Pregnancy increases a woman’s risk of influenza-associated complications because of the physiological changes induced during gestation. During pregnancy, a woman’s heart rate increases, while lung capacity and cell-mediated immunity both decrease during pregnancy (58). Epidemiological data obtained during the 1918 and 1957 influenza pandemics indicated that the risk of influenza-induced mortality was increased in pregnant women (59,60). Additional evidence for increased influenza-related morbidity during pregnancy is found in a study by Neuzil et al wherein influenza infection correlated with increased acute cardiopulmonary hospitalizations in pregnant women (61), while other studies have found that rates of hospitalization are increased in general in influenza-infected versus non-infected pregnant women (62). Case study analysis of pregnant women in the United States infected with the recent 2009 H1N1 influenza viruses also found an increased rate of hospitalization in infected pregnant women over infected members of the general population (63). Additionally, a study investigating the interferon responses to 2009 pandemic H1N1 influenza virus in peripheral blood mononuclear cells (PBMC) found that the PBMC from pregnant women produce significantly less type I and type II interferon in response to viral infection than non-pregnant women (64), suggesting that pregnant women have reduced antiviral immunity to influenza virus infection. Current epidemiological evidence regarding the risks and benefits associated with influenza vaccination during pregnancy are contradictory. While some population studies have found no significant differences between rates of hospitalization and infant morbidity due to influenza illness in vaccinated and unvaccinated pregnant women (65), others find that vaccination against influenza virus provides enhanced protection against influenza-induced disease and hospitalizations during pregnancy (66). Moreover, the effects of influenza viral load on fetal birth defects and psychiatric disorders are highly debated in the literature (67-69).
Individuals with preexisting medical conditions such as asthma and chronic obstructive pulmonary disease (COPD) are more likely to be hospitalized because of complications from influenza virus infection than infected individuals that do not have underlying medical conditions (70). Research shows that children with asthma and other chronic medical conditions are at enhanced risk for cardiopulmonary hospitalizations, outpatient visits and antibiotic treatment courses because of influenza virus infections (71). Moreover, examination of pediatric patients infected with the novel 2009 H1N1 influenza A virus found that children with asthma were more likely to suffer severe influenza-associated complications such as hospitalization and mortality (72-74). Additionally, respiratory infections, including influenza virus infections, have been associated with longer hospitalizations and impaired lung function in patients with COPD (75). Individuals with asthma and COPD are encouraged to receive influenza virus immunizations to prevent the increased morbidity associated with infection, and this recommendation has been formally endorsed for children with asthma by the Advisory Committee on Immunization Practices since 1964 (76). However, studies examining the role of influenza virus infection and vaccination directly on asthma and COPD exacerbations have conflicted in their results (77,78).
5a.
Family functioning
The effect of stress on susceptibility to influenza has been examined using several different types of stressors, primarily using experimental studies in mice. The only epidemiologic study to examine the relationship between stress and influenza virus infection looked at stress related to family functioning (79). The authors found significant increases in the risk of acquiring influenza B virus infection among dysfunctional families, specifically those that were perceived as rigid, chaotic, or enmeshed as compared with balanced families. In addition, family cohesion and adaptability was also associated with an increased risk of influenza virus infection.
5b. Restraint stress
The majority of experimental animal studies on stress and influenza susceptibility have used either restraint stress or exercise-related stress as models for stress exposure. Hermann et al. exposed three different strains of adult mice to continual restraint stress; the mice all exhibited decreased cellular and inflammatory immune responses when compared to control mice. There were no significant effects of stress on influenza-related mortality except in DBA/2 mice, which exhibited a decreased mortality rate in stress-exposed mice (80). Hunzeker et al. (81) examined the effect of restraint stress on natural killer (NK) cell activity and viral replication during mouse-adapted influenza A virus (PR8) infection. The authors found decreased expression of cytokines responsible for NK cell recruitment and function, while there was an increase in expression of anti-viral type I interferon. Age modified the effect of stress on influenza susceptibility in a study by Padgett et al (82), in which aged C57BL/6 mice had increased mortality after infection with mouse-adapted influenza PR8 virus compared to young mice, and restraint stress exacerbated the mortality rate among old mice but not young mice. Avitsur et al (83) found that influenza A virus (PR8)-infected mice subjected to restraint stress had increased expression of pro-inflammatory cytokines, and this effect was more pronounced in females.
5c. Exercise stress
Several studies have been done to examine the effects of moderate and severe exercise stress on susceptibility to influenza. Ilback et al (84) examined the effect of preconditioning exercise or exhaustive exercise on H3N2 influenza- and tularemia-associated mortality in Swiss-Webster inbred mice. Compared to sedentary mice that had not been exposed to any exercise regimen, preconditioned mice had a 25% decrease and exercise exhausted mice had a 33% increase in influenza-related mortality. Neither of the exercise regimens had an effect on tularemia mortality. The effect of severe exercise stress prior to influenza virus infection was examined in a study by Murphy et al (85). Mice were subjected to treadmill running for two hours (or until volitional fatigue) for three consecutive days, immediately followed by intranasal inoculation with influenza virus. Mice exposed to severe exercise stress had significantly increased mortality compared to resting controls, as evidenced by decreased percent surviving and decreased time to death. Exercise-stressed mice also had increased morbidity than sedentary mice, including an increased percentage showing symptoms, a shorter time to developing symptoms, an increased percentage of weight loss and an increased severity of symptoms.
5d. Stress early in life
Not only does stress have immediate effects on health and susceptibility to disease, but stress experienced early in life has been shown to have long term effects on health issues such as chronic diseases and mental health (86-88). Two studies have examined the effects of neonatal stress on susceptibility to influenza A virus infection later in life (89,90). In these studies, neonatal stress was induced by separating mouse pups from their mother for six hours per day for the first 14 days after birth. Mice that had been exposed to neonatal stress and infected with influenza A (PR8) virus as adults had increased viral loads, as well as more rapid kinetics of and increased sickness behavior. Overall, stressed mice had increased expression of pro-inflammatory cytokines following influenza virus infection, although the expression of some cytokines, including IL-1, TNF-α, and IFN-γ, was only elevated in female mice.
5e. Psychosocial stress
A mouse model of social conflict in which male mice are subjected to social reorganization (SRO) was used to evaluate the effects of psychosocial stress on influenza A (PR8) virus infection (91). After a period of initial observation, C57BL/6 inbred mice were classified as either ‘dominant’ or ‘subordinate’, and then dominant mice were switched between cages to create SRO. Mice infected with influenza virus following SRO had significantly higher mortality rates than control mice (56% vs. 11%), and ‘dominant’ mice had the highest mortality rates (86%) compared to ‘subordinate’ mice (48%). Histopathology of lung tissue suggested that the increased mortality was attributed to hyperinflammation in response to the viral infection.
Malnutrition is known to be associated with increased susceptibility to and severity of many infectious diseases (92,93). The effect of malnutrition on the ability to mount an adequate immune response is thought to be the mechanism responsible for this relationship. Some research also suggests that host nutritional status may also affect the virulence of the infectious agent (94-98)(98). Studies examining the effects of nutrition on susceptibility to influenza can be divided into two broad categories; the effects of protein-energy deficiencies and the effects of vitamin and micronutrient deficiencies or supplementation.
6a. Protein-energy deficiencies
6a.i. Protein deprivation
In 1979, Pollett et al. (99) conducted a study to examine the effect of protein-energy malnutrition (PEM), which is a common cause of immune deficiency in malnourished children, on susceptibility to influenza virus infection in mice. Beginning at 18 days after birth, C57BL/6 inbred mice were fed a low-protein diet (4% protein) and were infected intranasally with influenza virus 3-4 weeks later. Mice in the unexposed group were fed a normal diet containing 18-20% protein. Higher mortality rates and significantly decreased anti-influenza virus serum antibody titers were observed among protein-deprived mice. Additionally, viremia was observed in protein-deprived mice but not control mice, and viral loads persisted longer in the lungs of protein-deprived mice. A recent study by Taylor and colleagues further investigated the relevance of PEM to H1N1 influenza A virus susceptibility in mice and found that a low protein diet correlated with enhanced influenza-induced disease following PR8 and 2009 H1N1 virus infections based on its effects on tissue damage, inflammatory cell infiltration, viral persistence and virus-induced mortality (100). Taken together, these studies clearly demonstrate that a low protein diet is a significant susceptibility factor in susceptibility to influenza-induced disease in mice. However, further studies will be required to verify whether PEM has significant effects on influenza-associated illnesses in humans.
6a.ii. Caloric restriction
Dietary caloric restriction (CR) without malnutrition has been shown to extend the life span and preserve immune function of healthy rodents (101,102). Two studies have been done on the effect of caloric restriction on influenza susceptibility. The first study examined the effect of caloric restriction on H1N1 influenza susceptibility in aged mice (103). Aged C57BL/6 inbred mice that had been on a 40% CR diet since the age of 3 months as well as both young and aged mice fed a non-restricted diet were intranasally infected with 3 different doses of PR8 influenza virus. Aged CR mice had higher mortality for all three doses compared to both young and old non-diet restricted mice (100% vs. 40-60%). While non-diet restricted mice began to recover from weight loss at day five post infection, CR mice never recovered from disease-related weight loss and also experienced a 10-fold increase in viral titers in the lung. Based on the results of the first study, the investigators then sought to determine whether CR alone or CR in combination with advanced age was responsible for the inability to fight off influenza A virus (PR8) infection (104). Mice began a 40% CR diet at age 14 weeks and were challenged with influenza virus intranasally at 6 months of age. Again, the CR mice experienced significantly increased mortality and weight loss. In addition, increased viral titers, cellular infiltration and pathology were observed in the lungs of CR mice.
6a.iii. Obesity
In addition to protein-energy deficiencies, obesity was also proposed to be a possible risk factor for susceptibility to influenza because of the immune dysfunction observed in obese individuals. Prior to the 2009 H1N1 pandemic, the only studies that examined the relationship between obesity and influenza susceptibility were performed in mice. Smith et al (105) evaluated the effect of diet-induced obesity on susceptibility of mice to PR8 influenza A virus infection. C57BL/6 inbred mice were exposed to a high fat, high sucrose diet for 22 weeks and then challenged with influenza virus intranasally. Control mice were fed a low fat, no sucrose diet. Obese mice experienced significantly increased mortality (42% vs. 5.5%) and enhanced lung pathology. Immunologically, obese mice showed reduced expression of antiviral type I interferon and delayed expression of pro-inflammatory cytokines as well as decreased proportions and cytotoxicity of NK cells in the lung. A follow-up study (106) demonstrated that impaired recruitment of dendritic cells to the lungs affects antigen presentation in obese mice infected with influenza A virus.
In the wake of the 2009 H1N1 pandemic, many studies from countries across the globe demonstrated that obesity is a risk factor for hospitalization and death following 2009 H1N1 influenza virus infection, as reviewed by Fezeu et al. (107). Kwong and colleagues (108) examined the relationship between obesity and seasonal influenza in a Canadian cohort. Using the data from population health surveys conducted over 12 influenza seasons, they found that obese individuals were more likely to have been hospitalized for a respiratory illness such as influenza.
6b. Vitamins and micronutrients
6b.i. Selenium
Selenium is a trace mineral that is required for the production of many proteins (called selenoproteins), including the antioxidant enzyme glutathione peroxidase (GPx) (109). Dietary selenium is important for both innate and adaptive immune system function (109,110), and it is thought that these effects may be partly mediated by the antioxidant effects of selenium. The effects of selenium deficiency on the susceptibility to disease are a topic of intense investigation, and several experimental studies have been done to explore this relationship in the context of influenza infection. Beck et al (93) investigated the effects of selenium deficiency by exposing mice to a selenium-depleted diet for 4 weeks prior to challenge with a mild strain of H3N2 influenza virus. Selenium-deficient mice had significantly enhanced and longer duration of lung inflammation and increased amounts of cellular lung infiltrates following influenza virus infection. Cytokine profiles indicated a Th1-type immune response in control mice, while selenium-deficient mice exhibited a Th2-type immune response. In a follow-up to this study, the investigators found that viral isolates passaged through selenium-deficient mice caused more severe lung inflammation in infected mice than virus that was passaged through non-selenium deficient mice, indicating a change in virus virulence based on the host nutritional status (111). Interestingly, sequencing of the viral isolates showed that there were very few changes in the hemagglutinin or neuraminidase sequences, but there were many changes in the matrix protein coding sequences, and the changes were conserved among the three different isolates. The most recent study, performed by the before-mentioned group, used the same selenium depletion protocol but they challenged mice with a more virulent strain of influenza A virus, PR8 (98). In this study, selenium-deficient mice had increased survival rates when compared to control mice (50% vs. 100%), although there were no differences in lung pathology or viral titers in the lung between the two groups. Similar to the first study, the cytokine and chemokine profiles indicated a Th1-type immune response in control mice, and Th2-type response in selenium-deficient mice. Unlike experiments using the milder influenza virus strain, there were no mutations in the genomes of virus isolated from the selenium-deficient mice. The investigators attributed the reduced mortality rates to a decreased inflammatory response in the mice.
6b.ii. Antioxidants and vitamin E
One of the effects of influenza virus infection is an increase in the production of reactive oxygen species (ROS). The oxidative stress mediated by ROS is likely to play a role in the damage caused by influenza virus infection (112,113). A decrease in the concentration of antioxidants in the lung and liver has been observed in response to influenza A virus infection with H1N1 PR8 and H3N2 strains, which may be due to the increase in oxidants (113,114). The effects of dietary supplementation with antioxidants on the reduced severity of influenza virus infection have been investigated in two experimental studies. The first study examined the effect of vitamin E, which has known antioxidant effects among other benefits, on the severity of influenza virus infection in young and aged mice (114). Young (4 months) and aged (22 months) mice were fed a diet supplemented with 500 ppm vitamin E for 6 weeks prior to H3N2 influenza virus challenge. Age-matched controls were fed a diet with 30 ppm vitamin E. Vitamin E supplementation reduced lung virus titers on day five post-infection in young mice and on all days in aged mice. Vitamin E supplementation also enhanced NK cell activity in aged mice, and higher serum antibody titers were observed in both young and aged mice. A second study by the same group of researchers examined the effects of supplementation with several other antioxidants and combinations of antioxidants, including vitamin E, glutathione, vitamin E + glutathione, melatonin, and strawberry extract (115). Decreased viral titers in the lung, decreased weight loss, and increased food consumption was seen only in mice supplemented with vitamin E (when compared to the control group); no effects were seen in other groups, indicating that the effect of vitamin E on viral titers and weight loss may not be due solely to its antioxidant properties.
6b.iii. Polyunsaturated fatty acids
Polyunsaturated fatty acids, such as those found in dietary fish oil, are known to have anti-inflammatory properties and have beneficial effects for patients with chronic inflammatory diseases such as rheumatoid arthritis, inflammatory bowel disease, and cardiovascular disease (116-119). The same anti-inflammatory properties can also cause increased susceptibility to and severity of infections that require a strong inflammatory response to clear the infection. The inflammatory response is necessary for clearance of an influenza virus infection, but the inflammation is also responsible for much of the pathology associated with infection. In a study by Byleveld et al (120), BALB/c inbred mice were fed either a diet supplemented with fish oil or a diet supplemented with beef tallow (control group). Mice were fed the experimental diet for 14 days and then challenged with H3N2 influenza virus intranasally. All of the mice recovered from the infection, but the mice on the fish oil diet had increased weight loss and viral titers in the lung, as well as delayed viral clearance. The antibody response was also blunted in fish oil fed mice, with decreased levels of serum IgG and lung IgA and decreased expression of IFN-gamma. Schwerbrock et al (121) conducted a similar study in which C57BL/6 inbred mice were exposed to either a fish oil supplemented diet or a corn oil supplemented diet for 14 days prior to influenza A virus (PR8) challenge. Fish oil fed mice had delayed recovery from infection, increased mortality rates (51% vs. 10%), and a 7-fold increase in viral load. Despite the poorer outcome, the mice had reduced lung pathology, decreased lung neutrophils, NK cells and CD8 cells, and decreased cytokine and chemokine expression in the lung. These results are consistent with an impaired inflammatory response among mice with fish oil supplemented diets, which led to the inability to clear the infection.
6b.iv. Vitamin A
Vitamin A plays an important role in both innate and adaptive immunity and is required for the development and function of many types of lymphoid cells. The role of vitamin A deficiency in influenza susceptibility was examined in a study by Stephensen et al. (122). A diet deprived of vitamin A was fed to pregnant BALB/c dams and subsequent offspring after weaning. At seven weeks of age, the mice were intranasally infected with mouse-adapted H3N2 influenza virus. No differences were observed in survival, viral titers or clearance from the lung. Diminished serum antibody responses and lung IgA titers were seen in vitamin A-deficient mice. After the acute phase of infection, vitamin A-deficient mice had inflammatory lesions in their lungs that progressed to adenomatiod metaplasia, which was not observed in control mice.
6b.v. Quercetin
The relationship between stressful exercise, quercetin (a flavonoid found in many fruits and vegetables), and influenza susceptibility was examined in a study by Davis et al.(123). ICR inbred mice in quercetin treatment groups were fed quercetin by oral lavage for 7 days prior to viral challenge with influenza A PR8 virus. Mice in severe exercise exposed groups were subjected to 3 consecutive days of treadmill exercise until mice reached volitional fatigue, which was followed by intranasal challenge with influenza virus. Quercetin treatment offset the shortened time to sickness and increased morbidity seen in mice exposed to severe exercise, as well as the severity of symptoms. Quercetin treatment also offset the shortened time to death and mortality rate in mice exposed to severe exercise (74% mortality in severe exercise group; 52% mortality in mice fed quercetin who were exposed to severe exercise). Quercetin treatment alone also reduced influenza-induced mortality (28% mortality in quercetin-fed mice and 50% mortality in placebo non-exercised mice).Continued on Next Page »
(1) Pleschka S. Overview of Influenza Viruses. Curr Top Microbiol Immunol 2012 Nov 3.
(2) World Health Organization. Fact sheet: Influenza (Seasonal). 2009;211.
(3) Taubenberger JK, Baltimore D, Doherty PC, Markel H, Morens DM, Webster RG, et al. Reconstruction of the 1918 influenza virus: unexpected rewards from the past. MBio 2012 Sep 11;3(5):10.1128/mBio.00201-12. Print 2012.
(4) Chmielewski R, Swayne DE. Avian influenza: public health and food safety concerns. Annu Rev Food Sci Technol 2011;2:37-57.
(5) Perrone LA, Plowden JK, Garcia-Sastre A, Katz JM, Tumpey TM. H5N1 and 1918 pandemic influenza virus infection results in early and excessive infiltration of macrophages and neutrophils in the lungs of mice. PLoS Pathog 2008 Aug 1;4(8):e1000115.
(6) Steel J. New strategies for the development of H5N1 subtype influenza vaccines: progress and challenges. BioDrugs 2011 Oct 1;25(5):285-298.
(7) Mathews JD, Chesson JM, McCaw JM, McVernon J. Understanding influenza transmission, immunity and pandemic threats. Influenza Other Respi Viruses 2009 Jul;3(4):143-149.
(8) Juno J, Fowke KR, Keynan Y. Immunogenetic factors associated with severe respiratory illness caused by zoonotic H1N1 and H5N1 influenza viruses. Clin Dev Immunol 2012;2012:797180.
(9) Horby P, Sudoyo H, Viprakasit V, Fox A, Thai PQ, Yu H, et al. What is the evidence of a role for host genetics in susceptibility to influenza A/H5N1? Epidemiol Infect 2010 Nov;138(11):1550-1558.
(10) Horby P, Nguyen NY, Dunstan SJ, Baillie JK. The role of host genetics in susceptibility to influenza: a systematic review. PLoS One 2012;7(3):e33180.
(11) Huttunen R, Heikkinen T, Syrjanen J. Smoking and the outcome of infection. J Intern Med 2011 Mar;269(3):258-269.
(12) Jones RM. Critical review and uncertainty analysis of factors influencing influenza transmission. Risk Anal 2011 Aug;31(8):1226-1242.
(13) Karlsson EA, Beck MA. The burden of obesity on infectious disease. Exp Biol Med (Maywood) 2010 Dec;235(12):1412-1424.
(14) Albright FS, Orlando P, Pavia AT, Jackson GG, Cannon Albright LA. Evidence for a heritable predisposition to death due to influenza. J Infect Dis 2008 Jan 1;197(1):18-24.
(15) Olsen SJ, Ungchusak K, Sovann L, Uyeki TM, Dowell SF, Cox NJ, et al. Family clustering of avian influenza A (H5N1). Emerg Infect Dis 2005 Nov;11(11):1799-1801.
(16) Hidaka F, Matsuo S, Muta T, Takeshige K, Mizukami T, Nunoi H. A missense mutation of the Toll-like receptor 3 gene in a patient with influenza-associated encephalopathy. Clin Immunol 2006 May;119(2):188-194.
(17) Antonopoulou A, Baziaka F, Tsaganos T, Raftogiannis M, Koutoukas P, Spyridaki A, et al. Role of tumor necrosis factor gene single nucleotide polymorphisms in the natural course of 2009 influenza A H1N1 virus infection. Int J Infect Dis 2012 Mar;16(3):e204-8.
(18) Boon AC, de Mutsert G, Graus YM, Fouchier RA, Sintnicolaas K, Osterhaus AD, et al. The magnitude and specificity of influenza A virus-specific cytotoxic T-lymphocyte responses in humans is related to HLA-A and -B phenotype. J Virol 2002 Jan;76(2):582-590.
(19) Shashkov LA, Zhilova GP, Smorodintsev AA. Correlation between blood group factors and susceptibility to experimental influenzal infection in man. Bull Exp Biol Med 1974 Dec;77(6):670-672.
(20) Gottfredsson M, Halldorsson BV, Jonsson S, Kristjansson M, Kristjansson K, Kristinsson KG, et al. Lessons from the past: familial aggregation analysis of fatal pandemic influenza (Spanish flu) in Iceland in 1918. Proc Natl Acad Sci U S A 2008 Jan 29;105(4):1303-1308.
(21) Pitzer VE, Olsen SJ, Bergstrom CT, Dowell SF, Lipsitch M. Little evidence for genetic susceptibility to influenza A (H5N1) from family clustering data. Emerg Infect Dis 2007 Jul;13(7):1074-1076.
(22) Tumpey TM, Szretter KJ, Van Hoeven N, Katz JM, Kochs G, Haller O, et al. The Mx1 gene protects mice against the pandemic 1918 and highly lethal human H5N1 influenza viruses. J Virol 2007 Oct;81(19):10818-10821.
(23) Salomon R, Staeheli P, Kochs G, Yen HL, Franks J, Rehg JE, et al. Mx1 gene protects mice against the highly lethal human H5N1 influenza virus. Cell Cycle 2007 Oct 1;6(19):2417-2421.
(24) Vanlaere I, Vanderrijst A, Guenet JL, De Filette M, Libert C. Mx1 causes resistance against influenza A viruses in the Mus spretus-derived inbred mouse strain SPRET/Ei. Cytokine 2008 Apr;42(1):62-70.
(25) Boon AC, deBeauchamp J, Hollmann A, Luke J, Kotb M, Rowe S, et al. Host genetic variation affects resistance to infection with a highly pathogenic H5N1 influenza A virus in mice. J Virol 2009 Oct;83(20):10417-10426.
(26) Trammell RA, Liberati TA, Toth LA. Host genetic background and the innate inflammatory response of lung to influenza virus. Microbes Infect 2012 Jan;14(1):50-58.
(27) Srivastava B, Blazejewska P, Hessmann M, Bruder D, Geffers R, Mauel S, et al. Host genetic background strongly influences the response to influenza a virus infections. PLoS One 2009;4(3):e4857.
(28) Alberts R, Srivastava B, Wu H, Viegas N, Geffers R, Klawonn F, et al. Gene expression changes in the host response between resistant and susceptible inbred mouse strains after influenza A infection. Microbes Infect 2010 Apr;12(4):309-318.
(29) Boivin GA, Pothlichet J, Skamene E, Brown EG, Loredo-Osti JC, Sladek R, et al. Mapping of Clinical and Expression Quantitative Trait Loci in a Sex-Dependent Effect of Host Susceptibility to Mouse-Adapted Influenza H3N2/HK/1/68. J Immunol 2012 Mar 16.
(30) Bottomly D, Ferris MT, Aicher LD, Rosenzweig E, Whitmore A, Aylor DL, et al. Expression quantitative trait Loci for extreme host response to influenza a in pre-collaborative cross mice. G3 (Bethesda) 2012 Feb;2(2):213-221.
(31) Everitt AR, Clare S, Pertel T, John SP, Wash RS, Smith SE, et al. IFITM3 restricts the morbidity and mortality associated with influenza. Nature 2012 Mar 25;484(7395):519-523.
(32) Le Goffic R, Balloy V, Lagranderie M, Alexopoulou L, Escriou N, Flavell R, et al. Detrimental contribution of the Toll-like receptor (TLR)3 to influenza A virus-induced acute pneumonia. PLoS Pathog 2006 Jun;2(6):e53.
(33) Koyama S, Ishii KJ, Kumar H, Tanimoto T, Coban C, Uematsu S, et al. Differential role of TLR- and RLR-signaling in the immune responses to influenza A virus infection and vaccination. J Immunol 2007 Oct 1;179(7):4711-4720.
(34) Esposito S, Molteni CG, Giliani S, Mazza C, Scala A, Tagliaferri L, et al. Toll-like receptor 3 gene polymorphisms and severity of pandemic A/H1N1/2009 influenza in otherwise healthy children. Virol J 2012 Nov 15;9:270-422X-9-270.
(35) Arpaia N, Barton GM. Toll-like receptors: key players in antiviral immunity. Curr Opin Virol 2011 Dec;1(6):447-454.
(36) Mibayashi M, Martinez-Sobrido L, Loo YM, Cardenas WB, Gale M,Jr, Garcia-Sastre A. Inhibition of retinoic acid-inducible gene I-mediated induction of beta interferon by the NS1 protein of influenza A virus. J Virol 2007 Jan;81(2):514-524.
(37) Garcia-Sastre A, Biron CA. Type 1 interferons and the virus-host relationship: a lesson in detente. Science 2006 May 12;312(5775):879-882.
(38) Pang IK, Iwasaki A. Inflammasomes as mediators of immunity against influenza virus. Trends Immunol 2011 Jan;32(1):34-41.
(39) Crowe CR, Chen K, Pociask DA, Alcorn JF, Krivich C, Enelow RI, et al. Critical role of IL-17RA in immunopathology of influenza infection. J Immunol 2009 Oct 15;183(8):5301-5310.
(40) Khoufache K, LeBouder F, Morello E, Laurent F, Riffault S, Andrade-Gordon P, et al. Protective role for protease-activated receptor-2 against influenza virus pathogenesis via an IFN-gamma-dependent pathway. J Immunol 2009 Jun 15;182(12):7795-7802.
(41) Julkunen I, Sareneva T, Pirhonen J, Ronni T, Melen K, Matikainen S. Molecular pathogenesis of influenza A virus infection and virus-induced regulation of cytokine gene expression. Cytokine Growth Factor Rev 2001 Jun-Sep;12(2-3):171-180.
(42) Juno J, Fowke KR, Keynan Y. Immunogenetic factors associated with severe respiratory illness caused by zoonotic H1N1 and H5N1 influenza viruses. Clin Dev Immunol 2012;2012:797180.
(43) Kobasa D, Jones SM, Shinya K, Kash JC, Copps J, Ebihara H, et al. Aberrant innate immune response in lethal infection of macaques with the 1918 influenza virus. Nature 2007 Jan 18;445(7125):319-323.
(44) De Santo C, Salio M, Masri SH, Lee LY, Dong T, Speak AO, et al. Invariant NKT cells reduce the immunosuppressive activity of influenza A virus-induced myeloid-derived suppressor cells in mice and humans. J Clin Invest 2008 Dec;118(12):4036-4048.
(45) Topham DJ, Tripp RA, Doherty PC. CD8+ T cells clear influenza virus by perforin or Fas-dependent processes. J Immunol 1997 Dec 1;159(11):5197-5200.
(46) Huber VC, Lynch JM, Bucher DJ, Le J, Metzger DW. Fc receptor-mediated phagocytosis makes a significant contribution to clearance of influenza virus infections. J Immunol 2001 Jun 15;166(12):7381-7388.
(47) Nelli RK, Dunham SP, Kuchipudi SV, White GA, Baquero-Perez B, Chang P, et al. Mammalian innate resistance to highly pathogenic avian influenza H5N1 virus infection is mediated through reduced proinflammation and infectious virus release. J Virol 2012 Sep;86(17):9201-9210.
(48) Reading PC, Hartley CA, Ezekowitz RA, Anders EM. A serum mannose-binding lectin mediates complement-dependent lysis of influenza virus-infected cells. Biochem Biophys Res Commun 1995 Dec 26;217(3):1128-1136.
(49) Arulanandam BP, Raeder RH, Nedrud JG, Bucher DJ, Le J, Metzger DW. IgA immunodeficiency leads to inadequate Th cell priming and increased susceptibility to influenza virus infection. J Immunol 2001 Jan 1;166(1):226-231.
(50) Ali HM, Scott R, Toms GL. The effect of foster feeding and bottle feeding expressed breast-milk on the susceptibility of guinea-pig infants to influenza virus. Br J Exp Pathol 1989 Apr;70(2):183-191.
(51) Dengler L, May M, Wilk E, Bahgat MM, Schughart K. Immunization with live virus vaccine protects highly susceptible DBA/2J mice from lethal influenza A H1N1 infection. Virol J 2012 Sep 19;9:212-422X-9-212.
(52) Small PA,Jr, Waldman RH, Bruno JC, Gifford GE. Influenza infection in ferrets: role of serum antibody in protection and recovery. Infect Immun 1976 Feb;13(2):417-424.
(53) Peng X, Gralinski L, Ferris MT, Frieman MB, Thomas MJ, Proll S, et al. Integrative deep sequencing of the mouse lung transcriptome reveals differential expression of diverse classes of small RNAs in response to respiratory virus infection. MBio 2011 Nov 15;2(6):10.1128/mBio.00198-11. Print 2011.
(54) McElhaney JE, Effros RB. Immunosenescence: what does it mean to health outcomes in older adults? Curr Opin Immunol 2009 Aug;21(4):418-424.
(55) Marston BJ, Plouffe JF, File TM,Jr, Hackman BA, Salstrom SJ, Lipman HB, et al. Incidence of community-acquired pneumonia requiring hospitalization. Results of a population-based active surveillance Study in Ohio. The Community-Based Pneumonia Incidence Study Group. Arch Intern Med 1997 Aug 11-25;157(15):1709-1718.
(56) de Bruijn IA, Remarque EJ, Beyer WE, le Cessie S, Masurel N, Ligthart GJ. Annually repeated influenza vaccination improves humoral responses to several influenza virus strains in healthy elderly. Vaccine 1997 Aug-Sep;15(12-13):1323-1329.
(57) Sheahan T, Whitmore A, Long K, Ferris M, Rockx B, Funkhouser W, et al. Successful vaccination strategies that protect aged mice from lethal challenge from influenza virus and heterologous severe acute respiratory syndrome coronavirus. J Virol 2011 Jan;85(1):217-230.
(58) Tamma PD, Steinhoff MC, Omer SB. Influenza infection and vaccination in pregnant women. Expert Rev Respir Med 2010 Jun;4(3):321-328.
(59) Labant A, Greenawalt JA. Pandemic flu: a major concern for pregnant women. Nurs Womens Health 2009 Oct;13(5):374-382.
(60) FREEMAN DW, BARNO A. Deaths from Asian influenza associated with pregnancy. Am J Obstet Gynecol 1959 Dec;78:1172-1175.
(61) Neuzil KM, Reed GW, Mitchel EF, Simonsen L, Griffin MR. Impact of influenza on acute cardiopulmonary hospitalizations in pregnant women. Am J Epidemiol 1998 Dec 1;148(11):1094-1102.
(62) Cox S, Posner SF, McPheeters M, Jamieson DJ, Kourtis AP, Meikle S. Hospitalizations with respiratory illness among pregnant women during influenza season. Obstet Gynecol 2006 Jun;107(6):1315-1322.
(63) Jamieson DJ, Honein MA, Rasmussen SA, Williams JL, Swerdlow DL, Biggerstaff MS, et al. H1N1 2009 influenza virus infection during pregnancy in the USA. Lancet 2009 Aug 8;374(9688):451-458.
(64) Forbes RL, Wark PA, Murphy VE, Gibson PG. Pregnant women have attenuated innate interferon responses to 2009 pandemic influenza A virus subtype H1N1. J Infect Dis 2012 Sep 1;206(5):646-653.
(65) Black SB, Shinefield HR, France EK, Fireman BH, Platt ST, Shay D, et al. Effectiveness of influenza vaccine during pregnancy in preventing hospitalizations and outpatient visits for respiratory illness in pregnant women and their infants. Am J Perinatol 2004 Aug;21(6):333-339.
(66) Gendon I. Prevention of influenza in pregnant women and neonatal infants. Vopr Virusol 2009 Jul-Aug;54(4):4-10.
(67) Acs N, Banhidy F, Puho E, Czeizel AE. Maternal influenza during pregnancy and risk of congenital abnormalities in offspring. Birth Defects Res A Clin Mol Teratol 2005 Dec;73(12):989-996.
(68) Busby A, Dolk H, Armstrong B. Eye anomalies: seasonal variation and maternal viral infections. Epidemiology 2005 May;16(3):317-322.
(69) Brown AS, Begg MD, Gravenstein S, Schaefer CA, Wyatt RJ, Bresnahan M, et al. Serologic evidence of prenatal influenza in the etiology of schizophrenia. Arch Gen Psychiatry 2004 Aug;61(8):774-780.
(70) Glezen WP, Greenberg SB, Atmar RL, Piedra PA, Couch RB. Impact of respiratory virus infections on persons with chronic underlying conditions. JAMA 2000 Jan 26;283(4):499-505.
(71) Neuzil KM, Wright PF, Mitchel EF,Jr, Griffin MR. The burden of influenza illness in children with asthma and other chronic medical conditions. J Pediatr 2000 Dec;137(6):856-864.
(72) O'Riordan S, Barton M, Yau Y, Read SE, Allen U, Tran D. Risk factors and outcomes among children admitted to hospital with pandemic H1N1 influenza. CMAJ 2010 Jan 12;182(1):39-44.
(73) Plessa E, Diakakis P, Gardelis J, Thirios A, Koletsi P, Falagas ME. Clinical features, risk factors, and complications among pediatric patients with pandemic influenza A (H1N1). Clin Pediatr (Phila) 2010 Aug;49(8):777-781.
(74) Libster R, Bugna J, Coviello S, Hijano DR, Dunaiewsky M, Reynoso N, et al. Pediatric hospitalizations associated with 2009 pandemic influenza A (H1N1) in Argentina. N Engl J Med 2010 Jan 7;362(1):45-55.
(75) Papi A, Bellettato CM, Braccioni F, Romagnoli M, Casolari P, Caramori G, et al. Infections and airway inflammation in chronic obstructive pulmonary disease severe exacerbations. Am J Respir Crit Care Med 2006 May 15;173(10):1114-1121.
(76) Centers for Disease Control and Prevention (CDC). Influenza vaccination coverage among children with asthma--United States, 2004-05 influenza season. MMWR Morb Mortal Wkly Rep 2007 Mar 9;56(9):193-196.
(77) Dulek DE, Peebles RS,Jr. Viruses and asthma. Biochim Biophys Acta 2011 Nov;1810(11):1080-1090.
(78) Garvey C, Ortiz G. Exacerbations of chronic obstructive pulmonary disease. Open Nurs J 2012;6:13-19.
(79) Clover RD, Abell T, Becker LA, Crawford S, Ramsey CN,Jr. Family functioning and stress as predictors of influenza B infection. J Fam Pract 1989 May;28(5):535-539.
(80) Hermann G, Tovar CA, Beck FM, Allen C, Sheridan JF. Restraint stress differentially affects the pathogenesis of an experimental influenza viral infection in three inbred strains of mice. J Neuroimmunol 1993 Aug;47(1):83-94.
(81) Hunzeker J, Padgett DA, Sheridan PA, Dhabhar FS, Sheridan JF. Modulation of natural killer cell activity by restraint stress during an influenza A/PR8 infection in mice. Brain Behav Immun 2004 Nov;18(6):526-535.
(82) Padgett DA, MacCallum RC, Sheridan JF. Stress exacerbates age-related decrements in the immune response to an experimental influenza viral infection. J Gerontol A Biol Sci Med Sci 1998 Sep;53(5):B347-53.
(83) Avitsur R, Mays JW, Sheridan JF. Sex differences in the response to influenza virus infection: modulation by stress. Horm Behav 2011 Feb;59(2):257-264.
(84) Ilback NG, Friman G, Beisel WR, Johnson AJ, Berendt RF. Modifying effects of exercise on clinical course and biochemical response of the myocardium in influenza and tularemia in mice. Infect Immun 1984 Aug;45(2):498-504.
(85) Murphy EA, Davis JM, Carmichael MD, Gangemi JD, Ghaffar A, Mayer EP. Exercise stress increases susceptibility to influenza infection. Brain Behav Immun 2008 Nov;22(8):1152-1155.
(86) Russek LG, Schwartz GE. Narrative descriptions of parental love and caring predict health status in midlife: a 35-year follow-up of the Harvard Mastery of Stress Study. Altern Ther Health Med 1996 Nov;2(6):55-62.
(87) Solomon GF, Levine S, Kraft JK. Early experience and immunity. Nature 1968 Nov 23;220(5169):821-822.
(88) Kaufman J, Plotsky PM, Nemeroff CB, Charney DS. Effects of early adverse experiences on brain structure and function: clinical implications. Biol Psychiatry 2000 Oct 15;48(8):778-790.
(89) Avitsur R, Hunzeker J, Sheridan JF. Role of early stress in the individual differences in host response to viral infection. Brain Behav Immun 2006 Jul;20(4):339-348.
(90) Avitsur R, Sheridan JF. Neonatal stress modulates sickness behavior. Brain Behav Immun 2009 Oct;23(7):977-985.
(91) Sheridan JF, Stark JL, Avitsur R, Padgett DA. Social disruption, immunity, and susceptibility to viral infection. Role of glucocorticoid insensitivity and NGF. Ann N Y Acad Sci 2000;917:894-905.
(92) Louria DB. Undernutrition can affect the invading microorganism. Clin Infect Dis 2007 Aug 15;45(4):470-474.
(93) Beck MA, Nelson HK, Shi Q, Van Dael P, Schiffrin EJ, Blum S, et al. Selenium deficiency increases the pathology of an influenza virus infection. FASEB J 2001 Jun;15(8):1481-1483.
(94) Beck MA. Rapid genomic evolution of a non-virulent coxsackievirus B3 in selenium-deficient mice. Biomed Environ Sci 1997 Sep;10(2-3):307-315.
(95) Beck MA. Increased virulence of coxsackievirus B3 in mice due to vitamin E or selenium deficiency. J Nutr 1997 May;127(5 Suppl):966S-970S.
(96) Beck MA, Kolbeck PC, Rohr LH, Shi Q, Morris VC, Levander OA. Benign human enterovirus becomes virulent in selenium-deficient mice. J Med Virol 1994 Jun;43(2):166-170.
(97) Beck MA, Kolbeck PC, Shi Q, Rohr LH, Morris VC, Levander OA. Increased virulence of a human enterovirus (coxsackievirus B3) in selenium-deficient mice. J Infect Dis 1994 Aug;170(2):351-357.
(98) Li W, Beck MA. Selenium deficiency induced an altered immune response and increased survival following influenza A/Puerto Rico/8/34 infection. Exp Biol Med (Maywood) 2007 Mar;232(3):412-419.
(99) Pollett M, Mackenzie JS, Turner KJ. The effect of protein-deprivation on the susceptibility to influenza virus infection: a murine model system. Aust J Exp Biol Med Sci 1979 Apr;57(2):151-160.
(100) Taylor AK, Cao W, Vora KP, Cruz Jde L, Shieh WJ, Zaki SR, et al. Protein energy malnutrition decreases immunity and increases susceptibility to influenza infection in mice. J Infect Dis 2013 Feb;207(3):501-510.
(101) Weindruch R, Kayo T, Lee CK, Prolla TA. Microarray profiling of gene expression in aging and its alteration by caloric restriction in mice. J Nutr 2001 Mar;131(3):918S-923S.
(102) Weindruch R. The retardation of aging by caloric restriction: studies in rodents and primates. Toxicol Pathol 1996 Nov-Dec;24(6):742-745.
(103) Gardner EM. Caloric restriction decreases survival of aged mice in response to primary influenza infection. J Gerontol A Biol Sci Med Sci 2005 Jun;60(6):688-694.
(104) Ritz BW, Aktan I, Nogusa S, Gardner EM. Energy restriction impairs natural killer cell function and increases the severity of influenza infection in young adult male C57BL/6 mice. J Nutr 2008 Nov;138(11):2269-2275.
(105) Smith AG, Sheridan PA, Harp JB, Beck MA. Diet-induced obese mice have increased mortality and altered immune responses when infected with influenza virus. J Nutr 2007 May;137(5):1236-1243.
(106) Smith AG, Sheridan PA, Tseng RJ, Sheridan JF, Beck MA. Selective impairment in dendritic cell function and altered antigen-specific CD8+ T-cell responses in diet-induced obese mice infected with influenza virus. Immunology 2009 Feb;126(2):268-279.
(107) Fezeu L, Julia C, Henegar A, Bitu J, Hu FB, Grobbee DE, et al. Obesity is associated with higher risk of intensive care unit admission and death in influenza A (H1N1) patients: a systematic review and meta-analysis. Obes Rev 2011 Aug;12(8):653-659.
(108) Kwong JC, Campitelli MA, Rosella LC. Obesity and respiratory hospitalizations during influenza seasons in Ontario, Canada: a cohort study. Clin Infect Dis 2011 Sep;53(5):413-421.
(109) Hoffmann PR, Berry MJ. The influence of selenium on immune responses. Mol Nutr Food Res 2008 Nov;52(11):1273-1280.
(110) Wintergerst ES, Maggini S, Hornig DH. Contribution of selected vitamins and trace elements to immune function. Ann Nutr Metab 2007;51(4):301-323.
(111) Nelson HK, Shi Q, Van Dael P, Schiffrin EJ, Blum S, Barclay D, et al. Host nutritional selenium status as a driving force for influenza virus mutations. FASEB J 2001 Aug;15(10):1846-1848.
(112) Buffinton GD, Christen S, Peterhans E, Stocker R. Oxidative stress in lungs of mice infected with influenza A virus. Free Radic Res Commun 1992;16(2):99-110.
(113) Hennet T, Peterhans E, Stocker R. Alterations in antioxidant defences in lung and liver of mice infected with influenza A virus. J Gen Virol 1992 Jan;73 ( Pt 1)(Pt 1):39-46.
(114) Hayek MG, Taylor SF, Bender BS, Han SN, Meydani M, Smith DE, et al. Vitamin E supplementation decreases lung virus titers in mice infected with influenza. J Infect Dis 1997 Jul;176(1):273-276.
(115) Han SN, Meydani M, Wu D, Bender BS, Smith DE, Vina J, et al. Effect of long-term dietary antioxidant supplementation on influenza virus infection. J Gerontol A Biol Sci Med Sci 2000 Oct;55(10):B496-503.
(116) Calder PC. N-3 Polyunsaturated Fatty Acids, Inflammation, and Inflammatory Diseases. Am J Clin Nutr 2006 Jun;83(6 Suppl):1505S-1519S.
(117) Calder PC. Polyunsaturated fatty acids, inflammation, and immunity. Lipids 2001 Sep;36(9):1007-1024.
(118) Ruxton CH, Calder PC, Reed SC, Simpson MJ. The impact of long-chain n-3 polyunsaturated fatty acids on human health. Nutr Res Rev 2005 Jun;18(1):113-129.
(119) Benatti P, Peluso G, Nicolai R, Calvani M. Polyunsaturated fatty acids: biochemical, nutritional and epigenetic properties. J Am Coll Nutr 2004 Aug;23(4):281-302.
(120) Byleveld PM, Pang GT, Clancy RL, Roberts DC. Fish oil feeding delays influenza virus clearance and impairs production of interferon-gamma and virus-specific immunoglobulin A in the lungs of mice. J Nutr 1999 Feb;129(2):328-335.
(121) Schwerbrock NM, Karlsson EA, Shi Q, Sheridan PA, Beck MA. Fish oil-fed mice have impaired resistance to influenza infection. J Nutr 2009 Aug;139(8):1588-1594.
(122) Stephensen CB, Blount SR, Schoeb TR, Park JY. Vitamin A deficiency impairs some aspects of the host response to influenza A virus infection in BALB/c mice. J Nutr 1993 May;123(5):823-833.
(123) Davis JM, Murphy EA, McClellan JL, Carmichael MD, Gangemi JD. Quercetin reduces susceptibility to influenza infection following stressful exercise. Am J Physiol Regul Integr Comp Physiol 2008 Aug;295(2):R505-9.
(124) Arcavi L, Benowitz NL. Cigarette smoking and infection. Arch Intern Med 2004 Nov 8;164(20):2206-2216.
(125) Finklea JF, Sandifer SH, Smith DD. Cigarette smoking and epidemic influenza. Am J Epidemiol 1969 Nov;90(5):390-399.
(126) Kark JD, Lebiush M. Smoking and epidemic influenza-like illness in female military recruits: a brief survey. Am J Public Health 1981 May;71(5):530-532.
(127) Kark JD, Lebiush M, Rannon L. Cigarette smoking as a risk factor for epidemic a(h1n1) influenza in young men. N Engl J Med 1982 Oct 21;307(17):1042-1046.
(128) MacKenzie JS, MacKenzie IH, Holt PG. The effect of cigarette smoking on susceptibility to epidemic influenza and on serological responses to live attenuated and killed subunit influenza vaccines. J Hyg (Lond) 1976 Dec;77(3):409-417.
(129) Noah TL, Zhou H, Monaco J, Horvath K, Herbst M, Jaspers I. Tobacco smoke exposure and altered nasal responses to live attenuated influenza virus. Environ Health Perspect 2011 Jan;119(1):78-83.
(130) Wu W, Patel KB, Booth JL, Zhang W, Metcalf JP. Cigarette smoke extract suppresses the RIG-I-initiated innate immune response to influenza virus in the human lung. Am J Physiol Lung Cell Mol Physiol 2011 Jun;300(6):L821-30.
(131) Feng Y, Kong Y, Barnes PF, Huang FF, Klucar P, Wang X, et al. Exposure to cigarette smoke inhibits the pulmonary T-cell response to influenza virus and Mycobacterium tuberculosis. Infect Immun 2011 Jan;79(1):229-237.
(132) Horvath KM, Brighton LE, Zhang W, Carson JL, Jaspers I. Epithelial cells from smokers modify dendritic cell responses in the context of influenza infection. Am J Respir Cell Mol Biol 2011 Aug;45(2):237-245.
(133) Fernandez-Sola J, Junque A, Estruch R, Monforte R, Torres A, Urbano-Marquez A. High alcohol intake as a risk and prognostic factor for community-acquired pneumonia. Arch Intern Med 1995 Aug 7-21;155(15):1649-1654.
(134) Saitz R, Ghali WA, Moskowitz MA. The impact of alcohol-related diagnoses on pneumonia outcomes. Arch Intern Med 1997 Jul 14;157(13):1446-1452.
(135) de Roux A, Cavalcanti M, Marcos MA, Garcia E, Ewig S, Mensa J, et al. Impact of alcohol abuse in the etiology and severity of community-acquired pneumonia. Chest 2006 May;129(5):1219-1225.
(136) Meyerholz DK, Edsen-Moore M, McGill J, Coleman RA, Cook RT, Legge KL. Chronic alcohol consumption increases the severity of murine influenza virus infections. J Immunol 2008 Jul 1;181(1):641-648.
(137) Langlois RA, Meyerholz DK, Coleman RA, Cook RT, Waldschmidt TJ, Legge KL. Oseltamivir treatment prevents the increased influenza virus disease severity and lethality occurring in chronic ethanol consuming mice. Alcohol Clin Exp Res 2010 Aug;34(8):1425-1431.
(138) McGill J, Meyerholz DK, Edsen-Moore M, Young B, Coleman RA, Schlueter AJ, et al. Fetal exposure to ethanol has long-term effects on the severity of influenza virus infections. J Immunol 2009 Jun 15;182(12):7803-7808.
(139) Ciencewicki J, Jaspers I. Air pollution and respiratory viral infection. Inhal Toxicol 2007 Nov;19(14):1135-1146.
(140) Pearlman ME, Finklea JF, Shy CM, Van Bruggen J, Newill VA. Chronic oxidant exposure and epidemic influenza. Environ Res 1971 Apr;4(2):129-140.
(141) Kalpazanov Y, Stamenova M, Kurchatova G. Air pollution and the 1974-1975 influenza epidemic in Sofia; a statistical study. Environ Res 1976 Aug;12(1):1-8.
(142) Ravelli AC, Kreis IA. A time series analysis of sulphur dioxide, temperature, and influenza incidence in 1976-1987. Public Health Rev 1991 -1992;19(1-4):93-101.
(143) Wong TW, Lau TS, Yu TS, Neller A, Wong SL, Tam W, et al. Air pollution and hospital admissions for respiratory and cardiovascular diseases in Hong Kong. Occup Environ Med 1999 Oct;56(10):679-683.
(144) Goings SA, Kulle TJ, Bascom R, Sauder LR, Green DJ, Hebel JR, et al. Effect of nitrogen dioxide exposure on susceptibility to influenza A virus infection in healthy adults. Am Rev Respir Dis 1989 May;139(5):1075-1081.
(145) U.S. Environmental Protection Agency. Air Quality Criteria for Ozone and Related Photochemical Oxidants. 2006;EPA/600/R-05/004aF-cF(December).
(146) Noah TL, Zhou H, Zhang H, Horvath K, Robinette C, Kesic M, et al. Diesel exhaust exposure and nasal response to attenuated influenza in normal and allergic volunteers. Am J Respir Crit Care Med 2012 Jan 15;185(2):179-185.
(147) Jaspers I, Ciencewicki JM, Zhang W, Brighton LE, Carson JL, Beck MA, et al. Diesel exhaust enhances influenza virus infections in respiratory epithelial cells. Toxicol Sci 2005 Jun;85(2):990-1002.
(148) Ciencewicki J, Gowdy K, Krantz QT, Linak WP, Brighton L, Gilmour MI, et al. Diesel exhaust enhanced susceptibility to influenza infection is associated with decreased surfactant protein expression. Inhal Toxicol 2007 Nov;19(14):1121-1133.
(149) Hahon N, Booth JA, Green F, Lewis TR. Influenza virus infection in mice after exposure to coal dust and diesel engine emissions. Environ Res 1985 Jun;37(1):44-60.
(150) Zarkower A, Scheuchenzuber WJ, Burns CA. Effects of silica dust inhalation on the susceptibility of mice to influenza infection. Arch Environ Health 1979 Sep-Oct;34(5):372-376.
(151) Ali HM, Scott R, Toms GL. The susceptibility of breast-fed and cow's milk formula-fed infant guinea pigs to upper respiratory tract infection with influenza virus. Br J Exp Pathol 1988 Aug;69(4):563-575.
(152) Jakab GJ, Spannhake EW, Canning BJ, Kleeberger SR, Gilmour MI. The effects of ozone on immune function. Environ Health Perspect 1995 Mar;103 Suppl 2:77-89.
(153) Wolcott JA, Zee YC, Osebold JW. Exposure to ozone reduces influenza disease severity and alters distribution of influenza viral antigens in murine lungs. Appl Environ Microbiol 1982 Sep;44(3):723-731.
(154) Selgrade MK, Illing JW, Starnes DM, Stead AG, Menache MG, Stevens MA. Evaluation of effects of ozone exposure on influenza infection in mice using several indicators of susceptibility. Fundam Appl Toxicol 1988 Jul;11(1):169-180.
(155) Jakab GJ, Hmieleski RR. Reduction of influenza virus pathogenesis by exposure to 0.5 ppm ozone. J Toxicol Environ Health 1988;23(4):455-472.
(156) Jakab GJ, Bassett DJ. Influenza virus infection, ozone exposure, and fibrogenesis. Am Rev Respir Dis 1990 May;141(5 Pt 1):1307-1315.
(157) Hites RA. Dioxins: an overview and history. Environ Sci Technol 2011 Jan 1;45(1):16-20.
(158) Burleson GR, Lebrec H, Yang YG, Ibanes JD, Pennington KN, Birnbaum LS. Effect of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on influenza virus host resistance in mice. Fundam Appl Toxicol 1996 Jan;29(1):40-47.
(159) Yang YG, Lebrec H, Burleson GR. Effect of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on pulmonary influenza virus titer and natural killer (NK) activity in rats. Fundam Appl Toxicol 1994 Jul;23(1):125-131.
(160) Jain S, Kamimoto L, Bramley AM, Schmitz AM, Benoit SR, Louie J, et al. Hospitalized Patients with 2009 H1N1 Influenza in the United States, April-June 2009. N Engl J Med 2009 Oct 8.
(161) Jensen-Fangel S, Mohey R, Johnsen SP, Andersen PL, Sorensen HT, Ostergaard L. Gender differences in hospitalization rates for respiratory tract infections in Danish youth. Scand J Infect Dis 2004;36(1):31-36.
Table 1: Studies of host and environmental factors associated with susceptibility to influenza virus infection, by study type.
|
Host/environmental risk factor
|
Epidemiologic studies
|
Animal model studies
|
In vitro studies
|
|
Genetics
|
14-21
|
22-31
|
|
|
Immunity
-Natural immunity
-Immunosenescence
|
42
55, 56
|
32-40, 43-47, 49-53
57
|
47, 48
|
|
Pregnancy
|
60-69
|
|
|
|
Chronic Respiratory Conditions
|
70-78
|
|
|
|
Stress
-Family functioning
-Restraint stress
-Exercise stress
-Stress early in life
-Psychosocial stress
|
79
|
80-83
84, 85
86-90
91
|
|
|
Nutrition
-Protein-energy deficiencies
-Obesity
-Vitamin and micronutrient deficiencies
|
107*, 108
|
104-105, 108-109
110, 111
93, 98, 111, 113-114, 120-123
|
|
|
Smoking
|
125-129
|
131
|
130, 132
|
|
Alcohol
|
|
136-138
|
|
|
Pollutants
-General
-Diesel exhaust
-Ozone
-2,3,7,8-Tetrachlorodibenzo-p-dioxin
(TCDD)
|
140-144
146
|
148-150
153-156
158-159
|
147
|
Acknowledgements
This work was supported by the DoD-funded National Defense Science and Engineering Graduate (NDSEG) Fellowship awarded to Lauren M. Neighbours. We thank Bill Saunders and Chris Blanchette for their critical analysis of the manuscript and helpful comments.
