort studies Case/control studies Descriptive case studies

RCT's Reviews

Publication PubMed Not published in English Embase 1980 to present prior to 1980

Grading of Review Studies

Grade Level ofEvidence

Effectiveness Test Accuracy Efficiency

A 1 High qualityexperimentalstudies withoutheterogeneityand with preciseresults

High quality studies with ablind comparison of test toreference standard in anappropriate populationspectrum

High quality evaluations of importantalternative interventions comparing allrelevant outcomes against appropriatecost measurement, including a sensitivityanalysis

B 2/3 Low qualityexperimentalstudies, highqualitycontrolledobservationalstudies

Any one or two of thefollowing: Narrow population

spectrum Differential use of

reference standard Reference standard not

blind Case control study

Evaluations without relevant outcomesor without appropriate cost measurement

C 4 Low qualitycontrolledobservationalstudies, caseseries

Any three or more of theabove

Evaluations without sensible sensitivityanalysis

D 5 Expert opinion Expert opinion Expert opinionAdapted from (Sackett, Straus et al. 2000); (Khan and Kleijnen 2001)

Study Search

Adapted from (Khan and Kleijnen 2001)

Potentially relevant citations identified after liberal screening of theelectronic search (n=64)

Citations excluded with reasons (n= 32) after evaluation

Studies retrieved for more detailed evaluation (n=32)

Studies excluded (after evaluation of full text) from systematic reviewwith reasons (n=16)

Relevant studies included within systematic review (n=16)

Results

Included studies

Excluded studies

Prospective and retrospective studies

Study/Design Subjects Timescale Findings Grade Level of evidence

(Cassidy, Meadows et al. 1997) N = 116, m= 48, f =68 n/a No relationship B 3UK, Retrospective

(Swanson, Dibble etal. 1995) N = 70, m = 41%, F = 59% n/a supports relationship B 3US, Retrospective

(Swanson and Dibble 1993) N = 252, m = 59, f = 193 n/a supports relationship C 4US, Retrospective

(Brooks, Haywood et al. 1993) N = 90, 40 =m, 50 = f, n/a supports relationship B 3UK, Retrospective median age = 34,

range 19 - 60

(Keller, Jadack et al. 1991) N = 60, m =26, f =34, n/a No relationship C 4US, Retrospective mean age 31.7

(S.D =/- 8.1)

(Longo and Clum 1989) N = 46, m = 18, f = 28 n/a supports relationship B 3US, Retrospective

(VanderPlate and Kerrick 1985) N = 59, m =16, w = 43. n/a Contradictory relationship B 3US, Retrospective

(Silver, Auerbach et al. 1986) N = 67, m =32, f = 35, n/a supports relationship B 3US, Retrospective mean age = 33

range 20 - 65

(Bierman 1983) N = 375, m = 202, f = 173 n/a supports relationship C 4US, Retrospective

(Cohen, Kemeny et al. 1999) N = 58, all f, 6 months supports relationship B 3US, Prospective mean age = 31.8

(S.D +/- 5.8)

(Kemeny, Zegans et al. 1987) N = 36 f = 30, m = 6, 6 months No relationship B 3US, Prospective mean age 33.4,

(SD 9.5, range 18 -69)

(Rand, Hoon et al. 1990) N = 64, m = 13, f = 5, 6 months No relationship B 3US, Prospective mean age =27.9

(S.D +/- 5.7)

Intervention StudiesStudy Subjects Intervention Measures(VanderPlate and N = 4, all f Biofeedback, and 2 subjects given Electromyographic (EMG) biofeedback,Kerrick 1985)US Muscle relaxation treatment 2 subjects given progressive muscle relaxation treatment (PT)

Timescale6 monthsResultsBiofeedback resulted in a 72% and 7% decrease in recurrences,PT resulted in 66% and 100% reduction in recurrencesGradeBLevel of Evidence3

Longo, Clum etal. 1998) N = 31 not specified Psychosocial intervention, Profile of Mood States US social support, and Zung Depression Scale

waiting list control UCLA Loneliness Scale MHLC scales Hassles Scale and Contact Questionnaires.Timescale6 monthsResultsPerceived stress did not differ among treatment conditions Psychosocial interventions reduced the severity of recurrences GradeBLevel of Evidence3

Burnette, Koehn N = 8, all f Progressive muscle relaxation treatment Questionnaireset al. 1991)US Timescale

6 monthsResults5/8 participants reported a significant reduction in recurrence rate GradeBLevel of Evidence3

(Koehn, Burnette N = 4, all f Applied relaxation skills Daily diaryet al. 1993)US Pre and post treatment relaxation evaluations

Pre and post treatment relaxation application evaluationsTreatment satisfactionEMG measuresTimescale3 monthsResultsAll subjects reported post treatment reductions in herpes frequency. Statistically significant for 3/4 participantsGradeBLevel of Evidence3

Excluded Studies

Sixteen studies were excluded from the review. The excluded studies fit into four

categories

no specific measures of stress (Pederson and Stavraky 1987); (Hillard, Hillard et al.

1989); (Manne and Sandler 1984); (Luby and Klinge 1985); (Schofield, Minichiello

et al. 2000); (Jadack, Keller et al. 1991); (Stout and Bloom 1986)

case studies (Brown and Callen 1999); (Gould and Tissler 1984); (Lovejoy 1987)

secondary analysis (Dibble and Swanson 2000); (Kemeny, Cohen et al. 1989)

original scores not included (Derman 1986); (Guinan, MacCalman et al. 1981);

(Hoon, Hoon et al. 1991)

Gender

The majority of participants for all the studies were women with some studies made

up entirely of women.

No study indicated the sexual orientation of the participants.

Sample size

Sample size across all designs varied greatly, from N = 4 (VanderPlate and Kerrick

1985) to 375 (Bierman 1983).

The median range for the prospective and retrospective studies was between 60 - 70

participants.

Measures of stress

Measures of stress differed from study to study with some studies using a variety of

different and accepted methods.

Some used subjective methods.

Others used a combination of questionnaires and medical tests.

One study used CD4 and CD8 counts and one used lesion culture.

Health Behaviours

No record of health enhancing and impairing behaviours, such as diet, exercise,

alcohol and tobacco use, which can compromise or benefit health were indicated as

being measured in any of the studies.

Recruitment of participants

Patients were recruited from different sources ranging from GU clinic to newspaper

advertising or both.

Age

Age range where given also varied from 19 - 69 years.

Mean age varied where indicated but tended to be in the early 30’s

All of this indicates that in general the samples were not representative, but with the lack

of further information, we could assume that this was representative of the local

population diagnosed with genital herpes.

Principle Findings of the Review

The evidence suggests that there is a weak relationship between stress and recurrentgenital herpes.

Participants in the retrospective studies report that they experience increased stress priorto latent virus reactivation. However the results of the prospective studies do not supportthis conclusion, but one concludes that persistent stress can lead to reactivation.

The four intervention studies demonstrate that stress management training lead todecreased stress and recurrences and these studies represent the strongest evidence thatlinks stress and recurrent herpes.

A comparison of the studies was complicated by the differences in design and studiesthat included interventions and by the paucity of research in this field.

Limitations of the Review

This systematic review is based on work designed and completed by other researchers and the strengths and

weaknesses of these studies all have an impact on the findings of the review.

It is impossible to be certain that all available research has been discovered but in attempting to appraise and

offer a critical analysis of what has been available it could be said that this review has highlighted issues

mentioned by previous research in this field.

Inclusion of studies from the last twenty years only was intended to exclude the majority of

commentary/expert opinion type papers that existed up to this time.

The use of papers published in English only may again be another form of bias. Most studies were undertaken

in the US a resource rich country with ample resources for research and where HSV is considered to be a

major public health concern.

The following factors may have an impact on the results and the internal validity of the

primary studies;

History

History X Assignment

Maturation

Testing can have effects of its own.

Instrumentation/Raters.

Causation Table

Stress and recurrent Genital Herpes

Temporal Relation The cause does precede effect, but not alwaysPlausibility The association is consistent with other knowledgeConsistency Some consistencyStrength MediumDose-response relationship Relationship does existReversibility Difficult to be clear about reversibilityStudy Design Weak to medium study designJudging the evidence Limited evidence currently exists

Adapted from (Beaglehole, Bonita et al. 1993)

Model for further research

Information Required Information at

at Baseline 0,1,2,3,4,5,6 months

SexAgeSocial ClassMonths since diagnosisTreatment usedstress measures

CD4 countsCD8 countsNK countsFrequency of recurrenceStress measures/questionnaires

High frequency recurrers

Low frequency recurrers

Implications of research for practice

What advice are we providing?

What is the purpose of this advice?

Do we have to give ‘positive’advice?

Conclusions

The relationship between stress and recurrent genital

herpes is complicated.

The results of this systematic review suggest that there is

a relationship between stress and recurrent herpes

however the precise nature of this relationship needs to

explored further.

The relationship has not been established as a causal one.