Pathophysiology and Molecular Imaging of Diabetic Foot Infections

Abstract

Diabetic foot infection is the leading cause of non-traumatic lower limb amputations worldwide. In addition, diabetes mellitus and sequela of the disease are increasing in prevalence. In 2017, 9.4% of Americans were diagnosed with diabetes mellitus (DM). The growing pervasiveness and financial implications of diabetic foot infection (DFI) indicate an acute need for improved clinical assessment and treatment. Complex pathophysiology and suboptimal specificity of current non-invasive imaging modalities have made diagnosis and treatment response challenging. Current anatomical and molecular clinical imaging strategies have mainly targeted the host's immune responses rather than the unique metabolism of the invading microorganism. Advances in imaging have the potential to reduce the impact of these problems and improve the assessment of DFI, particularly in distinguishing infection of soft tissue alone from osteomyelitis (OM). This review presents a summary of the known pathophysiology of DFI, the molecular basis of current and emerging diagnostic imaging techniques, and the mechanistic links of these imaging techniques to the pathophysiology of diabetic foot infections.

Keywords: DWI; SPECT; X-ray; diabetic foot infection; molecular imaging; optical tomography; test predictive value.

Figure 1

Variations in foot wound location, presentation, and severity as illustrated by images (a–e). (a) Patient presenting with neuropathic ulcer under the proximal interphalangeal joint of the hallux. The ulcer is related to lack of joint motion at the first metatarsophalangeal joint. (b) Patient presenting with an infected ulcer following the flexor tendons of the foot. Notice a blow lesion at the plantar arch. Dry skin (xerosis) is a sign of autonomic neuropathy. (c) Patient presenting with Charcot foot deformity and overlying midfoot ulcer. Macerated skin around the edges of the ulcer and a sinus tract that extends to the bone is also seen. (d) Patient with an infected ulcer with abscess on the great toe and xerosis suggesting autonomic neuropathy. (e) Patient with a posterior heel ulcer containing a necrotic base and undermining of surrounding skin.

Figure 2

Anatomical Changes Associated with Diabetic Foot Pathophysiology. Diabetic neuropathy is a multi-faceted polyneuropathy related to an increased risk of ulceration, infection, and amputation. Sustained hyperglycemia damages the endothelial lining of the blood vessels in previously healthy tissue (a), leading to impaired circulation (b). Without sufficient vascular support, nerves die off and the skin may become dry and cracked as sweat secretions decrease (c). In the event of injury, numbness in the foot due to neuronal ischemia may mean that insults go undetected for some time (d). Fissures in the dried skin can harbor microorganisms, increasing the likelihood of wound infection. Initial microbial invasion of the trauma site leads to inflammation, vasodilation, and soft tissue necrosis (e). Decreased vascularization compromises immune response to infection and prolongs healing time. If the infection persists, usually because of delayed care or ineffective treatment, microbes may invade bone tissue, leading to osteomyelitis and bone deformation (f). White: neurons, red: arteries, blue: veins, purple: polymorphonuclear lymphocytes, green: microorganisms.

Figure 3

Microbiota of DFI of observed in subjects of an ongoing clinical study in a tertiary care facility in our medical center at the University of Texas Southwestern Medical Center. Microbiota of DFI in soft tissue biopsies (a) and bone biopsies (b) show that most microbes are aerobic (blue) and gram positive (purple), with Staphylococcus aureus being the most identified microorganism. The study was conducted according to the guidelines of the Declaration of Helsinki and approved by the Institutional Review Board (or Ethics Committee) of the University of Texas Southwestern Medical Center (IRB: 112016-043, approved November 2016). Informed consent was obtained from all subjects involved in the study.

Figure 4

Radiograph of a foot in a diabetic patient with a history of trauma to the great toe. Anteroposterior view of the left foot demonstrates soft tissue swelling and focal osteolysis to the distal phalanx of the great toe (arrow) with periostitis.

Figure 5

MR images of the foot in a 56-year-old male with DM and plantar ulcer with plantar ulcer below the 3rd metatarsal and suspected OM. Prior fracture deformity of the second metatarsal head and surgical resection of the third metatarsal are noted. T2-weighted fat suppressed image (a) and T2 Dixon water map (b) show marrow edema of the third metatarsal stump (arrows). In-phase T2 Dixon map (c) shows muscle fatty replacement from DM denervation change (arrow). Opposed-phase T2 Dixon map (d) shows marrow involvement by OM. DWI images (e,f) show marrow replacement by OM on low (a), high (b), and apparent diffusion coefficient (ADC) maps (g,h). Quantification of the marrow abnormality by ADC (h) measures 1.49 compared to normal marrow of 0.21, indicating no intra-osseous abscess, which would appear dark on ADC and bright on DWI. (i) Contrast-enhanced MR shows enhancement of the metatarsal stump.

Figure 6

Three-phase bone scan of an individual with confirmed DFI. Cellulitis is visualized in the right foot with OM in the first metatarsophalangeal region (arrow).

Figure 7

Biodistribution of ¹¹¹In-oxine WBC in a non-infected individual. Anterior (a) and posterior (b) planar images of a healthy patient 24 h after ¹¹¹In-oxine-labeled WBC injection. Uptake is seen in the spleen, liver, and bone marrow.

Figure 8

Dual tracer imaging using ¹¹¹ n-WBC and ^99mTc-sulfur colloid. Planar ¹¹¹In-WBC (a,b) and ^99mTc-sulfur colloid (c,d) images from a 62-year-old male with diabetes with a left foot abscess. There is spatial and intensity discordance in activity from the radionuclides. Anterior (a) and lateral (b) ¹¹¹In-WBC images show focus of increased activity in the left mid foot. Anterior (c) and lateral (d) ^99mTc-sulfur colloid images show diffuse activity throughout the mid and hind foot, suggesting the development of Charcot foot. Axial and sagittal ¹¹¹In-WBC SPECT/CT (e) localized activity to an abscess in the plantar aspect of the left mid foot. Osteomyelitis was excluded.

Figure 9

Planar scintigraphic and SPECT/CT ^99mTc-WBC images in an individual with DFI. The patient’s presentation was suspicious for OM involving the great toe. Planar images (a,b) demonstrate increased radiolabeled WBCs in the right forefoot, perhaps in the region of the toes. SPECT/CT (c–e) allows for precise localization of infection to the proximal phalanx of the right great toe.

Figure 10

¹⁸F-FDG PET/CT illustrating infection of the metatarsophalangeal joint. Increased ¹⁸F-FDG uptake in the first metatarsophalangeal joint is seen in the bone and soft tissues. Signal uptake in this region is much greater than that of the surrounding healthy tissue, indicating pathologically increased glucose metabolism. Image has been reproduced with permission from Iyengar et al., J Clin Orthop Trauma, published by Elsevier, 2021 [117].