International Immunopharmacology 100 (2021) 108084

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International Immunopharmacology
journal homepage: www.elsevier.com/locate/intimp

The role of serum macrophage migration inhibitory factor in preoperative

prediction of chronic rhinosinusitis with nasal polyps endotypes
Xuan Yuan a, b, 1, Shaobing Xie a, b, 1, Qiancheng Jing c, Yongchuan She d, Weihong Jiang a, b,
Hua Zhang a, b, Zhihai Xie a, b, *
a
Department of Otolaryngology Head and Neck Surgery, Xiangya Hospital of Central South University, Changsha, Hunan, China
b
Hunan Province Key Laboratory of Otolryngology Critical Diseases, Changsha, Hunan, China
c
Department of Otolaryngology Head and Neck Surgery, Changsha Central Hospital, University of South China, Changsha, Hunan, China
d
Department of Otolaryngology Head and Neck Surgery, Changsha Hospital of Traditional Chinese Medicine, Changsha, Hunan, China

A R T I C L E I N F O A B S T R A C T

Keywords: Background: Chronic rhinosinusitis with nasal polyps (CRSwNP) is a highly heterogeneous disease and can be
Macrophage migration inhibitory factor categorized into eosinophilic CRSwNP (eCRSwNP) and non-eosinophilic CRSwNP (neCRSwNP). Exploring
Biomarker effective biomarkers to distinguish endotypes is important for personalized therapies. The present study aims to
Chronic rhinosinusitis with nasal polyps
evaluate the predictive value of serum MIF in CRSwNP endotypes.
Eosinophil
Endotypes
Methods: One hundred and twenty CRSwNP patients, including 51 eCRSwNP and 69 neCRSwNP, 40 chronic
rhinosinusitis without nasal polyps (CRSsNP) patients and 40 healthy controls (HC) were enrolled. Serum MIF
levels were determined by enzyme-linked immunosorbent assay (ELISA). The patients’ clinical variables were
analyzed for correlations with serum MIF. Receiver operating characteristic (ROC) curve and multivariate
analysis were utilized to assess the predictive value of serum MIF in CRSwNP endotypes.
Results: The serum MIF levels were significantly higher in CRSwNP group than CRSsNP group and HC group (P <
0.001), and the serum MIF levels were increased in eCRSwNP compared to neCRSwNP group (P = 0.006).
Elevated serum MIF levels were significantly correlated with blood eosinophil (B-EOS) count (r = 0.411, P <
0.001), B-EOS percentage (r = 0.377, P < 0.001), visual analog scale score (r = 0.204, P = 0.025), tissue
eosinophil (T-EOS) count (r = 0.705, P < 0.001) and T-EOS percentage (r = 0.671, P < 0.001) in CRSwNP
patients. ROC curve demonstrated that serum MIF exhibited good preoperative prediction in CRSwNP endotypes
(area under the curve = 0.925, P < 0.001). Multivariate regression analysis showed that serum MIF was an
independent factor associated with CRSwNP endotypes.
Conclusions: This was the first study identifying serum MIF as a possible specific biomarker for preoperatively
distinguishing CRSwNP endotypes. Furthermore, the serum MIF levels were found to be closely associated with
the degree of mucosal eosinophil infiltration.

1. Introduction eosinophilic CRSwNP (neCRSwNP) according to the degree of infil­

trating eosinophils in the tissue [4,5]. In comparison with neCRSwNP,
Chronic rhinosinusitis (CRS), characterized by nasal discharge, nasal eCRSwNP exhibiteds more serious disease symptoms, poorer prognosis
obstruction, facial pain, and reduction of smell, is one of the most and a higher rate of reoccurrence because of its distinct inflammatory
prevalent chronic diseases [1]. Based on presence of nasal polyp, CRS is pathways and pathophysiological mechanisms [6–8]. Given that dis­
categorized into CRS with nasal polyps (CRSwNP) and CRS without tinguishing CRSwNP subtypes before surgery was pivotal to achieve
nasal polyps (CRSsNP)[2,3]. CRSwNP is a highly heterogeneous disease, personalized treatments and improve follow-up protocols. However,
and it is further grouped into eosinophilic CRSwNP (eCRSwNP) or non- there is a lack of simple and accurate biomarkers currently available in

* Corresponding author.at: Department of Otolaryngology Head and Neck Surgery, Xiangya Hospital of Central South University, No 87 Xiangya Road, Kaifu
District, Changsha 410008, China.
E-mail address: xiedoctor@csu.edu.cn (Z. Xie).
1
Xuan Yuan and Shaobing Xie contributed equally to this work

https://doi.org/10.1016/j.intimp.2021.108084
Received 26 March 2021; Received in revised form 30 June 2021; Accepted 17 August 2021
Available online 3 September 2021
1567-5769/© 2021 Elsevier B.V. All rights reserved.
X. Yuan et al. International Immunopharmacology 100 (2021) 108084

identify these endotypes during clinical practice. Therefore, identifying samples were centrifuged at 4 ◦ C (3000 rpm for 10 min), and the su­
specific biomarkers with high accuracy and reliability for distinguishing pernatants were obtained and stored in 1.5 mL ep tubes (NEST
CRSwNP endotypes is urgently needed. Biotechnology, Wuxi, China) at − 80 ◦ C for subsequent experiments. All
Macrophage migration inhibitory factor (MIF) is a multi-effect pro- serum samples were coded before the measurements. Serum MIF con­
inflammatory factor, which expressed in a variety of cells, such as centrations were detected using commercial ELISA kits (Multisciences,
monocytes, macrophages, eosinophils, neutrophils, B cells and T cells Hangzhou, China) according to the manufacturer’s instructions. All
[9,10]. Growing evidences have demonstrated that MIF exhibited serum samples were diluted 1:40 and run in duplicate to improve assay
important biological functions in promoting inflammatory response, precision.
antagonizing glucocorticoid effect and mediating the release of pro-
inflammatory factors [11–13]. Moreover, MIF also has been suggested 2.4. Statistical analysis
to affect eosinophil physiology, including promoting eosinophil differ­
entiation, activation, migration and survival [11,14], and be closely Quantitative variables with normal distribution were expressed as
involved in the pathogenesis of various inflammatory diseases, mean ± standard deviation, and one-way analysis of variance (ANOVA)
including allergic rhinitis [15], inflammatory bowel disease [16], or Student’s t test was applied for comparison; non-normal distributed
asthma [17], eosinophilic esophagitis [18], and atopic dermatitis[19]. variables were described as median and interquartile range, Krus­
Thus, it is reasonable to assume that MIF might also act an important kal–Wallis H test or Mann-Whitney U test was used. Categorical data
role in the pathogenesis of CRSwNP, and contribute to distinguishing its were expressed as number (%) and compared utilizing Chi-square test.
endotypes. Correlations between serum MIF level and laboratory and clinical
In this study, we aimed to investigate the changes of serum MIF characteristics were evaluated by Spearman correlation test. A receiver
levels in CRSwNP patients, and evaluated the predictive value of serum operating characteristic (ROC) curve was performed to determine the
MIF levels in CRSwNP endotypes. utility of serum MIF and other indications as markers in distinguishing
eCRSwNP. Logistic regression was used to detect potential factors
2. Materials and methods associated with eCRSwNP. For all tests, P < 0.05 was considered sta­
tistically significant. Statistical analysis and ROC were performed using
2.1. Participants and settings SPSS 23.0 (IBM Corp, Armonk, USA), and other figures were constructed
in GraphPad Prism (Version 7.0, Software Inc. La Jolla, CA, USA).
We recruited 120 consecutive CRSwNP patients and 40 CRSsNP
patients who underwent nasal endoscopic surgery between June 2018 3. Results
and December 2018 in our department. CRSwNP and CRSsNP were
diagnosed in accordance with the guidelines of the European Position 3.1. Demographic and clinical characteristics of participants
Paper on Rhinosinusitis and Nasal Polyps 2012 [20]. Exclusion criteria
are listed as follows: (1) fungal sinusitis or acute upper respiratory tract Demographic and clinical characteristics of all participants were
infection; (2) systemic inflammatory diseases, autoimmune diseases or shown in the Table 1. Among 120 CRSwNP patients, 51 (42.5%) patients
eosinophilic diseases; (3) nasal or sinus malignancy; (4) receiving were categorized into eCRSwNP group, and the other 69 (57.5%) pa­
immunotherapy, antibiotics, nasal or systemic corticosteroids, or anti- tients were classified into neCRSwNP group. Significant difference was
allergic drugs 30 days prior to surgery; (5) inflammatory, autoimmune observed in the rate of allergic rhinitis and asthma, blood eosinophil (B-
diseases or septic diseases; (6) age < 18 years or greater than 75 years EOS) count and percentage among three groups, and VAS score between
old; (7) severe heart and kidney dysfunction. All patients underwent CRSsNP group and CRSwNP group (all P < 0.05). Table 2 showed that
routine preoperative examination, including blood tests, rhinoendo­ the rate of allergic rhinitis and asthma, B-EOS count and percentage and
scopy, chest X-rays, electrocardiography and computed tomography VAS score were higher in eCRSwNP group than neCRSwNP group (all P
(CT) or magnetic resonance imaging (MRI). Nasal symptom scores were < 0.05). Fig. 1A-B presented the typical histological findings of
recorded using a visual analog scale (VAS) as previous study, and pre­ neCRSwNP and eCRSwNP. The tissue eosinophil (T-EOS) count and
operative CT score was obtained referring to Lund–Mackay staging percentage in eCRSwNP group were significantly elevated than in
system [21,22]. A total of 40 age- and gender-matched healthy controls neCRSwNP group (all P < 0.001, Fig. 1C-D).
(HCs) with no evidence of rhinitis or rhinosinusitis, diabetes mellitus,
severe heart and kidney dysfunction, or inflammatory or autoimmune
conditions were recruited as control group.
Table 1
2.2. Diagnosis of eCRSwNP and neCRSwNP The demographic and clinical characteristics of participants.
Variables HC(n = 40) CRSsNP(n = CRSwNP (n = P
Tissue specimens were obtained from with CRSwNP patients during 40) 120)
the surgery, and immersed in 10% formalin. Hematoxylin and eosin Age (years) 32.0 ± 7.7 35.3 ± 16.4 34.0 ± 13.8 0.136
(H&E) staining was conducted as our previous study described [23]. Gender (male), n 22 (55.0) 27 (56.5) 66 (52.9) 0.360
Briefly, the embedded tissues were sectioned into 5-μm sections, and (%)
Smoking, n (%) 14 (35.0) 16 (44.9) 53 (43.1) 0.581
stained with H&E for the visualization of eosinophils. The numbers of
BMI (kg/m2) 23.0 ± 1.9 22.9 ± 2.3 23.3 ± 2.1 0.577
inflammatory cells, including eosinophils, lymphocytes and neutrophils, Allergic rhinitis, n 0 (0) 5 (7.2) 20 (25.5) 0.002
were counted in 10 randomly selected high-power fields (HPF) by two (%)
different observers who were blinded to the clinical data. Tissue speci­ Asthma, n (%) 0 (0) 3 (8.7) 18 (29.4) 0.005
mens were defined as eCRSwNP when the tissue eosinophils (T-EOS) B-EOS count (106/ 105.5 ± 171.2 ± 83.5 323.8 ± 127.7 <0.001
L) 40.2
percentage was more than 10% of total inflammatory cells, otherwise
B-EOS percentage 1.5 ± 0.7 2.1 ± 1.0 3.7 ± 1.3 <0.001
regarded as neCRSwNP [24]. (%)
VAS score – 5.8 ± 1.7 6.4 ± 1.7 0.014
2.3. Sample collection and MIF levels measurement Lund-Mackay score – 16.7 ± 3.7 18.8 ± 3.9 0.573

CRSsNP, chronic rhinosinusitis without nasal polyps; CRSwNP, chronic rhino­

Five ml fresh venous blood were extracted from patients and HCs, sinusitis with nasal polyps; HC, healthy control; BMI, body mass index; B-EOS,
and stored at room temperature for 1 h after sampling. Collected blood blood eosinophil; VAS, visual analogue scale

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X. Yuan et al. International Immunopharmacology 100 (2021) 108084

Table 2 3.3. Evaluating the predictive value of serum MIF in distinguishing

The demographic and clinical characteristics between neCRSwNP group and CRSwNP endotypes
eCRSwNP.
Variables neCRSwNP(n = 69) eCRSwNP(n = 51) P In order to further assess the predictive value of serum MIF in dis­
Age (years) 33.0 ± 12.4 34.5 ± 14.1 0.538
tinguishing CRSwNP endotypes, ROC analysis and multivariate analysis
Gender (male), n (%) 39 (56.5) 27 (52.9) 0.714 were applied. The ROC analysis results in Fig. 4 exhibited that serum
Smoking, n (%) 31 (44.9) 22 (43.1) 0.855 MIF showed better accuracy and utility in distinguishing CRSwNP
BMI (kg/m2) 23.6 ± 2.2 22.9 ± 1.9 0.071 endotypes than B-EOS count, B-EOS percentage, VAS score, Lund-
Allergic rhinitis, n (%) 5 (7.2) 15 (25.5) 0.002
Mackay score. The detailed parameters of ROC analysis were dis­
Asthma, n (%) 6 (8.7) 13 (29.4) 0.021
B-EOS count (106/L) 195.4 ± 90.1 400.5 ± 156.4 <0.001 played in Table 3. Based on the optimal cutoff values of serum MIF,
B-EOS percentage (%) 2.4 ± 1.0 4.8 ± 1.5 <0.001 CRSwNP patients were classified into low MIF level group (<21.8 ng/
VAS score 5.8 ± 1.7 6.8 ± 1.6 0.002 ml, n = 72) and high MIF level group (≥21.8 ng/ml, n = 48). In the high
Lund-Mackay score 18.6 ± 4.0 19.0 ± 3.6 0.567 MIF level group, the T-EOS count and percentage and the rate of
neCRSwNP, non-eosinophilic chronic rhinosinusitis with nasal polyps; eCRSwNP were significantly higher than those in low MIF level group
eCRSwNP, eosinophilic chronic rhinosinusitis with nasal polyps; HC, healthy (all P < 0.001) (Table 4). Unadjusted and adjusted multivariate analysis
control; BMI, body mass index; B-EOS, blood eosinophil; VAS, visual analogue models both demonstrated that serum MIF and B-EOS percentage were
scale independent factors associated with eCRSwNP (P < 0.05) (Table 5).

3.2. MIF levels in CRSwNP patients and correlations with clinical 4. Discussion
variables
In the present study, we firstly demonstrated that MIF concentrations
As exhibited in the Fig. 2, serum MIF levels in CRSwNP group were were markedly increased in the serum of CRSwNP patients compared to
higher than CRSsNP group and HC group (P < 0.05), and serum MIF CRSsNP patients and HCs, especially in eCRSwNP patients. In addition,
levels were markedly increased in eCRSwNP group in comparison with the increased MIF levels were positively correlated with B-EOS count
neCRSwNP group and HC group (P < 0.05). Furthermore, the elevated and percentage, VAS score, T-EOS count and percentage in CRSwNP
serum MIF concentrations correlated positively with blood eosinophil patients. ROC curve and multivariate regression analysis demonstrated
(B-EOS) count (r = 0.411, P < 0.001), B-EOS percentage (r = 0.377, P < that serum MIF closely associated with CRSwNP endotypes. These re­
0.001), VAS score (r = 0.204, P = 0.025), T-EOS count (r = 0.705, P < sults indicated that serum MIF appeared to be an important biological
0.001) and T-EOS percentage (r = 0.671, P < 0.001) in CRSwNP patients indicator for distinguishing CRSwNP endotypes and contribute to the
(Fig. 3). understanding of underlying pathogenesis of eCRSwNP.

Fig. 1. Representative H&E staining in neCRSwNP and eCRSwNP samples. (A) neCRSwNP. (B) neCRSwNP. (C-D) Comparison of eosinophil count and percentage in
nasal polyps tissue under HPF between neCRSwNP group and eCRSwNP group. eCRSwNP, eosinophilic chronic rhinosinusitis with nasal polyps; neCRSwNP, non-
eosinophilic chronic rhinosinusitis with nasal polyps; H&E, hematoxylin and eosin; HPF, high-power field.

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X. Yuan et al. International Immunopharmacology 100 (2021) 108084

Fig. 2. Comparison of serum MIF concentrations among three groups. (A) MIF levels were significantly increased in CRSwNP group than CRSsNP group and HC
group, (B) serum MIF levels were markedly increased in eCRSwNP group than neCRSwNP group and HC group. MIF, macrophage migration inhibitory factor;
CRSsNP, chronic rhinosinusitis without nasal polyps; CRSwNP, chronic rhinosinusitis with nasal polyps; HC, healthy control; eCRSwNP, eosinophilic chronic rhi­
nosinusitis with nasal polyps; neCRSwNP, non-eosinophilic chronic rhinosinusitis with nasal polyps.

Fig. 3. Elevated MIF levels correlated with clinical variables in CRSwNP patients. Spearman correlation analysis showed that serum MIF levels positively correlated
with B-EOS count (A) and percentage (B), VAS score (C), T-EOS count (E) and percentage (F). MIF, macrophage migration inhibitory factor; CRSwNP, chronic
rhinosinusitis with nasal polyps; VAS, visual analog scale; B-EOS, blood eosinophil; T-EOS, tissue eosinophil.

MIF is a pluripotent cytokine which can be produced and secreted by patient and animal models, and contribute to the lung allergic inflam­
monocytes, macrophages and lymphocytes, and act as a crucial pro- matory response [11,28,29]. A recent study demonstrated that MIF ex­
inflammatory mediator and immune regulator in inflammatory and pressions were up-regulated in the allergen-induced skin tissue of atopic
allergic diseases [18,25–27]. Previous study reported that the MIF levels dermatitis murine models, and the elevated MIF level aggravated the
were markedly elevated in the serum and alveolar lavage fluid of asthma Th2 inflammatory response, and promoted the eosinophil recruitment in

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X. Yuan et al. International Immunopharmacology 100 (2021) 108084

Fig. 4. ROC curve of potential predictive indicators for distinguishing eCRSwNP. Serum MIF level exhibited better accuracy and reliability than B-EOS count and
percentage, VAS and Lund–Mackay score. ROC, receiver operating characteristic; eCRSwNP, eosinophilic chronic rhinosinusitis with nasal polyps; MIF, macrophage
migration inhibitory factor; B-EOS, blood eosinophil; VAS, visual analog scale.

Table 3
ROC analysis results of different variables for identifying eCRSwNP.
Variable AUC SE P 95 %CI cutoff value sensitivity specificity
6
B-EOS count (10 /L) 0.718 0.046 <0.001 0.627–0.809 193.5 0.882 0.522
B-EOS percentage (%) 0.781 0.041 <0.001 0.700–0.862 3.3 0.686 0.739
VAS score 0.626 0.052 0.019 0.523–0.728 12.5 0.961 0.087
Lund-Mackay score 0.431 0.053 0.198 0.326–0.536 6.5 0.451 0.768
Serum MIF level (ng/ml) 0.925 0.027 <0.001 0.872–0.978 21.8 0.804 0.957

eCRSwNP, eosinophilic chronic rhinosinusitis with nasal polyps; B-EOS, blood eosinophil; VAS, visual analog scale; ROC, receiver operating characteristics; MIF,
migration inhibitory factor; AUC, area under the curve; SE, standard error; CI, confidence interval

Table 4 Table 5
The relationship between the cutoff value of serum MIF level and distinguishing Unadjusted and adjusted logistic regression models for predicting eCRSwNP.
CRSwNP endotypes. Variable UnadjustedOR (95% CI) P AdjustedOR (95% CI) P
Variables High MIF level group Low MIF level group P
Allergic rhinitis 1.259 0.272 1.313 0.417
(≥21.8 ng/ml, n = 48) (<21.8 ng/ml, n = 72)
(0.874–1.632) (0.921–1.699)
T-EOS count (n) 413.8 ± 149.8 189.7 ± 88.3 <0.001 Asthma 1.736 0.198 1.845 0.275
T-EOS 5.0 ± 1.6 2.3 ± 1.0 <0.001 (0.949–2.301) (0.933–2.424)
6
percentage B-EOS count (10 /L) 2.126 0.086 1.934 0.154
(%) (0.939–2.812) (0.898–2.617)
eCRSwNP/ 45/3 3/69 <0.001 B-EOS percentage 2.348 0.012 2.401 0.030
neCRSwNP (%) (1.526–3.563) (1.632–3.369)
VAS score 1.324 0.496 1.277 0.429
CRSwNP, chronic rhinosinusitis with nasal polyps; eCRSwNP, eosinophilic (0.942–1.978) (0.813–2.032)
chronic rhinosinusitis with nasal polyps; neCRSwNP, non-eosinophilic chronic Serum MIF level 2.563 0.005 2.496 0.017
rhinosinusitis with nasal polyps; MIF, migration inhibitory factor; T-EOS, tissue (ng/ml) (1.616–4.337) (1.705–4.026)
eosinophil
eCRSwNP, eosinophilic chronic rhinosinusitis with nasal polyps; B-EOS, blood
eosinophil; VAS, visual analog scale; MIF, migration inhibitory factor; OR, odds
the skin [30]. In another study, Nakamaru et al found that MIF levels rate; CI, confidence interval;
were higher in the serum of allergic rhinitis patients, and the increased Adjusted for age, gender, smoking, BMI and Lund-Mackay score.
MIF levels associated with the nasal symptom scores [15]. Although MIF
is known as an important pro-inflammatory cytokine, its role in CRSwNP findings were in line with previous publications and suggested that
remains poorly clarified. In the present study, we observed that the serum MIF is pivotal in the pathophysiology of CRSwNP. However, the
serum MIF concentrations were markedly increased in CRSwNP patients underlying mechanisms were not clear.
in comparison with CRSsNP patients and HCs. Moreover, the increased On the other hand, we found that serum MIF levels were significantly
MIF levels associated with VAS score and other clinical variables. Our higher in eCRSwNP group than in neCRSwNP group, and the increased

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X. Yuan et al. International Immunopharmacology 100 (2021) 108084

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