What are the key differences between Löfgren syndrome and Heerfordt syndrome (uveoparotid fever) regarding organ involvement, clinical presentation, prognosis, and recommended treatment?

Löfgren Syndrome vs. Heerfordt Syndrome: Key Clinical Distinctions

Löfgren syndrome and Heerfordt syndrome are distinct acute presentations of sarcoidosis with fundamentally different organ involvement patterns, prognoses, and treatment approaches—Löfgren syndrome involves bilateral hilar lymphadenopathy with erythema nodosum and/or periarticular arthritis and carries an excellent prognosis, while Heerfordt syndrome (uveoparotid fever) involves uveitis, parotid gland swelling, facial nerve palsy, and fever, requiring more aggressive corticosteroid therapy.

Clinical Presentation

Löfgren Syndrome

• Classic triad: bilateral hilar lymphadenopathy, erythema nodosum, and/or periarticular arthritis (most commonly ankle involvement) 1
• Systemic features: typically presents without fever or B symptoms 2
• Age and demographics: affects young to middle-aged adults 3
• Skin manifestations: erythema nodosum is the hallmark cutaneous finding 1
• Joint involvement: acute periarticular arthritis, predominantly affecting ankles, which may mimic cellulitis 3

Heerfordt Syndrome (Uveoparotid Fever)

• Classic tetrad: fever, anterior uveitis, bilateral parotid gland swelling, and facial nerve palsy 4, 5
• Fever pattern: typically low-grade fever, though high fever with elevated TNF-α has been reported 6
• Age and demographics: most patients between 20-40 years of age, with female predominance 4, 7
• Neurologic involvement: seventh cranial nerve paralysis is a defining feature 1, 5
• Parotid involvement: symmetrical parotid enlargement is characteristic 1, 5

Organ Involvement Patterns

Löfgren Syndrome

• Thoracic: bilateral hilar lymphadenopathy is mandatory for diagnosis 1
• Skin: erythema nodosum (non-granulomatous inflammatory reaction) 1
• Musculoskeletal: periarticular arthritis without bone involvement 3
• Cardiac: rarely involved, but when present may indicate deviation from typical benign course 8
• Ocular: uveitis is NOT part of classic Löfgren syndrome and suggests more aggressive systemic disease 8

Heerfordt Syndrome

• Ocular: anterior uveitis is a core feature 4, 5, 6
• Salivary glands: bilateral parotid swelling with increased gallium-67 uptake 4, 7
• Neurologic: facial nerve palsy (seventh cranial nerve) 4, 5, 6
• Thoracic: hilar lymphadenopathy may be present but is not required for diagnosis 5
• Lacrimal glands: may show swelling 1

Diagnostic Approach

Löfgren Syndrome

• Biopsy requirement: when the classic triad is present, diagnosis is "highly likely" and biopsy is usually not required 8
• Imaging: chest X-ray, CT, or PET showing bilateral hilar lymphadenopathy 1
• Laboratory: elevated ACE levels may be present but are not required 1
• BAL findings: lymphocytosis with elevated CD4:CD8 ratio (e.g., 5.0) supports diagnosis 3

Heerfordt Syndrome

• Histologic confirmation: definitive diagnosis requires biopsy showing noncaseating granulomas consistent with sarcoidosis 4, 7
• Gallium-67 scan: shows increased uptake in ophthalmic lesions, parotid glands, and hilar regions 4, 7
• Clinical diagnosis: may be made based on characteristic tetrad when histology is unavailable 5
• Exclusion of alternatives: infectious, autoimmune, and malignant causes must be ruled out 1

Prognosis

Löfgren Syndrome

• Excellent prognosis: self-limited course with spontaneous resolution in most cases 8, 3
• Atypical features: development of uveitis or cardiac involvement suggests deviation from typical benign course and may indicate more aggressive systemic sarcoidosis 8
• Resolution: symptoms typically improve rapidly with conservative management 3

Heerfordt Syndrome

• Variable course: requires active treatment, particularly for facial palsy and uveitis 4, 7, 5
• Response to therapy: symptoms improve with corticosteroid therapy, often rapidly 5, 6
• Complications: facial nerve palsy and uveitis require prompt treatment to prevent permanent sequelae 5

Treatment Recommendations

Löfgren Syndrome

• First-line: NSAIDs for symptomatic relief of arthritis and erythema nodosum 3
• Observation: many cases resolve spontaneously without immunosuppression 8, 3
• Corticosteroids: reserved for severe or persistent symptoms 3
• Monitoring: if atypical features develop (uveitis, cardiac symptoms with abnormal EKG), comprehensive cardiac evaluation with MRI or PET is indicated 8

Heerfordt Syndrome

• Corticosteroids: prednisolone therapy is required, especially for facial palsy and uveitis 4, 7, 5
• Prompt initiation: early corticosteroid therapy leads to rapid symptom resolution 5, 6
• Multidisciplinary approach: coordination with ophthalmology for uveitis management and neurology for facial nerve palsy 5
• TNF-α monitoring: in cases with high fever, TNF-α levels may correlate with disease activity and treatment response 6

Critical Diagnostic Pitfalls

• Misdiagnosis of Löfgren syndrome: bilateral lower extremity erythema and swelling may be mistaken for cellulitis, leading to unnecessary antibiotic therapy 3
• Incomplete Heerfordt syndrome: not all four features need be present; incomplete forms exist (e.g., without uveitis) 5
• Uveitis in Löfgren syndrome: presence of uveitis should prompt reconsideration of diagnosis or recognition of atypical, more aggressive disease 8
• Fever patterns: while Heerfordt syndrome classically presents with low-grade fever, high fever does not exclude the diagnosis 6