Severe enterovirus infections in patients with immune-mediated inflammatory diseases receiving anti-CD20 monoclonal antibodies

Abstract

Objective: Patients with X linked agammaglobulinemia are susceptible to enterovirus (EV) infections. Similarly, severe EV infections have been described in patients with impaired B-cell response following treatment with anti-CD20 monoclonal antibodies (mAbs), mostly in those treated for haematological malignancies. We aimed to describe severe EV infections in patients receiving anti-CD20 mAbs for immune-mediated inflammatory diseases (IMIDs).

Methods: Patients were included following a screening of data collected through the routine surveillance of EV infections coordinated by the National Reference Center and a review of the literature. Additionally, neutralising antibodies were assessed in a patient with chronic EV-A71 meningoencephalitis.

Results: Nine original and 17 previously published cases were retrieved. Meningoencephalitis (n=21/26, 81%) associated with EV-positive cerebrospinal fluid (n=20/22, 91%) was the most common manifestation. The mortality rate was high (27%). EV was the only causal agents in all reported cases. Patients received multiple anti-CD20 mAbs infusions (median 8 (5-10)), resulting in complete B-cell depletion and moderate hypogammaglobulinemia (median 4.9 g/L (4.3-6.7)), and had limited concomitant immunosuppressive treatments. Finally, in a patient with EV-A71 meningoencephalitis, a lack of B-cell response to EV was shown.

Conclusion: EV infection should be evoked in patients with IMIDs presenting with atypical organ involvement, especially meningoencephalitis. Anti-CD20 mAbs may lead to impaired B-cell response against EV, although an underlying primary immunodeficiency should systematically be discussed.

Keywords: B-lymphocytes; antirheumatic agents; autoimmune diseases; rituximab.

Figure 1. Flow chart of the study.

Figure 2. Organ involvement in severe enteroviral infections. (A) Brain MRI taken in June 2022 showing centro-pontine fluid-attenuated inversion recovery (FLAIR) hyperintensity without enhancement for the patient presented in figure 3; (B) brain MRI showing complete regression of abnormalities in September 2022 (same patient); (C) diffuse myocardial oedema (MRI, T2 mapping); (D) septal, basal lateral and lateral medial enhancement (MRI, late gadolinium enhancement); (E) multifocal ground glass opacities; (F and G) lymphocytic myocarditis with interstitial T cell (G:CD3+ cells) foci, dystrophic myocytes, no giant cell or eosinophilic infiltration, no myocardial necrosis.

Figure 3. Sera neutralisation titre overtime in one of the reported patients with chronic EV-A71 meningoencephalitis. EV, enterovirus; EV+, positive EV RT-PCR in blood and cerebrospinal fluid (CSF); EV−, negative EV RT-PCR in blood and CSF; IVIg, intravenous immunoglobulin; PolyIg, polyvalent immunoglobulins used as a positive control. Each point represents a serum sample.