Neutrophil Lymphocyte Ratio: A Predictor of Disease Severity in Nasal Polyposis and Allergic Fungal Rhinosinusitis

Abstract

To evaluate Neutrophil Lymphocyte ratio (NLR) as a predictor of disease severity in Nasal Polyposis and Allergic Fungal Rhinosinusitis (AFRS). This was a prospective non-randomized interventional study. Disease severity was graded based on endoscopic and CT scoring. Patients were given pre-operative oral steroids for two weeks and taken up for surgery. The pre-treatment neutrophil lymphocyte ratios were calculated from the differential leucocyte counts and compared with the disease severity and post-operative values. In the interventional arms, the disease severity correlated with the NLR. The mean pre-treatment NLR showed a statistically significant change after the intervention at eight weeks. The NLR normalized in patients with nasal polyposis and continued to be higher in patients with AFRS. NLR correlated to the disease severity and showed a linear correlation with the extent of the disease. NLR could be a potential cost-effective marker for disease severity and prognostication.

Level of Evidence: Individual Cohort Study (2b)

Introduction

Allergic Fungal Rhinosinusitis (AFRS) is a variant of chronic rhinosinusitis characterized by nasal polyps, type I hypersensitivity, heterogeneous soft tissue density on computed tomography (CT), eosinophilic mucin with a positive fungal smear. Patients with AFRS are immunocompetent. The causative agents are dematiaceous fungal species (Bipolaris, Curvularia, Alternaria) and rarely Aspergillus. The condition is more prevalent in a warm and humid environment [1].

Altered leukocyte count correlates with systemic inflammation. Neutrophils are well recognized for their role in an acute inflammatory response, and the lymphocytes play a role in regulating and modulating the inflammation. Often, if one particular cell lineage increases as a part of an inflammatory process, the other cell types decrease. It would hence be logical to study the variations in neutrophil and lymphocyte counts to estimate systemic inflammation. The Neutrophil -Lymphocyte Ratio (NLR) in blood, has been considered as an indicator of cancer-associated inflammation and assess responses [2–4].

The lack of a cost-effective marker to predict severity and recurrences in nasal polyposis and AFRS adds to the financial burden. If the risk factors for recurrence could be determined before surgery, the patients at a higher risk to recur can be informed and observed more closely. NLR serves as a novel biomarker of inflammation, and the current study evaluated its utility as a predictor of disease severity and treatment outcomes.

Methodology

This study was conducted in the Department of Otolaryngology-Head and Neck Surgery, Post Graduate Institute of Medical Education and Research, Chandigarh between June 2015 and December 2016. The ethical committee of the institution approved the study, and a signed informed consent form was taken from each patient.

This was a prospective non-randomized interventional study. One hundred patients in the age group of 10–60 years participated in the study. Patients with ciliary motility disorders, chronic diseases, granulomatous diseases, generalized allergies, malignancy, and immunodeficiency syndromes were excluded. The control group included 30 patients undergoing nasal surgery for non-nasal symptoms/complaints (Group I). The interventional arms included thirty-five patients, each with a provisional diagnosis of nasal polyposis (Group II) and AFRS (Group III).

The presenting symptoms were evaluated and tabulated. All patients underwent a complete head and neck examination along with nasal endoscopy. Nasal polyps at endoscopy were scored from 0 to 3 points according to the Lund-Mackay score (hereon called the endoscopic severity score). A pre-treatment CT scan of the patient was used to score the disease severity as per the Lund-Mackay CT scoring (hereon called the CT Score).

Three ml of blood was drawn from all patients and sent for differential leukocyte count (DLC). Additional 3 ml of blood was drawn in patients with a diagnosis of AFRS for fungal specific IgE.

The NLR was calculated mathematically by dividing neutrophil count (%) by lymphocyte count (%). The mean NLR in Group I was taken as the normal reference value for the study. Peripheral blood eosinophilia was defined as Absolute Eosinophil Count (AEC) > 6.0 × 10⁸ cells/L. Patients in the interventional arms (Group II and III) were prescribed medical treatment that included intranasal and systemic corticosteroids, for two weeks and then taken up for endoscopic sinus surgery at the end of 2 weeks. The Messerklinger’s technique of sinus surgery and extended endoscopic endonasal procedure were performed as indicated in the interventional arm. Patients were discharged after the removal of the nasal pack 48 h after surgery as per the study protocol. Patients were prescribed nasal saline irrigation and called in for endoscopic suction clearance after two weeks. Patients with AFRS were additionally prescribed intra-nasal corticosteroid after two weeks of surgery.

Patients were followed up every month and were evaluated with nasal endoscopy at each visit. The total post-operative follow-up duration was eight weeks. At the end of the study, 3 ml of peripheral blood was collected in all the patients in the interventional arms (Group II and III) and sent for DLCs. The follow up endoscopic and CT scores were recorded.

Statistical analysis was done using the SPSS 22.0 version. Descriptive statistics were used to describe different variables and included measures of central tendency and dispersion for continuous variables and frequencies with their corresponding 95% CI (confidence interval).

Discrete categorical data was represented in the form of either a number or percentage (%). Continuous data, assumed to be normally distributed, was written in the form of its mean and standard deviation. Ratios were compared using Chi-square or Fisher’s exact test, depending on their applicability. Pearson’s correlation coefficient will be used to test the relationship between variables. All the statistical analyses were two-sided and were performed at a significance level of α = 0.05.

Results

The mean age of patients in the study was 30.4 ± 11.7 years. There were 62 male (62%) and 38 female (38%) patients in this study. Most common symptom recorded in the interventional arms, was nasal obstruction [68 of 70 patients (97%)] and only 4 of the 30 patients in the control arm had reported nasal obstruction (Table 1). The next common symptom, reported in the interventional arms was nasal discharge (88%) followed by hyposmia/anosmia (77%).

Table 1.

Presenting symptoms of the study population

Symptoms	Number of patients
	Group I (N = 30)	Group II (N = 35)	Group III (N = 35)
Nasal obstruction	4	35	33
Nasal discharge	3	32	30
Hyposmia/anosmia	2	28	26
Facial congestion	0	6	12
Facial pain	0	2	7
Fever	0	0	0
Headache	2	18	20
Cough/PND	1	13	20
Proptosis	0	0	7

The mean pre-treatment CT score was 0.7, 12.9 and 15.1 in Group I, II and III respectively and the difference was statistically significant (p < 0.01) (Fig. 1). The mean pre-treatment endoscopic severity score was 0.1, 2.8 and 3.4 in Group I, II and II, respectively (p < 0.05). The mean post-treatment LMS CTs in Group II was 0.75, and in Group III was 1.2 at the end of 8 weeks after surgery and was not statistically significant when compared to Group I (Table 2).

Fig. 1.

Severity score—Computed Tomography

Table 2.

Parameters analysed in the study

Parameters	Group I	Group II	Group III	p value
Mean age (years)	28	34	29	–
Male/female	22/8	19/16	22/13	–
Mean preoperative CT score	0.7	12.9	15.1	< 0.01
Mean post-operative CT score	NA	1.2	0.8
Mean endoscopic Score (preoperative)	0.1	2.8	3.4	< 0.05
Mean endoscopic score (post-operative)	NA	0	0.1
Bone erosion on CT	0	0	7	–
Mean pre treatment NLR	1.66 ± 0.33	2.03 ± 0.28	2.15 ± 0.62	< 0.01
Mean post-treatment NLR	1.66 ± 0.33	1.68 ± 0.43	1.78 ± 0.36	> 0.05

The pre-treatment total leukocyte count values in all the three arms were comparable and were not found to be statistically significant. The mean Pre-treatment NLR was 1.66 ± 0.33, 2.03 ± 0.28 and 2.15 ± 0.62 in Group I, II, and III respectively. Eosinophilia was noted in 22 of the 35 patients (63%) of patients in Group III as against 5 out of 35 patients (14%) in Group II, and 5 out of 30 (16%) in Group I. The mean post-treatment NLR in Group II was 1.68 ± 0.43 post treatment and 1.78 ± 0.36 in Group III (Fig. 2), (Table 2). There was a substantial decrease in the NLR in both Group II and Group III after treatment and was found to be statistically significant (p < 0.01) (Table 2), however this change as compared to the reference was not statistically significant (p > 0.05).

Fig. 2.

Neutrophil Lymphocyte Ratio (NLR)

Only seven patients in the study had radiological evidence of bone erosion preoperatively (Fig. 3). All these patients belonged to Group III. We followed this cohort of patients with additional interest. Their mean CT score, endoscopy score and NLR was higher than the rest of the study population. Following standard treatment, the change in their severity score and NLR was statistically significant (p < 0.01) and was also statistically significant when compared to the reference (p < 0.05).

Fig. 3.

CT image showing evidence of bone erosion and extensive disease

Disease severity determined by CT score and endoscopy score, was correlated with NLR in both Group II and Group III. In Groups II and III, there was a linear correlation between pre-treatment NLR and disease severity; however, this was not statistically significant (p > 0.05). Similarly, the post-treatment NLR was correlated with the outcome though not statistically significant.

Discussion

Nasal Polyposis and AFRS are common in the northern part of India. It causes significant morbidity and impairs the quality of life in these patients. Lack of awareness and insufficient treatment guidelines add to the woes. The condition predominantly affects adults and rare in children under 10 years of age [5]. In our study, 57 of the 70 cases (81%) were in the age group of 16 to 45 years, and this was consistent with other reports [6, 7].

Nasal obstruction was the most common symptom in patients in the interventional arms. About 20% of the patients in Group III had an intraorbital and intracranial (extradural) extension of the disease, and these patients had ignored their symptoms for a longer duration.

Low-grade inflammation measured by TLC has been linked as risk factors for developing chronic diseases. In our study, mean TLC in all the groups surprisingly was within the normal reference range` for an average Indian.

Post-treatment the TLC values in the interventional arms was again within the normal range for an average Indian, which rules out post-operative infections that could have altered our results.

Higher neutrophil counts mean more chronic inflammation. NLR serves as potential markers of inflammation and can be measured using routine peripheral blood samples at no additional cost [8]. In our study, the mean pre-operative NLR in Group II was 2.03 ± 0.28, and in Group III was 2.15 ± 0.62 and was similar to that noted by Osman Fatih et al. [9] and Giuseppe Brescia et al. [10] in their study.

Following complete treatment, it was expected that the disease burden would come down, and so would be the level of inflammation. This was reflected in the post-operative severity scoring (p < 0.01).

The post-operative NLR in Group II was 1.68 ± 0.56 and was similar to the control NLR (p > 0.05). A value closer to the control NLR value suggests better chances for a complete cure. Osman Faith et al. [9] in their study concluded that NLR could be used to predict probabilities of disease recurrence before endoscopic sinus surgery. In their study, patients with an NLR of 3.13 or higher were more likely to experience recurrence within two years after surgery. Giuseppe Brescia et al. [10] in their study also noted that patients with higher NLR had increased chances of recurrences after sinus surgery. However, they concluded that the ability of NLR to identify cases more likely to recur was insufficient to be implemented in clinical practice.

In Group III, the post-operative NLR was 1.78 ± 0.3 and was higher than control NLR. This suggests either incomplete surgical clearance or AFRS needs long term medical treatment post-surgery. As post-operative severity score supports complete clearance of the disease, it is likely that AFRS is more of systemic disease and requires long term treatment unlike nasal polyposis and goal of treatment of AFRS is to remove the disease entirely and prevent recurrences with long term therapy [11–13]. The present study results also support the need for systemic corticosteroids for a longer duration to tide over the inflammation in AFRS after surgery. We believe that AFRS should be looked as a systemic illness rather than mere localized disease.

The NLR in patients with bone erosion was higher than the rest of the study population, indicating a greater level of inflammatory response in them. Following surgery there was a significant change in NLR in these patients, yet higher than the mean reference, re-emphasising the need for long term post-operative steroids.

In a recent study by Ahmet et al. [14], evaluated a larger population of patients with a diagnosis of NP. They analysed the relationship of NLR, platelet lymphocyte ratio (PLR), eosinophil lymphocyte ratio (ELR) and red cell distribution width values with nasal polyposis, and whether this could be a predictive parameter for the severity of the disease and recurrence risk. Their conclusion was similar to the present study and suggested that NLR and PLR values had no statistically significant relationship with the severity and recurrence risk of nasal polyposis. They noted that ELR had a statistical correlation with severity in the NP group. We analysed our data for ELR retrospectively and found that ELR in our cohort did not have any statistically significant bearing on disease severity.

Mean NLR in the interventional arm had a linear correlation with disease severity (p > 0.05). As the aggressiveness of the disease increases the NLR also increases. Hence NLR could be used as an independent biomarker of inflammation correlating to disease severity in NP and AFRS.

The lack of long term follow-up, limited sample size and non-randomization of the study were inherent limitations in the study design. Future studies should look at randomizing patients and with larger sample size, with and without long term systemic treatment to overcome the inflammation.

Conclusion

NLR is a reliable, independent predictor of chronic inflammation and correlates to the severity of the disease in AFRS and nasal polyposis. Persistently higher NLR in AFRS even after treatment suggests the need for long-term anti-inflammatory drugs, which includes low dose steroids and intranasal steroids. NLR could be a potential cost-effective novel parameter for disease monitoring and prognostication. However, caution should be taken when using these hematological parameters till robust evidence is brought forward.

Funding

None.

Compliance with Ethical Standards

Conflict of interest

The authors declare that they have no conflict of interest.