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Abstract

Background:

Laryngopharyngeal reflux (LPR), allergic rhinitis (AR), and asthma are common airway disorders that often coexist, suggesting shared inflammatory mechanisms. LPR involves gastric reflux into the laryngopharynx, while AR and asthma are linked by the “united airway” hypothesis. Evidence indicates LPR may contribute to AR and asthma exacerbation, yet their interactions remain unclear. Understanding their interaction may enhance clinical outcomes.

Objective:

This systematic review aimed to evaluate the associations between LPR, AR, and asthma by analyzing studies that examined these conditions in various patient populations.

Methodology:

A comprehensive search of electronic databases, including PubMed, Scopus, and Google Scholar, was conducted for studies published up until 2024. Eligible studies were selected based on predefined inclusion criteria, and data on the prevalence, diagnostic methods, and associations between LPR, AR, and asthma were extracted. This systematic review was conducted and registered in PROSPERO (CRD42024588367). Statistical analysis was performed to determine the strength of the associations between these conditions.

Results:

The review identified significant associations between LPR and both AR and asthma. Multiple studies confirmed a positive correlation between LPR and AR, with worse AR symptoms observed in patients with more severe LPR. Additionally, a strong association between LPR and asthma was observed, particularly in patients with poorly-controlled asthma. The analysis also revealed a robust relationship between AR and asthma, consistent with the “united airway” hypothesis, which posits that the upper and lower airways share common inflammatory pathways. These findings suggest that the coexistence of these conditions may exacerbate symptoms and complicate management.

Conclusion:

This systematic review highlights the significant associations between LPR, AR, and asthma, emphasizing the importance of recognizing and addressing these comorbidities in clinical practice. The findings suggest that managing 1 condition may have a beneficial effect on the others, supporting a multidisciplinary approach to diagnosis and treatment.

Keywords

allergic rhinitis asthma laryngopharyngeal reflux airway inflammation systematic review

Introduction

Allergic rhinitis (AR), asthma, and laryngopharyngeal reflux (LPR) disease are prevalent chronic conditions that exhibit considerable overlap in their pathophysiology, clinical manifestations, and management strategies.¹ These disorders contribute significantly to the global burden of respiratory and gastrointestinal diseases, underscoring their widespread impact on public health.² Although each condition is distinct, their frequent co-occurrence in patients has prompted increasing interest in exploring potential interconnections and shared mechanisms underlying their development .²

AR is a chronic inflammatory disorder of the nasal mucosa triggered by allergens, leading to symptoms such as sneezing, nasal congestion, and rhinorrhea.^3,4 It is closely associated with asthma, a chronic inflammatory disease of the airways characterized by bronchial hyperresponsiveness, airway inflammation, and episodic airflow obstruction.⁵ The relationship between AR and asthma is well-documented, with extensive research indicating that AR serves as a significant risk factor for asthma development, particularly in individuals with inadequately-controlled rhinitis.^6,7

Conversely, LPR is characterized by the retrograde movement of gastric contents into the laryngopharyngeal region, resulting in symptoms such as chronic throat clearing, hoarseness, cough, and a sensation of a lump in the throat.^8,9 While LPR is classified as a subtype of gastroesophageal reflux disease (GERD), its potential role in the pathogenesis of AR and asthma has garnered increasing scientific attention.^1,10 Given the anatomical and physiological proximity of the upper airway, esophagus, and lower respiratory tract, it has been hypothesized that reflux may exacerbate or even contribute to the development of both AR and asthma.¹⁰

Emerging evidence suggests a bidirectional relationship among these conditions. AR and asthma may predispose individuals to LPR due to increased intra-abdominal pressure during episodes of coughing and sneezing, which can facilitate reflux.^1,11
-13 Conversely, LPR may exacerbate AR and asthma symptoms by inducing inflammation and hypersensitivity in the upper and lower airways.⁴

Considering the intricate interplay between these conditions, a comprehensive systematic review is warranted to clarify the nature of their correlation. The present study aimed to synthesize existing evidence to provide a comprehensive understanding of their interrelationship, which may have significant implications for the diagnosis, treatment, and management of individuals with these comorbid conditions. By examining shared pathophysiological mechanisms and potential therapeutic targets, this review seeks to contribute to a more integrated and effective approach to managing these frequently-coexisting disorders.

Despite the high prevalence of AR, asthma, and LPR, the precise nature of their interconnection remains inadequately understood, posing challenges for diagnosis and treatment.^2,3 This knowledge gap impedes the development of optimal, evidence-based therapeutic strategies, potentially leading to suboptimal patient outcomes. Addressing this issue, the current study seeks to systematically review and analyze existing literature to elucidate the correlation between AR, asthma, and LPR, thereby providing insights that may enhance clinical management and patient care.

Methodology

Study Design

The study utilized a systematic approach to investigate the correlation between AR, asthma, and LPR disease. The systematic review adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines to ensure a rigorous and transparent process in identifying, selecting, and analyzing relevant studies. This systematic review was preregistered in PROSPERO (CRD42024588367) to ensure methodological transparency and reduce reporting bias.

Eligibility Criteria

The inclusion criteria comprised studies that were randomized controlled trials (RCTs), cohort studies, case-control studies, cross-sectional studies, or retrospective studies. Eligible participants included adults diagnosed with AR, asthma, and/or LPR, and the outcomes of interest included studies reporting the prevalence of, the incidence of, or the correlation between AR, asthma, and LPR, as well as studies exploring pathophysiological mechanisms linking these conditions. Only studies published in English within the past 20 years were included to capture the most recent and relevant data. Exclusion criteria encompassed non-peer-reviewed articles such as editorials, commentaries, and letters to the editor, animal or in vitro studies, and studies lacking clear diagnostic criteria for AR, asthma, or LPR.

Search Strategy

A comprehensive literature search was conducted across several electronic databases, including PubMed, Cochrane Library, EMBASE, Scopus, and Web of Science. The search incorporated a combination of MeSH terms and free-text keywords, such as “Allergic Rhinitis,” “Asthma,” “Laryngopharyngeal Reflux,” “Gastroesophageal Reflux Disease,” “correlation,” “association,” “comorbidity,” and appropriate Boolean operators. The initial search results were imported into reference management software to manage citations and remove duplicates. Two independent reviewers screened the titles and abstracts of identified studies to determine eligibility, followed by a full-text review of potentially-eligible studies based on the inclusion and exclusion criteria. Discrepancies between the reviewers were resolved through discussion or consultation with a third reviewer.

Data Extraction

A standardized data extraction form was developed to collect relevant information from the included studies. Extracted data included study characteristics (author(s), publication year, country, study design, sample size, and follow-up duration), participant characteristics (age, gender, and diagnostic criteria for AR, asthma, and LPR), outcomes (prevalence and incidence rates, correlation coefficients, odds ratios [ORs], clinical outcomes, and management strategies), and methodological quality (risk-of-bias assessment). Two independent reviewers performed data extraction, resolving disagreements through discussion or by involving a third reviewer.

Quality Assessment

The methodological quality of the included studies was assessed using appropriate tools, including the Cochrane Risk of Bias tool for RCTs, the Newcastle-Ottawa Scale for cohort and case-control studies, and the Joanna Briggs Institute critical appraisal Tools for cross-sectional studies. Each study was evaluated for selection bias, performance bias, detection bias, attrition bias, and reporting bias. The risk of bias was categorized as low, moderate, or high, and studies with a high risk of bias were included in a sensitivity analysis to evaluate their impact on the overall findings.

Data Synthesis

A qualitative synthesis was conducted to summarize the findings from the included studies, focusing on the strength and direction of the association between AR, asthma, and LPR, as well as potential shared pathophysiological mechanisms. For the quantitative synthesis, statistical analyses were performed using Review Manager (RevMan), Version 5.4; The Cochrane Collaboration, London, UK and STATA software, Version 17; StataCorp LLC, College Station, TX, USA. Pooled ORs with 95% confidence intervals (CIs) quantified the association between AR, asthma, and LPR. A random-effects model was applied to account for heterogeneity, which was assessed using the I² statistic and Cochran’s Q test. Subgroup analyses were conducted based on factors such as study design, geographic location, and diagnostic criteria. Publication bias was assessed using funnel plots and Egger’s test.

Ethical Considerations

As the study was based on the analysis of previously-published data, it did not involve direct human or animal participation and did not require ethics approval. Nevertheless, ethical guidelines were followed to ensure the integrity and transparency of the research process, including proper citation of sources and adherence to reporting standards.

Results

Study Characteristics

This review included 14 studies that investigated the association between AR, LPR, and asthma (Figure 1).^1,14
-26 The studies included in this analysis encompass a variety of designs, populations, and geographical settings, as summarized in Table 1. Most studies were conducted in Asia (eg, Taiwan, China, and Japan), followed by Europe (eg, Belgium, Spain, and Italy) and the Middle East (eg, Saudi Arabia, Lebanon, and Syria). Sample sizes varied significantly, ranging from small-scale studies such as Komatsu et al with 31 participants²⁶ to large population-based studies such as Feng et al and Kung et al, each analyzing data for over 36 000 and 193 810 individuals, respectively.^20,23

Figure 1.

PRISMA figures showing the steps to choose the studies for systematic review. PRISMA, Preferred Reporting Items for Systematic Reviews and Meta-Analyses.

Table 1.

Study Characteristics.

Study	Year	Country	Study design	Sample size	Age (mean ± SD)	Gender (M/F)	Key population
Alharethy et al¹⁴	2018	Saudi Arabia	Cross-sectional	126	39.4 ± 21.2	56/70	Patients with suspected LPR
Hamdan et al¹⁵	2024	Lebanon	Cross-sectional	84	Not reported	N/A	Allergy patients with LPR symptoms
Feng et al²⁰	2021	Taiwan	Retrospective cohort	36 588 (AR); 36 588 (non-AR)	10.3 ± 4.9	N/A	Children with/without AR
Chang et al²¹	2022	China	Prospective case-control	102	Not reported	Not reported	Patients with suspected LPR attending ENT clinics
Wu and Liang²²	2016	China	Retrospective observational	30	Not reported	Not reported	Patients with LPR symptoms resistant to standard nasal-sinusitis treatment
Kakaje et al¹	2021	Syria	Cross-sectional	673	23.9 ± 6.6	170/503	General population surveyed online across Syria
Kung et al²³	2019	Taiwan	Retrospective cohort	193 810 (AR)	43.72 ± 16.9	Not reported	Patients diagnosed with AR with no prior history of GERD
Kurokawa et al²⁴	2022	Japan	Observational, cross-sectional	266	55.1 ± 15.6	80/186	Adult asthma patients with varying asthma control levels, assessed for reflux-related symptoms using the HARQ
Kilic et al²	2013	Turkey	Prospective cohort	50	10.8 ± 0.4	27/23	Pediatric asthma patients with mild-to-moderate asthma, grouped by controlled and uncontrolled asthma status
Komatsu et al²⁶	2013	USA	Retrospective review	31	53 (range: 23-74)	4/27	Adults with AOA
Scaramozzino et al¹⁶	2023	Italy	Clinical trial	80	20-60	50/30	Asthma patients with reflux asthma
Iqbal et al¹⁷	2024	Pakistan	Prospective cross-sectional	190	33.7 ± 13.3	84/106	Adults with asthma
Haccuria et al¹⁸	2018	Belgium	Prospective observational	78 (31 asthma, 23 rhinitis, 24 controls)	Not reported	Not reported	Patients with allergic asthma, rhinitis, and healthy controls
Acevedo-Prado et al¹⁹	2022	Spain	Multicenter, cross-sectional	21 420	6-7 and 13-14 y	Not reported	Children and adolescents in Galicia, Spain

Abbreviations: AOA, adult-onset asthma; AR, allergic rhinitis; GERD; gastroesophageal reflux disease; HARQ, hull airway reflux questionnaire; LPR, laryngopharyngeal reflux.

The studies targeted diverse populations, including patients with specific conditions such as asthma, AR, or LPR (Table 1). Age distributions spanned from pediatric populations^20,25 to adults.^17,24 Gender representation varied across studies, with a few failing to report gender data. Key populations included general community samples¹ and specific patient groups, such as those with suspected or confirmed LPR¹⁴ or asthma with or without reflux-related symptoms.

Diagnostic Tools and Measures

The methodologies employed for assessing LPR, AR, and asthma varied across studies, as detailed in Table 2. Tools for LPR assessment included symptom indices like the Reflux Symptom Index (RSI) and reflux-specific scores (eg, Hull airway reflux questionnaire [HARQ]) and objective measures such as 24 hour pH monitoring and hypopharyngeal multichannel intraluminal impedance. AR was often evaluated through questionnaires (eg, Score for Allergic Rhinitis [SFAR]) or clinical testing, while asthma diagnosis relied on standardized measures like the Asthma Control Test and spirometry.

Table 2.

Diagnostic Tools and Measures.

Study	LPR assessment	Allergy assessment	Asthma assessment	Key tools used
Alharethy et al¹⁴	24 h oropharyngeal pH monitoring	SFAR questionnaire	Not reported	SFAR, Ryan score
Hamdan et al¹⁵	RSI (>13), RSS (>13)	Allergy testing for specific allergens	Not reported	RSS, RSI, patient questionnaires
Feng et al²⁰	Not reported	National Health Insurance Database	National Health Insurance Database	Propensity score matching, Cox regression models
Chang et al²¹	24 h Dx-pH monitoring	SFAR	Not reported	Receiver operating characteristic curve analysis, statistical comparisons between LPR (+)and LPR (−)
Wu and Liang²²	LPR symptom scores over time	Symptom evaluation	Not reported	Nasal spray (azelastine hydrochloride) and anti-reflux therapy (mosapride + esomeprazole); LPR symptom scores
Kakaje et al¹	RSI	SFAR	Self-reported + demographic data	Surveys; bivariate Pearson correlation analysis between RSI and SFAR
Kung et al²³	Not reported	Medical history and diagnosis records	ICD codes from medical records	Cox regression models, Kaplan-Meier curves for GERD incidence stratified by AR and asthma
Kurokawa et al²⁴	HARQ (cutoff ≥13 for R+ group)	Not specified	ACT, FeNO, spirometry, capsaicin cough test	HARQ, FeNO, spirometry, capsaicin cough challenge test
Kilic et al²⁵	Flexible fiberoptic laryngoscopy and pH monitor	Allergy status not reported	ACT, asthma control defined by GINA guidelines	Reflux symptom questionnaire, 24 h double-probe pH monitoring, flexible laryngoscopy
Komatsu et al²⁶	HMII	Not assessed	Symptom improvement post-ARS; pulmonary function tests	HMII, high-resolution manometry, pH monitoring
Scaramozzino et al¹⁶	Not specified	Not assessed	ACT scores	Alginate therapy impact on ACT scores
Iqbal et al¹⁷	GERD score (FSSG SCALE)	Not assessed	ACT scores	FSSG SCALE for GERD, ACT for asthma control, SF-36 for QoL
Haccuria et al¹⁸	Not applicable	Sputum induction and FeNO testing	SBWT	FeNO measurement, SBWT for helium (He) and sulfur hexafluoride (SF6) to assess peripheral airway reactivity
Acevedo-Prado et al¹⁹	Not applicable	Questionnaire on rhinitis symptoms	ISAAC methodology	Validated ISAAC questionnaires, adjusted for environmental and parental factors

Abbreviations: ACT, Asthma Control Test; AR, allergic rhinitis; GERD, gastroesophageal reflux disease; GINA, global initiative for asthma; HARQ, hull airway reflux questionnaire; HMII, hypopharyngeal multichannel intraluminal impedance; ICD, international classification of diseases; ISAAC, international study of asthma and allergies in childhood; LPR, laryngopharyngeal reflux; RSI, Reflux Symptom Index; SBWT, single-breath washout test; SFAR, Score for Allergic Rhinitis.

Several studies employed advanced statistical models for analysis. For example, Feng et al and Kung et al utilized large administrative databases for retrospective cohort analyses,^20,23 while others like Chang et al used prospective designs with receiver operating characteristic curve analysis.²¹ Tools such as FeNO and capsaicin cough tests were used in specialized studies like Kurokawa et al to assess associations with reflux symptoms in patients with asthma.²⁴

Key Associations

LPR and AR Association

The relationship between LPR and AR was consistently observed across several studies (Table 3). Alharethy et al found that patients with LPR were more likely to have higher SFAR scores, indicating a positive association between AR and LPR severity (r = 0.35-0.5).¹⁴ Similarly, Chang et al identified a significant correlation between LPR and AR (OR = 2.372, P < .05), with 60% of LPR (+)patients also having AR.²¹ Kakaje et al further demonstrated a significant association between LPR symptoms and AR, with an OR of 2.592 (P < .0001).¹

Table 3.

Key Results.

Study	Prevalence (AR)	Prevalence (LPR)	LPR-AR association	LPR-asthma association	AR-asthma association
Alharethy et al¹⁴	84/126 (67%)	63/126 (50%)	LPR (+) group: higher SFAR scores; significant correlation between pH Ryan score and SFAR items (r = 0.35-0.5)	Not reported	Not reported
Hamdan et al¹⁵	57/84 (68%)	Not reported	Significant odds for RSS >13 in allergic patients (OR = 5.6, 95% CI: 1.15-27.37, P = .0345)	Not reported	Not reported
Feng et al²⁰	36 588 (AR cohort)	N/A	Adjusted HR for GERD in AR patients = 1.91 (95% CI: 1.73-2.11, P < .001)	AR (+)/asthma (−): increased GERD risk (HR = 1.85-2.74 depending on age group)	AR (+)/asthma (+): higher GERD risk than AR (−)/Asthma (−) group across all ages
Chang et al²¹	60% (LPR [+])	Not reported	AR significantly correlated with LPR (OR = 2.372, P < .05)	Not reported	Not reported
Wu and Liang²²	Not reported	100% (study population)	LPR symptoms associated with AR	Not reported	Not reported
Kakaje et al¹	50.7%	31.5%	LPR symptoms significantly associated with AR (OR = 2.592, P < .0001)	LPR symptoms significantly associated with asthma (OR = 3.096, P = .0002)	AR significantly associated with asthma (OR = 6.772, P < .0001)
Kung et al²³	100% (study population)	Not reported	AR significantly increased GERD risk (adjusted HR = 1.94, P < .001)	Not reported	AR with asthma increased GERD risk (adjusted HR = 1.98, P < .001)
Kurokawa et al²⁴	39.5% (HARQ ≥13)	Not assessed	Not directly addressed	Higher HARQ scores associated with poor asthma control, severe cough, and capsaicin cough sensitivity	AR more prevalent in uncontrolled asthma than in controlled asthma
Kilic et al²⁵	80% (pH abnormality)	70%	Not explicitly studied	No significant difference in asthma control between LPR (+) and LPR (−) patients	GERD and LPR independent of asthma control or atopy
Komatsu et al²⁶	70%	33%	Abnormal proximal exposure correlated	ARS improved asthma symptoms in 90%	GERD prevalence (41%), AR improved asthma
Scaramozzino et al¹⁶	Not specified	Not specified	Not explicitly measured	ACT improvement observed	Improved control with alginates
Iqbal et al¹⁷	71.6%	Not specified	Not explicitly measured	No significant correlation found	GERD negatively impacted QoL (specific domains)
Haccuria et al¹⁸	Not reported	Not reported	Not applicable	Not applicable	Peripheral airway dysfunction similar in AR and asthma patients
Acevedo-Prado et al¹⁹	29.4% (6-7 y), 46.2% (13-14 y)	Not reported	Not applicable	Not applicable	Rhinitis significantly increased asthma prevalence and severity

Abbreviations: ACT, asthma control test; AR, allergic rhinitis; CIs, confidence intervals; GERD, gastroesophageal reflux disease; HARQ, hull airway reflux questionnaire; LPR, laryngopharyngeal reflux; OR, odds ratio; SFAR, Score for Allergic Rhinitis.

Studies with larger cohorts also highlighted the connection between AR and LPR. Feng et al observed that AR significantly increased the risk of GERD (adjusted HR = 1.91, 95% CI: 1.73-2.11, P < .001), suggesting a broader association between upper and lower airway inflammatory conditions and reflux disorders.²⁰

LPR and Asthma Association

The association between LPR and asthma was explored in several studies. Kakaje et al reported a strong correlation between LPR symptoms and asthma (OR = 3.096, P = .0002), underscoring the interplay between reflux and respiratory symptoms.¹ Kurokawa et al identified higher HARQ scores in patients with poorly-controlled asthma, linking LPR symptoms to severe cough and heightened sensitivity to capsaicin cough tests (P < .05).²⁴

Conversely, Kilic et al found no significant impact of LPR on asthma control in pediatric patients, though abnormal pH monitoring was prevalent in 70% of the sample.²⁵ This suggests that while LPR is common in asthma patients, its role in asthma severity or control may vary.

AR and Asthma Association

The relationship between AR and asthma was one of the strongest associations observed. Feng et al found that AR combined with asthma increased the risk of GERD more than AR or asthma alone, highlighting the interconnection between these conditions.²⁰ Kakaje et al demonstrated that AR significantly correlated with asthma, with an OR of 6.772 (P < .0001) .¹

In a pediatric context, Acevedo-Prado et al found that rhinitis increased asthma prevalence and severity, with the highest OR observed for exercise-induced asthma in children aged 6 to 7 years (OR = 11.375).¹⁹ These findings emphasize the strong link between allergic conditions and airway hyperresponsiveness.

Statistical Analysis and Interpretation

The statistical methods and limitations for each study are detailed in Table 4. Across studies, ORs, correlation coefficients, and regression models were the primary tools for evaluating associations. Studies with large sample sizes (eg, Feng et al²⁰ and Kung et al²³) provided robust data but relied on administrative databases, limiting insights into symptom severity. Smaller studies (eg, Kilic et al²⁵ and Komatsu et al²⁶) offered detailed clinical evaluations but were often underpowered to draw definitive conclusions.

Table 4.

Statistical Analysis and Interpretation.

Study	Statistical methods	Key statistical findings	Limitations
Alharethy et al¹⁴	t-tests, correlation analysis	Significant differences in SFAR scores between LPR (+) and LPR (−) groups (P < .0001)	Small sample size, cross-sectional design
Hamdan et al¹⁵	ORs, P values	Allergic patients more likely to have positive RSS (OR = 5.6)	Limited sample, lack of significant RSI findings
Feng et al²⁰	Cox regression, Kaplan-Meier	AR significantly increased risk of GERD (HR = 1.91)	Pediatric population, potential confounders
Chang et al²¹	ROC curve, ORs	AR prevalence and SFAR significantly higher in LPR (+) patients (AR OR = 2.372, area under curve = 0.617)	Single-center study; limited generalizability
Wu and Liang²²	Repeated measures ANOVA	Significant reduction in LPR symptom scores posttreatment (P < .05)	Small sample size; no control group
Kakaje et al¹	Chi-square, OR, Pearson correlation	Significant association between LPR, AR, and asthma; moderate correlation between RSI and SFAR (r = 0.334, P < .0001)	Cross-sectional design limits causation inference
Kung et al²³	Cox regression, Kaplan-Meier analysis	AR patients had significantly higher GERD risk than non-AR patients (adjusted HR = 1.94, P < .001)	Retrospective design; reliance on administrative database codes; no data on LPR or asthma severity
Kurokawa et al²⁴	Multivariate analysis, Pearson correlations, P value comparisons	HARQ ≥13 associated with younger age, heightened capsaicin cough reflex sensitivity, and lower FeNO levels (P < .05)	Limited to self-reported data for HARQ; lack of direct biomarker assessment for LPR; generalizability limited
Kilic et al²⁵	ROC curves, positive and negative predictive values, pH monitoring comparisons	Reflux index ≥0.15 showed 91.4% sensitivity and 80% specificity. LPR not linked to asthma control status. Vocal nodules more common in LPR patients	Small sample size, no long-term follow-up, limited representation of severe asthma or exacerbation-prone cases
Komatsu et al²⁶	Comparative analysis, median (IQR)	90% asthma improvement post-ARS; significant esophageal injury in those with abnormal AR	Retrospective design, small sample size
Scaramozzino et al¹⁶	ROC	ACT score improvement statistically significant (P < .0001)	No specific prevalence data; limited sample size
Iqbal et al¹⁷	Cross-tabulation, P values (SF-36, ACT)	GERD patients had lower QoL scores in “role limitations,” “energy/fatigue,” and “pain”	Convenience sampling, no direct correlation between GERD and asthma control demonstrated
Haccuria et al¹⁸	ANOVA, P value analysis	Significant FeNO decrease after sputum induction in AR and asthma (P = .007 and P = .029); ΔSHe > ΔSSF6 in AR and asthma (P = .004 and P < .001)	Small sample size; lack of detailed demographic data; no direct comparison with LPR
Acevedo-Prado et al¹⁹	Logistic regression analysis	Significant OR for rhinitis and asthma symptoms (highest OR = 11.375 for EIA in 6-7 y); rhinitis prevalence was higher in the 13-14 y group than in the 6-7 y group	Cross-sectional design; limited to self-reported questionnaires; lack of direct clinical validation

Abbreviations: ACT, asthma control test; AR, allergic rhinitis; ARS, anti-reflux surgery; EIA, exercise-induced asthma; FeNO, fractional exhaled nitric oxide; HARQ, hull airway reflux questionnaire; IQR, interquartile range; GERD, gastroesophageal reflux disease; LPR, laryngopharyngeal reflux; OR, odds ratio; QoL, quality of life; ROC, receiver operating characteristic; RSI, Reflux Symptom Index; RSS, Reflux Symptom Score; SFAR, Score for Allergic Rhinitis.

Key statistical findings include the strong correlation between LPR, AR, and asthma observed in studies like Kakaje et al¹), with significant ORs for comorbid conditions. However, limitations such as cross-sectional designs, reliance on self-reported data, and small sample sizes restrict the generalizability of some findings. Overall, the studies highlight the complex interplay between reflux-related disorders, allergic conditions, and asthma.

Risk of Bias Assessment

The risk of bias assessment for the included studies revealed varying levels of concerns across different domains. Several studies, such as those by Alharethy et al and Kung et al, were classified as having “some concerns” overall, primarily due to isolated issues in specific domains. In contrast, studies by Hamdan et al, Feng et al, and Kilic et al were consistently rated with a low risk of bias across most domains, indicating stronger methodological rigor. Notably, domain-specific concerns were observed, such as in D3 and D5, where some studies like Chang et al and Scaramozzino et al demonstrated heightened risks. These findings highlight a mix of high-quality evidence and moderate concerns that necessitate cautious interpretation when integrating findings from these studies into the broader analysis (Figure 2).

Figure 2.

Risk-of-bias assessment among the included studies.

Discussion

The findings of this systematic review highlight significant associations between LPR, AR, and asthma. The results underscore the intricate interplay between reflux-related disorders and respiratory conditions, aligning with previous literature on the shared pathophysiological pathways linking these diseases.^27
-30 This discussion synthesizes the observed associations, their potential mechanisms, and their implications for clinical practice and future research.

LPR and AR Association

The positive association between LPR and AR observed in multiple studies supports the hypothesis of a shared inflammatory pathway. Alharethy et al demonstrated a significant correlation between the severity of LPR and AR symptoms, with higher reflux symptom scores associated with worse AR outcomes.¹⁴ This finding aligns with other research suggesting that nasal mucosa inflammation in AR may increase susceptibility to reflux by disrupting the nasopharyngeal barrier.^23,31
-33

Moreover, studies have suggested that the acidic content of refluxate in LPR may exacerbate nasal mucosal inflammation, further intensifying AR symptoms.^21,34,35 Such bidirectional interactions could explain the high prevalence of AR among LPR patients, as observed in large cohort studies like those by Feng et al.²⁰ These findings emphasize the need for clinicians to consider upper airway conditions as part of a comprehensive assessment in patients presenting with LPR symptoms.

LPR and Asthma Association

The association between LPR and asthma has been well-documented in the literature,^36
-38 and this review corroborates these findings. Kakaje et al reported a significant correlation between LPR and asthma, with an OR indicating a strong association between reflux symptoms and respiratory conditions.¹ The pathophysiological basis for this relationship is thought to involve micro aspiration of gastric contents and vagally-mediated reflexes, both of which can exacerbate bronchial hyperresponsiveness.^10,39

Interestingly, Kurokawa et al provided further evidence by showing that LPR symptoms were more severe in patients with poorly-controlled asthma, suggesting that uncontrolled reflux may contribute to asthma exacerbations.²⁴ However, the heterogeneity in diagnostic methods and patient populations across studies complicates the interpretation of this association. For example, Kilic et al found no significant impact of LPR on asthma control in pediatric patients, highlighting the potential age-dependent differences in the LPR-asthma relationship.²⁵

AR and Asthma Association

The robust association between AR and asthma is consistent with the “united airway” hypothesis, which posits that the upper and lower airways function as a continuous inflammatory unit.^40
-42 Feng et al observed that AR significantly increased the risk of asthma, and the presence of both conditions further heightened the likelihood of GERD.²⁰ This finding is consistent with previous studies, which reported that AR patients had a higher risk of asthma.^43,44

The strong correlation between AR and asthma observed in this review may be attributed to shared immunopathological mechanisms. AR triggers systemic inflammation and the release of cytokines, such as IL-4 and IL-13, which can exacerbate bronchial hyperresponsiveness and lead to asthma symptoms.^45,46 Additionally, untreated AR has been shown to impair asthma control, further supporting the need for an integrated approach to managing these comorbid conditions.

Role of Nonacid Components in the Unified Airway

Growing evidence indicates that the nonacid constituents of refluxate particularly pepsin and bile acids may represent a central pathogenic link between upper and lower airway disease, extending even to distal lung pathology such as idiopathic pulmonary fibrosis (IPF). Pepsin has been identified in the nasal cavity, middle ear, lungs, and bronchoalveolar lavage fluid of patients with IPF, despite being synthesized only in the stomach. Its detection in these distal sites provides strong evidence of microaspiration from silent LPR, capable of initiating epithelial injury, sustaining chronic inflammation, and promoting fibrotic remodeling independent of acid exposure.^47,48 Bile acids, frequently co-present with pepsin, have shown synergistic epithelial toxicity, amplifying inflammatory cascades and disrupting barrier integrity.⁴⁹ These observations align with the unified airway paradigm, suggesting that silent, nonacid LPR may serve as a persistent and underrecognized insult linking LPR, AR, asthma, and potentially IPF. Expanding diagnostic strategies beyond acid detection to identify and address nonacid reflux could therefore have implications not only for upper airway disease control but also for preventing progression of certain chronic lung diseases.

Implications for Clinical Practice

The overlapping symptoms and mechanisms of LPR, AR, and asthma call for a multidisciplinary approach to diagnosis and management. Screening for AR and asthma in patients with LPR, and vice versa, may improve patient outcomes by enabling early identification of comorbidities. Additionally, integrating gastroenterologists, pulmonologists, and otolaryngologists in patient management may optimize therapeutic interventions. Addressing 1 condition such as reducing reflux symptoms may help alleviate symptoms of the other conditions through shared inflammatory pathways. Management strategies should also consider the limitations of current diagnostic tools. For example, the reliance on symptom scores like the RSI or HARQ may underestimate the prevalence of asymptomatic reflux in asthma patients. Future studies should explore more robust biomarkers and objective diagnostic criteria to better delineate the relationships between these conditions.

Limitations and Future Research

Despite the compelling evidence, this review also highlights several limitations in the existing literature. Many studies were cross-sectional or retrospective, limiting causal inferences about the observed associations. Additionally, the variability in diagnostic tools and population characteristics across studies may have introduced heterogeneity into the results.

Future research should prioritize longitudinal studies with standardized diagnostic criteria to elucidate the causal pathways linking LPR, AR, and asthma. Investigating the role of novel biomarkers and genetic predispositions may also provide deeper insights into the mechanisms underlying these associations. Moreover, interventional studies evaluating the impact of treating 1 condition (eg, LPR) on the severity and control of comorbid AR or asthma could help establish evidence-based guidelines for integrated management.

Conclusion

The findings of this review highlight the significant associations between LPR, AR, and asthma, emphasizing the importance of a holistic and interdisciplinary approach to airway disease management. Recognizing and addressing the interplay between these conditions could improve patient outcomes and reduce the burden of respiratory and reflux-related disorders. Future studies should aim to address the limitations of current research and further clarify the mechanisms linking these complex conditions.

Footnotes

ORCID iDs

Laila Salah Aldokhail

Enar Mohammed Alotaibi

Yazeed Abdullah Asery

Ethical Considerations

This systematic review utilized previously-published data and did not involve human or animal subjects directly.

Author Contributions

L.S.A. conducted the literature search, creating data extracting sheet, introduction writing, and resolved any outstanding disagreements in screening. E.M.A. extracted data, methods writing, and revising the results. H.M.A. screened literatures and discussion writing. N.K.N. screened literatures, wrote the conclusion, and abstract formulation. Y.A.A. both wrote the discussion and references. B.I.A. and M.H. resolving any outstanding disagreements in screening, reviewed, and approved the final manuscript.

Funding

The authors received no financial support for the research, authorship, and/or publication of this article.

Declaration of Conflicting Interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

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Correlation Between Allergic Rhinitis,Asthma,and Laryngopharyngeal Reflux Disease: A Systematic Review

Abstract

Background:

Objective:

Methodology:

Results:

Conclusion:

Keywords

Introduction

Methodology

Study Design

Eligibility Criteria

Search Strategy

Data Extraction

Quality Assessment

Data Synthesis

Ethical Considerations

Results

Study Characteristics

Diagnostic Tools and Measures

Key Associations

LPR and AR Association

LPR and Asthma Association

AR and Asthma Association

Statistical Analysis and Interpretation

Risk of Bias Assessment

Discussion

LPR and AR Association

LPR and Asthma Association

AR and Asthma Association

Role of Nonacid Components in the Unified Airway

Implications for Clinical Practice

Limitations and Future Research

Conclusion

Footnotes

ORCID iDs

Ethical Considerations

Author Contributions

Funding

Declaration of Conflicting Interests

References