Discussion
There is a report that children with allergic rhinitis (AR) have significantly more sinusitis than those without AR.13It is also reported that the orbital complications of patients with acute bacterial sinusitis in the group with AR are more frequent than in the group without AR.14 Of course, the mechanism for this has not been clarified; however, allergic rhinitis induces edema in the tissues of the nasal cavity, increases exudates, and causes symptoms such as nasal congestion and runny nose. This can block the ostiomeatal unit, which can lead to complications such as sinusitis.
We have divided AR patients into a patient group and control group. The reason for this is that people with AR frequently use antihistamines. However, because too many antihistamines are being prescribed in combination these days, it is necessary to discuss whether they are beneficial or detrimental to health.
In our study, antihistamine was shown to be approximately 1.53 times more likely to lead to sinusitis in AH group than in non-AH group. Non-AH group during the first year of 2003 had a sinusitis rate of about 61% over the next 10 years whereas patients in the AH group during the first year of 2003 had a sinusitis rate of about 74% over the next 10 years.
Histamine is actually an important mediator in causing symptoms such as runny nose, nasal congestion, and sneezing. The histamine-binding receptors include H1 receptors and H2 receptors, and antihistamine drugs have effects according to the location of each receptor attached to these receptors. The receptor that plays a major role in the nasal cavity is the H1 receptor, and H1 receptor antagonists are generally used as antihistamine drugs to improve symptoms such as rhinorrhea, sneezing and itching in the nose. Antihistamine drugs are divided into first-generation drugs developed earlier and second-generation drugs developed later. First-generation antihistamines are lipophilic and have a characteristic of passing through the blood-brain barrier (BBB), and with complications such as sedation, fatigue, attention disturbance, drowsiness, etc. These first-generation antihistamines have an anticholinergic effect that increases the viscosity of rhinorrhea, thus the ciliary beat frequency is reduced in dried nasal mucosa.5 On the other hand, the second-generation antihistamines are lipophobic and do not pass through the BBB. However, these second-generation agents have no anticholinergic effect, and only have the effect of inhibiting histamine which is liberated from mast cells. Thus the second-generation antihistamines seem to have no beneficial effect on acute rhinosinusitis.5
Histamine also has a proinflammatory, immunomodulatory property.15,16 Histamine itself increases TNF-α induced E selectin, ICAM-1 expression, and increases IL-6 and IL-8 in endothelial cells.17,18 Indeed, H1 antihistamine reduces histamine-induced cytokine production and adhesion molecule expression in endothelial cells, and decreases ICAM expression. So antihistamines seem to play a beneficial role in chronic rhinosinusitis (CRS).19
When the mucociliary function is lowered, mucociliary clearance is delayed and movement of the mucus is disturbed. Unlike the lower airway, the upper airway, especially the sinus, can only be debrided by ciliary action.20 In addition to the ciliary beat frequency, this ciliary transport is also affected by fluids around cilia, i.e. mucus.21,22 This mucus is mainly secreted in goblet cells and consists of 1% NaCl, 0.5-1% free protein, 0.5-1% mucin (carbohydrate-rich glycoprotein) and the remainder water. Antihistamines alter the carbohydrate-water composition of mucus, resulting in ciliary stasis.23
We could not examine every single patient from a micro-perspective in the entire 1 million cohort, but we looked at it from a macro-perspective. In other words, we have confirmed that more sinusitis occurred in groups using antihistamines during a 10-year follow-up. Notably, in the subgroup analysis, the incidence of sinusitis according to the duration of antihistamine use was not significantly different.
The strength of this study is that it has a washout period of about 1 year (2002). First, we excluded patients with acute or chronic sinusitis complaints during the first year (2002). This is because antihistamine is an independent variable and sinusitis should be calculated as a dependent variable, thus eliminating possible interactions between the two variables. Second, all of the patients who used antihistamines for 1 year in 2002 were excluded. This was to prevent the residual effect of antihistamines. Finally, statistical validity was attained through a longitudinal study of about 10 years between AH patients who were recruited in 2003 and the control group obtained through propensity score matching.
The disadvantages of this study are: First, diagnosis of sinusitis and allergic rhinitis was made only by the diagnostic code without information such as CT or imaging tests. However, in this study, we tried to improve the diagnostic accuracy of allergic rhinitis by including patients who had had an allergic skin test or multiple allergen simultaneous test (MAST). Second, the results of this study did not consider family history, smoking history, drinking history, eating habits or other health-related indicators. Further research combining this information should be undertaken and would provide definitive results with regard to the effect of antihistamine on sinusitis.