
==== Front
Int Arch Allergy Immunol
Int Arch Allergy Immunol
IAA
IAA
International Archives of Allergy and Immunology
1018-2438
1423-0097
S. Karger AG Basel, Switzerland

38663361
538049
10.1159/000538049
Clinical Allergy – Systematic Review
Low-Level Laser Therapy for Allergic Rhinitis: A Systematic Review and Meta-Analysis
Effectiveness of Low-Level Laser Therapy for Allergic Rhinitis Nasal Symptoms
2733420
Rajai Firouzabadi Shahryar
2733421
Mohammadi Ida
2733422
Aarabi Aryan
2733423
Sadraei Samin
School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
Correspondence to: Shahryar Rajai Firouzabadi, shahryarrajai@sbmu.ac.ir
Prospero registration ID: CRD 42023487916.

Edited by: D.Y. Wang, Singapore.

25 4 2024
9 2024
185 9 871883
29 1 2024
22 2 2024
2024
© 2024 The Author(s). Published by S. Karger AG, Basel
2024
https://creativecommons.org/licenses/by-nc/4.0/ This article is licensed under the Creative Commons Attribution-NonCommercial 4.0 International License (CC BY-NC) (http://www.karger.com/Services/OpenAccessLicense). Usage and distribution for commercial purposes requires written permission.
Abstract

Introduction

Allergic rhinitis (AR) is a common allergic disorder that impairs social and physical functioning as well as quality of life. It is characterized by sneezing, rhinorrhea, congestion, and itching which respond suboptimally to drug therapy. Low-level laser therapy (LLLT) has anti-inflammatory and immunosuppressive properties that have shown promise in some studies. We aimed to systematically review LLLT’s effectiveness in treating AR and meta-analyze our findings.

Methods

A systematic search of PubMed, Scopus, and Web of Science was conducted on November 24, 2023. All studies investigating LLLT on AR were included, and a pre-post meta-analysis of nasal symptoms (rhinorrhea, nasal congestion, nasal itching, and sneezing) in the LLLT-treated arm was conducted. Rhinoconjunctivitis quality of life questionnaire (RQLQ) scores before and after LLLT were also meta-analyzed alongside a pairwise meta-analysis of LLLT with placebo, acupuncture, steroids/antihistamines, and ultraviolet lasers. A random-effects model was used with a conservative pre-post correlation of 0.4 and standardized mean difference (SMD) as the effect size.

Results

Sixteen studies were included in this review, and we found that nasal symptoms are alleviated post-LLLT in people with AR (SMD: −1.4, 95 CI: [−2.07 to −1.13], p value <0.001). RQLQ scores were also reduced after LLLT (SMD = −0.72, 95 CI: [−0.94 to −0.50], p value <0.001), and very few adverse events were reported. This meta-analysis, however, had significant publication bias and heterogeneity. When compared to a placebo, LLLT did not significantly improve nasal symptoms (SMD: −0.69, p value = 0.167), which might mean the post-LLLT nasal symptom alleviation is due to a placebo effect. Comparisons to other treatment modalities were too few to deduce anything meaningful, although it does appear that LLLT is less effective than UV lasers.

Conclusion

LLLT is most likely effective at alleviating nasal symptomology and has a low likelihood of adverse event incidence, yet more high-quality studies with larger sample sizes are needed to compare LLLT to a placebo to ensure its superiority to the placebo effect, as well as non-inferiority clinical trials to compare it to standard treatments.

Keywords

Low-level laser therapy
Allergic rhinitis
Hay fever
This study was not supported by any sponsor or funder.
==== Body
pmcIntroduction

Allergic rhinitis (AR) is the inflammation of the nasal passages following exposure to allergens, affecting 20–30% of adults and up to 40% of children globally [1]. Due to its high incidence and prolonged course, AR is a common physical and psychological burden for patients, with one study, in particular, finding people with AR have worse levels of physical and social functioning, overall health perception, physical and emotional role constraints, mental health, and pain when compared to healthy control subjects [1–3]. Other studies have found that people diagnosed with AR had significantly lower quality of life [4] and a lower quality of sleep [5] when compared to healthy controls as well.

AR has a wide spectrum of presentations, including sleep problems, headaches, nasal symptoms, ocular symptoms, and sinus pressure, yet it is typically characterized by nasal itching, sneezing, rhinorrhea, and nasal congestion caused by seasonal or perennial allergens [6, 7]. It develops after an initial period of sensitization toward a particular allergen, with subsequent exposures, resulting in an allergic response. This response has two phases: an initial phase driven by the release of inflammatory substances from preexisting granules inside mast cells, and a late phase marked by the arrival of inflammatory cells, largely influenced by mast cells and the mediators they produce [1, 8]. The degranulation of mast cells and the secretion of their mediators lead to the stimulation of nearby nerve endings, angiogenesis and vasodilation, and reflex genesis, causing nasal itching, nasal congestion and rhinorrhea, and sneezing, respectively [1, 9]. The arrival of inflammatory cells like eosinophils and inflammatory cytokines like IL-4 results in recurrent symptoms [7, 10].

The Allergic Rhinitis and its Impact on Asthma (ARIA) guideline for treating AR suggests oral antihistamines and intranasal corticosteroids be used for the treatment of AR [11]. However, in real practice, medication-assisted seasonal AR symptoms are not always adequately managed, and certain patients do not respond to treatment [12]. In addition to drug therapy, there are other methods for treating AR. Immunotherapy, acupuncture, and low-level laser therapy (LLLT) have also been investigated in the literature [13]. According to several trials on new treatment modalities for AR, LLLT has been shown to reduce symptoms and improve quality of life in AR patients [2].

LLLT is a novel therapeutic method that employs light with low intensity between 600 and 1,100 nm [14]. Low-level lasers have the ability to cause photochemical responses and enhance cell metabolism without releasing heat or causing tissue damage [15]. Because their density is less than 500 mW, they are called low-power lasers; they are also known as cool lasers or soft lasers [14, 15]. In addition, it has been reported that LLLT has anti-inflammatory and immunosuppressive properties both in vitro and in animal models of allergic inflammation, and the use of LLLT in patients with AR has been studied in some clinical trials [16]. The exact mechanism of LLLT’s anti-inflammatory effect is not fully understood, yet it has been shown to decrease TNF-α, cyclooxygenase-2, prostaglandin E2, and IL-1β, as well as lower the levels of signal molecules implicated in the inflammatory cascade [17].

Even though the above-mentioned evidence promotes the application of LLLT for AR, no systematic review has been conducted on the matter. Therefore, we aimed to evaluate the effectiveness and safety of LLLT for the treatment of AR by performing a meta-analysis comparing pre-LLLT nasal symptoms to post-LLLT nasal symptoms, alongside a meta-analysis of Rhinoconjunctivitis Quality of Life Questionnaire (RQLQ) scores before and after LLLT. We further attempted to calculate the incidence of adverse events after LLLT. A pairwise meta-analysis was also performed to compare the effectiveness of LLLT with placebo, ultraviolet lasers, and acupuncture.

Methods

This systematic review and meta-analysis was conducted in accordance with PRISMA guidelines [18] in search of articles reporting the application of LLLT for AR patients. The protocol for the review was prospectively registered on PROSPERO (CRD 42023487916).

Inclusion and Exclusion Criteria

Studies were included if they met the following criteria: population: participants with a diagnosis of AR; intervention: low-level lasers inserted inside the nostrils; comparator: the same patients before administration of LLLT; outcome: participant reported nasal symptom change scores including rhinorrhea, nasal congestion, nasal itching, and sneezing, all of which are components of the total nasal symptom score (TNSS) [19]; study design: observational studies or controlled trials. No language or publication year limitations were applied. Studies were excluded if their participants were only animals, low-level lasers were not applied inside the nostrils, the participants had rhinosinusitis instead of rhinitis, or if the participants had nonallergic rhinitis. Case reports were also excluded.

Search Strategy

An online database search was conducted on PubMed, Scopus, and Web of Science on November 24, 2023. The search strings consisted of synonyms for “allergic rhinitis” and “low-level laser therapy.” The reference list of the included papers was also manually checked for studies not found in our database search.

Study Selection

Two independent reviewers screened the studies in two phases. An initial title and abstract screening are followed by full text retrieval and assessment. Disagreements between the two were resolved through discussion.

Data Extraction

A predetermined data sheet was filled out by two independent reviewers with information regarding the following: first author and year of publication, study design, and type of comparator, if applicable, country, LLLT-treated sample size, sample gender, sample age, duration of rhinitis symptoms, laser type, laser therapy regimen, single-point laser duration, type of AR (seasonal or perennial), follow-up time, total nasal symptom score, rhinorrhea score, nasal congestion score, sneezing score, nasal itching score, adverse events, and Rhinoconjunctivitis Quality of Life Questionnaire score. Disagreements between the filled-out sheets were resolved through discussion between the two authors and an independent third reviewer.

Quality Assessment

Quality assessment was conducted using the National Heart, Lung, and Blood Institutes’ quality assessment tool for before-after studies [20] by two independent reviewers; disagreements were resolved by a third reviewer.

Statistical Analysis

All statistical analyses were done using Comprehensive Meta-Analysis software (CMA, version 3, NJ, USA) [21] with means and standard deviations and mean difference and standard deviation being the only acceptable data entry form for the meta-analysis. Mean nasal symptom change scores from baseline to the last follow-up for each included study were pooled with standardized mean difference (SMD) as the effect size. If possible, TNSS were calculated and used instead. A conservative pre-post correlation coefficient of 0.4 was used in a random-effects model with a p value <0.05 being statistically significant. Heterogeneity was assessed using the I2 statistic, with an I2 >50% showcasing significant heterogeneity [22]. Meta-regressions for the frequency of sessions, total time of LLLT, and type of study (controlled trial [CT] versus. non-CT), alongside a subgroup analysis of the type of nasal symptom investigated (rhinorrhea vs. nasal congestion vs. itching vs. sneezing), were also conducted to investigate heterogeneity.

Sensitivity Analysis and Publication Bias

Sensitivity analysis was conducted using the leave-one-out method and publication bias was assessed using funnel plot symmetry and Eggers regression test. Should publication bias be evident, Duval and Tweedie’s Trim and Fill method will be applied to measure the stability of our analyses.

Results

Our search yielded 611 articles, of which a total of 20 studies were selected for full text inspection after initial screening, and 16 of these were included in the review (Fig. 1). Half of these were published in the last 5 years [2, 23–29], demonstrating revived interest in this field. With the exception of 5 articles [23, 25, 27, 29, 30], the rest were clinical trials comparing LLLT to either a placebo [2, 24, 28, 31, 32], acupuncture [13, 26], or ultraviolet-based lasers [33–35]. The lasers used had a wave length between 630 and 940 nm and an output power of 4–40 mW. Sample sizes were relatively small, ranging between 11 and 50 individuals, mostly adults with the exception of two studies [13, 31] and gender equal with the exception of five studies [25, 27, 30, 33, 34]. Treatment regimens were quite heterogeneous, with one study applying LLLT only once [24], while another applied it 60 times during the course of 3 months [31]. Most of the included papers investigated the effects of LLLT on perennial AR [2, 13, 27, 30, 34–36], while only two studied its effects on seasonal AR [32, 33] (Table 1). The method for assessment of nasal symptoms was mostly numerical rating scales with the exception of two studies [25, 35] which used a visual analog scale instead.

Fig. 1. PRISMA flowchart.

Table 1. Table of characteristics for the included studies

Author, year, country	Study design	LLLT	LLLT-treated sample size	Treatment regimen	Type of AR, duration of symptoms	
age	single-point LLLT duration, follow-up time point	
gender (% male)	
Ailioaie et al. [31], 2000, Romania	Controlled trial	GaA1As diode lasers	32	2 sessions per day, 10 days a month for 3 months	NP	
WL = 630 and 670 nm	6 months–15 years	Total sessions = 60	
Dose/nostril = 0.5–2 J/cm2	At least 2 years	
OP = 6 mW	56.25%	 NP	
 3 months	
Bella et al. [35], 2017, Hungary	Controlled trial	A light filter	11	3 sessions for a week and twice a week for 5 weeks	Persistent AR	
WL = NP	NP	Total sessions = 13	
Dose/nostril = 1.6–2.7 J/cm2	NP	
OP = NP	NP	 2–3 min	
 1 day, 1 month	
Bouboulis et al. [23], 2023, USA	Case series	LumiMed Nasal Device	20	Twice a day for 10 days	Seasonal = 13, perennial = 7	
WL = 650–690 nm	Mean of 35 years	Total sessions = 20	
Dose/nostril = 12–24 J/cm2	NP	
OP = NP	45%	 10 s	
 Less than a day	
Cingi et al. [34], 2010, Turkey	Controlled trial	Low-intensity visible light	38	3 sessions per week for 2 weeks	Persistent AR	
WL = NP	NP	Total sessions = 6	
Dose/nostril = 1.6–2.4 J/cm2	At least 2 years	
OP = NP	31.57%	 2–3 min	
 1 month	
Emberlin et al. [32], 2009, UK	Controlled trial	SN-206 phototherapy device	50	3 sessions per day for 2 weeks	Seasonal	
WL = 652 and 940 nm	At least 18 years old	Total sessions = 42	
Dose/nostril = 0.54 J/cm2	NP	
OP = NP	58%	 3 min	
 250 min	
Jiang et al. [24], 2018, Taiwan	Controlled trial	Transverse many channels laser	30	1 session	NP	
WL = 660 nm	Mean of 45.4 years	Total sessions = 1	
Dose/nostril = 36 J	NP	
OP = 40 mW	60%	 15 min	
 30 min	
Jung et al. [2]¸ 2021, South Korea	Controlled trial	AlGaInP and GaAs diode laser	22	2 sessions per day for 4 weeks of total session = 56	Perennial AR, NP	
WL = 670 and 830 nm	NP	Dose/nostril = NP	
OP = 23 mW	NP	 20 min	
 4 weeks	
Kang et al. [26], 2022, South Korea	Controlled trial	COBISTOP-S laser	40	3 sessions per week for 4 weeks	NP	
WL = 650 nm	Mean of 18.4 years	Total sessions = 12	
Dose/nostril = NP	Mean of 46.2 weeks	
OP = 4 mW	42.50%	 20 min	
 5 weeks and 9 weeks	
Kang et al. [25]¸ 2023, South Korea	Observational study	Laser type not provided	21	3 sessions per day for 4 weeks	NP	
WL = 660 + 940 nm	Median of 41.9 years	Total sessions = 84	
Dose/nostril = NP	At least 2 years	
OP = 5 mW	28.57%	 NP	
 2 weeks and 4 weeks	
Koreck et al. [33], 2005, Hungary	Controlled trial	A light filter	24	3 sessions a week for 3 weeks	Seasonal	
WL = NP	Mean of 39.25 years	Total sessions = 9	
Dose/nostril = 0.06 – NP J/cm2	Mean of 10.375 years	
OP = NP	37.50%	 NP	
 Less than a week	
Koycu et al. [27], 2023, Turkey	Observational study	Hee Allergy Reliever laser	20	Twice a day for 2 weeks followed by once a day for 2 weeks	Persistent AR	
WL = 660 + 940 nm	Mean of 32.82 years	Total sessions = 42	
Dose/nostril = NP	At least 2 years	
OP = NP	31.81%	 2–3 min	
 Less than a week	
Kennedy et al. [28], 2020, UK	Controlled trial	Laser type not provided	32	Twice a day for 3 weeks	NP	
WL = 660 + 940 nm	At least 18 years old	Total sessions = 42	
Dose/nostril = NP	At least 2 years	
OP = NP	NP	 3 min	
 Less than a week	
Lee et al. [30], 2013, South Korea	Observational study	InGaAIP laser	42	Twice a day for 4 weeks	Perennial AR	
WL = 650 nm	Mean of 43.31 years	Total sessions = 56	
Dose/nostril = 1.5–2.5 J/cm2	At least 2 years	
OP = 5 mW	66.67%	 40 s	
 Less than a week	
Moustafa et al. [13], 2013, Egypt	Controlled trial	Bionase laser	20	Twice a week for 6 weeks, 4 times each session	Perennial AR	
WL = 660 nm	7–17 years old	Total sessions = 48	
Dose/nostril = 1.89 J	From 6 months to 5 years	
OP = 7 mW	60%	 4.5 min	
 1 month and 3 months & 1 year	
Neuman et al. [36], 1997, Israel	Controlled trial	Bionase laser	50	3 sessions per day for 2 weeks	Perennial AR	
WL = 660 nm	Total sessions = 42	
Mean of 26.5 years	Dose/nostril = 1 J	Mean of 5 years	
OP = 4 mW	 4.4 min	
60%	 Less than a day		
Park et al. [29], 2019, South Korea	Observational study	LumiTherapy NoseCare laser	15	3 sessions per day for 2 weeks	NP	
WL = 660 and 940 nm	Mean of 28.9 years	Total sessions = 42	
Total dose = 0.9 J	NP	
OP = 5 mW	NP	 3 min	
 NP	
AR, allergic rhinitis; NP, not provided; OP, output power; WL, wavelength.

Analysis of nasal symptoms before and after LLLT among 433 participants showed a significant reduction in symptoms (SMD: −1.4, 95 CI: [−2.07 to −1.13], p value <0.001), although high heterogeneity was observed (I2: 67.3%) (Fig. 2). Meta-regressions for the frequency of sessions, total time of LLLT, and type of study were all insignificant (p value >0.05, online suppl. eFig. 1; for all online suppl. material, see https://doi.org/10.1159/000538049). Subgroup analysis of the nasal symptom investigated showed no significant difference between rhinorrhea, nasal congestion, itching, and sneezing symptoms improvement (data not shown).

Fig. 2. Meta-analysis of nasal symptoms severity scores after LLLT using a random-effects model.

Sensitivity Analysis and Publication Bias

Sensitivity analysis using the leave-one-out method showed the results of our meta-analysis to be stable (Fig. 3). Publication bias measured using Eggers regression test demonstrated significant publication bias (p value <0.001) with an asymmetrical funnel plot. Duval and Tweedie’s Trim and Fill method showed the results of our analyses to be stable, however, even with the significant publication bias (Fig. 4).

Fig. 3. Sensitivity analysis using the leave-one-out method.

Fig. 4. Funnel plot for inspection of publication bias. Duval and Tweedie’s Trim and Fill method is colored in black.

Quality Assessment

Quality assessment showed all but 3 of the studies had a low risk of bias, with the rest having a moderate risk of bias [23, 26] or an unclear one due to a language barrier [29] (online suppl. eFig. 2). The most common cause of bias among the papers was the lack of a statistical method to examine changes of nasal symptoms from baseline to the end of intervention. Lack of regular nasal symptom assessment during the course of LLLT was another common cause of bias (Fig. 5).

Fig. 5. Quality assessment summary graph made using RevMan [37].

Rhinoconjunctivitis Quality of Life Questionnaire

RQLQ was reported in 4 on the included studies [2, 25, 26, 30] and calculated for 125 participants. Our meta-analysis showed its significant reduction following LLLT (SMD = −0.72, 95 CI: [−0.94 to −0.50], p value <0.001) with very low heterogeneity (I2: 0%).

Adverse Events

The adverse events of LLLT were only reported in a handful of studies and were very rare, with most studies reporting no adverse events at all. The most common adverse effects were nasal dryness, nose bleeds, and nasal pain, yet even these were rarely reported by participants (Table 2).

Table 2. Adverse events reported after LLLT

Author, year, LLLT-treated sample size	Adverse events among LLLT-treated participants	
nosebleed, %	nasal pain, %	headache, %	nasal burning, %	neck pain, %	common cold, %	skin rash, %	nasal dryness, %	
Bella et al. [35], 2017, 11	18.1	18.1	9	0	0	0	0	0	
Jiang et al. [24], 2018, 30	0	3.3	6.6	3.3	0	0	0	0	
Jung et al. [2], 2021, 22	0	0	0	0	0	0	0	0	
Kang et al. [26], 2022, 40	0	0	2.5	0	5	2.5	2.5	0	
Kang et al. [25], 2023, 21	0	0	0	0	0	0	0	4.76	
Kennedy et al. [28], 2020, 32	0	0	0	0	0	0	0	0	
Koreck et al. [33], 2005, 24	0	0	0	0	0	0	0	25	
Koycu et al. [27], 2023, 22	0	0	0	0	0	0	0	0	
Lee et al. [30], 2013, 42	0	0	0	0	0	0	0	0	
Moustafa et al. [13], 2013, 20	0	0	0	0	0	0	0	0	
Neuman et al. [36], 1997, 50	0	0	0	0	0	0	0	0	
Park et al. [29], 2019, 13	0	0	0	0	0	0	0	0	
Data are presented as percentage of LLLT-treated participant who experienced the adverse event.

Pairwise Meta-Analysis

LLLT was compared to placebo lasers, acupuncture, and ultraviolet lasers in 618 participants, and one study compared LLLT and intranasal steroids/oral antihistamines with intranasal steroids/oral antihistamines alone. A similar efficacy to acupuncture and a lower efficacy in comparison to ultraviolet lasers in reducing nasal symptoms were found. LLLT and intranasal steroids/oral antihistamines were similar to steroids and antihistamines alone. The effectiveness of LLLT to a placebo was also insignificant (−0.589 [−1.424, 0.246], p value = 0.167), although it leaned toward significantly reducing nasal symptoms. No direct comparison against intranasal steroids/oral antihistamines was found in the literature (Fig. 6).

Fig. 6. Pairwise meta-analysis of LLLT with placebo or other therapeutics using a random-effects model.

Discussion

This systematic review and meta-analysis aimed to assess the safety and effectiveness of LLLT in order to reduce symptoms of AR. The meta-analysis revealed that LLLT administration significantly decreases rhinitis nasal symptoms (online suppl. eFig. 3), yet this analysis was handicapped by significant publication bias and heterogeneity. In addition, we found that LLLT significantly elevates quality of life and has very few adverse events. Comparisons to other treatment modalities are too few to deduce anything meaningful, and further studies are needed to compare it to other treatment modalities, especially standard treatments. When compared to placebo, LLLT showed a similar efficacy, which could mean the before-after therapeutic effect we mentioned above is attributable to a placebo effect. The quality of the included studies was another point of concern, and we advise future clinical trials to assess nasal symptoms throughout the course of their treatment to ensure a low risk of bias.

The standard approach to AR’s management predominantly revolves around strategies aimed at mitigating and regulating the immune reactivity to allergenic stimuli. The frontline intervention for AR entails pharmacotherapy, and specifically either corticosteroids or antihistamines [38]. Surprisingly, there is no report in the literature comparing the effects of intranasal steroids/oral antihistamines with LLLT, and only one report comparing LLLT and intranasal steroids/oral antihistamines with intranasal steroids/oral antihistamines alone and concluded no statistical difference between the two arms [24]. Additionally, among the non-pharmacologic therapies, acupuncture has been suggested to have anti-inflammatory effects that mitigate rhinitis, and our analysis found that its efficacy is similar to that of LLLT. Among the treatments LLLT was compared to, only ultraviolet laser was shown to be more effective. UV’s superiority can be attributed to the fact that lower wavelengths have more pronounced effects on tissues [39] by attenuating the expression of proteins involved in inflammation such as IL-1a, IL-1β, IL-31, ICAM-1 protein, and E-selectin [40]. When compared to a placebo, however, LLLT was not significantly better in reducing nasal symptoms, yet a large portion of the confidence interval was in favor of LLLT, and 3 of the 4 studies used in the meta-analysis were in favor of LLLT as well, highlighting the need for further research comparing LLLT to a placebo. The similar result of LLLT compared to placebo may also explain the before-after therapeutic effect we observed in our meta-analysis, as the placebo effect in AR reduces nasal symptoms by 15% [41]. Two recent randomized clinical trials by Schaefer et al. [42, 43] have also shown that an open-label placebo improved symptoms of AR. With such a significant placebo effect in AR, the before-after therapeutic effect may be mostly due to the placebo effect, even though we used a pre-post coefficient of 0.4.

The anti-inflammatory properties of LLLT undergird its therapeutic effect on inflammatory diseases such as AR. A systematic review of LLLT in preclinical studies in inflammatory models has revealed that there is compelling evidence of an anti-inflammatory effect from LLLT strong enough to rival that of NSAIDs [44]. It was shown that LLLT exerts this effect in the initial phase of inflammation by cellular and biochemical reactions, i.e., lowering the expression of cyclooxygenase-2 [45], interleukin-1 [46], tumor necrosis factor-α [47], prostaglandin E2 [48], and plasminogen activator [49], thus lessening the eventual histological reaction to inflammation. During the secondary phase of the inflammation, the impact occurs via reducing the magnitude of the histological reaction to inflammation, i.e., decreasing edema [50] and neutrophil cell count [51] in the tissue. The superiority of these LLLT-induced effects to a placebo effect is not evident in our work, and further studies investigating LLLT’s anti-inflammatory effects in humans are required. Further studies are also needed to see whether these preclinical findings translate to human AR patients.

Besides being efficacious, the use of LLLT to treat AR is also without risk. Dryness of the nasal mucosa, erythema, pain, pruritus, and pigmentation are some of the potential adverse events [2], with very few of these events developing in the included studies. The risk of other adverse events was also very low among the studies, although the documentation of adverse events was not conducted in full, with some studies only logging adverse events reported by the patients instead of actively searching for adverse events. In addition, there is concern that LLLT increases the number of mast cells and their degranulation, as discovered by studies on injured cutaneous tissue [52]. This phenomenon, however, does not appear to be present in atopic animal models, which suggest that in fact, LLLT decreases mast cell numbers [53].

Our study has several limitations. First, we found our results to be heterogeneous (I2 = 67%) and could not justify this heterogeneity through our meta-regressions and subgroup analyses. Further, there was no study directly comparing LLLT to the standard therapy, intranasal steroids/oral antihistamines, and further studies are needed to bridge this gap in the literature. We recommend high-quality non-inferiority clinical trials with repeated assessments of nasal symptoms during treatment be conducted to fill in this gap. Significant publication bias is another limitation which may be due to the studies low sample sizes, rendering their findings insignificant and less likely to be published. Therefore, we suggest that future trial to increase their sample sizes as well. The small sample sizes of the included studies are another limitation, which could have affected our results. The self-report nature of nasal symptom improvement may have also affected our results in ways we cannot discern. We recommend future studies on the matter utilize rhinomanometry or acoustic rhinometry to avoid self-report bias.

Conclusion

LLLT is most likely an efficacious treatment of AR with a low risk of adverse events; however, as the current evidence has proven to be heterogeneous and comparisons to placebo have not yet shown significance, additional larger studies with high quality comparing LLLT to standard treatments and placebos are required to ensure its superiority to the placebo effect as well as non-inferiority to standard treatments before it can be added to a clinician’s armamentarium.

Statement of Ethics

An ethics statement is not applicable because this study is based exclusively on published literature.

Conflict of Interest Statement

The authors have no conflicts of interest to declare.

Funding Sources

This study was not supported by any sponsor or funder.

Author Contributions

Shahryar Rajai Firouzabadi: conceptualization, data curation, formal analysis, investigation, methodology, project administration, writing – original draft preparation, and writing – review and editing; Ida Mohammadi: data curation, investigation, methodology, project administration, writing – original draft preparation, and writing – review and editing; and Aryan Aarabi and Samin Sadraei: investigation and writing – original draft preparation.

Data Availability Statement

All relevant data are provided in the review. Further inquiries can be directed to the corresponding author.

Supplementary Material
==== Refs
References

1. Zoabi Y , Levi-SchafferF, EliasharR. Allergic rhinitis: pathophysiology and treatment focusing on mast cells. Biomedicines. 2022;10 (10 ):2486.36289748
2. Jung HJ , ChungYJ, ChoiYS, ChungPS, MoJH. Clinical efficacy and safety of low-level laser therapy in patients with perennial allergic rhinitis: a randomized, double-blind, placebo-controlled trial. J Clin Med. 2021;10 (4 ):772.33671931
3. Meltzer EO . Quality of life in adults and children with allergic rhinitis. J Allergy Clin Immunol. 2001;108 (1 Suppl l ):S45–53.11449206
4. Blaiss MS . Cognitive, social, and economic costs of allergic rhinitis. Allergy and asthma proceedings OceanSide Publications; 2000.
5. Komnos ID , MichaliMC, AsimakopoulosAD, BasiariLV, KastanioudakisIG. The effect of allergic rhinitis on quality of life in patients suffering from the disease: a case control study. Int J Otolaryngol Head Neck Surg. 2019;08 (04 ):121–31.
6. Costa TMR , CarneiroFM, OliveiraKAS, SouzaMFB, AvelinoMAG, WastowskiIJ. Rhinophototherapy, an alternative treatment of allergic rhinitis: systematic review and meta-analysis. Braz J Otorhinolaryngol. 2021;87 (6 ):742–52.33663975
7. Small P , KeithPK, KimH. Allergic rhinitis. Allergy Asthma Clin Immunol. 2018;14 (Suppl 2 ):51.30263033
8. Baraniuk JN . Pathogenesis of allergic rhinitis. J Allergy Clin Immunol. 1997;99 (2 ):S763–72.9042069
9. Togias A . Unique mechanistic features of allergic rhinitis. J Allergy Clin Immunol. 2000;105 (6 Pt 2 ):S599–604.10856164
10. Pawankar R , MoriS, OzuC, KimuraS. Overview on the pathomechanisms of allergic rhinitis. Asia Pac Allergy. 2011;1 (3 ):157–67.22053313
11. Klimek L , BachertC, PfaarO, BeckerS, BieberT, BrehlerR, . ARIA guideline 2019: treatment of allergic rhinitis in the German health system. Allergol Select. 2019;3 (1 ):22–50.32176226
12. Emeryk A , Emeryk-MaksymiukJ, JaneczekK. New guidelines for the treatment of seasonal allergic rhinitis. Postepy Dermatol Alergol. 2019;36 (3 ):255–60.31333340
13. Moustafa Y , KassabAN, El SharnoubiJ, YehiaH. Comparative study in the management of allergic rhinitis in children using LED phototherapy and laser acupuncture. Int J Pediatr Otorhinolaryngol. 2013;77 (5 ):658–65.23394792
14. AlGhamdi KM , KumarA, MoussaNA. Low-level laser therapy: a useful technique for enhancing the proliferation of various cultured cells. Lasers Med Sci. 2012;27 (1 ):237–49.21274733
15. Farivar S , MalekshahabiT, ShiariR. Biological effects of low level laser therapy. J Lasers Med Sci. 2014;5 (2 ):58–62.25653800
16. Bae JS , KimSH, KimJH, KimEH, LyuL, ChungPS, . Effects of low-level laser irradiation in a mouse model of allergic rhinitis. Lasers Surg Med. 2020;52 (4 ):347–57.31338850
17. Gao X , XingD. Molecular mechanisms of cell proliferation induced by low power laser irradiation. J Biomed Sci. 2009;16 (1 ):4–16.19272168
18. Page MJ , McKenzieJE, BossuytPM, BoutronI, HoffmannTC, MulrowCD, . The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. Int J Surg. 2021;88 :105906.33789826
19. Ellis AK , SolimanM, SteacyL, BoulayMÈ, BouletLP, KeithPK, . The Allergic Rhinitis–Clinical Investigator Collaborative (AR-CIC): nasal allergen challenge protocol optimization for studying AR pathophysiology and evaluating novel therapies. Allergy Asthma Clin Immunol. 2015;11 (1 ):16–0.25945101
20. Quality assessment tool for before-after (Pre-Post) studies with no control group. [cited 2021 July]; Available from: https://www.nhlbi.nih.gov/health-topics/study-quality-assessment-tools.
21. Borenstein M . Comprehensive meta-analysis software. Systematic reviews in health research: meta-analysis in context; 2022; p. 535–48.
22. Chochrane Handbook, Chapter 9.5.2: Identifying and measuring heterogeneity. Available from: https://handbook-5-1.cochrane.org/chapter_9/9_5_2_identifying_and_measuring_heterogeneity.htm.
23. Bouboulis D , HuffA, BurawskiL. Twenty cases of perennial and seasonal allergic rhinitis treated with LumiMed® Nasal Device. J Med Case Rep. 2023;17 (1 ):263.37312188
24. Jiang RS , WangJJ. Effect of red light rhinophototherapy on nasal patency in patients with allergic rhinitis. Int J Otolaryngol. 2018;2018 :6270614.30647740
25. Kang JW , LimJA, LeeHC, ParkJH, HanSH. Treatment effect of phototherapy with low-level energy in patients with allergic rhinitis: a single-arm observational study. Medicina. 2023;59 (2 ):226.36837427
26. Kang J , SonM, KimY, LeeE, HeoN, KimN, . Intranasal low-level laser therapy versus acupuncture treatment for allergic rhinitis: a randomized, noninferiority trial. Explore. 2022;18 (6 ):676–82.35246396
27. Koycu A , BasC, MusabakUH, ErbekSS, KocaHS, BabakurbanST, . Effects of combined visible and infrared light rhinophototherapy in patients with allergic rhinitis. Am J Rhinol Allergy. 2023;37 (1 ):65–73.36266929
28. Kennedy R , RobertsonL. Study on the effect of phototherapy for inhibition of symptoms associated with allergic rhinitis. Eur Ann Allergy Clin Immunol. 2020;52 (2 ):66–73.31594294
29. Park EW . Effect of red and infrared LED light therapy on allergic rhinitis. J Biomed Eng Res. 2019;40 (4 ):125–31.
30. Lee HM , ParkMS, ParkIH, LeeSH, LeeSK, KimKS, . A comparative pilot study of symptom improvement before and after phototherapy in Korean patients with perennial allergic rhinitis. Photochem Photobiol. 2013;89 (3 ):751–7.23253070
31. Ailioaie L , AilioaieC, TopoliceanuF. Self-organizing phenomena at membrane level and low level laser therapy of rhinitis. Proceedings of SPIE - The International Society for Optical Engineering; 2000.
32. Emberlin J , LewisR. Pollen challenge study of a phototherapy device for reducing the symptoms of hay fever. Curr Med Res Opin. 2009;25 (7 ):1635–44.19476405
33. Koreck AI , CsomaZ, BodaiL, IgnaczF, KenderessyAS, KadocsaE, . Rhinophototherapy: a new therapeutic tool for the management of allergic rhinitis. J Allergy Clin Immunol. 2005;115 (3 ):541–7.15753902
34. Cingi C , CakliH, YazA, SonguM, BalC. Phototherapy for allergic rhinitis: a prospective, randomized, single-blind, placebo-controlled study. Ther Adv Respir Dis. 2010;4 (4 ):209–13.20587541
35. Bella Z , KiricsiÁ, ViharosnéÉDR, DallosA, PerényiÁ, KissM, . Rhinophototherapy in persistent allergic rhinitis. Eur Arch Oto-Rhino-Laryngol. 2017;274 (3 ):1543–50.
36. Neuman I , FinkelsteinY. Narrow-band red light phototherapy in perennial allergic rhinitis and nasal polyposis. Ann Allergy Asthma Immunol. 1997;78 (4 ):399–406.9109708
37. Review manager 5 (RevMan 5). Copenhagen: The Cochrane Collaboration; 2020.
38. Sur DK , ScandaleS. Treatment of allergic rhinitis. Am Fam Physician. 2010;81 (12 ):1440–6.20540482
39. Taradaj J , HalskiT, KucharzewskiM, UrbanekT, HalskaU, KucioC. Effect of laser irradiation at different wavelengths (940, 808, and 658 nm) on pressure ulcer healing: results from a clinical study. Evid Based Complement Alternat Med. 2013;2013 :960240.24159357
40. Cios A , CieplakM, SzymańskiŁ, LewickaA, CierniakS, StankiewiczW, . Effect of different wavelengths of laser irradiation on the skin cells. Int J Mol Sci. 2021;22 (5 ):2437.33670977
41. Benninger M , FarrarJR, BlaissM, ChippsB, FergusonB, KrouseJ, . Evaluating approved medications to treat allergic rhinitis in the United States: an evidence-based review of efficacy for nasal symptoms by class. Ann Allergy Asthma Immunol. 2010;104 (1 ):13–29.20143641
42. Schaefer M , SahinT, BerstecherB. Why do open-label placebos work? A randomized controlled trial of an open-label placebo induction with and without extended information about the placebo effect in allergic rhinitis. PLoS One. 2018;13 (3 ):e0192758.29513699
43. Schaefer M , ZimmermannK, EnckP. A randomized controlled trial of effects of open-label placebo compared to double-blind placebo and treatment-as-usual on symptoms of allergic rhinitis. Sci Rep. 2023;13 (1 ):8372.37225724
44. Bjordal J , Lopes-MartinsRAB, JoensenJ, IversenVV. The anti-inflammatory mechanism of low level laser therapy and its relevance for clinical use in physiotherapy. Phys Ther Rev. 2010;15 (4 ):286–93.
45. Pourzarandian A , WatanabeH, RuwanpuraSMPM, AokiA, NoguchiK, IshikawaI. Er:YAG laser irradiation increases prostaglandin E production via the induction of cyclooxygenase-2 mRNA in human gingival fibroblasts. J Periodontal Res. 2005;40 (2 ):182–6.15733154
46. Shimizu N , YamaguchiM, GosekiT, ShibataY, TakiguchiH, IwasawaT, . Inhibition of prostaglandin E2 and interleukin 1-beta production by low-power laser irradiation in stretched human periodontal ligament cells. J Dent Res. 1995;74 (7 ):1382–8.7560389
47. Aimbire F , AlbertiniR, PachecoMTT, Castro-Faria-NetoHC, LeonardoPSLM, IversenVV, . Low-level laser therapy induces dose-dependent reduction of TNFalpha levels in acute inflammation. Photomed Laser Surg. 2006;24 (1 ):33–7.16503786
48. Sakurai Y , YamaguchiM, AbikoY. Inhibitory effect of low-level laser irradiation on LPS-stimulated prostaglandin E2 production and cyclooxygenase-2 in human gingival fibroblasts. Eur J Oral Sci. 2000;108 (1 ):29–34.10706474
49. Ozawa Y , ShimizuN, AbikoY. Low-energy diode laser irradiation reduced plasminogen activator activity in human periodontal ligament cells. Lasers Surg Med. 1997;21 (5 ):456–63.9365956
50. Honmura A , YanaseM, ObataJ, HarukiE. Therapeutic effect of Ga-Al-As diode laser irradiation on experimentally induced inflammation in rats. Lasers Surg Med. 1992;12 (4 ):441–9.1495372
51. Aimbire F , AlbertineR, de MagalhãesRG, Lopes-MartinsRAB, Castro-Faria-NetoHC, ZângaroRA, . Effect of LLLT Ga-Al-As (685 nm) on LPS-induced inflammation of the airway and lung in the rat. Lasers Med Sci. 2005;20 (1 ):11–20.15965713
52. Pereira MCM , de PinhoCB, MedradoARP, AndradeZA, ReisSRA. Influence of 670 nm low-level laser therapy on mast cells and vascular response of cutaneous injuries. J Photochem Photobiol B. 2010;98 (3 ):188–92.20117017
53. Kim YL , LimHS, LeeSM. Effect of low-level laser intervention on dermatitis symptoms and cytokine changes in DNCB-induced atopy mouse model: a randomized controlled trial. Exp Ther Med. 2021;22 (5 ):1196.34584541
