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The influence of sex hormones is recognized to account for the susceptibility and distinct outcomes of diverse infectious diseases. This review discusses several variables including differences in behavior and exposure to pathogens, genetic, and immunological factors. Understanding sex-based differences in immunity during different infectious diseases is crucial in order to provide optimal disease management for both sexes.
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DOI 10.1007/s15010-015-0791-9
Sex differences in immune responses to infectious diseases
Julia Fischer1,3,4 · Norma Jung1 · Nirmal Robinson2,3 · Clara Lehmann1,4
Received: 10 February 2015 / Accepted: 29 April 2015
© Springer-Verlag Berlin Heidelberg 2015
therefore is a risk factor for autoimmune diseases [4]. The
underlying mechanisms for these sexual differences are
diverse, which includes genetic, epigenetic, and hormonal
determinants of immunity. In this review, we will first dis-
cuss our current understanding of the differential immunity
between the sexes. In the second part, we will review the
current knowledge on sex-based differential immunological
responses during various infections.
Biological background, effects of sex hormones
on immunity
The X chromosome
Differential immunological responses observed in women
and men are attributed to the biased response from X chro-
mosome. The X chromosome is known to harbor majority
of the immune-related genes [3, 5]. The human X chro-
mosome encodes for a number of critical genes involved
in the regulation of immunity, such as Toll-like receptors
(TLR) 7 and 8 that play a central role in sensing viral
pathogens; FOXP3, a transcription factor for regulatory T
cells and CD40L (CD154) [6]. The X chromosome also
codes for crucial microRNAs (miR) that regulate immu-
nity. Among the X-linked microRNAs, miR-233 is widely
studied and has been shown to regulate neutrophil differ-
entiation. Similarly, miR-106A, miR-424, miR542, and
miR-503 have been shown to negatively regulate mono-
cyte differentiation [7]. Further, a large number of X-linked
miRNAs are reported to downregulate negative regulators
of immunity; such as forkhead box P3 (FOXP3), cytotoxic
T-lymphocyte-associated protein 4 (CTLA-4), programmed
cell death 1 (PDCD1) and members of casitas B-lineage
lymphoma (CBL) and suppressors of cytokine signaling
Purpose The influence of sex hormones is recognized
to account for the susceptibility and distinct outcomes of
diverse infectious diseases.
Methods This review discusses several variables includ-
ing differences in behavior and exposure to pathogens,
genetic, and immunological factors.
Conclusion Understanding sex-based differences in immu-
nity during different infectious diseases is crucial in order to
provide optimal disease management for both sexes.
Keywords Sex · Immunity · Infectious diseases
Sex-based differences on the outcome of numerous infec-
tious diseases are evident from many clinical studies [1].
In general, females show stronger humoral and cellular
immune responses to infection or antigenic stimulation
than the males [2, 3]. This enhanced level of immunity is
a double-edged sword: on one hand, it can provide protec-
tion against several pathogens. On the other hand, this can
lead to an aberrant pathogenic inflammatory response and
* Clara Lehmann
1 First Department of Internal Medicine, University
of Cologne, Kerpener Str. 62, 50934 Cologne, Germany
2 Institute for Medical Microbiology, Immunology
and Hygiene, University of Cologne, Cologne, Germany
3 CECAD Research Center, Cologne, Germany
4 German Center for Infection Research (DZIF), Partner Site
Bonn-Cologne, Cologne, Germany
J. Fischer et al.
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(SOCS) family. This is considered to be a cause for preva-
lent autoimmune disorders observed in women [8].
Females harbor two X chromosomes, whereas males
carry one X and one Y chromosome. In order to prevent
excessive responses from the X chromosome, the female
mammals have evolved a complex mechanism termed as
X-inactivation. Through this process one of the X chro-
mosomes is transcriptionally silenced during the develop-
ment process of a female. This leads to cellular mosaicism;
which means that either the X chromosome from paternal
or maternal origin is expressed in different cell popula-
tions. As a result, gene mutation in X-linked chromosome
is expressed in part of the cells in females, whereas all the
cells in males will exhibit the mutation. Cellular mosai-
cism has proven to provide immunological advantage for
the females. Diseases such as X-linked severe combined
immunodeficiency (XSCID) and immune dysregulation [9,
10], polyendocrinopathy, enteropathy, X-linked syndrome
(IPEX) harbor mutations in genes that are linked to the X
chromosome [11]. X-inactivation allows part of the cells to
express the wild type genes in females compared to none
of the cells in males. Therefore, these genetically inherited
diseases are more prevalent in males. In mouse models of
microbial sepsis, animals exhibiting cellular mosaicism for
Interleukin-1 receptor-associated kinase 1 (IRAK1) expres-
sion and NADPH oxidase 2 (NOX2) have shown improved
clinical phenotype in survival and bacterial clearance. Taken
together, inactivation of X chromosome equips females
with a wide reserve of proteins, which provide diversified
and effective immune responses. However, women are at a
higher risk of contracting autoimmune disorders and this is
attributed to gene dosage from X chromosome [6].
Immunomodulatory functions of sex steroid hormones
Sex hormones significantly affect the functions of immune
cells. This is evident from transcriptome analysis of periph-
eral blood monocytes (PBMCs) of men and women of all
ages. Data reveal that age and sex potently alter the tran-
scriptional responses in immune cells. Like other hormones,
sex steroids exert their function by binding to specific
receptors. Immune cells such as lymphocytes and myeloid
cells have been shown to express estrogens receptors (ER),
androgen receptors (AR), and progesterone receptors (PR).
The sex steroid receptors act as nuclear transcription factors
through different ligand-dependent or ligand-independent
mechanisms [12]. The expression of the hormone receptors
on immune cells clearly signifies that they have key immu-
noregulatory functions. The majority of the scientific work
has focused on the ER. Two subtypes of ER, ERα, and ERβ
are known so far and their roles in the immune regulation
are subject of current research. Most immune cells such
as B- and T-lymphocytes, dendritic cells, macrophages,
monocytes, natural killer cells, and mast cells express ERα,
while ERβ is infrequently expressed. The expression of ERs
is autoregulated [13]. ERα and ERβ deficient mice develop
fully established immune system. However, their immune
system becomes disoriented by age. Thus aged ERα knock-
out (ERα/) mice develop autoimmune disorders [14]
and aged ERβ/ mice develop chronic myeloid leukemia
[15]. Moreover, estradiol has been shown to increase both
the humoral and cell-mediated immune responses. Inter-
estingly, estrogen positively regulates TLR-mediated pro-
inflammatory pathways in murine macrophages and plas-
macytoid dendritic cells (pDCs). It enhances the cytotoxic
activity of natural killer cells (NK-cells) and also upregu-
lates pro-inflammatory cytokines such as TNF-α, IL-6, and
IL-1. Estradiol has also been reported to affect the function
of invariant natural killer T cells (iNKT). ERα deficiency,
ovariectomy, or continuous administration of estradiol leads
to altered production of interferon gamma (IFNγ) and IL-4
production [16]. In vivo administration of alpha-galactosyl-
ceramide (iNKT ligand) induces higher cytokine production
in female than in the male mice. However, the effect was not
observed in ovariectomized female mice, suggesting that the
increase in cytokine expression is an effect of estradiol [17].
Androgen Receptors and cognate receptors for proges-
terone have also been detected in immune cells, implicating
a direct effect of androgens on the development and func-
tion of immune system [1820]. However, the underlying
mechanisms are not well understood. Contrary to estrogens,
androgen and progesterone are known to be anti-inflamma-
tory. Testosterone reduces NK-cell activity and the secretion
of pro-inflammatory cytokines by downregulating NF-κB
signaling, but increases the production of anti-inflammatory
cytokines. It is also known to suppress the expression of
TLRs upon infection. Similar to testosterone, progesterone
also inhibits NF-κB-mediated pro-inflammatory cytokines
and increases anti-inflammatory signatures. During preg-
nancy, progesterone has been reported to skew the T cell
responses toward Th2 response [6]. This could partly explain
why pregnant women are more susceptible to infections such
as Listeria monocytogenes, Rubella virus, and Toxoplasma
gondii. Considering the differential immunoregulatory prop-
erties of sex steroid hormones, it is perceivable that hormo-
nal changes during menstrual cycle, menopause, and preg-
nancy could greatly influence the immune responses.
Viral infections
Human immunodeficiency virus
In the context of Human immunodeficiency virus (HIV)
infection, sex-based differences in the course of disease
progression have been reported: women have lower plasma
Sex differences in immune responses to infectious…
1 3
viral loads, higher CD4+ T cell counts, and higher risk of
progressing to AIDS than men [2123]. Moreover, women
are more prone to anti-retroviral drug-induced adverse
effects. Therefore, it has been suggested to revise treatment
recommendations for women and men [24, 25].
Persistent chronic inflammation in women contributes to
immune pathology and impairment of the immune system.
This could explain the faster disease progression observed
in chronically infected women despite similar pace of viral
replication compared to men. Meier et al. could demon-
strate that women have higher TLR-7-mediated response
of pDCs. This leads to elevated expression of interferon
alpha (IFN-α) and IFN-Stimulated Genes (ISGs) result-
ing in stronger secondary activation of CD8+ T cells [26].
IFN-alpha is known for its antiviral and immunomodula-
tory function but it also can cause immunopathologies [27].
Therefore, in HIV-infected women, IFN-α could be benefi-
cial through its antiviral activity, but in it might also have
deleterious contributions to chronic immune activation
associated with HIV disease progression.
Moreover, studies in rhesus macaques have also shown
differential susceptibility to intravaginal SIV infection dur-
ing luteal phase (high progesterone levels) compared to that
of the follicular phase (high estrogen levels) [28]. However,
understanding the underlying mechanisms involved in the
regulation of immune responses by sex hormones during
long-term HIV disease is crucial in order to develop indi-
vidualized treatment concepts that take sex-specific host
factors into account.
Hepatitis C
Numerous studies have demonstrated that women are more
likely to spontaneously clear Hepatitis C Virus (HCV) during
acute infection than males [29]. Moreover, the risk of cirrhosis
is higher for men than women during chronical stage of HCV
infection [30]. However, after menopause the sex differences
in chronic HCV disease are attenuated. Di Martino et al. [31]
observed that the accelerated rates of cirrhosis and fibrotic
progression in postmenopausal female can be prevented
through hormone substitution therapy. These differences in
clinical outcomes during the acute and chronic phase of infec-
tion could in part be explained by the increased response of
the TLR7/8 signaling pathway which in the context of HCV
infection proves to be beneficial. However, further research
is required to better understand the mechanisms behind the
potential effect of female sex on HCV viral control [29].
Bacterial infections
In General, men are more susceptible to bacterial infec-
tions than women. Thus, sex determinants are considered
to play a key role in immune response against bacterial
infections such as Mycobacterium spp., Listeria mono-
cytogenes, Treponema pallidum, Staphylococcus aureus,
Pseudomonas aeruginosa, Vibrio vulnificus, Borrelia burg-
dorferi, and Escherichia coli [32, 33].
In 2012, the analysis of the tuberculosis notification data
revealed a male-to-female ratio of 1.9:1 [34], which has
been consistent with the data from earlier years [35, 36].
Behavioral and physiological reasons are being discussed
as explanations. With regard to behavioral factors, smoking,
alcohol consumption, and mine-related silicosis, especially
in countries with high bacterial burden are correlated with
male sex. To study the physiological sex differences, animal
models have been used. One study demonstrated that fertile
male mice were more susceptible to infection with Myco-
bacterium marinum and Mycobacterium intracellulare.
Male mice exhibited severe disease pathology compared to
castrated male mice [37]. Few studies have examined sex
differences in humans. A study in patients of an American
institution for mentally ill patients showed that only 8.1 %
of castrated men died from tuberculosis compared to 20.6 %
of intact males. Another study in young Swedish women
who underwent oophorectomy due to salpingitis found that
the tuberculosis mortality rate increased to 7 % compared
to 0.7 % [38]. These differences are thought to be X-linked
immune responses. In mouse models of Mycobacterium spp
infections, the resistance offered by female mice has been
attributed to better anti-bacterial activity of macrophages
[39]. The susceptibility of male mice has been linked to
decreased production of antibodies against lipoarabinoman-
nan (lipid present in mycobacterial cell wall) [40].
Syphilis caused by Treponema pallidum also has been
reported to show sexual dimorphism. The resistance shown
by females has been correlated with increased CD4+ and
CD8+ T-cells [41]. Similarly, it has been observed that
females are more resistant to other bacterial infections
such as Staphylococcus aureus, Pseudomonas aeruginosa,
Vibrio vulnificus, Borrelia burgdorferi. Conversely, females
are susceptible to E. coli bacteremia. This bias is perhaps
due to E. coli associated urinary tract infection prevalent in
women. Women are prone to Listeria infection. It has been
reported that the susceptibility of mice to Listeria is linked
to increased IL-10 secretion by female mice. Female non-
obese diabetic mice have a higher incidence of developing
type I diabetes. This increased incidence is linked to the
difference in beneficial microbes colonizing the gut of male
and female mice. This trend was reversed by male castra-
tion, meaning androgens influence gut microbiota [42].
Thus sexual dimorphism plays a key role in the resistance
mechanisms against pathogens and maintaining a healthy
microbiota in the gut. However, to date there are no stud-
ies which define a complete explanatory mechanism for the
sexual dimorphism exhibited during infection.
J. Fischer et al.
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Parasitic infections
Parasites are phylogenetically diverse and they target dif-
ferent tissues. The influence of female and male sex hor-
mones on the immune responses toward different parasitic
infections is pathogen specific [43]. In studies which ana-
lyzed the sex-based differences in immunity toward dif-
ferent parasitic infections, males were found to be more
resistant to Trichomonas vaginalis [44] and Toxoplasma
gondii [45], while females were more resistant to infec-
tions with Leishmaniasis [46, 47], Trypanosoma cruzi and
Trypanosoma brucei [48], Giardia lamblia, and Schisto-
soma mansoni [49]. Animal models have been conducted
to analyze the sex-related differences in parasitic infection.
For instance, it was shown that testosterone influences the
disease outcome of Leishmania infection by affecting anti-
gen-presenting cells and T cells as well as rising an anti-
inflammatory T-helper 2 (Th2) response. In comparison
to females, male rodents present more lesions and higher
parasite burdens. This observation was explained by an
increased Th2 response including an augmented mRNA
expression of interleukin 4 (IL-4), interleukin 10 (IL-10),
transforming growth factor (TNF) β, and TNF-α [50, 51].
Moreover, the resistance of female hamsters toward Leish-
mania mexicana correlated with an increased expression of
IFNγ [50]. Overall, using Leishmania as a parasitic model
provides insights into how sex hormones can influence
immunological mechanisms.
Males have a higher susceptibility to many infectious path-
ogens compared to women. This can in part be explained
by stronger Th1 immune responses in women. However, in
some infections, females are at a risk of developing intensi-
fied immunopathology due to higher levels of pro-inflam-
matory immune responses (e.g., HIV infection). Never-
theless, this simplification does not apply to all infectious
conditions. Thus, as recognized by the National Institute of
Health (NIH), the significance of including sex as a criteria
in studies conducted with human subjects or on material of
human origin is mandatory to improve a better understand-
ing of the sex-related differences in immunity to infections
(NIH Policy and guideline on the inclusion and minori-
ties as subjects in Clinical Research, amended October,
accessed January 2015, [52].
Acknowledgements This review was written in honor of Gerd Fät-
kenheuer’s 60th birthday. He has been our teacher for over a decade
and we would like to thank him for his excellent teaching—both in
internal medicine and infectious diseases but also in science and poli-
tics. He taught us to systematically look for all the puzzle pieces, to
find a plausible diagnosis, to never give up, to take responsibility for
our decisions, and to never forget the ultimate goal—the best for the
patient. CL and JF are supported by the German Centre for Infec-
tion Research (DZIF). NR’s research is supported by funding from
Cologne Excellence Cluster on Cellular Stress Responses in Aging-
Associated Diseases (CECAD; funded by the DFG within the Excel-
lence Initiative by the German federal and state governments) and
Deutsche Forschungsgemeinschaft (SFB 670).
Conflict of interest The authors have no conflicts of interest.
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... Previous studies have revealed that sex has considerable effect on the outcome of infection and has been associated with underlying differences in immune responses leading to physiological and anatomical variances which may influence exposure, receptor recognition and even transmission of microorganisms. The X-linked nature of immune response proteins deeply marks the difference as women mount a stronger immune response to infections and vaccinations to outlive against men [11]. Several assumptions were made for the divergence impact of COVID-19 on age and gender [1]. ...
... The agespecific susceptibility profile suggested that those aged under 20 years were half as susceptible to SARS-CoV-2 infection as those aged over 20 years [29]. Least infected are the infants and children's group (0-5) followed by the school group (6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17). The possible cause of low infection may be attributed to several factors as inherent high immunity among children, vaccinations against other seasonal flu, school closure which reduces the social gathering [29]. ...
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As SARS-CoV-2 has rapidly spread all over the world, it is evident that patient’s gender, age, and comorbidity might render these patients more vulnerable to either increased mortality or increased risk of infection. In the first wave of pandemic, percentage of infection was 5% in May 2020, which rose to 23% in August. Towards the end of the year, it was around 1.8%. In second wave, infection gradually increases to 3.4% in the later part of March 2021, reaching maximum of 31% in April. of the recorded positive cases, infection rate in male population was comparatively higher them the female. In September 2020 where the rate of infection was highest in the first wave the male infectivity rate is 16% compared to 7.13% in females. In April 2021, male infection rate was at 21% compared to 9.7% in the female population. The positivity rate in male population was at 3.7% in third wave of infection. During this period the positivity rate in female population was at 1.87%. Our study shows the positivity rare was maximum in the age group of 18-29(25.5%) followed by 30-39(23.5%) and 40-49(17.2%) in 2020. Similar trend was observed in the year 2021 where the infection rate was 24.2%,23.6%,18.46% in the age group of 18-29,30-39 and 40-49 respectively. However, in 2022 maximum infection was recorded in the age group of 18-29 at around 29%, followed by age group of 30-39(20.9%) and 6-17(15%).
... Humorale Immunität · Zelluläre Immunität · Genetische Faktoren · Sexualhormone · Impfungen Geschlechtsspezifische Unterschiede in Disposition und Verlauf zahlreicher Infektionskrankheiten sind aus vielen klinischen Studien ersichtlich [13]. Frauen zeigen eine stärkere humorale und zelluläre Immunantwort auf Infektionen oder Antigenstimulation im Vergleich zu Männern [11]. Jedoch bedingt diese stärkere Immunantwort auch häufiger eine ab-errante Entzündungsreaktion, die einen Risikofaktor für Autoimmunerkrankungen darstellt [2]. ...
... Östrogene verstärken sowohl die humorale als auch die zellvermittelte Immunantwort. So führt eine Stimulation mit Östrogenen zu einer verstärkten Sekretion entzündungsfördernder Zytokine wie Tumor-Nekrose-Faktor α (TNF-α), Interleukin(IL)-6 und IL-1 [11]. ...
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The humoral and cellular immune responses to antigen stimulation, vaccinations and infections differ between women and men. Genetic, epigenetic and hormonal factors contribute to the sex-specific immunity. The expression of genes on the X‑chromosome and the effect of sex hormones substantially influence the immune defence against infections. Females show stronger cellular and humoral immune responses to infections than males, but the enhanced immune response often leads to aberrant inflammatory reactions and autoimmune diseases. Men are principally more prone to bacterial, viral and fungal infections and more often show severe disease courses. In contrast, a more reactive female immune system results in significantly more adverse reactions to vaccinations. In order to be able to better identify the multiple sex-specific that have an influence on the immune system, sex-specific differences should be investigated in a differentiated way. The better understanding of the sex-specific differences in the immune response will have a long-term influence on the prevention, diagnostics and treatment of infectious diseases, and will ultimately contribute to improving healthcare of both women and men.
... The mean time that elapsed between infection and VKH symptoms was 19.75 ± 6.57 days, and the median was 17.5 days. All the patients were women, which is consistent with women having more robust immune responses to infections than men [75,76]. The therapy used was oral steroids in all cases, with the addition of topical steroids for two cases and intravenous steroids for two cases. ...
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Vogt–Koyanagi–Harada (VKH) is a rare multisystem inflammatory disease affecting the eyes, ears, brain, skin, and hair. The Coronavirus Disease 2019 (COVID-19) is a new contagious infection that might trigger the onset of VKH disease, as previously proposed for other viruses. Moreover, after the mass vaccination against SARS-CoV-2 worldwide, cases of VKH disease associated with COVID-19 vaccination have been reported. We present an overview of VKH and a comprehensive literature revision of all the VKH cases described after COVID-19 infection and vaccination, adding our experience. No differences have been found considering epidemiology and clinical findings of the disease compared to those reported in the no-COVID era. All of the patients promptly responded to systemic and local corticosteroid therapy with a good final visual prognosis. Different possible pathogenetic mechanisms underlying the onset of VKH after COVID-19 vaccination are discussed, while the presence of the HLA DR4 antigen as a genetic predisposition for the onset of the disease after COVID-19 infection and vaccination is proposed. VKH disease is one of the most frequently reported uveitic entities after COVID-19 vaccination, but a good response to therapy should not discourage vaccination. Nevertheless, ophthalmologists should be alerted to the possibility of VKH occurrence or relapse after COVID-19 vaccination, especially in genetically predisposed subjects.
... There were also more male malaria patients than female and the male to female ratio also decreased over the three transmission seasons. In general, females show stronger humoral and cellular immune responses to infection or antigenic stimulation than males [20]. Gender-based occupational or behavioural factors have also been implicated in the gender differences seen in low transmission settings [15]. ...
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Background Malaria remains a major public health concern in The Gambia. The study assessed the trend of malaria admissions and outcome of adult patients admitted after the start of the COVID-19 pandemic in a tertiary hospital in The Gambia. Methods This was a retrospective hospital-based study and data was collected from the 18th October 2020 to 28th February 2023. Demographic data, clinical features, investigations, treatment, and outcomes were recorded. Results A total of 499 malaria cases were admitted to the hospital over the 29 months of the study period. Data from 320 (67.2% of the total cases) adult patients admitted into the internal medicine department were analysed. The median age was 22 years, range (15–90) and 189 (59.1%) cases were youth with a youth (15–24 years) to older adult (> 24 years) ratio of 1.4:1. The majority of the patients were male 199 (62.2) with a male to female ratio of 1.6:1. The total number of malaria cases admitted into the internal medicine department increased from 103 cases in 2021 to 182 cases in 2022and admission peaked in November in both years. The total number of admitted malaria cases during the peak of the malaria season also increased from 92 patients between September 2021 and December 2021 to 132 patients from September 2022 to December 2022.There was also an increase in both severe and uncomplicated malaria during the same period. The total mortality was 31 (9.7%) and the rate was similar in 2021 9 (8.7%) and 2022 15 (8.4%). Patients with impaired consciousness were more likely to die when compared to those without impaired consciousness [19 (23.6%) vs 12 (5%), p ≤ 0.001]. Patients with acute kidney injury were also more likely to die when compared with those without acute kidney injury [10 (20.4%) vs 15 (7.7%), p = 0.009]. Conclusion The findings show an emerging and consistent trend of malaria admissions and the outcome in the youth and older adult population after the start of the COVID-19 pandemic in The Gambia. This, therefore, suggests the need for the implementation of targeted malaria prevention interventions in this population to further prevent the spread of the disease to the more vulnerable population.
... Following this transformation, all assumptions for linear regression were satisfied such that the study hypotheses could be tested. Based on previous research, we examined the impact of relevant covariates including age [42], sex assigned at birth [43], race/ethnicity [6], BMI [42,44,45], allergies [46], current/recent illness [6], diabetes [42,44], cavities [47], gum bleeding [48], caffeine consumption [49], and recent tobacco smoking [50] on TNF-⍺ levels. None of these factors were found to have a significant impact on the outcome variable and thus none were included as covariates in our study. ...
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Our study is guided by Beck’s cognitive stress-vulnerability model of depression. We examined the associations between perceived everyday discrimination (PED) and TNF-⍺, an inflammatory biomarker associated with risk for severe illness, through the negative cognitive triad (NCT; negative thoughts about the self, world, and future) and depressive symptoms in adolescents. We utilized a sample of 99 adolescents (36.4% female; ages 13–16, M = 14.10, SD = 0.52) in our cross-sectional study. We used PROCESS and AMOS to compute regressions and direct, indirect, and total effects of PED, NCT aspects and depressive symptoms on TNF-⍺. Negative views of the self and world mediated between PED and depressive symptoms and that negative views of the self and future mediated between PED and TNF-⍺. In conclusion, Beck’s theory can be expanded to physical health providing directions for addressing mental and physical health simultaneously by restructuring adolescents’ negative view of the self.
... Men are more affected than women in our study, and they have higher death rates. According to similar studies, men might also have more severe forms of disease and the higher number of deaths is explained by the fact that testosterone is known to suppress the immune system, while estrogen can promote it; this could be why women have a stronger immune response against bacteria and viruses [7][8][9]. ...
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Objective: Observing the impact of the coronavirus disease 2019 (COVID-19) pandemic on digestive diseases in hospitalized patients at the Department of Gastroenterology-Hepatology in "Mother Teresa" University Hospital Center (UHC),Tirana. Methods: This retrospective study was carried out from June 2020 to December 2021 involving 41 cases of patients >18 years who were positive for COVID-19 infection detected by RT-PCR (Reverse Transcription-Polymerase Chain Reaction) assays of nasopharyngeal swab specimens. The severity of COVID-19 infection was evaluated by hematological/biochemical parameters, blood oxygenation/need for oxygen, radiological data on pulmonary CT imaging. Results: Out of 2527 hospitalized cases, 1.6% (41) were positive for the infection. The average age was 60.05 +/- 15.008 years. The group of age with more patients (48.8%) was 41-60 years. Infected males were higher than females (p<0.001). Out of the total, 21% were vaccinated at the diagnosis. Most patients came from urban areas, more than a half from the capital. Frequency of the digestive diseases was: cirrhosis 31.7%, pancreatitis 21.9%, alcoholic liver disease 21.9%, gastrointestinal hemorrhage 19.5%, digestive cancer 14.6%, biliary diseases 7.3%, inflammatory bowel disease (IBD) 2.4%, other digestive diseases 4.8%. Fever (90%) and fatigue (78.04%) were the dominant clinical signs. Biochemical and hematological parameters showed elevation of average value of aspartate amino transferase (AST), alanine transaminase (ALT) (AST>ALT, p<0.001), and bilirubin in all the patients. Higher levels of creatinine and significantly predictive value of systemic inflammation indices NLR (neutrophil to lymphocyte ratio ) and MLR (monocyte to lymphocyte ratio) were found in the fatality cases. Patients with cirrhosis had more severe form of COVID-19, lower blood oxygenation and needed treatment by O2-therapy (p<0.046). Death rate was 12%. A strong correlation was found between the need for O2-therapy and deaths (p<0.001) and between characteristic findings for COVID-19 in pulmonary CT imaging and low blood oxygenation (p<0.003). Conclusion: Comorbidity with chronic diseases, such as liver cirrhosis, has an important impact on the severity and mortality of the patients with COVID-19 infection. Inflammatory indices, such as NLR (neutrophil to lymphocyte ratio) and MLR (monocyte to lymphocyte ratio), are useful tools in predicting the evolution toward severe forms of the disease.
... Ayrıca cinsiyetler arasında IL-6 üretimindeki farklılıklar da gözlemlenmiştir (21). Ek olarak östrodiolün humoral ve hücre aracılı bağışıklık yanıtını uyardığı ve antikor üretimini artırdığı gösterilmiştir (22). Ayrıca kardiyovasküler sistem patolojileri başta olmak üzere komorbid hastalık varlığının da mortaliteyi artırdığı bildirilmiştir (5,23). ...
Objective: In the early stages of the worldwide coronavirus disease 2019 (COVID-19) pandemic, there aren’t many secondary intensive care unit publications. In our study, it was aimed to calculate the mortality rate and to determine the factors affecting mortality by retrospectively evaluating the data of COVID-19 patients hospitalized in a secondary intensive care unit. Methods: The files and records of patients aged 18 years and older who were positive for reverse transcriptase-polymerase chain reaction and followed in the secondary COVID-19 intensive care unit between January 2020 and July 2021, and their records in the hospital information system, were evaluated retrospectively. Demographic data, laboratory parameters, Sequential Organ Failure Assessment (SOFA) and Acute Physiology and Chronic Health Evaluation II (APACHE II) scores and clinical data of the patients were recorded. The data of living and deceased patients were compared. Regression analysis was performed for data with risk factors. Results: Archive records of a total of 227 patients were reviewed. The all cause mortality rate was 53.3%, and the median length of stay in the intensive care unit was 5 years. There was a significant difference in age (p<0.001), need for invasive mechanical ventilation (p<0.001), hospitalization saturation (p=0.016), ferritin (p<0.001), D-Dimer p(<0.001), APACHE II (p<0.001) and SOFA (p<0.001) scores between the living and deceased patient groups. Conclusion: Due to the increased number of patients and workload at the beginning of the COVID-19 pandemic, patient follow-up was carried out under difficult conditions in all intensive care units, especially in the secondary care units. In this period, we think that easily accessible biomarkers that can be used to predict mortality in secondary intensive care units may play a role in planning the treatment and referral processes of patients, and may have positive effects on patient outcomes by using the facilities more efficiently. Keywords: COVID-19, intensive care unit, mortality, risk factor
... Intriguingly, these pathologies are increasingly recognized as being driven by defects in the lung epithelium, primarily AT2 cells (Camelo et al., 2014;Katzen and Beers, 2020;Parimon et al., 2020), reinforcing the relevance of the AT2 transcriptomic differences between the sexes. However, females are more likely to develop ARDS after traumatic injury (Heffernan et al., 2011), and once ARDS has developed women are at higher risk of death (McNicholas et al., 2019), which may reflect the fact that females have stronger immune responses compared with males (Fischer et al., 2015;Klein and Flanagan, 2016). How biallelic ACE2 expression, and whether there are sex differences in ACE2 protein levels in AT2 cells, contributes to ARDS-induced disease warrants further investigation. ...
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Sex differences exist for many lung pathologies, including COVID-19 and pulmonary fibrosis, but the mechanistic basis for this remains unclear. Alveolar type 2 cells (AT2s), which play a key role in alveolar lung regeneration, express the X-linked Ace2 gene that has roles in lung repair and SARS-CoV-2 pathogenesis, suggesting that X chromosome inactivation (XCI) in AT2s might impact sex-biased lung pathology. Here we investigate XCI maintenance and sex-specific gene expression profiles using male and female AT2s. Remarkably, the inactive X chromosome (Xi) lacks robust canonical Xist RNA “clouds” and less enrichment of heterochromatic modifications in human and mouse AT2s. We demonstrate that about 68% of expressed X-linked genes in mouse AT2s, including Ace2, escape XCI. There are genome-wide expression differences between male and female AT2s, likely influencing both lung physiology and pathophysiologic responses. These studies support a renewed focus on AT2s as a potential contributor to sex-biased differences in lung disease.
Experimental approaches are among the most powerful tools available to biologists, yet in many disciplines their results have been questioned due to an underrepresentation of female animal subjects. In parasitology, experiments are crucial to understand host-parasite interactions, parasite development, host immune responses, as well as the efficacy of different control methods. However, distinguishing between species-wide and sex-specific effects requires the balanced inclusion of both male and female hosts in experiments and the reporting of results for each sex separately. Here, using data from over 3600 parasitological experiments on helminth-mammal interactions published in the past four decades, we investigate patterns of male versus female subject use and result reporting practices in experimental parasitology. We uncover multiple effects of the parasite taxon used, the type of host used (rats and mice for which subject selection is fully under researcher control versus farm animals), the research subject area and the year of publication, on whether host sex is even specified, whether one or both host sexes have been used (and if only one then which one), and whether the results are presented separately for each host sex. We discuss possible reasons for biases and unjustifiable selection of host subjects, and for poor experimental design and reporting of results. Finally, we make some simple recommendations for increased rigour in experimental design and to reset experimental approaches as a cornerstone of parasitological research.
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Clinical features applicable to the entire spectrum of viral meningitis are limited, and prognostic factors for adverse outcomes are undetermined. This nationwide population-based prospective cohort study included all adults with presumed and microbiologically confirmed viral meningitis in Denmark from 2015 until 2020. Prognostic factors for an unfavourable outcome (Glasgow Outcome Scale score of 1-4) 30 days after discharge were examined by modified Poisson regression. In total, 1066 episodes of viral meningitis were included, yielding a mean annual incidence of 4.7 episodes per 100,000 persons. Pathogens were enteroviruses in 419/1066 (39%), herpes simplex virus type 2 in 171/1066 (16%), varicella-zoster virus in 162/1066 (15%), miscellaneous viruses in 31/1066 (3%), and remained unidentified in 283/1066 (27%). The median age was 33 years (IQR 27-44), and 576/1066 (54%) were females. In herpes simplex virus type 2 meningitis, 131/171 (77%) were females. Immunosuppression (32/162 [20%]) and shingles (90/149 [60%]) were frequent in varicella-zoster virus meningitis. The triad of headache, neck stiffness, and hyperacusis or photophobia was present in 264/960 (28%). The median time until lumbar puncture was 3.0 hours (IQR 1.3-7.1), and the median CFS leukocyte count was 160 cells/µL (IQR 60-358). The outcome was unfavourable in 216/1055 (20%) 30 days after discharge. Using unidentified pathogen as the reference, the adjusted relative risk of an unfavourable outcome was 1.34 (95% CI 0.95-1.88) for enteroviruses, 1.55 (95% CI 1.00-2.41) for herpes simplex virus type 2, 1.51 (95% CI 0.98-2.33) for varicella-zoster virus, and 1.37 (95% CI 0.61-3.05) for miscellaneous viruses. The adjusted relative risk of an unfavourable outcome was 1.34 (95% CI 1.03-1.75) for females. Timing of acyclovir or valacyclovir was not associated with the outcome in meningitis caused by herpes simplex virus type 2 or varicella-zoster virus. In summary, the outcome of viral meningitis was similar among patients with different aetiologies, including those with presumed viral meningitis but without an identified pathogen. Females had an increased risk of an unfavourable outcome. Early antiviral treatment was not associated with an improved outcome in meningitis caused by herpes simplex virus type 2 or varicella-zoster virus.
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To the Editor—The journal's recent supplement on sex differences in susceptibility and response to infectious diseases was an excellent initiative for promoting research on a neglected topic of major interest [1–8]. If, in general, males show a higher susceptibility to many infectious diseases, the reviews displayed a number of infectious and autoimmune diseases for which females are more vulnerable. Differential vulnerability between males and females may come from exposure, infection (local or systemic), immune reaction, or a combination of these factors. Evidence came mainly from medicine, epidemiology (direct observation), and biology (animal models and in vivo observation). I address another dimension: demographic evidence.
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Background & objectives: Leishmaniasis has an annual incidence of 0.5-1.5 million new cases and is endemic in 88 countries throughout the world. About 90% of cases of cutaneous leishmaniasis (CL) are reported from seven countries including Iran. Evidence suggests the increased annual incidence of this disease in Iran. Intracellular protozoan parasite, Leishmania, is an obligatory parasite. Sandflies transfer infectious forms of the parasite or its metacyclic promastigotes to its vertebrate hosts such as humans by biting. In order to review the epidemiology of CL in Isfahan, Iran, factors such as incidence, disease causes, geographic features, age, and sex distribution, nationality, and occupation of patients, and the clinical spectrum of disease were evaluated. Methods: During the study, 1315 patients with CL, who referred to the Dermatology and Leishmaniasis Research Center at Isfahan, were evaluated. Results: The highest prevalence of CL was observed in fall (54%) and in northern areas of Isfahan (60.9%). Although CL was prevalent in both men and women, it had higher incidence in men (61.8%). The majority of patients (31.2%) aged 21-30 yr old. Most lesions were nodule-shaped (36.5%) and in upper extremities (48.3%) particularly in men (32.4%). While 81.2% of the subjects were Iranian, others were Afghani or with other nationalities. Most patients had multiple lesions on their bodies and 141 individuals (10.7%) had a previous history of disease. Among all occupations, the highest prevalence of CL was detected in students (18.1%). The response to treatment with compounds of meglumine antimoniate (glucantime) was better than other treatments. Interpretation & conclusion: Unfortunately, the results showed that the prevalence of CL has been increasing annually in some provinces of Iran, especially in Isfahan Province. Nevertheless, further studies are required to determine the vectors, reservoirs, and species of disease and to design appropriate strategies to control the disease.
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Infectious disease incidence is often male-biased. Two main hypotheses have been proposed to explain this observation. The physiological hypothesis (PH) emphasizes differences in sex hormones and genetic architecture, while the behavioral hypothesis (BH) stresses gender-related differences in exposure. Surprisingly, the population-level predictions of these hypotheses are yet to be thoroughly tested in humans. For ten major pathogens, we tested PH and BH predictions about incidence and exposure-prevalence patterns. Compulsory-notification records (Brazil, 2006-2009) were used to estimate age-stratified ♂:♀ incidence rate ratios for the general population and across selected sociological contrasts. Exposure-prevalence odds ratios were derived from 82 published surveys. We estimated summary effect-size measures using random-effects models; our analyses encompass ∼0.5 million cases of disease or exposure. We found that, after puberty, disease incidence is male-biased in cutaneous and visceral leishmaniasis, schistosomiasis, pulmonary tuberculosis, leptospirosis, meningococcal meningitis, and hepatitis A. Severe dengue is female-biased, and no clear pattern is evident for typhoid fever. In leprosy, milder tuberculoid forms are female-biased, whereas more severe lepromatous forms are male-biased. For most diseases, male bias emerges also during infancy, when behavior is unbiased but sex steroid levels transiently rise. Behavioral factors likely modulate male-female differences in some diseases (the leishmaniases, tuberculosis, leptospirosis, or schistosomiasis) and age classes; however, average exposure-prevalence is significantly sex-biased only for Schistosoma and Leptospira. Our results closely match some key PH predictions and contradict some crucial BH predictions, suggesting that gender-specific behavior plays an overall secondary role in generating sex bias. Physiological differences, including the crosstalk between sex hormones and immune effectors, thus emerge as the main candidate drivers of gender differences in infectious disease susceptibility.
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The risk of progression from exposure to the tuberculosis bacilli to the development of active disease is a two-stage process governed by both exogenous and endogenous risk factors. Exogenous factors play a key role in accentuating the progression from exposure to infection among which the bacillary load in the sputum and the proximity of an individual to an infectious TB case are key factors. Similarly endogenous factors lead in progression from infection to active TB disease. Along with well-established risk factors (such as human immunodeficiency virus (HIV), malnutrition, and young age), emerging variables such as diabetes, indoor air pollution, alcohol, use of immunosuppressive drugs, and tobacco smoke play a significant role at both the individual and population level. Socioeconomic and behavioral factors are also shown to increase the susceptibility to infection. Specific groups such as health care workers and indigenous population are also at an increased risk of TB infection and disease. This paper summarizes these factors along with health system issues such as the effects of delay in diagnosis of TB in the transmission of the bacilli.
Numerous investigations have revealed a bias toward males in the susceptibility to and severity of a variety of infectious diseases, especially parasitic diseases. Although different external factors may influence the exposure to infection sources among males and females, one recurrent phenomenon indicative of a hormonal influence is the simultaneous increase in disease occurrence and hormonal activity during the aging process. Substantial evidence to support the influence of hormones on disease requires rigorously controlled human population studies, as well as the same sex dimorphism being observed under controlled laboratory conditions. To date, only very few studies conducted have fulfilled these criteria. Herein, we introduce tropical infectious diseases, including amebiasis, malaria, leishmaniasis, toxoplasmosis, schistosomiasis, and paracoccidioidomycosis, in which hormones are suspected to play a role in disease processes. We summarize the most recent findings from epidemiologic studies in humans and from hormone replacement studies in animal models, as well as data regarding the influence of hormones on immune responses underlying the pathology of the diseases.
Unlabelled: Although 20%-40% of persons with acute hepatitis C virus (HCV) infection demonstrate spontaneous clearance, the time course and factors associated with clearance remain poorly understood. We investigated the time to spontaneous clearance and predictors among participants with acute HCV using Cox proportional hazards analyses. Data for this analysis were drawn from an international collaboration of nine prospective cohorts evaluating outcomes after acute HCV infection. Among 632 participants with acute HCV, 35% were female, 82% were Caucasian, 49% had interleukin-28 (IL28)B CC genotype (rs12979860), 96% had injected drugs ever, 47% were infected with HCV genotype 1, and 7% had human immunodeficiency virus (HIV) coinfection. Twenty-eight percent were HCV antibody negative/RNA positive at the time of acute HCV detection (early acute HCV). During follow-up, spontaneous clearance occurred in 173 of 632, and at 1 year after infection, 25% (95% confidence interval [CI]: 21, 29) had cleared virus. Among those with clearance, the median time to clearance was 16.5 weeks (IQR: 10.5, 33.4), with 34%, 67%, and 83% demonstrating clearance at 3, 6, and 12 months. Adjusting for age, factors independently associated with time to spontaneous clearance included female sex (adjusted hazards ratio [AHR]: 2.16; 95% CI: 1.48, 3.18), IL28B CC genotype (versus CT/TT; AHR, 2.26; 95% CI: 1.52, 3.34), and HCV genotype 1 (versus non-genotype 1; AHR: 1.56; 95% CI: 1.06, 2.30). The effect of IL28B genotype and HCV genotype on spontaneous clearance was greater among females, compared to males. Conclusions: Female sex, favorable IL28B genotype, and HCV genotype 1 are independent predictors of spontaneous clearance. Further research is required to elucidate the observed sex-based differences in HCV control.
The significant contributions of sex to an immune response, specifically in the context of the sex bias observed in susceptibility to infectious and autoimmune diseases and their pathogenesis, have until recently, largely been ignored and understudied. This review highlights recent findings related to sex-specific factors that provide new insights into how sex determines the transcriptome, the microbiome, and the consequent immune cell functional profile to define an immune response. Unquestionably, accumulating data confirm that sex matters and must be a consideration when decisions around therapeutic intervention strategies are developed.
Gender bias and the role of sex hormones in autoimmune diseases are well established. In specific pathogen-free nonobese diabetic (NOD) mice, females have 1.3-4.4 times higher incidence of type 1 diabetes (T1D). Germ-free (GF) mice lost the gender bias (female-to-male ratio 1.1-1.2). Gut microbiota differed in males and females, a trend reversed by male castration, confirming that androgens influence gut microbiota. Colonization of GF NOD mice with defined microbiota revealed that some, but not all, lineages overrepresented in male mice supported a gender bias in T1D. Although protection of males did not correlate with blood androgen concentration, hormone-supported expansion of selected microbial lineages may work as a positive-feedback mechanism contributing to the sexual dimorphism of autoimmune diseases. Gene-expression analysis suggested pathways involved in protection of males from T1D by microbiota. Our results favor a two-signal model of gender bias, in which hormones and microbes together trigger protective pathways.