Any podiatric medical student could tell you that the “gold standard” for the diagnosis of osteomyelitis is bone biopsy. This is obviously an important diagnosis to reach with a high degree of confidence. From a clinical standpoint, we utilize bone biopsy results: to decide on the course and duration of antibiotic therapy; to determine the need for subsequent wound debridement; as an indication for hyperbaric oxygen therapy; to assess the timing of wound closure; and to ascertain the level of lower extremity amputation.1-13
From a research standpoint, we use bone biopsy as the standard reference marker when examining the reliability of other diagnostic techniques for osteomyelitis including: clinical findings (such as the “probe to bone” test); laboratory values (such as erythrocyte sedimentation rate (ESR) and C-reactive protein); and advanced imaging analyses (such as magnetic resonance imaging (MRI) and bone scans).
The somewhat surprising problem is that there is actually no standardized or uniform definition for the term “bone biopsy.” To demonstrate this point, consider the classic 1995 study by Grayson and colleagues.14 That same podiatric medical student from our introductory sentence could probably also tell you that this study demonstrated an 89 percent positive predictive value of the “probe to bone” test for the diagnosis of osteomyelitis.
However, think about the study design utilized by the authors in this study. There were really two variables for the authors to consider: (1) whether the pedal ulcer probed to bone and (2) whether the underlying bone had osteomyelitis. Grayson and co-workers did not utilize the probe to bone test to primarily diagnose osteomyelitis in this study so the authors needed some other “standard” way to arrive at the diagnosis of osteomyelitis in the first place. In this study, the authors chose to utilize the histopathologic analysis of bone as their standard reference marker and definition for the term bone biopsy.14 In other words, a pathologist looked at a specimen of bone under a microscope and arrived at a diagnosis.
In recent years, several studies (most notably one by Lavery and co-authors in 2007) have attempted to replicate the findings of the Grayson study.15 Lavery and colleagues concluded that although the probe to bone test may remain an important diagnostic tool, it probably doesn’t have as high a positive predictive value as initially thought. Which standard reference marker did these authors utilize? Bone biopsy of course. However, in this case, the authors defined bone biopsy as the microbiologic analysis of bone. In other words, they sent a specimen of bone for culture and sensitivity analysis. No pathologist was required.
Accordingly, we have two important studies with both analyzing bone biopsy as the standard reference marker for the diagnosis of osteomyelitis but utilizing two different definitions and diagnostic tests for the term “bone biopsy.” The intention of this brief column is to review the intrinsic problems with both the microbiologic and histopathologic analysis of bone, and emphasize a comprehensive diagnostic approach to diabetic foot osteomyelitis.
Microbiologic bone culture for the diagnosis of diabetic foot osteomyelitis presents a unique set of challenges in terms of its reliability as a standard diagnostic procedure. The majority of diabetic foot wounds result from contiguous extension and therefore any sample runs the risk of contamination by contiguous soft tissues. Several studies have demonstrated that culture results from bone vary considerably from culture results of the tissue immediately surrounding bone.7-9 Additionally, culture results may misrepresent the number and type of infecting organisms within a sample. Whenever possible, one should utilize a transcutaneous biopsy through unaffected skin or only obtain specimens with a sterile instrument following complete debridement and irrigation.
Another important consideration regarding the microbiologic analysis of a bone biopsy specimen is the variable time frames in which patients are off antibiotics prior to specimen collection. This could obviously have an effect on the culture and sensitivity analysis. There is no formal recommendation for how long a patient should be cleared from antibiotics for a valid sample and this is often unrealistic for a patient fighting acute diabetic foot disease.
The histopathologic analysis also faces challenges with reliability and standardization. Our pathologist colleagues do not have a consistent classification for what they are looking at under that microscope. Through the limited clinical studies that have attempted to define bone samples affected by osteomyelitis, it is obvious that analysis is very subjective from a pathologist’s point of view.
Highlighting this subjective component is a study from our hospital that attempted to quantify the reliability of the histopathologic analysis of bone with respect to the diagnosis of diabetic foot osteomyelitis.16 The study design consisted of four pathologists, blinded to previous reports, who attempted to place a bone specimen into one of three diagnostic categories: “no evidence of osteomyelitis;” “no definitive findings of osteomyelitis but cannot be ruled out;” or as “findings consistent with osteomyelitis.”
Surprisingly, the results showed the pathologists to be in complete agreement with respect to the diagnosis in only 33 percent of the cases.16 Researchers also found that 41 percent of the time, one pathologist diagnosed a sample as no evidence of osteomyelitis while at least one other pathologist diagnosed that same sample as consistent with osteomyelitis. These results indicate that the use of histopathologic analysis for the diagnosis of diabetic foot osteomyelitis falls short of the “gold standard.”
Further complicating matters is a 2011 study by Weiner and colleagues who examined cases in which clinicians attempted both histology and microbiology for diagnosis.17 They found that in 34 percent of cases, the microbiologic assessment was positive while the histopathologic assessment was negative or vice versa. In other words, the microbiologic and histopathologic analyses demonstrated much less than perfect agreement with each other.
There is no doubt that the accurate diagnosis of osteomyelitis is necessary to ensure appropriate treatment and achieve successful patient outcomes. Recently, the International Working Group of the Diabetic Foot released a consensus statement and outlined a comprehensive diagnostic protocol for the diagnosis of osteomyelitis.2 In the creation of this protocol, the authors outlined different categories of confidence based on clinical, laboratory and imaging analyses.
The “unlikely” category of osteomyelitis is defined as the probability of osteomyelitis being less than 10 percent with no need for further investigation or treatment. In order to be classified in this category, one of the following three criteria must be satisfied: (1) normal MRI; (2) normal bone scan; or (3) a superficial ulcer present for less than two weeks with no signs/symptoms of inflammation and normal X-rays.
Possible osteomyelitis is defined as the probability being 10 to 50 percent with future treatment and investigation usually advised. A diabetic foot wound falls into this category if it meets one of the following criteria: (1) plain radiographs demonstrating cortical destruction; (2) a MRI with bone edema or cloaca; (3) a positive probe to bone test; (4) visible cortical bone; (5) an ESR > 70 mm/hr; (6) a non-healing wound despite adequate offloading and perfusion for greater than six weeks; or (7) an ulcer present for greater than two weeks with clinical evidence of infection.
Probable osteomyelitis is defined as a probability between 51 to 90 percent with a foot that you should consider treating, but further investigation may be needed. In order to satisfy this category, one must meet one of the following criteria: (1) visible cancellous bone in clinical evaluation of the ulcer; (2) a MRI showing bone edema with other signs of osteomyelitis; (3) a bone sample with positive culture (but negative histology); or (4) a bone sample with positive histology (but negative culture).
Definite (“beyond a reasonable doubt”) osteomyelitis is defined as having a probability of osteomyelitis greater than 90 percent that clinicians should treat as osteomyelitis. The criteria for this category includes: (1) a bone sample with both positive culture and histology; (2) definite purulence identified in bone intraoperatively; (3) an intraosseous abscess on MRI; or (4) an atraumatically detached bone fragment removed from the ulcer.
Unfortunately, clinicians should no longer consider the bone biopsy, as a stand-alone test, to be the “gold standard” for diagnosing osteomyelitis in the diabetic foot. Although it will certainly remain an important tool to help assist in the diagnosis, recent studies show that this may not be the gold standard as we originally thought. Both the microbiologic and histopathologic analyses of bone present with their own intrinsic problems.
Therefore, physicians should use a more comprehensive approach when attempting to reach the diagnosis. At our facility, we utilize the consensus guidelines of the International Working Group on the Diabetic Foot and encourage everyone to examine their own practices relative to this protocol.
Dr. Pirozzi is a resident within the Temple University Hospital Podiatric Surgical Residency Program at Temple University Hospital in Philadelphia.
Dr. Meyr is an Assistant Professor in the Department of Podiatric Surgery at the Temple University School of Podiatric Medicine in Philadelphia.
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