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The significance of neutrophil-lymphocyte ratio, platelet-lymphocyte ratio and lymphocyte-monocyte ratio in predicting peripheral arterial disease, peripheral neuropathy, osteomyelitis and amputation in diabetic foot infection
Accepted Manuscript The significance of neutrophil-lymphocyte ratio, platelet-lymphocyte ratio and lymphocyte-monocyte ratio in predicting peripheral arterial disease, peripheral neuropathy, osteomyelitis and amputation in diabetic foot infection Tuna Demirdal, Pinar Sen PII: DOI: Reference:
S0168-8227(18)30602-8 https://doi.org/10.1016/j.diabres.2018.08.009 DIAB 7481
To appear in:
Diabetes Research and Clinical Practice
Received Date: Revised Date: Accepted Date:
12 April 2018 10 July 2018 13 August 2018
Please cite this article as: T. Demirdal, P. Sen, The significance of neutrophil-lymphocyte ratio, platelet-lymphocyte ratio and lymphocyte-monocyte ratio in predicting peripheral arterial disease, peripheral neuropathy, osteomyelitis and amputation in diabetic foot infection, Diabetes Research and Clinical Practice (2018), doi: https://doi.org/ 10.1016/j.diabres.2018.08.009
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Title: The significance of neutrophil-lymphocyte ratio, platelet-lymphocyte ratio and lymphocyte-monocyte ratio in predicting peripheral arterial disease, peripheral neuropathy, osteomyelitis and amputation in diabetic foot infection Running Title: Diabetic foot infections Tuna Demirdal1 ; Prof., Pinar Sen1; M.D. 1
:Izmir Katip Celebi University Ataturk Training and Research Hospital, Department of
Infectious Diseases and Clinical Microbiology Corresponding Author: Pinar Sen, M.D., Izmir Katip Celebi University Ataturk Training and Research Hospital, Department of Infectious Diseases and Clinical Microbiology E-mail: [email protected] Adress: Izmir Katip Celebi University Ataturk Research and Training Hospital 35360, Karabaglar/Izmir, Turkey. Tel: +905058946042, Fax: +902322431530 Conflict of interest: None declared. Acknowledgments: None declared. Abstract Aims: The aim of the study was to evaluate the value of neutrophil to lymphocyte ratio(NLR), platelet to lymphocyte ratio(PLR) and lymphocyte to monocyte ratio(LMR) in predicting peripheral arterial disease, peripheral neuropathy, osteomyelitis and need for amputation in diabetic foot infection(DFI). Methods: A total of 280 patients were analyzed retrospectively. The NLR,PLR and LMR were evaluated statistically in DFI. Results: A total of 280 patients were enrolled in the study. PLR was significantly higher in osteomyelitis and NLR was found higher in peripheral arterial disease in DFI
(p=0.008,p=0.007). A PLR of >187.3 was calculated as the cut off value with 67.9% sensitivity and 59.1% specificity in predicting osteomyelitis. A NLR of >6.5 was calculated as the cut off with 53.3% sensitivity and 63% specificity in predicting peripheral arterial disease. NLR, PLR and LMR had a predictive value in predicting amputation in DFI (p<0.001, p<0.001,p=0.006). NLR and PLR were higher in patients who required amputation than in patients who required debridement/drainage (p<0.001,p=0.002). NLR was significant in determining amputation levels (minor or major)(p=0.013). Conclusions: NLR can predict peripheral arterial disease and elevated PLR can predict osteomyelitis in DFI. NLR, PLR and LMR are predictive of the need for amputation in DFI. Key words: diabetes, foot, infection, lymphocyte, ratio Introduction Diabetic foot ulcers are an important problem with serious consequences for both patients and health care systems. In diabetic patients, foot ulcer prevalence ranges from 4-10% and the lifetime incidence may increase up to 25% (1). Longer diabetes duration, insulin use, poor glycemic control, age, Charcot deformity, foot insensitivity, foot ischemia, history of ulcer/amputation have been shown as risk factors for foot ulceration (2). Among these factors, long-term complications of diabetes include vasculopathy and neuropathy are most strongly associated with development of diabetic foot ulcers (2,3). Infection is a common problem that affects more than half of diabetic foot ulcers and osteomyelitis develops in 20% of moderate infections and 50-60% of severe infections (3). The risk of amputation in the presence of osteomyelitis in diabetic foot infections (DFI) is significantly higher than isolated soft tissue infections (3,4). Early diagnosis and appropriate treatment of osteomyelitis are crucial for the prevention of lower extremity amputation in DFI (4). However, despite advanced imaging techniques and laboratory tests, it may be difficult to diagnose and treat osteomyelitis. Because histological and bone culture studies, which are the
most appropriate methods in the diagnosis of osteomyelitis, are difficult, invasive and timeconsuming, and long-term antimicrobial therapy and/or surgical intervention are needed for treatment (5). Chronic inflammation is implicated in the pathogenesis of diabetes and the development of diabetic complications (6). White blood cell (WBC) count, C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) are routinely used laboratory markers of inflammation. Recently, it has been pointed out that the changes in the rate of circulating leukocytes are simple, rapid and novel promising inflammation parameter in many diseases (7,8). Early detection of vasculopathy, neuropathy and osteomyelitis is essential for early diagnosis of high-risk diabetic foot and timely treatment. Early recognition of need for amputation is also crucial in terms of limiting amputation level and decreasing mortality. Despite the close association between inflammation and diabetes, the role of leukocyte subtypes in DFI was analyzed in a limited number of studies. To our knowledge, this is the first study to investigate the distribution of circulating neutrophil, lymphocyte, monocyte and platelet parameters in DFI in terms of complications and clinical course in a single study. In the present study, we aimed to evaluate the value of neutrophil to lymphocyte ratio (NLR), platelet to lymphocyte ratio (PLR) and lymphocyte to monocyte ratio (LMR) in predicting peripheral arterial disease, peripheral neuropathy, osteomyelitis and need for amputation in DFI. Subjects, Materials and methods Patients A total of 280 consecutive patients who were hospitalized in our Infectious Disease Clinic were analyzed retrospectively from February 2010 through March 2016 at the Katip Celebi University Ataturk Training and Research Hospital, Izmir, Turkey. The study protocol was
approved by our local ethics committee. Patients were enrolled the study if they were diabetic and hospitalized for DFI. The exclusion criteria were age less than 18 years, pregnancy, malignancy, autoimmune disorder, underlying haematological disease, glucocorticoid use, other foci of infection and previous antibiotic use. The data of the patients including demographics, type of diabetes, disease duration, clinical findings (presence of chronic ulcer, osteomyelitis, peripheral vasculopathy or neuropathy), laboratory parameters, results of microbiological cultures, treatment type (medical, debridement/drainage, minor or major amputation), history of previous debridement/amputation and treatment outcome were obtained from medical records. Treatment outcome was defined as complete recovery, development of chronic ulcer or reoperation requirement. Assessment of clinical features DFI was defined on the basis of the clinical signs of inflammation such as warmth, tenderness, redness, pain or swelling. In addition, purulent or nonpurulent secretions and foul odor were also regarded as sign of infection (5). Diagnosis of osteomyelitis was based on clinical, laboratory and imaging findings. Peripheral arterial disease was diagnosed by a vascular surgeon from faint/nonpalpable distal pulses and confirmed by imaging methods. Peripheral neuropathy was diagnosed by a neurologist and was defined as loss of sensation, foot deformity, tingling sensation and/or decreased vibratory sensation in either foot of patients. Minor amputation was defined as partial foot amputation involving infected tissue and bone with the preservation of ankle joint (9). Proximal amputation including ankle joint was defined as major amputation (9). Laboratory analysis Infection markers such as WBC, ESR, CRP and procalcitonin (PCT) were examined as laboratory tests. Wound swab samples, deep tissue samples and blood samples were analyzed microbiologically. All laboratory studies were analyzed according to the standard procedures
of our laboratory department. Venous blood samples were obtained simultaneously to determine the level of biomarkers on the first day after admission before receiving antimicrobial therapy. The NLR, PLR and LMR were calculated using neutrophil, lymphocyte, monocyte and platelet levels in the complete blood count measurement. NLR, PLR and LMR values were analyzed statistically in terms of predicting peripheral arterial disease, peripheral neuropathy, osteomyelitis and need for amputation in DFI. Statistical analysis Statistical analyses were performed using the SPSS software version 24. The variables were investigated using the Kolmogorov-Smirnov test. Descriptive analyses were presented using means and standard deviations for normally distributed variables. Student’s t-test was used to compare these parameters. The Chi-square test was used for the comparison of independent groups. The receiver operating characteristic curves (ROC) analyzes, sensitivity and specificity values were calculated by using MedCalc version 14 (MedCalc Software). P value <0.05 was considered statistically significant. Results Study Population A total of 280 patients were enrolled in the study including 198 (70.7%) men and 82 (29.3%) women. The mean age was 59.5±11.1 years. Ten (3.6%) of the patients were type 1 diabetes and 260 (96.4%) of them were type 2 diabetes and mean duration of diabetes was 13.6±9.5 years. The time from foot ulcer development to hospital admission was 10.6±5.3 days. The proportion of oral antidiabetic drug users was 17.7% and the proportion of insulin users was 71.9% while the proportion of patients who did not receive any antidiabetic treatment was 10.4%. The causes of the DFI were as follows; ischemic ulcer (51.6%), trauma (23.9%), neuropathic ulcer (7.5%), toenail fungus (6.3%), burn injury (3.8%), post surgical infection (3.8%), ingrown toenails (0.6%) and idiopathic (2.5%). Of these patients, 47.1% had right
foot wound, 44.5% had left foot wound and 8.4% had bilateral wounds. Anatomical distribution of the foot lesions was as follows; fingertips and/or toes (33.7%), heel (11.4%), midfoot (33.7%), hallux (1.3%) and multiple regions (19.9%). Among all patients, 53.6% had chronic foot ulcers, 54.2% had osteomyelitis, 43.7% had peripheral arterial disease and 6.8% had peripheral neuropathy. There were 24 (8.6%) patients with prior history of debridement and 46 (16.4%) patients had a history of surgery. Treatment modalities included medical treatment (96, 34.9%), debridement/drainage (70, 25.5%), minor amputation (43, 15.6%) and major amputation (66, 24%). Two hundred seventy-five patients were evaluated for treatment modality because 5 patients died before any effective treatment. Follow-up data was available for 231 of the 280 patients; 123 patients completely recovered, 42 patients developed a chronic foot ulcer and 66 patients required reoperation. The overall mortality rate was found 2.8%. Distribution of microorganisms Blood cultures were positive in 3 patients and all isolates were Staphylococcus aureus (S.aureus). Two patients had methicillin-susceptible S.aureus (MSSA) and 1 patient had methicillin resistant S.aureus (MRSA) in blood cultures. Positive wound cultures were yielded from 157 patients, 69.8% of them were Gram-negative and 29.6% of them were Gram-positive bacteria. There was only one patient with fungal aetiology (0.6%). More than one organism was isolated in 15 patients. Pseudomonas aeruginosa was the most frequently isolated bacterium. Among the 22 S.aureus strains isolated from the wound culture, 17 strains were MSSA and 5 strains were MRSA. Microorganisms isolated from soft tissue specimens were shown in Table 1. Laboratory Findings The mean values of laboratory values on admission were as follows; blood glucose levels 251.8±128.1 mg/dl, HbA1c 9.4±2.3%, haemoglobin 11.1±1.9 g/dl, WBC 13586.4±6889.9
k/ul, neutrophil 11092±6730.7 k/ul, lymphocyte 1758.8±893.9 k/ul, monocyte 806.9±400.5 k/ul, platelet 377278.6±142179.5 k/ul, CRP 13.3±10.8 mg/dl, ESH 83.2±30.9 mm/h, PCT 2.7±12.4 ng/ml, NLR 8.4±7.9, PLR 261.7±162.6 and LMR 2.7±1.9. The mean value of PLR was significantly higher in patients with osteomyelitis (p=0.008). On the contrary, NLR and LMR had no diagnostic value in predicting osteomyelitis (p=0.121, p=0.617) (Table 2). The area under the receiver operating characteristic (ROC) curve (AUC) value for PLR was 0.611 (95% confidence interval (CI), 0.519-0.703) with the cut off point of 187.3 in predicting osteomyelitis. Applying ROC curve at the cut off point of 187.3, PLR yielded 67.9% sensitivity and 59.1% specificity (Table 3) (Figure 1). Mean NLR value was found higher in peripheral arterial disease in DFI (p=0.007). However, no significant difference was found in terms of PLR and LMR values in the prediction of arterial disease (p=0.052, p=0.191) (Table 2). The significant cut-off value of NLR was determined as 6.5 and AUC was 0.588 (95% CI, 0.516-0.660) in distinguishing arterial disease (Table 3) (Figure 1). The initial values of NLR, PLR and LMR in amputated patients were significantly different from medically treated patients (Table 2). Both NLR and PLR values were higher in amputated patients (11.2±9.4 and 310.9±200.9) compared with medically treated patients (6.6±6.8 and 218±120.1) (p<0.001, p<0.001). On the contrary, LMR value was found statistically lower in amputated group than medically treated group (2.3±2 and 3.1±2, p=0.006). Mean NLR and PLR values of amputated patients (11.2±9.4 and 310.9±200.9) was higher than those treated with debridement/drainage (6±3.4 and 232.5±86.2) (p<0.001, p=0.002). Additionally, NLR value of patients undergoing major amputation was different significantly than those who undergoing minor amputation (12.9±9.8 and 8.5±8.1, p=0.013). ROC curve analyses and AUC values according to the amputation status were given in Table 3 and Figure 1.
NLR, PLR and LMR values were insignificant in predicting peripheral neuropathy and treatment outcome in patients with DFI (Table 2). Discussion The present study represents the first study to investigate the values of NLR, PLR and LMR in predicting osteomyelitis, peripheral vascular disease, peripheral neuropathy, and need for amputation in DFI. There are several main findings of our study. First, elevated NLR was found in patients with peripheral arterial disease and in patients who require amputation. Among patients who need amputation, NLR value was also found higher in patients who need major amputation. Second, increased PLR was found in patients with diabetic foot osteomyelitis and in patients undergoing amputation. But unlike NLR, PLR was not significant in patients who need major amputation. Third, LMR was useful only in distinguishing amputated patients from medically treated patients. Furthermore, unlike NLR and PLR, lower levels of LMR were associated with risk of amputation. And fourth, NLR, PLR and LMR values were insignificant in predicting peripheral neuropathy and treatment outcome in patients with DFI. Urgent aggressive debridement to remove dead tissues, appropriate antimicrobial therapy, improvement of metabolic control, determination and treatment of predisposing factors such as peripheral vascular disease and neuropathy are necessary for wound healing and limb salvage (3). Therefore, early detection of peripheral vasculopathy, peripheral neuropathy and osteomyelitis as well as timely surgical interventions are essential factors for early diagnosis and timely treatment of high-risk diabetic foot. The pathopysiological conditions including inflammation, endothelial dysfunction and procoagulant imbalance play an important role in the development of both diabetes and diabetes-related complications (10). The interplay between metabolic and inflammatory disorders in diabetic patients cause tissue damage and ultimately nephropathy, retinopathy,
neuropathy, microangiopathy and macrovascular complications occur in the majority of diabetic patients (10,11). Some investigations have indicated that changes in circulating inflammatory biomarkers that play a role in this pathopysiological process may offer new perspectives on the early diagnosis and targeted therapy in diabetes and its complications (6,8,12,13). The systemic inflammatory process leads to changes in neutrophil, lymphocyte, monocyte and platelet levels (8). There are many studies indicating that NLR, PLR and LMR may predict systemic inflammation and these markers may be useful in many diseases (6-8). Despite the close association between inflammation and diabetes, the value of these biomarkers in DFI has not been well studied. Abnormal immune functions of leukocytes appear due to impaired glucose metabolism in diabetes (14). Defective neutrophil function has been determined as a major factor for the development of infection in diabetes (14). Endothelial damage, which is reported to cause worse outcome in diabetic wounds, is caused by the effects of inflammatory mediators released from neutrophils (15). Moreover, these inflammatory mediators induce thrombocytosis by stimulating megakaryocytes (16). Therefore, it has been suggested that increased level of platelet is indicative of prothrombotic activity and ongoing inflammatory condition (17). Lymphocyte levels are also influenced by inflammatory states. Lymphocytes represent a modulatory effect on controlling inflammation and lymphocytopenia occurs due to accelerated apoptosis of lymphocytes during systemic inflammation (16,18). Additionally studies have stated that, in diabetic patients, hyperglycemia causes an increase in reactive oxygen species and lymphocyte levels may decrease as a result of oxidative DNA damage in lymphocytes (19). The high NLR, high PLR and low LMR detected in our study may be attributed to an opposite effect of inflammation on lymphocyte counts. The combined effect of peripheral arterial disease and neuropathy are among the most common reasons of diabetic foot ulcers and DFI (2,3). Although the contribution of
inflammatory process to the pathogenesis of diabetic neuropathy has not yet been fully elucidated, the role of systemic inflammation is widely recognized in the development and progression of atherosclerosis which is closely related to peripheral arterial disease (3,5,6). Neutrophil counts increases in atherosclerotic plaque, which plays proinflamatory role and leads to adhesion and transmigration of platelet and monocytes through the vessel wall (20). Gary et al. demonstrated that elevated NLR with a cut off 3.95, elevated PLR with a cut off 150 and decreased LMR with a cut off 3.1 were associated with a high risk for critical limb ischemia in peripheral arterial disease (20,21). In another study, NLR was correlated with the severity of peripheral arterial disease (22). However in these studies diabetic and non-diabetic patients were assessed together. Furthermore, all patients had peripheral arterial disease and no diagnostic evaluation was performed in terms of peripheral arterial disease. According to best of our knowledge, this is the first report to evaluate the value of NLR, PLR and LMR in predicting peripheral arterial disease in diabetic patients. We found that only NLR>6.5 was associated with peripheral arterial disease in patients with DFI. Although PLR and LMR are not found useful in predicting peripheral arterial disease, we conclude that PLR and LMR, which are indicated to be useful in determining vascular endpoint such as critical limb ischemia and myocardial infarction (20), may be beneficial to predict severity of peripheral arterial disease in DFI. In addition, since all 3 inflammatory markers examined in our study were found insignificant in discriminating peripheral neuropathy, we suggest that the contribution of other pathological processes may be greater than inflammation in the pathogenesis of diabetic neuropathy. Some immunological defects including lymphocyte and macrophage dysfunction have been reported in chronic osteomyelitis (23). Among NLR, PLR and LMR, we observed that only NLR was evaluated in terms of osteomyelitis in a few study. Yapıcı et al. demonstrated that NLR was significantly higher in patients with osteomyelitis than in patients without
osteomyelitis in DFI (12.3±8.6 and 6.0±3.7, p= 0.004) (12). However, cut-off, sensitivity and specificity values of NLR were not reported in this study. Ong et al. also reported that NLR was higher in diabetic patients with osteomyelitis than in those with noninfected ulcer (3.51±2.42 and 7.59±8.19, p= 0.0229) (24). In this study, the cut off value for NLR was 3.5 with 35.6% sensitivity and 71.4% specificity in discriminating infection in diabetic foot. Additionally, Schattner et al. reported that thrombocytosis is a new promising laboratory finding in discriminating osteomyelitis in chronic leg ulcers (25). In our study, only PLR was predictive of osteomyelitis in DFI. We anticipate that cytokine-induced reactive thrombocytosis secondary to infection leads to an increase in PLR, thus PLR may be a useful biomarker in predicting osteomyelitis in DFI. However, it is necessary to eliminate other causes of thrombocytosis to obtain reliable results in predicting osteomyelitis. Additionally, normal or low levels of PLR may not be used to rule out osteomyelitis. There is a need for prospective extensive research in this regard. The leading etiological cause of nontraumatic lower limb amputation is diabetes (26). In recent publications, elevated NLR and PLR were reported to be associated with risk of amputation (26-28). In a study conducted by Tasoglu et al., preoperative NLR≥5.2 was found to be independent predictive factor for amputation in acute limb ischemia (27). In another study, increased NLR and PLR were associated with extremity amputation in acute arterial occlusions (28). However, diabetes-related lower extremity amputation was not assessed in these studies. Only one other study, need for amputation was evaluated in patients with DFI and NLR was found to be a predictor of amputation (12). But, cut off value for predicting amputation was not determined in this study. We demonstrated that all three inflammatory biomarkers had a predictive value in predicting amputation in DFI. In addition, our findings take this one step further. We observed that NLR and PLR were also significantly higher in patients who required amputation than in patients who required debridement/drainage.
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occlusions?
Table 1. Causative microorganisms isolated from soft tissue specimens Microorganisms
Number (n)
Percent (%)
Pseudomonas aeruginosa
33
19.2
Escherichia coli
31
18
Staphylococcus aureus
22
12.8
Enterococcus
15
8.7
Streptococcus
13
7.6
Klebsiella pneumoniae
13
7.6
Proteus mirabilis
12
6.9
Acinetobacter baumanii
10
5.8
Enterobacter
6
3.5
Citrobacter
6
3.5
Morganella morganii
4
2.3
Serratia marcescens
3
1.7
Gemella morbillorum
1
0.6
Pasteurella pneumotropica
1
0.6
Achromobacter
1
0.6
Candida albicans
1
0.6
Table 2. NLR, PLR and LMR values according to clinical status, treatment type and treatment outcome Parameters Osteomyelitis Peripheral
NLR Yes
7.9±7.5
Peripheral neuropathy
0.121
PLR
p
261±161.9 200.9±85.4
LMR 2.9±1.9
0.008
No
6.2±5.6
Yes
9.9±9.3
No
7.1±6.1
247±147.5
2.8±1.8
Yes
9.8±11.5
285.8±207.4
3.1±2.9
No
6.6±5.8
arterial disease
p
287.4±175.7
222.7±96.2
0.617
2.5±1.8 0.052
0.007
0.158
2.8±1.7
p
0.117
0.191
2.9±1.8
0.797
Treatment type
Amputation status
Amputation
11.2±9.4
Medical
6.6±6.8
Amputation
11.2±9.4
Debridement/ drainage Major Amputation Minor Amputation
6±3.4
<0.001
310.9±200.9 218±120.1
<0.001
310.9±200.9 <0.001
12.9±9.8
232.5±86.2
3.1±2
0.002
2.8±1.7
0.093
2.3±2.3 0.053
0.013
0.006
2.3±2
340.8±209.4
8.5±8.1
2.3±2
264.9±179.9
0.719 2.4±1.6
Treatment outcome Yes
8.6±8.4
No
7.5±6.8
Chronic
Yes
6.3±5.7
wound
No
8.1±7.5
Re-operation
0.305
0.143
256.8±143.8 244.9±155 238.1±138.4 250.6±154.7
0.591
0.630
2.7±2.4 2.9±1.9 3.2±2 2.8±2
0.468
0.223
Complete
Yes
7.9±7.1
recovery
No
7.7±7.5
0.840
247.3±160.8
0.910
249.5±141.4
2.8±1.8
0.783
2.9±2.2
NLR: neutrophil to lymphocyte ratio, PLR: Platelet to lymphocyte ratio, LMR: Lymphocyte to monocyte ratio
Table 3. NLR, PLR and LMR values in predicting osteomyelitis, peripheral arterial disease, peripheral neuropathy and need for amputation in diabetic foot infections. Variables
AUC
p value
Cut
Sensitivity
Specificity
off*
(%)**
(%)**
+LR
-LR
+PV
-PV
(%)
(%)
Osteomyelitis NLR
0.556
0.244
>6.9
39.7 (28.8-51.5)
77.3 (65.3-86.7)
1.7
0.8
67.4
52
PLR
0.611
0.018
>187.3
67.9 (56.4-78.1)
59.1 (46.3-71)
1.7
0.5
66.2
60.9
LMR
0.513
0.793
≥3.8
28.2 (18.6-39.5)
81.8 (70.4-90.2)
1.6
0.9
64.7
49.1
Peripheral arterial disease NLR
0.588
0.016
>6.5
53.3 (43.4-63)
63 (54.4-71.1)
1.4
0.7
52.8
63.5
PLR
0.568
0.069
>317.5
33.6 (24.8-43.4)
80.4 (72.8-86.7)
1.7
0.8
57.1
61
LMR
0.569
0.065
≤1.6
42.9 (33.5-52.9)
73.7 (65.5-80.9)
1.6
0.8
56.1
62.3
Peripheral neuropathy NLR
0.532
0.712
>8.4
42.1 (20.3-66.5)
76.9 (60.7-88.9)
1.8
0.7
47.1
73.2
PLR
0.528
0.765
>394.6
31.6 (12.6-56.6)
94.9 (82.7-99.4)
6.2
0.7
75
74
LMR
0.560
0.484
≤2.3
63.2 (38.4-83.7)
57.9 (40.8-73.7)
1.5
0.6
42.9
75.9
NLR
0.674
<0.0001
>8.2
53.2 (43.4-62.8)
77.1 (70-83.3)
2.3
0.6
60.4
71.5
PLR
0.634
0.0002
>337.8
35.8 (26.8-45.5)
89.8 (84.1-93.9)
3.5
0.7
69.6
68
Amputation
LMR
0.656
<0.0001
≤2.1
65.1 (55.4-74)
66.7 (58.9-73.8)
1.9
0.5
56.3
NLR: neutrophil to lymphocyte ratio, PLR: Platelet to lymphocyte ratio, LMR: Lymphocyte to monocyte ratio, AUC: Area under the receiver operating characteristic curve, LR: Likelihood ratio, PV: Predictive value *Youden index was used in determining cut off value ** Presented with 95% confidence interval
74.3
Figure l. Receiver operating characteristic curves (ROC) analysis for various cutoff levels of NLR, PLR and LMR in differentiating peripheral arterial disease (1-a, 1-b, 1-c), peripheral neuropathy (2-a, 2-b, 2-c), osteomyelitis (3-a, 3-b, 3-c) and need for amputation (4-a, 4-b, 4-c) in diabetic foot infection NLR: neutrophil to lymphocyte ratio, PLR: Platelet to lymphocyte ratio, LMR: Lymphocyte to monocyte ratio
Highlights
Elevated NLR was found in patients with peripheral arterial disease and in patients who require amputation.
Increased PLR was found in patients with diabetic foot osteomyelitis and in patients undergoing amputation.
LMR was useful only in distinguishing amputated patients from medically treated patients.
NLR, PLR and LMR were predictive of the need for surgical intervention in DFI.
NLR, PLR and LMR values were insignificant in predicting peripheral neuropathy and treatment outcome in patients with DFI.
S0168-8227(18)30602-8 https://doi.org/10.1016/j.diabres.2018.08.009 DIAB 7481
To appear in:
Diabetes Research and Clinical Practice
Received Date: Revised Date: Accepted Date:
12 April 2018 10 July 2018 13 August 2018
Please cite this article as: T. Demirdal, P. Sen, The significance of neutrophil-lymphocyte ratio, platelet-lymphocyte ratio and lymphocyte-monocyte ratio in predicting peripheral arterial disease, peripheral neuropathy, osteomyelitis and amputation in diabetic foot infection, Diabetes Research and Clinical Practice (2018), doi: https://doi.org/ 10.1016/j.diabres.2018.08.009
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Title: The significance of neutrophil-lymphocyte ratio, platelet-lymphocyte ratio and lymphocyte-monocyte ratio in predicting peripheral arterial disease, peripheral neuropathy, osteomyelitis and amputation in diabetic foot infection Running Title: Diabetic foot infections Tuna Demirdal1 ; Prof., Pinar Sen1; M.D. 1
:Izmir Katip Celebi University Ataturk Training and Research Hospital, Department of
Infectious Diseases and Clinical Microbiology Corresponding Author: Pinar Sen, M.D., Izmir Katip Celebi University Ataturk Training and Research Hospital, Department of Infectious Diseases and Clinical Microbiology E-mail: [email protected] Adress: Izmir Katip Celebi University Ataturk Research and Training Hospital 35360, Karabaglar/Izmir, Turkey. Tel: +905058946042, Fax: +902322431530 Conflict of interest: None declared. Acknowledgments: None declared. Abstract Aims: The aim of the study was to evaluate the value of neutrophil to lymphocyte ratio(NLR), platelet to lymphocyte ratio(PLR) and lymphocyte to monocyte ratio(LMR) in predicting peripheral arterial disease, peripheral neuropathy, osteomyelitis and need for amputation in diabetic foot infection(DFI). Methods: A total of 280 patients were analyzed retrospectively. The NLR,PLR and LMR were evaluated statistically in DFI. Results: A total of 280 patients were enrolled in the study. PLR was significantly higher in osteomyelitis and NLR was found higher in peripheral arterial disease in DFI
(p=0.008,p=0.007). A PLR of >187.3 was calculated as the cut off value with 67.9% sensitivity and 59.1% specificity in predicting osteomyelitis. A NLR of >6.5 was calculated as the cut off with 53.3% sensitivity and 63% specificity in predicting peripheral arterial disease. NLR, PLR and LMR had a predictive value in predicting amputation in DFI (p<0.001, p<0.001,p=0.006). NLR and PLR were higher in patients who required amputation than in patients who required debridement/drainage (p<0.001,p=0.002). NLR was significant in determining amputation levels (minor or major)(p=0.013). Conclusions: NLR can predict peripheral arterial disease and elevated PLR can predict osteomyelitis in DFI. NLR, PLR and LMR are predictive of the need for amputation in DFI. Key words: diabetes, foot, infection, lymphocyte, ratio Introduction Diabetic foot ulcers are an important problem with serious consequences for both patients and health care systems. In diabetic patients, foot ulcer prevalence ranges from 4-10% and the lifetime incidence may increase up to 25% (1). Longer diabetes duration, insulin use, poor glycemic control, age, Charcot deformity, foot insensitivity, foot ischemia, history of ulcer/amputation have been shown as risk factors for foot ulceration (2). Among these factors, long-term complications of diabetes include vasculopathy and neuropathy are most strongly associated with development of diabetic foot ulcers (2,3). Infection is a common problem that affects more than half of diabetic foot ulcers and osteomyelitis develops in 20% of moderate infections and 50-60% of severe infections (3). The risk of amputation in the presence of osteomyelitis in diabetic foot infections (DFI) is significantly higher than isolated soft tissue infections (3,4). Early diagnosis and appropriate treatment of osteomyelitis are crucial for the prevention of lower extremity amputation in DFI (4). However, despite advanced imaging techniques and laboratory tests, it may be difficult to diagnose and treat osteomyelitis. Because histological and bone culture studies, which are the
most appropriate methods in the diagnosis of osteomyelitis, are difficult, invasive and timeconsuming, and long-term antimicrobial therapy and/or surgical intervention are needed for treatment (5). Chronic inflammation is implicated in the pathogenesis of diabetes and the development of diabetic complications (6). White blood cell (WBC) count, C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) are routinely used laboratory markers of inflammation. Recently, it has been pointed out that the changes in the rate of circulating leukocytes are simple, rapid and novel promising inflammation parameter in many diseases (7,8). Early detection of vasculopathy, neuropathy and osteomyelitis is essential for early diagnosis of high-risk diabetic foot and timely treatment. Early recognition of need for amputation is also crucial in terms of limiting amputation level and decreasing mortality. Despite the close association between inflammation and diabetes, the role of leukocyte subtypes in DFI was analyzed in a limited number of studies. To our knowledge, this is the first study to investigate the distribution of circulating neutrophil, lymphocyte, monocyte and platelet parameters in DFI in terms of complications and clinical course in a single study. In the present study, we aimed to evaluate the value of neutrophil to lymphocyte ratio (NLR), platelet to lymphocyte ratio (PLR) and lymphocyte to monocyte ratio (LMR) in predicting peripheral arterial disease, peripheral neuropathy, osteomyelitis and need for amputation in DFI. Subjects, Materials and methods Patients A total of 280 consecutive patients who were hospitalized in our Infectious Disease Clinic were analyzed retrospectively from February 2010 through March 2016 at the Katip Celebi University Ataturk Training and Research Hospital, Izmir, Turkey. The study protocol was
approved by our local ethics committee. Patients were enrolled the study if they were diabetic and hospitalized for DFI. The exclusion criteria were age less than 18 years, pregnancy, malignancy, autoimmune disorder, underlying haematological disease, glucocorticoid use, other foci of infection and previous antibiotic use. The data of the patients including demographics, type of diabetes, disease duration, clinical findings (presence of chronic ulcer, osteomyelitis, peripheral vasculopathy or neuropathy), laboratory parameters, results of microbiological cultures, treatment type (medical, debridement/drainage, minor or major amputation), history of previous debridement/amputation and treatment outcome were obtained from medical records. Treatment outcome was defined as complete recovery, development of chronic ulcer or reoperation requirement. Assessment of clinical features DFI was defined on the basis of the clinical signs of inflammation such as warmth, tenderness, redness, pain or swelling. In addition, purulent or nonpurulent secretions and foul odor were also regarded as sign of infection (5). Diagnosis of osteomyelitis was based on clinical, laboratory and imaging findings. Peripheral arterial disease was diagnosed by a vascular surgeon from faint/nonpalpable distal pulses and confirmed by imaging methods. Peripheral neuropathy was diagnosed by a neurologist and was defined as loss of sensation, foot deformity, tingling sensation and/or decreased vibratory sensation in either foot of patients. Minor amputation was defined as partial foot amputation involving infected tissue and bone with the preservation of ankle joint (9). Proximal amputation including ankle joint was defined as major amputation (9). Laboratory analysis Infection markers such as WBC, ESR, CRP and procalcitonin (PCT) were examined as laboratory tests. Wound swab samples, deep tissue samples and blood samples were analyzed microbiologically. All laboratory studies were analyzed according to the standard procedures
of our laboratory department. Venous blood samples were obtained simultaneously to determine the level of biomarkers on the first day after admission before receiving antimicrobial therapy. The NLR, PLR and LMR were calculated using neutrophil, lymphocyte, monocyte and platelet levels in the complete blood count measurement. NLR, PLR and LMR values were analyzed statistically in terms of predicting peripheral arterial disease, peripheral neuropathy, osteomyelitis and need for amputation in DFI. Statistical analysis Statistical analyses were performed using the SPSS software version 24. The variables were investigated using the Kolmogorov-Smirnov test. Descriptive analyses were presented using means and standard deviations for normally distributed variables. Student’s t-test was used to compare these parameters. The Chi-square test was used for the comparison of independent groups. The receiver operating characteristic curves (ROC) analyzes, sensitivity and specificity values were calculated by using MedCalc version 14 (MedCalc Software). P value <0.05 was considered statistically significant. Results Study Population A total of 280 patients were enrolled in the study including 198 (70.7%) men and 82 (29.3%) women. The mean age was 59.5±11.1 years. Ten (3.6%) of the patients were type 1 diabetes and 260 (96.4%) of them were type 2 diabetes and mean duration of diabetes was 13.6±9.5 years. The time from foot ulcer development to hospital admission was 10.6±5.3 days. The proportion of oral antidiabetic drug users was 17.7% and the proportion of insulin users was 71.9% while the proportion of patients who did not receive any antidiabetic treatment was 10.4%. The causes of the DFI were as follows; ischemic ulcer (51.6%), trauma (23.9%), neuropathic ulcer (7.5%), toenail fungus (6.3%), burn injury (3.8%), post surgical infection (3.8%), ingrown toenails (0.6%) and idiopathic (2.5%). Of these patients, 47.1% had right
foot wound, 44.5% had left foot wound and 8.4% had bilateral wounds. Anatomical distribution of the foot lesions was as follows; fingertips and/or toes (33.7%), heel (11.4%), midfoot (33.7%), hallux (1.3%) and multiple regions (19.9%). Among all patients, 53.6% had chronic foot ulcers, 54.2% had osteomyelitis, 43.7% had peripheral arterial disease and 6.8% had peripheral neuropathy. There were 24 (8.6%) patients with prior history of debridement and 46 (16.4%) patients had a history of surgery. Treatment modalities included medical treatment (96, 34.9%), debridement/drainage (70, 25.5%), minor amputation (43, 15.6%) and major amputation (66, 24%). Two hundred seventy-five patients were evaluated for treatment modality because 5 patients died before any effective treatment. Follow-up data was available for 231 of the 280 patients; 123 patients completely recovered, 42 patients developed a chronic foot ulcer and 66 patients required reoperation. The overall mortality rate was found 2.8%. Distribution of microorganisms Blood cultures were positive in 3 patients and all isolates were Staphylococcus aureus (S.aureus). Two patients had methicillin-susceptible S.aureus (MSSA) and 1 patient had methicillin resistant S.aureus (MRSA) in blood cultures. Positive wound cultures were yielded from 157 patients, 69.8% of them were Gram-negative and 29.6% of them were Gram-positive bacteria. There was only one patient with fungal aetiology (0.6%). More than one organism was isolated in 15 patients. Pseudomonas aeruginosa was the most frequently isolated bacterium. Among the 22 S.aureus strains isolated from the wound culture, 17 strains were MSSA and 5 strains were MRSA. Microorganisms isolated from soft tissue specimens were shown in Table 1. Laboratory Findings The mean values of laboratory values on admission were as follows; blood glucose levels 251.8±128.1 mg/dl, HbA1c 9.4±2.3%, haemoglobin 11.1±1.9 g/dl, WBC 13586.4±6889.9
k/ul, neutrophil 11092±6730.7 k/ul, lymphocyte 1758.8±893.9 k/ul, monocyte 806.9±400.5 k/ul, platelet 377278.6±142179.5 k/ul, CRP 13.3±10.8 mg/dl, ESH 83.2±30.9 mm/h, PCT 2.7±12.4 ng/ml, NLR 8.4±7.9, PLR 261.7±162.6 and LMR 2.7±1.9. The mean value of PLR was significantly higher in patients with osteomyelitis (p=0.008). On the contrary, NLR and LMR had no diagnostic value in predicting osteomyelitis (p=0.121, p=0.617) (Table 2). The area under the receiver operating characteristic (ROC) curve (AUC) value for PLR was 0.611 (95% confidence interval (CI), 0.519-0.703) with the cut off point of 187.3 in predicting osteomyelitis. Applying ROC curve at the cut off point of 187.3, PLR yielded 67.9% sensitivity and 59.1% specificity (Table 3) (Figure 1). Mean NLR value was found higher in peripheral arterial disease in DFI (p=0.007). However, no significant difference was found in terms of PLR and LMR values in the prediction of arterial disease (p=0.052, p=0.191) (Table 2). The significant cut-off value of NLR was determined as 6.5 and AUC was 0.588 (95% CI, 0.516-0.660) in distinguishing arterial disease (Table 3) (Figure 1). The initial values of NLR, PLR and LMR in amputated patients were significantly different from medically treated patients (Table 2). Both NLR and PLR values were higher in amputated patients (11.2±9.4 and 310.9±200.9) compared with medically treated patients (6.6±6.8 and 218±120.1) (p<0.001, p<0.001). On the contrary, LMR value was found statistically lower in amputated group than medically treated group (2.3±2 and 3.1±2, p=0.006). Mean NLR and PLR values of amputated patients (11.2±9.4 and 310.9±200.9) was higher than those treated with debridement/drainage (6±3.4 and 232.5±86.2) (p<0.001, p=0.002). Additionally, NLR value of patients undergoing major amputation was different significantly than those who undergoing minor amputation (12.9±9.8 and 8.5±8.1, p=0.013). ROC curve analyses and AUC values according to the amputation status were given in Table 3 and Figure 1.
NLR, PLR and LMR values were insignificant in predicting peripheral neuropathy and treatment outcome in patients with DFI (Table 2). Discussion The present study represents the first study to investigate the values of NLR, PLR and LMR in predicting osteomyelitis, peripheral vascular disease, peripheral neuropathy, and need for amputation in DFI. There are several main findings of our study. First, elevated NLR was found in patients with peripheral arterial disease and in patients who require amputation. Among patients who need amputation, NLR value was also found higher in patients who need major amputation. Second, increased PLR was found in patients with diabetic foot osteomyelitis and in patients undergoing amputation. But unlike NLR, PLR was not significant in patients who need major amputation. Third, LMR was useful only in distinguishing amputated patients from medically treated patients. Furthermore, unlike NLR and PLR, lower levels of LMR were associated with risk of amputation. And fourth, NLR, PLR and LMR values were insignificant in predicting peripheral neuropathy and treatment outcome in patients with DFI. Urgent aggressive debridement to remove dead tissues, appropriate antimicrobial therapy, improvement of metabolic control, determination and treatment of predisposing factors such as peripheral vascular disease and neuropathy are necessary for wound healing and limb salvage (3). Therefore, early detection of peripheral vasculopathy, peripheral neuropathy and osteomyelitis as well as timely surgical interventions are essential factors for early diagnosis and timely treatment of high-risk diabetic foot. The pathopysiological conditions including inflammation, endothelial dysfunction and procoagulant imbalance play an important role in the development of both diabetes and diabetes-related complications (10). The interplay between metabolic and inflammatory disorders in diabetic patients cause tissue damage and ultimately nephropathy, retinopathy,
neuropathy, microangiopathy and macrovascular complications occur in the majority of diabetic patients (10,11). Some investigations have indicated that changes in circulating inflammatory biomarkers that play a role in this pathopysiological process may offer new perspectives on the early diagnosis and targeted therapy in diabetes and its complications (6,8,12,13). The systemic inflammatory process leads to changes in neutrophil, lymphocyte, monocyte and platelet levels (8). There are many studies indicating that NLR, PLR and LMR may predict systemic inflammation and these markers may be useful in many diseases (6-8). Despite the close association between inflammation and diabetes, the value of these biomarkers in DFI has not been well studied. Abnormal immune functions of leukocytes appear due to impaired glucose metabolism in diabetes (14). Defective neutrophil function has been determined as a major factor for the development of infection in diabetes (14). Endothelial damage, which is reported to cause worse outcome in diabetic wounds, is caused by the effects of inflammatory mediators released from neutrophils (15). Moreover, these inflammatory mediators induce thrombocytosis by stimulating megakaryocytes (16). Therefore, it has been suggested that increased level of platelet is indicative of prothrombotic activity and ongoing inflammatory condition (17). Lymphocyte levels are also influenced by inflammatory states. Lymphocytes represent a modulatory effect on controlling inflammation and lymphocytopenia occurs due to accelerated apoptosis of lymphocytes during systemic inflammation (16,18). Additionally studies have stated that, in diabetic patients, hyperglycemia causes an increase in reactive oxygen species and lymphocyte levels may decrease as a result of oxidative DNA damage in lymphocytes (19). The high NLR, high PLR and low LMR detected in our study may be attributed to an opposite effect of inflammation on lymphocyte counts. The combined effect of peripheral arterial disease and neuropathy are among the most common reasons of diabetic foot ulcers and DFI (2,3). Although the contribution of
inflammatory process to the pathogenesis of diabetic neuropathy has not yet been fully elucidated, the role of systemic inflammation is widely recognized in the development and progression of atherosclerosis which is closely related to peripheral arterial disease (3,5,6). Neutrophil counts increases in atherosclerotic plaque, which plays proinflamatory role and leads to adhesion and transmigration of platelet and monocytes through the vessel wall (20). Gary et al. demonstrated that elevated NLR with a cut off 3.95, elevated PLR with a cut off 150 and decreased LMR with a cut off 3.1 were associated with a high risk for critical limb ischemia in peripheral arterial disease (20,21). In another study, NLR was correlated with the severity of peripheral arterial disease (22). However in these studies diabetic and non-diabetic patients were assessed together. Furthermore, all patients had peripheral arterial disease and no diagnostic evaluation was performed in terms of peripheral arterial disease. According to best of our knowledge, this is the first report to evaluate the value of NLR, PLR and LMR in predicting peripheral arterial disease in diabetic patients. We found that only NLR>6.5 was associated with peripheral arterial disease in patients with DFI. Although PLR and LMR are not found useful in predicting peripheral arterial disease, we conclude that PLR and LMR, which are indicated to be useful in determining vascular endpoint such as critical limb ischemia and myocardial infarction (20), may be beneficial to predict severity of peripheral arterial disease in DFI. In addition, since all 3 inflammatory markers examined in our study were found insignificant in discriminating peripheral neuropathy, we suggest that the contribution of other pathological processes may be greater than inflammation in the pathogenesis of diabetic neuropathy. Some immunological defects including lymphocyte and macrophage dysfunction have been reported in chronic osteomyelitis (23). Among NLR, PLR and LMR, we observed that only NLR was evaluated in terms of osteomyelitis in a few study. Yapıcı et al. demonstrated that NLR was significantly higher in patients with osteomyelitis than in patients without
osteomyelitis in DFI (12.3±8.6 and 6.0±3.7, p= 0.004) (12). However, cut-off, sensitivity and specificity values of NLR were not reported in this study. Ong et al. also reported that NLR was higher in diabetic patients with osteomyelitis than in those with noninfected ulcer (3.51±2.42 and 7.59±8.19, p= 0.0229) (24). In this study, the cut off value for NLR was 3.5 with 35.6% sensitivity and 71.4% specificity in discriminating infection in diabetic foot. Additionally, Schattner et al. reported that thrombocytosis is a new promising laboratory finding in discriminating osteomyelitis in chronic leg ulcers (25). In our study, only PLR was predictive of osteomyelitis in DFI. We anticipate that cytokine-induced reactive thrombocytosis secondary to infection leads to an increase in PLR, thus PLR may be a useful biomarker in predicting osteomyelitis in DFI. However, it is necessary to eliminate other causes of thrombocytosis to obtain reliable results in predicting osteomyelitis. Additionally, normal or low levels of PLR may not be used to rule out osteomyelitis. There is a need for prospective extensive research in this regard. The leading etiological cause of nontraumatic lower limb amputation is diabetes (26). In recent publications, elevated NLR and PLR were reported to be associated with risk of amputation (26-28). In a study conducted by Tasoglu et al., preoperative NLR≥5.2 was found to be independent predictive factor for amputation in acute limb ischemia (27). In another study, increased NLR and PLR were associated with extremity amputation in acute arterial occlusions (28). However, diabetes-related lower extremity amputation was not assessed in these studies. Only one other study, need for amputation was evaluated in patients with DFI and NLR was found to be a predictor of amputation (12). But, cut off value for predicting amputation was not determined in this study. We demonstrated that all three inflammatory biomarkers had a predictive value in predicting amputation in DFI. In addition, our findings take this one step further. We observed that NLR and PLR were also significantly higher in patients who required amputation than in patients who required debridement/drainage.
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occlusions?
Table 1. Causative microorganisms isolated from soft tissue specimens Microorganisms
Number (n)
Percent (%)
Pseudomonas aeruginosa
33
19.2
Escherichia coli
31
18
Staphylococcus aureus
22
12.8
Enterococcus
15
8.7
Streptococcus
13
7.6
Klebsiella pneumoniae
13
7.6
Proteus mirabilis
12
6.9
Acinetobacter baumanii
10
5.8
Enterobacter
6
3.5
Citrobacter
6
3.5
Morganella morganii
4
2.3
Serratia marcescens
3
1.7
Gemella morbillorum
1
0.6
Pasteurella pneumotropica
1
0.6
Achromobacter
1
0.6
Candida albicans
1
0.6
Table 2. NLR, PLR and LMR values according to clinical status, treatment type and treatment outcome Parameters Osteomyelitis Peripheral
NLR Yes
7.9±7.5
Peripheral neuropathy
0.121
PLR
p
261±161.9 200.9±85.4
LMR 2.9±1.9
0.008
No
6.2±5.6
Yes
9.9±9.3
No
7.1±6.1
247±147.5
2.8±1.8
Yes
9.8±11.5
285.8±207.4
3.1±2.9
No
6.6±5.8
arterial disease
p
287.4±175.7
222.7±96.2
0.617
2.5±1.8 0.052
0.007
0.158
2.8±1.7
p
0.117
0.191
2.9±1.8
0.797
Treatment type
Amputation status
Amputation
11.2±9.4
Medical
6.6±6.8
Amputation
11.2±9.4
Debridement/ drainage Major Amputation Minor Amputation
6±3.4
<0.001
310.9±200.9 218±120.1
<0.001
310.9±200.9 <0.001
12.9±9.8
232.5±86.2
3.1±2
0.002
2.8±1.7
0.093
2.3±2.3 0.053
0.013
0.006
2.3±2
340.8±209.4
8.5±8.1
2.3±2
264.9±179.9
0.719 2.4±1.6
Treatment outcome Yes
8.6±8.4
No
7.5±6.8
Chronic
Yes
6.3±5.7
wound
No
8.1±7.5
Re-operation
0.305
0.143
256.8±143.8 244.9±155 238.1±138.4 250.6±154.7
0.591
0.630
2.7±2.4 2.9±1.9 3.2±2 2.8±2
0.468
0.223
Complete
Yes
7.9±7.1
recovery
No
7.7±7.5
0.840
247.3±160.8
0.910
249.5±141.4
2.8±1.8
0.783
2.9±2.2
NLR: neutrophil to lymphocyte ratio, PLR: Platelet to lymphocyte ratio, LMR: Lymphocyte to monocyte ratio
Table 3. NLR, PLR and LMR values in predicting osteomyelitis, peripheral arterial disease, peripheral neuropathy and need for amputation in diabetic foot infections. Variables
AUC
p value
Cut
Sensitivity
Specificity
off*
(%)**
(%)**
+LR
-LR
+PV
-PV
(%)
(%)
Osteomyelitis NLR
0.556
0.244
>6.9
39.7 (28.8-51.5)
77.3 (65.3-86.7)
1.7
0.8
67.4
52
PLR
0.611
0.018
>187.3
67.9 (56.4-78.1)
59.1 (46.3-71)
1.7
0.5
66.2
60.9
LMR
0.513
0.793
≥3.8
28.2 (18.6-39.5)
81.8 (70.4-90.2)
1.6
0.9
64.7
49.1
Peripheral arterial disease NLR
0.588
0.016
>6.5
53.3 (43.4-63)
63 (54.4-71.1)
1.4
0.7
52.8
63.5
PLR
0.568
0.069
>317.5
33.6 (24.8-43.4)
80.4 (72.8-86.7)
1.7
0.8
57.1
61
LMR
0.569
0.065
≤1.6
42.9 (33.5-52.9)
73.7 (65.5-80.9)
1.6
0.8
56.1
62.3
Peripheral neuropathy NLR
0.532
0.712
>8.4
42.1 (20.3-66.5)
76.9 (60.7-88.9)
1.8
0.7
47.1
73.2
PLR
0.528
0.765
>394.6
31.6 (12.6-56.6)
94.9 (82.7-99.4)
6.2
0.7
75
74
LMR
0.560
0.484
≤2.3
63.2 (38.4-83.7)
57.9 (40.8-73.7)
1.5
0.6
42.9
75.9
NLR
0.674
<0.0001
>8.2
53.2 (43.4-62.8)
77.1 (70-83.3)
2.3
0.6
60.4
71.5
PLR
0.634
0.0002
>337.8
35.8 (26.8-45.5)
89.8 (84.1-93.9)
3.5
0.7
69.6
68
Amputation
LMR
0.656
<0.0001
≤2.1
65.1 (55.4-74)
66.7 (58.9-73.8)
1.9
0.5
56.3
NLR: neutrophil to lymphocyte ratio, PLR: Platelet to lymphocyte ratio, LMR: Lymphocyte to monocyte ratio, AUC: Area under the receiver operating characteristic curve, LR: Likelihood ratio, PV: Predictive value *Youden index was used in determining cut off value ** Presented with 95% confidence interval
74.3
Figure l. Receiver operating characteristic curves (ROC) analysis for various cutoff levels of NLR, PLR and LMR in differentiating peripheral arterial disease (1-a, 1-b, 1-c), peripheral neuropathy (2-a, 2-b, 2-c), osteomyelitis (3-a, 3-b, 3-c) and need for amputation (4-a, 4-b, 4-c) in diabetic foot infection NLR: neutrophil to lymphocyte ratio, PLR: Platelet to lymphocyte ratio, LMR: Lymphocyte to monocyte ratio
Highlights
Elevated NLR was found in patients with peripheral arterial disease and in patients who require amputation.
Increased PLR was found in patients with diabetic foot osteomyelitis and in patients undergoing amputation.
LMR was useful only in distinguishing amputated patients from medically treated patients.
NLR, PLR and LMR were predictive of the need for surgical intervention in DFI.
NLR, PLR and LMR values were insignificant in predicting peripheral neuropathy and treatment outcome in patients with DFI.