JAGS 38:1188-1194, 1990
Are Stressful Life Events Risk Factors for Herpes Zoster? A
Kenneth Schmader, MD,*t Stephanie Studenski, MD, MPH,*t Julia MacMillan, MPH,* Seymour Gruferman, MD, DrPH,* and Harvey J. Cohen, MD*t .007), or 6 months before (35 versus 16, odds ratio 2.00, To determine if psychologically stressful life events are risk factors for herpes zoster, we conducted a case-control 95% CZ 1.04, 3.93, P = .012). The mean number of total life events was significantly higher in cases at 6 months study of zoster and self-reported recent negative fife before zoster (case f = 2.64, control f = 1.82, P = .008), events and major changes in spousal relationships. The but there were no signficant differences at 2, 3, or 12 subjects were 101 healthy community-dwelling cases of months before. There were no significant differences bezoster and 101 healthy controls matched for age, sex, and tween case subjects and control subjects for spousal race and generated by random digit dialing. The Geriatric events, or any given single life event. In conclusion, we Scale of Recent Life Events was administered to case and found that whereas patients with herpes zoster expericontrol subjects, and additional questions were asked reenced the same kinds of life events in the year preceding garding the perception of the life event. The results showed that case subjects experienced negative life events the illness as did control subjects, recent events perceived as stressful were significantly more common among pasignificantly more often than subjects in the control tients with zoster. These results provide supportive evigroups in the 2 months before zoster onset by analysis of dence that stressful life events may be risk factors for the discordant pairs (26 versus 10, odds ratio 2.60, 95% confidence interval [CZ] 1.13, 6.27, P = .012), 3 months be- reactivation of varicella-zoster virus. J Am Geriatr SOC fore (29 versus l l , odds ratio 2.64, 95% Cl 1.20, 6.04, P = 38:1188- 1194, 1990
H
erpes zoster is caused by the reactivation of varicella -zoster virus (VZV); the mechanism of reactivation is unknown. Aging and immunosuppression are the only clearly documented risk factors for this phenomenon and may be interrelated. Several investigators have detected evidence of diminished T lymphocyte function with aging in general and in response to VZV in particular.'-4 Other investigators have found diminished T lymphocyte function after bereavement, a stressful life event common to the elderly.5~6These observations led us to con-
.~
From the *Division of Geriatrics, Department of Medicine and the Center for the Study of Aging and Human Development Duke University Medical Center; and the tGeriatric Research Education and Clinical Center, Durham Veterans Administration Medical Center, Durham, North Carolina. Supported by the A. W. Mellon Foundation. Dr. Schmader was a Veterans Administration and Duke Endowment Geriatric Fellow and a Brookdale Foundation National Fellow during conduct of this work. Presentedat the Forty-Sixth Annual ScientificMeeting of the American Geriatrics Society May 13, 1989, Boston, Massachusetts. Address correspondence and reprint requests to Kenneth Schmader, MD, at the Center for the Study of Aging and Human Development, Box 3003, Duke University Medical Center, Durham, NC 27710.
0 1990 by the American Geriatrics Society
sider whether stressful life events in the elderly could increase the probability of VZV reactivation, presumably by adversely affecting T lymphocyte function in the setting of already declining cell-mediated immunity with aging. Hence, to understand VZV reactivation better and to provide a clinical correlate for the above observation, we conducted a case-control study designed to answer the question: Are stressful life events predisposing factors for the development of herpes zoster? We hypothesized that recent stressful life events would be more frequent in patients with zoster than in matched controls.
METHODS Subjects Case subjects were community-dwelling elders over the age of 50 years with herpes zoster. Control subjects were also community-dwelling elders over 50 years old. Both potential case and control subjects were excluded if they had dementia, admitted to memory problems or had difficulty answering routine personal questions; had immunosuppressive diseases including Hodgkin's disease, other lymphomas, leukemias, multiple myeloma, solid tumors, and acquired immunodeficiency syndrome; used immuno0002-8614/90/$3.50
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suppressive therapies, including corticosteroidsand antineoplasticagents; received radiation therapy within 12 months; or experienced spinal cord trauma within 2 weeks of zoster onset. Patients with second, third, or repeated episodes, or with involvement limited to around the mouth, lips, genitalia, buttocks, or fingers, were excluded to avoid including recurrent herpes simplex infections. Herpes zoster was defined clinically as a varicelliform skin eruption consisting of unilateral grouped vesicles on an erythematous base in a linear, dermatomal distribution, preceded by a prodrome of pain or paresthesias and followed by healing over a few weeks. A specific list of criteria was generated incorporating the characteristics of this definition. A detailed history and the criteria were utilized in all cases. Additional confirmatory evidence was also sought, such as persistent pain (postherpeticneuralgia), positive Tzanck smear, antigen detection, and viral culture. Subjects were also asked if they had seen a physician for their condition and received a diagnosis of shingles or herpes zoster. Subjects had to meet the above definition and have their illness diagnosed as zoster by their physician to be identified as a case.
STRESS AND ZOSTER
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the elderly and developed from prior research. We did not use questions on major and minor illnesses, menopause, and moves to the home for the aged. We measured four spousal events (death of spouse, divorce, marital separation, and marriage) because these events have been identified as important stressors in previous studies and are well accepted as major life changes.9 Also, in order to detect events that the subjects in this particular study perceived as stressful, we asked, ”Did this have a negative, neutral, or positive effect on you?“ for every “yes” response to a given life event. We considered the meaning of any experienced events for the subjects to be central to the concept of stressful because different individuals may react in different ways to the same kind of life event. Hence, we defined as stressful a life event the subject experienced and perceived as having a negative effect on him or her (“negative” life events). Data Collection The data were collected by an experienced telephone interviewer who was aware of “case” or ”control” status but was blinded to the study hypothesis. The interviewer’s technique was reviewed before the start of the study and assessed by direct observation in an adjacent room, without that person’s knowledge, intermittently throughout the study for both case and control subjects. The principal investigator (K.S.) determined case eligibility by interview and specific criteria mentioned. This process took place at the Durham Veterans Affairs Medical Center by telephone contact with potential cases and physicians before any interviewer contact. The episode of zoster had to have occurred within 12 months of determination of eligibility. The interviewer obtained informed consent from eligible case subjects and then administered the GSRLE. After the cases were completed, she performed random digit dialing to locate controls, then obtained informed consent from eligible controls and subsequently administered the GSRLE. Life events were sought in the year preceding the zoster in the case subjects and for the same time period in a given matched control subject. Assuming a 15% incidence of at least one ”spousal event” 10 in the cases, we estimated that a sample size of 82 subjects in each group would give us 80% power to detect an odds ratio of 2.5 (a = .05).
Sampling Process Case subjects were located in our outpatient clinics and recruited through physicians and other health-care providers by letter, telephone, and posted notices. Case subjects were also recruited in the community by letters and phone calls to community agencies dealing with the elderly and by advertising in local newspapers and senior bulletins. All advertisements mentioned only that the study involved a questionnaire about shingles. A random sample of controls was located by random digit dialing, as previously described,’ and matched for sex, race, and age within 5 years. Briefly, the age, race, and sex match was determined for a given case subject. For each index case, a two-digit random number list was generated via computer at the Duke Center for Aging Computing and Statistical Laboratory. The last two digits of the case subject’s telephone number were then replaced by a two digit random number. Calls were made using the first five digits of the case‘s phone number and successive random numbers until a matched control was reached. Calls with no answer were repeated three times during different parts of the day and on different days before dialing the next number. Statistical Analysis In keeping with the study deprocedures the subjects were in accord sign, matchng was retained for the statistical analyses. with the Of, and were approved by, the Some descriptive statistics are presented for each of the Institutional Review Board of Duke University Medical two groups. McNemar,s test was used to caseCenter. control discordance in negative and spousal life events Instrument The instrument used to identify life and, for the sake of completeness, in individual life events was the Geriatric Scale of Recent Life Events events.” The odds ratios and confidence intervals were (GSRLE) (Kiyak, Liang, Kahana).* This questionnaire estimated by Woolf ’s method.12 The paired t-test was consists of items from the Social Readjustment Ratings employed to test group differences in total life events Scale (Holmes, Rahe)9plus additional items relevant to and duration of interview.13
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TABLE 1. CHARACTERISTICS OF SUBJECTS Characteristic
Case
Control
68.8 8.7 (50-90)
69.2 f 9.2 (50-94)
77 24
77 24
5 96
5 96 56
*
Age (years)* Sex Female (n) Male (n) Race Black (n) White (n) Marital status (96 married)
53
* Age data are expressed as mean k SD, with the range given in parentheses.
RESULTS One hundred eighty-seven potential cases of herpes zoster were collected over a 3-month period. Fifteen potential subjects were excluded for not having zoster, 17 for an immunosuppressive condition, four for memory impairment, three for being less than 50 years old, one for recent trauma, and 43 for having experienced zoster more than 1 year before contact (total exclusion, n = 83). One hundred four cases remained that met eligibility criteria; 101 consented to participate and were included in the study. Ninety percent of cases were located from the community and 10% from outpatient clinical settings. All case subjects had seen a physician for their condition and said that they had received a diagnosis of shingles or zoster. One hundred one matched controls were located by random digit dialing and consented to participate in the study. Nine other controls were identified during this process but five refused to participate and four were excluded because of memory impairment. The mean number of calls needed to locate a control was 69 (range, 1 to 204). The number of calls necessary to reach a control may exceed the number of two-digit random numbers because the total of two-digit numbers is limited to one hundred. This phenomenon occurred for five cases. In those instances, the interviewer substituted the first three digits of an adjacent area’s telephone exchange for the case’s telephone exchange and then used a new set of random numbers to continue calling. The mean difference in the duration of the interview (case minus control) was 1.97minutes (not statistically significant). Table 1 gives the characteristics of the study population. The mean age of the case subjects was 68.8 (standard deviation, 8.7 years; range, 50 to 90); that of the control subjects was 69.2 (standard deviation, 9.2 years, range, 50 to 94). Ninety-six percent were white and 77% were women. Fifty-three percent of cases and 56% of controls were married at the time of the interview. Table 2 shows the percentage of subjects experiencing
individual life events in each group. This provides an indication of the types of life events experienced by the subjects. There were no statistically significant differences between case and control subjects for any single event. The total numbers of life events (including negative, neutral, and positive ones) were then examined at different time intervals. Table 3 shows the number of subjects and the mean, standard deviation, and range of life events in cases and controls. The summary statistics are shown for the two groups separately for descriptive purposes. The case-minus-control differences show directional consistency (a tendency toward more events in the case subjects, as evidenced by means greater than zero). The number of life events experienced within 6 months of zoster onset was statistically significantly greater in the cases (P = 0.008). However, total life events in the preceding year and within 2 or 3 months before zoster did not differ significantly between groups. The number of negative events over the full 1-year period was slightly more common in cases than controls (case mean, 1.77; SD, 1.98; control mean, 1.25; SD, 1.56; mean case-control difference, 0.52; SD, 2.65; P = .49). We then examined the presence or absence of negative or spousal events, rather than the number of life events, in the subjects because these measurements have greater clinical relevance and because a given subject may have experienced more than one negative or spousal life event. Table 4 summarizes negative and spousal life events in the subjects, the focus of the study hypothesis. For this assessment, the subject was counted only once even if he or she experienced more than one negative or spousal life event. In order to test for significant differences between case and control subjects within the match, the distribution of discordant pairs was examined by McNemar’s test. A discordant pair existed when a case subject experienced a negative or spousal event but the matched control subject did not in Table 4) or the opposite, when a (designated “case case did not experience the event but the matched control did (designated ”control +”). Table 4 shows the numbers of subjects who experienced negative life events in case and control subjects separately (for descriptive purposes) and the respective discordant pairs in the first three rows. The last row concerns subjects who experienced spousal events. Regarding negative life events, the number of case-positive discordant pairs within 2 months before zoster onset was significantly greater than control-positive pairs. (26 versus 10; odds ratio, 2.60; 95% confidence interval [CI], 1.13, 6.27). Overall, 27 cases and 11 controls experienced a negative life event within this time period. To investigate alternative definitions of the relationship of the recentness of negative events to zoster onset, we examined 3- or 6-month time periods, with
+”
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TABLE 2. INDIVIDUAL LIFE EVENTS IN CASE AND CONTROL SUBJECTS ~~
Events
Case Subjects (n = 101)
Control Subjects (n = 101)
Loss of vision Difficulty walking Divorce Important friendship ends Marital separation Serious family illness Gains new family member Close friend dies Family get-togethers change Family member achievement Personal achievement Gives up control of money Financial situation worse Financial situation better Changes work conditions Changes residence (move) Sells major belonging Fired from job Retirement Loses valuable object Child marries Large loan Trouble with neighbor Trouble with social security Spouse dies Marriage Reconciliation with spouse Increasing number of arguments with spouse Fewer arguments with spouse Family member dies Family member health improves Church-more active Church-less active Trips from home stops driving Crime victim Goes to jail Unemployed Promotion Demotion Grandchild gets married Arguments with workers/boss Spouse affair Sexual difficulties You have affair Reduces recreational activities Minor legal violation Age discrimination Sleep difficulties Eating difficulties Trouble with children Shunned by family/friends
0 9 0 6
O*
* AII individual event differences were nonsignificant by McNemar's test.
1 33 30 13 17 19 10 2 6 12 14 7 3 0 4 7 6 7 5 3 3 0 1 4 5 15 21 8 25 76 6 3 0 0 1 0 10 2 0 7 1 27 2 2 18 10 12 5
6 1 3 1 20 26 17 16 21 14 2 3 10 6 8 8
0 4 4 5 6 1 1 3 1 0 3 4 14 21 8 14 72 3 2 0 0 3 0 2 3 0 3 0 18 7 4 20 13 7 7
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TABLE 3. TOTAL LIFE EVENTS IN HERPES ZOSTER AND CONTROLS
Total life events within Case subjects Control subjects Case-control Total life events within Case subjects Control subjects Case-control Total life events within Case subjects Control subjects Case-control Total life events within Case subjects Control subjects Case-control
n
Mean
SD
Range
P Value
101 101 101 6 months before zoster 101 101 101 3 months 101 101 101 2 months 101 101 101
5.38 4.62 0.76
3.13 2.96 4.46
0, 14 0, 14 -9, 13
.093*
2.64 1 .82 0.82
2.23 1.90 3.07
0, 9 0, 8 -6, 9
.008
1.29 1.02 0.27
1.34 1.27 1.92
0, 6 0, 7 -7, 6
.165
0.90 0.75 0.15
1.16 1.03 1.55
0, 6 0, 6 -6, 6
.338
one year
* Paired t-test employed for the case-control group difference.
similar findings for 3 months (29 versus 11; odds ratio, 2.64; 95% CI 1.20, 6.04) and 6 months (35 versus 16; odds ratio, 2.00; 95% CI 1.04,3.93). Thirty-two case and 14 control subjects reported negative life events within 3 months, whereas 41 case and 22 control subjects did at 6 months. There was no statistically significant difference in the number of case-versus-control discordant pairs regarding spousal life events, i.e., death of spouse, divorce, marital separation, or marriage.
DISCUSSION The significance of herpes zoster in the immunocompetent host lies not only in the prolonged pain of its elderly victims but also in the overt manifestation of latent viral reactivation in the aged. The pathobiologic mechanisms for this phenomenon are not well understood, although immunosuppression plays an important role. The identification of other risk factors should help elucidate basic mechanisms of reactivation. The
concept of stressful life events as risk factors for zoster is theoretically appealing because these events may enhance susceptibility to illness. In fact, the idea that stress predisposes to zoster is commonly held in medical circ l e but ~ ~is ~untested. We targeted recent life events in our hypothesis because of prior studies demonstrating in vitro lymphocyte dysfunction 2 months after bereavement. However, we found no evidence that life events involving the spouse, including bereavement, were associated with zoster. Also, there was no difference between case and control subjects in total life events 2 or 3 months preceding zoster, although a statistically significant result for case subjects (compared with control subjects) was found at 6 months. These data suggest that the number of life events during the prior 6 months were associated with zoster, but the impact of this finding is diluted by the negative result at 3 months. The most noticeable difference was detected when we accounted
TABLE 4. NEGATIVE AND SPOUSAL LIFE EVENTS IN HERPES ZOSTER AND CONTROLS
Events
No. of Case Subiects (n = 101)
"Negative" $ 5 2 months 5 3 months 5 6 months Spousals * Case discordant pair,
+
27 32 41 4
No. of Control Subiects (n = ioii
Caset
Controlt
Odds Ratiot
95% CIt
11 14 22 6
26 29 35 3
10 11 16 5
2.60 2.64 2.00 0.67
1.13, 6.27 1.20, 6.04 1.04, 3.93 0.12, 3.22
Discordant Pairs*
+
Pt .012
.007 .012 NS
case subject experienced event but matched control subject did not; control discordant pair, matched control subject experienced event but case subject did not. t Odds ratios and confidence intervals (C1) estimated by Woolf's method. McNemar's test used to obtain P value. $ Life events perceived by the subject as having a negative effect on him or her within 2, 3, and 6 months of zoster onset. 5 Death of spouse, divorce. marital separation, or marriage during the preceding year,
IAGS-NOVEMBER 1990-VOL 38, NO. 11
for the subjects' interpretation of life events. Life events perceived as having a negative effect within 2, 3, or 6 months of zoster onset were significantly more frequent among case subjects than among control subjects. These data suggest that negative life events areassociated with increased probability of herpes zoster in the elderly. It is possible that negative life experiences may increase the likelihood of VZV reactivation in the elderly through suppression of immune function because stressful life events have in a number of studies been associated with changes in immune parameters.15 This is the first study of latent VZV reactivation and stressful life events. Although the epidemiology and natural history of herpes simplex virus (HSV) reactivation is significantly different than that of VZV, investigations of stressful life events and recurrent orolabial or genital HSV infections may be relevant because of the similarity in pathobiology involved. Katcher et a1 administered the Holmes and Rahe Life Change Index to young nursing students and then recorded herpes labialis recurrence over the next 6 to 12 months.16 There was no correlation between life events and orolabial HSV recurrence. Schmidt et a1 measured "negative, stressprovoking" life events as part of a multiple component stress q~estionnaire.1~ The questionnaire was administered to young adult volunteers with recurrent herpes labialis when no lesions were present and within 3 days after the appearance of lesions. The authors found an increased level of stressful life events in the week before recurrence compared with baseline responses, particularly those events involving spousal, other family, or other close relationships. In regard to studies of genital HSV, Goldmeier et a1gave a life-events questionnaire to young adults during their first attack of genital herpes and then measured time to recurrence over the ensuing 24 weeks. The recurrence of genital HSV was not influenced by life events.'* Silver et a1 administered the Life Experience Survey, which asks subjects to evaluate whether a life event had a positive or negative impact on their lives, to young and middle-aged adults with recurrent genital HSV.19 Negative life events were unrelated to frequency of recurrence or pain but were associated with duration of recurrence. VanderPlate et a1 administered the Schedule of Recent Events (SRE) to young adult volunteers with a history of genital herpes and asked subjects to recall their number of recurrences.2o Recent life events (as measured by SRE scores) were significantly associated with HSV recurrence when the first attack of genital herpes was less than 4 years previous; there was no association when disease duration was greater than 4 years. Finally, Kememy et a1gave the Life Experience Survey (and four other stress scales) monthly for 6 months to young and middle-aged adults with genital herpes and monitored HSV recurrence during the same time period.21 Negative life events did not correlate with HSV recurrence. Hence, the results of these studies conflicted and the
STRESS A N D ZOSTER
1193
majority demonstrated negative findings. Only two of the above studies examined recent, negatively perceived events, and these two had opposite results.17,21All of the studies relied on subjective assessment of exposure, and none had a control group nor included elderly subjects. Study methodology varied widely, which makes further comparisons difficult. Our study found a consistent positive association only for recent, negatively perceived events. Methodologic limitations are important to consider in the interpretation of our findings. Volunteer and/or nonrespondent biases are potential sources of sampling errors relevant to this study. However, a large proportion of available cases was probably entered into the study considering the incidence of zoster (3 per 1000/year)22at a mean age of 68 and the population of Durham County over age 50 (35,000).Also, because our recruitment techniques mentioned only shingles, and not life events, it seems likely that respondents and nonrespondents with zoster would have experienced similar life events. The cases were representative of herpes zoster patients in that they were otherwise healthy, community-dwelling elders with typical episodes of zoster; the skew toward white women in the study population should be noted, however. Unblinded data collection, recall biases, and the use of life-events scales are potentially important sources of measurement biases that are relevant to this study. We found it impossible to blind the interviewer to case or control status because that person also performed the random digit dialing. Nonetheless, the interviewer was blinded to the study hypothesis and performed the interviewing process in a uniform manner for all participants. Cases might be more likely to recall certain life events in order to explain their episode of zoster. However, we found no statistically significant difference in total life events experienced between case and control subjects within 2,3,or 12 months of zoster onset. Conversely, fall-offin recall with time is a potential problem that might have occurred with some subjects. Cases might also have perceived life events differentlyin order to explain their episode of zoster, a bias we find difficult to dismiss completely. Life-events scales and stressful life-events research in general have received reasonable criticisms.23,2* Many retrospective investigations have found an association between stress and illness that prospective studies later failed to demonstrate. This study is also retrospective,so it is not possible to ascertain causality.The measurement of the magnitude of events with these scales is a problem that was addressed by additional questions on the subject's interpretation of the event. The appropriateness and testing of the scales in the elderly is another potential problem addressed by the use of the GSRLE. The reliability and validity of the GSRLE are comparable to other life-events scales.8 With regard to statistical issues, we targeted spousal
1194 SCHMADER ET AL
and recent negative life events in our hypothesis and analysis, so the likelihood of obtaining significant results by chance from so few primary analyses is very low. Particular individual events were not the focus of the study, so the data on individual life events (Table 2) are provided only for information. The likelihood of obtaining a significant result by chance from the analysis of those 52 single events is certainly much higher, but no significant associations were found. There were methodologc advantages to this study. The cases were carefully defined and selected. Random digit dialing generated a random sample of age-, sex-, and race-matched controls from the community. The cases and controls were chosen according to the same eligibility criteria and had the same baseline susceptibility to various life events. In conclusion, we found that although patients with herpes zoster experienced the same kinds of overall life events in the year preceding the illness as did control subjects, and that events involving the spouse were also equally common, recent events perceived as stressful events were significantly more common among patients with zoster. These results provide supportive evidence that stressful life events may be risk factors for the development of herpes zoster. These provocative, preliminary findings need confirmation from future investigations employing a prospective, cohort design.
ACKNOWLEDGMENTS We are indebted to Linda George, PhD, for her advice, Monice Arnold for her work as the study interviewer, Dana Mlekush for technical assistance, a n d to the kind participants in the study.
REFERENCES Adler WH, Nagel JE: Clinicalimmunology,in Andres R, Bierman EL, Hazzard WR, (eds): Principles of Geriatric Medicine. New York, McGraw-Hill, 1985, pp 418-423. Miller AE: Selective decline in cellular immune response to varicella-zoster in the elderly. Neurology 30:582, 1980 Berger R, Forest G, Just M: Decrease of the lymphoproliferative response to varicella-zoster antigen in the aged. Infect lmmunol 32:24, 1981 Burke BL, Steele RW, Beard OW, et al: Immune responses to varicella-zoster in the aged. Arch Intern Med 142:291, 1982
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5 . Bartop RW, Luckhurst E, Lazarus L, et al: Depressed lymphocyte function after bereavement. Lancet i:834, 1977 6. Schleifer SJ,Keller SE, Camerino M: Suppression of lymphocyte stimulation following bereavement. JAMA 250:374, 1983 7. Robertson SJ, GNffeI'Inan SG, Cohen HJ: Hospital versus random digit dialing controls in the elderly: observations from two case-control studies. J Am Geriatr Soc 36:119, 1988 8. Kiyak A, Liang J, Kahana E: The geriatric scale of recent life events, in Mangen DJ, Peterson WA, (eds):Research Instruments in Social Gerontology. Vol. 1, Clinical and Social Psychology. Minneapolis, MN: University of Minnesota Press, 1982, pp 171-172 9 . Holmes TH, Rahe RH: The social readjustment rating scale. J Psychosom Med 11:213,218, 1967 10. Wilson RW Assessing the impact of life change events, in Palmore E, Busse EW, Maddox GL, Nowlin JB, Siegler IC (eds): Normal Aging, III. Durham, NC: Duke University Press, 1985, pp 356-373 11. McNemar Q: Note on the sampling error of the differences between correlated proportions or percentages. Psychometrika 12:153, 1947 12. SchlesselmanJJ: Basic methods of analysis, in Case-ControlStudies. New York, Oxford University Press, 1982, pp 176-178 13. Armitage P, Beny D: Statistical methods in medical research. Oxford, Blackwell Scientific Press, 1987, pp 104-106 14. Juel-Jensen BE: Provocation of zoster, in Juel-Jensen BE, MacCallum FO (eds):Herpes Simplex,Varicella and Zoster. Philadelphia, JB Lippincott, 1972, pp 99-103 15. JemmottJB, Locke SE: Psychosocialfactors, immunologicmediation and human susceptibility to infectious diseases: how much do we know? Psychol Bull 95:78, 1984 16. Katcher AH, Brightman V, Luborsky L, et al: Prediction of the incidence of recurrent herpes labialis and systemic illness from psychological measurements. J Dent Res 52:49, 1973 17. Schmidt DD, Zyzanski S, Ellner J, et al: Stress as a precipitating factor in subjects with recurrent herpes labialis. J Fam Pract 20:359, 1985 18. Goldmeier D, Johnson A, JeffriesD, et al: Psychological aspects of recurrences of genital herpes. J Psychosom Res 30:601, 1986 19. Silver PS, Averbach SM, Vishniavsky N, et al: Psychological factors in recurrent genital herpes infections: stress, coping style, social support, emotional dysfunction and symptom recurrence. J Psychosom Res 30:163, 1986 20. VanderPlate C, Aral SO, Magder L: The relationship among genital herpes simplex virus, stress, and social support. Health Psychol 7:159, 1988 21. Kemeny ME, Cohen F, Zegans LS, et al: Psychologicalandimmunological predictors of genital herpes recurrence. Psychosom Med 51:195, 1989 22. Ragozzino MW, Melton LJ, Kurland LT, et al: Population-based study of herpes zoster and its sequellae. Medicine 61:310, 1982 23. Dohrenwend BS, Dohrenwend BP: Some issues in research on stressful life events. J Nerv Ment Dis 166:7, 1978 24. Rabkin JG,Streuning E L Life events, stress, and illness. Science 194:1013, 1976
Are Stressful Life Events Risk Factors for Herpes Zoster? A
Kenneth Schmader, MD,*t Stephanie Studenski, MD, MPH,*t Julia MacMillan, MPH,* Seymour Gruferman, MD, DrPH,* and Harvey J. Cohen, MD*t .007), or 6 months before (35 versus 16, odds ratio 2.00, To determine if psychologically stressful life events are risk factors for herpes zoster, we conducted a case-control 95% CZ 1.04, 3.93, P = .012). The mean number of total life events was significantly higher in cases at 6 months study of zoster and self-reported recent negative fife before zoster (case f = 2.64, control f = 1.82, P = .008), events and major changes in spousal relationships. The but there were no signficant differences at 2, 3, or 12 subjects were 101 healthy community-dwelling cases of months before. There were no significant differences bezoster and 101 healthy controls matched for age, sex, and tween case subjects and control subjects for spousal race and generated by random digit dialing. The Geriatric events, or any given single life event. In conclusion, we Scale of Recent Life Events was administered to case and found that whereas patients with herpes zoster expericontrol subjects, and additional questions were asked reenced the same kinds of life events in the year preceding garding the perception of the life event. The results showed that case subjects experienced negative life events the illness as did control subjects, recent events perceived as stressful were significantly more common among pasignificantly more often than subjects in the control tients with zoster. These results provide supportive evigroups in the 2 months before zoster onset by analysis of dence that stressful life events may be risk factors for the discordant pairs (26 versus 10, odds ratio 2.60, 95% confidence interval [CZ] 1.13, 6.27, P = .012), 3 months be- reactivation of varicella-zoster virus. J Am Geriatr SOC fore (29 versus l l , odds ratio 2.64, 95% Cl 1.20, 6.04, P = 38:1188- 1194, 1990
H
erpes zoster is caused by the reactivation of varicella -zoster virus (VZV); the mechanism of reactivation is unknown. Aging and immunosuppression are the only clearly documented risk factors for this phenomenon and may be interrelated. Several investigators have detected evidence of diminished T lymphocyte function with aging in general and in response to VZV in particular.'-4 Other investigators have found diminished T lymphocyte function after bereavement, a stressful life event common to the elderly.5~6These observations led us to con-
.~
From the *Division of Geriatrics, Department of Medicine and the Center for the Study of Aging and Human Development Duke University Medical Center; and the tGeriatric Research Education and Clinical Center, Durham Veterans Administration Medical Center, Durham, North Carolina. Supported by the A. W. Mellon Foundation. Dr. Schmader was a Veterans Administration and Duke Endowment Geriatric Fellow and a Brookdale Foundation National Fellow during conduct of this work. Presentedat the Forty-Sixth Annual ScientificMeeting of the American Geriatrics Society May 13, 1989, Boston, Massachusetts. Address correspondence and reprint requests to Kenneth Schmader, MD, at the Center for the Study of Aging and Human Development, Box 3003, Duke University Medical Center, Durham, NC 27710.
0 1990 by the American Geriatrics Society
sider whether stressful life events in the elderly could increase the probability of VZV reactivation, presumably by adversely affecting T lymphocyte function in the setting of already declining cell-mediated immunity with aging. Hence, to understand VZV reactivation better and to provide a clinical correlate for the above observation, we conducted a case-control study designed to answer the question: Are stressful life events predisposing factors for the development of herpes zoster? We hypothesized that recent stressful life events would be more frequent in patients with zoster than in matched controls.
METHODS Subjects Case subjects were community-dwelling elders over the age of 50 years with herpes zoster. Control subjects were also community-dwelling elders over 50 years old. Both potential case and control subjects were excluded if they had dementia, admitted to memory problems or had difficulty answering routine personal questions; had immunosuppressive diseases including Hodgkin's disease, other lymphomas, leukemias, multiple myeloma, solid tumors, and acquired immunodeficiency syndrome; used immuno0002-8614/90/$3.50
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suppressive therapies, including corticosteroidsand antineoplasticagents; received radiation therapy within 12 months; or experienced spinal cord trauma within 2 weeks of zoster onset. Patients with second, third, or repeated episodes, or with involvement limited to around the mouth, lips, genitalia, buttocks, or fingers, were excluded to avoid including recurrent herpes simplex infections. Herpes zoster was defined clinically as a varicelliform skin eruption consisting of unilateral grouped vesicles on an erythematous base in a linear, dermatomal distribution, preceded by a prodrome of pain or paresthesias and followed by healing over a few weeks. A specific list of criteria was generated incorporating the characteristics of this definition. A detailed history and the criteria were utilized in all cases. Additional confirmatory evidence was also sought, such as persistent pain (postherpeticneuralgia), positive Tzanck smear, antigen detection, and viral culture. Subjects were also asked if they had seen a physician for their condition and received a diagnosis of shingles or herpes zoster. Subjects had to meet the above definition and have their illness diagnosed as zoster by their physician to be identified as a case.
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the elderly and developed from prior research. We did not use questions on major and minor illnesses, menopause, and moves to the home for the aged. We measured four spousal events (death of spouse, divorce, marital separation, and marriage) because these events have been identified as important stressors in previous studies and are well accepted as major life changes.9 Also, in order to detect events that the subjects in this particular study perceived as stressful, we asked, ”Did this have a negative, neutral, or positive effect on you?“ for every “yes” response to a given life event. We considered the meaning of any experienced events for the subjects to be central to the concept of stressful because different individuals may react in different ways to the same kind of life event. Hence, we defined as stressful a life event the subject experienced and perceived as having a negative effect on him or her (“negative” life events). Data Collection The data were collected by an experienced telephone interviewer who was aware of “case” or ”control” status but was blinded to the study hypothesis. The interviewer’s technique was reviewed before the start of the study and assessed by direct observation in an adjacent room, without that person’s knowledge, intermittently throughout the study for both case and control subjects. The principal investigator (K.S.) determined case eligibility by interview and specific criteria mentioned. This process took place at the Durham Veterans Affairs Medical Center by telephone contact with potential cases and physicians before any interviewer contact. The episode of zoster had to have occurred within 12 months of determination of eligibility. The interviewer obtained informed consent from eligible case subjects and then administered the GSRLE. After the cases were completed, she performed random digit dialing to locate controls, then obtained informed consent from eligible controls and subsequently administered the GSRLE. Life events were sought in the year preceding the zoster in the case subjects and for the same time period in a given matched control subject. Assuming a 15% incidence of at least one ”spousal event” 10 in the cases, we estimated that a sample size of 82 subjects in each group would give us 80% power to detect an odds ratio of 2.5 (a = .05).
Sampling Process Case subjects were located in our outpatient clinics and recruited through physicians and other health-care providers by letter, telephone, and posted notices. Case subjects were also recruited in the community by letters and phone calls to community agencies dealing with the elderly and by advertising in local newspapers and senior bulletins. All advertisements mentioned only that the study involved a questionnaire about shingles. A random sample of controls was located by random digit dialing, as previously described,’ and matched for sex, race, and age within 5 years. Briefly, the age, race, and sex match was determined for a given case subject. For each index case, a two-digit random number list was generated via computer at the Duke Center for Aging Computing and Statistical Laboratory. The last two digits of the case subject’s telephone number were then replaced by a two digit random number. Calls were made using the first five digits of the case‘s phone number and successive random numbers until a matched control was reached. Calls with no answer were repeated three times during different parts of the day and on different days before dialing the next number. Statistical Analysis In keeping with the study deprocedures the subjects were in accord sign, matchng was retained for the statistical analyses. with the Of, and were approved by, the Some descriptive statistics are presented for each of the Institutional Review Board of Duke University Medical two groups. McNemar,s test was used to caseCenter. control discordance in negative and spousal life events Instrument The instrument used to identify life and, for the sake of completeness, in individual life events was the Geriatric Scale of Recent Life Events events.” The odds ratios and confidence intervals were (GSRLE) (Kiyak, Liang, Kahana).* This questionnaire estimated by Woolf ’s method.12 The paired t-test was consists of items from the Social Readjustment Ratings employed to test group differences in total life events Scale (Holmes, Rahe)9plus additional items relevant to and duration of interview.13
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TABLE 1. CHARACTERISTICS OF SUBJECTS Characteristic
Case
Control
68.8 8.7 (50-90)
69.2 f 9.2 (50-94)
77 24
77 24
5 96
5 96 56
*
Age (years)* Sex Female (n) Male (n) Race Black (n) White (n) Marital status (96 married)
53
* Age data are expressed as mean k SD, with the range given in parentheses.
RESULTS One hundred eighty-seven potential cases of herpes zoster were collected over a 3-month period. Fifteen potential subjects were excluded for not having zoster, 17 for an immunosuppressive condition, four for memory impairment, three for being less than 50 years old, one for recent trauma, and 43 for having experienced zoster more than 1 year before contact (total exclusion, n = 83). One hundred four cases remained that met eligibility criteria; 101 consented to participate and were included in the study. Ninety percent of cases were located from the community and 10% from outpatient clinical settings. All case subjects had seen a physician for their condition and said that they had received a diagnosis of shingles or zoster. One hundred one matched controls were located by random digit dialing and consented to participate in the study. Nine other controls were identified during this process but five refused to participate and four were excluded because of memory impairment. The mean number of calls needed to locate a control was 69 (range, 1 to 204). The number of calls necessary to reach a control may exceed the number of two-digit random numbers because the total of two-digit numbers is limited to one hundred. This phenomenon occurred for five cases. In those instances, the interviewer substituted the first three digits of an adjacent area’s telephone exchange for the case’s telephone exchange and then used a new set of random numbers to continue calling. The mean difference in the duration of the interview (case minus control) was 1.97minutes (not statistically significant). Table 1 gives the characteristics of the study population. The mean age of the case subjects was 68.8 (standard deviation, 8.7 years; range, 50 to 90); that of the control subjects was 69.2 (standard deviation, 9.2 years, range, 50 to 94). Ninety-six percent were white and 77% were women. Fifty-three percent of cases and 56% of controls were married at the time of the interview. Table 2 shows the percentage of subjects experiencing
individual life events in each group. This provides an indication of the types of life events experienced by the subjects. There were no statistically significant differences between case and control subjects for any single event. The total numbers of life events (including negative, neutral, and positive ones) were then examined at different time intervals. Table 3 shows the number of subjects and the mean, standard deviation, and range of life events in cases and controls. The summary statistics are shown for the two groups separately for descriptive purposes. The case-minus-control differences show directional consistency (a tendency toward more events in the case subjects, as evidenced by means greater than zero). The number of life events experienced within 6 months of zoster onset was statistically significantly greater in the cases (P = 0.008). However, total life events in the preceding year and within 2 or 3 months before zoster did not differ significantly between groups. The number of negative events over the full 1-year period was slightly more common in cases than controls (case mean, 1.77; SD, 1.98; control mean, 1.25; SD, 1.56; mean case-control difference, 0.52; SD, 2.65; P = .49). We then examined the presence or absence of negative or spousal events, rather than the number of life events, in the subjects because these measurements have greater clinical relevance and because a given subject may have experienced more than one negative or spousal life event. Table 4 summarizes negative and spousal life events in the subjects, the focus of the study hypothesis. For this assessment, the subject was counted only once even if he or she experienced more than one negative or spousal life event. In order to test for significant differences between case and control subjects within the match, the distribution of discordant pairs was examined by McNemar’s test. A discordant pair existed when a case subject experienced a negative or spousal event but the matched control subject did not in Table 4) or the opposite, when a (designated “case case did not experience the event but the matched control did (designated ”control +”). Table 4 shows the numbers of subjects who experienced negative life events in case and control subjects separately (for descriptive purposes) and the respective discordant pairs in the first three rows. The last row concerns subjects who experienced spousal events. Regarding negative life events, the number of case-positive discordant pairs within 2 months before zoster onset was significantly greater than control-positive pairs. (26 versus 10; odds ratio, 2.60; 95% confidence interval [CI], 1.13, 6.27). Overall, 27 cases and 11 controls experienced a negative life event within this time period. To investigate alternative definitions of the relationship of the recentness of negative events to zoster onset, we examined 3- or 6-month time periods, with
+”
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TABLE 2. INDIVIDUAL LIFE EVENTS IN CASE AND CONTROL SUBJECTS ~~
Events
Case Subjects (n = 101)
Control Subjects (n = 101)
Loss of vision Difficulty walking Divorce Important friendship ends Marital separation Serious family illness Gains new family member Close friend dies Family get-togethers change Family member achievement Personal achievement Gives up control of money Financial situation worse Financial situation better Changes work conditions Changes residence (move) Sells major belonging Fired from job Retirement Loses valuable object Child marries Large loan Trouble with neighbor Trouble with social security Spouse dies Marriage Reconciliation with spouse Increasing number of arguments with spouse Fewer arguments with spouse Family member dies Family member health improves Church-more active Church-less active Trips from home stops driving Crime victim Goes to jail Unemployed Promotion Demotion Grandchild gets married Arguments with workers/boss Spouse affair Sexual difficulties You have affair Reduces recreational activities Minor legal violation Age discrimination Sleep difficulties Eating difficulties Trouble with children Shunned by family/friends
0 9 0 6
O*
* AII individual event differences were nonsignificant by McNemar's test.
1 33 30 13 17 19 10 2 6 12 14 7 3 0 4 7 6 7 5 3 3 0 1 4 5 15 21 8 25 76 6 3 0 0 1 0 10 2 0 7 1 27 2 2 18 10 12 5
6 1 3 1 20 26 17 16 21 14 2 3 10 6 8 8
0 4 4 5 6 1 1 3 1 0 3 4 14 21 8 14 72 3 2 0 0 3 0 2 3 0 3 0 18 7 4 20 13 7 7
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TABLE 3. TOTAL LIFE EVENTS IN HERPES ZOSTER AND CONTROLS
Total life events within Case subjects Control subjects Case-control Total life events within Case subjects Control subjects Case-control Total life events within Case subjects Control subjects Case-control Total life events within Case subjects Control subjects Case-control
n
Mean
SD
Range
P Value
101 101 101 6 months before zoster 101 101 101 3 months 101 101 101 2 months 101 101 101
5.38 4.62 0.76
3.13 2.96 4.46
0, 14 0, 14 -9, 13
.093*
2.64 1 .82 0.82
2.23 1.90 3.07
0, 9 0, 8 -6, 9
.008
1.29 1.02 0.27
1.34 1.27 1.92
0, 6 0, 7 -7, 6
.165
0.90 0.75 0.15
1.16 1.03 1.55
0, 6 0, 6 -6, 6
.338
one year
* Paired t-test employed for the case-control group difference.
similar findings for 3 months (29 versus 11; odds ratio, 2.64; 95% CI 1.20, 6.04) and 6 months (35 versus 16; odds ratio, 2.00; 95% CI 1.04,3.93). Thirty-two case and 14 control subjects reported negative life events within 3 months, whereas 41 case and 22 control subjects did at 6 months. There was no statistically significant difference in the number of case-versus-control discordant pairs regarding spousal life events, i.e., death of spouse, divorce, marital separation, or marriage.
DISCUSSION The significance of herpes zoster in the immunocompetent host lies not only in the prolonged pain of its elderly victims but also in the overt manifestation of latent viral reactivation in the aged. The pathobiologic mechanisms for this phenomenon are not well understood, although immunosuppression plays an important role. The identification of other risk factors should help elucidate basic mechanisms of reactivation. The
concept of stressful life events as risk factors for zoster is theoretically appealing because these events may enhance susceptibility to illness. In fact, the idea that stress predisposes to zoster is commonly held in medical circ l e but ~ ~is ~untested. We targeted recent life events in our hypothesis because of prior studies demonstrating in vitro lymphocyte dysfunction 2 months after bereavement. However, we found no evidence that life events involving the spouse, including bereavement, were associated with zoster. Also, there was no difference between case and control subjects in total life events 2 or 3 months preceding zoster, although a statistically significant result for case subjects (compared with control subjects) was found at 6 months. These data suggest that the number of life events during the prior 6 months were associated with zoster, but the impact of this finding is diluted by the negative result at 3 months. The most noticeable difference was detected when we accounted
TABLE 4. NEGATIVE AND SPOUSAL LIFE EVENTS IN HERPES ZOSTER AND CONTROLS
Events
No. of Case Subiects (n = 101)
"Negative" $ 5 2 months 5 3 months 5 6 months Spousals * Case discordant pair,
+
27 32 41 4
No. of Control Subiects (n = ioii
Caset
Controlt
Odds Ratiot
95% CIt
11 14 22 6
26 29 35 3
10 11 16 5
2.60 2.64 2.00 0.67
1.13, 6.27 1.20, 6.04 1.04, 3.93 0.12, 3.22
Discordant Pairs*
+
Pt .012
.007 .012 NS
case subject experienced event but matched control subject did not; control discordant pair, matched control subject experienced event but case subject did not. t Odds ratios and confidence intervals (C1) estimated by Woolf's method. McNemar's test used to obtain P value. $ Life events perceived by the subject as having a negative effect on him or her within 2, 3, and 6 months of zoster onset. 5 Death of spouse, divorce. marital separation, or marriage during the preceding year,
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for the subjects' interpretation of life events. Life events perceived as having a negative effect within 2, 3, or 6 months of zoster onset were significantly more frequent among case subjects than among control subjects. These data suggest that negative life events areassociated with increased probability of herpes zoster in the elderly. It is possible that negative life experiences may increase the likelihood of VZV reactivation in the elderly through suppression of immune function because stressful life events have in a number of studies been associated with changes in immune parameters.15 This is the first study of latent VZV reactivation and stressful life events. Although the epidemiology and natural history of herpes simplex virus (HSV) reactivation is significantly different than that of VZV, investigations of stressful life events and recurrent orolabial or genital HSV infections may be relevant because of the similarity in pathobiology involved. Katcher et a1 administered the Holmes and Rahe Life Change Index to young nursing students and then recorded herpes labialis recurrence over the next 6 to 12 months.16 There was no correlation between life events and orolabial HSV recurrence. Schmidt et a1 measured "negative, stressprovoking" life events as part of a multiple component stress q~estionnaire.1~ The questionnaire was administered to young adult volunteers with recurrent herpes labialis when no lesions were present and within 3 days after the appearance of lesions. The authors found an increased level of stressful life events in the week before recurrence compared with baseline responses, particularly those events involving spousal, other family, or other close relationships. In regard to studies of genital HSV, Goldmeier et a1gave a life-events questionnaire to young adults during their first attack of genital herpes and then measured time to recurrence over the ensuing 24 weeks. The recurrence of genital HSV was not influenced by life events.'* Silver et a1 administered the Life Experience Survey, which asks subjects to evaluate whether a life event had a positive or negative impact on their lives, to young and middle-aged adults with recurrent genital HSV.19 Negative life events were unrelated to frequency of recurrence or pain but were associated with duration of recurrence. VanderPlate et a1 administered the Schedule of Recent Events (SRE) to young adult volunteers with a history of genital herpes and asked subjects to recall their number of recurrences.2o Recent life events (as measured by SRE scores) were significantly associated with HSV recurrence when the first attack of genital herpes was less than 4 years previous; there was no association when disease duration was greater than 4 years. Finally, Kememy et a1gave the Life Experience Survey (and four other stress scales) monthly for 6 months to young and middle-aged adults with genital herpes and monitored HSV recurrence during the same time period.21 Negative life events did not correlate with HSV recurrence. Hence, the results of these studies conflicted and the
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majority demonstrated negative findings. Only two of the above studies examined recent, negatively perceived events, and these two had opposite results.17,21All of the studies relied on subjective assessment of exposure, and none had a control group nor included elderly subjects. Study methodology varied widely, which makes further comparisons difficult. Our study found a consistent positive association only for recent, negatively perceived events. Methodologic limitations are important to consider in the interpretation of our findings. Volunteer and/or nonrespondent biases are potential sources of sampling errors relevant to this study. However, a large proportion of available cases was probably entered into the study considering the incidence of zoster (3 per 1000/year)22at a mean age of 68 and the population of Durham County over age 50 (35,000).Also, because our recruitment techniques mentioned only shingles, and not life events, it seems likely that respondents and nonrespondents with zoster would have experienced similar life events. The cases were representative of herpes zoster patients in that they were otherwise healthy, community-dwelling elders with typical episodes of zoster; the skew toward white women in the study population should be noted, however. Unblinded data collection, recall biases, and the use of life-events scales are potentially important sources of measurement biases that are relevant to this study. We found it impossible to blind the interviewer to case or control status because that person also performed the random digit dialing. Nonetheless, the interviewer was blinded to the study hypothesis and performed the interviewing process in a uniform manner for all participants. Cases might be more likely to recall certain life events in order to explain their episode of zoster. However, we found no statistically significant difference in total life events experienced between case and control subjects within 2,3,or 12 months of zoster onset. Conversely, fall-offin recall with time is a potential problem that might have occurred with some subjects. Cases might also have perceived life events differentlyin order to explain their episode of zoster, a bias we find difficult to dismiss completely. Life-events scales and stressful life-events research in general have received reasonable criticisms.23,2* Many retrospective investigations have found an association between stress and illness that prospective studies later failed to demonstrate. This study is also retrospective,so it is not possible to ascertain causality.The measurement of the magnitude of events with these scales is a problem that was addressed by additional questions on the subject's interpretation of the event. The appropriateness and testing of the scales in the elderly is another potential problem addressed by the use of the GSRLE. The reliability and validity of the GSRLE are comparable to other life-events scales.8 With regard to statistical issues, we targeted spousal
1194 SCHMADER ET AL
and recent negative life events in our hypothesis and analysis, so the likelihood of obtaining significant results by chance from so few primary analyses is very low. Particular individual events were not the focus of the study, so the data on individual life events (Table 2) are provided only for information. The likelihood of obtaining a significant result by chance from the analysis of those 52 single events is certainly much higher, but no significant associations were found. There were methodologc advantages to this study. The cases were carefully defined and selected. Random digit dialing generated a random sample of age-, sex-, and race-matched controls from the community. The cases and controls were chosen according to the same eligibility criteria and had the same baseline susceptibility to various life events. In conclusion, we found that although patients with herpes zoster experienced the same kinds of overall life events in the year preceding the illness as did control subjects, and that events involving the spouse were also equally common, recent events perceived as stressful events were significantly more common among patients with zoster. These results provide supportive evidence that stressful life events may be risk factors for the development of herpes zoster. These provocative, preliminary findings need confirmation from future investigations employing a prospective, cohort design.
ACKNOWLEDGMENTS We are indebted to Linda George, PhD, for her advice, Monice Arnold for her work as the study interviewer, Dana Mlekush for technical assistance, a n d to the kind participants in the study.
REFERENCES Adler WH, Nagel JE: Clinicalimmunology,in Andres R, Bierman EL, Hazzard WR, (eds): Principles of Geriatric Medicine. New York, McGraw-Hill, 1985, pp 418-423. Miller AE: Selective decline in cellular immune response to varicella-zoster in the elderly. Neurology 30:582, 1980 Berger R, Forest G, Just M: Decrease of the lymphoproliferative response to varicella-zoster antigen in the aged. Infect lmmunol 32:24, 1981 Burke BL, Steele RW, Beard OW, et al: Immune responses to varicella-zoster in the aged. Arch Intern Med 142:291, 1982
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5 . Bartop RW, Luckhurst E, Lazarus L, et al: Depressed lymphocyte function after bereavement. Lancet i:834, 1977 6. Schleifer SJ,Keller SE, Camerino M: Suppression of lymphocyte stimulation following bereavement. JAMA 250:374, 1983 7. Robertson SJ, GNffeI'Inan SG, Cohen HJ: Hospital versus random digit dialing controls in the elderly: observations from two case-control studies. J Am Geriatr Soc 36:119, 1988 8. Kiyak A, Liang J, Kahana E: The geriatric scale of recent life events, in Mangen DJ, Peterson WA, (eds):Research Instruments in Social Gerontology. Vol. 1, Clinical and Social Psychology. Minneapolis, MN: University of Minnesota Press, 1982, pp 171-172 9 . Holmes TH, Rahe RH: The social readjustment rating scale. J Psychosom Med 11:213,218, 1967 10. Wilson RW Assessing the impact of life change events, in Palmore E, Busse EW, Maddox GL, Nowlin JB, Siegler IC (eds): Normal Aging, III. Durham, NC: Duke University Press, 1985, pp 356-373 11. McNemar Q: Note on the sampling error of the differences between correlated proportions or percentages. Psychometrika 12:153, 1947 12. SchlesselmanJJ: Basic methods of analysis, in Case-ControlStudies. New York, Oxford University Press, 1982, pp 176-178 13. Armitage P, Beny D: Statistical methods in medical research. Oxford, Blackwell Scientific Press, 1987, pp 104-106 14. Juel-Jensen BE: Provocation of zoster, in Juel-Jensen BE, MacCallum FO (eds):Herpes Simplex,Varicella and Zoster. Philadelphia, JB Lippincott, 1972, pp 99-103 15. JemmottJB, Locke SE: Psychosocialfactors, immunologicmediation and human susceptibility to infectious diseases: how much do we know? Psychol Bull 95:78, 1984 16. Katcher AH, Brightman V, Luborsky L, et al: Prediction of the incidence of recurrent herpes labialis and systemic illness from psychological measurements. J Dent Res 52:49, 1973 17. Schmidt DD, Zyzanski S, Ellner J, et al: Stress as a precipitating factor in subjects with recurrent herpes labialis. J Fam Pract 20:359, 1985 18. Goldmeier D, Johnson A, JeffriesD, et al: Psychological aspects of recurrences of genital herpes. J Psychosom Res 30:601, 1986 19. Silver PS, Averbach SM, Vishniavsky N, et al: Psychological factors in recurrent genital herpes infections: stress, coping style, social support, emotional dysfunction and symptom recurrence. J Psychosom Res 30:163, 1986 20. VanderPlate C, Aral SO, Magder L: The relationship among genital herpes simplex virus, stress, and social support. Health Psychol 7:159, 1988 21. Kemeny ME, Cohen F, Zegans LS, et al: Psychologicalandimmunological predictors of genital herpes recurrence. Psychosom Med 51:195, 1989 22. Ragozzino MW, Melton LJ, Kurland LT, et al: Population-based study of herpes zoster and its sequellae. Medicine 61:310, 1982 23. Dohrenwend BS, Dohrenwend BP: Some issues in research on stressful life events. J Nerv Ment Dis 166:7, 1978 24. Rabkin JG,Streuning E L Life events, stress, and illness. Science 194:1013, 1976
