Randomized trial to evaluate azithromycin's effects on serum and upper airway IL-8 levels and recurrent wheezing in infants with respiratory syncytial virus bronchiolitis

Avraham Beigelman, Megan Isaacson-Schmid, Geneline Sajol, Jack Baty, Oscar M Rodriguez, Erin Leege, Kevin Lyons, Toni L Schweiger, Jie Zheng, Kenneth B Schechtman, Mario Castro, Leonard B Bacharier, Avraham Beigelman, Megan Isaacson-Schmid, Geneline Sajol, Jack Baty, Oscar M Rodriguez, Erin Leege, Kevin Lyons, Toni L Schweiger, Jie Zheng, Kenneth B Schechtman, Mario Castro, Leonard B Bacharier

Abstract

Background: Respiratory syncytial virus (RSV) bronchiolitis in infancy is a major risk factor for recurrent wheezing and asthma. Because azithromycin attenuated neutrophilic airway inflammation in a murine viral bronchiolitis model, demonstration of similar effects in human subjects might provide a strategy for the prevention of postbronchiolitis recurrent wheezing.

Objectives: We sought to investigate whether azithromycin treatment during RSV bronchiolitis reduces serum and nasal lavage IL-8 levels and the occurrence of postbronchiolitis recurrent wheezing.

Method: We performed a randomized, double-masked, placebo-controlled proof-of-concept trial in 40 otherwise healthy infants hospitalized with RSV bronchiolitis who were treated with azithromycin or placebo for 14 days. IL-8 levels were measured in nasal lavage fluid and serum on randomization, day 8, and day 15 (nasal lavage only). The occurrence of wheezing episodes was assessed monthly over the ensuing 50 weeks.

Results: Compared with placebo, azithromycin treatment did not reduce serum IL-8 levels at day 8 (P = .6) but resulted in a greater decrease in nasal lavage fluid IL-8 levels by day 15 (P = .03). Twenty-two percent of azithromycin-treated participants experienced at least 3 wheezing episodes compared with 50% of participants in the placebo group (P = .07). Azithromycin treatment resulted in prolonged time to the third wheezing episode (P = .048) and in fewer days with respiratory symptoms over the subsequent year in comparison with placebo (36.7 vs 70.1 days, P = .01).

Conclusion: In this proof-of-concept study azithromycin treatment during RSV bronchiolitis reduced upper airway IL-8 levels, prolonged the time to the third wheezing episode, and reduced overall respiratory morbidity over the subsequent year.

Keywords: Azithromycin; IL-8; respiratory syncytial virus; wheezing.

Copyright © 2014 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

Figures

Figure 1
Figure 1
Participants flow of the APW-RSV trial APW-RSV: Azithromycin to Prevent Wheezing following RSV Bronchiolitis. aPatients were screened for eligibility if they were hospital in St. Louis children’s Hospital during the RSV season with lower respiratory tract symptoms, and had a positive nasopharyngeal swab result confirming infection with RSV. bSome patients were excluded based on more than one exclusion criteria. Details for those screened but not eligible were not collected. COne of the patients who was lost to follow-up had 11 (out of 12) months of follow-up, and contributed all biological samples for cytokine measurements.
Figure 2
Figure 2
APW-RSV Study design Hx/PE: History/Physical exam; Sx: Symptom
Figure 3
Figure 3
Mean serum IL-8 levels (on a logarithmic scale) between randomization to day 8. p=0.62 for the change in serum IL-8 concentration measured between randomization and day 8 compared between the treatment groups
Figure 4
Figure 4
Mean nasal lavage IL-8 levels (on a logarithmic scale) over the treatment period. * p=0.03 for the change in nasal lavage IL-8 concentration measured between randomization and day 15 compared between the treatment groups.
Figure 5
Figure 5
Probability of not having at least three episodes of wheezing

References

    1. Simoes EA. Respiratory syncytial virus infection. Lancet. 1999;354:847–52.
    1. Carroll KN, Wu P, Gebretsadik T, Griffin MR, Dupont WD, Mitchel EF, et al. Season of infant bronchiolitis and estimates of subsequent risk and burden of early childhood asthma. J Allergy Clin Immunol. 2009;123:964–6.
    1. Glezen WP, Taber LH, Frank AL, Kasel JA. Risk of primary infection and reinfection with respiratory syncytial virus. American journal of diseases of children. 1986;140:543–6.
    1. Leader S, Kohlhase K. Respiratory syncytial virus-coded pediatric hospitalizations, 1997 to 1999. Pediatr Infect Dis J. 2002;21:629–32.
    1. Leader S, Kohlhase K. Recent trends in severe respiratory syncytial virus (RSV) among US infants, 1997 to 2000. J Pediatr. 2003;143:S127–32.
    1. Sigurs N, Bjarnason R, Sigurbergsson F, Kjellman B, Bjorksten B. Asthma and immunoglobulin E antibodies after respiratory syncytial virus bronchiolitis: a prospective cohort study with matched controls. Pediatrics. 1995;95:500–5.
    1. Sigurs N. Epidemiologic and clinical evidence of a respiratory syncytial virus-reactive airway disease link. Am J Respir Crit Care Med. 2001;163:S2–6.
    1. Sigurs N, Bjarnason R, Sigurbergsson F, Kjellman B. Respiratory syncytial virus bronchiolitis in infancy is an important risk factor for asthma and allergy at age 7. Am J Respir Crit Care Med. 2000;161:1501–7.
    1. Sigurs N, Gustafsson PM, Bjarnason R, Lundberg F, Schmidt S, Sigurbergsson F, et al. Severe respiratory syncytial virus bronchiolitis in infancy and asthma and allergy at age 13. Am J Respir Crit Care Med. 2005;171:137–41.
    1. Bacharier LB, Cohen R, Schweiger T, Yin-Declue H, Christie C, Zheng J, et al. Determinants of asthma after severe respiratory syncytial virus bronchiolitis. J Allergy Clin Immunol. 2012;130:91–100. e3.
    1. Escobar GJ, Ragins A, Li SX, Prager L, Masaquel AS, Kipnis P. Recurrent wheezing in the third year of life among children born at 32 weeks’ gestation or later: relationship to laboratory-confirmed, medically attended infection with respiratory syncytial virus during the first year of life. Arch Pediatr Adolesc Med. 2010;164:915–22.
    1. Escobar GJ, Masaquel AS, Li SX, Walsh EM, Kipnis P. Persistent recurring wheezing in the fifth year of life after laboratory-confirmed, medically attended respiratory syncytial virus infection in infancy. BMC Pediatr. 2013;13:97.
    1. Blom D, Ermers M, Bont L, van Aalderen WM, van Woensel JB. Inhaled corticosteroids during acute bronchiolitis in the prevention of post-bronchiolitic wheezing. Cochrane Database Syst Rev. 2007:CD004881.
    1. Ermers MJ, Rovers MM, van Woensel JB, Kimpen JL, Bont LJ. The effect of high dose inhaled corticosteroids on wheeze in infants after respiratory syncytial virus infection: randomised double blind placebo controlled trial. BMJ. 2009;338:b897.
    1. Zomer-Kooijker K, van der Ent CK, Ermers MJ, Rovers MM, Bont LJ Group RSVCS. Lack of long-term effects of high-dose inhaled beclomethasone for respiratory syncytial virus bronchiolitis: a randomized placebo-controlled trial. Pediatr Infect Dis J. 2014;33:19–23.
    1. Bulow SM, Nir M, Levin E, Friis B, Thomsen LL, Nielsen JE, et al. Prednisolone treatment of respiratory syncytial virus infection: a randomized controlled trial of 147 infants. Pediatrics. 1999;104:e77.
    1. Jartti T, Lehtinen P, Vanto T, Hartiala J, Vuorinen T, Makela MJ, et al. Evaluation of the efficacy of prednisolone in early wheezing induced by rhinovirus or respiratory syncytial virus. Pediatr Infect Dis J. 2006;25:482–8.
    1. Simoes EA. Treatment and prevention of respiratory syncytial virus lower respiratory tract infection. Long-term effects on respiratory outcomes. Am J Respir Crit Care Med. 2001;163:S14–7.
    1. Peng WS, Chen X, Yang XY, Liu EM. Systematic review of montelukast’s efficacy for preventing post-bronchiolitis wheezing. Pediatr Allergy Immunol. 2014;25:143–50.
    1. Bisgaard H, Flores-Nunez A, Goh A, Azimi P, Halkas A, Malice MP, et al. Study of montelukast for the treatment of respiratory symptoms of post-respiratory syncytial virus bronchiolitis in children. Am J Respir Crit Care Med. 2008;178:854–60.
    1. Berry M, Morgan A, Shaw DE, Parker D, Green R, Brightling C, et al. Pathological features and inhaled corticosteroid response of eosinophilic and non-eosinophilic asthma. Thorax. 2007;62:1043–9.
    1. Everard ML, Swarbrick A, Wrightham M, McIntyre J, Dunkley C, James PD, et al. Analysis of cells obtained by bronchial lavage of infants with respiratory syncytial virus infection. Arch Dis Child. 1994;71:428–32.
    1. Marguet C, Bocquel N, Benichou J, Basuyau JP, Hellot MF, Couderc L, et al. Neutrophil but not eosinophil inflammation is related to the severity of a first acute epidemic bronchiolitis in young infants. Pediatr Allergy Immunol. 2008;19:157–65.
    1. Friedlander AL, Albert RK. Chronic macrolide therapy in inflammatory airways diseases. Chest. 2010;138:1202–12.
    1. Cameron EJ, McSharry C, Chaudhuri R, Farrow S, Thomson NC. Long-term macrolide treatment of chronic inflammatory airway diseases: risks, benefits and future developments. Clin Exp Allergy. 2012;42:1302–12.
    1. Simpson JL, Powell H, Boyle MJ, Scott RJ, Gibson PG. Clarithromycin targets neutrophilic airway inflammation in refractory asthma. Am J Respir Crit Care Med. 2008;177:148–55.
    1. Beigelman A, Mikols CL, Gunsten SP, Cannon CL, Brody SL, Walter MJ. Azithromycin attenuates airway inflammation in a mouse model of viral bronchiolitis. Respir Res. 2010;11:90.
    1. Diagnosis and management of bronchiolitis. Pediatrics. 2006;118:1774–93.
    1. Reis EA, Hagan JE, Ribeiro GS, Teixeira-Carvalho A, Martins-Filho OA, Montgomery RR, et al. Cytokine response signatures in disease progression and development of severe clinical outcomes for leptospirosis. PLoS Negl Trop Dis. 2013;7:e2457.
    1. Wright AK, Bangert M, Gritzfeld JF, Ferreira DM, Jambo KC, Wright AD, et al. Experimental human pneumococcal carriage augments IL-17A-dependent T-cell defence of the lung. PLoS Pathog. 2013;9:e1003274.
    1. James KM, Gebretsadik T, Escobar GJ, Wu P, Carroll KN, Li SX, et al. Risk of childhood asthma following infant bronchiolitis during the respiratory syncytial virus season. J Allergy Clin Immunol. 2013;132:227–9.
    1. Yoshihara S, Kusuda S, Mochizuki H, Okada K, Nishima S, Simoes EA, et al. Effect of palivizumab prophylaxis on subsequent recurrent wheezing in preterm infants. Pediatrics. 2013;132:811–8.
    1. Blanken MO, Rovers MM, Molenaar JM, Winkler-Seinstra PL, Meijer A, Kimpen JL, et al. Respiratory syncytial virus and recurrent wheeze in healthy preterm infants. N Engl J Med. 2013;368:1791–9.
    1. McNamara PS, Smyth RL. The pathogenesis of respiratory syncytial virus disease in childhood. Br Med Bull. 2002;61:13–28.
    1. Lotz MT, Peebles RS., Jr Mechanisms of respiratory syncytial virus modulation of airway immune responses. Curr Allergy Asthma Rep. 2012;12:380–7.
    1. van Drunen Littel-van den Hurk S, Watkiss ER. Pathogenesis of respiratory syncytial virus. Curr Opin Virol. 2012;2:300–5.
    1. Smyth RL, Mobbs KJ, O’Hea U, Ashby D, Hart CA. Respiratory syncytial virus bronchiolitis: disease severity, interleukin-8, and virus genotype. Pediatr Pulmonol. 2002;33:339–46.
    1. Diaz PV, Gaggero AA, Pinto RA, Mamani R, Uasapud PA, Bono MR. Levels of inflammatory cytokines and plasma cortisol in respiratory syncytial virus bronchiolitis. Rev Med Chil. 2013;141:574–81.
    1. Tahan F, Ozcan A, Koc N. Clarithromycin in the treatment of RSV bronchiolitis: a double-blind, randomised, placebo-controlled trial. Eur Respir J. 2007;29:91–7.
    1. Korppi M. Macrolides and bronchiolitis in infants. Eur Respir J. 2007;29:1283–4. author reply 4–5.
    1. Tahan F. From the authors. European Respiratory Journal. 2007;29:1284–5.
    1. Beringer P, Huynh KM, Kriengkauykiat J, Bi L, Hoem N, Louie S, et al. Absolute bioavailability and intracellular pharmacokinetics of azithromycin in patients with cystic fibrosis. Antimicrob Agents Chemother. 2005;49:5013–7.
    1. Olsen KM, San Pedro G, Gann LP, Gubbins PO, Halinski DM, Campbell GD., Jr Intrapulmonary pharmacokinetics of azithromycin in healthy volunteers given five oral doses. Antimicrob Agents Chemother. 1996;40:2582–5.
    1. Wilms EB, Touw DJ, Heijerman HG. Pharmacokinetics of azithromycin in plasma, blood, polymorphonuclear neutrophils and sputum during long-term therapy in patients with cystic fibrosis. Ther Drug Monit. 2006;28:219–25.
    1. Grayson MH, Cheung D, Rohlfing MM, Kitchens R, Spiegel DE, Tucker J, et al. Induction of high-affinity IgE receptor on lung dendritic cells during viral infection leads to mucous cell metaplasia. J Exp Med. 2007;204:2759–69.
    1. Danesi R, Lupetti A, Barbara C, Ghelardi E, Chella A, Malizia T, et al. Comparative distribution of azithromycin in lung tissue of patients given oral daily doses of 500 and 1000 mg. J Antimicrob Chemother. 2003;51:939–45.
    1. Ballard HO, Anstead MI, Shook LA. Azithromycin in the extremely low birth weight infant for the prevention of bronchopulmonary dysplasia: a pilot study. Respir Res. 2007;8:41.
    1. Bisgaard H, Hermansen MN, Buchvald F, Loland L, Halkjaer LB, Bonnelykke K, et al. Childhood asthma after bacterial colonization of the airway in neonates. N Engl J Med. 2007;357:1487–95.
    1. Kloepfer KM, Lee WM, Pappas TE, Kang TJ, Vrtis RF, Evans MD, et al. Detection of pathogenic bacteria during rhinovirus infection is associated with increased respiratory symptoms and asthma exacerbations. J Allergy Clin Immunol. 2014
    1. Gielen V, Johnston SL, Edwards MR. Azithromycin induces anti-viral responses in bronchial epithelial cells. Eur Respir J. 2010 Online ahead of print.
    1. Asada M, Yoshida M, Suzuki T, Hatachi Y, Sasaki T, Yasuda H, et al. Macrolide antibiotics inhibit respiratory syncytial virus infection in human airway epithelial cells. Antiviral Res. 2009
    1. Yamaya M, Shinya K, Hatachi Y, Kubo H, Asada M, Yasuda H, et al. Clarithromycin inhibits type a seasonal influenza virus infection in human airway epithelial cells. J Pharmacol Exp Ther. 2010;333:81–90.
    1. Carroll KN, Wu P, Gebretsadik T, Griffin MR, Dupont WD, Mitchel EF, et al. The severity-dependent relationship of infant bronchiolitis on the risk and morbidity of early childhood asthma. J Allergy Clin Immunol. 2009;123:1055–61. 61 e1.

Source: PubMed

Sponzoři a spolupracovníci

Zdravotní podmínky

Drogové intervence

3
Předplatit