Circadian rhythm refers to changes in the individual 24-hour physiological, biochemical, and biological processes. Disturbances in circadian rhythm might affect physiological and behavioral functions which can lead to development of various diseases. A circadian rhythm disturbance usually manifested in the form of sleep-wake cycle disruption, in which human internal clock is not in synchronize with environmental light and dark stimulus. This so-called disturbance is usually known as jetlag. Meanwhile, there is a condition when one individual prefers to be more active and less active throughout the day and it is known as chronotype, which is believed to be inherited genetically [1-3].

Human chronotype in general is grouped into morning (early) and evening (late) chronotype based on the preferred timing of sleep. Morning chronotype person prefer to be active in the morning, sleep early, and has their best concentration, mental, and physical performance in the morning. Meanwhile, evening chronotype person prefer to sleep late, get up later, and reach their best performance during the second half of the day. People with a morning chronotype tend to have an endogenous circadian rhythm that aligns harmoniously with exogenous stimuli, resulted in rhythmic bodily function which is a characteristic of good health [4]. Conversely, evening type showed desynchronization between endogenous rhythm and exogenous stimuli, leads to circadian disruption which is harmful to health [4]. According to recent studies, there is a growing number of teenagers and late adolescents who has evening chronotype, especially in big cities and metropolitan areas [2,3]. Lately, evening chronotype is frequently associated with several health issues, such as allergic, metabolic, or psychiatric diseases [5]. Prior study carried out in India, conducted on 13 to 14-year-olds children, reported an increased risk of rhinitis and rhinoconjunctivitis in evening chronotypes compared to morning chronotypes [6].

Allergic rhinitis is one of the most common allergic diseases in teenagers and late adolescents, which has negative impact on patient’s quality of life [7]. Allergic rhinitis reaches up to 30% of children population and commonly occurred before the age of 20 years [8,9]. Aside from genetics and sensitization, environment and lifestyle are well-known risk factors for allergic diseases [7]. A global meta-analysis showed sex-related differences in rhinitis prevalence with a switch at around puberty from a male predominance to a female predominance [10]. Sedentary lifestyle is also associated with the increased risk of allergic rhinitis [11,12]. Therefore, this study aims to confirm prior findings and further shed light on the relationship between chronotype and allergic rhinitis in adolescents in Jakarta.

This cross-sectional study was conducted on students that were randomly chosen from four high schools in the Jagakarsa subdistrict of South Jakarta, a metropolitan urban area, from February to April 2023. This study was ethically approved by Faculty of Medicine Universitas Indonesia (No. KET-1412/UN2.F1/ETIK/PPM.00.02./2022). All participants lived in the same district as the school, ensuring a consistent local environment throughout the study. While we did not explicitly identify the socioeconomic status of the subjects, the subjects consist of students from both public and private schools suggests a heterogeneous socioeconomic background among the participants. The minimum sample size was 67 subjects for each chronotype group, based on calculation for two-tailed analysis of two independent groups with different proportions, with a 5% significancy level and 80% power. The inclusion criteria were students aged 15–20 years and willing to participate in the research. The data collection process was carried out after obtaining study location permit from the institution then collective informed consent were gathered from the higher authorities of each school. Enrolled subjects filled out 4 questionnaires consisted of the International Study of Asthma and Allergy in Childhood (ISAAC) Phase III core questionnaire, the Reduced Version Morningness-Eveningness Questionnaire (rMEQ), the Epworth Sleepiness Scale (ESS) questionnaire, and the Tobacco use and Smoking section of the Risk Factor for Non-Communicable Diseases 2011 Cohort Study Questionnaire.

ISAAC questionnaire has been translated and validated in Indonesian language (Cronbach’s alpha=0.68) in previous studies [13]. The ISAAC questionnaire was used to identify allergic rhinitis, asthma and eczema. A yes answer to question No. 1 and 2 in each allergic rhinitis, asthma and eczema section were reliable for the presence of disease. Additionally, a yes answer for question no. 7 and no. 8 in asthma section was also used to identify the presence of asthma. We did not conduct other examination since this was a survey study.

We used the rMEQ [4,6] to classify chronotype into true morning and evening type. Subjects will be classified as evening type when the total score is between 4–17 and morning type between 18–25. The rMEQ was translated into Indonesian and tested for its internal validity and reliability by the investigators of this study (Cronbach’s alpha=0.87).

ESS was used to evaluate the presence of excessive daytime sleepiness related to sleep disturbance. Score between 0–5 classifed as lower normal, 6–10 higher normal, 11–12 mild excessive, 13–15 moderate excessive, 16–24 severe excessive. Score between 11–24 classified as having excessive daytime sleepiness. The ESS questionnaire has been validated in Indonesian language (Cronbach’s alpha=0.65) [14].

The Tobacco Use and Smoking section of the Risk Factor for Non-Communicable Diseases 2011 Cohort Study Questionnaire was used to identify smoking habit [15]. Smoking was classified only based on history of smoking in the last 12 months.

Subjects who failed to fill out the questionnaires were excluded from the analysis. Analysis was done using SPSS 23.0 (IBM Corp., Armonk, NY, USA) which included univariate analysis, bivariate analysis, bivariate analysis using a chi-square test, and multivariate analysis using a double logistic regression test.

A total of 200 subjects were enrolled in the study, of which four (2%) had to be withdrawn from analysis due to their failure to fill out the questionnaires. Analysis was done on 196 subjects, which were composed of 91 (46.4%) male students and 105 (53.6%) female students, with an average age of 16.3 years old. There were 127 (64.8%) subjects with morning chronotypes and 69 (35.2%) subjects with evening chronotypes. Fifty-five (28.1%) subjects reported to have allergic rhinitis in the last 12 months. Table 1 shows the distribution of respondents based on chronotype and allergic rhinitis. Of the 69 students with evening chronotypes, 29 students were boys and 40 were girls. Meanwhile, 14 boys and 41 girls re-ported of having allergic rhinitis symptoms.

For covariate variables observed in Table 2, only 21 subjects had asthma and 19 had eczema. Almost half of studied subjects (45.4%) suffered from excessive daytime sleepiness and 27 (13.8%) subjects smoked in the last 12 months.

Based on bivariate analysis shown in Table 3, this study found that evening chronotype is significantly correlated with allergic rhinitis (p=0.011). The odds of allergic rhinitis is 2.27 greater (95% CI, 1.198–4.311) in students with evening chronotype than those with morning chronotype. There is also a significant correlation between asthma and allergic rhinitis (p=0.002). Subjects with a history of asthma in the last 12 months were 4.09 times (95% CI, 1.614–10.377) more likely to suffer from allergic rhinitis compared to those without. This study did not find any significant correlation between eczema, sleep disturbances, and history of smoking with allergic rhinitis (p>0.05).

Further analysis using logistic regression test found that asthma had a higher odds ratio for allergic rhinitis than evening chronotype. Moreover, the interaction in logistic regression analysis was not significant between the two variables (p>0.05) as shown in Table 4, meaning that asthma has no significant effect on the relationship between evening chronotype and allergic rhinitis. However, this study did not investigate or analyze the association between asthma and evening chronotypes.

This study found that 35.2% of students were classified as evening chronotypes, while majority of students were classified as morning chronotypes (64.8%). The result is similar to a previous study conducted on high school students in Norway, which found 39.9% of students as evening, 52.3% as intermediate, and only 7.8% as morning chronotypes [16]. Another study by Figueiredo and Vieira [17] reported that 20% of children aged 6–11 years old are categorized as evening chronotype. Compared to other age groups, teenagers and late adolescents have a higher proportion of those with evening chronotypes. Shifting towards evening chro-notypes among teenagers and late adolescents is associated with factors related to sedentary lifestyle and puberty. The ubiquitous use of electronic devices and increase in caffeine intake among this age group plays role in the shift to a late evening chronotype. In addition, the gonadal hormones released during puberty are known to modulate the central circadian pacemaker at the suprachiasmatic nucleus (SCN) which increase the SCN’s photic sensitivity and cause changes in the clock gene [15,17]. Skewed to eveningness is an alarming situation, as few studies also show that having evening chronotype may result in social jetlag due to a disruption in the circadian rhythm and high-risk behavior [3,16,17-19].

Allergic rhinitis is commonly found in teenagers and adolescents. Based on a study conducted by ARIA, the prevalence of allergic rhinitis is approximately 10%–25% of the world population, most of whom are teenagers and adolescents [7]. Our study found that 55 out of 196 students (28.1%) have allergic rhinitis. Of the 69 students with an evening chronotype, 27 (39.1%) had allergic rhinitis with a female predominance (74.5%), which shows a significant relationship between the evening chronotype and allergic rhinitis. In addition, our study reported that the odds of allergic rhinitis occurrence are 2.27 times higher in students with evening chronotypes compared to those with morning chronotypes. This result is in line with a previous study by Haldar et al. [6] which stated that in 13–14 years old adolescents, those with evening chronotypes are 2–4 times more likely to suffer from rhinitis symptoms than non-evening types (relative risk=2.97 [2.14– 4.11]). Similar results are also found in another study by Chen et al. [20], which reported that there is a higher allergic rhinitis OR in 7–12 years old adolescents with evening chronotype than those with morning chronotypes.

Human endogenous circadian rhythm regulates physiological, biological, and metabolic processes within a 24-hour cycle in harmony with environmental stimulus. This circadian clock is regulated by the central oscillator, namely the SCN of the hypothalamus, which synchronizes peripheral oscillators in all peripheral cells or organs. In the immune system, circadian rhythm regulates the activation, function, and trafficking of leukocytes such as T cells, B cells, basophils, mast cells, and macrophages which affect cytokine and histamine production. This regulation controls immune responses, inflammation, and maintenance of tissue integrity which influence the manifestation and severity of allergic diseases. Through the hypothalamic-pituitary-adrenal axis, the circadian rhythm also regulates the production of hormones such as glucocorticoids which modulate inflammatory pathways and immune responses, consequently affecting allergic diseases outcome [21-26].

Teenagers and adolescents with evening chronotypes are at a higher risk of experiencing disruptions in their circadian rhythms due to the misalignment of their bodies’ circadian clock with their daily activities. According to previous studies, disruption in the circadian rhythm can cause the deregulation of defense mechanisms in the airways which increases the body’s susceptibility to allergens [5,6,22]. Mast cell and basophil activation, which plays a role in allergic sensitization, are normally increased during the resting phase. However, studies have demonstrated circadian disruptions lead to increased mast cell activation during the active phase. As a result, mast cells become more easily activated at any time of day [22,27,28].

Both innate and adaptive immune response are mediated in circadian manner, ranging from leukocytes mobilization, cytokine release, and T cell differentiation. Circadian rhythm disturbances also affect the balance between Th1 and Th2 responses, leading to an increase in Th2 response, which can contribute to development of allergic diseases. It can also decrease the number of regulatory T cells (Tregs), which are crucial for preventing allergic diseases, thus potentially triggering such conditions [5].

In evening chronotypes, high artificial light exposure may suppress the production of melatonin, an immunomodulator that potentially has a role in allergy. Melatonin is known to have an effect on IFN-γ production by Treg. Reduced IFN-γ synthesis due to low melatonin level impairs Th1/Th2 homeostasis, shifting towards Th2 predominance [29-32].

All the mechanisms mentioned above can lead to an increased frequency, duration, and severity of allergic symptoms; symptoms will tend to occur all day rather than just during rest, affecting daily activities more.

Looking down from a different angle, the relationship between chronotype and allergic rhinitis most likely is bidirectional. Allergic rhinitis might act as a risk factor for chronotype shifting, from morning type towards evening type. The symptoms of allergic rhinitis can detrimentally affect one’s ability to enjoy and carry out daily activities, especially for teenagers and late adolescents who need to be active in their day-to-day lives. Studies also showed that sleeping disorders are prevalent in allergic rhinitis patients. In allergic rhinitis, several allergy-related mediators (histamine, Cys-Leukotriene, interleukin, prostaglandins, and neuropeptides) have effect on sleep. Peak histamine release occurs at night, triggers nocturnal symptoms which can hinder one’s ability to fall asleep and maintain sleep. High histamine level disrupts sleep-wake cycle, causing frequent arousal or fragmented sleep. Interleukin-4 and interleukin-10 level is associated with inhibition of sleep and increase sleep latency. Substance P, a neuropeptide, increases rapid eye movement (REM) sleep latency. All the above immunology mechanism drives a person to have a tendency to sleep late at night, causing shift towards evening chronotype. Therefore, we concluded that the relationship between chronotype and allergic rhinitis is reciprocal. However, due to its cross-sectional design, our study can only show a correlative rather than a causative relationship between chronotype and allergic rhinitis [5,7,21,22,31,33,34].

This study also found that there is a significant relationship between asthma and allergic rhinitis. The relationship between asthma and allergic rhinitis can be explained by the same genetic inheritance pattern of the two and the united airway disease (UAD) concept. The UAD concept postulates that the upper respiratory tract and the lower respiratory tract form a continuous existence in a continuum and is seen as a united system morphologically as well as physiologically, including its immune response. Based on the UAD concept, upper respiratory tract diseases like allergic rhinitis and lower respiratory tract diseases like asthma, commonly occurs with each other. Stimulation by allergens on the upper respiratory tract can induce inflammation on the lower respiratory tract and vice versa [35-38].

Despite being an allergic disease, eczema does not correlate significantly with allergic rhinitis. This may be caused by a specific history of disease for allergic diseases called the “atopic march.” The atopic march describes a phenomenon where certain allergic symptoms occur and subsides earlier than others. Eczema often occurs at earlier childhood ages whereas rhinitis and asthma occur later in adolescence, which happens because sensitization of allergens needs a longer time for asthma and rhinitis to occur. This may explain the absence of a significant correlation between eczema and allergic rhinitis [39,40].

This study shows no significant relationship between sleep disturbance and allergic rhinitis despite prior studies showing otherwise. However, an important finding from this study is the high proportion of students with excessive day time sleepiness (45.4%) regardless of their chronotype and/or presented diseases. This is an alarming situation since adolescents should be in a productive phase with an optimal physical, mental, and cognitive conditions. A lot of factors may come into play, hence the need for further studies regarding daytime sleepiness and its relationship with allergic rhinitis [41-43].

This study also found that there were no significant relationship between smoking and allergic rhinitis. Prior studies showed mixed results. One study showed that exposure to tobacco smoke at an early age can increase the incidence of allergic rhinitis symptoms. Passive or actively inhaled tobacco smoke can act as an irritant that alters the nasal microbiome, affects the inflammatory pattern, and causes epithelial dysfunction. The result of this study might show an insignificant relationship between smoking and allergic rhinitis because the questionnaire that was used to evaluate the samples’ smoking habits did not specify the duration and chronicity of smoking, frequency of smoking, or the number of cigarettes consumed daily [44,45].

Our study had several limitations. This study did not analyze other factors that could influence allergic rhinitis or chronotype, such as duration of artificial light exposure, presence of academic stressors, consumption of allergy or other medication, caffeine consumption, physical activity, and genetic predisposition. Furthermore, this study was a questionnaire-based study that relied solely on the subject’s answer. Despite the promising findings, we could not establish a causal relationship between chronotype and allergic rhinitis due to its cross-sectional design. Therefore, further research using a longitudinal design is needed to elaborate the reciprocal relationship between these factors. Studies incorporating biomarker measurements and actigraphy would also be ideal for advancing the concept of chronotherapy in allergy treatment.

In conclusion, this cross-sectional study found a significant relationship between evening chronotype and allergic rhinitis, with no confounding factors distorting the relationship between the two variables. Logistic regression analysis confirmed that none of the variables tested in the study influenced the relationship between chronotype and allergic rhinitis. Additionally, the study revealed a high proportion of students experiencing excessive daytime sleepiness, regardless of their chronotype or presence of disease, which warrants special attention. The study of chronobiology and sleep in adolescents remains an important area for research, as this age group is undergoing crucial developmental stages. Although the results of this study are promising for the prevention of allergic rhinitis, it should be interpreted with caution.