Severe Tick-Borne Encephalitis (TBE) in a Patient with X-Linked Agammaglobulinemia; Treatment with TBE Virus IgG Positive Plasma, Clinical Outcome and T Cell Responses

Abstract

Purpose: A patient with X-linked agammaglobulinemia (XLA) and severe tick-borne encephalitis (TBE) was treated with TBE virus (TBEV) IgG positive plasma. The patient's clinical response, humoral and cellular immune responses were characterized pre- and post-infection.

Methods: ELISA and neutralisation assays were performed on sera and TBEV PCR assay on sera and cerebrospinal fluid. T cell assays were conducted on peripheral blood the patient and five healthy vaccinated controls.

Results: The patient was admitted to the hospital with headache and fever. He was not vaccinated against TBE but receiving subcutaneous IgG-replacement therapy (IGRT). TBEV IgG antibodies were low-level positive (due to scIGRT), but the TBEV IgM and TBEV neutralisation tests were negative. During hospitalisation his clinical condition deteriorated (Glasgow coma scale 3/15) and he was treated in the ICU with corticosteroids and external ventricular drainage. He was then treated with plasma containing TBEV IgG without apparent side effects. His symptoms improved within a few days and the TBEV neutralisation test converted to positive. Robust CD8⁺ T cell responses were observed at three and 18-months post-infection, in the absence of B cells. This was confirmed by tetramers specific for TBEV.

Conclusion: TBEV IgG-positive plasma given to an XLA patient with TBE without evident adverse reactions may have contributed to a positive clinical outcome. Similar approaches could offer a promising foundation for researching therapeutic options for patients with humoral immunodeficiencies. Importantly, a robust CD8⁺ T cell response was observed after infection despite the lack of B cells and indicates that these patients can clear acute viral infections and could benefit from future vaccination programs.

Keywords: CD8+ T cells; X-linked agammaglobulinemia; immunodeficiency; neutralising antibodies; tetramers; tick-borne encephalitis.

Fig. 1

Neuroimaging demonstrating TBE meningoencephalitis. At admission day 1 (D1), brain computed tomography (CT) was normal. Brain magnetic resonance imaging (MRI) on day 3 (lower left panel) revealed edema (arrows) in the thalami bilaterally, superior vermis and medially in the cerebellum. Spinal MRI on day 5 (lower right panel) revealed leptomeningeal enhancement (arrows). On day 6, obstructive hydrocephalus occurred, and the patient was treated with ventricular drainage (arrow), which reconciled the increased pressure (D9), and the drainage could subsequently be removed without hydrocephalus (D14, D15). At a brain CT scan 5.5 months later due to trauma (acute right frontoparietal extracranial hematoma present), extensive brain calcifications in the cerebellar parenchyma had developed (arrows)

Fig. 2

Timeline for symptoms, treatments, and diagnostic results. ICU = intensive care unit, sc = subcutaneous, IgG = immunoglobulin G, IVIG = intravenous immunoglobulin, GCS = Glasgow Coma Scale, d = day, TBE = Tick-borne encephalitis, CSF = cerebrospinal fluid, PCR = polymerase chain reaction, Complex PCR = generic PCR for TBEV proteins; NS3 = specific PCR for TBEV NS3 protein and CT levels = cycle threshold levels

Fig. 3

CD4⁺ and CD8⁺ T cell responses to tick-borne encephalitis virus in a patient with XLA. Cluster of differentiation = CD, Dimethyl sulfoxide = DMSO, Non-structural protein 5 = NS5, Ligand = L, Human leucocyte antigen = HLA. Peripheral blood mononuclear cells (PBMCs) were incubated in the presence of three different Tick-borne encephalitis virus (TBEV) peptide pools (NS5, peptide E and peptide C) for 12 h at 37 °C. A) Antigen-specific memory CD4⁺ T cell response was measured by the proportion of CD69⁺CD40L⁺ co-expressing cells and B) co-expression of CD69⁺4-1BB⁺ was considered as antigen-specific memory CD8⁺ T cells. C) Bar plots showing the frequency (percent) of memory CD4⁺ T cells and memory CD8⁺ T cells in response to three TBEV peptide pools from the X-linked agammaglobulinemia (XLA) patient before, three months after and 18 months after TBEV infection. Memory T cell frequency was only measured for the five healthy vaccinated controls at one time point. The frequency of the T cells obtained in di-methyl sulfoxide (DMSO) treated PBMC cultures were used as a control to measure both CD4⁺ and CD8⁺ T cell response to the peptide pools. D) Representative flow cytometry plots showing HLA-A2 tetramer-specific memory CD8⁺ T cells in the XLA patient before, three and 18 months after TBEV infection as well as in one vaccinated healthy control