Prognostic Role of Neutrophil to Lymphocyte Ratio in Allergic Rhinitis: A Systematic Review and Meta-analysis

Abstract

One of the crucial triggers of allergic diseases is an inflammatory reaction and neutrophil to lymphocyte ratio (NLR) is one of the systemic inflammation biomarkers. Our review aimed to evaluate role of NLR in predicting severity and comorbidities of allergic rhinitis (AR). We systematically searched Scopus, Web of Science, and PubMed to find relevant studies. Standardized mean difference (SMD) with a 95% confidence interval (CI) was reported. Due to the high levels of heterogeneity, the random-effects model was used to generate pooled effects. Eleven articles were included in the systematic review, among which ten were included in meta-analysis including 1122 healthy controls and 1423 patients with AR. We found that patients with AR had a significantly higher level of NLR than healthy controls (SMD = 0.19, 95%CI = 0.03–0.36, P = 0.03). In addition, patients with moderate to severe AR had significantly higher levels of NLR compared to those with mild AR (SMD = 0.41, 95%CI = 0.20–0.63, P < 0.001). Interestingly, it was found that NLR could associate with some comorbidities of AR, like asthma. Our results confirmed that NLR could assist clinicians in predicting the severity and comorbidities of AR.

Supplementary Information

The online version contains supplementary material available at 10.1007/s12070-023-04148-8.

Introduction

About 15–25% of people globally suffer from allergic rhinitis (AR) [1]. Nasal congestion, runny nose, sneezing, and itching are all symptoms of AR. AR, a heterogeneous illness, is an IgE-mediated immunologic response to aeroallergens that causes systemic and localized nasal inflammation [2]. Exposure to outdoor or indoor allergens can sensitize patients suffering from AR [3]. Although AR is not a life-threatening illness, it can impair daily routine life by reducing the quality of life, decreasing sleep quality, and negatively affecting patients’ performance at work.

There is a link between AR and systemic inflammation, as demonstrated in prior studies [4]. Also, NLR can be a crucial sign of systemic inflammation and can be easily measured by taking a patient’s blood sample [5–7]. According to previous investigations, several human illnesses have been linked to increased levels of neutrophil-to-lymphocyte ratio (NLR) [8]. In various medical diseases, such as pharyngitis, obstructive sleep apnea, malignancies, sepsis, infectious diseases, major cardiac events, and ischemic stroke NLR has been widely associated with disease progression and patient outcomes [9–18]. These relationships can demonstrate that mentioned illnesses might develop due to severe inflammation and immune system dysfunction.

As previously mentioned, the role of inflammation was proved in AR, so studying NLR in this disease makes sense. We conducted this systematic review and meta-analysis to assemble all information on the prognostic role of the NLR in AR and determine whether NLR is associate with disease severity and comorbidities. By doing this, we aim to improve clinicians’ understanding of AR and the role of inflammation in this disorder.

Materials and Methods

This meta-analysis was carried out based on the Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) guideline.

Literature Search Strategy

We carried out a systematic search using various combinations of the keywords “Allergic rhinitis,” “neutrophil to lymphocyte ratio,” and “NLR” in the SCOPUS, PUBMED, and WEB OF SCIENCE databases from the beginning to July 2023 to find studies that assessed the relationship between AR and NLR. Also, we carefully reviewed relevant articles’ reference lists for potentially related studies.

Inclusion/Exclusion Criteria

PICOS (population, intervention, control, outcomes, and study design) principle was followed for study selection.

Primary Outcome

The PICO for the primary outcome, which was the differences between patients with moderate to severe AR and those with mild AR in NLR level, was as follows:

1. Population: Patients with moderate to severe AR

2. Intervention: Severe nasal polyps

3. Control: Patients with mild AR

4. Outcomes. NLR

Secondary Outcome

For the secondary outcome, which was the differences in NLR level between AR patients and healthy controls, the PICO was as follows:

1. Population: AR patients

2. Intervention: Diagnosed AR

3. Control: Healthy controls

4. Outcomes: NLR

In addition, we included studies reporting the relationship between NLR and AR commodities for qualitative review.

The articles’ language or publication date had no impression on reviewing them. Studies were excluded if 1) the data was insufficient; 2) they were duplicated articles; 3) participants were a known case of infections, severe systematic diseases, or autoimmune problems; and 4) letters, reviews, case reports, or conference reports.

Using the exclusion and inclusion criteria, two reviewers independently chose articles that fulfilled the requirements. The selected studies by the two reviewers were compared, and any disagreements between the lists were settled by discussion or via contact with the corresponding author.

Data Extraction

In the meta-analysis, the extracted data from the included articles were as follows: The study design, the sample size, the number of cases and controls, the age group (children or adults), the first author’s name, the nation, the publication year, the severity of AR, and the mean and standard deviation of the NLR.

Studies with a sample size of more than 200 were categorized as large. Two reviewers independently extracted the data using the abovementioned inclusion and exclusion criteria. Any disagreements were cleared up by discussion.

Quality Assessment

Two reviewers independently evaluated the included studies’ quality using the Newcastle–Ottawa Scale (NOS), which has a total score range of 0 to 9. (0–3: low quality, 4–6: moderate quality, and 7–9: high quality). The reviewers settled the differences by discussion.

Statistical Analysis

Standardized mean difference (SMD) and 95% confidence interval (CI) were used to compare the differences in NLR levels between groups. The between-study heterogeneity was assessed using Cochran’s x²-based Q-statistic test and was quantified by the I² value.

Heterogeneity was considered statistically significant if the I² > 50% or P < 0.10. For the pooling analysis, there were two potential models; if significant heterogeneity was confirmed, the random-effect model was used. Otherwise, the other model, the fixed-effect model, was applied. Furthermore, subgroup analysis was carried out according to study design, sample size, NOS score, and age group. By using the Egger’s and Begg’s tests and visual checking of the funnel plot, publication bias was detected. If the P < 0.10, it was deemed statistically significant.

This meta-analysis was conducted with the help of the STATA software package (Version 10, Stata Corporation, College Station, TX). All P values are two-tailed.

Results

Search Results and Included Studies

Our initial search yielded a total of 135 results. Figure 1 shows the multiple stages of study selection. Finally, eleven articles were included in the systematic review[19–29], among which ten were included in meta-analysis[19–26, 28, 29], including 1122 healthy controls and 1423 patients with AR. Table 1 shows the general features of the included articles in meta-analysis.

Fig. 1.

PRISMA 2020 Flow diagram for new systematic reviews, which includes searches of databases, registers, and other sources

Table 1.

General characteristics of included studies in meta-analysis

First author	Year	Country	Design	Sample size	Age group	Allergic rhinitis						Heathy controls		NOS score
						Total		Mild		Moderate to severe		N	NLR
						N	NLR	N	NLR	N	NLR
Dogru	2015	Turkey	R	618	Children	438	1.77 ± 1.67	132	1.58 ± 1.21	306	1.85 ± 1.82	180	1.70 ± 1.65	8
Akgedik	2017	Turkey	R	135	Adults	60	1.56 ± 0.67	–	–	–	–	75	1.72 ± 0.61	6
Ekisi	2019	Turkey	R	196	Children	136	1.65 ± 0.90	45	1.48 ± 0.73	91	1.90 ± 1.13	60	1.42 ± 0.93	6
Goker	2019	Turkey	P	452	Adults	209	2.02 ± 1.24	76	1.62 ± 0.59	133	2.25 ± 1.45	243	1.70 ± 0.65	7
Ha	2019	Korea	P	271	Children	99	1.18 ± 1.69	–	–	–	–	172	1.02 ± 0.50	8
Yazici	2019	Turkey	R	92	Adults	46	2.04 ± 0.70	–	–	–	–	46	1.93 ± 0.70	6
Cansever	2022	Turkey	R	360	Children	200	1.64 ± 1.29	–	–	–	–	160	1.18 ± 0.31	6
Branika	2020	Poland	P	44	Adults	44	–	24	1.91 ± 2.11	20	5.19 ± 9.72	–	–	7
Rohila	2023	India	P	140	Adults	70	1.92 ± 0.66	35	1.68 ± 0.33	35	2.15 ± 0.81	70	1.54 ± 0.48	7
Selcuk	2022	Turkey	R	237	Adults	121	2.17 ± 1.15	–	–	–	–	116	2.27 ± 0.98	8

N Number; NLR Neutrophil to lymphocyte ratio; NOS Newcastle–ottawa quality assessment scale; R Retrospective; P Prospective

Primary Outcome: Differences Between Patients with AR and Healthy Controls in NLR Level

Patients with moderate to severe AR had significantly higher levels of NLR compared to those with mild AR (SMD = 0.41, 95%CI = 0.20–0.63, P < 0.001, Fig. 2).

Fig. 2.

Meta-analysis of differences in NLR level between patients with AR and healthy controls

classifying studies into two groups of studies on children and adults revealed that NLR was higher in moderate to severe AR than other group in both groups of studies (SMD = 0.24, 95%CI = 0.01- 0.47, P = 0.03, SMD = 0.57, 95%CI = 0.34- 0.80, P < 0.001, respectively, Figure S1).

Subgrouping according to study design showed higher levels of NLR among patients with more severe form than other group among either retrospective (SMD = 0.24, 95%CI = 0.01–0.47, P = 0.03) or prospective (SMD = 0.57, 95%CI = 0.34–0.80, P < 0.01) studies (Figure S2).

Classifying studies into two groups of high and moderate quality studies revealed that NLR was higher in moderate to severe AR than other group in both groups of studies (SMD = 0.43, 95%CI = 0.15–0.71, P < 0.01, SMD = 0.41, 95%CI = 0.05–0.77, P = 0.02, respectively, Figure S3).

When classifying studies according to sample size, we found higher level of NLR among patients with moderate to severe AR compared to other group in small studies (SMD = 0.53, 95%CI = 0.27–0.79, P = 0.03) but not in large studies (SMD = 0.33, 95%CI =  − 0.02–0.68, P = 0.06, Figure S4).

Secondary Outcome: Differences Between Patients with AR and Healthy Controls in NLR Level

Significantly higher values of NLR was observed in AR patients compared to healthy controls (SMD = 0.19, 95%CI = 0.03–0.36, P = 0.03, Fig. 2).

Subgroup analysis based on age group yielded that that AR patients had a significantly higher level of NLR compared to healthy controls among children (SMD = 0.22, 95%CI = 0.02–0.43, P = 0.03) but not among adults (SMD = 0.16, 95%CI =  − 0.13–0.46, P = 0.28, Figure S5).

Subgroup analysis based on design of studies showed that the NLR level of patients with AR was significantly higher compared to that of healthy controls in prospective studies (SMD = 0.35, 95%CI = 0.11–0.60, P = 0.03), but not in retrospective studies (SMD = 0.10, 95%CI =  − 0.11–0.32, P = 0.5, Figure S6).

Subgroup analysis based on NOS scores of included studies demonstrated that the NLR level of patients with AR was similar to that of healthy controls in moderate (SMD = 0.17, 95%CI =  − 0.14 –0.49, P = 0.27) or high-quality studies (SMD = 0.20, 95%CI =  − 0.01–0.41, P = 0.06, Figure S7, Fig. 3).

Fig. 3.

Meta-analysis of differences in NLR level between patients with moderate to severe AR and those with mild AR

In the subgroup analysis according to sample size, we found that the NLR level of patients with AR was similar to that of healthy controls in either large (SMD = 0.18, 95%CI =  − 0.01–0.38, P = 0.06) or small studies (SMD = 0.19, 95%CI = 0.03–0.38, P = 0.27, Figure S8).

Publication Bias

Funnel plots showed no publication bias among studies on either primary (Egger’s test P = 0.06, Begg’s test P = 0.4) or secondary outcome (Egger’s test P = 0.6, Begg’s test P = 0.5, Fig. 4).

Fig. 4.

Funnel plot assessing publication bias; A) Primary outcome: differences in NLR level between patients with moderate to severe AR and those with mild AR; B) Secondary outcome: the differences in NLR level between patients with AR and healthy controls

Other Results

AR had two main subtypes: persistent and intermittent. Two studies compared NLR levels of patients with these two different types to evaluate if clinicians predict persistency of AR in patients [20, 27]. Kant et al. in 2021 conducted a retrospective study on 45 patients with intermittent AR and 160 patients with persistent AR and found that patients with intermittent type had significantly higher levels of NLR (2.17 ± 0.6) compared to other group (2.04 ± 0.8) (P = 0.04). NLR > 1.62 could predict persistent AR, with specificity of 88.1%, sensitivity of 42.8%, and AUC of 0.602 [27].

In contrast, Cansever et al. reported that patients with persistant type had higher level of NLR (n = 87, NLR = 2.49 ± 1.58) compared to other group (n = 113, NLR = 0.98 ± 0.26, P < 0.001) in a retrospective study in Turkey [20].

In addition, AR patients are at greater risk of rhino-sinusitis, asthma, and other related upper airway diseases. Interestingly, it was found that NLR could associate with some comorbidities of AR. For example, Akgedik et al. conducted a retrospective study, on 143 patients with AR, of which 83 had asthma as a major comorbidity of AR and compared them in NLR level. It was reported that AR patients with asthma had higher level of NLR (median = 1. 83, 95%CI = 1.43–2.45) compared to AR patients without asthma (median = 1.66, 95%CI = 1.07–1.96) [19].

In addition, Selçuk et al.,in 2023, in a retrospective study on 121 patients with AR and 101 patients with non-allergic rhinitis, found no difference between these two groups in NLR (2.17 ± 1.15 vs. 2.35 ± 1.01, respectively, P = 0.10) [29].

Discussion

The main finding of our meta-analysis was that patients with AR had a significantly higher level of NLR compared to healthy controls.

As AR is related to systemic inflammation in addition to nasal mucosa inflammation, it often co-occurs with other inflammatory diseases like sinusitis and asthma. In patients with seasonal allergic rhinitis who did not have asthma, nasal allergen provocation resulted in inflammatory alterations in the lower and upper airways, including increased bronchial hyperreactivity, increased adhesion molecule expression, and eosinophil infiltration [30, 31]. These findings show that an allergic nasal response causes inflammatory alterations throughout the body. Allergen exposure in sensitized individuals stimulates immune cells, such as dendritic cells, mast cells, mononuclear cells, TH lymphocytes, and others, both in lymphatic tissues related to the nose and within the nostrils [32]. Some of these TH cells move to the bone marrow, where they induce the production of inflammatory cells like mast cell precursors, eosinophils, and basophils [32–34].

There are several studies about the association between disease severity and NLR levels. According to a study, NLR levels were higher in patients with Behcet disease, a systemic inflammatory vascular illness, than healthy controls [35]. Similarly, it was observed that NLR levels rose with increasing Bell’s palsy grade according to another investigation. The disease is caused by facial nerve paralysis as a consequence of inflammation [36]. According to a study of individuals with IgA nephropathy, elevated NLR scores indicate more severe renal inflammation and a lower response to corticosteroid therapy [37]. These investigations came to two conclusions: first, inflammatory disorders cause greater NLR values than healthy people, and second, higher NLR values associated with the severity of the inflammatory condition. Higher NLR levels in severe inflammation imply neutrophil participation in the inflammatory process, the generation of inflammatory cytokines, and the modulation of numerous immunological responses by lymphocytes [37]. This condition confirms the relationship between illness severity and NLR, which is the most crucial finding of our research. In the literature, severity assessments include the acoustic rhinometry, VAS visual analog score, nasal cytology, and nitric oxide (NO) levels [38]. We recommend NLR as a marker of AR severity since they are simple, inexpensive, non-invasive, and widely accessible.

As mentioned earlier, inflammation affects AR, and a high NLR value may be a suitable biomarker for inflammation and AR. In order to recognize the relationship between NLR and AR, it is also essential to comprehend the function of neutrophils and lymphocytes in AR. NLR is calculated as a simple ratio of neutrophils, proinflammatory cells, lymphocytes, and regulatory immune cells. As a consequence, increased NLR implies increased inflammation, which contributes to the development of AR.

Prior study on neutrophil participation in AR has been considerable. When diseases like inflammation and infection occur, the bone marrow produces more neutrophils, and these cells go to the target tissues. These transient cells will leave the bone marrow in the absence of infection and perish within the boundaries of the bloodstream [39]. Since allergic rhinitis also relates to inflammation, blood neutrophils are expected to rise and move into the nose in AR patients. This observation is supported by the fact that neutrophils are among the most prevalent cells in studies examining nasal cytology in AR patients [40–42]. Since neutrophils enter the nose via the blood, an increase in NLR is predicted when blood neutrophils rise.

Lymphocytes are the other component of the NLR ratio. Th2 and Treg are primarily involved in allergic rhinitis, with Th17 having a noticeable impact in severely affected individuals and those with asthma [43]. Those with allergic rhinitis have an excess of Th2 cells in their nasal mucosa, which correlates with local eosinophils. In perennial rhinitis, IgE-producing plasma cells and memory Th2 cell population rise in afflicted areas [44]. CCR4 is the chemokine receptor that characterizes Th2 cells, and its ligands, macrophage-derived cytokine (MDC) and TARC, are elevated in APCs and nasal epithelial cells of allergic rhinitis. These numbers can be decreased by immunotherapy [44, 45]. Treg cells affect the inflammatory process in a variety of ways. Treg cells can suppress inflammation by secreting interleukins and can cause apoptosis in inflammatory T-cells like Th2 by expressing CD279 (aka programmed death 1) and CD152 (aka cytotoxic T-lymphocyte antigen) [45, 46]. The cytokine milieu, produced by monocytes and epithelial cells in the nose, can adversely affect the regulatory function of Tregs and other subsets of T cells related to allergic rhinitis [47].

Th17 is a type of T-cell associated with a fibrosis response in numerous autoimmune illnesses and asthma, and these cells are also linked to the neutrophilic inflammation of several asthma subtypes [47, 48]. Recent investigations found that elevated levels of Th17 can predict unsuccessful immunotherapy, and they discovered that patients suffering from severe allergic rhinitis had exhibited higher levels of Th17 [49–51].

Limitations and Strengths

This meta-analysis had a few limitations that should be mentioned. First, we discovered a high level of heterogeneity among the included studies. The random effect model was used to solve this matter; however, more than this model may be needed to completely eliminate heterogeneity. Second, the majority of the included articles were retrospective. The results of retrospective studies are not generally as strong as prospective studies. Third, most of the included articles were performed in Turkey. Further studies in other countries are needed to make a solid judgment on the role of NLR in AR. Even so, our study had three main strengths. First, to the best of our knowledge, this study was the first meta-analysis that explored the relationship between NLR and AR. Second, we created clear criteria for inclusion and exclusion and screened the articles based on these criteria. Third, a reliable and thorough literature search was done in this study because the reference lists of the resulting articles were screened, and the search was not limited to language or date.

Conclusion

This study demonstrated that NLR levels are increased in patients with AR than those without.

Our findings confirm the link between higher AR risk and elevated NLR levels. NLR is a distinct inflammatory marker whose increase in AR suggests an immune system imbalance in the disease’s etiology. Additionally, our results suggest that NLR is a potential biomarker that is simple to incorporate into clinical settings and can help predict and prevent AR. Finally, with the creation of novel indicators and therapeutic methods, we can more effectively manage and prevent AR to reduce long-term morbidity and mortality.

Supplementary Information

Below is the link to the electronic supplementary material.

Author contributions

Conceptualization: S.K and M.S; Methodology: M.K; Formal analysis and investigation: M.K, S.K; Writing—original draft preparation: A.M, A.G; Writing—review and editing: A.G, A.B, S. FN; All authors read and approved the final manuscript and are responsible for data review.

Funding

There was no funding support.

Data availability

All data generated or analyzed during this study are included in this published article.

Declarations

Conflict of interest

The authors declare that there is no conflict of interest regarding the publication of this article.

Ethical approval

This study is a systematic review and meta-analysis and does not require ethical approval.