A case of VEXAS (vacuoles, E1 enzyme, X‐linked, autoinflammatory, somatic) syndrome presenting as progressive multisystem involvement with parenchymal infiltrates following infection with Epstein Barr virus

Abstract

VEXAS (vacuoles, E1 enzyme, X‐linked, autoinflammatory, and somatic) syndrome is a rare multisystem disease affecting predominantly males over 50 and manifesting as widespread progressive inflammatory sequelae and haematological dysfunction. We describe a patient who presented with systemic symptoms of fevers, night sweats and weight loss, and developed progressive inflammatory sequelae including cutaneous lesions, haematological dysfunction, lymphadenopathy, migratory inflammatory arthropathies, with new pulmonary infiltrates, following infection with Epstein Barr Virus. Laboratory investigations, bronchoscopy, bone marrow biopsy and imaging were consistent with an inflammatory aetiology. The constellation of organ system involvement, laboratory, biopsy, and imaging results were suspicious for VEXAS syndrome, and this diagnosis was confirmed by identification of a somatic mutation in the UBA1 gene following extensive exclusion of infectious and autoimmune causes. Interestingly the onset of the VEXAS syndrome coincided with serological confirmation of Epstein Barr Virus raising the importance of further exploration into the underlying aetiology of VEXAS syndrome.

VEXAS syndrome is a multisystem disease manifesting as progressive inflammatory sequelae, however the underlying aetiology remains unclear. This case report describes a patient diagnosed with VEXAS who developed multi‐organ inflammation, including rapidly progressive pulmonary infiltrates following infection with Epstein Barr Virus.

INTRODUCTION

VEXAS syndrome (vacuoles, E1 enzyme, X‐linked, autoinflammatory, and somatic) is a rare multisystem disorder, first described in 2020, affecting males over age 50. It manifests as inflammatory sequalae, most commonly cutaneous lesions, arthropathies, pulmonary involvement, polychondritis and haematological dysfunction. As a heterogenous condition, VEXAS syndrome can be a diagnostic challenge, mimicking vasculitis, myositis, systemic lupus erythematosus and hemophagocytic lymphohistiocytosis. ¹ , ² Pulmonary manifestations include neutrophilic alveolitis, ground glass and consolidative infiltrates, mediastinal lymphadenopathy, and pleural effusions. ³ , ⁴ Somatic mutations of the UBA1 gene forms the basis of the autoimmune phenomenon of VEXAS syndrome and these mutations may be precipitated by viral infection. The UBA1 gene is responsible for production of ubiquitin‐activating enzyme E1 with downstream effects of protein degradation. The UBA1 variant is c1225 > Cp(Met31THr) with variant allele frequency of 76%.

CASE REPORT

A 64‐year‐old male presented with a haemoglobin of 65 g/L, and systemic symptoms of night sweats, subjective fevers and rigors, 4 kg weight loss, migratory polyarthritis and relapsing vasculitic‐type rashes affecting the torso and limbs. The polyarthritis commenced in the ankles, progressed to knees, elbows and then hands (metacarpophalangeal and proximal interphalangeal joint involvement), with duration of 3–5 days for each joint group before resolution and migration. He was previously well with no significant medical history. He had no allergies, no regular medications, was a recently reformed smoker (10 pack‐year history) and consumed minimal alcohol. He subsequently developed dyspnoea, pleuritic chest pain and cough with rapidly progressive radiological infiltrates and mediastinal lymphadenopathy, following serological diagnosis of Epstein Barr Virus.

Examination revealed mild tachypnoea, oxygen‐saturations 97% on room air. Chest auscultation demonstrated scattered crepitations, predominantly in the left lower lobe. He had pallor of conjunctivae and palmar creases, no palpable lymphadenopathy, abdominal tenderness or palpable organomegaly. Fading macular papular rash was noted on lower limbs.

Laboratory investigations revealed: haemoglobin 65 g/L, white cell count 5.95 × 10⁹/L, platelet count 194 × 10⁹/L, mean cell volume 105.9 fL. Electrolytes, urea, creatinine and liver function within normal parameters, albumin 29 g/L, LDH 217 U/L. Inflammatory markers CRP 50.5 mg/L, ESR 120 mm, ferritin elevated 642ug/L, iron and transferrin within normal limits. Coagulation studies, thyroid function, B12, folate, ACE, copper level, CD subsets all within normal limits. Direct antiglobulin test normal, haptoglobin elevated 2.86 g/L. Autoimmune panel (ANA and ENA), vasculitic screen (MPO, PR3), myositis immunoblot, ds‐DNA, RF, anti CCP, C3 and C4 levels, cryoglobulin, IgG/A/M within normal limits.

Epstein Barr virus IgG detected, viral capsule antigen IgG 696 U/mL, IgM positive 47.1 U/mL, Epstein Barr Virus nucleic amplification test not detected in blood. The remaining extensive infective screen was negative.

Serial CT chest, abdomen and pelvis demonstrated acute new pulmonary changes: multiple nodular opacities bilaterally, consolidative confluent disease in the left lower lobe and mediastinal lymphadenopathy (Figure 1). Fluorodeoxyglucose‐positron emission tomography scan demonstrated new intensively avid (SUVmax 11.6) left lower lobe consolidation, focal areas of right lower lobe FDG avidity, avid mediastinal lymphadenopathy (SUVmax 5.3), increased metabolic marrow activity and diffusely increased splenic activity (Figure 2).

FIGURE 1.

Computed tomography chest demonstrating bilateral nodular opacities with consolidative confluence in the left lower lobe.

FIGURE 2.

Fluorodeoxyglucose‐positron emission tomography demonstrating intense avidity in the consolidative change in the left lower lobe and moderate avidity in the subcarinal lymph node.

Bronchoscopy with subcarinal lymph node needle aspirate demonstrated focal necrosis and inflammation, no granulomas, micro‐organisms, or evidence of malignancy. Pathogens were not isolated on bronchial washings.

Skin biopsy demonstrated florid necrotising vasculitis, immunofluorescence negative for IgA, IgG, IgM, C3 and fibrinogen.

Initial bone marrow biopsy showed increased cellularity (80%–90%), myeloid hyperplasia, marked neutrophilia, no excess blasts or evidence of lymphoma or dysplasia, consistent with floridly reactive bone marrow secondary to infection or inflammation. Flow cytometry demonstrated no atypical expression of lymphoid markers. Subsequent review identified vacuoles in cells from several lineages. While no karyotypic abnormalities were identified, a variant of the DNMT3A gene was identified, with a variant allele frequency of 47%. Whilst vacuoles were seen in multiple lineages on bone marrow examination, a diagnosis of myelodysplastic syndrome could not be made on the basis of bone marrow morphology. and as such the DNMT3A variant may be Clonal Haematopoiesis of Indeterminant potential (CHIP).

The diagnosis of VEXAS syndrome was confirmed with peripheral blood genetic testing somatic variant detected in the UBA1 gene.

Following commencement of corticosteroid (prednisolone 25 mg), the patient demonstrated rapid resolution of inflammatory symptoms, including dyspnoea, and haemoglobin increment. Inflammatory markers normalized, with demonstration of significant radiological improvement of pulmonary infiltrates. At the time of writing, symptoms, signs and inflammatory marker abnormalities have recurred following prednisolone wean to below 15 mg/day, requiring consideration of a steroid sparing agent.

DISCUSSION

This case demonstrates the diagnostic challenge VEXAS poses and the syndrome's mimic nature. There are currently no established guidelines for diagnosis, and a high index of suspicion is needed in male patients over age 50 with multi‐system inflammatory sequelae and bone marrow dysfunction. VEXAS syndrome consistently presents with haematological abnormalities including macrocytic anaemia, thrombocytopenia and lymphopenia. ³ The other most common manifestations are cutaneous, affecting >80% of patients, and pulmonary affecting >50%. Pulmonary involvement includes radiological ground glass opacities, consolidation, mediastinal lymphadenopathy, and less commonly pleural effusion. Bronchoalveolar lavage demonstrates neutrophilic alveolitis and biopsy demonstrates parenchymal inflammation.

Diagnosis is confirmed by the presence of vacuoles in bone marrow and mutation in the UBA1 gene. VEXAS syndrome is an acquired UBA1 gene deficiency in the haematopoietic progenitor cells. It occurs predominantly in males, as the UBA1 gene is located on the X‐chromosome and the unmatched allele offers a protective role in females. There is one recorded case of the UBA1 mutation detected in bronchoalveolar lavage, suggesting direct parenchymal organ damage. ³ , ⁴

There is ongoing investigation to establish optimal treatment recommendations. Current therapy includes corticosteroids and supportive management. Other modalities used on an individual basis are aimed at targeting the clonal population, including tocilizumab, tofacitinib, hypomethylating agents (azacitidine) and bone marrow transplantation.

Interestingly, our patient developed rapid disease progression following infection with Epstein Barr Virus. Literature review identified one case of VEXAS exacerbation associated with SAR‐Cov‐2 infection, requiring increased corticosteroid for disease control, and one case of VEXAS diagnosed in a patient with Long Covid. SAR‐Cov‐2 infection has been associated with mutations of UBA1 genes thus facilitating autoinflammation. ⁵ Further research is required to investigate the possible autoinflammation pathway associated with viral infection and development of this condition.

In this case, VEXAS diagnosis was confirmed after extensive investigation, highlighting the importance of thorough and broad clinical suspicion in patients with systemic inflammatory disease features and pulmonary infiltrates.

AUTHOR CONTRIBUTIONS

Jelena Solujic: Primary author of manuscript; original draft preparation; consent and discussion with patient; data curation. Emily Lawton: Second author and supervisor of manuscript; editing and review of manuscript. Phan Nguyen: Additional author of manuscript; patient care at time of diagnosis. Peter Bardy: Additional author and editing of manuscript; patient care throughout and ongoing patient review. Yao Ly: Additional author; patient care at time of diagnosis.

CONFLICT OF INTEREST STATEMENT

Phan Nguyen is an Editorial Board member of Respirology Case Reports and a co‐author of this article. He was excluded from all editorial decision‐making related to the acceptance of this article for publication. The other authors have nothing to declare.

ETHICS STATEMENT

The authors declare that appropriate written informed consent was obtained for the publication of this manuscript and accompanying images.

Solujic J, Nguyen P, Bardy P, Ly Y, Lawton E. A case of VEXAS (vacuoles, E1 enzyme, X‐linked, autoinflammatory, somatic) syndrome presenting as progressive multisystem involvement with parenchymal infiltrates following infection with Epstein Barr virus. Respirology Case Reports. 2024;12(10):e70037. 10.1002/rcr2.70037

DATA AVAILABILITY STATEMENT

Data available on request from the authorsThe data that support the findings of this study are available from the corresponding author upon reasonable request.