Determine Efficacy of a Short Course of Montelukast in Children with Intermittent Asthma and Viral Infection

Authors

1 1Department of Pediatric Allergy-immunology, Mashhad University of Medical Science, Mashhad, Iran.

2 2Department of Pediatric Gastroenterology, Mashhad University Of Medical Science, Mashhad , Iran.

Abstract

Introduction
Mild intermittent asthma is common in children and viral infections are responsible for the majority of exacerbations. As leukotrienes are potent inflammatory mediators, some studies have shown that Montelukast, a leukotriene receptor antagonist, may be effective on reduction of asthma symptom. To determine whether a short course of Montelukast in asthmatic children with common cold would modify the severity of an asthma episode.  
 
Materials and Methods
Children, aged 6-12 years with intermittent asthma participated in this randomized, double-blind, placebo-controlled clinical trial. Treatment with Montelukast or placebo was initiated at the onset of viral upper respiratory tract infection and continued for 7 days. Primary outcomes included the clinical manifestation: duration of episodes, daily symptom, nights symptoms and activity limitation. Secondary outcomes included the need for beta agonist usage, oral prednisolone, physician visit, hospital admission and school absence.
 
Results                                                             
A total of 187 children with intermittent asthma were randomized, 93 to Montelukast group and 94 to placebo group. Montelukast significantly decreased the cough by 17.3% (P<0.001), nighttime awakenings by 5.4% (P=0.01), interference with normal activity by 6% (P<0.01), time off from school by 6% (P<0.01), β-agonist usage by 17.2% (P<0.001) and doctor visits by12.2% (P<0.01) compared to placebo. Whereas there was a non significant reduction in wheezing, tachypnea, respiratory distress, asthma exacerbation, oral prednisolone and hospitalization (P=0.8).
 
Conclusion                                                      
A short course of Montelukast, introduced at the first sign of a viral infection, results in a reduction in cough, β-agonist use and nights awakened, time off from school and limitation of activity. More studies are needed to evaluate the optimal dose and duration of treatment.

Keywords


Introduction

Asthma is a major public health problem with a huge social and economic burden affecting 300 million people worldwide. Intermittent asthma, is the most common pattern of childhood asthma, accounting for up to 75% of children with asthma (1).

Viral respiratory infections are the major cause of acute asthma exacerbations in this patients (2-9). Acute exacerbations are also associated with decreased lung growth  and add substantially to both the cost and morbidity associated with asthma (10-13). Leukotrienes are important inflammatory mediators in allergic and non allergic inflammation of the entire airways (14-16). Montelukast, a leukotriene receptor antagonist, has a rapid onset of action and may be effective on reduction of asthma exacerbation if use at early onset of viral upper respiratory tract infection (17-20). The objective of the study was to determine the efficacy of a short course of Montelukast in children with intermittent asthma and viral infection.

 

Materials and Methods

This was a randomized, double-blind, placebo-controlled clinical trial carried out between September 2011 and September 2013 in Allergy Research Center, Qaem university hospital, Mashhad, Iran. The study was approved by the Human Research Ethics Committees of each participating center, and a written, informed consent was obtained from the parent.

Eligibility criteria were as follows: Children with intermittent asthma aged between 6 to 12 years, asymptomatic between episodes, no asthma medication between episodes.

Exclusion criteria were: any underlying disease such as heart disease or cystic fibrosis, taking antihistamine or Montelu- kast, missing follow up visits and environ- mental exposures such as tobacco smoke.

The patients were visited at early manifestations of viral respiratory infection. Montelukast was given at the dose of 5 mg for 7 days. Patients could receive inhaled β-agonist and oral prednisolone according to a customized asthma management plan. Each patient followed for 2 months by phone call at the end of first month and physician visit at the end of 2nd month. A symptom diary was completed by parents.

Primary outcomes included the clinical manifestation: duration of episodes, daily symptom, night time symptoms and activity limitation. Secondary outcomes included the need for beta agonist usage, oral prednisolone, physician visit, hospital admission and school absence.

The principal analyses were intention-to-treat analyses, but sensitivity analyses and a per protocol analysis were also done on the primary endpoint. Between-group compare- sons of categorical data were assessed using the chi-square test. Between-group compare- sons for continuous data were made using the nonparametric Mann-Whitney test, and hence medians and interquartile ranges are reported.

 

Results

A total of 200 patients were recruited, 187 patients were randomized into two treatment groups (93 cases in Montelukast group and 94 cases in placebo group). The baseline characteristics of the patients are described in (Table 1).

 

Table 1: Baseline characteristics of patients

 

Case

Number(Percent)

Control

Number(Percent)

P value

Male

47(50.5%)

47(50%)

0.86

Mean age(year)

7.2

7.5

0.7

FH of asthma

                9( 9.6%)

8(8.5%)

0.67

FH of allergic rhinitis

9(9.6%)

6(6.4%)

0.18

FH of eczema

11(11.8%)

9(9.5%)

0.5

FH of allergy

16(17.2%)

18(19.1%)

0.74

 

There were no significant differences between the two treatment groups for baseline characteristics.

There was significant difference in the incidence of day cough, night cough and activity limitation between the two groups but not for wheeze, breathlessness and tachypnea (Table 2).

 

Table 2: Comparing clinical manifestation of patients between two groups

 

Case

Control

P value

Day cough

19(20.4%)

35(37.2%)

<0.001

Night cough

4(4.3%)

9(9.6%)

<0.01

Wheeze

2(2.1%)

3(3.1%)

0.8

Activity limitation

4(4.3%)

10(10.6%)

<0.01

 

There was also significant difference in the incidence of time off school and Pediatrician visits and β-agonists use between the two groups but not for oral prednisolone useage and hospital admission rate (Table 3).

 

Table 3: Comparing treatments and complications between two groups.

 

Case

Control

P value

β-agonists use

19(20.4%)

36(38.3%)

<0.001

Oral prednisolone

2(2.1%)

3(3.1%)

0.8

Physician visit

17(18.3%)

29(30.8%)

<0.01

Hospital admission

2(2.1%)

3(3.1%)

0.8

School absence

4(4.3%)

10(10.6%)

<0.01

    

Discussion

This study demonstrated that in children with intermittent asthma, a short course of Montelukast at the onset of viral respiratory infection results in a significant reduction in day cough (16.8% reduction), night cough, activity disturbed and use of β-agonists and 12.5% fewer  Pediatrician visits and emergency department attendances. Although there was no significant effect on wheezing,respiratory distress and tachypnea  and oral prednisolone use, hospital admission. There was no adverse effect of montelukast happened in our patients.

Epidemiologic studies have detected viral upper respiratory infections in about 85% of childhood asthma exacerbations (1-4). Cysteinyl leukotrienes that are released in virus-associated wheeze mediate abnorma lities of lung function including mucus production, decreased mucociliary clearance, changes in vascular permeability, and smooth muscle contraction (14-16). Montelukast is an oral specific Cysteinyl leukotriene receptor antagonist with rapid onset of action, together with an excellent safety profileand bronchoprotective effects for 20 to 24 hours (17-26).

Beyond the use of β-agonists, the current approaches to management of mild intermittent asthma have resulted in little or no benefits in modifying the course of the illness. Bisgaard et al.was determined a 31% reduction in the rate of asthma exacerbations and reduction in the overall rate of corticosteroid use of 32% with long course of Montelukast as controller (23). Because children with intermittent asthma are asymptomatic for the majority of the time, the early use of intermittent therapy may provide a clinically and cost-effective alternative approach to management. Robertson et al.  showed that in this patients, short course montelukast therapy results in 14% reduction in asthma symptoms, the number of nights with disturbed sleep reduced by 8.6% and child days absent from school were reduced by 37%. There was no significant difference in the median number of β-agonist used per episode or oral steroid use (22).

Im summary, for children with intermittent asthma, a course of parent-initiated montelukast at the onset of a viral respiratory infection or common cold results in a significant reduction in asthma symptoms, pediatrician visits, β-agonist use, and the modest reduction in activity disturbed and absence from school.

 

1. Liu A, Covar R, Spahn J, Leung DYM. Childhood asthma, In Kliegman R, Stanton B, St.Geme J, Schor N, Behrman R, editors, Nelson textbook of pediatrics 19th ed. New York: Judith Fletcher;2011.p.780-801.

2. Johnston SL, Pattemore PK, Sanderson G, Smith S, Lampe F, Josephs L, Symington P, O Toole S, Myint SH, Tyrell DA.Community study of role of viral infections in exacerbations of asthma in 9 11year old children, BMJ 2008;310:1225-9.

3. Mallia P, Johnston SL. How viral infections cause exacerbation of airway disease.Chest 2006; 130:1203-10.

4. Jackson DJ, Johnston SL. The role of viruses in acute exacerbations of asthma, J Allergy Clin Immunol 2010; 125(6):1178-87.

5. Wu P. Hartert TV: Evidence for a causal relationship between respiratory syncytial virus infection and asthma, Expert Rev Anti Infect Ther 2011; 9(9):731-45.

6. Hansbro NG, Horvat JC, Wark PA, Hansbro PM. Understanding the mechanisms of viral induced asthma: new therapeutic directions, Pharmacol Ther 2008; 117(3):313-53.

7. Bizzintino J, Lee WM, Laing IA, Vang F, Pappas T, Zhang G, Martin AC, Khoo SK, Cox DW, Geelhoed GC, et al. Association between human rhinovirus C and severity of acute asthma in children, Eur Respir J 2011;37(5):1037-42.

8. Calhoun WJ, Dick EC, Schwartz LB, Busse WW. A common cold virus, rhinovirus 16, potentiates airway inflammation after segmental antigen bronchoprovocation in allergic subjects. J Clin Invest. 1994 Dec; 94(6):2200-8.

9. Busse WW, Lemanske RF Jr, Gern JE. Role of viral respiratory infections in asthma and asthma exacerbations, Lancet 2010; 376 (9743): 826-34.

10. Holtzman MJ, Byers DE, Benoit LA, Battaile JT, You Y, Agapov E, Park C, Grayson MH, Kim EY, Patel AC. Immune pathways for translating viral infection into chronic airway disease, Adv Immunol 2009;102:245-76.

11. Fraenkel DJ, Bardin PG, Sanderson G, Lampe F, Johnston SL, Holgate ST. Lower airways inflammation during rhinovirus colds in normal and in asthmatic subjects, Am J Respir Crit Care Med 1995; 151(3 Pt 1):879-86.

12. Wark PA, Johnston SL, Bucchieri F, Powell R, Puddicombe S, Laza-Stanca V, Holgate ST, Davies DE. Asthmatic bronchial epithelial cells have a deficient innate immune response to infection with rhinovirus, J Exp Med 2005; 201(6):937-47.

13. Rakes GP, Arruda E, Ingram JM, Hoover GE, Zambrano JC, Hayden FG, Platts-MillsTA, Heymann PW. Rhnovirus and respiratory syncytial virus in wheezing children requiring emergency care: IgE and eosinophil analyses, Am J Respir Crit Care Med 1999;159:785-90.

14. Oommen A, Grigg J. Urinary leukotriene E4 in preschool children with acute clinical viral wheeze,Eur Respir J 2010;21:149-54.

15. Van Schaik SM, Trstram DA, Nagpal IS, Hintz KM, Welliver RC. Increased production of INF-gamma and cysteinyl leukotrenes in virus-induced wheezing, J Allergy Clin Immunology 2003;103:630-6.

16. Barnes NC, Smith LJ. Physiological effects of the leukotrienesin humans.New York:Marcel Dekker;1998.pp. 193-245.

17. Takemura M, Niimi A, Matsumoto H, Ueda T, Matsuoka H, Yamaguchi M. Physiological and anti inflammatory effect of montelukast in cough vaeiant asthma. Kayoto respiratory medicine 2012;83(4):308-15.

18. Kozer E, Lotem Z, Elgarushe M, Torgovicky R, Cohen R, Berkovitch M. RTC of montelukast as prophylaxis for upper respiratory tract infection, J Allergy Clin Immunol 2012; 129 (2): 285-90.

19. Kim CK, Choi J, Kim HB, Callaway Z, Shin BM, Kim JT, Fujisawa T, Koh YY. A randomized intervention of montelukast for post-bronchiolitis: effect on eosinophil degranulation, J Pediatr 2010; 156:749–54.

20. Kirsten M, Jennifer P, Rose F, Cheri A, Katie L, Jack A. Effects of Montelukast in

Subjects With Asthma AfterExperimental Inoculation with Rhinovirus-16, J of Wisconsin-Madison 2009;12:58-86.

21. Johnston NW, Mandhane PJ, Dai J, Duncan JM, Greene JM, Lambert K, et all. Attenuation of the September epidemic of asthma-exacerbations in children: a randomized, controlled trial of Montelukast added to usual therapy, Pediatrics 2007; 120:e702–e12.

22. Robertson CF, Henry RL, Mellis C, Fitzgerald D, Glasgow N, Zheng X, et all. Short course montelukast for intermittent asthma in children: the Pre-empt study [abstract], Am J Respir Crit Care Med 2007;175:323-29.

23. Bisgaard H, Zielen S, Garcia-Garcia ML, Johnston SL, Gilles L, Menten J, et all. Montelukast reduces asthma exacerbations in         2-to 5-year-old children with intermittent asthma, Am J Respir Crit Care Med 2005Nov; 171: 315–22.

24. Knorr B, Matz J, Bernstein JA, Nguyen H, Seidenberg BC, Reiss TF, et all. Montelukast for chronic asthma in 6- to 14- year-old children: a randomized, double-blind trial, Pediatric Montelukast Study Group, JAMA 1998Apr; 279: 1181–86.

 

25. Bisgaard H, Garcia-Garcia ML, Johnston SL,

Gilles L, Menten J, Tozzi CA, Polos P. Montelukast reduces viral-induced asthma exacerbations: The PREVIA Study, Eur Respir J 2008Apr; 24: 212-18.

26. Knorr B, Franchi LM, Bisgaard H, Vermeulen JH, LeSouef P, Santanello N, et all. a leukotriene receptor antagonist, for the treatment of persistent asthma in children aged 6 to 14 years, Am J Respir Crit Care Med 2008; 167: 379–83.