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Is Asthma an Infectious Disease?*: Thomas A. Neff Lecture FREE TO VIEW

Robert F. Lemanske, Jr., MD
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*From the Departments of Pediatrics and Medicine, Division of Pediatric Allergy, Immunology, and Rheumatology, University of Wisconsin Medical School, Madison, WI.

Correspondence to: Robert F. Lemanske, Jr, MD, Department of Pediatrics, University of Wisconsin Hospital, 600 Highland Ave, K4/916, Madison, WI 53792



Chest. 2003;123(3_suppl):385S-390S. doi:10.1378/chest.123.3_suppl.385S-a
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Respiratory tract infections caused by viruses, Chlamydia, and Mycoplasma have been implicated in the pathogenesis of asthma. Of these respiratory pathogens, viruses have been demonstrated to be associated with asthma epidemiologically in at least two ways. First, during infancy, certain viruses have been implicated as potentially being responsible for the inception of the asthmatic phenotype. Second, in patients with established asthma, particularly children, viral upper respiratory tract infections play a significant role in producing acute exacerbations of airway obstruction that may result in frequent outpatient visits or in hospitalizations. For infections with other microbial agents, recent attention has focused on Chlamydia and Mycoplasma as potential contributors to both exacerbations and the severity of chronic asthma in terms of loss of lung function or medication requirements. In an attempt to address the question posed in the title, this article will briefly review these various associations as they pertain to the pathogenesis of asthma in both children and adults.

Acute viral infections have been demonstrated to be temporally associated with a number of important clinical consequences1including the following: the development of wheezing-associated illnesses in infants and small children28; the initiation of acute exacerbations of asthma both in children and adults2,6,910; and the induction of short-term and long-term alterations in airway physiology, including increasing airway responsiveness11and creating abnormalities in airflow,12lung volumes1314 and gas exchange.15Moreover, certain viral infections, especially respiratory syncytial virus (RSV) infections, may also contribute to the inception of childhood asthma in the first decade of life.16

RSV Infections

In infants, infection with RSV has received much attention because of its predilection to produce a pattern of symptoms termed bronchiolitis, which parallels many of the features of childhood and adult asthma.17From 1980 to 1996, rates of hospitalization of infants with bronchiolitis increased substantially, as did the proportion of hospitalizations for total and lower respiratory tract (LRT) infections that were associated with bronchiolitis.18RSV causes about 70% of these episodes. However, RSV bronchiolitis represents only the most severe fraction of cases in that by age 1 year, 50 to 65% of children will have been infected with this virus, and by age 2 years nearly 100% will have been infected.19 Children aged 3 to 6 months are most prone to developing LRT symptoms, suggesting that a developmental component (eg, lung and/or immunologic maturation) may be involved as well.,19Although controversy exists regarding the relevance of antecedent RSV infections and the development of recurrent wheezing,20two long-term prospective studies2122 of large numbers of children have demonstrated that RSV infections are a significant independent risk factor for subsequent frequent wheezing at least within the first decade of life. It remains to be established, however, how RSV infections produce these outcomes due to the fact that virtually all children have been infected with this virus before their second birthday. Some of the factors that have been evaluated include the immune response (both innate and adaptive)2324 to the virus and host-related differences (ie, gender, lung size, and passive smoke exposure25) that may predispose an infant or child to lower airway physiologic alterations as a consequence of the infection. Finally, the severity of the lower airway injury (ie, the development of bronchiolitis) also may influence the emergence of both asthma and allergic sensitization.,22

Viral Infections Other Than RSV

From a number of epidemiologic observations, it appears that other viral infections during infancy and early childhood that have a predisposition for lower airway involvement (eg, parainfluenza and influenza A) also can be associated with chronic LRT symptoms including asthma.17,2628 As previously stated, premorbid measurements of lung function indicate that children with reduced levels of lung function in infancy appear to be at increased risk for the development of chronic LRT sequelae following viral infections.17 Whether this defect is alone responsible for these developments is presently unknown. Furthermore, the likelihood and ability of one virus (ie, RSV) to be responsible for these outcomes (due to either virus-specific factors or host-specific factors) also has not been well defined.,24 Indeed, recent data29 would indicate that rhinovirus (RV)-induced bronchiolitis, although less frequent than that induced by RSV, may cause more severe patterns of disease during infancy.

Epidemiologic studies6 have detected viral upper respiratory tract infections in 85% of childhood asthma exacerbations and in over half of adult exacerbations. These upper respiratory tract infections are probably responsible for seasonal peaks of asthma-related hospital admissions.3031 RV is the most common culprit in adults and older children, while RSV is most commonly involved in children under age 2 years of age.6,3233 Thus, both RV and RSV infections have been linked with both asthma inception and asthma exacerbations.

Despite the significant epidemiologic associations of naturally acquired RV infections with asthma exacerbations, it is noteworthy that experimentally induced RV infections generally provoke only small increases in measurements of airflow obstruction.12 Furthermore, although RV inoculation clearly can increase airway responsiveness and shift the pattern of lower airway response to allergen in allergic rhinitis patients,34allergen priming of the upper airway does not appear to augment inflammatory or physiologic responses in either the upper or lower airway following experimental viral infection.35Nonetheless, upper airway cytokine profiles following natural viral infections may differ chronically in patients with histories of allergic airway disease.36

The ability of RV to produce common cold-like symptoms in healthy individuals while producing significant alterations in lower airway physiology in asthmatic patients would indicate that either the immunoinflammatory response to the virus is different in patients with asthma, the consequences of this response in the lower airway is altered, or both. Although RV infections are considered to affect primarily the upper airway, evidence3738 indicates that this microbe is capable of infecting the lower airway as well. Due to a tendency for increased expression of intercellular adhesion molecule-1 on airway epithelial cells (the cell surface receptors for the major group of RVs) in patients with asthma, it is possible that this would be one mechanism responsible for increased viral entry and replication in these individuals. Once the immune response to the virus was initiated by the host, a variety of cytokine and cellular pathways would be activated.39Recent reports have indicated that the qualitative nature of this immunoinflammatory response may be different in the asthmatic patient as well. These differences may include a reduced production of interleukin-12 and interferon-γ,4041 and a diminished production of antigen-presenting cell surface markers following viral exposure.42Taken together, these differences may explain, at least in part, why RV infections are associated more frequently with LRT involvement in asthmatic patients, and why LRT symptoms in these individuals are more severe and longer lasting.43

Allergy and Viral Infections as Cofactors

In addition to premorbid lung function, the influence of atopy on the development of the asthmatic phenotype in relationship to viral infections also has been evaluated. Interactions between these two factors appear to be bidirectional and dynamic in that the atopic state can influence the lower airway response to viral infections,25,44viral infections can influence the development of allergen sensitization,4547 and interactions can occur when individuals are exposed simultaneously to both allergens and viruses.34,4849 Indeed, experimentally induced RV infections in patients with allergic rhinitis can alter the pattern of their lower airway response to allergen challenge by significantly enhancing their propensity to develop late asthmatic responses.34 As noted in a number of animal models, the sequence and timing (developmental aspect) of both the allergic sensitization and virus inoculation may significantly influence whether or not enhanced airway inflammation and responsiveness occur following allergen exposure.5054

Asthma Chronicity

In contrast to viral illnesses, the imprecision of current diagnostic laboratory tests in temporally correlating other microbial infections with the onset of acute asthma symptom exacerbations has made verification of any etiologic relationship challenging. However, since bacterial infections are known to impair mucociliary clearance and to increase mucus production in the lung,55it has been proposed that certain bacterial infections may cause chronic lower airway inflammation. Organisms primarily implicated in this process include Chlamydia pneumoniae56 and Mycoplasma pneumoniae.,55,57 If these agents contribute to asthma pathogenesis, the evidence thus far most closely links them with disease chronicity, severity, and/or instability.

The data to support a potential role for these agents in asthma is most convincing for C pneumoniae. The major impedance in studying the contribution of this organism to asthma pathogenesis has been the lack of a sensitive, specific, reliable, and convenient diagnostic laboratory test.58 Based on this lack of precision, it is not surprising that serologic testing for C pneumoniae antigens using a variety of techniques in adult patients have produced conflicting results regarding the role of this organism in asthma.,56,5963

Unfortunately, the use of more sophisticated techniques may not provide any more sensitivity or specificity. A recent report57 evaluated a group of adult patients with chronic asthmatic by serology, multiple airway cultures, and by polymerase chain reaction (PCR) technology specific for C pneumoniae. Of the 55 asthmatic patients evaluated, 7 had positive PCR identification and 18 had positive serologic results (3 of the 7 patients who were PCR-positive for C pneumoniae). None were culture-positive for C pneumoniae.,57 These results further illustrate the difficulties that various investigators have confronted in establishing cause-and-effect relationships between C pneumoniae and both acute and chronic asthmatic symptoms.

Despite these shortcomings, a number of observations are noteworthy. Historically, the first potential association between asthma and C pneumoniae was reported in 199164in a study in which 9 of 19 wheezing adult asthmatic patients were found to have serologic evidence of current or recent infection with C pneumoniae. These initial findings were later extended by the demonstration that adults with recently diagnosed asthma had serologic evidence of chronic respiratory tract infection with C pneumoniae65 It was additionally found that acute wheezing illnesses due to C pneumoniae infection could herald the development of chronic asthma in previously asymptomatic individuals.66

In school-age children with wheezing, an unexpectedly high prevalence of low-grade C pneumoniae infection also has been reported.67 In this study, 108 children (age range, 9 to 11 years) with asthma symptoms longitudinally maintained (for 13 months) a daily diary of respiratory symptoms and peak flow rates. Nasal aspirates were obtained when respiratory symptoms were reported. The presence of infection was investigated by PCR for C pneumoniae, and C pneumoniae secretory IgA was detected by amplified enzyme immunoassay. C pneumoniae detections were similar between the symptomatic and asymptomatic episodes (23% vs 28%, respectively). Children who reported multiple episodes also tended to remain PCR-positive for C pneumoniae, suggesting the presence of chronic infection. Furthermore, the number of C pneumoniae-specific secretory IgA antibodies were more than seven times greater in subjects who reported four or more exacerbations in the study compared to those who reported just one. Although no evidence linking acute infection with C pneumoniae and acute exacerbations of asthma could be demonstrated, the evidence for chronic infection with C pneumoniae was more common in children with higher rates of exacerbations. It is interesting to speculate that chronic C pneumoniae infection promotes ongoing airway inflammation that increases susceptibility to other exacerbating stimuli such as viruses, allergens, or both.

Thus far, the most comprehensive evaluation of the role of both C pneumoniae and M pneumoniae infections in patients with chronic asthma was recently reported by Martin et al.57 This group of investigators evaluated 55 adult patients with chronic asthma (mean [± SD] FEV1, 69.3 ± 2.1% of predicted) and 11 control subjects by using PCR, culture, and serology to detect M pneumoniae species, C pneumoniae species, and viruses from the nasopharynx, lung, and blood. BAL fluid cell count and differential count, as well as tissue morphometry, also were evaluated. Fifty-six percent of the asthmatic patients had a positive PCR finding for M pneumoniae (n = 25) or C pneumoniae (n = 7), which were mainly found in BAL fluid or biopsy samples. Only 1 of 11 control subjects had a positive PCR finding for M pneumoniae. A distinguishing feature between patients with positive and negative PCR results was the significantly greater number of tissue mast cells in the group of patients who were PCR-positive. Cultures for both organisms were negative in all patients. Although these intriguing findings suggested that these organisms may play a role in the pathophysiology of asthma in some patients, the specificity of these findings to asthma and to the phenotypic and genotypic characteristics of the at-risk patient need further delineation.

To further substantiate the contribution of C pneumoniae to asthma, appropriate pharmacologic intervention trials would be of great interest. Recently, roxithromycin was administered for 6 weeks to a group of adult asthmatic patients who had serologic evidence of concurrent infection with C pneumoniae.68Following treatment, a small but significant improvement in both morning and evening peak expiratory flow rates was observed. Although these short-term effects were statistically significant, the clinical relevance of the changes was questionable (treated group, 15 L/min; control group, 3 L/min). In addition, these improvements were not sustained when evaluated 3 and 6 months following the discontinuation of therapy. Finally, since a C pneumoniae-negative population of asthmatic patients was not evaluated also in parallel, it is difficult to ascertain whether the observed positive effects were related to an antimicrobial effect, an antiinflammatory effect, or both.69

M pneumoniae also has been associated with chronic asthma. This organism is a common cause of upper respiratory tract and LRT disease in humans, and infection with it has been documented in ≤ 25% of children with wheezing.5 Whether M pneumoniae infection or airway localization in asthmatic patients is due to the presence of underlying airway inflammation in asthma per se, or whether the organism plays a more direct role in the pathogenesis of asthma in some patients, either acutely or chronically, is still unresolved.

Since it is doubtful that asthma is a single disease entity, it is not possible to state that infections per se are the cause of asthma. However, as reviewed, infections of the respiratory tract may influence asthma pathogenesis in a number of ways, including disease inception, exacerbation, and disease severity over time. As better diagnostic tests become available with which to establish direct cause-and-effect relationships between respiratory tract pathogens and the various clinical features of asthma, it is conceivable that new therapeutic approaches will become available that not only target disease modification but disease prevention as well.

Abbreviations: LRT = lower respiratory tract; PCR = polymerase chain reaction; RSV = respiratory syncytial virus; RV = rhinovirus

This research was supported by National Institutes of Health grants 1PO1AI50500, 2P50HL56396, and 1RO1HL61879.

Cypcar, D, Stark, J, Lemanske, RF, Jr. (1992) The impact of respiratory infections on asthma.Pediatr Clin North Am39,1259-1276
 
Johnston, SL, Pattemore, PK, Sanderson, G, et al Role of virus infections in children with recurrent wheeze or cough.Thorax1993;48,1055-1060
 
Minor, TE, Baker, JW, Dick, EC, et al Greater frequency of viral respiratory infections in asthmatic children as compared with their nonasthmatic siblings.J Pediatr1974;85,472-477
 
Minor, TE, Dick, EC, DeMeo, AN, et al Viruses as precipitants of asthmatic attacks in children.JAMA1974;227,292-298
 
Henderson, FW, Clyde, WA, Collier, AM, et al The etiologic and epidemiologic spectrum of bronchiolitis in pediatric practice.J Pediatr1979;95,183-190
 
Johnston, SL, Pattemore, PK, Sanderson, G, et al Community study of role of viral infections in exacerbations of asthma in 9–11 year old children.BMJ1995;310,1225-1228
 
Carlsen, KH, Orstavik, I, Leegaard, J, et al Respiratory virus infections and aeroallergens in acute bronchial asthma.Arch Dis Child1984;59,310-315
 
Mertsola, J, Ziegler, T, Ruuskanen, O, et al Recurrent wheezy bronchitis and viral respiratory infections.Arch Dis Child1991;66,124-129
 
Nicholson, KG, Kent, J, Hammersley, V, et al Risk factors for lower respiratory complications of rhinovirus infections in elderly people living in the community: prospective cohort study.BMJ1996;313,1119-1123
 
Rylander, E, Eriksson, M, Pershagen, G, et al Wheezing bronchitis in children: incidence, viral infections, and other risk factors in a defined population.Pediatr Allergy Immunol1996;7,6-11
 
Empey, DW, Laitinen, LA, Jacobs, L, et al Mechanisms of bronchial hyperreactivity in normal subjects after upper respiratory tract infection.Am Rev Respir Dis1976;113,131-139
 
Grünberg, K, Timmers, MC, de Klerk, EPA, et al Experimental rhinovirus 16 infection causes variable airway obstruction in subjects with atopic asthma.Am J Respir Crit Care Med1999;160,1375-1380
 
Wohl, MEB, Stigol, L, Mead, J Resistance of the total respiratory system in healthy infants with bronchiolitis.Pediatrics1969;43,495-509
 
Stokes, GM, Milner, AD, Hodges, IGC, et al Lung function abnormalities after acute bronchiolitis.J Pediatr1981;98,871-874
 
Hall, CB, Hall, WJ, Gala, CL, et al Long-term prospective study of children after respiratory syncytial virus infection.J Pediatr1984;105,358-364
 
Castro-Rodríguez, JA, Holberg, CJ, Wright, AL, et al Association of radiologically ascertained pneumonia before age 3 yr with asthmalike symptoms and pulmonary function during childhood: a prospective study.Am J Respir Crit Care Med1999;159,1891-1897
 
Landau, LI Bronchiolitis and asthma: are they related?Thorax1994;49,293-296
 
Shay, DK, Holman, RC, Newman, RD, et al Bronchiolitis-associated hospitalizations among US children, 1980–1996.JAMA1999;282,1440-1446
 
Openshaw, PJM Immunopathological mechanisms in respiratory syncytial virus disease.Springer Semin Immunopathol1995;17,187-201
 
Reijonen, TM, Kotaniemi-Syrjänen, A, Korhonen, K, et al Predictors of asthma three years after hospital admission for wheezing in infancy.Pediatrics2000;106,1406-1412
 
Stein, RT, Sherrill, D, Morgan, WJ, et al Respiratory syncytial virus in early life and risk of wheeze and allergy by age 13 years.Lancet1999;354,541-545
 
Sigurs, N, Bjarnason, R, Sigurbergsson, F, et al Respiratory syncytial virus bronchiolitis in infancy is an important risk factor for asthma and allergy at age 7.Am J Respir Crit Care Med2000;161,1501-1507
 
Welliver, RC Immunologic mechanisms of virus-induced wheezing and asthma.J Pediatr1999;135,S14-S20
 
Wennergren, G, Kristjansson, S Relationship between respiratory syncytial virus bronchiolitis and future obstructive airway diseases.Eur Respir J2001;18,1044-1058
 
Martinez, FD, Wright, AL, Taussig, LM, et al Asthma and wheezing in the first six years of life.N Engl J Med1995;332,133-138
 
Eriksson, M, Bennet, R, Nilsson, A Wheezing following lower respiratory tract infections with respiratory syncytial virus and influenza A in infancy.Pediatr Allergy Immunol2000;11,193-197
 
Korppi, M, Reijonen, T, Poysa, L, et al A 2- to 3-year outcome after bronchiolitis.Am J Dis Child1993;147,628-631
 
Wennergren, G, Amark, M, Amark, K, et al Wheezing bronchitis reinvestigated at the age of 10 years.Acta Paediatr1997;86,351-355
 
Papadopoulos, NG, Moustaki, M, Tsolia, M, et al Association of rhinovirus infection with increased disease severity in acute bronchiolitis.Am J Respir Crit Care Med2002;165,1285-1289
 
Johnston, SL, Pattemore, PK, Sanderson, G, et al The relationship between upper respiratory infections and hospital admissions for asthma: a time-trend analysis.Am J Respir Crit Care Med1996;154,654-660
 
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References

Cypcar, D, Stark, J, Lemanske, RF, Jr. (1992) The impact of respiratory infections on asthma.Pediatr Clin North Am39,1259-1276
 
Johnston, SL, Pattemore, PK, Sanderson, G, et al Role of virus infections in children with recurrent wheeze or cough.Thorax1993;48,1055-1060
 
Minor, TE, Baker, JW, Dick, EC, et al Greater frequency of viral respiratory infections in asthmatic children as compared with their nonasthmatic siblings.J Pediatr1974;85,472-477
 
Minor, TE, Dick, EC, DeMeo, AN, et al Viruses as precipitants of asthmatic attacks in children.JAMA1974;227,292-298
 
Henderson, FW, Clyde, WA, Collier, AM, et al The etiologic and epidemiologic spectrum of bronchiolitis in pediatric practice.J Pediatr1979;95,183-190
 
Johnston, SL, Pattemore, PK, Sanderson, G, et al Community study of role of viral infections in exacerbations of asthma in 9–11 year old children.BMJ1995;310,1225-1228
 
Carlsen, KH, Orstavik, I, Leegaard, J, et al Respiratory virus infections and aeroallergens in acute bronchial asthma.Arch Dis Child1984;59,310-315
 
Mertsola, J, Ziegler, T, Ruuskanen, O, et al Recurrent wheezy bronchitis and viral respiratory infections.Arch Dis Child1991;66,124-129
 
Nicholson, KG, Kent, J, Hammersley, V, et al Risk factors for lower respiratory complications of rhinovirus infections in elderly people living in the community: prospective cohort study.BMJ1996;313,1119-1123
 
Rylander, E, Eriksson, M, Pershagen, G, et al Wheezing bronchitis in children: incidence, viral infections, and other risk factors in a defined population.Pediatr Allergy Immunol1996;7,6-11
 
Empey, DW, Laitinen, LA, Jacobs, L, et al Mechanisms of bronchial hyperreactivity in normal subjects after upper respiratory tract infection.Am Rev Respir Dis1976;113,131-139
 
Grünberg, K, Timmers, MC, de Klerk, EPA, et al Experimental rhinovirus 16 infection causes variable airway obstruction in subjects with atopic asthma.Am J Respir Crit Care Med1999;160,1375-1380
 
Wohl, MEB, Stigol, L, Mead, J Resistance of the total respiratory system in healthy infants with bronchiolitis.Pediatrics1969;43,495-509
 
Stokes, GM, Milner, AD, Hodges, IGC, et al Lung function abnormalities after acute bronchiolitis.J Pediatr1981;98,871-874
 
Hall, CB, Hall, WJ, Gala, CL, et al Long-term prospective study of children after respiratory syncytial virus infection.J Pediatr1984;105,358-364
 
Castro-Rodríguez, JA, Holberg, CJ, Wright, AL, et al Association of radiologically ascertained pneumonia before age 3 yr with asthmalike symptoms and pulmonary function during childhood: a prospective study.Am J Respir Crit Care Med1999;159,1891-1897
 
Landau, LI Bronchiolitis and asthma: are they related?Thorax1994;49,293-296
 
Shay, DK, Holman, RC, Newman, RD, et al Bronchiolitis-associated hospitalizations among US children, 1980–1996.JAMA1999;282,1440-1446
 
Openshaw, PJM Immunopathological mechanisms in respiratory syncytial virus disease.Springer Semin Immunopathol1995;17,187-201
 
Reijonen, TM, Kotaniemi-Syrjänen, A, Korhonen, K, et al Predictors of asthma three years after hospital admission for wheezing in infancy.Pediatrics2000;106,1406-1412
 
Stein, RT, Sherrill, D, Morgan, WJ, et al Respiratory syncytial virus in early life and risk of wheeze and allergy by age 13 years.Lancet1999;354,541-545
 
Sigurs, N, Bjarnason, R, Sigurbergsson, F, et al Respiratory syncytial virus bronchiolitis in infancy is an important risk factor for asthma and allergy at age 7.Am J Respir Crit Care Med2000;161,1501-1507
 
Welliver, RC Immunologic mechanisms of virus-induced wheezing and asthma.J Pediatr1999;135,S14-S20
 
Wennergren, G, Kristjansson, S Relationship between respiratory syncytial virus bronchiolitis and future obstructive airway diseases.Eur Respir J2001;18,1044-1058
 
Martinez, FD, Wright, AL, Taussig, LM, et al Asthma and wheezing in the first six years of life.N Engl J Med1995;332,133-138
 
Eriksson, M, Bennet, R, Nilsson, A Wheezing following lower respiratory tract infections with respiratory syncytial virus and influenza A in infancy.Pediatr Allergy Immunol2000;11,193-197
 
Korppi, M, Reijonen, T, Poysa, L, et al A 2- to 3-year outcome after bronchiolitis.Am J Dis Child1993;147,628-631
 
Wennergren, G, Amark, M, Amark, K, et al Wheezing bronchitis reinvestigated at the age of 10 years.Acta Paediatr1997;86,351-355
 
Papadopoulos, NG, Moustaki, M, Tsolia, M, et al Association of rhinovirus infection with increased disease severity in acute bronchiolitis.Am J Respir Crit Care Med2002;165,1285-1289
 
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