Effect of Dietary Modification for Targeting Histamine Activity in Patients of Allergic Rhinitis: a Randomised Open Label Study

Allergic Rhinitis refers to immunoglobulin E mediated inflammation of the nasal cavity. Mast cell activation releases histamine, the inflammatory mediator that plays a central role in the biochemical mechanism of this disease. It is metabolised by Diamine Oxidase (DAO) and Histamine N-methyltransferase (HNMT). In this randomised open label study, we recruited 60 patients out of which 30 patients were provided standard treatment and 30 were provided standard treatment along with instructions for dietary modification. The dietary modification consisted of excluding commonly consumed histamine-rich foods and foods containing pro-histamine or anti-DAO active constituents. Each patient was followed up 3 times over the course of 15 days. The patients in the dietary modification group showed significant improvement in rhinitis symptoms within 7 days, while the control group’s improvement was not significant in the same amount of time. The overall improvement between the first and last visits was more significant in the dietary modification group as compared to the control group. Thus, the exclusion of histamine-rich foods and foods containing pro-histamine or anti-DAO compounds may be recommended to patients of allergic rhinitis for quicker and better recovery. This approach may also be explored in other conditions where histamine is implicated such as asthma and infections caused by coronaviruses. rhinitis responsiveness appropriate by RCAT has 6 items that include nasal congestion, sneezing, watery eyes, avoiding activities which predispose to allergy, how well allergic symptoms were controlled last week and sleep problems caused by rhinitis. For each of the items, responses are measured on 5-point Likert-type scales. RCAT scores range from 6 to 30, with higher scores indicating better rhinitis control. Anterior Rhinoscopy Score has 4 items which includes nasal discharge, nasal mucosa colour, inferior turbinate hypertrophy and nasal obstruction. The score ranges from 0 to 1, lower score indicating better rhinitis control.


Introduction
Rhinitis is the inflammation of the mucous membrane inside the nose which is defined by a combination of two or more nasal symptoms-running, blocking, itching and sneezing1. Allergic rhinitis (AR) is a nasal airway disease that occurs when these symptoms are the result of Immunoglobulin E (IgE) mediated inflammation following exposure to an allergen2. AR is a global health problem that is increasing in prevalence3,4. Globally, allergic rhinitis affects between 10% and 30% of the population5. Reported incidence of allergic rhinitis in India also ranges between 20% and 30%6.
Histamine is a biogenic amine that plays an important role in the IgE-mediated inflammatory response within the body. Endogenous histamine is synthesized from L-histidine by enzymedependent histidine decarboxylation [ Fig. 1]. Most of the synthesis of histamine takes place in mast cells and basophils, which store it in large quantities and release it when they are degranulated in response upon immunological or non-immunological stimulus. Other cells such as dendritic cells and lymphocytes secrete histamine immediately after producing it upon stimulation7, 8. Certain foods that are rich in histamine can also increase the bioavailability of histamine [Fig 1]. The released histamine produces diverse biological effects including inflammation, vasodilation, decreased peripheral resistance, airway smooth muscle contraction, and sensory nerve stimulation 9,10.
In a healthy individual, histamine is broken down on a regular basis by two enzymes: Diamine Oxidase (DAO) and Histamine N-methyltransferase (HNMT) [Fig. 2]. DAO is found in the intestinal mucosa and is the primary enzyme for the metabolism of histamine in gut and extracellular space, while HNMT is the primary enzyme for the degradation of histamine in intracellular tissues. Histamine intolerance can occur when DAO or HNMT enzyme activity is insufficient. It is described as an excess of histamine in the blood circulation, gives rise to an array of symptoms that are typical in allergic reactions 11.
Histamine, its activators and DAO inhibitor are present in some everyday dietary products such as egg white, tomatoes, peanuts, almonds, alcohol etc. [See Table 1]. These food products may increase histamine bioavailability, increase its activity or decrease the activity of DAO. Thus, consumption of these food products can exacerbate the inflammatory symptoms of rhinitis. Through this study, we aim to assess the effect of restricting the dietary intake of these foods on the severity of symptoms in patients of allergic rhinitis. responsiveness and is deemed acceptable and appropriate by patients. RCAT has 6 items that include nasal congestion, sneezing, watery eyes, avoiding activities which predispose to allergy, how well allergic symptoms were controlled last week and sleep problems caused by rhinitis. For each of the items, responses are measured on 5-point Likert-type scales. RCAT scores range from 6 to 30, with higher scores indicating better rhinitis control. Anterior Rhinoscopy Score has 4 items which includes nasal discharge, nasal mucosa colour, inferior turbinate hypertrophy and nasal obstruction. The score ranges from 0 to 1, lower score indicating better rhinitis control.
Patients were randomized by computer generated tables into 2 subgroups comprising 30 patients in each group. The allocation of patients into two groups was done by serially numbered opaque sealed envelope technique. Patients in Group 1 were given Standard treatment of allergic rhinitis and patients in Group 2 were given standard treatment along with dietary modification in which pictorial list of food items to be avoided in the diet was given [See Annexure 3]. The food items listed were all known to contain high levels of histamine or pro-histamine active constituents or inhibitors of diamine oxidase. All 60 patients were asked to record food items consumed at home daily. Patients were followed up at the end of 3, 10 and 15 days and they were re-assessed on the grounds of RCAT score and Anterior Rhinoscopy score. If the subject did not come for follow up a telephonic counselling was done for reporting in the hospital. If the subject did not agree, RCAT was assessed on phone and included in the result separately.

Results
This study was conducted on a total of 60 patients of age group varying from 14 years to 60 years.
Maximum number of patients fell into the age group of 20-30 years. Out of 60 patients, males were 36 (60%) and females were 24 (40%). The flowchart of the follow up is depicted in Figure 3. The mean RCAT scores for each group are listed in Table 2(a), 2(b), 2(c) and 2(d) for intragroup comparison and in Table 3 for intergroup comparison. The changes in scores with each visit are depicted graphical in Between the second and the third visit, there was a further increase (15.89%) in the mean RCAT value of the DM group. However, the mean RCAT value of the control group decreased (-4.69%) during the same time. While the intragroup changes in the mean RCAT value for neither of the two groups was not significant, the difference between the improvement of the DM group and the deterioration of the control group was significant (p=0.046).
There was an increase in the mean RCAT values for both the groups between visit 3 to visit 4. The increase in the score of the DM group (10.29%) was relatively more than the increase (8.93%) in the score of the control group, but neither of the two increases was significant.
The overall increase in the mean RCAT value between visit 1 to 4 was significant in the DM group (69.66%, p=0.009) and the control group (28.79%, p=0.031), both. While this increase was relatively more in the dietary modification group, the difference between the improvements was not significant (p=0.115).    The changes in SIGN score are listed in Table 4. The change in SIGN score between visit 1 and visit 2 was relatively more, indicating no improvement, in the control group (0.21±0.71) than that in the DM group (0.07±0.73). The difference was not found to be statistically significant (p=0.733).
The changes in SIGN score from visit 2 to visit 3 and from visit 3 to visit 4 were relatively more in the DM group (0.11±0.78, 0.29±0.76) than in the control group (0.00±0.68, 0.11±0.60). However, the differences between the changes of the two groups were not found to be statistically significant (p=0.829, p=0.606).
The overall change in SIGN score from visit 1 to visit 4 was relatively more in the DM group (0.43±1.27) than in the control group (0.33±0.71), but the difference between these was not statistically significant (p=1.000).  In the parallel study of 252 allergic rhinitis patients that were provided dietary counselling, 202 patients followed the diet. Out of the patients that followed the diet, 185 (91.58%) patients reported satisfactory improvement in symptoms, while 17 (8.42%) reported no improvement in their symptoms. All the 50 patients that did not follow the dietary suggestions did not report any relief in symptoms [ Fig. 6].
Interestingly, the patients who were relieved of symptoms of allergic rhinitis on dietary intervention, remained symptoms free for almost 9 months. However, symptoms of rhinitis recurred in 85 patients.
They reported in OPD again and were counselled to follow dietary advice and all of them showed marked improvement in their symptoms in next 6 months.

Discussion
The exclusion of DAO inhibitors, histamine rich foods, and histamine activators, and the inclusion of foods suspected to be anti-histamic resulted in 91.58% of patients that followed the advice being relieved of symptoms in the parellel study.  Table 1) may help in the recovery of COVID-19 patients.

Conclusion
Despite the advances in otolaryngology, there is a great scope for improving the management of common conditions such as Allergic Rhinitis and Asthma. The quality of life of patients gets hampered as these conditions impair sleep quality and cognitive function which leads to further irritability and fatigue.
The restriction in the intake of foods containing diamine oxidase inhibitors and pro-histaminic foods (viz. eggs, tomatoes, peanuts, fish, preserved meat etc.) seems to have a significant role in the control of symptoms of allergic rhinitis, as indicated by the better improvement in the RCAT scores and Anterior Rhinoscopy scores of the dietary modification group compared to that of the control group.
This study highlights how simple dietary modification can alleviate symptoms faster and to a greater extent than standard treatment alone. This is because diet is the primary source of all the raw materials required for every reaction in the body.
While there is a need to further explore this approach with a bigger sample size, the employment of such dietary modification alongside standard treatment does not seem to pose any risk as long as the nutritional intakes of the patients remain adequate. Therefore, the dietary modification followed by the patients in this study may be advised to patients of allergic rhinitis and other conditions with elevated histamine levels, in addition to their standard treatments.   Percentage of Change in RCAT Score Between Visits Change of Sign Score Between Visits

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