Protective and Harmful Effects of Viral Infections in Childhood on Wheezing Disorders and Asthma

PETER J. M. OPENSHAW and COLIN HEWITT

Department of Respiratory Medicine, National Heart and Lung Institute, Imperial College School of Medicine at St. Mary's, London; and Centre for Mechanisms of Human Toxicity, University of Leicester, Leicester, United Kingdom

	INTRODUCTION

TOP INTRODUCTION WHAT DO WE KNOW? WHAT DO WE NEED... HOW CAN WE ACHIEVE... REFERENCES

It seems certain that environmental (not genetic) factors are responsible for the remarkable increase in prevalence of allergic respiratory diseases over the last 20 yr (1). One such factor might be improved hygiene, which has led to fewer childhood infections. However, it is well established that respiratory syncytial virus (RSV) infections cause many exacerbations in older children with asthma. In addition, many studies show that children with bronchiolitis are much more likely to suffer recurrent wheezing during the first 7-10 yr of life. It is not clear whether bronchiolitis reveals a preexisting weakness in the lungs, which later manifests as recurrent wheeze, or whether bronchiolitis itself causes persistent effects that could be avoided if RSV infections could be prevented (Figure 1). This is currently one of the most important unanswered questions in RSV research (2, 3).

View larger version (15K): [in this window] [in a new window]   Figure 1.   The "alternative" views of the association between RSV infection in infancy and the later development of inflamed lungs prone to recurrent wheezing and asthma in later childhood. In the first scenario, bronchiolitis causes persistent abnormalities, manifested as asthma. In the second, bronchiolitis reveals an inherent predisposition, later manifested as asthma.

It seems that viral infections have both positive and negative influences on the development of airway inflammation, wheezing, and asthma. In this review, we summarize the evidence that viral infections influence the development of persistent airway inflammation, discuss some of the ways in which viral infections might affect the establishment of asthma, identify areas in which more information is needed, and try to define how this information could be obtained.

	WHAT DO WE KNOW?

TOP INTRODUCTION WHAT DO WE KNOW? WHAT DO WE NEED... HOW CAN WE ACHIEVE... REFERENCES

Role of Viruses in Asthma In Exacerbation

Common colds are the most frequent cause of asthma exacerbation in school-age children, accounting for some 80% of acute episodes. Among children with asthma, about 85% of colds are associated with increased asthma symptoms (4). Viral infections are also present in up to 80% of adults with asthma with exacerbations (5), whereas experimental rhinovirus-16 inoculation in adults with allergic rhinitis alters the response to allergen bronchoprovocation, favoring development of the late-phase response (6). Virally infected patients with asthma have enhanced cytokine responses (7), apparently leading to prolonged lymphocyte and eosinophil accumulation in the lungs (8).

The possible mechanisms of exacerbations have been extensively reviewed (9). These include additive airway inflammation resulting from the inflammatory response to viral infection in an already inflamed mucosa and loss of epithelium, both of which lead to a reduced number of chemoreceptors, impaired clearance of material from the lung, and increased penetration of antigen through the damaged mucosa.

Do Viral Infections Lead to the Development of Asthma?

There is strong evidence linking RSV infection in infancy with a subsequent increase in pulmonary symptoms. This association persists for 8-13 yr (10), while histamine hyperresponsiveness is evident for at least 10 yr after bronchiolitis (11). In one study of 48 children who had suffered from infantile bronchiolitis, 44 (92%) had symptoms suggestive of asthma in the 5 yr of follow-up and 25 had clinically confirmed asthma (12). In a second study of 73 children with a history of bronchiolitis for an average of 6 yr, wheezing was reported in 42.5% of children previously admitted with bronchiolitis, compared with 15.1% of control subjects (13). Similarly, of 47 infants hospitalized with RSV bronchiolitis at a mean age of 3.5 mo, 23% were diagnosed with asthma in the ensuing 3 yr, compared with 1% of control subjects (14). In this latter study, a positive test for serum IgE antibodies was found in 32% of the patients with bronchiolitis compared with 9% of controls. Long-term follow-up of children with lower respiratory tract symptoms during RSV infection in infancy showed a strong association with recurrent wheeze. There was also an increase in reversible airflow obstruction in such children but no association with atopic asthma that increases in frequency during childhood. In contrast, the effect of infantile RSV infection declines during childhood and becomes unmeasurable by the age of 13 yr (15).

Animal experiments support the hypothesis that there is a causal link between viral bronchiolitis and asthma. In guinea pigs, RSV infection causes increased sensitivity to inhaled histamine for at least 6 wk, which is associated with viral persistence in the lung (16). Brown Norway rats develop chronic, episodic, and reversible airway obstruction after bronchiolitis. In this mode, a strong CD4⁺ T cell response is present, with reduced interferon  (IFN-) production, persistent inflammation, fibrosis, and deposition of extracellular matrix material leading to airway remodeling (17). Further mechanisms by which viral infections could affect later development of lung disease are virus chronicity, persistence or latency (18), and provision of a local foothold for other infections (19).

The mouse model of RSV bronchiolitis demonstrates that enhanced T cell responses are associated with increased severity of disease (3). In particular, prior sensitization with a formalin-inactivated RSV vaccine or the attachment protein (G) expressed by recombinant vaccinia virus leads to a helper T cell type 2 (Th2)-driven augmented disease, contrasting with the usual helper T cell type 1 (Th1) response seen in primary viral infections. The Th2 cell-driven lung eosinophilia seen in this model is linked to the inability of the G protein to stimulate CD8⁺ T cells, emphasizing the important noncytolytic regulatory role of CD8⁺ cells (20).

There is also strong evidence from animal models that viral infections interact with inhaled allergens to promote the development of airway inflammation and atopy. Uninfected mice do not develop IgE antibody against inhaled antigen (ovalbumin), but during acute influenza infection sensitization takes place (21). When antigen exposure coincides with influence infection, airway responsiveness to inhaled methacholine increases and serum IgE rises; however, neither influenza A virus nor ovalbumin alone causes these changes (22). Inhaled nebulized ovalbumin induces systemic sensitization if the protein is inhaled in the presence, but not in the absence, of acute viral infections. This sensitization is sufficient to cause acute anaphylactic collapse during subsequent cutaneous challenge with ovalbumin (23). These data suggest that viral inflammation allows inhaled antigen to penetrate the barrier of the respiratory mucosa, promoting systemic sensitization.

In conclusion, although there is no proof of a causal link between RSV bronchiolitis and the later development of asthma and atopy, there is strong evidence from animal studies that makes a causal link highly plausible.

Protective Effects of Childhood Infections

There has been considerable interest in the role of infection in immune maturation. In a completely clean environment, perhaps our immune system does not develop in an appropriate way and produces aberrant (allergic) responses.

The possibility that common childhood infections could play a protective role in the development of allergic disease was suggested by long-term British cohort studies, showing a consistent relationship between birth order and the risk of atopy; the presence of older siblings appearing to protect younger children (24, 25). More recently, a study from Guinea-Bissau showed that children with a clinical history of measles were less likely to develop atopy than measles-vaccinated children (26). The increase in atopic diseases in developed countries has thus been ascribed to the decreased cross-infection rates because of decreased family size (27), now often referred to as the hygiene hypothesis.

Martinez and colleagues examined the relationships between lower respiratory tract illness (LRIs) in the first 3 yr of life and atopy or serum IgE levels. Nonwheezing LRI was associated with lower IgE levels and less skin test reactivity than wheezing LRI and absent LRI. At the age of 9 mo, children with nonwheezing LRI have higher IFN- production from mononuclear cells than the other groups. Martinez and coworkers argue that the immune responses to respiratory viral infections that do not induce wheeze promote the development of Th1 cells while suppressing Th2 cells (28).

Surveys conducted soon after the reunification of East and West Germany showed a higher frequency of respiratory symptoms in the East German children (42 versus 27%) but a lower prevalence of asthma (3.8 versus 5.4%) (29). These findings have been used to support the argument that communal living, pollution, and respiratory infections protect against asthma and atopy. The apparent protective effects of tuberculin sensitization (30) and hepatitis virus infection (31) could also be explained in this way.

There are plausible immunological mechanisms for the protective effect of infections in the development of atopic disease. Atopy is related to the expression of allergen-specific responses with production of Th2 cytokines such as interleukin 4 (IL-4) and IL-5, which promote IgE production and eosinophilia (32). In nonatopic individuals, the T cell system is based on a Th1 phenotype with production of IFN- and inhibition of Th2 cells. Fetally derived allergen-reactive T cells exhibiting a Th2 phenotype exist, which indicates intrauterine T cell priming (33). The continuation of these fetal allergen-specific Th2 responses during infancy, which are associated with a decreased capacity to produce IFN-, has been demonstrated in atopic neonates (34).

Environmental factors such as microbial agents (viruses and other intracellular organisms, including mycobacteria) may then exert their effects during early life by assisting the maturation of adaptive immune responses, thereby promoting Th1 cell development. Activated macrophages and dendritic cells produce IL-12, which induces natural killer cells and Th1 cells to produce IFN-. IFN- provides the environment for the differentiation of antigen-specific CD4⁺ T cells into Th1 cells and CD8⁺ T cells into type 1 cytolytic T cells (Tc1 cells), resulting in even higher levels of IFN- production. In the absence of such stimuli, it seems that Th2-biased neonatal immune responses persist and that allergen-specific Th2 response become entrenched. Normal maturation may be slow and inefficient in children predisposed to atopy (34), while maturation is promoted by repeated exposure to ingested and inhaled bacteria and by some childhood viral infections. The interactive factors that may influence the development of asthma are summarized in Figure 2 (35).

View larger version (37K): [in this window] [in a new window]   Figure 2.   Interactions between protective and promoting influences on the development of asthma. [Reproduced by permission from Openshaw, P. J. M., and G. Walzl. J. R. Soc. Med. 1999;92:495-499 (35).]

	WHAT DO WE NEED TO KNOW?

TOP INTRODUCTION WHAT DO WE KNOW? WHAT DO WE NEED... HOW CAN WE ACHIEVE... REFERENCES

1. Although there is ample evidence that RSV bronchiolitis in animal models results from T cell-mediated immunopathology, solid evidence is difficult to obtain from human studies. In particular, the relative importance of T cells producing different patterns of cytokines (Th1 versus Th2), cytolytic T cells, and polymorphonuclear cells and the role of different chemokines in RSV disease awaits proper definition. This is important, because specific immune intervention (with antibodies that deplete specific subsets of T cells or block specific cytokines or chemokines that are pathogenic, yet do not contribute to protection) could help children with bronchiolitis. Moreover, such treatments might affect the establishment of persistent airway inflammation.

2. The discovery of sequence and structural homology between a conserved region of the attachment protein G and the tumor necrosis factor receptor (36) raises the intriguing possibility that this protein, displayed on cells or produced as a soluble decoy, could modify host immune responses to the advantage of the virus. The significance of this homology remains unknown.

3. We also need to know whether preventing RSV infection during a critical window of childhood development would prevent the establishment of airway inflammation in young children, and the subsequent development of asthma.

4. It is plausible that an antigenically richer (dirtier) environment during early childhood would reverse the increasing prevalence of asthma and atopy; specifically, we need to know if administering live viral vaccines, bacteria, or mycobacteria or their products in early childhood would prevent recurrent childhood wheeze, asthma, or atopy from developing.

5. We also need to know more about the possible role of medication given to children, including the effect of courses of antibiotics given for childhood ailments (37), and the effect of switching treatment of febrile illnesses in childhood from aspirin to paracetamol (38).

	HOW CAN WE ACHIEVE THIS?

TOP INTRODUCTION WHAT DO WE KNOW? WHAT DO WE NEED... HOW CAN WE ACHIEVE... REFERENCES

1. Prospective interventional studies with anti-RSV antibodies (39) should be performed to determine whether delaying first RSV infection reduces the risk of recurrent wheezing and asthma in later life (40). These studies should be undertaken in children at high risk of developing atopic disease. Late results from such studies are beginning to appear and should indicate whether RSV actively promotes the later development of recurrent wheeze, or whether bronchiolitis is just a marker of genetic susceptibility to recurrent airway inflammation (Figure 1).

2. We also need to know more about how infections in childhood could have delayed adverse effects. This could be explored in animal models, determining how infections modify the immune response to subsequently encountered antigens. Specifically, the role of dual infections needs to be explored. Because so many common infections occur in childhood, many infections occur just before, at the same time, or just after other infections either in the respiratory tract or elsewhere. To date there have been few studies on the role of natural killer cells and other components of the innate immune response in this regard, but this should be studied in both animal models and in humans. The number of possible variables makes these studies difficult to do, but they are essential.

3. We also need to know if there is a possibility of preventing atopy and asthma by administering mycobacteria, either in the form of BCG (30) or Myobacterium vaccae (41). Studies of this type are underway.

4. Finally, new methods are needed to measure the balance of microbial flora in the pharynx, the lung, and the bowel of individuals with asthma and atopy. Quantification of different bacterial species (including those that are difficult to grow in culture) might lead to the identification of bacteria that are lacking. If differences are found, deliberately altering microbial commensal populations could perhaps reverse the trend to increasing numbers of patients with asthma and atopy and might even be effective in those with established disease.

	Footnotes

Correspondence and requests for reprints should be addressed to Prof. Peter Openshaw, Respiratory Medicine, Imperial College, St. Mary's Hospital, London W2 1PG, UK. E-mail: p.openshaw{at}ic.ac.uk

	References

TOP INTRODUCTION WHAT DO WE KNOW? WHAT DO WE NEED... HOW CAN WE ACHIEVE... REFERENCES

1. Woolcock, A. J., and J. K. Peat. 1997. Evidence for the increase in asthma worldwide. Ciba Found. Symp. 206: 122-134 [Medline].

2. Hussell, T., and P. J. M. Openshaw. 1999. Recent developments in the biology of respiratory syncytial virusare vaccines and new treatments just round the corner? Curr. Opin. Microbiol. 2: 410-414 . [Medline]

3. Openshaw, P. J. M.. 1995. Immunopathological mechanisms in respiratory syncytial virus disease. Semin. Immunopathol. 17: 187-201 [Medline].

4. Johnston, S. L., P. K. Pattemore, G. Sanderson, S. Smith, F. Lampe, L. Josephs, P. Symington, S. O'Toole, S. H. Myint, D. A. Tyrrell, and S. T. Holgate. 1995. Community study of role of viral infections in exacerbations of asthma in 9-11 year old children. Br. Med. J. 310: 1225-1229 [Abstract/Free Full Text].

5. Nicholson, K. G., J. Kent, and D. C. Ireland. 1993. Respiratory viruses and exacerbations of asthma in adults. Br. Med. J. 307: 982-986 .

6. Calhoun, W. J., C. A. Swenson, E. C. Dick, L. B. Schwartz, R. F. Lemanske Jr., and W. W. Busse. 1991. Experimental rhinovirus 16 infection potentiates histamine release after antigen bronchoprovocation in allergic subjects. Am. Rev. Respir. Dis. 144: 1267-1273 [Medline].

7. Teran, L. M., S. L. Johnston, J. M. Schroeder, M. K. Church, and S. T. Holgate. 1997. Role of nasal interleukin-8 in neutrophil recruitment and activation in children with virus-induced asthma. Am. J. Respir. Crit. Care Med. 155: 1362-1366 [Abstract].

8. Fraenkel, D. J., P. G. Bardin, G. Sanderson, F. Lampe, S. L. Johnston, and S. T. Holgate. 1995. Lower airways inflammation during rhinovirus colds in normal and in asthmatic subjects. Am. J. Respir. Crit. Care Med. 151: 879-886 [Abstract].

9. Bardin, P. G., S. L. Johnston, and P. K. Pattemore. 1992. Viruses as precipitants of asthma symptoms: II. Physiology and mechanisms. Clin. Exp. Allergy 22: 809-822 [Medline].

10. Connochie, K. M., and K. J. Roghmann. 1989. Wheezing at 8 and 13 years: changing importance of bronchiolitis and passive smoking. Pediatr. Pulmonol. 6: 138-146 [Medline].

11. Pullan, C. R., and E. N. Hey. 1982. Wheezing, asthma, and pulmonary dysfunction 10 years after infection with respiratory syncytial virus in infancy. Br. Med. J. 284: 1665-1669 .

12. Sly, P. D., and M. E. Hibbert. 1989. Childhood asthma following hospitalization with acute viral bronchiolitis in infancy. Peditar. Pulmonol. 7: 153-158 [Medline].

13. Murray, M., M. S. Webb, C. O'Callaghan, A. S. Swarbrick, and A. D. Milner. 1992. Respiratory status and allergy after bronchiolitis. Arch. Dis. Child. 67: 482-487 [Abstract/Free Full Text].

14. Sigurs, N., R. Bjarnason, F. Sigurbergsson, B. Kjellman, and B. Björkstén. 1995. Asthma and immunoglobulin E antibodies after respiratory syncytial virus bronchiolitis: a prospective cohort study with matched controls. Pediatrics 95: 500-505 [Abstract/Free Full Text].

15. Stein, R. T., D. Sherrill, W. J. Morgan, C. J. Holberg, M. Halonen, L. M. Taussig, A. L. Wright, and F. D. Martinez. 1999. Respiratory syncytial virus in early life and risk of wheeze and allergy by age 13 years. Lancet 354: 541-545 [Medline].

16. Robinson, P. J., R. G. Hegele, and R. R. Schellenberg. 1997. Allergic sensitization increases airway reactivity in guinea pigs with respiratory syncytial virus bronchiolitis. J. Allergy Clin. Immunol. 100: 492-498 [Medline].

17. Kumar, A., R. L. Sorkness, M. R. Kaplan, and R. F. Lemanske Jr.. 1997. Chronic, episodic, reversible airway obstruction after viral bronchiolitis in rats. Am. J. Respir. Crit. Care Med. 155: 130-134 [Abstract].

18. Dakhama, A., T. Z. Vitalis, and R. G. Hegele. 1997. Persistence of respiratory syncytial virus (RSV) infection and development of RSV-specific IgG1 response in a guinea-pig model of acute bronchiolitis. Eur. Respir. J. 10: 20-26 [Abstract].

19. Openshaw, P. J. M.. 1991. When we sneeze, does the immune system catch a cold? Br. Med. J. 303: 935-936 .

20. Hussell, T., A. Georgiou, T. E. Sparer, S. Matthews, P. Pala, and P. J. M. Openshaw. 1998. Host genetic determinants of vaccine-induced eosinophilia during respiratory syncytial virus infection. J. Immunol. 161: 6215-6222 [Abstract/Free Full Text].

21. Sakamoto, M., S. Ida, and T. Takishima. 1984. Effect of influenza virus infection on allergic sensitization to aerosolized ovalbumin in mice. J. Immunol. 132: 2614-2617 [Abstract].

22. Suzuki, S., Y. Suzuki, N. Yamamoto, Y. Matsumoto, A. Shirai, and T. Okubo. 1998. Influenza A virus infection increases IgE production and airway responsiveness in aerosolized antigen-exposed mice. J. Allergy Clin. Immunol. 102: 732-740 [Medline].

23. O'Donnell, D. R., and P. J. M. Openshaw. 1998. Anaphylactic sensitisation to aeroantigen during respiratory virus infection. Clin. Exp. Allergy 28: 1501-1508 [Medline].

24. Butland, B. K., D. P. Strachan, S. Lewis, J. Bynner, N. Butler, and J. Britton. 1997. Investigation into the increase in hay fever and eczema at age 16 observed between the 1958 and 1970 British birth cohorts. Br. Med. J. 315: 717-721 [Abstract/Free Full Text].

25. Strachan, D. P., J. M. Griffiths, and H. R. Anderson. 1994. Allergic sensitization and position in the sibship: a national study of young British adults. Thorax 49: 1053 .

26. Shaheen, S. O., P. Aaby, A. J. Hall, D. J. Barker, C. B. Heyes, A. W. Shiell, and A. Goudiaby. 1996. Measles and atopy in Guinea-Bissau. Lancet 347: 1792-1796 [Medline].

27. Strachan, D. P.. 1994. Is allergic disease programmed in early life? Clin. Exp. Allergy 24: 603-605 [Medline].

28. Martinez, F. D., D. A. Stern, A. L. Wright, L. M. Taussig, and M. Halonen. 1995. Association of non-wheezing lower respiratory tract illnesses in early life with persistently diminished serum IgE levels. Group Health Medical Associates. Thorax 50: 1067-1072 [Abstract/Free Full Text].

29. Von Mutius, E., F. D. Martinez, C. Fritzsch, T. Nicolai, G. Roell, and H. H. Thiemann. 1994. Prevalence of asthma and atopy in two areas of West and East Germany. Am. J. Respir. Crit. Care Med. 149: 358-364 [Abstract].

30. Shirakawa, T., T. Enomoto, S. Shimazu, and J. M. Hopkin. 1997. The inverse association between tuberculin responses and atopic disorder. Science 275: 77-79 [Abstract/Free Full Text].

31. Matricardi, P. M., F. Rosmini, L. Ferrigno, R. Nisini, M. Rapicetta, P. Chionne, T. Stroffolini, P. Pasquini, and R. D'Amelio. 1997. Cross sectional retrospective study of prevalence of atopy among Italian military students with antibodies against hepatitis A virus. Br. Med. J. 314: 999-1003 [Abstract/Free Full Text].

32. Romagnani, S.. 1992. Induction of TH1 and TH2 responses: a key role for the "natural" immune response? Immunol. Today 13: 379-381 [Medline].

33. Prescott, S. L., C. Macaubas, B. J. Holt, T. B. Smallacombe, R. Loh, P. D. Sly, and P. G. Holt. 1998. Transplacental priming of the human immune system to environmental allergens: universal skewing if initial T cell responses toward the Th2 cytokine profile. J. Immunol. 160: 4730-4737 [Abstract/Free Full Text].

34. Prescott, S. L., C. Macaubas, T. Smallacombe, B. J. Holt, P. D. Sly, and P. G. Holt. 1999. Development of allergen-specific T-cell memory in atopic and normal children. Lancet 353: 196-200 [Medline].

35. Openshaw, P. J. M., and G. Walzl. 1999. Infections prevent the development of asthmatrue, false, or both? J. R. Soc. Med. 92: 495-499 [Medline].

36. Langedijk, J. P., B. L. de Groot, H. J. Berendsen, and J. T. van Oirschot. 1998. Structural homology of the central conserved region of the attachment protein G of respiratory syncytial virus with the fourth subdomain of 55-kDa tumor necrosis factor receptor. Virology 243: 293-302 [Medline].

37. Mattes, J., and W. Karmaus. 1999. The use of antibiotics in the first year of life and the development of asthma: which comes first? Clin. Exp. Allergy 29: 729-732 [Medline].

38. Varner, A. E., W. W. Busse, and R. F. Lemanske Jr.. 1998. Hypothesis: decreased use of pediatric aspirin has contributed to the increasing prevalence of childhood asthma. Ann. Allergy Asthma Immunol. 81: 347-351 [Medline].

39. Simoes, E. A., H. M. Sondheimer, F. H. Top Jr., H. C. Meissner, R. C. Welliver, A. A. Kramer, and J. R. Groothuis. 1998. Respiratory syncytial virus immune globulin for prophylaxis against respiratory syncytial virus disease in infants and children with congenital heart disease. J. Pediatr. 133: 492-499 [Medline].

40. The IMpact-RSV Study Group. 1998. Palivizumab, a humanized respiratory syncytial virus monoclonal antibody, reduces hospitalization from respiratory syncytial virus infection in high-risk infants. Pediatrics 102: 531-537 [Abstract/Free Full Text].

41. Wang, C. C., and G. A. Rook. 1998. Inhibition of an established allergic response to ovalbumin in BALB/c mice by killed Mycobacterium vaccae. Immunology 93: 307-313 [Medline].