Sleep Disorders in Children with Asthma

Abstract

Asthma and sleep disorders are both common in childhood, and often co-exist in the same child. Moreover, studies have shown that in many children the rate of one is influenced by the other. Sleep disorders can be classified into six different groups – insomnia, hypersomnia, parasomnia, movement disorders, circadian disorders and sleep-related breathing disorders. Children with asthma often present with complaints of insomnia with poor sleep quality, difficulty falling asleep and sleep disruptions. These complains are often associated with asthma control. They may also complain of daytime sleepiness and have higher rates of parasomnias such as night terrors and nocturnal enuresis when compared with their healthy peers. Whether movement and circadian disorders are also more prevalent in children with asthma is less clear. Finally, there is a complex bidirectional interaction between sleep-related breathing disorders and asthma: poor sleep and sleep disorders may worsen asthma, and asthma, particularly when it is poorly controlled, may impair sleep.

In the current review we examine the association of each of the sleep disorders with asthma and review the common pathophysiological pathways. We hope to convince the reader that appropriate management of asthma must include inquiries into the patient’s sleep, and vice versa.

INTRODUCTION

Asthma and sleep disorders are both common in childhood. While asthma prevalence varies depending on the patients’ age group, gender, race, socioeconomic background and additional factors, overall prevalence is approximately 9% in the pediatric population in the United States ⁽¹⁾, and thus asthma is considered the most common non-communicable chronic disease in childhood ⁽²⁾. Obstructive sleep apnea syndrome (OSAS), the most severe form of sleep-disordered breathing, affects 1–6% of the population ⁽³⁾. General sleep complaints are often much more prevalent, with bedtime problems and night waking consistent with behavioral insomnia in approximately 20–30% of young children ⁽⁴⁾. It is therefore not surprising that there are many children in whom both asthma and sleep disorders coexist. Moreover, studies have shown that in many of these children the rate of one is influenced by the other. In this review we will address the different sleep disorders seen in children with asthma. The international classifications of sleep disorders is divided into six different sections of sleep disorders: insomnia, hypersomnia, parasomnia, sleep-related movement disorders, circadian disorders and sleep-related breathing disorders. We will address the association between asthma and each of them (Figure 1), as well as the effect that sleep disorders have on asthma control. When appropriate we will also discuss the common pathophysiological mechanisms. We hope to convince the reader that appropriate management of asthma must include inquiries into the patient’s sleep and vice versa.

Figure 1 – The relationship between asthma and sleep disorders.

Solid lines represent known association, whereas dashed lines unclear or unknown relationships. EDS: excessive daytime sleepiness.

INSOMNIA

Insomnia is defined as a persistent difficulty with sleep initiation, duration, consolidation or quality ⁽⁵⁾. There are multiple reasons for sleep disruptions in asthma. Symptoms of asthma often occur at night or on waking up – to such a degree that night-time awakenings are included in the determination of asthma control and the evaluation of treatment ⁽⁶⁾.

Insomnia is prevalent in children with asthma across different ages. In a study of children aged 1–4 years with no asthma, well controlled asthma and poorly controlled asthma, those with worse asthma control had poorer sleep patterns, more difficulty falling asleep, and more sleep disruptions ⁽⁷⁾. Even children with well controlled asthma had more frequent and longer night awakenings, and parents reported that their sleep quality was poorer, compared with children with no asthma ⁽⁷⁾. A study of older children (mean age 8.9±2.1 years) with mild to moderate asthma during a month of relative stability found that nocturnal awakening occurred in one third of the children, and appeared to be an indicator of increasing asthma severity ⁽⁸⁾. Another study in this age group found that general sleep problems were more frequent in children with poor asthma control, and poor sleep hygiene was associated with poor asthma control ⁽⁹⁾. Youth aged 12–17 years with severe asthma show insufficient weekday sleep compared with healthy controls, and almost twice as many complained of insomnia compared with those with mild or moderate asthma ⁽¹⁰⁾. Desager et al. reported that the relationship between asthma and poor sleep quality in children 6–14 years old persisted after correction for snoring and sleep related breathing disorders (SRBD), with a twofold higher risk for difficulty falling asleep and a fourfold higher risk for restless sleep ⁽¹¹⁾. Several other studies have shown that not only is the child’s sleep affected, but so is the parents’, with interrupted poor sleep quality in parents of children with asthma ^{(7, 12)}.

Beyond patient-reported symptoms, sleep abnormalities in asthma have also been shown with objective measures. A retrospective review of polysomnography records of children and adolescents showed significantly longer sleep latency in girls with asthma and shorter sleep duration in boys with asthma, compared to their peers without asthma ⁽¹³⁾. Similarly, a study of elementary school children reported that those with asthma had longer sleep latencies and less slow wave sleep on polysomnography compared to those without asthma, although that study recruited by purposive sampling and therefore may have suffered from selection bias ⁽¹⁴⁾. Finally, actigraphy studies have shown poorer sleep quality in children with asthma than controls, with increased activity levels and overall less quiet sleep ⁽¹⁵⁾.

Sleep quality worsens in parallel with asthma severity ^{(8, 12)}. A study of school-aged urban children with persistent asthma evaluated actigraphy as well as objective home-based measures of asthma control and twice daily spirometry. Criteria for persistent asthma included caregiver report of a current prescription for an asthma controller medication, and/or report of recurrent daytime or nighttime symptoms, activity limitation, rescue medication use, or 2 or more oral steroid bursts the prior 12 months ⁽¹⁶⁾. This study reported an association between lower FEV1 and poorer sleep quality. They had also shown that on a particular night, better evening lung function were associated with improved sleep efficiency that night ⁽¹⁶⁾.

In addition to the direct impact of asthma symptoms on sleep, asthma medications – both controllers and rescue medications – may also play a role. While better asthma control may improve sleep quality, some bronchodilators may cause a stimulant like effect, thereby negatively affecting sleep ⁽¹⁷⁾. Montelukast is a leukotriene receptor antagonist commonly used as controller medication for pediatric asthma and possible therapy for mild pediatric OSAS. The FDA issued a black box warning in 2020 for montelukast due to its mental health side effects that include trouble sleeping and sleep walking, among other potentially serious events ⁽¹⁸⁾. Initial studies on montelukast had shown improved sleep ⁽¹⁹⁾, but a study published in 2019 in school-aged children with asthma presenting to emergency departments or hospitals with a neuropshychiatric event revealed that children who experienced such an event had nearly twice the odds of having montelukast among their prescribed medications. Notably, over a quarter of the patients presented for a sleep disturbance ⁽²⁰⁾. Systemic steroids are known to affect sleep and sleep architecture in healthy adults ⁽¹⁷⁾. Studies in children with childhood leukemia have shown an increase in sleep disturbances and night awakenings during periods of steroid therapy ⁽²¹⁾. Inhaled corticosteroids (ICS), the current first line controller treatment for asthma, may improve asthma thereby improving sleep; at the same time, some systemic absorption exists and they may therefore have a negative impact on sleep causing insomnia ⁽¹⁷⁾. Thus, asthma medications may act as a double-edged sword, improving sleep when asthma is not well controlled but possibly hampering sleep by their side effects. It is therefore crucial that parents are warned about these side effects, and that providers balance benefits vs risks and follow guidelines by using the least amount of medication that is sufficient to achieve adequate asthma control.

While this review focuses on the long-term relationships between asthma and sleep, asthma exacerbations may also result in acute sleep disturbances. Hospitalization per se –for asthma or other reasons– can result in poor-quality sleep during the admission, resulting in altered sleep schedules and affecting the child’s behavior and mood ⁽²²⁾. Sleep can be influenced by noise from other parents, staff and medical electronic devices as well as ward-based routines and physical environment such as room lighting and temperature. In a study in which parents completed a sleep diary, 52.3% of children had poor sleep, with half of those reporting low sleep efficiency and three or more night awakenings on the sleep diary ⁽²³⁾. Sleep disturbances during hospitalization may differ by age group, with younger children reporting later bedtimes and shorter total sleep time, while adolescents wake up later and sleep longer, and both age groups experiencing an increase in night awakenings ⁽²⁴⁾. In the pediatric intensive care unit, physical, environmental and pharmacologic factors may have an even bigger role in sleep disruption ⁽²⁵⁾. As noted before, medications may add to the effect admission have sleep, with evidence that short courses of systemic steroids may affect sleep ⁽²⁶⁾. However, we found no studies specifically on whether asthma exacerbations have an impact on sleep beyond what is seen from the general effects of being in the hospital.

Finally, it has become evident that poor sleep may have an effect on asthma control. Poor sleep quality predicts worse asthma symptoms the following day ⁽²⁷⁾. In a cross-sectional study of 24,612 high school students in the US who participated in the National Youth Risk Behavior Survey, 13.1% of whom reported current asthma, multivariable analysis revealed that shorter sleep duration was significantly associated with a ~15% higher odds of asthma ⁽²⁸⁾. And a preliminary study of sleep manipulation that compared children whose sleep was restricted to ≤6.5 hours with children that had a 10-hour sleep opportunity, showed an 8.4% decrease in peak expiratory flows and an increase in asthma symptoms interfering with activities following sleep restriction ⁽²⁹⁾. However, to our knowledge there are no randomized trials in children showing that treatment of insomnia leads to sustained improvements in lung function or asthma control.

HYPERSOMNIA AND EXCESSIVE DAYTIME SLEEPINESS

Excessive daytime sleepiness is a common complaint in pediatric asthma, often secondary to the disrupted sleep as described in the preceding section. In a study of the general pediatric population, subjective sleepiness was found in approximately 15% of children. Asthma was among the strong predictors of sleepiness identified ⁽³⁰⁾. Children with asthma and their parents report higher rates of morning tiredness than healthy children and decreased daytime alertness on questionnaires ⁽¹⁵⁾. Both asthma severity and symptom frequency are associated with more frequent daytime sleepiness in both children and adolescents ^{(10, 31)}. On the other hand, better adherence to asthma controller medications is linked to improvement in excessive daytime sleepiness, emphasizing the secondary nature of the complaint ⁽¹⁹⁾. Daytime sleepiness affects quality of life, with a path analysis study showing that sleepiness mediates the association between asthma control and quality of life ⁽³²⁾.

Narcolepsy is a sleep disorder characterized by excessive daytime sleepiness and episodes of cataplexy in the severe forms. Immune dysregulation and skewing of the immune system towards a TH2 phenotype may play a role in the pathophysiology of both narcolepsy and of childhood asthma ⁽³³⁾. Interestingly, one retrospective analysis examined prevalence of atopic conditions in children with narcolepsy and found that presence of atopy (allergic rhinitis, atopic dermatitis and asthma) was significantly associated with the cataplexy-negative phenotype ⁽³⁴⁾. These findings suggest that atopy may provide some protection against the severe form of narcolepsy, although prospective studies are needed to delineate this association better.

PARASOMNIAS

Parasomnias are behavioral phenomena that occur out of sleep. They are largely divided between non-REM (NREM) parasomnias that include disorders such as confusional arousal, sleep talking (somniloquy), sleep walking (somnambulism), and night terrors; and REM parasomnias such as nightmare disorder. Nocturnal enuresis is also included in this group of disorders ⁽⁵⁾.

Night terrors occur in almost 50% of toddlers and preschoolers with poorly controlled asthma, compared with 20% of those with well controlled asthma and only 2% of their peers without asthma ⁽⁷⁾. The authors suggested the trigger for the night terrors was sleep disruption caused by the asthma ⁽⁷⁾. Fagnano et al. used a validated questionnaire that includes a domains for parasomnias, and reported more frequent sleep terrors associated with more severe nocturnal symptoms of asthma in children aged 3–10 years ⁽¹²⁾.

As noted above, some sleep disturbances may be secondary to medications used for asthma. Analysis of adverse drug reactions to montelukast reported to the Netherlands Pharmacovigilance Center, Lareb, and the WHO Global database, VigiBase® reported odds ratios of 56.7 (56.1–57.4) and 78.0 (69.9–87.1), respectively, for nightmares in pediatric patients ⁽³⁵⁾. Although causality is difficult to assess, the close time sequence between exposure to montelukast and the nightmares, the lack of exposure to other medications, and the quick resolution of nightmares in most cases after montelukast withdrawal, as well as a positive re-challenge in several patients, strongly suggest such a causal relationship ⁽³⁶⁾.

Nocturnal enuresis is defined as recurrent involuntary voiding during sleep in children older than 5 years old, that occurs at least twice per week, for at least three months ⁽⁵⁾. It is associated with difficulty arousing from sleep and seen in sleep disorders that fragment sleep, and usually improves after treatment ⁽⁵⁾. Several studies have shown higher rates of nocturnal enuresis in children with asthma compared with healthy controls ⁽³⁷⁾. A recent study of school-aged children reported a prevalence of 26% in children with asthma, compared with 11.5 % in controls ⁽³⁸⁾. Among children with asthma, disease severity and atopy were risk factors, independent from a family history of enuresis ⁽³⁸⁾.

MOVEMENT DISORDERS

Sleep related movement disorders are relatively simple, usually stereotyped movements that disrupt sleep or its onset. Two of the most common of this group of disorders are the restless legs syndrome (RLS) and periodic limb movement disorder (PLMD). RLS consists of an urge to move the legs, usually with an uncomfortable or unpleasant sensation. PLMD is characterized by repetitive stereotyped movements on polysomnography. To be considered disorders they must interrupt sleep or cause daytime sleepiness or fatigue ⁽⁵⁾.

In adults with asthma there is an increased rate of RLS compared with healthy individuals ⁽³⁹⁾. This is inversely associated with asthma control, as well as with depression and anxiety, but not associated with asthma medications use ⁽³⁹⁾. We are unaware of any studies on RLS in children, although one abstract presented at the 2017 American Thoracic Society Conference reported increased periodic limb movements, which may support a diagnosis of RLS, in children with uncontrolled asthma compared with those with well controlled asthma ⁽⁴⁰⁾. However, PLMD may be secondary to OSA and 72% of those with PLMD in this study had OSA. Though they found no association between PLMD and OSA in their sample, this finding should therefore be interpreted with caution ⁽⁴⁰⁾.

CIRCADIAN DISORDERS

The circadian system has a clear effect on asthma and the respiratory system, as evidenced by the prominence of nocturnal symptoms in asthma. In fact, studies in both healthy individuals and individuals with asthma have shown diurnal rhythms in pulmonary functions. Spengler and Shea demonstrated changes in FEV1 during a 41-hour routine spent in a constant environment with low lighting; though subjects remained awake throughout the study, the lowest values were recorded during the usual sleep period ⁽⁴¹⁾. However, whether there is an association between chronotype and asthma, or between circadian disorders such as the delayed sleep phase and asthma, is less clear. Circadian disorders often emerge during adolescence along with the natural developmental delay in the circadian system. Children with asthma have more difficulty waking up and show a preference for later bedtimes than controls ⁽¹⁵⁾, but to our knowledge no studies have evaluated the prevalence of delayed sleep phase disorder in asthma, nor have they studied whether having a delayed sleep phase worsens asthma control. Since these are treatable disorders, this is an important knowledge gap that should be addressed in future studies.

A person’s chronotype is their preference for a specific time for sleep and activity, often categorized into morning types (“larks”) and evening types (“owls”), wherein most people belong to intermediate types. Adolescents with evening chronotypes have an ~85% higher risk of wheezing and 2.7-fold higher risk of asthma than their morning-type peers (23.6% vs 6.2%) ⁽⁴²⁾. Whether the evening preference is primary or secondary to the asthma symptoms or therapies cannot be determined, and therefore the authors of this study appropriately note that additional studies will be needed to understand the mechanisms behind these associations ⁽⁴²⁾.

SLEEP-RELATED BREATHING DISORDERS

Sleep related breathing disorders (SRBD) include several conditions characterized by respiratory abnormalities during sleep. The most common of these are the obstructive SRBD, of which there is a severity spectrum that ranges from primary or habitual snoring to obstructive sleep apnea syndrome (OSA) ⁽⁴³⁾. Multiple studies have investigated the association between asthma and SRBD, showing an overlap between the two. The term “alternative overlap syndrome” was coined in 2013 to differentiate it from the COPD – OSA overlap syndrome, and to promote further investigation in the area of obstructive lungs disease and OSA syndrome in adults, OLDOSA ⁽⁴⁴⁾. Though this term has not been formally adopted in pediatric pulmonology, it is used often. Since the coexistence of both SRBD and obstructive lung disease in a child can have a cumulative effect on morbidity, the need for early recognition of this condition has been stressed ⁽⁴⁵⁾.

Several systematic reviews have examined the association between SRBD and asthma. Malakasioti et al. found an increased prevalence of snoring or elevated apnea-hypopnea index (AHI) in epidemiologic studies covering over 25,000 children with history of wheezing or asthma. However, only one of these studies utilized polysomnographies for the diagnosis of SRBD ⁽⁴⁶⁾, while the remaining based the diagnosis on symptom questionnaires ^{(45, 47–49)}. The authors proposed the association might be bidirectional, as there was also evidence for higher likelihood of wheezing in children with an increased AHI ⁽⁴⁵⁾. A later review by Sanchez et al. showed that children with asthma had a higher risk for habitual snoring and OSA than those without asthma, and that children with SRBD had a higher risk of asthma ⁽⁵⁰⁾. Of eleven studies describing the prevalence and risk factors of SRBD, with data on asthma, in only one did a history of asthma decrease the odds of having OSA on polysomnography, a study of inner city, mostly African American children ⁽⁵¹⁾. In a large scale epidemiological study of 20,672 Chinese children, both habitual snoring and OSA were statistically significant predictors of asthma ⁽⁵²⁾. In addition to the epidemiological study the authors performed a metanalysis of all published cross-sectional and cohort studies on the correlation between SRBD and asthma, in which SRBD was correlated with a ~60% higher odds of asthma (odds ratio 1.58, 95%CI 1.35–1.80) ⁽⁵²⁾. These reviews have also analyzed the positive effect of SRBD treatment on asthma outcomes, including a reduction in asthma exacerbations and medication use following adeno-tonsillectomy ^(53–56). One caveat to these analyses is the heterogeneity of studies, with different methods for the diagnosis of both asthma and SRBD. The majority of studies are based on history or questionnaires, with only a few using objective testing such as spirometry for asthma and polysomnography for SRBD. However, a large database of 13,506 children with asthma that had undergone adenotonsillectomy compared them to 27,012 matched controls who did not have the surgery ⁽⁵⁷⁾. Comparing the year after adenotonsillectomy with the year before, the surgery was associated with a 30% reduction in acute asthma exacerbations, a 37.9% reduction in acute status asthmaticus, a 25.6% reduction in asthma-related emergency room visits, and a 35.8% reduction in asthma-related hospitalizations. In addition, there was a significant reduction in prescription refills for most asthma medications. These effects were almost not apparent in the control group.

The association between asthma and SRBD can be explained in several ways including common risk factors, and similar pathophysiological causes. The pathophysiology of SRBD includes an interaction between static factors such as the narrowing of the airway by lymphatic and soft tissues and dynamic factors that narrow the airway such as the neuromuscular tone and airway collapsibility ⁽⁵⁸⁾. This may partly explain why the risk of SRBD appears to be “dose dependent” on the severity of lower respiratory problems, in that persistent wheeze carries a greater risk than occasional wheeze ⁽⁴⁶⁾, and poorly controlled asthma has been shown to correlate with more severe OSA ⁽⁵⁹⁾.

Inflammation, systemic and local, lies at the cornerstone of the pathophysiology of both asthma and SRBD. Inflammation in SRBD has been extensively studied with evidence of elevated levels of inflammatory mediators such as the leukotrienes, in adenoids and tonsils, and systemic markers of inflammation such as hs-CRP, IL-17 and IL-23 in the plasma of children with SRBD ^{(60, 61)}. Furthermore, levels of these cytokines decrease after treatment for SRBD ⁽⁶⁰⁾. Asthma represents a heterogenous syndrome with multiple inflammatory mechanisms involved referred to as clinical phenotypes or endotypes separated according to such criteria as clinical, immunological, genetic and environmental features ^{(62, 63)}. This shared inflammatory pathophysiological basis in SRBD and asthma is reflected in both diseases’ response to similar medications such as the leukotriene receptor antagonists. Whether the same inflammatory processes lead to both diseases or inflammation at one site leads to inflammation at the other, according to the united airway theory, discussed below, remains unclear but there is likely a contribution of both.

As noted before, asthma and OSA both have high rates in the community. Furthermore, they share common risk factors, including obesity, gastroesophageal reflux disease, and African-American descent (Figure 2) ⁽⁶²⁾. In children, the main cause of SRBD is narrowing of the upper airway by lymphatic tissue, including tonsils and adenoids ⁽⁶⁴⁾. However, an increasing rate of obesity among children ⁽⁶⁵⁾ has led to increasing rates of SRBD with a pathophysiology closer to the OSA seen in adults⁽⁶⁶⁾, and thus high rates of persistence after surgery ⁽⁶⁷⁾. Obesity’s effect on asthma risk is dose-dependent ⁽⁶⁸⁾ and makes asthma less responsive to treatment ⁽⁶⁹⁾. One study found that adjustment for SRBD attenuated the association between obesity and wheeze, but not the association between obesity and asthma. The authors concluded that both SRBD and obesity were independently associated with asthma and wheeze ⁽⁷⁰⁾.

Figure 2 – Factors that contribute to sleep disorders in asthma.

GERD: Gastroesophageal reflux disease.

Another factor associated with both asthma and SRBD is rhinitis. The “united airway disease” theory links rhinitis and asthma, as the upper and lower airway represent a unified morphological and functional unit ⁽⁷¹⁾. Both rhinitis and asthma share chronic inflammation of the airway, and combined management of the two is required for optimal control of either ⁽⁷¹⁾. Rhinitis is also associated with SRBD in children, independent of atopy, gender, age, BMI or ethnicity ⁽⁷²⁾ and its treatment can improve objective measures of SRBD ⁽⁷³⁾.

Finally, it should be noted that at times parents’ distinction between symptoms of SRBD and symptoms of asthma may be difficult, especially in younger children. Both may cause noisy and labored breathing during sleep and, as we have discussed, asthma that is not well controlled can disrupt sleep continuity.

In summary, there is clear evidence for overlap between asthma and SRBD, however, its cause remains unclear and is likely multifactorial (Figure 2). It is evident that there is a bidirectional causality with asthma serving as a risk factor for OSAS while OSAS acts as a risk factor for asthma. However, the majority of studies reporting this association share several common flaws. Some studies may reflect specific populations, such as limited age spans, urban adolescents, African Americans, Latino etc., and thus not be generalizable; while others on the contrary lack specificity in terms of the population investigated. Over the past few decades it has become increasingly clear that asthma does not represent one disease but rather multiple different phenotypes leading to similar signs and symptoms but differing in many other aspects ⁽⁶³⁾. The same is likely true for sleep disorders, with growing evidence in adult SRBD of different phenotypes – some of which may overlap– and novel attempts at phenotype-directed approaches for precision medicine ⁽⁷⁴⁾. Much like one cannot (should not) study or treat wheeze in a preschool child and atopic asthma in a teenager in the same way, not all patients with asthma and SRBD will be the same, and therefore studies need to be carefully designed keeping disease heterogeneity in mind. Future studies will have to aim to phenotype both asthma and SRBD and find where the associations between the two conditions are present to guide personalized investigations and therapies.

LIMITATIONS

As noted in prior sections, causality cannot be inferred from observational studies on the association between sleep disorders and asthma. Furthermore, both are relatively common and share several risk factors, which could act as confounders and are difficult to disentangle. Examples include a history of prematurity, considered a risk factor for asthma as well as SRBD and poor sleep ^(75–77); obesity, which serves as a clear risk factor for both and has been associated with short sleep duration ^{(62, 75, 78)}; low socioeconomic status ^{(79, 80)}; and race ^{(80, 81)}. Furthermore, though this review attempts to describe the association between asthma and the different sleep disorders, it is important to note that these disorders may overlap. For instance, SRBD is associated with insomnia, hypersomnia, and parasomnias such as bedwetting, and only a few studies have attempted to separate these associations ⁽¹¹⁾. These limitations do not rule out the associations described above, but they do emphasize the need for additional, prospective –and when possible interventional– studies.

CONCLUSION

In this review we have detailed the association of several pediatric sleep disorders with asthma and the common pathophysiological pathways and theories for this association. Until we can identify those children at risk, we hope this review has emphasized the need to address both. In the asthma clinic the practitioner should inquire into the child’s sleep, just as a sleep clinic visit should include questions of nocturnal cough and wheezing for possible asthma.