13. CMV Reactivation in refractory ANCA-associated vasculitis
Authors: Hassan Neelam , Gunawardena Harsha 
Published: September 2019

Abstract

Introduction
The anti-neutrophil cytoplasmic antibody (ANCA) - associated vasculitides are a heterogeneous group of rare multisystem disorders characterised by inflammation and necrosis of small and medium blood vessels. Early diagnosis and prompt initiation of immunosuppressive treatment are essential to induce and maintain remission of disease, and thereby prevent severe life- or organ-threatening complications.
We present a challenging case of a patient presenting with progressive lung lesions in the context of known ANCA-associated vasculitis (AAV), despite escalating immunosuppressive treatment.

Case description
A 66-year old-female was diagnosed in 2010 with cANCA (PR3) positive vasculitis with lung involvement. Remission was induced with high dose steroids and cyclophosphamide. Methotrexate was given as maintenance treatment until 2013 when she had a significant renal relapse treated with plasma exchange, steroids and cyclophosphamide. Her maintenance treatment was changed to mycophenolate. She had a further lung relapse in 2014, treated successfully with high dose steroids and rituximab. She was eventually weaned off all treatment in 2017.
She was admitted to hospital in 2019 with dry cough, dyspnoea and sinus congestion. She was noted to have several purpuric lesions on her limbs. Her CRP was elevated at 123 with a stable eGFR of 77. ANCA screen was negative. Chest Xray revealed bilateral consolidation. She was initially treated with six pulses of 500mg of IV methylprednisolone and one pulse of rituximab as an inpatient over the course of 2 weeks, with broad spectrum antibiotic cover. Despite this, she continued to deteriorate with a worsening purpuric rash and increasing oxygen requirement. She underwent plasma exchange with little improvement. CT of her chest revealed multiple progressive bilateral cavitating lesions.
It was noted that her IgG levels were low (3.72) following rituximab, increasing her risk of infection. An atypical infection screen was performed and she was discovered to have cytomegalovirus (CMV) reactivation with high viral titres of 56889. She underwent bronchoscopic alveolar lavage which was positive for CMV on PCR. CT guided lung biopsy revealed necrotising granulomatous inflammation with occasional CMV positive nuclei.
She was given valganciclovir and IV immunoglobulin, and her prednisolone dose was reduced to 10mg. This resulted in her viral load reducing to undetectable levels, her CRP improving to 23 and immunoglobulins normalising. This correlated with a clinical improvement allowing the patient to be discharged home.

Discussion
The patient in this case appeared in the first instance to have another flare of her AAV. However the flare was atypical in that it was not associated with an increase in her cANCA titre and it did not respond quickly to steroids as had been the case on each previous occasion. This prompted a reassessment of her case and investigation into other potential causes for her deterioration.
CMV is a persistent herpesvirus which can affect up to 75% of healthy individuals. The primary infection is rarely symptomatic but can be associated with significant morbidity and mortality in immunocompromised patients. Pulmonary CMV disease can mimic pulmonary disease associated with vasculitis. CMV can also directly damage endothelial cells and cause an occlusive vasculitis itself.
The patient was immunosuppressed, increasing her risk of acquiring primary CMV infection or developing CMV reactivation. She was given further potent immunosuppression during her admission. Serology is often unreliable in immunosuppressed patients and in this case her CMV IgG was positive with a negative IgM, indicating past CMV infection only. It is important to send samples for viral PCR to detect and diagnose active infection, and allow treatment to be initiated promptly.
The lung biopsy was felt to be more in keeping with active AAV, although occasional CMV positive nuclei were present. The patient was therefore managed as having CMV reactivation in the context of active AAV.
Treatment of viral infection can pose further challenges when trying to manage coexistent active vasculitis as highlighted in this case. Close monitoring of the patient was required, together with a multidisciplinary approach involving input from colleagues in infectious diseases and immunology, to allow the patient to be managed safely and effectively. Prophylactic antiviral therapy may need to be considered if further immunosuppression is required in future.

Key learning points
CMV reactivation can complicate treatment of ANCA associated vasculitis. Clinicians should have a low threshold to test for CMV in immunocompromised patients with vasculitis, particularly in cases which are atypical or refractory to standard treatment. Viral PCR should be tested, as serology can often be unreliable in immunosuppressed patients.

Conflict of interest
The authors declare no conflicts of interest.