Combined Allergic Rhinitis and Asthma Syndrome

Introduction

The increasing recognition over the last 50 years that allergic rhinitis and allergic asthma frequently co-exist has led to the concept that these seemingly separate disorders are manifestations of the same disease expressed to a greater or lesser extent in either the upper or the lower airways. In some patients rhinitis predominates and asthma is undiagnosed or sub-clinical, in others it is reversed, while in many both are clinically expressed.

This concept has important implications for both the diagnosis and the management of these extremely common and potentially disabling illnesses. As a result, new disease terminologies have been introduced, namely "United Airways Disease," "Allergic Rhinobronchitis," or "Combined Allergic Rhinitis and Asthma Syndrome (CARAS)." At the present time there is no consensus as to which of these names should become the accepted international notation. Based on our readers' feedback, the term Combined Allergic Rhinitis and Asthma Syndrome is used.

Purpose

The aims of this Allergy Update are: 

1. To present the evidence that supports the introduction of the new disease terminology - Combined Allergic Rhinitis and Asthma Syndrome.

2. To discuss the underlying mechanisms.

3. To review the impact that the treatment of either the upper or the lower respiratory tract has on the other.

4. To indicate the likely benefit to patient care of the appropriate diagnosis and treatment of Combined Allergic Rhinitis and Asthma Syndrome.

Definition

Concurrent clinical or sub-clinical upper and lower respiratory tract symptoms.

Evidence for Combined Allergic Rhinitis and Asthma Syndrome

Anatomical and physiological

The respiratory tract is lined from the nasal ostia to the respiratory bronchioles by ciliated epithelium. However, there are differences, particularly in the physiological mechanisms leading to reduction in airflow. In the upper airway, obstruction results primarily from vascular engorgement of the mucosa, while in the lung, bronchoconstriction is, in large part, the result of contraction of the encircling smooth muscle, which is not present in the upper airways. The upper and lower airways are functionally linked: stimulation of the nasal mucosa may result in changes in bronchial hyperresponsiveness. It is speculated that nasal and sinusal receptor stimulation affects trigeminal afferent nerves and likely stimulates parasympathetic fibers via the vagus nerve, resulting in subsequent changes of bronchomotor tone.

Clinical

Rhinitis is often defined as a "risk factor" for the development of asthma. This definition is not completely accurate, since rhinitis may also represent an early stage of Combined Allergic Rhinitis and Asthma Syndrome. It has however been shown that persistent rhinitis is an independent risk factor for asthma, even in the absence of any marker of atopic status.

The coexistence of sinusitis and asthma, especially in children, is known, and infection of the paranasal sinuses is frequently implicated in the development of disease of the lower respiratory tract in allergic patients. Sinusitis and/or adenoiditis have been shown by endoscopic assessment to occur in more than 50% of children with asthma.

Because of the contiguous anatomical relationships of the sinuses to the nasal mucosa, it is rare to find inflammation of the sinuses without nasal mucosal involvement, and a more appropriate term for this condition is rhinosinusitis. Infected sinuses are a reservoir of proliferating bacteria and are frequently associated with worsening of asthma. Endotoxins from the cell walls of gram-negative bacteria have potent pro-inflammatory properties, and inhalation of endotoxin has been shown to induce airway narrowing and hyperresponsiveness in patients with asthma.

Epidemiological

Clinical observations during the 1960s showed that there was an association between allergic rhinitis and allergic asthma. In a study of the effectiveness of specific immunotherapy, approximately 50% of a control group of children, who received no immunotherapy, developed asthma within a few years.

A survey of 99 patients followed up for 10 years after the initial diagnosis of allergic rhinitis, allergic asthma or both, showed that: 

• 32% of rhinitis patients developed asthma;

• 50% of patients with asthma alone developed rhinitis.

A number of studies from around the world have shown that:

• 70-90% of patients with asthma have concomitant rhinitis;

• 40-50% of patients with allergic rhinitis have concomitant allergic asthma.

Sinusitis has been shown in different studies to occur in up to: 

• 25-70% of adults with asthma;

• 20-60% of children with asthma;

• 50% of patients with inhalant allergies.

Airway hyperresponsiveness, measured by methacholine challenge, has been demonstrated in:

• 15-65% of patients with allergic rhinitis.

The Underlying Mechanisms Leading to Combined Allergic Rhinitis and Asthma Syndrome

Physical

The upper respiratory tract functions as a physical filter, resonator, heat exchanger and humidifier, so that inhaled air arrives into the bronchi at a temperature of approximately 37 degrees C and almost completely water saturated. Inhaled particles greater than 5-6 microns are retained in the nose. Failure of some upper airway function may result in an alteration to the homeostasis of the lower respiratory tract. Oral hyperventilation with cold air in patients with asthma decreases the forced expiratory volume and also increases nasal resistance.

Allergen exposure

The development of either upper or lower airway symptoms can depend on the particular allergen to which the sensitized individual is exposed. Seasonal allergens, for example grass or tree pollens, can cause intermittent symptoms, e.g. intermittent/ seasonal allergic rhinoconjunctivitis, while allergens which are present year-round, such as animal danders and house dust mites, are more likely to cause persistent symptoms of rhinitis and/or asthma. In part this may be related to the size of the allergenic particles, since pollens are generally approximately 5 microns in size and are likely to be filtered out in the upper airway cavity. Mouth breathing, when nasal obstruction is present, excludes the upper airway filter, thus increasing the possibility of lower respiratory tract symptoms. House dust mites and pet allergens are smaller (approximately 1 micron) and readily penetrate into the lower airways.

Immunologic

Inflammation of the nasal and bronchial mucosa plays a critical role in the pathogenesis of allergic asthma and rhinitis. Both upper and lower airways demonstrate a similar inflammatory cell mucosal infiltrate although differences exist in the extent of the inflammatory indices in allergic rhinitis and asthma. The immunopathologic response, chronic allergic inflammation, is similar in the upper and lower airways. It involves Th2 lymphocytes, mast cells, basophils, eosinophils, IgE, cytokines such as IL-4, IL-5, IL-13, RANTES and GM-CSF, chemical mediators of inflammation such as histamine and leukotrienes, and adhesion molecules.

Allergic rhinitis and asthma are also unified by a systemic immunologic response to airborne allergens. This is evidenced by peripheral blood eosinophilia, the presence of a common progenitor cell for eosinophils, basophils and mast cells in the blood, and by reactivity of polymorphonuclear blood cells (PMBC) to specific allergen stimulation, resulting in increased IL-4 production and reduced interferon-gamma production compared to PMBC from healthy subjects.

In a sensitized individual, IgE binds to tissue mast cells and circulating basophils, which are then activated, following allergen exposure, to release histamine, leukotrienes, and other mediators. This activation results in the immediate nasal symptoms of itch, sneezing and rhinorrhoea, which are neurally mediated, and nasal obstruction, which is vascular in origin. In the lower airways the immediate symptoms are bronchoconstriction and hypersecretion of mucus, giving rise to cough, breathlessness, tightness in the chest and wheezing.

Nasal challenge testing in asthmatics causes non-specific bronchial hyperresponsiveness, and bronchial challenge testing in subjects with rhinitis leads to an asthmatic response, with recruitment of inflammatory cells and pro-inflammatory mediators. This suggests that the upper and lower airway may be considered as a unique entity influenced by a common, evolving inflammatory process, which may be sustained and amplified by interconnected mechanisms.

Even in the absence of symptoms, continuous exposure to low levels of allergen results in an inflammatory infiltration and ICAM-1 expression, which is known as "minimal persistent inflammation" (MPI). ICAM-1 is the major receptor for the rhinovirus. Rhinoviruses are the most common cause of asthma exacerbations. It is likely that the exacerbations result from intensification of existing airway inflammation. Rhinovirus infections increase airway responsiveness, promote the development of late phase reactions to inhaled allergen, enhance eosinophil recruitment to the airway following allergen challenge, possibly through stimulation of cytokine production, and are associated with increased eosinophilic inflammation of the airway mucosa.

Epithelial shedding is more pronounced in the bronchi than in the nose. Airway remodelling exists microscopically in most, if not all asthmatics, but may not be so obvious in rhinitis where the epithelium remains intact. It is possible that the maintenance of epithelial integrity in patients with rhinitis, but not in patients with asthma, may result from the epithelial cell’s capacity to synthesize and release key anti-inflammatory products which prevent injury following eosinophil-induced inflammation.

Current research is focusing on what local mechanisms, such as local tissue production of IgE and selective homing of T-lymphocytes, determine whether the major inflammatory response to allergen occurs either in the upper or lower airways.

The Impact that the Treatment of Either the Upper or the Lower Respiratory Tract Has on the Other

Similarities

Treatment for Combined Allergic Rhinitis and Asthma Syndrome should be directed at the underlying inflammatory processes common to allergic rhinitis and asthma.

Differences

The adrenergic control of the upper and lower airways differs. The vascularity of the nasal mucosa means that symptoms of nasal blockage can be readily altered by pharmacological agents such as alpha-adrenergic agonists, which act as vasoconstrictors. The smooth muscle of the bronchial wall relaxes effectively with bronchodilators such as beta2-adrenergic agonists.

Effect of nasal treatment on asthma

Intranasal glucocorticoids improve allergic rhinitis symptoms but also improve symptoms of asthma and reduce bronchial hyperresponsiveness.

H₁ antagonists, in the doses ordinarily used for seasonal allergic rhinitis, may also improve concurrent mild seasonal asthma symptoms, although no significant improvement in pulmonary function normally occurs. However administration of an antihistamine plus pseudoephedrine has been shown to improve asthma symptoms, peak expiratory flow rate, and reduce bronchodilator requirements in patients with seasonal allergic rhinitis and mild asthma.

In children, upper respiratory infections and asthma exacerbations can be controlled by continuous antihistamine treatment. In the ETAC (Early Treatment of the Atopic Child) study, continuous antihistamine treatment has been shown to reduce the number of at-risk children who subsequently develop asthma.

Antibiotic therapy for sinus disease in children has been shown to improve lower airway symptoms.

Improvement in asthma has been shown after sinus surgery in patients with either nasal polyposis, or rhinosinusitis, and asthma.

Treatment of concomitant rhinitis and asthma

Care should be given when prescribing topical corticosteroids for both rhinitis and asthma so that the total dose of corticosteroid does not exceed recommended levels. However, there are patients with severe disease in whom recommended levels are exceeded so that systemic glucocorticosteroids, which cause more side effects, can be avoided.

Allergen immunotherapy (allergy vaccination) is an important therapeutic tool for the management of Combined Allergic Rhinitis and Asthma Syndrome, and it is indicated in patients with concomitant rhinitis and asthma. Immunotherapy can modify the natural history of the disease and maintains its effects for years after discontinuation. Sublingual-swallow immunotherapy seems to be particularly suitable for pediatric patients because it can be given orally. More comparative studies are needed between allergen immunotherapy by injection (vaccination) versus sublingual-swallow immunotherapy to determine if sublingual-swallow immunotherapy is equally effective.

A new class of drugs, the humanized monoclonal anti-IgE antibodies, which are administered by injection, have also been shown to affect both the upper and lower airways symptoms of Combined Allergic Rhinitis and Asthma Syndrome.

The Likely Benefit to Patient Care of the Appropriate Diagnosis and Treatment of Combined Allergic Rhinitis and Asthma Syndrome

Diagnosis

All patients presenting with allergic rhinitis and/or sinusitis should be evaluated for the presence of asthma by history, chest examination and, if possible, by assessment of airflow obstruction before and after the administration of a bronchodilator. The presence of non-specific bronchial responsiveness should also be assessed, where possible.

Patients with asthma as the prime presenting disease should be asked about intermittent or persistent nasal symptoms.

Treatment

Uncontrolled allergic rhinitis can lead to worsening of co-existing asthma. Prompt and effective treatment of nasal disease can have a marked beneficial effect on preventing the development of asthma and on existing asthma symptoms.

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