Recurrent Fever and Cutaneous Nodules: Leprosy Masquerading as AAV

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Recurrent Fever and Cutaneous Nodules: Leprosy Masquerading as Anti-Neutrophil Cytoplasmic Antibodies Associated Vasculitis

Introduction

In regions where leprosy remains endemic, the disease often presents diagnostic challenges due to its ability to mimic autoimmune disorders such as anti-neutrophil cytoplasmic antibodies (ANCA)-associated vasculitis (AAV). This case report highlights a 26-year-old farmer from Yunnan Province, China, initially misdiagnosed with AAV, whose symptoms were ultimately attributed to multi-bacillary leprosy with a type II lepra reaction. The case underscores the importance of considering infectious etiologies in patients with overlapping rheumatologic and dermatologic manifestations, particularly in high-burden areas.

Clinical Presentation and Initial Management

The patient’s symptoms began in September 2016 with painless cutaneous nodules on his chest, followed by gradual involvement of his limbs, face, and trunk. Within two weeks, he developed a high-grade fever (39.5°C) and peripheral limb numbness. Notably absent were systemic symptoms such as cough, diarrhea, arthralgia, or myalgia. Initial laboratory findings revealed leukocytosis (elevated white blood cell count and neutrophil percentage) and positive serology for ANCA and myeloperoxidase-ANCA (MPO-ANCA). Imaging studies, including chest computed tomography (CT), showed no abnormalities. Based on these findings, a provisional diagnosis of AAV was made, and the patient received pulse methylprednisolone (80 mg/day) and cyclophosphamide (0.4 g biweekly for four doses).

While treatment initially reduced fever and skin lesions, symptoms recurred whenever prednisone was tapered below 20–30 mg/day. Over two years, the patient experienced cyclical episodes of fever, worsening cutaneous nodules, and progressive sensory deficits. Referral to a tertiary care center (West China Hospital) prompted a comprehensive re-evaluation.

Comprehensive Evaluation at the Tertiary Center

Physical Examination
Upon admission, multiple discrete red nodules (0.5–1.0 cm) with variable firmness were observed on the face, trunk, and limbs (Figure 1). Mild lymphadenopathy (0.5–1.0 cm) was noted in cervical, axillary, and inguinal regions. Neurological assessment revealed reduced superficial sensation in the forearms and right lower limb.

Laboratory and Imaging Findings
Repeated testing confirmed leukocytosis (23.63 × 10⁹/L; neutrophils 84.7%), elevated inflammatory markers (C-reactive protein: 164 mg/L; erythrocyte sedimentation rate: 43 mm/h), and persistent MPO-ANCA positivity. Procalcitonin levels (0.07 ng/mL) ruled out bacterial sepsis. Urinalysis and imaging of the head, chest, and abdomen remained unremarkable. Electroneuromyography identified peripheral nerve damage in the right common peroneal and bilateral ulnar nerves.

Definitive Diagnostic Procedures
A smear of fluid from an ulcerated nodule revealed abundant acid-fast bacilli. Subsequent histopathology of an inguinal lymph node biopsy demonstrated non-caseating granulomas with neutrophilic and lymphocytic infiltration. Polymerase chain reaction (PCR) confirmed Mycobacterium leprae infection, confirming multi-bacillary leprosy complicated by a type II (erythema nodosum leprosum) reaction.

Clinical and Diagnostic Challenges

1. Overlapping Features of Leprosy and AAV

The patient’s fever, cutaneous nodules, and ANCA positivity aligned with AAV, particularly microscopic polyangiitis (MPA). The 2017 American College of Rheumatology criteria for AAV assign 6 points to MPO-ANCA positivity alone, sufficient for an MPA classification. However, key discrepancies emerged:

  • Cutaneous Lesions: Leprosy-related nodules typically lack the ulceration or purpura seen in vasculitis.
  • Neurological Involvement: AAV predominantly affects small vessels, causing mononeuritis multiplex, whereas leprosy targets peripheral nerves directly.
  • ANCA Specificity: AAV is strongly associated with proteinase 3 (PR3)-ANCA or MPO-ANCA, but ANCA positivity in leprosy is nonspecific and likely driven by polyclonal B-cell activation or molecular mimicry.

2. Sociocultural Barriers to Diagnosis

Leprosy remains stigmatized in endemic regions, leading patients to conceal exposure histories. The patient denied contact with leprosy patients, delaying suspicion of the disease. Stigma exacerbates underreporting and complicates contact tracing, perpetuating transmission.

3. Limitations of Current Diagnostic Frameworks

The provisional AAV classification criteria prioritize serology and organ involvement but lack specificity for distinguishing mimics like leprosy. This case illustrates the need for integrating infectious disease evaluations in patients with atypical or refractory AAV phenotypes.

Leprosy Epidemiology and Diagnostic Pitfalls

Globally, leprosy incidence has declined marginally from 258,133 new cases in 2007 to 214,783 in 2016, with China reporting 677 cases in 2016. Endemic provinces like Yunnan, Guizhou, and Sichuan account for most Chinese cases. Delayed diagnosis remains pervasive: A retrospective analysis (1989–2011) found an average diagnostic delay of 3.9 years (range: 1–23 years), with 76% of cases progressing to multi-bacillary disease.

Early symptoms—transient skin lesions, peripheral neuropathy, and low-grade fever—are nonspecific. Leprosy reactions (type I reversal reactions and type II erythema nodosum leprosum) further mimic autoimmune flares, characterized by neutrophilic inflammation and systemic symptoms.

Pathogenesis of ANCA Positivity in Leprosy

Leprosy-associated ANCA production may arise through:

  1. Molecular Mimicry: M. leprae heat shock protein 65 shares epitopes with human cytokeratin 10, triggering cross-reactive antibodies.
  2. Polyclonal B-Cell Activation: Chronic antigenemia drives nonspecific antibody production, including rheumatoid factor, anti-nuclear antibodies, and ANCA.
  3. Immune Complex Deposition: Vasculitic features may result from antibody-mediated vascular inflammation, complicating differentiation from true vasculitis.

Management and Outcomes

The patient was transferred to a leprosy control center for multidrug therapy (MDT) with rifampicin, dapsone, and clofazimine. At seven-month follow-up, skin nodules and fever had resolved, but residual peripheral neuropathy persisted, highlighting the irreversible nature of advanced nerve damage.

Implications for Clinical Practice

  1. Infectious Mimics in Suspected Vasculitis: Leprosy, tuberculosis, and fungal infections must be excluded in endemic regions.
  2. Biopsy as a Diagnostic Cornerstone: Early skin or nerve biopsy with acid-fast staining and PCR is critical in atypical presentations.
  3. Sociocultural Sensitivity: Clinicians must address stigma-related barriers through nonjudgmental history-taking and community education.

Conclusion

This case exemplifies the diagnostic complexity of leprosy in an era of declining incidence but persistent endemicity. ANCA positivity, cutaneous lesions, and neurologic deficits should not prematurely anchor clinicians to autoimmune diagnoses without excluding infectious mimics. Enhanced awareness, integration of biopsy findings, and refinement of vasculitis classification criteria are essential to mitigate diagnostic delays and prevent irreversible morbidity.

doi:10.1097/CM9.0000000000000937

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