Keys To The Diagnostic Workup For Patients With Diabetic Foot Infections

Delays in diagnosing diabetic foot infections can increase the risk of complications. Accordingly, these authors offer a closer look at pertinent principles in the diagnostic workup ranging from insights on the patient history and physical exam to key tips on laboratory studies and imaging studies.

Diabetes accounts for more than 60 percent of all non-traumatic amputations that occur in the United States every year.1 Diabetic foot infections are the primary cause of amputation in up to half of these cases.1 The majority of these infections are secondary to a foot ulcer with 10 to 60 percent being complicated by underlying osteomyelitis based on severity of infection ranging from mild to severe respectively.2-5

   The clinical appearance of a patient with a diabetic foot infection often does not correlate with the severity of infection.5-7,8 A delay in appropriate treatment of a moderate or severe diabetic foot infection increases both the risk and level of amputation.7 Proper workup of a patient presenting with a diabetic foot infection is paramount in establishing severity and initiating appropriate treatment.

   The initial part of an evaluation involves obtaining a thorough history from the patient. One should follow a standard format (i.e. history of present illness, past medical history, past surgical history, medications, allergies and tobacco/alcohol and illicit drug use). Questions should be specific in regard to the duration of diabetes; the duration of the ulcer if present; and any previous history of ulceration, infection and amputation.

   Research has shown that patients are at greater risk for severe infection if they have a diagnosis of diabetes for more than 10 years, prolonged duration of ulceration and a previous history of diabetes-related complications of the lower extremities.4,9,10 Document tobacco use as it is a primary contributing factor to the development of peripheral arterial disease, which is a major risk factor for lower extremity amputation in patients with diabetes.4,6

   The physical examination should occur in a methodical manner to ensure you do not miss any steps in proper clinical assessment of the patient. First assess the patient’s vital signs to ensure he or she is clinically stable prior to performing a focused examination of the lower extremity. Patients who are febrile and systemically labile have a severe infection, and should be admitted for prompt initiation of treatment.

   The difficulty comes in assessing patients with a diabetic foot infection as they often appear less toxic than the severity of their infection would indicate. Approximately 50 percent of patients are afebrile and without leukocytosis at presentation.5-7,8,11 This is where a thorough, focused examination of the lower extremity, laboratory studies and imaging tests are paramount in helping determine the severity of the infection.

Pertinent Pointers On The Vascular Examination

One should assess the vascular status of all patients with a Doppler. This will negate the potential of falsely palpating pulses in a foot with compromised vascularity. Assess the dorsalis pedis, posterior tibial and peroneal arteries. In addition, one should perform Doppler examination of the first interspace. This connection between the dorsal and plantar vascular supply can become critical in dictating the viability of amputation levels, especially in patients with compromised vascularity.

   Also assess the dorsal digital arteries in conditions localized to a digit. Upon hearing a biphasic or triphasic arterial signal, the physician can feel more confident that distal arterial flow is adequate for healing as these signals correlate with a palpable pulse, which may be difficult to assess in a swollen limb.

   Aragon-Sanchez and colleagues found that limb salvage with surgical procedures localized to the foot occurred more than 90 percent of the time in patients with a limb- or life-threatening infection and at least one palpable pedal pulse.12 If monophasic signals are audible, obtain a vascular consultation. If necessary, one should administer appropriate antibiotics and maintain a clean and dry wound until vascular intervention is complete.

Evaluating The Neurological And Musculoskeletal Systems

When a patient with diabetes presents with a diabetic foot infection secondary to a foot ulcer, one can assume the patient has some component of peripheral neuropathy.

   A simple test to assess for peripheral neuropathy is the Ipswich Touch Test.13 To perform this test, the physician lightly touches or rests the tip of the index finger on the dorsum of the hallux and the tips of the first, third and fifth toes. Research has found the Ipswich Touch Test to have a 76 percent sensitivity, 90 percent specificity, a positive predictive value of 89 and negative predictive value of 77 in comparison to a vibratory threshold of ≥ 25 mV and 10-g monofilament testing at six sites on the foot for accurate diagnosis of peripheral neuropathy.13 The study also found the test to have significant interoperator reproducibility.

   The musculoskeletal examination should focus on the area from the knee to the toes. One should document a rapid assessment of muscle strength and any present deformities, including reducibility or rigidity of the deformities. Physicians can perform a more thorough musculoskeletal examination once there has been adequate treatment of the infection as this may include some level of amputation of the foot to garner control.

What The Research Shows On Wound Depth, Osteomyelitis And Other Dermatological Findings

Dermatological examination of the patient should first begin with exposure of both lower extremities from the knee to the toes. Cleanse the extremities with an antimicrobial cleanser as proper skin assessment cannot occur on skin of poor hygiene. One should take longitudinal and depth measurement of all ulcerations, including any undermining of the skin. Research has shown that wounds larger than 2 cm2 and deeper than 3 mm are associated with underlying osteomyelitis, increasing the risk of amputation.1,3,5,10 Assess wound depth by inserting a sterile cotton tip applicator, measuring stick or metal probe to the depths of the wound until you feel an endpoint.

   The landmark study by Grayson and colleagues reported that the ability to probe to bone at the base of the wound was a clinical sign of underlying osteomyelitis.14 Other authors subsequently criticized this study, noting that Grayson and colleagues performed it in patients who were hospitalized for severe diabetic foot infections and had a high pre-test prevalence of osteomyelitis.15-17

   Lavery and co-workers found that the negative predictive value of the probe to bone test was of greater clinical significance in the outpatient setting, ruling out osteomyelitis in wounds that did not probe to bone.17 However, they did agree that the ability to probe to bone in patients with severe diabetic foot infections, who have a high pretest probability of osteomyelitis, was a quick and effective means in aiding in the diagnosis.

   Assess the periwound skin for crepitus, induration and the extent of erythema. Crepitus is a late finding on physical exam. This finding should expedite transfer to the operating room for immediate surgical intervention. Assess erythema surrounding the ulcer using the erythema elevation test. This test differentiates between erythema secondary to inflammation, peripheral arterial disease and infection.

   Perform the test by having the patient lie flat on his or her back, and elevate the affected extremity above the level of the heart for three to five minutes. Erythema secondary to inflammation or peripheral arterial disease will dissipate with elevation of the limb. Erythema secondary to infection will not. Then demarcate the extent of erythema with an indelible marker and your initials, date and time/place to allow for assessment of progression or regression after the initiation of antibiotic therapy.

What A Close Reading Of Laboratory Studies Can Reveal

Complete blood count (CBC) with differential. A CBC with differential will allow assessment of the white blood cell count (WBC), hematocrit, hemoglobin and platelet count. Patients with diabetes and a moderate or severe diabetic foot infection present with a normal WBC more than 50 percent of the time.5-8,11

   However, a WBC >10.0 x 103 µL should raise concern for a deep space abscess or necrotizing type infection. Studies have shown that elevated WBC following medical or surgical intervention is an indicator of poor outcomes, necessitating further surgical intervention and/or amputation.3,5,18,19 Hematocrit and hemoglobin levels are often low in patients with chronic osteomyelitis.3,19 Consider transfusion in patients in whom amputation is warranted as the total blood loss from a partial foot amputation can be several hundred cubic centimeters.

   Basic metabolic panel (BMP). The BMP allows for assessment of electrolyte abnormalities, renal function and the patient’s current glucose level. Hyperglycemia may be one of the only markers of moderate or severe infection in patients with diabetes. Electrolyte abnormalities, particularly hypo- or hyperkalemia, must be stable prior to any surgical intervention. Assessment of renal function is crucial in the consideration of certain antibiotic dosing.

   Erythrocyte sedimentation rate (ESR). The ESR is an indirect measure of acute phase reactants, which increase in inflammatory or infectious conditions. An increase in acute phase reactants alters the normal negative charge of an erythrocyte, affecting the rate it descends in a sample of anticoagulated blood.8 Perform the test using the Westergren method by placing a diluted and anticoagulated sample of venous blood in a 2.5 mm diameter, 250 mm graduated cylinder. Then record the rate of erythrocyte sedimentation in millimeters per hour.8 Normal levels are 0 to 15 mm/hr for men and 0 to 20 mm/hr for women with a standard deviation of 4 mm/hr.8

   With increasing age, adjust the levels of ESR by dividing the age by two for men and adding 10 to the age and dividing by two for women.8 Factors that can elevate the ESR are age, female gender, pregnancy, oral contraceptive use, malignancy, myocardial infarction, morbid obesity, trauma and heparin use.8,20 Researchers have reported an ESR ≥ 70 mm/hr to be the optimal cutoff for positive correlation with the presence of osteomyelitis with a reported sensitivity of 90 percent, specificity of 94 to 100 percent, a positive predictive value of 81 to 95 percent, and a negative predictive value of 66 to 89 percent.8,19,20

   C reactive protein (CRP). The CRP is a hepatically produced peptide that is released in inflammatory and infectious conditions. A normal CRP level is <10 mg/L.2 Its use as an aid in the diagnosis of moderate or severe diabetic foot infections has not been consistently reported due to the wide range of reported optimal cutoff values, ranging from >3 mg/dL to 100 mg/dL for being diagnostic for the presence of osteomyelitis.3,10,21,22 The value of obtaining a CRP has been more of a supportive role when one combines it with other laboratory studies, physical exam and imaging findings.2

   Procalcitonin. Procalcitonin is a hormone secreted by non-neuroendocrine parenchymal cells. Normal levels are <0.10 mg/mL.2 Procalcitonin can remain low in viral infections and inflammatory diseases, and be more specific to bacterial infections, rising within two hours of onset.2,23,24

   Uzun and colleagues found that procalcitonin, CRP, WBC and ESR were all significantly elevated in patients with diabetes and a skin/soft tissue infection.23 The authors noted a reported sensitivity of 59 percent, specificity of 100 percent, a positive predictive value of 100 percent and a negative predictive value of 67 percent. Mutluogu and co-workers found that an elevated procalcitonin was not as predictive in cases of osteomyelitis.24 When comparing procalcitonin, CRP, ESR and WBC, an elevated ESR was the only laboratory value to play a diagnostic role in the presence of osteomyelitis.

   Hemoglobin A1c (HgBA1c). Hemoglobin A1c gives an estimate of the daily glucose levels of patients over the past 120 days. Recent studies have shown decreased wound healing with HgBA1c levels of less than 7 percent.25,26

   Christman and colleagues found a decrease in daily wound healing by 0.028 cm2 for every 1 percent increase of HgBA1c over 7 percent. This rate decreased to 0.022 cm2 per day in patients with a neuropathic ulcer.25 Aragon-Sanchez and colleagues reported on the importance of perioperative glycemic control in comparison to preoperative glycemic control in reducing the risk of amputation in patients with diabetes and osteomyelitis.26 Obtaining a baseline HgBA1c at admission can help guide perioperative and postoperative glycemic control.

What About Nutritional Markers?

One should assess nutritional status in all patients with diabetes as they are at increased risk for being malnourished.22,27 Adequate nutrition is critical for wound healing. An albumin of >3.5 mg/dL can result in decreased healing times in patients.22 A prealbumin of >15 mg/dL can be the single best predictor of survival in patients on hemodialysis and the best predictor of response in treatment of critically ill patients with sepsis.27

   The half-life of albumin is 14 to 21 days. Prealbumin has a half-life of two to three days. Given its shorter half-life, one can reassess prealbumin every two to three days to determine if implemented measures to boost nutritional status are effective. Rising prealbumin levels indicate that a minimum of 65 percent of nutritional requirements is being provided.27

When Should You Obtain A Wound Culture?

One should only obtain wound cultures for clinically infected ulcers. Intraoperative cultures are preferred. However, one can obtain cultures in the clinical setting if it occurs in the proper fashion. Cleanse the lower extremity and wound with an antimicrobial cleanser both prior to and following adequate debridement of the ulceration. Then insert the culture swab into the depths of the wound.

   Send specimens for gram stain, aerobic and anaerobic culture and sensitivities utilizing the appropriate culture tubes. Consider obtaining fungal cultures in wounds of more than six months duration. Results of fungal cultures can take over four weeks to return. One can send a sample of tissue for a KOH prep to determine the potential need for fungal coverage.

Assessing Imaging Studies

Plain film radiographs. Plain film radiographs are the first line in imaging evaluation of a diabetic foot infection. Bilateral films are recommended to assess for subtle differences using the contralateral foot as a “control.”28 Radiograph review should occur from the skin to the bones to ensure all soft tissue and osseous findings are noted.29 Soft tissue emphysema should prompt rapid surgical intervention.

   Osseous changes indicating possible osteomyelitis will not be evident on radiographs until there is a 35 to 50 percent reduction in osseous density. It can take a minimum of 10 to 14 days for initial osseous changes, such as periosteal reaction, to be evident.28,30 One can assume the duration of ulceration and infection to be more than 30 days when frank osseous destruction is present on radiographs that correlate to the osseous structures that lie beneath the ulceration on the foot.

   Plain film radiographs have a low sensitivity (54 percent) and specificity (68 percent) for detecting acute osteomyelitis. The primary factor for this is the time at which radiographs were taken due to the lag time from osseous infection to positive radiographic findings.30

   Nuclear medicine imaging studies (Tc99 and indium-111 WBC labeled scan). Three phase bone scans have an 81 percent sensitivity and a 28 percent specificity for detecting osteomyelitis of the lower extremity. The addition of an indium-111 labeled leukocyte scan decreases sensitivity to 74 percent and increases specificity to 68 percent. Despite this improvement from a three phase bone scan alone, an indium-111 labeled leukocyte scan still only has a low to moderate accuracy in diagnosing osteomyelitis.30

   Capriotti and colleagues performed a meta-analysis of nuclear medicine imaging studies in the diagnosis of osteomyelitis.31 Their results were divided into an imaging algorithm for forefoot and rearfoot ulcerations. The study authors found the most optimal use for nuclear medicine studies is in clinical situations in which there is a low suspicion for acute osteomyelitis. If radiographs were negative for any concerning findings, study authors recommended a three phase bone scan. If the results of the three phase bone scan were positive, the study authors recommended WBC scintigraphy. If this exam was positive, Capriotti and co-workers recommended obtaining an MRI or performing a bone biopsy to confirm the presence or absence of osteomyelitis.31

   Magnetic resonance imaging (MRI). Researchers have found MRI to be the gold standard for imaging acute osteomyelitis with a sensitivity of 90 percent and a specificity of 79 percent.30 It is the one imaging study with the best predictive value for acute osteomyelitis. A physician can feel confident in ruling out osteomyelitis if the MRI is negative for any findings concerning for osteomyelitis. The main limiting factor in obtaining MRI is the cost.1

Taking The Final Step Toward Determining Infection Severity

Once a thorough workup of a patient who presents with a diabetic foot infection is complete, all the information one has gathered can help in determining the severity of the infection, prompting initiation of appropriate medical and/or surgical therapy.

   Two classification systems exist in regard to determining the severity of infection. The International Working Group on the Diabetic Foot developed the first classification system in 2003.32 The Infectious Disease Society of America (IDSA) developed the second system in 2004.33 Both classification systems are similar and rely on local and systemic signs to assess for severity of infection.

   Lavery and colleagues validated the IDSA classification system in 2007.9 In their retrospective review of 1,666 patients with a diabetic foot infection, they found that patients who presented with a moderate or severe infection have an increased incidence of hospitalization and amputation.9

   While infection is a clinical diagnosis, true severity may be masked in patients with diabetes. The workup of a diabetic foot infection presented here outlines how to perform a thorough history, focusing on pertinent questions to ask the patient, a thorough focused lower extremity examination, what laboratory tests to order and what imaging studies to consider to properly assess the severity of the infection.

   Several studies have shown that one cannot determine the severity of a diabetic foot infection based on a single history, physical exam, laboratory or imaging finding.1-3,34 Rather, a combination of all of these findings should dictate the proper treatment pathway to follow — such as outpatient versus inpatient management or medical versus surgical therapy — for appropriate treatment.

   Dr. Schade is the Chief of the Limb Preservation Service and Director of the Complex Lower Extremity Surgery and Research Fellowship at Madigan Healthcare System in Tacoma, Wash. She is an Associate of the American College of Foot and Ankle Surgeons.

   Dr. Higa is the Fellow in the Complex Lower Extremity Surgery and Research Fellowship at Madigan Healthcare System in Tacoma, Wash. He is an Associate of the American College of Foot and Ankle Surgeons.

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