|Year : 2020 | Volume
| Issue : 1 | Page : 11-16
The effect of neutrophil-lymphocyte ratio and thrombocyte index on inflammation in patients with periodic fever, aphthous stomatitis, pharyngitis, and adenitis syndrome
Vildan Gungorer1, Alaaddin Yorulmaz2, Husamettin Vatansev3, Sukru Arslan1
1 Department of Pediatric Rheumatology, Selçuk University Medical School, Konya, Turkey
2 Department of Pediatrics, Selçuk University Medical School, Konya, Turkey
3 Department of Medical Biochemistry, Selçuk University Medical School, Konya, Turkey
|Date of Web Publication||30-Mar-2020|
Dr. Vildan Gungorer
Department of Pediatric Rheumatology, Selçuk University Medical School, Konya
Source of Support: None, Conflict of Interest: None
Background: The periodic fever, aphthous stomatitis, pharyngitis, and adenitis (PFAPA) syndrome is the most common periodic fever syndrome in childhood. Its pathogenesis and etiology remain unknown. This study aimed to determine whether or not the neutrophil-to-absolute lymphocyte ratio (NLR) and thrombocyte indices could be used as subclinical inflammation markers in healthy control group children and children with PFAPA syndrome during the attacks and attack-free periods.
Materials and Methods: Twenty-eight children with PFAPA syndrome that presented to our clinic were enrolled in this study. As a control group, healthy children that presented to the general pediatrics polyclinic with the exact same age and sex as the patient group were recruited. The medical records of all participants were evaluated retrospectively.
Results: The leukocyte and neutrophil counts, NLRs, platelet count-to-absolute lymphocyte ratios (PLRs), and C-reactive protein levels of the patients with PFAPA syndrome during the attack period were found to be significantly higher than during the attack-free period. Similarly, during the attack period, the leukocyte and neutrophil counts, NLRs, and PLRs were significantly higher compared to the healthy control group. Patients with PFAPA syndrome during the attack-free periods were compared with the control group, and their mean platelet volume (MPV) values were significantly lower than the control group.
Conclusions: MPV in PFAPA syndrome patients was significantly lower during the inflammation. We observed a significant decrease in MPV values during the attack-free period compared to the control group, suggesting that subclinical inflammation continues in the attack-free period in PFAPA syndrome.
Keywords: Adenitis syndrome, aphthous stomatitis, inflammation, mean platelet volume, periodic fever, pharyngitis
|How to cite this article:|
Gungorer V, Yorulmaz A, Vatansev H, Arslan S. The effect of neutrophil-lymphocyte ratio and thrombocyte index on inflammation in patients with periodic fever, aphthous stomatitis, pharyngitis, and adenitis syndrome. Indian J Rheumatol 2020;15:11-6
|How to cite this URL:|
Gungorer V, Yorulmaz A, Vatansev H, Arslan S. The effect of neutrophil-lymphocyte ratio and thrombocyte index on inflammation in patients with periodic fever, aphthous stomatitis, pharyngitis, and adenitis syndrome. Indian J Rheumatol [serial online] 2020 [cited 2021 Jan 15];15:11-6. Available from: https://www.indianjrheumatol.com/text.asp?2020/15/1/11/280257
| Introduction|| |
The periodic fever, aphthous stomatitis, pharyngitis, and adenitis (PFAPA) syndrome, which is one of the hereditary fever syndromes or autoinflammatory diseases, is a clinical entity consisting of periodic fever associated with aphthous stomatitis, pharyngitis, and cervical adenitis. The characteristic feature of the syndrome is fever, with sudden onset that can reach 41°C, last for 3–6 days, and occur at regular intervals every 3–6 weeks. Recurrent fever episodes may last for many years; however, as the child grows, the time between the episodes becomes longer. This syndrome usually resolves spontaneously within a few years, without causing any long-term sequelae. Additional manifestations have occasionally been reported, including malaise, nausea, vomiting, headache, arthralgia, abdominal pain, cough, diarrhea, and hepatosplenomegaly., Patients are healthy between episodes and exhibit normal growth.,
As there has been an awareness of PFAPA syndrome for 30 years, many probable causes regarding its etiology, including infectious agents, immunological mechanisms, and genetic predisposition, have been investigated with different studies from various countries to date. The clinical findings of the disease are defined better now, but its pathogenesis and etiology remain unknown. It has been proposed that it is based on the impaired response of T-helper 1 cells, which are the part of the innate immunity response., In the presence of normal procalcitonin levels, elevated C-reactive protein (CRP) with increased interleukin-1 (IL-1) β and IL-6 indicates that the etiology is based on an immunological mechanism. During febrile episodes, elevated levels of the cytokines tumor necrosis factor-alpha (TNF-α), interferon gamma, IL-6, and IL-1 β have been detected.
There are no laboratory tests specific to the diagnosis of PFAPA syndrome. Certain blood tests, including white blood cell count, CRP, and erythrocyte sedimentation rate (ESR), are often elevated. The absolute neutrophil-to-absolute lymphocyte ratio (NLR), platelet count-to-absolute lymphocyte ratio (PLR), mean platelet volume (MPV), and red cell distribution width (RDW) may be indicators of systemic subclinical inflammation., NLR, PLR, RDW, and MPV have been associated with other diseases, such as chronic inflammation in cardiovascular diseases, malignancies, ulcerative colitis, hepatic cirrhosis, and systemic lupus erythematosus. Recent studies have suggested that NLR and MPV are significantly higher in patients with familial Mediterranean fever More Details (FMF).,,,
As it has been predicted that PFAPA is a congenital immune system disorder, we have conceived that the autoinflammatory process in this disease might affect the thrombocyte indices. In this study, we aimed to investigate whether or not the NLR and thrombocyte indices could be used as subclinical inflammation markers in the healthy control group and in children with PFAPA syndrome during attacks and attack-free periods.
| Materials and Methods|| |
Twenty-eight children that presented to the pediatric rheumatology polyclinic of the Selçuk University Faculty of Medicine Hospital/Konya in Turkey due to recurrent fever and throat infection and were diagnosed with PFAPA syndrome were enrolled in this study. PFAPA syndrome was diagnosed using Padeh's diagnostic criteria [Table 1]. As a control group, healthy children from the same sociodemographic area who had the exact same age and sex as the patient group and presented to the general pediatrics policlinic for several reasons, without any chronic disease and infection symptoms, were recruited. The medical records of all of the patients were evaluated retrospectively with regard to demographic, clinical, and laboratory data. The obtained data were collected by computerizing, and the information was not used for any other purposes.
Patients with chronic infection, immune deficiency syndromes, malignancies, autoimmune diseases, and periodic fever syndromes (including FMF and cyclic neutropenia) were excluded from the study. In addition, patients that had bacterial reproduction on their throat culture were excluded from the study. A neutrophil count lower than 1500 C/μL was considered neutropenia for the complete blood cell count analyses.
Sex, age at diagnosis, clinical findings, characteristics of the attacks, response to corticosteroid treatment during attacks, presence of other findings accompanying attacks, clinical data, laboratory findings, and demographic data, such as family history, were studied. The clinical and hematological values of the patients were recorded during the attack periods. An attack-free period was accepted as at least 1 week after the end of the last attack. Patients were observed at least three times during the attack to monitor the clinical features and response to steroid treatment. The patient's fever was recorded with an electronic thermometer in degree Celsius.
The laboratory test results from the blood drawn from the PFAPA syndrome patients during the attack and attack-free periods were analyzed. The complete blood count test was performed 1 h after collecting the blood into tubes containing EDTA using a hemogram device (Sysmex XE-2100, Sysmex Corp. Kobe, Japan) following the manufacturer's instructions. The white blood cell count (C/μL), neutrophil count (C/μL), lymphocyte count (C/μL), hemoglobin (Hb) level (gr/dL), platelet count (C/μL), MPV (fL), platelet distribution width (PDW) (fL), plateletcrit (μg/L), CRP (mg/dL), and ESR (mm/saat) values were recorded. The NLR was obtained by dividing the number of neutrophils by the lymphocyte count, and the PLR was obtained by dividing the platelet count by the lymphocyte count.
This study was ethically approved by the Ethics Committee of Selçuk University on February 6, 2019. It was conducted in accordance with the 1964 Helsinki declaration and its later amendments.
The SPSS version 21.0 (SPSS Inc., Chicago, Illinois, USA) Statistical Software Package for the Social Sciences was used to analyze the data obtained from the study. The distribution of the variables was analyzed with histograms, and the Kolmogorov–Smirnov test to explore the normality, and adequate transformations were performed in case of skewness. Metadata statistical methods included mean ± standard deviation. The paired sample t-test was used to compare two dependent numerical variables with a normal distribution. When the comparison of two independent numerical variables had a normal distribution, Student's t-test was used, and the Mann–Whitney U-test was used if it did not show normal distribution. The Chi-square test was used for the categorical variables. The statistical significance level was set at P < 0.05 (bilateral).
| Results|| |
Nineteen patients were male (67.9%), and nine patients were female (32.1%). The female–male ratio was 0.47. The ages of the patients varied between 1 and 9 years of age. The mean age of the patients was 53.71 ± 24.88 months (14–108 months). The mean age of the females was 63.00 ± 30.05 months, whereas the mean age of the males was 49.32 ± 21.54 months. This difference was not statistically significant (P = 0.236). Twenty-eight healthy children, including 19 (67.9%) males and nine (32.1%) females, identically to the patient group, were included in the study. The mean age of the control group was 53.85 ± 25.34 (13–108) months. There was no statistically significant difference between the patient group and the healthy group in sex and age distribution. The demographic characteristics of the patients are shown in [Table 2].
Regarding the evaluation of body weight for age of the patients, two (7.1%) patients had body weights in the 3rd–10th percentile, 25 (89.3%) patients had body weights in the 10th–90th percentile, and one (3.6%) patient had a bodyweight in the 90th–97th percentile. For the length for age of the patients, three (10.7%) patients had lengths in the 3rd–10th percentile, 24 (85.7%) patients had lengths in the 10th–90th percentile, and one (3.6%) patient had lengths in the 90th–97th percentile.
The age of onset of complaints was 32.51 ± 9.08 months. The mean age at the diagnosis was 53.77 ± 25.37 months. The average delay in the diagnosis was 20.57 ± 14.13 months. None of the patients had undergone tonsillectomy. One or more family members of six (14.8%) of the patients had similar complaints when they were similarly aged. There was no statistically significant difference between female and male patients for onset of attacks, delay in diagnosis, duration of attacks, frequency of attacks, duration of fever during attacks, and level of fever during attacks (P > 0.05).
The remarkable finding that was seen in all patients was high fever that was resistant to antipyretics used during attacks. The clinical features of the patients with PFAPA syndrome are shown in [Table 3].
|Table 3: Clinical characteristics of patients followed with periodic fever, aphthous stomatitis, pharyngitis, and adenitis syndrome|
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The leukocyte counts, neutrophil counts, NLR, PLR, and CRP levels of the patients with PFAPA syndrome during the attack period were found to be significantly higher than during the attack-free period. The laboratory findings of the patients are summarized extensively in [Table 4].
|Table 4: The comparison of laboratory characteristics of patients with periodic fever, aphthous stomatitis, pharyngitis, and adenitis|
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The lymphocyte counts and platelet counts of the patients were detected to be significantly lower during the attack period than during the attack-free period. However, PDW, plateletcrit, MPV, and ESR values did not show a significant difference between the attack periods and attack-free periods. Similarly, during the attack period, leukocyte and neutrophil counts, NLR, and PLR were significantly higher compared to the healthy control group. The lymphocyte count and MPV values of the patients during attacks were significantly lower than the control group. However, no significant difference in platelet count, PDW, and plateletcrit levels between patients during attacks and the healthy control group was found. When patients with PFAPA syndrome during attacks and attack-free periods were compared with the healthy control group, their MPV values were significantly lower. When comparing white blood cell count, neutrophil count, lymphocyte count, NLR, platelet count, PLR, PDW, and plateletcrit values between the attack-free period and the control group, no significant differences were found.
| Discussion|| |
PFAPA syndrome, the most common periodic fever syndrome in childhood, was first described in 1987 by Marshall et al. in a report based on 12 children. The syndrome is diagnosed clinically and by the exclusion of the other diseases. In 1989, Thomas et al. proposed the first diagnostic criteria to make it easier to diagnose. According to these criteria, the association of one or more of the symptoms of aphthous stomatitis, pharyngitis, and cervical adenitis with regularly recurring fevers in children <5 years of age suggests PFAPA syndrome., The dramatic response to single-dose oral steroid administration is unique to PFAPA syndrome and may be used as a diagnostic criterion. However, as the syndrome is also defined in adults, using age as a diagnostic criterion is not applicable.,, Therefore, we used the Padeh's diagnostic criteria to diagnose our patients.
The pathogenesis and the effect of genetics on the pathogenesis remain unknown. The disease is considered to be caused by impaired response of the immune system with the influence of environmental factors., While both the CRP level and procalcitonin level increase in bacterial infections, only the CRP level increases in PFAPA syndrome, with the procalcitonin level remaining normal., Increased levels of CRP in the presence of increased IL-1 β and IL-6 indicate that the etiology is based on an immunological mechanism. Patients are completely asymptomatic during the intervals between episodes, and CRP levels and leukocyte counts are normal., In our study, we compared the blood test results of attack and attack-free periods and found that the ESR was lower during the attack-free periods than during attacks, but the difference was not statistically significant. Our explanation for this situation is that the decrease in ESR takes longer than the decrease in CRP levels (about 2 weeks).
Platelets are activated by various cytokines. IL-6 and TNF-α contribute to the inflammation process by platelet activation. Platelets do not have a nucleus and are produced from megakaryocytes in the bone marrow. Apart from their antithrombotic effects, they are considered to play an important role in inflammation by secreting proinflammatory cytokines, which leads to leukocyte migration and binding to endothelial cells. Large platelets are more reactive; they produce more cytokines and thromboxane A2, as their granule contents are denser than smaller platelets, and the need for them increases in the acute stage of inflammation. Thus, in the case of inflammation, it is thought that MPV decreases due to the consumption of larger circulating platelets. In addition, it has been suggested that the overproduction of proinflammatory cytokines and acute-phase reactants may affect the process of megakaryopoiesis, and subsequently, release small volume platelets from the bone marrow, thereby reducing MPV.
MPV, one of the platelet indices used to assess platelet activation and function, and plateletcrit, the percentage of platelets in the blood, are universally available with routine blood counts by automated hemograms, and their clinical importance is becoming more clear thanks to many recently conducted studies., MPV is widely used to determine thrombocyte activity, and there are studies showing that it is a useful marker of inflammation in evaluating disease activity and response to treatment in many chronic diseases., In 1983, Robbins and Barnard reported for the first time that platelet counts increased and MPV decreased in infectious diseases. It has been shown in the literature that MPV values are different in different diseases. MPV increases in various diseases, such as myocardial infarction, sepsis, diabetes mellitus, and cerebrovascular disease, whereas it decreases in some diseases, such as rheumatoid arthritis, FMF, and ulcerative colitis.,, Tekin et al. found that the MPV values measured during attacks and attack-free intervals were significantly lower than the control group. Moreover, the MPV values were found to be significantly lower during attacks than during attack-free intervals. In another study, there was no significant increase in MPV values in patients with acute rheumatic fever; however, a significant increase was seen in platelet and plateletcrit values in the early and late periods. Similarly, to the results of the study by Tekin et al., while the MPV values during an attack were lower than in controls, there was no significant difference between attack and attack-free periods in our study. Unexpectedly, when we compared the patients in the attack-free period with the control group, we found that the MPV values in the PFAPA syndrome patients during attack-free periods were significantly lower than the control group. This circumstance suggests to us that the inflammation process continues, although subclinically, during attack-free periods. In this respect, we consider that in addition to single-dose steroid treatment, which is typically administered to patients during the attack period, as the subclinical inflammation persists, the long-term anti-inflammatory treatment choice that is administered for other autoinflammatory diseases should not be ignored.
Our study is the first study comparing the control group and the attack-free period in PFAPA syndrome, and we believe that there should be other studies with a larger population for more definite conclusions. There are some studies in the literature showing that the frequency of attacks decreases with regular colchicine and cimetidine instead of steroid administration. However, no data are presented in these studies regarding the presence of subclinical inflammation in patients with frequent attacks, but there is research for an alternative therapy to tonsillectomy.
In addition, in our study, the platelet values during the attack-free period were higher than in the attack period. We think that single-dose steroid administration or the rapid consumption of platelets during attacks may cause this situation. There are not many studies regarding PDW and plateletcrit in the literature. In fact, in our study, we could not find a significant difference between the groups in terms of plateletcrit and PDW.
| Conclusion|| |
We observed that MPV was significantly lower during inflammation compared to the control group. We observed a significant decrease in MPV values during the attack-free period compared to the control group, suggesting that subclinical inflammation continues in the attack-free period in PFAPA syndrome. In light of these findings, we believe that this study will contribute to understanding PFAPA syndrome and its treatment with a new perspective.
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Conflicts of interest
There are no conflicts of interest.
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[Table 1], [Table 2], [Table 3], [Table 4]