Editorial Commentary:Bone of Contention: Diagnosing Diabetic Foot Osteomyelitis

Development of osteomyelitis of the foot is a potentially catastrophic event for a person with diabetes. The high success rates achieved with antimicrobial therapy for most infectious diseases have not yet been achieved for bone infections because of their unique physiological and anatomical characteristics [1]. When a foot ulcer becomes infected and the infection spreads to bone, the risk of limb amputation, with its substantial associated morbidity and mortality, is dramatically increased [2]. Furthermore, diabetic foot osteomyelitis often requires surgical therapy and/or prolonged antibiotic therapy. Because the key to successful management is early diagnosis, making an accurate diagnosis of this entity is crucial. Unfortunately, it is also difficult. Two main issues complicate making a correct diagnosis of osteomyelitis in the diabetic foot [3]. First, as with other types of bone infection, it usually takes a couple of weeks before there is sufficient loss of bone to be apparent on plain radiographs. Second, patients with longstanding diabetes often have peripheral neuropathy, which may both obscure clinical symptoms of infection [4] and predispose to neuro-osteoarthropathy. This noninfectious entity, often called Charcot foot, can be difficult to differentiate from bone infection [5]. Examination of a bone sample, with microbiological or histopathologic evaluation, is generally accepted as the criterion standard for diagnosis of osteomyelitis [6, 7]. Unfortunately, this safe and relatively simple procedure is not widely used and can yield results that are either false positive (caused by specimen contamination during the procedure) or false negative (caused by prior antibiotic therapy or erroneous sampling of an uninfected area). Thus, many investigations have undertaken a search of clinical, laboratory, or imaging findings that may help in the diagnosis of osteomyelitis. In this issue of Clinical Infectious Diseases, Dinh et al. [8] present the results of a meta-analysis of studies examining the diagnostic accuracy of various clinical and imaging methods for diabetic patients with a foot ulcer. They elected to include only studies that used histopathologic examination or culture of a bone specimen as the reference for diagnosis of osteomyelitis. Although this criterion adds rigor to their findings, it allowed them to select only 9 studies for their analysis. By contrast, a systematic review of diagnostic tests for diabetic foot osteomyelitis (published since the submission of the article by Dinh et al. [8]) that included some patients from whom no bone specimen was obtained reported data from 21 publications [9]. This study and the one by Dinh et al. [8] are otherwise very similar, seeking articles addressing the same question for the same types of patients over the same period. Surprisingly and for unclear reasons, only 4 of the same studies were selected by both groups for inclusion in their analyses. Thus, which evidence is useful for diagnosis of diabetic foot osteomyelitis? Both Dinh et al. [8] and Butalia et al. [9] concluded that the presence of exposed or visible bone correlated with bone infection, but this conclusion was based on only 2 studies. There was insufficient data to support the value of any other clinical finding, except perhaps the presence of a foot ulcer with a size >2 cm2. Butalia at al. [9] reviewed the value of laboratory tests and concluded—again based on only 2 studies—that an erythrocyte sedimentation rate >70 mm/h significantly increased the probability of osteomyelitis. With regard to imaging studies, both reviews concluded that MRI is the most accurate of the available tests. Plain radiography and WBC radionuclide scans are moderately helpful, but bone scans are too nonspecific to be useful. It is not easy to directly compare the findings of the 2 studies, because the systematic review by Butalia et al. [9] reported likelihood ratios for the various diagnostic tests, and the meta-analysis by Dinh et al. [8] provided pooled diagnostic ORs and Q* values (i.e., a summary receiver operating characteristic that is less affected by heterogeneity). It is worth considering diagnostic methods that neither study discussed, because these methods have not been subject to rigorous investigation. Experienced clinicians have advocated some clinical findings that may suggest osteomyelitis. These include the presence of a break in the skin—especially a chronic ulcer that is overlying a bony prominence—that affects the forefoot (or the heel) rather than the midfoot and that is deep [3]. Similarly, an ulcer that is not healing (or especially, deepening) despite appropriate care and pressure off-loading suggests underlying osteomyelitis [10]. Although both reviews recommended the probe-to-bone test, the test must be performed as described in the studies demonstrating its usefulness (i.e., after debridement of the soft-tissue wound and with a sterile metal—not a wooden or plastic—probe). Also, as with other diagnostic tests, the performance characteristics of the probe-to-bone test depend on the pretest probability of osteomyelitis in the tested population [11]. With regard to available laboratory tests, leukocytosis is infrequent in patients with diabetic foot osteomyelitis [12], but C-reactive protein measurement may be useful, because the C-reactive protein level is often elevated in patients with bone infection but is normal in patients with Charcot foot [13, 14]. More recently, the serum procalcitonin level has been shown to be a useful diagnostic marker of diabetic foot infection [15, 16], but additional investigations are required to determine the value of this test, especially for diagnosis of osteomyelitis. With regard to imaging tests, there are some promising diagnostic approaches. It may be possible to overcome the lack of sensitivity of negative plain radiograph findings for a patient with an acute soft-tissue wound by providing appropriate treatment (including for any infection) and then repeating the radiography assessment a few weeks later. Negative follow-up radiograph findings make the presence of osteomyelitis unlikely, and the development of new findings of bony erosion suggests that is osteomyelitis present [10]. Of course, newer diagnostic methods are continually being evaluated. One method that is particularly promising is the positron emission tomography scan with 18F-fluorodeoxyglucose imaging [17]. Studies have revealed that this method can detect clinically unsuspected osteomyelitis [14] and can accurately distinguish osteomyelitis from Charcot foot [18]. A different approach to this diagnostic dilemma is to develop a consensus scheme that integrates the results of a range of clinical, laboratory, and imaging findings. This technique has been used in several clinical situations, such as the Duke criteria for endocarditis, in which there is not a single criterion sufficiently reliable for making a diagnosis. To that end, the International Working Group on the Diabetic Foot appointed an expert advisory group to suggest criteria for the diagnosis of diabetic foot osteomyelitis that could be used in future research [19]. The group stratified levels of diagnostic certainty, based on the posttest probabilities of various diagnostic tests (depending on their relative values), into 4 categories of likelihood: definite (>90%), probable (51%–90%), possible (10%–50%), and unlikely (⩾10%). In addition to using an individual criterion, they proposed combinations of test results that would determine the diagnostic category. The scheme may be useful for initial decisions regarding whether additional diagnostic testing is needed or whether initiation of empirical antibiotic therapy is appropriate. It also allows for changing the level of diagnostic certainty over time as the course of infection evolves. Of course, this proposed scheme should currently only be used for research purposes and must undergo validation for use in clinical trials. The meta-analysis by Dinh et al. [8] is a useful review of the current methods for diagnosis of osteomyelitis of the foot in patients with diabetes. Make no bones about it, with the combination of some promising new diagnostic tests, the systematic review by Butalia et al. [9], and the proposed research consensus scheme from the International Working Group on the Diabetic Foot, we are finally approaching the point of having the ability to accurately diagnose this relatively frequent and potentially devastating infection. Potential conflicts of interest. B.A.L.: no conflicts.