Atopy bronchial - ThoraxAddress for reprint requests: Professor MX FitzGerald, Medical Professorial Unit, University College Dublin, St Vincent's Hospital, ElmPark,Dublin4, Eire. and

Thorax, 1980, 35, 807-813

Atopy and bronchial reactivity in older patients withcystic fibrosisM J TOBIN, 0 MAGUIRE, D REEN, E TEMPANY, AND M X FITZGERALD

From the Medical Professorial Unit, University College Dublin, St Vincent's Hospital andChildren's Research Centre, Our Lady's Hospitalfor Sick Children, Dublin

ABSTRACT We studied 25 adolescent and adult patients with cystic fibrosis (CF) and 25 controlsubjects to determine if the prevalence of atopy and bronchial hyperreactivity was increased in thisdisease. Results showed that atopic symptoms, as defined by history, were more frequently presentin the CF patients. Prick testing of the skin produced positive reactions in 88 % of the CF group and360% of the control subjects (p <0 001), and the mean number of reactions per subject was signifi-cantly higher in the former group (p < 0 001); reactions to fungal antigens were strikingly positive inthe CF group. The CF patients had a significantly higher mean serum IgG4 (p <000 1), IgE (p <00 1),and higher mean eosinophil count (p > 0 05). Clear-cut bronchial hyperreactivity was demonstratedin the CF group compared with control subjects. Bronchial provocation with 400 jig of histamineled to a greater than 15 % fall in the preinhalation FEV, in 35 % of the CF subjects compared with40% of the control group, with a mean percentage fall of 15 % and 3 % respectively (p < 0 00 1). Inthe CF group a greater than 15 % rise in PEFR occurred in 32% after inhalation of the parasym-patholytic, ipratropium bromide (54 jig), and in 270% after inhalation of the sympathomimetic,fenoterol (400 pg). No correlation was found between bronchial reactivity and atopic status, HLAphenotype pattern, or disease severity. The cause of the increased prevalence of atopy and bronchialreactivity in CF patients remains unknown. However, it is clear that a trial of bronchodilatortherapy is warranted in adolescents and young adults with CF.

An increased prevalence of atopy in patientswith cystic fibrosis (CF) was first reported byLowe in 1949.1 Since that time, a number ofauthors studying a variety of atopic indices havepublished results, some confirming the associa-tion,2-6 others disputing it. 7-9 Because of theseconflicting results, and because of the differencein methodology used to assess atopy, we under-took a study to define the prevalance of atopyin a group of adolescents and young adults withCF, by examining a comprehensive range ofatopic indices. Furthermore, we carried out HLAphenotyping to determine if those CF patientswith atopic features constituted a separate.genetically linked subgroup.The related problem of bronchial reactivity

was studied by spirometric measurements before

Presented in part at the Joint Thoracic Society and British ThoracicAssociation Meeting, February 1980.

Address for reprint requests: Professor MX FitzGerald, MedicalProfessorial Unit, University College Dublin, St Vincent's Hospital,Elm Park, Dublin 4, Eire.

and after inhalation challenge with a broncho-constrictor, histamine, and two bronchodilators,a beta2 adrenergic agonist, fenoterol, and aparasympatholytic, ipratropium bromide.

Methods

Twenty-five documented CF patients, with anage range from 10 to 32 years (mean 17 yr)were studied. A control group consisted of 25healthy individuals, with an age range from 10to 28 years (mean 15-2 yr). The male-femaleratio was identical in each group (2 1:1). Thepatients were divided into three groups ofseverity on the basis of clinical and radiologicalfindings.'0 Consent to carry out the study wasobtained from parents of all subjects under 18years of age.

ALLERGIC PROFILEBoth patients and control subjects were ques-tioned about a history of wheezing, allergicrhinitis, eczema, "hives", angioneurotic oedema,

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M J Tobin, 0 Maguire, D Reen, E Tempany, and M X FitzGerald

drug allergy, nasal polyposis, and a family his-tory of allergy. Skin hypersensitivity tests wereperformed with a diluent control, a positive con-trol (histamine add phosphate), and the follow-ing 13 Bencard allergen extracts: house-dust,D pteronyssinus, grass pollen, Timothy grass,tree pollen, feathers, cat fur, Aspergillus fumi-gatus, Aspergillus terreus, Cladosporium herba-rum, and three mixed mould extracts, M5, M1O,and Ml1. The skin tests were performed bythe modified prick method on the volar aspectof the forearm, and the weal size in millimetreswas recorded 20 minutes after the introductionof the allergen.

Total blood eosinophil counts were determinedby the chamber method, using an eosin-acetonediluent. The total serum IgE was determined bythe radioimmunoassay technique, and serumIgG4 by a microscale version of a radial im-munodiffusion method (antisera obtained fromSeward Laboratories, London)." These testswere performed without knowledge of thepatients' skin reactivity. Precipitins againstAspergillus fumigatus were determined by theagar-gel diffusion technique, as described byLongbottom and Pepys.12

GENETIC STUDIESHLA phenotyping was performed by the micro-lymphocytoxicity technique. The followingHLA-A, -B, and -C antigens were determined.HLA-A: -1, -2, -3, -9(w 23, w 24), -1 -(25, 26)

-1 1, -28, -29, -w 23, -w 24, -w 30,31, 32.

HLA-B: -5, -7, -8, -12, -13, -14, -15, -17, -18,-27, -40, -w 16, -w21, -w22, -w 35.

HLA-C: -wi, -w2, -w3, -w4.

BRONCHIAL CHALLENGEThe spirometric measurements made included de-termination of peak expiratory flow rate (PEFR)using a Wright Peak Flow meter, forced vitalcapacity (FVC) and forced expiratory volume inone second (FEV,) using a dry spirometer (Vitalo-graph). The best of three attempts was recordedand corrected to BTPS. Not all measurementscould be made in all patients during every phaseof the study. Routine bronchodilators were pre-viously withheld according to the protocol ofChai et al.'3 No patient was receiving antihista-mine therapy at the time of the study. Bothgroups were challenged with the bronchocon-strictor, histamine acid phosphate 400 jig, takenas four individual puffs from a metered inhaler(courtesy of Riker Laboratories). Forced expira-tory volume in one second and FVC were per-

formed before the challenge and repeated fiveminutes later; the percentage change was re-corded. On two separate days, the CF group, butnot the control subjects inhaled bronchodilators.On the first day, the beta2 adrenergic agonist,fenoterol (400 ug), was inhaled in two puffs, andon the second day, the parasympatholytic, ipra-tropium bromide (54 ulg) was inhaled as threepuffs from a metered dose inhaler. Forced expira-tory volume in one second, FVC, and PEFRwere performed at 15, 30, and 60 minutes afteradministration of each of the two bronchodi-lators; the maximum rise was recorded, and thepercentage change from baseline was calculated.

Differences between groups were tested withStudents' t, Mann-Whitney U, chi2 and Fisher'sexact probability tests, as appropriate. Linearregression analysis was used to look for correla-tion between values.

Results

The results of the atopic questionnaire are shownin table 1. All atopic features were reported morecommonly in the CF patients, including a markedincrease in the reported prevalence of suchfeatures in their first degree relatives.

ALLERGIC PROFILEThe CF group had significantly more positiveskin tests than the control subjects, 88% com-pared with 36% (p<0-001) and the mean num-ber of reactions per individual, 5-5 and 1-5 res-pectively, was also significantly higher (p<0-001).Both groups were similar in having the greatestnumber of positive reactions to house-dust,but the CF group had a far greater numberof reactions to the fungal antigens - A fumi-gatus, A terreus, C herbarum, and a group ofmixed moulds (table 2). The two groups showed

Table 1 Atopic questionnaire in cystic fibrosis patientsand control subjects

Cysticfibrosis Control p value*patients subjects(n =25) (n =25)

Wheeze/asthma 445% 125% 0-013Allergic rhinitis 20% 0 0 025Hives 72% 485% NSEczema 8% 45% NSNasal polyposis 245% 4,% =0049Angioneurotic oedema 0 0 NSFamily history of atopy 76% 24% <0 001

*Fisher's exact probability test, cystic fibrosis patients versus controlsubjects.NS=not significant.

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A topy and bronchial reactivity in older patients with cystic fibrosis

Table 2 Hypersensitivity skin tests in 25 cvstic fibrosis patients and 25 control subjects

CFpatients Control subjectsNumber Weal Mean Number Weal Meanpositive diameter weal size positive diameter weal size

>5 mm (mm) >5 mm (mm)

House dust 19 6 4-5 7 3 4-7A fumigatus 18 12 6-4 1 0 2-0D pteronyssinus 14 5 4-1 6 5 6-8A terreus 14 6 4-1 2 0 1-5Cat fur 13 2 3-7 5 2 4-0Mixed moulds M5 12 1 2-9 0 0 0

M1o 8 0 2 5 1 0 3 0Mul 8 0 2-8 2 0 2-0

Grass pollen 7 4 8-6 6 1 2-8Feathers 7 1 2 7 5 1 3-4Timothy grass 6 4 11-0 2 0 2-0C herbarum 6 0 3 0 0 0 0Tree pollen 5 0 2-8 1 0 2-0Control (diluent) 4 0 3 0 0 0 0

little difference in the degree of reactivity topollens and feathers, antigens frequently associ-ated with common atopic disorders. In contrastto the high prevalence of positive reactions toA fumigatus extract, only one patient had preci-pitins to the fungus in his serum.Serum immunoglobulin E was increased above

100 U/ml in 46% of the CF patients, comparedwith 21% of the control subjects (figure) and themean level was significantly higher in the formergroup (p<0 01). Total blood eosinophil countwas elevated above 400 cells/mm3 in 33% of theCF subjects compared with 16% of the controls,and the mean count in the former was higher(375/mm3 and 268/mm3 respectively), althoughthis difference did not reach statistical signific-ance. Similarly, mean serum IgG4 was signific-antly higher in the CF patients than the controlgroup (p<0 001, figure). A significant correlationbetween the subject's age and the level of IgG4was found in the CF patients (r= +0547,p<001) but not the control subjects. No signi-ficant correlation was detected between serumIgG4 and IgE levels.

GENETIC STUDIESHLA phenotyping in the total CF group and inthose patients with marked atopic featuresshowed no statistically significant difference fromthe pattern obtained in a group of 253 Irish con-trol subjects (Reen, unpublished data).

BRONCHIAL PROVOCATIONThe results of spirometric testing before andafter bronchial challenge with histamine andbronchodilators are shown in tables 3 and 4. Themean basal FEV1 was significantly lower in theCF group compared with control subjects, 2-06(60% of predicted normal value) and 3-14 (101 %

of predicted) litres respectively (p<001). Afterinhalation of histamine, a greater than 15% fallin the preinhalation FEV1 was found in 35%of the CF subjects compared to 4% of the con-trol subjects (p<0-05), with a mean percentage200001

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Table 3 Comparison of histamine inhalation (400 jg) in cystic fibrosis patients and control subjects

Control subjects CFpatients ValuePre Post Pre Post

Number of subjects 25 25 20 20FEV, Mean±SD (ml) 3144±911 3051 +869 2058 ±1134 1795 ±1067

Mean % change±SD -2 8±46 -15*2±13 <0 001FVC Mean±SD (ml) 3444±1018 3407±980 2648±1085 2380±1156

Mean %change±SD -0916±5-1 -12-9±13-5 <0001

Table 4 Influence of bronchodilators in cysticfibrosis patients

Ipratropium bromide (54 pg) Fenoterol (400 jig)Pre Post Pre Post

Number of subjects 22 22 22 22FEV1 Mean±SD (ml) 1920±1052 2045±1105 1925±1050 2118±41058

Mean % change ±SD 47-5±8-2 +9-6±6-4FVC Mean±SD (ml) 2501 ±967 2675±938 2545±1076 2770±1048

Mean %change±SD +8-9±13-2 +11-9±101PEFR Mean ±SD (I/min) 309 ±108 331 ±109 303 ±122 331±116

Mean % change±SD +8-2±9-2 +12-2±13-3

fall of 15-2% and 2-8% and mean absolute fallsof 263 and 93 ml respectively (p<0 001). A trivialrise in FEV1 after inhalation of histamineoccurred in one of the CF patients and five ofthe control subjects. A less striking effect on theFVC was observed, with a greater than 15%fall in the preinhalation value occurring in 25%of the CF patients compared with none of thecontrol subjects (p<005); the mean percentagefall was 13% and 1 % and the mean absolute fallwas 268 and 37 ml respectively (p<0001). Therelationship between severity of the underlyingairway obstruction and the response to histaminechallenge was examined. Regression analysis ofbasal FEV1 against percentage change afterhistamine showed no correlation. Two patientswith basal FEV1 levels which were 98 % and102% of the predicted normal values had fallsof 22% and 19% in FEV1 respectively, indicat-ing that bronchoconstriction was not confinedto patients with reduced baseline values.The results of bronchodilator administration in

the CF group are set out in table 4. After ipratro-pium bromide, a greater than 15% rise in PEFR,FEV1, and FVC occurred in 32%, 23%, and 27%respectively. The patient group as a whole showeda mean percent rise in PEFR, FEV1, and FVCof 8-2%, 7*5%, and 8-9%, and a mean absoluterise of 22 1/min, 125 ml, and 174 ml respectively.Inhalation of fenoterol induced a greater than15% rise in PEFR, FEV1, and FVC in 27%,14%, and 18% of the patients, with a mean per-centage rise of 12-2%, 9-6%, and 11-9%, and amean absolute rise of 28 1/min, 193 ml, and225 ml respectively.

GRADING OF DISEASE SEVERITYThe patients were divided into three groups inincreasing order of severity: group 1 consistedof 10 patients, group 2 of six, and group 3 ofnine. In these three small subgroups, it was notpossible to relate clearly the severity of diseasewith the number of atopic features present, orthe degree of bronchial reactivity.

Discussion

This comprehensive study of atopic indices inCF, has permitted us to confirm and extendprevious observations on this association. OurCF patients, compared with control subjects,demonstrated a striking prevalence of atopicfeatures as judged by prick testing of the skin,total serum IgE levels, total eosinophil counts,serum IgG4 levels, and an atopic questionnaire.The related problem of bronchial reactivity hasbeen similarly defined in more detail, using avariety of bronchoconstrictor and bronchodilatorchallenges. Comparing our data with results ofprevious studies, interesting differences and simi-larities are noted.

Positive skin tests were observed morefrequently in the CF group than in the controlgroup, 88% and 36% respectively, and theformer also had significantly more reactions perindividual. In contrast to the previous reports ofa relatively low frequency of reactions to house-dust and house-dust mite in CF patients,6 14 15

they produced the greatest number of positivereactions in our patients. The increased sensitivityto house-dust and house-dust mite noted in our

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patients may reflect the fact that they were olderthan the patients in other studies. This is inaccordance with the results of another study ofours'6 which showed that the frequency of posi-tive skin tests in CF increases with age. Anincreased prevalence of sensitivity to fungal anti-gens, as observed in our study, has been noted byprevious authors.2 3101417 Total IgE levels weresignificantly higher in the CF group. Thissupports a similar finding by Wallwork,'8 butcontrasts with Bardana's'9 report of normal IgEvalues in a study of 61 CF patients. In thepresent study, elevated IgE levels were foundpredominantly in subjects displaying the greatestdegree of skin reactivity.Serum IgG4, the IgG subclass known to be

associated with some atopic reactions,20 21 againwas significantly higher in the CF group. Thisconfirms a similar finding by Shakib.22 We foundno significant correlation between individual IgEand IgG4 levels, which suggests that eachimmunoglobulin reflects a different pathway inthe pathogenesis of atopy in CF.The reason for the increased prevalence of

atopy in CF is unknown. One possibility is thatthe phenomenon is acquired as a result ofincreased antigen access to the IgE producingcells in the submucosa. Mechanisms which mightbe responsible include abnormal mucosal permea-bility, a defective secretory IgA system,23trapping of antigen in infected areas of the lung,or failure of antigen clearance because of a cilio-toxic factor. An alternative explanation is thatthere is a genetic linkage between the CF geneand genes controlling atopic response. In ourstudy, there was a significantly increased familyhistory of atopy in the CF group. However, onemust have reservations about comparisonsbetween historical data derived from frequentlyinterviewed patients, and those obtained fromhealthy control subjects. Although Warner24found an increased personal history of atopy andpositive skin tests in a study of obligate heterozy-gotes, a separate study of ours'6 suggests thatthere is no significant difference between positiveskin tests in obligate heterozygotes and controlsubjects. In view of Soothill's25 finding of anincreased prevalence of HLA-A1 and B8 amonginfants with positive skin tests, we examined theHLA phenotype pattern of our patients, but failedto detect linkage of atopy to any particular HLAantigen.The frequent association of bronchial hyper-

reactivity with atopy has led a number ofinvestigators to study the response to inhaledbronchoconstrictors and bronchodilators in CF.

Haluszka26 and Mellis27 performed bronchialprovocation in CF, using varying doses of hista-mine, and found a positive response in 68% and24% respectively. In contrast, we used a fixeddose of histamine (400 ,g) and demonstrated agreater than 15% fall in FEV, in 35% of the CFgroup, compared with 4% of the control group,with a mean percentage fall of 15% and 3%respectively. We found no significant correlationbetween bronchial reactivity to histamine and thedegree of airway obstruction in our CF patients.Indeed, two patients with basal FEV, levels whichwere 98% and 102% of the predicted normalvalues showed marked drops of 22% and 19%respectively. This contrasts with the assertion ofMellis2T that significant bronchoconstriction onlyoccurred in those patients whose basal pulmonaryfunction was abnormal.

This bronchoconstrictor response may resulteither from a direct local effect on airway smoothmuscle or from vagally mediated reflex broncho-constriction. 28 Empey29 demonstrated markedhistamine reactivity after an upper respiratorytract infection, presumably the result of epithelialdamage and exposure of nerve endings. Possibly,in CF there may be increased sensitivity of thebronchial mucosal receptors caused by chronicinfection. Furthermore, the ability to form hista-mine is increased in chronic inflammatory condi-tions, because of adaptation in the production ofhistidine decarboxylase, and this might also con-tribute to the bronchial hyperirritability in thisdisease.30

There have been conflicting reports on theresponse to bronchodilators in CF. After inhala-tion of nebulised adrenaline or isoprenaline, somefound a reduction in airway obstruction,31-34others noted no change.35-38 The parasympatheticantagonist atropine sulphate was used in onestudy and found to be superior to isoprenaline.34As isoprenaline and atropine are now unsuitablefor clinical use, we examined the response to aselective beta2 adrenergic agonist, fenoterol, anda parasympatholytic, ipratropium bromide. Bothwere administered by metered dose inhalers, inwhich they are routinely prescribed, and so theresults have more direct implications than if thedrugs were administered from a special nebuliseror by a positive pressure device. Although themean rise in PEFR after each agent was undra-matic, almost half the patients experienced agreater than 15% rise in PEFR after inhalation of-ipratropium bromide or fenoterol or both. Suchan increment is often clinically worthwhile, parti-cularly in those patients with reduced baselinevalues. The fact that more patients responded to

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the parasympatholytic, ipratropium bromide,than to fenoterol is in accordance with Mitchell'sobservations,39 that 51 % of unselected CFpatients had a positive response to methacoline.The more selective responsiveness to a para-sympatholytic agent in our patients is similar tothe pattern observed in chronic bronchitis by someworkers.40 41The cause of the bronchial hyperreactivity in

cystic fibrosis is unknown. Although there is a dis-puted association between bronchial hyper-reactivity and atopic status in asthmatics,42-43 wefound no association between atopy and bronchialresponsiveness to histamine, fenoterol, or ipra-tropium bromide in our cystic fibrosis subjects.This contention is supported by two other studiesin CF, which have shown no correlation betweenexercise-induced bronchial lability4 or histamine-induced bronchonstriction27 and atopic status.Authors have contended that atopy amelior-

ates,9 44 worsens,5 17 or has no effect6 45 on thenatural history of CF. In the present study, awide spectrum of disease severity was observed,and no clear relationship with either atopicstatus or bronchial reactivity was observed. It isdifficult, however, to draw conclusions from thesmall number of patients studied.Our results show that there is a higher

prevalence of atopy in CF as determined by acomprehensive group of atopic indices. The causeof atopy in this disease remains unknown. It maybe caused by increased antigen access or theremay be genetic linkage between atopy and CF.No relationship was found between atopic statusand severity of the underlying condition, suggest-that atopic status is not of prognostic value inCF. Likewise, the degree of atopy did not cor-relate with the degree of bronchial reactivity. Asa significant proportion of the patients showreversibility in airway obstruction, a trial ofbronchodilator therapy, with a beta2 adrenergicagonist or a parasympatholytic or both, shouldbe considered in adolescent and young adultswith cystic fibrosis.

We are grateful to the Medical Research Councilof Ireland who supported this study. We areindebted to the control subjects and the patientswho took part in this study and without whoseco-operation it would not have succeeded. Wethank Mr L Daly, Department of CommunityMedicine and Epidemiology, University College,Dublin for providing statistical guidance, andMr M Cogan, Mrs G Lawless, and Mrs N Martinfor technical assistance.

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3 Warren CPW, Tai E, Batten JC, Hutchcroft BJ,Pepys J. Cystic fibrosis-immunological reactionsto A fumigatus and common allergens. ClinAllergy 1975; 5:1-12.

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Documents

Atopy bronchial - ThoraxAddress for reprint requests: Professor MX FitzGerald, Medical Professorial Unit, University College Dublin, St Vincent's Hospital, ElmPark,Dublin4, Eire. and