What are the differential diagnoses for a patient with a history of reactive airway disease (RAD) presenting with lower respiratory tract infection (LRTI) and erythema nodosum?

Differential Diagnoses for a 50-Year-Old Female with History of Reactive Airway Disease Presenting with LRTI and Erythema Nodosum

Primary Diagnostic Consideration

The combination of LRTI and erythema nodosum in this patient most strongly suggests an underlying infectious etiology, with tuberculosis, sarcoidosis, and streptococcal infection being the leading differential diagnoses that must be systematically evaluated. 1, 2

Key Differential Diagnoses

Infectious Etiologies (Most Common)

Tuberculosis (Primary or Reactivation)

• Erythema nodosum occurs in 7% of tuberculosis cases presenting with this cutaneous manifestation 2
• TB is a critical diagnosis that must be ruled out before initiating any immunosuppressive therapy 3
• The patient's history of "reactive airway disease" may have been misdiagnosed chronic TB or recurrent respiratory infections 1
• Risk stratification for tuberculosis is mandatory in all patients with erythema nodosum and LRTI 4

Streptococcal Pharyngitis/Post-Streptococcal Syndrome

• This is the single most common identifiable cause of erythema nodosum, accounting for 32% of secondary cases 1, 2
• Recent upper respiratory tract infections and sore throat are statistically significant predictors of streptococcal-associated erythema nodosum 5
• ASO titer changes on serial testing (2-4 weeks apart) help confirm recent streptococcal infection 5, 2

Mycoplasma pneumoniae

• Accounts for 3% of erythema nodosum cases and commonly causes LRTI 2
• Should be considered given the patient's respiratory symptoms and previous "reactive airway disease" label 4

Deep Fungal Infections (Coccidioidomycosis, Histoplasmosis)

• In endemic areas, coccidioidomycosis is a common cause of erythema nodosum with LRTI 3
• Geographic history is essential to assess this risk 1

Bartonella henselae

• Accounts for 3% of cases and can present with respiratory involvement 2
• Inquire about cat exposure or scratches 1

Non-Infectious Systemic Diseases

Sarcoidosis

• Represents 11-18% of erythema nodosum cases 2
• Frequently presents with bilateral hilar lymphadenopathy and respiratory symptoms that may mimic asthma or LRTI 1, 2
• The patient's prior "reactive airway disease" diagnosis warrants reconsideration in this context 4

Inflammatory Bowel Disease (Crohn's Disease, Ulcerative Colitis)

• Accounts for 2-4% of erythema nodosum cases 1, 2
• Inquire specifically about diarrhea, abdominal pain, or gastrointestinal symptoms 5

Behçet's Syndrome

• Represents 2% of cases 2
• Look for oral/genital ulcers, uveitis, and pathergy 1

Drug-Induced Erythema Nodosum

Medication Review

• Oral contraceptives are a recognized cause 1
• Certain antibiotics can trigger erythema nodosum 1, 5
• Review all medications started within 2-6 weeks before symptom onset 1

Idiopathic

• Represents 32-51% of cases when no underlying cause is identified after thorough evaluation 5, 2
• This is a diagnosis of exclusion only after systematic workup 1

Essential Diagnostic Workup

Mandatory Initial Testing

Laboratory Evaluation

• Complete blood count with differential (leukocytosis suggests infection) 5, 2
• Erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) - elevated levels more common in secondary versus idiopathic erythema nodosum 5, 2
• Throat culture or rapid streptococcal antigen test 1, 5
• Anti-streptolysin O (ASO) titers on two occasions 2-4 weeks apart 5, 2

Tuberculosis Screening

• Purified protein derivative (PPD) tuberculin skin test or interferon-gamma release assay (IGRA) 1, 5, 2
• This must be performed before considering any corticosteroid therapy 3

Imaging

• Chest radiograph or CT scan to evaluate for pneumonia, tuberculosis, sarcoidosis (bilateral hilar lymphadenopathy), or fungal infection 5, 2

Tissue Diagnosis

• Deep incisional or excisional biopsy of erythema nodosum lesion if diagnosis uncertain 1
• Biopsy shows septal panniculitis without vasculitis and presence of radial granulomas 1

Additional Testing Based on Clinical Suspicion

If Sarcoidosis Suspected

• Serum angiotensin-converting enzyme (ACE) level 1
• Serum calcium level 1

If Mycoplasma Suspected

• Mycoplasma pneumoniae IgM and IgG antibodies 2
• PCR testing if available 4

If Endemic Fungal Infection Suspected

• Coccidioides, Histoplasma serologies based on geographic exposure 3

If Inflammatory Bowel Disease Suspected

• Stool cultures and fecal calprotectin 5
• Consider colonoscopy if gastrointestinal symptoms present 1

If Bartonella Suspected

• Bartonella henselae serology 2

Critical Clinical Pitfalls to Avoid

Do Not Assume "Reactive Airway Disease" is the Correct Diagnosis

• Many systemic diseases (tuberculosis, sarcoidosis, fungal infections) can present with chronic respiratory symptoms misattributed to asthma or bronchitis 4, 1
• The combination of LRTI and erythema nodosum demands reconsideration of the underlying respiratory diagnosis 2

Never Initiate Corticosteroids Before Ruling Out Tuberculosis

• Steroid treatment is rarely justified and should only be used after tuberculosis and other treatable infections have been excluded 3
• Immunosuppression can lead to disseminated tuberculosis if present 1

Do Not Overlook Seasonal and Geographic Patterns

• Erythema nodosum cases predominate in winter and spring, correlating with streptococcal pharyngitis peaks 2
• Endemic fungal infections require specific geographic exposure history 3

Recognize That Erythema Nodosum Frequently Recurs

• Over 50% of patients experience subsequent attacks 3
• Recurrent episodes may continue for months to years 3
• Long-term follow-up is essential even after initial episode resolves 5

Distinguish Between Erythema Nodosum Symptoms and Underlying Disease

• Erythema nodosum itself causes malaise, fever, and arthritis in 70% of cases 3
• These systemic symptoms must be differentiated from the precipitating infectious or inflammatory process 3

Management Approach

Treat the Underlying Cause

• Management is expectant, with treatment directed at the identified underlying condition 3
• Streptococcal infections require appropriate antibiotic therapy 1, 2
• Tuberculosis requires standard multi-drug anti-tuberculous therapy 2, 6
• Sarcoidosis may require systemic corticosteroids only after infection excluded 1

Supportive Care for Erythema Nodosum

• Nonsteroidal anti-inflammatory drugs (NSAIDs) for pain management 1
• Erythema nodosum is self-limited, typically resolving within 3-6 weeks without ulceration or scarring 1, 5
• Bed rest and leg elevation may provide symptomatic relief 1

Close Follow-Up

• Regular monitoring is required given the high recurrence rate 5, 3
• Serial clinical and laboratory assessments to ensure resolution of underlying condition 5