What is the differential diagnosis and management for a middle-aged patient with asthma, lung consolidations, marked eosinophilia (high peripheral eosinophil count), and positive Rheumatoid Arthritis (RA) factor, who has refused bronchoscopy and has a negative Anti-Neutrophil Cytoplasmic Antibodies (ANCA) test?

Differential Diagnosis and Management

Primary Diagnosis: Eosinophilic Granulomatosis with Polyangiitis (EGPA)

Your patient's presentation of asthma, lung consolidations, marked eosinophilia (8000 cells/μL), and negative ANCA is highly consistent with EGPA, and you should proceed with this diagnosis and initiate treatment with systemic glucocorticoids immediately while completing the diagnostic workup. 1

Why EGPA is the Leading Diagnosis

The clinical constellation is classic for EGPA:

• Asthma is present in >90% of EGPA cases 2, 3
• Marked peripheral eosinophilia (your patient has 8000 cells/μL, well above the typical >1500 cells/μL threshold) 1
• Lung consolidations (bilateral pulmonary infiltrates occur in 86% of EGPA) 2, 3
• Negative ANCA does NOT rule out EGPA - only 30-40% of EGPA patients are ANCA-positive 1

The positive rheumatoid factor is a red herring; RF can be positive in various inflammatory conditions and does not exclude EGPA 4.

ANCA-Negative Phenotype Implications

Your patient's ANCA-negative status actually places them at HIGHER risk for cardiac involvement and carries worse overall survival, making urgent evaluation and treatment critical. 1, 3

ANCA-negative patients more frequently develop:

• Cardiac involvement (cardiomyopathy, myocarditis) - a leading cause of death in EGPA 3, 5
• Gastrointestinal involvement 3, 5
• Respiratory manifestations 1

In contrast, ANCA-positive patients have more vasculitic features (glomerulonephritis, peripheral neuropathy, purpura) 1, 3.

Complete Differential Diagnosis

While EGPA is most likely, you must systematically exclude:

1. Allergic Bronchopulmonary Aspergillosis (ABPA)

• Check: Specific IgE and IgG for Aspergillus species 1
• Search for Aspergillus in sputum (since bronchoscopy refused) 1
• ABPA typically has very high total IgE (>1000 IU/mL) and lacks systemic vasculitis 2

2. Idiopathic Hypereosinophilic Syndrome (HES)

• Distinguished by absence of asthma and vasculitis 1
• Check tryptase and vitamin B12 levels 1

3. Parasitic Infections

• Serologic testing for toxocariasis is mandatory 1
• Consider strongyloides and other helminths based on exposure history 1

4. Other Eosinophilic Pneumonias

• Chronic eosinophilic pneumonia, acute eosinophilic pneumonia 1, 2
• Usually lack systemic vasculitis features 1

5. Other Vasculitides

• Granulomatosis with polyangiitis (GPA) - typically c-ANCA/PR3-ANCA positive, lacks eosinophilia 1
• Microscopic polyangiitis - lacks asthma and eosinophilia 1

Immediate Diagnostic Workup

Laboratory Tests (Priority Order)

Complete immediately:

• Specific IgE and IgG for Aspergillus fumigatus 1
• Serologic testing for toxocariasis 1
• HIV testing 1
• Tryptase and vitamin B12 levels 1
• Total IgE level 1
• Sputum examination for Aspergillus species 1

Await pending autoimmune panel results but do not delay treatment 1

Imaging Studies

High-resolution CT chest (if not already done):

• Look for "fluffy" or nodular migratory infiltrates, ground glass opacities (86%), peripheral nodules (25%), bronchial wall thickening and bronchiectasis (66%) 1

CT sinuses:

• Evaluate for chronic rhinosinusitis/nasal polyposis (present in 43-95% of EGPA) 2, 3

Critical Organ Assessment for Poor Prognosis

Because ANCA-negative status increases cardiac risk, immediately evaluate for life-threatening organ involvement: 1, 3

1. Cardiac evaluation (URGENT):

   • ECG, troponin, BNP 1
   • Echocardiogram to assess for cardiomyopathy, pericardial effusion 1, 3
   • Consider cardiac MRI if abnormalities detected 1

2. Renal function:

   • Urinalysis with microscopy, serum creatinine 1
   • Less likely with ANCA-negative status but must exclude 1, 3

3. Neurologic assessment:

   • Examine for mononeuritis multiplex, peripheral neuropathy 1, 2
   • Consider nerve conduction studies if symptoms present 1

4. Gastrointestinal:

   • Assess for abdominal pain, GI bleeding 1, 3

Management Strategy

Immediate Treatment (Do Not Wait for Complete Workup)

Initiate high-dose systemic glucocorticoids immediately - prednisone 1 mg/kg/day (typically 40-60 mg daily) 2, 6, 4, 7. All EGPA patients require corticosteroids 7.

Risk Stratification Using Five-Factor Score (FFS)

Assess for poor prognostic factors that require additional immunosuppression 1, 5, 7:

• Cardiac involvement (most critical in ANCA-negative patients) 3, 5
• Gastrointestinal involvement 5, 7
• Renal insufficiency (creatinine >1.58 mg/dL) 5, 7
• Central nervous system involvement 5, 7
• Age >65 years 5, 7

Treatment Algorithm Based on Severity

If ANY poor prognostic factors present (especially cardiac involvement):

• Add cyclophosphamide for induction therapy 6, 7
• Consider rituximab for severe/refractory disease 6
• Consider mepolizumab (anti-IL-5 biologic) for severe or refractory disease 2, 6

If no poor prognostic factors:

• Glucocorticoids alone may suffice initially 7
• Add methotrexate or azathioprine as steroid-sparing maintenance therapy 2, 4, 7

Steroid Tapering and Remission Goals

• Target remission: absence of clinical signs/symptoms with prednisone ≤7.5 mg/day 1
• Taper slowly over months to minimize relapse risk 1, 7
• Relapses are common (especially in ANCA-positive patients, though your patient is ANCA-negative) 1, 5, 7

Critical Pitfalls to Avoid

1. Do not delay treatment waiting for bronchoscopy or biopsy results - clinical diagnosis with supportive labs is sufficient to start therapy 1, 2

2. Do not be falsely reassured by negative ANCA - 60-70% of EGPA patients are ANCA-negative, and these patients have WORSE prognosis due to cardiac involvement 1

3. Do not miss cardiac involvement - this is the leading cause of death in EGPA, especially in ANCA-negative patients like yours 3, 5

4. Do not attribute positive RF to rheumatoid arthritis - RF can be positive in many inflammatory conditions; focus on the EGPA diagnosis 4

5. Do not undertreate based on lack of biopsy - histologic confirmation shows vasculitis in only a minority of sinonasal biopsies (35-100% show eosinophilia, but necrotizing vasculitis rarely seen) 1

Monitoring and Follow-up

• Monitor eosinophil count as disease activity marker 1
• Regular cardiac monitoring given ANCA-negative status 3
• Screen for treatment-related complications (infections, osteoporosis, diabetes) 1
• Assess for relapse with any new symptoms 1, 7