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LUNG BIOAVAILABILITY OF SPACERS
Correspondence LUNG BIOAVAILABILITY OF SPACERS To the Editor: We read with interest the recent article by Goldberg et al1 that compared adrenal suppression with budesonide delivered via dry powder inhaler vs pressurized metered-dose inhaler (pMDI) plus spacer and showed greater bioavailability of the former device. Pointedly, no mention was given by the authors in the “Methods” section on the precise technique that was used with the large volume spacer and whether the plastic spacer had been primed before use in the study. This is important because electrostatic charge and handling of plastic spacers may greatly influence the lung deposition and hence the systemic bioavailability of drug absorbed from the lung.2,3 One way of alleviating the problem with static is to use a metal spacer,4 which is currently available in Europe for use with budesonide pMDI (NebuChamber; AstraZeneca, Kings Langley, England). For example, in one study5 that evaluated the lung bioavailability of salbutamol, for the same nominal dose delivered via the 250-mL metal NebuChamber compared with the dry powder Turbuhaler, the former produced a 1.9-fold (95% confidence interval, 1.6 to 2.2) greater lung dose, in keeping with improved deposition from the metal spacer device. This is the opposite of the findings of Goldberg et al,1 where the lung dose of budesonide from the Turbuhaler was superior to the plastic spacer. Further studies are therefore indicated to compare the relative lung bioavailability of budesonide given via the dry powder Turbuhaler compared with an optimally primed and handled plastic spacer or, more preferably, a metal spacer to truly evaluate the relative efficiency of lung delivery from these devices. CATHERINE JACKSON, MBChB, MRCGP Tayside Centre for General Practice University of Dundee Dundee, United Kingdom
spacer handling on salbutamol lung deposition in asthmatic children. Br J Clin Pharmacol. 2002;54:544 –547. 4. Bisgaard H, Anhoj J, Klug B, Berg E. A non-electrostatic spacer for aerosol delivery. Arch Dis Child. 1995;73:226 –230. 5. Lipworth BJ, Clark DJ. Lung bioavailability of salbutamol given by dry powder inhaler (Turbuhaler) and small volume antistatic metal spacer (Airomir CFC-free pMDI plus NebuChamber). Eur Respir J. 1997;10:1820 –1823.
Response: We thank the authors for their comments. In our study,1 patients were instructed to use their large-volume spacers exactly according to the manufacturer’s instructions. The manufacturer’s instructions do not include priming of the spacers. Therefore, the results of our study are applicable to “real life.” Furthermore, as the authors of this letter have recently shown, used spacers had a similar relative lung dose of salbutamol compared with benzalkonium chloride–primed spacers.2 In that study, new spacers delivered the same dose as primed spacers after 5 days of use with two puffs twice a day. In our study, children used the spacer for 28 days with two puffs a day. Assuming that 5 days are needed to prime the spacers, there are at least 23 days during which the spacers were primed. Since most of the decrease in urinary free cortisol is already evident by 2 weeks of treatment,3 no further decrease of urinary free cortisol is anticipated after the 4-week treatment period. Our study was not aimed to analyze the systemic availability of inhaled medications delivered by a nonelectrostatic metal spacers. Therefore, no conclusions can be drawn about systemic bioavailability of inhaled corticosteroids. It is important, however, to be aware of the increased dose delivered via this type of spacers. Further studies need to be performed to define systemic availability of drugs delivered by spacers. SHMUEL GOLDBERG, MD Pediatric Pulmonology Shaare-Zedek Medical Center Jerusalem, Israel EITAN KEREM, MD Department of Pediatrics Hadassah University Hospital Mount Scopus Jerusalem, Israel
BRIAN LIPWORTH, MD, FRCP, FRCPE Asthma and Allergy Research Group Ninewells Hospital, University of Dundee Dundee, United Kingdom REFERENCES 1. Goldberg S, Einot T, Algur N, Schwartz S, Greenberg AC, et al. Adrenal suppression in asthmatic children receiving low-dose inhaled budesonide: comparison between dry powder inhaler and pressurized metered-dose inhaler attached to a spacer. Ann Allergy Asthma Immunol. 2002;89:566 –571. 2. Anhoj J, Bisgaard H, Lipworth BJ. Effect of electrostatic charge in plastic spacers on the lung delivery of HFA-salbutamol in children. Br J Clin Pharmacol. 1999;47:333–336. 3. Lipworth BJ, Lee DK, Anhoj J, Bisgaard H. Effect of plastic
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REFERENCES 1. Goldberg S, Einot T, Algur N, Schwartz S, Greenberg AC, et al. Adrenal suppression in asthmatic children receiving low-dose inhaled budesonide: comparison between dry powder inhaler and pressurized metered-dose inhaler attached to a spacer. Ann Allergy Asthma Immunol. 2002;89:566 –571. 2. Lipworth BJ, Lee DK, Anhoj J, Bisgaard H. Effect of plastic
ANNALS OF ALLERGY, ASTHMA, & IMMUNOLOGY
spacer handling on salbutamol lung deposition in asthmatic children. Br J Clin Pharmacol. 2002;54:544 –597. 3. Nicolaizik WH, Marchant JL, Preece MA, Warner JO. Endocrine and lung function in asthmatic children on inhaled corticosteroids. Am J Respir Crit Care Med. 1994;150:624 – 628.
IMPLICATIONS OF NOMENCLATURE—AND ON THE INTERPRETATION To the Editor: In a recent commentary “The implications of nomenclature,”1 Dr. Dreborg advocates the European Academy of Allergology and Clinical Immunology (EAACI) position paper.2 He criticizes clinical trials, the publication of which preceded the publication of the new nomenclature, for not having used the proposed new EAACI nomenclature. According to the EAACI nomenclature atopy is defined as a personal or familial tendency to produce IgE antibodies in response to low doses of allergens, usually proteins, and to develop typical symptoms such as asthma, rhinoconjunctivitis, or eczema/dermatitis. In stating for example, “atopy, ie, IgE antibody formation” and “ atopy was not prevented,” Dr. Dreborg’s interpretation seems to differ from that of Professor S.G. Johansson, the first author of the position paper in question. Professor Johansson advises authors of the EAACI journal as follows: “atopy, ie, constitutional trait” and “prevention of atopy is not possible” (letter, April 3, 2002). No advice is given, however, on what are the uniform criteria for respective tendencies. This is particularly important, as the nomenclature2 states, “Nor can a positive skin prick test or the presence of IgE antibody per se be a criterion for atopy.” Consequently, in prevention studies targeting at-risk populations, atopy cannot be the outcome but atopic disease. Furthermore, in clinical evidence-based medicine, the primary aim is to diminish morbidity. Therefore, the best advice for scientists is to report on clinical outcomes by following strict diagnostic criteria, eg, for atopic eczema the Hanifin criteria,3 and to report skin prick test results as they are. This is particularly in infancy because in prospective follow-up studies the threshold determinations and age effects of these measurements should be accounted for.4 For clinicians the best advice is to read the excellent critical commentary by Hanifin,4 who states that any new proposal needs to improve accuracy of diagnosis based on pathogenesis and thus result in better care of patients. Dr. Dreborg also states that “preventive measures should be tested against a single mechanism of disease rather than against a disease caused by several mechanisms.” On this basis, currently available treatments of allergic disease and those being studied should be abandoned as they target endorgan pathogenesis or only one of the mechanisms involved in the pathogenesis. For probiotic research, the new era has already begun. The effects of probiotics are now recognized as strain-specific. Instead of abandoning successful strains, optimal combinations of strains may offer solutions for the management of diseases.5
VOLUME 90, JUNE, 2003
KIRSI LAIHO, PhD* ARTHUR OUWEHAND, PhD† SEPPO SALMINEN, PhD† ERIKA ISOLAURI, PhD* * Department of Paediatrics and † Department of Biochemistry and Food Chemistry University of Turku Turku, Finland REFERENCES 1. Dreborg S. The implications of nomenclature. Ann Allergy Asthma Immunol. 2002;89:S83–S85. 2. Johansson SG, Hourihane JO, Bousquet J, Bruijnzeel-Koomen C, Dreborg S, et al. A revised nomenclature for allergy. An EAACI position statement from the EAACI nomenclature task force. Allergy. 2001;56:813– 824. 3. Hanifin JM. Atopic dermatitis in infants and children. Pediatr Clin North Am. 1991;38:763–789. 4. Hanifin JM. Atopiform dermatitis: do we need another confusing name for atopic dermatitis? Br J Dermatol. 2002;147: 430 – 432. 5. Laiho K, Ouwehand A, Salminen S, Isolauri E. Inventing probiotic functional food for patients with allergic disease. Ann Allergy Asthma Immunol. 2002;89:S75–S82.
Response: IMPLICATIONS OF NOMENCLATURE ON THE INTERPRETATION OF RESULTS OF CLINICAL TRIALS In a piece of correspondence1 in this issue “The implications of nomenclature,” Dr. Isolauri and her group respond to my description of the proposed new nomenclature for allergy as proposed by the European Academy of Allergology and Clinical Immunology (EAACI).2 In my commentary,3 I do not criticize the article by the Finnish group in the Lancet.4 I discussed clinical trials on allergy and atopy in general, with the paper by Isolauri et al4 as an example in which the nomenclature was not in accordance with the proposal by the EAACI proposal on allergy nomenclature,2 and the conclusions drawn were confusing. Certainly, at the time of the publication of the Lancet article, Dr. Isolauri did not know our final proposal, despite it having been discussed among many pediatricians in Europe during several years. As one of two pediatricians among the authors, I set up a reference panel of pediatricians within different areas of pediatrics and at intervals I asked them for their opinion on the proposal. Dr. Isolauri and her group make a number of remarks to be commented on. “Dr. Dreborg’s interpretation seems to differ from that of Professor S.G. Johansson, the first author of the position paper in question.” Comment: The group agreed on the paper before publication and it was approved by the EAACI Executive Committee.
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spacer handling on salbutamol lung deposition in asthmatic children. Br J Clin Pharmacol. 2002;54:544 –547. 4. Bisgaard H, Anhoj J, Klug B, Berg E. A non-electrostatic spacer for aerosol delivery. Arch Dis Child. 1995;73:226 –230. 5. Lipworth BJ, Clark DJ. Lung bioavailability of salbutamol given by dry powder inhaler (Turbuhaler) and small volume antistatic metal spacer (Airomir CFC-free pMDI plus NebuChamber). Eur Respir J. 1997;10:1820 –1823.
Response: We thank the authors for their comments. In our study,1 patients were instructed to use their large-volume spacers exactly according to the manufacturer’s instructions. The manufacturer’s instructions do not include priming of the spacers. Therefore, the results of our study are applicable to “real life.” Furthermore, as the authors of this letter have recently shown, used spacers had a similar relative lung dose of salbutamol compared with benzalkonium chloride–primed spacers.2 In that study, new spacers delivered the same dose as primed spacers after 5 days of use with two puffs twice a day. In our study, children used the spacer for 28 days with two puffs a day. Assuming that 5 days are needed to prime the spacers, there are at least 23 days during which the spacers were primed. Since most of the decrease in urinary free cortisol is already evident by 2 weeks of treatment,3 no further decrease of urinary free cortisol is anticipated after the 4-week treatment period. Our study was not aimed to analyze the systemic availability of inhaled medications delivered by a nonelectrostatic metal spacers. Therefore, no conclusions can be drawn about systemic bioavailability of inhaled corticosteroids. It is important, however, to be aware of the increased dose delivered via this type of spacers. Further studies need to be performed to define systemic availability of drugs delivered by spacers. SHMUEL GOLDBERG, MD Pediatric Pulmonology Shaare-Zedek Medical Center Jerusalem, Israel EITAN KEREM, MD Department of Pediatrics Hadassah University Hospital Mount Scopus Jerusalem, Israel
BRIAN LIPWORTH, MD, FRCP, FRCPE Asthma and Allergy Research Group Ninewells Hospital, University of Dundee Dundee, United Kingdom REFERENCES 1. Goldberg S, Einot T, Algur N, Schwartz S, Greenberg AC, et al. Adrenal suppression in asthmatic children receiving low-dose inhaled budesonide: comparison between dry powder inhaler and pressurized metered-dose inhaler attached to a spacer. Ann Allergy Asthma Immunol. 2002;89:566 –571. 2. Anhoj J, Bisgaard H, Lipworth BJ. Effect of electrostatic charge in plastic spacers on the lung delivery of HFA-salbutamol in children. Br J Clin Pharmacol. 1999;47:333–336. 3. Lipworth BJ, Lee DK, Anhoj J, Bisgaard H. Effect of plastic
674
REFERENCES 1. Goldberg S, Einot T, Algur N, Schwartz S, Greenberg AC, et al. Adrenal suppression in asthmatic children receiving low-dose inhaled budesonide: comparison between dry powder inhaler and pressurized metered-dose inhaler attached to a spacer. Ann Allergy Asthma Immunol. 2002;89:566 –571. 2. Lipworth BJ, Lee DK, Anhoj J, Bisgaard H. Effect of plastic
ANNALS OF ALLERGY, ASTHMA, & IMMUNOLOGY
spacer handling on salbutamol lung deposition in asthmatic children. Br J Clin Pharmacol. 2002;54:544 –597. 3. Nicolaizik WH, Marchant JL, Preece MA, Warner JO. Endocrine and lung function in asthmatic children on inhaled corticosteroids. Am J Respir Crit Care Med. 1994;150:624 – 628.
IMPLICATIONS OF NOMENCLATURE—AND ON THE INTERPRETATION To the Editor: In a recent commentary “The implications of nomenclature,”1 Dr. Dreborg advocates the European Academy of Allergology and Clinical Immunology (EAACI) position paper.2 He criticizes clinical trials, the publication of which preceded the publication of the new nomenclature, for not having used the proposed new EAACI nomenclature. According to the EAACI nomenclature atopy is defined as a personal or familial tendency to produce IgE antibodies in response to low doses of allergens, usually proteins, and to develop typical symptoms such as asthma, rhinoconjunctivitis, or eczema/dermatitis. In stating for example, “atopy, ie, IgE antibody formation” and “ atopy was not prevented,” Dr. Dreborg’s interpretation seems to differ from that of Professor S.G. Johansson, the first author of the position paper in question. Professor Johansson advises authors of the EAACI journal as follows: “atopy, ie, constitutional trait” and “prevention of atopy is not possible” (letter, April 3, 2002). No advice is given, however, on what are the uniform criteria for respective tendencies. This is particularly important, as the nomenclature2 states, “Nor can a positive skin prick test or the presence of IgE antibody per se be a criterion for atopy.” Consequently, in prevention studies targeting at-risk populations, atopy cannot be the outcome but atopic disease. Furthermore, in clinical evidence-based medicine, the primary aim is to diminish morbidity. Therefore, the best advice for scientists is to report on clinical outcomes by following strict diagnostic criteria, eg, for atopic eczema the Hanifin criteria,3 and to report skin prick test results as they are. This is particularly in infancy because in prospective follow-up studies the threshold determinations and age effects of these measurements should be accounted for.4 For clinicians the best advice is to read the excellent critical commentary by Hanifin,4 who states that any new proposal needs to improve accuracy of diagnosis based on pathogenesis and thus result in better care of patients. Dr. Dreborg also states that “preventive measures should be tested against a single mechanism of disease rather than against a disease caused by several mechanisms.” On this basis, currently available treatments of allergic disease and those being studied should be abandoned as they target endorgan pathogenesis or only one of the mechanisms involved in the pathogenesis. For probiotic research, the new era has already begun. The effects of probiotics are now recognized as strain-specific. Instead of abandoning successful strains, optimal combinations of strains may offer solutions for the management of diseases.5
VOLUME 90, JUNE, 2003
KIRSI LAIHO, PhD* ARTHUR OUWEHAND, PhD† SEPPO SALMINEN, PhD† ERIKA ISOLAURI, PhD* * Department of Paediatrics and † Department of Biochemistry and Food Chemistry University of Turku Turku, Finland REFERENCES 1. Dreborg S. The implications of nomenclature. Ann Allergy Asthma Immunol. 2002;89:S83–S85. 2. Johansson SG, Hourihane JO, Bousquet J, Bruijnzeel-Koomen C, Dreborg S, et al. A revised nomenclature for allergy. An EAACI position statement from the EAACI nomenclature task force. Allergy. 2001;56:813– 824. 3. Hanifin JM. Atopic dermatitis in infants and children. Pediatr Clin North Am. 1991;38:763–789. 4. Hanifin JM. Atopiform dermatitis: do we need another confusing name for atopic dermatitis? Br J Dermatol. 2002;147: 430 – 432. 5. Laiho K, Ouwehand A, Salminen S, Isolauri E. Inventing probiotic functional food for patients with allergic disease. Ann Allergy Asthma Immunol. 2002;89:S75–S82.
Response: IMPLICATIONS OF NOMENCLATURE ON THE INTERPRETATION OF RESULTS OF CLINICAL TRIALS In a piece of correspondence1 in this issue “The implications of nomenclature,” Dr. Isolauri and her group respond to my description of the proposed new nomenclature for allergy as proposed by the European Academy of Allergology and Clinical Immunology (EAACI).2 In my commentary,3 I do not criticize the article by the Finnish group in the Lancet.4 I discussed clinical trials on allergy and atopy in general, with the paper by Isolauri et al4 as an example in which the nomenclature was not in accordance with the proposal by the EAACI proposal on allergy nomenclature,2 and the conclusions drawn were confusing. Certainly, at the time of the publication of the Lancet article, Dr. Isolauri did not know our final proposal, despite it having been discussed among many pediatricians in Europe during several years. As one of two pediatricians among the authors, I set up a reference panel of pediatricians within different areas of pediatrics and at intervals I asked them for their opinion on the proposal. Dr. Isolauri and her group make a number of remarks to be commented on. “Dr. Dreborg’s interpretation seems to differ from that of Professor S.G. Johansson, the first author of the position paper in question.” Comment: The group agreed on the paper before publication and it was approved by the EAACI Executive Committee.
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