Low-Level Laser Therapy for Allergic Rhinitis: A Systematic Review and Meta-Analysis Open Access

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.

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).

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.

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.

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.

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 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.

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 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.

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.

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).

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).

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).

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%).

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).

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).

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.

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.

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

The authors have no conflicts of interest to declare.

This study was not supported by any sponsor or funder.

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.

Prospero registration ID: CRD 42023487916.Edited by: D.Y. Wang, Singapore.

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