Pediatric sleep apnea and viral respiratory infections: what do clinicians need to know?

KEYWORDS:

• OSA
• pediatrics
• virus
• airway
• children

Obstructive sleep apnea (OSA) is the most common form of sleep-disordered breathing in children occurring in approximately 1% to 5% of the pediatric population [1]. OSA is characterized by repetitive episodes of upper airway obstruction that cause intermittent hypoxia and/or frequent arousals [1]. OSA affects all pediatric age groups with two clear peak periods. The first peak is in the preschool age, corresponding to the time of adeno-tonsillar hypertrophy, and the second is during adolescence when obesity becomes more prevalent [1]. Early diagnosis of the condition is essential to reduce the occurrence of complications over time. Untreated OSA has been associated with behavioral problems, learning difficulties, cardiovascular complications, and growth retardation. Risk factors for pediatric OSA include prematurity, obesity, allergic rhinitis, and syndromic conditions [1]. Investigating additional OSA risk factors in children may lead to interventions that reduce health-related costs and long-term complications of this prevalent condition.

The role of viral respiratory infections as a critical risk factor for OSA [1 has been postulated for several years. Snow et al. first described a significant association between severe bronchiolitis caused by respiratory syncytial virus (RSV) and the development of OSA in 21 children with OSA and 63 controls [2]. The association of viral infections and OSA is also supported by a nationwide population-based cohort study in Taiwan that found a significant association between enterovirus infection and pediatric sleep disorders after adjusting for age, sex, urbanization atopic disease, and perinatal complications [3]. Data from the Danish National Patient Registry (2998 patients aged 0–19 years) also found that the diagnosis of pediatric OSA was linked to a higher incidence of respiratory infections [4]. More recently, in a large longitudinal birth cohort (Boston Birth Cohort, n = 3114), our team identified that severe viral respiratory infections occurring during early infancy increase the risk of developing OSA in school-age years [5]. The longitudinal association between severe viral respiratory infection during the first two years of life and OSA diagnosis at 5 years of age was still present after adjusting by other OSA risk factors, including severe prematurity and maternal or childhood obesity (adjusted hazard ratio, 1.53; 95% CI, 1.15 to 2.05). Collectively, these results provide strong evidence that early life viral respiratory infections are an important risk factor for the development of OSA in the pediatric population.

An interesting finding of our study is that RSV bronchiolitis during infancy conferred two times higher odds of developing OSA by 5 years of age (odds ratio, 2.09; 95% CI, 1.12 to 3.88) [5]. The association between severe viral bronchiolitis and] subsequent OSA indicates that respiratory viruses may alter upper and lower airways in early life predisposing children to develop both respiratory conditions. In the upper airways, the nasopharyngeal space is the most common site of obstruction in children with OSA and it is also where respiratory viruses first replicate [1]. The mechanisms by which viruses may alter nasopharyngeal structure and function are still unclear. Nonetheless, there is evidence that in addition to causing nasopharyngeal edema and inflammation, RSV infections can trigger long-term alterations in airway hyperresponsiveness due to neuroinflammatory factors present in the upper and lower airways [6]. Since some children with severe virus-induced bronchiolitis develop increased bronchial responsiveness over time, it is possible that something similar occurs in the nasopharynx leading to upper airway hyperreactivity due to virus-induced dysregulation of neuroimmunomodulatory pathways [6].

Viruses may also promote enlargement of upper airway lymphoid tissue (tonsils and adenoids), which is critical to OSA pathogenesis in children. There is evidence that respiratory viruses are detected in OSA hypertrophic tonsils [7], suggesting the presence of virus-induced molecular factors driving local lymphoproliferation, inflammation, and remodeling. In this regard, we have previously reported that viral respiratory infections in children are associated with increased nasopharyngeal levels of miR-155 [8], a potent inducer of follicular T-helper and B-cell proliferation and differentiation. In addition, respiratory viruses also induce the secretion of nasopharyngeal pro-inflammatory cytokines and growth factors such as vascular endothelial growth factor (VEGF) [9], which may contribute to the enlargement of lymphoid tissues. Viruses can also play a role exacerbating upper airway inflammation in OSA, a consistent feature of this condition caused by snoring, recurrent upper airway collapse, and chronic soft-tissue damage. Prior studies have identified increased levels of airway proinflammatory cytokines (e.g. TNF-alpha, IL-6, and IL-1alpha) in adenoid and tonsillar tissues of children with OSA [10]. As respiratory viruses are known to induce proinflammatory cytokines in the upper airway of children [9], these findings suggest a mechanistic link between viral infections and worsening of the pro-inflammatory state in the nasopharynx of children with OSA. Collectively, all these factors may contribute to increasing nasopharyngeal resistance in the relatively narrow upper airways of young children, which could predispose to both, OSA and clinically relevant viral respiratory infections.

Along with the increasingly recognized role of viral infections, pathogenic microbiota in the upper airway has also be postulated as a contributing factor for OSA pathogenesis. A recent study by Sarmiento Varón et al. [11] demonstrated that the tonsils in children with OSA have a defective regulatory B cell compartment that is accompanied by tonsillar microbial populations dominated by Firmicutes (predominantly Streptococcus and Staphylococcus), Proteobacteria (mostly Neisseria and Hemophilus), Bacteroidetes (principally Prevotella), Actinobacteria and Fusobacterium [11]. Another study demonstrated significant differences in the local lymphocyte response and bacterial community composition in the tonsillar samples of OSA patients [12]. As the nasopharyngeal microbiome changes dramatically during viral infections in children [13], it is possible that recurrent and/or severe viral respiratory infections exacerbate the microbial and immune abnormalities of the nasopharyngeal tissue of children with OSA and that this may play a significant role in the pathogenesis of sleep-disordered breathing in the pediatric population.

It is also important to emphasize that the link between viral infections and OSA seems to be bidirectional. Sleep-disordered breathing is a critical risk factor for severe viral respiratory infections as recently reported during the COVID-19 pandemic [14]. Rögnvaldsson et al. identified that OSA was associated with two-fold increase in risk of severe SARS-CoV-2 infections, and the association was not explained by obesity or other comorbidities [14]. Several physiological and molecular mechanisms may underlie the contribution of OSA to poor outcomes during viral respiratory infections. Aside from upper airway obstruction, OSA can lead to sleep fragmentation and circadian dysregulation, both of which can alter antiviral immune responses [15]. The pro-inflammatory state of OSA may also contribute to worsening of airway inflammation and facilitate the inception of cytokine storms as reported in adult and pediatric SARS-CoV-2 cases with multi-organ failure.

In summary, there is compelling evidence that viral infections contribute to the development of nasopharyngeal obstruction and OSA pathogenesis in young children. OSA is also an important risk factor for severe viral respiratory infections. Much is unknown about this bidirectional relationship and in-depth investigation of how viral respiratory infections disrupt airway homeostasis and development in early childhood is required to understand the pathogenesis of pediatric OSA. An important clinical implication at this time is that pediatricians must always ask about snoring during and after severe viral respiratory illnesses in children. This simple intervention can have a dramatic impact on the early detection and treatment of OSA and thus improve the well-being and sleep quality of hundreds of thousands of children and families affected by this prevalent and serious condition.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This manuscript was supported by NIH Grants HL141237, HL159595, HL145669 (awarded to G. Nino) and Johns Hopkins School of Medicine Clinician Scientist and the American Academy of Asthma, Allergy and Immunology (AAAAI) Foundation Faculty Development Awards (awarded to M.J. Gutierrez). This paper was supported by funding from NIH grants (GN) HL141237, HL145669, and (MJG) HD104933 and the American Academy of Asthma, Allergy, and Immunology Foundation Faculty Development Award.