Assessing the Role of Antiinflammatory Medications in ... - ATS Journals

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(4), thereby reproducing previous findings by Brouillette and colleagues (5). Furthermore, our group has now conclusively demonstrated that combination ...
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AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE VOL 173 2006

3. Padoan M, Pozzato V, Simoni M, Zedda L. Milan G, Bononi I, Piola C, Maestrelli P, Boschetto P, Mapp CE. Long-term follow-up of toluene diisocyanate-induced asthma. Eur Respir J 2003;21:637–640. 4. Maghni K, Lemiere C, Ghezzo H, Yuquan W, Malo JL. Airway inflammation after cessation of exposure to agents causing occupational asthma. Am J Respir Crit Care Med 2004;169:367–372. 5. Perfetti L, He´bert J, La Palme Y, Ghezzo H, Gautrin D, Malo JL. Changes in IgE-mediated allergy to ubiquitous inhalants after removal from or diminution of the exposure to the agent causing occupational asthma. Clin Exp Allergy 1998;28:66–73. 6. Nguyen B, Ghezzo H, Malo JL, Gautrin D. Time course of onset of sensitization to common and occupational inhalants in apprentices. J Allergy Clin Immunol 2003;111:807–812. 7. Moscato G, Dellabianca A, Perfetti L, Brame B, Galdi E, Niniano R, Paggiaro PL. Occupational asthma: a longitudinal study on the clinical and socioeconomic outcome in workers with occupational asthma. Chest 1999;115:249–256.

Assessing the Role of Antiinflammatory Medications in Children with Mild Sleep-disordered Breathing To The Editor :

We read with interest the article by Goldbart and colleagues reporting improvement in polysomnography indices and decrease of adenoidal size after a course of montelukast was administered to children with mild sleep-disordered breathing (1). As was emphasized in the accompanying editorial (2), obstructive sleep apnea in children may have an immunologic/inflammatory component. Thus, antiinflammatory medications could be useful in children with mild forms of the disorder for whom adenotonsillectomy is not indicated. At least one other report supports the previous concept (3). In an open-label study, 27 children with snoring and an apnea– hypopnea index (AHI) of 1 to 10 episodes per hour were treated with nasal budesonide for 4 weeks. Mean AHI decreased from 5.2 (⫾ 2.2) to 3.2 (⫾ 1.5) in Alexopoulos and colleagues’ study (3) as compared with a decrease from 3.0 (⫾ 0.22) to 2.0 (⫾ 0.3) episodes per hour in the montelukast trial (1). Twelve of 14 children with an AHI of more than 5 at baseline had an index of less than 5 episodes per hour post-treatment. Respiratory movement/arousal index and oxygenation indices improved significantly. According to the perceptions of the children’s parents, their child’s breathing was better after treatment in 23 of 27 subjects. A decrease in frequency of snoring and difficulty breathing was maintained for 9 months after the budesonide course. In the paper by Goldbart and colleagues (1), novel and interesting data are presented supporting increased leukotriene receptor expression and higher levels of leukotrienes in adenotonsillar tissue from children with sleep-disordered breathing than from those with recurrent tonsilitis. It should be recognized that the authors undertook a more challenging task compared with the goal of the study by Alexopoulos and colleagues (3). Participants in the montelukast study had a more narrow range of AHI (1–5 episodes/h) than subjects in the budesonide trial (1–10 episodes/h) (1, 3). It is somewhat difficult to appreciate the clinical significance of a decrease in the mean AHI from 3 to 2 episodes per hour, especially without concomitant improvement in oxygenation indices (1). Additional outcome measures such as frequency of symptoms, parents’ perception about their child’s breathing during sleep, or parameters associated with work of breathing (e.g., paradoxical breathing) could have further clarified the clinical significance of the authors’ important and thought-provoking findings. Future studies, using changes in cognitive function (4),

school performance (5), or even indices of inflammation (e.g., C-reactive protein) (6) as outcome variables, could assess the role of antiinflammatory medications in reducing morbidity associated with sleep apnea in children. Conflict of Interest Statement : None of the authors have a financial relationship with a commercial entity that has an interest in the subject of this manuscript.

Athanasios G. Kaditis Emmanouel I. Alexopoulos George A. Syrogiannopoulos University of Thessaly School of Medicine Larissa, Greece References 1. Goldbart AD, Goldman JL, Veling MC, Gozal D. Leukotriene modifier therapy for mild sleep-disordered breathing in children. Am J Respir Crit Care Med 2005;172:364–370. 2. Arens R. Is it time to consider a new treatment for children with sleepdisordered breathing? Am J Respir Crit Care Med 2005;172:264–265. 3. Alexopoulos EI, Kaditis AG, Kalampouka E, Kostadima E, Angelopoulos NV, Mikraki V, Skenteris N, Gourgoulianis K. Nasal corticosteroids for children with snoring. Pediatr Pulmonol 2004;38:161–167. 4. Montgomery-Downs HE, Crabtree VM, Gozal D. Cognition, sleep and respiration in at-risk children treated for obstructive sleep apnoea. Eur Respir J 2005;25:336–342. 5. Gozal D. Sleep-disordered breathing and school performance in children. Pediatrics 1998;102:616–620. 6. Tauman R, Ivanenko A, O’Brien LM, Gozal D. Plasma C-reactive protein levels among children with sleep-disordered breathing. Pediatrics 2004;113:e564–e569.

From the Authors:

We read with interest the comments of Dr. Kaditis and colleagues regarding our recent publication in the Journal (1). We certainly concur that inflammatory/immunologic mechanisms contribute to the pathogenesis of obstructive sleep apnea (OSA) in children. We have previously published evidence on the increased transcriptional and translational regulation of corticosteroid and leukotriene receptors in the upper airway lymphadenoid tissue of children with OSA (2, 3). In the study under discussion, we further found that leukotriene concentrations are increased in the lymphadenoid tissue taken from children with OSA (1). Taken together, these findings would suggest a favorable response to treatment with antiinflammatory agents such as intranasal steroids or leukotriene modifiers. To substantiate this hypothesis, a group from Greece reported recently how nasal budesonide ameliorated the severity of OSA in children with mild to moderate sleep-disordered breathing (4), thereby reproducing previous findings by Brouillette and colleagues (5). Furthermore, our group has now conclusively demonstrated that combination therapy with intranasal budesonide and oral montelukast effectively normalized sleep breathing patterns and sleep architecture in children with residual mild OSA after adenotonsillectomy (6). However, in all our studies we restricted our recruitment to a symptomatic group whose severity of disease would not routinely justify other available interventions such as surgery. In other words, we applied antiinflammatory therapy to the low end of severity and yet found significant improvements in sleep fragmentation and respiratory disturbance, even if these were comparatively minor. There is clearly a need to better establish the polysomnographic cut-off values for which antiinflammatory therapy is best indicated, the duration of such therapy, and the risk of recurrence on discontinuation of therapy. We wholeheartedly concur with

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Kaditis and colleagues that improved phenotypic characterization of study patients with OSA participating in any form of double-blind randomized trials of antiinflammatory therapy, including quality of life, levels of circulating inflammatory markers, and end-organ morbidity (neurobehavioral and cardiovascular), will be critical to better delineate the value of such interventions. Conflict of Interest Statement : A.D.G. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. D.G. is currently the recipient of an investigator-initiated grant from AstraZeneca Ltd. for an unrelated research project on the effect of intranasal budesonide in mild sleep-disordered breathing in children. He serves on the national speaker bureau of Merck

Aviv D. Goldbart David Gozal Kosair Children’s Hospital and Research Institute Louisville, Kentucky References 1. Goldbart AD, Goldman JL, Veling MC, Gozal D. Leukotriene modifier therapy for mild sleep-disordered breathing in children. Am J Respir Crit Care Med 2005;172:364–370. 2. Goldbart AD, Veling MC, Goldman JL, Li RC, Brittian KR, Gozal D. Glucocorticoid receptor subunit expression in adenotonsillar tissue of children with obstructive sleep apnea. Pediatr Res 2005;57:232–236. 3. Goldbart AD, Goldman GL, Li RC, Brittian KR, Tauman R, Gozal D. Differential expression of cysteinyl leukotriene receptors 1 and 2 in tonsils of children with obstructive sleep apnea syndrome or recurrent infection. Chest 2004;126:13–18. 4. Alexopoulos EI, Kaditis AG, Kalampouka E, Kostadima E, Angelopoulos NV, Mikraki V, Skenteris N, Gourgoulianis K. Nasal corticosteroids for children with snoring. Pediatr Pulmonol 2004;38:161–167. 5. Brouillette RT, Manoukian JJ, Ducharme FM, Oudjhane K, Earle LG, Ladan S, Morielli A. Efficacy of fluticasone nasal spray for pediatric obstructive sleep apnea. J Pediatr 2001;138:838–844. 6. Kheirandish L, Goldbart AD, Gozal D. Intranasal steroids and oral leukotriene modifier therapy in residual sleep-disordered breathing following tonsillectomy and adenoidectomy in children. Pediatrics (In press)

Lack of Directly Observed Treatment Affects Tuberculosis Relapse Rates To the Editor :

The findings of Seyler and colleagues as reported in their recent article regarding risk factors for tuberculosis relapse among patients receiving antiretroviral treatment for HIV infection are potentially important (1). However, self-administration of antituberculosis drugs in the Ivory Coast likely affected reported tuberculosis relapse rates. Patients who self-administer antituberculosis treatment are much more likely to relapse than patients who receive directly observed therapy (2, 3). In addition, self-administration of antituberculosis treatment increases the likelihood of inconsistent treatment; patients whose treatment is irregular or interrupted are 2.5 times more likely to relapse than adherent patients (4). Directly observed antituberculosis treatment reduces the risk of relapse and death (5). Whether post-treatment prophylaxis would be indicated among patients who received optimal directly observed therapy for tuberculosis is not yet known. Conflict of Interest Statement : T.R.F. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript.

Thomas R. Frieden Commissioner New York City Department of Health and Mental Hygiene New York, New York References 1. Seyler C, Toure S, Messou E, Bonard D, Gabillard D, Anglaret X. Risk factors for active tuberculosis after antiretroviral treatment initiation in Abidjan. Am J Respir Crit Care Med 2005;172:123–127. 2. Balasubramanian VN, Oommen K, Samuel R. DOT or not? Direct observation of anti-tuberculosis treatment and patient outcomes, Kerala State, India. Int J Tuberc Lung Dis 2000;4:409–413. 3. Weis SE, Slocum PC, Blais FX, King B, Nunn M, Matney GB, Gomez E, Foresman BH. The effect of directly observed therapy on the rates of drug resistance and relapse in tuberculosis. N Engl J Med 1994;330: 1179–1184. 4. Thomas A, Gopi PG, Santha T, Chandrasekaran V, Subramani R, Selvakumar N, Eusuff SI, Sadacharam K, Narayanan PR. Predictors of relapse among pulmonary tuberculosis patients treated in a DOTS programme in South India. Int J Tuberc Lung Dis 2005;9:556–561. 5. Alwood K, Keruly J, Moore-Rice K, Stanton DL, Chaulk CP, Chaisson RE. Effectiveness of supervised, intermittent therapy for tuberculosis in HIV-infected patients. AIDS 1994;8:1103–1108.

From the Authors:

We agree with Dr. Frieden’s comment on our recent article (1). Increasing or decreasing the likelihood of inconsistent treatment could decrease or increase the rate of tuberculosis (TB) recurrence, and therefore the incidence of active TB under highly active antiretroviral therapy (HAART) in adults with TB history at HAART start. In the conclusion section of our article, we suggested that further studies of TB risk factors in HAARTtreated patients in sub-Saharan Africa should include TB past history at baseline. Frieden rightly points out that key characteristics of the previous TB episode should also be taken into consideration. This includes self-delivery of drugs, but also drug resistance and TB treatment regimen (2). Conflict of Interest Statement : None of the authors have a financial relationship with a commercial entity that has an interest in the subject of this manuscript.

Catherine Seyler Euge`ne Messou Siaka Toure Xavier Anglaret Programme PAC-CI Centre Hospitalier Universitaire de Treichville Abidjan, Coˆte d’Ivoire and INSERM U593—Universite´ Victor Segalen Bordeaux 2 Bordeaux, France References 1. Seyler C, Toure S, Messou E, Bonard D, Gabillard D, Anglaret X. Risk factors for active tuberculosis after antiretroviral treatment initiation in Abidjan. Am J Respir Crit Care Med 2005;172:123–127. 2. Mallory KF, Churchyard GJ, Kleinschmidt I, De Cock KM, Corbett EL. The impact of HIV infection on recurrence of tuberculosis in South African gold miners. Int J Tuberc Lung Dis 2000;4:455–462.