What are the differential diagnoses for toe gangrene and how should it be evaluated and managed?

Differential Diagnosis of Toe Gangrene

Toe gangrene results primarily from ischemia, infection, or a combination of both, and must be immediately classified as wet (infected) versus dry (non-infected) gangrene, as this distinction determines urgency of surgical intervention. 1

Primary Etiologies

Ischemic Causes

• Peripheral arterial disease (PAD) is the most common etiology, resulting from chronic arterial occlusion that fails to meet basal metabolic tissue requirements 2, 3
• Embolic phenomena including cholesterol emboli ("blue toe syndrome") can cause digital gangrene even with palpable pedal pulses 2, 4
• Critical limb ischemia (CLI) defined as chronic (>2 weeks) ischemic rest pain or tissue loss with objectively proven arterial occlusive disease 3
• Thrombotic microangiopathy from hematologic disorders (essential thrombocythemia, polycythemia vera, thrombocytosis) causing vasospasm and digital ischemia 5, 4

Infectious Causes

• Clostridial gas gangrene (myonecrosis) from C. perfringens, C. septicum, presenting with severe pain, bronze-to-purplish skin, bullae, and crepitus 3
• Polymicrobial necrotizing soft tissue infection involving aerobic and anaerobic flora, particularly in diabetic patients 3
• Fournier gangrene when involving digits as extension from perineal/genital infection 3

Diabetic Foot Complications

• Neuro-ischemic ulceration progressing to gangrene in patients with both neuropathy and PAD 6, 3
• Wagner grade 4 (forefoot gangrene) or grade 5 (whole foot gangrene) classification 3

Other Causes

• Mechanical trauma in setting of compromised perfusion 2
• Vasculitic disorders including Churg-Strauss syndrome and other granulomatous diseases 2
• Cold exposure in susceptible individuals 4
• Pharmacological sensitivity or drug-induced vasospasm 2
• Monoclonal gammopathy with hyperviscosity 4

Critical Clinical Distinction: Wet vs. Dry Gangrene

Wet Gangrene (Infected)

• Presence of infection plus ≥2 inflammatory signs: edema, erythema >0.5 cm, purulent discharge, local warmth, pain/tenderness 1, 6
• Moist, swollen tissue with foul odor and discharge; poorly demarcated borders 1
• May progress rapidly through fascial planes with systemic signs (fever, leukocytosis, sepsis) 1, 3
• Requires immediate hospitalization within 24 hours and urgent surgical debridement without waiting for revascularization 1

Dry Gangrene (Non-infected)

• Mummified, desiccated, black tissue that is hard and well-demarcated without active infection 1
• Typically painless in diabetic patients due to neuropathy; remains stable without systemic inflammatory response 1
• Absent foot pulses indicate ischemic etiology 1
• Conservative management with autoamputation may be considered in poor surgical candidates, though this approach is controversial and associated with worse outcomes 7, 8

Diagnostic Evaluation Algorithm

Vascular Assessment (Perform First)

• Palpate dorsalis pedis and posterior tibial pulses bilaterally 6, 9
• Measure ankle-brachial index (ABI) using Doppler; ABI <0.9 indicates PAD 6, 9
• If ABI 0.9-1.3 with triphasic waveform, PAD is excluded 6
• If ABI >1.3 or unreliable (arterial calcification in diabetes), measure toe-brachial index (TBI); TBI <0.75 or toe pressure <30 mmHg indicates PAD and inability to heal—refer immediately for vascular evaluation 6
• Transcutaneous oxygen pressure (TcPO₂) or skin perfusion pressure if needed 3, 9

Infection Assessment

• Diagnose infection clinically by presence of ≥2 signs: erythema, warmth, induration, pain/tenderness, OR purulent discharge 6, 1
• Grade infection severity using IDSA/IWGDF system (Grade 1-4) 6
• Probe-to-bone test for osteomyelitis in deep/longstanding wounds 6
• Plain radiographs to screen for osteomyelitis and gas in tissue 6
• Absence of fever or leukocytosis does NOT exclude severe infection in diabetic patients 1

Neurological Assessment

• Test for loss of protective sensation (LOPS) using 10-g monofilament at multiple plantar sites 6
• Confirm with additional test: pinprick, temperature, ankle reflexes, or 128-Hz tuning fork 6

Hematologic Workup (If Normal Pulses Present)

• Complete blood count to evaluate for thrombocytosis, polycythemia, or leukemia 5, 4
• Serum protein electrophoresis if monoclonal gammopathy suspected 4
• Consider JAK2 mutation testing if essential thrombocythemia suspected 5

Additional Risk Stratification

• WIfI classification (Wound, Ischemia, foot Infection) provides 1-year amputation risk and revascularization benefit 3, 9
• Document diabetes control (HbA1c), smoking, prior ulceration/amputation, retinopathy, nephropathy 6

Management Approach

Wet Gangrene (Infected)

• Immediate hospitalization within 24 hours 1
• Urgent surgical debridement of infected necrotic tissue without waiting for revascularization 1
• Broad-spectrum antibiotics combined with aggressive surgical intervention 1, 3
• Do not wait for tissue demarcation—infection extends rapidly through compartments 1

Dry Gangrene (Non-infected)

• Early surgical intervention is preferred to improve quality of life, as waiting for autoamputation leads to worse outcomes 8
• Conservative approach with autoamputation may be considered only in poor surgical candidates without infection 1, 7
• Adherent eschar (especially heel) should be left in place until it softens, provided no underlying infection 1
• Vascular consultation for revascularization if significant ischemia present 9

Clostridial Gas Gangrene

• Meticulous intensive care, aggressive surgical debridement, high-dose penicillin or ampicillin 3
• Role of hyperbaric oxygen remains unclear 3

Hematologic Disorders

• Treat underlying condition (e.g., hydroxyurea for essential thrombocythemia) 5
• Anti-platelet aggregation agents may provide relief 4

Critical Pitfalls to Avoid

• Absence of pain does NOT rule out severe ischemia or infection in neuropathic diabetic patients 1, 6
• Do not assume dry gangrene is stable—assess repeatedly for superimposed infection, which changes management urgency 1
• Do not delay vascular assessment—ischemic limbs require early vascular consultation regardless of gangrene type 1
• Clinical signs of inflammation are sufficient to trigger immediate action—do not wait for laboratory confirmation 1
• Toe pressure <30 mmHg predicts inability to heal—immediate vascular referral is mandatory 6
• Gangrene with normal pedal pulses requires hematologic workup—embolic or thrombotic microangiopathy must be excluded 4, 5

Urgent Referral Indicators (Within 24 Hours)

• Wet gangrene with clinical signs of infection 1
• Abscess or phlegmon formation 1
• Systemic signs (fever, sepsis) 1
• Rapidly progressive necrosis 1
• Critical limb ischemia with tissue loss 1
• Dorsal erythema or fluctuance over plantar wound (suggests deep compartment involvement) 1