Association between allergic disease and reactivity to recombinant Der p 2 allergen of house dust mites in a tropical situation

562 Lynch et al.

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TABLE I. Increase in total and peanut-specific IgE during PEG-ADA therapy Age (mos)

Total IgE (ng/ml)

Peanut-specific IgE (kIUA/L)

2.5 5 11 19 24 34

,2 15.8 96 1105 1629 5099

, 0.35 — — 17.9 — 94.7

toxic effects of adenosine and 2’-deoxyadenosine accumulation.1 By eliminating toxic ADA substrates, PEGADA permits recovery of endogenous immune function. Although correction of metabolic abnormalities is nearly always achieved, and most patients have derived clinical benefit, improvement in immune function is variable and usually partial. Most patients remain lymphopenic, and as many as 20% show relatively little improvement in in vitro lymphocyte function.1 Specific IgG antibody responses have been documented in patients treated with PEG-ADA,1 and elevated serum IgE has been found in some ADA-deficient patients with less severe degrees of immunodeficiency.4 However, there have been no previous reports of high levels of IgE or hypersensitivity reactions mediated by allergen-specific IgE in ADAdeficient patients with SCID treated with PEG-ADA. The production of specific IgE antibodies, as demonstrated in this patient, demonstrates the successful interaction of a number of elements of the immune system

involved in producing this antibody. Specifically, IgE production requires the interaction of antigen-specific T cells that can secrete IL-4 and IL-5 with antigen-specific B cells.5 Intravenous immunoglobulin contains insignificant levels of IgE and therefore cannot be the source of antibody. Because this patient has a strong family history of atopy, we suspect that the predilection for IgE production is a result of an inherited disposition toward atopy rather than as a specific result of PEG-ADA treatment. Thus this patient with ADA-deficient SCID demonstrates that PEG-ADA therapy can reconstitute an allergen-specific IgE response. Unfortunately, a consequence of the successful treatment of this patient was the development of life-threatening allergies.

REFERENCES 1. Hershfield MS, Mitchell BS. Immunodeficiency diseases caused by adenosine deaminase deficiency and purine nucleoside phosphorylase deficiency. In: Scriver CR, Beaudet AL, Sly WS, Vlle D, editors. The metabolic and molecular bases of inherited disease. New York: McGraw-Hill; 1995. p. 1725-68. 2. Bollinger ME, Arredondo-Vega FX, Santisteban I, Schwartz K, Hershfield MS, Lederman HM. Brief report: hepatic dysfunction as a complication of adenosine deaminase deficiency. N Engl J Med 1996;334:1367-71. 3. Bernhisel-Broadbent J, Taylor S, Sampson HA. Cross-allergenicity in the legume botanical family in children with food hypersensitivity. J Allergy Clin Immunol 1989;84:701-9. 4. Ozsahin H, Arredondo-Vega FX, Santisteban I, Fuhrer H, Tuchschmid P, Jochum W, et al. Adenosine Deaminase (ADA) deficiency in adults. Blood 1997;89:2849-55. 5. Geha RS. Regulation of IgE synthesis in humans. J Allergy Clin Immunol 1992;90:143-50.

Association between allergic disease and reactivity to recombinant Der p 2 allergen of house dust mites in a tropical situation Neil R. Lynch, PhD,a Franca S. Puccio, BSc,a Maria C. Di Prisco, MD, PhD,a Jaime E. Escudero, MD,b Marianella Nozzolino, MD,b Lee A. Hazel,c Wendy A. Smith, BSc,c and Wayne R. Thomas, PhDc Caracas, Venezuela, and Subiaco, Australia

From aInstituto de Biomedicina, Universidad Central de Venezuela, Caracas; bAmbulatorio Norte, Ministerio de Sanidad y Asistencia Social, Caracas; and cInstitute for Child Health Research, Princess Margaret Hospital for Children, Subiaco. Supported by Projects CONICIT RPV170041, BID BTS 65, World Bank VEN/002/96/14, Congresso de la Republica/Ministerio de Educacio ´n/UCV and CDCH/UCV. Reprint requests: Neil R. Lynch, PhD, Instituto de Biomedicina, Aptdo. 4043, Caracas 1010A, Venezuela. J Allergy Clin Immunol 1998;101:562-4. Copyright © 1998 by Mosby, Inc. 0091-6749/98 $5.00 1 0 1/54/88668

Abbreviation used WME: Whole mite extract

Immediate hypersensitivity skin tests with allergenic extracts provide a useful aid in the diagnosis of allergic diseases. Although positivity in these tests is directly related to the presence of IgE antibody against the allergen tested, this is not necessarily synonymous with a

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Lynch et al. 563

FIG. 1. Percentage of children who had positive skin test reactions with WME or Der p 2 and who either did or did not report allergic symptoms. Note that reactivity of children with positive reactions to WME to glutathione-S-transferase fusion partner of recombinant Der p 2 allergen was 11%.

disease state, because persons with an atopic disposition can show skin test reactivity without manifesting allergic symptoms.1 This frequently occurs in tropical situations in which helminthic infection is endemic, because these parasites can nonspecifically potentiate the synthesis of IgE antibody against common environmental allergens without this having evident clinical consequences.2 These observations indicate that the possession of specific IgE antibody and sensitized mast cells, along with exposure to the appropriate allergen, are not in themselves sufficient for the expression of the physiologic changes that are recognized as the symptoms of allergic disease.3 In this study we related allergic history with the reactivity to extracts of the house dust mite Dermatophagoides pteronyssinus and one of its principal allergens (Der p 2) in a group of 6-year-old schoolchildren who underwent a routine medical examination in Caracas, Venezuela (latitude, 10° N), and in whom helminthic infection is endemic (point prevalence of 28% and accumulative prevalence of almost 100%). Ascaris lumbricoides and Trichuris trichuria were the dominant parasites.4 We obtained the permission of the Ethical

Committee of the Institute of Biomedicine for this study, as well as that of the medical service where the children were examined. These tests were also ratified by the National Council of Scientific and Technological Investigation of Venezeula and the Academic Council of the Medical Faculty of the Central University of Venezeula. The informed consent of the legal guardians of the children was also obtained. Ninety-one children were examined medically, and their accompanying parent was questioned with emphasis on the establishment of a history of allergic disease, taking respiratory symptoms into particular account. Rhinitis was reported in 27% of the children, and asthma was reported in 16%, with the combined prevalence of disease being 35%. All of the children were then skin prick tested with an extract of D. pteronyssinus (whole mite extract [WME]; Commonwealth Serum Laboratories, Melbourne, Australia), which is by far the most important aeroallergen in Venezeula.4 Thirty percent of the group were found to have positive immediate reactions (wheal diameter, $3 mm) to this allergen. These children were then tested with recombinant Der p 2 that had been prepared as a fusion protein with glutathione-S-transferase and puri-

564 Romano et al.

fied by affinity chromatography.5 This allergen was used at concentrations that started at 0.1 mg/ml and increased in 10-fold steps until a positive reaction occurred, but the concentration did not exceed 100 mg/ml. Only 41% of the children who had positive reactions to WME also reacted to Der p 2. When the children who had positive reactions to these tests were divided according to whether they had a recent history of allergic disease, we found that 48% of the persons who had positive reactions to WME did not report clinically relevant respiratory symptoms. In contrast, this occurred in only 18% of those with positive reactions to Der p 2 (p , 0.001) (Fig. 1). We have previously shown that over 80% of Venezuelan patients attending an allergy clinic are sensitive to house dust mites, and the positive skin test reactions to WME and Der p 2 are very similar.6 Therefore the present results suggest that in the situation of endemic helminthic infection that exists in this country, positive skin test reactions to WME in an unselected group of children does not necessarily indicate an allergic condition. However, testing with purified Der p 2 allergen better discriminates between a nonsymptomatic atopic state and clinically relevant allergy. This might indicate that although many components of house dust mites can stimulate IgE antibody synthesis, the responses against

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some of these allergens, such as Der p 2, are more closely associated with the manifestation of clinical symptoms than others. REFERENCES 1. Pastorello EA, Incorvaia C, Ortolani C, Bonini S, Canonica GW, Romanagni S, et al. Studies on the relationship between the level of specific IgE antibodies and the clinical expression of allergy. I. Definition of levels distinguishing patients with symptomatic from patients with asymptomatic allergy to common aeroallergens. J Allergy Clin Immunol 1995;96:580-7. 2. Lynch NR. Influence of socio-economic level on helminthic infection and allergic reactivity in tropical countries. In: Moqbel R, editor. Allergy and immunity to helminthic infection: Common mechanisms or divergent pathways? London: Taylor & Francis; 1992. p. 51-62. 3. Aalberse R. Atopy and the ectopic immune response. Immunol Cell Biol 1996;74:201-5. 4. Hagel I, Lynch NR, Di Prisco MC, Lopez RI, Garcia N. Int Arch Allergy Immunol 1993;101:209-14. 5. Chua KY, Dilworth RJ, Thomas WR. Expression of Dermatophagoides pteronyssinus allergen, Der p II, in Escherichia coli and the binding studies with human IgE. Int Arch Allergy Appl Immunol 1990;91:124-9. 6. Lynch NR, Thomas WR, Garcia N, Di Prisco MC, Puccio F, Lopez R. Biological activity of recombinant Der p 2, 5 and 7 allergens of the house dust mite D. pteronyssinus. Int Arch Allergy Immunol 1997;114: 59-67.

Selective type-1 hypersensitivity to cefuroxime Antonino Romano, MD,a, d Donato Quaratino, MD,a Alberto Venuti, MD,a Lennart Venemalm, MD,b Cristobalina Mayorga, PhD,c and Miguel Blanca, MDc Rome and Troina, Italy, Uppsala, Sweden, and Malaga, Spain

Cefuroxime is a second-generation semisynthetic cephalosporin that is widely used for treatment of respiratory tract infections. Both the sodium salt for parenteral administration and the acetyloxy ethyl ester (cefuroxime axetil) for oral use are generally well tolerated. This report describes a case of anaphylactic shock provoked by cefuroxime axetil, in which specific IgE to the latter drug was demonstrated. CASE REPORT A 58-year-old woman was prescribed cefuroxime axetil tablets (500 mg three times a day) for pharyngitis. Fifteen minutes after taking the first tablet, she had generalized urticaria, facial From athe Department of Internal Medicine and Geriatrics, UCSC– Allergy Unit, Rome; bPharmacia and Upjohn, Uppsala; cResearch Unit for Allergic Diseases, Carlos Haya Hospital, Malaga; and dIRCS Oasi Maria S.S., Troina. Reprint requests: Antonino Romano, MD, Ambulatorio di Allergologia, Complesso Integrato Columbus, Via Pineta Sacchetti 506, 00168 Rome, Italy. J Allergy Clin Immunol 1998;101:564-5. Copyright © 1998 by Mosby, Inc. 0091-6749/98 $5.00 1 0 1/54/88658

angioedema, shortness of breath, dizziness, tachycardia, and severe hypotension. Two hours after treatment in the emergency department with subcutaneous adrenaline, 6-methylprednisolone (80 mg intravenously), and chlorphenamine (10 mg intravenously), her symptoms had largely disappeared, and she was completely asymptomatic after 24 hours. Eight months earlier, she had tolerated intramuscular cefuroxime, and before that she had tolerated ampicillin and amoxicillin. Her personal and family histories were negative for allergic disease. One month after the reactive episode, an allergologic work-up was performed.

Skin tests The patient underwent skin tests (skin prick and intradermal) with penicilloyl polylysine (Allergopen, Reinbeck, Germany), minor determinant mixture (Allergopen), sodium penicillin G diluted in 0.9% NaCl and administered at increasing concentrations (0.1 IU/ml to 10,000 IU/ml), ampicillin, amoxicillin, cefuroxime, cephalothin, ceftazidime, cefamandole, and ceftriaxone. Ampicillin, amoxicillin, cefurixome, cephalothin, ceftazidime, cefamandole, and ceftriaxone were diluted in 0.9% NaCl and used at concentrations of 1 and 20 mg/ml. All haptens were used for skin prick testing on skin of the