What is the differential diagnosis for a 28-year-old female (F) patient with skin lesions, who developed bilateral foot swelling after wading in flood waters, and has a history of allergic reactions to certain medications, previous surgeries, and symptoms of dyspnea on exertion, orthopnea, and bilateral knee pain?

Differential Diagnosis

This 28-year-old woman presents with a complex picture of bilateral lower extremity skin lesions following flood water exposure, systemic symptoms suggesting hypothyroidism, and features concerning for an underlying connective tissue disease, requiring consideration of infection, autoimmune disease, drug reaction, and endocrine-mediated skin pathology.

Primary Diagnostic Considerations

Severe Diabetic Foot Infection (Despite No Known Diabetes)

• Clinicians should diagnose infection based on the presence of at least 2 classic symptoms or signs of inflammation (erythema, warmth, tenderness, pain, or induration) or purulent secretions 1
• This patient demonstrates multiple criteria: tender lesions, purulent whitish discharge, progressive erosions and ulcers, and marked pain 1
• The presence of dystrophic nails, thickened shiny skin with fissuring, and crusted erosions over the dorsum and toes are consistent with moderate to severe diabetic foot infection 1
• Secondary findings that raise suspicion include non-purulent secretions (if present), friable granulation tissue, and the chronicity of non-healing wounds 1
• Evaluate for undiagnosed diabetes immediately with HbA1c and fasting glucose, as this presentation is highly suspicious for diabetic foot complications 1
• The bilateral knee pain and systemic symptoms (dyspnea on exertion, orthopnea) may indicate systemic inflammatory response to severe infection 1

Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis (SJS/TEN)

• The development of multiple red, slightly elevated lesions after four days of antibiotic treatment, with progression to pustules and erosions, raises concern for drug-induced SJS/TEN 1
• SJS is characterized by epidermal detachment <10% body surface area plus widespread purpuric macules or flat atypical targets 1
• Cutaneous pain is a prominent early feature in SJS/TEN, and the presence of this symptom should alert the physician to incipient epidermal necrolysis 1
• The patient's history of allergic reactions to certain medications increases risk for drug hypersensitivity reactions 1
• However, the absence of mucosal involvement (oral lesions negative) and the localized distribution primarily to extremities makes classic SJS/TEN less likely 1
• The pustular nature with purulent discharge is atypical for SJS/TEN, which typically presents with flaccid bullae and denuded dermis 1

Chronic Venous Insufficiency with Secondary Infection

• Chronic venous insufficiency with lipodermatosclerosis presents with swelling, skin changes including hemosiderin staining, and induration of the lower legs 2
• The diffuse hyperpigmentation, xerosis, marked scaling, and lichenification are consistent with chronic venous stasis changes 2
• Bilateral symmetric swelling suggests systemic causes such as heart failure, which correlates with her dyspnea on exertion and 2-pillow orthopnea 2
• The thickened, shiny skin with fissuring provides entry points for secondary bacterial infection, explaining the pustules and purulent discharge 2
• Pitting edema suggests venous insufficiency or heart failure, while non-pitting edema with firm, bumpy texture indicates advanced lymphedema with fibrotic changes 2

Hypothyroidism with Secondary Skin Manifestations

• The physical examination findings of coarse hair, round puffy face, and eyebrow thinning are classic for hypothyroidism 3
• Hypothyroidism causes myxedema with non-pitting edema, xerosis, and impaired wound healing 3
• The dyspnea on exertion and orthopnea may reflect hypothyroid-induced heart failure or pericardial effusion 3
• Hypothyroidism significantly impairs immune function and wound healing, predisposing to severe infections 3
• Check TSH, free T4, and thyroid antibodies (anti-TPO, anti-thyroglobulin) to evaluate for autoimmune thyroiditis 3

Systemic Lupus Erythematosus or Mixed Connective Tissue Disease

• The provisional diagnosis of "unspecified connective tissue disease" with multiple system involvement (skin, joints, possible cardiac/pulmonary) suggests autoimmune etiology 4, 5
• Autoimmune disorders present with symptoms involving multiple organ systems including fever, fatigue, joint pain, rash, ulcers, and muscle weakness 4
• The bilateral knee pain, skin lesions, and systemic symptoms (dyspnea, orthopnea) fit this pattern 4
• Autoimmune manifestations often affect patients with immunodeficiency states, and early recognition is pivotal 5
• The history of two spontaneous abortions may suggest antiphospholipid syndrome as part of a connective tissue disease 5

Critical Diagnostic Workup

Immediate Evaluation

• Obtain plain radiographs of both feet in two planes as the first investigation for any suspected musculoskeletal pathology with swelling 1, 6
• Assess for osteomyelitis, soft tissue gas, foreign bodies, and Charcot arthropathy 1
• Obtain wound cultures from tissue samples (not swabs) via image-guided aspiration if deep infection suspected 1, 2
• Check inflammatory markers: CBC with differential, ESR, CRP (elevated CRP predicts worse outcomes and need for amputation) 1
• Screen for diabetes: HbA1c, fasting glucose 1, 7
• Evaluate thyroid function: TSH, free T4, anti-TPO antibodies 3

Vascular Assessment

• Assess the affected limb for arterial ischemia, as peripheral arterial disease is present in 20-30% of persons with diabetes and up to 40% of those with diabetic foot infection 1
• Determine ankle-brachial index (ABI) using sphygmomanometers and hand-held Doppler; ABI ≤0.90 confirms peripheral arterial disease 1, 7
• If ABI >1.40 (falsely elevated due to calcified vessels), obtain toe-brachial index with TBI <0.70 indicating PAD 7
• Examine for cool skin, bruits, elevation pallor, and dependent rubor to assess for PAD 7
• Duplex Doppler ultrasound is recommended as initial evaluation to assess venous and arterial systems 2

Advanced Imaging

• MRI is most accurate for defining bone infection and provides reliable imaging of deep soft-tissue infections 1, 2
• MRI of the entire foot compartment is indicated when infection cannot be excluded on radiographs 1, 6
• Nuclear medicine studies including radiolabeled WBC scintigraphy and [18F]FDG PET/CT help differentiate osteomyelitis from Charcot foot 1
• Accurate differential diagnosis between osteomyelitis, soft tissue infection, and Charcot foot is crucial because these conditions require different treatments 1, 7

Cardiac and Systemic Evaluation

• Check BNP/NT-proBNP to confirm or exclude heart failure given dyspnea on exertion and orthopnea 2
• Assess renal function, liver function, and albumin levels for systemic causes of edema 2
• Consider echocardiography if heart failure suspected 2

Autoimmune Workup

• ANA, anti-dsDNA, complement levels (C3, C4), rheumatoid factor 4, 5
• Antiphospholipid antibodies (lupus anticoagulant, anticardiolipin, anti-β2-glycoprotein I) given obstetric history 5
• Consider skin biopsy of lesional and perilesional skin for direct immunofluorescence 4

Management Algorithm

Step 1: Rule Out Life-Threatening Infection

• Start broad-spectrum antibiotics immediately after cultures if severe infection suspected (systemic signs, extensive tissue involvement, or rapidly progressive) 1, 6
• Consult infectious disease specialist and surgeon with diabetic foot experience 1
• Provide well-coordinated approach by multidisciplinary diabetic foot care team including infectious disease, surgery, and endocrinology 1

Step 2: Address Underlying Endocrine Dysfunction

• If hypothyroidism confirmed, initiate levothyroxine replacement (improves wound healing and immune function) 3
• If diabetes confirmed, achieve glycemic control (target HbA1c <7% for wound healing) 1

Step 3: Optimize Wound Healing

• Offload pressure from affected areas (total contact casting or specialized footwear if diabetic foot) 1
• Assess and optimize vascular supply; consider vascular surgery consultation if ABI <0.5 or TBI <0.3 1, 7
• Debride necrotic tissue and manage wound care with appropriate dressings 1

Step 4: Treat Underlying Autoimmune Disease

• If connective tissue disease confirmed, consult rheumatology for immunosuppressive therapy 4, 5
• Consider that autoimmune manifestations occur in up to 30% of immunodeficiency patients and require tailored treatment 5

Critical Pitfalls to Avoid

• Do not assume normal inflammatory markers exclude severe infection—elevations are absent in up to one-half of patients, even with severe diabetic foot infection 1
• Do not delay evaluation for undiagnosed diabetes—this presentation is highly suspicious for diabetic foot complications even without known diabetes history 1, 7
• Do not overlook hypothyroidism as a contributing factor—the classic physical findings (coarse hair, puffy face, eyebrow thinning) significantly impair wound healing and immune function 3
• Do not rely solely on clinical examination to exclude peripheral arterial disease—up to 30-60% of PAD patients are asymptomatic or have atypical symptoms 7
• Do not dismiss the bilateral nature as excluding vascular causes—bilateral venous insufficiency with heart failure can present this way 2
• Do not forget that flood water exposure creates high risk for atypical organisms including Vibrio species, Aeromonas, and fungal infections requiring specific antimicrobial coverage 1
• Do not overlook drug reaction—the temporal relationship between antibiotic initiation and lesion development requires consideration of drug hypersensitivity, though the pustular purulent nature makes this less likely than infection 1