Gender Differences in Stress and Upper Respiratory Tract Infections: A Closer Look

doi:10.21203/rs.3.rs-5000233/v1

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Research Article

Gender Differences in Stress and Upper Respiratory Tract Infections: A Closer Look

https://doi.org/10.21203/rs.3.rs-5000233/v1

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Background:

Infectious diseases are influenced by both sex and gender, with psychosocial stress potentially playing a critical role, particularly in upper respiratory tract infections (URTIs). Despite existing evidence, a comprehensive analysis of the interplay between sex, gender, stress, and RTIs is lacking.

Methods:

Our monocentric, prospective study included 273 healthy individuals (cohort H) and 194 patients with hematological cancer (cohort P) who had undergone stem cell transplantation, enrolled between 11/2013 and 05/2017. Eligible participants were aged 18 years or older. Data collection encompassed demographics, household composition, smoking behavior, cancer-related characteristics, RTI-symptoms, and perceived stress, measured using the 4-item perceived stress scale (PSS-4). Participants were categorized based on biological sex, without assessing gender identity. For analysis, we assumed that sex and gender were aligned.

Results:

In cohort H, 50% of the participants were female, with most individuals aged ≤ 30 years. Women experienced notably more moderate to severe URTI symptoms than men (57% vs. 36%, p < .001, φ = 0.210). Additionally, women across all age groups also exhibited higher PSS-4 levels than men [t(271) = 2.84, p < .001, d = -0.636] and the PSS-4 was significantly affected by sex [F(1, 261) = 22.22, p < 0.001, η² 0.078]. In cohort P, 40.5% of the patients were female, with the majority aged ≥ 30 years. The occurrence and severity of RTI symptoms were more pronounced in men than women. The PSS-4 was not affected by sex. Unlike in cohort H, a significant correlation between the PSS-4 and RTI symptoms was found for both sexes in cohort P. In both groups, the lowest stress levels were observed in individuals over 60 years old.

Conclusion

Perceived stress was higher in younger women, as was the occurrence and severity of URTIs. However, a significant correlation between stress and URTIs was found only in patients with cancer, suggesting a more complex interaction between sex, gender, stress and URTIs in individuals with compromised health as compared to healthy individuals, which deserves further study.

Trial registration:

Registry: the German Clinical Trials Register

Gender disparities

stress

upper respiratory tract infections (URTIs)

stem cell transplantation

psychosocial factors

health behavior

cancer

Both psychosocial and biological factors decisively affect the susceptibility, progression, and outcomes of infectious diseases. During the pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), for example, transmission rates were highest in precarious and overcrowded housing conditions. Furthermore, incidence and mortality were disproportionately elevated among socioeconomically disadvantaged and socially marginalized groups, with men facing a greater risk of severe outcomes and mortality compared to women within these populations (1–4). Further relevant risk factors identified include age, obesity, and multimorbidity (5, 6). Notably, similar patterns are also observed in other infectious diseases (7–10). This potpourri of aggravating factors strongly supports the interplay between psychosocial and biological determinants within different population subgroups.

The influence of sex (biological) and gender (socially constructed) on respiratory infectious diseases has been described previously, although their roles have yet to be fully explored (11, 12). For example, women are more commonly affected by mild upper respiratory tract infections (URTIs) such as sinusitis, tonsillitis, and otitis, while men tend to experience more severe lower respiratory tract infections (LRTIs), including bacterial and viral pneumonia (13–17). For example, in seasonal influenza, hospitalization rates are higher in males than in females across all age groups, with mortality rates peaking among children and the elderly (18–20). Notably, data from Denmark reveal that the risk of hospitalization changes at puberty, with women of reproductive age being at higher risk (21). In cases of pandemic influenza and outbreaks, disease severity tends to be greater in women of reproductive age compared to their male counterparts (22, 23). For instance, during the H1N1 pandemic in 2009, Kumar et al. reported that the majority of critically ill patients were young women, a finding echoed by other researchers (22, 24, 25). Several factors may contribute to these findings. The social construct of gender often assigns specific roles to women and men; for instance, women being more likely to take on caregiving responsibilities that involve extended contact with children or elderly people, spend more time at home, or work in health-related and care-taking fields, which leads to differing exposure patterns to pathogens. Moreover, women experience higher levels of psychosocial stress, increased health awareness, and greater utilization of the healthcare system are reported among women. Additionally, there are notable sex differences in genetic and epigenetic factors, as well as in steroid hormone levels, which affect comorbidities and immune responses (12, 24, 26–28).

The human immune response consists of two components: the innate and adaptive immune responses. Both components are essential for combating pathogens causative for infectious diseases while being influenced by several factors such as biological sex, age, reproductive status, and psychosocial stress (27, 29). Notably, adult premenopausal females tend to exhibit more robust innate and adaptive immune responses compared to males (30, 31).

Stress, a key mediator of health disparities, affects men and women differently, with women generally experiencing and/ or reporting more stress (32, 33). Stress can be defined as a threat to an individual’s integrity, which leads to a temporary adaptive process in the individual by triggering the release of stress-mediators, such as cortisol and catecholamines, through the activation of the hypothalamic-pituitary-adrenal axis (HPA) and the sympathetic axis (SA), increasing physiological responses necessary for the 'fight or flight' response (34–37). Both chronic stress and insufficient recovery contribute to overstimulation and exhaustion of the stress response, which can result in long-term health issues such as hypertension, diabetes, depression, and increased susceptibility to infections (38, 39). Cohen et al. first explored the relationship between stress and URTIs (40). In several viral challenge studies, higher levels of stress were associated with an increased likelihood of developing URTIs. Notably, individuals with higher PSS scores reported more severe symptoms and greater mucus production. Key stressors identified included chronic stress (≥ 1month), social conflicts, and job insecurity (41–44). While numerous studies over the few past decades have confirmed the link between perceived stress and the occurrence of URTIs, these analyses often lack gender disaggregation and do not thoroughly examine the complex interplay between sex, gender, stress, and URTIs (45–49). To address this gap, we conducted a post-hoc analysis of two prospectively recruited study cohorts to test the hypotheses that women experience higher stress levels than men, resulting in increased susceptibility to community-acquired respiratory viruses (CARV) and a greater burden of symptoms. We thereby explored how this might depend on age and pre-infection health by examining different age groups and performing the analysis in both a healthy cohort and a cancer cohort to understand whether stress and URTI patterns differ significantly between these populations.

Study Design and Population

This post hoc analysis is based on a monocentric, prospective study conducted at the University Hospital Jena, Germany. A total of 467 individuals were prospectively enrolled between November 2013 and May 2017, all during periods of CARV circulation. The study population comprised 273 healthy individuals (cohort H), primarily students and researchers at the University of Jena, and 194 patients who had undergone hematopoietic stem cell transplantation for cancer treatment at the University Hospital Jena (cohort P) and had thus an impaired immune system function. Eligible participants were aged 18 years or older. The study included at least three visits within 28 days for both cohorts. After providing written informed consent, participants completed an enrollment interview, which included questions about demographics, household composition (number of people and children per household), smoking behavior, and, if applicable, cancer specific features (immunosuppression, graft versus host disease (GvHD), and days since transplantation). Participants were categorized based on biological sex, without assessing gender identity. For analysis, we assumed alignment between sex and gender. The terms "males" and "men" as well as "women" and "females" were used interchangeably. During each visit, further surveys assessed the frequency and severity of URTI-associated symptoms (burden of URTI) and perceived stress. Additionally, upper respiratory tract specimens were collected and tested for respiratory viruses by multiplex PCR. Data on epidemiology were published by Rachow et al (50). The current analysis focuses solely on the first visit. Due to significant differences between them, the characteristics of cohorts H and P were analyzed separately.

Measures

Perceived stress was measured using the German version of the 4-item Perceived Stress Scale (PSS-4), which consists of four general questions about feelings and thoughts. This scale quantifies the extent to which respondents felt their lives were unpredictable, uncontrollable, and overwhelming over the past month (33, 51). The PSS-4 includes the following items: 1) How often have you felt that you were unable to control the important things in your life? 2) How often have you felt confident about your ability to handle your personal problems? 3) How often have you felt that things were going your way? 4) How often have you felt that difficulties were piling up so high that you could not overcome them? (51). In accordance with Herrero et al., responses were scored on a five-point scale, ranging from never (1) to very often (5) (52). After reversing the scores for the two positively worded items (Items 2 and 3), a total PSS-4 score was calculated by summing all four items. The internal consistency in the current study was Cronbach alpha = .78.

The study was approved by the local ethics committee (Nr. 3891-09/13) and is registered at German Clinical Trials Register (DRKS00005367).

Statistical analysis

Categorical variables were described as counts and percentages, while continuous variables were presented as means with standard deviation (± SD) or as medians with interquartile ranges (IQR). Where appropriate, data were analyzed with the Chi-square or Fisher’s exact test. The Phi coefficient (Φ) was used to assess relationships for categorical variables. For comparisons of continuous data, the two-sided t-test was employed. Cronbach`s alpha was used to examine internal reliability. Pearson`s correlation coefficient was used to measure the strength and direction of linear relationship between the PSS-4 and continuous variables (e.g., number of symptoms, age, number of housemates and children, number of cigarettes pe day). The pattern of relationship was visualized using scatterplots. Additionally, a one-way analysis of variance (ANOVA) was conducted to test the effect of sex, along with other covariates (e.g., smoking behavior, living/ housing situation, age in categories) on the PSS-4. Effect sizes were calculated for t-test (Cohens` d) and for analysis of covariance (ANCOVA, eta-square: η²). Effect sizes were interpreted according to Cohen’s benchmarks: small (d ≥ .2; η² = .01), medium (d ≥ .5; η² = .06), and large (d ≥ .8; η² = .14) (53). A significance level of 0.05 was used for all statistical tests. The analyses were performed using SPSS version 26 (IBM Inc., Armonk, NY).

Cohort H

The first cohort comprised 273 healthy individuals. An equal number of women and men were included, with the majority being under 30 years of age (Table 1). In both women and men, the number of individuals living alone was comparable, while women were more likely to have children compared to men (12% vs. 7.5%, p = 0.302), with most children being 10 years of age or younger. A slightly higher proportion of men than women reported regular smoking. Additionally, the average number of cigarettes smoked per day was nearly twice as high among male participants compared to their female counterparts (M = 11.65 (SD = 7.31) vs M = 6.95 (SD = 5.42), p = 0.068).

Table 1

Characteristics of the study samples, cohort H: healthy individuals
cohort H	Women, n/N (%) 137/273 (50)	Men, n/N (%) 136/273 (50)	p-value
Age
Median (IQR)	24 (20–29)	27 (22.25–36.75)	0.006
≤ 30, n/N (%)	108/137 (79)	90/136 (66)	0.198
31–40, n/N (%)	9/137 (6.5)	15/136 (11)
41–50, n/N (%)	6/137 (4.5)	12/136 (9)
51–60, n/N (%)	8/137 (6)	12/136 (9)
> 60, n/N (%)	6/137 (4.5)	7/136 (5)
Housing / living situation
Living alone, n/N (%)	27/137 (19.5)	24/136 (17.5)	0.756
Children, n/N (%)	16/135 (12)	10/134 (7.5)	0.302
Number of children, mean (+/-SD)	1.38 (+/-0.62)	1.5 (+/-0.53)	0.602
Smoking, n/N (%)	14/137 (10)	23/136 (17)	0.155
Number of cigarettes/ day, mean (+/-SD)	6.95 (+/-5.42)	11.65 (+/-7.31)	0.068
SD – standard deviation, IQR – interquartile range

At the time of sampling, the overall occurrence of symptoms did not differ significantly between sexes; however, further analysis revealed that women were significantly more likely to experience moderate and/or severe symptoms (Table 2, suppl. Figure 1a). Specifically, 57% of female participants and 36% of male participants reported experiencing moderate to severe symptoms, while 43.5% of females and 26.5% of males reported severe symptoms. The association between sex and severity of symptoms was weak (φ = 0.210, p = 0.181). Common symptoms included cough, sore throat, cold, and headache. Among all healthy participants, fewer than 10% tested positive for CARV-infection via PCR.

Table 2

Number and severity of URTI symptoms in the study samples at the time of sampling, cohort H: healthy individuals
Cohort H	Women, n/N (%) 137/273 (50)	Men, n/N (%) 136/273 (50)	p-value	Effect size
Symptoms at time of sampling
Symptoms at time of sampling, n/N (%)	113/137 (82.5)	106/136 (78)	0.366
No. of symptoms, Mean (+/- SD)	2.45 (+/- 1.67)	2.04 (+/- 1.65)	0.074
Moderate to severe symptoms, n/N (%)	78/137 (57)	49/136 (36)	< 0.001	φ 0.210
No. of moderate to severe symptoms, Mean (+/- SD)	0.88 (+/- 1.53)	0.64 (+/- 1.17)	0.142
Severe symptoms, n/N (%)	60/137 (43.5)	36/136 (26.5)	0.003	φ 0.181
No. of severe symptoms, Mean (+/- SD)	0.29 (+/- 0.71	0.16 (+/- 0.53)	0.088
PCR confirmed CARV-infection, n/N (%)	8/137 (6)	7/136 (5)	1.000
SD – standard deviation

In comparing the mean PSS-4 between women and men, women scored significantly higher than men [t(271) = 2.84, p < 0.001, d = 0.636]. Here, Cohens’ d indicates a medium to large effect size. Significant differences were observed for each of the four items (suppl. table 1, suppl. Figure 2a).

Detailed results on perceived stress among females and males across various age groups and living situations are presented in Table 3, Fig. 1a and Fig. 2. Notable peaks in perceived stress were observed in women under 30 years [t(196) = 2.78, p < 0.001, d = 0.601] and those aged 51 to 60 years [t(10) = 3.4, p = 0.415, d = 0.491]. However, the lowest level of the PSS-4 was found in women over 60. Pearson’s correlation coefficient indicated no significant association between PSS-4 scores and the number of URTI symptoms (Fig. 1a, Table 4). In contrast, among men, the PSS-4 decreased with increasing age, showing a statistically significant inverse correlation (r = -0.214, p = 0.013, Fig. 1a and 2, Table 4).

The lowest level of PPS-4 scores was found in men over 60. Correlations between PSS-4 scores and the number of URTI symptoms, daily cigarette consumption, and the number of children or housemates were not statistically significant. When sex was treated as an independent variable and the PSS-4 as a dependent variable, analysis of (co)variance revealed a significant effect for sex [F(1, 261) = 22.22, p < 0.001, η² = 0.078] and for age categories (≤ 30, 31–40, 41–50, 51–60, > 60 years) [F(4, 261) = 5.39, p = 0.021, η² = 0.02) on the PSS-4 score (Table 3).

Table 3

Perceived stress (means and standard deviations of PSS-4 scores) in the study samples, cohort H: healthy individuals.
cohort H	Women, n/N (%) 137/273 (50)	Men, n/N (%) 136/273 (50)	p-value	Effect size
All healthy individuals	10.4 (+/-2.78)	8.6 (+/- 2.89)	< 0.001	d 0.636°
Age*			0.020*	0.020*
≤ 30, (n = 198)	10.59 (+/-2.74)	8.92 (+/- 2.83)	< 0.001	d 0.662
31–40, (n = 24)	9.78 (+/- 3.63)	8.4 (+/- 2.92)	0.318	d 0.431
41–50, (n = 18)	9.33 (+/- 2.16)	8.25 (+/-2.41)	0.368	d 0.463
51–60, (n = 20)	10.71 (+/- 1.7)	7.58 (+/- 3.48)	0.041	d 1.053
> 60, (n = 13)	8.67 (+/- 3.56)	7.0 (+/- 3–22)	0.415	d 0.491
Housing / living situation
Living alone*			0.727*
Yes, (n = 51)	10.33 (+/-2.77)	8.6 (+/-2.83)
No, (n = 222)	10.7 (+/-2.87)	8.58 (+/- 3.23)
Children*			0.864*
Yes, (n = 26)	10.13 (+/- 2.80)	8.0 (+/- 2.40)
No, (n = 243)	10.46 (+/- 2.8)	8.67 (+/-2.94)
Smoking *			0.244*
Yes, (n = 37)	10.43 (+/- 3.01	8.13 (+/- 2.65)
No, (n = 236)	10.4 (+/-2.77)	8.7 (+/-2.94)
ANCOVA, covariates; °ANCOVA: p < 0.001, η² 0.078 SD – standard deviation

Table 4

Associations between study variables (Pearson correlation coefficients) in cohort H, female above and male below the diagonal
	No. of symptoms	No. of moderate to severe symptoms	PSS	Age	No. of daily cigarettes	No. of housemates	No. of children
No. of symptoms	1	.721*	− .006	− .098	.127	− .044	.129
No. of moderate to severe symptoms	.647*	1	− .158	.101	.146	− .055	.117
PSS	.161	.110	1	− .150	− .084	− .034	− .045
Age	− .047	.057	− .214**	1	.206	− .010	.272*
No. of daily cigarettes	.359	.082	− .262	.156	1	− .751**	.023
No. of housemates	− .024	− .018	.058	− .162	− .061	1	.271*
No. of children	.044	.006	.058	.195**	.249	.193**	1
the correlation is significant at a level of 0.05 (both sides), the correlation is significant at a level of 0.01 (both sides) PSS, Perceived stress scale;*

Cohort P

The second cohort comprised 194 stem cell recipients with a higher proportion of males (59.5% vs. 40.5%) and an older average age (Table 5). Analysis of patients’ data revealed minimal differences between sexes. Notably, male patients were slightly more likely to have children (31% vs 24%, p = 0.445) and to live alone (19% vs 10.5%, p = 0.136). Again, smoking prevalence was higher among men, although women reported a greater average number of cigarettes smoked per day (M = 10.13 (SD = 9.2) vs. M = 4.78 (SD = 5.2), p = 0.070). The stem cell specific data indicated comparable characteristics between both sexes. Immunosuppression was observed in 58% of female patients and 63.5% of male patients (p = 0.557), while GvHD affected 36.5% of females and 38.5% of males (p = 0.881). Most patients participated in the trial more than 100 days after their stem cell transplantation.

Table 5

Characteristics of the study samples, cohort P: cancer patients.
cohort P	Women, n/N (%) 79/194 (40.5)		Men, n/N (%) 115/194 (59.5)	p-value
Age
Median (IQR)	57 (49–63)		56 (49–62)	0.144
≤ 30, n/N (%)	4/79 (5)		4/115 (3.5)	0.811
31–40, n/N (%)	9/79 (11.5)		9/115 (8)
41–50, n/N (%)	11/79 (14)		20/115 (17.5)
51–60, n/N (%)	31/79 (39)		50/115 (43.5)
> 60, n/N (%)	24/79 (30.5)		32/115 (28)
Housing / living situation
Living alone, n/N (%)	7/68 (10.5)		19/100 (19)	0.136
Children, n/N (%)	17/71 (24)		33/107 (31)	0.445
Number of children, mean (+/-SD)	1.38 (+/-0.65)		1.31 (+/-0.54)	0.280
Smoking, n/N (%)	8/72 (11)		18/108 (16.5)	0.395
Number of cigarettes/ day, mean (+/-SD)	10.13 (+/-9.2)		4.78 (+/-5.2)	0.070
Stem cell specific features
Immunosuppression, n/N (%)	46/79 (58)		73/115 (63.5)	0.557
GvHD, n/N (%)	29/79 (36.5)		44/115 (38.5)	0.881
Days after SCT, Median (IQR)	648 (100–1,636)		686 (144–2,180)	0.770
≤ 100d, n/N (%)	20/79 (25.5)		22/115 (19)	0.554
> 100d, n/N (%)	59/79 (74.5)	93/115 (81)
SD – standard deviation, IQR – interquartile range, d – days

At the time of sampling, men exhibited a significantly higher likelihood of experiencing URTI symptoms compared to women (68% vs 83%, p = 0.021, φ = -0.177, Table 6). Additionally, although not statistically significant, moderate to severe and severe URTI symptoms were more prevalent among men. The most frequently reported URTI symptoms included cold, myalgia, and headache (suppl. Figure 1b). PCR confirmed CARV-infections were detected in 11.5% and 15% for female and male patients, respectively.

Table 6

Number and severity of URTI symptoms in the study samples at the time of sampling, cohort P: stem cell patients
Cohort P	Women, n/N (%) 79/194 (40.5)	Men, n/N (%) 115/194 (59.5)	p-value	Effect size
Symptoms at time of sampling
Symptoms at time of sampling, n/N (%)	51/75 (68)	94/113 (83)	0.021	φ -0.177
No. of symptoms, Mean (+/- SD)	2.20 (+/- 2.22)	2.65 (+/- 2.10)	0.155
Moderate to severe symptoms, n/N (%)	21/79 (26.5)	37/115 (32)	0.188
No. of moderate to severe symptoms, Mean (+/- SD)	1.47 (+/- 1.99)	1.48 (+/- 1.75)	0.971
Severe symptoms, n/N (%)	6/79 (7.5)	13/115 (11.5)	0.467
No. of severe symptoms, Mean (+/- SD)	0.44 (+/-1.01)	0.44 (+/-0.93)	0.998
PCR confirmed CARV-infection, n/N (%)	9/79 (11.5)	18/115 (15.5)	0.527
SD – standard deviation

Women scored slightly higher on the PSS-4 compared to men [t(183) = 3.60, p = 0.084, d = 0.241]. This trend was evident across all PSS-4 items, particularly for the item regarding the perception of difficulties piling up to an overwhelming extent [t(185) = 1.12, p = 0.030, d = -0.328] (suppl. table 1, suppl. Figure 2b). In female patients, the PSS-4 decreased with increasing age (r = -0.261, p = 0.026, Fig. 1b, Fig. 2, and Table 7). Conversely, male patients exhibited the lowest level of perceived stress at age 30 or younger [t(6) = 3.1, p = 0.117, d = 1.292], while those aged 41 to 50 reported the highest levels [t(28) = 3.78, p = 0.895, d = 0.051] (Fig. 1b, Fig. 2, and Table 7). A Pearson’s correlation analysis revealed statistically significant associations between the PSS-4 and the number of moderate to severe (r = 0.196, p = 0.038) and severe URTI symptoms (r = 0.269, p = 0.004, Fig. 1b, Table 8), but no significant correlation with age. A negative correlation was found between age and the total number of URTI symptoms (r = -0.251, p = 0.026). In a one-way ANCOVA, age was the only covariate that significantly affected the PSS-4, with categories defined as ≤ 30, 31–40, 41–50, 51–60, and > 60 years [F(4, 156) = 5.14, p = 0.025, η² = 0.032], Table 7).

Table 7

Perceived stress (means and standard deviations of PSS-4 scores) in the study samples, cohort P: stem cell patients
Cohort P	Women, n/N(%) 79/194 (40.5)	Men, n/N (%) 115/194 (59.5)	p-value	Effect size
All patients	9.27 (+/- 3.56)	8.85 (+/- 3.64)	0.084	d 0.241
Age*			0.023*	0.033*
≤ 30, (n = 8)	11.25 (+/-4.03)	7.25 (+/- 1.71)	0.117	d 1.292
31–40, (n = 18)	10.44 (+/-3.35)	8.78 (+/- 2.63)	0.259	d 0.552
41–50, (n = 31)	10.45 (+/- 3.3)	10.26 (+/-4.03)	0.895	d 0.051
51–60, (n = 81)	9.35 (+/- 3.62)	8.57 (+/-3.88)	0.403	d 0.203
> 60, (n = 56)	7.83 (+/-3.34)	8.65 (+/-3.33)	0.376	d -0.246
Housing / living situation
Living alone*			0.182*
Yes, (n = 26)	8.57 (+/- 2.57)	8.42 (+/- 2–54)
No, (n = 142)	9.55 (+/-3.74)	8.88 (+/- 3.57)
Children*			0.702*
Yes, (n = 50)	9.75 (+/-4.04)	8.75 (+/- 4.27)
No, (n = 128)	9.17 (+/-3.5)	8.89 (+/- 3.36)
Smoking *			0.179*
Yes, (n = 26)	10.13 (+/-3.8)	10.17 (+/-5.04)
No, (n = 154)	9.33 (+/-3.59)	8.71 (+/-3.29)
ANCOVA, covariates; °ANCOVA: p < 0.001, η² 0.078 SD – standard deviation

Table 8

Associations between study variables (Pearson correlation coefficients) in cohort P, female above and male below the diagonal
	No. of symptoms	No. of moderate to severe symptoms	PSS	Age	No. of daily cigarettes	No. of housemates	No. of children
No. of symptoms	1	.891*	.385*	− .251**	.268	.082	.147
No. of moderate to severe symptoms	.814*	1	.371*	− .214	.047	− .031	.034
PSS	.149	.196*	1	− .261**	.573	.298**	.161
Age	− .021	− .088	− .014	1	− .022	− .126	− .185
No. of daily cigarettes	− .093	− .046	.035	− .269	1	− .785*	.236
No. of housemates	− .021	− .067	− .027	− .121	.659*	1	.593*
No. of children	− .104	− .026	− .096	− .066	.788*	.761*	1
the correlation is significant at a level of 0.05 (both sides), the correlation is significant at a level of 0.01 (both sides) PSS, Perceived stress scale*

The purpose of this post hoc analysis was to evaluate the relationship between perceived stress and the burden of URTIs in both healthy individuals and patients with compromised immune systems due to stem cell transplantation for cancer treatment, with a particular focus on gender disparities. We proposed two hypotheses: first, that women experience higher levels of perceived stress than men; and second, that the PSS-4 correlates with the occurrence and severity of URTIs, resulting in a greater burden of URTIs in distressed individuals. To address these hypothesizes, our study population comprised two distinct cohorts. The first cohort consisted of healthy individuals predominantly aged 20 to 30, with a balanced sex ratio and sociodemographic factors. However, we found that women were more likely to have children and smoke less. The second cohort exhibited markedly different characteristics, with the majority aged 50 to 60 and a male-biased sex ratio. In this cohort, male patients were more likely to live alone, have children, and smoke fewer cigarettes per day than their female counterparts. With respect to sex differences, our results support the hypothesis, although the observations related to their interaction with URTIs are less definitive.

Consistent with our first hypothesis, women, particularly those of reproductive age, reported markedly higher stress levels than men in both cohorts. Notably, a shift was observed in elderly patients, with men reporting higher stress levels than their female counterparts. Both sex and age significantly affected stress levels among healthy individuals, whereas, in cancer patients, only age emerged as a relevant factor impacting stress levels.

Numerous global studies support our findings, indicating that women generally experience higher levels of stress than men (32, 33, 54). A German study by Klein et al. found that women scored significantly higher on stress scales than men (d = .18), with these results being consistent across various age groups (32). Cohen and Williamson demonstrated that perceived stress, as measured by the PSS, tends to decrease with age regardless of sex. Additional factors associated with perceived stress include income, education, race, marital status, and household composition, with women consistently reporting higher PSS scores than men across these variables (33). Similarly, a large American survey revealed that individuals aged 18 to 46 reported the highest stress levels, while those aged 66 and older reported the lowest (55, 56). The same survey indicated that men tend to be less aware of stress and its potential effects on both physical and mental health. This lack of awareness may contribute to a lower perception and report of stress, while simultaneously increasing the risk of chronic illnesses (57).The reduction of stress in older adults can be attributed to varying stress sources and the implementation of more effective coping strategies as individuals age (55, 58–60). In 2023, new data from the American Psychological Association (APA) indicated a rise in average stress levels, particularly among individuals aged 18 to 44 and women. This increase appears to be exacerbated by a polycrisis caused by factors such as the coronavirus disease 2019 (COVID-19) pandemic, global conflicts, racism and racial injustice, inflation, and climate-related disasters (56, 61). Additionally, some studies indicate that women demonstrate a stronger humoral response to stress, evidenced by higher levels of catecholamines and IL-6 (54, 62).

As noted in the introduction, women often bear a greater burden of unpaid caregiving responsibilities and may face role conflicts that exacerbate stress. These gendered roles, combined with socioeconomic pressures, could influence both the perception of stress and the susceptibility to URTIs, especially in the reproductive years. Our study, however, did not collect detailed data on these psychosocial dimensions, highlighting a need for future research to explore why stress levels fluctuate throughout a lifetime and how these factors interact with biological determinants in shaping health outcomes in men and women.

As mentioned earlier, stress levels tend to decrease with age, and our study supports this trend, particularly among healthy individuals. However, it also revealed an unexpected trend in stress levels among female and male patients as they age. Specifically, male patients over 60 reported experiencing higher stress levels than their female counterparts. This observation may be linked to shifts in caregiving responsibilities, the psychological impact of chronic illness or the persistence of work-related stress despite declining biological capacities.

There is a lack of sex-disaggregated data on perceived stress levels among patients with cancer. Both cancer diagnosis and treatment introduce various stressors that can be potentially traumatic. Nevertheless, it is generally anticipated that stress levels will diminish with effective treatment outcomes, improved disease control, and the passage of time (63, 64). For instance, in a cohort of women with breast cancer, perceived stress was highest at the onset of treatment and decreased significantly over the following 24 months (65). In a study comprising elderly patients with colorectal cancer in remission and their healthy partners, men, including both patients and healthy husbands, consistently reported higher stress levels than their female counterparts. Notably, these men also reported receiving more support from their wives than the women reported receiving from their husbands (66).. In our cohort, most patients had a minimum of 100 days between the survey and stem cell transplantation, indicating they were already familiar with their disease. This suggests a degree of adaptation may have occurred. However, one-third of the patients reported experiencing GvHD, which could serve as a potential stressor, alongside concerns about relapse or disease progression. Importantly, disease activity, including remission status, was not evaluated in this study.

Our second hypothesis was partially supported. Among healthy individuals, women exhibited a higher likelihood of experiencing both stress and moderate to severe symptoms of URTIs. However, we found no significant correlations between perceived stress and the number or severity of URTI symptoms. Nonetheless, there was a slight trend indicating increased stress levels and a greater burden of URTIs correlate among young adult women. This trend aligns with findings from Groer et al. who reported that premenopausal women experience more symptoms of infectious diseases during their perimenstrual period compared to midcycle, a pattern corresponding with increased levels of perceived stress (67). It should be noted that the menstrual cycle phases of the participants were not documented in our study. As a result, the potential interaction between stress and URTIs may be confounded by the inclusion of women at different stages of their menstrual cycles. As previously discussed, premenopausal women exhibit heightened vulnerability to URTIs and pandemic influenza infections than their male counterparts in reproductive age, with notable sex differences in the severity and morbidity of pandemic influenza (12–15, 22, 23). This heightened risk may be particularly pronounced during periods of low estradiol levels, such as the perimenstrual period or postpartum, given that sex steroids exhibit distinct immunomodulatory effects that vary with concentration. Specifically, estradiol demonstrates pro-inflammatory properties at lower levels and anti-inflammatory effects at higher concentrations. Similar effects are reported for progesterone (27, 68, 69). In a study of 118 pregnant women with COVID-19, fewer than 8% experienced severe pneumonia, with the majority of exacerbations occurring postpartum (70). In contrast, research on pandemic influenza highlights distinct dynamics, with an association of severe infectious courses in pregnant women (22, 71, 72). Data from Robinson et al. indicate that the influenza A virus disrupts the menstrual cycle. Notably, administering high doses of estradiol to infected female mice mitigated the adverse effects of the virus (73). These complex findings highlight the importance of the female menstrual cycle, as well as pregnancy-related hormonal changes in the context of infectious diseases.

Among patients, men were more likely to contract URTIs, although the severity of symptoms did not differ significantly between sexes. For both male and female patients, the number of URTI symptoms was positively correlated with perceived stress, a finding consistent with the work of Cohen et al. (40). In our cohort, URTIs were most common among premenopausal women, followed by male patients. For those who underwent stem cell transplantation, age, long-term effects of treatment, and general morbidity should be considered as contributing factors to the occurrence of URTIs (74).

Limitations

In our analysis, response and selection bias may affect the external validity of our results. Specifically, participants aged 41 and older were underrepresented among healthy individuals, while those aged 50 years or younger were underrepresented among patients. Additionally, the healthy cohort primarily consisted of students or employed individuals, whose life circumstances and stressors may differ from other groups. Furthermore, the questionnaire did not capture information on gender, socioeconomic factors, social support, cultural influences, migration, or data on the underlying hematological diseases and comorbidities. To gain a more comprehensive understanding of stress and its complexities, particularly its interaction with infectious diseases, a longitudinal approach is essential. This method allows for the identification of potential confounders and monitoring of changes over time. Furthermore, it is crucial to assess sex steroid levels. It is also important to note that our data predate the COVID-19 pandemic, which likely exacerbated stress disparities between sexes, with women experiencing greater stress regardless of age (56).

To conclude, women, particularly premenopausal women, experience higher stress levels than men. This trend was also reflected in the occurrence and severity of URTIs, although a statistically significant correlation between stress and URTI burden was found only among cancer patients. These findings indicate a complex interplay between sex, gender, stress, and URTIs, potentially moderated by additional factors such as vaccination status, comorbidities, health behaviors in patients with cancer, and social interaction frequency. Our results underscore the pressing need for public health strategies that incorporate both biological and psychosocial factors. Given the ongoing challenges posed by infectious diseases, understanding of these dynamics is essential for developing interventions that address the specific needs of various population subgroups.

ANCOVA

analysis of covariance

ANOVA

one–way analysis of variance

APA

American Psychological Association

CARV

community–acquired respiratory viruses

COVID

19–coronavirus disease 2019

GvHD

graft versus host disease

HPA

hypothalamic–pituitary–adrenal axis

IQR

Interquartile ranges

LRTI

lower respiratory tract infection

mean

PSS

perceived stress scale

sympathetic axis

SARS

CoV–2

standard deviation

URTI

upper respiratory tract infection

Ethics approval and consent to participate.

The study was approved by the local ethics committee (Nr. 3891-09/13), and all participants provided written informed consent prior to their involvement.

Consent for publication

Not applicable.

Availability of data and materials

The dataset used and analyzed during the current study are available from the corresponding author on reasonable request.

Conflict of Interests

The authors declare no conflict of interest.

Funding Information

Deutsche Jose Carreras Leukämie-Stiftung,Grant/Award Number: DJCLS SP 15/01

Authors’ contributions

TR, MvLT: study design, conceptualization. JK, SK, PS, IH: recruitment and database setup. JK, SK, PS: Sample collection / PCR. MMR: statistical analysis, data interpretation and manuscript preparation. MvLT, JR:supervision, conceptual advice, and critical revision of the manuscript.EP, LA: critical revision of the manuscript. All authors: acquisition of data; all authors revised and approved the final version of the manuscript.

Acknowledgements

The authors thank the study participants and research staff for their contributions.

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Gender Differences in Stress and Upper Respiratory Tract Infections: A Closer Look

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