Respiratory comorbidities in severe asthma: focus on the pediatric age

ABSTRACT

Introduction

Asthma comorbidities are a frequent cause of adverse outcomes, such as poor asthma control, frequent asthma attacks, reduced quality of life, and higher healthcare costs. Comorbidities are well-known treatable traits whose proper management can help achieve optimal asthma control. Although multimorbidity is frequent among asthmatics, comorbidities are still a potential cause of misdiagnosis and under or over treatments, and little is known about their impact on severe pediatric asthma.

Areas covered

We provided a comprehensive, 5-year updated review focusing on the main respiratory comorbidities in severe asthma, particularly in epidemiology, pathogenesis, and current and future therapies.

Expert opinion

Respiratory comorbidities have unique characteristics in childhood. Their management must be multidisciplinary, age-specific, and integrated. Further longitudinal studies are needed to understand better the mutual interrelation and synergistic effect between asthma and its respiratory comorbidities, the identification of common, treatable risk factors leading to potential asthma prevention, the effectiveness of actual and future target-therapies, and the correlation between long-lasting respiratory comorbidities and poor lung function trajectories.

KEYWORDS:

• Asthma comorbidities
• breathing pattern disorders
• bronchiectasis
• inducible laryngeal obstructions
• obstructive sleep apnea
• pediatrics
• rhinitis
• rhinosinusitis
• severe asthma
• severe asthma with fungal sensitization

1. Defining severe asthma in pediatrics: from difficult-to-treat to severe therapy resistant asthma

Asthma is the most common chronic respiratory disease of childhood, affecting about 10–20% of children and adolescents worldwide [1,2]. Although most asthma cases are mild or moderate, severe asthma – accounting for barely 17% of asthmatic subjects of any age and <2% of asthmatic children – is a significant cause of mortality, morbidity, and relevant healthcare costs [3]. With the gradual increase of awareness and better understanding of disease complexity and heterogeneity, the definition of severe asthma has evolved over the years. Therefore, severe asthma is now considered as an umbrella term, including difficult-to-treat and severe therapy-resistant asthma (STRA) [4]. According to Global Initiative for Asthma (GINA) document, difficult-to-treat asthma is asthma that remains uncontrolled despite the use of medium or high doses of inhaled corticosteroids (ICS) plus long-acting β2 agonists (LABA) or which requires such treatments to preserve symptom control[3]. This aspect mostly depends on concomitant modifiable factors (the so-called treatable traits) whose effective management may lead to optimal asthma control [5]. The ‘treatable traits’ include many features of asthma management, such as misdiagnosis, incorrect therapeutic prescription, wrong inhaler technique, poor adherence to treatments, outdoor and indoor exposure to allergens or pollutants, psychological or socio-cultural disadvantage, and, significantly, comorbidities [6–8]. Significantly, before looking for treatable traits, all alternative diagnosis mimicking asthma symptoms but requiring therapies different from asthma ones (such as immunodeficiencies, cystic fibrosis, vascular rings, inhaled foreign bodies, bronchopulmonary dysplasia, congenital respiratory malformations, primary ciliary dyskinesia, etc) must be ruled out [3].

Conversely, only 5% of severe asthmatics have real STRA, defined as asthma that remains uncontrolled despite good adherence to maximal anti-asthmatic therapies and adequate efforts to address any treatable traits (or asthma which worsens as soon as high-dose treatments are stepped down) [9]. The failure of conventional asthma therapies in some patients has led to the attempt to sub-classify asthma into specific ‘phenotypes’ (a set of observable characteristics derived from the interaction between genotype and environment) and ‘endotypes’ (a set of molecular and functional pathways underlying different pathogenetic mechanisms) [10]. This topic represents an extensively discussed field of research whose description goes beyond the scope of this review [10]. Notably, the molecular and inflammatory characteristics of STRA are still a matter of debate in children and adolescents.

For this reason, asthma comorbidities have been extensively studied over the years in search of epidemiological links and shared pathogenetic pathways as potential therapeutic targets. Respiratory comorbidities are particularly relevant due to their anatomical and functional continuity with the bronchi. This review aims to provide a comprehensive and updated focus on the main respiratory comorbidities of difficult-to-treat asthma, especially in the pediatric age. First, our literature research was conducted on the MEDLINE database (PubMed) and limited to English-written, full-text articles, and reviews published in the last five years. ‘Severe asthma’ or ‘difficult to treat asthma’ and ‘comorbidities’ were used as main keywords. Secondly, we paired ‘severe asthma’ or ‘difficult to treat asthma’ with specific terms regarding any respiratory comorbidity (such as ‘bronchiectasis’, ‘obstructive sleep apnea’, etc.). Then, we filtered results by age (< 18 years) to keep a pediatric focus. For the same reason, chronic obstructive pulmonary disease was excluded from our research. Finally, we completed our study by including a few other significant papers derived from the reference lists of the articles we found, together with the latest version of relevant documents regarding asthma comorbidities, such as the GINA main report [3] and the European Respiratory Society (ERS) guidelines for bronchiectasis management [11].

1.1. Comorbidities in difficult-to-treat asthma: what’s the matter?

Comorbidities are ‘one or more diseases or disorders occurring concurrently with a primary disease or disorder’ [12]. They are frequent in asthma at all ages, especially in the case of severe asthma. Both pediatric and adult subjects with difficult-to-treat asthma often suffer from concomitant multi-comorbidities, which worsen asthma control and quality of life (QoL), increasing the risk of asthma attacks, hospital admissions, and emergency department visits [13–17]. Since some comorbidities may present with asthma-mimicking symptoms, this could lead to misdiagnosis and subsequent side effects of unnecessary therapies (such as growth issues, osteoporosis, or adrenal suppression in the case of chronic oral steroids or high-dose ICS over-use [12,13,18]. At the same time, the physician’s and pediatrician’s potential unfamiliarity with some less frequent comorbidities – still deeply under-diagnosed – could hinder the access to appropriate add-on therapies, thus preventing optimal asthma control. A recent, cross-sectional, adult-limited study proved that comorbidities might affect more than 60% of asthmatic adults: significantly, about 15% of them may have up to 4 comorbidities simultaneously [19]. Regarding the pediatric population, a newly published, monocentric, cross-sectional Italian study detected comorbidities in up to 87% of the 508 asthmatic children (aged 5 to 17 years). Mainly, respiratory comorbidities alone affected 37% of them, whereas joined respiratory and non-respiratory comorbidities were found in another 40% [16].

Beyond the mere epidemiological correlation, evidence of potential shared pathogenetic pathways between asthma and some comorbidities has recently emerged [12]. This topic is a fascinating, still not a well-known field of research, which raises questions on how comorbidities can affect specific asthma phenotypes and vice versa in a mutual pathogenetic interplay.

Asthma comorbidities are traditionally classified as respiratory and extra-respiratory diseases, which may be either allergic or nonallergic [13–15]. In addition, respiratory comorbidities may be further sub-classified depending on their involvement in upper or middle-to-lower airways. Interestingly, respiratory and extra-respiratory comorbidities often coexist in asthmatic subjects, further complicating diagnosis and management [13–15].

Table 1 summarizes the main respiratory comorbidities of asthma, including specific clinical symptoms and signs, pathogenetic mechanisms, helpful screening tools, and current or future promising therapies, as discussed in the following sections.

Table 1. Main respiratory comorbidities of asthma, including clinical symptoms, pathogenetic mechanisms, screening tools and current/promising therapies.

DISEASE	SYMPTOMS AND SIGNS		PATHOGENESIS	SCREENING TOOLS	CURRENT / FUTURE THERAPIES
UPPER AIRWAYS
AR	Nasal itch and congestion Sneezing Rhinorrhea Post-nasal drip		IgE-mediated type 2 inflammation	SNQ CARAT CARATkids	Trigger avoidance nasal rinses topic or systemic H1-antihistamines INCS
NAR Infectious Non infectious			Eosinophilic, neutrophilic and/or mast-cell nasal infiltrates		AIT Anti-IgE Anti-IL4 and IL-13 Anti-TSLP, anti-IL25 and anti-IL33
CRS CRSwNP CRSsNP	Nasal obstruction Nasal discharge Facial pain Facial pressure Smell loss Cough		Eosinophils, ILC2, TH2, mast-cells, basophils Neutrophils, IL6, IL8, IL17, TNFα	SNOT-22 SNQ EP30S	NSAIDs Endoscopic sinus surgery Anti-IgE Anti-IL5/IL-5Rα Anti-IL4 and IL-13 Anti-ILC2 and anti-TSLP
OSA	Attention deficit Behavioral alterations Daily sleepiness Gasping Nighttime sweating Enuresis Snoring Nocturnal dyspnea		Vagal hypertone T-cell infiltration IL-6 TFNα CRP	PSQ Berlin Questionnaire STOP-Bang questionnaire	cPAP Weight loss Positional therapy Maxillofacial expanders ICS Anti-leukotrienes
ILO	Stridor Syncope Throat tightness Dry cough Glottic wheeze		Abnormal glottic abduction or supraglottic narrowing in response to harmless stimuli Abnormal glottic abduction during exercise	VCDQ PVCDI PVFMD-SQ	Breathing exercises CPAP Intubation Heliox Speech therapy
EILO	Dyspnea during exercise				Botulin injections Psychotherapy Supraglottoplasty Inhaled anticholinergics
MIDDLE-TO-LOWER AIRWAYS
BREATHING PATTERN DISORDERS	Disproportioned dyspnea at rest Breathlessness Frequent yawning Frequent sighing Chest tightness Short expiratory breath-holding times	Stress-induced vagal hypertone Hypocapnia Increased individual sensitivity to airway caliber changes		Nijmegen Questionnaire BPAT Structured light plethysmography	Patient reassurance Breathing techniques Lotorp method Cognitive behavioral therapy Mindfulness techniques
FUNGALDISEASES AFRS SAFS CFB CFB/SAFS ABPM ABPA	Recurrent wheezing Productive cough Hemoptysis Low-grade fever Weight loss Malaise Black mucus plugs	Fungal hypersensitivity Airways colonization Epithelial damage Type-2 inflammation Oxidative stress		None	Long-term OCS Anti-fungal (controversial) Macrolides Anti-IgE Anti-IL33 ST2-antagonists Anti-endothelin-1R anti-IL17Rα
BE	Productive cough Mucopurulent sputum RLRI Dyspnea Wheezing	Chronic neutrophilic and/or eosinophilic inflammation Impaired mucociliary clearance Increased mucus production Airways remodeling		Bronchiectasis severity index Longitudinal HRCT	Inhaled hyperosmolar agents Airway clearance techniques Pulmonary rehabilitation Long-term macrolides

ABPA: allergic bronchopulmonary aspergillosis; ABPM: allergic bronchopulmonary mycosis; AFRS: allergic fungal rhinosinusitis; Anti-endothelin-1R: anti-endothelin-1-receptor; AIT: allergic immunotherapy; AR: allergic rhinitis; BE: bronchiectasis; BPAT: Breathing Pattern Assessment Tool; CARAT: Control Allergic Rhinitis and Asthma Test; CARATkids: Control Allergic Rhinitis and Asthma Test in children; CFB: chronic fungal bronchitis; cPAP: Continuous Positive Airway Pressure; CRP: C-reactive protein; CRS: chronic rhinosinusitis; CRSsNP: chronic rhinosinusitis without nasal polyposis; CRSwNP: chronic rhinosinusitis with nasal polyposis; EILO: exercise induced laryngeal obstruction; EP30S: European Position Paper on Rhinitis and Nasal Polyposis Questionnaire; HRCT: high resolution computer tomography; ICS: inhaled corticosteroids; IgE: immunoglobulin E; IL: interleukin; anti-IL17Rα: interleukin-17 receptor alpha; ILO: inducible laryngeal obstruction; INCS: intranasal corticosteroids; NAR: nonallergic rhinitis; NSAIDs: non-steroidal anti-inflammatory drugs; OCS: oral corticosteroids; OSA: obstructive sleep apnea; PSQ: Pediatric Sleep Questionnaire; PVCDI: Pittsburgh Vocal Cord Disfunction Index; PVFMD-SQ: Paradoxical Vocal Fold Movement Disorder Screening Questionnaire; RLRI: recurrent lower respiratory infections; SAFS: severe asthma with fungal sensitization; SNQ: sinonasal questionnaire; SNOT-22: sinonasal outcome-test-22; STOP-Bang: snoring, tiredness, observed apnea, high BP, BMI, age, neck circumference, and male gender; TH2: T helper 2 cells; TNFα: tumor necrosis factor alpha; TSLP: thymic stromal lymphopoietin; VCDQ: vocal cord dysfunction questionnaire

2. Upper airways comorbidities

2.1. Allergic and nonallergic rhinitis

Rhinitis is an inflammatory disease of the nasal mucosa in response to different stimuli, leading to nasal congestion, rhinorrhea, nasal itch, post-nasal drip, and sneezing [20]. Additional symptoms include mouth breathing, frequent throat clearing and nose rubbing [21]. Rhinitis is a widespread condition, and it is highly recurrent among asthmatic subjects, although still partially underdiagnosed and, consequently, undertreated. The etiological classification of rhinitis includes nonallergic rhinitis (NAR), whose triggers are represented by infective agents, drugs, cold, irritants, and hormones, and allergic rhinitis (AR), an IgE-mediated disease secondary to exposure to specific aeroallergens [21]. AR can be further classified according to symptoms, persistence, and disease severity. AR can be mild or moderate-to-severe according to the absence or presence of nighttime or troublesome symptoms limiting daily activities [20] and intermittent or persistent no matter the severity, depending on whether the symptoms last less than or more than four days a week or four weeks a year, respectively [22].

Being mostly underdiagnosed or misdiagnosed, the role of NAR among asthmatics is poorly understood. It seems to regard about 15% of adults [21], although its prevalence could be even higher [23], and it is mainly described as idiopathic or vasomotor [24,25]. According to the prevailing cells of the inflammatory infiltrate, it can be classified into nonallergic rhinitis with eosinophils (NARES), NAR with neutrophils (NARNE), and NAR with mast-cells (NARMA), and NAR with eosinophils and mast-cells (NARESMA). Interestingly, a retrospective Italian study focusing on pediatric age proved a higher prevalence of NARES and NARNE among children and adolescents, with children suffering from NARES being more predisposed to asthma and respiratory sleep disorders [24]. This aspect underlines the importance of adequately assessing NAR, too, in the management of pediatric asthma.

The association between AR and asthma is well-known. AR has a prevalence of 40% among adults and up to 65% in severe asthmatic adults [21]. Among asthmatic children, AR prevalence is even more relevant. Indeed, an Italian multicentric task force coordinated by the Italian Society of Pediatric Allergy and Immunology focusing on uncontrolled pediatric asthma (the ControL’asma project) proved that 90% of the 465 children and adolescents enrolled suffered from concomitant AR, mainly resistant to standard therapies [26,27].

Since the early 2000s, it has been proved that the strong association between AR and asthma lies in a typical pathogenetic process. Allergic and nonallergic affection of upper airways can influence lower airways and vice versa, a theory named ‘united airway disease’ [28–30]. This mutual influence depends not only on anatomical continuity but also on many different functional connections, such as lower airways’ hyperreactivity secondary to post-nasal drip; broncho-constriction induced by vagal-mediated nasal-bronchial reflexes; loss of nasal filter function, with lower airways exposure to colder, un-purified, dry air; and mouth breathing, with higher allergen load in the lower airways [13,30]. A pro-inflammatory role for regulatory T cells (Treg) dysfunction and type 2 innate lymphoid cells (ILC2) in both asthma and AR has become increasingly evident over the years [13]. ILC2 cells have been identified as critical cellular actors in the promotion of eosinophilic nonallergic response since they induce the release of type-2 cytokines as a response to ‘alarmins’ release (such as thymic stromal lymphopoietin (TSLP), interleukin (IL)-25 and IL-33) by the damaged airway epithelium [31]. The result is the induction of a two-step allergic response, with an early phase characterized by nasal itching, sneezing, and rhinorrhea secondary to histamine release and a late phase depending on IL-4 and IL-5 release by eosinophils and TCD4+ lymphocytes, leading to nasal congestion and increased rhinorrhea [30].

As comorbidity, AR leads to poorer asthma control and QoL, frequent asthma attacks, accelerated lung function decline, nocturnal symptoms worsening, and increased missing days at school [12,32]. Furthermore, AR severity is strictly linked to asthma severity in Pediatrics [12,32], and it is considered a contributing cause to the development of severe asthma. Since severe asthma among children is mostly eosinophilic and allergic, pediatric STRA and AR are considered two distinct but mutually influencing manifestations of the same eosinophilic inflammation in response to common aeroallergens [13].

Useful questionnaires such as the sinonasal questionnaire (SNQ) allow quick identification of AR symptoms [12]. In the presence of high SNQ scores, it is essential to perform skin prick test or serum total and specific-IgE dosage to identify and avoid allergens in all the children’s environments (id est, school, home, or gym). Nasal cytology must be performed in agreement with ENT specialists to rule out NAR. Given the high prevalence of asthma in subjects with AR, respiratory function tests are recommended even without specific symptoms of bronchial disease [30]. This aspect may allow evaluating early signs of lower airway involvement, such as alteration of forced expiratory flow between 25% and 75% (FEF_25-75%) [33]. Finally, being frequently the comorbidities, the use of specific questionnaires contemporary assessing both AR and allergic asthma, such as the Control Allergic Rhinitis and Asthma Test (CARAT) and its pediatric version CARATkids, can be beneficial [34].

Over the years, evidence has shown that rhinitis treatment improves asthma outcomes. First-line therapies include allergens and irritants avoidance, saline nasal irrigation and topic or systemic H1-antihistamine drugs, which can be coupled to intranasal corticosteroids (INCS) in the case of moderate-to-severe rhinitis [22,32]. Anti-leukotrienes can be considered an add-on therapy any time that conventional drugs are ineffective or poorly tolerated, having the advantage of treating both the upper and lower airways simultaneously. Conversely, oral corticosteroids (OCS) are limited to selected, refractory cases [20]. Leading to a long-lasting immunological and clinical tolerance towards aero-allergens, allergen immunotherapy (AIT) is nowadays the only etiologic therapy for AR and well or partially controlled asthma when other therapies are ineffective, as ‘add-on therapy’, reducing symptoms and drugs use. This treatment consists of the repeated administration of allergen extracts via subcutaneous (SCIT) or sublingual route (SLIT), which can improve both rhinitis symptoms and asthma symptoms [35]. AIT is contraindicated in subjects with poorly controlled asthma. There are still issues regarding its long-term benefits after treatment discontinuation or its potential use as a preventive therapy for allergic asthma. Some authors documented that grass pollen AIT in children with seasonal allergic rhinitis can prevent asthma symptoms, but further studies are required to demonstrate the efficacy of immunotherapy to other allergens such as house dust mites in preventing asthma [36]. It has been documented that a three-year course of SCIT significantly reduced the occurrence of asthma in children with rhinitis caused by grass and/or birch pollen after 3 and 10 years. In a large retrospective real-life study, Zielen showed for the tablet formulation in patients >5 years of age that the relative risk reduction of asthma occurrence was around 30% during the treatment and around 40% during the follow-up. However the heterogeneity of the studies is a major problem in drawing a firm conclusion about whether AIT treatment is effective in preventing asthma [37,38].

Finally, biologic therapies (i.e. human monoclonal antibodies targeting specific molecules) are a particularly promising treatment for children with AR and concomitant difficult-to-treat-asthma. In clinical trials, omalizumab (an anti – IgE) and dupilumab (an anti IL-4/IL-13) have shown the best results in managing pediatric AR and concomitant severe asthma [39]. Moreover, omalizumab could reduce side effects and promote immune tolerance if pre-administered or co-administered with AIT in children with moderate-to-severe AR. Finally, considering the role of epithelial alarmins in inducing nonallergic eosinophilic inflammation of both upper and lower airways, anti-TSLP, anti-IL25 and anti-IL33 may be future promising therapies in the field [39].

2.2. Chronic rhinosinusitis and asthma

Chronic rhinosinusitis (CRS) is an inflammatory disease of the nose and the paranasal sinuses, lasting at least 12 weeks without complete clinical resolution or recurring more than four times/year with an asymptomatic interval of at least ten days [40]. It is characterized by nasal discharge or congestion associated with facial pain or pressure and/or cough. CRS accounts for two distinct phenotypes, which can be both allergic or nonallergic: CRS with nasal polyposis (CRSwNP) and CRS without nasal polyposis (CRSsNP) [13,40,41]. Both significantly impact asthma prognosis, leading to lower asthma control, poorer QoL, and a higher risk of asthma attacks [13,14,17]. CRS globally affects about 40–50% of adult subjects with difficult-to-treat-asthma [12]. CRSwNP is particularly common among subjects with late-onset eosinophilic asthma, mainly adults and adolescents, whereas it is much rarer among children. CRSwNP is a troublesome disease that poorly responds to standard conservative therapies and often requires periodic surgical revisions [41].

Conventionally, CRSwNP is considered a ‘type-2 high’ inflammatory disease and CRSsNP a ‘type-2 low’ one, although CRS endotypes have proved poor longitudinal stability [42]. Dawei et al. recently proposed a new, cluster-analysis-derived classification specifically addressing CRSwNP with comorbid asthma [43]. They identified three distinct clinical phenotypes with a particular demographic, clinic, and inflammatory features: a form of child-onset, atopic CRS, with less severity, less disease duration, better lung function, and eosinophilic inflammation; a less atopic, adult-onset CRS with evidence of non-eosinophilic inflammation; and finally, a more severe form of adult-onset CRS in smokers, with prevalent non-atopic, eosinophilic inflammation, worse lung function and computed tomographic (CT) alterations often needing surgical therapy. This final phenotype shows a poor response to steroid therapy, according to the evidence that smoking is a well-known cause of persistent, steroid-refractory nasal polyposis [43–45]. However, it seems to have a promising, good response to non-steroidal anti-inflammatory drugs (NSAIDs). Further studies are needed to understand if such a classification can lead to personalized therapies improving asthma and CRS control and its feasibility among asthmatic adolescents.

CRSwNP has been long considered an asthma precursor in adults, making the identification and appropriate management of nasal polyposis a critical issue for asthma prevention. Recently, some authors tried to identify risk factors for CRSwNP to evolve in bronchial asthma, highlighting the importance of higher sputum IL-5 and IL-9 levels, the presence of aspirin hypersensitivity reactions, or the identification of specific IgE against S. aureus enterotoxin [43]. This evidence could lead in the future to new endotype-driven, preventive treatments.

It has recently been proved that CRSwNP can follow asthma development, too [46]. As seen for AR, there is a strict link between asthma and CRSwNP, sharing common genetic, anatomical, molecular, and immunological characteristics in the context of the united airway disease [47]. Among all, immunity system commitment seems a critical issue: as a matter of fact, the role of bone marrow CD34+ hematopoietic cells’ early commitment towards a type-2 response has been called into question, with secondary migration of differentiated cells to the sinuses and the bronchi, the final sites of inflammation [30]. Furthermore, asthma led to amplification of the inflammatory response in CRS subjects, with higher sinus TNFα levels and higher identification of inflammatory markers in adenoids, such as epithelial grow factors (EGF), eotaxin, fibroblast growing factor 2 (FGF2), and platelet-derived growth factor subunit A (PDGFA) [30]. Furthermore, the finding of ILC2 cells in sinus mucosa and their association with systemic and bronchial eosinophils further strengthened the evidence of common, shared pathogenesis between the two diseases [48,49]. Finally, alterations in mucociliary clearance, superimposed infections, and upper airways remodeling are considered critical, too [21]. Once considered the outcome of chronic, long-lasting inflammation, airway remodeling is recognized as an early event in the pathogenesis of asthma depending on lower epithelial cell dysfunctions [31]. In the upper airways, damaged epithelial cells act similarly, releasing IL-13, transforming growth factor beta (TGFβ), vascular endothelial growth factor (VEGF), and matrix metalloproteinases, converting undifferentiated mesenchymal cells into fibroblasts. This mechanism leads to globet cell hyperplasia, subepithelial edema, basal membrane thickening (which have proven to be associated with higher blood and sputum eosinophils), collagen deposition, and fibrosis [49]. Upper airway remodeling could also occur in neutrophilic CRSsNP, depending on T helper (TH) 17 and ILC3 releasing IL-17A, with IL-8 increasing levels and higher fibroblasts proliferation [40].

Proper CRS diagnosis requires collaboration with ENT specialists in the search for endoscopic (nasal polyposis, middle meatus disease) and CT alterations (sinus or osteo-meatal complex mucosal changes) [21,30,40]. Validated screening tools may be used in all cases of CRS-comorbid-asthma, such as the sinonasal outcome-test-22 (SNOT-22), the SNQ, or the European Position Paper on Rhinitis and Nasal Polyposis Questionnaire (EP30S) [12,40]. Since CRS seem to be frequently associated with vocal fold motion dysfunction (VFMD) [13], we suggest ruling out this condition in any case of CRS with asthma-mimicking symptoms.

First-line therapies for CRS include local nasal rinses and INCS, which are particularly effective in the case of CRSsNP [40]; however, the effect of those therapies on asthma outcomes is still controversial [50]. OCS are recommended only for short therapeutic cycles, immediately before or after endoscopic surgery [51]. Contrarywise this, CRSwNP therapy is primarily surgical, with endoscopic treatment followed by topic corticosteroids to prevent NP recurrence, which is exceptionally high. The earlier the endoscopic treatment is performed, the greater the prevention of inflammatory spread in the lower airways [52]. In the case of non-eosinophilic forms of CRS, long-lasting low-dose macrolides may be proposed, although this is supported by few studies [53]. Finally, refractory CRSwNP with concomitant severe asthma may be managed with biologic treatments [54]. In adults with refractory CRSwNP, dupilumab leads to better outcomes in terms of QoL, nasal polyp score, mean daily nasal congestion score, and SNOT-22 [55]. Studies are promising for mepolizumab (anti-IL5) and ongoing for benralizumab (anti-IL5R) and omalizumab [56].

Surprisingly, in some patients with CRSwNP-comorbid-asthma biologic treatments have proven helpful in asthma management, with less benefit in assessing CRSwNP: this may depend on an unequal severity of the two concomitant diseases, individual or local pharmacokinetic differences, or different coexisting inflammatory pathways [49]. The proper study of these and other factors influencing treatment response may lead to a better patient selection or different administration schedules in the future [57].

2.3. NSAIDs-exacerbated respiratory disease

Aspirin Exacerbated Respiratory Disease (AERD), or NSAIDs-exacerbated respiratory disease, is a subtype of CRSwNP-comorbid-asthma. The disease usually presents in the third decade with CRS, followed some years later by late-onset, non-atopic, eosinophilic, difficult-to-treat asthma and, finally, by recurrent nasal polyposis and hypersensitivity reactions to aspirin and other NSAIDs [58]. AERD affects 5–10% of subjects with CRS, 15–40% of subjects with NP, and 7% with asthma [30]. AERD is believed to be exceptionally rare in the pediatric age due to the reduced use of aspirin among children to avoid the so-called Reye syndrome. However, using other NSAIDs such as ibuprofen in predisposed adolescents may lead to upper and lower airway symptoms, with frequent asthma attacks and overuse of OCS [58]. The key feature of such disease consists of dysregulation of cyclooxygenase (COX) and 5-lipoxygenases activity, with greater production of pro-inflammatory, bronchoconstrictive cysteinyl-leukotrienes and prostaglandin D2 (PGD2) and concomitant reduction of anti-inflammatory prostaglandin E2 (PGE2) [30]. This mechanism finally led to persistent, refractory eosinophilic inflammation on the upper and lower airways. Therefore, in addition to NSAIDs avoidance (with the alternative use of selective COX-2 inhibitors or acetaminophen), antileukotrienes or 5-lipoxygenase inhibitors are the preferred therapeutic options [58]. Currently, NSAIDs desensitization is the only etiologic therapy available, improving both upper and lower airway symptoms [59]. Finally, even in AERD, biological drugs seem promising and well-tolerated, although further studies are needed [55].

2.4. Obstructive sleep apnea

Obstructive sleep apnea (OSA) is a form of transient and recurrent mechanical obstruction of the upper airways occurring during sleep, with pharyngeal collapse leading to episodic nocturnal apnea or hypopnea, sudden arousal, and sleep fragmentation [60]. OSA is the most frequent sleep-related breathing disorder, especially in childhood, as it can affect about 6% of children and adolescents and up to 30% of pediatric asthmatics [60,61]. This prevalence could be even greater among pediatric subjects with difficult-to-treat asthma, considering that polysomnographic studies among severe asthmatic adults have shown a prevalence of up to 90% [61]. Since OSA may lead to serious, preventable long-term consequences, such as cardiovascular diseases, metabolic dysfunctions, or cognitive-behavioral sequelae, its early detection and proper treatment are particularly critical, especially in the pediatric age [61]. OSA symptoms may be daily and nocturnal, with some unique pediatric features. Daily sleepiness is rare in children, whereas attention deficit and behavioral alterations are the leading daily symptoms. As regards pediatric nocturnal symptoms, gasping, nocturnal dyspnea, nighttime sweating, enuresis, or chest-abdomen paradoxical movements are far more prevalent than snoring [60]. Furthermore, children may show a high-arched palate, microretrognathia, midface hypoplasia, and a prevalence of mouth breathing [15].

As stated before, OSA is a common asthma comorbidity, although the causal relationship between the two diseases is still poorly understood. OSA’s typical alternation of hyper and hypoxia is thought to increase bronchial oxidative stress. Furthermore, upper airway collapse is known to induce hyper vagal tone – which can be responsible for bronchial hyperreactivity – and mucosal T-cells infiltration, finally leading to lower airways’ neutrophilic inflammation [12,15]. Finally, OSA is associated with systemic inflammation, too, as proved by higher blood levels of IL-6, TFNα, and C-reactive protein no matter the body mass index [62,63].

The relationship between OSA and asthma (especially nighttime, difficult-to-treat asthma) is mutual: nocturnal asthma may lead to hypoxia, worsening OSA severity. Moreover, lower airways inflammation and asthma treatment with ICS may lead to structural alterations of upper airways, with altered pharyngeal patency [61,64]. Different asthma comorbidities may alter pharyngeal collapsibility, too. OSA is frequently associated with AR, NAR, and gastroesophageal reflux disease (GERD), whose overlapping symptoms could sometimes lead to OSA and/or asthma misdiagnosis [65]. Specific biomarkers, such as neutrophil to lymphocyte ratio, have been suggested as discriminating factors for OSA diagnosis [62].

Regardless of its association with other asthma comorbidities, OSA is responsible for worse asthma nocturnal symptoms, poorer asthma control, higher recurrence of asthma attacks, worse QoL, and poor school performance [60].

OSA diagnosis requires polysomnography, performed by referred specialists in specific clinics, and an endoscopic evaluation by ENT colleagues. Because asthmatic subjects have an increased risk of developing OSA, we suggest considering polysomnography in all asthmatic children having poor nighttime symptom control despite standard therapies. In addition, specific questionnaires – such as the Berlin questionnaire, the Pediatric Sleep Questionnaire (PSQ), or the STOP-bang questionnaire – can be used as quickly, feasible and easy-to-use tools to identify subjects who may suffer from OSA alone or OSA-concomitant-asthma [66,67]. Notably, the Berlin questionnaire has been proven helpful in identifying asthmatic subjects at increased risk of developing OSA [17], whereas PSQ has been validated for pediatric asthma, too [68]. In addition, such tools are also helpful in the early identification of pediatric neuro-behavioral morbidity [60].

Continuous Positive Airway Pressure (CPAP) is the leading therapy for OSA in children and adults. CPAP seems to be beneficial for concomitant asthma, too: in fact, it leads to better asthma control in the long run [12], improving lung function and QoL [60], and lower levels of inflammatory and oxidative markers in exhaled breath condensate, such as 8-isoprostane or IL-6 [69]. In the case of moderate-to-severe OSA, adenotonsillectomy is the preferred therapy. Weight loss, positional therapy, and maxillofacial expanders can be used as additional therapies [61].

Whether OSA-comorbid-asthma is a specific phenotype of pediatric difficult-to-treat asthma is still a matter of debate: ICS or antileukotrienes may be proposed as add-on therapies in subjects suffering from asthma and OSA [12].

2.5. Inducible laryngeal obstructions

Inducible laryngeal obstructions (ILO) are a group of laryngeal dysfunctions leading to hyperresponsiveness to different environmental stimuli in the upper airways. Since both glottic and extra-glottic dysfunctions can occur, ILO is the preferred terminology, replacing the more limiting definition of ‘paradoxical vocal fold motion disorders’ [70].

ILO is one of the commonest yet less known asthma comorbidities. Since they present a considerable symptom overlap with asthma, they have the most significant risk of asthma misdiagnosis and side effects due to unnecessary treatments [71]. Depending on the population’s size and characteristics, ILO has a prevalence of 20–50% among adults with difficult-to-treat asthma [13]. Their Incidence in pediatric difficult-to-treat asthma is still unknown, although they seem more prevalent among adolescent girls. Exercise-inducible laryngeal obstructions (EILO) are a specific, particularly frequent subtype of ILO, which are commonly misdiagnosed as exercise-induced asthma (EIA) [72]. A study conducted on a pediatric secondary care respiratory service identified EILO in 25% of the subjects who were previously thought to have EIA [73].

Upper airway narrowing is a physiological, neuro-mediated process protecting lower airways from harmful stimuli. In ILO, such physiological response develops aberrantly, leading to an involuntary abnormal glottic abduction or supra-glottic narrowing after exposure to harmless stimuli – such as perfumes, cold air, physical exercise, post-nasal drip, GERD, upper airway viruses, or, sometimes, allergens [70,74]. This laryngeal narrowing occurs during the inspiratory phase of breathing, leading to a variable degree of reversible, extra-thoracic obstruction. In addition, anxiety, and psychological issues are frequent findings among subjects with ILO and must be ruled out correctly [75].

Although mainly considered a mimicking disease rather than a feature of a specific asthma sub-phenotype, ILO may profoundly impact asthma control, symptoms, and QoL, leading to impaired exercise tolerance [71].

Diagnosis of ILO must be suspected in the presence of increasing breathing difficulties with prolonged inspiration, and every time asthma or exercise-induced asthma poorly responds to anti-asthmatic relievers [70]. Stridor, dry barking cough, and throat tightness are typical symptoms of ILO at all ages [74,76,77]. As observed in EIA, dyspnea occurs during exercise, not after exercise. The characteristic glottic wheeze, mostly detectable at anterior neck auscultation, could be transmitted to lower lung fields, further complicating the differential diagnosis with asthma [74,77]. Specific questionnaires, such as the Pittsburgh Vocal Cord Dysfunction Index (PVCDI), have been proposed for differential diagnosis, but they still need pediatric validation [78]. Other questionnaires, such as the Vocal Cord Dysfunction Questionnaire (VCDQ) or the Paradoxical Vocal Fold Movement Disorder Screening Questionnaire (PVFMD-SQ), proved low diagnostic sensitivity and specificity [79].

Since laryngoscopy may be inconclusive at rest, the diagnostic gold standard for ILO is direct endoscopic visualization of abnormal glottic or supraglottic response during a controlled exposure to specific irritants [80]. Dynamic CT is an emerging, less invasive alternative test [12]. Anyway, standardization is lacking in both techniques, especially in Pediatrics [74]. Spirometry is not a diagnostic test for ILO, as it is often negative in well-being subjects. Nevertheless, it can be particularly informative in the symptomatic phase, showing a typical attenuation of the inspiratory flow and a blunting of the expiratory curve [12].

Breathing exercises are the preferred therapy in the acute phase, with the final aim to open the glottis [75]. CPAP, endotracheal intubation, or Heliox, a mixture of helium and oxygen, are rare emergency therapy in highly severe cases [77]. Speech therapy is the first-line choice for chronic management; further therapeutic options include botulin injection of vocal folds, psychotherapy, or laser supraglottoplasty in selected cases [70,81]. Recently, a role for inhaled anticholinergic agents has been proposed in children with EILO, but further studies are needed.

3. Middle and lower airways comorbidities

3.1. Breathing pattern disorders

Dysfunctional breathing (DB) or breathing pattern disorders are a group of intermittent, chronic breathing alterations in which abnormal diaphragm and intercostal muscle activity lead to ineffective breath [70]. Their prevalence is estimated at 40% among severe asthmatic adults – mostly with late-onset, non-eosinophilic asthma – and 25% among asthmatic adolescents, although underdiagnosis and misdiagnosis are frequent [12,82].

DB includes many conditions such as hyperventilation, periodic deep sighing, thoraco-abdominal asynchrony, thoracic-prevalent breathing, or forced abdominal expiration, which could lead to hypocapnia and emotional distress [70,83,84]. Dyspnea at rest, breathlessness, frequent yawning and sighing, and chest tightness are the main reported symptoms, together with general malaise, fatigue, and abdominal bloating [13,15,83–85]. Obesity, anxiety, depression, and panic disorders are common additional findings [81–85]. Typically, DB symptoms start suddenly without other apparent causes and are disproportionate to objective findings, with very short expiratory breath-holding times [76,83,85].

Hypocapnia and emotional stress are the main pathogenetic mechanisms leading to bronchial hyperreactivity [15,70,83]. Furthermore, increased individual sensitivity to bronchial caliber changes, with exaggerated hyperventilation response to increased airway resistance, may explain the frequent association of DB and asthma [85]. DB worsen asthmatic QoL, increasing symptom perception and limiting everyday activities [15,70,83]. Diagnosis requires subjective tools such as the Nijmegen Questionnaire, focusing on hyperventilation self-perception, and more objective tools such as the Breathing Pattern Assessment Tool (BPAT), intended for doctors after at least one minute of clinical observation of the patient’s breathing [70,86]. Objective tools for DB are lacking, but their development is particularly challenging since such devices may make patients acutely aware of their breathing patterns, affecting the result. In this regard, new technologies such as structured light plethysmography might help to identify better breathing patterns in the future [87]. DB management is non-pharmacologic, with breathing exercise as the preferred chronic treatment [70]. Thoracic mobilization with the Lotorp method, cognitive behavioral therapy, and mindfulness techniques may be proposed as add-on therapies [12,70]. However, patients’ reassurance is mandatory, as is a clear explanation of the functional nature of the disease.

3.2. Asthma and fungal respiratory diseases

The relationship between asthma and fungi is among the most controversial and discussed. Fungal exposure is ubiquitous in many different environments, such as homes, schools, or barns. Moreover, fungal sensitization seems relatively widespread [88], especially in polysensitized pediatric subjects with difficult-to-treat-asthma: as a matter of fact, a cross-sectional study by Vicencio et al. proved that, on a sample of 68 moderate-to-severe asthmatic subjects aged from 2 to 20 years, almost 40% of them had sensitization to at least one fungus [89]. Nevertheless, specific guidelines are still lacking for the pediatric age, and validated pediatric definitions and classifications are missing. Therefore, most of the diagnostic and therapeutic approach is dangerously derived from evidence in adults, not considering children’s uniqueness. In this regard, Bush et al. reviewed the main peculiarities of fungal respiratory comorbidities in asthmatic children, globally defined as ‘fungal asthma’ [90]. This umbrella term included three different fungal-related asthma comorbidities with distinct pathogenetic mechanisms: severe asthma with fungal sensitization (SAFS), depending on hypersensitivity to fungal aeroallergens; chronic fungal bronchitis (CFB), in which bronchial epithelium damage occurs, secondary to fungal proteases; and a mixed form, characterized by bronchial tissue damage finally leading to eosinophilic inflammation and increased aeroallergen exposure and sensitization [90].

Fungal colonization may evolve in CFB depending on complex host-fungus interactions (such as virulence, invasiveness, or immunocompetence) [88]. Since local immunodepression secondary to ICS is critical, their use must be limited by proper asthma diagnosis and staging.

SAFS is a form of uncontrolled, exacerbation-prone STRA with sensitization to one or more fungi (such as A. fumigatus, C. Albicans, and many more) in the absence of immunological criteria for allergic bronchopulmonary aspergillosis (ABPA). Sensitization is preferentially detected by performing both skin tests and specific serum IgE dosage since they seem to show poor concordance in identifying fungal sensitization when used alone. SAFS airway inflammation is typically type-2 in nature and primarily steroid-resistant: this may depend on IL-33, an alarmin produced by damaged airway epithelial cells, leading to mast-cell activation, ILC2 recruitment, and fibroblast-mediated airway remodeling. Recently, Singh et al. described a peculiar ‘fungal atopic march’ from allergic fungal rhinosinusitis (AFR) to SAFS and, finally, allergic bronchopulmonary mycosis (ABPM), whose most frequent variant is ABPA [90].

AFR is primarily unilateral and mainly affects adolescents. It depends on a hypersensitivity reaction to fungi (mostly Aspergillus), leading to nasal polyposis, trapped fungi within the sinuses, and ‘eosinophilic mucin’ production, a pathognomonic type of mucin with fungal hyphae, necrotic eosinophils and Charcot-Leyden crystals within. Headache, anosmia, nasal obstruction or discharge, telecanthus, and proptosis are the main symptoms whose remission requires endoscopic resection [90].

ABPM is a rare comorbidity of severe adult asthma and pediatric cystic fibrosis, whereas it is infrequent among asthmatic children [90]. Only a few thermotolerant fungi are capable of growth at body temperature, an essential prerequisite in the pathogenesis of ABPM. In predisposed subjects, Aspergillus spp.’s small spores may germinate in lower airways, exposing pathogen-associated molecular patterns (PAMPS), which lead to airway epithelial toll-like receptors (TLR) activation, pro-inflammatory type 2 response, oxidative stress and, finally, bronchial hyperreactivity. Pathogenesis seems to depend on both Aspergillus-specific IgE-mediated type I hypersensitivity and Aspergillus-specific IgG-mediated type III reactions [12,30,91]. Untreated ABPA may lead to accelerated lung function decline, poorer asthma control, failure to thrive, and a higher incidence of bronchiectasis; it is unknown whether its proper management is beneficial for concomitant asthma [12,92]. ABPA’s main symptoms include recurrent wheezing, productive cough, hemoptysis, low-grade fever, weight loss, malaise, and the pathognomonic presence of black mucus plugs [93].

ABPA diagnosis requires the presence of difficult-to-treat asthma, coupled with specific clinical (immediate hypersensitivity to A. fumigatus), biohumoral (> 1000 serum eosinophils/L; total IgE > 1000 IU/mL; high Aspergillus-specific IgE and IgG – especially IgG4 -; positive Aspergillus serum precipitins) and radiological findings (lung opacities on thoracic radiography, central bronchiectasis on high-resolution CT [HRCT]), which guarantee high diagnostic specificity [94]. Clinicians revised the original criteria in 2013 to search for greater diagnostic sensitivity [91] and modified them to diagnose ABPM [95] quickly. In the absence of specific screening tools, lower serum chitotriosidase levels, high levels of IL-17 on BAL an IL-1α and IL-1β in the sputum can be used as pediatric markers of increased susceptibility to fungal respiratory diseases [96].

First-line strategies in pediatric management of fungal respiratory disease with concomitant asthma are to reduce environmental exposure to fungi and to optimize conventional anti-asthmatic treatments. Depending on the pathogenesis, suggested add-on therapies for fungal respiratory diseases include itraconazole (whose cost/effectiveness is particularly controversial in Pediatrics) [12,15,90], macrolides in the case of neutrophilic infiltration, and eventually anti-TH2 drugs in the case of fungal hypersensitivity [90].

ABPA management requires long-term OCS treatment with slow tapering for at least 4–6 months, eventually coupled with antifungal drugs as a steroid-sparing strategy, contemporary lowering fungal burden [12,15,97]. Since azoles increased both steroid concentrations with a higher risk of Cushing syndrome, their use as add-on-therapy must be carefully weighed in Pediatrics [97]. Surgical treatments are limited to forms with necrotizing pneumonia and aspergillosis. Recently, anti-IgE treatment has been proven effective in reducing asthma attacks in adults with ABPA [98], and it is also a promising treatment for pediatric SAFS [98]. Finally, other monoclonals such as anti-IL33, IL-1-receptor-like-1-antagonists (ST2-antagonists), anti-IL17 receptor alfa (anti-IL17Rα), and anti-endothelin 1 receptor are currently under study as future, specific therapeutic targets [99,100].

3.3. Bronchiectasis in severe asthma

Bronchiectasis (BE) is a chronic irreversible bronchial dilatation clinically associated with productive cough, mucopurulent sputum, and recurrent or persistent bronchial infections [13]. BE seems to be one of the commonest comorbidities of asthma, with a prevalence of 20% among asthmatic adults and 60% in the case of long-lasting, difficult-to-treat asthma [12,101]. Being considered the final result of many years of chronic, poorly controlled asthma, BE was considered quite rare among children. Nevertheless, a recent cross-sectional study detected BE in about 1/3 of symptomatic children with STRA, underlining its importance even in the pediatric age [102]. BE pathogenesis consists of a vicious circle of increased mucus production (with concomitant impaired mucociliary clearance) and chronic bronchial inflammation, leading to structural damage to the lungs, irreversible bronchial dilatation, and flow obstruction [12,15,101,102]. In addition, this mechanism predisposes to bacterial colonizations and infections, further worsening bronchial inflammation.

As asthma comorbidity, bronchiectasis worsens lung function and increases asthma severity, leading to recurrent lower respiratory infections (RLRI), extremely frequent asthma attacks, and a higher risk of chronic respiratory failure [101,102].

If BE consists of a specific asthma sub-phenotype is still debated [101,103]. Some studies reported a higher prevalence of BE among subjects with high systemic eosinophils and late-onset eosinophilic asthma [12,103], whereas others showed an association between BE and neutrophilic asthma [104]. Furthermore, BE may exist alone without asthma, so proper differential diagnosis is critical. Recently, a cytological classification of BE has been proposed, including neutrophilic BE and eosinophilic/mixed BE. The former is an early-onset form of BE with higher serum IL-8 levels, frequently irreversible obstruction, lower atopy, and poor steroid response. The latter is a late-onset form characterized by more elevated serum IL-13 levels, higher fractional exhaled nitric oxide (FeNO), greater severity, more frequent asthma attacks, but a better response to steroid therapy [101,105].

BE presence must be suspected in any case of long-lasting, exacerbation-prone, difficult-to-treat asthma with poor response to standard therapies or difficult-to-treat asthma with RLRI [101]. ABPA and CRS must be ruled out since they are frequent findings in subjects suffering from BE [103]. In patients with difficult to treat asthma, the presence of bronchiectasis should certainly be considered a comorbidity, however it is always important in these patients to exclude other diagnoses such as cystic fibrosis, alpha 1 trypsin deficiency, infectious causes, immune disorders, chronic aspiration, DCP and structural airway abnormalities that explain persistent and sometimes delayed respiratory symptoms. Although non-diagnostic, lung function tests showing irreversible broncho-obstruction suggest BE: 50% of subjects with eosinophilic BE show reversible obstruction [106]. FeNO may help to correctly identify subjects with BE-overlapping-asthma [107] or distinguish neutrophilic from eosinophilic BE [105]. In contrast, sputum cultures may help detect bacteria such as Pseudomonas aeruginosa or Haemophilus influenzae [101].

The gold standard for BE diagnosis is HRCT. ERS/ATS guidelines recommend HRCT assessment in all children with ‘atypical’ difficult-to-treat asthma to rule out comorbidities and alternative diagnoses [4]. In addition, asthmatic subjects may frequently suffer from reversible, self-limiting bronchial dilatation, so longitudinal HRCT monitoring is critical to correctly identify real, irreversible BE [101]. Finally, HRCT provides a concomitant assessment of airway early remodeling, such as bronchial wall thickening or air trapping, allowing early imaging monitoring. Although an up-and-coming field of research, whether early identification and treatment of such alterations may lead to asthma improvement or prevention is still to be proven [101].

The key to BE therapy is properly treating bronchial secretions with inhaled hyperosmolar agents, airway clearance techniques, and pulmonary rehabilitation, thus preventing lung function decline and asthma attacks [11,12,101,103]. Add-on therapy with long-term macrolides may help to reduce the risk of asthma attacks, especially in the case of neutrophilic BE. ICS are not recommended for BE without comorbid asthma since they could increase the risk of bacterial infections due to local immune system impairment, especially in case of prolonged administration of high doses of ICS [108]. Finally, Mepolizumab has recently been studied as a therapeutic option for difficult-to-treat-asthma with comorbid BE, potentially improving bronchial inflammation, asthma control, and asthma attacks [109], but evidence are still lacking.

4. Conclusions

In recent years, increasing attention has been paid to the early identification and proper management of treatable traits in difficult-to-treat-asthma. In this regard, management of respiratory asthma comorbidities is a substantial issue due to their pervasive effects on asthma outcomes. Proper identification of asthma comorbidities in the context of the so-called multidimensional assessment may reduce asthma misdiagnosis and the subsequent healthcare costs and side effects of unnecessary treatments, improving patients’ health and QoL [110]. The presence of comorbidities must always be ruled out in severe asthma and vice versa; respiratory comorbidities must be suspected whenever severe asthma seems unresponsive to conventional therapies despite good adherence to treatments. Once detected, comorbidities must be carefully staged, differing from asthma severity. Moreover, since comorbidities are dynamic diseases, their periodic re-assessment is recommended as part of routine clinical practice in asthma management.

Although the most well-known comorbidities can be easily identified and treated in a primary care setting, a multidisciplinary evaluation specifically targeting pediatric age – including pediatric radiologists, dedicated physiotherapists, or ENTs – is crucial for less known, still underdiagnosed comorbidities to ensure the most suitable therapy while avoiding unnecessary, invasive examinations. Even so, in the suspect of middle-to-lower airways comorbidities, we recommend an HRCT scan in every child with ‘atypical’ difficult-to-treat asthma, as ERS/ATS guidelines state.

Due to the many peculiarities of the pediatric age in epidemiology, clinical presentation, and endotypes, further pediatric-targeted studies are needed to define specific diagnostic criteria, validated screening tools, and targeted therapeutic approaches. Nevertheless, this approach may better understand the mutual interrelation among concomitant respiratory diseases, ultimately leading to effective, steroid-sparing, tailored therapies, including the fascinating, emerging possibility of combining biological therapies with AIT for better tolerability and immune tolerance.

5. Expert opinion

As for pediatric STRA, whose phenotypes profoundly differ from those described in adults, asthmatic respiratory comorbidities have unique characteristics in childhood. Unfortunately, many lesser-known comorbidities are still largely underdiagnosed, thus leading to suboptimal management of asthma and its comorbidities. On the contrary, there is still a disproportion between identified treatable traits and effectively treated ones. In this regard, the search for comorbidities must not be a mere collection of diagnoses but should be aimed at creating integrated therapies.

In the literature, some respiratory comorbidities are known to impact asthma outcomes significantly, but benefits after their treatment are few. Contrarywise this, other respiratory comorbidities, apparently having the most negligible impact on asthma, give the most remarkable improvements when treated [5]. Therefore, more real-life longitudinal studies are needed to understand better the mutual interrelation and synergistic effect between asthma and respiratory comorbidities, the effectiveness of targeted therapies, and the correlation between long-lasting respiratory comorbidities and poor lung function trajectories.

Another critical issue is the use of many different terms to indicate the same comorbidity: this can make the literature search dispersive; therefore, we hope for the introduction and the use of shared terminologies, such as ILO in the case of the previously used PVCMD definition.

It is well known that respiratory comorbidities may share some common, potentially treatable risk factors with asthma. In the short term, their early identification could lead to the creation of predictive scores and the development of specific preventive strategies contrasting the onset of asthma and its comorbidities.

The validation of specific, feasible screening tools for pediatric respiratory comorbidities is another desirable, easy-to-reach goal: their routinary use could allow patients and doctors to assess and detect each respiratory asthma comorbidities quickly, alone, or – even more interestingly – in combinations. Moreover, since some questionnaires seem to correlate with specific biomarkers of certain comorbidities, further research could lead to non-invasive disease phenotyping.

In the long term, a better understanding of how respiratory diseases mutually affect each other could lead to the creation of specific clinical algorithms or the identification of unique biohumoral or radiological early biomarkers. Once identified, further longitudinal studies will prove their stability over time, and cluster analysis may show their clinical utility as phenotyping or prognostic tools. In this regard, nasal transcriptomes are promising tools, faithfully reproducing the transcriptional state of the lower airways within a mini-invasive specimen [111]. However, to our knowledge, no study has focused on how (if any) further respiratory comorbidities can modulate nasal transcriptome expressions, so this could be a complex but exciting field of research.

Finally, an asthmatic ‘multimorbidity signature’ has been detected recently, including eight genes primarily involved in eosinophilic-immune response and signal transduction. These genes proved to be globally over-expressed in all types of asthma comorbidity, paving the way for target-therapies development. In this regard, therapies addressing innate immunity and airway epithelial dysfunction are the most promising, especially considering the emerging role of ILC2 cells in both upper and lower airways – a proper ‘cell proof’ of the united airway disease.

Article highlights

• Respiratory asthma comorbidities are frequent treatable traits whose management can significantly improve outcomes in difficult-to-treat asthma.

• Children and adolescents possess unique characteristics in terms of clinical presentation, endotyping, and therapeutic approach, which must be taken into account while ruling out comorbidities.

• Further studies focusing on pediatric age may clarify the mutual interrelation among coexisting respiratory diseases, ultimately leading to integrated, effective, steroid-sparing therapies.

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.

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Funding

This paper was not funded.