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The association between stress and episodes of symptom

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					 The association between stress and episodes
of symptom manifestation of genital herpes: a
     systematic review of the literature




                  Eamann Breen
            The Mortimer Market Centre
"No article that succeeds in being published is
accompanied 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          Immune               Effect
Increase in   system/endocrine      Virus reactivation
stress        system
               Psychological well
              being
                    Aims and Objectives
  The 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?
                           Definition
  A 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 Technology
Assessment - 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-response           Is variance associated with cause and effect
relationship
Reversibility           Does removal of possible cause lead to reduction
                        of disease risk
Study Design            Is the evidence based on strong study design
Judging the evidence    How many lines of evidence lead to that
                        conclusion
Adapted 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 of    Effectiveness      Test Accuracy                     Efficiency
            Evidence
    A       1           High quality       High quality studies with a       High quality evaluations of important
                        experimental       blind comparison of test to       alternative interventions comparing all
                        studies without    reference standard in an          relevant outcomes against appropriate
                        heterogeneity      appropriate population            cost measurement, including a sensitivity
                        and with precise   spectrum                          analysis
                        results
    B       2/3         Low quality        Any one or two of the             Evaluations without relevant outcomes
                        experimental       following:                        or without appropriate cost measurement
                        studies, high       Narrow             population
                        quality                 spectrum
                        controlled          Differential       use     of
                        observational           reference standard
                        studies             Reference standard not
                                                blind
                                            Case control study
    C       4          Low quality         Any three or more of the      Evaluations without sensible sensitivity
                       controlled          above                         analysis
                       observational
                       studies, case
                       series
    D      5           Expert opinion      Expert opinion                Expert opinion
      Adapted from (Sackett, Straus et al. 2000); (Khan and Kleijnen 2001)
Study Search
                 Potentially relevant citations identified after liberal screening of the
                                        electronic 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 review
                          with reasons (n=16)




                     Relevant studies included within systematic review (n=16)



Adapted from (Khan and Kleijnen 2001)
    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       3
UK, Retrospective

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

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

(Brooks, Haywood et al. 1993)           N = 90, 40 =m, 50 = f,      n/a         supports relationship        B       3
UK, Retrospective                       median age = 34,
                                        range 19 - 60

(Keller, Jadack et al. 1991)            N = 60, m =26, f =34,       n/a         No relationship              C       4
US, Retrospective                       mean age 31.7
                                        (S.D =/- 8.1)

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

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

(Silver, Auerbach et al. 1986)          N = 67, m =32, f = 35,      n/a         supports relationship        B       3
US, Retrospective                       mean age = 33
                                        range 20 - 65

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

(Cohen, Kemeny et al. 1999)             N = 58, all f,              6 months    supports relationship        B       3
US, 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       3
US, 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       3
US, Prospective                         mean age =27.9
                                        (S.D +/- 5.7)
Intervention Studies
Study                  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)
                                                                                        Timescale
                                                                                        6 months
                                                                                        Results
                                                                                        Biofeedback resulted in a 72% and 7% decrease in recurrences,
                                                                                        PT resulted in 66% and 100% reduction in recurrences
                                                                                        Grade
                                                                                        B
                                                                                        Level of Evidence
                                                                                        3

Longo, Clum et
al. 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.
                                                                                        Timescale
                                                                                        6 months
                                                                                        Results
                                                                                        Perceived stress did not differ among treatment conditions
                                                                                        Psychosocial interventions reduced the severity of recurrences
                                                                                        Grade
                                                                                        B
                                                                                        Level of Evidence
                                                                                        3

Burnette, Koehn        N = 8, all f           Progressive muscle relaxation treatment   Questionnaires
et al. 1991)
US                                                                                      Timescale
                                                                                        6 months
                                                                                        Results
                                                                                        5/8 participants reported a significant reduction in recurrence rate
                                                                                        Grade
                                                                                        B
                                                                                        Level of Evidence
                                                                                        3

(Koehn, Burnette       N = 4, all f           Applied relaxation skills                 Daily diary
et al. 1993)
US                                                                                      Pre and post treatment relaxation evaluations
                                                                                        Pre and post treatment relaxation application evaluations
                                                                                        Treatment satisfaction
                                                                                        EMG measures
                                                                                        Timescale
                                                                                        3 months
                                                                                        Results
                                                                                        All subjects reported post treatment reductions in herpes frequency.
                                                                                        Statistically significant for 3/4 participants
                                                                                        Grade
                                                                                        B
                                                                                        Level of Evidence
                                                                                        3
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 recurrent
  genital herpes.

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

 The four intervention studies demonstrate that stress management training lead to
  decreased stress and recurrences and these studies represent the strongest evidence that
  links stress and recurrent herpes.

 A comparison of the studies was complicated by the differences in design and studies
  that 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 always
Plausibility                 The association is consistent with other knowledge
Consistency                  Some consistency
Strength                     Medium
Dose-response relationship   Relationship does exist
Reversibility                Difficult to be clear about reversibility
Study Design                 Weak to medium study design
Judging 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



Sex                      CD4 counts                High frequency recurrers
Age                      CD8 counts
Social Class             NK counts                 Low frequency recurrers
Months since diagnosis   Frequency of recurrence
Treatment used           Stress measures/
stress measures          questionnaires
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.

				
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