Treatment of bronchiolitis with montelukast
Characteristics of respiratory syncytial virus-induced bronchiolitis co-infection with Mycoplasma pneumoniae and add-on therapy with montelukast Sheng-Hua Wu, Xiao-Qing Chen, Xia Kong, Pei-Ling Yin, Ling Dong, Pei-Yuan Liao, JiaMing Wu Nanjing, China
Methods: Children with respiratory syncytial virus (RSV)-induced bronchiolitis were divided into two groups: RSV+MP group and RSV group. Each group was randomly divided into two subgroups: one received routine and placebo treatment, while the other received routine and montelukast treatment for 9 months. The cumulative numbers of wheezing episodes and recurrent respiratory tract infections were recorded. Blood parameters were determined. Results: Patients in the RSV+MP group exhibited an older average age, fever, more frequent flaky and patchy shadows in chest X-rays, more frequent extrapulmonary manifestations, and longer hospital stays compared with patients in the RSV group. Additionally, higher baseline blood eosinophil counts, eosinophil cationic protein (ECP), total immunoglobulin E (IgE), interleukin (IL)-4, IL-5, IL-4/interferon-γ ratios, leukotriene (LT) B4, and LTC4, and lower baseline lipoxin A4 (LXA4)/LTB4 ratios were observed in the RSV+MP group compared
Author Affiliations: Department of Pediatrics, First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing 210029, China (Wu SH, Dong L); Department of Pediatrics, Jiangsu Maternity and Children Healthcare Hospital, Nanjing 210036, China (Chen XQ); Department of Pediatrics, Nanjing First Hospital Affiliated to Nanjing Medical University, Nanjing 210006, China (Kong X, Yin PL); Department of Pediatrics, Central Hospital of Tengzhou, Tengzhou 277500, China (Liao PY); Department of Pediatrics, Qidong People's Hospital, 753 Central Jianghai Road, Qidong 226200, China (Wu JM) Corresponding Author: Sheng-Hua Wu, MD, PhD, Department of Pediatrics, First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing 210029, China. (Tel: +86-025-83718836 ext. 8104; Fax: +86-025-83724440; Email: [email protected]) doi: 10.1007/s12519-015-0024-4 ©Children's Hospital, Zhejiang University School of Medicine, China and Springer-Verlag Berlin Heidelberg 2015. All rights reserved.
World J Pediatr, Online First, April 2015 . www.wjpch.com
with the RSV group. Montelukast treatment decreased the cumulative numbers of recurrent wheezing episodes and recurrent respiratory tract infections at 9 and 12 months. This efficacy may be related to the montelukast-induced reductions in peripheral eosinophil counts, ECP and total IgE, as well as the montelukast-dependent recovery in T helper (Th) 1/Th2 balance and LXA 4/LTB4 ratios in children with bronchiolitis. Conclusions: RSV bronchiolitis with MP infection was associated with clinical and laboratory features that differed from those of RSV bronchiolitis without MP infection. Add-on therapy with montelukast for 9 months was beneficial for children with bronchiolitis at 9 and 12 months after the initiation of treatment. World J Pediatr April 2015; Online First Key words: bronchiolitis; leukotrienes; montelukast; Mycoplasma pneumoniae; respiratory syncytial virus
Introduction
A
cute bronchiolitis is predominantly a viral disease. Respiratory syncytial virus (RSV) is responsible for more than 50% of cases of acute bronchiolitis, and other agents including parainfluenza, adenovirus, Mycoplasma, and so on, also lead to this disease.[1] Severe RSV bronchiolitis with recurrent wheezing episodes (≥3 episodes) in early infancy is a strong risk factor for the occurrence of allergic asthma in early adolescence.[2] Recently, Mycoplasma pneumoniae (MP) infection has been recognized as a causative agent of asthma.[3] MP infection can precede the onset of asthma, promote exacerbation of asthmatic symptoms, and cause difficulties with asthma management.[3] Many cases of MP bronchiolitis in adults have been reported previously.[4] However, the influence of MP infection on bronchiolitis remains unclear. Therefore, this study was designed to investigate the clinical 1
Original article
Background: The influence of Mycoplasma pneumoniae (MP) infection on bronchiolitis remains unclear. Additionally, reports on the efficacies of leukotriene receptor antagonists in the treatment of bronchiolitis have been inconclusive.
World Journal of Pediatrics
Original article
Clinical Trial Registry (www.chictr.org; registration number: ChiCTR-TRC-13003735). A total of 270 children with acute bronchiolitis were recruited from the Departments of Pediatrics of the First Affiliated Hospital with Nanjing Medical University, Jiangsu Maternity and Children Healthcare Hospital, Nanjing First Hospital Affiliated to Nanjing Medical University, Central People's Hospital of Tengzhou, and Qidong People's Hospital from March 2012 to March 2013 (Fig. 1). The parents or guardians of the enrolled children provided informed consent for their children to participate in this study. The protocol was approved by the ethics committees of the above-mentioned hospitals. The diagnosis of bronchiolitis was based on clinical assessment of acute bronchiolitis as recommended by the American Academy of Pediatrics.[10] Patients were included in the study if they met the following inclusion criteria: age of 2 to 24 months, diagnosis of RSV bronchiolitis, and the first episode of RSV bronchiolitis with a respiratory symptom duration of less than 7 days. The RSV infection was confirmed by both identification of RSV-RNA in the nasopharyngeal aspirates and RSVimmunoglobulin (Ig) M in the serum, and MP infection was confirmed by both identification of MP-DNA in the nasopharyngeal aspirates and MP-IgM in the serum. Assessment of bronchiolitic episode severity was based on the clinical asthma score, as reported by Parkin et al.[11] Patients whose bronchiolitic symptoms persisted for more than 7 days from onset, those who experienced more than one episode of bronchiolitis, those with a history of intubation, underlying cardiopulmonary, laryngeal, tracheobronchial or other infectious disease, those with immunodeficiency, or those who had been on any steroid treatment within the previous 2 weeks were excluded from the study. Fifty-seven normal healthy,
and laboratory characteristics of children with RSV bronchiolitis co-infection with MP. Additionally, severe RSV bronchiolitis may be associated with enhanced T helper (Th) 2 responses, such as overexpression of interleukin (IL)-4.[5] However, it is still unclear whether the increased Th2 responses occur in children with RSV bronchiolitis co-infection with MP. Thus, we also investigated Th1/Th2 cytokines production in children with RSV bronchiolitis co-infection with MP. Leukotrienes (LTs) are important pro-inflammatory mediators of airway inflammation in asthma. [6] Our previous study suggested that children with severe asthma generated insufficient amounts of lipoxin A4 (LXA4), a native inhibitor of LTs, but overproduced LTs.[7] Diminished LXA 4 biosynthesis and enhanced generation of cysteinyl-LTs (CysLTs) have also been found in adults with severe asthma. [8] CysLTs are increased in respiratory secretions obtained from infants with acute RSV bronchiolitis, suggesting a possible role of CysLTs in the pathogenesis of the disease.[9] To the present, no studies have reported the production of LXA4 in patients with bronchiolitis. Therefore, this study aimed to explore the generation of LXA4 and LTs in children with RSV bronchiolitis with or without MP infection. In addition, the results of published randomized controlled trials (RCTs) describing the efficacy of LT receptor antagonists (LTRAs) in the treatment of RSV bronchiolitis have been inconclusive.[6] Thus, in this study, we explored the efficacy of add-on therapy with montelukast in the treatment of bronchiolitis.
Methods
Patients The clinical trial was registered with the Chinese Admitted (n=270)
RSV and MP examination
Randomized allocation R+P-treated group (n=26) Discontinued (n=3) Lack of efficacy (n=1) Withdrew (n=1) Lost to follow up (n=1)
RSV+MP (n=52) R+M-treated group (n=26)
Discontinued (n=5) Side reaction (n=3) Withdrew (n=1) Lost to follow up (n=1)
Compledted (n=23)
Compledted (n=21)
Excluded (n=89) Did not meet inclusion criteria (n=61) Meet exclusion criteria (n=22) Refused (n=6)
RSV alone (n=130) R+P-treated group (n=65)
Randomized allocation
R+M-treated group (n=65)
Discontinued (n=8) Lack of efficacy (n=3) Withdrew (n=3) Lost to follow up (n=2) Compledted (n=57)
Discontinued (n=11) Side reaction (n=8) Withdrew (n=2) Lost to follow up (n=1)
Compledted (n=54)
Fig. 1. Flow chart of study enrollment. RSV: respiratory syncytial virus; MP: Mycoplasma pneumoniae; R: routine treatment; P: placebo treatment; M: montelukast treatment.
2
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Treatment of bronchiolitis with montelukast age- and sex-matched children served as controls. The clinical data of all enrolled children are listed in Table.
Treatment protocol In this prospective, randomized, placebo-controlled, double-blind, parallel-group study conducted in five medical centers, every pair of patients with comparable age distributions and clinical asthma scores in the RSV
Table. Clinical data of patients with bronchiolits before treatment and those of controls RSV+MP group (n=52) RSV group (n=130) Controls (n=57) P-treated (n=26) M-treated (n=26) P-treated (n=65) M-treated (n=65) Male/female 18/8 16/10 47/18 45/20 39/18 * * 10.3±4.7 5.5±3.2 5.7±3.6 8.9±5.8 Age (mon) 11.8±4.5 * * Fever (>37.5°C) (%) 42.3 46.1 13.8 12.3 0 * * 42.3 12.3 13.8 0 Flaky shadow in X-ray (%) 38.4 * * 61.5 16.9 20.0 0 Extrapulmonary findings (%) 69.2 † † † † 11.5 16.9 18.4 5.2 Atopic dermatitis (%) 15.3 Asthma in family (%) 3.8 3.8 3.1 1.5 1.7 Clinical asthma score (0-10) 6.8±1.6 6.5±1.7 6.4±1.8 6.6±1.7 0 Inhaled oxygen (%) 23.1 19.2 21.5 24.6 0 3-drugs inhalation (%) 100 100 100 100 0 Systemic corticosteroids (%) 30.7 26.9 24.6 23.0 0 * * 100 10.7 16.9 0 Antibiotics (%) 100 * * 15.8±4.2 6.9±3.2 7.5±3.9 0 Length of hospital stay (d) 14.6±3.5 *† *† † † Blood eosinophil (cells/μL) 249±84 259±92 166±49 158±56 94±56 *† *† † † 91.6±34.7 58.3±22.6 46.7±23.2 12.3±6.8 Serum IL-4 (pg/mL) 88.4±26.7 *† *† † † 132.2±45.4 84.9±31.3 91.8±36.6 15.2±6.2 Serum IL-5 (pg/mL) 126.1±42.8 † † † † Serum IFN-γ (IU/mL) 39.8±18.2 41.9±19.2 42.9±22.6 43.6±21.7 27.3±14.9 *† *† † † 2.49±0.82 1.21±0.75 1.12±0.68 0.45±0.29 Serum IL-4/IFN-γ 2.24±0.81 *† *† † † 152.6±35.5 83.0±38.2 88.6±22.9 20.6±13.6 Serum total IgE (IU/mL) 143.2.3±32.1 † † * * † † 92.4±17.8 39.7±16.2 38.9±15.9 7.5±4.2 Serum ECP (ng/mL) 86.9±18.4 † † † † Blood LXA4 (ng/mL) 4.4±2.3 4.5±2.5 4.9±2.2 5.1±3.7 1.4±0.6 *† *† † † 85.8±35.2 84.9±32.3 63.2±24.1 68.9±22.1 12.4±5.2 Blood LTB4 (pg/mL) *† *† † † 123.6±43.1 127.4±42.8 72.9±23.9 82.7±26.1 12.7±5.3 Blood LTC4 (pg/mL) *† *† † † Blood LXA4/LTB4×1000 51.4±19.7 53.1±20.1 77.8±27.5 74.0±26.9 112.9±45.1 RSV: respiratory syncytial virus; MP: Mycoplasma pneumoniae; P: placebo treatment; M: montelukast treatment; 3-drugs inhalation: budesonide, salbutamol sulfate and ipratropium bronude; IL: interleukin; IFN-γ: interferon-γ; ECP: eosinophil cationic protein; LXA4: lipoxin A4; LT: leukotriene. *: P
Characteristics of respiratory syncytial virus-induced bronchiolitis co-infection with Mycoplasma pneumoniae and add-on therapy with montelukast Sheng-Hua Wu, Xiao-Qing Chen, Xia Kong, Pei-Ling Yin, Ling Dong, Pei-Yuan Liao, JiaMing Wu Nanjing, China
Methods: Children with respiratory syncytial virus (RSV)-induced bronchiolitis were divided into two groups: RSV+MP group and RSV group. Each group was randomly divided into two subgroups: one received routine and placebo treatment, while the other received routine and montelukast treatment for 9 months. The cumulative numbers of wheezing episodes and recurrent respiratory tract infections were recorded. Blood parameters were determined. Results: Patients in the RSV+MP group exhibited an older average age, fever, more frequent flaky and patchy shadows in chest X-rays, more frequent extrapulmonary manifestations, and longer hospital stays compared with patients in the RSV group. Additionally, higher baseline blood eosinophil counts, eosinophil cationic protein (ECP), total immunoglobulin E (IgE), interleukin (IL)-4, IL-5, IL-4/interferon-γ ratios, leukotriene (LT) B4, and LTC4, and lower baseline lipoxin A4 (LXA4)/LTB4 ratios were observed in the RSV+MP group compared
Author Affiliations: Department of Pediatrics, First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing 210029, China (Wu SH, Dong L); Department of Pediatrics, Jiangsu Maternity and Children Healthcare Hospital, Nanjing 210036, China (Chen XQ); Department of Pediatrics, Nanjing First Hospital Affiliated to Nanjing Medical University, Nanjing 210006, China (Kong X, Yin PL); Department of Pediatrics, Central Hospital of Tengzhou, Tengzhou 277500, China (Liao PY); Department of Pediatrics, Qidong People's Hospital, 753 Central Jianghai Road, Qidong 226200, China (Wu JM) Corresponding Author: Sheng-Hua Wu, MD, PhD, Department of Pediatrics, First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing 210029, China. (Tel: +86-025-83718836 ext. 8104; Fax: +86-025-83724440; Email: [email protected]) doi: 10.1007/s12519-015-0024-4 ©Children's Hospital, Zhejiang University School of Medicine, China and Springer-Verlag Berlin Heidelberg 2015. All rights reserved.
World J Pediatr, Online First, April 2015 . www.wjpch.com
with the RSV group. Montelukast treatment decreased the cumulative numbers of recurrent wheezing episodes and recurrent respiratory tract infections at 9 and 12 months. This efficacy may be related to the montelukast-induced reductions in peripheral eosinophil counts, ECP and total IgE, as well as the montelukast-dependent recovery in T helper (Th) 1/Th2 balance and LXA 4/LTB4 ratios in children with bronchiolitis. Conclusions: RSV bronchiolitis with MP infection was associated with clinical and laboratory features that differed from those of RSV bronchiolitis without MP infection. Add-on therapy with montelukast for 9 months was beneficial for children with bronchiolitis at 9 and 12 months after the initiation of treatment. World J Pediatr April 2015; Online First Key words: bronchiolitis; leukotrienes; montelukast; Mycoplasma pneumoniae; respiratory syncytial virus
Introduction
A
cute bronchiolitis is predominantly a viral disease. Respiratory syncytial virus (RSV) is responsible for more than 50% of cases of acute bronchiolitis, and other agents including parainfluenza, adenovirus, Mycoplasma, and so on, also lead to this disease.[1] Severe RSV bronchiolitis with recurrent wheezing episodes (≥3 episodes) in early infancy is a strong risk factor for the occurrence of allergic asthma in early adolescence.[2] Recently, Mycoplasma pneumoniae (MP) infection has been recognized as a causative agent of asthma.[3] MP infection can precede the onset of asthma, promote exacerbation of asthmatic symptoms, and cause difficulties with asthma management.[3] Many cases of MP bronchiolitis in adults have been reported previously.[4] However, the influence of MP infection on bronchiolitis remains unclear. Therefore, this study was designed to investigate the clinical 1
Original article
Background: The influence of Mycoplasma pneumoniae (MP) infection on bronchiolitis remains unclear. Additionally, reports on the efficacies of leukotriene receptor antagonists in the treatment of bronchiolitis have been inconclusive.
World Journal of Pediatrics
Original article
Clinical Trial Registry (www.chictr.org; registration number: ChiCTR-TRC-13003735). A total of 270 children with acute bronchiolitis were recruited from the Departments of Pediatrics of the First Affiliated Hospital with Nanjing Medical University, Jiangsu Maternity and Children Healthcare Hospital, Nanjing First Hospital Affiliated to Nanjing Medical University, Central People's Hospital of Tengzhou, and Qidong People's Hospital from March 2012 to March 2013 (Fig. 1). The parents or guardians of the enrolled children provided informed consent for their children to participate in this study. The protocol was approved by the ethics committees of the above-mentioned hospitals. The diagnosis of bronchiolitis was based on clinical assessment of acute bronchiolitis as recommended by the American Academy of Pediatrics.[10] Patients were included in the study if they met the following inclusion criteria: age of 2 to 24 months, diagnosis of RSV bronchiolitis, and the first episode of RSV bronchiolitis with a respiratory symptom duration of less than 7 days. The RSV infection was confirmed by both identification of RSV-RNA in the nasopharyngeal aspirates and RSVimmunoglobulin (Ig) M in the serum, and MP infection was confirmed by both identification of MP-DNA in the nasopharyngeal aspirates and MP-IgM in the serum. Assessment of bronchiolitic episode severity was based on the clinical asthma score, as reported by Parkin et al.[11] Patients whose bronchiolitic symptoms persisted for more than 7 days from onset, those who experienced more than one episode of bronchiolitis, those with a history of intubation, underlying cardiopulmonary, laryngeal, tracheobronchial or other infectious disease, those with immunodeficiency, or those who had been on any steroid treatment within the previous 2 weeks were excluded from the study. Fifty-seven normal healthy,
and laboratory characteristics of children with RSV bronchiolitis co-infection with MP. Additionally, severe RSV bronchiolitis may be associated with enhanced T helper (Th) 2 responses, such as overexpression of interleukin (IL)-4.[5] However, it is still unclear whether the increased Th2 responses occur in children with RSV bronchiolitis co-infection with MP. Thus, we also investigated Th1/Th2 cytokines production in children with RSV bronchiolitis co-infection with MP. Leukotrienes (LTs) are important pro-inflammatory mediators of airway inflammation in asthma. [6] Our previous study suggested that children with severe asthma generated insufficient amounts of lipoxin A4 (LXA4), a native inhibitor of LTs, but overproduced LTs.[7] Diminished LXA 4 biosynthesis and enhanced generation of cysteinyl-LTs (CysLTs) have also been found in adults with severe asthma. [8] CysLTs are increased in respiratory secretions obtained from infants with acute RSV bronchiolitis, suggesting a possible role of CysLTs in the pathogenesis of the disease.[9] To the present, no studies have reported the production of LXA4 in patients with bronchiolitis. Therefore, this study aimed to explore the generation of LXA4 and LTs in children with RSV bronchiolitis with or without MP infection. In addition, the results of published randomized controlled trials (RCTs) describing the efficacy of LT receptor antagonists (LTRAs) in the treatment of RSV bronchiolitis have been inconclusive.[6] Thus, in this study, we explored the efficacy of add-on therapy with montelukast in the treatment of bronchiolitis.
Methods
Patients The clinical trial was registered with the Chinese Admitted (n=270)
RSV and MP examination
Randomized allocation R+P-treated group (n=26) Discontinued (n=3) Lack of efficacy (n=1) Withdrew (n=1) Lost to follow up (n=1)
RSV+MP (n=52) R+M-treated group (n=26)
Discontinued (n=5) Side reaction (n=3) Withdrew (n=1) Lost to follow up (n=1)
Compledted (n=23)
Compledted (n=21)
Excluded (n=89) Did not meet inclusion criteria (n=61) Meet exclusion criteria (n=22) Refused (n=6)
RSV alone (n=130) R+P-treated group (n=65)
Randomized allocation
R+M-treated group (n=65)
Discontinued (n=8) Lack of efficacy (n=3) Withdrew (n=3) Lost to follow up (n=2) Compledted (n=57)
Discontinued (n=11) Side reaction (n=8) Withdrew (n=2) Lost to follow up (n=1)
Compledted (n=54)
Fig. 1. Flow chart of study enrollment. RSV: respiratory syncytial virus; MP: Mycoplasma pneumoniae; R: routine treatment; P: placebo treatment; M: montelukast treatment.
2
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Treatment of bronchiolitis with montelukast age- and sex-matched children served as controls. The clinical data of all enrolled children are listed in Table.
Treatment protocol In this prospective, randomized, placebo-controlled, double-blind, parallel-group study conducted in five medical centers, every pair of patients with comparable age distributions and clinical asthma scores in the RSV
Table. Clinical data of patients with bronchiolits before treatment and those of controls RSV+MP group (n=52) RSV group (n=130) Controls (n=57) P-treated (n=26) M-treated (n=26) P-treated (n=65) M-treated (n=65) Male/female 18/8 16/10 47/18 45/20 39/18 * * 10.3±4.7 5.5±3.2 5.7±3.6 8.9±5.8 Age (mon) 11.8±4.5 * * Fever (>37.5°C) (%) 42.3 46.1 13.8 12.3 0 * * 42.3 12.3 13.8 0 Flaky shadow in X-ray (%) 38.4 * * 61.5 16.9 20.0 0 Extrapulmonary findings (%) 69.2 † † † † 11.5 16.9 18.4 5.2 Atopic dermatitis (%) 15.3 Asthma in family (%) 3.8 3.8 3.1 1.5 1.7 Clinical asthma score (0-10) 6.8±1.6 6.5±1.7 6.4±1.8 6.6±1.7 0 Inhaled oxygen (%) 23.1 19.2 21.5 24.6 0 3-drugs inhalation (%) 100 100 100 100 0 Systemic corticosteroids (%) 30.7 26.9 24.6 23.0 0 * * 100 10.7 16.9 0 Antibiotics (%) 100 * * 15.8±4.2 6.9±3.2 7.5±3.9 0 Length of hospital stay (d) 14.6±3.5 *† *† † † Blood eosinophil (cells/μL) 249±84 259±92 166±49 158±56 94±56 *† *† † † 91.6±34.7 58.3±22.6 46.7±23.2 12.3±6.8 Serum IL-4 (pg/mL) 88.4±26.7 *† *† † † 132.2±45.4 84.9±31.3 91.8±36.6 15.2±6.2 Serum IL-5 (pg/mL) 126.1±42.8 † † † † Serum IFN-γ (IU/mL) 39.8±18.2 41.9±19.2 42.9±22.6 43.6±21.7 27.3±14.9 *† *† † † 2.49±0.82 1.21±0.75 1.12±0.68 0.45±0.29 Serum IL-4/IFN-γ 2.24±0.81 *† *† † † 152.6±35.5 83.0±38.2 88.6±22.9 20.6±13.6 Serum total IgE (IU/mL) 143.2.3±32.1 † † * * † † 92.4±17.8 39.7±16.2 38.9±15.9 7.5±4.2 Serum ECP (ng/mL) 86.9±18.4 † † † † Blood LXA4 (ng/mL) 4.4±2.3 4.5±2.5 4.9±2.2 5.1±3.7 1.4±0.6 *† *† † † 85.8±35.2 84.9±32.3 63.2±24.1 68.9±22.1 12.4±5.2 Blood LTB4 (pg/mL) *† *† † † 123.6±43.1 127.4±42.8 72.9±23.9 82.7±26.1 12.7±5.3 Blood LTC4 (pg/mL) *† *† † † Blood LXA4/LTB4×1000 51.4±19.7 53.1±20.1 77.8±27.5 74.0±26.9 112.9±45.1 RSV: respiratory syncytial virus; MP: Mycoplasma pneumoniae; P: placebo treatment; M: montelukast treatment; 3-drugs inhalation: budesonide, salbutamol sulfate and ipratropium bronude; IL: interleukin; IFN-γ: interferon-γ; ECP: eosinophil cationic protein; LXA4: lipoxin A4; LT: leukotriene. *: P
