A Case for Serial Radiographs and Modulation of Pro-Inflammatory Cytokines.
Osteomyelitis presents in 3 different stages with poorly defined transitions: acute, subacute, and chronic.5 The transition from acute to subacute or chronic indicates that therapeutic measures have been inadequate or inappropriately treated.6 Osteomyelitis is most commonly caused by Staphylococcus aureus, β-haemolytic streptococci, and in some cases, aerobic gram-negative rods,7 with most diabetic foot ulcers being polymicrobial.8 Most diabetic foot infections result from contiguous spread of infection from adjacent soft tissue, but can result from direct inoculation of a penetrating injury.10
Diabetic pre-ulceration typically starts with repetitive trauma and or prolonged pressure/shear. This results in a repetitive ischemic reperfusion injury and local tissue ischemia inducing chronic inflammation in pre-ulcerative tissue.11-20 The pathological features of an ischemic-reperfusion injury include accumulation of leukocytes in blood vessel lumens and leukocyte extravasation, elevated expression of inflammatory cytokines with tissue destruction proteinases, and fibrosis of microvessels, which are all features seen in other types of ischemia-reperfusion injury.13-21 This is an important and often over looked stage in the development of diabetic foot ulcers because the diabetic foot is already highly compromised and deep within the chronic inflammatory phase of healing even before the ulcer appears.
Once bacteria gain access to soft tissue they begin to multiply, leading to an ever increasing inflammatory response. This inflammatory response increases edema and induration which further compromises surrounding tissue and the periosteum by reducing blood flow and causing thrombosis within the vessels, resulting in hypoxic tissue and bone infarctions.22 Unchecked, this infection will propagate on and beneath the periosteum, stripping it from its bond with the cortical bone, allowing the infection to track along its length and around its circumference.23 Since the outer aspect of the cortical bone is vascularized by the periosteum, its loss results in extensive necrosis that can involve the entire bone.22 Once cortical bone is exposed the infection can quickly gain access to the bone marrow via Volkmann’s and Haversian canals.24
Soft tissue infections in the diabetic foot ulcer are often clinically obvious, but the diagnosis of underlying osteomyelitis can be challenging.25 Accurate diagnosis of osteomyelitis is necessary to ensure appropriate treatment. Bone histology and bone cultures are the gold standard in diagnosing osteomyelitis.25 However, this criteria can be difficult to satisfy in many cases, so it is common for clinical diagnosis to be based on a range of clinical and imaging features.22 In Wagner grade 1 and 2 ulcers, osteomyelitis should be suspected with two main conditions: no healing (or no depth decrease) in spite of appropriate care and off-loading, and/or visible or palpated bone with a metal probe.44
There is general agreement that magnetic resonance imaging (MRI) is the most useful imaging study for diagnosing underlying osteomyelitis in diabetic foot ulcers.26-31 Plain film radiography represents an important assessment tool for evaluating infection, foreign bodies, and deformities and represent the gold standard of initial care.30-31,43 In the non-healing diabetic foot ulcer this radiography with become invaluable if the ulcer fails to progress in the initial 30 days of care.
Bone infections can precede radiological changes by up to four weeks, although in most instances changes can be seen at 14 days.22,25,30-31,43 Unfortunately, radiographies have poor sensitivity to detect early stages of osteomyelitis.3,32-33 However, there are a number of articles that reported at 28 days after inoculation more than 90% of all cases will have diagnostic changes that can be seen on routine radiographs.36-40 This fact seems surprising since this author and others were unable to find any evaluation of the role of serial radiographs in the diagnosis of osteomyelitis.34-35 Serial radiographs can be persuasive if they demonstrate progressive changes of bone resorption, cortical destruction, and periosteal elevation.27,34,41,42 Combining serial radiograph results with fine-needle bone biopsies, taken from the ulcer’s margin provide bone and fluid for both histological and microbiologic analyses, thereby achieving the gold standard of care.45 Fine-needle bone biopsies have a reported sensitivity for osteomyelitis of 87% and a specificity of 93% 45and can be performed in the clinical setting or with radiological guidance to ensure placement directly into the suspected lesion.23,45-48
Since osteomyelitis is an inflammatory disorder, there may be a need for the addition of Doxycycline (DOX) and or other chemically modified tetracyclines (CMT) in its treatment. Some antimicrobial agents given to cure infections can also modify the host immune response. DOX and other CMT have potential ‘non-antibiotic’ anti-inflammatory activities.49-53 There is evidence that DOX and CMTs inhibit pro-inflammatory cytokines, including tumor necrosis factor (TNF-α) and interleukin-1β (IL-1β).49-56 These cytokines have long been recognized as bone-resorbing cytokines and are produced in high numbers in bone infected with osteomyelitis.57 Chronic diabetic ulcer fluid has been found to contain up to a 100-fold increase in the levels of these cytokines.58-63 Researchers have suggested that elevated TNF-α and IL-1β levels induced by infection may be related to bone damage in early osteomyelitis.64 One group of researchers studying the efficacy of DOX in the treatment of bone and prosthetic joint infections, treated 11 patients with acute and chronic osteomyelitis. All patients had DOX added to their treatment regiment for a median of 120 days with no serious side effects and successful outcomes in all patients.65 Other researchers have reported evidence that DOX and CMT inhibit osteoclast-mediated bone resorption by inducing apoptosis of osteoclasts.66-71
There is also a reported synergistic effect between DOX/CMTs and non-steroidal ant-inflammatory (NSAIDS) drugs in different animal and human models of disease. In the arthritic joint, oral Doxycycline uptake is increased by as much as 150%. This phenomenon facilitates its uptake into therapeutic target areas. The combination of these two therapies has significantly decreased tissue destruction and inflammation when used in rheumatoid and osteoarthritis.72-77 Although NSAIDs do not directly affect MMP functions, researchers have found that they do potentiate the anti-collagenolytic/proteolytic potential of DOX/CMT by reducing edema, thereby facilitating its entry into sites of inflammation.72
There clearly seems to be evidence available to support a clinical trial of the addition of Doxycycline and or other chemically modified tetracyclines in the treatment of osteomyelitis. It seems that a well developed trial would include an arm with NSAIDs. Evidence already exists to support the use of serial radiographs in the diagnosis of osteomyelitis in non-healing diabetic foot ulcers. The only thing that appears to be missing is a valid clinical trial to support it use.
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