The Journal of Foot & Ankle Surgery 61 (2022) 384−389

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The Journal of Foot & Ankle Surgery

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A Systematic Review and Meta-Analysis of the Effectiveness of LRINEC Score

for Predicting Upper and Lower Extremity Necrotizing Fasciitis
Arthur Tarricone, DPM, MPH1, Karla De La Mata, DPM2, Allen Gee, MS3,
Wayne Axman, DPM, FACFAS, FACFAO4, Cristina Buricea, DPM5,
Mark G. Mandato, DPM, DABFAS6, Michael Trepal, DPM, FACFAS7,8, Prakash Krishnan, MD9
1
Podiatric Resident Physician - PGY-2, SUNY Downstate Medical Center, University Hospital of Brooklyn, Brooklyn, NY
2
Podiatric Resident Physician - PGY-2, Lenox Hill Hospital at Northwell Health, New York, NY.
3
Research Assistant, Icahn School of Medicine at Mount Sinai, New York, NY.
4
Chief of Podiatry, NYC Health, Hospitals/Queens Hospital Center, Jamaica, NY.
5
Podiatric Surgeon, NYC Health, Hospitals/Queens Hospital Center, Jamaica, NY,
6
Chief of Podiatry, NYC Health, Hospitals/ Kings County Hospital Center, Brooklyn, NY.
7
Podiatric Residency Director at SUNY Downstate Medical Center, University Hospital of Brooklyn, Brooklyn, NY.
8
Vice President for Academic Affairs and Dean, Professor of Surgical Sciences at New York College of Podiatric Medicine, New York, NY.
9
Director of Endovascular Intervention, Icahn School of Medicine at Mount Sinai, New York, NY.

A R T I C L E I N F O A B S T R A C T

Level of Clinical Evidence: 2 This review and meta-analysis aims to assess the prognostic value of the Laboratory Risk Indicator for Necrotizing
Keywords: Fasciitis (LRINEC) score for detecting necrotizing fasciitis in the extremities. The LRINEC score has been validated
diabetic foot infections in multiple studies as a clinical tool for differentiating necrotizing fasciitis from non-necrotizing infections how-
extremities ever many studies do not specify the location of infection. As the prevalence of diabetes and diabetic foot infec-
lower extremities tions continues to rise, the utility of LRINEC scores in these populations becomes of increased importance. Four
LRINEC databases were reviewed for citations between January 2010 and December 2020. English, full text articles report-
necrotizing fasciitis ing the diagnostic effects of LRINEC were utilized in the systematic review portion of this paper. Further inclusion
of 2 £ 2 tables and discussion specific to the extremities were applied for citations implemented in the meta-anal-
ysis. Of the 111 results, 12 citations (n = 932) were included in this review. The diagnostic sensitivity of the LRINEC
score ranged from 36% to 77% while specificity ranged from 72% to 93%. Cumulative odds ratio for LRINEC ≥6
among the 4 studies assessing extremity necrotizing fasciitis was 4.3 with p value of <.05. Sensitivity, specificity,
positive predictive value, and negative predictive value was 49.39%, 83.17%, 34.91%, and 89.99%, respectively.
Accuracy, the classification by whether a patient was correctly classified, was 77.95%. LRINEC score is effective at
distinguishing necrotizing fasciitis from other soft tissue infections however the LRINEC’s score greatest clinical
application may be its ability to rule out necrotizing fasciitis while its ability to accurately identify the presence of
infection remains suboptimal.
© 2021 by the American College of Foot and Ankle Surgeons. All rights reserved.

Diabetes mellitus (DM) remains a serious public health concern cur-
rently affecting 12% of adults and rising in prevalence to 25% in the
elderly (>65 years of age) (1). DM affects every organ system in the
body and has been associated with increased morbidity, mortality, and
nontraumatic lower extremity amputations (2). Diabetic foot infections
remain a serious complication that affects 1 out of every 4 diabetics and
has been associated with a mortality of 5% within the first 12 months
and increases to 42% within 5 years (3,4).
Financial Disclosure: No financial support was received.
Conflict of Interest: All authors have no financial conflict of interest to report.
Address correspondence to: Arthur Tarricone, DPM, MPH, SUNY Downstate Medical
Center − University Hospital of Brooklyn, 450 Clarkson Avenue, Brooklyn, NY 11203.
E-mail address: tarria01@outlook.com (A. Tarricone).
Necrotizing fasciitis (NF) is a serious medical infection that can
quickly spread across the body and lead to death if left untreated (5).
The most common predisposing factor to necrotizing fasciitis is DM,
where an estimated 60% of the patients diagnosed with NF share this
comorbidity (6). Although NF is a relatively rare disease, with a preva-
lence of 0.4 cases per 100,000 persons, case fatality rates have been
estimated to be an upwards of 30%, while amputation rates range
between 8% and 26% depending on the spread of the infection (7-10). In
addition to clinical challenges, the economic burden for NF is costly,
with hospital costs summing up to $100,000 per admission (8,11,12).
Due to the high mortality associated with this condition, early diag-
nosis and treatment are critical to the overall prognosis of a patient,
possibly preventing both amputation and mortality (6). The current

1067-2516/$ - see front matter © 2021 by the American College of Foot and Ankle Surgeons. All rights reserved.
https://doi.org/10.1053/j.jfas.2021.09.015
 A. Tarricone et al. / The Journal of Foot & Ankle Surgery 61 (2022) 384−389
gold standard for diagnosis of NF is tissue biopsy (5). However, early
presentations of necrotizing fasciitis are nonspecific, with symptoms
including swelling, erythema, and tenderness to palpation, similar to
the symptoms of cellulitis, resulting in a number of difficulties in early
clinical decision-making (13,14).
The Laboratory Risk Indicator for Necrotizing Fasciitis (LRINEC) Scor-
ing System, developed by Wong et al, aims to mediate this diagnostic
challenge by providing a quicker method to distinguish necrotizing fas-
ciitis from other soft tissue infections (15). The LRINEC score is tabu-
lated using 6 different metrics, C-reactive protein, white blood cells,
hemoglobin, sodium, creatinine, and glucose, with scores ranging
between 0 (low risk) and 13 (high risk) (15,16). Although many studies
have been conducted to evaluate LRINEC’s utility in diagnosing NF, the
effectiveness has largely been based on general infections and limited
research is available on infection specifically affecting the extremities.
NF continues to be a challenge to the medical field, bringing
immense risk especially to immunocompromised and diabetic popula-
tions (17). Early diagnosis and treatment is imperative to the survival of
the patient. The aim of this systematic review and meta-analysis is to
assess the current literature for the efficacy of the LRINEC score as a
prognostic tool for NF that specifically affects the extremities and dia-
betic populations and to evaluate the relationship between elevated
LRINEC score and major adverse limb events (MALE) and mortality.
Systematic Review and Meta-Analysis Methodology
Two sets of literature searches were conducted across 4 databases: PubMed, Embase,
Scopus, and Cochrane Library from November 19, 2020 to Dec 3, 2020. The first search
that encompasses the data included in the systematic review portion of this paper utilizes
the key words “necrotizing fasciitis” OR “Gangrene” AND “LRINEC.” The second set of
searches was conducted on PubMed, Embase, Scopus and Cochrane Library for meta-
analysis of extremities only. Key words used for this section were “Necrotizing Fasciitis”
OR “Gangrene” AND “extremities” AND “LRINEC.” The use of “extremities” was automati-
cally changed to “limb” while searching on the Embase database.
The following inclusion and exclusion criteria were used for article selection for the
systematic review. Citations must contain English abstracts or an English version of the
paper, full length texts, and have a prospective, retrospective, or randomized controlled
trial design. Studies must also have met the criteria of recruiting adults (age > 18), utilized
the LRINEC score to diagnose patients suspected of having necrotizing fasciitis, and report
a sensitivity and specificity value. Systematic reviews, meta-analyses, and case studies
were excluded.
Further inclusions were then applied for the meta-analysis section of this paper.
Inclusions consisted of the presence of a 2 £ 2 table of true positive, false positive, true
negative, and false negative values, either extractable or calculable from the results pre-
sented. Exclusion criteria for the meta-analysis portion consisted of studies that did not
have a 2 £ 2 or comparable group containing true negative or false negative data, were
systematic, or case design in nature. After all databases were screened, Endnote X7
Fig. 1. Forest plot for odds ratio of having necrotizing fasciitis and presenting with a LRINEC score ≥6.
385
(Clarivate Analytics) was utilized to check and delete duplicate articles. Two reviewers (A.
T. and W.A.) independently examined and screened titles and abstracts for preliminary
screening based on inclusion and exclusion criteria. Afterward, full texts of the possible
articles were reviewed and finalized for inclusion into this review. Any disagreements
were resolved through consensus.
One investigator completed the data extraction for article publication date, author,
study design, patient demographics, mean age, amputation, LRINEC scores, and mortality.
The primary outcomes assessed in this review were LRINEC scores, sensitivity, speci-
ficity, positive predictive value (PPV), and negative predictive value (NPV). Secondary to
these outcomes were mortality and MALE defined as the need for surgical debridement,
skin graft, or amputation. The absence of secondary outcomes did not exclude a citation
from being eligible in this review.
Embase
Results 117
After applying filters for “retrospective studies,” “controlled clinical trials,” “prospec-
tive trial,” and “randomized controlled trial,” 25 results remained. Titles and abstracts
were screened, and 4 results remained for independent evaluation.
PubMed
Results 92
After applying filters for “Last 10 Years” “Human,” “English,” and “Clinical Trials,” 58
results remained for independent evaluation. “Full text” filter was then applied, excluding
another 2 articles, leaving 56 results. Additional exclusions were made if the article did
not specifically discuss NF or use the LRINEC score system. Five articles remained and
were included in this review.
Statistical Analysis
Compilation of data was done through Microsoft Office Excel and flow diagrams in
Microsoft Office PowerPoint. Comprehensive Meta-Analysis Software (Biostat, Engle-
wood, NJ, 2006) was utilized to calculate odds ratios and effect sizes for LRINEC Score and
NF, MALE, and mortality. Statistic heterogeneity was evaluated using Cochranes Q-test
and I2 statistic. A p value of <.05 was considered statistically significant for the Q-test
while I2 statistic ranged from 0% to 100%, with higher values indicating higher heteroge-
neity (Fig. 1). The same Comprehensive Meta-Analysis program was used to generate the
forest plots integrated in the figures of this review. Global sensitivity, specificity, PPV, and
NPV for the citations referenced in the meta-analysis were calculated through SAS version
9.3 (SAS, Cary, NC) statistical software.
Results
Systematic Review of NF in Extremities
The initial literature review search produced 209 articles across all
databases. After applying filters for English, humans, and full text, 167
results remained. Titles and abstracts were screened, resulting in 9
386 A. Tarricone et al. / The Journal of Foot & Ankle Surgery 61 (2022) 384−389
citations. After full text examination, one citation’s reference was found
and determined to meet the inclusion criteria for our review (18). In
addition, 2 articles were determined to not meet the inclusion criteria
of reporting LRINEC sensitivity for NF, and were excluded, leaving 8
results in total. Control groups were absent from 3/8 citations (Fig. 2)
(19-21).
Fig. 2. Flowchart for article reviewing process.
Extremities (Meta-Analysis)
The initial search criterion produced 36 citations. Titles and
abstracts were screened, excluding another 31 articles. Of the remain-
ing 5, one contained incomplete data as the publication was still being
processed by the journal company. Four citations were therefore eligi-
ble and included in the meta-analysis (Fig. 2).
Patient Populations (Systematic Review)
Hsiao et al examined 106 patients with NF and 825 patients with
cellulitis in Taiwan based clinics. Among the NF population 48.1% had
DM and among the cellulitis population 43.9% had DM (22). Burner et al
assessed 80 patients with NF exclusively from emergency department
data records, where 80% were males and 49% had diabetes (19). This
patient population also had an average age of 47.5 +/- 1.4 years. Al-Hin-
dawi examined a northern European population of 74 in-hospital
patients (20). Hodgins et al examined 46 patients with an average age
of 59.4 years. The median LRINEC score for all the subjects was 7, and
11 patients had DM. In addition, the majority of infections were of the
groin or lower extremities (21). Narasimhan et al examined a database
of an indigenous patient population in northern Australia and utilized a
cutoff of ≥5 to diagnose NF, different from previous studies. Ninety-
three patients with NF were included in this study, 30 (32.3%) of which
presented with diabetes, and overall had an average LRINEC score of 7
(range 6-9) (23). The most commonly infected region were the lower
extremities (n = 54) followed by upper extremities (n = 20). Chao et al
examined a hospital bacteriology database of 125 consecutive patients
who presented with skin and soft tissue infections, 72 of whom were
confirmed to have NF (24). The average age of this population was
63 years, and 22/72 (30.5%) patients with NF also presented with diabe-
tes. Neeki et al examined 2 populations, one with cellulitis and one
with NF, summing to a total of 1083 patients (25). Liao et al conducted
a validation study in Taiwan, also comparing a group with NF with a
group with cellulitis (18). Sensitivities, specificities, PPVs, and NPVs for
each study are summarized in Table 1. In each study, NF was verified
through various methods including pathological reports, International
Classification of Disease codes, and physician clinical diagnosis.
Secondary Outcomes
Among the articles in this review, 4 provided upper and lower limb
event values and 6 provided mortality data related to NF. The total
number of adverse limb events for NF subjects from these articles was
n = 203, with individual study rates ranging from 27% to 95% (3 of 4
studies were above 88%), and cumulatively an 89% MALE rate (sum of
MALE in NF divided by total MALE in NF from all articles) (21,23,24).
Three studies, 2 of which that were incorporated in the meta-analysis,
indicated amputation rates, with a total of 12 amputations occurring in
patients with NF (24,26,27). Out of the 6 articles that presented mortal-
ity data, a total of 77 patients with NF died, with individual study rates
ranging between 8% and 35%, and a cumulative rate of 18.3% (19,21-
24). Cumulative mortality for subjects with NF was indicated in 3
extremity exclusive articles, with rates ranging from 0% to 27% while
rates among the articles that were inclusive of all body parts ranged
from 9% to 28% (Table 1).
Topographical Location
NF generally affects the truncal, perineum, and extremities, but loca-
tion varied around the body across each study in this review (28). Hsiao
et al examined a cohort with NF exclusively on the upper and lower
extremities. Hodgins et al, Chao et al, and Narasimhan et al examined
cohorts with NF affecting the extremities, as well as on the trunk, head,
 A. Tarricone et al. / The Journal of Foot & Ankle Surgery 61 (2022) 384−389 387

Table 1
Characteristics of studies included in this review

LRINEC Average Sensitivity Specificity Positive Negative MALE (NF) MALE MALE Mortality in Mortality in Mortality
Cutoff LRINEC Predictive Predictive (NF) (%) (no NF) Confirmed (NF) Confirmed (no NF)
Score Value Value (NF) %

Hsiao et al 6.00 3.30 43.00 83.00 25.00 92.00 N.R N.R N.R 9.00 8.49 18.00
Burner et al 6.00 N.R 77.00 N.R 76.00 34.00 N.R N.R N.R 28.00 35.00 N.R
Al-Hindawi et al 6.00 N.R 43.00 N.R N.R N.R N.R N.R N.R N.R N.R N.R
Hodgins et al 6.00 7.00 65.00 N.R N.R N.R 43.00 93.48 N.R 13.00 28.26 N.R
Narasimhan et al 6.00 N.R 76.00 93.00 96.00 88.00 93.00 94.90 127.00 9.00 9.18 1.00
Chao et al 2.00 2.40 71.00 83.00 85.00 65.00 64.00 88.89 13.00 15.00 20.83 3.00
Neeki et al 6.00 N.R 36.20 89.20 0.00 100.00 N.R N.R N.R N.R N.R N.R
Liao et al 6.00 N.R 59.20 83.80 37.90 92.50 N.R N.R N.R N.R N.R N.R
Yoon et al 6.00 N.R 70.00 72.00 70.00 72.00 N.R N.R N.R N.R N.R N.R
Novoa-Parra et al 6.00 N.R 72.70 82.60 N.R N.R 3.00 N.R N.R 3.00 N.R N.R
Leiblein et al 6.00 N.R 71.43 75.00 N.R N.R 0.00 N.R N.R 0.00 N.R 3.00
Abbreviation: NR, not reported.

and neck. The remaining studies did not specify the topographical loca- the true positive, false positive, true negative, and false negative values,
tion of infection. Overall, NF most commonly affected the limbs, having the global sensitivity, specificity, PPV, and NPV was 49.39%, 83.17%,
percent prevalence ranging between 48% and 100% with higher rates in 34.91%, and 89.99%, respectively. Accuracy, the classification by
the lower as opposed to upper extremities (21,22). whether a patient was correctly classified, was 77.95%.

Patient Populations—Meta-Analysis
The performed searches tabulated a total of 36 studies. After inde-
pendent evaluation and application of inclusion/exclusion criteria, 4
studies were determined eligible in their discussion of LRINEC applica-
tion for necrotizing fasciitis of the extremities. Yoon et al characterized
a cohort of 144 patients presenting with cellulitis or necrotizing fasciitis
within South Korean hospitals. Nineteen subjects had their upper
extremities affected while 125 subjects had their lower extremities
affected (29). The population characteristics and statistical results for
Hsiao et al are described above. Novoa-parra et al similarly compared a
group of 55 patients with severe cellulitis to a group of 11 patients with
necrotizing fasciitis through various Spanish hospitals (26). Leiblein
et al compared the efficacy in the LRINEC score at differentiating two
different necrotizing soft tissue infections: necrotizing fasciitis and gas
gangrene in a level 1 German trauma center. The average age of the
population with gas gangrene infected extremities was 70 years while
the average age of the population with NF infected extremities was
44 years (27). The description for Hsiao et al.’s population is described
in a prior paragraph.
Sensitivity and Specificity—Meta-Analysis
The breakdown of LRINEC scores in the Yoon et al trial was as fol-
lows: Cellulitis group, <6 (n = 41), ≥6 (n = 8), NF group <6 (n = 20), ≥6
(n = 27). Utilizing this cutoff, the sensitivity, specificity, PPV, and NPV as
calculated by Yoon et al, was 70%, 72%, 70%, and 72%, respectively. The
average LRINEC score for NF patients in the Novoa-parra et al trial was
6, while sensitivity and specificity values were 72.7% and 82.6%, respec-
tively. The average LRINEC score as calculated for the gas gangrene and
NF populations was 8.3 and 7.4 points respectively (Table 2). Combining
Odds Ratios
The odds ratios for presenting with a LRINEC score ≥6 and having NF
for each study are described in Fig. 1. The generated forest plot depicts
odds ratios ranging between 0.833 and 12.667. P values indicate signifi-
cance in whether LRINEC scores ≥6 are associated with NF diagnosis,
where p ≤ .05 is considered significant. Overall, the cumulative odds
ratio for the 4 studies was 4.285 (p < 0.01; Fig. 1).
Discussion
This systematic review evaluated the current literature surrounding
the effectiveness of the LRINEC score in NF diagnoses. NF is a life-threat-
ening infection, and utilizing reliable, accurate, and quick diagnostic
tools are imperative to the clinical success of managing the condition.
The LRINEC Scoring System was designed to facilitate this challenge,
integrating laboratory values into a scaled score to categorize people
that are at high risk of NF. Although LRINEC was presented as an effec-
tive tool for NF diagnosis in the Wong et al study, subsequent trials
amongst different patient population have established varying conclu-
sions.
Current sensitivity data that utilizes the general cutoff of 6 points
has varied, ranging between 43% and 77% with cumulative sensitivity,
specificity, PPV, and NPV represented in this meta-analysis as 49.39%,
83.17%, 34.91%, and 89.9%, respectively. As shown, the LRINEC score
often missed the true number of people who present with NF, prompt-
ing the need of additional tools to accurately diagnose the infection. On
the contrary, LRINEC did show a strong negative predictive value
(>90%) across 3 different studies and cumulative score of 89.9%, indicat-
ing that the score has greater potential at excluding NF.

Table 2
2 £ 2 characteristics of studies used in meta-analysis

Design Cutoff NF + NF - LRINEC <6 LRINEC ≥6 Diabetes Nondiabetes

Yoon et al Retrospective 6 47 49 61 35 32 124

Hsiao et al Prospective 6 106 825 746 185 413 518
Novoa-parra et al Retrospective 6 11 23 22 12 10 24
Leiblein et al Retrospective 6 7 4 3 8 3 8
388 A. Tarricone et al. / The Journal of Foot & Ankle Surgery 61 (2022) 384−389
In addition, our meta-analysis indicates that the odds of having a
LRINEC score ≥6, patients were 4.285 times more likely to have a diag-
nosis of NF in the lower extremities as opposed to presenting with a
LRINEC score <6 and an accuracy of 77.95% of correctly predicting the
infection. However, this score was calculated off a small number of
studies (n = 4) with 2 consisting of small case populations (<20
patients). Furthermore, secondary outcomes of MALE and mortality
were indicated in 3 of the 4 meta-analysis studies. However, these out-
comes were not categorized by LRINEC ≥6 and <6, and therefore odds
ratios were not calculated. While we predict the existence of a positive
trend between LRINEC scores and both clinical outcomes, further stud-
ies are necessary to explore this hypothesis.
Regardless, misdiagnosing remains a problem for NF, especially
amongst diabetic cohorts. This possible limitation in the LRINEC score is
particularly relevant in that NF has an increased prevalence in diabetics .
In a large study of 670 patients, it was determined that LRINEC scores are
commonly much greater within patients who have diabetes as opposed
to those who do not (30). Plausible explanation for this phenomenon is
inherent in the laboratory values collected for the score, which are often
elevated in people who have diabetes. White blood cells, sodium, and
glucose are anthropometrics that are commonly elevated in the entire
diabetic population while decreased hemoglobin values have a suspected
association to Type 1 Diabetes (31). Given the nature of diabetics and
patients with chronic disease, there is the likelihood to overestimate LRI-
NEC scores in this population, and thereby bias a positive diagnosis of
NF. Despite this issue, there is limited information surrounding diabetic
specific scores and NF, with only one trial performing a subgroup analy-
sis for diabetes only (25). Furthermore, each study’s cohort consisted of
<50% diabetics amongst their cohorts. The inconclusive details for the
aforementioned suggest further investigation is needed of patients with
diabetics in order to determine the effectiveness of LRINEC Scores as an
early diagnostic tool for NF diagnosis.
Further limitations in this review stem from the design of specific
studies, where n = 4 researchers examined cohorts exclusively with NF.
This may have produced unintended selection bias. Also reiterating the
rarity of NF, at 0.4 cases per 100,000 people, screening tests are inher-
ently flawed in capturing diseases like NF. Positive results are more
likely false positive within the 99,999.6 remaining individuals of the
population. However, when studies include a cohort who all present
with the desired study outcome such as NF, there are no false positive
possibilities for the LRINEC to detect, only false negatives. This process
of working retrospectively can become flawed due to the Bayes Theo-
rem, as the true probability of a test to detect rare diseases is dependent
on both the desired event along with all other potential outcomes.
In conclusion, overall, the LRINEC score has been validated multiple
times, showing promise in certain populations at diagnosing NF. How-
ever, trials have been predominantly retrospective in their design, and
even fewer focus on elucidating the score for NF of the lower extremi-
ties in diabetic populations—a location and subgroup that are at the
highest risk for the condition. Furthermore, multiple parameters that
compose LRINEC are inherently affected in patients presenting with
diabetes and would be categorized as high risk for NF. A skew in scoring
would likely incur problems in assessing individuals with diabetes and
suspected NF, thereby a leading to a number of misdiagnoses. In order
to bring the LRINEC score into fruition, additional research with pro-
spective and randomized controlled designs are still necessary to deter-
mine the forms of NF diagnostics that would ensure adequate
management of the infection.
Acknowledgments
This manuscript is not under consideration in any other journals, the
manuscripts contents have not been previously published, all authors
have read and approved the manuscript. This manuscript is a system-
atic review and study level meta-analysis, as such no human or animal
subjects were included. All studies included were approved by their
respective ethics committees or institutional review boards. All authors
contributed equally in the creation of this text.
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