What is the differential diagnosis for cellulitis in a patient with a history of recurrent infections or compromised immune system?

Differential Diagnosis for Cellulitis

The differential diagnosis for cellulitis must prioritize distinguishing life-threatening necrotizing soft tissue infections from benign mimics, as time to surgical intervention directly impacts mortality in necrotizing fasciitis. 1

Life-Threatening Conditions Requiring Urgent Surgical Evaluation

Necrotizing Fasciitis

• Pain disproportionate to physical findings is the hallmark early sign that distinguishes necrotizing infection from simple cellulitis 1
• Systemic toxicity with fever, tachycardia, hypotension, or shock suggests necrotizing infection requiring immediate surgical consultation 1
• Late findings include violaceous bullae, cutaneous hemorrhage, skin sloughing, skin anesthesia, and rapid progression 1
• Gas in soft tissues on imaging is specific but present in <50% of cases and only in advanced disease 1
• The LRINEC score (≥8) has 75% risk for necrotizing infection but lacks sensitivity to rule out the diagnosis—clinical judgment supersedes any scoring system 1
• Imaging should never delay surgical consultation when necrotizing infection is suspected 1

Polymicrobial vs Monomicrobial Necrotizing Infections

• Monomicrobial forms caused by S. pyogenes, S. aureus, V. vulnificus, or A. hydrophila typically follow minor trauma or varicella with 50-70% mortality 1
• Polymicrobial forms (average 5 organisms) arise from bowel flora in four settings: post-abdominal surgery/trauma, decubitus/perianal abscess, injection drug use sites, or spread from Bartholin/vulvovaginal abscess 1

Superficial Infections That Mimic Cellulitis

Erysipelas

• Fiery red, tender plaque with sharply demarcated, raised borders distinguishes erysipelas from cellulitis's ill-defined margins 1
• Almost exclusively caused by streptococcal species (S. pyogenes), rarely S. aureus 1
• Facial involvement strongly suggests Group A Streptococcus; lower extremity may be non-GAS streptococci 1

Impetigo

• Discrete purulent lesions in superficial epidermis, highly contagious, predominantly in children 1
• Caused by β-hemolytic Streptococcus and/or S. aureus, with rising CA-MRSA prevalence 1

Non-Infectious Mimics (Critical to Recognize)

Venous Stasis Dermatitis

• Bilateral lower extremity involvement with chronic edema, hemosiderin deposition, and absence of fever 2
• Often misdiagnosed as cellulitis leading to unnecessary antibiotic courses 2

Deep Vein Thrombosis

• Unilateral leg swelling with warmth and erythema mimics cellulitis 2
• Absence of fever and presence of Homan's sign may help differentiate, but ultrasound is definitive 2

Contact Dermatitis

• History of exposure to irritant/allergen with pruritus more prominent than pain 2
• Well-demarcated distribution corresponding to contact pattern 2

Panniculitis

• Inflammation of subcutaneous fat presenting as tender nodules or plaques 2
• Skin biopsy may be required for definitive diagnosis 2

Complex Abscesses Requiring Drainage

Simple vs Complex Abscesses

• Simple abscess: incision and drainage alone without antibiotics if erythema/induration limited to defined abscess area 1
• Complex abscesses (perianal, perirectal, IV drug injection sites) require drainage PLUS broad-spectrum antibiotics covering Gram-positive, Gram-negative, and anaerobes 1
• Add antibiotics for simple abscess only if: systemic signs present, immunocompromised, incomplete source control, or significant surrounding cellulitis 1

Key Clinical Features for Hospitalization

Admit patients with any of the following: 1, 3

• Systemic toxicity: fever/hypothermia, tachycardia (>100 bpm), hypotension (SBP <90 mmHg)
• Laboratory markers: elevated creatinine, low bicarbonate, elevated CPK (2-3× normal), marked left shift, CRP >13 mg/L
• Failure of outpatient therapy after 24-48 hours
• Concern for necrotizing infection or deeper involvement
• Severe immunocompromise

Diagnostic Approach in Immunocompromised/Recurrent Infections

When to Pursue Aggressive Diagnosis

• Blood cultures positive in only 5-27% of cases—reserve for patients with systemic toxicity, malignancy, neutropenia, or unusual predisposing factors 3, 4
• Needle aspiration or punch biopsy for Gram stain/culture if diagnosis uncertain or treatment failing 1
• Pathogen isolation rate <20% in nonpurulent cellulitis—clinical diagnosis usually sufficient 5

Recurrent Cellulitis Considerations

• Identify and treat predisposing conditions: tinea pedis, venous insufficiency, lymphedema, obesity, chronic wounds 3, 6
• Consider prophylactic antibiotics (oral penicillin/erythromycin twice daily or IM benzathine penicillin every 2-4 weeks) for ≥3-4 episodes/year despite treating predisposing factors 3
• Recurrence uncommon unless predisposing factors persist 5, 6

Common Pitfalls to Avoid

• Do not delay surgical consultation for imaging when necrotizing infection suspected—clinical judgment is paramount 1
• Do not assume bilateral lower extremity erythema is bilateral cellulitis—consider venous stasis dermatitis 2
• Do not obtain blood cultures for typical cellulitis without systemic features—yield is <5% 3
• Do not treat simple abscesses with antibiotics alone—drainage is primary treatment 1
• Failure to improve with appropriate first-line antibiotics after 48-72 hours mandates reassessment for resistant organisms, cellulitis mimics, or underlying complications 3, 7