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Compartmentalization of the immune response in varicella zoster virus immune restoration disease causing transverse myelitis

Clark, Benjamin Ma; Krueger, Romano Gb; Price, Patriciaa,c; French, Martyn Aa,c

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Patients with HIV-1 infection who have a virological response to antiretroviral therapy may experience infectious/inflammatory disease in the first few months of therapy [1]. We have argued that this results from the restoration of an immunopathological response to the antigens of opportunistic pathogens [2–4], and is therefore immune restoration disease (IRD). There are currently no diagnostic criteria for IRD, partly because pathogenic mechanisms are heterogeneous and complex. Here we illustrate their complexity by describing a case of varicella zoster virus (VZV) IRD in which the immune response was localized to the central nervous system.

A 48-year-old man who was co-infected with HIV-1 and hepatitis C virus from a previous blood transfusion presented with a 10-day history of evolving weakness of the right leg. He had been commenced on a highly active antiretroviral therapy (HAART) regimen consisting of soft gel saquinavir 1000 mg twice a day, ritonavir 100 mg twice a day, and tenofovir 300 mg once a day one month before presentation. He was infected with multidrug-resistant HIV-1 and had taken no therapy for the 6 months before commencing the new HAART regimen. Before recommencing HAART, his blood CD4 T-cell count was 7 cells/μl and the plasma HIV-RNA level was greater than 75 000 copies/ml.

On initial examination, the patient was unable to weight bear. There was reduced muscle power in the right leg, in particular the hip and knee flexors. Pin-prick and temperature sensation were reduced on the left side to a sensory level of T5. Proprioception was lost in the joints distal to the right ankle. A magnetic resonance imaging scan revealed lesions within the right side of the spinal cord at the levels of T3, T5 and T8/9, with no enhancement after the injection of radiocontrast medium and no expansion of the cord at these levels. There were no lesions within the brain. The clinical and radiological findings were consistent with multilevel infective transverse myelitis.

The cerebrospinal fluid (CSF) protein level was elevated at 0.88 g/l (0.15–0.45), and the leukocyte count was 4 × 106/l (99% mononuclear cells). Bacterial, mycobacterial and viral cultures were negative. DNA from herpes simplex virus (HSV) 1 and 2, cytomegalovirus, Epstein–Barr virus, adenovirus and enteroviruses was not detectable by polymerase chain reaction. However, DNA from VZV was detected. The serum contained IgG antibodies to VZV, HSV-1 and cytomegalovirus but not to HSV-2. IgG antibodies to VZV were present in the CSF, but a comparison of titres of antibody to VZV and rubella virus in the CSF and serum showed no evidence of intrathecal VZV antibody production. The plasma HIV-RNA level had fallen to 246 copies/ml but the blood CD4 T-cell count was only 10 cells/μl.

A presumptive diagnosis of IRD causing transverse myelitis was made before the results of the virological tests on the CSF were available. The patient was given 1 g methylprednisolone intravenously on three consecutive days. The power in his right leg and the abnormal sensation began to improve after the second dose, and continued to do so over the following days. He was able to weight bear and began to mobilize. When the VZV polymerase chain reaction result became available on day 5 after admission, he was given additional valaciclovir therapy. On review 5 weeks after presentation he was walking with the aid of a stick. Power in the hip and knee flexors had improved to 4/5. However, there was increased muscle tone in the right leg associated with brisk reflexes, and the sensory deficit on the left side had not improved. At that time, the plasma HIV-RNA level had declined further to less than 50 copies/ml and the CD4 T-cell count had risen to 30 cells/μl. However, 16 weeks after presentation the plasma HIV-RNA level was 76 100 copies/ml and the blood CD4 T-cell count was 24 cells/μl, despite good adherence to therapy.

At presentation, samples of blood and CSF were collected to compare the immunophenotype and activation status of lymphocyte subpopulations. CSF samples were analysed according to Kleine et al. [5]. Blood lymphocytes comprised 1% CD4 T cells, 65% CD8 T cells and 13% natural killer (NK) cells (CD3, CD16+, CD56+). In contrast, CSF lymphocytes comprised 27% CD4 T cells, 46% CD8 T cells and 11% NK cells. Furthermore, the activation status of the cells differed between blood and CSF (Fig. 1). Expression of the ‘early activation marker’ CD69 was high on 25% of CD4 T cells, 41% of CD8 T cells and 51% of NK cells in the CSF compared with less than 2% of CD4 and CD8 T cells and 13% of NK cells in the blood. In addition, expression of the ‘late activation marker’ CD38 was high on 95% of CD4 T cells and 80% of CD8 T cells in the CSF (data not shown). Genetic studies revealed that the patient was HLA-A03, 68; HLA-B44, 35; HLA-DRB1*01, *11 and carried alleles 1 and 2 at position 1188 in the IL12B 3’ untranslated region (UTR), allele 1 alone at IL6-174 and allele 1 alone at TNFA-308.

Fig. 1.
Fig. 1.:
Percentages of CD4 and CD8 T cells (CD3+) and natural killer cells (CD3, CD16+, CD56+), and the proportion of those cells with high CD69 expression, in the cerebrospinal fluid and blood.

This patient developed multilevel transverse myelitis associated with VZV infection after achieving a virological response to HAART. This was associated with activated lymphocytes in the CSF without a change in the CD4 T-cell count, or the presence of activated CD8 T, cells in the blood. These findings suggest that the myelitis resulted from an immune response to VZV that was localized to the spinal cord. Furthermore, the majority of activated lymphocytes in the CSF were NK cells and CD8 T cells, suggesting that these cells were mediating an immune response. The findings are therefore in accord with those of Domingo et al. [6], who showed that VZV IRD of the peripheral nerves was associated with an increase in the blood CD8 T-cell count. They may also explain the association of herpesvirus IRD with allele 1 of the IL12B 3'UTR locus [7] because IL-12 is an important component of the innate response to viruses, including herpesviruses, and affects NK cells and CD8 T cells [8–11].

The progression of the myelitis in our patient was arrested by intravenous methylprednisolone therapy. However, permanent neurological disability resulted. As more patients with advanced immunodeficiency are given HAART, because of late presentation [12] or drug-resistant HIV requiring novel HAART regimens, more will be at risk of IRD in the central nervous system. This can cause serious morbidity and occasionally mortality [3,13–15]. Strategies for avoiding IRD should therefore be considered. With respect to herpesvirus IRD, patients such as the one described here, who have risk factors of a CD4 T-cell count of less than 50 cells/μl [3], disease susceptibility genes such as allele 1 at position 1188 of the IL12B 3'UTR region and HLA-B44 [7,16], and serological evidence of a herpesvirus infection, might be evaluated for subclinical infection of the nervous system and given pre-emptive antiviral therapy before commencing HAART if infection is present. This strategy should be tested in a randomized clinical study.


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