management of acute bronchiolitis - adc.bmj.com · managementofacute bronchiolitis moderate-severe...

Archives of Disease in Childhood 1994; 71: 463-469

PERSONAL PRACTICE

Management of acute bronchiolitis

Karl Rakshi, Jonathan M Couriel

As winter approaches, paediatricians steelthemselves for the annual flood of babies withacute bronchiolitis. It is the commonest lowerrespiratory tract infection in infants. Around10% of babies develop bronchiolitis in theirfirst year and a fifth of these are admitted tohospital.' In this children's hospital between200 and 260 infants are admitted with thedisease each winter. The epidemic imposesgreat strains on the hospital: for example, inthe first eight weeks of 1993, there were 179admissions of infants with bronchiolitis, with amean length of stay of 4-5 days. We ventilate12-25 babies for bronchiolitis each winter:they occupy a total of 70-190 days a year onthe intensive care unit.Many aspects of management remain

controversial. For example, what is the mostreliable way of assessing the severity ofbronchiolitis? What is the role of electronicmonitoring, or ribavirin (tribavirin), ofphysiotherapy? Are bronchodilators helpful?If babies cannot feed, should they be givenintravenous or nasogastric fluids? Whichbabies need intensive care? How can we reducecross infection? In this paper we examine theseand other controversies in the care of the childwith bronchiolitis.

Booth Hall Children'sHospital (University ofManchester School ofMedicine),Charlestown Road,Blackley, ManchesterM9 7AAK RakshiJ M Couriel

Correspondence to:Dr Couriel.

Aetiology and pathophysiologyIt is helpful to have a clear understandingof the aetiology and pathophysiology ofbronchiolitis. Acute bronchiolitis is due to viralcolonisation of the bronchiolar mucosa.

Respiratory syncytial virus (RSV) is thepathogen in 70-85% of cases, the remainderbeing caused by parainfluenza, influenza,and adenoviruses.' 2 Dual infection with otherviruses, or organisms such as Chlamydiatrachomatis or Mycoplasma pneumonia, is morecommon than previously thought, occurringin at least 5-10% of cases of RSV lowerrespiratory infection.3 4The virus replicates rapidly in the bron-

chiolar epithelium, causing necrosis of theciliated cells and proliferation of non-ciliatedcells. The ciliary damage impairs clearance ofsecretions. This, combined with increasedmucus secretion and desquamation of cells,leads to bronchiolar obstruction, atelectasis,and hyperinflation. The peribronchial tissuesshow inflammatory infiltration, submucosaloedema, and congestion. An associatedinterstitial pneumonia may occur. Structuralrecovery usually occurs in two to three weeks.

Occasionally, and particularly if adenovirusserotype 7 or 21 is the pathogen, there ispermanent bronchiolar damage with persistentsegmental or lobar atelectasis and hyperinfla-tion (bronchiolitis obliterans).The acute functional consequences of

these changes are small airways obstruction,gas trapping, and impaired gas exchange.Thoracic gas volume and respiratory resistancerise, and expiratory flow rates and dynamiccompliance fall.' 2 5 The work of breathingand oxygen consumption are increased.6Impaired ventilation, combined with ventila-tion perfusion imbalance, and in some infants,hypoventilation due to apnoea or exhaustion,lead to hypoxaemia and hypercarbia. ' 7 8

DiagnosisAccurate diagnosis is based on the clinicalfeatures. Fever and a nasal discharge precede adry cough and increasingly rapid, distressedbreathing. Wheezing is often, but not always,audible. Feeding difficulties due to dyspnoeaare often the reason for admission. Centralapnoea with cyanosis is seen in 10-20% ofbabies admitted with bronchiolitis.9-11 Apnoeausually occurs early in the illness: it can be thepresenting feature, preceding the features ofairways obstruction.

Examination reveals tachycardia andtachypnoea, with subcostal, intercostal, andsupraclavicular recession. Unlike the breathingpattern seen in croup or pneumonia, there islittle sternal recession, as gas trapping preventsthis. The sternum is prominent, the chestappears barrel shaped, and the liver isdisplaced downwards, indicating hyper-inflation. The child has a short, dry, wheezycough. There are fine inspiratory cracklesand/or high pitched expiratory wheezes inall lung fields. In severe cases there may beirregular breathing, cyanosis or pallor. Feveris present in most infants; conjunctivitis,pharyngitis, or otitis media in a minority.

Identifying the high risk infantCertain infants are at high risk of severe illness,respiratory failure requiring ventilatory support,and of dying with bronchiolitis (table 1).Children with chronic lung disease, congenitalheart disease, or immunodeficiency are atparticularly high risk.'2-15 Infants aged less than6 weeks and those born prematurely are also atrisk: apnoea is common in these babies.9

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Table 1 Risk factors for severe bronchiolitis

Age less than 6 weeks at presentationApnoeaPreterm birthUnderlying disordersLung disease (for example bronchopulmonary dysplasia,

cystic fibrosis)Congenital heart diseaseImmunodeficiency (congenital or acquired)Multiple congenital abnormalitiesSevere neurological disease

In a case-control study of 33 infantsventilated for RSV bronchiolitis and 99 infantspositive for RSV who were not ventilated, 39%of the ventilated infants had apnoea beforeadmission and 63% had apnoea before ventila-tion was started (T G Powell, J M Couriel,unpublished data). Apnoea was significantlymore frequent in infants born prematurely.The median postconceptional age was 19 daysin the ventilated group and 122 days in thecontrols. Over 90% of the ventilated infantsweighed less than 5 kg on admission. Othershave shown that low birth weight, pretermdelivery, neonatal respiratory disease, andyoung age are all risk factors for respiratoryfailure.'6 Infants with any of these factors needclose observation.

Differential diagnosisOther conditions can mimic bronchiolitis andmay easily be overlooked (table 2). Forexample, we have seen children with previouslyunsuspected cystic fibrosis, aspiration pneu-monitis, congenital cardiac and lung defects,and immune deficiency, with a misdiagnosis ofbronchiolitis. Careful attention to the preced-ing history, examination, and chest radiographusually allows other causes to be identified. Itmay be impossible to distinguish between thefirst episode of asthma and acute bronchiolitis.Even when the diagnosis of bronchiolitis is

certain, an underlying congenital abnormalityor dual infection should be considered if theillness is severe, prolonged, or atypical. Forexample, babies with congenital heart defects,and particularly those with pulmonary hyper-tension, may be asymptomatic until theydevelop bronchiolitis, when they deterioraterapidly.

InvestigationsInvestigations often add little to management.A chest radiograph typically shows hyper-inflation, with depressed and flatteneddiaphragms. A third of infants have collapse or

consolidation, particularly in the upper lobes.Unfortunately, there is no correlation betweenthese findings and the severity of the illness.'7It has been suggested that chest radiographsshould not be done routinely in bronchiolitis:they should be reserved for infants with severe

disease, sudden deterioration, or an underlyingcardiac or respiratory disorder.'7 Full bloodcounts and serum electrolytes are normal inover 80% of children admitted with bron-chiolitis.'8 Electrolyte disturbances, mostnotably hyponatraemia, are uncommon unlessthere is severe disease.'9 20 Arterial blood gases

Table 2 Differential diagnosis of acute bronchiolitis

PulmonaryAsthmaPneumonia

Infective - for example RSV, Chiamydia trachomatisAspiration - for example with gastro-oesophageal refluxOpportunistic, secondary to immunodeficiency- for

example, Pneumocystis carinii, cytomegalovirusCongenital lung disease - for example, congenital lobaremphysema, lung cysts

Cystic fibrosisInhaled foreign bodyNon-pulmonaryCongenital heart disease - for example obstructed pulmonaryvenous drainage, VSD

SepticaemiaSevere metabolic acidosis

VSD=ventricular septal defect.

should be performed only in severe cases.Arterial carbon dioxide levels may be above10 kPa in infants admitted to hospital.' 7

Respiratory syncytial virus and the otherrespiratory viruses can be identified by fluores-cent antibody techniques or by culture ofnasopharyngeal secretions. Although rapidviral identification has been used to isolatechildren positive for RSV,21 the lack of apositive result does not preclude a diagnosisof bronchiolitis or affect outcome. Viralidentification is desirable rather than essential.

Assessing and monitoring severityHypoxia is the most vital physiologicalconsequence of bronchiolitis. However,hypoxia can be difficult to detect clinically ininfants with respiratory infections.22 Fewclinical scores for bronchiolitis have beenvalidated against arterial oxygen levels.Mulholland et al compared blood gases withoxygen saturation (Sao2) measured by pulseoximetry and clinical signs in infants withbronchiolitis.8 Crackles and cyanosis corre-lated with arterial oxygen but respiratory rate,heart rate, and recession did not predicthypoxaemia. Others have found that clinicalsigns correlate poorly with hypoxaemia.7 22-24Pulse oximetry is the most reliable method toassess the severity of illness and the oxygenneeds in bronchiolitis.

Pulse oximeters are not universally available,and serial clinical assessments are still essentialto monitor the progress of the disease. Pulseoximetry also has important limitations.25-27Serious errors in Sao2 can occur with poorapplication of the sensor, especially if thereis a gap between sensor and skin so thatlight bypasses the tissue bed.26 Significanthypoxaemic episodes may be missed with themovement artefact that can occur duringcrying or procedures.27 Oximetry can beunreliable if there is anaemia, hypotension, orhypothermia. Different makes of pulseoximeter have different normal values.Monitors are inaccurate once the Sao2 fallsbelow 80%. Nevertheless, the advantages ofoximeters in providing continuous, instan-taneous, and non-invasive measures of arterialoxygen levels far outweigh their limitations.We routinely measure Sao2 at presentation

in all infants with bronchiolitis. We alsomonitor Sao2 continuously in infants with

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moderate-severe disease, and particularly allthose receiving oxygen or with risk factors(table 1). In young infants and those bornpreterm, we also use respiration monitors(Graseby MR10) to detect central apnoea.

Preventing cross infectionMany children who are admitted to hospitalwithout RSV infection acquire the diseasefrom other infants. Cross infection is animportant cause of morbidity and death,particularly in children with pre-existingcardiorespiratory disease. Cross infection ratesof 15-30% have been recorded with RSV.28The virus is shed in large quantities in respira-tory secretions and is easily passed frompatient to patient. The hands of healthprofessionals and family members are themost important vectors; droplet spread is lessimportant.One careful study showed that a com-

bination of rapid virus identification, cohortnursing, and the use of gowns and glovesreduced the cross infection rate from 26% to9O/%.21 In this study, isolation of RSV positivebabies and handwashing were ineffective bythemselves. Others have found isolation andhandwashing to be effective in reducinghospital acquired RSV infections and havestated that virus identification, gloves, andgowns are unnecessary.29 30 We use isolationand handwashing.

TreatmentMany different forms of treatment are used inthe care of infants with acute bronchiolitis:most are of unproved or limited benefit.Adequate hydration and oxygenation, minimalhandling, and the early recognition andtreatment of complications are the foundationof good care.

FLUIDSDespite poor feeding, severe dehydration isuncommon in bronchiolitis. Hyponatraemiadue to increased secretion of antidiuretichormone does occur in RSV infections,particularly in infants with high levels ofcarbon dioxide tension and those needingventilation.'9 20 We, and others, have seenseizures and severe recurrent apnoeasassociated with hyponatraemia.19 Fluid intakeshould be restricted to two thirds of the normaldaily allowance and electrolyte concentrationscarefully monitored in all infants with severebronchiolitis.20

Practices differ in the way that fluids aregiven to infants who cannot feed adequately.In theory, obstructing a nostril increasesrespiratory resistance and the work of breath-ing and should be avoided in respiratorydistress. A dilated stomach may furtherembarrass ventilation. In practice, manyinfants with mild-moderate bronchiolitistolerate a nasogastric tube satisfactorily. If thepassage of a tube increases respiratory distress,then it should be removed. In sick children

receiving oxygen, those with very rapidrespiratory rates, or those with apnoeas, wegive fluids intravenously.

OXYGENOxygen is the only agent that consistentlyreduces hypoxaemia in bronchiolitis. Asdescribed already, clinical assessment is oflimited reliability in detecting hypoxaemia:ideally, the amount of oxygen an infantrequires should be assessed by their Sao2levels. We aim to maintain the Sao2 above93-95% and adjust the inspired oxygenconcentration accordingly. Oxygen should bewarm and humidified. It can be delivered intoa headbox or tent. Some babies toleratefacemasks or short nasal prongs poorly.Nasopharyngeal oxygen is effective in childrenwith respiratory distress,31 but has not beenassessed specifically in acute bronchiolitis.

BRONCHODILATORSThe value of bronchodilators in bronchiolitisremains controversial. In North America,nebulised 3 agonists or adrenaline are widelyused,32 but in Britain they are regarded asineffectual.33-5 These views reflect differencesin definition of the disease: many Americanstudies of bronchiolitis include children whowould be diagnosed as having asthma in theUK.1 35

Several studies have shown improved lungmechanics after bronchodilators. Soto et alfound a significantly improved specificconductance in 30% of infants with RSVbronchiolitis given nebulised salbutamol.36Tepper et al showed improved expiratoryflow rates with orciprenaline in some infants.37In infants ventilated for bronchiolitis,nebulised isoetharine improved expiratoryflow.38 Nebulised ipratropium bromidereduced the work of breathing in bronchiolitis,but produced no clinical improvement.6 39The clinical response to bronchodilators has

also been studied. Two studies of childrenwith wheeze showed a transient improvementin some respiratory signs after nebulisedsalbutamol.40 41 However, these studiesincluded children up to the age of 21 months,only half the subjects had proved RSVinfection, and the studies lasted only 2-4hours. Wang et al showed no improvement inSao2 or clinical score with regular nebulisedsalbutamol and/or ipratropium bromide ininfants with mild bronchiolitis.42 Ho et alfound a fall in Sao2 with nebulised salbutamolin RSV positive infants.43 Sanchez et alcompared salbutamol to nebulised racemicadrenaline in patients with acute bronchiolitis.Salbutamol had no effect on clinical score,Sao2, or respiratory resistance. Adrenalineimproved respiratory rate and inspiratory andexpiratory resistance.44 There is no clearevidence that oral or intravenous amino-phylline is beneficial in bronchiolitis.45 46How should we interpret these results?

What does a change in clinical score or lungmechanics after one or two doses of a

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bronchodilator mean in an illness that lasts fordays? There is no convincing evidence thatbronchodilators produce a clinically significantimprovement in infants with viral bronchio-litis.33-35 We do not routinely use them inbronchiolitis. A trial ofnebulised salbutamol oripratropium is reasonable in older infantswhere distinction from asthma may bedifficult, or in children with bronchiolitis andbronchopulmonary dysplasia, who sometimesrespond. Because bronchodilators may worsenhypoxaemia in wheezy infants, we stronglyrecommend that they are given in oxygen andthat careful clinical and Sao2 monitoring isused to assess their effect.

RIBAVIRINRibavirin is a synthetic nucleoside with viro-static activity against many viruses includingRSV. An aerosol from a small particle aerosolgenerator is delivered to a headbox, facemask,or oxygen tent for 12-20 hours a day for 3-5days. It can be given through a ventilatorcircuit if valves are used in the inspiratory lines,a breathing circuit filter is placed in theexpiratory line, and filters are replacedregularly to prevent deposition of the drugwithin the ventilator.47 48 Side effects are rarein patients or health workers.49 Because of atheoretical risk of teratogenicity, pregnantwomen should avoid exposure to ribavirin.15

Early studies of ribavirin in RSV bronchio-litis showed improved clinical signs andoxygenation. However, the design of thesestudies was flawed.50 51 In previously wellchildren with bronchiolitis, there is noconvincing evidence ribavirin expeditesrecovery or reduces complications.The American Academy of Pediatrics has

recommended the use of ribavirin in certaininfants with RSV infection.'5 These includeinfants with congenital heart or chronic lungdisease, impaired, multiple abnormalities,preterm infants and those less than 6 weeks ofage, and infants ventilated for RSV infection.Few British paediatricians follow this advice.We are unconvinced there is evidence tosupport these indications. For example, whileprematurity and young age are risk factors forsevere disease, we do not know that givingribavirin to infants with these factors isbeneficial. Similarly, the value of ribavirin inventilated children is unclear.

Several studies have suggested that ribavirinmay benefit infants with bronchiolitis andunderlying cardiopulmonary disease.50 Inbabies with bronchopulmonary dysplasia orheart disease, clinical scores improved morerapidly in those given ribavirin, but there wasno reduction in hospital stay or need foroxygen.52 In another study, high risk infantswith RSV infection were treated with ribavirinand their outcome was compared withunmatched low risk 'controls'.53 There wasmore rapid clinical improvement and fewerdays of ventilation with ribavirin, but the twogroups were too dissimilar to draw any conclu-sions. Groothuis et al studied early ribavirintreatment in children with RSV infection

and bronchopulmonary dysplasia or heartdisease.54 After three days, the improvementsin Sao2 and oxygen needs were greater withribavirin than placebo. Respiratory scores andduration of hospital stay were not improved.

Only one study has shown a benefit ofribavirin on the duration of ventilation.48Ventilated infants with RSV infection wererandomised to receive either ribavirin or sterilewater aerosols. The duration of ventilation,supplementary oxygen, and hospital stay weremarkedly less in the ribavirin group.Unfortunately, this study used nebulisedwater, a known bronchial irritant, as placebo.55The mean length of ventilation in the placebogroup was 10 days, but other studies havereported a mean length of ventilation of fourdays in infants not given ribavirin. 14 It ispossible the nebulised water prolongedventilation in the placebo group. Anothersimilar study of ventilated infants comparedribavirin with saline aerosol: ribavirin andplacebo patients did not differ in the durationof ventilation, oxygen treatment, or hospitalstay.47 Both studies excluded infants present-ing with apnoea: we know of no studies thatshow ribavirin reduces apnoea.

In 1988, Isaacs and others made a strongcase for a multicentre controlled trial of nebu-lised ribavirin in infants with cardiopulmonarydisease and babies under 6 weeks old whodeveloped RSV infection.5' The need for sucha trial remains, given the uncertain efficacy andthe significant cost of ribavirin. Until then, wewill use ribavirin in patients with proved RSVinfection and cystic fibrosis, severe immuno-deficiency, congenital heart disease andpulmonary hypertension, and in infants withbronchopulmonary dysplasia and pre-existingoxygen dependence.

CORTICOSTEROIDSCorticosteroids are of no value in viral bron-chiolitis. In a controlled study, betamethasonehad no effect on respiratory signs or lengthof admission.56 Tal et al reported a benefitin children given dexamethasone plus salbuta-mol, but this study included children withasthma.57 In a recent study, infants withbronchiolitis received intravenous hydro-cortisone and oral prednisolone, or placebo.Steroids had no effect on length of admission,lung function, or clinical recovery.58

ANTIBIOTICSAcute bronchiolitis is always viral in origin.Hall et al showed that the risk of secondarybacterial infection in children who had nounderlying pulmonary or immune disorderwas less than 2% in 565 hospitalised infantswith RSV infection.59 Although secondaryinfection is uncommon, dual infection withRSV and bacteria or other organisms should beconsidered if there are atypical clinical orradiological features. For example we recentlytreated an infant with RSV bronchiolitisand severe hypoxaemia requiring mechanicalventilation. As the chest radiograph and the

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clinical course were not typical of bronchiolitis,other organisms were urgently sought.C trachomatis was identified in nasal andtracheal secretions and erythromycin wasstarted. Thirteen RSV positive infants in thestudy of Hall et al had concurrent bacterialinfection (for example meningitis, urinary tractinfection) at presentation.59We give antibiotics to all infants who present

with recurrent apnoea, particularly if there iscirculatory impairment, as the possibility ofsepticaemia cannot be excluded. We wouldconsider antibiotics in infants with an acuteclinical deterioration, a high white cell count,a raised C reactive protein, or progressiveinfiltrative changes on chest radiography.60We favour intravenous cefotaxime, addingerythromycin if there is evidence of chlamydialinfection.

ASSISTED VENTILATIONThe decision to ventilate an infant withbronchiolitis is based primarily on clinicalgrounds. Recurrent apnoea with severe oxygendesaturation and progressive or persistentacidosis (pH <7 20), are absolute indicationsfor ventilation. We would ventilate mostinfants with a combination of disturbedconscious level, deteriorating chest movement,and persistently low Sao2 levels (<85%)despite high inspired oxygen concentrations(>60%). Increasing tachypnoea and tachy-cardia indicate deterioration but are not inthemselves indications for ventilation. There isno absolute value of arterial carbon dioxidetension that indicates the need for ventilation:infants with levels greater than 12 kPa havebeen managed without ventilation.

There needs to be close cooperationbetween paediatricians, anaesthetists, andnursing staff. We mainly use time cycledpressure limited ventilators. In older infantsand those with severe atelectasis, we use timecycled volume controlled ventilators (SiemensServo 900C). We have not found nasopharyn-geal continuous positive airways pressureuseful in avoiding the need for full ventilation.

Ventilator settings are tailored to thepatient's needs and blood gases. Expiration isdependent on airway resistance and pulmonarycompliance. Infants with bronchiolitis havepoor compliance and increased resistance.Adequate expiratory times are needed to allowexpiration and avoid hyperinflation. We use

slow rates (10-25 breaths/min) with longexpiratory times (2-3 seconds). Because ofdecreased compliance, relatively long inspira-tory times (1-1.5 seconds) are used. Peakinspiratory pressures are kept as low as possiblebut pressures over 40 cm H20 may beneeded.6' The value of positive end expiratorypressure is unproved and it may be harmful.62We aim to maintain arterial pH greater than7-28 and arterial oxygen tension greater than10 kPa. It is not necessary to increaseventilation to achieve normal arterial carbondioxide tension levels. Provided a high carbondioxide tension does not reflect tube blockage,pneumothorax or ventilator failure, and as long

as the arterial pH is acceptable, we accept highlevels of carbon dioxide tension.An active approach to weaning from ventila-

tion is important. Endotracheal intubationleads to retained secretions, atelectasis, andfluctuating degrees of hypoxaemia due toventilation-perfusion mismatch: this problemworsens with prolonged ventilation and the useof muscle relaxants. Once oxygen require-ments are 40-50% or less and peak inspiratorypressures are less than 20-22 cm H20, wechange to endotracheal continuous positiveairways pressure (4-7 cm H2O). If the infant isstable for 8-12 hours we then extubate.Most of our ventilated infants are initially

sedated with a continuous infusion ofmidazolam for 12-24 hours. We avoidprolonged use of midazolam because we areconcerned about possible neurotoxicity.For further sedation we use nasogastricchloral hydrate or intravenous morphine.Neuromuscular blockade with atracurium isused in infants who need high inspiratorypressures and in those in whom distress ispreventing effective ventilation. Fluids arerestricted to 60-80 ml/kg/day. Nasogastricmilk is started as early as possible, usually afterthe first 24 hours of ventilation. Althoughsecondary bacterial infection is uncommon,most infants we ventilate receive antibioticsbecause of infiltrates on the chest radiograph.

In infants whose condition deterioratesdespite maximal ventilator support, extracor-poreal membrane oxygenation (ECMO)should be considered. A preliminary report ofECMO in 12 infants with bronchiolitis andrefractory hypoxia despite maximal ventilationis encouraging.63 Seven infants survived:associated bronchopulmonary dysplasia didnot predict a worse outcome. The results ofclinical trials in the UK and from NorthAmerica may clarify the role of ECMO inbronchiolitis.

SEDATIONAgitation should suggest hypoxia and theneed for oxygen. We do not use sedationexcept during ventilation. High doses ofchloral hydrate (70-100 mg/kg) can cause afall in oxygen saturation with respiratorydepression.64 There is no evidence that lowerdoses help or harm. Parents and skilled nursesare important in allaying anxiety.

PHYSIOTHERAPYBabies with respiratory distress often show afall in Sao2 when handled or upset. Minimalhandling is an important aspect of care.Physiotherapy, which is still used in some unitsfor infants with bronchiolitis, is not only of nobenefit, but may cause deterioration.65

ConclusionsOver 30 years ago, Reynolds and Cooke wrotethat 'oxygen is vitally important in bronchio-litis: there is little evidence that any othertreatment is useful'.66 This statement is still

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largely true. We are better at diagnosing andassessing the illness and at limiting the damageof complications such as respiratory failure orcross infection. Novel therapies such as passiveimmunisation with high titre RSV immuno-globulin67 68 may prove to be helpful in thefuture. But there is currently no treatmentwhich has convincingly been shown to reducethe severity or duration of viral bronchio-litis in the majority of infants. This commoncondition still merits our respect and closeattention.

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Screening for neuroblastoma - biological characteristicsofthe tumours

Mass screening of 6 month old children for neuroblastoma usingurinary catecholamine analyses was started in Japan in 1985.The tumours detected appeared to have a good prognosis andoverall mortality from the disease did not fall (see Archivist1991; 66: 1007). A recent paper (Sachiyo Suita and colleagues,Journal of Pediatric Surgery 1994; 29: 599-603) gives moreinformation about these tumours.

Between 1985 and 1990 in the Kyushu area of Japan therewere 199 newly diagnosed cases of neuroblastoma. Ninety fourof these had advanced disease (stages III and IV) and are thesubject of this paper. Of these 94, 18 had been detected throughthe screening programme and 76 presented clinically.The tumours detected by mass screening and those detected

clinically differed considerably in their biological characteristics.Thus the following favourable features were found in the massscreening group: no N-myc oncogene amplification (14 of 18),favourable histological classification (10 of 10), aneuploidnuclear DNA content (three of three), and S-100 proteinpositive (three of three). In the non-mass screening group thefindings were: no N-myc oncogene amplification (30 of 45),favourable histology (four of 15), aneuploid nuclear DNAcontent (three of 10), and S-100 protein positive (11 of 21).Treatment in the mass screening group was variable but

generally less aggressive than in the patients who presentedclinically. Nevertheless, there were no deaths in the first groupbut fewer than a quarter of the second group survived for fouryears.

There seems no doubt, therefore, that the tumours detectedby screening are different and carry a much better prognosis.Whether they would regress without treatment is still uncertain.The authors suggest a treatment approach to these tumoursincluding less aggressive chemotherapy. They do not appear toconsider the possibility of abandoning the screening programme.Whether repeated or later screening would be more beneficial isnot known.

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