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.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
References
Ailes EC, Newsome K, Williams JL, McIntyre AF, Jamieson DJ, Finelli L, Honein MA (2013) CDC pregnancy flu line: monitoring severe illness among pregnant women with influenza. Matern Child Health J. doi:10.1007/s10995-013-1415-6
Arima Y, Vong S (2013) Human infections with avian influenza A(H7N9) virus in China: preliminary assessments of the age and sex distribution. Western Pac Surveill Response J 4(2):1–3. doi:10.5365/wpsar.2013.4.2.005
Arnold AP, Chen X (2009) What does the “four core genotypes” mouse model tell us about sex differences in the brain and other tissues? Front Neuroendocrinol 30(1):1–9. doi:10.1016/j.yfrne.2008.11.001
Arnold AP, Lusis AJ (2012) Understanding the sexome: measuring and reporting sex differences in gene systems. Endocrinology 153(6):2551–2555
Bean-Mayberry B, Yano EM, Mor MK, Bayliss NK, Xu X, Fine MJ (2009) Does sex influence immunization status for influenza and pneumonia in older veterans? J Am Geriatr Soc 57(8):1427–1432. doi:10.1111/j.1532-5415.2009.02316.x
Beau AB, Hurault-Delarue C, Vidal S, Guitard C, Vayssiere C, Petiot D, Montastruc JL, Damase-Michel C, Lacroix I (2014) Pandemic A/H1N1 influenza vaccination during pregnancy: a comparative study using the EFEMERIS database. Vaccine 32(11):1254–1258. doi:10.1016/j.vaccine.2014.01.021
Beigi RH (2012) Influenza during pregnancy: a cause of serious infection in obstetrics. Clin Obstet Gynecol 55(4):914–926. doi:10.1097/GRF.0b013e31827146bd
Blanchon T, Mentre F, Charlois-Ou C, Dornic Q, Mosnier A, Bouscambert M, Carrat F, Duval X, Enouf V, Leport C (2011) Factors associated with clinical and virological response in patients treated with oseltamivir or zanamivir for influenza A during the 2008–2009 winter. Clin Microbiol Infect. doi:10.1111/j.1469-0691.2011.03751.x
Bobjer J, Katrinaki M, Tsatsanis C, Lundberg Giwercman Y, Giwercman A (2013) Negative association between testosterone concentration and inflammatory markers in young men: a nested cross-sectional study. PLoS ONE 8(4):e61466. doi:10.1371/journal.pone.0061466
Bouman A, Heineman MJ, Faas MM (2005) Sex hormones and the immune response in humans. Hum Reprod Update 11(4):411–423
Bouvier NM, Lowen AC (2010) Animal Models for Influenza Virus Pathogenesis and Transmission. Viruses 2(8):1530–1563. doi:10.3390/v20801530
Briand S, Fukuda K (2009) Avian influenza A (H5N1) virus and 2 fundamental questions. J Infect Dis 199(12):1717–1719. doi:10.1086/599209
Brisken C (2013) Progesterone signalling in breast cancer: a neglected hormone coming into the limelight. Nat Rev Cancer 13(6):385–396. doi:10.1038/nrc3518
Butts CL, Shukair SA, Duncan KM, Bowers E, Horn C, Belyavskaya E, Tonelli L, Sternberg EM (2007) Progesterone inhibits mature rat dendritic cells in a receptor-mediated fashion. Int Immunol 19(3):287–296
Case LK, Toussaint L, Moussawi M, Roberts B, Saligrama N, Brossay L, Huber SA, Teuscher C (2012) Chromosome y regulates survival following murine coxsackievirus b3 infection. G3 (Bethesda) 2(1):115–121. doi:10.1534/g3.111.001610
Cate TR, Couch RB, Parker D, Baxter B (1983) Reactogenicity, immunogenicity, and antibody persistence in adults given inactivated influenza virus vaccines - 1978. Rev Infect Dis 5(4):737–747
CDC (2014a) Avian Influenza A (H7N9) Virus. Centers for Disease Control and Prevention. http://www.cdc.gov/flu/avianflu/h7n9-virus.htm
CDC (2014b) Highly Pathogenic Avian Influenza A (H5N1) Virus. Centers for Disease Control Prevention. http://www.cdc.gov/flu/avianflu/h5n1-virus.htm
CDC (2014c) Laboratory-confirmed influenza hospitalizations, 2009–2010. Centers for Disease Control and Prevention. http://gis.cdc.gov/grasp/fluview/FluHospChars.html
CDC (2014d) Laboratory-Confirmed Influenza Hospitalizations, 2013–2014. Centers for Diseases Control and Prevention. http://gis.cdc.gov/grasp/fluview/FluHospChars.html
Chambers CD, Johnson D, Xu R, Luo Y, Louik C, Mitchell AA, Schatz M, Jones KL, Group OCR (2013) Risks and safety of pandemic h1n1 influenza vaccine in pregnancy: birth defects, spontaneous abortion, preterm delivery, and small for gestational age infants. Vaccine 31(44):5026–5032. doi:10.1016/j.vaccine.2013.08.097
Chan KH, Zhang AJ, To KK, Chan CC, Poon VK, Guo K, Ng F, Zhang QW, Leung VH, Cheung AN, Lau CC, Woo PC, Tse H, Wu W, Chen H, Zheng BJ, Yuen KY (2010) Wild type and mutant 2009 pandemic influenza A (H1N1) viruses cause more severe disease and higher mortality in pregnant BALB/c mice. PLoS ONE 5(10):e13757. doi:10.1371/journal.pone.0013757
Chor JS, Ngai KL, Goggins WB, Wong MC, Wong SY, Lee N, Leung TF, Rainer TH, Griffiths S, Chan PK (2009) Willingness of Hong Kong healthcare workers to accept pre-pandemic influenza vaccination at different WHO alert levels: two questionnaire surveys. Br Med J 339:b3391
Christian LM, Porter K, Karlsson E, Schultz-Cherry S, Iams JD (2013) Serum proinflammatory cytokine responses to influenza virus vaccine among women during pregnancy versus non-pregnancy. Am J Reprod Immunol 70(1):45–53. doi:10.1111/aji.12117
Chudasama RK, Patel UV, Verma PB (2013) Characteristics of Hospitalized Patients with Severe and Non-Severe Pandemic Influenza A (H1N1) in Saurashtra Region, India (Two Waves Analysis). J Family Med Prim Care 2(2):182–187. doi:10.4103/2249-4863.117397
Cook IF (2009) Sex differences in injection site reactions with human vaccines. Hum Vaccin 5(7):441–449
Cowling BJ, Jin L, Lau EH, Liao Q, Wu P, Jiang H, Tsang TK, Zheng J, Fang VJ, Chang Z, Ni MY, Zhang Q, Ip DK, Yu J, Li Y, Wang L, Tu W, Meng L, Wu JT, Luo H, Li Q, Shu Y, Li Z, Feng Z, Yang W, Wang Y, Leung GM, Yu H (2013) Comparative epidemiology of human infections with avian influenza A H7N9 and H5N1 viruses in China: a population-based study of laboratory-confirmed cases. Lancet 382(9887):129–137. doi:10.1016/s0140-6736(13)61171-x
Cox S, Posner SF, McPheeters M, Jamieson DJ, Kourtis AP, Meikle S (2006) Hospitalizations with respiratory illness among pregnant women during influenza season. Obstet Gynecol 107(6):1315–1322
Creanga AA, Kamimoto L, Newsome K, D’Mello T, Jamieson DJ, Zotti ME, Arnold KE, Baumbach J, Bennett NM, Farley MM, Gershman K, Kirschke D, Lynfield R, Meek J, Morin C, Reingold A, Ryan P, Schaffner W, Thomas A, Zansky S, Finelli L, Honein MA (2011) Seasonal and 2009 pandemic influenza A (H1N1) virus infection during pregnancy: a population-based study of hospitalized cases. Am J Obstet Gynecol 204(6 Suppl 1):S38–S45
Crighton EJ, Moineddin R, Mamdani M, Upshur RE (2004) Influenza and pneumonia hospitalizations in Ontario: a time-series analysis. Epidemiol Infect 132(6):1167–1174
Crighton EJ, Elliott SJ, Kanaroglou P, Moineddin R, Upshur RE (2008) Spatio-temporal analysis of pneumonia and influenza hospitalizations in Ontario, Canada. Geospatial Health 2(2):191–202
D’Agostino P, Milano S, Barbera C, Di Bella G, La Rosa M, Ferlazzo V, Farruggio R, Miceli DM, Miele M, Castagnetta L, Cillari E (1999) Sex hormones modulate inflammatory mediators produced by macrophages. Ann N Y Acad Sci 876:426–429
Dai R, Phillips RA, Ahmed SA (2007) Despite inhibition of nuclear localization of NF-kappa B p65, c-Rel, and RelB, 17-beta estradiol up-regulates NF-kappa B signaling in mouse splenocytes: the potential role of Bcl-3. J Immunol 179(3):1776–1783
De Clercq E (2006) Antiviral agents active against influenza A viruses. Nat Rev Drug Discov 5(12):1015–1025
de Jong MD, Simmons CP, Thanh TT, Hien VM, Smith GJ, Chau TN, Hoang DM, Chau NV, Khanh TH, Dong VC, Qui PT, Cam BV, Hado Q, Guan Y, Peiris JS, Chinh NT, Hien TT, Farrar J (2006) Fatal outcome of human influenza A (H5N1) is associated with high viral load and hypercytokinemia. Nat Med 12(10):1203–1207. doi:10.1038/nm1477
Doyle TJ, Goodin K, Hamilton JJ (2013) Maternal and neonatal outcomes among pregnant women with 2009 pandemic influenza A(H1N1) illness in Florida, 2009–2010: a population-based cohort study. PLoS ONE 8(10):e79040. doi:10.1371/journal.pone.0079040
Dudley JP (2009) Age-specific infection and death rates for human A(H5N1) avian influenza in Egypt. Euro Surveill 14(18)
Dudley JP, Mackay IM (2013) Age-specific and sex-specific morbidity and mortality from avian influenza A(H7N9). J Clin Virol 58(3):568–570. doi:10.1016/j.jcv.2013.09.004
Dunn SE, Ousman SS, Sobel RA, Zuniga L, Baranzini SE, Youssef S, Crowell A, Loh J, Oksenberg J, Steinman L (2007) Peroxisome proliferator-activated receptor (PPAR)alpha expression in T cells mediates gender differences in development of T cell-mediated autoimmunity. J Exp Med 204(2):321–330
Elenkov IJ, Wilder RL, Bakalov VK, Link AA, Dimitrov MA, Fisher S, Crane M, Kanik KS, Chrousos GP (2001) IL-12, TNF-alpha, and hormonal changes during late pregnancy and early postpartum: implications for autoimmune disease activity during these times. J Clin Endocrinol Metab 86(10):4933–4938. doi:10.1210/jcem.86.10.7905
Endrich MM, Blank PR, Szucs TD (2009) Influenza vaccination uptake and socioeconomic determinants in 11 European countries. Vaccine 27(30):4018–4024
Engler RJ, Nelson MR, Klote MM, VanRaden MJ, Huang CY, Cox NJ, Klimov A, Keitel WA, Nichol KL, Carr WW, Treanor JJ (2008) Half- vs full-dose trivalent inactivated influenza vaccine (2004–2005): age, dose, and sex effects on immune responses. Arch Intern Med 168(22):2405–2414. doi:10.1001/archinternmed.2008.513
Eshima N, Tokumaru O, Hara S, Bacal K, Korematsu S, Tabata M, Karukaya S, Yasui Y, Okabe N, Matsuishi T (2011) Sex- and age-related differences in morbidity rates of 2009 pandemic influenza A H1N1 virus of swine origin in Japan. PLoS ONE 6(4):e19409. doi:10.1371/journal.pone.0019409 PONE-D-10-04813 [pii]
Falsey AR, Treanor JJ, Tornieporth N, Capellan J, Gorse GJ (2009) Randomized, double-blind controlled phase 3 trial comparing the immunogenicity of high-dose and standard-dose influenza vaccine in adults 65 years of age and older. J Infect Dis 200(2):172–180. doi:10.1086/599790
Fasina FO, Ifende VI, Ajibade AA (2010) Avian influenza A(H5N1) in humans: lessons from Egypt. Euro Surveill 15(4):19473
Fish EN (2008) The X-files in immunity: sex-based differences predispose immune responses. Nat Rev Immunol 8(9):737–744
Fofie AE, Fewell JE, Moore SL (2005) Pregnancy influences the plasma cytokine response to intraperitoneal administration of bacterial endotoxin in rats. Exp Physiol 90(1):95–101. doi:10.1113/expphysiol.2004.028613
Furman D, Hejblum BP, Simon N, Jojic V, Dekker CL, Thiebaut R, Tibshirani RJ, Davis MM (2013) Systems analysis of sex differences reveals an immunosuppressive role for testosterone in the response to influenza vaccination. Proc Natl Acad Sci U S A. doi:10.1073/pnas.1321060111
Gagnon A, Miller MS, Hallman SA, Bourbeau R, Herring DA, Earn DJD, Madrenas J (2013) Age-specific mortality during the 1918 influenza pandemic: unravelling the mystery of high young adult mortality. PLoS ONE 8(8):e69586. doi:10.1371/journal.pone.0069586
Gao R, Cao B, Hu Y, Feng Z, Wang D, Hu W, Chen J, Jie Z, Qiu H, Xu K, Xu X, Lu H, Zhu W, Gao Z, Xiang N, Shen Y, He Z, Gu Y, Zhang Z, Yang Y, Zhao X, Zhou L, Li X, Zou S, Zhang Y, Li X, Yang L, Guo J, Dong J, Li Q, Dong L, Zhu Y, Bai T, Wang S, Hao P, Yang W, Zhang Y, Han J, Yu H, Li D, Gao GF, Wu G, Wang Y, Yuan Z, Shu Y (2013) Human infection with a novel avian-origin influenza A (H7N9) virus. N Engl J Med 368(20):1888–1897. doi:10.1056/NEJMoa1304459
Gold SM, Chalifoux S, Giesser BS, Voskuhl RR (2008) Immune modulation and increased neurotrophic factor production in multiple sclerosis patients treated with testosterone. J Neuroinflammation 5:32. doi:10.1186/1742-2094-5-32
Griffioen M, Halsey N (2014) Gender differences in immediate hypersensitivity reactions to vaccines: a review of the literature. Public Health Nurs 31(3):206–214. doi:10.1111/phn.12073
Griffiths PD, Ronalds CJ, Heath RB (1980) A prospective study of influenza infections during pregnancy. J Epidemiol Community Health 34(2):124–128
Guan Y, Poon LL, Cheung CY, Ellis TM, Lim W, Lipatov AS, Chan KH, Sturm-Ramirez KM, Cheung CL, Leung YH, Yuen KY, Webster RG, Peiris JS (2004) H5N1 influenza: a protean pandemic threat. Proc Natl Acad Sci U S A 101(21):8156–8161
Hapgood JP, Africander D, Louw R, Ray RM, Rohwer JM (2013) Potency of progestogens used in hormonal therapy: toward understanding differential actions. J Steroid Biochem Mol Biol. doi:10.1016/j.jsbmb.2013.08.001
Hardy JM, Azarowicz EN, Mannini A, Medearis DN Jr, Cooke RE (1961) The effect of Asian influenza on the outcome of pregnancy, Baltimore, 1957–1958. Am J Public Health Nation Health 51:1182–1188
Harris JW (1919) Influenza occurring in pregnant women: a statistical study of thirteen hundred and fifty cases. J Am Med Assoc 72(14):978–980. doi:10.1001/jama.1919.02610140008002
Hien ND, Ha NH, Van NT, Ha NT, Lien TT, Thai NQ, Trang VD, Shimbo T, Takahashi Y, Kato Y, Kawana A, Akita S, Kudo K (2009) Human infection with highly pathogenic avian influenza virus (H5N1) in northern Vietnam, 2004–2005. Emerg Infect Dis 15(1):19–23
Jacobs JH, Archer BN, Baker MG, Cowling BJ, Heffernan RT, Mercer G, Uez O, Hanshaoworakul W, Viboud C, Schwartz J, Tchetgen Tchetgen E, Lipsitch M (2012) Searching for sharp drops in the incidence of pandemic A/H1N1 influenza by single year of age. PLoS ONE 7(8):e42328. doi:10.1371/journal.pone.0042328
Jain S, Kamimoto L, Bramley AM, Schmitz AM, Benoit SR, Louie J, Sugerman DE, Druckenmiller JK, Ritger KA, Chugh R, Jasuja S, Deutscher M, Chen S, Walker JD, Duchin JS, Lett S, Soliva S, Wells EV, Swerdlow D, Uyeki TM, Fiore AE, Olsen SJ, Fry AM, Bridges CB, Finelli L, Pandemic Influenza AVHIT (2009) Hospitalized patients with 2009 H1N1 influenza in the United States, April-June 2009. N Engl J Med 361(20):1935–1944. doi:10.1056/NEJMoa0906695
Jain R, Ray JM, Pan JH, Brody SL (2012) Sex hormone-dependent regulation of cilia beat frequency in airway epithelium. Am J Respir Cell Mol Biol 46(4):446–453. doi:10.1165/rcmb.2011-0107OC
Jamieson DJ, Honein MA, Rasmussen SA, Williams JL, Swerdlow DL, Biggerstaff MS, Lindstrom S, Louie JK, Christ CM, Bohm SR, Fonseca VP, Ritger KA, Kuhles DJ, Eggers P, Bruce H, Davidson HA, Lutterloh E, Harris ML, Burke C, Cocoros N, Finelli L, MacFarlane KF, Shu B, Olsen SJ (2009) H1N1 2009 influenza virus infection during pregnancy in the USA. Lancet 374(9688):451–458. doi:10.1016/s0140-6736(09)61304-0
Jensen-Fangel S, Mohey R, Johnsen SP, Andersen PL, Sorensen HT, Ostergaard L (2004) Gender differences in hospitalization rates for respiratory tract infections in Danish youth. Scand J Infect Dis 36(1):31–36
Jimenez-Garcia R, Hernandez-Barrera V, de Andres AL, Jimenez-Trujillo I, Esteban-Hernandez J, Carrasco-Garrido P (2010) Gender influence in influenza vaccine uptake in Spain: time trends analysis (1995–2006). Vaccine 28(38):6169–6175. doi:10.1016/j.vaccine.2010.07.029
Jones LA, Kreem S, Shweash M, Paul A, Alexander J, Roberts CW (2010) Differential modulation of TLR3- and TLR4-mediated dendritic cell maturation and function by progesterone. J Immunol 185(8):4525–4534. doi:10.4049/jimmunol.0901155
Kalaitzidis D, Gilmore TD (2005) Transcription factor cross-talk: the estrogen receptor and NF-kappaB. Trends Endocrinol Metabol 16(2):46–52. doi:10.1016/j.tem.2005.01.004
Kalinchenko SY, Tishova YA, Mskhalaya GJ, Gooren LJ, Giltay EJ, Saad F (2010) Effects of testosterone supplementation on markers of the metabolic syndrome and inflammation in hypogonadal men with the metabolic syndrome: the double-blinded placebo-controlled Moscow study. Clin Endocrinol (Oxf) 73(5):602–612. doi:10.1111/j.1365-2265.2010.03845.x
Kayali G, Webby RJ, Ducatez MF, El Shesheny RA, Kandeil AM, Govorkova EA, Mostafa A, Ali MA (2011) The epidemiological and molecular aspects of influenza H5N1 viruses at the human-animal interface in Egypt. PLoS ONE 6(3):e17730. doi:10.1371/journal.pone.0017730
Khan KN, Masuzaki H, Fujishita A, Kitajima M, Sekine I, Matsuyama T, Ishimaru T (2005) Estrogen and progesterone receptor expression in macrophages and regulation of hepatocyte growth factor by ovarian steroids in women with endometriosis. Hum Reprod 20(7):2004–2013. doi:10.1093/humrep/deh897
Khurana S, Verma N, Talaat KR, Karron RA, Golding H (2012) Immune response following H1N1pdm09 vaccination: differences in antibody repertoire and avidity in young adults and elderly populations stratified by age and gender. J Infect Dis 205(4):610–620. doi:10.1093/infdis/jir791
Kilbourne ED (2006) Influenza pandemics of the 20th century. Emerg Infect Dis 12(1):9–14. doi:10.3201/eid1201.051254
Klein SL (2012) Sex influences immune responses to viruses, and efficacy of prophylaxis and treatments for viral diseases. BioEssays 34(12):1050–1059. doi:10.1002/bies.201200099
Klein SL, Jedlicka A, Pekosz A (2010a) The Xs and Y of immune responses to viral vaccines. Lancet Infect Dis 10(5):338–349. doi:10.1016/S1473-3099(10)70049-9
Klein SL, Passaretti C, Anker M, Olukoya P, Pekosz A (2010b) The impact of sex, gender and pregnancy on 2009 H1N1 disease. Biol Sex Differ 1(1):5. doi:10.1186/2042-6410-1-5
Kocar IH, Yesilova Z, Ozata M, Turan M, Sengul A, Ozdemir I (2000) The effect of testosterone replacement treatment on immunological features of patients with Klinefelter’s syndrome. Clin Exp Immunol 121(3):448–452
Koopman P, Gubbay J, Vivian N, Goodfellow P, Lovell-Badge R (1991) Male development of chromosomally female mice transgenic for Sry. Nature 351(6322):117–121. doi:10.1038/351117a0
Kovats S, Carreras E, Agrawal H (2010) Sex steroid receptors in immune cells. In: Klein SL, Roberts CW (eds) Sex hormones and immunity to infection. Springer, Berlin, pp 53–92
Kraus TA, Sperling RS, Engel SM, Lo Y, Kellerman L, Singh T, Loubeau M, Ge Y, Garrido JL, Rodriguez-Garcia M, Moran TM (2010) Peripheral blood cytokine profiling during pregnancy and post-partum periods. Am J Reprod Immunol 64(6):411–426. doi:10.1111/j.1600-0897.2010.00889.x
Kumar A, Zarychanski R, Pinto R, Cook DJ, Marshall J, Lacroix J, Stelfox T, Bagshaw S, Choong K, Lamontagne F, Turgeon AF, Lapinsky S, Ahern SP, Smith O, Siddiqui F, Jouvet P, Khwaja K, McIntyre L, Menon K, Hutchison J, Hornstein D, Joffe A, Lauzier F, Singh J, Karachi T, Wiebe K, Olafson K, Ramsey C, Sharma S, Dodek P, Meade M, Hall R, Fowler RA (2009) Critically ill patients with 2009 influenza A(H1N1) infection in Canada. JAMA 302(17):1872–1879
Kyurkchiev D, Ivanova-Todorova E, Hayrabedyan S, Altankova I, Kyurkchiev S (2007) Female sex steroid hormones modify some regulatory properties of monocyte-derived dendritic cells. Am J Reprod Immunol 58(5):425–433. doi:10.1111/j.1600-0897.2007.00526.x
Lai JJ, Lai KP, Zeng W, Chuang KH, Altuwaijri S, Chang C (2012) Androgen receptor influences on body defense system via modulation of innate and adaptive immune systems: lessons from conditional AR knockout mice. Am J Pathol 181(5):1504–1512. doi:10.1016/j.ajpath.2012.07.008
Larcombe AN, Foong RE, Bozanich EM, Berry LJ, Garratt LW, Gualano RC, Jones JE, Dousha LF, Zosky GR, Sly PD (2011) Sexual dimorphism in lung function responses to acute influenza A infection. Influenza Other Respir Viruses. doi:10.1111/j.1750-2659.2011.00236.x
Lee JH, Ulrich B, Cho J, Park J, Kim CH (2011) Progesterone promotes differentiation of human cord blood fetal T cells into T regulatory cells but suppresses their differentiation into Th17 cells. J Immunol 187(4):1778–1787. doi:10.4049/jimmunol.1003919
Lenz F (1931) Morbidic hereditary factors. Macmillan, New York
Li Q, Zhou L, Zhou M, Chen Z, Li F, Wu H, Xiang N, Chen E, Tang F, Wang D, Meng L, Hong Z, Tu W, Cao Y, Li L, Ding F, Liu B, Wang M, Xie R, Gao R, Li X, Bai T, Zou S, He J, Hu J, Xu Y, Chai C, Wang S, Gao Y, Jin L, Zhang Y, Luo H, Yu H, He J, Li Q, Wang X, Gao L, Pang X, Liu G, Yan Y, Yuan H, Shu Y, Yang W, Wang Y, Wu F, Uyeki TM, Feng Z (2014) Epidemiology of human infections with avian influenza A(H7N9) virus in China. N Engl J Med 370(6):520–532. doi:10.1056/NEJMoa1304617
Libert C, Dejager L, Pinheiro I (2010) The X chromosome in immune functions: when a chromosome makes the difference. Nat Rev Immunol 10(8):594–604
Liem NT, Tung CV, Hien ND, Hien TT, Chau NQ, Long HT, Hien NT, le Mai Q, Taylor WR, Wertheim H, Farrar J, Khang DD, Horby P (2009) Clinical features of human influenza A (H5N1) infection in Vietnam: 2004–2006. Clin Infect Dis 48(12):1639–1646. doi:10.1086/599031
Liu SL, Wang J, Yang XH, Chen J, Huang RJ, Ruan B, He HX, Wang CM, Zhang HM, Sun Z, Xie L, Zhuang H (2013) Pandemic influenza A(H1N1) 2009 virus in pregnancy. Rev Med Virol 23(1):3–14. doi:10.1002/rmv.1712
Liva SM, Voskuhl RR (2001) Testosterone acts directly on CD4+ T lymphocytes to increase IL-10 production. J Immunol 167(4):2060–2067
Lorenzo ME, Hodgson A, Robinson DP, Kaplan JB, Pekosz A, Klein SL (2011) Antibody responses and cross protection against lethal influenza A viruses differ between the sexes in C57BL/6 mice. Vaccine 29(49):9246–9255. doi:10.1016/j.vaccine.2011.09.110
Louie JK, Acosta M, Winter K, Jean C, Gavali S, Schechter R, Vugia D, Harriman K, Matyas B, Glaser CA, Samuel MC, Rosenberg J, Talarico J, Hatch D, California Pandemic (H1N1) Working Group (2009) Factors associated with death or hospitalization due to pandemic 2009 influenza A(H1N1) infection in California. JAMA 302(17):1896–1902. doi:10.1001/jama.2009.1583
Louie JK, Acosta M, Jamieson DJ, Honein MA, California Pandemic Working G (2010) Severe 2009 H1N1 influenza in pregnant and postpartum women in California. N Engl J Med 362(1):27–35. doi:10.1056/NEJMoa0910444
Louik C, Ahrens K, Kerr S, Pyo J, Chambers C, Jones KL, Schatz M, Mitchell AA (2013) Risks and safety of pandemic H1N1 influenza vaccine in pregnancy: exposure prevalence, preterm delivery, and specific birth defects. Vaccine 31(44):5033–5040. doi:10.1016/j.vaccine.2013.08.096
Malkin CJ, Pugh PJ, Jones RD, Kapoor D, Channer KS, Jones TH (2004) The effect of testosterone replacement on endogenous inflammatory cytokines and lipid profiles in hypogonadal men. J Clin Endocrinol Metab 89(7):3313–3318. doi:10.1210/jc.2003-031069 89/7/3313 [pii]
Maltezou HC, Drakoulis N, Siahanidou T, Karalis V, Zervaki E, Dotsikas Y, Loukas YL, Theodoridou M (2011) Safety and Pharmacokinetics of Oseltamivir for Prophylaxis of Neonates Exposed to Influenza H1N1. Pediatr Infect Dis J. doi:10.1097/INF.0b013e3182472f28
Mao G, Wang J, Kang Y, Tai P, Wen J, Zou Q, Li G, Ouyang H, Xia G, Wang B (2010) Progesterone increases systemic and local uterine proportions of CD4+CD25+ Treg cells during midterm pregnancy in mice. Endocrinology 151(11):5477–5488. doi:10.1210/en.2010-0426
Marcelin G, Aldridge JR, Duan S, Ghoneim HE, Rehg J, Marjuki H, Boon AC, McCullers JA, Webby RJ (2011) Fatal outcome of pandemic H1N1 2009 influenza virus infection is associated with immunopathology and impaired lung repair, not enhanced viral burden, in pregnant mice. J Virol 85(21):11208–11219. doi:10.1128/JVI. 00654-11
Markle JG, Fish EN (2014) SeXX matters in immunity. Trends Immunol 35(3):97–104. doi:10.1016/j.it.2013.10.006
Marzi M, Vigano A, Trabattoni D, Villa ML, Salvaggio A, Clerici E, Clerici M (1996) Characterization of type 1 and type 2 cytokine production profile in physiologic and pathologic human pregnancy. Clin Exp Immunol 106(1):127–133
McKay LI, Cidlowski JA (1999) Molecular control of immune/inflammatory responses: interactions between nuclear factor-kappa B and steroid receptor-signaling pathways. Endocr Rev 20(4):435–459
Medina RA, Garcia-Sastre A (2011) Influenza A viruses: new research developments. Nat Rev Microbiol 9(8):590–603. doi:10.1038/nrmicro2613
Meier A, Chang JJ, Chan ES, Pollard RB, Sidhu HK, Kulkarni S, Wen TF, Lindsay RJ, Orellana L, Mildvan D, Bazner S, Streeck H, Alter G, Lifson JD, Carrington M, Bosch RJ, Robbins GK, Altfeld M (2009) Sex differences in the Toll-like receptor-mediated response of plasmacytoid dendritic cells to HIV-1. Nat Med 15(8):955–959. doi:10.1038/nm.2004
Memoli MJ, Harvey H, Morens DM, Taubenberger JK (2013) Influenza in pregnancy. Influenza Other Respir Viruses 7(6):1033–1039. doi:10.1111/irv.12055
Merrill RM, Beard JD (2009) Influenza vaccination in the United States, 2005–2007. Med Sci Monit 15(7):PH92–PH100
Mjosberg J, Svensson J, Johansson E, Hellstrom L, Casas R, Jenmalm MC, Boij R, Matthiesen L, Jonsson JI, Berg G, Ernerudh J (2009) Systemic reduction of functionally suppressive CD4dimCD25highFoxp3+ Tregs in human second trimester pregnancy is induced by progesterone and 17{beta}-estradiol. J Immunol 183(1):759–769
Moorman JE, Rudd RA (2007) National surveillance for asthma- United States, 1980–2004. MMWR Surveillance summaries: morbidity and mortality weekly report, vol 56. CDC
Morens DM, Taubenberger JK, Fauci AS (2008) Predominant role of bacterial pneumonia as a cause of death in pandemic influenza: implications for pandemic influenza preparedness. J Infect Dis 198(7):962–970. doi:10.1086/591708
Moro PL, Tepper NK, Grohskopf LA, Vellozzi C, Broder K (2012) Safety of seasonal influenza and influenza A (H1N1) 2009 monovalent vaccines in pregnancy. Expert Rev Vaccines 11(8):911–921. doi:10.1586/erv.12.72
Mosby LG, Rasmussen SA, Jamieson DJ (2011) 2009 pandemic influenza A (H1N1) in pregnancy: a systematic review of the literature. Am J Obstet Gynecol 205(1):10–18. doi:10.1016/j.ajog.2010.12.033
Musabak U, Bolu E, Ozata M, Oktenli C, Sengul A, Inal A, Yesilova Z, Kilciler G, Ozdemir IC, Kocar IH (2003) Gonadotropin treatment restores in vitro interleukin-1beta and tumour necrosis factor-alpha production by stimulated peripheral blood mononuclear cells from patients with idiopathic hypogonadotropic hypogonadism. Clin Exp Immunol 132(2):265–270
Neuzil KM, Reed GW, Mitchel EF, Simonsen L, Griffin MR (1998) Impact of influenza on acute cardiopulmonary hospitalizations in pregnant women. Am J Epidemiol 148(11):1094–1102
Ng WF, To KF (2007) Pathology of human H5N1 infection: new findings. Lancet 370(9593):1106–1108. doi:10.1016/s0140-6736(07)61490-1
Nguyen DC, Masseoud F, Lu X, Scinicariello F, Sambhara S, Attanasio R (2011) 17beta-Estradiol restores antibody responses to an influenza vaccine in a postmenopausal mouse model. Vaccine 29(14):2515–2518. doi:10.1016/j.vaccine.2011.01.080
Nichol KL, Margolis KL, Lind A, Murdoch M, McFadden R, Hauge M, Magnan S, Drake M (1996) Side effects associated with influenza vaccination in healthy working adults. A randomized, placebo-controlled trial. Arch Intern Med 156(14):1546–1550
Nogueira PJ, Nunes B, Machado A, Rodrigues E, Gomez V, Sousa L, Falcao JM (2009) Early estimates of the excess mortality associated with the 2008–9 influenza season in Portugal. Euro Surveill 14(18)
Noymer A, Garenne M (2000) The 1918 influenza epidemic’s effects on sex differentials in mortality in the United States. Popul Dev Rev 26(3):565–581
Oliveira W, Carmo E, Penna G, Kuchenbecker R, Santos H, Araujo W, Malaguti R, Duncan B, Schmidt M (2009) Pandemic H1N1 influenza in Brazil: analysis of the first 34,506 notified cases of influenza-like illness with severe acute respiratory infection (SARI). Euro surveillance : bulletin Europeen sur les maladies transmissibles. Eur Commun Dis Bull 14(42)
Olsen NJ, Kovacs WJ (1996) Gonadal steroids and immunity. Endocr Rev 17(4):369–384
Ontario (2009) Ontario novel H1N1 influenza A virus epidemiological summary. Ministry of Health
Opstelten W, van Essen GA, Ballieux MJ, Goudswaard AN (2008) Influenza immunization of Dutch general practitioners: vaccination rate and attitudes towards vaccination. Vaccine 26(47):5918–5921. doi:10.1016/j.vaccine.2008.08.049
Pazos M, Sperling RS, Moran TM, Kraus TA (2012a) The influence of pregnancy on systemic immunity. Immunol Res 54(1–3):254–261. doi:10.1007/s12026-012-8303-9
Pazos MA, Kraus TA, Munoz-Fontela C, Moran TM (2012b) Estrogen mediates innate and adaptive immune alterations to influenza infection in pregnant mice. PLoS ONE 7(7):e40502. doi:10.1371/journal.pone.0040502 PONE-D-11-22626 [pii]
Pinheiro I, Dejager L, Libert C (2011) X-chromosome-located microRNAs in immunity: might they explain male/female differences? The X chromosome-genomic context may affect X-located miRNAs and downstream signaling, thereby contributing to the enhanced immune response of females. BioEssays. doi:10.1002/bies.201100047
Pisitkun P, Deane JA, Difilippantonio MJ, Tarasenko T, Satterthwaite AB, Bolland S (2006) Autoreactive B cell responses to RNA-related antigens due to TLR7 gene duplication. Science 312(5780):1669–1672
Pittman PR (2002) Aluminum-containing vaccine associated adverse events: role of route of administration and gender. Vaccine 20(Suppl 3):S48–S50
Purtilo DT, Sullivan JL (1979) Immunological bases for superior survival of females. Am J Dis Child 133(12):1251–1253
Qi X, Cui L, Xu K, Wu B, Tang F, Bao C, Zhu Y, Zhou MH, Wang H (2014) Avian influenza A(H7N9) virus infection in pregnant woman, China, 2013. Emerg Infect Dis 20(2):333–334. doi:10.3201/eid2002.131109
Quach C, Piche-Walker L, Platt R, Moore D (2003) Risk factors associated with severe influenza infections in childhood: implication for vaccine strategy. Pediatrics 112(3 Pt 1):e197–e201
Roberts CW, Walker W, Alexander J (2001) Sex-associated hormones and immunity to protozoan parasites. Clin Microbiol Rev 14(3):476–488
Robinson DP, Klein SL (2012) Pregnancy and pregnancy-associated hormones alter immune responses and disease pathogenesis. Horm Behav 62(3):263–271. doi:10.1016/j.yhbeh.2012.02.023
Robinson DP, Huber SA, Moussawi M, Roberts B, Teuscher C, Watkins R, Arnold AP, Klein SL (2011a) Sex chromosome complement contributes to sex differences in Coxsackievirus B3 but not Influenza A virus pathogenesis. Biol Sex Differ 2(1):8. doi:10.1186/2042-6410-2-8
Robinson DP, Lorenzo ME, Jian W, Klein SL (2011b) Elevated 17beta-estradiol protects females from influenza a virus pathogenesis by suppressing inflammatory responses. PLoS Pathog 7(7):e1002149. doi:10.1371/journal.ppat.1002149 PPATHOGENS-D-11-00385 [pii]
Robinson DP, Hall OJ, Nilles TL, Bream JH, Klein SL (2014) 17beta-estradiol protects females against influenza by recruiting neutrophils and increasing virus-specific CD8 T cell responses in the lungs. J Virol. doi:10.1128/JVI. 02081-13
Rogers VL, Sheffield JS, Roberts SW, McIntire DD, Luby JP, Trevino S, Wendel GD Jr (2010) Presentation of seasonal influenza A in pregnancy: 2003–2004 influenza season. Obstet Gynecol 115(5):924–929. doi:10.1097/AOG.0b013e3181da0c5e
Rojas-Suarez J, Paternina-Caicedo A, Cuevas L, Angulo S, Cifuentes R, Parra E, Fino E, Daza J, Castillo O, Pacheco A, Rey G, Garcia S, Pena I, Levinson A, Bourjeily G (2014) Maternal mortality due to pandemic influenza A H1N1 2009 virus in Colombia. J Perinat Med 42(1):19–26. doi:10.1515/jpm-2013-0140
Rowe JH, Ertelt JM, Xin L, Way SS (2012) Pregnancy imprints regulatory memory that sustains anergy to fetal antigen. Nature 490(7418):102–106. doi:10.1038/nature11462
Saito S, Nakashima A, Shima T, Ito M (2010) Th1/Th2/Th17 and regulatory T-cell paradigm in pregnancy. Am J Reprod Immunol 63(6):601–610. doi:10.1111/j.1600-0897.2010.00852.x
Schatz M, Camargo CA Jr (2003) The relationship of sex to asthma prevalence, health care utilization, and medications in a large managed care organization. Annals Allergy Asthma Immunol 91(6):553–558. doi:10.1016/s1081-1206(10)61533-5
Schatz M, Clark S, Camargo CA Jr (2006) Sex differences in the presentation and course of asthma hospitalizations. Chest 129(1):50–55
Schumacher M, Hussain R, Gago N, Oudinet JP, Mattern C, Ghoumari AM (2012) Progesterone synthesis in the nervous system: implications for myelination and myelin repair. Front Neurosci 6:10. doi:10.3389/fnins.2012.00010
Sedyaningsih ER, Isfandari S, Setiawaty V, Rifati L, Harun S, Purba W, Imari S, Giriputra S, Blair PJ, Putnam SD, Uyeki TM, Soendoro T (2007) Epidemiology of cases of H5N1 virus infection in Indonesia, July 2005-June 2006. J Infect Dis 196(4):522–527. doi:10.1086/519692
Serfling RE, Sherman IL, Houseworth WJ (1967) Excess pneumonia-influenza mortality by age and sex in three major influenza A2 epidemics, United States, 1957–58, 1960 and 1963. Am J Epidemiol 86(2):433–441
Shu Y, Yu H, Li D (2006) Lethal avian influenza A (H5N1) infection in a pregnant woman in Anhui Province, China. N Engl J Med 354(13):1421–1422. doi:10.1056/NEJMc053524
Singh AK, Cydulka RK, Stahmer SA, Woodruff PG, Camargo CA Jr (1999) Sex differences among adults presenting to the emergency department with acute asthma. Multicenter Asthma Research Collaboration Investigators. Arch Intern Med 159(11):1237–1243
Skowronski DM, Janjua NZ, Kwindt TL, De Serres G (2013) Virus-host interactions and the unusual age and sex distribution of human cases of influenza A(H7N9) in China, April 2013. Euro Surveill 18(17):20465
Smith-Bouvier DL, Divekar AA, Sasidhar M, Du S, Tiwari-Woodruff SK, King JK, Arnold AP, Singh RR, Voskuhl RR (2008) A role for sex chromosome complement in the female bias in autoimmune disease. J Exp Med 205(5):1099–1108. doi:10.1084/jem.20070850
Straub RH (2007) The complex role of estrogens in inflammation. Endocr Rev 28(5):521–574. doi:10.1210/er.2007-0001
Subbarao K, Swayne DE, Olsen CW (2006) Epidemiology and control of human and animal influenza. In: Kawaoka Y (ed) Influenza virology: current topics. Caister Academic, Norfolk, pp 229–281
Sun J, Madan R, Karp CL, Braciale TJ (2009) Effector T cells control lung inflammation during acute influenza virus infection by producing IL-10. Nat Med 15(3):277–284. doi:10.1038/nm.1929
Tamma PD, Ault KA, del Rio C, Steinhoff MC, Halsey NA, Omer SB (2009) Safety of influenza vaccination during pregnancy. Am J Obstet Gynecol 201(6):547–552. doi:10.1016/j.ajog.2009.09.034
Tate MD, Deng YM, Jones JE, Anderson GP, Brooks AG, Reading PC (2009) Neutrophils ameliorate lung injury and the development of severe disease during influenza infection. J Immunol 183(11):7441–7450. doi:10.4049/jimmunol.0902497
Tate MD, Brooks AG, Reading PC, Mintern JD (2012) Neutrophils sustain effective CD8(+) T-cell responses in the respiratory tract following influenza infection. Immunol Cell Biol 90(2):197–205. doi:10.1038/icb.2011.26
Teilmann SC, Clement CA, Thorup J, Byskov AG, Christensen ST (2006) Expression and localization of the progesterone receptor in mouse and human reproductive organs. J Endocrinol 191(3):525–535. doi:10.1677/joe.1.06565
Uchide N, Ohyama K, Bessho T, Takeichi M, Toyoda H (2012) Possible roles of proinflammatory and chemoattractive cytokines produced by human fetal membrane cells in the pathology of adverse pregnancy outcomes associated with influenza virus infection. Mediat Inflamm 2012:270670. doi:10.1155/2012/270670
Vaillant L, La Ruche G, Tarantola A, Barboza P (2009) Epidemiology of fatal cases associated with pandemic H1N1 influenza 2009. Euro Surveill 14(33)
Vanders RL, Gibson PG, Murphy VE, Wark PA (2013) Plasmacytoid dendritic cells and CD8 T cells from pregnant women show altered phenotype and function following H1N1/09 infection. J Infect Dis 208(7):1062–1070. doi:10.1093/infdis/jit296
Villa E, Karampatou A, Camma C, Di Leo A, Luongo M, Ferrari A, Petta S, Losi L, Taliani G, Trande P, Lei B, Graziosi A, Bernabucci V, Critelli R, Pazienza P, Rendina M, Antonelli A, Francavilla A (2011) Early menopause is associated with lack of response to antiviral therapy in women with chronic hepatitis C. Gastroenterology 140(3):818–829. doi:10.1053/j.gastro.2010.12.027
Wang CS, Wang ST, Chou P (2002) Efficacy and cost-effectiveness of influenza vaccination of the elderly in a densely populated and unvaccinated community. Vaccine 20(19–20):2494–2499
Wang C, Yu H, Horby PW, Cao B, Wu P, Yang S, Gao H, Li H, Tsang TK, Liao Q, Gao Z, Ip DK, Jia H, Jiang H, Liu B, Ni MY, Dai X, Liu F, Van Kinh N, Liem NT, Hien TT, Li Y, Yang J, Wu JT, Zheng Y, Leung GM, Farrar JJ, Cowling BJ, Uyeki TM, Li L (2014) Comparison of Patients Hospitalized With Influenza A Subtypes H7N9, H5N1, and 2009 Pandemic H1N1. Clin Infect Dis. doi:10.1093/cid/ciu053
WHO (2009) Pandemic influenza A (H1N1) 2009 virus vaccine - conclusions and recommendations from the October 2009 meeting of the immunization Strategic Advisory Group of Experts. Wkly Epidemiol Rec 84(49):505–508
WHO (2013) Update on human cases of influenza at the human-animal interface, 2012. Weekly Epidemiological Record 88
WHO (2014a) Influenza update number 205. World Health Organization
WHO (2014b) WHO Global Epidemiological Surveillance Standards for Influenza. World Health Organization
WHO (2014c) WHO risk assessment of human infection with avian influenza A(H7N9) virus. World Health Organization
WHO (2014d) World: affected areas with confirmed cases of H5N1 avian influenza since 2003, status as of 24-Jan-2014 (latest available update) World Health Organization, http://gamapserver.who.int/mapLibrary/app/searchResults.aspx
Woolston WJ, Conley DO (1918) Epidemic pneumonia (spanish influenza) in pregnancy: effect in one hundred and one cases. J Am Med Assoc 71(23):1898–1899. doi:10.1001/jama.1918. 02600490030008
Yang P, Pang X, Deng Y, Ma C, Zhang D, Sun Y, Shi W, Lu G, Zhao J, Liu Y, Peng X, Tian Y, Qian H, Chen L, Wang Q (2013) Surveillance for avian influenza A(H7N9), Beijing, China, 2013. Emerg Infect Dis 19(12):2041–2043. doi:10.3201/eid1912.130983
Yang S, Chen Y, Cui D, Yao H, Lou J, Huo Z, Xie G, Yu F, Zheng S, Yang Y, Zhu Y, Lu X, Liu X, Lau SY, Chan JF, To KK, Yuen KY, Chen H, Li L (2014) Avian-origin influenza A(H7N9) infection in influenza A(H7N9)-affected areas of China: a serological study. J Infect Dis 209(2):265–269. doi:10.1093/infdis/jit430
Yu H, Gao Z, Feng Z, Shu Y, Xiang N, Zhou L, Huai Y, Feng L, Peng Z, Li Z, Xu C, Li J, Hu C, Li Q, Xu X, Liu X, Liu Z, Xu L, Chen Y, Luo H, Wei L, Zhang X, Xin J, Guo J, Wang Q, Yuan Z, Zhou L, Zhang K, Zhang W, Yang J, Zhong X, Xia S, Li L, Cheng J, Ma E, He P, Lee SS, Wang Y, Uyeki TM, Yang W (2008) Clinical characteristics of 26 human cases of highly pathogenic avian influenza A (H5N1) virus infection in China. PLoS ONE 3(8):e2985. doi:10.1371/journal.pone.0002985
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2015 Springer International Publishing Switzerland
About this chapter
Cite this chapter
Peretz, J., Hall, O.J., Klein, S.L. (2015). Sex Differences in Influenza Virus Infection, Vaccination, and Therapies. In: Klein, S., Roberts, C. (eds) Sex and Gender Differences in Infection and Treatments for Infectious Diseases. Springer, Cham. https://doi.org/10.1007/978-3-319-16438-0_6
Download citation
DOI: https://doi.org/10.1007/978-3-319-16438-0_6
Publisher Name: Springer, Cham
Print ISBN: 978-3-319-16437-3
Online ISBN: 978-3-319-16438-0
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)