Introduction

During the past 10 to 20 years, significant progress has been made in understanding the mechanisms of allergic rhinitis (AR). Considerable advances have been made in its pharmacotherapy as well. Unfortunately, the growth of knowledge about AR has not halted its sharp rise in prevalence during the same period.

AR is the most common chronic condition in both the adult and paediatric populations, affecting 10-30% of adults and 20-40% of children. Half the patients with AR experience symptoms up to 4 months per year, whereas 20% are symptomatic for more than 9 months of the year. In addition

to the symptoms of rhinorrhoea, nasal congestion, pruritus, postnasal drip, and sneezing many AR patients also experience headache and fatigue. Chronic nasal obstruction can cause severe complications in children, with excessive mouth breathing resulting in facial abnormalities such as increased facial length, high arched palate and dental malocclusions. AR is also associated with conjunctivitis, loss of olfaction and taste, sleep apnea and an increased frequency of asthma. Two common medical conditions, otitis media and sinusitis, often result from the resulting respective obstruction of the eustachian tube and sinus ostia.

AR is an inflammatory disease

Minimal Persistent Inflammation

 

Recently, a new hypothesis proposed that the presence of AR symptoms alone is not the only parameter to suggest rhinitic inflammation. In fact, it has been shown that even when exposure to allergen is too low to provoke symptoms, there is still inflammatory infil-tration in the nasal mucosa. Obviously, this concept has profound implications for AR management. Minimal persistent inflammation has become an important hypothesis, and it has now been confirmed in studies of patients with seasonal and perennial allergy.

In a study reported by Ciprandi et al, in patients with SAR the total symptom score for AR followed the pollen level closely. When the pollen count was low, the symptoms were low or nonexistent. In contrast, the inflammatory parameters [eosinophils, neutrophils, and intracellular adhesion molecule-1 (ICAM-1)] were elevated in the nasal scrapings throughout the entire pollen season, even with low pollen count and low or absent symptoms. Furthermore, the inflammation persisted up to 4 weeks after the end of the pollen season. Similarly, patients with perennial AR (sensitive to dust mite) showed an inflammatory infiltration in the conjunctival and nasal epithelia and a weak expression of ICAM-1/CD54 even when they were totally symptom-free. The patients' relatives and healthy volunteers had few inflammatory cells and no ICAM-1/CD54 expression. A detectable level of house-dust mite was found in all participants' houses, and although no correlation was found between dust mite exposure level and inflammatory parameters, the data suggested that even a low exposure level was sufficient to induce a subclinical inflammation in sensitive patients.

If both inflammation and hyperresponsiveness can persist without symptoms, then symptoms can no longer be considered the unique markers of allergic disease. The underlying goal of treatment guidelines for AR is the effective treatment of symptoms, but this concept of minimal persistent inflammation suggests a different approach to therapy in which symptoms can be considered the “tip of the iceberg” of the allergic reaction, with inflammation and hyperresponsiveness representing the submerged iceberg.

When patients with SAR are asked if they experience sneezing, cough or fatigue outside pollen season, they generally claim not to have any symptoms. Indeed, any symptoms they experience will be mild, and patients will have long adapted to them. Outside pollen season, when winter's cold, dry air may be irritating, patients who begin to sneeze or cough more than usual will probably assume they have a cold when they may actually be experiencing symptoms from persistent allergic inflammation instead. One might speculate that the SAR patient could be constantly exposed to some level of indoor pollen outside the pollen season. During the peak season, the pollen in the air settles into the household's carpets, upholstered furniture, mattress, pillows, and drapes. With this pollen in the house it might be possible that the patient would be exposed when sleeping from the pillow or mattress or when lying on the floor or an upholstered couch. This might lead to a minimal inflammatory process in the nose.

Another possible explanation for this proposed theory of minimal persistent inflammation is the observation that many SAR patients also have evidence of perennial AR, although they may not express symptoms. If this is the case, then patients who only complain of their seasonal allergies may be exposed to perennial allergens, which could cause minimal persistent inflammation and a constant underlying allergic response. If there is a minimal persistent inflammation in the nose of these SAR patients, then they might have a priming effect, which could lead to symptoms when they are re-exposed to allergens, even at a low dose.

Clinical observations in the last decade have provided compelling evidence for an interrelationship between asthma and AR. More detailed consideration on the mechanism of inflammation suggests a strong relationship between the nose and the bronchi, and minimal persistent inflammation suggests that this important link can be present without symptoms.

Therefore, any optimal therapeutic strategy for AR should focus on minimizing inflammatory phenomena rather than only on alleviating acute symptoms. This could be achieved by using persistent treatment with anti-inflammatory agents throughout the entire period of allergen exposure and after suspected contact with the allergen subsequently.

 

Therapeutic implications of minimal persistent inflammation

Conclusions

 

Instead of considering AR as a disease of acute symptoms, it needs to be understood as a chronic inflammatory disease that involves a level of persistent inflammation even in the absence of symptoms. AR should be considered a systemic inflammatory disease that manifests itself as specific, observable symptoms in the upper airway. In this light, therapeutic agents that address the major inflammatory elements in AR, which include activated eosinophils, cysteinyl leukotrienes (CystLTs), and histamines, should be re-evaluated as a part of new management strategies for achieving effective, persistent control.

References
1. Ann Allergy Asthma Immunol 2003; 91: 131-140.
2. Ann Allergy Asthma Immunol 2003; 90 (Suppl 3): 7-12.