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Re: Oral steroids and inflammatory markers in asthma

Although the paper of El-Radhi et al[1] presents interesting data about decreases in inflammatory markers during the resolution of acute asthma, some of their conclusions are not valid. First, acute asthma has a tendency to resolve without corticosteroid therapy.[2] Since all of the children with acute asthma (quite rightly) received steroids, the observed effect may equally reflect processes associated with spontaneous resolution. Indeed, corticosteroids do not inhibit the release of eosinophil cationic protein (ECP) from eosinophils.[3] Second, the normal controls are inadequate. Atopy per se is associated with increased serum levels of ECP,[4] and it is therefore to be expected that the asymptomatic atopic asthmatics will have higher ECP levels than the mostly non-atopic controls.

References

(1) El-Radhi AS, Hogg CL, Bungre JK, Bush A, Corrigan CJ. Effect of oral glucocorticoid treatment on serum inflammatory markers in acute asthma. Arch Dis Child 2000;83:158-62.

(2) Gleeson JG, Loftus BG, Price JF. Placebo controlled trial of systemic corticosteroids in acute childhood asthma. Acta Paediatr Scand 1990;79:1052-8.

(3) Venge P, Bystrom J, Carlson M, et al. Eosinophil cationic protein (ECP): molecular and biological properties and the use of ECP as a marker of eosinophil activation in disease. Clin Exp Allergy 1999;29:1172-86.

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Re: Re: Oral steroids and inflammatory markers in asthma

Dear Editor,

We thank Dr Grigg for his interest in our work.[1] We agree that the asthma attacks may have resolved spontaneously in some cases, which was precisely why we stated that the markers fell in association with steroid therapy, and nowhere implied causality. Nevertheless, the statistical analysis suggests that the chances this occurred at random are extremely low.

We agree that corticosteroids do not inhibit, except at very high concentrations, degranulation of the eosinophils induced by incubation with opsonised particles, such as Sepharose beads in vitro.[2] However, there is overwhelming evidence that cytokines such as IL-5 prime eosinophils for increased release of granule proteins in this situation,[3,4] and that they inhibit cytokine-mediated prolongation of eosinophil survival.[5] These observations, coupled with the abundant evidence that corticosteroids reduce the expression of eosinophil-active cytokines, such as IL-5, provide a convincing chain of evidence linking the clinical use of corticosteroids with reduced release of eosinophil granule proteins in vivo.

With regard to the controls in this study the ratio of atopic to non- atopic asthmatics was 4:1 and of atopic to non-atopic controls was 3:1. These differences are not significant by chi-squared testing. Whilst we agree that more controls might have strengthened our conclusions, nonetheless the evidence of unresolved inflammation after an apparently clinically adequate course of prednisolone, as shown by the elevated levels of IL-5 and sCD25, remains strong.

ANDREW BUSH
Reader and Honorary Consultant
Royal Brompton Hospital
Sydney Street, London SW3 6NP, UK
Email: a.bush@rbh.nthames.nhs.uk

CLAIRE HOGG
Specialist Registrar, Paediatrics
Royal Brompton Hospital
Email: c.hogg@rbh.nthames.nhs.uk

CHRIS J CORRIGAN
Senior Lecturer, Dept Resp Med & Allergy
Thomas Guy House, Guy’s Hospital, London SE1 9RT, UK
Email: chris.corrigan@kcl.ac.uk

References
(1) Grigg J. Oral steroids and inflammatory markers in asthma. Arch Dis Child [Rapid Response] 16 August 2000.

(2) Kita H, Abu-Ghazaleh R, Sanderson CJ, et al. Effect of steroids on immunoglobulin-induced eosinophil degranulation. J Allergy Clin Immunol 1991;87:70-7.

(3) Kita H, Weiler DA, Abu-Ghazaleh RI, et al. Release of granule proteins from eosinophils cultured with IL-5. J Immunol 1992;149:629-35

(4) Fujisawa T, Abu-Ghazaleh RI, Kita M, Sanderson CJ, Gleich GJ. Regulatory effect of cytokines on eosinophil degranulation. J Immunol 1990;144:642-6.

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Re: Treatment of pediatric asthma is controversial

The treatment of childhood asthma is controversial: although oral glucocorticoid treatment in children with asthma was associated with clinical improvement.[1] There are concerns about corticosteroids, since stopping drug treatment in children with asthma results in clinical deterioration,[2] or in the return of bronchial hyperresponsiveness within two weeks,[3] with the obvious conclusion that the nature of drug treatment is suppressive rather than curative. More importantly, despite prednisolone treatment in acute asthma, reduction of symptoms and normalisation of pulmonary function there is evidence of continuing airway inflammation .[1]

However such negative results could be greatly reduced if more and more pediatricians adopted the practice of prescribing reduced doses.[4,5] Using the lowest possible dose and/or alternate-day dosing appears to be safer,[4] and growth rates[4] and endocrine and lung function return to normal.[5]

To reduce the risk of systemic effects, it has been suggested to prefer long acting drugs and start treatment at 3 PM, since there are no differences compared to qid dosing, nor influences on 24-h cortisolemia and cortisoluria.[6] Completely ignored[1] or disregarded[7] is the issue of specific immunotherapy (SIT) in children. We have recently demonstrated that 27/29 (93,1%) controlled studies in 2.042 children and as many controls have shown the effectiveness of SIT in pediatric age in the treatment of asthma due to pollens, house dust mites (Der p), epidermal derivatives, and moulds (p<0.0001).[8] In all studies the children of the control groups were treated with the available drugs, and cared for by their doctors as the children of the study group. Therefore 93,1% of the studies have confirmed the SIT positive influence on the natural history with a total remission of asthmatic symptoms in the children who regularly completed the SIT cycle.[8] In addition severe adverse reactions during SIT are almost non existent in children.[9]

From an immunological point of view, oral glucocorticoid treatment in the children with asthma was associated with significant reductions in serum concentrations of IL-5, sCD25, and ECP. However, serum concentrations of IL-5, sCD25, and ECP remained significantly higher than in controls, even after treatment with oral glucocorticoids (p=0.03).[1] Regarding SIT, allergen-induced, in vitro production of certain cytokines such as IL-4 and IL-10 decreased after SIT; IL-13 (which can induce IgG4 and IgE antibody production by B cells) increased after SIT.[10] Therefore IL-13 might play an important role in the generation of IgG4-blocking antibody during SIT.[10] More consistent with the reversal of Th2 T cells and associated cytokines (IL-4 and IL-5) into TH1 T cells and Th1-like cytokines (IL-2 and IFN-gamma) is the production of IL-12.[11] Thus, the potential ability to shift the Th1/Th2 balance of immune response to allergens creates a favourable cytokine microenvironment to suppress the allergic reaction in the asthmatic airway.[12] Accordingly, the production of IL-5 in asthmatic children treated with corticosteroids[1] does not appear to be a positive effect.

Arnaldo Cantani, MD, PhD
Professor of Pediatrics
Allergy and Clinical Immunology Division

Monica Micera, MD
University of Roma "La Sapienza"
Viale Regina Elena 324, I 00161 Roma

References
(1) El-Radhi AS, Hogg CL, Bungre JK, Bush A, Corrigan CJ. Effect of oral glucocorticoid treatment on serum inflammatory markers in acute asthma. Arch Dis Child 2000;83:158-62.

(2) Waalkens HJ, Van Essen-Zandvliet EE, Hughes MD, et al. Cessation of long-term treatment with inhaled corticosteroid (budesonide) in children with asthma results in deterioration. Am Rev Respir Dis 1993;148:1252-7.

(3) Simons FER, Dolovic J, Moothe DW, et al. A comparison of beclomethasone, salmeterol, and placebo in children with asthma. N Engl J Med 1997;337:1659-65.

(4) Kamada AK, Szefler SJ. Glucocorticoids and growth in asthmatic children. Pediatr Allergy Immunol 1995;6:145-54.

(5) Nicolaizik WH, Marchart JL, Pearce MA, Warner JO. Endocrine and lung function in asthmatic children on inhaled corticosteroids. Am J Respir Crit Care Med 1994;150:624-8.

(6) Pincus DJ, Szefler SJ, Ackerson LM, Martin RJ. Chronotherapy of asthma with inhaled steroids: The effect of dosage timing on drug efficacy. J Allergy Clin Immunol 1995;95:1173-8.

(7) WHO Position Paper Allergen immunotherapy: therapeutic vaccines for allergic diseases. Allergy 1998;53(suppl 44):1-42.

(8) Cantani A, Arcese G, Lucenti P, Gagliesi D, Bartolucci M. A three year prospective study of allergen immunotherapy to inhalant allergens: evidence of safety and efficacy in 300 children with allergic asthma. J Invest Allergol Clin Immunol 1997;7:90-7.

(9) Cantani A, Gagliesi D. Specific immunotherapy in children. Allergy 1996;51:265-6.

(10) Lu FM, Chou CC, Chiang BL, Hsieh KH. Immunologic changes during immunotherapy in asthmatic children: increased IL-13 and allergen-specific IgG4 antibody levels. Ann Allergy Asthma Immunol 1998;80:419-23.

(11) Durham SR, Till SJ. Immunological changes associated with allergen immunotherapy. J Allergy Clin Immunol 1998;102:157-64.