why do wheeze? · (urti) and infant wheezing. all respiratory viruses have been implicated but in a...

Archives of Disease in Childhood 1996; 74: 251-259

CURRENT TOPIC

Why do viruses make infants wheeze?

Ian M Balfour-Lynn

Many infants wheeze whenever they have acold. On average, preschool children andinfants catch 6-8 colds per year, althoughthey are certainly exposed to far more respira-tory viruses. Even if the child becomesinfected, he may remain asymptomatic andsubclinical infections are likely to be com-mon. If, on the other hand, the child becomessymptomatic, the illness and symptoms maybe limited to the upper respiratory tract aloneor a lower respiratory illness may develop aswell (fig 1). The wheezing is a result of thislower respiratory illness and is associated withpartial obstruction of the larger airways. It isnot clear what determines the outcome, butthe interaction between the competence ofthe host defence and the intrinsic pathogenic-ity of the virus is central to the process. Thisreview considers how viruses cause wheezingtogether with the reasons why only certaininfants wheeze.

EpidemiologyThere is a striking temporal associationbetween viral upper respiratory tract infection(URTI) and infant wheezing. All respiratoryviruses have been implicated but in a reviewof over 20 studies, Pattemore et al showedthat the principal ones involved were rhi-novirus, respiratory syncytial virus (RSV),and parainfluenza virus.1 The age of thechildren studied had the greatest influence onwhich viruses were isolated with RSV and

Virus

No infection

Infection

No symptoms

URT symptoms

Direct infection

Respiratory Unit,Great Ormond StreetHospital for ChildrenNHS Trust, GreatOrmond Street,London WC1N 3JH

Correspondence to:Dr Balfour-Lynn.

!

LRT symptoms

lediatorsteflexes

Figure 1 Relationship of viral infection to upperrespiratory tract (URT) and lower respiratory tract (LRT)symptoms.

parainfluenza predominating in infancy. Thispicture may now be changing, however, andutilising newer techniques of RNA analysis,2it may be that rhinovirus will be shown tohave a greater role in infant wheezing thanpreviously suspected. It is not clear why theseparticular viruses are the ones usually associ-ated with wheezing, but it is probably relatedto the frequency with which these virusesinfect this age group. The large number of dif-ferent rhinovirus serotypes also means newinfections will continue throughout childhooddue to lack of cross immunity. Finally, theremay be some inherent property possessed bythese viruses, the nature of which is stillunknown.The exact incidence of infant wheezing is

difficult to determine. However, recent datafrom the longitudinal Tuscon Children'sRespiratory Study have revealed that 20% ofall children have at least one episode of awheezing illness in their first year.3 They alsoestimate that over 40% of the children havewheezed at least once during the first threeyears of life.4

How viruses cause wheezing(1) AIRWAY HYPERREACTIVITYAlmost all respiratory viral infections caninduce a state of bronchial hyperreactivity innormal individuals. If an underlying state ofhyperreactivity is already present, as is the casein asthmatic children, then the additionalinsult of a viral infection will exacerbate thisand lead to a greater degree of airway obstruc-tion. Increased airway responsiveness to anumber of agents has been demonstrated inboth natural and experimental viral infections(reviewed by Bardin et al 5) and the hyperreac-tivity may last as long as 6-7 weeks.6 Not allstudies, however, have demonstrated this butdifferent results are probably due to methodo-logical discrepancies.

Bronchial hyperresponsiveness may resultfrom direct viral injury to airway epithelium bya number of mechanisms, including increasedpermeability to antigen, changes in osmolarityof the epithelial lining fluid, and loss of pro-posed epithelial derived relaxant factors.7Epithelial damage by the virus may also lead toexposure and sensitisation of cholinergicsensory nerve fibres normally protected by theepithelium.6 Repair of this damaged epithe-lium would account for the return to normalairway reactivity after six weeks. Recent

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interest has focused on the role of nitric oxidein airway reactivity. Initial work suggests adeficiency in endogenous nitric oxide produc-tion in airway epithelium after a viral infectionmay contribute to airway hyperresponsive-ness.8

Overall, virus induced alteration in airwayreactivity is probably not a major factor ininfancy, although it certainly accounts forexacerbations in older children with estab-lished atopic asthma.

(2) DIMINISHED LUNG FUNCTIONStudies of normal adults with viral respiratoryinfections showed that viruses cause small air-way obstruction, although the function of thelarge airways is unaltered (reviewed byBusse9). Although these changes may not beclinically apparent, the effect persisted in someof the subjects for up to eight weeks. Studieshave also demonstrated alterations in lungfunction in infants hospitalised with acutebronchiolitis (reviewed by Stark and Busse'0),as well as infants and children with acuteURTI. "I These alterations included lower flowrates, increased inspiratory and expiratoryresistance, and increased thoracic gas volumes.Some of the changes persisted in the bronchio-litic infants for over a year, but lung functionwas normal in the infants with a simple URTIwithin one month." It would seem thereforethat respiratory viruses may transiently affectlung function in adults and children of all ages,but the effects usually remain subclinical.However, if lung function is already compro-mised, as it may be in those prone to wheezing(see later), then the effects of viruses may bemore noticeable.

Altered [-adrenergic function may partlyaccount for virus induced changes in lungfunction and several animal and in vitro studiessupport this idea. In particular, granulocytestaken from asthmatics responded less well to3-adrenergic stimulation than those taken

from normal subjects and the response wasfurther diminished during exacerbationscaused by viral infection.'2 It has also beendemonstrated that there are structural similari-ties between the cell surface receptors for cer-tain viruses and P-adrenergic receptors thatmay account for the interaction between res-piratory viruses and impaired 3-adrenergicfunction. 13

Viral damage to airway epithelium may alsolead to bronchoconstriction by altering themetabolism of substance P, a neuropeptidethat contributes to bronchomotor tone(reviewed by Stark and Busse'0). Animal workhas shown that destruction of airway epithe-lium by influenza virus reduced the enzymaticaction of enkephalinase, a neutral endopepti-dase that normally degrades substance p. 14 It ispossible that epithelial destruction and loss ofneutral endopeptidase caused by viral infectionmay lead to bronchoconstriction and hyper-responsiveness, via the unchecked activity ofsubstance P on the airways.'4 It is not yetknown whether similar effects are seen inhumans after viral infections.

(3) AIRWAY INFLAMMATIONRelease of bronchospastic and inflammatorymediators in the airways during viral infectionmay result in airway narrowing. As well as con-traction of bronchial smooth muscle, the nar-rowing is due to a combination of vascularengorgement, cellular infiltration of airwaywalls, and mucosal and submucosal oedema.Numerous inflammatory cells have been impli-cated in this process; they may be recruited tothe site by chemical messengers released byvirally damaged cells. In turn the recruitedcells release mediators that promote airwaynarrowing and further cell recruitment. Even ifthe infection is limited to the upper respiratorytract, inflammatory mediators producedlocally in the nose may act on the lower airwaysto produce symptoms.

(A) Inflammatory cellsMast cells may be central to the process as theyrelease both histamine and leukotriene (LT)C4; both these mediators have been shown tobe raised in respiratory secretions of infantswith viral wheeze.'5 16 Furthermore, animalstudies have shown that viral infection can leadto mast cell hyperplasia and increased activitywith associated bronchial hyperresponsive-ness. 17

Neutrophils may play an important part inthe transient airway hyperreactivity seen afterviral infections, as they have a central role inviral airway inflammation. Markedly raisednumbers of neutrophils have been found innasal biopsy specimens of subjects withrhinovirus URTIs.18 Neutrophils were alsothe predominant inflammatory cell seen inbronchial secretions of children with lower res-piratory tract infection due to RSV.19Neutrophils have also been shown to displayenhanced adhesion to airway epithelial cellsinfected with RSV or parainfluenza virus.20Finally, neutrophils release a number of toxicoxygen metabolites which are damaging to air-way tissues and could lead to airway inflamma-tion, obstruction, and hyperresponsiveness.

Eosinophils release a large number of media-tors such as LTC4 and platelet activatingfactor, but also release basic proteins such asmajor basic protein and eosinophilic cationicprotein, which are toxic to airway epithelium.Release of major basic protein may alsoupregulate the contractile response of airwaysmooth muscle.2' Eosinophilic infiltration is aprominent feature of asthma and may also playa part in viral wheeze. In vitro work has shownthat RSV activates human eosinophils and astudy measuring the concentration ofeosinophilic cationic protein in nasopharyngealsecretions of infants found significantly highervalues in those with RSV induced wheezingcompared with infants with URTI alone.22Against the role of eosinophils, a recent studyshowed few present in bronchial lavage ofinfants with RSV bronchiolitis.19

Macrophages are abundant throughout therespiratory tract and alveolar macrophages arethought to be the first line of defence againstboth viral and bacterial infections. The

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mechanism of the antiviral activity may bepartly due to a direct effect on viral replicationor the release of interferon and other cytokines.Infection of alveolar macrophages by RSVleads to increased secretion of tumour necrosisfactor-alpha (TNF-ao) as well as interleukin(IL)-6 and IL-8.23 24T lymphocytes have been found to have an

increasingly important role in the pathogenesisof both adult and childhood asthma, particu-larly in terms of immunoregulation andcytokine production.2526 Two types of Thelper (Th) cells have been identified, definedby their cytokine secretion patterns; Thl cellssecrete IL-2, interferon gamma, andlymphotoxin, whereas Th2 cells secrete IL-4,IL-5, IL-6, and IL- 10, with several othercytokines secreted by both types (reviewed byMosmann27). Several features of the allergicasthmatic response are mediated by Th2cytokines, particularly in relation to IgE pro-duction and eosinophil and mast cell activity.Although it is the Thl response classicallyassociated with antiviral immunity, the RSV Gprotein primarily promotes a Th2 like responsewhich could account for some of the RSVlower airway symptomatology.28

Basophils may have a role in the pathogenesisof viral wheezing but this is not yet fully estab-lished. However, IgE dependent histaminerelease is enhanced after incubation of humanbasophils with several respiratory viruses.29 30This enhanced histamine release also occurredif the basophils were incubated with interferon,a product of virus infected cells, instead of thevirus itself.29 If these in vitro findings apply tothe human airway during natural infection,then migration of basophils followed byenhanced mediator release may account forsome of the bronchoconstriction seen in acutebronchiolitis.

(B) Inflammatory mediatorsProduction of inflammatory mediators maywell be the key to viral wheezing, although itis unlikely any single mediator is the mainculprit. It is worth briefly reviewing the more

important mediators that have so far beenimplicated, but it should be stressed that find-ing raised levels of a particular mediator duringepisodes of viral wheezing does not necessarilyimply cause, only association.

Histamine - raised concentrations have beenmeasured in the nasopharyngeal secretions ofinfants with RSV infection'5 and in bronchialsecretions of animals infected with para-influenza 3 virus.31 As well as local production,plasma concentrations of histamine have beenfound to be raised in infants with RSV bron-chiolitis.32 Lack of therapeutic success withantihistamines, however, must throw doubt on

the relevance of these findings.Lipoxygenase products - the cysteinyl

leukotrienes are a group of lipid inflammatorymediators derived from arachidonic acid viathe 5-lipoxygenase pathway (reviewed byHenderson and Barnes et al33 34). They are

released by all the primary inflammatory cellsthat mediate lung inflammation as well as

pulmonary endothelial and epithelial cells.LTC4 and LTD4 are the most active com-pounds and are potent bronchoconstrictors,affecting both small and large airways.Leukotrienes have also been shown to increasevascular permeability and increase mucus pro-duction. Certain respiratory viruses (RSV,parainfluenza 3, and influenza A) have beenshown to induce release of LTC4 intonasopharyngeal secretions.35 LTC4 release wasparticularly enhanced during RSV infectionand was detected more often and in higherconcentrations in those infants who developedbronchiolitis with wheezing rather than upperrespiratory symptoms alone.16 Treatment ofRSV bronchiolitis with ribavirin led to adecline in leukotriene concentrations in thenasopharyngeal secretions over the first weekin contrast to infants who received 3-agonistsonly.36 A more recent study measuringsystemic leukotriene production found noalteration in urinary LTE4 concentrationsduring acute episodes of viral wheezing ininfants.37 The large body of work onleukotrienes, particularly in adults, wouldseem to indicate that they do have an import-ant role in wheezing conditions. It will be inter-esting to see whether leukotriene antagonists,which will soon be licensed for adult use, willfind an eventual niche in the treatment ofinfant wheezing.

Cyclo-oxygenase products of arachidonic acidinclude the prostaglandins and thromboxane.Both prostaglandins D2 and F2,, are potentbronchoconstrictors. Plasma levels of theprimary metabolite of PGF2,a were shown tobe raised in infants with RSV bronchiolitis;furthermore, those with recurrent wheezingafter the infection had the highest initialvalues.38 It has also been shown that RSV anti-body complexes cause increased release ofthromboxane, another bronchoconstrictor,from neutrophils.39 Prostaglandin E2, on theother hand, seems to have an inhibitory effectand may protect the airways from bronchocon-striction; it is suggested that viral damage ofthe epithelium may result in loss of these pro-tective prostaglandins.7

Platelet activating factor, which is released bymacrophages, eosinophils and neutrophils, caninduce a sustained inflammatory response inthe airway, similar to that found with viralinfection. Platelet activating factor also stimu-lates airway mucus production, impairsmucociliary clearance, and increases pul-monary microvascular permeability.40 In vitrowork with mononuclear phagocytes has shownthat RSV caused a sustained stimulation ofplatelet activating factor synthesis that paral-leled viral replication and it has been suggestedthat production of platelet activating factormay have a critical role in the inflammatoryresponse to RSV,41 although the evidence isstill largely circumstantial.

Complement - C3a and C5a (the anaphylo-toxins) have been shown to induce broncho-constriction as well as induce release ofhistamine, prostaglandins, and leukotrienes;C5a is also chemotactic for several inflamma-tory cells.34 The significance is that increases in

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both C3a and C5a have been demonstrated inthe upper airways during influenza A infec-tion.42 Furthermore, RSV infected cells havebeen shown to activate complement, whichincreases adherence of neutrophils to theinfected cells and enhances neutrophil medi-ated cytotoxicity (reviewed by Faden andOgra43).

Kinins - bradykinin and other related kininsare potent vasoactive peptides that can causebronchoconstriction.34 Studies with rhinovirushave shown a close association between symp-toms of a cold and raised concentrations ofbradykinin and lysylbradykinin in nasal secre-tions.44 Similar infection of bronchial epithe-lium by rhinovirus could cause release of thesekinins which might account for symptoms ofcough and wheeze with enhanced bronchialhyperresponsiveness.5

(C) CytokinesCytokines are extracellular signalling proteinssecreted by specific effector cells with the abilityto modify the behaviour of other closely adja-cent cells.45 There are many different cytokinesand new ones are being recognised and classi-fied all the time. They interact through a com-plex network, influencing the inflammatory andimmune responses, so the effects of combina-tions of cytokines cannot always be predictedbased on knowledge of the action of individualones. Many cytokines are involved with the air-way inflammation found in asthma, mainly dueto their influences on eosinophil activity and IgEsynthesis.46 Certain cytokines may also beinvolved in viral wheezing, although there is lessdirect evidence. These include IL-2, IL-6, IL-8,and IL- 1.47-50 Two other cytokines are dis-cussed in more detail as it is likely they have animportant role.TNF-a - viruses are capable of enhancing

production of TNF-ot and animal studies haveshown that TNF-ot can have adverse effectson lung function (reviewed by Kips et al 51).TNF-ot also induces an influx of inflammatorycells into tissues, mainly due to its ability toincrease expression of adhesion molecules onendothelial cells. Recent work has shown thatnasal TNF-ox concentrations were significantlyincreased in infants during acute wheezyepisodes associated with respiratory tract infec-tions, and this was particularly associated withthe presence of RSV.37As already mentioned, interferon enhances

IgG mediated histamine release after exposureto several respiratory viruses.29 The interactionbetween interferon and RSV infection isinteresting. RSV has been shown to be acutelysensitive to both interferons alfa and gammawhich inhibit its growth. Yet in vitro andclinical work has shown that interferon pro-duction seems to be suppressed by RSV,although this may return to normal in therecovery phase.52 The effect may be virusspecific as nasal titres of interferon weredetectable less often and at lower levels inchildren with RSV compared with influenza orparainfluenza infections.53 54 It has also beenshown that a small group of wheezy infants

with recurrent URTIs consistently appearedunable to make interferon alfa during the acuteepisodes, although severity of illness was un-affected by interferon alfa production.55

(D) Adhesion moleculesAdhesion molecules are receptors located onvascular endothelium and airway epitheliumwith the corresponding ligands located on cir-culating leucocytes. The endothelial expres-sion of adhesion molecules at the site ofinflammation mediates the cell mediatedimmune response.56 Intercellular adhesionmolecule-1 (ICAM-1) has been shown to actas a neutrophil and eosinophil receptor on air-way epithelial cells57 and induces antigen-induced bronchial hyperresponsiveness.58 Ithas recently been shown by several investiga-tors that the majority of rhinoviruses attach tothe surface of cells via a receptor identified asICAM-1 (reviewed by Johnston et al59). Ifinfection with rhinovirus leads to upregulationof ICAM- 1 expression in the lower airways thismay account for rhinovirus induced neutrophilinflux, hyperresponsiveness, and wheeze. Invitro work has also shown that humanbronchial and nasal epithelial cells infectedwith RSV or parainfluenza virus expressedincreased concentrations of ICAM- 1, whichled to enhanced levels of eosinophil andneutrophil adhesion.60 61 Further evidence thatICAM-1 may have a role in modifying airwayinflammation is provided by the fact that itsexpression is increased by several cytokines. Asunderstanding of adhesion moleculesincreases, it is likely that they will be seen tohave a part to play in the pathogenesis of air-way inflammation and wheezing.

WVhy certain infants wheeze(1) RISK FACTORS IN THE HOSTViral responsiveness describes susceptibilityto symptomatic viral infection and is one ofthe variables determining predisposition towheeze. Several factors, both endogenous andexogenous, place some infants at a higher riskof developing viral wheeze. However, 20% of3 year old wheezy children do not have any ofthe recognised major risk factors, so there mustbe other inherent factors that are as yetunknown.4Age and sex - viral wheezing is commonest in

young infants. Severe wheezing is unusualunder 2 months and there is a sharp decline inincidence by 2 years. This is mainly due toimmunological factors, although airway sizemay also be important. Wheezing due to RSV,parainfluenza 1 and 3, and adenovirus (but notrhinovirus) is far commoner in males; this maybe related to differences in lung function andrelative airway size.62

Socioeconomic factors - the risk of seriousRSV illness is much greater in infants from lowincome families, most likely related to crowdedliving conditions and large families. Thepresence of older siblings increases the risk ofbronchiolitis mainly due to the introductioninto the home of viruses that the older sibling

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has picked up at nursery or school. For similarreasons, there is a greater risk of wheezinglower respiratory illness among children whoattend day care centres. However, day-care hasa protective effect if the mother is a heavysmoker (over one pack of cigarettes per day).63

Passive smoking - exposure to cigarettesmoke leads to a fourfold increased risk ofbronchiolitis and a threefold increased risk ofany lower respiratory illness; these illnesses arealso contracted at an earlier age.63 The risk isrelated to maternal rather than paternal smok-ing and may be partly due to the longer timemothers generally spend with their infants.However, preliminary work has also suggestedthere are alterations in the developing lungs ofthe fetus due to mothers smoking during preg-nancy that results in diminished lung functionat birth and altered airway reactivity in the first10 weeks of life.64

Breast feeding - breast feeding seems to con-fer a degree of protection against wheezinglower respiratory illness and in particularRSV,65 although the essential role is not theprevention of infections but reduction inseverity of the illness. RSV neutralising activityhas been detected in colostrum and is largelydue to secretory IgA.66 The RSV specificlymphoproliferative response may be sup-pressed in breast fed babies, which mayaccount for why they are less severelyaffected.67 This in turn may be due to seruminterferon alfa which is found more often andat higher concentrations in breast fed babiesand is associated with suppression of thelymphoproliferative response to RSV.68Atopy - studies that have examined the

association of viral wheeze with atopy give con-flicting results (reviewed by Skoner andCaliguiri69). This is partly due to difficulties indefining and diagnosing atopy in the veryyoung. It has been shown, however, that therisk of developing a wheezing illness in the firstyear of life was inversely related to the cordblood IgE concentrations.70 No relationshipwas found in the second year, and by the thirdyear of life the relationship had reversed so thatthe risk was directly related to the IgE concen-trations.71 So although atopy might affect viralwheezing, it is unlikely it plays an importantpart in young infants. Interestingly, it is nowemerging that early viral respiratory infectionsmay actually have a protective role against thedevelopment of atopy in later life.72

Pulmonary factors - the importance of base-line lung function as a risk factor for wheezinghas been demonstrated in a study thatmeasured lung function in infants before theyhad contracted any lower respiratory ill-nesses.73 Infants with diminished airway con-ductance had a 3-6 times greater risk ofwheezing in the first year of life. Furthermore,this risk of wheezing was still in evidence atthree year follow up.74 It would seem thatnarrower or smaller airways may be more likelyto become obstructed when infected, leadingto wheezing and hyperinflation. Early lungdamage also increases the risk of lower respira-tory illness and wheezing. Premature infantshave a greater risk of wheezing, particularly if

they required mechanical ventilation andinfants with bronchopulmonary dysplasia areat grave risk of developing life threateningbronchiolitis.75 As well as this, some infantsdisplay enhanced airway reactivity, althoughthe role in wheezing lower respiratory illness isunclear; it would seem, however, that under-lying bronchial hyperresponsiveness is not afeature of infant wheezing.76

(2) ALTERATIONS IN IMMUNE RESPONSE TOVIRUSESThere is increasing evidence that some infantshave an immature or abnormal immuneresponse to some respiratory viruses, and par-ticularly RSV. Immune dysregulation couldlead to an increased number of infections, butit is not clear whether wheezy infants are moresusceptible to colds or whether colds aresimply more noticeable in them due to addi-tional symptoms of cough and wheeze. It islikely that both factors apply, however. Onestudy has found that asthmatic children had agreater incidence of viral infection comparedwith their non-asthmatic siblings (due mainlyto an increase in rhinovirus77); another, how-ever, showed that asthmatic children withrhinovirus have a higher incidence of symp-toms than other children.78 Immune dysregu-lation could also mean the microbe has agreater effect on the host. If defence isimpaired the virus could cause greater damage,and this is particularly true of immunodeficientstates - for example children on cytotoxic orimmunosuppressive treatment may developsevere and often fatal infections with measles,chickenpox, RSV, influenza, and parainfluenzaviruses. Equally, an exaggerated or exuberantimmune response may also be harmful to thehost.

(A) Cell mediated immunityCell mediated immunity (CMI) is important inantiviral defence but there is evidence it mayalso contribute to the pathological process.

Protective effect of CMI - children withimpaired CMI show a prolonged shedding ofRSV, 40-112 days compared with the usualmean of seven days.79 These children alsodevelop RSV pneumonia at an age when this israther uncommon (over 3 years old). Althougha 10 year prospective study did not find anyevidence that CMI contributed significantly tothe outcome of RSV infection,80 virus specificcellular cytotoxic activity has been demon-strated in infants with acute RSV infection,usually within one week.81 The activity was agedependent with the response found in 65% ofthose aged 6-24 months but in only 35-38% ofthose aged 5 months or less; this may accountfor the severity of the disease in the youngerage group.82 The reason for the relatively poorCMI response in the young may be immuno-logical immaturity, but it is more likely that thegreater response seen in older children is areflection of previous RSV infection; theenhanced response may simply representbooster effects secondary to stimulation of

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memory cells. Another possibility is that theCMI response in those under 6 months isinhibited by high levels of pre-existing mater-nally derived RSV antibody.

Pathological effect of CMI - studies on therelationship of the cellular response to RSVwith age have not produced consistent find-ings. Using different methodology to that ofChiba et al,82 other workers have found a

significant CMI response in 78% of infantsunder 6 months compared with 46% over 6months.83 The greater CMI response in theage group most severely affected by RSVwould indicate that CMI is involved in thepathogenesis of RSV. As well as this, exagger-ated cellular responses were associated withsevere pulmonary disease in infants withnatural RSV infection who had previously beenimmunised with RSV vaccine.84 It has alsobeen shown that infants who developed RSVspecific CMI within a few days of infection hada clinical illness characterised by broncho-spasm85; whereas CMI developed more gradu-ally in those who developed upper respiratoryillness or pneumonia. In addition, the infantswith a high degree of RSV specific CMI activ-ity 3-9 weeks after onset of infection were

more prone to wheezing over the next sixmonths. It seems that although a heightened Tcell response is necessary to clear the virus, air-way injury occurs as the virus is eradicated.'0CMI contributes to host defence against RSVat the same time as enhancing the pathologicalprocess.

(B) Humoral immunityThe humoral immune system has an importantrole against respiratory viruses, confirmed bythe beneficial effect on incidence and severityof RSV bronchiolitis in children given prophy-lactic RSV immune globulin.86

Effect of age - in a similar way to the CMIresponse, age has an important effect on

humoral immunity. Infants under 6-8 monthsmount a poor antibody response to RSV infec-tion compared with older infants, and there isoften a failure to develop a protective secretoryIgA or neutralising IgG response.87 In particu-lar, the effect of age is primarily on theresponse to the F (fusion) surface glycoproteinof RSV.88 This poor antibody response isthought to be due to immaturity of theimmune system, but while this may accountfor the general age distribution of the disease itdoes not account for the differences in diseaseseverity seen among individuals of the same

age.Maternal antibodies - the presence of pas-

sively acquired maternal antibodies in theserum of young infants may have an immuno-suppressive effect on the development of theinfant's own immune response, although it isprimarily the response to the G glycoprotein ofRSV that is affected by maternal antibodies.88There is contrasting evidence as to whetherthese matemal antibodies are harmful or help-ful. It has been hypothesised that due to lack ofspecific secretory IgA during the initialchallenge with RSV, the maternal IgG could

diffuse to the lumen of the infant airways andform immune complexes.89 Phagocytosis ofthese RSV:IgG immune complexes has beenshown to stimulate release of inflammatorymediators by neutrophils which could con-tribute to the pathological process.90 Con-versely, there is evidence that maternalantibodies have a protective role. RSV infec-tion is commonest under the age of 6 monthswhen these antibody titres are at their highest.As well as this, infants with the highest titres oftransplacentally acquired RSV specific IgGtend to develop less severe RSV pneumoniathan those with lower titres and have signifi-cantly fewer infections.9'

Serum IgG subclasses - there have beenseveral reports of various IgG subclass abnor-malities associated with infant wheezing,although the importance of these associationsis not clear. One study found IgG, concentra-tions were significantly lower in the infantswith bronchiolitis compared to healthy agematched controls.92 The other IgG subclassesdid not differ between the two groups but 23%of the wheezy infants had IgG, deficiency. Itwas felt that the low IgG, concentrations mightrender the infants more susceptible to RSVinfection as IgG, and IgG3 are the predomi-nant isotypes produced against RSV in child-ren under 2 years. However, a recent study on86 infants (median age 2 months) with RSVbronchiolitis found all the infants had normalsubclass concentrations and there was norelation between the severity of RSV infectionand immunoglobulin or IgG subclass concen-trations.93As well as the various combinations of sub-

class deficiencies, there are reports of raisedIgG4 associated with atopy and wheezing.94The role of IgG4 is uncertain, it has been pro-posed that it acts as a reaginic antibody on thesurface of mast cells, but it has also beenargued that it serves as a blocking or regulatoryantibody. One study has shown that serumconcentrations of virus specific IgG4 weresignificantly higher in infants who wheezedwith RSV than in those who had upper respira-tory symptoms only, although it was not clearwhether the IgG4 contributed to the severity ofthe wheezing.95

(C) Mucosal immunityThe common respiratory viral infections enterthe host via the airways, and some will thenprogress distally to the parenchyma of thelung. It is for this reason that mucosal immu-nity has such an important role in the fightagainst these viruses, as it provides the host'sfirst line of defence.

Local IgA production - IgA is the pre-dominant immunoglobulin in respiratorysecretions, where it is found in its dimeric formknown as secretory IgA (sIgA). Concentrationsof nasal sIgA may determine susceptibilityto respiratory infection. It has been shownthat infants who mount a greater nasal non-specific IgA response have fewer respiratoryinfections, although the frequency of infectionwas not associated with the baseline nasal IgA

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Why do viruses make infants wheeze? 257

Virus

Airwayepithelial injury

Inflammation Bronchoconstriction- BronchialBroncocontricton ~ hyperreactivity

Mediators Socioeconomic Passive

MedatokesI factors smokingCytokines I { + Age

Airway narrowingin a 4 Host susceptibility

susceptible hostt ~~~Sex

Immune Underlying AtoPYresponse lung function

WheezeFigure 2 Multifactorial association between respiratory viruses and wheezing.

concentrations.96 However, a recent study hasshown that wheezy infants mount a normalnasal IgA response to viral infection whencompared to their non-wheezing siblings withsimple URTIs.97

Local IgE production - Welliver and his col-leagues have implicated IgE in the pathogene-sis of viral wheezing (reviewed by Stark andBusse'0). They found significantly higher titresof RSV specific IgE in nasopharyngeal secre-tions in those who wheezed compared withthose with non-wheezing RSV infection; simi-lar results were found in parainfluenza infec-tion. The original specific IgE response wasfound to be predictive of future wheezing atboth four and seven to eight year follow up.98This work only proves an association betweenthe production of RSV IgE and wheezing,although it is possible that virus specific IgEantibody becomes mast cell bound and inter-acts with viral antigen, leading to the release ofvasoactive and inflammatory mediators whichcause airway narrowing. The bronchoconstric-tor mediator LTC4, detected in the naso-pharyngeal secretions of infants with RSVbronchiolitis, was positively correlated withRSV IgE titres.16The reason why certain children are prone to

a hyperactive IgE response may be relatedto abnormal T cell regulatory mechanisms.Welliver et al have shown a reduced number ofOKT8 antigen positive cells (suppressor/cyto-toxic T lymphocytes) during convalescence inthose who wheezed with RSV compared withthose with upper respiratory illness alone.99There was also an inverse correlation betweenRSV IgE in nasopharyngeal secretions andOKT8 positive cells in peripheral blood and it issuggested that these cells may include some thatare responsible for suppression of IgE produc-tion. It is unknown whether this abnormal IgEregulation is virus induced or constitutionally

determined. Host factors which regulate theresponse of T lymphocytes to RSV may becritical in determining the clinical outcome ofRSV infection.

ConclusionsAlmost certainly the association betweenviruses and wheezing is multifactorial, as is theunderlying predisposition to wheeze (fig 2). Itis clear that the interaction between theimmune system and the development ofinflammation is extremely complex. Futurework in molecular biology, particularly on thegenetics and regulation of cytokine production,may establish whether some children have apredilection for excessive inflammation.Advances in viral detection will prove to behelpful and further progress in mucosalimmunology may reveal a subtle deficiency inthe way wheezy infants respond to respiratoryviruses. Advances continue to be made frombronchial biopsy and lavage studies in adultasthma, but caution is warranted as many ofthe findings may not be applicable to infantwheezing. Our understanding will continue tobe advanced by epidemiological research, par-ticularly the long term study being undertakenin Tuscon.100 Despite methodological difficul-ties, valuable insight can be gained from infantlung function studies and the value of clinicalstudies must also not be overlooked. Finally, arecent international workshop has gone a longway towards defining many of the questionsrelated to infant wheezing that now need to beanswered. 101

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