SEVERE

EVANS,
Am J LESERMAN,
LIFE
Psychiatry
STRESS154:5,
PERKINS,
AS PREDICTOR
May 1997
ET AL.

Severe Life Stress as a Predictor of Early Disease Progression

in HIV Infection

Dwight L. Evans, M.D., Jane Leserman, Ph.D., Diana O. Perkins, M.D.,

Robert A. Stern, Ph.D., Carol Murphy, R.N., Beiyao Zheng, M.S., David Gettes, B.S.,
Jeffrey A. Longmate, Ph.D., Susan G. Silva, Ph.D., Charles M. van der Horst, M.D.,
Colin D. Hall, M.D., James D. Folds, Ph.D., Robert N. Golden, M.D., and John M. Petitto, M.D.

Objective: Although there is evidence that stress is associated with alterations in immunity,
the role of emotional factors in the onset and course of immune-based diseases such as cancer
and AIDS has not been established. This prospective study was designed to test the hypothesis
that stressful life events accelerate the course of HIV disease. Method: Ninety-three HIV-posi-
tive homosexual men who were without clinical symptoms at the time of entry into the study
were studied for up to 42 months. Subjects received comprehensive medical, neurological,
neuropsychological, and psychiatric assessments every 6 months, including assessment of
stressful life events during the preceding 6-month interval. Several statistical approaches were
used to assess the relation between stress and disease progression. Results: The time of the first
disease progression was analyzed with a proportional hazard survival method, which demon-
strated that the more severe the life stress experienced, the greater the risk of early HIV disease
progression. Specifically, for every one severe stress per 6-month study interval, the risk of
early disease progression was doubled. Among a subset of 66 subjects who had been in the
study for at least 24 months, logistic regression analyses showed that higher severe life stress
increased the odds of developing HIV disease progression nearly fourfold. The degree of dis-
ease progression was also predicted by severe life stress when a proportional odds logistic
regression model was used for analysis. Conclusions: This report presents the first evidence
from a prospective research study that severe life event stress is associated with an increased
rate of early HIV disease progression.
(Am J Psychiatry 1997; 154:630634)

T here has been considerable popular enthusiasm

for the concept that stress influences the immune
system and is involved in the onset and course of im-
mune-based physical diseases such as cancer and AIDS
(13). Many investigations have demonstrated altera-
tions in laboratory measures of immunity in association
with stress and depression, but prospective studies de-
signed to establish whether stressful life events can
Received May 1, 1996; revision received Nov. 7, 1996; accepted
Dec. 19, 1996. From the Departments of Psychiatry, Medicine,
Neuroscience, Pharmacology, and Biostatistics, University of Florida
College of Medicine; and the Departments of Psychiatry, Medicine,
Microbiology and Immunology, and Neurology and the General
Clinical Research Center, University of North Carolina School of
Medicine, Chapel Hill. Address reprint requests to Dr. Evans, Depart-
ment of Psychiatry, University of Florida College of Medicine, P.O.
Box 100256, Gainesville, FL 32610-0256.
Supported in part by NIMH grants MH-44618, MH-19111, and
MH-33127 and NIH grant RR-00046 from the Division of Research
Resources.
The authors thank Kandice Smith for her assistance in preparing the
manuscript.
modify the progression of immune-based diseases are
generally lacking (4, 5). Although there is not sufficient
evidence to support a clear relation between stressful
life events and the onset of breast cancer (6), there are
a few studies suggesting that stress may influence the
progression and recurrence of cancer. In one prospec-
tive study (7), stressful life events were found to in-
crease the likelihood of recurrence of breast cancer in
women. In addition, in a landmark study, Spiegel and
colleagues (8) found that women with metastatic breast
cancer who were randomly assigned to a supportive/ex-
pressive group therapy intervention lived longer than
women who received the same conventional cancer
treatment but did not participate in the behavioral
group therapy. The influence of this intervention has
been attributed to its stress-buffering properties.
Appreciation of the multifactorial nature of HIV dis-
ease has led to recent efforts to identify factors that ac-
count for the substantial variance in HIV disease prog-
ression, particularly since such knowledge could have
important treatment implications (9). It has been un-

630 Am J Psychiatry 154:5, May 1997


clear whether stressful life events could also accelerate
the course of HIV disease. A recent meta-analytic study
(10) found no evidence that stress or depression affects
the course of HIV infection and noted that future stud-
ies should assess prospectively the effects of population-
specific stressors on HIV disease progression. Our pro-
spective study was designed to test this hypothesis
systematically. In this article we present the first evi-
dence from a prospective research study that severe life
event stress is associated with an increased rate of early
HIV disease progression in men. The measurement of
stress was based on a comprehensive, interview-based
assessment, and our analyses focused on severe life
stress because previous research has suggested that it is
a better predictor of medical illness than less severe life
stress (11, 12).
METHOD
Data were collected in North Carolina as part of an ongoing lon-
gitudinal study. The study was approved by the University of North
Carolina School of Medicine Committee for the Protection of the
Rights of Human Subjects, and all subjects provided written informed
consent. We studied 93 HIV-positive homosexual men, all of whom
were without clinical symptoms at the time of entry into the study
group. These study participants were gathered from rural and urban
areas of the state through state health departments, advertisements in
gay publications and gay organizations, and word of mouth. All po-
tential participants were screened to exclude 1) those with fewer than
10 years of education; 2) those who were younger than 18 years of
age or older than 51; 3) those with previous intravenous drug use as
a risk factor for HIV; 4) those with substantial medical or neuro-
logical illness (heart, lung, kidney, liver, thyroid, and gastrointesti-
nal disease, diabetes, arthritis, cancer, head injury, stroke, seizures,
attention deficit disorder, loss of consciousness, surgery in the last
6 months, deafness, and blindness); 5) those with past treatment
for alcoholism or current heavy alcohol consumption (more than
60 drinks per month); 6) those with present or past heavy use of
recreational drugs (e.g., marijuana, phencyclidine, cocaine, LSD);
7) those currently taking medications with known or suspected ef-
fects on the immune system (e.g., anticonvulsants, antihistamines, anti-
hypertensive drugs, steroids, anti-inflammatory drugs, antibiotics);
and 8) those with symptoms of active bacterial or viral infections such
as colds or flu at the time of data collection. Persons testing positive
for HIV were further screened to include only those considered to be
without symptoms, that is, not meeting the 1987 criteria of the Cen-
ters for Disease Control (CDC) for AIDS or AIDS-related complex
(e.g., night sweats, herpes zoster, oral candidiasis, hairy leukoplakia,
unexplained fever or diarrhea, shingles, unexplained weight loss or
fatigue in the presence of other symptoms). All subjects were free of
medications known to affect immune response, recreational drugs,
and major alcohol consumption for at least 2 weeks before the study.
No subject was taking an antiretroviral drug at the time of entry into
the study.
Monitoring of Clinical Disease Status
HIV status was confirmed by HIV antibody screening with an
ELISA test (Abbott Laboratories) and by Western blot testing accord-
ing to the method described by the CDC. Each subject received a
comprehensive assessment by specialists in psychiatry, neuropsychol-
ogy, infectious diseases, and neurology, including physical, neuro-
logical, and neuropsychological examinations, in addition to life
stress and psychiatric interview assessments. These were performed
at 6-month intervals.
At each study visit, stressful life events over the preceding 6 months
were measured. We used the 1993 CDC criteria to quantify disease
Am J Psychiatry 154:5, May 1997
EVANS, LESERMAN, PERKINS, ET AL.
progression, which is defined as a change of one or more stages (e.g.,
from A2 to B2) in the nine HIV disease stages. To rule out the possi-
bility that severe life stress could result from disease progression, in
all of the analyses, HIV-related stresses were omitted, and only
stresses that preceded disease progression were counted (for example,
if the subjects first change in disease stage was noted to have occurred
during the 18- to 24-month assessment visit, severe stress per unit of
time was calculated for the first 18 months). Thus, the level of severe
life stress preceding disease progression (stress per unit of time) was
computed for each subject and entered into the analyses.
Assessment of Stressful Life Events and Psychiatric Status
To obtain information about stressful life events and difficulties,
we used a semistructured interview that is a modified version of the
Psychiatric Epidemiology Research Interview (13). Trained inter-
viewers questioned subjects in detail about the events and difficulties
they endorsed, and these stresses were later rated with the use of a
method similar to that developed by Brown and Harris (14), which
has been modified by Grant et al. (11) for studies of HIV infection.
Two raters (J.L., C.M.) were trained in the rating method at the HIV
Neurobehavioral Research Center in San Diego. On the basis of this
training, we subsequently developed a stress rating manual contain-
ing a detailed set of norms and vignettes for rating each of 111
stresses. Subjects indicated which of the 111 stresses they had experi-
enced during the preceding 6 months (e.g., death of mate, arrest,
trouble with boss, chronic financial difficulty, breakup of love rela-
tionship). The stress ratings were designed to measure stressful life
events and difficulties objectively by taking into account the contex-
tual aspects of each stress. The norms for each stress were thus based
on the degrees of threat that most people would experience given
particular circumstances (e.g., financial impact, degree of control, life
threat, personal involvements, nature of relationship to others in-
volved). The degree of threat refers to the unpleasantness and uncer-
tainty that most people would experience given the same circum-
stances experienced by the subject. For example, the long-term stress
associated with the breakup of a committed relationship was based
on the length of time the two were together, whether the subject lived
with the person, whether the subject had control over the decision,
and any other extenuating circumstances. The contextual threat rat-
ing is made independent of the subjects rating of the threat and of the
subjects way of coping with the stressor. We removed from the stress
scores any stresses that could be caused by disease progression (e.g.,
onset of symptoms of AIDS-related complex, job loss due to demen-
tia, mate leaving because disease worsened). Furthermore, the contex-
tual threat rating, independent of the subjects rating, helps eliminate
the possibility that worsening disease may lead to poorer coping and
higher stress scores. In these ways, we attempted to avoid confound-
ing the independent and dependent variables and thus tried to exclude
the possibility that worsening disease might have caused the stress.
One of the two trained raters used the manual to rate the long-term
impact of each stressful event on a scale from 0 (no threat) to 4 (most
severe threat). Subjects were then given a stress score based on the
total of severe stress ratings (those rated 3 or 4). The following are
examples of severe stresses: death of a family member or close friend,
life-threatening illness or deteriorating health of a close family mem-
ber or close friend, serious assault, rejection after disclosure of HIV
status, and breakup with a long-term committed partner. Raters
agreed on the exact severe stress rating in 81% of cases (kappa=0.70)
and disagreed on whether a stress was severe only 2% of the time.
Current and lifetime DSM-III-R axis I diagnoses were assessed by
a trained psychiatric clinician with a modified version of the Struc-
tured Clinical Interview for DSM-III-R (15, 16) at the subjects entry
into the study and at every 6-month visit. Diagnoses were assigned at
a diagnostic conference after review of all available clinical informa-
tion. We have used a videotape format to assess interrater reliability,
which has been good (kappa=0.75 for major depression and
kappa=0.72 for anxiety disorders). Trained psychiatric clinicians fur-
ther evaluated symptoms of depression with the 17-item Hamilton
Depression Rating Scale (17) at entry into the study and at every 6-
month visit. Interrater reliability for the Hamilton depression scale
has been excellent (intraclass correlation coefficients of 0.99).
631
SEVERE LIFE STRESS AS PREDICTOR
FIGURE 1. Effect of High and Low Stress on HIV Disease Progression
in 93 Mena
aWithout control for other variables.
Statistical Analyses
We used three approaches to deal with the complexities of the
disease progression categories, analyzing the time from entry into
the study to the first disease progression, the incidence of first prog-
ression events, and the severity of the first disease progression. The
time to the first disease progression (for all 93 subjects) was ana-
lyzed by proportional hazard (Cox model) survival analysis (18).
This model was chosen because it could accommodate varying
times under study for the different subjects, as well as control for
other important predictors of disease progression. The survival
analysis (PROC PHREG, SAS [19]) was used to determine whether
severe life stress (stress/time) from entry into the study to the time
period before disease progression was a significant predictor of
first disease progression. For subjects with at least 24 months of
follow-up, the probability that any progression was observed dur-
ing the follow-up was modeled as a function of average stress over
all visits by means of logistic regression (20). The severity of the
first progression event was incorporated into the analysis with the
use of the proportional odds logistic regression model (20). These
last two analyses were used to provide confirmation of the results
of the survival analysis. In all three approaches, stress was repre-
sented in the analysis as the mean severe stress score from all visits
before disease progression. With this approach, the visits over
which stress is averaged depend on the outcome, but no mechanism
that would bias the results on this account is apparent to us. The
other potential influences on disease progression included in the
model were age, race, education, tobacco use, CD4+ cell count at
the time of entry into the study, and antiviral drug use.
RESULTS
The majority of the subjects (79%) were white, the
median age at study entry was 29 years, and the average
number of years of education was 14. All subjects were
without symptoms (1993 CDC-defined HIV stage A) at
study entry. Analyses for the 93 subjects showed that in
38% (N=35) of them, HIV disease progressed at least
one stage. The results of the survival analysis indicate
that the more severe the life stress experienced, the
greater the risk of early HIV disease progression (pa-
rameter estimate=0.23; Wald 2=4.85, df=1, p=0.03;
risk ratio=2.0). Thus, for every one unit (one severe
632
stress per 6-month study interval; range=0 to 3.3 units),
the risk of disease progression doubled. A graphical
presentation of the survival curves for the low- and high-
stress groups (based on a mean split) is given in figure
1. In this context, survival implies no progression in
disease state.
To gain a better understanding of the relation be-
tween severe life stress and first disease progression, we
then focused on those subjects (N=66) who had been in
the study group for at least 24 months. This subgroup
represents individuals who have been followed for a
longer time and therefore have a higher likelihood of
experiencing disease progression. Among these 66
HIV-positive men, 42% (N=28) progressed one or
more CDC stages, and 24% (N=16) progressed to clini-
cal stage B or C during 2442 months of follow-up. We
conducted analyses using logistic regression to examine
disease progression in these subjects. The analyses
showed that higher severe life stress increased the odds
of developing HIV disease progression nearly fourfold
(parameter estimate=0.44; Wald 2=5.57, df=1, p=0.02;
odds ratio=3.7). To determine whether the severity or
degree of disease progression was also predicted by
level of life stress (defined by the number of CDC stages
a subject advanced), we used a proportional odds logis-
tic regression model. Higher levels of stress predicted
greater severity of first disease progression (parameter
estimate=0.14; Wald 2=3.48, df=1, p=0.06).
To examine the influence of depression on the timing
of disease progression, we used the Hamilton depres-
sion scores, summed over all visits preceding any dis-
ease progression. We found no significant effect of de-
pression on disease progression and no significant
interaction between depression and stress for the time
until disease progression, after controlling for the other
predictors in the model.
DISCUSSION
These findings represent the first demonstration from
a prospective clinical study that severe life stress is as-
sociated with an increased rate of early HIV disease
progression. The findings build on earlier suggestions
that psychosocial factors such as stress and depression
may be predictive of human morbidity and mortality
(21). More recently, the influence of psychosocial fac-
tors on the course and outcome of medical illnesses in
general, as well as specific illnesses such as cardiovas-
cular disease, has been studied. For example, there is
evidence suggesting that depression is associated with
increased mortality in elderly nursing home patients
(22) and in patients after myocardial infarction (23).
Furthermore, since the initial report by Bartrop et al.
(24) that demonstrated reduced lymphocyte function
following the severe stress of bereavement, extensive in-
vestigation has been devoted to the effects of stress and
depression on immunity.
Although there is now considerable evidence that
stress and depression are associated with alterations in
Am J Psychiatry 154:5, May 1997

cell-mediated immunity, the role of emotional factors in
the onset and course of immune-based diseases has not
been firmly established (2, 4, 10). In fact, McGee and
colleagues (6) recently concluded that the studies avail-
able so far do not permit any firm conclusions regard-
ing the relation between life events and the onset of
breast cancer. However, several reports suggest that
stress is associated with the host defense against viral
infection as well as cancer. Specifically, it has been dem-
onstrated that psychosocial stress is associated with a
higher rate of acute infectious respiratory illness (i.e.,
the common cold) (25), and life event stress has been
associated with recurrence of breast cancer in women
(7). Similarly, psychosocial interventions (group psy-
chotherapy/social support aimed at reducing stress)
have been reported to increase survival in women with
recurrent breast cancer (8) and in women and men with
malignant melanoma (26). Although the potential bio-
logical mechanisms underlying these findings have not
been elucidated, Fawzy and colleagues (27) found an
increase in natural immunity (natural killer cell activity)
in patients with malignant melanoma who received a
group intervention.
Since the beginning of the AIDS epidemic, consider-
able attention has been focused on the effect of psy-
chosocial factors on the clinical course and outcome of
HIV infection. At present, however, the findings of
studies assessing the effects of stress and depression on
HIV disease progression have been inconsistent. In
part, this may be due to the methods used to address
this question. Most of the available data are derived
from population-based epidemiological studies, which
have understandably relied solely on self-report ques-
tionnaires to measure life stress and depression. It has
been emphasized that considerable measurement error
may be associated with questionnaire-generated esti-
mates of stress or depression (13, 14, 28, 29). For ex-
ample, one large community-based study (30) found no
relation between depressive symptoms and either a
drop in CD4+ cells or progression of HIV infection,
while a similar study that used the same self-report
questionnaire to measure depressive symptoms (31)
found a significant relation between depression and
CD4+ cell decline. Similarly, Rabkin et al. (32) and
Perry et al. (33) used clinician-administered assess-
ments of life events and found no relation between life
events and CD4+ cell decline over 6 and 12 months,
respectively. The authors of a recent meta-analytic re-
view (10) concluded that neither stress nor depressive
symptoms appear to accelerate HIV disease prog-
ression, but they found that stressed HIV-infected indi-
viduals exhibit reductions in the number and function
of natural killer cells; the authors recommended that
future investigations focus on population-specific
stressors to determine whether reduction in killer lym-
phocytes influences HIV disease progression.
For these reasons, longitudinal cohort studies using
more in-depth psychiatric and psychosocial assessment
methods are critical for gaining a better understanding
of the effects of psychosocial variables on immunity and
Am J Psychiatry 154:5, May 1997
EVANS, LESERMAN, PERKINS, ET AL.
HIV disease progression. However, studies of this type
are labor-intensive. A potential limitation of this ap-
proach, which applies to the present study, is the rela-
tively small size of the study group in comparison with
groups in larger population-based investigations.
Nonetheless, it is notable that Ramirez and colleagues
(7), using interview-based stress assessments quite simi-
lar to those used in our study, showed that severe life
stress increased the likelihood of relapse in women with
breast cancer nearly sixfold. The present study used
comprehensive interview-based assessments to quantify
life stresses as well as depression. Thus, the advantages
compared to questionnaire-generated measures of
stress and depression (30, 31) or less comprehensive in-
terview-based assessments (32, 33) could be a substan-
tial factor accounting for our prospective observation
that severe life stress predicts both the likelihood and
severity of early HIV disease progression measured by
CDC stage.
It is important to note that stress was assessed every
6 months in this study and that only stresses that pre-
ceded disease progression were counted. Thus, if the
subjects first disease change occurred between the 24-
month and the 30-month assessments, severe stress per
unit of time was calculated for the first 24 months;
stress during the 24- to 30-month period was not
counted, in order to rule out the possibility that the
disease change preceded the stressful life event. We
also eliminated life event stresses caused by HIV dis-
ease progression, since disease progression itself could
result in stress. In addition, the stress rating was objec-
tive and independent of the subjects perception of or
way of coping with the stress, in order to avoid the
possibility that disease progression would result in
worse stress ratings.
In summary, converging evidence obtained from sev-
eral different statistical analytic strategies in the present
study demonstrates that severe life event stress is pre-
dictive of early HIV disease progression in men. These
prospective data show that greater levels of severe stress
are associated with both an increased likelihood and
greater severity of early HIV disease progression. The
increased risk ratio observed in the subjects studied for
a longer period of time (24 months or more) appears to
be related to the greater time frame in which to assess
severe life stress and the greater percentage of patients
who have experienced disease progression over this ex-
tended time frame. Since only 42% of the subjects ex-
perienced disease progression during the course of the
current study, continued assessment of this ongoing
study group and future analyses may demonstrate
greater effects of stress on disease progression as sub-
jects experience a greater rate and degree of disease
progression. Thus, our current estimate may well un-
derestimate the true risk ratio and therefore under-
state the actual influences of severe stress on disease
progression. It is critical to note that only severe stress
had an effect on early HIV disease progression; the lev-
els of stress common to everyday living did not have
this effect. Further study will be necessary 1) to shed
633
SEVERE LIFE STRESS AS PREDICTOR
light on the potential immune or other biological fac-
tors that may underlie this relationship; 2) to estimate
the true risk/ odds ratio of severe life stress and early
HIV disease progression; 3) to determine whether stress
predicts faster progression and the likelihood of ad-
vanced HIV disease progression and survival; and 4) to
replicate these findings in HIV-positive women.
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