Archives of Disease in Childhood, 1980, 55, 348-353

Allergic bronchopulmonary aspergillosis complicatingcystic fibrosis in childhoodM J BRUETON, L P ORMEROD, K J SHAH, AND CHARLOTTE M ANDERSON

Institute ofChildHealth, University ofBirmingham, and Children's Hospital, Birmingham

SUMMARY Allergic bronchopulmonary aspergillosis, known to be associated with cystic fibrosis inolder patients, occurred in 7 young atopic children with cystic fibrosis. The diagnosis was suggestedby the onset of, or the increase in, asthmatic symptoms accompanied by major chest x-ray changesranging from total collapse of a lung or lobe to extensive but changing areas of consolidation. Eachof the children had a blood eosinophilia, positive type I skin tests to Aspergillus fumigatus, andreversible airways obstruction. Most had a positive type III skin test and circulating precipitins toA. fumigatus, with raised IgE levels which contained specific antibodies to the fungus on radio-allergosorbent (RAST) test. None had advanced suppurative chest disease of cystic fibrosis. Nonewas given specific antifungal agents; two received systemic treatment with corticosteroids, the othersreceived additional drugs for their asthma. Two developed total collapse of one lung, one child beingonly 2 years old. Five have had recurrences of pulmonary shadowing typical of allergic aspergillosisbut are not showing significant progression of their cystic fibrosis lung disease. Our experiencesuggests that there should be an increased awareness of this condition, particularly its associationwith extensive pulmonary collapse or consolidation in children with cystic fibrosis who are atopic.

Aspergillusfamigatus is probably the most importantcause of mycotic bronchopulmonary infection inwestern Europe. The clinical effect of infection withthis ubiquitous mould depends on the immunologicalstatus of the host.' In atopic individuals, allergicbronchopulmonary aspergillosis occurs morecommonly than aspergillomas or invasive asper-gillosis. The allergic form is characterised by thepresence of asthma, pulmonary infiltrates which areoften transient, eosinophilia, and positive immediateskin tests to A. fumigatus. The condition was firstdescribed in 1952 by Hinson et al.,2 and since thenhas been increasingly recognised in asthmaticpatients.3-4 Those usually affected are young adultsbut, in retrospect, the first pulmonary infiltrationmight have occurred in their childhood.5Mearns et al.6 reported an association between

Institute of Child Health, BirminghamCHARLOT M ANDERSON, professor of paediatrics and child

healthWestminister Children's Hospital, LondonM J BRUETON, senior lecturer in child healthNorth Manchester General Hospital, ManchesterL P ORMEROD, senior medical registrarDepartment of Radiodiagnosis, Children's Hospital,BirminghamK J SHAH, consultant radiologist

allergic aspergillosis and cystic fibrosis (CF) in 1965.Batten7 described some older patients in 1967, andsubsequently an incidence of 0 5 O/o8 and 5 %'9 wasreported among adolescents and young adultswith CF. We have recently recognised this com-plication rather more frequently in young childrenwith CF who are predisposed by having reversibleairways obstruction and atopy. The purpose of thispaper is to describe the spectrum of features seen insuch children, with particular reference to allergicaspergillosis as a cause of extensive pulmonarycollapse and consolidation. The results of investiga-tions on 7 patients are given in the Table.The criteria for making the diagnosis of allergic

aspergillosis were pulmonary opacity with bloodeosinophilia, a positive type I prick test reaction toan extract of A. famigatus, and the presence ofreversible airways obstruction. Supportive evidenceincluded the presence of serum precipitins to A.famigatus, culture of the fungus from the sputum,and the presence of radioallergosorbent- (RAST-)specific IgE antibodies to A. fumigatus (Table). Thediagnosis of CF was made in all 7 children usingstandard criteria, including persistently raised sweatsodium and chloride concentrations (>60 mmol/l).All the children were being treated with antibiotics

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Allergic bronchopulmonary aspergillosis complicating cystic fibrosis in childhood 349

Table Details of investigations concerning the diagnosis of allergic aspergillosis and atopy in 7 patients withcystic fibrosis

Case Asthma % Type I Serum Culture from Type III Serum IgE* Serum IgE RAST- Bloodreversibility of skin test precipitins to sputum of A. skin test (lU/mi) (IU/ml) after specific IgE eosinophilFEV1 A. Jumigatus fumigatus* resolution of to A. count*

x-ray changes fumigatus ( x 109/1)

1 Too young for Positive Negative - Positive 8000 200 3+ 1.6spirometry

2 20 Positive Positive Positive Negative 500 110 0 2-93 15 Positive Positive Positive Positive NA 50 1+ 1-054 15 Positive Negative Positive Positive 1200 - 2+ 1-65 30 Positive Positive - Positive 2960 1100 NA 176 25 Positive Positive - Negative 1672 1100 3+ 1*57 17.5 Positive Positive - Positive 1950 1000 3+ 0.8

At time of changes in x-rays. NA = not available.

relevant to pathogenic organisms in their sputum orcough swabs, physiotherapy, intermittent inhalationtherapy, and pancreatic supplements.

Case reports

The clinical details of the patients illustratingdifferent features and modes of presentation aregiven below.The following 2 patients each experienced massive

collapse of the lung-Case 1 at age 2j years andCase 2 at 6 years.

Case 1. This boy, born in England of Pakistaniparents, was diagnosed as having CF at age onemonth. He remained well without persistent coughuntil aged 21 years although some wheezing had beennoted with upper respiratory infections and when hewas excited. Chest x-rays showed only minor changesofincreased lung markings and a little overdistention.In January 1978, when aged 2i years, he wasadmitted to hospital because wheezing had becomesevere and persistent, and he was dyspnoeic andpyrexial. Clinical and x-ray examination (Fig. la)showed total collapse of the right lung. Extraphysiotherapy and parenteral antibiotics failed tobring about improvement, nor did nebulisedsalbutamol and disodium cromoglycate have anyeffect, and the lung remained collapsed. Broncho-scopy did not show any mucous plug or extrinsicpressure on the bronchi. As a pronounced eosino-philia was present, allergic bronchopulmonaryaspergillosis was suspected and investigations (Table)confirmed this. Oral treatment with corticosteroidswas started and was accompanied by considerablere-aeration of the lung (Fig. lb). One year later thepatient is still well and maintained on nebulisedsalbutamol and disodium cromoglycate, in additionto normal treatment for CF, but there is some

Fig. la (Case 1). Total collapse of the right lungand shift of the heart and mediastinal structures tothe right side.

residual opacity in the right upper lobe. Serum IgEconcentration has fallen to 200 IU/ml and there is noblood eosinophilia.To our knowledge this boy is the youngest patient

to be reported with allergic bronchopulmonaryaspergillosis and CF. This case is also unusual in thatthe condition was recognised at the time of the boy'sillness, as in most reported cases the diagnosis hasbeen made retrospectively. Only 3 other childrenwith allergic aspergillosis who were less than 2 yearsold have been reported and none of them suffersfrom CF.1011

Case 2. This boy was diagnosed as having CF at

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350 Brueton, Ormerod, Shah, and Anderson

Fig. lb (Case 1). Re-expansion of the right lung afew weeks later. Now residual partial collapse of rightupper lobe and little opacity at the right base medially.

age one month; he developed extensive collapse ofthe left lung at age 6 years. He had wheezed a greatdeal during his first year or so, but was otherwisewell with a relatively clear chest x-ray until 6 yearswhen he suddently became dyspnoeic; collapse of leftlower lobe and dense opacity in the left upper lobewere demonstrated. Blood eosinophilia was present.The x-ray features resolved during the next 2 monthswith no specific treatment except increased physio-therapy but, a year later, the whole right lungcollapsed. Results of investigations were then asshown in the Table. At bronchoscopy copiousbrown sputum which cultured A. fugimatus wasaspirated from the right main bronchus. Withintensive physiotherapy, regular nebulised disodiumcromoglycate, and salbutamol, a mucus plug wasproduced and the right lung then re-expanded. Sincethen there have been no further episodes of grosspulmonary opacity with accompanying eosinophiliaand he has remained well.

Five patients have shown the more usuallyrecognised clinical pattern of allergic aspergillosis inthe adult asthmatic patient, with changing areas ofopacity in the lung fields, usually resolving with theuse of antiasthmatic drugs, as exemplified by thefollowing child.

well on treatment until age 6 years when broncho-spasm was noted for the first time. The peripheraleosinophil count, IgE level, and chest x-ray werenormal. She was given bronchodilators with improve-ment but a year later she developed a persistent, drycough and became anorexic. Chest x-ray showedlarge rounded areas of consolidation in both upperlobes and considerable patchy opacity in the rightlower lobe (Fig. 2). Computerised axial tomography(CAT) scan of the thorax showed dilated bronchi inthe right upper lobe. Investigations were as shownin the Table and reversible airways obstruction wasdemonstrated. Administration of salbutamol anddisodium cromoglycate was accompanied by con-siderable clearing of the x-ray changes in the rightlung field. The IgE level dropped to 50 IU/ml. Sixmonths later there was still an opacity in the leftupper lobe but no symptoms accompanied this andduring the next months it partially cleared. About 9months later she was wheezing on exercise and anew opacity in the right upper lobe appeared. Thisis currently resolving with extra physiotherapy andbronchodilators.

The following boy posed a more difficult problemboth in diagnosis and management.

Case 4. This boy was diagnosed as having CF at oneyear and remained extremely well until 8 yearswithout persistent respiratory symptoms and with anormal chest x-ray and normal growth. In February

Fig. 2 (Case 3). Large and rounded areas ofCase 3. This girl was born in 1970 and diagnosed as consolidation in both upper lobes andpatchyhaving CF in the first month of life. She had been peribronchial opacity in the right lower lobe.

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Fig. 3a (Case 4). Development of large area ofcontsolidation in the right upper lobe and extensiveopacity in the lower lobe with wheeze and cough.

1978 he suddently started to wheeze and coughpersistently, appetite waned, and he lost weight.Reversible airways obstruction was demonstrated.The chest x-ray now showed pronounced consolida-tion in the right upper and lower lobes (Fig. 3a).Investigations were as shown in the Table.

Despite intensive physiotherapy, he produced littlesputum but Proteus vulgaris sensitive to gentamicinwas grown persistently, together with A. fumigatus.As the patient was still anorexic and losing weight, acourse of intravenous gentamicin was started, as wellas oral corticosteroids as wheezing was still verypronounced and had not responded to salbutamoland disodium cromolgycate. There was resolution ofthe eosinophilia and of the patchy opacity in the rightlower lobe but the right upper lobe consolidationpersisted. CAT showed dilated bronchi and multiplecavities in the lobe (Fig. 3b). At bronchoscopybrownish tenacious material in which fungal hyphaewere seen on microscopical examination wasaspirated from the right upper lobe bronchus. Aprofuse growth of P. vulgaris was again obtained,together with A. fumigatus. Intravenous gentamicinwas continued. During the days after the broncho-scopy he coughed up large volumes of thick brownsputum containing seed-like solid bits and x-rayimprovement followed. Wheezing was still diflcult tocontrol at home so he was continued on salbutamol,disodium cromoglycate, and a small dose of cortico-steroids and, two months later, he had regained hisweight, had no cough or wheezing, and considerable

Fig. 3b (Case 4). CAT scan (antero-posterior) of theright upper lobe showing in detail rounded area ofconsolidation with muiltiple cavities within it.

Fig. 3c (Case 4). Considerable clearance of rightupper lobe lesion over a period ofa few months. Nowresidual changes of dilatation of bronchi andpatchyopacity in both upper lobes and to a lesser extent inthe right lower lobe.

clearing had occurred in the right upper lobe (Fig. 3c).The corticosteroid dose was reduced but, afteranother 2 months, consolidation recurred in theright lower lobe, clearing with increase in the

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corticosteroid dose. He recently developed consolida-tion in the left upper lobe, not at first accompanied bycough or wheeze, but later copious brownish sputumwas again produced. Inhaled gentamicin andincrease in corticosteroids have resulted in resolution.We have not as yet been able to stop his cortico-steroids altogether.The relevant investigatory details of the remaining

3 patients are given in the Table. A 7-year-oldboy (Case 5) had three episodes of pulmonaryconsolidation within one year, all clearing withantiasthmatic treatment and leaving him with normalrespiratory function tests and no reversible bronchialobstruction.The 2 remaining patients also illustrate that in our

series, contrary to those recorded by others,9 theepisodes of allergic aspergillosis occurred in patientswith CF whose lungs were not severely affected andwho have remained well after their episodes. Case 6,a girl with CF diagnosed at 9 months, had remainedwell without cough or sputum until 9 years when shepresented with a dry irritating cough and broncho-spasm. Consolidation was present in the right upperlobe but there was no sputum and no pathogenicorganisms were isolated from the cough swab.Investigations (Table) indicated allergic aspergillosis.Treatment with disodium cromoglycate andbronchodilators initiated improvement and thesymptoms and x-ray changes resolved and have notrecurred in the succeeding 3 years. However her IgEserum level remains high at 1100 IU/ml, she showsreversible airways obstruction, and still receivestreatment with disodium cromoglycate andsalbutamol.Case 7, a girl diagnosed as having CF at 2 years,

was quite well until she developed her first episode ofallergic aspergillosis at 4 years, and she has had 3recurrences since but no general deterioration inrespiratory function.

Discussion

This experience of allergic bronchopulmonaryaspergillosis in patients with CF suggests that thereshould be an increased awareness of the conditionand of its association with extensive pulmonarycollapse, or with varying areas of consolidation. It isnot clear why we have seen so many cases recently. Itseems unlikely that such major x-ray changes couldearlier have been missed in our clinic. At the same

time, it seems clear that asthmatic symptoms are

now more common in patients with CF.12 Does thisrepresent an increased incidence of atopy in patientswith CF generally? Or does it reflect increasingactivation of an atopic predisposition, which is

associated with CF lung damage or with some aspectsof therapy ?Turner et aL'3 have pointed out that, unlike many

atopic individuals, patients with CF are likely toshow positive skin reactions to the moulds,particularly A. fumigatus. Schwartz et al.'4 showedthat serum precipitins to A. fumigatus were presentin up to 30% of patients with CF. Silverman et al.15suggested that the relatively high prevalence ofatopyin children with CF was not due to increasedhypersensitivity to the common allergens, grasspollens and house dust mite, as for these allergens thefigures for normal children were comparable withthose for children with CF (34% and 29 %), but tothe high prevalence ofhypersensitivity to A. fumigatus(35 %). It is interesting to note that the spore count ofA. fumigatus in the atmosphere is highest in springand autumn, which correlates with the timing of theillnesses in our patients.

Contrary to other reports and to the suggestions ofSilverman et al.'5 that the development of hyper-sensitivity to A. fumigatus was associated withincreasingly severe lung damage from CF, it wasquite striking that our children were among thosewho had been progressing well and none was amongthose of our clinic with poor 'Shwachman scores.'Furthermore most of our patients appear to havemade good recoveries although there have beenrecurrences.

There is no place for specific treatment withantifungal agents in allergic bronchopulmonaryaspergillosis but, if the asthmatic symptoms and thelung opacities or collapse do not improve with thedisodium cromoglycate and salbutamol (oral orinhaled), together with intensified physiotherapy,oral corticosteroids are indicated.'6 The use ofcorticosteroids cannot be recommended in childrenwithout due consideration, particularly in thepresence of serious pulmonary infection. Howevertreatment with corticosteroids did not lead to aworsening of chest infection in CF and in 2 of ourpatients corticosteroids were associated with rapidand extensive resolution of the x-ray findings and thesymptoms.The immunological features of allergic broncho-

pulmonary aspergillosis were characterised byMcCarthy and Pepys'7 as a mixture of type I IgE-mediated and type IlI immunecomplex-mediatedhypersensitivity reactions. The use of IgE measure-ments in diagnosis and prediction of the diseasecourse is important. Rosenberg et al.18 found thatspecific IgE concentration increased in each of theirpatients before exacerbation and fell duringtreatment, rising again before further relapse. Case2, who had high levels during exacerbations, now, 2

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Allergic bronchopulmonary aspergillosis complicating cystic fibrosis in childhood 353

years after his last episodes of pulmonary shadowing,has an IgE level of 110 IU/ml, and is RAST-negativefor A. fumigatus. We are now following a furtherpatient with CF who has asthma, peripheral eosino-philia, circulating precipitins, and positive im-mediate and late skin tests to A. fumigatus. Sixmonths ago her IgE level was 7000 IU/ml,RAST + + for A. fumigatus but, at that time, therewere no typical radiological opacities, only minorchanges of CF. However she now shows nodularupper lobe opacity and collapse of the right middlelobe. Rosenberg et al.19 reported three similar caseswith normal chest x-rays when blood eosinophils andIgE levels were high. They had proximalbronchiectasis on bronchography and were thoughtto have been observed at an early stage in theevolution of the disease. It is therefore clear that acritical appraisal in relation to allergic broncho-pulmonary aspergillosis is required in any child withCF who develops asthma.

We thank Dr J H Parker, Department of Pathology,Shrewsbury Hospital, and Dr T G Merrett,Pharmacia RAST Allergy Unit, Benenden ChestHospital, Cranbrook, Kent, for the measurementof RAST-specific IgE antibodies to A. fumigatus.

References

Pepys J. Hypersensitivity diseases of the lungs due tofungi and organic dusts. Basel: Karger, 1969.

2 Hinson K F W, Moon A J, Plummer N S. Broncho-pulmonary aspergillosis: a review and a report of eightnew cases. Thorax 1952; 7: 317-33.

3 Agbayani B F, Norman P S, Wickerwerder W L. Theincidence of allergic aspergillosis in chronic asthma. JAllergy Clin Immunol 1967; 40: 319-26.

4 Malo J L, Inouye T, Hawkins R, Simon G, Turner-Warwick M, Pepys J. Studies in chronic allergic broncho-pulmonary aspergillosis. IV. Comparison with a group ofasthmatics. Thorax 1977; 32: 275-80.

5 Berger I, Phillips W L, Shenker I R. Pulmonary

aspergillosis in childhood. A case report and discussion.Clin Pediatr (Phila) 1972; 11: 178-82.

6 Mearns M, Young W, Batten J. Transient pulmonaryinfiltrations in cystic fibrosis due to allergic aspergillosis.Thorax 1965; 20: 385-92.

7 Batten J C. Allergic aspergillosis in cystic fibrosis.International conference on cystic fibrosis of the pancreas(mucoviscidosis), Berne/Grindelwald, 1966. Part I. ModProblPaediatr 1967; 10: 227-36.

8 Wood R E, Boat T E, Doershuk C F. State of the art:cystic fibrosis. Am Rev Respir Dis 1976; 113: 833-78.

9 Mitchell-Heggs P, Mearns M, Batten J C. Cystic fibrosisin adolescents and adults. QJMed 1976; 45: 479-504.

10 Katz R M, Kniker W T. Infantile hypersensitivitypneumonitis as a reaction to organic antigens. N Engl JMed 1973; 288: 233-7.Imbeau S A, Cohen M, Reed C E. Allergic broncho-pulmonary aspergillosis in infants. Am J Dis Child 1977;131: 1127-30.

12 Warner J 0, Taylor B W, Norman A P, Soothill J F.Association of cystic fibrosis with allergy. Arch Dis Child1976; 51: 507-11.

1 Turner M W, Warner J 0, Stokes C R, Norman A P.Immunological studies in cystic fibrosis. Arch Dis Child1978; 53: 631-8.

14 SchwartzR H, JohnstoneD E, Holsclaw D S, Dooley R R.Serum precipitins to Aspergillus fumigatus in cysticfibrosis. AmJ Dis Child 1970; 120: 432-3.

15 Silverman M, Hobbs F D R, Gordon I R S, Carswell F.Cystic fibrosis, atopy, and airways lability. Arch Dis Child1978; 53: 873-7.

16 McCarthy D S, Pepys J. Allergic bronchopulmonaryaspergillosis: clinical immunology. I. Clinical features.Clin Allergy 1971; 1: 261-86.

17 McCarthy D S, Pepys J. Allergic bronchopulmonaryaspergillosis: clinical immunology. II. Skin, nasal, andbronchial tests. Clin Allergy 1971; 1: 415-32.

18 Rosenberg M, Patterson R, Roberts M. Immunologicresponses to therapy in allergic bronchopulmonaryaspergillosis: serum IgE value as an indicator andpredictor of disease activity. JPediatr 1977; 91: 914-7.

19 Rosenberg M, Mintzer R, Aaronson D W, Patterson R.Allergic bronchopulmonary aspergillosis in three patientswith normal chest X-ray films. Chest 1977; 72: 597-600.

Correspondence to Professor Charlotte M Anderson,Institute of Child Health, The Nuffield Building,Francis Road, Birmingham B16 8ET.

Received 19 June 1979

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