What are the effects of rhinitis on patients with asthma?

KEYWORDS:

• Asthma
• integrated management
• rhinitis
• therapy
• united airway disease

1. Introduction

‘Merging two streets in only one way’ should be the right way to approach the airways diseases, taking into account the unbreakable relationship between the upper and lower airways, in health as well as in disease. Although upper and lower airways diseases share the same pathophysiological features, their management and treatment are commonly applied in an undesirable and independent manner, counteracting the concept of unified airways observed several years ago [1].

2. Rhinitis and asthma: a dog biting its tail

The increase in rate of allergic rhinitis (AR) in patients with asthma as well as the changes in asthma prevalence in subjects with AR is not a coincidence [2,3]. As stated in the World Health Organization document ‘The allergic rhinitis impact on asthma (ARIA)’, AR sharply appears as a risk factor for asthma development [2] as well as it is one of the most frequently reported asthma comorbid conditions [4]. Due to the bidirectional cross-talk occurring between the upper and lower respiratory tracts, both bronchial inflammation and lower airway dysfunction have been observed in rhinitic patients [4,5]. Also, the airway remodeling occurring in AR influences the clinical expression and natural evolution of asthma including severity, exacerbations, and progression of disease. Moreover, AR appears to be a negative early-life predictive factor for an accelerated decline in lung function. Interestingly, a persistent, severe, and protracted history of AR is associated both with a major airway dysfunction and with a severe asthma phenotype [4,6].

3. Rhinitis and asthma: a continuum of disease

No boundaries but an anatomical and pathophysiological continuum between upper and lower airways is the assumption on which the ‘united airway disease’ concept is based [7].

Anatomically, a ciliated epithelium with mucinous glands, a rich vascularity and a dense adrenergic and vagal innervation feature the surface of the whole respiratory tract [8].

Several triggers are shared by AR and asthma. When physical triggers (e.g. air pollution, cold air, physical exercise, and professional exposure) affects the upper respiratory tract functions, such as nasal filter, resonance, air humidification, and heating, an increase in nasal resistance and an alteration of the homeostasis of the lower respiratory tract can occur [8]. Also, nasal exposure to numerous triggers (e.g. allergens, cigarette smoke, air pollution, infectious agents) may cause a significant pulmonary allergic or non-allergic inflammation, leading to a dramatic decline in respiratory functions [5,8].

All these functional events induce the innate and adaptive immune response, resulting both in localized and in systemic inflammatory changes, involving nasal and bronchial mucosa. In fact, AR and asthma are united by a similar immune response, although differences exist in the extent of the immune response. The same inflammatory cells (mast cells, T lymphocytes, and eosinophils) and mediators (allergen-specific T-helper (Th)2 cell response, immunoglobulin (Ig)E-mediated reaction) affect the architecture and the functions of upper and lower airways, thus, the contribution of lower airway pathology to the onset of AR as well as the contribution of upper airway pathology to the onset of asthma appears well evident.

In line with these findings, researchers focused their attention to identify common inflammatory molecules that, acting as biomarkers both in AR and asthma [9,10], may both guide treatment selection processes and allow to apply the ‘precision medicine’ approach not only for AR and asthma separately, but also for the treatment of overlapping AR-asthma [7,11]. Recently, all cellular, humoral, molecular, and functional biomarkers, investigated in clinical trials recruiting patients with AR and concomitant asthma, have been reviewed by EAACI Taskforce [12], suggesting the possibility of their use also in united airway diseases. Specifically, the identification of biomarkers could pave the way for research efforts aimed at establishing a causative relationship between AR and asthma development. Moreover, the validation of biomarkers, also in a clinical setting, would allow to predict and monitor the severity and clinical course of united airway diseases, piloting patient-targeted interventions and meeting the criteria of personalized medicine.

4. Rhinitis and asthma: thinking to a common treatment

It has been demonstrated that the treatment of AR improves coexisting asthma and related outcomes, thus, a common therapy for both airway diseases would be a desirable therapeutic option [4,13,14]. (A list of key literature of the review is summarized in Table 1).

Table 1. List of the key papers included in the review.

Year	Type of article	Population	^aRef.
2016	Revision of ARIA guidelines on diagnosis and therapeutic management of allergic rhinitis	Pediatric	[2]
2017	Extensive review focusing on upper airway pathology as the main comorbity of severe asthma	Adults Children	[5]
2017	Review of evidence supporting the hypothesis of United Airway as a single entity	Pediatric	[8]
2017	European position paper on biomarkers for monitoring clinical efficacy of allergen immunotherapy for allergic rhinitis and allergic asthma	Children Adults	[12]
2018	Extensive review of current evidence and clinical evaluation of treatable traits in difficult asthma	Adults	[4]
2018	Review of management of asthma associated with ear, nose and throat comorbidities	Children Adults	[13]
2018	Consensus Statement on allergic rhinitis	Children Adults	[15]
2018	Updated review on the clinical indications of allergen immunotherapy, with particular reference to pediatric asthma	Pediatric	[16]

^a ref.: reference

Although the evidence for benefit of allergen avoidance in patients with AR and asthma are still inconclusive, this environmental measure could be considered as part of a more complete therapeutic approach to AR with asthma [13,15].

The use of antihistamines in the treatment of asthma could be justified by the evidence that increased serum histamine levels are detected during asthma attacks. Nevertheless, the current guidelines do not recommend H1-antihistamines for treating asthma [2,13,15]. In fact, although H1-antihistamine administration is significantly associated with an improvement in AR and asthma symptoms, pulmonary function testing failed to demonstrate a significant impact on the lung function [2,13,15].

In subjects with AR and asthma, intranasal corticosteroids, preventing the lower bronchial hyperresponsiveness, decrease disease severity, asthma symptom scores and rescue medication use as well as improve lung function [13,15].

Although evidence-based recommendations do not indicate the anti-leukotrienes as monotherapy for AR, literature findings showed an improvement both of nasal and bronchial symptoms as well as reduction of rescue medication use [13,15].

To date, allergen immunotherapy represents the only disease-modifying treatment for IgE-mediated AR [16,17]. Via its capacity to modulate allergic inflammation [18], allergen immunotherapy has been recently approved as add-on treatment in house dust mite-sensitized asthmatic patients with coexisting AR, showing a forced expiratory volume in 1 s (FEV1) major than 70% predicted and reporting exacerbations despite inhaled corticosteroids therapy. Evidence documented that allergen immunotherapy improves asthma symptoms and bronchial hyperresponsiveness, and it decreases the need for pharmacotherapy in the short term. Moreover, allergen immunotherapy has been associated with a lower AR and asthma progression as well as a less frequent asthma onset [16,19].

Actually, allergen immunotherapy has been recommended only for house dust mite-sensitized subjects; however, numerous trials are investigating the allergen immunotherapy effectiveness using other allergen extracts [19].

Lastly, whether the effectiveness of omalizumab is undoubted in asthma, few literature data are evaluating the efficacy of omalizumab for the treatment of moderate to severe IgE-mediated asthma and persistent AR [20]. Satisfactory results are coming from the administration of omalizumab in addition to allergen immunotherapy in reducing symptoms and improving quality of life for AR patients with asthma. Further studies are needed to evaluate the effectiveness of other biologics (anti-interleukin (IL)4, IL-4 receptor monoclonal antibodies, anti-IL5) for the treatment of coexistent AR and asthma [15].

5. Conclusions

A growing body of evidence supports an integrated view of upper and lower airways, considered as a unified anatomical and functional unit, both in health and in disease. In line with this concept, the term ‘united airway diseases’ was coined to suggest AR and asthma as different manifestations of the same inflammatory process. In parallel, the understanding of the negative impact of AR on concomitant asthma has grown together with the evidence suggesting that an appropriate treatment of AR results in significant improvements of asthma.

Consequently, experimental and clinical studies have been performed in order to identify biological agents which, playing a role both in AR and in asthma pathogenesis, can provide new insights towards a personalized biomarker-based targeted therapy. To date, although many therapeutic options are currently available to treat AR and asthma separately, there is a lack of integrated strategy ensuring a combined treatment. Except for allergen immunotherapy, whose benefit has been proven in AR with concomitant asthma, the needed of ‘united’ therapeutic approach for ‘united airway diseases’ is increasingly evident.

6. Expert opinion

The anatomical and pathophysiological continuity between upper and lower airways justifies the integrated view of respiratory tree, from the tip of nose to the alveoli. Thus, the ‘united airway diseases’ terms well explain the unbreakable relationship between upper and lower respiratory tracts. There is also clinical evidence supporting the concept of united airway diseases. As well as AR represents a significant risk factor and comorbidity of asthma, the latter is associated with a greater risk both of allergic sensitization and AR. Accordingly, AR and asthma appear as different conditions resulting from the same inflammatory and remodeling processes.

The understanding of a bidirectional and negative impact between upper and lower airway diseases has grown in parallel with the evidence suggesting that treating coexisting AR significantly improves asthma. Thus, several cellular, humoral, molecular mediators have been investigated to identify potential biomarkers that, reflecting the inflammatory status common to AR and asthma, may allow to predict and monitor the severity and clinical course of united airway diseases. Nevertheless, the management and treatment of united airway diseases are commonly applied in an undesirable and independent manner, counteracting the concept of unified airways. Moreover, the limited set of the proven interventions on patients with coexisting AR and asthma are, to date, still weak to draw definitive conclusions. The lack of strong clinical evidence and of integrated therapeutic strategy accentuates the imperative necessity to develop an ‘united’ therapeutic approach for ‘united airway diseases’ as well as to apply piloting patient-targeted interventions, meeting the criteria of personalized medicine.

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.

Reviewers disclosure

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

Additional information

Funding

This paper was not funded.

Appendix 1.

Literature review search strategies

• 1. Rhinitis

• 2. Asthma

• 3. ‘united airway disease’.ti.ab

• 4. humans

• 5. 1 or 2 or 3

• 6. 1 and 2 and 3 and 4

• 7.Guideline/or practice guideline/

• 8. Guidelines as topic/or practice guidelines as topic/

• 9. (guideline* or algorithm* or standard*).ti.ab.

• 10. ‘best practice’.ti.ab.

• 11. ‘clinical pathway’.ti.ab.

• 12. 8 or 9 or 10

• 13. 8 and 9 and 10