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Reply to the Letter of Dr. Feinberg in J Allergy Clin Immunol 1990;85: 141–2
VOLUME 86 NUMBER 1
Correspondence
the differences between their findings and our findings are the dosages used. We did not exceed the 2 mg/day dosage recommended by the manufacturer. The authors do not comment on the side effects noted by the four patients treated with the relatively high doses used by them. Since we have observed side effects even at the lower doses, such as weight gain, I would caution against the initial use of the high doses in this indication, since in about two thirds of the patients, the lower dose is sufficient. At the higher doses, the anticholinergic effects, such as male impotence, become more prominent and bothersome, according to my experience. Cholinergic urticaria is a disease of unknown etiology, with a wide range in the severity of symptoms and the response to therapy. Based on our experience with the 13 patients with cholinergic urticaria, we had suspected that the nonresponder group represented patients in which divergent pathomechanisms might be involved. The study by McClean et al. might instead suggest that the nonresponsive group merely has more severe disease. More extended, ascending dose studies with associated monitoring of mediator release in a larger group of patients with cholinergic urticaria might provide some answers to these questions.
B. M. Czarnetzki Hautklinik der FUB Klinikum Rudolph Virchow Augustenburgerplatz 1 D-IO00 Berlin 65, West Germany
REFERENCES 1. McClean SP, Arreaza EE, Lett-BrownMA, Grant JA. Refractory cholinergic urticaria successfully treated with ketotifen. J ALLERGYCLINIMMUNOL1989;83:738-41. 2. Cap J-P, SchwanitzHJ, CzarnetzkiBM. Die Wirkungvon Ketotifen bei der Urticaria factitia und der Urticaria cholinergica im gekreuzten Doppelblindversuch.Hautarzt 1985;36:509.
Reply to the Letter of Dr. Feinberg in J ALLERGYCLIN IMMUNOL 1990;85:141-2 To the Editor: We were very glad to learn from Professor Feinberg's letter that our observations in humans of long-standing inflammatory changes after allergen challenge of sensitized conjunctiva are in agreement with observations of Tuffin and Feinberg in allergic guinea pigs. Since similar findings were more recently reported also by Allansmith et al.1 in sensitized rats, it appears that allergen challenge causes a constant pattern of cellular response in different species. The paper of Tuffin and Feinberg is a remarkable pioneer work in this field. The letter of Feinberg asks for a commentary on two interesting hypotheses. Feinberg speculates that histamine induces neutrophil accumulation because of the vasodilation and increased permeability, whereas release of chemotactic tactor, such as eosinophilic chemotactic factor-A and platelet-activating
139
factor, which occurs in allergen challenge, is necessary to recruit eosinophils. This hypotl~esis is attractive and prompts us to experimental validation. 'In fact, we recently reported 2 that histamine challenge also causes in humans a different conjunctival response from allergen challenge. However, Woodward et al. 3 reported conjunctival eosinophil infiltration evoked by histamine in guinea pigs. Regarding the role of inflammatory cells in the site of inflammation and the possibility that inflammatory cells are only innocent bystanders, our recent work should not confirm this hypothesis in human conjunctiva. In fact, we were recently able to demonstrate that the increase of the dose of allergen causes a dose-dependent increase of inflammatory cell recruitment. When large allergen doses are used, histologic changes are paralleled by clinical symptoms. 4 These studies and other studies performed during 24-hour observation periods5 appear to indicate three possibilities depending on the dose of allergen used for provocation. When low doses of allergen are used, inflammatory changes occur without clinical signs of both early and late-phase reaction. When intermediate doses of allergen are used, the clinical late-phase reaction is followed by longstanding inflammatory changes that extinguish and are not accompanied by clinical late-phase reaction. When large allergen doses are used, inflammatory cell recruitment is more marked and is Often associated with clinical symptoms. Since unpublished observations from our group also demonstrate that harmful eosinophil products, such as eosinophil cationic protein and eosinophil peroxidase are significantly increased 6 hours after challenge, we prefer therefore to believe that inflammatory cells recruited by allergen challenge not only "pass through," but are themselves responsible for amplifying inflammation and causing symptoms. We think that Professor Feinberg's letter raises a very important question on the role of inflammatory cells recruited by allergen challenge not only for histopathologic studies of tissue specimens but also for establishing the targets of a correct therapeutic strategy.
Se. Bonini 1 Clinica Medica Policlinico Umberto 1 00161 Rome, Italy St. Bonini Institutes of Clinica Medica (First) and of Pathology University of Rome La Sapienza A. Vecchione D. M. Naim Institute of Ophthalmology University of Rome Tor Vergata M. R. Allansmith F. Balsano Eye Research Institute Harvard Medical School, Boston
140
Correspondence
REFERENCES 1. Allansmith MR, Baird RS, Greiner JV, Bloch KJ. Late-phase reactions in ocular anaphylaxis in the rat. J ALLERGYCLINIMMtmOL 1984;73:49-55. 2. Bonini St, Bonini Se, Allansmith MR, et al. Topical histamine testing for conjunctival hyperreactivity in vernal conjunctivitis. Invest Ophthalmol Vis Sci [in press]. 3. Woodward DF, Spada CS, Hawley SB, Nieves AL. Conjunctival eosinophil infiltration evoked by histamine and immediate hypersensitivity. Modification by H 1- and H2-receptor blockade. Invest Ophthalmol Vis Sci 1986;27:1495-1503.
J. ALLERGY CLIN. IMMUNOL. JULY 1990
4. Bonini St, Bonini Se, Todini V, Adriani E, Allansmith MR. Late-phase ocular reaction induced by conjunctival allergen challenge: a dose-response study in humans [Abstract]. J ALLERGYCLIN IMMUNOL1988;81 : 173. 5. Bonini St, Bonini Se, Todini V, De Martiis A, Peppagallo P, Allansmith MR. Persistent inflammatory changes in the conjunctival late-phase reaction of humans [Abstract]. Invest Ophthalmol Vis Sci 1988;29:230.
Bound volumes available to subscribers Bound volumes of THE JOURNALOF ALLERGYAND CLINICALIMMUNOLOGYare available to subscribers (only) for the 1990 issues from the Publisher, at a cost of $45.00 ($57.00 international) for Vol. 85 (January-June) and Vol. 86 (July-December). Shipping charges are included. Each bound volume contains a subject and author index, and all advertising is removed. Copies are shipped within 30 days after publication of the last issue in the volume. The binding is durable buckram with the journal name, volume number, and year stamped in gold on the spine. Payment must accompany all orders. Contact Mosby-Year Book, Inc., Circulation Department, 11830 Westline Industrial Dr., St. Louis, MO 63146-3318; phone (800) 325-4177, ext. 7351.
Subscriptions must be in force to qualify. Bound volumes are not available in place of a regular journal subscription.
Correspondence
the differences between their findings and our findings are the dosages used. We did not exceed the 2 mg/day dosage recommended by the manufacturer. The authors do not comment on the side effects noted by the four patients treated with the relatively high doses used by them. Since we have observed side effects even at the lower doses, such as weight gain, I would caution against the initial use of the high doses in this indication, since in about two thirds of the patients, the lower dose is sufficient. At the higher doses, the anticholinergic effects, such as male impotence, become more prominent and bothersome, according to my experience. Cholinergic urticaria is a disease of unknown etiology, with a wide range in the severity of symptoms and the response to therapy. Based on our experience with the 13 patients with cholinergic urticaria, we had suspected that the nonresponder group represented patients in which divergent pathomechanisms might be involved. The study by McClean et al. might instead suggest that the nonresponsive group merely has more severe disease. More extended, ascending dose studies with associated monitoring of mediator release in a larger group of patients with cholinergic urticaria might provide some answers to these questions.
B. M. Czarnetzki Hautklinik der FUB Klinikum Rudolph Virchow Augustenburgerplatz 1 D-IO00 Berlin 65, West Germany
REFERENCES 1. McClean SP, Arreaza EE, Lett-BrownMA, Grant JA. Refractory cholinergic urticaria successfully treated with ketotifen. J ALLERGYCLINIMMUNOL1989;83:738-41. 2. Cap J-P, SchwanitzHJ, CzarnetzkiBM. Die Wirkungvon Ketotifen bei der Urticaria factitia und der Urticaria cholinergica im gekreuzten Doppelblindversuch.Hautarzt 1985;36:509.
Reply to the Letter of Dr. Feinberg in J ALLERGYCLIN IMMUNOL 1990;85:141-2 To the Editor: We were very glad to learn from Professor Feinberg's letter that our observations in humans of long-standing inflammatory changes after allergen challenge of sensitized conjunctiva are in agreement with observations of Tuffin and Feinberg in allergic guinea pigs. Since similar findings were more recently reported also by Allansmith et al.1 in sensitized rats, it appears that allergen challenge causes a constant pattern of cellular response in different species. The paper of Tuffin and Feinberg is a remarkable pioneer work in this field. The letter of Feinberg asks for a commentary on two interesting hypotheses. Feinberg speculates that histamine induces neutrophil accumulation because of the vasodilation and increased permeability, whereas release of chemotactic tactor, such as eosinophilic chemotactic factor-A and platelet-activating
139
factor, which occurs in allergen challenge, is necessary to recruit eosinophils. This hypotl~esis is attractive and prompts us to experimental validation. 'In fact, we recently reported 2 that histamine challenge also causes in humans a different conjunctival response from allergen challenge. However, Woodward et al. 3 reported conjunctival eosinophil infiltration evoked by histamine in guinea pigs. Regarding the role of inflammatory cells in the site of inflammation and the possibility that inflammatory cells are only innocent bystanders, our recent work should not confirm this hypothesis in human conjunctiva. In fact, we were recently able to demonstrate that the increase of the dose of allergen causes a dose-dependent increase of inflammatory cell recruitment. When large allergen doses are used, histologic changes are paralleled by clinical symptoms. 4 These studies and other studies performed during 24-hour observation periods5 appear to indicate three possibilities depending on the dose of allergen used for provocation. When low doses of allergen are used, inflammatory changes occur without clinical signs of both early and late-phase reaction. When intermediate doses of allergen are used, the clinical late-phase reaction is followed by longstanding inflammatory changes that extinguish and are not accompanied by clinical late-phase reaction. When large allergen doses are used, inflammatory cell recruitment is more marked and is Often associated with clinical symptoms. Since unpublished observations from our group also demonstrate that harmful eosinophil products, such as eosinophil cationic protein and eosinophil peroxidase are significantly increased 6 hours after challenge, we prefer therefore to believe that inflammatory cells recruited by allergen challenge not only "pass through," but are themselves responsible for amplifying inflammation and causing symptoms. We think that Professor Feinberg's letter raises a very important question on the role of inflammatory cells recruited by allergen challenge not only for histopathologic studies of tissue specimens but also for establishing the targets of a correct therapeutic strategy.
Se. Bonini 1 Clinica Medica Policlinico Umberto 1 00161 Rome, Italy St. Bonini Institutes of Clinica Medica (First) and of Pathology University of Rome La Sapienza A. Vecchione D. M. Naim Institute of Ophthalmology University of Rome Tor Vergata M. R. Allansmith F. Balsano Eye Research Institute Harvard Medical School, Boston
140
Correspondence
REFERENCES 1. Allansmith MR, Baird RS, Greiner JV, Bloch KJ. Late-phase reactions in ocular anaphylaxis in the rat. J ALLERGYCLINIMMtmOL 1984;73:49-55. 2. Bonini St, Bonini Se, Allansmith MR, et al. Topical histamine testing for conjunctival hyperreactivity in vernal conjunctivitis. Invest Ophthalmol Vis Sci [in press]. 3. Woodward DF, Spada CS, Hawley SB, Nieves AL. Conjunctival eosinophil infiltration evoked by histamine and immediate hypersensitivity. Modification by H 1- and H2-receptor blockade. Invest Ophthalmol Vis Sci 1986;27:1495-1503.
J. ALLERGY CLIN. IMMUNOL. JULY 1990
4. Bonini St, Bonini Se, Todini V, Adriani E, Allansmith MR. Late-phase ocular reaction induced by conjunctival allergen challenge: a dose-response study in humans [Abstract]. J ALLERGYCLIN IMMUNOL1988;81 : 173. 5. Bonini St, Bonini Se, Todini V, De Martiis A, Peppagallo P, Allansmith MR. Persistent inflammatory changes in the conjunctival late-phase reaction of humans [Abstract]. Invest Ophthalmol Vis Sci 1988;29:230.
Bound volumes available to subscribers Bound volumes of THE JOURNALOF ALLERGYAND CLINICALIMMUNOLOGYare available to subscribers (only) for the 1990 issues from the Publisher, at a cost of $45.00 ($57.00 international) for Vol. 85 (January-June) and Vol. 86 (July-December). Shipping charges are included. Each bound volume contains a subject and author index, and all advertising is removed. Copies are shipped within 30 days after publication of the last issue in the volume. The binding is durable buckram with the journal name, volume number, and year stamped in gold on the spine. Payment must accompany all orders. Contact Mosby-Year Book, Inc., Circulation Department, 11830 Westline Industrial Dr., St. Louis, MO 63146-3318; phone (800) 325-4177, ext. 7351.
Subscriptions must be in force to qualify. Bound volumes are not available in place of a regular journal subscription.