Years ago, infantile asthma and viral laryngotracheobronchitis with wheezing were considered to be distinct entities, and it was a darn poor pediatrie resident who couldn't tell them apart. When those residents went into practice, they frequently were confronted with children who did exactly as their mothers claimed; they wheezed with nearly every upper respiratory infection they caught from their siblings or peers. Antibiotics and expectorants didn't seem to help much, but bronchodilators did help. Allergy workups usually were negative or noncontributory to the wheezing episodes. In frustration, terms such as "asthmatic bronchitis" or "asthma-like illness" began to appear in the pediatrie jargon in an attempt to explain the beneficial effect of bronchodilators without labeling the child with the then -deprecatory label of "asthmatic." Some of the children went on to develop classic childhood asthma and some did not.
The classic paper of Williams and McNichol1 in 1969 described children from New Zealand who wheezed after evidence of a viral respiratory infection. This study introduced the term "wheezy bronchitis" into general pediatrie usage in the United States, a name which seemed to combine the bronchospastic and viral-associated aspects of the illness. Realization of the nature of bronchial hyperreactivity in recent years has suggested a more appropriate name, "para- infectious bronchial hyperreactivity" or PIBH. The cumbersome nature of both the descriptive term and the acronym led to an even more modern term, "viral-associated wheezing." Although this description can be applicable to patients of all ages, pediatricians usually associate viral -associated wheezing with infants and toddlers who begin wheezing shortly after the appearance of coryzal symptoms and who, untreated, will cough and wheeze for 3 to 10 days after the onset of the illness. They will then be nearly symptom free until the next episode of coryzal illness. Many of these children will be completely free of these symptoms by age 5 or 6.
Who are these children with wheezy bronchitis and why do they wheeze with even trivial viral respiratory illnesses? We will consider several aspects of this condition: effect of viral illness on the airway anatomy, effect of the illness on autonomie function, possible contribution of IgE mediated bronchospasm, and long-term sequelae.
Pediatricians are familiar with epidemic bronchiolitis. The nonresponse of this condition to bronchodilators and corticosteroids is probably due to the pathophysiology, in which the diameter of small airways is reduced by cellular edema and increased serous respiratory secretions. Spasm of bronchial smooth muscle and mucus plugging apparently do not play a major role in this disease as larger airways may be effected but not to the point of symptomatic obstruction. The inflammation associated with viral infection is known to have a number of other effects on respiratory epithelium.2 There may be a transient disruption of optimal respiratory ciliary function. Damage of the epithelium may result in the elaboration of "neoantigens," immunologie binding sites on epithelial cells which may foster attack by microorganisms or autoantibodies. The production of interferon has been postulated as a factor enhancing the release of mediators from basophils.3 Inflamed epithelial tissue shows increased contractile response to substance P.* The loss of a number of epithelial factors due to cellular damage may contribute to increased airway reactivity. 5
The association of infections and wheezing seems limited to viral infections. Most studies have been unable to correlate wheezing with the presence of bacteria in the respiratory tract. The one exception to this seems to be a close association of wheezing and sinusitis.6'7 The exact mechanism for this is not well known, although the possibility of cholinergic stimulation with reflex wheezing has been proposed. The concept of "bacterial allergy," or allergy to bacteria present as normal flora or pathogens in the respiratory tract has been out of fashion for the past 15 years or so. IgE to common airway pathogens has been demonstrated in adult patients with bronchitis and with asthma, but there is little information about the possible role of this in wheezing.8
The contribution of the autonomie nervous system to the problem of viral-induced wheezing has generated much speculation. There is considerable experimental evidence that the inflammation of epithelial tissue by viral infection increases the number and availability of cholinergic airway- irritant receptors.9 This increased cholinergic output, mediated by the vagus nerve, is responsible for increased airway smooth muscle tone. Such sensitivity in infected guinea pigs can be prevented by interruption of the vagus nerve. !0 This is manifested clinically by an increased sensitivity to the bronchoconstrictive effects of an inhaled cholinergic agonist such as methacholine following a viral respiratory infection. Empey et al11 noted that such sensitivity in nonasthmatic volunteers persisted for up to 6 weeks. There is some suggestion that atopic individuals may have more lung muscarinic receptors than do normal individuals and that such receptors may be even more active during viral infection.9'11
Szentivanyi12 proposed 20 years ago that asthma was in part due to a relative deficiency in ßadrenergic receptors in lung tissue. Although some experimental evidence supports this theory, the fact that normal individuals do not wheeze when given ß-adrenergic antagonists makes it unlikely that the ß-receptor system is solely responsible for the development of asthma. It is more probable that asthmatic individuals have a relatively decreased ß-receptor density or affinity and that an increase in cholinergic stimuli and receptors produces an abnormal balance of airway tone. Several papers have suggested that airway segments from experimental animals and leukocytes from normal and asthmatic subjects infected with virus exhibit ß-adrenergic hyporesponsiveness. l3'15 The amino acid sequences of several respiratory viruses show homology with certain segments of the ß-receptor proteins. 16
The role of viral respiratory infections in the development of allergy has been of considerable interest for many years. In longitudinal study, Frick et al17 noted that children from atopic families appeared to develop allergic symptoms and specific IgE antibody after viral upper respiratory infections. Viral infections in experimental animals increase the permeability of the respiratory epithelium to antigens.18 Children with bronchopulmonary dysplasia and smokers have higher plasma concentrations of IgE than do normal controls, again reflecting the effect of epithelial damage.19 Welliver and his group20 have studied the possible effect of IgE on respiratory syncytial virus (RSV) on wheezing. They noted that RSV-induced wheezing was associated with the presence of anti-RSV IgE and histamine in respiratory secretions. They also found that cellbound IgE was more common in RSV infections with wheezing than in RSV infections without wheezing.21 Busse and his group22 have studied the effect of viral infection on basophil mediator release. During an experimental rhinovirus respiratory infection in nine subjects, basophil histamine release secretion to antigen, but not to a nonimmunologic secretagogue, was enhanced. Zimmerman et al,23 however, performed extensive immunologie studies of young children with asthma, 28% of whom were considered to be highly atopic by their criteria. They concluded that asthma seemed to be a function of viral infections in infancy and that the development of allergic antibodies was an independent function which may add to the severity of the disease.
Although we have focused attention on that group of children who seem to outgrow their wheezing in childhood, a considerable body of data suggests that viral respiratory infections may have long-lasting sequelae. A number of studies have associated childhood illness with evidence of airway obstruction on pulmonary function testing in later childhood, adolescence, and adulthood. The effects seem most notable in tests reflecting function in small airways and lung parenchyma. 19 This was particularly evident on 10-year follow-up of children who had been hospitalized for bronchiolitis.24 The effect of mild bronchiolitis not requiring hospitalization has produced mixed results. 25·26 In both instances, the prevalence of wheezing seemed to decrease with time. Children with a history of croup also seem to have more bronchial hyperreactivity.27
Although it seems clear that viral infections can cause wheezing, some evidence suggests that asthmatic children are more prone to viral infections. Minor et al28 found that asthmatic children had a higher rate of viral infection than did their nonasthmatic siblings. Of interest also is evidence that children who develop wheezing with RSV bronchiolitis are more likely to have a family history of asthma.29 The possibility of a genetic predisposition to the development of bronchial hyperreactivity merits investigation.30
Patients who develop viral-induced wheezing usually respond well to a comprehensive ambulatory program for the management of asthma. In the United States, the first approach is to attempt to obtain a plasma concentration of theophylline in the low therapeutic range (6 to 12 ^gImL) by an oral sustained-release theophylline product. This can be supplemented by an aerosolized ß-adrenergic agent delivered by metered-dose inhaler and spacer in older children or by a powered nebulizer and mask for infants. Children who do not tolerate oral theophylline may benefit from an oral sympathomimetic, although as yet there is little experience with a sustained action product which will last during the hours of sleep. Parents are instructed to have the medication on hand and to begin treatment at the first sign of coryza in the patient or in his siblings, failure to begin bronchodilator therapy before the onset of wheeze may risk the development of wheezing unresponsive to oral therapy, which may require hospitalization. One of the most common diagnoses of referrals to our university pediatrie chest clinic is a child who has been hospitalized for recurrent bronchiolitis and pneumonia with each episode of respiratory infection. Prompt treatment with the medications listed above usually will prevent the hospitalization and, often, the wheezing.
Do the children with "wheezy bronchitis" have asthma? Williams and McNichol would say yes! In their landmark paper on this subject, they concluded that all of their subsets had wheezing on a multifactorial basis. l Zimmerman and the others from the Toronto group would agree.22 They believe that the tendency to develop bronchial hyperreactivity is a genetic predisposition. They accept the concept of Cloutier et al31 that asthma is a spectrum of reactivity that may include episodes manifested only by cough or increased respiratory secretions. This genetic predisposition may, or perhaps must, be unmasked by a viral respiratory infection. Sibbald et al32 studied three groups of children: asthmatic, wheezy bronchitic, and controls. The percentage of children with at least one asthmatic relative was significantly higher in both wheezy groups than in controls. Wheezy bronchitis also tended to be more prevalent in the relatives of both wheezy groups than in the relatives of controls, although this did not reach significance. This group also suggested that the two forms of wheezy illness share a common genetic defect.
Differences have been found between populations of children who wheeze only with infection and those who wheeze from other causes. The wheezy bronchitic group of Williams and McNichol were significantly less atopic than the asthmatic group. l Taussig and Lebowitz33 confirmed this finding and showed that the wheezy bronchitis group had fewer abnormalities in pulmonary function. Zimmerman et al2î explain this as the action of two genetic tendencies. The presence of a genetic tendency toward atopy will not make people wheeze, but a genetic tendency toward the development of bronchial hyperreactivity following viral infections may lead to the production of allergic antibodies because of airway inflammation.
To answer the question posed by the title of this article, I think we can conclude that wheezy bronchitis is a genetic disorder similar if not identical to asthma, which usually is unmasked by a viral lower respiratory infection. There is some merit to retaining the term since these patients tend to wheeze only with respiratory infections and this tendency usually, but not always, is outgrown in early childhood. The wheezy attacks are treated with standard asthma medications and often can be prevented if therapy is begun early in the course of the infection.
Is our current attitude of therapeutic nihilism toward most viral respiratory infections in infancy and early childhood appropriate if these predispose to the development of bronchial hyperreactivity later in life? There currently is substantial debate about the appropriate role of the use of aerosolized ribavirin in the treatment of viral bronchiolitis. Some advocate its usage only for life- threatening cases because of the cost of hospitalization and medication. Others cite some of the papers quoted here and the long-term follow-up of Burrows et al19 who showed that adult patients with a history of lower respiratory infection in childhood had substantially more pulmonary disease. Advocates of early intervention with ribavirin believe that such treatment may prevent some of these long-term problems. Early reports of the benefit of intranasal interferon Ct2 *n tne prevention of respiratory infections due to rhinovirus suggest that this agent also may be useful in the prevention of viral-induced wheezing in a selected population.34
What is the role, if any, of anti-inflammatory agents in viral respiratory disease? There is little evidence for benefit of corticosteroids in the immedi' ate treatment of viral bronchiolitis, but there have been no long-term follow-up studies of such treat' ment. Is there a role for cromolyn sodium as an anti-inflammatory agent in the prevention of bron' chial hyperreactivity as a sequelae of such infec' tions?35 What about nonsteroidal ami- inflammatory drugs? It is possible that clinical trials in the near future will demonstrate benefit to therapeutic inter' vention, either anti-viral or anti- inflammatory, for viral respiratory infections in children with a family history of wheezing sequelae after such infections.
1. Williams H1 McNichol K- Prevalence, natural history, and relationship erf wheezy bronchitis and asthma in children. An epidemiological study. BrMeJJ 1969; iv:321.
2. Laitien L, Heino M, Laitinen A, et al. Damage of the airway epithelium and bronchial hyperreactivity in patients with asthma. Am Rev ResfHr Dis 1985; 131:599.
3. Ida S. Hooks], Siiaganaian R. et al. Enhancement of IgE-mediated his tarn ine release from human baaophits by viruses: Role of interferon. J ?f Mf¿ 1977; 145:892.
4. Saban R, Dick E. Fishleder R, et al. Enhancement by parainfluema 3 infection of contractile responses to substance P and capsakin in airway smooth muscle (torn guinea pig. Am Reti Sapa* DK 1987; 136:586.
5. Hogg J. Bronchial permeability and its relationship to airways hyperreactivity. ] Atiero Clin immurai 1981; 67:421.
6. Slavi n R, Cannon R. Fnedman W, et al. Sinusitis and bronchial asthma. !Aaergy CIm íimnunoÍ 1980; 66:250
7. Rachelefsky G. KaE R, Siegel S. Chronic sinus disease with associated reactive airway disease in children. Pediatrics 1984; 73:526.
8. Pauwels R, Vershraegen G, \&n der Straeton M. IgE antibodies to bacteria in patients with bronchial asthma. AUergy 1980; 157:665.
9. Casale T N euromet nanismi of asthma. Ann Aliergy 1987; 59(391. 10. Bucknet C, Songsindej V, Dick E, et al. In vivo and in vitro studies on the use of the guinea pig as a model for virus-provoked airway hyperreactiviry. Am Rev Rapir Dis 1985; Iî2i305.
10. Buckner C, Songsirdei V, Dick E, étal. In vivo and in vitro studies on the use of the guinea pig as a model for virus-provoked airway hyperreactiviry. Am Rev Rejpir Du 1985; 132:305.
1 1 . Empey D, Laitinen L, Jacobs L, et al. Mechanisms of bronchial hypeireaccivity in normal subjects after upper tespiratory infection. Am Rev Hespir Dis 1980; 113:131.
12. Szentivanyi A: The ß-adrenergic theory of the atopic abnormality in bronchial asthma, i täergyCHn Immunoi 1968; «:203.
13. Buckner C, Clayton D, Am-Shoka A, et al. Parainfluenza 3 infection blocks the ability of a ß-adrenergic receptor agonist to inhibit antigen' induced contraction of guinea pig isolated airway smooth muscle. } Clin Invest 1981; 67:376.
14. Busse W, Cooper W, Warshauer D, et al. Impairment of isoproterenol, H2 histamine, and prostaglandm E] response of human gianulocytes after incubation in vitro with live influenza vaccines. Am Rev Resprr Dis 1979; 119:561.
15. Busse W. Decreased granulocyte response to isoproterenol in asthma during upper respiratory infections. Am Rev RespriDii 1977; 115:783.
16. Co M1 Gaul ton G, Tominga A, et al. Structural similarities between the mammalian ß-adrenergic and reovitus type 3 receptors. Proc Noli Acad Sci USA 1985; 82:5315.
17. Prick O, German D, Mills]· Development of altergyin children: 1. Association with vims infections. i ABergy CIm fmmunol 1979; 64:127.
18. Richardson J1 de Notants A, rerguson C, et al. Effects of a viral laryngpnacheitis on the epithelial barrier of chicken airways, lab fnve« 1981; 44: 144.
19. Burrows B, Ha Ionen M, Barbee R, et al. The relationship of immunoglobulin E to cigarette smoking. Am Rw Restar Dií 1981; 124:523.
20. Welliver R, Wong D, Sun M. et al. The development of respiratory syncytial virus-specific IgE and the release of histamine in nasopharyngeal secretions after infections. N EngiJ Mid 1981; 305:841
21. Welliver R. Kaul T, Ogra P. The appearance of cell-bound IgE in respiratory tract epithelium after respiratory syncytial virus infection. N Engi ] Med 1980; 303:1198.
22. Caddy ], Busse W. Enhanced IgE -dependen! basophil histamine release and airway reactivity in asthma. Am R» Respa Dis 1986; 132:969.
23. Zimmerman B. Chambers C, rbrsythe S. The highly atopic infam and chronic asthma. } AUergj Om immurai 19; 81:71.
24 Pulían C, Hey N. Wheeling, asthma, and pulmonary dysfunction 10 years after infection with respiratory syncytial virus in infancy. BrMeJJ 1982; iv:1665.
25. Twiggs ], !,arson L. O*Connell, E. et al. Respiratory syncytial virus infection: 10-year follow up. CKn Pedifltr 1981; 20:187.
26. McConnochie K., Roghman K. Predicting clinically significant tower respiratory tract illness in childhood following mild bronchiolitis. An J Du CfiiU 1985; 139:625.
27. Gurwitz D, Corey M. Urvison H. Pulmonary function and bronchial reactivity in children after croup. Am Rev Rtsfnr Du 1980; 122:95.
28. Minor T, Baker J, Dick E. et al. Greater frequency of viral respiratory infections in asthmatic children as compared with their non-asthmatic siblings. } Pedían 1974; 85:472.
29. Rooney }, Williami H. The relationship between proved viral bronchiolitis and subsequent wheeling. ) Pcdutr 1971; 79:744.
30. Li]1 OOmnellE. Viral infections and asthma. Arm ABtrgy 59:321.
31. Clouliet M, Laughlin G- Chronic tough in children: A manifestation of airway hyperreactivity. Pediatrics 1981; 67:6.
32. Sibbald B, HOrn M, Gregg I. A family study of the genetic basis of asthma and wheüy bronchitis. Arch Du CJuU 1980; 55:354.
33. Taussig L, Lebowitz M. Coi^fi and vfactf syndmmts in children. 1976; 1 14:45.
34. Douglas R1 Moore B, Miles H, et al. Prophylactic efficacy of intranasal alpha-2 interferon against rhinovirus infections in the family setting, N Engl } Med 1986; 314:65.
35. Cockcroft D. Airway hyperresponsivenest: Therapeutic implications. Ann Autrgj 1987; 59:405.