‡ These are co-first authors.
Although several previous studies have examined the association between the platelet to lymphocyte ratio (PLR) and acute appendicitis (AA), findings have been controversial. We aimed to systematically assess the available evidence to elucidate the overall relationship between the PLR and AA.
Pubmed and Embase databases were searched for all available published literature before August, 2019 b
Eleven articles met the inclusion criteria and included in this study. Meta-analysis showed that the level of PLR in the AA group was significantly higher than that in the control group (SMD: 1.19, 95% CI: 0.75 to 1.62, P<0.001). A series of subgroup analyses were conducted to investigate the heterogeneity, showing a significant increase in PLV levels in adults with age ≥30 years (SMD: 1.46, 95% CI: 0.89 to 2.02),compared to those in adult <30 years(SMD: 0.58, 95% CI: 0.12 to 1.04) or in children (SMD: 1.03, 95% CI: 0.51 to 1.56). Compared to non-AA controls, a significant increased PLR level was also observed in non-perforated AA (SMD: 1.23, 95% CI: 0.88 to 1.59) and in AA patients during pregnancy (SMD: 0.70, 95% CI: 0.36 to 1.04), while not in perforated AA (SMD: 2.28, 95% CI: -1.72 to 6.28).
A significant increase in PLR level is found in patients with AA, indicating that PLR is a promising biomarker for AA. PLR provides a convenient option for emergency department to quickly screen for clinically or radiologically confirmed AA awaiting appendectomy, especially for pregnant women suspected of having AA. More high-quality evidence is needed to further confirm the diagnostic accuracy of PLR for AA.
All relevant data are within the manuscript and its Supporting Information files.
Acute appendicitis (AA) affects approximately 50000 and 300000 individuals annually who receive appendectomies in the UK and in the US, respectively [
Due to the uncertainty of its aetiology, the confirmation or elimination of the diagnosis of appendicitis is the primary concern. If AA is suspected, how to stratify simple and complex appendicitis is also highly significant. Though several diagnostic approaches have been widely applied in clinical practice [
In the last decades, findings from studies on commonly used blood biomarkers are used to aid the diagnosis of suspected AA patient, especially in children, pregnant women or women of fertile age, and elderly patients. Those inflammatory markers, such as C-reactive protein (CRP), mean platelet volume (MPV), platelet (PLT), platelet distribution width (PDW) and red blood cell distribution width (RDW) or other blood biomarkers, can help identify AA with a certain specificity and sensitivity [
Recent, increasing evidence suggests that platelet to lymphocyte ratio (PLR) may serve as an inflammatory marker used as a diagnostic or prognostic indicator for various diseases [
This study was performed and reported according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) statement [
In August, 2019, a comprehensive literature search was performed using online databases b
Two independent authors screened the searched relevant studies based on each record’s title or abstract. Full texts were further read after the initial screening process according to the eligibility criteria. Disagreements were resolved by discussion or by a third author by tracing the original article.
Studies were consider eligible if they satisfied the following criteria: (1) provided the association between the PLR level and AA; (2) the mean concentration and its standard difference (SD) of the PLR level could be obtained from original studies for both AA patients and controls (healthy controls, healthy pregnant women, outpatient clinic patients without AA, and patients with negative appendectomy) or could be calculated using the indirect methods [
Pairs of independent authors extracted data from the published articles using a predefined data abstraction form. Variables concerning the study design, population characteristics and laboratory index were investigated including first author, publication year, study country and design, sample size of the study, sex percent, mean age of the participants, the blood index studied, and the type of appendicitis.
The quality of each included study was evaluated using the Newcastle–Ottawa Quality Assessment Scale (NOS) [
All analyses were performed using the STATA software (version 12.0; Stata Corporation). Data were collected as means ± standard deviation (SD) to estimate the pooled effect estimates. Meta-analysis was carried out using standardized mean difference (SMD) and 95% confidence limit (CI) for assessing the association between the PLR levels and AA. The random effects model, a most common and conservative approach to combine study estimates, was applied for all meta-analyses considering the between-study difference [
Cochran’s Q test and I2 statistic were evaluated to assess the inter-study heterogeneity. I2 of 0–25%, 26–50%, 51–75% and 76–100% indicates insignificant heterogeneity, low heterogeneity, moderate heterogeneity, and high heterogeneity, respectively [
Publication bias was assessed by visual inspection of the funnel plot symmetry and quantitatively by Egger’s and Begg’s tests, with a P value less than 0.05 indicating significant publication bias [
Our initial literature search through databases identified a total of 5446 records. After removing 1214 duplicates, the remaining 4232 records were reviewed based on the title or abstract reading by two independent authors. During this stage, 4208 irrelevant studies were excluded. Twenty-four articles were retrieved and reviewed based on full text. Finally, 11 articles met the inclusion criteria and were included in our meta-analysis [
The baseline characteristics of each included study are shown in
Study | Year | Country | Sample size | Case no. | Controls and no. | Sex (male)/female % | Age(mean), years | Biomarker studied | Appendicitis type |
---|---|---|---|---|---|---|---|---|---|
Pehlivanli F | 2019 | Turkey | 558 | 458/14 | Negative appendectomy; 86 | Males 55.2%; Females 44.8% | 34.24 | WBC, PLT, MPV, NLR, PLR | Acute appendicitis, perforated appendicitis |
Yazar FM | 2018 | Turkey | 640 | 511/54 | Negative appendectomy; 75 | Positive appendectomy (Males 54.7%; Females 45.3%); Negative appendectomy (Males 45.3%; Females 54.7%) | Positve appendectomy 39.23: Negative appendectomy 35.27 | WBC, CRP, NLR, PLR | Acute appendicitis |
Cinar H | 2018 | Turkey | 94 | 40/7 | Healthy pregnant women under routine pregnancy follow-up at the obstetrics clinics; 47 | Females 100.0% | Group A 27; Group B 25.14; Control group 29.74 | WBC, MPV, NLR, PLR | Acute focal appendicitis, acute suppurated appendicitis, acute perforated appendicitis, and acute gangrenous appendicitis |
Nazik S | 2017 | Turkey | 63 | 30 | Healthy control subjects; 33 | Males 65.08%; Females 34.92% | 9.34 | ESR,CRP, WBC, MPV, NLR, PLR, Ischemia-modified albumin | Acute appendicitis and perforated appendicitis |
2017 | Turkey | 569 | 475 | Negative appendectomy; 94 | Males 55.94%; Females 44.05% | 40 | PLR | Acute appendicitis | |
Mehmet Ü | 2017 | Turkey | 569 | 455 | Patients with a normal appendix having other complaints in ED excluding abdominal pain; 114 | Males 55.36%; Females 44.64% | 31.97 | WBC, PLT, Neutrophil, Lymphocyte, NLR, PLR, PDW | Acute appendicitis |
Toktas O | 2017 | Turkey | 60 | 30 | Healthy control subjects; 30 | Males 71.67%; Females 28.33% | 28.5 | Platelet, MPV, RDW, Neutrophil, Lymphocyte, NLR, PLR, Leukocyte | Acute appendicitis |
Shin DH | 2017 | Korea | 650 | 615 | Negative appendectomy; 35 | Males 51.2%; female 48.8% | 33 | WBC, NLR, LMR, PLR, DNI, CRP | Non-complicated appendicitis, complicated appendicitis |
Ulukent SC | 2016 | Turkey | 191 | 97 | Healthy control subjects in outpatient clinics; 94 | Appendicitis: males 59.8%; Females 40.2%;Control: Males 63.8%; Females 36.2% | Appendicitis 39; Control 34 | Leukocyte count, neutrophil percentage, NLR, PLR, MPV, RDW, PDW and CRP | Acute appendicitis |
Acar E | 2016 | Turkey | 476 | 215/200 | Patients without any complaints at the outpatient clinics; 61 | Male 53.5%; female 46.5% | 31.6 | WBC, RDW, MPV, neutrophil, lymphocyte, NLR and PLR. | Acute appendicitis |
Yazar FM | 2015 | Turkey | 122 | 28/35 | Healthy pregnant control; 29/30 | Females 100.0% | Appendectomy group 26.93; Healthy pregnant control group 29.62 | WBC, CRP, NLR, PLR | Acute appendicitis |
Abbreviations: CRP: C-reactive protein; DNI: Delta neutrophil index; ED, emergency department; ESR: Erythrocyte sedimentation rate; MPV: Mean platelet volume; NLR: Neutrophil to lymphocyte ratio; PDW: Platelet distribution width; PLT: Platelet; PLR: Platelet to lymphocyte ratio; RDW: Red cell distribution of width; WBC: White blood cell.
Eleven case-control studies involving 3006 cases and 698 controls examined the association between PLR level and AA. Meta-analysis found that PLR levels were significantly higher in patients with AA (SMD: 1.19, 95% CI: 0.75 to 1.62, P<0.001) than that of the controls, with high inter-study heterogeneity (I2 = 95.2%) (
We conducted several preplanned subgroup analyses and sensitivity analyses by several variables. Analyses stratified by study sample size revealed that PLR level was significantly related to AA for studies with both small sample size (<500) (SMD: 1.15; 95% CI: 0.22 to 2.08; P = 0.015) and large sample size (≥500) (SMD: 1.21; 95% CI: 0.76 to 1.67; P <0.001). When we stratified studies by study region, a statistically significant relationship was noted for studies conducted in Europe (SMD: 1.12; 95% CI: 0.66 to 1.57; P <0.001) and in Asia (SMD: 1.90; 95% CI: 1.54 to 2.25; P = 0.003). The associations were also significant in studies with both adult patient age ≥30 years (SMD: 1.46; 95% CI: 0.89 to 2.02; P = 0.004), adult patient age <30 years (SMD: 0.58; 95% CI: 0.12 to 1.04; P = 0.472) and children. Sensitivity analyses revealed significant associations when involving only non-perforated AA (SMD: 1.23; 95% CI: 0.88 to 1.59; P<0.001) or AA during pregnancy (SMD: 0.70; 95% CI: 0.36 to 1.04; P = 0.037), but not perforated AA (SMD: 2.28; 95% CI: -1.72 to 6.28; P = 0.263). The PLR level was not found significantly different among complicated AA compared to that in non-complicated AA. According to the analysis by study quality, a higher PLR level was found in studies with both high quality (NOS score≥7) (SMD: 0.95; 95% CI: 0.57 to 1.32; P <0.001) and moderate or low quality (SMD: 1.84; 95% CI: 0.56 to 3.11; P = 0.005). Based on the analyses by control subjects, significant associations were found among healthy control subjects (SMD: 0.77; 95% CI: 0.46 to 1.07; P <0.001) and control subjects with negative appendectomy (SMD: 1.40; 95% CI: 1.05 to 1.74; P <0.001). The detailed results of subgroup analyses for associations between PLR levels and AA are presented in
Variable | SMD | 95%CI | Degree heterogeneity (I2 statistics; %) | No. of included Studies | ||
---|---|---|---|---|---|---|
Total | 1.19 | 0.75 to 1.62 | 95.2 | <0.001 | 11 | NA |
Sample size | 0.149 | |||||
<500 | 1.15 | 0.22 to 2.08 | 96.4 | 0.015 | 6 | |
≥500 | 1.21 | 0.76 to 1.67 | 94.0 | <0.001 | 5 | |
Study region | <0.001 | |||||
Europe | 1.12 | 0.66 to 1.57 | 95.2 | <0.001 | 10 | |
Asia | 1.90 | 1.54 to 2.25 | - | 0.003 | 1 | |
Age (Mean/median) | 0.001 | |||||
Adult <30 years | 0.58 | 0.12 to 1.04 | 61.7 | 0.472 | 3 | |
Adult ≥30 years | 1.46 | 0.89 to 2.02 | 96.8 | 0.004 | 7 | |
Children | 1.03 | 0.51 to 1.56 | - | - | 1 | |
Appendicitis type | <0.001 | |||||
Perforated AA | 2.28 | -1.72 to 6.28 | 98.9 | 0.263 | 2 | |
Non-perforated AA | 1.23 | 0.88 to 1.59 | 75.6 | <0.001 | 2 | |
AA during pregnancy | 0.70 | 0.36 to 1.04 | 77.1 | 0.037 | 2 | |
Study quality | <0.001 | |||||
NOS score≥7 | 0.95 | 0.57 to 1.32 | 90.3 | <0.001 | 8 | |
NOS score <7 | 1.84 | 0.56 to 3.11 | 98.0 | 0.005 | 3 | |
Control subject | <0.001 | |||||
Healthy subjects | 0.77 | 0.46 to 1.07 | 77.1 | <0.001 | 3 | |
Negative appendectomy | 1.40 | 1.05 to 1.74 | 85.2 | <0.001 | 4 | |
Healthy pregnant women | 0.66 | -0.06 to 1.37 | 33.3 | 0.074 | 2 | |
Non-AA outpatients or ED patients | 1.90 | -0.91 to 4.71 | 99.4 | 0.185 | 2 |
Abbreviations: AA, acute appendicitis; CI, confidence interval; ED, emergency department; NA, not available; SMD, standardized mean difference.
A funnel plot was generated to investigate the potential publication bias of the 11 included studies. Both Egger’s (P = 0.573) and Begg’s (P = 1.000) indicated that no significant publication bias existed in these studies (
To the best of our knowledge, this meta-analysis is the first attempt to demonstrate the association between the PLR level and AA. A comprehensive literature search of all observational studies assessing this relationship was performed. The findings indicate that the PLR level is significantly higher in AA individuals compared to the non-AA ones which is in line with previous reports [
Numerous reports have revealed that systemic inflammatory response can induce neutrophilia and lymphocytopenia [
This study has important clinical relevance and implications. As a promising diagnostic biomarker, PLR has great potential to help in the diagnosis and decision-making of suspected appendicitis in selected populations and conditions. We found that the diagnostic implication of PLR may play an important role for participants whose age ≥30 years, pregnant women, and AA without progression to perforation. For areas with limited medical resources, due to the limited access to CT or MRI scan at the emergency department, PLR can be used as an effective rapid alternative to auxiliary diagnosis. Our study shows that PLR levels in pregnant women with appendicitis are significantly higher than those without appendicitis, which indicates that the measurement of PLR level provides an important, safe, rapid and radiation-free auxiliary diagnosis method for pregnant women suspected of appendicitis. PLR also has potential value in differentiating perforated appendicitis from nonperforated appendicitis, although large prospective studies are needed further confirmation.
The PLR, like many blood inflammatory indicators, are commonly used, non-invasive and cost-effective blood biomarkers, which can be easily available in the emergency department, even in small hospitals. However, the value of the PLR in AA has only been examined in few studies. A study conducted by Celik et al. [
In this study, the reasons to select SMD as the statistical parameter for this kind of meta-analysis were explained as follows. First, the current literature search did not yield sufficient eligible studies for diagnostic meta-analysis combining the sensitivity and sensitivity of PLR as effect estimates. Instead, 11 studies could be identified providing means and SDs of PLR levels for both AA patients and controls, which could be used as an alternative effect estimate to conduct a meta-analysis. Thus, SMD is a suitable substitute as a statistical parameter to demonstrate the associations between PLR levels (a continuous measure outcome) and AA. Second, a research article published in 2019 [
Considerable inter-study heterogeneity was detected in our meta-analysis, though we conducted several subgroup analyses. The results of subgroup analyses for relationship between the PLR level and AA indicated that the heterogeneity could partly attribute to variables regarding differences in patient age, appendicitis type and control subjects. However, these variables could not account for all of the heterogeneity. Perhaps further larger well-designed prospective cohort studies or clinical trials are warranted in the future to better demonstrate the relationship between the PLR level and AA.
The present meta-analysis has several advantages. Firstly, this is the first meta-analysis of the relationship between PLR level and AA. From the pooled analysis, we found that patients with AA had significant higher PLR level than the non-AA controls. Moreover, multiple analyses including the “leave-one-out” sensitivity analysis, trim and fill method and subgroup analyses confirmed this association was stable. In addition, the results of subgroup analyses were mostly consistent with those of the main analysis, which also indicated our findings were convincing. Secondly, random-effects model, a more conservative approach, was used when we pooled effect estimates, making the results of our meta-analysis more accurate. Thirdly, publication date and language limits were not restricted for literature search, making the results less possible to leading to publication bias.
This meta-analysis should still be interpreted with caution due to the limitations in several aspects. First, despite that all studies used blood sample analyzer to evaluate PLR levels, the sample collection time and reference values were varied, which can lead to heterogeneous results. Second, besides the lack of diagnostic accuracy studies, the results of this meta-analysis were mainly based on observational studies, mostly case-control studies, which is a limitation of critical importance for demonstrating a causal relationship between PLR level and AA. However, observational study results may also provide significant preliminary data to justify further larger trials and well-designed prospective cohort studies. Third, there seem to be patients mostly from one continent of Europe. The variations on the ethnicity of the population are still under investigation. Because limited number of studies is involved, multi-ethnic cohort studies are warranted to confirm our findings. Fourth, it is known that systemic inflammatory response might induce an increase in blood PLR. It is quite obvious that AA can also lead to the PLR increase. Diagnosis of AA can be challenging due to the fact that a variety of acute gastrointestinal and gynaecologic diseases can mimic the symptoms of AA. Therefore, more high quality evidence should be accumulated before definite conclusions could be drawn. Last but not least, as we extracted estimates using indirect methods in 5 studies, this method might have led to overestimation or underestimation of the sample of SD and thereby causing inaccuracy of the effect estimates.
In conclusion, this meta-analysis shows a significant increase in PLR level in patients with AA, indicating that PLR is a promising biomarker for AA. PLR provides a convenient option for emergency department to quickly screen for clinically or radiologically confirmed AA awaiting appendectomy, especially for pregnant women suspected of having AA. For areas with limited medical resources, due to the limited access to CT or MRI scans in emergency department, PLR can be used as an effective and rapid alternative to auxiliary diagnosis. However, more high-quality evidence is needed to further confirm the diagnostic accuracy of PLR for AA, and whether PLR combined with other blood biomarkers will yield better predictive value needs to be further studied.
Supplementary search strategies.
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We sincerely thank all authors who provided published data for our meta-analysis.