The “one airway, one disease” concept [13] has successfully taken root in the medical community, although it is far from being a reality in clinical practice. In fact, there are currently no consensus guidelines for ARD patients. Thus, management is not based on homogeneous criteria and requires the use of 2 separate guidelines, 1 for asthma and 1 for rhinoconjunctivitis.
This consensus study aimed to collect expert opinions from Spanish allergologists about the symptoms, classification, diagnosis, and treatment of ARD to provide a comprehensive approach for clinical practice. A major goal was to address the importance of the allergen as the modulator of individual variability in clinical expression based on the duration and intensity of exposure.
ARD: Definition
Given the publication of the ARIA guidelines in 2001 [1], the panel agreed that “there is abundant evidence confirming the notion of one airway, one disease as the conceptual basis of the management of patients diagnosed with rhinoconjunctivitis and/or asthma” (item 1). Therefore, it follows that “the definition of ARD as a single entity that includes rhinoconjunctivitis and asthma would facilitate its management” (item 2), especially when allergy is its main cause. Finally, the experts of this consensus agreed on the definition that “ARD is an altered state of health caused by the generation of IgE antibodies to airborne allergens leading to various clinical manifestations in the upper and/or lower airway” (item 3).
Allergic inflammation is present in both the upper airway and the lower airway [14, 15], although it may be of locally different intensity (items 4, 17, 18). Therefore, a unified assessment of the airway is necessary, irrespective of whether symptoms of both asthma and rhinoconjunctivitis are present at a given time in a patient (item 9).
The concept of ARD is based on the allergic origin of the disease, and its clinical spectrum includes conjunctivitis, rhinitis, and/or asthma. Not all clinical manifestations must occur simultaneously in ARD patients, although the risk of developing the other clinical manifestations of ARD in the future is greater than in the general population [16].
The allergen as a key factor in ARD
In ARD patients, allergens and clinical exacerbations are the main triggers of inflammation (acute and chronic). The ARD consensus highlights the importance of considering allergic sensitization in diagnostic and therapeutic decisions.
Various airborne allergens can induce a variety of respiratory symptoms with a wide spectrum of severity [17]. Furthermore, sensitization to several agents (polysensitization) can also substantially modify the clinical features and prognosis of ARD patients [18]. As shown by several studies, specific allergens more frequently induce symptoms in the upper respiratory tract than in the lower respiratory tract (item 27) [19]. In addition, some airborne allergens are related to the most severe forms of asthma (item 28) [20] or persistent forms of asthma [21], and some allergens can lead to worse quality of life than others owing to the characteristics of their exposure (item 29) [22]. Age at sensitization and allergen involved have even been linked to the appearance of specific symptoms [23]. Sensitization to certain allergens, for instance Alternaria species, has also been noted as a risk factor for exacerbations [24], severe exacerbations, and even death from asthma [25]. Furthermore, recent studies have linked specific allergens to various late reactions in asthma: whereas house dust mites induce more severe late reactions than pollens, animal dander allergens are related to reactions of intermediate intensity [26].
Other factors modulate the clinical response to the allergen. These include “allergenic pressure”, which is the combination of both intensity and duration of exposure to an airborne allergen. The experts agreed that “a patient with ARD can manifest allergic rhinoconjunctivitis after being exposed to a specific allergen and asthma after exposure to a different one” (item 32) and “in the same patient, the presence of rhinoconjunctivitis and/or asthma at a particular time may depend on the intensity and duration of exposure to the allergen” (item 33).
For the experts consulted, unlike non-allergic asthma or rhinitis, “control of ARD varies significantly depending on the intensity of exposure to the responsible allergen” (item 41).
Contact with an allergen causes pathophysiological changes that affect the development of symptoms triggered not only by allergens, but also by other agents, such as infectious microorganisms (item 23). These symptoms are more intense when patients are exposed to both an allergen and an infectious agent [27]. Recent studies have linked the persistence of asthma after removing the allergenic trigger in individuals with ARD with the activation of Th2-mediated myeloid dendritic cells [28]. The experts agreed that the allergic nature/substrate of ARD might also influence the persistence of respiratory symptoms during periods of no exposure to an allergen (item 46).
Specific aspects of the diagnosis of ARD
The expert panel agreed that control of ARD depends on a comprehensive diagnosis, including identification of the causative allergen/s and its/their clinical relevance (item 41).
It is well known that “patients with ARD may not meet functional and inflammatory criteria for rhinitis and/or asthma when allergen exposure is not present” (item 47), as occurs in individuals sensitized to pollens out of season [29].
Allergen exposure can influence the results of the diagnostic tests most commonly used in rhinoconjunctivitis and asthma. Whereas allergy tests (skin prick test, specific IgE, allergen challenge) are still useful when patients have no symptoms (item 49), lung function tests may fail to detect bronchial involvement (item 50). Thus, the diagnosis of allergic rhinitis can be made independently of the allergenic exposure. However, according to guidelines, diagnosis of asthma requires the objective demonstration of lower respiratory tract involvement (reversible obstruction, hyperresponsiveness) [7].
Specific aspects of treatment of ARD: drug therapy
The expert panel agreed that the therapeutic and diagnostic approach to ARD patients cannot be solely and strictly based on the recommendations of current guidelines. Adjustment of drugs and doses is based on the severity of symptoms in previous allergen exposures and does not follow the frequently recommended “step-up” strategy (item 58), especially in patients with seasonal manifestations.
Although a personalized treatment plan is recommended, we may use the “maximum severity of symptoms recorded in previous exposures” as a guide to establishing future treatments (item 57). This must be registered in the medical history (Items 34 and 35) and is particularly important if therapeutic recommendations are given when patients are not exposed to the allergens.
In the opinion of the expert panel, unlike non-allergic rhinitis and asthma, maintenance therapy may only be administered to ARD patients during allergen exposure (item 55) [9]. However, maintenance therapy may also be used over longer periods to ensure good control (item 56).
Specific aspects of treatment of ARD: AIT
As suggested previously [30], there is a common underlying pathogenic mechanism in all patients with ARD, despite differences in clinical manifestations and types of allergic sensitization. Identification of the causative allergen and prescription of an allergen-oriented treatment improve disease control and prognosis, irrespective of whether asthma and rhinoconjunctivitis appear simultaneously or sequentially. Allergen immunotherapy (AIT) is an etiology-based treatment and should be considered a first-line option in ARD based on the clinical relevance of allergen sensitization, in which exposure to an allergen elicits allergic symptoms with significant intensity or duration.
However, contrary to published evidence [31] and the opinion of the expert panel, some guidelines [8, 9] do not consider AIT to be first-line treatment. The experts agreed that “failure of drug therapy is not a prerequisite for AIT in patients with ARD” (item 62), and that “most of these patients will benefit from treatment with AIT to slow disease progression” (item 64). This consensus advocates for early indication of AIT under the premise that immunotherapy is most effective in the early stages of ARD (item 63) when the optimal dose is applied, thus combining efficacy and safety.
“Unlike pharmacological treatment, AIT improves the prognosis of ARD” (item 66), mostly in monosensitized patients and when an adequate immune response is observed [32]. There is sufficient evidence to support the observation that “most patients with ARD will benefit from treatment with AIT to reduce the severity of symptoms and the use of medication and to improve quality of life” (item 65) [33,34,35]. Likewise, substantial evidence indicates a preventive effect in the progression from allergic rhinitis to asthma [36] (item 68), especially in children [37].
Some of the authors on the panel agreed that “AIT decreases the occurrence of new sensitizations in ARD patients” (item 67) [38, 39], although consensus was not reached. The experts considered that only some studies in children treated with pollen AIT have demonstrated the development of fewer new sensitizations when compared with those not treated with AIT. Furthermore, this has not been demonstrated for every allergen or in adults treated with AIT.
Polysensitization is an important factor when determining the prognosis of ARD and the indication for AIT (item 70). In polysensitized patients, both maintenance treatment strategies (item 61) and AIT composition (item 69) must be tailored after taking into consideration the most clinically relevant allergen. Therefore, AIT has proven to alleviate patients’ overall symptoms owing to its effect on reducing the most relevant allergen-related symptoms [40].
However, polysensitization does not necessarily mean polyallergy [41]. Molecular diagnosis and knowledge of the predominant allergen are very useful for selecting genuinely polyallergic patients to receive AIT. It has been shown that the final composition of the AIT prescribed may need to be modified in up to 50% of patients when molecular diagnosis is used instead of the classic approach [42].
The inclusion of more than 1 allergen in AIT must be considered when there is more than 1 relevant allergen. The authors of this consensus advocate administration of the complete doses of each allergen to ensure the effectiveness of AIT, although this issue warrants further research (item 71).
Classification of patients with ARD
ARD is not reflected in the main clinical practice guidelines. Consequently, given that allergy is the most important cause of persistent rhinoconjunctivitis and asthma, the absence of specific references to patients with ARD [9] is remarkable. It is also interesting that the defining characteristics of ARD, such as the clinical variability conditioned by allergen exposure, have not been assessed. Therefore it is difficult to classify ARD patients according to the criteria currently proposed by guidelines (item 36).
The difficulty in fitting patients diagnosed with ARD with the guidelines lies in the fact that “the current classification is based on the assessment of the intensity and frequency of symptoms of rhinoconjunctivitis and asthma separately and does not assess the specific aspects of the causative allergens” (item 37). However, the expert panel agreed that “besides the intensity and duration, the description of ARD symptoms should also consider other aspects such as the frequency of the episodes, seasonality, and recurrence of symptoms at certain times” (item 38). The assessment of these aspects would enable a better approach in ARD patients.
The dynamic nature of allergic diseases has previously been described [37]. Indeed, “the clinical manifestations of ARD may be variable at different times in the patient’s life” (item 8), with variation in the preponderance of nasal over bronchial symptoms [43]. Therefore, appropriate control of these patients requires the evaluation of the whole airway, even though symptoms may not be present at a given time.
The panel of experts highlighted the existence of several unmet needs. 1) Patients diagnosed with ARD require a specific classification that gives prominence to the causative agent (item 39). 2) It is necessary to propose a classification for diagnosis and treatment of ARD that simultaneously takes into account the severity, control, and clinical characteristics of the airborne allergens involved (Item 40). 3) The development of diagnostic and therapeutic approaches that take allergen exposure and the patient’s environment into account would be useful in daily clinical practice. Multiple allergens are frequently implicated in ARD, making it very difficult to identify the most important one. Furthermore, we must bear in mind the existence of other factors not related to the allergen that might contribute to the onset of symptoms. 4) Rhinitis and asthma are currently classified, treated, and evaluated using different guidelines. However, the expert panel recommends a holistic approach to ARD patients, taking into account the clinical expression of respiratory disease at different levels and including its severity and level of control after treatment (Figs. 1, 2). It would be desirable to use questionnaires on disease control [44] and quality of life [45] to provide a global evaluation of ARD.