Comment
Gustoimages/Science Photo Library
Wheezing in young children: WAITing for pharmacogenomics?
Published Online September 17, 2014 http://dx.doi.org/10.1016/ S2213-2600(14)70189-4 See Articles page 796
776
In The Lancet Respiratory Medicine, Chinedu Nwokoro and colleagues’1 WAIT trial assesses the effectiveness of intermittent montelukast for treatment of wheezing episodes in 1358 children aged 10 months to 5 years who had had two or more wheeze episodes, with at least one episode in the preceding 3 months. There was no difference in the primary outcome of unscheduled medical attendances for wheezing episodes between children in the montelukast and placebo groups (mean 2·0 [SD 2·6] vs 2·3 [2·7]; incidence rate ratio [IRR] 0·88, 95% CI 0·77–1·01; p=0·06). However, the subgroup of patients who carried the wild type (common) genotype of the 5-lipoxygenase (ALOX5) gene promoter, which encodes a key enzyme in the leukotriene synthesis pathway, had significantly reduced unscheduled severe medical attendances for wheezing episodes (2·0 [2·7] vs 2·4 [3·0]; IRR 0·80, 95% CI 0·68–0·95; p=0·01). Prevention of wheeze episodes in children younger than 5 years has important benefit in terms of improvements in quality of life for children and their families, and reductions in health-care costs. However, an additional long-term benefit could be a change in the natural history of airway disease in these children. Asthma begins in childhood,2 and wheezing episodes—a classic finding in people with asthma— generally happen in the first few years of life and are typically associated with viral respiratory-tract infections. These early wheezing episodes can have longterm consequences. Children diagnosed with asthma at a young age have significantly impaired lung function3,4 and at least one aspect of airway remodelling-increased thickness of the reticular basement membranewhich seems to start as early as age 2–3 years5 and can be as severe in children of this age as it can in adult asthmatics.6 A model of airway inflammation suggests that airway remodelling is driven by both the frequency and severity of airway inflammatory events.7 In a followup assessment of young adults from the Dunedin Birth Cohort, Sears and colleagues stated that “The challenge [in asthma] is to develop identification and treatment strategies applicable to early childhood that would reduce these adverse outcomes”.3 Could use of montelukast in children with the responsive ALOX5 genotype represent such an early
intervention? The answer requires replication of the present study and additional long-term follow up studies, but the concept is exciting. Additional support for a salutory effect of montelukast in the present study was provided by results of the secondary outcomes. In the entire study group, need for rescue oral corticosteroids was substantially decreased with 0·26 uses per child in the montelukast group versus 0·33 in the placebo group. This difference between the active and placebo treatment groups was statistically significant (p=0·03) and clinically relevant, irrespective of the genotype. Additionally, time to first hospital admission was longer in children in the montelukast group than in those in the placebo group (p=0·04). Although the results are encouraging, they should be viewed with caution. The findings are concordant with some pharmacogenetic studies of the effect of modifying response to leukotrienes, but discordant with others.8 Of perhaps greater concern is biological plausibility. Leukotriene E4 (LTE4), the urinary metabolite of cysteinyl leukotrienes, measured at recruitment was raised in carriers of the mutant genotype, showing no beneficial effect from montelukast. This result is paradoxical. ALOX5 is in the promoter region of the gene and the wild-type gene variant functions as a more effective promoter of gene expression and thus increases leukotriene production. This action suggests individuals with a more effective promoter produce more leukotriene and are thus more responsive to its inhibition. A possible explanation is that LTE4 was measured at baseline, whereas generation of leukotrienes during inflammatory events is what leads to wheezing episodes. Unfortunately, LTE4 was not measured during exacerbations. Viral respiratory-tract infections are common, but no clinically useful approaches exist to decrease the prevalence of colds, which are the main trigger for wheezing episodes in children younger than 5 years. Therefore, if prevention of lifelong decrease in lung function is an aim, approaches to decrease the severity of wheezing episodes triggered by these infections should be considered. Not all the children in this study will continue to wheeze. In the Tucson Children’s Respiratory Study, the www.thelancet.com/respiratory Vol 2 October 2014
Comment
investigators developed a clinical index to define future asthma risk: the Asthma Predictive Index (API).9 The API was applied to children who had wheezing episodes by age 3 years to define those who would have persistent asthma by age 6 years. The scoring was positive with either one major risk factor (a parental history of asthma or physician diagnosed atopic dermatitis) or two of three minor risk factors (allergic rhinitis, eosinophilia, or wheezing without colds). Subsequent investigators have modified the original API, with removal of allergic rhinitis as a minor criterion and addition of allergic sensitisation either to aeroallergens as a major criterion, or to milk, egg, or peanut as a minor criterion.10 Nwokoro and colleagues refer to the Acute Intermittent Management Study (AIMS)11 and state that intermittent therapy showed no overall benefit in that study. That statement is correct for the trial’s primary outcome measure, which focused on the proportion of episode-free days during the 12 month trial in which the children were treated with intermittent leukotriene receptor antagonist (montelukast) or intermittent inhaled corticosteroid (budesonide) compared with placebo. However, intermittent treatment for 1 week with either montelukast or budesonide at the start of a wheezing episode produced a significant decrease in symptom severity, including less trouble breathing and less interference with activities, and the total symptom score. Of particular interest, in the modified API-positive group, there was even greater improvement for both trouble breathing and interference with activities that were reduced by 40–50% with intermittent treatment using either montelukast, or budesonide, compared with placebo. Furthermore, wheezing was significantly reduced by montelukast in the modified API-positive group. Are we ready to begin genotyping high-risk children to institute a personalised prevention strategy for wheezing episodes? The frequency and severity of wheezing episodes in children younger than 5 years is an important burden for children, their families, and the health-care system. No gold-standard biological methods are presently available to diagnose asthma. Clinical scores are commonly used in primary care practices to predict risk for cardiovascular events, presence of dementia, and other health-care issues. These scores can help to direct diagnosis and treatment www.thelancet.com/respiratory Vol 2 October 2014
approaches. Genotyping is now standard practice in various clinical scenarios in which genotype might have an important effect on diagnosis and treatment response. The costs of genotyping are decreasing rapidly and would be more than offset by savings in health-care use if the results from Nwokoro and colleagues’ study can be verified. We are almost there, and investigators have suggested that genomic sequencing might eventually become standard for screening of newborn babies.12 Before use of such genomic data for diagnostic and therapeutic purposes is considered, the validity of studies such as the WAIT trial should be confirmed. *Allan B Becker, Peter D Paré Section of Allergy and Clinical Immunology, Department of Pediatrics and Child Health, University of Manitoba, Winnipeg, MB R3E 0Z2, Canada (ABB); and University of British Columbia Center for Heart Lung Innovation, St Paul’s Hospital, Vancouver, BC, Canada (PDP) [email protected] We have no competing interests. Copyright © Becker and Paré. Open Access article distributed under the terms of CC BY. 1
2
3
4 5
6
7
8
9
10 11
12
Nwokoro C, Pandya H, Turner S, et al. Intermittent montelukast in children aged 10 months to 5 years with wheeze (WAIT trial): a multicentre, randomized, placebo-controlled trial. Lancet Respir Med 2014; published online Sept 9. http://dx.doi S2213-2600(14)70186-9. Yunginger JW, Reed CE, O’Connell EJ, et al. A community-based study of the epidemiology of asthma. Incidence rates, 1964–1983. Am Rev Respir Dis 1992; 146: 888–94. Sears MR, Greene JM, Willan AR, et al. A longitudinal, population-based, cohort study of childhood asthma followed to adulthood. N Engl J Med 2003; 343: 1414–22. Phelan PD, Robertson CF, Olinsky A. The Melbourne Asthma Study: 1964–1999. J Allergy Clin Immunol 2002; 109: 189–94. Saglani S, Payne DN, Zhu J et al. Early detection of airway wall remodeling and eosinophilic inflammation in preschool wheezers. Am J Respir Crit Care Med 2007; 176: 858–64. Payne DN, Rogers AV, Adelroth E, et al. Early thickening of the reticular basement membrane in children with difficult asthma. Am J Respir Crit Care Med 2003; 167: 78–82. Chernyavsky IL, Croisier H, Chapman LA, et al. The role of inflammation resolution speed in airway smooth muscle mass accumulation in asthma: insight from a theoretical model. PloS One 2014; 9: e90162. Tse SM, Tantisira K, Weiss ST. The pharmacogenetics and pharmacogenomics of asthma therapy. Pharmacogenomics J 2011; 11: 383–92. Castro-Rodriguez JA, Holberg CJ, Wright AL et al. A clinical index to define risk of asthma in young children with recurrent wheezing. Am J Respir Crit Care Med 2000; 162: 1403–06. Bacharier LB, Guilbert TW. Diagnosis and management of early asthma in preschool-aged children. J Allergy Clin Immunol 2012; 130: 287–96. Bacharier LB, Phillips BR, Zeiger RS et al. Episodic use of an inhaled corticosteroid or leukotriene receptor antagonist in preschool children with moderate-to-severe intermittent wheezing. J Allergy Clin Immunol 2008; 122: 1127–35. Levy HL. Newborn screening: the genomic challenge. Mol Genet Genomic Med 2014; 2: 81–84.
777
Gustoimages/Science Photo Library
Wheezing in young children: WAITing for pharmacogenomics?
Published Online September 17, 2014 http://dx.doi.org/10.1016/ S2213-2600(14)70189-4 See Articles page 796
776
In The Lancet Respiratory Medicine, Chinedu Nwokoro and colleagues’1 WAIT trial assesses the effectiveness of intermittent montelukast for treatment of wheezing episodes in 1358 children aged 10 months to 5 years who had had two or more wheeze episodes, with at least one episode in the preceding 3 months. There was no difference in the primary outcome of unscheduled medical attendances for wheezing episodes between children in the montelukast and placebo groups (mean 2·0 [SD 2·6] vs 2·3 [2·7]; incidence rate ratio [IRR] 0·88, 95% CI 0·77–1·01; p=0·06). However, the subgroup of patients who carried the wild type (common) genotype of the 5-lipoxygenase (ALOX5) gene promoter, which encodes a key enzyme in the leukotriene synthesis pathway, had significantly reduced unscheduled severe medical attendances for wheezing episodes (2·0 [2·7] vs 2·4 [3·0]; IRR 0·80, 95% CI 0·68–0·95; p=0·01). Prevention of wheeze episodes in children younger than 5 years has important benefit in terms of improvements in quality of life for children and their families, and reductions in health-care costs. However, an additional long-term benefit could be a change in the natural history of airway disease in these children. Asthma begins in childhood,2 and wheezing episodes—a classic finding in people with asthma— generally happen in the first few years of life and are typically associated with viral respiratory-tract infections. These early wheezing episodes can have longterm consequences. Children diagnosed with asthma at a young age have significantly impaired lung function3,4 and at least one aspect of airway remodelling-increased thickness of the reticular basement membranewhich seems to start as early as age 2–3 years5 and can be as severe in children of this age as it can in adult asthmatics.6 A model of airway inflammation suggests that airway remodelling is driven by both the frequency and severity of airway inflammatory events.7 In a followup assessment of young adults from the Dunedin Birth Cohort, Sears and colleagues stated that “The challenge [in asthma] is to develop identification and treatment strategies applicable to early childhood that would reduce these adverse outcomes”.3 Could use of montelukast in children with the responsive ALOX5 genotype represent such an early
intervention? The answer requires replication of the present study and additional long-term follow up studies, but the concept is exciting. Additional support for a salutory effect of montelukast in the present study was provided by results of the secondary outcomes. In the entire study group, need for rescue oral corticosteroids was substantially decreased with 0·26 uses per child in the montelukast group versus 0·33 in the placebo group. This difference between the active and placebo treatment groups was statistically significant (p=0·03) and clinically relevant, irrespective of the genotype. Additionally, time to first hospital admission was longer in children in the montelukast group than in those in the placebo group (p=0·04). Although the results are encouraging, they should be viewed with caution. The findings are concordant with some pharmacogenetic studies of the effect of modifying response to leukotrienes, but discordant with others.8 Of perhaps greater concern is biological plausibility. Leukotriene E4 (LTE4), the urinary metabolite of cysteinyl leukotrienes, measured at recruitment was raised in carriers of the mutant genotype, showing no beneficial effect from montelukast. This result is paradoxical. ALOX5 is in the promoter region of the gene and the wild-type gene variant functions as a more effective promoter of gene expression and thus increases leukotriene production. This action suggests individuals with a more effective promoter produce more leukotriene and are thus more responsive to its inhibition. A possible explanation is that LTE4 was measured at baseline, whereas generation of leukotrienes during inflammatory events is what leads to wheezing episodes. Unfortunately, LTE4 was not measured during exacerbations. Viral respiratory-tract infections are common, but no clinically useful approaches exist to decrease the prevalence of colds, which are the main trigger for wheezing episodes in children younger than 5 years. Therefore, if prevention of lifelong decrease in lung function is an aim, approaches to decrease the severity of wheezing episodes triggered by these infections should be considered. Not all the children in this study will continue to wheeze. In the Tucson Children’s Respiratory Study, the www.thelancet.com/respiratory Vol 2 October 2014
Comment
investigators developed a clinical index to define future asthma risk: the Asthma Predictive Index (API).9 The API was applied to children who had wheezing episodes by age 3 years to define those who would have persistent asthma by age 6 years. The scoring was positive with either one major risk factor (a parental history of asthma or physician diagnosed atopic dermatitis) or two of three minor risk factors (allergic rhinitis, eosinophilia, or wheezing without colds). Subsequent investigators have modified the original API, with removal of allergic rhinitis as a minor criterion and addition of allergic sensitisation either to aeroallergens as a major criterion, or to milk, egg, or peanut as a minor criterion.10 Nwokoro and colleagues refer to the Acute Intermittent Management Study (AIMS)11 and state that intermittent therapy showed no overall benefit in that study. That statement is correct for the trial’s primary outcome measure, which focused on the proportion of episode-free days during the 12 month trial in which the children were treated with intermittent leukotriene receptor antagonist (montelukast) or intermittent inhaled corticosteroid (budesonide) compared with placebo. However, intermittent treatment for 1 week with either montelukast or budesonide at the start of a wheezing episode produced a significant decrease in symptom severity, including less trouble breathing and less interference with activities, and the total symptom score. Of particular interest, in the modified API-positive group, there was even greater improvement for both trouble breathing and interference with activities that were reduced by 40–50% with intermittent treatment using either montelukast, or budesonide, compared with placebo. Furthermore, wheezing was significantly reduced by montelukast in the modified API-positive group. Are we ready to begin genotyping high-risk children to institute a personalised prevention strategy for wheezing episodes? The frequency and severity of wheezing episodes in children younger than 5 years is an important burden for children, their families, and the health-care system. No gold-standard biological methods are presently available to diagnose asthma. Clinical scores are commonly used in primary care practices to predict risk for cardiovascular events, presence of dementia, and other health-care issues. These scores can help to direct diagnosis and treatment www.thelancet.com/respiratory Vol 2 October 2014
approaches. Genotyping is now standard practice in various clinical scenarios in which genotype might have an important effect on diagnosis and treatment response. The costs of genotyping are decreasing rapidly and would be more than offset by savings in health-care use if the results from Nwokoro and colleagues’ study can be verified. We are almost there, and investigators have suggested that genomic sequencing might eventually become standard for screening of newborn babies.12 Before use of such genomic data for diagnostic and therapeutic purposes is considered, the validity of studies such as the WAIT trial should be confirmed. *Allan B Becker, Peter D Paré Section of Allergy and Clinical Immunology, Department of Pediatrics and Child Health, University of Manitoba, Winnipeg, MB R3E 0Z2, Canada (ABB); and University of British Columbia Center for Heart Lung Innovation, St Paul’s Hospital, Vancouver, BC, Canada (PDP) [email protected] We have no competing interests. Copyright © Becker and Paré. Open Access article distributed under the terms of CC BY. 1
2
3
4 5
6
7
8
9
10 11
12
Nwokoro C, Pandya H, Turner S, et al. Intermittent montelukast in children aged 10 months to 5 years with wheeze (WAIT trial): a multicentre, randomized, placebo-controlled trial. Lancet Respir Med 2014; published online Sept 9. http://dx.doi S2213-2600(14)70186-9. Yunginger JW, Reed CE, O’Connell EJ, et al. A community-based study of the epidemiology of asthma. Incidence rates, 1964–1983. Am Rev Respir Dis 1992; 146: 888–94. Sears MR, Greene JM, Willan AR, et al. A longitudinal, population-based, cohort study of childhood asthma followed to adulthood. N Engl J Med 2003; 343: 1414–22. Phelan PD, Robertson CF, Olinsky A. The Melbourne Asthma Study: 1964–1999. J Allergy Clin Immunol 2002; 109: 189–94. Saglani S, Payne DN, Zhu J et al. Early detection of airway wall remodeling and eosinophilic inflammation in preschool wheezers. Am J Respir Crit Care Med 2007; 176: 858–64. Payne DN, Rogers AV, Adelroth E, et al. Early thickening of the reticular basement membrane in children with difficult asthma. Am J Respir Crit Care Med 2003; 167: 78–82. Chernyavsky IL, Croisier H, Chapman LA, et al. The role of inflammation resolution speed in airway smooth muscle mass accumulation in asthma: insight from a theoretical model. PloS One 2014; 9: e90162. Tse SM, Tantisira K, Weiss ST. The pharmacogenetics and pharmacogenomics of asthma therapy. Pharmacogenomics J 2011; 11: 383–92. Castro-Rodriguez JA, Holberg CJ, Wright AL et al. A clinical index to define risk of asthma in young children with recurrent wheezing. Am J Respir Crit Care Med 2000; 162: 1403–06. Bacharier LB, Guilbert TW. Diagnosis and management of early asthma in preschool-aged children. J Allergy Clin Immunol 2012; 130: 287–96. Bacharier LB, Phillips BR, Zeiger RS et al. Episodic use of an inhaled corticosteroid or leukotriene receptor antagonist in preschool children with moderate-to-severe intermittent wheezing. J Allergy Clin Immunol 2008; 122: 1127–35. Levy HL. Newborn screening: the genomic challenge. Mol Genet Genomic Med 2014; 2: 81–84.
777
