Cardiol Young 2005; IS: 266-273© Cambridge University Press

ISSN 1047-9511

Original Article

Acute and long-term effects of infection by the respiratorysyncytial virus in children with congenital cardiacmalformations

Timothy F. Feltes,^ Jessie R. Groothuis^

^Section of Pediatric Cardiology, Ohio State University and The Heart Center at Children's Hospital, Columbus, Ohio;^Hollis-Eden Pharmaceuticals, Inc., San Diego, California, United States of America

Abstract All newborn infants have limited pulmonary reserve compared with older children. This puts themat increased risk of respiratory complications, such as those associated with infection by the respiratory syncy-tial virus. Young children with congenital cardiac disease are particularly likely to suffer severe disease relatedto infection by the virus. In these children, the extreme vulnerability of the lung to pulmonary oedema is com-pounded by the additional burden caused by the respiratory syncytial virus.

In addition to the well-documented acute pulmonary effects of infection with the respiratory syncytialvirus, there may also be consequent long-term respiratory morbidity. Clinical studies have shown that infectionby the virus in infancy is associated with a higher risk of developing subsequent bronchial obstructive disease.Much debate surrounds the mechanisms underlying this association. It is thought that a combined immuno-logieal and neurogenic response mechanism is likely. Prevention of severe respiratory disease in infants andyoung children with congenital heart disease due to infection by the virus may, therefore, offer both immedi-ate and long-term benefits. Indeed, an increasing body of evidence supports this hypothesis, indicating a clin-ical rationale for prophylaxis against the virus in infancy, in order to reduce the chance of developing reactiveairways disease and asthma in later life.

Keywords: Pulmonary oedema; congestive heart failure; reactive airways disease; asthma; prophylaxis; palivizumab

INFANTS AND YOUNG CHILDREN WITH CONGENITALcardiac disease are more likely to be hospitalised,and have greater morbidity and mortality associ-

ated with a lower respiratory illness, due to infectionby the respiratory syncytial virus than infants withoutheart disease. ̂ "̂ This is particularly apparent whenpatients with congenital heart disease with a historyof recent bronchiolitis due to the respiratory syncytialvirus undergo corrective surgery."* The combination ofthe underlying cardiac physiology, the immaturecharacteristics of the lung with limited reserve.

complex cardiopulmonary interactions, and presenceof heart failure, lays the foundation for a "perfectstorm" brought about by the acute effects of respira-tory syncytial viral bronchiolitis. The cumulativeeffects of direct cytopathology produced by the bron-chiolitis, along with secondary inflammatory changesin the lung, compromise the patient with congenitalheart disease, often resulting in an inability to returnto baseline. The clinician may frequently face the needto intervene surgically on behalf of the child underless than ideal conditions, and at greater risk.

Correspondence to: Timothy F. Feltes, Section of Pediatric Cardiology, OhioState University and The Heart Center at Children's Hospital, 700 Children'sDtive, Columbus, OH 43205, United States of America. Tel: + 1 6l4 722 2565;Fax: +1 614 722 2549; E-mail: tfeltes@chi.osu.edu

Accepted for publication 23 Decembet 2004

The newborn lung

There are approximately 20 million alveoluses in thenewborn lung, this number increasing to about 300million by the age of 8 years, and between 200 and

Vol. 15, No. 3 Feltes and Groothuis: Pulmonary effects of respiratory syncytial virus 267

600 million by adulthood.^ ^ Due to their smalldiameter, the airways of newborns have greater resist-ance compared with the older child.'' This necessitatesan increased workload for ventilation, a phenomenonthat can increase dramatically with even minor Iumi-nal compromise. Increased peripheral resistanceaffects ventilatory distribution, and makes newbornsmore vulnerable to hypoxaemia. Obviously, any pre-maturity of the lung will further compound theseabnormalities.

Depending upon the type of cardiac defect present,the lung of the infant may be over-circulated, as forexample in the setting of ventricular septal defect,or under-circulated as with tetralogy of Fallot. Pul-monary over-circulation associated with left-to-rightshunting may result in mucosal oedema, and Iuminalembarrassment, as well as vascular and/or cardiaccompression of the large bronchuses. In the under-circulated lung, as seen with right-to-left shunting,lung volume may be decreased, and airways may inturn be globally small.^

Infants also lack effective collateral ventilation, sothat the plugging by mucus of a single airway duringan infection of the lower respiratory tract can easilyresult in atelectasis and abnormal exchange of gases.The cellular debris and oedema often associated withinfection-related inflammation can also produce rela-tively greater obstruction in the small airways ofinfants.

Fluid filtration in the newborn lung

Efficient exchange of gases in the lung is dependentupon maintaining a dry interface between the alveo-luses and the capillaries. Simply stated, the amountof fluid produced in the lung must be less than orequal to the amount of fluid that is eliminated. Other-wise, accumulation of fluid, and oedema, will resultover time. In the mature lung, multiple safety factorsassure this favourable balance. In a series of experi-ments in dogs, in which the left atrial pressure wassequentially increased, Guyton and Lindsey^° demon-strated that, despite increases in the microvascularhydrostatic pressure, the principal driving pressurefor fluid filtration in the lung, balance was main-tained over a wide range of left atrial pressures.'° Thesafety factors include, but are not limited to, vascularrecruitability, integrity of the interstitial matrix, lowendothelial and epithelial oncotic and hydrostaticconductance, active sodium uptake from the alveo-luses, and effective lymphatic drainage. In the new-born, there are maturational differences that lessenthe capacity of the safety factors. Likewise, the changesassociated with congestive heart failure may furtherlimit the ability of the newborn lung to compensateduring respiratory syncytial viral bronchiolitis.

Lack of vascular recruitment

Postnatal pulmonary vascular and lymphatic devel-opment parallel growth of the airways.' As alveolusesare added while the lung matures, vascular and lymph-atic surface area increases, so that pulmonary vascu-lar resistance and the ability to drain fluid from thelung increases with age. At birth, the pulmonaryvascular bed of the newborn lung is nearly fullyrecruited.' ̂ This is vastly different, however, from theadult pulmonary vascular bed, which is primarilyrecruited in the base and middle lobes. In the adult,when flow of blood to the lungs increases, for example,as a result of exercise, an increase in left atrial pressureor stress causes additional pulmonary vascular chan-nels to be recruited. Thus, despite an increase in pul-monary flow, the microvascular hydrostatic pressuredoes not increase significantly, thanks to a decreasein pulmonary vascular resistance. Furthermore, notonly are vascular channels recruited, but also add-itional lymphatics that can drain interstitial fluid.

In contrast, because the pulmonary resistance isrelatively fixed in the newborn, further increases inflow of blood necessitate an increase in microvascularhydrostatic pressure. This results in increased trans-vascular fluid filtration. Likewise, no additionallymphatic channels are recruited to drain the inter-stitial fluid.

Interstitial matrix and structural integrityof the microvasculatureThe two primary classes of molecules of the intersti-tial matrix include collagen, principally type IV, andproteoglycans, which are polysaccharide-protein con-jugates. ̂ '̂̂ ^ The collagen is responsible for main-taining alveolar-capillary integrity. While renderingsome structural support, the proteoglycans serve asignificant role in lung fluid maintenance.^^

The proteoglycans are hydrophilic molecules.With an increase in pulmonary microvascular hydro-static pressure, transvascular filtration increases.Interstitial water is then bound to the proteoglycans,being held in reserve until it can be drained by thelymphatic system. This maintains a dry interfacebetween the alveoluses and the capillaries. These mol-ecules, coupled with the capacitance of the inter-stitium, are likely to account for the lack ofdevelopment of pulmonary oedema during acuteincreases in pulmonary microvascular hydrostaticpressure.^ There are no data to suggest that thenewborn lung does not share similar safety factorsagainst oedema as does the mature lung. In the pres-ence of heart failure, however, transvascular fiuid fil-tration increases, and the interstitium can becomedistended. With this, the proteoglycans are stretched,and can lose their ability to bind water, which can then

268 Cardiology in the Young June 2005

enter the alveolar space. In the presence of highmicrovascular hydrostatic pressure, it is possible thatcapillary endothelium, and possibly the alveolarepithelium, lose their sieving properties, allowingproteins and solutes to leak into the interstitium andalveoluses. In cases of extreme pressure in animal mod-els, there is interruption of the endothelium and alve-oluses, a condition referred to as "stress failure".^^'^'This can lead to interstitial and alveolar haemorrhage.Fu et al. demonstrated that pressure-induced micro-fractures of the capillary endothelium and alveolarepithelium occur at much lower microvascular hydro-static pressures in newborn animals than in adults.

The chronic effects of heart failure can increase thealveolar capillary interface with basal laminar thicken-ing brought about by added matrix deposition. Thisthickening can add resistance to gas exchange acrossthe alveolar capillary interface, and make the patientmore vulnerable to hypoxaemic complications.

Endothelial dysfunction in patients with heart fail-ure may alter pulmonary haemodynamics and affectfluid filtration in the lung.^^ Patients who have highpulmonary flow have elevated levels of endothelin inthe serum.^^ A powerful vasoconstrictor, endothelincan cause an increase in microvascular hydrostaticpressure. Likewise, decreased local production of nitricoxide may also contribute to altered pulmonary vas-cular tone and increased microvascular hydrostaticpressure.

Impaired sodium pump function

Recently, another important mechanism has beenrecognised for the elimination of excess fluid fromthe airways, namely the active uptake of alveolarsodium.^"'̂ ^ The type II bronchial epithelial cells areasymmetrical, with the apical portion facing the air-way and the basolateral portion facing the pulmonaryinterstitium. Sodium is actively pumped from thealveolar space by active epithelial sodium channelsalong the apical pole. Sodium is then pumped fromthe bronchial epithelial cell into the interstitium bybasolateral sodium-potassium ATPase pumps. Theosmotic gradient created by this ion shift draws waterout of the alveolar space. The activity of these sodiumpumps is enhanced by catecholamines, steroids, thy-roid hormones and inhibitors of acetylcholine esterase,but is reduced by various factors that are present incongenital heart disease and congestive heart failure,including atrial natriuretic peptide, cytokines and thepresence of alveolar hypoxia. ̂ '̂̂ ^

Decreased lymphatic drainage

The majority of pulmonary lymphatic channels even-tually drain into the thoracic duct, which in turn

drains into the central venous system. Drake et al.have demonstrated that increasing the central venouspressure can affect drainage through the thoracicduct. In the fetal and newborn lamb, Johnson et al.demonstrated that the flow of lymph through thelungs ceases at much lower central venous pressuresthan it does in the adult sheep. This may have sig-nificant clinical implications for patients with con-genital heart disease and heart failure. This relativesensitivity to central venous hypertension mayexplain, at least in part, altered pulmonary mechanicsin conditions such as chronic lung disease, for example,bronchopulmonary dysplasia, those with an unstableearly bidirectional Glenn anastomosis, and those withright heart failure from congenital cardiac disease.^'

Little is known regarding the control of lymphaticvascular smooth muscle. In some lymphatic beds,such as that in the mesentery, an intrinsic pulsatilityof the lymphatic mural smooth muscle occurs, whichpresumably helps drive lymph toward the centralvenous system. Inhibitors of this pulsatility includenitric oxide, and nitrogen-bearing vasodilators suchas sodium nitroprusside.^^ Although unproven, thisinhibition, if it exists, in the pulmonary lymphaticbed may have clinical implications for the patient withcongenital heart disease or congestive heart failure inwhom vasodilators are being used.

The factors outlined above, which may be com-pounded by congenital heart disease, increase the sus-ceptibility of the infant lung to further respiratorycomplications, for example those arising from infectionby the respiratory syncytial virus.

Acute effects of the respiratory syncytialvirus on the lung

For the child with congenital heart disease, develop-ment of respiratory syncytial viral bronchiolitis canbe the final component of the "perfect storm" thatleads to a disastrous outcome. Not only is the patientat risk of serious morbidity and mortality associatedwith the acute disease, but the effects of illness canconfound future scheduled surgical management.

So, what are the characteristics of acute respiratorysyncytial viral bronchiolitis? Certainly bronchialepithelial sloughing, impaired surfactant production,and airway obstruction, can lead to segmental atelec-tasis and alveolar hyperinflation - evident on thetypical chest radiograph in respiratory syncytial viralbronchiolitis.^^ There is strong evidence that thepathophysiology goes well beyond these directcytopathological effects. Carpenter et al.̂ ^ demon-strated that pulmonary oedema occurs in animalswith respiratory syncytial viral bronchiolitis, especiallyin the presence of hypoxia. The fact that respiratorysyncytial viral bronchiolitis results in significant

Vol. 15, No. 3 Feltes and Groothuis: Pulmonary effects of respiratory syncytial virus 269

Table. Aetiologies of pulmonary oedema: risk factors for development of pulmonary oedema are outlined as a function of immaturity of thelung, events occurring during heart failure and during acute respiratory syncytial virus lower respiratory tract infection. Columns indicatewhether risk results in increased lung fluid formation or elimination.

Increased lung fluid formation Decreased lung fluid elimination

Maturational factorsReduced pulmonary vascular recruitabilityPulmonary endothelial/epithelial risk of microfracturing

Heart failureIncreased pulmonary blood flowIncreased pulmonary microvascular hydrostatic pressurePossible pulmonary vascular inflammatory responseEndothelial pulmonary dysfunctionEndothelial permeability changeImpaired pulmonary interstitial matrix

Acute respiratory syncytial virus lower respiratory tractinfectionPerivascular inflammation with- endothelial permeability change- possible bronchial epithelial permeability changeIncreased pulmonary microvascular hydrostatic pressure

Vulnerable pulmonary lymphatic dysfunctionNon-recruitable pulmonary lymphatics

Impaired lymphatic function due to central venous hypertensionImpaired bronchial epithelial sodium pumpsNonrecruitable pulmonary lymphaticsUnknown effect of heart failure treatment on lymphatic pulsatility

Virus and hypoxia-impaired bronchial epithelial sodium pumpsPossible impaired lymphatic function secondary to centralvenous hypertension

perivascular infiltrates strongly suggests that aninflammatory component exists in these patients.^^This inflammatory response, in turn, leads to alteredvascular tone and permeability changes of the alveolar-capillary interface (Table).

Infected bronchial epithelial cells release pro-inflammatory cytokines and chemokines, for example,interleukin-1, interleukin-6, interleukin-8, andtumour necrosis factor-alpha, which in turn recruitinflammatory cells, including T lymphocytes, intothe lung.^° T lymphocytes then produce additionalcytokines which are patterned by either a T helper cellsof either type 1 or 2 profile. An antiviral response ofthe type 1 helper cells, which is typical of a matureresponse, is characterised by cytokines that includeinterleukin-12 and interferon activity. A responseby the type 2 helper cells, characterised by produc-tion of interleukin-4, and interleukin-5, promoteseosinophilia, and may enhance an inflammatory state.The airway secretions of infants with respiratory syn-cytial viral bronchiolitis reflect a response patternedby the type 2 helper cells.̂ ^"^^ As a result, cytokineswith vasoactive effects linger in the lung of thepatient infected by the respiratory syncytial virus.^^

The permeability characteristics of the capillaryendothelium may be altered by cytokines. Vascularpermeability factor has been found in increasedamounts in the airways of children with respiratorysyncytial viral bronchiolitis. Due to the increasedoncotic and hydraulic conductance of the micro-vascular bed, there is increased transcapillary filtration,overloading an already taxed ability to drain theinterstitium of the patient with congenital heart dis-ease. Less well known are the effects of these cytokineson the alveolar epithelial cells that are normallyalmost impervious to water and solutes.

The vasoactive effects of the perivascular inflam-matory response in respiratory syncytial viral bron-chiolitis may also contribute to formation of oedema.Cytokine-induced production of endothelin in thelung results in increased pulmonary vascular tone,increasing pulmonary microvascular hydrostatic pres-sure, which promotes free water filtration.^^ Thishypothesis, compounded by a change in oncotic con-ductance as described earlier is strengthened by aseries of experiments by Carpenter and Stenmark,in which they demonstrated a reduction in formationof pulmonary oedema and extravasation of proteinin animals with hypoxic respiratory syncytial viralbronchiolitis pre-treated with endothelin receptor

^5

Respiratory syncytial viral bronchiolitis may alsodirectly alter the expression and activity of sodiumchannels, important for elimination of excess fluidfrom the airways. This has been shown to occur duringinfection with other viral pathogens, such as theinfluenza virus and adenovirus.̂ " '̂̂ ^ In addition,hypoxia is thought to impair alveolar liquid clearanceby inhibiting epithelial sodium transport.̂ '̂̂ '̂̂ ^ Thus,the respiratory syncytial virus may directly and indir-ectly, via associated regional hypoxia, impair fluidclearance mechanisms.

The development of pulmonary oedema due toinfection by the respiratory syncytial virus, there-fore, involves the interplay of multiple factors. Inoverview, raised hydrostatic forces act to increaseleakage of fluid into the lung interstitium, accentu-ated under conditions where there is direct injury tothe capillaries. Together with concurrent impair-ments of the protective mechanisms for the alveolarclearance of liquids, alveolar flooding can result(Fig. 1).29

270 Cardiology in the Young June 2005

RSV

Fluid Alveolar lumen

D Epithelium

Interstitium

ii D Endothelium

oCapillary lumen

Hydrostatic forces

Clearance of fluid fromalveolus or interstitium

Figure 1.Potential aetiology of pulmonary oedema in respiratory syncytialviral (RSY) infection.^'^ Adapted, with permission, from CarpenterTC, Stenmark KR. Predisposition of infants with chronic lungdisease to respiratory syncytial virus-induced respiratory failure: avascular hypothesis. Pediatr Infect Dis J 2004; 23 (1 Suppl):S33-S40.

Long-term effects of the respiratory syncytialvirus on the lung

The effects of infection by the respiratory syncytialvirus are not only confined to acute morbidity; theremay also be long-term sequels. This has been clearlyillustrated by a number of studies linking infectionto the incidence of subsequent reactive disease of theairways or asthma.""^^^

While the majority of clinical studies in this areaare retrospective, perhaps the most convincing clinicalevidence to date comes from a prospective controlledstudy by Sigurs et al., ' in which previously healthychildren have now been followed up for 7.5 years. Atthis time, the cumulative prevalence of asthma wassignificantly higher in those infected by the respira-tory syncytial virus group than in the control group(p < 0.0001, 95% confidence interval of2.79—30.55). Furthermore, the cumulative prevalenceof "any wheezing" was also significantly differentbetween the two groups (p < 0.001, 95% confidenceinterval of 1.40-2.79). Similar patterns were seen upto 7.5 years of age in the occurrence of current asthmaand current "any wheeze" (Fig. 2).

The authors concluded that the results of thislong-term prospective study, together with data froma number of other studies of index children and com-parison groups,''^ provide strong evidence that respira-tory syncytial viral bronchiolitis in infancy isassociated with a higher risk of developing subsequentbronchial obstructive disease. This supports thetheory that the respiratory syncytial virus plays a

• 1 yearB 3 years• 7.5 years

RSV ControlsAny wheezing

RSV ControlsAsthma

Figure 2.The occurrence of current asthma and "any wheezing' in 47 chil-dren hospitalised with respiratory syncytial virus (RSV) ininfancy, compared with that in 93 matched controls, at 1 year, 3years and 7.5 years of age. ' "Current" is defined as beingduring the preceding year. *p 0.003; **p < 0.001; ***p < 0.0001;^p 0.004 Reproduced, with permission, from Sigurs N, BjamasonR, Sigurbergsson P, Kjellman B. Respiratory syncytial virus bron-chiolitis in infancy is an important risk factor for asthma andallergy at age 7. Am J Respir Crit Care Med 2000; 161:1501-1507.

significant role in influencing the mechanismsinvolved in the development of asthma and allergyat least in some children.

A number of theories have been proposed toexplain the potential cellular and molecular mech-anisms underlying the association between respira-tory syncytial viral infection and subsequent reactiveairways disease and asthma. The virus may predis-pose to reactive disease or asthma by altering airwayimmune responses, and/or by dysregulating neuralcontrol of the airways."* '̂"*^^^

Infection may lead to a loss of chemoreceptors andbreakdown of the normal anatomical barriers to anti-gens, via epithelial and cilial damage. The virus isalso known to induce significant local inflammation,with profuse release of cytokines, ' and it is possiblethat these inflammatory mediators may alter the localimmune memory in the lung. Studies in animalmodels suggest that respiratory syncytial virus infec-tion at an early age shifts the subsequent immuneresponse pattern, from a protective immunity medi-ated by Type 1 helper cells to an allergic or atopicresponse mediated by the type 2 helper cells. Thesestudies suggest that it is the timing of the initialinfection that determines any potential subsequentdisruption of the normal balance of the helpercells. 2.50,51 ̂ strategy of delaying respiratory syncy-tial viral infection beyond infancy by prophylaxis maytherefore have the potential to reduce respiratory mor-bidity in later childhood by interrupting the processesintrinsic in alteration of airway immune responses.

Vol. 15, No. 3 Peltes and Groothuis: Pulmonary effects of respiratory syncytial virus 271

Another mechanism that may have implicationsfor the management of vulnerable infants andyoung children, such as those with congenital heartdisease, is neurogenic-mediated pulmonary inflam-mation^ '̂̂ '̂̂ '̂'̂ caused by respiratory syncytial virus-induced damage to sensory nerve fibres in the lung.This damage results in the release of substanceP, a very potent inflammatory mediator, whichleads to recruitment of leucocytes, mast cells andeosinophils, and an increase in levels of inflamma-tory cytokines. The respiratory syncytial virus mayalso act to increase the expression of nerve growthfactor, and neurotrophin receptors, thereby triggeringother inflammatory and neuronal pathways that con-tribute to inflammation and hyper-reactivity of theairways.

It is our belief that, in reality, the mechanismsoutlined above may be linked, and that a combinedneuroimmune response may underlie the proposedconnection between respiratory syncytial viral infec-tion in infancy and development of reactive airwaysdisease and asthma in later life.

Long-term benefits of prevention of respiratorysyncytial viral infection

Asthma is a major clinical problem, affecting as manyas 300 million individuals worldwide. With such anextensive prevalence, the global economic and per-sonal burden resulting from this disease is enormous.'

Considering the increasing body of evidence report-ing a link between respiratory syncytial viral infectionin infancy and development of subsequent reactive air-ways disease and asthma in later life, it follows thatthere may be long-term health and economic benefitsof preventing infection by the respiratory syncytialvirus. Prophylaxis in infancy, therefore, provides anexciting prospect as a strategy for abrogating subse-quent development of persistent wheezing andasthma-like symptoms in later childhood.

This rationale is supported by animal studies whichshow that the monoclonal antibody palivizumab(Synagis ), can inhibit respiratory syncytial virus-induced neurogenic-mediated inflammation in ratairways (Fig. 3).^' Palivizumab was effective ininhibiting neurogenic inflammation when given 24hours before, or 72 hours after, intranasal respiratorysyncytial virus inoculation. As no direct effect wasobserved in pathogen-free rats, it was concluded thatthe anti-inflammatory effect of palivizumab resultsfrom inhibition of viral entry into the airway epithe-lium. It is also proposed that palivizumab may havetherapeutic activity when administered early afterupper respiratory tract infection, prior to the estab-lishment of widespread infection in the lungs. Thissuggests that administration of palivizumab not only

24 hours beforeRSV inoculation

72 hours afterRSV inoculation

IIntranasal administration

Figure 3.The effect of palivizumab on respiratory syncytial virus (RSV)-induced neurogenic inflammation in rats.^^ ***p < 0.001.Reproduced, with permission, from Piedimonte G, King KA,Holmgren NL, Bertrand PJ, Rodriguez MM, Hirsch RL. Ahumanized monoclonal antibody against respiratory syncytial virus(palivizumab) inhibits RSV-induced neurogenic-mediated inflam-mation in rat airways. Pediatr Res 2000; 47: 351—356.

prevents respiratory syncytial viral infection but, ifinfection does occur, it may limit the severity of theacute airway inflammation, thereby potentially pro-tecting against subsequent reactive airways diseaseor asthma.

To extrapolate these findings to the clinical situ-ation, a multinational, prospective, case-controlledobservational study is being conducted to determinewhether prophylaxis leads to a decreased incidenceand severity of subsequent reactive airways disease inchildren. The study, which was initiated in 2001,has enrolled high-risk preterm infants, less than orequal to 35 weeks gestation, without chronic lungdisease from centres based in Germany, Spain, TheNetherlands, Sweden, Poland and Canada. Theseinfants will be followed up for a total of three years.The primary endpoints include incidence of asthma,defined as three episodes of physician-documentedwheeze, or recurrent wheezing repotted by caregivers.The secondary endpoints include hospitalisation forrespiratory illness and use of medications for reactiveairways disease. Interim findings were presented atthe meeting of the European Respiratory Society inGlasgow.' It was demonstrated that prophylaxiswith palivizumab in preterm infants reduced recur-rent wheezing and asthma in the subsequent 1 and1.5—2 years compared with control preterm infantswho had not been thus treated.

Results from this study are eagerly awaited, asclinical evidence of an effective therapeutic strategythat protects against development of reactive air-ways disease or asthma would have healthcare andeconomic benefits on a global scale.

272 Cardiology in the Young June 2005

Conclusions

It is extremely important to protect vulnerable infantsand young children with congenital heart disease fromthe additional acute pulmonary morbidity that resultsfrom severe respiratory syncytial viral infection. It isalso becoming increasingly apparent that infection bythe respiratory syncytial virus may have long-termeffects on the lung, manifested as an increase in theincidence of subsequent reactive disease of the airwaysand asthma. Such long-term effects may have wide-spread implications, and impose additional burdenson health and quality of life, particularly for thosewith congenital heart disease.

The potential for prophylaxis in young childrenagainst the respiratory syncytial virus in order toprevent the potential subsequent recurrence of react-ive airways disease or asthma in later life is an excit-ing therapeutic prospect, and one which could havewidespread clinical impact. Future developments inthis area are awaited with anticipation.

Acknowledgements

We are grateful to Thomson ACUMED® for someeditorial assistance in the development of this paper.Sources of fmancial support: This paper is based onpresentations given at a meeting funded by an unre-stricted educational grant from Abbott Laboratories.

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