Epstein-Barr virus reactivation induced myeloperoxidase-specific antineutrophil cytoplasmic antibody (MPO-ANCA)-associated vasculitis

Abstract

We present a patient with systemic symptoms including 4 months of dyspnoea worsened with exertion, fatigue, rhinorrhoea, intermittent facial swelling, generalised lymphadenopathy and weight loss. Laboratory studies demonstrated proteinuria and eosinophilia. His serology was consistent with Epstein-Barr Virus (EBV) reactivation. A lymph node biopsy was consistent with EBV-associated reactive lymphoid hyperplasia. He was told to continue symptomatic treatment for EBV infection. After several admissions, vasculitis workup and myeloperoxidase-antineutrophil cytoplasmic autoantibody (ANCA) studies were positive. Evolution of clinical symptoms, laboratory parameters and our literature review suggested the diagnosis of EBV-associated ANCA vasculitis. Steroids were started after the patient continued to deteriorate; the viral load started increasing, so we added valganciclovir with favourable clinical response and no relapse during the follow-up for 6 months. This suggests that with evidence of viraemia (primary or reactivation), antiviral treatment likely has clinical benefit while immunosuppression is being considered.

Background

Epstein-Barr virus (EBV)-associated diseases are an important global health concern. This ubiquitous, human gammaherpesvirus has an aetiological and pathogenic role in a variety of chronic infections, human malignancies and non-neoplastic diseases. EBV-infected individuals have higher frequency of autoimmune conditions, including vasculitis associated with antineutrophil cytoplasmic antibodies (ANCA).^1–8 Although multiple autoantibodies may develop during infection, in particular antimyeloperoxidase (MPO) antibodies, not all of them lead to a manifestation of vasculitis. Diagnosis is challenging, as symptoms from the MPO-ANCA-associated vasculitis usually overlap with EBV infection symptoms. Early recognition of this association allows for the best options for treatment, preserving the function of the affected organs and decreasing mortality.

Case presentation

A 70-year-old man presented with 4 months of dyspnoea worsened with exertion, rhinorrhoea, fatigue, intermittent facial swelling, generalised lymphadenopathy and weight loss of 35 lbs. His medical history was significant for myocardial infarction, hypertension. Two months after the illness started, he began having progressive dyspnoea limiting his daily activities, returned to the hospital, and was found to be hypoxic with an Sp02 of 88% at room air and a new uncontrolled hypertension with systolic blood pressures over 170 mm Hg.

Laboratory studies revealed new sustained proteinuria and eosinophilia. EBV-specific serology was consistent with EBV reactivation. An axillary lymph node biopsy demonstrated EBV-encoded RNA (EBER) probe scattered positivity, consistent with EBV-associated reactive lymphoid hyperplasia. Supportive care for EBV infection did not produce symptomatic relief or decrease in illness severity. Persistent and worsening symptoms prompted a subsequent hospitalisation, showing high MPO-ANCA titres and suggesting EBV-induced ANCA-associated vasculitis. Corticosteroid treatment conferred some immediate clinical benefits in controlling the disease but led to symptoms relapse. Increased EBV viral load was found and valganciclovir was added to regimen. This helped with resolution of clinical, biochemical and immunological abnormalities in the first month of treatment. The patient was followed 6 months after improvement of clinical condition with no relapse in symptoms.

Investigations

The patient’s chemistry revealed hypercalcaemia with a serum calcium level of 12.6 mg/dL and ionised calcium 1.26 mmol/L. Parathyroid hormone (PTH) was <6 pg/mL (reference 18–84), PTH-related peptide 2.6 pmol/L (reference <2.3) and 25-hydroxy vitamin D 110 ng/mL (reference 30–100). Total protein was 8.8 g/dL (reference 6.1–8.2), and serum/urine protein electrophoresis showed polyclonal gammopathy without an M-spike. It was discovered the patient was taking 50 000 IU of vitamin D weekly for the past 2 years until 7 weeks prior to presentation, when it was decreased to 5000 IU daily as his 25-hydroxy vitamin D level was 50.4 ng/mL. His vitamin D, calcium and protein levels improved with cessation of supplemental intake and fluid resuscitation.

His white cell count demonstrated an eosinophil count of 2100 cells/µL (26%). Biochemical markers showed an erythrocyte sedimentation rate elevated at 80 mm/hour and C reactive protein 13.8 mg/L (reference ≤10). Random urine protein/creatinine ratio was significantly elevated at 1.15 mg/mg (reference <0.18). Serum EBV studies showed EBV viral capsid antigen (VCA) IgG 566 U/mL (reference <18), EBV-VCA IgM <36 U/mL (reference <36), EBV-nuclear antigen D IgG 25.2 U/mL (reference <18), and EBV serum viral load 426 copies/mL (reference <200). ANCA screen and antiproteinase 3 antibodies were negative, while MPO antibodies were positive at 2.4 U (reference <0.4). A chest X-ray did not show any infiltrates. CT angiogram of the chest showed bilateral hilar and mediastinal lymphadenopathy. PET scan revealed mildly hypermetabolic splenomegaly, mildly hypermetabolic prominent nasopharyngeal lymphoid tissue, mild diffusely increased marrow uptake and mild mesenteric oedema.

The patient underwent a bone marrow biopsy, showing mild hypercellularity 40% with increased eosinophils and scattered paratrabecular lymphoid aggregates composed of a mixture of T cells, B cells and mast cells. Flow cytometry and karyotype revealed no significant abnormalities. The palpable left axillary lymph node was excised, revealing benign-appearing lymphoid follicles with reactive germinal centres and a mixed interfollicular population composed of predominantly small lymphocytes. Additionally, there were mature plasma cells, histiocytes, occasional immunoblastic appearing cells and scattered eosinophils. An EBER probe showed scattered positivity, consistent with EBV-associated reactive lymphoid hyperplasia.

Differential diagnosis

Initial differential diagnoses based on the diffuse lymphadenopathy and hypercalcaemia included malignancy (lymphoma, multiple myeloma) or a multisystemic granulomatous disease such as sarcoidosis. The bone marrow biopsy and lymph node biopsy did not support these diagnoses.

Another diagnosis on the differential was chronic active EBV, consisting of illness lasting >6 months; infiltration of tissues with lymphocytes; elevated EBV DNA, RNA or proteins in affected tissues; and the absence of any other immunosuppressive condition.^{9 10} The patient did not meet criteria for diagnosis.

The workup and concurrent renal involvement supported eosinophilic granulomatosis with polyangiitis (formerly Churg-Strauss) or other vasculitic process as highest on the differential. However, the resolution of symptoms with targeted antiviral therapy pointed more to interrelationship between EBV and vasculitis, and the patient was diagnosed with MPO-ANCA vasculitis related to EBV reactivation.

Treatment

The patient was started on prednisone 60 mg daily. He was followed outpatient, where he initially had improvement of symptoms within a few days of starting the steroids. Follow-up labs after 1 week showed his EBV serum viral load increased to 2407 copies/mL and urine protein/creatinine ratio also increased to 3.0 mg/mg. The patient had an additional 10 lb weight loss with polyuria. He was started on valganciclovir 900 mg every 12 hours by mouth in addition to the prednisone.

Outcome and follow-up

He continued the valganciclovir and a prednisone taper for approximately 1 month, after which time his urine protein/creatinine improved significantly to 0.5 mg/mg. MPO antibodies and EBV viral load became undetectable, and the eosinophilia resolved. His blood pressure became well controlled again. The patient is so far asymptomatic with no sign of relapse after 6 months.

Discussion

Antibodies to EBV have been demonstrated in all population groups; approximately 90%–95% of adults are seropositive as the disease is directly transmitted between humans through saliva. EBV results in primary lytic infection, followed by viral latency; it can then switch between latent and lytic life cycle.⁵ Based on positive EBV VCA IgG and nuclear antigen IgG antibodies, along with increasing EBV serum viral load and lymph node with positive EBER staining, we considered this reactivation.

Rarely, primary EBV infection may contribute to the initiation or exacerbation of ANCA-associated vasculitis,^{1 2} and some case reports suggest that EBV reactivation can do the same.⁴ We report a case of MPO-ANCA vasculitis likely triggered by EBV reactivation. Although a causal link could not be proved, it is thought that EBV viraemia contributes to the initiation and exacerbation of the vasculitis.^1–3 Proposed mechanisms include molecular mimicry, superantigens, cell activation by Toll-like receptors and autoreactive T cells.^{1 7 8}

In conclusion, our patient has EBV reactivation induced MPO-ANCA vasculitis. His clinical picture and laboratory markers improved with steroids and valganciclovir. It took about 4 months to make the diagnosis after initial presentation to medical services. Although the in vivo aetiology is not clear, the induction of MPO-ANCA is multifactorial and we can speculate that EBV is a possible trigger. It is thought that a combination of genetic, immunological, infectious and environmental factors could trigger this process. The diagnosis of EBV reactivation versus vasculitis is challenging since symptoms may overlap, so it is important to recognise this potential association. This case illustrates the role of steroids for the MPO-ANCA vasculitis and concurrent antiviral therapy due to an increasing EBV viral load.

Learning points.

• Epstein-Barr Virus (EBV) can induce myeloperoxidase-antineutrophil cytoplasmic autoantibody (MPO-ANCA) vasculitis and this diagnosis is challenging since symptoms may be overlapping with EBV Infection. Early recognition is important to request the appropriate serology, serum viral load, and begin treatment to preserve organ function.

• EBV-induced MPO-ANCA vasculitis can be treated with steroids and if viral load subsequently increases, antivirals may have a role suppressing the virus.

• Treatment of the underlying infection is important to revert vasculitis.

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