Систематический обзор и мета-анализ: корреляция между назальной обструкцией и инфекционными заболеваниями среднего уха

Актуальность. Назальная обструкция — симптом, проявляющийся в снижении потока воздуха через нос. Носовая полость соединяется со средним ухом, поэтому патологические процессы в носу могут влиять на состояние среднего уха.
Цель: Данный систематический обзор и мета-анализ были проведены для оценки взаимосвязи между назальной обструкцией и инфекционными заболеваниями среднего уха.Материалы и методы. В рамках данного исследования выполнены систематический обзор и мета-анализ. Поиск литературы проводили в следующих пяти базах данных: Pubmed, CENTRAL, DOAJ, TRIP и BMC; авторы стремились найти клинические испытания и наблюдательные исследования по данной теме. Для оценки взаимосвязи между назальной обструкцией и инфекциями среднего уха с помощью мета-анализа были рассчитаны отношение рисков (ОР) и стандартизованная разница средних (SMD) с 95% доверительными интервалами (ДИ). Анализ данных проводили с помощью программы Review Manager (RevMan) версии 5.4.0. Результаты. Всего в данный систематический обзор было включено 13 исследований, по результатам 9 из них авторы провели мета-анализ. Суммарное ОР показало тенденцию к развитию среднего отита в популя- ции с назальной обструкцией (ОР = 1,30; 95% ДИ, 0,41–4,10, p = 0,65). Анализ подгрупп не выявил значимых различий (p = 0,78) между этими показателями в отношении возникновения инфекционных заболеваний среднего уха (SMD = 0,04; 95% ДИ, -0,26–0,35). Была выявлена ассоциация между аллергической обструк- цией носа и возникновением инфекций среднего уха (ОР = 1,17; 95% ДИ, 0,08–17,64), однако этот результат не был статистически значимым (p = 0,91).
Выводы. Не было выявлено значимой связи между назальной обструкцией и инфекционными заболева- ниями среднего уха, которые могут быть вызваны различными факторами.
Ключевые слова: мета-анализ, инфекции среднего уха, назальная обструкция, средний отит, систематический обзор
Конфликт интересов. Авторы заявляют об отсутствии конфликта интересов.
Финансирование. Работа выполнена без спонсорской поддержки.

Introduction. Nasal obstruction is a symptom that manifests itself in reduced airflow through the nose. The nasal cavity is linked to the middle ear, so that pathological processes in the nose may also affect the condition of the middle ear.
Objective: This systematic review and meta-analysis were conducted to assess the relationship between nasal obstruction and middle ear infection.
Materials and Methods. This study involves a systematic review and a meta-analysis. Our literature search included the following five databases: Pubmed, CENTRAL, DOAJ, TRIP, and BMC; we aimed to find clinical trials and observational studies related to this topic. The risk ratio (RR) and standardized mean difference (SMD) with 95% confidence intervals (CI) were calculated to evaluate the relationship between nasal obstruction and middle ear infections through meta-analysis. Data were analyzed using the Review Manager (RevMan) version 5.4.0.
Results. A total of 13 studies were included in this systematic review, and we conducted a meta-analysis of 9 of them. The cumulative RR showed a tendency to develop otitis media in the population with nasal obstruction (RR
= 1.30; 95% CI, 0.41–4.10, p = 0.65). Subgroup analysis showed no significant difference (p = 0.78) between these indicators in relation to the occurrence of middle ear infection (SMD = 0.04; 95% CI, -0.26–0.35). An association with allergy was found in the nasal obstruction with the occurrence of middle ear infections (RR = 1.17; 95% CI, 0.08–17.64), but this result was not statistically significant (p = 0.91).
Conclusions. There was no significant relationship between nasal obstruction and middle ear infection, which is affected by various factors.
Keywords: A meta-analysis, middle ear infection, nasal obstruction, otitis media, systematic review
Conflict of interests. All authors have no conflict of interests
Financing. The authors report no involvement in the research by the sponsor that could have influenced the outcome of this work.

Introduction
Nasal obstruction is a symptom that manifests itself as reduced airflow through the nose. Anatomical changes in nasal structures and inflammatory processes such as allergies, toxins, infections, and foreign particles can cause nasal obstruction, which then disrupts nasal physiology such as nasal cycle and nasal airflow resistance [1]. It is more likely that most patients experience a severe degree of obstruction and have more than one anatomic cause for their nasal obstruction; however, the prevalence of such anatomic causes has not been reported [2].
Nasal obstruction can cause additional issues, such as in the ears. If there are disturbances in the nasal tract, ears will be affected; a middle ear infection (otitis media, OM) may occur. OM often begins when viral or bacterial infections that cause sore throat, colds, or other respiratory or breathing problems spread to the middle ear. As the infection worsens, too much fluid in the ear can pressure the eardrum and eventually tear it [3].
A nasal obstruction such as septal deviation also causes a decrease in ipsilateral nasal airflow and otherwise increase on contralateral, resulting in changes in the airflow patterns. This may affect the Eustachian tube function and mucociliary clearance time (MCT) itself. The MCT is the key defense mechanism in the upper airways to remove debris-laden mucus in the sinuses via wave actions of cilias[4], and it can be affected by environmental heat, moisture, trauma, smoking, viral and bacterial infections such as OM, chronic rhinosinusitis, allergic rhinitis (AR), adenoid hypertrophia, septum deviation, surgery, cystic fibrosis, chronic bronchitis, and asthma [5]. Furthermore, changes may also be experienced on the side not affected by septal deviation due to other nasal obstructions such as turbinate hypertrophy [6]. Therefore, clinicians suggest an intervention to deal with the nasal obstruction before conducting middle ear surgeries [7].
However, the clinical significance of the relationship between nasal obstruction and middle ear infection is still generally debatable. A preliminary search found that several previous systematic reviews were focused more on the effectiveness of surgery or medication specifically for several causes of nasal obstruction [7]. Therefore, a more in-depth systematic review of the relationship between them is required. confidence intervals (CI) were calculated to evaluate the relationship between nasal obstruction and middle ear infections through meta- analysis. Effect assessments were conducted using relative effect measurement in the form of RR and SMD with random-effects model and 95% CI, considering the heterogeneity (I2) between studies. Data were analyzed using the Review Manager (RevMan) version 5.4.0.

Materials and Methods
Study Design
This study included a systematic review and meta-analysis evaluating the relationship between nasal obstruction and middle ear infection.
Searching Strategies
Research articles were collected from the following five databases. The articles were then filtered using filters in each database according to eligibility criteria.
Data Collection Process
Included studies were extracted to obtain required data, following a matrix table based on the PEO framework
Data Analysis
All OM types were considered as the primary outcomes, and its complaints were considered as the secondary ones. The risk ratio (RR) and standardized mean difference (SMD) with 95%
Results Study Characteristics
A total of 13 articles that met the eligibility criteria were included in this review. The total number of participants from studies included in this review was 41,620. Their age ranged from 5 months to 59 years. Most of the participants were aged 18 years old. However, the exact number is uncertain due to the unmentioned frequency of participants per age range.Risk of Bias Within Studies
A total of five studies presented high quality, while another observational study and RCTs got the scores <7 and <3, respectively Result of Individual Studies There were 10 out of 13 studies that explained a positive relationship between nasal obstruction and middle ear infections. All studies with the RCT design, cross-sectional, and case-control generally showed a positive relationship. Meanwhile, all three cohort studies showed a negative relationship between the two variables [10-12]. These positive relationships were found in studies with participants ranging from pre-school children to adolescents. Participants aged 18 years, and another one was in a group of children. In addition, a partial negative association that was found in one study [20], other than the previous three studies, also occurred in the pediatric age group. Insignificant relationships obtained from four studies were derived from the results of the examination of nasal flow resistance and mucociliary transport time in subjects with chronic OM, mobility of tympanic membrane in subjects with nasal obstruction, the results of acoustic rhinometry in subjects with chronic OM, and the results of hearing threshold and duration of OME in subjects with adenoid hypertrophy. Synthesis of Results Meta-analysis of nine studies was performed if the studies had similar comparisons and outcomes. Effect measurements were done using relative effect measurement, namely the RR, and absolute effect measurement, namely, the SDM with random-effects model and CI95%, considering the presence of heterogeneity between studies. Data were analyzed using the Review Manager (RevMan) version 5.4.0. Seven studies were assessed to obtain an association between two variables based on their prevalence [8,9,13,14,16,17,19]. The cumulative RR indicated a tendency to develop OM in the population with nasal obstruction (RR = 1.30; 95% CI, 0.41–4.10). However, this relationship was not statistically significant (p = 0.65). The heterogeneity test showed the presence of heterogeneity in these studies (–2 = 301.91; df = 6; I2 = 98%). A visual funnel plot analysis showed asymmetry, which indicates publication bias.. Two studies [10,11] were analyzed in a subgroup analysis for several indicators regarding nasal obstruction and its association with the incidence of middle ear infection. Fig. 4 showed no significant difference (p = 0.78) between these indicators in relation to incidence of middle ear infection (SMD = 0.04; 95% CI, –0.26–0.35). Heterogeneity test showed heterogeneity in these studies (–2= 7.86; df = 2; I2 = 74.6%). Concerning allergy and atopy, two studies [13,16] were analyzed to compare AR and NAR to the occurrence of middle ear infection based on allergy test and family history of diseases. Fig. 5 indicates that there was a relationship in nasal obstruction between allergy with the emergence of middle ear infections (RR = 1.17; 95% CI, 0.08–17.64), but this result was not statistically significant (p = 0.91). The heterogeneity test showed heterogeneity in these studies (–2 = 17.48; df = 1; I2 = 94%). Discussion Summary of Evidence The option to treat nasal obstruction before middle ear infection is widely practiced by clinicians considering a connection between nose and ear anatomically and physiologically [7]. This review and meta-analysis showed a 1.3 times greater likelihood of subjects with nasal obstruction to develop middle ear infections (OM). However, this value did not reach statistical significance. Several factors might play a role in the relationship between these two variables. Although several studies revealed that nasal obstruction had important roles in the pathological condition of the middle ear, three studies [10-12] were unable to show a clear association between nasal obstruction and middle ear infections. Another consideration is that those studies with negative results were cohort studies intended to assess disease course over a longer time. Another study that found an insignificant relationship between two variables showed that changes in one of the indicators of middle ear condition, which is tympanic membrane mobility, were not affected by acute nasal obstruction. However, it is believed that removing nasopharyngeal secretions can restore normal pressure to the middle ear and normalize Eustachian tube function acutely [20]. This is in line with the consideration that inflammatory and infectious conditions causing edema of the nasal mucosa, compared to structural disorders such as septal deviation [14], are considered to play a greater role in nasal obstruction and etiopathogenesis of chronic OM[11]. The distribution of study countries of origin in this review was quite even, with the predominance of studies from the Asian continent. Most of the studies were conducted in subtropical countries with various seasons, including winter. Certain seasons are considered to contribute to allergens’ presence that triggers the emergence of nasal obstruction such as rhinitis, which then affects the middle ear condition. Middle ear infections such as OME were twice more frequent in winter than summer, as indicated by the number of children diagnosed with OME in that season [21]. Other studies also reported the need to analyze factors of the season at the birthplace of study subjects [18,22]. winter was considered to increase the frequency of the ear and upper respiratory system infections, including seasonal influenza. Having close contact with household members during winter increases the chance of spreading the infection to children [21]. Allergies are considered to play a role in nasal obstruction with middle ear infections outcome through several theories that explain that the Eustachian tube dysfunction caused by allergic inflammation occurs due to retrograde spread of edema, decreased mucociliary function, excessive venous dilation, and mucus hypersecretion [22]. An onset of nasal obstruction symptoms, such as in AR, is associated with the development of comorbidities, including OM and accompanying complaints [9]. Studies on children with a history of OME showed that 89% of these children had a history of AR, and some of them were accompanied by asthma and eczema through history, physical examination, and supporting examinations such as nasal smears, skin prick tests, number of eosinophils, and total IgE [23]. This could be related to allergy or atopy march, a course of allergy events that begins with atopic eczema and is followed by AR and/or asthma in early childhood and remains until several years later [24]. In children with a family having an allergies history, rhinovirus was found in their tympanic cavity [25]. In contrast, other studies have shown that allergies have very little effect on the pathogenesis of chronic OM disease in the age group 6–7 years. There was no difference in the prevalence of allergy complaints in children with OME inserted with ventilation tubes compared to the control group. The high prevalence of nasal obstruction symptoms in children with OME came from other accompanying nasal obstructions such as adenoid hyperplasia, resulting from allergic rhinitis [26]. This is in line with the results of a meta-analysis conducted from two studies with children who found allergies affected only 1.17 times to middle ear infections compared to nasal obstruction without allergies. However, the role of allergy or atopy in the pathogenesis of middle ear infections, especially OME, is still generally debatable. There are several possible mechanisms in which OM is triggered by nasal obstruction. Eustachian tube dysfunction is suspected to be associated with OM due to nasal obstruction. Abnormal values of the Eustachian tube function assessed by tympanometry were higher in patients with AR than in healthy individuals. Abnormal mucociliary activity due to nasal obstruction facilitated the aspiration of nasopharyngeal secretions containing pathogenic bacteria into the Eustachian tube [27,28]. Studies in this review reported a large number of study subjects from the pediatric age group. This may be due to differences in anatomy and physiology of structures associated between children and adults, such as the Eustachian tube and host immune factors [21]. Eustachian tube or auditory tube/pharyngotympanic tube is a canal connecting the nasopharynx to the anterior wall of the middle ear so that the air pressure in the tympanic cavity and nasopharynx or air pressure on both sides of the tympanic membrane remains balanced [29,30]. The eustachian tube is formed by cartilages in the anterior two-thirds (medial) and by bone in the posterior (lateral) third. The Eustachian tube is tilted downward by 45 degrees. The diameter of the Eustachian tube is different for each part. For the bony part, tubal diameter reaches 3–6 mm. When it reaches a point of transition to cartilage (isthmus), the diameter becomes narrower (about 1–2 mm) [29]. The Eustachian tube in children is more horizontal and shorter with a narrower lumen than in adults. The length of the Eustachian tube in infants is only 21 mm compared to the length of the tube in adults, which reaches 31–38 mm. Mucosal folds in the Eustachian tube lumen are found to be more numerous than in adult lumen tubes. These anatomical immaturities make it easy for infection to spread to the middle ear in children compared to adults due to poor mucociliary transport function, presence of pathogenic reflux, and inflammatory or allergic mediators from the nasopharynx, even nasogastric reflux to the middle ear [28,30,31]. Nasal obstruction is generally associated with chronic OM through allergic and upper respiratory tract infection mechanisms [32]. However, biofilms in the nose and nasopharynx independently can be the influencing factors for chronic nasal obstruction or chronic OM. Nasal biofilms cause an increase in nasal resistance, leading to Eustachian tube dysfunction as well[ 33,34]. Biofilm is a community of bacterial sessile in extracellular polymer matrix from its synthesis. This community is resistant to cell membrane disruption and has a low metabolic rate. Adhesion of biofilms on mucosal surfaces will cause host immunity disorders [21]. Increased biofilm represents a chronic inflammatory condition, such as middle ear infection and nasal obstruction caused by chronic rhinosinusitis and chronic tonsilloadenoiditis. However, the contribution of biofilms found in the middle ear accompanied by nasal obstruction to the pathogenesis of middle ear infections such as OME is still uncertain. The formation of biofilms may be a secondary effect of viral respiratory tract infection, which then triggers inflammation and mucus production, which then causes nasal obstruction [21,35]. Bacteriological culture examination on the aspiration of middle ear fluid showed the most common positive results of respiratory tract bacteria: Streptococcus pneumoniae, Haemophilus influenza, and Moraxella catarrhalis [36,37]. The culture found the most positive bacteria forming biofilms were Staphylococcus epidermidis which is commonly found in the normal nasal cavity, followed by Staphylococcus aureus, Klebsiella spp, and Proteus mirabilis in low frequency by tube method examination in patients with acute rhinosinusitis [38,39]. Approximately 66% of simple culture techniques yield negative findings for bacteria compared to polymerase chain reaction techniques, for which 36% showed positive results of S. pneumoniae intracellularly [37]. This evidence supports the existence of a defense mechanism for persistent bacteria through the formation of biofilms [21]. Two of three studies [10,11] with negative associations were included in the review to assess the unilateral middle ear infection incidence. Risk factors for middle ear infection, both unilateral and bilateral, were considered the same. Therefore, a study should focus more on patients as an analysis unit than the ear because the ear is not an independent variable [21]. Other factors were assessed in several studies, including sex and exposure to cigarettes/smoking. The difference in the risk of middle ear infection incidence in men and women is relatively small in epidemiology. However, women are considered more at risk because of changes in hormone levels, especially progesterone, that occur during pregnancy, oral contraceptive drug use, and other conditions that induce mucosal hypertrophy [21,31]. Smoking is a risk factor because it causes mucosal inflammation and continues to develop mucosal hypertrophy. A decrease in function of mucociliary transport occurs through an increase in viscosity of secretions and damage to cilia[31]. Conclusions This review revealed that there was no significant relationship between nasal obstruction and middle ear infection. Both variables can be considered when deciding whether to perform a nasal obstruction intervention before the middle ear infection intervention.