CLINICAL INVESTIGATION

Neutrophil-To-Lymphocyte Ratio: An Emerging

Marker Predicting Prognosis in Elderly Adults with
Community-Acquired Pneumonia
Emanuela Cataudella, MD,* Chiara M. Giraffa, MD,* Salvatore Di Marca, MD,*
Alfredo Pulvirenti, PhD, Salvatore Alaimo, PhD, Marcella Pisano, MD,*
Valentina Terranova, MD,* Thea Corriere, MD,* Maria L. Ronsisvalle, MD,*
Rosario Di Quattro, MD,* Benedetta Stancanelli, MD, PhD,* Mauro Giordano, MD,
Carlo Vancheri, MD, PhD, and Lorenzo Malatino, MD*

RESULTS: NLR predicted 30-day mortality (P < .001)

OBJECTIVES: To explore the performance of the neu-
trophil-to-lymphocyte ratio (NLR), an index of systemic
inflammation that predicts prognosis of several diseases, in
a cohort of elderly adults with community-acquired pneu-
monia (CAP).
DESIGN: Prospective clinical study from January 2014 to
July 2016.
SETTING: Unit of Internal Medicine, University of Cata-
nia, Catania, Italy.
PARTICIPANTS: Elderly adults admitted for CAP
(N = 195).
MEASUREMENTS: Clinical diagnosis of CAP was
defined as the presence of a new infiltrate on plain chest
radiography or chest computed tomography associated
with one or more suggestive clinical features such as dysp-
nea, hypo- or hyperthermia, cough, sputum production,
tachypnea (respiration rate >20 breaths per minute),
altered breath sounds on physical examination, hypoxemia
(partial pressure of oxygen <60 mmHg), leukocytosis
(white blood cell count >10,000/lL). Clinical examination,
traditional tests such as Pneumonia Severity Index (PSI);
Confusion, Urea, Respiratory rate, Blood pressure, aged
65 and older (CURB-65), and NLR were evaluated at
admission. The accuracy and predictive value for 30-day
mortality of traditional scores and NLR were compared.
From the *Unit of Internal Medicine, Department of Clinical and
Experimental Medicine, School of Emergency Medicine, University of
Catania, Cannizzaro Hospital; Unit of Bioinformatics and Computer
Science, Department of Clinical and Experimental Medicine, University of
Catania, Catania; Department of Medical, Surgical, Neurologic,
Metabolic and Geriatric Sciences, School of Emergency Medicine, Second
University of Naples, Naples; and Unit of Lung Diseases, Department of
Clinical and Experimental Medicine, University of Catania, Catania, Italy.
Address correspondence to Prof. Lorenzo Malatino, Chief and Chairman
of Internal Medicine, University of Catania, c/o Cannizzaro Hospital, via
Messina 829, 95126 Catania, Italy. E-mail: malatino@unict.it
DOI: 10.1111/jgs.14894
and performed better than PSI (P < .05), CURB-65,
C-reactive protein, and white blood cell count (P < .001)
to predict prognosis. No deaths occurred in participants
with a NLR of less than 11.12. Thirty-day mortality was
30% in those with a NLR between 11.12% and 13.4%
and 50% in those with a NLR between 13.4 and 28.3. All
participants with a NLR greater than 28.3 died within
30 days.
CONCLUSIONS: These results would encourage early
discharge of individuals with a NLR of less than 11.12,
short-term in-hospital care for those with a NLR between
11.12 and 13.4, middle-term hospitalization for those with
a NLR between 13.4 and 28.3, and admission to a respira-
tory intensive care unit for those with a NLR greater than
28.3. J Am Geriatr Soc 2017.
Key words: community-acquired pneumonia; CAP;
NLR; prognostic score; elderly adults
C ommunity-acquired pneumonia (CAP) is one of the
most-common infectious diseases needing hospitaliza-
tion. It is associated with high morbidity and mortality,
and it has a high incidence and risk of death in elderly
adults. In Europe, mortality for CAP varies widely, rang-
ing from less than 1% to 48%; hospitalization rates range
from 22% to 42%. In the United States, it is the fifth
cause of death in people aged 65 and older.13 Moreover,
the economic burden for individuals with CAP is high.
Inappropriate treatment of outpatients and delayed admis-
sion of individuals hospitalized for CAP were associated
with greater mortality. Several predictors of mortality in
individuals with CAP have been developed to identify indi-
viduals at risk of poor outcomes early 4,5 and to evaluate

JAGS 2017
2017, Copyright the Authors
Journal compilation 2017, The American Geriatrics Society 0002-8614/17/$15.00
2 CATAUDELLA ET AL.
appropriateness of treatment. The Pneumonia Severity
Index (PSI) and Confusion, Urea, Respiratory rate, Blood
pressure, aged 65 and older (CURB-65) are the most
widely known scores for this purpose. PSI is a prediction
tool that the American Thoracic Society (ATS) and Infec-
tious Diseases Society of America (IDSA) recommend. It
stratifies individuals with CAP into five strata of risk of
short-term mortality; Classes I and II indicate low risk of
death and can be treated on an outpatient bases, Classes
IV and V indicate high risk of death and should usually be
hospitalized, and Class III indicates intermediate risk.6 The
PSI score takes a long time to calculate, so its usefulness in
clinical practice is debated. Recently, the British Thoracic
Society recommended a system using CURB-65 to stratify
prognosis of individuals with CAP.7 Similar to PSI, CURB-
65 divides individuals with CAP into three groups; scores
of 0 or 1 suggest outpatient treatment, a score of 2 is
intermediate, and scores of 35 indicate the need hospital-
ization. CURB-65 is easier to manage than PSI but has
lower sensitivity in predicting mortality. In addition, the
specificity of CURB-65 and PSI is weak. Moreover, neither
score assesses the host inflammatory response, which is
currently considered a critical aspect in the prognosis of
individuals with CAP.810 By contrast, the neutrophil-to-
lymphocyte ratio (NLR) is a simple, rapid, inexpensive
marker of systemic inflammation, like C-reactive protein
(CRP) and white blood cell (WBC) count, and predicts
prognosis in various pathological conditions.1114 It is cal-
culated as the ratio of neutrophil count to lymphocyte
count, usually from a peripheral blood sample. Recently, a
prospective study assessed the value of NLR in a young
adult mixed population admitted to an emergency depart-
ment with CAP and found that NLR predicts severity of
CAP with greater accuracy than CURB-65,15 but there are
no studies performed only in elderly adults comparing tra-
ditional scores (PSI, CURB-65) with NLR in a clinical set-
ting often associated with several comorbidities. The
current study thus prospectively compared the prognostic
value of the NLR, PSI, and CURB-65 in elderly adults
with CAP hospitalized in a department of medicine.
METHODS
Study Population
This prospective study included 195 elderly adults (aged
65) consecutively admitted with CAP to the Department
of Internal Medicine, Cannizzaro Hospital, Catania, Italy,
from January 2014 to July 2016. Clinical diagnosis of
CAP was defined as the presence of a new infiltrate on
plain chest radiography (CXR) or chest computed tomog-
raphy (CT) associated with one or more suggestive clinical
features such as dyspnea, hypo- or hyperthermia, cough,
sputum production, tachypnea (respiration rate >20
breaths per minute), altered breath sounds on physical
examination, hypoxemia (partial pressure of oxygen
(pO2 < 60 mmHg), leukocytosis (WBC count >10,000/
lL).16 Criteria for exclusion were younger than 65, noso-
comial pneumonia (individuals from any type of healthy
care facility were excluded), lung cancer, acute heart fail-
ure, hematological disease, current immunosuppressive
therapy, and other active infections.
2017 JAGS
Information was collected on participant characteris-
tics, clinical features, and laboratory results and entered
into an electronic database. Information was collected on
age, sex, smoking status, degree of autonomy, comorbidi-
ties (diabetes mellitus, chronic obstructive pulmonary dis-
ease, heart disease, cancer, cerebrovascular disease, renal
disease, chronic liver disease, malnutrition, obesity, and
immobilization syndrome), clinical symptoms and signs
(mental status, body temperature, blood pressure, heart
and respiratory rate, oxygen saturation), laboratory data
before initiation of antibiotic treatment (CRP level, WBC
count, neutrophil count, lymphocyte count, NLR, urea
nitrogen levels), and radiological findings (infiltrate, pleural
effusion). CRP levels were measured using an automated
latex-enhanced turbidimetric immunoassay (Unicel DxC
600i, Beckman Coulter, Milan, Italy). Total WBC, neu-
trophil, and lymphocyte counts were determined using a
hematology analyzer (Coulter LH 750, Beckman Coulter).
NLR was calculated as absolute neutrophil count divided
by absolute lymphocyte count. In Cannizzaro Hospital, the
upper limit of the normal range of the neutrophil count is
7.8 9 103/lL, and the lower limit of the normal range of
the lymphocyte count is 0.6 9 103/lL. As used in a previ-
ous prospective study,15 a cut-off point of 10.0 was used
for the NLR to evaluate sensitivity and specificity in pre-
dicting prognosis of individuals with CAP.
The prognosis of individuals with CAP was assessed
using PSI and CURB-65 scores as well as NLR. Functional
status was assessed using the Katz Index of Independence in
Activities of Daily Living (ADLs) 17 and the Instrumental
Activity of Daily Living (IADL) scale.18 The ADL scale rates
the adequacy of performance of six functions (bathing, dress-
ing, toileting, transferring, continence, feeding); a score of 6
indicates full function, and a score of 0 indicates severe func-
tional impairment. The IADL scale evaluates eight realms of
self-reported function (telephoning, shopping, food prepara-
tion, housekeeping, doing laundry, use of transportation,
taking medications, financial behavior), attempting to assess
everyday functional competence in elderly adults.
The study was conducted in accordance with the
amended Declaration of Helsinki. All participants provided
written consent.
Statistical Analysis
The minimum sample size to obtain a power of 80% at a
significance level of 0.05 was estimated. Following a previ-
ous study,15 in which a cut-off of 10 for the NLR was used,
an effect size of 0.47 was estimated. With this effect size, a
minimum sample size of 70 participants in each group was
obtained. Therefore, on the whole, 102 subjects showed
NLR<10 and 93 NLR>10. Continuous data are expressed
as means  standard deviations and categorical data as fre-
quencies and percentages. Proportions were compared using
the chi-square test with Yates correction for continuity or
Fisher exact test, as appropriate; continuous variables were
compared using the Student t-test. KaplanMeier curves
were plotted for the primary end point (to establish the rela-
tionship between risk of mortality and NLR, PSI and
CURB-65, respectively). Receiver operating characteristic
(ROC) curves were constructed to evaluate the sensitivity
and specificity of CRP, PSI, CURB-65 score, and NLR to
JAGS 2017 NLR PREDICTS PROGNOSIS IN INDIVIDUALS WITH CAP 3

predict survival. P .05 was considered statistically signifi-

Table 2. Clinical and Laboratory Data of Study
cant. To establish the robustness of predictor variables, the
Population
sample dataset was consecutively and randomly partitioned
into two subgroups: 100 participants as a learning data set Mean  Standard
(training group) and 95 participants (testing group) as a Parameter Deviation
dataset for testing. Such random partitioning was repeated
Age 80.3  7.5
1,000 times, and the final performance of the models was
Confusion, urea, respiratory rate, blood 2.4  0.8
determined as the average of all observed performances. pressure, aged 65 score
Risk models were developed using logistic regression,19 Pneumonia severity index score 124.2  30.7
decision-tree induction from class-labelled training Heart rate, bpm 89.7  18.3
records,20 and Cox proportional hazard models.21 The Systolic blood pressure, mmHg 132  26.9
training set was composed of records in which one attribute Diastolic blood pressure, mmHg 74  14
was the dependent variable and the remaining attributes White blood cell count, cells/lL 12,63  5.7
were the predictor variables; the individual records are the Neutrophil count, cells/lL 5,11  10.1
Lymphocyte count, cells/lL 1,19  0.8
tuples for which the class label is known. Statistical analysis
Neutrophil-to-lymphocyte ratio 12.7  12.9
was performed using tools for survival analysis and recur- Hemoglobin, g/dL 11.5  2.2
sive partitioning analysis within the R Statistical software Hematocrit, % 37.3  6.7
(https://www.r-project.org). Positive and negative predictive Erythrocyte sedimentation rate, mm/h 38.5  15.7
values were calculated for main potential predictors, and a C-reactive protein, mg/dL 14.3  11.3
multivariate logistic regression model was constructed to Ferritin, ng/mL 499  453.9
identify variables with the highest prognostic power. Serum creatinine, mg/dL 1.2  0.6
Glomerular filtration rate, mL/min per 1.73 m2 59.1  26.2
Chronic kidney disease, stage 2.6  0.9
RESULTS Blood urea nitrogen, mg/dL 73.1  44.8
Glycemia, mg/dL 138.8  68.4
During the study period, 195 individuals consecutively ad- Sodium, mmol/L 138.7  5.7
mitted with CAP were evaluated. The main demographic Potassium, mmol/L 4  0.6
and clinical characteristics of participants included in the Chloride, mmol/L 99.5  7.9
study are summarized in Table 1. Mean age was 80.3, D-dimer, ng/mL 860.5  987.2
Brain natriuretic peptide, pg/mL 222.6  225.1
pH 7.3  0.3
Table 1. Baseline Characteristics of Study Population Partial pressure of carbon dioxide, mmHg 47.7  16.3
In our database of 195 subjects, 49 died and 146 sur- Partial pressure of oxygen, mmHg 55.3  12.7
vived. Bicarbonate, mmol/L 29.8  6.7
Overall hospital stay, days 13.9  5.1
Characteristic n (%)

Sex
Male 120 (61.5)
Female 75 (38.5)
Age with 71.3% (n = 139) aged 75 and older; 120 (61.5%)
6575 56 (28.7) were male, and 75 (38.5%) were female. Forty-three
7686 98 (50.3) (22%) were smokers, and cerebrovascular disease (56.4%)
8797 41 (21) was the most common comorbidity. Fifty-two (26.7%)
Confusion 76 (39) were totally independent in ADLs and IADLs, 73 (36.9%)
Hyperpyrexia 88 (45.1) had moderate functional impairment, and 70 (36.4%) had
Dyspnea 160 (82)
severe functional impairment. The mean length of hospital-
Cough 62 (31.8)
Respiratory rate, breaths per minute ization was 13.9  5 days.
>30 44 (22.6) Mean CURB-65 score was 2.4  0.8; 20 (10.3%) had
2030 96 (49.2) a CURB-65 score of 1, 87 (44.6%) a score of 2, 67
<20 55 (28.2) (34.3%) a score of 3, and 21 (10.8%) a score of 4. Mean
Smoker PSI was 124.2  30.7; six participants (3.1%) were in the
No 99 (50.8) second class, 35 (17.9%) in the third class, 85 (43.6%) in
Yes 43 (22) the fourth class, and 70 (35.9%) in the fifth class. Thirty-
Former 53 (27.2)
day mortality was 25% (n = 49), and the 3-month
Immobilization syndrome 68 (34.9)
Malnutrition 58 (29.7) rehospitalization rate was 34% (49/146). Clinical and
Obesity 46 (23.6) laboratory data are reported in Table 2.
Diabetes mellitus 60 (30.8)
Chronic kidney disease (estimated glomerular filtration 45 (23)
rate <60 mL/min per 1.73 m2)
Prognostic Power of NLR
Heart failure 58 (29.7) A multivariate linear regression analysis was preliminarily
Cerebrovascular disease 110 (56.4) conducted to establish the predictive power of all consid-
Chronic obstructive pulmonary disease 88 (45.1)
ered variables. The analysis clearly identified NLR as the
Oral corticosteroids 58 (29.7)
Non invasive ventilation 29 (14.9) most-discriminant variable. In the logistic regression analy-
sis, NLR was significantly (P < .001) associated with 30-
4 CATAUDELLA ET AL.
day mortality. NLR predicted mortality better than PSI,
CURB-65 score, CRP, and WBC count. The NLR had the
largest area under the ROC curve (AUC = 0.94) (Fig-
ure S1), followed by the PSI (0.87), CURB-65 score (0.61),
WBC count (0.55), and CRP (0.49) (Figure S2). The differ-
ences between the ROC curves were significant (P < .05,
NLR vs PSI; P < .001 NLR vs CURB-65, CRP, and WBC
count). The results of predictive values computed for the
best regression model for each variable further confirmed
these data (Table 3).
The relationships between the likelihood of survival
and of 3-month rehospitalization (Figure 1) and the NLR
were analyzed. The increase in NLR paralleled the increase
in likelihood of rehospitalization, whereas an opposite
trend was shown for likelihood of survival.
Finally, 30-day mortality was evaluated using a
machine learning model based on decision tree induction. A
decision tree to predict 30-day mortality was built using
NLR as the predictor variable (Figure S3). The tree initially
split participants in two main groups according to NLR
(13.4, >13.4) and then stratified further into two sub-
groups. The first group included 115 participants with a
NLR of 11.12 or less; no death was registered in this group.
The second group included 13 participants with a NLR
between 11.12 and 13.4; this group had a mortality of 30%.
The third group consisted of 48 participants with a NLR
between 13.4% and 28.3%; 50% of these participants died.
The fourth group consisted of 19 participants with a NLR
greater than 28.3; all of these participants died.
Table 3. Positive Predicted Values (PPVs) and Negative
Predicted Values (NPVs) for Best Logistic Regression
Predictors for Each Analyzed Variable
PPV
Variable
Neutrophil-to-lymphocyte ratio 100
Pneumonia severity index 80
Confusion, urea, respiratory rate, 36
blood pressure, aged 65
White blood cell 50
C-reactive protein 57
Data were derived using logistic regression. No cut-off values were given.
A B
1.0
0.8
0.6
Survival rate
0.4
0.2
0.0
0 20 40 60
NLR
Figure 1. (A) Survival at 30 days according to neutrophil-to-lymphocyte ratio. (B) Rehospitalization at 3 months according to
neutrophil-to-lymphocyte ratio. Lighter curves show 95% confidence intervals.
2017 JAGS
DISCUSSION
To the best of the authors knowledge, this is the first
study to evaluate the potential of NLR in elderly adults
hospitalized with CAP. It demonstrated that the perfor-
mance of NLR as a prognostic marker is better than that
of conventional infection markers such as CRP and WBC
count and clinical scores such as PSI and CURB-65.
The host inflammatory response plays an important
role in pneumonia development and progression, especially
in elderly adults. Noninvasive biomarkers of inflammation,
such as CRP, erythrocyte sedimentation rate, WBC count,
pro-calcitonin, interleukin (IL)-6, IL-8, interferon-alpha,
and tumor necrosis factor alpha have been widely used to
improve the accuracy of diagnosis, because the results of
specimen cultures and laboratory and radiologic evalua-
tions are not always useful, but most of these markers are
expensive and are not always routinely used in clinical prac-
tice. Therefore, there is still a need for new simple, specific
and not expensive biomarkers for the diagnosis and follow-
up of CAP. Neutrophilia and lymphocytopenia are physio-
logical responses of the innate immune system to systemic
inflammation. Lymphocytopenia consists of accelerated
apoptosis and margination of lymphocytes within the retic-
uloendothelial system, liver, and splanchnic lymphatic sys-
tem and of redistribution of lymphocytes within the
lymphatic system. Neutrophilia is the opposite phenomenon
during systemic inflammation as a result of demargination
of neutrophils and stimulation of stem cells by growth fac-
tors (granulocyte-colony stimulating factor).2224
It has been reported that, with severe infections or sys-
temic inflammation, NLR increased as a consequence of
severity of clinical status and clinical outcome.25 NLR was
also associated with prognosis in various diseases, such as
NPV acute coronary syndrome, acute pancreatitis, and ulcera-
tive colitis.2628 Furthermore, many cancer survival studies
% have suggested that NLR is a significant predictor of over-
all and disease-specific survival.2931 Age is a covariate of
78 NLR that increases in elderly adults. A prospective study
78 32
78
showed that NLR may reflect Alzheimers diseasere-
lated systemic inflammatory processes, and age was shown
76 to be a dominant covariate that must be considered in the
76 statistical evaluation of the results. Recently, NLR was
found to have greater prognostic power that traditional
infection markers (CRP, WBC count, neutrophil count) in
0.8
Cumulative Incidence
0.6
0.4
0.2
0.0
80 0 5 10 15 20 25
NLR
JAGS 2017
a young-adult mixed population admitted to an emergency
department with CAP,15 but the prognostic power of NLR
in elderly adults hospitalized with CAP was unclear.
In the present prospective study, NLR was the best pre-
dictor of mortality in elderly adults with CAP. The AUC of
the NLR (0.94) was significantly higher than that of tradi-
tional infection markers such as CRP (0.49) and WBC
count (0.55) and of validated and commonly used mortality
predictive scores such as PSI (0.87) and CURB-65 (0.61).
Furthermore, NLR predicted 3-month rehospitalization but
did not predict 30-day mortality of individuals with CAP
by the most frequent comorbidities in elderly adults, such
as diabetes mellitus, chronic obstructive pulmonary disease,
heart failure, and immobilization syndrome.
The limitation of this study is that it was a single-cen-
ter survey, although data from ROC analyses, likelihood
of survival and rehospitalization, and random partitioning
of the sample (bootstrapping technique), which statistically
resembles external validation of the data, give ground to
the power of the results.
In conclusion, NLR showed emerging prognostic
value in predicting 30-day mortality and 3-month rehos-
pitalization rates. The NLR may provide clinicians with
quick stratification of patients into different prognostic
categories. By evaluating 30-day mortality depending on
NLR (Fiugre S3), elderly adults with CAP may be man-
aged as follows: discharge and outpatient follow-up when
NLR is less than 11.12, short-term in-hospital care when
NLR is between 11.12 and 13.4, middle-term hospitaliza-
tion when NLR is between 13.4 and 28.3, admission to
a respiratory intensive care unit when NLR is greater
than 28.3. Further prospective multicenter studies are
needed to confirm whether data from this proof-of-con-
cept study can help reduce the mortality of elderly adults
admitted for CAP.
ACKNOWLEDGMENTS
Conflict of Interest: None of the authors have any conflict
of interest to declare.
Author Contributions: Cataudella, Giraffa, Di Marca,
Stancanelli: acquisition of subjects and data, preparation
of manuscript. Vancheri, Pisano, Terranova, Corriere,
Ronsisvalle, Di Quattro: acquisition of subjects and data.
Pulvirenti, Alaimo, Giordano: analysis and interpretation
of data. Malatino: study concept and design, preparation
of manuscript.
Sponsors Role: This study had no sponsor support.
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SUPPORTING INFORMATION
Additional Supporting Information may be found in the
online version of this article:
Figure S1. Receiver operating characteristic curve for
neutrophil-to-lymphocyte ratio.
2017 JAGS
Figure S2. Receiver operating characteristic curves
for (A) Pneumonia Severity Index, (B) Confusion
UreaRespiratory rateBlood pressureaged >65, (C) C-
reactive protein, and (D) white blood cell count.
Figure S3. Decision tree according to neutrophil-
to-lymphocyte ratio (NLR).
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