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Sex Differences in Influenza Virus Infection, Vaccination, and Therapies
Abstract
Males and females differ in the likely outcome of influenza virus infection and vaccination. Following infection with pandemic and outbreak strains of influenza viruses, females of reproductive ages (15-49 years of age) experience a worse outcome than their male counterparts. Among females of reproductive ages, pregnancy is one factor linked to an increased risk of severe outcome of influenza, although it is not the sole factor explaining the female preponderance of severe disease. The sex bias in disease outcome is reversed in children under the age of 10 years and adults over the age of 65 years, where males appear to be more likely to be hospitalized or die from influenza. Small animal models of influenza virus infection illustrate that inflammatory immune responses also differ between the sexes and impact the outcome of infection. Males and females also generally respond differently to influenza vaccines and antiviral treatments, with females on average initiating higher humoral immune responses following vaccination and experiencing more adverse reactions to vaccines and drug treatments than males. Small animal models further show that elevated immunity following vaccination in females compared with males leads to greater cross protection against novel influenza viruses. We hypothesize that sex steroid hormones, including estrogens, progesterone, and androgens, as well as genetic differences between the sexes, may play roles in modulating sex differences in immune responses to influenza virus infection and vaccination. © Springer International Publishing Switzerland 2015. All rights are reserved.
... Age variations in the rates of different subtypes of influenza infections have been reported in several studies [5][6][7][8][9]. Sex disparities in the infection have not been studied extensively [10] but they may exist due to the difference in hormonal and immune responses to the infection [10][11][12][13][14][15][16][17]. Giefing-Kroll and colleagues (2015) reported sex disparities in influenza infections, with premenopausal women susceptible to pandemic influenza and men to seasonal influenza. ...
... While this observation may be confounded by the greater healthcare utilisation in women compared to men observed in Australia [25] and by targeted vaccination campaigns, the sex disparity could also be due to pregnancy-related immune-suppression. Immune responses can be suppressed during the menstrual cycle and pregnancy [10,[12][13][14]19]. Inclusion of pregnancy and menstrual status in notification databases would allow for further investigation of the influence of these factors. ...
Background
Influenza is a global infectious disease with a large burden of illness and high healthcare costs. Those who experience greater burden of disease include younger and older people, and pregnant women. Although there are known age and sex susceptibilities, little is known about how the interaction of age and sex may affect a population’s vulnerability to infection with different subtypes of influenza virus.
Methods
Laboratory-confirmed cases of influenza notified between 1 January 2009 and 31 December 2015 obtained from the Australian Government National Notifiable Diseases Surveillance System Influenza Public Data Set were analysed by age, sex and virus subtype. Age standardised notification rates per 100,000 population were calculated separately for females and males and used to generate female-to-male ratios with 95% confidence intervals for influenza A and B, and for virus subtypes A(H1N1)pdm09 and A(H3N2).
Results
334,560 notifications for influenza A (all notifications), A(H1N1)pmd09, A(H3N2) and B subtypes from a total of 335,414 influenza notifications were analysed. Male notification rates were significantly higher for the 0 to 4 years old age group regardless of virus type or subtype; and higher for those aged 0 to 14 years and those 85 years and older for influenza types A and B and subtype A(H1N1)pdm09. Female notification rates were significantly higher for A(H1N1)pdm09 in those aged 15 to 54 years, for Type A and sub-type A(H3N2) in those aged 15 to 69 years, and for Influenza B in those aged 20 to 74 years.
Conclusions
We observed a female dominance in notification rates throughout the adult age groups, which could possibly be related to health seeking behaviours. However, differences in health seeking behaviours cannot explain the variations observed across virus subtypes in the particular age groups with higher female notifications. Depending on their age, females may be more susceptible to certain subtypes of influenza virus. These observations suggest that there is an interaction between age and sex on susceptibility to influenza infection which varies by the subtype of the virus. The inclusion of pregnancy and menopausal status in surveillance data may assist development of targeted public health approaches during the emergence of new subtypes of influenza virus. Targeted vaccination campaigns may need to take into consideration specific age and sex groups who have a greater susceptibility to influenza infection as well as those who experience a greater burden of illness.
... Differences observed between cisgender men and cisgender women must be interpreted as a combination of both biological and psychosocial differences-and not solely sex differences. For example, there is increasing evidence that responses to influenza infection and vaccination differ by sex [42][43][44][45] and that this can be partly attributed to variations in sex hormones. However, work from different scientific fields suggests that environment-(and therefore gender-) related factors can induce variation in sex hormone levels [46,47]. ...
Although sex and gender are recognized as major determinants of health and immunity, their role is rarely considered in clinical practice and public health. We identified six bottlenecks preventing the inclusion of sex and gender considerations from basic science to clinical practice, precision medicine and public health policies. (i) A terminology-related bottleneck, linked to the definitions of sex and gender themselves, and the lack of consensus on how to evaluate gender. (ii) A data-related bottleneck, due to gaps in sex-disaggregated data, data on trans/non-binary people and gender identity. (iii) A translational bottleneck, limited by animal models and the underrepresentation of gender minorities in biomedical studies. (iv) A statistical bottleneck, with inappropriate statistical analyses and results interpretation. (v) An ethical bottleneck posed by the underrepresentation of pregnant people and gender minorities in clinical studies. (vi) A structural bottleneck, as systemic bias and discriminations affect not only academic research but also decision makers. We specify guidelines for researchers, scientific journals, funding agencies and academic institutions to address these bottlenecks. Following such guidelines will support the development of more efficient and equitable care strategies for all.
... This difference is not significant, p > 0.05. This result differs from some studies where female sex was a risk factor [11] [12] [13] but is similar to those found in many African countries [4] [5]. ...
... Similar to other lung-diseases [20,21] and previous findings in asthma [10], we find that hospital admission due to asthma is sex-biased. This raised the question if asthma develops differently in males and females due to differences in perinatal factors. ...
Asthma is the most common non-communicable pulmonary condition, affecting prepubertal boys more often than girls. This study explored how maternal and perinatal risk factors are linked to poorly controlled childhood asthma in a sex dependent manner. This single centre study was performed at a metropolitan teaching hospital in Western Sydney, Australia, using electronical obstetric records from 2000 to 2017 and electronical pediatric records from 2007 to 2018. The data of 1694 children with complete entries were retrospectively analysed. Risk factors for multiple hospital admission for asthma were selected by backward-eliminated Poisson regression modelling. Selection stability of these parameters was independently confirmed using approximated exhaustive search. Sex-specific regression models indicated that most notably parity (RR[95%CI] for parity = 3; 1.85[1.22–2.81]), birth length z-score (1.45[1.23–1.70]) and birth weight z-score (0.77[0.65–0.90]) contributed to multiple asthma admissions in girls, while boys were affected most prominently by maternal BMI (e.g. BMI 35–39.9; 1.92[1.38–2.67]) and threatened preterm labor (1.68[1.10–2.58]). Allergic status was a risk factors for both boys and girls (1.47[1.18–1.83] and 1.46[1.13–1.89]). Applying ROC analysis, the predictive modelling of risk factors for hospital admissions showed an incremental increase with an AUC of 0.84 and 0.75 for girls and boys respectively for >3 hospital admissions. Multiple hospital admissions for asthma are associated with maternal and perinatal risk factors in a sex and birth order dependent manner. Hence, prospective risk stratification studies aiming to improve childhood asthma control are warranted to test the clinical utility of these parameters. Furthermore, the influence of the early in utero environment on male-female differences in other communicable and non-communicable respiratory conditions should be considered.
... A meta-analysis suggests that severity and clinical outcome of patients with viral infections vary by sex and age. For example, young adult women demonstrate more severe clinical outcome by influenza virus infection compared to age-matched male participants (Peretz et al., 2015). Similarly, the severity of influenza virus infection changes during pregnancy in women (Straub, 2007). ...
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused corona virus disease 2019 (COVID-19) pandemic and led to mass casualty. Even though much effort has been put into development of vaccine and treatment methods to combat COVID-19, no safe and efficient cure has been discovered. Drug repurposing or drug repositioning which is a process of investigating pre-existing drug candidates for novel applications outside their original medical indication can speed up the drug development process. Raloxifene is a selective estrogen receptor modulator (SERM) that has been approved by FDA in 1997 for treatment and prevention of postmenopausal osteoporosis and cancer. Recently, raloxifene demonstrates efficacy in treating viral infections by Ebola, influenza A, and hepatitis C viruses and shows potential for drug repurposing for the treatment of SARS-CoV-2 infection. This review will provide an overview of raloxifene’s mechanism of action as a SERM and present proposed mechanisms of action in treatment of viral infections.
Influenza causes substantial morbidity and mortality each year globally, with periodic pandemics. For annually occurring seasonal influenza, influenza A and influenza B viruses are responsible for most of the burden. Both of these viruses are constantly evolving, and influenza A viruses have the ability to change dramatically, with pandemic potential. For seasonal influenza in Japan, usually a greater burden is due to influenza A, although influenza B detections increase later in the season and there have been some years where influenza B predominated with a large public health impact. Usually, seasonal influenza activity peaks in the winter and remains low during the summer; seasonality, however, varies by year and location (Okinawa shows less distinct seasonality), and pandemics have occurred outside the regular season. Compared to young adults, children and the elderly normally experience higher influenza morbidity. However, the relative burden for each age group may vary by season, and young adults may be considerably affected in a pandemic. These evolving and unpredictable epidemiologic features of influenza highlight the importance of continuous and timely surveillance, with careful assessments by time, place, person, and virus.
Influenza causes an acute infection characterized by virus replication in respiratory epithelial cells. The severity of influenza and other respiratory diseases changes over the life course and during pregnancy in women, suggesting that sex steroid hormones, such as estrogens, may be involved. Using primary, differentiated human nasal epithelial cell (hNEC) cultures from adult male and female donors, we exposed cultures to the endogenous 17β-estradiol (E2) or select estrogen receptor modulators (SERMs), then infected cultures with a seasonal influenza A virus (IAV) to determine whether estrogenic signaling could affect the outcome of IAV infection and whether these effects where sex-dependent. Estradiol, raloxifene, and bisphenol A decreased IAV titers in hNECs from female, but not male, donors. The estrogenic decrease in viral titer was dependent on the genomic estrogen receptor- 2 (ESR2) as neither genomic ESR1 nor non-genomic GPR30 were expressed in hNEC cultures and addition of the genomic ER antagonist ICI 182,780 reversed the antiviral effects of E2. Treatment of hNECs with E2 had no effect on interferon or chemokine secretion, but significantly downregulated cell metabolic processes, including genes that encode for zinc finger proteins, many of which contain estrogen response elements in their promoters. These data provide novel insights into the cellular and molecular mechanisms of how natural and synthetic estrogens impact IAV infection in respiratory epithelial cells derived from humans.
Avian influenza A (H5N1) viruses cause severe disease in humans, but the basis for their virulence remains unclear. In vitro and animal studies indicate that high and disseminated viral replication is important for disease pathogenesis. Laboratory experiments suggest that virus-induced cytokine dysregulation may contribute to disease severity. To assess the relevance of these findings for human disease, we performed virological and immunological studies in 18 individuals with H5N1 and 8 individuals infected with human influenza virus subtypes. Influenza H5N1 infection in humans is characterized by high pharyngeal virus loads and frequent detection of viral RNA in rectum and blood. Viral RNA in blood was present only in fatal H5N1 cases and was associated with higher pharyngeal viral loads. We observed low peripheral blood T-lymphocyte counts and high chemokine and cytokine levels in H5N1-infected individuals, particularly in those who died, and these correlated with pharyngeal viral loads. Genetic characterization of H5N1 viruses revealed mutations in the viral polymerase complex associated with mammalian adaptation and virulence. Our observations indicate that high viral load, and the resulting intense inflammatory responses, are central to influenza H5N1 pathogenesis. The focus of clinical management should be on preventing this intense cytokine response, by early diagnosis and effective antiviral treatment.
Inactivated influenza vaccines have been given to pregnant women since 1964. Since 2004, the Advisory Committee on Immunization Practices has recommended that pregnant women receive trivalent inactivated influenza vaccine at any time during pregnancy. Studies conducted before 2009 did not identify any safety concerns after trivalent inactivated influenza vaccine in mothers or their infants. During the 2009–2010 influenza A (H1N1) influenza vaccination program, several monitoring systems were established or enhanced to assess whether adverse events were associated with H1N1 2009 monovalent vaccines (2009 H1N1 influenza vaccines). Data from these systems did not identify any safety concerns in pregnant women who received 2009 H1N1 influenza vaccines or their infants. Although live attenuated influenza vaccines are not recommended in pregnant women, a small number of studies have not shown any safety concern among pregnant women or their infants who were inadvertently exposed to these vaccines. This review summarizes US and international safety data for influenza vaccines in pregnant women with an emphasis on 2009 H1N1 influenza vaccines.
Unlabelled:
17β-Estradiol (E2) treatment limits the pathology associated with pulmonary diseases caused by pathogens, allergens, and asthma, partly by reducing the production of proinflammatory cytokines and chemokines. To test the hypothesis that E2 protects against influenza A virus (IAV) infection by altering the recruitment and activity of innate immune cells and T cells, chemokine concentrations were measured and innate and adaptive immune cells were enumerated from the lungs of E2- and placebo-treated ovariectomized female C57BL/6 mice following infection. Females treated with E2 experienced less morbidity but had similar lung virus titers to placebo-treated females. Females treated with E2 had lower induction of CCL2 but higher CCL3 and CXCL1 responses in their lungs than placebo-treated females. Pulmonary recruitment of neutrophils, NK cells, macrophages, and dendritic cells was increased following infection, but only neutrophil numbers were greater in E2-treated than placebo-treated females. Neutrophils enhance the responses of influenza virus-specific CD8 T cells to promote virus clearance and improve the outcome of infection. Total numbers of virus-specific CD8 T cells were not altered by treatment with E2, but the proportion of gamma interferon (IFN-γ)- and tumor necrosis factor alpha (TNF-α)-producing, virus-specific CD8 T cells was increased. Neutrophil depletion in E2-treated females increased morbidity, reduced pulmonary production of chemoattractants for neutrophils, and reduced IFN-γ production by virus-specific CD8 T cells. Neutrophils mediate both inflammation and tissue repair during IAV infection and are regulated by E2 to improve the outcome of influenza in females.
Importance:
Severe influenza is associated with excessive inflammation that leads to tissue damage. We demonstrate that estradiol (E2) is a potent anti-inflammatory hormone that reduces the severity of influenza A virus infection in females. Treatment of female C57BL/6 mice with E2 does not affect virus replication but rather alters the production of chemokines, pulmonary recruitment of neutrophils, and the cytokine responses of virus-specific CD8 T cells to protect females against severe influenza.
Background:
Influenza A(H7N9) viruses isolated from humans show features suggesting partial adaptation to mammals. To provide insights into the pathogenesis of H7N9 virus infection, we compared risk factors, clinical presentation, and progression of patients hospitalized with H7N9, H5N1, and 2009 pandemic H1N1 (pH1N1) virus infections.
Methods:
We compared individual-level data from patients hospitalized with infection by H7N9 (n = 123), H5N1 (n = 119; 43 China, 76 Vietnam), and pH1N1 (n = 3486) viruses. We assessed risk factors for hospitalization after adjustment for age- and sex-specific prevalence of risk factors in the general Chinese population.
Results:
The median age of patients with H7N9 virus infection was older than other patient groups (63 years; P < .001) and a higher proportion was male (71%; P < .02). After adjustment for age and sex, chronic heart disease was associated with an increased risk of hospitalization with H7N9 (relative risk, 9.68; 95% confidence interval, 5.24-17.9). H7N9 patients had similar patterns of leukopenia, thrombocytopenia, and elevated alanine aminotransferase, creatinine kinase, C-reactive protein, and lactate dehydrogenase to those seen in H5N1 patients, which were all significantly different from pH1N1 patients (P < .005). H7N9 patients had a longer duration of hospitalization than either H5N1 or pH1N1 patients (P < .001), and the median time from onset to death was 18 days for H7N9 (P = .002) vs 11 days for H5N1 and 15 days for pH1N1 (P = .154).
Conclusions:
The identification of known risk factors for severe seasonal influenza and the more protracted clinical course compared with that of H5N1 suggests that host factors are an important contributor to H7N9 severity.
In India, the first case of 2009 pandemic influenza A (H1N1) virus infection was reported in May 2009 and the same in Saurashtra region in August 2009. We describe the epidemiology and factors associated with severe and non-severe cases of 2009 influenza A (H1N1) infection reported in the Saurashtra region.
From September 2009 to January 2011, we reported 511 patients who were infected with 2009 influenza A (H1N1) virus and admitted in different hospitals of Rajkot city. Real-time reverse transcriptase polymerase chain reaction (RT-PCR) testing was used to confirm infection. Factors associated with severe cases were determined by comparing with non-severe cases.
Out of 511 patients, 140 had severe disease (requiring intensive care or died) and 371 non-severe diseases (admitted in wards and survived). Median age of 30 years; median time of 5 days from onset of illness to diagnosis, and 4 days median time was reported for hospital stay among severe disease patients. More than half (60.7%) were females. Out of the patients with severe disease, 52.1% patients residing in urban area (OR = 1.68, CI = 1.13-2.49). Significant association was reported among severe disease patients for delayed referral from general practitioner/physician after initial treatment. All patients received antiviral drug, however, only 27.1% received within 2 days of illness. Presence of coexisting condition (pregnancy (OR = 0.19, CI = 0.08-0.48) was strongly associated with severe disease.
Delayed referral from general practitioner/physician, duration of antiviral treatment, presence of coexisting condition (i.e., pregnancy) were responsible for intensive care or mortality among severe influenza A (H1N1) illness.
The Centers for Disease Control and Prevention implemented the Pregnancy Flu Line (PFL) during the influenza A(H1N1)pdm09 (pH1N1) pandemic and continued operation through the 2010-2011 influenza season to collect reports of intensive care unit (ICU) admissions and deaths among pregnant women with influenza. The system documented the severe impact of influenza on pregnant women during both seasons with 181 ICU/survivals and 37 deaths reported during the 2009 fall pandemic wave and 69 ICU/survivals and ten deaths reported in the subsequent influenza season (2010-2011). A health department survey suggests PFL participants perceived public health benefits and minimum time burdens.
Significance
There are marked differences between the sexes in their immune response to infections and vaccination, with females often having significantly higher responses. However, the mechanisms underlying these differences are largely not understood. Using a systems immunology approach, we have identified a cluster of genes involved in lipid metabolism and likely modulated by testosterone that correlates with the higher antibody-neutralizing response to influenza vaccination observed in females. Moreover, males with the highest testosterone levels and expression of related gene signatures exhibited the lowest antibody responses to influenza vaccination. This study generates a number of hypotheses on the sex differences observed in the human immune system and their relationship to mechanisms involved in the antibody response to vaccination.
During surveillance for pneumonia of unknown etiology and sentinel hospital-based surveillance in Beijing, China, we detected avian influenza A(H7N9) virus infection in 4 persons who had pneumonia, influenza-like illness, or asymptomatic infections. Samples from poultry workers, associated poultry environments, and wild birds suggest that this virus might not be present in Beijing.
Aims:
The 2009 H1N1 pandemic illustrated the higher morbidity and mortality from viral infections in peripartum women. We describe clinical features of women who recently died of H1N1 in Colombia.
Methods:
This is a case series study that was gathered through a retrospective record review of all maternal H1N1 deaths in the country. The national mortality database of confirmed mortality from H1N1 in pregnancy and up to 42 days after delivery was reviewed during the H1N1 season in 2009. Women with H1N1 infections were confirmed by the laboratory of virology. Demographic, clinical, and laboratory data were reviewed. Statistical analyses were performed and median values of non-parametric data were reported with inter-quartile range (IQR).
Results:
A total of 23 H1N1 maternal deaths were identified. Eighty-three percent occurred in the third trimester. None of the mothers who died had received influenza vaccination. The median time from symptom onset to the initiation of antiviral treatment was 8.8 days (IQR 5.8-9.8). Five fatalities did not receive any anti-viral therapy. Median PaO2/FiO2 on day 1 was 80 (IQR, 60-98.5). All patients required inotropic support and mechanical ventilation with barotrauma-related complications of mechanical ventilation occurring in 35% of patients.
Conclusion:
In Colombia, none of the women suffering H1N1-related maternal deaths had received vaccination against the disease and most had delayed or had no anti-viral therapy. Given the lack of evidence-based clinical predictors to identify women who are prone to die from H1N1 in pregnancy, following international guidelines for vaccination and initiation of antiviral therapy in suspected cases would likely improve outcomes in developing countries.
Pregnant women have been identified as a high risk group for severe illness with 2009 pandemic influenza A(H1N1) virus infection (pH1N1). Obesity has also been identified as a risk factor for severe illness, though this has not been thoroughly assessed among pregnant women. The objectives of this study were to provide risk estimates for adverse maternal and neonatal outcomes associated with pH1N1 illness during pregnancy and to assess the role of obesity in these outcomes.
We established a retrospective population-based cohort of all live births occurring in Florida during the first 15 months of the pandemic. Illness with pH1N1 during pregnancy was ascertained through record linkage with the Florida state notifiable disease surveillance database. Data from the birth record, including pre-pregnancy body mass index, were analyzed to assess risk of adverse outcomes associated with pH1N1 illness.
A total of 194 women were identified through surveillance with pH1N1 illness during pregnancy. Children born to women with pH1N1 illness during pregnancy were at increased risk for low birth weight [OR (95%CI): 1.78 (1.11-2.860)], premature birth [2.21 (1.47-3.330)], and infant death [4.46 (1.80-11.00)], after adjusting for other factors. Women with pH1N1 illness during pregnancy were at increased risk for severe outcomes including admission to an intensive care unit. Obesity was an observed risk factor, both for the more severe pH1N1 illness detected through surveillance, and for severe maternal outcomes.
Case-patients in this analysis likely represent the most severely ill subset of all women infected with pH1N1 during pregnancy, limiting the generalizability of these findings to more severely ill patients rather than influenza infection in general. Nevertheless, these results suggest that more severe pH1N1 illness during pregnancy is associated with adverse neonatal outcomes and that pregnant women should continue to be targeted for appropriate prophylaxis and early treatment.
The worldwide spread of a novel influenza A (H1N1) virus in 2009 showed that influenza remains a significant health threat, even for individuals in the prime of life. This paper focuses on the unusually high young adult mortality observed during the Spanish flu pandemic of 1918. Using historical records from Canada and the U.S., we report a peak of mortality at the exact age of 28 during the pandemic and argue that this increased mortality resulted from an early life exposure to influenza during the previous Russian flu pandemic of 1889-90. We posit that in specific instances, development of immunological memory to an influenza virus strain in early life may lead to a dysregulated immune response to antigenically novel strains encountered in later life, thereby increasing the risk of death. Exposure during critical periods of development could also create holes in the T cell repertoire and impair fetal maturation in general, thereby increasing mortality from infectious diseases later in life. Knowledge of the age-pattern of susceptibility to mortality from influenza could improve crisis management during future influenza pandemics.
Serological surveillance conducted in areas of an outbreak of influenza A(H7N9) infection in China found no seropositivity
for antibodies specific for avian-origin influenza A(H7N9) among 1129 individuals of the general population, whereas >6% of
396 poultry workers were positive (on the basis of a hemagglutination inhibition titer of ≥ 80) for this subtype, confirming
that infected poultry is the principal source of human infections and that subclinical infections are possible. Fourteen days
after symptom onset, elevated levels of antibodies to A(H7N9) were found in 65.8% of patients (25/38) who survived but in
only 28.6% of those (2/7) who died, suggesting that the presence of antibodies may improve clinical outcome in infected patients.
Background:
Pregnant women are a high-risk group during influenza pandemics. In this study we determined whether plasmacytoid dendritic cells (pDCs) and CD8 T cells from pregnant women display altered activity following in vitro infection with 2009 pandemic swine influenza (H1N1/09).
Methods:
Peripheral blood mononuclear cells (PBMCs) were isolated from pregnant (n = 26) and nonpregnant (n = 28) women. DC subtypes were enumerated from PBMCs. PBMCs were infected with H1N1/09 and CD86, human leukocyte antigen-DR (HLA-DR), and programmed death ligand 1/2 (PDL1/2) measured on pDCs. PD receptor 1 (PD1) was measured on CD8 T cells. Interferon-alpha (IFN-α), interleukin-2 (IL-2), tumor necrosis factor-alpha (TNFα), and IFN-gamma were measured from culture supernatant.
Results:
pDC (ie, CD303(+)/CD1c(-) PBMCs) percentages were lower in pregnant compared with nonpregnant women (P < .05). Following H1N1/09 infection, pDCs from pregnant women showed higher expression of CD86 (P < .01), HLA-DR (P < .001), and PDL1 (P < .001) compared with nonpregnant women. Expression of PD1 on CD8 T cells was higher during pregnancy (P < .05). Following H1N1/09 infection, PBMCs from pregnant women displayed reduced IFN-α (P < .01), IL-2 (P < .01), and IFN-γ (P < .01) compared with nonpregnant women. Blocking PDL1 during H1N1/09 infection increased these cytokines during pregnancy (P < .05).
Conclusion:
Altered maternal cellular antiviral activity is implicated in the increased morbidity during pregnancy following influenza pandemics.
Understanding the biology of the breast and how ovarian hormones impinge on it is key to rational new approaches in breast cancer prevention and therapy. Because of the success of selective oestrogen receptor modulators (SERMs), such as tamoxifen, and aromatase inhibitors in breast cancer treatment, oestrogens have long received the most attention. Early progesterone receptor (PR) antagonists, however, were dismissed because of severe side effects, but awareness is now increasing that progesterone is an important hormone in breast cancer. Oestrogen receptor-α (ERα) signalling and PR signalling have distinct roles in normal mammary gland biology in mice; both ERα and PR delegate many of their biological functions to distinct paracrine mediators. If the findings in the mouse model translate to humans, new preventive and therapeutic perspectives might open up.
Low grade systemic inflammation (LGSI) as well as androgen deficiency has in older men been associated with several pathologies, including cardiovascular disease (CVD). We wanted to investigate whether low testosterone levels are linked to biomarkers of LGSI already in young age, before any concurrent manifestations of CVD or other systemic diseases.
Nested cross-sectional study.
Forty subfertile biochemically hypogonadal (n = 20) or eugonadal (n = 20) men (mean age 37 years, SD = 4.3) and 20 age-matched controls were randomly selected from an ongoing study on male subfertility. Subjects comprised male partners in infertile couples in whom also subnormal sperm concentration was present. Blood sampling, interviews, and anthropometric measures were undertaken. Serum levels of testosterone, LH, estradiol, SHBG, and 21 LGSI-markers were assessed.
Among 21 inflammatory markers, macrophage inflammatory protein 1-alpha (MIP1a) (ß = -0.025; p = 0.028), 1-beta (MIP1B) (ß = -0.015; p = 0.049) and tumor necrosis factor alpha (TNFa) (ß = -0.015; p = 0.040) showed negative association to total testosterone (TT) levels. MIP1a (ß = -1.95; p = 0.001) and TNFa (ß = -0.95; p = 0.014) showed negative association to calculated free testosterone (cFT) levels. Compared to men with normal TT and cFT levels, TNFa levels were higher in men with subnormal levels of TT (mean ratio 1.61; p = 0.006) and cFT (mean ratio 1.58; p = 0.007). Also, MIP1a levels were higher in men with subnormal levels of TT (mean ratio 1.84; p = 0.030).
Subnormal testosterone may already in young age associate to LGSI, which might be a part of the mechanism underlying adverse health outcomes of male hypogonadism.
Background
The first identified cases of avian influenza A(H7N9) virus infection in humans occurred in China during February and March 2013. We analyzed data obtained from field investigations to describe the epidemiologic characteristics of H7N9 cases in China identified as of December 1, 2013.
Methods
Field investigations were conducted for each confirmed case of H7N9 virus infection. A patient was considered to have a confirmed case if the presence of the H7N9 virus was verified by means of real-time reverse-transcriptase–polymerase-chain-reaction assay (RT-PCR), viral isolation, or serologic testing. Information on demographic characteristics, exposure history, and illness timelines was obtained from patients with confirmed cases. Close contacts were monitored for 7 days for symptoms of illness. Throat swabs were obtained from contacts in whom symptoms developed and were tested for the presence of the H7N9 virus by means of real-time RT-PCR.
Results
Among 139 persons with confirmed H7N9 virus infection, the median age was 61 years (range, 2 to 91), 71% were male, and 73% were urban residents. Confirmed cases occurred in 12 areas of China. Nine persons were poultry workers, and of 131 persons with available data, 82% had a history of exposure to live animals, including chickens (82%). A total of 137 persons (99%) were hospitalized, 125 (90%) had pneumonia or respiratory failure, and 65 of 103 with available data (63%) were admitted to an intensive care unit. A total of 47 persons (34%) died in the hospital after a median duration of illness of 21 days, 88 were discharged from the hospital, and 2 remain hospitalized in critical condition; 2 patients were not admitted to a hospital. In four family clusters, human-to-human transmission of H7N9 virus could not be ruled out. Excluding secondary cases in clusters, 2675 close contacts of case patients completed the monitoring period; respiratory symptoms developed in 28 of them (1%); all tested negative for H7N9 virus.
Conclusions
Most persons with confirmed H7N9 virus infection had severe lower respiratory tract illness, were epidemiologically unrelated, and had a history of recent exposure to poultry. However, limited, nonsustained human-to-human H7N9 virus transmission could not be ruled out in four families.
Background:
Infection of poultry with influenza A subtype H7 viruses occurs worldwide, but the introduction of this subtype to humans in Asia has not been observed previously. In March 2013, three urban residents of Shanghai or Anhui, China, presented with rapidly progressing lower respiratory tract infections and were found to be infected with a novel reassortant avian-origin influenza A (H7N9) virus.
Methods:
We obtained and analyzed clinical, epidemiologic, and virologic data from these patients. Respiratory specimens were tested for influenza and other respiratory viruses by means of real-time reverse-transcriptase-polymerase-chain-reaction assays, viral culturing, and sequence analyses.
Results:
A novel reassortant avian-origin influenza A (H7N9) virus was isolated from respiratory specimens obtained from all three patients and was identified as H7N9. Sequencing analyses revealed that all the genes from these three viruses were of avian origin, with six internal genes from avian influenza A (H9N2) viruses. Substitution Q226L (H3 numbering) at the 210-loop in the hemagglutinin (HA) gene was found in the A/Anhui/1/2013 and A/Shanghai/2/2013 virus but not in the A/Shanghai/1/2013 virus. A T160A mutation was identified at the 150-loop in the HA gene of all three viruses. A deletion of five amino acids in the neuraminidase (NA) stalk region was found in all three viruses. All three patients presented with fever, cough, and dyspnea. Two of the patients had a history of recent exposure to poultry. Chest radiography revealed diffuse opacities and consolidation. Complications included acute respiratory distress syndrome and multiorgan failure. All three patients died.
Conclusions:
Novel reassortant H7N9 viruses were associated with severe and fatal respiratory disease in three patients. (Funded by the National Basic Research Program of China and others.).
Please cite this paper as: Memoli et al. (2012) Influenza in pregnancy. Influenza and Other Respiratory Viruses 00(00), 000–000.
The 2009 pandemic served as a strong reminder that influenza-induced disease can have a great impact on certain at-risk populations and that pregnant women are one such important population. The increased risk of fatal and severe disease in these women was appreciated more than 500 years ago, and during the last century, pregnant women and their newborns have continued to be greatly affected by both seasonal and pandemic influenza. In this review, we briefly discuss the data collected both before and after the 2009 pandemic as it relates to the impact of influenza on pregnant women and their fetuses/newborns, as well as risk variables, clinical features, clues to pathophysiologic mechanisms, and approaches to treatment and prevention.
Pregnancy is an intricately orchestrated process where immune effector cells with fetal specificity are selectively silenced. This requires the sustained expansion of immune-suppressive maternal FOXP3(+) regulatory T cells (T(reg) cells), because even transient partial ablation triggers fetal-specific effector T-cell activation and pregnancy loss. In turn, many idiopathic pregnancy complications proposed to originate from disrupted fetal tolerance are associated with blunted maternal T(reg) expansion. Importantly, however, the antigen specificity and cellular origin of maternal T(reg) cells that accumulate during gestation remain incompletely defined. Here we show that pregnancy selectively stimulates the accumulation of maternal FOXP3(+) CD4 cells with fetal specificity using tetramer-based enrichment that allows the identification of rare endogenous T cells. Interestingly, after delivery, fetal-specific T(reg) cells persist at elevated levels, maintain tolerance to pre-existing fetal antigen, and rapidly re-accumulate during subsequent pregnancy. The accelerated expansion of T(reg) cells during secondary pregnancy was driven almost exclusively by proliferation of fetal-specific FOXP3(+) cells retained from prior pregnancy, whereas induced FOXP3 expression and proliferation of pre-existing FOXP3(+) cells each contribute to T(reg) expansion during primary pregnancy. Furthermore, fetal resorption in secondary compared with primary pregnancy becomes more resilient to partial maternal FOXP3(+) cell ablation. Thus, pregnancy imprints FOXP3(+) CD4 cells that sustain protective regulatory memory to fetal antigen. We anticipate that these findings will spark further investigation on maternal regulatory T-cell specificity that unlocks new strategies for improving pregnancy outcomes and novel approaches for therapeutically exploiting T(reg) cell memory.
Upon insult, such as infection or tissue injury, the innate and adaptive immune systems initiate a series of responses to defend the body. Recent studies from immune cell-specific androgen receptor (AR) knockout mice demonstrated that androgen and its receptor (androgen/AR) play significant roles in both immune regulations. In the innate immunity, androgen/AR is required for generation and proper function of neutrophils; androgen/AR also regulates wound healing processes through macrophage recruitment and proinflammatory cytokine production. In adaptive immunity, androgen/AR exerts suppressive effects on development and activation of T and B cells. Removal of such suppression causes thymic enlargement and excessive export of immature B cells. Altogether, androgen/AR plays distinct roles in individual immune cells, and targeting androgen/AR may help in treatment and management of immune-related diseases.
Pregnant women are at an increased risk of influenza-associated adverse outcomes, such as premature delivery, based on data from the latest pandemic with a novel influenza A (H1N1) virus in 2009-2010. It has been suggested that the transplacental transmission of influenza viruses is rarely detected in humans. A series of our study has demonstrated that influenza virus infection induced apoptosis in primary cultured human fetal membrane chorion cells, from which a factor with monocyte differentiation-inducing (MDI) activity was secreted. Proinflammatory cytokines, such as interleukin (IL)-6, tumor necrosis factor (TNF)-
α
, and interferon (IFN)-
β
, were identified as a member of the MDI factor. Influenza virus infection induced the mRNA expression of not only the proinflammatory cytokines but also chemoattractive cytokines, such as monocyte chemoattractant protein (MCP)-1, regulated on activation, normal T-cell expressed and secreted (RANTES), macrophage inflammatory protein (MIP)-1
β
, IL-8, growth-regulated oncogene (GRO)-
α
, GRO-
β
, epithelial cell-derived neutrophil-activating protein (ENA)-78, and interferon inducible protein (IP)-10 in cultured chorion cells. These cytokines are postulated to associate with human parturition. This paper, therefore, reviews (1) lessons from pandemic H1N1 2009 in pregnancy, (2) production of proinflammatory and chemoattractive cytokines by human fetal membranes and their functions in gestational tissues, and (3) possible roles of cytokines produced by human fetal membranes in the pathology of adverse pregnancy outcomes associated with influenza virus infection.
During the 2009 H1N1 pandemic (pH1N1), morbidity and mortality sparing was observed among the elderly population; it was hypothesized that this age group benefited from immunity to pH1N1 due to cross-reactive antibodies generated from prior infection with antigenically similar influenza viruses. Evidence from serologic studies and genetic similarities between pH1N1 and historical influenza viruses suggest that the incidence of pH1N1 cases should drop markedly in age cohorts born prior to the disappearance of H1N1 in 1957, namely those at least 52-53 years old in 2009, but the precise range of ages affected has not been delineated.
To test for any age-associated discontinuities in pH1N1 incidence, we aggregated laboratory-confirmed pH1N1 case data from 8 jurisdictions in 7 countries, stratified by single year of age, sex (when available), and hospitalization status. Using single year of age population denominators, we generated smoothed curves of the weighted risk ratio of pH1N1 incidence, and looked for sharp drops at varying age bandwidths, defined as a significantly negative second derivative. Analyses stratified by hospitalization status and sex were used to test alternative explanations for observed discontinuities. We found that the risk of laboratory-confirmed infection with pH1N1 declines with age, but that there was a statistically significant leveling off or increase in risk from about 45 to 50 years of age, after which a sharp drop in risk occurs until the late fifties. This trend was more pronounced in hospitalized cases and in women and was independent of the choice in smoothing parameters. The age range at which the decline in risk accelerates corresponds to the cohort born between 1951-1959 (hospitalized) and 1953-1960 (not hospitalized).
The reduced incidence of pH1N1 disease in older individuals shows a detailed age-specific pattern consistent with protection conferred by exposure to influenza A/H1N1 viruses circulating before 1957.
Pregnancy is a leading risk factor for severe complications during an influenza virus infection. Women infected during their second and third trimesters are at increased risk for severe cardiopulmonary complications, premature delivery, and death. Here, we establish a murine model of aerosolized influenza infection during pregnancy. We find significantly altered innate antiviral responses in pregnant mice, including decreased levels of IFN-β, IL-1α, and IFN-γ at early time points of infection. We also find reduced cytotoxic T cell activity and delayed viral clearance. We further demonstrate that pregnancy levels of the estrogen 17-β-estradiol are able to induce key anti-inflammatory phenotypes in immune responses to the virus independently of other hormones or pregnancy-related stressors. We conclude that elevated estrogen levels result in an attenuated anti-viral immune response, and that pregnancy-associated morbidities occur in the context of this anti-inflammatory phenotype.
Coxsackievirus B3 (CVB3) contributes to the development of myocarditis, an inflammatory heart disease that predominates in males, and infection is a cause of unexpected death in young individuals. Although gonadal hormones contribute significantly to sex differences, sex chromosomes may also influence disease. Increasing evidence indicates that Chromosome Y (ChrY) genetic variants can impact biological functions unrelated to sexual differentiation. Using C57BL/6J (B6)-ChrY consomic mice, we show that genetic variation in ChrY has a direct effect on the survival of CVB3-infected animals. This effect is not due to potential Sry-mediated differences in prenatal testosterone exposure or to differences in adult testosterone levels. Furthermore, we show that ChrY polymorphism influences the percentage of natural killer T cells in B6-ChrY consomic strains but does not underlie CVB3-induced mortality. These data underscore the importance of investigating not only the hormonal regulation but also ChrY genetic regulation of cardiovascular disease and other male-dominant, sexually dimorphic diseases and phenotypes.
Lymphocytes and myeloid cells express estrogen, progesterone, and androgen receptors, and studies show that sex steroid hormones directly modulate their activation, lifespan, and functional response during innate and adaptive immunity. Hematopoietic progenitors also express estrogen and androgen receptors, and profound effects of sex hormones on development of lymphoid and myeloid cells have been reported. The sex steroid receptors act as nuclear transcription factors, via multiple ligand-dependent or ligand-independent mechanisms. Sex steroid receptors also mediate rapid signaling events that synergize with membrane receptor signaling. The basis of sex-based differences in immunity will be clarified by determination of the potentially diverse molecular mechanisms by which sex steroid receptor signaling regulates immune cell development and function.
Background:
Concern about side effects is a barrier to influenza vaccination. This randomized, double-blind, placebo-controlled trial assessed side effects following vaccination among healthy working adults.Methods:
Healthy working adults were recruited during October and November 1994 and were randomized to receive influenza vaccine or placebo injections. Local and systemic symptoms during the week following the injection were evaluated through structured telephone interviews.Results:
Of 849 subjects enrolled in the study, 425 received a placebo and 424 received influenza vaccine. Base-line characteristics were similar between the groups, and 99% of subjects completed interviews to assess side effects after the study injection. No differences were seen between the 2 groups for the systemic symptoms of fever, myalgias, fatigue, malaise, or headaches. Overall, 35.2% of placebo and 34.1% of vaccine recipients reported at least 1 of these systemic symptoms (P=.78,χ2). Vaccine recipients reported a higher rate of arm soreness at the injection site than did placebo recipients (63.8% vs 24.1%, P<.001). Local reactions were mild in both groups and infrequently resulted in decreased use of the arm. After logistic regression, female sex (odds ratio [OR], 1.5; 95% confidence interval [CI], 1.1-2.1), age younger than 40 years (OR, 1.6; 95% CI, 1.2-2.2), and coincidental upper respiratory tract illness (OR, 4.6; 95% CI, 3.2-6.6) were independently associated with higher rates of systemic symptoms. In the multivariate model, vaccine again was not associated with systemic symptoms (OR, 0.9; 95% CI, 0.7-1.2).Conclusions:
Influenza vaccination of healthy working adults is not associated with higher rates of systemic symptoms when compared with placebo injection. These findings should be useful to physicians and other health care providers as they counsel patients to take advantage of an important opportunity for disease prevention and health protection.Arch Intern Med. 1996;156:1546-1550
There is a need for additional information on the fetal risks and relative safety of the pandemic H1N1 monovalent or trivalent influenza (pH1N1)-containing vaccines in women exposed during pregnancy.
To assess risks and relative safety of the pH1N1-containing vaccines, we conducted a prospective cohort study of pH1N1-vaccine-exposed and unexposed comparison women residing in the U.S. or Canada who were recruited during pregnancy and followed to outcome between October 2009 and August 2012. For exposure to the pH1N1 vaccine, adjusted relative risks (RRs) and 95% confidence intervals (CIs) were estimated for major birth defects and infants small for gestational age. Adjusted hazard ratios (HRs) and 95% CIs were estimated for spontaneous abortion and preterm delivery for time-varying exposure.
There were 1032 subjects available for analysis; 841 women were exposed to a pH1N1-containing vaccine in pregnancy, and 191 women were unexposed to any influenza vaccine in pregnancy. Nine of 328 (2.7%) first-trimester-exposed pregnancies resulted in an infant with a major birth defect compared to 6/188 (3.2%) in the unexposed (adjusted RR 0.79, 95% CI 0.26-2.42). The HR for spontaneous abortion was not elevated (adjusted HR 0.92, 95% CI 0.31-2.72). Adjusted HRs for preterm delivery were elevated for exposure anytime in pregnancy (3.28, 95% CI 1.25-8.63), specifically with exposure in the 1st or 2nd trimester. However, the mean decrease in gestational age in the exposed pregnancies was approximately three days. Adjusted RRs for small for gestational age infants on weight and length approximated 1.0.
For the 2009-12 influenza seasons combined, we found no meaningful evidence of increased RR or HR for major birth defects, spontaneous abortion, or small for gestational age infants. There was some evidence of an increased HR for preterm delivery following pH1N1-influenza vaccine exposure; however the decrease in gestational age on average was approximately three days.
Objective
To examine published studies of immediate hypersensitivity reactions (IHS) following vaccination and to determine whether women are at an increased risk of developing IHS after vaccination.Design and SamplePubMed was reviewed for vaccine articles reporting IHS by gender through June 2012. Data were abstracted on type of study, vaccine, hypersensitivity reaction, and statistic reported.MeasuresArticles were included if they described experimental, quasi-experimental, correlational or descriptive studies and IHS was reported by gender.ResultsOf 847 articles found in PubMed, 11 met the inclusion criteria. In eight studies, more women than men reported IHS, in two studies more men than women reported IHS and in one study the count was even.Conclusion
Limited data from these studies suggest that women may have higher rates of IHS reactions following vaccination than men. Limitations to the available data include the lack of denominator data and that the definition of IHS was not consistent across the studies. Large-scale population-based studies are indicated to determine if there are differences in rates by gender and biologic basis for these differences.
To evaluate the risk of adverse pregnancy outcomes following A/H1N1 vaccination in pregnant women.
This observational cohort study compared vaccinated and non-vaccinated pregnant women in EFEMERIS, a French prescription database including pregnant women. Women who ended their pregnancy in South Western France between October 21, 2009 and November 30, 2010 (the period of the French vaccination campaign) were included. Two non-vaccinated women were individually matched to each vaccinated woman by month and year of pregnancy onset. Conditional logistic regression and Cox proportional hazards regression were used to evaluate associations between each outcome (all-cause pregnancy loss, preterm delivery, small for gestational age (SGA) and neonatal pathology) and A/H1N1 vaccination during pregnancy.
1645 women of the 12,120 (13.6%) in the database who were administered A/H1N1 vaccine during pregnancy were compared to 3290 non-vaccinated women. Most were vaccinated in December 2009 (61%) with a non-adjuvanted vaccine (93%). The risks of pregnancy loss (adjusted HR=0.56; 95% CI=0.31-1.01), of preterm birth (adjusted HR=0.82; 95% CI=0.64-1.06), and of neonatal pathology (adjusted OR=0.70; 95% CI=0.49-1.02) did not differ between the vaccinated and the non-vaccinated groups. The rate of SGA was lower in the vaccinated group than in the non-vaccinated group (0.5% vs. 1.4%; adjusted OR=0.36; 95% CI=0.17-0.78).
There was no significant association between adverse pregnancy outcomes and vaccination with a non-adjuvanted A/H1N1 vaccine during pregnancy.
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.
We used data on age and sex for 136 laboratory confirmed human A(H7N9) cases reported as of 11 August 2013 to compare age-specific and sex-specific patterns of morbidity and mortality from the avian influenza A(H7N9) virus with those of the avian influenza A(H5N1) virus. Human A(H7N9) cases exhibit high degrees of age and sex bias: mortality is heavily biased toward males >50 years, no deaths have been reported among individuals <25 years old, and relatively few cases documented among children or adolescents. The proportion of fatal cases (PFC) for human A(H7N9) cases as of 11 August 2013 was 32%, compared to a cumulative PFC for A(H5N1) of 83% in Indonesia and 36% in Egypt. Approximately 75% of cases of all A(H7N9) cases occurred among individuals >45 years old. Morbidity and mortality from A(H7N9) are lowest among individuals between 10 and 29 years, the age group which exhibits the highest cumulative morbidity and case fatality rates from A(H5N1). Although individuals <20 years old comprise nearly 50% of all human A(H5N1) cases, only 7% of all reported A(H7N9) cases and no deaths have been reported among individuals in this age group. Only 4% of A(H7N9) cases occurred among children<5 years old, and only one case from the 10 to 20 year age group. Age- and sex-related differences in morbidity and mortality from emerging zoonotic diseases can provide insights into ecological, economic, and cultural factors that may contribute to the emergence and proliferation of novel zoonotic diseases in human populations.
We estimated exposure prevalence and studied potential risks for preterm delivery (PTD) and specific birth defects associated with exposure to the unadjuvanted pH1N1-containing vaccines in the 2009-2010 and 2010-2011 influenza seasons. We used data from 4 regional centers in the United States collected as part of the Slone Epidemiology Center's Birth Defects Study. For PTD, propensity score-adjusted time-varying hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated for exposure anytime in pregnancy and for each trimester. For 41 specific major birth defects, propensity score-adjusted odds ratios (ORs) and 95% confidence intervals (CIs) were estimated. Among 4191 subjects, there were 3104 mothers of malformed (cases) and 1087 mothers of nonmalformed (controls). Exposure prevalences among controls were 47% for the 2009-2010 season and 38% for the 2010-2011 season; prevalence varied by geographic region. Results for PTD differed between the two seasons, with risks above and below the null for the 2009-2010 and 2010-2011 seasons, respectively. For 41 specific birth defects, most adjusted ORs were close to 1.0. Three defects had adjusted ORs>2.0 and four had risks<0.5; however, 95% CIs for these were wide.
Among women exposed to pH1N1 vaccine, we found a decreased risk for PTD in the 2010-2011 season; risk was increased in 2009-2010, particularly following exposure in the first trimester, though the decrease in gestational length was less than 2 days. For specific major defects, we found no meaningful evidence of increased risk for specific congenital malformations following pH1N1 influenza vaccinations in the 2009-2010 and 2010-2011 seasons.
CD4+CD25high regulatory T cells (Tregs) are implicated in the maintenance of murine pregnancy. However, reports regarding circulating Treg frequencies in human pregnancy are inconsistent, and the functionality and phenotype of these cells in pregnancy have not been clarified. The aim of this study was to determine the frequency, phenotype, and function of circulating Tregs in the second trimester of human pregnancy and the influence of progesterone and 17β-estradiol on Treg phenotype and frequency. Based on expressions of Foxp3, CD127, and HLA-DR as determined by multicolor flow cytometry, we defined a proper CD4dim CD25 high Treg population and showed, in contrast to most previous reports, that this population was reduced in second trimester of pregnancy. Unexpectedly, Foxp3 expression was decreased in the Treg, as well as in the CD4+ population. These changes could be replicated in an in vitro system resembling the pregnancy hormonal milieu, where 17β-estradiol, and in particular progesterone, induced, in line with the pregnancy situation, a reduction of CD4dimCD25highFoxp3+ cells in PBMC from nonpregnant women. By coculturing FACS-sorted Tregs and autologous CD4+CD25- responder cells, we showed that Tregs from pregnant women still displayed the same suppressive capacity as nonpregnant women in terms of suppressing IL-2, TNF-α, and IFN-γ secretion from responder cells while efficiently producing IL-4 and IL-10. Our findings support the view of hormones, particularly progesterone, as critical regulators of Tregs in pregnancy. Furthermore, we suggest that in the light of the results of this study, early data on circulating Treg frequencies in pregnancy need reevaluation.
The novel influenza A H7N9 virus emerged recently in mainland China, whereas the influenza A H5N1 virus has infected people in China since 2003. Both infections are thought to be mainly zoonotic. We aimed to compare the epidemiological characteristics of the complete series of laboratory-confirmed cases of both viruses in mainland China so far.
An integrated database was constructed with information about demographic, epidemiological, and clinical variables of laboratory-confirmed cases of H7N9 (130 patients) and H5N1 (43 patients) that were reported to the Chinese Centre for Disease Control and Prevention until May 24, 2013. We described disease occurrence by age, sex, and geography, and estimated key epidemiological variables. We used survival analysis techniques to estimate the following distributions: infection to onset, onset to admission, onset to laboratory confirmation, admission to death, and admission to discharge.
The median age of the 130 individuals with confirmed infection with H7N9 was 62 years and of the 43 with H5N1 was 26 years. In urban areas, 74% of cases of both viruses were in men, whereas in rural areas the proportions of the viruses in men were 62% for H7N9 and 33% for H5N1. 75% of patients infected with H7N9 and 71% of those with H5N1 reported recent exposure to poultry. The mean incubation period of H7N9 was 3·1 days and of H5N1 was 3·3 days. On average, 21 contacts were traced for each case of H7N9 in urban areas and 18 in rural areas, compared with 90 and 63 for H5N1. The fatality risk on admission to hospital was 36% (95% CI 26-45) for H7N9 and 70% (56-83%) for H5N1.
The sex ratios in urban compared with rural cases are consistent with exposure to poultry driving the risk of infection-a higher risk in men was only recorded in urban areas but not in rural areas, and the increased risk for men was of a similar magnitude for H7N9 and H5N1. However, the difference in susceptibility to serious illness with the two different viruses remains unexplained, since most cases of H7N9 were in older adults whereas most cases of H5N1 were in younger people. A limitation of our study is that we compared laboratory-confirmed cases of H7N9 and H5N1 infection, and some infections might not have been ascertained.
Ministry of Science and Technology, China; Research Fund for the Control of Infectious Disease and University Grants Committee, Hong Kong Special Administrative Region, China; and the US National Institutes of Health.
In the latter part of October, 1918, when the epidemic of influenza was at its peak in this locality, the seriousness of the disease as seen in pregnant women caused considerable alarm among those in charge of obstetric cases. It soon became apparent that there was a great diversity of experience as regards the mortality, some of the practitioners losing most of their cases, others very few. In addition to its importance in contributing toward a more definite knowledge concerning the prognosis of influenza in pregnant women, it has seemed to me that a statistical study based on a large number of cases would also be of value in showing the effect of the influenza on the course of pregnancy. Owing to its severity and wide occurrence, and to the fact that it was especially prevalent among young women of the child-bearing age, the epidemic offered the best opportunity we
During the recent epidemic of pneumonia, or so-called Spanish influenza, 2,154 patients were admitted to Cook County Hospital between Sept. 18 and Nov. 5, 1918. Of this number, 101 were pregnant women.Of these 101 cases of pneumonia, complicated by pregnancy, fifty-two died, giving a mortality of 51.4 per cent., as compared with a mortality of 719, or 33.3 per cent., of the 2,154 patients admitted to the general hospital. This shows a relatively higher death rate by 18.1 per cent. in the pregnant women. These apparently high percentages of mortality may be explained in part by the condition of the average patient on entrance to this hospital.The Cook County Hospital received by far the largest majority of the patients during this epidemic, all of whom were from the poorer classes of the population. The patients were all extremely ill on entrance, many dying in ambulances on the way
This study aimed to comprehensively describe inflammatory responses to trivalent influenza virus vaccine (TIV) among pregnant women and determine whether responses differ compared to non-pregnancy.
Twenty-eight pregnant and 28 non-pregnant women were vaccinated. Serum cytokines were measured at baseline, and 1, 2, and 3 days post-vaccination. Anti-influenza antibody titers were measured at baseline and 1 month post-vaccination.
Overall, following vaccination, tumor necrosis factor (TNF)-α and interleukin(IL)-6 increased significantly, peaking at 1 day post-vaccination (P's < 0.001). Pregnant versus non-pregnant women showed no differences in IL-6, TNF-α, or IL-1β responses. Pregnant women showed no change in IL-8 and increases in migration inhibitory factor (MIF), while non-pregnant showed decreases in both. Pregnancy did not significantly alter antibody responses.
Inflammatory responses to TIV are mild, transient, and generally similar in pregnant and non-pregnant women. Given the variability evidenced, vaccination may provide a useful model for studying individual differences in inflammatory response propensity.
Influenza infection during pregnancy imparts disproportionate morbidity and mortality. This has been primarily noted during occasional influenza pandemics but also during seasonal epidemics. The majority of pregnant women who contract influenza appear to have a mild, self-limited course. However, influenza produces a severe life-threatening respiratory illness among a non-negligible and partially unpredictable portion of susceptible pregnant women. Influenza vaccination is the most effective way to prevent this occasionally fatal infection and is recommended for all pregnant women lacking contraindication. Antiviral medications are indicated for both prophylaxis and treatment for suspected and/or confirmed influenza infection during pregnancy.
The intensity and prevalence of viral infections are typically higher in males, whereas disease outcome can be worse for females. Females mount higher innate and adaptive immune responses than males, which can result in faster clearance of viruses, but also contributes to increased development of immunopathology. In response to viral vaccines, females mount higher antibody responses and experience more adverse reactions than males. The efficacy of antiviral drugs at reducing viral load differs between the sexes, and the adverse reactions to antiviral drugs are typically greater in females than males. Several variables should be considered when evaluating male/female differences in responses to viral infection and treatment: these include hormones, genes, and gender-specific factors related to access to, and compliance with, treatment. Knowledge that the sexes differ in their responses to viruses and to treatments for viral diseases should influence the recommended course of action differently for males and females.
Editor's suggested further reading in BioEssays X-chromosome-located microRNAs in immunity: Might they explain male/female differences Abstract
The “four core genotypes” (FCG) model comprises mice in which sex chromosome complement (XX vs. XY) is unrelated to the animal’s gonadal sex. The four genotypes are XX gonadal males or females, and XY gonadal males or females. The model allows one to measure (1) the differences in phenotypes caused by sex chromosome complement (XX vs. XY), (2) the differential effects of ovarian and testicular secretions, and (3) the interactive effects of (1) and (2). Thus, the FCG model provides new information regarding the origins of sex differences in phenotype that has not been available from studies that manipulate gonadal hormone levels in normal XY males and XX females. Studies of the FCG model have uncovered XX vs. XY differences in behaviors (aggression, parenting, habit formation, nociception, social interactions), gene expression (septal vasopressin), and susceptibility to disease (neural tube closure and autoimmune disease) not mediated by gonadal hormones. Some sex chromosome effects are mediated by sex differences in dose of X genes or their parental imprint. Future studies will identify the genes involved and their mechanisms of action.
Background:
The objective of this study was to assess the predictive effects of socioeconomic factors to explain influenza vaccination coverage rates in 11 European countries.
Methods:
Data from national household surveys collected over up to seven consecutive seasons between 2001/2002 and 2007/2008 were analyzed to assess the associations of socioeconomic factors with immunization against influenza.
Results:
In total, data from 92,101 household contacts representative for the national non-institutionalized population aged above 14 years were analyzed. Influenza vaccination coverage rates in Europe remain suboptimal with little or no progress in the last years. The results of this study indicate that gender, household income, size of household, educational level and population size of living residence may significantly contribute to explain chances of getting immunized against influenza apart from the known risk factors age and chronic illness. The effect of these socioeconomic factors was differently expressed among the countries and could not be explained solely on basis of economic characteristics of these countries.
Conclusions:
Future measures should address inequalities to achieve the WHO target by 2010 with an influenza vaccination rate of 75% in the elderly. National vaccination campaigns may need to take socioeconomic segments of the population here identified as less likely of getting the influenza vaccine into account.
Adaptations in maternal systemic immunity are presumed to be responsible for observed alterations in disease susceptibility and severity as pregnancy progresses. Epidemiological evidence as well as animal studies have shown that influenza infections are more severe during the second and third trimesters of pregnancy, resulting in greater morbidity and mortality, although the reason for this is still unclear. Our laboratory has taken advantage of 20 years of experience studying the murine immune response to respiratory viruses to address questions of altered immunity during pregnancy. With clinical studies and unique animal model systems, we are working to define the mechanisms responsible for altered immune responses to influenza infection during pregnancy and what roles hormones such as estrogen or progesterone play in these alterations.