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Severe anaphylaxis to kiwi fruit: Immunologic changes related to successful sublingual allergen immunotherapy
1406 Letters to the Editor
prevalence of positive SPT results was 28%, which compared with 45.2% for the control group. This study also shows that the frequency of positive results of SPTs to aeroallergens and of respiratory atopic diseases increased even in this population considered at low risk of developing atopy, probably as consequence of both the normal increase in positive SPT results with age and the increase of atopy and allergic diseases observed in the last 20 years in our region.4 It has been speculated that the lower prevalence of atopy in patients with BT might be due to allergen-specific IgG acquired early in life through transfusions, which could suppress the synthesis of allergen-specific IgE,3 or to chronic viral infections.5 The role of splenectomy remains unclear. Theoretically, the higher incidence of bacterial infection after splenectomy might deviate T-cell cytokine response toward the TH1 phenotype and a lower incidence of atopy. In this study, we found that splenectomy in patients with BT is associated with a lower incidence of atopy and atopic diseases, though the difference was not significant. In conclusion, at a mean age of 28 years, patients with BT are still less atopic than the members of a general population. It seems that the atopy inhibitory factor (or factors) that acts in the first years of life has a long-term effect or is still active in adult life. Elio Novembre, MDa Antonella Cianferoni, MDa Lucetta Capra, MDb Roberto Bernardini, MDa Neri Pucci, MDa Enrico Lombardi, MDa Alberto Vierucci, MDa aPediatric Allergy and Pulmonology Center Anna Meyer Children Hospital Department of Pediatrics University of Florence bDepartment of Pediatrics S. Anna Hospital Ferrara Italy Funded by the University of Florence, Italy. REFERENCES
Letters to the Editor
1. Dreborg S, Frew A. Allergen standardization and skin tests. Position paper. Allergy 1993;48:48-82. 2. Ellwood P, Asher MI, Bjorksten B, Burr M, Pearce N, Robertson CF. Diet and asthma, allergic rhinoconjunctivitis and atopic eczema symptom prevalence: an a ecological analysis of the International Study of Allergies in Childhood (ISAAC) data. ISAAC Phase One Study Group. Eur Respir J 2001;17:436-43. 3. Vierucci A, De Martino M, Di Palma A, Novembre E, Rossi ME, Resti M, et al. The multitransfused beta-thalassemic child: a model for the study of IgE response. Ann Allergy 1986;56:158-61. 4. Lombardi E, Novembre E, Cianferoni A, Bernardini R, Ingargiola A, Frangini L, et al. The relationship between skin test reactivity to specific allergens and symptoms in a school age population in Central Italy. Am J Resp Crit Care Med 1998;157:A47. 5. Matricardi PM, Rosmini F, Ferrigno L, Nisini R, Rapicetta N, Chionne P, et al. Cross sectional retrospective study of prevalence of atopy among Italian military students with antibodies against hepatitis A virus. BMJ 1997;314:999-1003. doi:10.1067/mai.2003.1478
J ALLERGY CLIN IMMUNOL JUNE 2003
Severe anaphylaxis to kiwi fruit: Immunologic changes related to successful sublingual allergen immunotherapy To the Editor: Sublingual swallow allergen immunotherapy (SLIT) with standardized extracts has been shown to reduce clinical symptoms in a variety of IgE-mediated respiratory allergic diseases.1-4 Although it appears also as a reasonable route of allergen delivery for desensitization protocols in food-induced allergic reactions, it is usually not applied because of the lack of standardized extracts, the inconsistency in allergen uptake, and the possibility of therapy-related life-threatening anaphylactic symptoms in such patients. We present the case of a 29-year-old white woman who had several episodes of severe anaphylaxis after consumption of kiwi fruit, including 3 episodes of allergic shock with loss of consciousness and subsequent hospitalization. For the first 2 episodes, the symptoms started shortly after ingestion of pure fresh kiwi preparations without concomitant consumption of additional foods, pointing to the causative role of kiwi. Most remarkably, in a third episode anaphylaxis had been elicited by minute amounts of kiwi left on a knife that was subsequently used to prepare a strawberry dessert served to the patient in a restaurant. In addition, the patient had a 15-year history of seasonal rhinitis during the grass pollen season. Her physical examination revealed an otherwise healthy patient. Allergy diagnosis included positive skin prick test (SPT) reactions to kiwi, grass pollen, house dust mite, and crab meat (extracts from Allergopharma, Reinbek, Germany). A large panel of routinely tested seasonal and perennial aeroallergens, as well as food allergens, including birch pollen and latex, elicited negative results. When SPTs were performed with undiluted fresh kiwi extract, the patient had severe systemic symptoms, such as pharyngeal swelling and generalized urticaria. In the patient’s serum specific IgE (CAP-FEIA; Pharmacia, Uppsala, Sweden) was found against kiwi (Actinidia chinensis; 28.0 kU/L; normal range, <0.35 kU/L), crab meat (Peneaus indicus; 3.18 kU/L), and timothy grass pollen (Phleum pratense; 29.0 kU/L; Fig 1).5 Western blot analysis of kiwi and timothy pollen extracts revealed specific IgE reactivity to the 30-kd major kiwi allergen, previously identified as Act c 1,6-8 and various IgE reactivities to timothy grass pollen allergens (Fig 2). A subsequent detailed analysis with recombinant allergens revealed dominant IgE reactivity with the P pratense allergens Phl p 1 and Phl p 4. SPTs and serologic analysis for specific IgE against a variety of other allergens, including birch pollen and latex, showed negative results. Because of the life-threatening nature of anaphylaxis and the impossibility of allergen avoidance (unawareness of kiwi exposure in prepared meals), indication for immunotherapy was given, and SLIT was started with kiwi fruit extract. To this end, a stock solution was prepared by means of homogenization and filtration of fresh
J ALLERGY CLIN IMMUNOL VOLUME 111, NUMBER 6
Letters to the Editor 1407
kiwi pulps, adjustment of the protein content to 1 mg/mL, and serial dilution of the extract in sterile H2O. Aliquots were kept frozen at –20°C. The patient was administered the diluted kiwi extract sublingually 3 times a day. We started with 0.1 mL of a 10–4 dilution (one tenth of the lowest positive concentration in SPTs) and gradually increased the dose in 2-hour intervals, with a maximum of 3 applications per day. Several times during increases in dose, the patient reacted with mild (rhinitis) to severe (pharyngeal swelling, dyspnea, and nausea) symptoms, after which the dose was decreased (severe) or repeated (mild). After a dose of 1 mL of undiluted kiwi extract was reached, the patient was subsequently given a 1-cm3 cube of fresh kiwi that was tolerated well without any adverse reactions. The patient was then advised to continue this application on a daily basis as maintenance therapy. At the time maintenance therapy was begun (July 3, 2001), the patient had a reduced SPT reaction to kiwi (lowest positive dilution now 10–1 compared with 10–3 before SLIT), an increase in kiwi-specific serum IgE to greater than 100 kU/L, and a clear-cut increase in kiwispecific IgG4 compared with pretherapy values (82.2 µg/L before therapy to 774 µg/L after therapy). These results were mirrored in immunoblots in which the presence of specific IgG4 reactivity to the 30-kd major kiwi allergen was detected (Fig 2). Specific IgE levels against latex and birch pollen extracts were again found to be negative, and the pattern of reactivity to timothy grass pollen remained unchanged. These immunologic reac-
tions corresponded to a successful SLIT to kiwi with a switch from allergen-specific IgE to the more protective allergen-specific IgG4. Six weeks later (August 15, 2001), near the end of the grass pollen season in Bavaria, serum was obtained for new controls. Again specific IgE and IgG4 to the 30-kd kiwi protein was identified, but in addition, specific IgE and IgG4 antibodies were also found against latex (Hevea brasiliensis) and birch pollen (Betula verrucosa), mainly to the major allergens Hev b 1 and Bet v 2, respectively (Fig 2). Both allergens are known to exhibit cross-reactivity to kiwi as to timothy grass pollen antigens.6-8 Interestingly, by means of detailed analysis of the antibody reactivity pattern of antibodies to timothy grass pollen, we found induction of specific IgE (Fig 1) and IgG4 (data not shown) to the grass pollen allergens Phl p 5, Phl p 6, and Phl p 12, which had not been present previously. Western blot (Fig 2) and CAP-FEIA (not shown) inhibition tests with purified kiwi and P pratense pollen extracts showed that the specific IgE, as well as the specific IgG4 (not shown), against latex and birch pollen were cross-absorbable with the P pratense extract but only partially with kiwi extract. The findings at this point were in accordance with those of a successful SLIT that caused an increase in IgG4 antibodies to the kiwi 30-kd major allergen and a concomitant induction of IgE and IgG4 antibodies to Bet v 2 from birch pollen, Hev b 1 from latex, and Phl p 5, Phl p 6, and Phl p 12 from timothy grass after seasonal
Letters to the Editor
FIG 1. Time axis and time points for the determination of specific IgE antibodies during the course of sublingual SLIT with kiwi. Five weeks were needed before maintenance therapy was reached (May 29 to July 3, 2001). Serum samples were analyzed before initiation of kiwi SLITs (A), immediately after reaching the full maintenance dose (B), and 6 weeks later (C), which correlated with the end of the grass pollen season in Bavaria. Birch pollen season ended in early May. Thus an exposure to birch pollen can be excluded for the observed immunologic changes. Specific IgE levels were analyzed by using whole extracts for timothy grass pollen (Phl p), kiwi (Act c), latex (Hev b), and birch pollen (Bet v), as well as recombinant allergens for various timothy grass (Phl p 1, 4-7, 11, and 12) and birch pollen (Bet v 1, 2, and 4) allergens. Reagents were obtained through Pharmacia (Uppsala, Sweden) and ADL-Matritech, (Freiburg, Germany) and were used as recommended.5
1408 Letters to the Editor
J ALLERGY CLIN IMMUNOL JUNE 2003
FIG 2. Western blot (WB) analysis for specific IgE (lanes 1-3) and specific IgG4 (lanes 4-6) against kiwi, timothy grass pollen, latex, and birch pollen. Samples were obtained before starting SLITs (lanes 1 and 4), immediately after reaching the full maintenance dose (lanes 2 and 5), and 6 weeks later after the end of the grass pollen season (lanes 3 and 6). Additionally, the serum samples were cross-absorbed with kiwi (*K, lane 7), and timothy grass pollen (Phleum pratense; *P, lane 8) extracts and specific IgE reactivity was analyzed. The Western blot shows de novo induction of specific IgE and IgG4 antibodies against Hev b 1 and Bet v 2, as well as several P pratense antigens that were cross-absorbable with P pratense extract but only partially with kiwi extract. The incomplete cross-absorbability for timothy grass pollen–reactive IgE by the timothy pollen extract is due to the very high titer of P pratense–specific IgE at that time (compare lanes 3 and 8 of the timothy grass pollen blot). Western blot reagents for timothy pollen, birch pollen, and latex were obtained through DPC (Los Angeles, Calif), and blots for kiwi were prepared according to standard protocols.
Letters to the Editor
exposure to grass pollen under ongoing maintenance SLITs with kiwi. We tested the patient for clinical relevance of the de novo–induced IgE sensitizations to birch pollen and latex. SPT responses were positive for both birch pollen and latex. However, nasal challenge with birch pollen extract produced negative results, as did skin exposure to powdered latex gloves for 30 minutes. Thus the induction of IgE antibodies against latex and birch pollen was without clinical relevance. The most probable explanation for this finding is the concomitant induction of protective IgG4 antibodies during de novo sensitization (Fig 2). However, this explanation is questioned by some studies on allergen immunotherapy.9 But why did the patient at the same time have IgE and IgG4 antibodies against P pratense allergens that crossreacted with birch pollen and latex allergens? One can speculate that through the successful ongoing SLITs with kiwi, the immune reaction pattern was modulated
toward a TH1 or T-regulatory phenotype that helped to induce a more general tolerization toward the encountered new allergens. However, more data and larger studies on the follow-up of other patients is required to elucidate this hypothesis. We gratefully acknowledge the skillful technical assistance of Mrs B. Heuser and Mrs J. Grosch. We further thank the staff of the Allergy Unit of the Department of Dermatology and Allergy, as well as Drs Klemm and Groer for their help with the SLIT protocol. The data on the grass and birch pollen counts for the Munich area were kindly provided by the German pollen information agency (Deutscher Polleninformationsdienst, Bad Lippspringe). This work was supported in part by grant 01GC0104 from the German Federal Ministery of Science and Education (BMBF) to M.M. and M.O. Martin Mempel, MDa,b,c Jürgen Rakoski, MDa Johannes Ring, MD, PhDa,b,c Markus Ollert, MDa,b,c aDepartment of Dermatology and Allergy
bClinical
Research Division of Molecular and Clinical Allergotoxicology Technische Universität München (TUM) Biedersteiner Str. 29 D-80802 Munich, Germany cDivision of Environmental Dermatology and Allergy GSF/TUM GSF National Research Center for Environment and Health Neuherberg, Germany REFERENCES 1. Passalacqua G, Albano M, Fregonese L, Riccio A, Pronzato C, Mela GS, et al. Randomised controlled trial of local allergoid immunotherapy on allergic inflammation in mite-induced rhinoconjunctivitis. Lancet 1998;351:629-32. 2. Pajno GB, Morabito L, Barberio G, Parmiani S. Clinical and immunologic effects of long-term sublingual immunotherapy in asthmatic children sensitized to mites: a double-blind, placebo-controlled study. Allergy 2000;55:842-9. 3. Guez S, Vatrinet C, Fadel R, André C. House-dust-mite sublingual-swallow immunotherapy (SLIT) in perennial rhinitis: a double-blind, placebocontrolled study. Allergy 2000;55:369-75. 4. Vourdas D, Syrigou E, Potamianou P, Carat F, Batard T, Andre C, et al. Double-blind, placebo-controlled evaluation of sublingual immunotherapy with standardized olive pollen extract in pediatric patients with allergic rhinoconjunctitvitis and mild asthma due to olive pollen sensitization. Allergy 1998;53:662-72. 5. Rossi RE, Monasterolo G, Monasterolo S. Measurement of IgE antibodies against purified grass-pollen allergens (Phl p 1, 2, 3, 4, 5, 6, 7, 11, and 12) in sera of patients allergic to grass pollen. Allergy 2001;56:1180-5. 6. Pastorello EA, Pravettoni V, Ispano M, Farioli L, Ansaloni R, Rotondo F, et al. Identification of the allergenic components of kiwi fruit and evaluation of their cross-reactivity with timothy and birch pollens. J Allergy Clin Immunol 1996;98:601-10. 7. Gall H, Kalveram K-J, Forck G, Sterry W. Kiwi fruit allergy: a new birch pollen-associated food allergy. J Allergy Clin Immunol 1994;94:70-6. 8. Vocks E, Borga A, Szliska C, Seifert HU, Seifert B, Burow G, et al. Common allergenic structures in hazelnut, rye grain, sesame seeds, kiwi, and poppy seeds. Allergy 1993;48:168-72. 9. Ewan PW, Deighton J, Wilson AB, Lachmann PJ. Venom-specific IgG antibodies in bee and wasp allergy: lack of correlation with protection from stings. Clin Exp Allergy 1993;23:647-60. doi:10.1067/mai.2003.1497
Oral tacrolimus for severe recalcitrant atopic eczema To the Editor: The patient is a 19-year-old man who has had eczema his entire life, with generalized eczema, including his scalp, hands, and feet, developing within 1 month of birth. To date, he has not had asthma, rhinitis, or conjunctivitis. Exacerbations are not related to specific foods or allergen exposure, except for cat allergen, which causes severe pruritus and worsening eczema. Symptoms are also exacerbated by “weather changes” and sweating associated with physical activities. Swimming in a chlorinated pool relieves symptoms to some extent. Before age 7 years, various treatment programs, such as coal tar, oatmeal baths, antibiotic therapy, and topical triamcinolone cream, resulted in no long-term relief. Various dust mite prevention programs, including the use of a special vacuum, hot-water clothes washing, covering mattresses and pillows, and removing carpets, did not result in improvement. About age 7 years, he began taking systemic glucocorticosteroids intermittently throughout each year for more than half of the year. His symp-
toms resulted in poor attendance during middle school, eventually necessitating home schooling during the last 3 years of high school. He was first seen by Dr Lockey in May 1998. At that time, he had intractable pruritus and severe eczema covering his entire body. Laboratory studies revealed an IgE level of 4962 IU/mL (normal, 0-149 IU/mL), a RAST score to peanut of +4 and mite of +5 (class +1-+5), and positive prick-puncture test responses to a variety of different aeroallergens, including pollen (+4), dog (+3), dust mite (+4), cat (+2), and molds (+4) (+2 is defined as a wheal <3 mm with erythema of >20 mm, +3 as a wheal >3 mm with surrounding erythema, and +4 as a wheal with pseudopods and surrounding erythema). He was treated with prevention, topical glucocorticosteroids, hydroxyzine hydrochloride and then doxepin hydrochloride, lubricants, and eventually immunotherapy. The immunotherapy was discontinued after 1 year because it caused his atopic dermatitis to flare. By December 1998, he began taking prednisone every other day continuously, with periodic bursts and intermittent oral antibiotics for worsening eczema. Attempts to decrease the glucocorticosteroids resulted in exacerbations. He was given a diagnosis of osteopenia (total T score of 1.72) in 1999, for which he is being treated with alendronate. In March 2000, he was consulted at National Jewish Medical and Research Center, Denver, Colorado, and started on a treatment regimen of high-dose prednisone, topical tacrolimus, 10 mg of monteleukast daily, and hot-water baths, followed by full-body triamcinolone cream topped with wet wraps and a lubricant. This resulted in substantial improvement of his symptoms. He was tapered from prednisone and discharged taking 2 mg of prednisone daily with continuation of the same treatment program. Within 1 month of return to Florida, on the same regimen, the eczema symptoms returned to pretreatment levels. He once again began to have flares of eczema necessitating short bursts of prednisone (45-60 mg in divided doses daily), with maintenance at about 15 mg every other day. The increase in symptoms on return to Florida could be due to an increased allergen burden in the patient’s home because of its tropical locale. In May 2002, he began oral tacrolimus therapy. The dose was increased from 1 mg twice daily to 5 mg twice daily to achieve therapeutic levels, with resultant improvement in his pruritus and eczema and discontinuation of his oral prednisone by September 2002. The severe rash and lichenified skin has shown great improvement. His symptoms improved, and the systemic glucocorticosteroids were discontinued by September 2002. As of September 2002, he began to attend junior college and now rides his dirt bike outdoors, both activities that used to severely exacerbate his disease. He continues to do well as of mid-February 2003. He is more affable, has a higher energy level, and has lost approximately 14 pounds, which is attributed to a decrease in appetite. He has not required systemic glucocorticosteroids since they were discontinued.
Letters to the Editor
Letters to the Editor 1409
J ALLERGY CLIN IMMUNOL VOLUME 111, NUMBER 6
prevalence of positive SPT results was 28%, which compared with 45.2% for the control group. This study also shows that the frequency of positive results of SPTs to aeroallergens and of respiratory atopic diseases increased even in this population considered at low risk of developing atopy, probably as consequence of both the normal increase in positive SPT results with age and the increase of atopy and allergic diseases observed in the last 20 years in our region.4 It has been speculated that the lower prevalence of atopy in patients with BT might be due to allergen-specific IgG acquired early in life through transfusions, which could suppress the synthesis of allergen-specific IgE,3 or to chronic viral infections.5 The role of splenectomy remains unclear. Theoretically, the higher incidence of bacterial infection after splenectomy might deviate T-cell cytokine response toward the TH1 phenotype and a lower incidence of atopy. In this study, we found that splenectomy in patients with BT is associated with a lower incidence of atopy and atopic diseases, though the difference was not significant. In conclusion, at a mean age of 28 years, patients with BT are still less atopic than the members of a general population. It seems that the atopy inhibitory factor (or factors) that acts in the first years of life has a long-term effect or is still active in adult life. Elio Novembre, MDa Antonella Cianferoni, MDa Lucetta Capra, MDb Roberto Bernardini, MDa Neri Pucci, MDa Enrico Lombardi, MDa Alberto Vierucci, MDa aPediatric Allergy and Pulmonology Center Anna Meyer Children Hospital Department of Pediatrics University of Florence bDepartment of Pediatrics S. Anna Hospital Ferrara Italy Funded by the University of Florence, Italy. REFERENCES
Letters to the Editor
1. Dreborg S, Frew A. Allergen standardization and skin tests. Position paper. Allergy 1993;48:48-82. 2. Ellwood P, Asher MI, Bjorksten B, Burr M, Pearce N, Robertson CF. Diet and asthma, allergic rhinoconjunctivitis and atopic eczema symptom prevalence: an a ecological analysis of the International Study of Allergies in Childhood (ISAAC) data. ISAAC Phase One Study Group. Eur Respir J 2001;17:436-43. 3. Vierucci A, De Martino M, Di Palma A, Novembre E, Rossi ME, Resti M, et al. The multitransfused beta-thalassemic child: a model for the study of IgE response. Ann Allergy 1986;56:158-61. 4. Lombardi E, Novembre E, Cianferoni A, Bernardini R, Ingargiola A, Frangini L, et al. The relationship between skin test reactivity to specific allergens and symptoms in a school age population in Central Italy. Am J Resp Crit Care Med 1998;157:A47. 5. Matricardi PM, Rosmini F, Ferrigno L, Nisini R, Rapicetta N, Chionne P, et al. Cross sectional retrospective study of prevalence of atopy among Italian military students with antibodies against hepatitis A virus. BMJ 1997;314:999-1003. doi:10.1067/mai.2003.1478
J ALLERGY CLIN IMMUNOL JUNE 2003
Severe anaphylaxis to kiwi fruit: Immunologic changes related to successful sublingual allergen immunotherapy To the Editor: Sublingual swallow allergen immunotherapy (SLIT) with standardized extracts has been shown to reduce clinical symptoms in a variety of IgE-mediated respiratory allergic diseases.1-4 Although it appears also as a reasonable route of allergen delivery for desensitization protocols in food-induced allergic reactions, it is usually not applied because of the lack of standardized extracts, the inconsistency in allergen uptake, and the possibility of therapy-related life-threatening anaphylactic symptoms in such patients. We present the case of a 29-year-old white woman who had several episodes of severe anaphylaxis after consumption of kiwi fruit, including 3 episodes of allergic shock with loss of consciousness and subsequent hospitalization. For the first 2 episodes, the symptoms started shortly after ingestion of pure fresh kiwi preparations without concomitant consumption of additional foods, pointing to the causative role of kiwi. Most remarkably, in a third episode anaphylaxis had been elicited by minute amounts of kiwi left on a knife that was subsequently used to prepare a strawberry dessert served to the patient in a restaurant. In addition, the patient had a 15-year history of seasonal rhinitis during the grass pollen season. Her physical examination revealed an otherwise healthy patient. Allergy diagnosis included positive skin prick test (SPT) reactions to kiwi, grass pollen, house dust mite, and crab meat (extracts from Allergopharma, Reinbek, Germany). A large panel of routinely tested seasonal and perennial aeroallergens, as well as food allergens, including birch pollen and latex, elicited negative results. When SPTs were performed with undiluted fresh kiwi extract, the patient had severe systemic symptoms, such as pharyngeal swelling and generalized urticaria. In the patient’s serum specific IgE (CAP-FEIA; Pharmacia, Uppsala, Sweden) was found against kiwi (Actinidia chinensis; 28.0 kU/L; normal range, <0.35 kU/L), crab meat (Peneaus indicus; 3.18 kU/L), and timothy grass pollen (Phleum pratense; 29.0 kU/L; Fig 1).5 Western blot analysis of kiwi and timothy pollen extracts revealed specific IgE reactivity to the 30-kd major kiwi allergen, previously identified as Act c 1,6-8 and various IgE reactivities to timothy grass pollen allergens (Fig 2). A subsequent detailed analysis with recombinant allergens revealed dominant IgE reactivity with the P pratense allergens Phl p 1 and Phl p 4. SPTs and serologic analysis for specific IgE against a variety of other allergens, including birch pollen and latex, showed negative results. Because of the life-threatening nature of anaphylaxis and the impossibility of allergen avoidance (unawareness of kiwi exposure in prepared meals), indication for immunotherapy was given, and SLIT was started with kiwi fruit extract. To this end, a stock solution was prepared by means of homogenization and filtration of fresh
J ALLERGY CLIN IMMUNOL VOLUME 111, NUMBER 6
Letters to the Editor 1407
kiwi pulps, adjustment of the protein content to 1 mg/mL, and serial dilution of the extract in sterile H2O. Aliquots were kept frozen at –20°C. The patient was administered the diluted kiwi extract sublingually 3 times a day. We started with 0.1 mL of a 10–4 dilution (one tenth of the lowest positive concentration in SPTs) and gradually increased the dose in 2-hour intervals, with a maximum of 3 applications per day. Several times during increases in dose, the patient reacted with mild (rhinitis) to severe (pharyngeal swelling, dyspnea, and nausea) symptoms, after which the dose was decreased (severe) or repeated (mild). After a dose of 1 mL of undiluted kiwi extract was reached, the patient was subsequently given a 1-cm3 cube of fresh kiwi that was tolerated well without any adverse reactions. The patient was then advised to continue this application on a daily basis as maintenance therapy. At the time maintenance therapy was begun (July 3, 2001), the patient had a reduced SPT reaction to kiwi (lowest positive dilution now 10–1 compared with 10–3 before SLIT), an increase in kiwi-specific serum IgE to greater than 100 kU/L, and a clear-cut increase in kiwispecific IgG4 compared with pretherapy values (82.2 µg/L before therapy to 774 µg/L after therapy). These results were mirrored in immunoblots in which the presence of specific IgG4 reactivity to the 30-kd major kiwi allergen was detected (Fig 2). Specific IgE levels against latex and birch pollen extracts were again found to be negative, and the pattern of reactivity to timothy grass pollen remained unchanged. These immunologic reac-
tions corresponded to a successful SLIT to kiwi with a switch from allergen-specific IgE to the more protective allergen-specific IgG4. Six weeks later (August 15, 2001), near the end of the grass pollen season in Bavaria, serum was obtained for new controls. Again specific IgE and IgG4 to the 30-kd kiwi protein was identified, but in addition, specific IgE and IgG4 antibodies were also found against latex (Hevea brasiliensis) and birch pollen (Betula verrucosa), mainly to the major allergens Hev b 1 and Bet v 2, respectively (Fig 2). Both allergens are known to exhibit cross-reactivity to kiwi as to timothy grass pollen antigens.6-8 Interestingly, by means of detailed analysis of the antibody reactivity pattern of antibodies to timothy grass pollen, we found induction of specific IgE (Fig 1) and IgG4 (data not shown) to the grass pollen allergens Phl p 5, Phl p 6, and Phl p 12, which had not been present previously. Western blot (Fig 2) and CAP-FEIA (not shown) inhibition tests with purified kiwi and P pratense pollen extracts showed that the specific IgE, as well as the specific IgG4 (not shown), against latex and birch pollen were cross-absorbable with the P pratense extract but only partially with kiwi extract. The findings at this point were in accordance with those of a successful SLIT that caused an increase in IgG4 antibodies to the kiwi 30-kd major allergen and a concomitant induction of IgE and IgG4 antibodies to Bet v 2 from birch pollen, Hev b 1 from latex, and Phl p 5, Phl p 6, and Phl p 12 from timothy grass after seasonal
Letters to the Editor
FIG 1. Time axis and time points for the determination of specific IgE antibodies during the course of sublingual SLIT with kiwi. Five weeks were needed before maintenance therapy was reached (May 29 to July 3, 2001). Serum samples were analyzed before initiation of kiwi SLITs (A), immediately after reaching the full maintenance dose (B), and 6 weeks later (C), which correlated with the end of the grass pollen season in Bavaria. Birch pollen season ended in early May. Thus an exposure to birch pollen can be excluded for the observed immunologic changes. Specific IgE levels were analyzed by using whole extracts for timothy grass pollen (Phl p), kiwi (Act c), latex (Hev b), and birch pollen (Bet v), as well as recombinant allergens for various timothy grass (Phl p 1, 4-7, 11, and 12) and birch pollen (Bet v 1, 2, and 4) allergens. Reagents were obtained through Pharmacia (Uppsala, Sweden) and ADL-Matritech, (Freiburg, Germany) and were used as recommended.5
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J ALLERGY CLIN IMMUNOL JUNE 2003
FIG 2. Western blot (WB) analysis for specific IgE (lanes 1-3) and specific IgG4 (lanes 4-6) against kiwi, timothy grass pollen, latex, and birch pollen. Samples were obtained before starting SLITs (lanes 1 and 4), immediately after reaching the full maintenance dose (lanes 2 and 5), and 6 weeks later after the end of the grass pollen season (lanes 3 and 6). Additionally, the serum samples were cross-absorbed with kiwi (*K, lane 7), and timothy grass pollen (Phleum pratense; *P, lane 8) extracts and specific IgE reactivity was analyzed. The Western blot shows de novo induction of specific IgE and IgG4 antibodies against Hev b 1 and Bet v 2, as well as several P pratense antigens that were cross-absorbable with P pratense extract but only partially with kiwi extract. The incomplete cross-absorbability for timothy grass pollen–reactive IgE by the timothy pollen extract is due to the very high titer of P pratense–specific IgE at that time (compare lanes 3 and 8 of the timothy grass pollen blot). Western blot reagents for timothy pollen, birch pollen, and latex were obtained through DPC (Los Angeles, Calif), and blots for kiwi were prepared according to standard protocols.
Letters to the Editor
exposure to grass pollen under ongoing maintenance SLITs with kiwi. We tested the patient for clinical relevance of the de novo–induced IgE sensitizations to birch pollen and latex. SPT responses were positive for both birch pollen and latex. However, nasal challenge with birch pollen extract produced negative results, as did skin exposure to powdered latex gloves for 30 minutes. Thus the induction of IgE antibodies against latex and birch pollen was without clinical relevance. The most probable explanation for this finding is the concomitant induction of protective IgG4 antibodies during de novo sensitization (Fig 2). However, this explanation is questioned by some studies on allergen immunotherapy.9 But why did the patient at the same time have IgE and IgG4 antibodies against P pratense allergens that crossreacted with birch pollen and latex allergens? One can speculate that through the successful ongoing SLITs with kiwi, the immune reaction pattern was modulated
toward a TH1 or T-regulatory phenotype that helped to induce a more general tolerization toward the encountered new allergens. However, more data and larger studies on the follow-up of other patients is required to elucidate this hypothesis. We gratefully acknowledge the skillful technical assistance of Mrs B. Heuser and Mrs J. Grosch. We further thank the staff of the Allergy Unit of the Department of Dermatology and Allergy, as well as Drs Klemm and Groer for their help with the SLIT protocol. The data on the grass and birch pollen counts for the Munich area were kindly provided by the German pollen information agency (Deutscher Polleninformationsdienst, Bad Lippspringe). This work was supported in part by grant 01GC0104 from the German Federal Ministery of Science and Education (BMBF) to M.M. and M.O. Martin Mempel, MDa,b,c Jürgen Rakoski, MDa Johannes Ring, MD, PhDa,b,c Markus Ollert, MDa,b,c aDepartment of Dermatology and Allergy
bClinical
Research Division of Molecular and Clinical Allergotoxicology Technische Universität München (TUM) Biedersteiner Str. 29 D-80802 Munich, Germany cDivision of Environmental Dermatology and Allergy GSF/TUM GSF National Research Center for Environment and Health Neuherberg, Germany REFERENCES 1. Passalacqua G, Albano M, Fregonese L, Riccio A, Pronzato C, Mela GS, et al. Randomised controlled trial of local allergoid immunotherapy on allergic inflammation in mite-induced rhinoconjunctivitis. Lancet 1998;351:629-32. 2. Pajno GB, Morabito L, Barberio G, Parmiani S. Clinical and immunologic effects of long-term sublingual immunotherapy in asthmatic children sensitized to mites: a double-blind, placebo-controlled study. Allergy 2000;55:842-9. 3. Guez S, Vatrinet C, Fadel R, André C. House-dust-mite sublingual-swallow immunotherapy (SLIT) in perennial rhinitis: a double-blind, placebocontrolled study. Allergy 2000;55:369-75. 4. Vourdas D, Syrigou E, Potamianou P, Carat F, Batard T, Andre C, et al. Double-blind, placebo-controlled evaluation of sublingual immunotherapy with standardized olive pollen extract in pediatric patients with allergic rhinoconjunctitvitis and mild asthma due to olive pollen sensitization. Allergy 1998;53:662-72. 5. Rossi RE, Monasterolo G, Monasterolo S. Measurement of IgE antibodies against purified grass-pollen allergens (Phl p 1, 2, 3, 4, 5, 6, 7, 11, and 12) in sera of patients allergic to grass pollen. Allergy 2001;56:1180-5. 6. Pastorello EA, Pravettoni V, Ispano M, Farioli L, Ansaloni R, Rotondo F, et al. Identification of the allergenic components of kiwi fruit and evaluation of their cross-reactivity with timothy and birch pollens. J Allergy Clin Immunol 1996;98:601-10. 7. Gall H, Kalveram K-J, Forck G, Sterry W. Kiwi fruit allergy: a new birch pollen-associated food allergy. J Allergy Clin Immunol 1994;94:70-6. 8. Vocks E, Borga A, Szliska C, Seifert HU, Seifert B, Burow G, et al. Common allergenic structures in hazelnut, rye grain, sesame seeds, kiwi, and poppy seeds. Allergy 1993;48:168-72. 9. Ewan PW, Deighton J, Wilson AB, Lachmann PJ. Venom-specific IgG antibodies in bee and wasp allergy: lack of correlation with protection from stings. Clin Exp Allergy 1993;23:647-60. doi:10.1067/mai.2003.1497
Oral tacrolimus for severe recalcitrant atopic eczema To the Editor: The patient is a 19-year-old man who has had eczema his entire life, with generalized eczema, including his scalp, hands, and feet, developing within 1 month of birth. To date, he has not had asthma, rhinitis, or conjunctivitis. Exacerbations are not related to specific foods or allergen exposure, except for cat allergen, which causes severe pruritus and worsening eczema. Symptoms are also exacerbated by “weather changes” and sweating associated with physical activities. Swimming in a chlorinated pool relieves symptoms to some extent. Before age 7 years, various treatment programs, such as coal tar, oatmeal baths, antibiotic therapy, and topical triamcinolone cream, resulted in no long-term relief. Various dust mite prevention programs, including the use of a special vacuum, hot-water clothes washing, covering mattresses and pillows, and removing carpets, did not result in improvement. About age 7 years, he began taking systemic glucocorticosteroids intermittently throughout each year for more than half of the year. His symp-
toms resulted in poor attendance during middle school, eventually necessitating home schooling during the last 3 years of high school. He was first seen by Dr Lockey in May 1998. At that time, he had intractable pruritus and severe eczema covering his entire body. Laboratory studies revealed an IgE level of 4962 IU/mL (normal, 0-149 IU/mL), a RAST score to peanut of +4 and mite of +5 (class +1-+5), and positive prick-puncture test responses to a variety of different aeroallergens, including pollen (+4), dog (+3), dust mite (+4), cat (+2), and molds (+4) (+2 is defined as a wheal <3 mm with erythema of >20 mm, +3 as a wheal >3 mm with surrounding erythema, and +4 as a wheal with pseudopods and surrounding erythema). He was treated with prevention, topical glucocorticosteroids, hydroxyzine hydrochloride and then doxepin hydrochloride, lubricants, and eventually immunotherapy. The immunotherapy was discontinued after 1 year because it caused his atopic dermatitis to flare. By December 1998, he began taking prednisone every other day continuously, with periodic bursts and intermittent oral antibiotics for worsening eczema. Attempts to decrease the glucocorticosteroids resulted in exacerbations. He was given a diagnosis of osteopenia (total T score of 1.72) in 1999, for which he is being treated with alendronate. In March 2000, he was consulted at National Jewish Medical and Research Center, Denver, Colorado, and started on a treatment regimen of high-dose prednisone, topical tacrolimus, 10 mg of monteleukast daily, and hot-water baths, followed by full-body triamcinolone cream topped with wet wraps and a lubricant. This resulted in substantial improvement of his symptoms. He was tapered from prednisone and discharged taking 2 mg of prednisone daily with continuation of the same treatment program. Within 1 month of return to Florida, on the same regimen, the eczema symptoms returned to pretreatment levels. He once again began to have flares of eczema necessitating short bursts of prednisone (45-60 mg in divided doses daily), with maintenance at about 15 mg every other day. The increase in symptoms on return to Florida could be due to an increased allergen burden in the patient’s home because of its tropical locale. In May 2002, he began oral tacrolimus therapy. The dose was increased from 1 mg twice daily to 5 mg twice daily to achieve therapeutic levels, with resultant improvement in his pruritus and eczema and discontinuation of his oral prednisone by September 2002. The severe rash and lichenified skin has shown great improvement. His symptoms improved, and the systemic glucocorticosteroids were discontinued by September 2002. As of September 2002, he began to attend junior college and now rides his dirt bike outdoors, both activities that used to severely exacerbate his disease. He continues to do well as of mid-February 2003. He is more affable, has a higher energy level, and has lost approximately 14 pounds, which is attributed to a decrease in appetite. He has not required systemic glucocorticosteroids since they were discontinued.
Letters to the Editor
Letters to the Editor 1409
J ALLERGY CLIN IMMUNOL VOLUME 111, NUMBER 6