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Exacerbations

The Asthma Paradox

University of Southampton, Southampton General Hospital, Southampton, United Kingdom

Considering the enormous amount of knowledge that has been gained in our understanding of the inflammatory mechanisms of asthma, it is disappointing that we still know very little about asthma exacerbations. This is all the more surprising when it is realized that exacerbations are manifestations of asthma that cause the greatest concern to patients, account for the largest proportion of the health costs of this disease, and can be life threatening. The majority of asthma research into mechanisms has focused on the allergic pathways, and this is also reflected in the way that the pharmaceutical industry has sought new treatments, relying largely on antigen sensitization and animal challenge models to screen new drugs. Maybe this concentration on the importance of the allergic pathways helps explain why there have been no highly innovative treatments found for asthma other than improvements made to known drug classes or those predicted from knowledge on disease mechanisms obtained over 25 years ago.

Although allergen exposure can trigger asthma exacerbations, this is not the commonest cause. Both in adults and in children, the majority of asthma exacerbations are caused by respiratory virus infections of which rhinoviruses (RVs) are by far the most frequent (1). For example, a recent Australian study has reported that 78% of acute asthma exacerbations were virus-associated, and of these, 83% were RVs (2). The marked increase in asthma exacerbations in both children and adults that occurs in the fall, winter, and early spring months is predominantly virus-related, with RVs dominating (3, 4). Beyond causing the common cold, RVs predominately infect the conducting airways, although occasionally they are responsible for pneumonia, especially in immunocompromised children (5). Virus-induced exacerbations of asthma represent a major unmet clinical need in this disease.

RVs gain access to the airway via the epithelium where they bind and are internalized by intercellular adhesion molecule-1 (ICAM-1) in the case of the major RV subclass and low-density lipoprotein receptors for the minor RV subclass. Once inside the epithelial cell, the virus triggers a set of molecular pathways leading to the activation of the transcription factor nuclear factor-B and the secretion of a range of cytokines and chemokines that include interleukin 17F (IL-17F), granulocyte-macrophage colony–stimulating factor, IL-8, and Gro, which recruit neutrophils as well as CD4⁺ and CD8⁺ lymphocytes into the airways. This inflammatory signature is different from that seen with allergen exposure and helps to explain why virus-induced exacerbations in most parts are refractory to inhaled or oral corticosteroids, both in adults (6, 7) and in children (8, 9). In this issue of the Journal (pp. 1037–1040), Xatzipsalti and colleagues have investigated whether RV infection is accompanied by viraemia in groups of 1- to 14-year-old children experiencing an exacerbation of asthma, bronchiolitis, the common cold, or pneumonia (10). Although they were unable to grow live virus from the blood of none of the children, in a significant proportion of cases they were able to detect RV by polymerase chain reaction. Successful detection was dependent on obtaining the blood sample within 24 hours of the start of symptoms and was five times greater if the child was experiencing an exacerbation of asthma. A history of asthma also markedly increased the risk of rhinoviraemia (odds ratio, 5.8; p = 0.012). Neither age nor corticosteroid use proved to be a risk factor for rhinoviraemia.

The authors offer two explanations for their findings. They suggest that viraemia may be a route through which RV spreads from the nasal mucosa to the lower respiratory tract. However, as with other viruses that restrict themselves to the respiratory tract and where the principal site of viral entry is the epithelium, this seems somewhat unlikely, especially since the 2- to 3-day interval between upper and lower airway symptoms would accommodate direct viral transmission from the upper to the lower airways (1). An alternative is that virus gains access to the blood due to a defect in innate and/or adaptive immune responses designed to limit viral spread. Their finding that rhinoviremia was more frequent in severe rather than mild asthma exacerbations (86 vs. 33%) supports this view. When compared with normal control subjects, we have recently shown that asthmatic epithelial cells in culture have an impaired ability to clear RV after infection and that this is accompanied by reduced apoptosis (11). Rather, the infected asthmatic epithelial cells hold onto the RV longer, allowing greater replication and eventually resulting in cytotoxic cell death with release of inflammatory mediators along with large numbers of intact viruses that will infect neighboring cells. If apoptosis is inhibited in RV-infected normal epithelial cells, then the asthma phenotype appears with increased cell cytotoxicity and greatly increased virus shedding. The cause of this abnormal epithelial response to RV infection in asthma has been shown to be a major defect in the virus-induced generation of the cytokine IFN-, with exogenous IFN- able to restore the virus protection observed in epithelial cells from normal airways. This asthma-related defect in epithelial innate immunity would be expected to facilitate virus penetration into the airway tissue and subsequently into the circulation.

In adults with asthma, there is also some evidence for an impaired adaptive immune response on RV infection with reduced IFN- production by circulating mononuclear cells both in vivo (12) and when infected in vitro (13). Recently, Copenhaver and colleagues have reported that, in infants, impaired cord blood IFN- responsiveness of mononuclear cells, when stimulated with the nonspecific mitogen phytohemagglutinin (PHA), is also a risk factor for RV-induced wheezing (14).

A crucial question that remains to be answered is the role of RV, and indeed other respiratory viruses, in the origins and persistence of asthma. Although at one time considered to be protective against asthma and atopy in susceptible children, there is mounting evidence that respiratory virus infection early in life may trigger the onset of asthma. In children aged 4 to 12 years with an acute asthma exacerbation, RV was detected in nasal aspirates in 82% of cases and in over half these, RV nucleic acid was still detectable after 6 weeks. Even at 6 months after infection, 25% of the children still had RV present in their nasal secretions, with persistence correlating with initial asthma severity (15). Thus, although RV and other respiratory viruses are major causes of acute asthma exacerbations, their role in the persistence of asthma remains unknown but could be important.

It is clear from the impact that respiratory viruses, and especially RV, have on the lives of patients with asthma patients that new treatments are needed beyond corticosteroids, which have limited efficacy in this situation. Although soluble ICAM-1 has been shown to be particularly active, IFN- or an agent that induces this in the airways is likely to be more effective because not only will it replace a cytokine crucial to antivirus defense across a range of viruses but it will also trigger secondary immune responses, including the production of IFN- (16). A possible precedent for this approach was demonstrated by Simon and colleagues who, in an open study, have shown that 1 to 2 years of regular treatment with low-dose intravenous IFN- in 10 patients with corticosteroid-refractory severe asthma not only resulted in an impressive increase in FEV₁, increasing from 50 to 90% predicted, but also enabled a halving of the mean daily oral prednisolone dose, accompanied by an increase in IFN- and IL-10 production by stimulated circulating mononuclear cells ex vivo (17).

FOOTNOTES

Conflict of Interest Statement: S.T.H. is the cofounder and consultant for Synairgen. Synairgen has an interest in the use of interferons in the treatment of lung disease. The University of Southampton is part owner of the spin-out company Synairgen.

REFERENCES

1. Johnston SL, Pattemore PK, Sanderson G, Smith S, Lampe F, Josephs L, Symington P, O'Toole S, Myint SH, Tyrrell DAJ, et al. Community study of role of viral infections in exacerbations of asthma in 9–11 year old children. Br Med J 1995;310:1225–1228.[Abstract/Free Full Text]
2. Grissell TV, Powell H, Shafren DR, Boyle MJ, Hensley MJ, Jones PD, Whitehead BF, Gibson PG. Interleukin-10 gene expression in acute virus-induced asthma. Am J Respir Crit Care Med 2005;172:433–439.[Abstract/Free Full Text]
3. Johnston SL, Pattemore PK, Sanderson G, Smith S, Campbell MJ, Josephs LK, Cunningham A, Robinson BS, Myint SH, Ward ME, et al. The relationship between upper respiratory infections and hospital admissions for asthma: a time trend analysis. Am J Respir Crit Care Med 1996;154:654–660.[Abstract]
4. Johnston NW, Johnston SL, Duncan JM, Greene JM, Kebadze T, Keith PK, Roy M, Waserman S, Sears MR. The September epidemic of asthma exacerbation in children: a search for etiology. J Allergy Clin 2005;115:230–232.
5. Papadopoulos NG. Do rhinoviruses cause pneumonia in children? Paediatric Respir Rev 2004;5(Suppl A):S191–S195.[CrossRef]
6. Tattersfield AE, Postma DS, Barnes PJ, Svensson K, Bauer CA, O'Byrne PM, Lofdahl CG, Pauwels RA, Ullman A. Exacerbations of asthma: a descriptive study of 425 severe exacerbations. The FACET International Study Group. Am J Respir Crit Care Med 1999;160:594–599.[Abstract/Free Full Text]
7. Harrison TW, Oborne J, Newton S, Tattersfield AE. Doubling the dose of inhaled corticosteroid to prevent asthma exacerbations: randomised controlled trial. Lancet 2004;363:271–275.[CrossRef][Medline]
8. Doull IJ, Lampe FC, Smith S, Schreiber J, Freezer NJ, Holgate ST. Effect of inhaled corticosteroids on episodes of wheezing associated with viral infection in school age children: randomised double blind placebo controlled trial. BMJ 1997;31:858–862.
9. Wilson NM, Silverman M. Treatment of acute, episodic asthma in preschool children using intermittent high dose inhaled steroids at home. Arch Dis Child 1990;65:407–410.[Abstract/Free Full Text]
10. Xatzipsalti M, Kyrana S, Tsolia M, Psarras S, Bossios A, Laza-Stanca V, Johnston S, Papadopoulos NG. Rhinovirus viremia in children with respiratory infections. Am J Respir Crit Care Med 2005;172:1037–1040.[Abstract/Free Full Text]
11. Wark PA, Johnston SK, Bucchieri F, Powell R, Puddicombe S, Laza Stance V, Holgate ST, Davies DE. Asthmatic bronchial epithelial cells have a deficient innate immune response to infection with rhinovirus. J Exp Med 2005;201:937–947.[Abstract/Free Full Text]
12. Papadopoulos NG, Stancia LA, Papi A, Holgate ST, Johnson SL. A defective type 1 response to rhinovirus in atopic asthma. Thorax 2002;57:328–332.[Abstract/Free Full Text]
13. Brooks GD, Buckta KA, Swenson CA, Gern JE, Busse WW. Rhinovirus induced interferon- and airway responsiveness in asthma. Am J Respir Crit Care Med 2003;168:1091–1094.[Abstract/Free Full Text]
14. Copenhaver CC, Gern JE, Li Z, Shult PA, Rosenthal LA, Mikus LD, Kirk CJ, Roberg KA, Anderson EL, Tisler CJ, et al. Cytokine response patterns, exposure to viruses and respiratory infections in the first year of life. Am J Respir Crit Care Med 2004;170:175–180.[Abstract/Free Full Text]
15. Kling S, Donninger H, Williams Z, Vermeulen J, Weinberg E, Latiff K, Ghildyal R, Bardin P. Persistence of rhinovirus RNA after asthma exacerbation in children. Clin Exp Allergy 2005;35:672–678.[CrossRef][Medline]
16. Doyle S. Vaidya S, O'Connell R, Dadgostar H, Dempsey P, Wu T, Rao G, Sun R, Haberland M, Modlin R, Cheng G. IRF3 mediates a TLR3/TLR4-specific antiviral gene program. Immunity 2002;17:251–263.[CrossRef][Medline]
17. Simon HU, Seelbach H, Ehmann R, Schmitz M. Clinical and immunological effects of low-dose IFN-alpha treatment in patients with corticosteroid resistant asthma. Allergy 2003;58:1250–1255.[CrossRef][Medline]

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