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INTRODUCTION
METHODS
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Psychological stress can lead to asthma exacerbations in some patients. It is our hypothesis that the stress effect can occur through an
enhancement of allergic inflammatory response. To investigate this
possibility, airway antigen challenge was evaluated in 20 college students with mild asthma during both a low-stress phase (midsemester or two weeks postfinal examination) and a stress phase (final
examination week). Subjects completed questionnaires to assess
psychological state and underwent inhaled antigen challenge. Sputum samples were collected before challenge, and six and 24 hours
and seven days postchallenge. Leukocytes were counted and eosinophil-derived neurotoxin (EDN) was measured in sputum supernates. Sputum cells were cultured and stimulated ex vivo with phytohemagglutinin (10 µg/ml), and culture supernates were assayed for interleukin-5 (IL-5) and interferon-
by enzyme-linked immunosorbent
assay. Sputum eosinophils and EDN levels significantly increased at
six and 24 hours postchallenge and were enhanced during the stress phase (p < 0.01). IL-5 generation by sputum cells was also increased at 24 hours during stress and correlated with airway eosinophils (rs = 0.65, p < 0.05). Students' anxiety and depression scores were
significantly higher during the examination period. Our findings suggest that stress associated with final examinations can act as a
cofactor to increase eosinophilic airway inflammation to antigen
challenge and thus may enhance asthma severity.
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INTRODUCTION |
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ABSTRACT
INTRODUCTION
METHODS
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Keywords: stress; allergy; sputum induction; eosinophil; interleukin-5
Stress and other psychologic factors have long been hypothesized to be associated with asthma symptoms and in some individuals may cause a reduction in pulmonary function (1, 2). For example, in response to an acutely distressful experience, such as watching emotionally charged films (3) or listening to stressful interactions (4), some asthma patients experience increased bronchoconstriction. Asthma may also be exacerbated by depression and anxiety, especially in patients who have low social support (5-7). These observations suggest a role for psychologic factors in the course and severity of asthma.
The mechanisms linking stress and asthma, however, are not
well defined. One contributing factor may be the effect of stress on inflammatory and immune processes. Psychologic stress activates the hypothalamic-pituitary-adrenocortical axis and sympathetic nervous system, increasing the secretion of cortisol and
catecholamines (8). Cortisol and catecholamines are known to
affect natural killer cell activity, T-cell proliferation, expression
of interleukin (IL)-2 receptor, interferon (IFN)- generation,
and the expression of IL-12 and its receptor (9). By suppressing
cell-mediated immunity and Th1-type cytokines, such as IL-12
and IFN-, the experience of stress may shift the immune response toward a Th2 phenotype, which could aggravate existing
inflammation and be reflected in an enhanced inflammatory response following an inhaled antigen exposure.
In a pilot study, we had evaluated the effect of acute stress,
a 30-minute stressful interview, on the airway response to inhaled antigen and the generation of cytokines by peripheral blood mononuclear cells (PBMC). Using this protocol, we did
not find the acutely stressful interview to have an effect on the airway response to antigen or the in vitro generation of cytokines by circulating PBMC. In contrast, in another study, we
did find that a more sustained stressful life event, academic examinations, was associated with greater changes in the immune responses (10). When cytokine generation by PBMC
was evaluated before, during, and after final examination
week, different Th2 cytokine profiles were observed in healthy
and asthmatic students. In normal students, IL-5 generation was
decreased during examinations, whereas in students with asthma,
higher levels of IL-5 and lower levels of IL-2 and IFN- were
maintained during this stressful school examination period. A
similar pattern was found in IL-4 production, thus suggesting a
stress-induced propagation of Th2 activity.
The goal of the following study was to test the hypothesis that a relatively chronic stressful life event, such as final examinations, would enhance the airway inflammatory response to antigen. Specifically, we postulated that increased IL-5 generation would promote eosinophil recruitment to the airway in response to allergen exposure during the examination week.
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METHODS |
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INTRODUCTION
METHODS
RESULTS
DISCUSSION
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Subjects
Twenty undergraduate college students (nine males, 11 females) with mild allergic asthma were studied (Table 1). Each subject had a positive skin-prick test and a history of asthma with previous use of asthma medication. During the study, no subjects required inhaled corticosteroids, had evidence of a respiratory infection, or had an asthma exacerbation within the previous four weeks. The study was approved by the University of Wisconsin-Madison Health Sciences Committee, and informed consent was obtained from each subject.
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Study Design
The study design was a randomized, two-period crossover study (Figure 1). A screening evaluation included baseline spirometry, methacholine responsiveness, and skin-prick test. A graded inhaled antigen challenge (ragweed, cat dander, or house dust mite) was performed to determine the dose of antigen that caused an immediate fall in forced expiratory volume in 1 second (FEV1) of at least 20% (see online data supplement). This same dose of antigen was given for the subsequent antigen inhalation challenges in each study phase. Subjects were evaluated on two separate occasions. The low-stress assessment was conducted during midsemester or at least two weeks after final examinations. The duration of final examination time lasts around 7-10 days. The stress phase took place during the final examination week (after three examinations and before the last one). Study phases were randomized to control for an order effect. At the initial visit in each study phase, psychological questionnaires (Speilberger's State Trait Anxiety Inventory [STAI] [11], Beck's Depression Inventory [BDI] [12]) were administered to determine anxiety and depression levels. Baseline spirometry was performed before whole lung antigen inhalation challenge. Sputum was induced before challenge and again six and 24 hours postantigen challenge. In six subjects, sputum samples were also obtained seven days postchallenge. Blood samples were collected at each sputum induction to determine the white blood cell count and differential. All the baseline samples were obtained in the morning during either the low-stress or the stress phase.
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Sputum
Sputum inductions were performed as previously described (13). Sputum samples were treated with 0.1% dithiothreitol (Sputolysin; Calbiochem Corp., San Diego, CA). Sputum cells were collected for cell
counts and differential. Adequate sputum cells were obtained from 11 out of 20 subjects for cell culture experiments. Sputum cells were cultured (48 hours) with 10 µg/ml phytohemagglutinin (PHA; Sigma, St.
Louis, MO), and cytokines (IL-5 and IFN-) were measured by enzyme-linked immunosorbent assay (13). The coating antibodies and biotinylated detection antibodies were purchased from PharMingen (San
Diego, CA). The sensitivities for IL-5 and IFN- detection were less
than 3 pg/ml and less than 12 pg/ml, respectively. Eosinophil-derived
neurotoxin (EDN) in sputum supernates was determined by competitive radioimmunoassay with a sensitivity of 2 ng/ml (14).
Plasma Cortisol Levels
Plasma samples were obtained between 8:00 and 10:00 A.M. before antigen challenge, and cortisol levels were determined by radioimmunoassay (Coat-A-Count Cortisol Kit; Diagnostic Products Corporation, Los Angeles, CA) with a sensitivity of 0.2 µg/dl.
Statistical Analysis
Data are presented as median with interquartiles of 25 and 75% or mean ± SEM (for normally distributed data). Wilcoxon's signed rank test (or a paired t test for normally distributed data) was used to compare different time points with their own baseline. Correlations were determined using Spearman's rank order correlation test. A p value of less than 0.05 was considered significant. Statistical analyses were performed using the SigmaStat software package (Jandel Scientific Software, San Rafael, CA).
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RESULTS |
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METHODS
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DISCUSSION
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Subject Characteristics
The decrease in lung function in response to inhaled antigen challenge was identical during the final examination and low-stress phases. The immediate drop in FEV1 was 21 ± 2% (mean ± SEM) in the examination and 19 ± 2% in the low-stress phase. The semester examinations did not have an effect on baseline lung function as measured by FEV1 (92.4 ± 2.4% low-stress versus 92.1 ± 2.8% during stress). All subjects produced a sputum sample when they inhaled hypertonic saline for 20 minutes. The percentage of squamous and epithelial cell contamination in the whole sputum samples was 23.8 ± 1.5%. The sputum leukocytes viability was 76.4 ± 0.7%. All subjects tolerated sputum induction with no adverse effects.
Effect of Final Examination on Plasma Cortisol Levels and Anxiety/Depression Indices
Plasma cortisol levels were not significantly increased during examination week (21.9 ± 2.1 µg/dl low-stress versus 24.6 ± 2.7 µg/dl stress). The psychological assessment indicated that although none of the students exhibited clinical levels of anxiety or depression, there was a small but significant increase in their emotional distress, as indicated by increases in STAI (30 ± 0.9 low-stress versus 33 ± 0.8 stress) and BDI scores (1.7 ± 0.5 low-stress versus 3.4 ± 0.8 stress) during the final examination week (Figure 2).
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Effect of Final Examination on Sputum and Blood Leukocytes After Antigen Challenge
As seen in Figure 3A, antigen challenge increased sputum total leukocytes at six and 24 hours postantigen challenge (p < 0.01) during both the examination and low-stress phases. However, the increase in sputum leukocytes was greater in the final examination week (148 [81-185] × 104 per gram sputum at six hours and 161 [92-288] × 104 per gram sputum at 24 hours postantigen challenge; medians with 25-75% interquartile range) when compared with the low-stress phase (79 [53-190] × 104 per gram sputum at six hours and 105 [62-215] × 104 per gram sputum at 24 hours, p < 0.01, respectively). This increase in sputum leukocytes was limited primarily to eosinophils. The baseline level of sputum eosinophils was similar during the examination (1.0% [0.1-2.5%]) and low-stress phase (1.0% [0.5- 2.5%]) (Figure 3B). After antigen challenge, the percentage of sputum eosinophils increased significantly during both study phases; however, sputum eosinophilia was greater at the time of final examinations compared with the low-stress phase (7.0% [3.0-11.0%] low-stress versus 10.5% [6.5-15.0%] stress, p < 0.05, at six hours and 7.0% [4.0-12.0%] low-stress versus 11.3% [4.8-20.8%] stress, p < 0.01, at 24 hours postantigen challenge). Furthermore, in the stress phase, sputum eosinophil counts remained detectable on Day 7 postantigen challenge (2.3% [1.0-6.0%] low-stress versus 10.3% [0.1-17.5%] stress). In addition, the percentages of sputum lymphocytes during the stress phase were increased six hours postantigen challenge when compared with the low-stress phase (7.0% [5.0-9.5%] low-stress versus 8.8% [7.0-12.0%] stress, p < 0.01) (Figure 3C). The increase in sputum eosinophils and lymphocytes resulted in a corresponding reduction in the percentage of sputum macrophages and neutrophils following antigen challenge during both phases (data not shown).
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p < 0.05, 
p < 0.01, stress versus low-stress.
During final examinations, the percentage of blood eosinophil counts was significantly increased at baseline and 24 hours postantigen challenge compared with the low-stress phase (2.0% [1.0-2.0%] low-stress versus 2.5% [2.0-5.0%] stress at baseline and 2.5% [2.0-4.0%] low-stress versus 5.0% [3.0-6.0%] stress at 24 hours, p < 0.05). Again, there was a marginal increase in blood eosinophils seven days postantigen challenge during examination week (1.5% [1.0-4.0%] low-stress versus 3.5% [3.0- 7.0%] stress) (Figure 4). Total peripheral white blood cell counts as well as lymphocyte, neutrophil, and monocyte differentials were unaffected by stress or antigen-challenge (data not shown).
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Effect of Final Examination on Sputum EDN Release After Antigen Challenge
Compared with preantigen challenge values, the levels of EDN in sputum supernatant fluid were significantly increased at six and 24 hours postantigen challenge during both the examination and low-stress phases (p < 0.01) (Figure 5). At six hours postantigen challenge, the levels of sputum EDN during examination week (366 ng/ml [194-622 ng/ml]) were significantly higher than those in the low-stress phase (288 ng/ml [101-447 ng/ml], p < 0.05).
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Effect of Final Examination on the Relationship of Changes in Pulmonary Function and Sputum Eosinophils
Although the changes in the percent predicted FEV1 between
baseline and 24 hours postantigen challenge were small during
the stress phase, the sputum eosinophils had a significant inverse correlation with the percentage change in FEV1 24 hours
postantigen challenge ([(24-hour FEV1 
baseline FEV1)/baseline FEV1] × 100; rs = 0.72, p = 0.001) (Figure 6). In other
words, at 24 hours postantigen challenge, subjects with a greater
increase in sputum eosinophils had a greater fall in their FEV1.
There was no correlation between sputum eosinophils and the
percentage change in FEV1 during the low-stress phase.
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Effect of Final Examination on PHA-induced Cytokine Production from Sputum Cells After Antigen Challenge
Eleven of 20 subjects produced a sufficient number of cells
(> 2 × 106 leukocytes) to perform cell culture experiments.
Spontaneous secretion of cytokines from unstimulated sputum
cells was below detection during both the examination and low-stress phases. At baseline and six hours postantigen challenge,
PHA-induced IL-5 generation by sputum cells was low, but detectable (Table 2). During the low-stress phase, there were no
significant changes in PHA-induced cytokine generation. In
contrast, during the final examinations, sputum samples obtained 24 hours postantigen challenge had a significant increase
in IL-5 production (78 pg/ml [63-95 pg/ml]) compared with the
baseline (17 pg/ml [4-36 pg/ml], p < 0.01) and the low-stress
phase at 24 hours postantigen challenge (18 pg/ml [6-51 pg/ml],
p < 0.01). Furthermore, during examination week, PHA-induced
sputum cell production of IL-5 significantly correlated with the
absolute number of sputum eosinophils at 24 hours postantigen
challenge (rs = 0.65, p < 0.05). PHA-induced IFN- generation
was significantly decreased at six hours postantigen challenge
during the stress phase (p < 0.05) (Table 2).
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Effect of Final Examination on IFN-/IL-5 Ratios and
Relationship to Sputum Eosinophils After
Antigen Challenge
PHA-induced sputum cell production of cytokines was also
evaluated as the ratio IFN-/IL-5. An increase in this ratio
would indicate a skew toward a Th1 response. The ratio IFN-/
IL-5 was significantly decreased at six hours (3 [1-7], p < 0.05)
and 24 hours (4 [3-5], p < 0.01) postantigen challenge compared with their baseline (12 [5-37]) during the stress phase
(Table 2). A small, but significant, decrease in the IFN-/IL-5
ratio was also noted at six hours postchallenge (p < 0.05) in
the low-stress phase. These ratios returned to baseline values
by Day 7 postantigen challenge (Table 2). Furthermore, during
the stress phase, the ratio IFN-/IL-5 had a striking inverse correlation with the absolute number of sputum eosinophils at 24 hours postantigen challenge (rs = 0.72, p < 0.01, Figure 7).
There was no correlation between IFN-/IL-5 ratio and sputum eosinophils during the low-stress phase.
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DISCUSSION |
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INTRODUCTION
METHODS
RESULTS
DISCUSSION
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In the present study, we found that a final examination period,
and presumably the stress associated with this event, was associated with enhanced sputum eosinophilia and EDN levels at six and 24 hours postantigen challenge. Moreover, during this stressful period, the decrease in FEV1 (before challenge to 24 hours postantigen challenge) correlated with the increase in
airway eosinophils 24 hours after antigen challenge. To our
knowledge, this is the first study to show that allergen-induced
airway eosinophilia can be significantly augmented during a
period of stress. In addition, we demonstrated that following
antigen challenge, the increase in PHA-induced IL-5 generation by sputum cells was further enhanced during examination
week and correlated with the airway eosinophilia. This change
resulted in a greater decrease in the IFN-/IL-5 ratio during
examination week, which showed a striking correlation with the recruitment of eosinophils to the airway. Our data suggest that psychologic stress associated with final examinations may augment the allergic response to inhaled allergen and this may become a potential mechanism for asthma exacerbations.
Psychologic stress has historically been implicated as a significant contributor to the onset and exacerbation of asthma symptomatology (15), but the underlying mechanisms linking stress and asthma have not been well defined. It is proposed that stress modulates immune responses, leading to altered cell trafficking and functions, such as lymphocyte proliferation, natural killer cell cytotoxicity (16), and lymphocyte production of cytokines (17-19). Prior studies on the effects of stress and school examinations on immune responses have typically relied on an analysis of peripheral blood cells, which may not necessarily be reflective of cells at specific tissue sites such as the airways. Our findings indicate that stress may increase recruitment of eosinophils into the airways and also magnify EDN release at this time. These findings further confirm that stress can be a factor in amplifying airway inflammation to an allergic stimulus and thus contribute to asthma exacerbations.
Psychological stress has been shown to shift the relative proportion and trafficking of Th1 and Th2 cells to a Th2 phenotype (10, 20, 21). T-cell cytokines and chemokines, principally IL-4 (22, 23), IL-5 (13, 24, 25), eotaxin (24, 26), and RANTES (27, 28), have been reported to regulate the development of airway eosinophilia. Our evaluation of IL-5 generation relied on stimulation of sputum cells with PHA. We could not measure IL-5 directly in the sputum supernate from the induced samples. It is possible that cytokines and chemokines are degraded by proteinases or bind to sputum mucus, becoming undetectable (29). In previous studies (13, 30), we have found that the ex vivo generation of IL-5 by bronchoalveolar lavage and sputum cells may be a surrogate marker of in vivo airway cell cytokine generation. In the present study, we determined sputum cell production of cytokines ex vivo as an indicator of the cell's capability to generate cytokines in vivo. During the stress period, we noted that the degree of PHA-induced IL-5 generation was significantly increased from sputum cells obtained 24 hours after antigen challenge and that these values correlated with the absolute numbers of sputum eosinophils. Interestingly, during the final examination phase, the percentage of blood eosinophils was significantly increased both at the baseline assessment (preantigen challenge) and 24 hours postantigen challenge compared with the low-stress phase. We speculate that the change in circulating, i.e., constitutive, concentrations of eosinophils represents an alteration in the baseline values themselves and reflects the effect of stress on this parameter. Furthermore, the change in baseline circulating eosinophil values may provide more eosinophils for recruitment to the lung and thus the increase in sputum eosinophils during the final examination period. The source of increased peripheral blood eosinophils has not been determined, but may be due to the increased production and release from bone marrow or other organs (e.g., spleen and liver), margination to blood vessel walls, and recirculation (if it occurs) from the tissues.
We (10), and others (20, 31), have previously demonstrated changes in cytokine release during a time of stress. However, the observation of an increase in IL-5 and a shift toward a Th2 phenotype in airspace cells in asthma patients during stress is new and may indicate an alteration in airway inflammation. Several investigators (32-34) have noted that stress-induced change in immune response can be site-specific, such that cells in one region are inhibited, while unaffected or even enhanced in other tissues. Our data suggest that psychologic stress associated with school examinations can produce a shift in the Th1/Th2 cytokine balance toward a Th2 response and result in greater airway eosinophilia.
The use of induced sputum following allergen challenge allowed us to obtain markers of airway inflammation and cytokine generation during two typical periods in the academic life of asthmatic students. There are, however, limitations to our study. First, the stress of the final examination was not sufficient to cause a significant deterioration in lung function or to spontaneously worsen their asthma symptoms. The absence of significant pulmonary changes may relate to our selection of only patients with mild asthma. Furthermore, the intrinsic psychologic makeup of the stressed individual may affect their responses. For example, four subjects withdrew from our study during the examination week because of their associated stress at that time, suggesting that subjects who completed the study were possibly better able to cope with such stressful situations. Nonetheless, even in these students, who did not overtly manifest stress or increased asthma symptoms, the percent change in FEV1 after antigen challenge was significantly correlated with their airway eosinophilia. Thus, the stress appeared to act as a cofactor to the allergic reaction to prime or enhance the airway to a second stimulus, i.e., inhaled antigen. We cannot exclude the possibility that subjects had other factors, i.e., greater environmental allergen exposure or changes in life style (e.g., dietary or sleep patterns), which also contributed to the response to inhaled allergen. Kiecolt-Glaser and Glaser (35), however, reported that although it is known that students sleep less and alter their dietary patterns during examination week, studies have not been able to relate the degree of immune changes on the basis of either sleep disruption or changes in eating behavior. To minimize the effects of environmental allergen exposure on our study parameters, we randomized the timing of the initial antigen challenge to control for order effects and the relationship to seasonal periods. Consequently, some antigen challenges were performed at the end of the fall semesters, i.e., January, and some were performed at the end of spring semesters, i.e., May/ June. Because the changes in response to inhaled antigen were similar following the examination, we feel that this may represent the effects of the examination and not a challenge associated with environmental antigen exposure.
It should also be acknowledged that it is difficult to objectively define and quantify stress in humans. Nonetheless, our psychological assessment did document a small increase in negative emotion, both anxiety and dysphoria, in these psychologically normal students. As noted by others (20, 31, 36), we could not show a sustained increase in cortisol levels. But it is possible that other stress hormones (e.g., corticotrophic hormone releasing factor, epinephrine, norepinphrine, or other catecholamines) have a greater influence on stress-induced immune changes (37). In addition, it is possible that whereas the blood was collected during the early morning, the effects of daily stress are more manifest in association with the afternoon and evening levels of hormone activity (38).
In conclusion, this is the first study to indicate that at the time of stress, there is a significant increase in the number of eosinophils recruited into the airway following an inhaled antigen challenge and enhanced PHA-induced IL-5 generation by sputum cells. These data raise the possibility that stress enhances the likelihood of an eosinophil-driven inflammatory response to antigens. The simultaneous increase in peripheral blood eosinophils further raises the possibility that there is also a stimulus to the bone marrow or other sites of eosinophil production or storage, which would augment the production of eosinophils that can then be recruited into the airway if exposure to an allergen occurs.
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Footnotes |
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Correspondence and requests for reprints should be addressed to Dr. William W. Busse, Head of the Section of Allergy and Immunology, University of Wisconsin Hospital, K4/910-9988, 600 Highland Avenue, Madison, WI 53792. E-mail: wwb{at}medicine.wisc.edu
(Received in original form September 19, 2001 and accepted in revised form January 10, 2002).
This article has an online data supplement, which is accessible from this issue's table of contents online at www.atsjournals.orgAcknowledgments: The authors wish to thank Ann Dodge, B.S.N., and Mary Jo Jackson, B.S.N., for assistance with patient recruitment, screening, and sputum inductions.
This work was supported in part by a grant from the Fetzer Institute and an institutional Specialized Center of Research grant, HL56396, from the National Institutes of Health.
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References |
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INTRODUCTION
METHODS
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