Respiratory syncytial virus infections in the adult asthmatic--mechanisms of host susceptibility and viral subversion

Blair D Westerly, R Stokes Peebles Jr, Blair D Westerly, R Stokes Peebles Jr

Abstract

Respiratory syncytial virus (RSV), a single-stranded RNA virus of the Paramyxoviridae family, is a major cause of bronchiolitis in infants and is also conjectured to be an early-life influence on the development of asthma. Although the data supporting a role for RSV in bronchiolitis in children are robust and evidence to support its role in juvenile asthmatics exists, RSV's role in asthma pathogenesis in adults is not as clearly defined. The authors review the literature to further elucidate RSV's impact on adult asthmatics, including its importance as a cause of asthma exacerbations. They examine the morbidity associated with RSV infection and how the immune response may differ between adult asthmatics and nonasthmatics. They review the responses by specific cell types from adults with asthma that are stimulated by RSV. They also consider the role of early-life exposure to RSV and its contribution to asthma in adults. Lastly, they review the mechanisms by which RSV evades normal host immune responses and subverts these responses to its benefit.

Conflict of interest statement

The authors declare no conflict of interest.

Copyright © 2010 Elsevier Inc. All rights reserved.

References

    1. Sigurs N, Gustafsson PM, Bjarnason R, Lundberg F, Schmidt S, Sigurbergsson F, et al. Severe respiratory syncytial virus bronchiolitis in infancy and asthma and allergy at age 13. Am J Respir Crit Care Med. 2005;171(2):137–141.
    1. Stein RT, Sherrill D, Morgan WJ, Holberg CJ, Halonen M, Taussig LM, et al. Respiratory syncytial virus in early life and risk of wheeze and allergy by age 13 years. Lancet. 1999;354(9178):541–545. [see comments]
    1. Falsey AR, Hennessey PA, Formica MA, Cox C, Walsh EE. Respiratory syncytial virus infection in elderly and high-risk adults. N Engl J Med. 2005;352(17):1749–1759.
    1. Beasley R, Coleman ED, Hermon Y, Holst PE, O’Donnell T, Tobias M. Viral respiratory tract infection and exacerbations of asthma in adult patients. Thorax. 1988;43(9):679–683.
    1. Glezen WP, Greenberg SB, Atmar RL, Piedra PA, Couch RB. Impact of respiratory virus infections on persons with chronic underlying conditions. JAMA. 2000;283(4):499–505.
    1. Harju TH, Leinonen M, Nokso-Koivisto J, Korhonen T, Raty R, He Q, et al. Pathogenic bacteria and viruses in induced sputum or pharyngeal secretions of adults with stable asthma. Thorax. 2006;61(7):579–584.
    1. Teichtahl H, Buckmaster N, Pertnikovs E. The incidence of respiratory tract infection in adults requiring hospitalization for asthma. Chest. 1997;112(3):591–596.
    1. Nicholson KG, Kent J, Ireland DC. Respiratory viruses and exacerbations of asthma in adults. BMJ. 1993;307(6910):982–986.
    1. Sokhandan M, McFadden ERJ, Huang YT, Mazanec MB. The contribution of respiratory viruses to severe exacerbations of asthma in adults. Chest. 1995;107(6):1570–1574. [see comments]
    1. Ayres JG, Noah ND, Fleming DM. Incidence of episodes of acute asthma and acute bronchitis in general practice 1976–87. Br J Gen Pract. 1993;43(374):361–364.
    1. Pattemore PK, Johnston SL, Bardin PG. Viruses as precipitants of asthma symptoms. I. Epidemiology. Clin Exp Allergy. 1992;22(3):325–336.
    1. Abramson M, Pearson L, Kutin J, Czarny D, Dziukas L, Bowes G. Allergies, upper respiratory tract infections, and asthma. J Asthma. 1994;31(5):367–374.
    1. Dowell SF, Anderson LJ, Gary HEJ, Erdman DD, Plouffe JF, File TMJ, et al. Respiratory syncytial virus is an important cause of community- acquired lower respiratory infection among hospitalized adults. Journal of Infectious Diseases. 1996;174(3):456–462.
    1. Fleming DM, Cross KW. Respiratory syncytial virus or influenza? Lancet. 1993;342(8886–8887):1507–1510.
    1. Griffin MR, Coffey CS, Neuzil KM, Mitchel EF, Jr, Wright PF, Edwards KM. Winter viruses: influenza- and respiratory syncytial virus-related morbidity in chronic lung disease. Arch Intern Med. 2002;162(11):1229–1236.
    1. Hall CB, Long CE, Schnabel KC. Respiratory syncytial virus infections in previously healthy working adults. Clin Infect Dis. 2001;33(6):792–796.
    1. Moineddin R, Nie JX, Domb G, Leong AM, Upshur RE. Seasonality of primary care utilization for respiratory diseases in Ontario: a time-series analysis. BMC Health Serv Res. 2008:8160.
    1. Thompson WW, Shay DK, Weintraub E, Brammer L, Cox N, Anderson LJ, et al. Mortality associated with influenza and respiratory syncytial virus in the United States. JAMA. 2003;289(2):179–186.
    1. Zambon MC, Stockton JD, Clewley JP, Fleming DM. Contribution of influenza and respiratory syncytial virus to community cases of influenza-like illness: an observational study. Lancet. 2001;358(9291):1410–1416.
    1. Guidry GG, Black-Payne CA, Payne DK, Jamison RM, George RB, Bocchini JA., Jr Respiratory syncytial virus infection among intubated adults in a university medical intensive care unit. Chest. 1991;100(5):1377–1384.
    1. Duncan CB, Walsh EE, Peterson DR, Lee FE, Falsey AR. Risk factors for respiratory failure associated with respiratory syncytial virus infection in adults. J Infect Dis. 2009;200(8):1242–1246.
    1. Gill MA, Palucka AK, Barton T, Ghaffar F, Jafri H, Banchereau J, et al. Mobilization of plasmacytoid and myeloid dendritic cells to mucosal sites in children with respiratory syncytial virus and other viral respiratory infections. J Infect Dis. 2005;191(7):1105–1115.
    1. Gill MA, Long K, Kwon T, Muniz L, Mejias A, Connolly J, et al. Differential recruitment of dendritic cells and monocytes to respiratory mucosal sites in children with influenza virus or respiratory syncytial virus infection. J Infect Dis. 2008;198(11):1667–1676.
    1. Henderson FW, Collier AM, Clyde WA, Jr, Denny FW. Respiratory-syncytial-virus infections, reinfections and immunity. A prospective, longitudinal study in young children. N Engl J Med. 1979;300(10):530–534.
    1. Popow-Kraupp T, Lakits E, Kellner G, Kunz C. Immunoglobulin-class-specific immune response to respiratory syncytial virus structural proteins in infants, children, and adults. J Med Virol. 1989;27(3):215–223.
    1. Falsey AR, Singh HK, Walsh EE. Serum antibody decay in adults following natural respiratory syncytial virus infection. J Med Virol. 2006;78(11):1493–1497.
    1. Lee FE, Walsh EE, Falsey AR, Betts RF, Treanor JJ. Experimental infection of humans with A2 respiratory syncytial virus. Antiviral Res. 2004;63(3):191–196.
    1. Mills J, Van Kirk JE, Wright PF, Chanock RM. Experimental respiratory syncytial virus infection of adults. Possible mechanisms of resistance to infection and illness. J Immunol. 1971;107(1):123–130.
    1. Walsh EE, Falsey AR. Humoral and mucosal immunity in protection from natural respiratory syncytial virus infection in adults. J Infect Dis. 2004;190(2):373–378.
    1. Hall CB, Walsh EE, Long CE, Schnabel KC. Immunity to and frequency of reinfection with respiratory syncytial virus. J Infect Dis. 1991;163(4):693–698.
    1. Falsey AR, Walsh EE, Looney RJ, Kolassa JE, Formica MA, Criddle MC, et al. Comparison of respiratory syncytial virus humoral immunity and response to infection in young and elderly adults. J Med Virol. 1999;59(2):221–226.
    1. Walsh EE, Falsey AR. Age related differences in humoral immune response to respiratory syncytial virus infection in adults. J Med Virol. 2004;73(2):295–299.
    1. Falsey AR, McCann RM, Hall WJ, Tanner MA, Criddle MM, Formica MA, et al. Acute respiratory tract infection in daycare centers for older persons. J Am Geriatr Soc. 1995;43(1):30–36.
    1. Gardner EM, Murasko DM. Age-related changes in Type 1 and Type 2 cytokine production in humans. Biogerontology. 2002;3(5):271–290.
    1. Looney RJ, Falsey AR, Walsh E, Campbell D. Effect of aging on cytokine production in response to respiratory syncytial virus infection. J Infect Dis. 2002;185(5):682–685.
    1. Po JL, Gardner EM, Anaraki F, Katsikis PD, Murasko DM. Age-associated decrease in virus-specific CD8+ T lymphocytes during primary influenza infection. Mech Ageing Dev. 2002;123(8):1167–1181.
    1. Zhang Y, Luxon BA, Casola A, Garofalo RP, Jamaluddin M, Brasier AR. Expression of respiratory syncytial virus-induced chemokine gene networks in lower airway epithelial cells revealed by cDNA microarrays. J Virol. 2001;75(19):9044–9058.
    1. Falsey AR, Walsh EE. Humoral immunity to respiratory syncytial virus infection in the elderly. J Med Virol. 1992;36(1):39–43.
    1. Walsh EE, Peterson DR, Falsey AR. Risk factors for severe respiratory syncytial virus infection in elderly persons. J Infect Dis. 2004;189(2):233–238.
    1. Terrosi C, Di GG, Martorelli B, Valentini M, Cusi MG. Humoral immunity to respiratory syncytial virus in young and elderly adults. Epidemiol Infect. 2009;137(12):1684–1686.
    1. Ostler T, Davidson W, Ehl S. Virus clearance and immunopathology by CD8(+) T cells during infection with respiratory syncytial virus are mediated by IFN-gamma. Eur J Immunol. 2002;32(8):2117–2123.
    1. Cherrie AH, Anderson K, Wertz GW, Openshaw PJ. Human cytotoxic T cells stimulated by antigen on dendritic cells recognize the N, SH, F, M, 22K, and 1b proteins of respiratory syncytial virus. J Virol. 1992;66(4):2102–2110.
    1. Lee FE, Walsh EE, Falsey AR, Liu N, Liu D, Divekar A, et al. The balance between influenza- and RSV-specific CD4 T cells secreting IL-10 or IFNgamma in young and healthy-elderly subjects. Mech Ageing Dev. 2005;126(11):1223–1229.
    1. Effros RB. Replicative senescence of CD8 T cells: effect on human ageing. Exp Gerontol. 2004;39(4):517–524.
    1. de Bree GJ, Heidema J, van Leeuwen EM, van Bleek GM, Jonkers RE, Jansen HM, et al. Respiratory syncytial virus-specific CD8+ memory T cell responses in elderly persons. J Infect Dis. 2005;191(10):1710–1718.
    1. Anderson LJ, Tsou C, Potter C, Keyserling HL, Smith TF, Ananaba G, et al. Cytokine response to respiratory syncytial virus stimulation of human peripheral blood mononuclear cells. J Infect Dis. 1994;170(5):1201–1208.
    1. Noah TL, Becker S. Chemokines in nasal secretions of normal adults experimentally infected with respiratory syncytial virus. Clin Immunol. 2000;97(1):43–49.
    1. Groskreutz DJ, Monick MM, Powers LS, Yarovinsky TO, Look DC, Hunninghake GW. Respiratory syncytial virus induces TLR3 protein and protein kinase R, leading to increased double-stranded RNA responsiveness in airway epithelial cells. J Immunol. 2006;176(3):1733–1740.
    1. Zhang Y, Wang Y, Gilmore X, Xu K, Wyde PR, Mbawuike IN. An aged mouse model for RSV infection and diminished CD8(+) CTL responses. Exp Biol Med (Maywood ) 2002;227(2):133–140.
    1. Gentile DA, Doyle WJ, Zeevi A, Howe-Adams J, Kapadia S, Trecki J, et al. Cytokine gene polymorphisms moderate illness severity in infants with respiratory syncytial virus infection. Hum Immunol. 2003;64(3):338–344.
    1. Gentile DA, Doyle WJ, Zeevi A, Piltcher O, Skoner DP. Cytokine gene polymorphisms moderate responses to respiratory syncytial virus in adults. Hum Immunol. 2003;64(1):93–98.
    1. Genovese M, Van den Bosch F, Roberson S, Bojin S, Biagini I, Ryan P, et al. LY2439821, a Humanized anti-IL-17 monoclonal antibody, in the treatment of patients with rheumatoid arthritis. Arthritis Rheum. 2010
    1. Faden H, Kaul TN, Ogra PL. Activation of oxidative and arachidonic acid metabolism in neutrophils by respiratory syncytial virus antibody complexes: possible role in disease. J Infect Dis. 1983;148(1):110–116.
    1. Richardson JY, Ottolini MG, Pletneva L, Boukhvalova M, Zhang S, Vogel SN, et al. Respiratory syncytial virus (RSV) infection induces cyclooxygenase 2: a potential target for RSV therapy. J Immunol. 2005;174(7):4356–4364.
    1. Richardson JY, Ottolini MG, Pletneva L, Boukhvalova M, Zhang S, Vogel SN, et al. Respiratory syncytial virus (RSV) infection induces cyclooxygenase 2: a potential target for RSV therapy. J Immunol. 2005;174(7):4356–4364.
    1. Henderson WR, Jr, Lewis DB, Albert RK, Zhang Y, Lamm WJ, Chiang GK, et al. The importance of leukotrienes in airway inflammation in a mouse model of asthma. J Exp Med. 1996;184(4):1483–1494.
    1. Henderson WR, Jr, Tang LO, Chu SJ, Tsao SM, Chiang GK, Jones F, et al. A role for cysteinyl leukotrienes in airway remodeling in a mouse asthma model. Am J Respir Crit Care Med. 2002;165(1):108–116.
    1. Panuska JR, Midulla F, Cirino NM, Villani A, Gilbert IA, McFadden ER, Jr, et al. Virus-induced alterations in macrophage production of tumor necrosis factor and prostaglandin E2. Am J Physiol. 1990;259(6 Pt 1):L396–L402.
    1. Hart CM. Nitric oxide in adult lung disease. Chest. 1999;115(5):1407–1417.
    1. Kao YJ, Piedra PA, Larsen GL, Colasurdo GN. Induction and regulation of nitric oxide synthase in airway epithelial cells by respiratory syncytial virus. Am J Respir Crit Care Med. 2001;163(2):532–539.
    1. Gentile DA, Doyle WJ, Belenky S, Ranck H, Angelini B, Skoner DP. Nasal and oral nitric oxide levels during experimental respiratory syncytial virus infection of adults. Acta Otolaryngol. 2002;122(1):61–66.
    1. Kaul P, Singh I, Turner RB. Effect of nitric oxide on rhinovirus replication and virus-induced interleukin-8 elaboration. Am J Respir Crit Care Med. 1999;159(4 Pt 1):1193–1198.
    1. Murphy AW, Platts-Mills TA, Lobo M, Hayden F. Respiratory nitric oxide levels in experimental human influenza. Chest. 1998;114(2):452–456.
    1. Patel JA, Kunimoto M, Sim TC, Garofalo R, Eliott T, Baron S, et al. Interleukin-1 alpha mediates the enhanced expression of intercellular adhesion molecule-1 in pulmonary epithelial cells infected with respiratory syncytial virus. American Journal of Respiratory Cell & Molecular Biology. 1995;13(5):602–609.
    1. Becker S, Koren HS, Henke DC. Interleukin-8 expression in normal nasal epithelium and its modulation by infection with respiratory syncytial virus and cytokines tumor necrosis factor, interleukin-1, and interleukin-6. American Journal of Respiratory Cell & Molecular Biology. 1993;8(1):20–27.
    1. Jamaluddin M, Garofalo R, Ogra PL, Brasier AR. Inducible translational regulation of the NF-IL6 transcription factor by respiratory syncytial virus infection in pulmonary epithelial cells. J Virol. 1996;70(3):1554–1563.
    1. Mastronarde JG, He B, Monick MM, Mukaida N, Matsushima K, Hunninghake GW. Induction of interleukin (IL)-8 gene expression by respiratory syncytial virus involves activation of nuclear factor (NF)-kappa B and NF-IL-6. J Infect Dis. 1996;174(2):262–267.
    1. Mastronarde JG, Monick MM, Mukaida N, Matsushima K, Hunninghake GW. Activator protein-1 is the preferred transcription factor for cooperative interaction with nuclear factor-kappaB in respiratory syncytial virus-induced interleukin-8 gene expression in airway epithelium. J Infect Dis. 1998;177(5):1275–1281.
    1. Noah TL, Becker S. Respiratory syncytial virus-induced cytokine production by a human bronchial epithelial cell line. Am J Physiol. 1993;265(5 Pt 1):L472–L478.
    1. Mellow TE, Murphy PC, Carson JL, Noah TL, Zhang L, Pickles RJ. The effect of respiratory synctial virus on chemokine release by differentiated airway epithelium. Exp Lung Res. 2004;30(1):43–57.
    1. Noah TL, Wortman IA, Becker S. The effect of fluticasone propionate on respiratory syncytial virus-induced chemokine release by a human bronchial epithelial cell line. Immunopharmacology. 1998;39(3):193–199.
    1. Becker S, Reed W, Henderson FW, Noah TL. RSV infection of human airway epithelial cells causes production of the beta-chemokine RANTES. Am J Physiol. 1997;272(3 Pt 1):L512–L520.
    1. Gehlhar K, Bilitewski C, Reinitz-Rademacher K, Rohde G, Bufe A. Impaired virus-induced interferon-alpha2 release in adult asthmatic patients. Clin Exp Allergy. 2006;36(3):331–337.
    1. Grissell TV, Powell H, Shafren DR, Boyle MJ, Hensley MJ, Jones PD, et al. Interleukin-10 gene expression in acute virus-induced asthma. Am J Respir Crit Care Med. 2005;172(4):433–439.
    1. van Scott MR, Justice JP, Bradfield JF, Enright E, Sigounas A, Sur S. IL-10 reduces Th2 cytokine production and eosinophilia but augments airway reactivity in allergic mice. Am J Physiol Lung Cell Mol Physiol. 2000;278(4):L667–L674.
    1. Hancock GE, Scheuer CA, Sierzega R, Pryharski KS, McBride JT, Watelet LF, et al. Adaptive immune responses of patients with asthma to the attachment (G) glycoprotein of respiratory synctial virus. J Infect Dis. 2001;184(12):1589–1593.
    1. O’Sullivan S, Cormican L, Faul JL, Ichinohe S, Johnston SL, Burke CM, et al. Activated, cytotoxic CD8(+) T lymphocytes contribute to the pathology of asthma death. Am J Respir Crit Care Med. 2001;164(4):560–564.
    1. Coyle AJ, Erard F, Bertrand C, Walti S, Pircher H, Le Gros G. Virus-specific CD8+ cells can switch to interleukin 5 production and induce airway eosinophilia. Journal of Experimental Medicine. 1995;181(3):1229–1233.
    1. Bjornsson E, Hjelm E, Janson C, Fridell E, Boman G. Serology of respiratory viruses in relation to asthma and bronchial hyperresponsiveness. Ups J Med Sci. 1996;101(2):159–168.
    1. Wilkinson TM, Donaldson GC, Johnston SL, Openshaw PJ, Wedzicha JA. Respiratory syncytial virus, airway inflammation, and FEV1 decline in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2006;173(8):871–876.
    1. Douville RN, Bastien N, Li Y, Simons FE, HayGlass KT. Adult asthmatics display exaggerated IFNgamma responses to human metapneumovirus and respiratory syncytial virus. Biochem Cell Biol. 2007;85(2):252–258.
    1. Haynes LM, Moore DD, Kurt-Jones EA, Finberg RW, Anderson LJ, Tripp RA. Involvement of toll-like receptor 4 in innate immunity to respiratory syncytial virus. J Virol. 2001;75(22):10730–10737.
    1. Skoner DP, Gentile DA, Angelini B, Doyle WJ. Allergy skin test responses during experimental infection with respiratory syncytial virus. Ann Allergy Asthma Immunol. 2006;96(6):834–839.
    1. Hirose H, Matsuse H, Tsuchida T, Fukahori S, Fukushima C, Mizuta Y, et al. Cytokine production from peripheral blood mononuclear cells of mite allergen-sensitized atopic adults stimulated with respiratory syncytial virus and mite allergen. Int Arch Allergy Immunol. 2008;146(2):149–155.
    1. Pala P, Message SD, Johnston SL, Openshaw PJ. Increased aeroallergen-specific interleukin-4-producing T cells in asthmatic adults. Clin Exp Allergy. 2002;32(12):1739–1744.
    1. Piippo-Savolainen E, Remes S, Korppi M. Does blood eosinophilia in wheezing infants predict later asthma? A prospective 18–20-year follow-up. Allergy Asthma Proc. 2007;28(2):163–169.
    1. Piippo-Savolainen E, Korppi M, Korhonen K, Remes S. Adult asthma after non-respiratory syncytial virus bronchiolitis in infancy: subgroup analysis of the 20-year prospective follow-up study. Pediatr Int. 2007;49(2):190–195.
    1. Korppi M, Piippo-Savolainen E, Korhonen K, Remes S. Respiratory morbidity 20 years after RSV infection in infancy. Pediatr Pulmonol. 2004;38(2):155–160.
    1. Welliver RC. Immunologic mechanisms of virus-induced wheezing and asthma. Journal of Pediatrics. 1999;135(2 Pt 2):14–20. [Review] [41 refs]
    1. Collins PL, Crowe JE., Jr . Respiratory Syncytial Virus and Metapneumovirus. In: Knipe DM, Howley PM, editors. Fields Virology. 5. Philadelphia: Lippincott Williams & Wilkins; 2007. pp. 1602–41.
    1. Takeuchi O, Akira S. MDA5/RIG-I and virus recognition. Curr Opin Immunol. 2008;20(1):17–22.
    1. Wilkins C, Gale M., Jr Recognition of viruses by cytoplasmic sensors. Curr Opin Immunol. 2010;22(1):41–47.
    1. Ling Z, Tran KC, Teng MN. Human respiratory syncytial virus nonstructural protein NS2 antagonizes the activation of beta interferon transcription by interacting with RIG-I. J Virol. 2009;83(8):3734–3742.
    1. Swedan S, Musiyenko A, Barik S. Respiratory syncytial virus nonstructural proteins decrease levels of multiple members of the cellular interferon pathways. J Virol. 2009;83(19):9682–9693.
    1. Spann KM, Tran KC, Collins PL. Effects of nonstructural proteins NS1 and NS2 of human respiratory syncytial virus on interferon regulatory factor 3, NF-kappaB, and proinflammatory cytokines. J Virol. 2005;79(9):5353–5362.
    1. Moore EC, Barber J, Tripp RA. Respiratory syncytial virus (RSV) attachment and nonstructural proteins modify the type I interferon response associated with suppressor of cytokine signaling (SOCS) proteins and IFN-stimulated gene-15 (ISG15) Virol J. 2008:5116.
    1. Lo MS, Brazas RM, Holtzman MJ. Respiratory syncytial virus nonstructural proteins NS1 and NS2 mediate inhibition of Stat2 expression and alpha/beta interferon responsiveness. J Virol. 2005;79(14):9315–9319.
    1. Ramaswamy M, Shi L, Varga SM, Barik S, Behlke MA, Look DC. Respiratory syncytial virus nonstructural protein 2 specifically inhibits type I interferon signal transduction. Virology. 2006;344(2):328–339.
    1. Elliott J, Lynch OT, Suessmuth Y, Qian P, Boyd CR, Burrows JF, et al. Respiratory syncytial virus NS1 protein degrades STAT2 by using the Elongin-Cullin E3 ligase. J Virol. 2007;81(7):3428–3436.
    1. Munir S, Le NC, Luongo C, Buchholz UJ, Collins PL, Bukreyev A. Nonstructural proteins 1 and 2 of respiratory syncytial virus suppress maturation of human dendritic cells. J Virol. 2008;82(17):8780–8796.
    1. Bitko V, Shulyayeva O, Mazumder B, Musiyenko A, Ramaswamy M, Look DC, et al. Nonstructural proteins of respiratory syncytial virus suppress premature apoptosis by an NF-kappaB-dependent, interferon-independent mechanism and facilitate virus growth. J Virol. 2007;81(4):1786–1795.
    1. Kotelkin A, Belyakov IM, Yang L, Berzofsky JA, Collins PL, Bukreyev A. The NS2 protein of human respiratory syncytial virus suppresses the cytotoxic T-cell response as a consequence of suppressing the type I interferon response. J Virol. 2006;80(12):5958–5967.

Source: PubMed

Sponsorer og samarbejdspartnere

Medicinske tilstande

Narkotikainterventioner

3
Abonner