Mapping the infectious burden in VEXAS syndrome: a systematic review and rationale for prevention

Infections are increasingly recognised as a major cause of morbidity and mortality in patients with vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic (VEXAS) syndrome. We conducted a systematic review to characterise the infectious burden of VEXAS syndrome and propose preventive strategies. We included 57 studies (813 patients) showing that infections in patients with VEXAS syndrome were frequent, severe in 40-60% of cases, and fatal in 6-15% of cases. Pulmonary infections were most common, followed by cutaneous infections and bacteraemia. Opportunistic pathogens, such as Pneumocystis jirovecii, Legionella pneumophila, non-tuberculous mycobacteria, and varicella zoster virus, were frequently reported, even in patients not receiving immunosuppressive therapy, which suggests intrinsic immune dysfunction. Prophylaxis with co-trimoxazole (or other Pneumocystis prophylaxis, such as atovaquone or pentamidine) and valaciclovir should particularly be considered for patients at high risk of infection, including those receiving immunosuppressive therapy and those with lymphopenia, pMet41Val mutation, or previous severe or recurrent infections. Posaconazole might be appropriate in patients with neutropenia who are taking azacitidine. Vaccination against Streptococcus pneumoniae, varicella zoster virus, influenza, and SARS-CoV-2 is recommended. These data highlight the need to integrate infectious risk into VEXAS syndrome management and to evaluate preventive strategies in prospective studies.