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| |
Received: 30 August 2021    Revised: 22 October 2021    Accepted: 31 October 2021

DOI: 10.1111/ijlh.13768

ORIGINAL ARTICLE

Age-­and sex-­specific pediatric reference intervals for

neutrophil-­to-­lymphocyte ratio, lymphocyte-­to-­monocyte
ratio, and platelet-­to-­lymphocyte ratio

Julia Moosmann1  | Anja Krusemark2 | Sven Dittrich1 | Tatjana Ammer3,4 |

Manfred Rauh2 | Joachim Woelfle2 | Markus Metzler2 | Jakob Zierk2

1
Department of Pediatric Cardiology,
University Hospital Erlangen, Erlangen,
Germany
2
Department of Pediatrics and Adolescent
Medicine, University Hospital Erlangen,
Erlangen, Germany
3
Chair of Medical Informatics, Friedrich-­
Alexander-­University Erlangen-­
Nuremberg, Erlangen, Germany
4
Roche Diagnostics GmbH, Penzberg,
Germany
Correspondence
Julia Moosmann, University Hospital
Erlangen, Department of Pediatric
Cardiology, Loschgestr. 15, 91054,
Erlangen, Germany.
Julia.moosmann@uk-erlangen.de
Abstract
Introduction: Neutrophil-­to-­lymphocyte ratio (NLR), platelet-­to-­lymphocyte ratio
(PLR), and lymphocyte-­to-­monocyte ratio (LMR) are emerging biomarkers for sys-
temic inflammation and have been shown to predict morbidity and mortality for
several diseases. However, lack of pediatric reference intervals (RIs) prevents their
comprehensive use in patient care and medical research.
Material and Methods: We calculated reference intervals and corresponding confi-
dence intervals for NLR, PLR, and LMR from birth to 18  years using a data-­mining
approach: We analyzed 232 746 blood counts from 60 685 patients performed during
patient care and excluded patients with elevated C-­reactive protein and procalcitonin.
Test results were separated according to age and sex, and the distribution of physi-
ological ratios was estimated using an indirect approach (refineR). Additionally, we
investigated the ratios’ diagnostic benefit for different inflammatory diseases (acute
appendicitis, asthma, Bell's palsy, Henoch-­Schonlein purpura, and cystic fibrosis) using
the newly obtained reference intervals.
Results: We estimated age-­and sex-­specific reference intervals from birth to adult-
hood for NLR, PLR, and LMR. Analyses in pediatric inflammatory diseases showed
that PLR and LMR were poor markers to detect the examined inflammatory diseases,
while NLR was significantly increased in patients with appendicitis and asthma.
Conclusion: We provide pediatric reference intervals for NLR, PLR, and LMR to im-
prove the interpretation of these biomarkers in children.

KEYWORDS
blood components, inflammation, leukocytes, monocytes, neutrophils, platelets

1  |  I NTRO D U C TI O N diagnose medical conditions. In addition to individual cell types rel-

ative and absolute concentrations, ratios of different cell types have
The complete blood count (CBC) is used comprehensively in clini- been suggested to improve medical decision-­making. Specifically,
cal healthcare to review individuals’ overall health and monitor or neutrophil-­to-­lymphocyte ratio (NLR), platelet-­to-­lymphocyte ratio

This is an open access article under the terms of the Creat​ive Commo​ns Attri​butio​n-­NonCo​mmerc​ial-­NoDerivs License, which permits use and distribution in
any medium, provided the original work is properly cited, the use is non-­commercial and no modifications or adaptations are made.
© 2021 The Authors. International Journal of Laboratory Hematology published by John Wiley & Sons Ltd.

|
296    
wileyonlinelibrary.com/journal/ijlh Int J Lab Hematol. 2022;44:296–301.

MOOSMANN et al.
(PLR), and lymphocyte-­to-­monocyte ratio (LMR), which can all be
calculated using the CBC, have proven to be clinically useful bio-
markers for various diseases.
Neutrophil-­
to-­
lymphocyte ratio has been extensively studied
as a prognostic biomarker in infectious diseases,1 postoperative
2,3 4,5
complications, and in oncologic diseases. Further, it has been
proposed as a predictor for mortality and outcome in cardiovascu-
lar diseases (eg, myocardial infarction and cardiac failure).6 Similarly,
PLR, a marker for inflammation and thrombosis has been associ-
ated with increased mortality and complications for cardiovascular
events, including ST Elevation Myocardial Infarction (STEMI) and
pulmonary embolism.7,8 In addition, LMR has evolved as a prognostic
marker for solid tumors.9,10
All three parameters are simple, inexpensive, objective, and rap-
idly available biomarkers for inflammation, derived from a routine
CBC. Most data on NLR, PLR, and LMR are based on adult studies
including recently published reference intervals (RIs) for the adult
11
population. However, all current pediatric studies are based on
case-­control comparisons only. To consider these parameters as
meaningful biomarkers in the pediatric population, validated RIs
are needed. As pediatric laboratory analytes underlie substantial
changes from the neonatal period to adolescence, it is essential to
establish separate validated RIs for NLR, PLR, and LMR for children
to allow classification of samples in the context of intra-­and interin-
dividual variation. The aim of this report is to establish RIs for chil-
dren of all ages for NLR, PLR, and LMR.
2  |  M ATE R I A L A N D M E TH O DS
2.1  |  Study population
All measurements for lymphocytes, neutrophils (segmented and
banded), platelets, and monocytes performed between 01.01.2010
and 31.12.2019 in patients from 0 to 18  years at the University
Hospital Erlangen, Department of Pediatrics and Adolescent
Medicine were retrieved from the laboratory's database. Both in-­and
outpatient samples were selected and no stratification according to
ethnicity was performed. The dataset was divided according to sex
and age (18 age groups). We excluded test results from oncologic pa-
tients and patients from pediatric and neonatal intensive care units.
Additionally, we removed results from patients with an increased C-­
reactive protein (CRP ≥ 5 mg/L) or procalcitonin (PCT ≥ 0.5 ng/mL)
within ±3 days (relative to the CBC). If multiple measurements from
a single individual were available, one measurement was randomly
selected per age group (Figure 1).
For the analysis of specific diseases (Appendicitis, asthma, cystic
fibrosis [CF], Bell's palsy, Henoch–­Schonlein purpura [HSP]), labora-
tory test results were selected from patients who received the re-
spective diagnosis within one week (±7 days). We included n = 321
patients with appendicitis, n = 1,124 patients with asthma, n = 112
patients with CF, n = 204 patients with Bell's palsy and n = 452 pa-
tients with HSP.
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      297
2.2  |  Analytical procedures
We analyzed the three ratios NLR, PLR, and LMR calculated from
the absolute number of neutrophils, platelets, lymphocytes, and
monocytes. Leucocyte subsets and total blood counts were meas-
ured on a Sysmex XE 2100 hematological analyzer (Sysmex Europe,
Norderstedt, Germany), in accordance with standard operating
procedures. All measurements have been performed in the pedi-
atric laboratory of the Department of Pediatrics and Adolescent
Medicine, University Hospital Erlangen, Germany, and quality con-
trol according to German regulations was performed and passed.
Both machine-­counted and microscopic leukocyte subtypes were
used for further analyses. If both data sets were available, the mi-
croscopic findings were used. Measurements from both in-­and out-
patients have been included, and nearly all samples were analyzed
within 2 hours of specimen collection, without differences between
in-­and outpatient samples.
2.3  |  Calculation of reference intervals
Reference intervals and corresponding confidence intervals (CIs)
were calculated with an indirect data mining approach described
and validated previously. The applied refineR algorithm assumes
that the input dataset is composed of a major fraction of physiologi-
cal test results and a minor fraction of pathological test results. It
is presumed that the physiological results can be described with a
parametric distribution (Box-­Cox-­transformed normal distribution),
whereas for the pathological results no specific distribution is as-
sumed. refineR uses an inverse modeling approach, thereby trying
to fit a model that best explains the observed data in the original
domain. In a data pre-­processing step, the algorithm first determines
a region around the main peak and computes a histogram represen-
tation of the data. Afterward, the algorithm estimates a Box-­Cox-­
transformed normal distribution and identifies the model that yields
a maximum log-­likelihood describing the histogram of the routine
data. The optimal model is then utilized to estimate RIs, and confi-
dence intervals are calculated via bootstrapping. The refineR algo-
rithm has been shown to outperform other indirect algorithms for
datasets with a high fraction and overlap of pathological test results,
for example, the kosmic algorithm.12
2.4  |  Ethics
This study was approved by the institutional review board of the
University Hospital Erlangen (reference number 97_17 Bc).
3  |  R E S U LT S
For the analysis, 232  746 full blood counts from 60  685 patients
from birth to 18 years of age were available. The study population
 |
298      MOOSMANN et al.
F I G U R E 1  Flowchart presenting the steps of inclusion and exclusion of subjects
was divided into age groups of one year and by sex. For NLR, we had
mean of 1,448 patients (range: 729-­2969), for PLR mean of 2291
patients (range: 1340-­9103) and LMR mean of 2284 patients (range:
1332-­9063) per sex-­specific age group. The corresponding number
of patients per age group is shown in Figure 1.
We calculated age-­and sex-­specific RIs and CIs for NLR, PLR,
and LMR. Age-­dependent RIs and CIs for children from the first year
of life to 18 years are shown in Figure 2A-­C and in the Table S1-­S3.
All three ratios showed substantial age-­specific dynamics, especially
in the first years of life. NLR (Figure 2A) and LMR (Figure 2C) re-
vealed a similar pattern of age-­dependent changes during the first
two years of life including wider RIs. NLR showed higher values di-
rectly after birth, and LMR a sharp increase between year one and
two, with a narrowing of the RIs in the following years. NLR showed
wider RIs for the first year of life and after puberty in the age groups
from 15 to 18 years. From the age of 3-­18 years, the 50th percentile
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of NLR is constantly increasing from 0.99 to 1.76 for both male and
female individuals. LMR is slightly decreasing from a maximum of
5.78 for girls and 5.58 for boys at 1-­2 years to a minimum of 3.73 for
females and 3.55 for males during adolescence (age groups of 16-­17
and 17-­18 years).
For PLR (Figure 2B), we identified a constant increase from a
minimum of 61.36 (male) and 63.36 (female) at the first year of life to
112.6 (male) and 118.78 (female) at 17-­18 years.
No significant sex differences between male and female children
were found for all three parameters (NLR: P  = 1.0; PLR: P  =.752;
LMR: P = .827).
We analyzed the proportion of NLR, PLR, and LMR ratios outside
of the newly established RIs for patients with a concurrent diagnosis
of an inflammatory disease. Of particular interest were diseases for
which significantly altered ratios have been published: asthma, Bell's
palsy, appendicitis, HSP, and CF. We found that 65.7% of patients with

MOOSMANN et al.
F I G U R E 2  Reference intervals (RIs) and confidence intervals (CIs) for (A) Neutrophil-­to-­lymphocyte ratio (NLR), (B) Platelet-­to-­
lymphocyte ratio (PLR) and (C) Lymphocyte-­to-­monocyte ratio (LMR) from birth to 18 years.).▲, ● and ▼ represent 2.5th, 50th, and 97.5th
percentiles, and vertical bars show the respective 90% CIs)
appendicitis show a higher NLR than the calculated upper reference
limit, while LMR test results were below calculated RIs in 33.6%, 31.4%
of PLR values were above age-­and sex-­specific RIs (Figure S1).
For asthma, we identified 20.6% of patients with higher NLR val-
ues than calculated RIs and 11.7% with higher PLR values (Figure S2).
Similar results have been found in patients with CF. Here, 22.7% of
the patients had pathological NLR values and in 12.5% had PLR test
results above the calculated RI (Figure S3).
In patients with Bell's palsy and HSP, we identified 9.9% and
13.9% of NLR values higher than the RIs, for LMR: 8.8% and 6.9%
and for PLR 7.8% and 8.2%, respectively (Figures  S4 and S5, see
Table S4 for details).
4  |  D I S C U S S I O N
Neutrophil-­to-­lymphocyte ratio, PLR, and LMR can be calculated
using the differential blood count. In recent years, these biomark-
ers have seen a substantial clinical and scientific appraisal. However,
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      299
their application in the pediatric setting has been limited because
validated pediatric RIs were missing. RIs are an essential tool for the
interpretation of individual patients’ laboratory test results and fa-
cilitate decision-­making in the clinical setting. In this study, we pro-
vide the first age-­and sex-­specific RIs for NLR, PLR, and LMR for
pediatric patients from birth to adulthood.
Across the different age groups, NLR increases with age due to
an increase in neutrophils from neonates to adolescents.13 Further,
there is a decrease in lymphocytes from birth until the age of 18,
influencing the NLR.13 Similarly, PLR showed a continuous increase
over the investigated age range, mainly due to a higher platelet count
in the first months of life, which decreases afterward during child-
hood.14 A rising PLR despite falling platelets is related to an even
greater decrease in lymphocytes.13,14 Both monocytes and lympho-
cytes decrease until adulthood. As the decrease of the lymphocytes
is proportionally higher than that of monocytes, this results in a de-
crease of LMR over time.
Recently, Fei et al published adult RIs for NLR and PLR from 18
to 70 and older. NLR increased constantly from 18 to >70 years of
 |
300      MOOSMANN et al.
age. PLR decreases from younger to the older male population. For
female, PLR increases to a maximum between 41 and 50 years and
11
then slowly decreases to a minimum between 61 and 70 years.
comparison, the RIs established by us exceed those from Fei et al,
highlighting different dynamics in children, and hence the need for
pediatric RIs.
The study did not observe a difference in sex for NLR, but an
increase of PLR with age for the female and a decrease for the male
population, which results in a significant sex difference for PLR.11
14
Despite sex-­specific differences for platelets during childhood we
did not observe any significant differences between male and fe-
male for PLR in children.
To explore the diagnostic benefit of NLR, PLR, and LMR in the
clinical context we analyzed the proportion of ratios outside the
newly created RIs in diagnoses where previous studies reported sig-
nificant differences. It was described that NLR is a more sensitive
method to diagnose appendicitis than white blood cell count alone
15
suggesting a cut off value of NLR above 3.5, and PLR has been
reported as a good predictive parameter for acute appendicitis.16
We identified 65.7% of patients with acute appendicitis presenting
with increased NLR above the RI, therefore NLR might be a reliable
additional parameter in the diagnosis of acute abdominal symptoms.
Additionally, for LMR and PLR, more than 1/3 of the patients with
appendicitis showed increased ratios.
In the study of Kim et al, higher NLR was associated with in-
creased risk of renal impairment or gastrointestinal involvement due
to HSP.17,18 In our dataset, NLR was a weak parameter to predict HSP
in general. However, we were only able to evaluate whether patients
with HSP showed increased values, we did not investigate whether
there was a higher incidence of renal involvement. Another pediatric
study investigating patients in the age of 9-­18 years with CF showed
that a higher NLR (NLR ≥3) correlates with clinical status including
lower body mass index and reduced forced expiratory volume per
second (FEV1). However, in patients older than 16 years the 97.5th
percentile of NLR is >3.1.19 We have found that 22.7% of CF patients
in our dataset had pathological NLR values above the age-­and sex-­
specific RIs.
In pediatric patients with asthma, NLR was reported to be
higher in comparison to healthy children with a mean NLR of 2.07
compared to 1.77 in healthy controls. 20 According to our analy-
sis, both values would still be within the age-­appropriate normal
range. In our cohort, 20.6% of asthma patients presented with
NLR >97.5th percentile, whereas PLR and LMR were weaker pre-
dictive parameters.
Most of the studies investigating one of the three biomarkers in
children are based on case-­control comparisons. When comparing
these data with the RIs for children that we have generated accord-
ingly, we identified that although significant differences were found
in several studies, the values are often within the age-­appropriate
RIs, as seen in the asthma study. 20 Therefore, we assume that this
might reduce the ratios’ value for individual decision-­making. The
study of Jaszczura et al reported significantly elevated NLR and
PLR in patients with immunoglobulin A vasculitis and systemic in-
volvement compared to children without systemic involvement. The
1751553x, 2022, 2, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/ijlh.13768 by Readcube (Labtiva Inc.), Wiley Online Library on [30/10/2022]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
reported mean PLR of 139 is still within the established age-­and sex-­
specific RI for 6-­year-­olds. 21 The NLR value was above the 97.5th
In percentile with 2.77 and a cut off value to predict systemic involve-
ment of 2.73.
The case-­control comparisons without consideration of RIs make
it difficult to assess their clinical impact. Therefore, we suggest that
NLR, PLR, and also LMR in children have to be discussed critically as
biomarkers and the RIs have to be considered in order to obtain a
clinical relevance.
5  |  LI M ITATI O N S
We used an indirect approach (refineR) to establish pediatric RIs,
although so-­
c alled direct approaches are considered the gold
standard. 22 This approach was selected, as ethical and practical
objections limit the establishment of pediatric RIs using direct
approaches, especially, when fine-­grained age-­resolution and in-
clusion of infants is required. Importantly, we filtered the dataset
(exclusion of intensive care patients and oncological patients) and
removed samples from children with elevated inflammatory mark-
ers (CRP and PCT) to reduce the proportion of abnormal test re-
sults in the input datasets. Additionally, the used refineR algorithm
has been shown to generate valid RIs even in the setting of a high
proportion of pathological values in the input dataset. We ana-
lyzed the proportion of NLR, PLR, and LMR ratios outside of the
newly established RIs for patients with a concurrent diagnosis of
an inflammatory disease. However, we did not perform a sensitiv-
ity analysis of how well the values predict the disease, as this was
outside the scope of our study.
6  |  CO N C LU S I O N
Comprehensive RIs that cover all age ranges from birth to adulthood
are essential for the evidence-­based interpretation of pediatric test
results. We established RIs for NLR, PLR, and LMR to enable an im-
proved assessment of these biomarkers in the clinical context during
childhood.
AC K N OW L E D G M E N T S
The presented work was performed in fulfillment of the require-
ments for obtaining the degree “Dr med” at “Friedrich-­Alexander
University of Erlangen-­Nürnberg (FAU)” of Anja Krusemark. Open
access funding enabled and organized by ProjektDEAL.
C O N FL I C T O F I N T E R E S T
The authors have no competing interests.
AU T H O R C O N T R I B U T I O N S
JM designed the study, analyzed, and interpreted the data, and wrote
the manuscript. TA developed the refineR algorithm, analyzed, and
interpreted the data. AK, SD, MM, MR, and JW acquired, analyzed,
and interpreted the data. JZ designed the study, developed the
 |

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MOOSMANN et al.       301

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ORCID
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