Haematopoietic Stem Cell Transplant for Norovirus-Induced Intestinal Failure in X-linked Agammaglobulinemia

Ben M. J. Shillitoe,Iolo Doull,Stephen Jolles,Mike Cosgrove,Mark Ponsford,Siske Struik,Jennifer Evans,Mary A. Slatter,Andrew R. Gennery

doi:10.1007/s10875-021-01088-2

Abstract

Since the first clinical description in 1952, immunoglobulin replacement therapy remains the mainstay of treatment of patients with X-linked agammaglobulinemia (XLA). However, this therapy only replaces IgG isotype and does not compensate for the loss of Bruton tyrosine kinase in non-B-lymphocytes. Patients may still therefore develop complications despite current standard of care. Here, we describe an XLA patient with persistent chronic norovirus infection, refractory to treatment and causing intestinal failure. The patient underwent haematopoietic stem cell transplantation, curing XLA and allowed clearance of norovirus prior to humoral immunoreconstitution, suggesting non-humoral immunodeficiency in these patients.

Highlights

X-linked agammaglobulinemia (XLA) is caused by defects in the gene encoding Bruton’s tyrosine kinase (BTK), characterised by the absence of peripheral circulating CD19 + B-lymphocytes and agammaglobulinemia
Haematopoietic stem cell transplantation (HSCT) is not routinely offered for XLA patients, as immunoglobulin replacement therapy (IgRT) is accepted as an effective therapy, and it is generally believed that the benefits of haematopoietic stem cell transplantation (HSCT) do not outweigh the risks
We describe an XLA patient with persistent severe chronic norovirus-associated enteropathy resulting in intestinal failure and requiring parental nutrition (PN), for whom HSCT was performed to offer cure of XLA and clearance of norovirus infection

Summary

Introduction

X-linked agammaglobulinemia (XLA) is caused by defects in the gene encoding Bruton’s tyrosine kinase (BTK), characterised by the absence of peripheral circulating CD19 + B-lymphocytes and agammaglobulinemia. Haematopoietic stem cell transplantation (HSCT) is not routinely offered for XLA patients, as IgRT is accepted as an effective therapy, and it is generally believed that the benefits of HSCT do not outweigh the risks. As IgRT contains only the IgG isotype, XLA patients receiving treatment remain IgM and IgA deficient. BTK is expressed in all myeloid cells and may play important immune functions beyond B-lymphocytes [4]. This is supported by the presentation of XLA patients with infections other than encapsulated infection such as giardia and enterovirus [5, 6]. Up to 26% of patients present with neutropenia and infections with pseudomonas [7]. The failure to compensate for the loss of IgA, Journal of Clinical Immunology (2021) 41:1574–1581

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