Exercise-induced bronchoconstriction, skin sensitivity,

rchives of Disese in Childhood, 1976, 51, 912. Exercise-induced bronchoconstriction, skin sensitivity, nd serum IgE in children with eczem J. F. PRICE, J. J. COGSWELL, M. C. JOSEPH, nd G. M. COCHRNE From the Deprtments of Peditrics, Medicine, nd Immunology, Guy's Hospitl, London Price, J. F., Cogsweil, J. J., Joseph, M. C., nd Cochrne, G. M. (1976). rchives ofdisese in Childhood, 51, 912. Exercise-induced bronchoconstriction, skin sensitivity, nd serum IgE in children with eczem. Forty-two children with eczem were studied for exercise-induced sthm (EI), skin sensitivity to prick testing, blood eosinophil count, nd immunoglobulins. 29 hd fll in pek expirtory flow rte fter exercise greter thn 20% nd of these, 23 hd symptoms of wheezing. 13 of the eczemtous children showed fll of less thn 20%. The children with EI showed greter cutneous sensitivity (P<0-001) nd higher totl serum IgE (P <0 *025). 3 of the group with fll of less thn 20% hd llergic rhinitis with skin sensitivity to grss pollen. The remining 10 hd no clinicl evidence of llergic disese, other thn eczem nd skin sensitivity, nd totl IgE fell within the norml rnge. It is suggested tht in proportion of children with eczem there is little evidence of reginic llergy. Bronchoconstriction fter exercise is physiologicl chrcteristic which helps to distinguish sthmtic children from normls (Jones, Buston, nd Whrton, 1962). bnorml bronchil lbility hs lso been shown in dults (Jones nd Jones, 1966) nd in children with pst history of wheezing (Konig, Godfrey, nd brhmov, 1972). sthm nd eczem re commonly ssocited in individuls nd fmilies (Edgren, 1943; Stifler, 1965). These conditions, together with llergic rhinitis, urticri, nd certin food llergies, hve become grouped under the heding 'topy', though when the term ws originlly conceived (Coc nd Cooke, 1923) infntile eczem ws regrded seprtely. topic subjects typiclly show the cpcity to synthesize IgE reginic ntibody, nd show skin sensitivity to one or severl common llergens. High levels of totl nd specific IgE hve been observed in ptients with topic eczem (Juhlin et l., 1969; Ogw, et l., 1971; Stone, Muller, nd Gleich, 1973; Johnson et l., 1974; Hoffmn et l., 1975). Mny of the ptients in these studies lso hd clinicl evidence of wheezing. The purpose of this study ws to investigte the incidence of exerciseinduced sthm (EI) in group of children with eczem, nd to exmine the reltion between EI, skin sensitivity, nd totl IgE. Received 2 pril 1976. Ptients Ninety children were invited by letter to their prents to tke prt in the study, nd 42 were studied with prentl consent. peditric dermtologist's dignosis of topic eczem nd n ge rnge between 5 nd 14 were the only two criteri for selection. Men ge of the 42 children (24 mles, 18 femles) ws 9 yers. The dignosis of topic eczem ws mde on clinicl grounds; personl or fmily history of topy, flexurl distribution, nd severe pruritus with lichenifiction. further 15 children (12 mles, 3 femle) who were sibs of the eczemtous ptients were lso studied nd their ges rnged from 5-13 yers (men 9 yers). Method The children ttended the Respirtory Function Lbortory for bout 2 hours when the following were crried out. (1) clinicl history nd exmintion. (2) Physiologicl tests of ventiltion before nd fter exercise chllenge. (3) Prick tests to determine skin sensitivities to 23 common llergens. (4) Venous blood smples tken for blood eosinophil count nd serum immunoglobulins. The studies were crried out during July to October 1974, in constnt hospitl environment. No observtions were mde of irborn llergens or locl wether conditions. Clinicl evlution. One of us (J.J.C.), independently of the other observers, crried out full history nd exmintion using stndrd questionnire. 912 rch Dis Child: first published s 10.1136/dc.51.12.912 on 1 December 1976. Downloded from http://dc.bmj.com/ on 8 My 2018 by guest. Protected by copyright.

Exercise-induced bronchoconstriction, skin sensitivity, nd serum IgE in children with eczem 913 history from the ptient of periodic wheeze or brethlessness ws ccepted s positive history of sthm. Clinicl quntifiction (mild, moderte, severe) of the skin lesions ws mde. None of the children ws receiving systemic steroids, nd none hd been given bronchodiltor therpy for 6 hours or ntihistmines for 24 hours before the study. No child hd been given hyposensitiztion immunotherpy during the yer before the study. Physiologicl ssessment. stndrd exercise test ws performed by ll children (Connolly nd Godfrey, 1970) of running down flt hospitl corridor for 6 minutes t speed sufficient to produce pulse rte of 170/min. Pek expirtory flow rte (PEFR) ws mesured ech minute with Wright Pek Flow Meter before, during, nd for 15 minutes fter running. t tht stge bronchodiltor erosol (200 pg slbutmol) ws given nd further one-minute run performed to produce mximl dilttion. The expected vlues for PEFR were tken from Godfrey, Kmburoff, nd Nirn (1970). The results re expressed s % fll in PEFR clculted: % Fll= Initil PEFR-Lowest PEFR fter exercise Initil PEFR x 100. In the presenttion of the dt the norml rnge for EI ws tken from the work of Silvermn nd nderson (1972). Skin tests. Skin sensitivity ws ssessed using the prick test with 23 common llergens. Stndrd test solutions were used (mnufctured by Bencrd, Beechm Group Ltd.). The presence of whel of 3 mm in dimeter t 15 minutes ws regrded s positive rection. In one cse 2 mm whel rection occurred to the control solution nd there 5 mm whel ws tken s positive. Serum immunoglobulins. Ser were seprted t room temperture nd stored t -70 C until tested. Serum Ig, IgG, nd IgM were mesured by rdil immunodiffusion. Serum IgE levels were mesured by using Phdebs Rdioimmunosorbent Test Kits. Stndrd curves were generted using n IgE stndrd clibrted ginst the World Helth Orgniztion, British Reserch Stndrd for Humn Serum Immunoglobulin E 68/341. Duplicte ssys were set up simultneously for ll smples nd stndrds. The test ws repeted if there ws vrition >2% from the men of the percentge binding of the duplictes. Results were expressed s units (IU) reltive to the reference stndrd. ll unknown serum smples were diluted ten times with buffer before ssy. Correction ws mde for serum fctor interferences by multiplying the Men Count Rte of the Zeros (MRCO) by fctor of 0-96. The count rte for ech of the unknown ser ws expressed s percentge of this serum fctor corrected MRCO. The method is then regrded s being ccurte over the rnge 10-4000 IU IgEfml, with coefficient of vrition in our hnds of 15%. nlysis. The mens of the indices for the different groups were compred by Student's 't' test. Differences were considered significnt when P <0 05. Results The 42 children with eczem were divided into two clinicl groups comprising 23 children with history of present nd pst wheezing, nd 19 in whom there ws no history of respirtory symptoms. The physiologicl response to exercise in the two clinicl groups is shown in Fig. 1. Children with 80-70 - 60-50 - <i 40-30 - 20-10 - I- + 2SD Eczem 9 Eczem plus sthm of ' Sibs Normls FIG. 1.-Percentge fll in pek expirtory flow-rte (PEFR) fter exercise of 19 children with history of eczem only nd 23 with history of wheezing pst or present. The norml rnge is tken from Silvermn nd nderson (1972). history of sthm showed men fll in PEFR of 47% (21-74%). The 19 nonwheezy eczemtous children showed lower men of 17% but wide rnge (0-66%). 10 hd fll in PEFR greter thn 11%, the upper limit of norml quoted for EI (Silvermn nd nderson, 1972). 9 sibs showed borderline responses. Using the physiologicl dt it ws decided to divide the eczemtous children into 3 groups, those with per cent fll in PEFR fter exercise <20% (group 1), between 20 nd 40% (group 2), nd >40% (group 3) (Fig. 2). n upper limit of norml of 20% fll in PEFR ws chosen rbitrrily, s this would comprise group with indisputble bnorml broncholbility. 13 of the 19 children with eczem only hd fll <20% in PEFR, while ll children with both eczem nd respirtory symptoms hd fll of t lest 20%. The ge distribution (Tble I), morphology, nd distribution of skin lesions, nd fmily history of topic disorders ws similr in the three groups. rch Dis Child: first published s 10.1136/dc.51.12.912 on 1 December 1976. Downloded from http://dc.bmj.com/ on 8 My 2018 by guest. Protected by copyright.

914 r x to.0 0 z 16 14 12 Eczem only (19) Eczem plus sthm (23) < 20 20-40 >40 1 20-40 >40 FIG. 2.-Histogrm showing the number of subjects in ech clinicl group with % fll in PEFR fter exercise of <20%, 20-40%, or >40%. However, those children with fll of >40% tended to hve the erliest ge of onset, nd to be the lest severely ffected by their eczem (Tble II). comprison ws mde of skin sensitivity, serum totl IgE, nd eosinophil counts in the three groups. The results of the reltive skin sensitivities re shown in Fig. 3. Skin tests were not completed in one child who hd percentge fll in PEFR of 55 %. The children in group 1 hd significntly fewer positive skin tests thn those in groups 2 nd 3 (P <0-001). 3 mm or greter whel in re- Price, Cogswell, Joseph, nd Cochrne 9 81-3 7- i 6- n X 5 -._ 4 - r: L -_ :Z 1. 2 - zi <20 20-40 >40 % Fll in PEFR fter exercise Eczem only,eczem nd sthm FIG. 3.-Totl number of positive skin tests % fll in PEFR fter exercise. relted to sponse to Dermtophgoides pteronyssinus or D. frine occurred in only one child in group 1 but ws seen in 10 out of the 15 tested in group 3 (Tble III). The totl blood eosinophil count per mm3 showed considerble overlp in ll three groups (Tble IV). TBLE I ge distribution of children with eczem fter division into the groups defined by the fll in PEFR fter exercise TBLE II Clinicl dt relting the ge of onset of eczem nd severity of eczem to the three groups defined by fll in PEFR fter exercise Group ge of onset of eczem (yr) u. s es I^^- - Severity of eczem 0-1 1-5 5 0 + ++ +++ (1) <20% fll in PEFR on exercise (n = 13) 7 5 1 1 5 4 3 (2) 20-40% fll in PEFR on exercise (n = 13) 9 3 1 1 7 3 2 (3) >40% fll in PEFR on exercise (n = 16) 13 2 1 3 4 9 0 rch Dis Child: first published s 10.1136/dc.51.12.912 on 1 December 1976. Downloded from http://dc.bmj.com/ on 8 My 2018 by guest. Protected by copyright.

Exercise-induced bronchoconstriction, skin sensitivity, nd serum IgE in children with eczem 915 TBLE III Skin rection to D. pteronyssinus or D. frine No. % Fll in PEFR Skin rection to house mite (whel dimeter) 3 mm-5 mm 5 mm-10 mm Totl 13 <20 0 1 1 13 20-40 4 4 8 15 >40 5 5 10 TBLE IV Men blood eosinophil count relted to the fll in PEFR fter exercise However, there ws significnt difference between the mens in group 1 nd group 3 (P <0 02), nd the mens of groups 2 nd 3 were outside the norml rnge quoted by Horn et l. (1975). The eosinophil count ws not mesured in 3 children. The children ll hd norml levels of IgG nd IgM nd there ws no difference mong the three groups. One child in group 1 hd Ig deficiency. Totl Ig tended to be lower in the group with norml broncholbility. The results for totl IgE re shown in Fig. 4. IgE is plotted on log scle. The men for ech group is indicted. The norml rnge is bsed upon the figures quoted for Berg nd Johnsson by Hvnen et l. (1973). Levels >600 IU/ml were considered to be high for children over the ge of 5 yers, i.e. >2 SD from the men. Results chieved with the Phdebs IgE test hve been shown to be comprble with those obtined with the rdioimmunosorbent technique used by Berg nd Johnsson (Hvnen et l., 1973). ll 13 children in group 1 hd totl serum IgE levels within the norml rnge. 6 in group 2 nd 10 in group 3 hd levels >600 IU/ml. Group 1 is significntly different from group 2 (P<0 025) nd group 3 (P<0-005). Discussion This study hs confirmed tht eczemtous children with history of wheezing hve exerciseinduced sthm which distinguishes them from normls (Silvermn nd nderson, 1972). The children with eczem s the only symptom showed mixed physiologicl response to exercise, 9 of the U, 02 0. 4000-1000 - 500-100 - 50-10 m I I < 20 20-40 >40 Norml rnge ± 2SD % Fll in PEFR fter exercise *Eczem only Eczem nd sthm FIG. 4.-Totl IgE relted to % fll in PEFR fter exercise. IgE levels re expressed in IU/ml on log scle. The brs indicte the men in ech group. Norml vlues re tken from Berg nd Johnsson. 19 with norml response, 10 out of 19 showing percentge fll of greter thn 11%, nd 6 of them showing clerly sthmtic response to exercise with percentge fll of greter thn 20%. The t 0 I I I I rch Dis Child: first published s 10.1136/dc.51.12.912 on 1 December 1976. Downloded from http://dc.bmj.com/ on 8 My 2018 by guest. Protected by copyright.

916 Price, Cogswell, Joseph, nd Cochrne clinicl severity of the eczem ws not necessrily relted to the presence of, or degree of, bronchoconstriction nd in 3 of the 5 children grded s hving severe eczem there ws no EI. The effect of exercise in incresing irwys resistnce in sthmtics is well documented (Jones et l., 1962; McNeill et l., 1966; Fitch nd Morton, 1971). Incresed irwys resistnce fter exercise hs lso been shown in nonsthmtic reltives of sthmtic children (Konig nd Godfrey, 1973) nd in children with pst history of wheezy bronchitis (Konig et l., 1972). In n epidemiologicl study of 817 12-yer-old children, Burr, Eldridge nd Borysiewicz (1974) found tht children with history of wheezing showed fll in PEFR on exercise, while children with other topic disorders showed something of the sme tendency though their percentge fll in PEFR fter exercise overlpped those of the control group. The results of the present study showed similr overlp. Whether children with eczem nd bnorml bronchil lbility will eventully develop symptoms ttributble to sthm is not yet known, but it is of interest tht 2 children in group 2 hve ttended peditricins with sthmtic symptoms since the study ws crried out. However, it is not possible to sy whether these children hve developed sthm or re now wre of the mechnism of their previous symptoms, but the impression is tht before the study their bronchil lbility ws not severe enough to led to symptoms. The study hs shown tht eczemtous children with bronchil response to exercise of less thn 20% fll in PEFR hve norml serum IgE levels (<600 IU/ml). Significntly higher levels of IgE were found in those children with incresed bronchil lbility. Other workers hve lso found tht serum IgE levels re highest in those children who hve two or more topic disorders together (Hvnen et l., 1973; Wood nd Oliver, 1972; Berg nd Johnsson, 1969). Some ptients with topic ezcem s the only symptom hve been reported to hve very high serum IgE concentrtions (Juhlin et l., 1969). This hs not been our experience in this study except in one eczemtous child who showed n bnorml physiologicl response to exercise. In those children with history of wheezing ttcks the mjority, but not ll, hd serum IgE levels bove the norml rnge (600 IU/ml). We hve shown tht eczemtous children who show bnorml bronchil lbility hve greter number of hypersensitivity rections to common llergens on skin testing. House mite sensitivity ws gretest in the group with the most lbile bronchil rections to exercise. In view of our findings of high IgE levels in the bnormlly lbile group, the skin testing results re not expected since reltion between skin sensitivities nd IgE levels in topic subjects hs been estblished (Wood nd Oliver, 1972; Hvnen et l., 1973). Eosinophil counts tended to be higher in those eczemtous children with the most lbile bronchi but there ws considerble overlp in ll three physiologicl groups. It hs recently been suggested tht in dults 350 eosinophils/mm3 is the upper limit of norml (Horn et l., 1975) nd it is of interest tht the mjority of overtly wheezy children hd counts bove this level. In the group of children with fll in PEFR of less thn 20% in response to exercise 3 hd n eosinophil count >350 eosinophils/mm3 but 2 of these hd symptoms of llergic rhinitis. 29 of our 42 children hd fll in PEFR greter thn 20% fter exercise. This group with clerly bnorml bronchil responses were lso chrcterized by incresed cutneous sensitiztions nd high serum IgE levels. Our dt indicte tht the mjority of children with eczem who present t dermtology clinic will hve history of wheezing, high eosinophil count, high IgE level, number of skin sensitivities, nd exercise-linked sthm. In the mjority of our eczemtous ptients there is predisposition to develop sthm nd n interdependent inheritnce is suggested. However, 13 eczemtous children showed no evidence of EI. 3 of these gve history of llergic rhinitis nd showed positive skin rection to grss pollen. The remining 10 children, with morphologiclly identicl dermtitis gve no history of llergic disese other thn eczem, hd little skin sensitivity nd norml levels of IgE. It my be tht eczem nd broncholbility re inherited independently but in the mjority of ptients both occur nd only in minority is eczem inherited lone. Thus ptients with eczem nd no evidence of EI, norml levels of IgE, nd lck of skin sensitivity my well constitute seprte group with different pthophysiologicl mechnism for their eczem; or eczem in ll ptients is not ssocited with reginic llergy but the rised IgE levels nd skin sensitivity found in the mjority of ptients with eczem is dependent on the tendency for combined inheritnce of sthm nd eczem. We thnk Miss J. Crter for technicl ssistnce. We re grteful to Drs. R. S. Wells nd L. Stinumler for llowing us to study their ptients; to Dr. T. J. H. Clrk for encourgement nd dvice; nd to Miss Lynd Buss for typing the mnuscript. G. M. C. ws supported by Sir Philip Oppenheimer, rch Dis Child: first published s 10.1136/dc.51.12.912 on 1 December 1976. Downloded from http://dc.bmj.com/ on 8 My 2018 by guest. Protected by copyright.

Exercise-induced bronchoconstriction, skin sensitivity, nd serum IgE in children with eczem 917 Friends of Guy's Hospitl. J. F. P. ws supported by grnt from Beechm Reserch Lbortories. REPERENcs Berg, T., nd Johnsson, S. G. 0. (1969). IgE concentrtions in children with topic diseses. Interntionl rchives of llergy nd pplied Immunology, 36, 219. Burr, M. L., Eldridge, B.., nd Borysiewicz, L. K. (1974). Pek expirtory flow rtes before nd fter exercise in school children. rchives of Disese in Childhood, 49, 923. Coc,. F., nd Cooke, R.. D. (1923). On the clssifiction of the phenomenon of hypersensitiveness. Journl of Immunology, 8, 163. Connolly, N. M., nd Godfrey, S. (1970). ssessment of the child with sthm. Journl of sthm Reserch, 8, 31. Edgren, G. (1943). Prognose und erblichkeitsmomente bei ekzem infntum. ct Peditric, 30, Suppl. 2. Fitch, K. D., nd Morton,. R. (1971). Specificity of exercise in exercise-induced sthm. British Medicl Journl, 4, 577. Godfrey, S., Kmburoff, P. L., nd Nirn, J. F. (1970). Spirometry, lung volumes nd irwys resistnce in norml children ged 5 to 18 yers. British Journl of Diseses of the Chest, 64, 15. Hvnen, J., mlie, P.., Hvtum, M., Oseid, S., Veggn, T., nd s, K. (1973). IgE concentrtions in llergic sthm in children. rchives of Disese in Childhood, 48, 850. Hoffmn, D. R., Ymmoto, F. Y., Geller, B., nd Hddd, Z. (1975). Specific IgE ntibodies in topic eczem. journl of llergy nd Clinicl Immunology, 55, 256. Horn, B. R., Robin, E. D., Theodore, J., nd Vn Kessel,. (1975). Totl eosinophil counts in the mngement of bronchil sthm. New Englnd Journl of Medicine, 292, 1152. Johnson, E. E., Irons, J. S., Ptterson, R., nd Roberts, M. (1974). Serum IgE concentrtions in topic dermtitis. Journl of llergy nd Clinicl Immunology, 54, 94. Jones, R. H. T., nd Jones, R. S. (1966). Ventiltory cpcity in young dults with history of sthm in childhood. British Medicl journl, 11, 976. Jones, R. S., Buston, M. H., nd Whrton, M. J. (1962). The effect of exercise on ventiltory function in the child with sthm. British Journl of Diseses of the Chest, 56, 78. Juhlin, L., Johnsson, S. G. O., Bennich, H., Hogmn, C., nd Thyresson, N. (1969). Immunoglobulin E in dermtoses: levels in topic dermtitis nd urticri. rchives of Der?tology, 100, 12. Konig, P., nd Godfrey, S. (1973). Prevlence of exercise induced bronchil lbility in fmilies of children with sthm. rchives of Disese in Childhood, 48, 513. Konig, P., Godfrey, S., nd brhmov,. (1972). Exerciseinduced bronchil lbility in children with history of wheezy bronchitis. rchives of Disese in Childhood, 47, 578. McNeill, R. S., Nirn, J. R., Millr, J. S., nd Ingrm, C. G. (1966). Exercise-induced sthm. Qurterly J'ournl of Medicine, 35, 55. Ogw, M., Berger, P.., Mclntyre, 0. R., Clendenning, W. B., nd Ishizk, K. (1971). IgB in topic dermtitis. rchives of Der?tology, 103, 575. Silvermn, M., nd nderson, S. D. (1972). The stndrdiztion of exercise tests in sthmtic children. rchives of Disese in Childhood, 47, 882. Stifler, W. C. (1965). 21 yer follow-up of infntile eczem. J7ournl of Peditrics, 66, 166. Stone, S. P., Muller, S.., nd Gleich, G. J. (1973). IgE in topic dermtitis, 1973. rchives of Derntology, 108, 806. Wood, C. B. S., nd Oliver, J. (1972). Serum IgE in sthmtic children; reltion to ge, sex, eczem nd skin sensitivity tets. rchives of Disese in Childhood, 47, 890. Correspondence to Dr. J. F. Price, The Hospitl for Sick Children, Gret Ormond Street, London WC1N 3JH. rch Dis Child: first published s 10.1136/dc.51.12.912 on 1 December 1976. Downloded from http://dc.bmj.com/ on 8 My 2018 by guest. Protected by copyright.