Guide
Leukotriene (LT) is one of the metabolites of arachidonic acid and an important inflammatory mediator in allergic reactions, playing an important role in the pathogenesis of various allergic diseases. LT receptor antagonists (LTRs) have been widely used in pediatric allergic diseases, but there are still some challenges, especially after the US Food and Drug Administration (FD) issued a black box warning after 2009, and parents are increasingly concerned about the side effects of such drugs.
Therefore, starting from 2023, the Continental Rhinology Research Collaboration Group convened young and middle-aged rhinology experts in China to formulate this consensus, which elaborates on the clinical application of LTRA in common childhood allergic rhinitis (AR), as well as drug safety and adverse reactions, based on the introduction of leukotrienes and their receptors, the relevant classification of LTRA and the pharmacological mechanism of action, aiming to guide clinicians to standardize the use of LTRA in the treatment of AR in children. This article screens the clinical application of LTRA in children with AR and the safety and adverse reactions of LTRA in this consensus.
Clinical application
At present, domestic and foreign guidelines recommend LTRA as a first-line treatment for allergic diseases in children. The new edition of the Chinese Guidelines for the Diagnosis and Treatment of Allergic Rhinitis (2022, Rev.) recommends oral LTRA as the commonly used first-line treatment for AR. Guidelines for the diagnosis and treatment of allergic rhinitis in children (Rev. 2022), developed in the same year, emphasize that LTRA can be used alone in the clinical treatment of AR, but it is more recommended to use it in combination with antihistamines and/or nasal corticosteroids.
1
Monotherapy versus placebo
A range of studies have shown that montelukast is more effective than placebo in controlling symptoms and improving quality of life; Piatti et al. also found that zafirlukast significantly reduced the number of eosinophils in nasal lavage fluid and improved nasal resistance, suggesting that LTRA is mainly suitable for AR with nasal congestion as the main complaint; Long-term use of Promikalast not only improves nasal symptoms in children with AR during pollen season, but also delays the onset of nasal symptoms, deterioration of quality of life, and concomitant drug use, thereby playing a preventive role.
2
LTRA versus other drugs
There appear to be conflicting results for the clinical efficacy of LTRA in the treatment of AR in children compared to antihistamines. Montelukast is similar to pseudoephedrine in reducing nasal congestion, but pseudoephedrine is more effective. Compared with montelukast monotherapy, nasal glucocorticoids (nasal corticosteroids) monotherapy may improve AR symptoms and significantly reduce the IL-5/γ-interferon ratio in nasal lavage. These results suggest that montelukast appears to have less benefit than nasal hormone therapy in children with AR.
A series of meta-analyses found that montelukast was similar to antihistamine (loratadine) monotherapy for AR, but not as effective as nasal corticosteroids. In addition, a recent meta-analysis found that montelukast was superior to oral antihistamines only for improving nocturnal nasal symptoms, and inferior to oral antihistamines in terms of daytime nasal symptoms, nasal symptom composite scores, daytime ocular symptom scores, and rhinoconjunctivitis quality of life scores, as well as inferior efficacy to nasal hormones.
3
Combination therapy versus monotherapy
Several studies have suggested that LTRA should not be routinely used in AR patients receiving nasal cormone therapy, as none of their trial results suggest a significant benefit of adding an LTRA. In addition, the combination of LTRA+ antihistamines is superior to monotherapy in both pediatric and adult AR patients.
However, for patients with moderate-to-severe AR who have not responded well to nasal corticosteroid therapy for nasal symptoms (particularly nasal congestion), the combination of LTRA should be recommended to improve efficacy.
4
Specifications for clinical application
Montelukast is an oral medication that is available in film-coated tablets, chewable tablets, or granules. In the treatment of perennial AR, it is suitable for patients > 6 months, for patients aged 6~23 months, oral granules can be used, the recommended dose is 4 mg for patients aged 6 months ~ 5 years, 5 mg for patients aged 6~14 years, and 10 mg for patients aged 15 years and older. Montelukast is suitable for seasonal AR patients aged >2 years, the recommended dose is 4 mg for patients aged 2~5 years, and the recommended dose for 6 years and older is the same as for perennial AR. The course of treatment is 2~4 weeks, the efficacy is evaluated after treatment, and the symptom relief is maintained for 1 month, and if there is no remission, it is necessary to confirm whether the diagnosis is correct. Prophylactic medication is suitable for AR in all age groups, especially for asthma with AR, which should be taken 2~3 weeks before the epidemic season.
Safety and adverse effects
1
safety
Several clinical results have shown that montelukast is generally well tolerated in children, with a similar incidence of adverse reactions to placebo and no impact on physical development in prepubertal children.
2
Adverse effects
Total adverse reactions
The overall incidence of adverse reactions in LTRA was similar to that of placebo, with asthma, upper respiratory tract infection, cough, fever, and headache most commonly reported after the marketing of montelukast. Shamrani et al. concluded that the most common adverse effects of montelukast in children were sleep disturbance, agitation, pain, and hyperactivity.
Neuropsychiatric event risk and prevention
At present, there is no consensus on the research on the neuropsychiatric effects of montelukast. Montelukast has been reported to be associated with events such as nightmares, unspecified anxiety, aggression, and sleep disturbances. However, these studies did not determine whether montelukast was associated with these neuropsychiatric events. A retrospective analysis of data from the FDA's Merck clinical trial showed no statistically significant difference in the incidence of behavior-related adverse events between the montelukast and placebo groups, and no more patients with suicidal ideation were found in the montelukast group than in the placebo group; The use of montelukast in people with asthma also does not significantly increase the risk of suicide.
However, physicians should be aware of the possible risk of neuropsychiatric events when using the drug, inform them of the risks at the time of prescribing, and arrange follow-up visits. Monitor the patient's behavior and mood changes during the medication, and discontinue the medication once signs of neuropsychiatric events, such as irritability and aggressive behavior, appear.
Other monitoring matters
Liver function must be monitored regularly when using LTRA therapy. Although in most cases, discontinuation completely reverses the dysfunction, in rare cases, patients even progress to liver failure.
summary
Numerous high-quality basic and clinical studies have shown that LTRA is safe and effective in the treatment of AR in children. In the future, with the deepening of LTRA-related research, its clinical application will continue to be standardized and accurate, and more and more children with allergic diseases will also benefit from it.
Reference: Chinese Rhinology Research Collaboration Group. Expert consensus on the clinical application of leukotriene receptor antagonists in children with allergic rhinitis. Chinese Journal of Eye and Otolaryngology Vol. 24 No. 3 May 2024.161~169.