Received: 5 March 2023 Accepted: 21 July 2023

DOI: 10.1111/ijlh.14163

ORIGINAL ARTICLE

The role of blood inflammatory markers in the preoperative

diagnosis of acute appendicitis

Alper Adir 1 | Andrei Braester 1,2 | Perelstein Natalia 2 | Dally Najib 2,3 |
1,2 1,2 1,2 1,2
Luiza Akria | Celia Suriu | Barhoum Masad | Waksman Igor

1
Azrieli Faculty of Medicine, Bar Ilan
University, Safed, Israel Abstract
2
Hematology Institute, Galilee Medical Center, Introduction: Acute appendicitis (AA) requires a prompt diagnosis. According to post-
Nahariya, Israel
3
operative pathological results, a significant number of appendectomies are performed
Hematology Institute, Ziv Medical Center,
Safed, Israel on a normal appendix (NA). The aim of this study is to evaluate the role of preopera-
tive inflammatory markers in supporting and improving the clinical diagnosis of AA,
Correspondence
Andrei Braester, Hematology Institute, Galilee extracting more information from CBC parameters.
Medical Center, P.O. Box 21, 22100 Nahariya,
Methods: The study is a retrospective one. The histopathological results of operated
Israel.
Email: braester@bezeqint.net appendix from 102 patients, who underwent appendectomy for clinically suspected
AA, were extracted from the Galilee Medical Center systems. Two patient groups
(NA and true AA) were compared for neutrophil to lymphocyte ratio (NLR), platelet
to lymphocyte ratio (PLR), monocyte to lymphocyte ratio (MLR) and mean platelet
volume (MPV). The obtained data were statistically analyzed, using the independent
sample t test and Mann–Whitney test. Category data have been compared among
groups with the chi-squared test. The primary endpoint of our research was to assess
the predictive power of blood biomarkers.
Results: Patients with suspected AA, based on clinical picture and contrast enhanced
computed tomography (CECT), and with MLR-value ≥0.3357 were 5.25 times more
likely than normal to have AA. Patients with NLR-value ≥3.2223 were 7 times more
likely than normal to have AA. The differences in PLR and MPV values were not sta-
tistically significant.
Conclusions: The NLR and MLR biomarkers can assist in diagnosis of AA. This can be
particularly helpful in cases where CECT is contraindicated, as in pregnant women or
children.

KEYWORDS
acute appendicitis, Alvaro score, computed tomography, inflammatory blood biomarkers, mean
platelet volume, monocyte/lymphocyte ratio, negative appendix, neutrophil/lymphocyte ratio,
platelet/lymphocyte ratio, Ripasa score

1 | BAC KGROU ND

AA is an inflammation of the appendix, which occurs when the inside

of the appendix is blocked and is the cause for the most common
abdominal surgical emergency. Delayed diagnosis of AA could lead to
Alper Adir and Andrei Braester and Barhoum Masad and Waksman Igor contributed equally
to this work. complications, such as perforated appendix, peritonitis, sepsis,

58 © 2023 John Wiley & Sons Ltd. wileyonlinelibrary.com/journal/ijlh Int J Lab Hematol. 2024;46:58–62.

ADIR ET AL.
increased morbidity and mortality. Appendicitis may be caused by var-
ious infectious pathogens in the digestive tract, such as viruses, bacte-
ria, or parasites, or can happen when the appendix is blocked or
trapped by stool (fecalith). Tumors can sometimes cause AA as the
blood supply to the appendix is stopped when the swelling and sore-
ness get worse.1 Without proper blood flow, the appendix starts to
decay. Ongoing inflammation and infection can cause perforation of
the appendix, leading to peritonitis. The incidence of AA in the popu-
lation is 220 cases per 100 000, with a mortality of 0.43/100000, as
of 2019.2 The diagnosis of AA is predominantly clinical, supported by
imaging data. Acute appendicitis can be difficult to diagnose unless
the patient shows typical symptoms, which are only present in about
half of all cases. The histopathological examination of excised appen-
dix shows sometimes findings compatible with NA. Ovarian cyst is the
most common diagnosis mistaken for AA in younger women, whereas
malignant disease of the ovary was the most common condition mis-
take for AA in women aged 45 years and older.3 A NA, also known as
“white appendix” is the removal of a healthy appendix during surgery.
NA can result in dire consequences and in the latest decades several
clinical scores have been developed to improve the diagnosis and min-
imize the possibility of a NA excision. There are two well-known
scores currently used: Alvarado and Ripasa scores. Alvarado score
was proposed for the first time in 1986 and it is one of the most
widely used in the diagnosis of AA.4
The Ripasa is one of the more recently developed scoring sys-
tems.5 The Alvarado score uses leukocytosis >10 000 with left shift
(neutrophils >75%), while the Ripasa score uses only leukocytosis.6
In our Medical Center we use (sporadically) Ripasa score.
These scores improved the diagnostic accuracy, but insufficiently,
so the use of imaging method, such as computed tomography (CT) is
7,8
also required.
There was a significant reduction in the NA excision in patients
who presented to the emergency department when associated with a
significant increase of preoperative abdominal CT.8 The sensitivity
and specificity of CT for diagnosing AA are high, yet contrast
enhanced computed tomography (CECT) is preferable.8 Biomarkers
CBC derived, like neutrophil-to-lymphocyte ratio (NLR), platelet to
lymphocyte ratio (PLR), monocyte to lymphocyte ratio (MLR) and
mean platelet volume (MPV) are less investigated for diagnosis of AA
and more for postoperative course or for the complications poten-
tial.4,9,10 We intended to evaluate the ability to prevent NA excision
through assessment of these inflammatory biomarkers.
2 | METHODS
We conducted a retrospective analysis of inflammatory biomarkers. CT
data and histopathological results of excised appendix in adults
(>18 year-old) with a preoperative diagnosis of AA in a single medical
center and in one (out of two) surgical departments during the study
period (June 2021–December 2021). The approval from the Institutional
Review Board (IRB, Helsinki Committee) of Galilee Medical Center
(GMC) was obtained prior to the start of the study. We included in this
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59
study 102 participants who had appendectomy for suspected AA, based
on clinical, laboratory (for inflammatory biomarkers) and CT data. The
102 patients were divided in two subgroups, 51 consecutive patients
with histopathological analysis positive for acute appendicitis and 51 con-
secutive patients with a normal histopathological analysis (“white appen-
dix”). The preoperative clinical picture and laboratory results were
assessed by a senior surgeon and the preoperative CT was assessed by
the radiologist on duty and a second examination was performed after
operation by a senior radiologist (always the same). The preoperative
values of blood inflammatory biomarkers were divided into two groups:
one group linked to postoperative NA findings in the histological exami-
nation and the second group linked to sick appendix, according to histo-
pathological examination. All the excised appendixes were analyzed by
the same pathologist. The inclusion criteria were: patients >18 years old,
patients which perform a CECT, with a suspicion of AA.
Exclusion criteria were: age < 18 years old, pregnant women, nor-
mal CECT, patients with another known infectious or inflammatory
disease.
All the information was collected from GMC database. We state
that all CBC have always been done with the same hematology ana-
lyzer, Sysmex XN-1000.
The results were subject to statistical tools that were used to
illustrate the relationship between blood biomarkers and pathological
findings.
2.1 | Statistical analysis
The results were subjected to statistical analyses in order to study the
relationship between blood biomarkers and pathological findings. Uni-
variate analysis and comparison among groups: the data were com-
pared among groups using the independent sample t test and Mann–
Whitney test. The choice between the tests was made according to
the groups size and the distribution of the variables that were com-
pared. Category data has been compared among groups with the chi-
square test. We calculated the sensitivity, the specificity and the 95%
confidence interval (CI) for each biomarker or the CECT result, versus
the pathological response, considered as the gold standard. In addi-
tion, we determined a threshold value (cut-off) based on our data for
the various biomarkers and the CECT score using ROC (receiver oper-
ator curve). The statistical analysis was performed using IBM SPSS
Statistics, version 27.0.
3 | RE SU LT S
According to our statistical results, the absolute neutrophil count
(ANC) and absolute monocyte count (AMC) are higher in the AA
group (Table 1). This result can be explained by the fact that AA is
mostly a result of bacterial infection, which normally leads to an
increase in the number of neutrophils and monocytes. We have also
found increased values statistically significant for NLR and MLR in the
AA group (Table 1). We suggest two cut-off values: 3.2223 and
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60 ADIR ET AL.

TABLE 1 Inflammatory biomarkers.

NA N = 51 AA N = 51 p-value
Neutrophils (K/μL) p < 0.001a
Mean (SD) 6.25 (2.96) 9.82 (3.51)
Median (IQR) 5.87 (4.10–7.61) 9.68 (7.41–12.05)
Platelets (K/μL) 0.518b
Mean (SD) 254 (67.86) 246.08 (54.75)
Median (IQR) 258 (206–280) 250 (211–268)
Monocytes (K/μL) 0.013b
Mean (SD) 0.70 (0.27) 0.84 (0.28)
Median (IQR) 0.690 (0.49–0.90) 0.86 (0.68–1.00)
Lymphocytes (K/μL) 0.037b
Mean (SD) 2.34 (0.91) 2.00 (0.71)
Median (IQR) 2.10 (1.70–2.82) 2.00 (1.48–2.49)
MPV (fL) 0.170b
Mean (SD) 10.802 (0.889) 10.506 (1.06)
Median (IQR) 10.800 (10.10–11.30) 10.6 (9.8–11.1)
NLR p < 0.001a
Mean (SD) 3.16 (2.27) 5.75 (3.58)
Median (IQR) 2.34 (1.73–3.70) 5.15 (2.95–8.16)
PLR 0.226a
Mean (SD) 126.19 (68.24) 141.497 (69.55)
Median (IQR) 102.61 (91.28–153.62) 120.98 (90.28–173.79)
MLR p < 0.001a
Mean (SD) 0.32 (0.15) 0.459 (0.22)
Median (IQR) 0.26 (0.23–0.38) 0.42 (0.32–0.54)

Note: A p-value ≤0.05 was considered significant.

a
Mann–Whitney U test.
b
Independent sample t test.

0.3357 for NLR and MLR, respectively. These values are the most
appropriate combination of both high sensitivity and specificity. The
NLR value of 3.2223 has a sensitivity of 74.55% and a specificity of
70.7%. In addition, the result of the logistic regression analysis shows
that NLR values of 3.22 or higher had seven times higher risk for
acute appendicitis ( p < 0.001). We chose ROC (receiver operating
characteristic curve) to simulate in a graph the relationship between a
true-positive rate (sensitivity) and a false-positive rate (1-specifity) for
NLR and MLR (Figures 1 and 2) and we specified AUC (Tables 2
and 3). For MLR, the cut-off value of 0.3357 showed sensitivity of
70.8% and specificity of 68.6% and MLR ≥0.3357 had 5.250 times
higher risk for AA (p < 0.001). In contrast to some studies that
showed an increase of PLR and a decrease in MPV during AA, we
could not find statistically proven links between AA and PLR or MPV
(Table 1).11 Surprisingly, the absolute lymphocyte count (ALC) was
higher in NA. As for the platelets size (MPV), recent studies illustrate
an inverse relationship between MPV and disease activity, where
MPV decreases as the inflammatory disease worsens.12
Both MPV and PLR results show sensitivity and specificity of
F I G U R E 1 ROC curve simulates in graph the relationship
50% each. We conclude that MPV and PLR cannot be used as a between true-positive rate (sensitivity) and false-positive rate
“screening tool” for AA. (1-specifity) for NLR.
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ADIR ET AL. 61

Because we used the same CBC analyzer, Sysmex XN-1000,
though the results are reliable and are not transferable across differ-
ent hematology analyzers.
4 | DISCUSSION
The issue of negative appendectomy is still a significant challenge in
the surgical management of patients suspected of acute appendicitis.
Overdiagnosis expose the patient to an unnecessary operation and
underdiagnosis exposes the patient to a high morbidity and mortality,
due to delayed treatment. The difficulty in preoperatively diagnosing
acute appendicitis is manifested by the negative laparotomy rates of
10%–15% in men and as high as 45% in women of childbearing age.
In one study, the sensitivity and specificity of the Alvarado score
were 83.3% and 41%, respectively.13 Alvarado score has a modified
version: modified Alvarado scoring system (MASS).14
Memon and his colleagues evaluate the usefulness of the Alvarado
scoring system in reducing the percentage of negative appendectomy
and found that the sensitivity and specificity of the Alvarado scoring
system were 93.5% and 80.6% respectively. The positive and negative
predictive values were 92.3% and 83.3%, respectively, and the accuracy
was 89.8%.15 In another article, Ripasa score was found better than
Alvarado score: the sensitivity and specificity of the Alvarado scoring
system were 53.95% and 70.18%, respectively. Positive and negative
predictive values of Alvarado were 70.69% and 53.33%, respectively. In
contrast, the sensitivity, specificity, and positive and negative predictive
values of the Ripasa scoring system were 93.42%, 45.61%, 69.61%, and
83.87%, respectively.16 Although Ripasa and Alvarado scores are the
most commonly used in clinical practice, there is no clear indication yet
for choosing the appropriate scoring system for patients at risk of AA. It
appears that Ripasa score has a significantly higher sensitivity and diag-
nostic accuracy. Ripasa score is the score used in our medical center for
preoperative “data processing.” But currently, the Alvaro and/or Ripasa
scores are not sufficient to be used alone in differential diagnosis of
AA. Despite the high sensitivity and specificity, predictive value of
Alvarado/Ripasa scores and the better CT results, the number of white
appendix in post-operative histopathological examination remains too
high.17 In our research we tried to assess the role of blood biomarkers
in AA diagnosis. We found that NLR and MLR have a role in diagnosis
of AA, in contrast to PLR and MPV, which do not assist in the differen-
tial diagnosis. The absolute lymphocyte count is higher in the white
appendectomy. In our study, the statistical analysis revealed cut-off
values for NLR and MLR, which can be different in other studies. In

F I G U R E 2 ROC curve simulates in graph the relationship recent studies, the above-mentioned biomarkers demonstrated a prom-
between true-positive rate (sensitivity) and false-positive rate ising ability to predict inflammatory diseases. Several studies show a
(1-specifity) for MLR. strong link between certain inflammatory blood biomarkers and AA.

TABLE 2 NLR—area under the curve.

Test result variable(s): NLR
Asymptotic 95% confidence interval

Area SEa Asymptotic sig.b Lower bound Upper Bound

0.793 0.044 p < 0.001 0.706 0.880
a
Under the nonparametric assumption.
b
Null hypothesis: true area = 0.5.

TABLE 3 MLR—area under the

Test result variable(s): MLR
curve.
Asymptotic 95% confidence interval
a b
Area SE Asymptotic sig. Lower bound Upper bound
0.730 0.051 p < 0.001 0.630 0.829
a
Under the nonparametric assumption.
b
Null hypothesis: true area = 0.5.

62
A recently published meta-analysis shows a link between decreased
MPV values and AA, primarily in patients >30 years old.18 Furthermore,
several studies show that we can rule out AA in the presence of normal
biomarkers. Regarding AA, there are novel findings regarding blood
count, including increased absolute neutrophil count, decreased lym-
phocyte count, and increased platelet count.14
5 | C O N CL U S I O N
Our results show that novel promising blood biomarkers, like NLR and
MLR, may play a significant role in the diagnosis of AA. These bio-
markers may become particularly useful when the clinical findings or
imaging results are inconclusive, or when CT is contraindicated, such
as in pregnant women or children, or in resource-limited environ-
ments, where the access to surgery is limited or where repeated imag-
ing is not readily available. It is possible that a combination of clinical,
imaging and laboratory findings (including NLR and MLR) can achieve
the best diagnostic result, and minimize the percentage of white
appendectomy. There is no doubt that a prospective study is neces-
sary to really validate our findings.
AUTHOR CONTRIBUTIONS
Andrei Braester and Waksman Igor designed the study; Alper Adir,
Andrei Braester participated in data analysis; Alper Adir, Andrei Brae-
ster, Barhoum Masad reviewed the manuscript. Perelstein Natalia per-
formed the CT interpretation. Luiza Akria and Celia Suriu calculated
the NLR, MLR, and PLR values. Waksman Igor, Alper Adir, Andrei
Braester, and Barhoum Masad participated in writing the draft of the
manuscript. Andrei Braester wrote the final article. Dally Najib was
responsible with project administration and supervision. All authors
contributed to the article and approved the submitted version.
ACKNOWLEDGMENTS
The authors thank Dr Regina Michelis for help in editing and proof-
reading of the manuscript and Dr Orly Yakir for statistical analysis.
CONF LICT OF IN TE RE ST ST AT E MENT
The authors declare no conflict of interest.
DATA AVAI LAB ILITY S TATEMENT
The data that support the findings of this study are available on
request from the corresponding author. The data are not publicly
available due to privacy or ethical restrictions.
ORCID
Andrei Braester https://orcid.org/0000-0002-1567-7562
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How to cite this article: Adir A, Braester A, Natalia P, et al.
The role of blood inflammatory markers in the preoperative
diagnosis of acute appendicitis. Int J Lab Hematol. 2024;46(1):
58‐62. doi:10.1111/ijlh.14163