Tomas Bergström

Varicella-zoster virus CNS disease - viral load, clinical manifestations and sequels.

BACKGROUND Real-time polymerase chain reaction (PCR) analysis of cerebrospinal fluid (CSF) samples has improved the diagnosis of varicella-zoster virus (VZV) infection of the central nervous system (CNS). The VZV viral load in the CSF obtained from VZV-related neurological syndromes is not known. OBJECTIVES To investigate VZV viral loads associated with VZV-related neurological syndromes, and to describe the clinical manifestations and sequels in patients with VZV DNA in the CSF. STUDY DESIGN Patients in the Western Gotaland region of Sweden with CNS symptoms and VZV DNA in the CSF, during 1995-2006 were retrospectively identified. The diagnoses, laboratory tests (including virus quantity), antiviral treatment, and neurological complications were studied. RESULTS Ninety-seven patients with VZV DNA in the CSF detected by PCR were identified. In 66 patients in whom VZV DNA levels were determined, significantly higher viral loads were found in those with encephalitis and acute aseptic meningitis compared to patients with cranial nerve affection (including Ramsay Hunt syndrome). Fifty patients had a follow-up; 34 (68%) had neurological symptoms 1 month after acute disease and 25 (50%) had neurological complications 3 months after discharge. A minimum yearly incidence of 1.8 per 100,000 of PCR diagnosed VZV CNS infections was estimated. CONCLUSIONS VZV was the most common alpha-herpesvirus detected in CSF samples from patients with CNS symptoms in the Western Gotaland region of Sweden. CSF viral loads were higher in patients with encephalitis and acute aseptic meningitis than in other CNS syndromes caused by VZV. A majority of the patients that were seen in follow-up had neurological symptoms and sequels.

LIR-1 expression on lymphocytes, and cytomegalovirus disease in lung-transplant recipients

Human cytomegalovirus infection is a major cause of morbidity after lung transplantation. LIR-1 (leucocyte immunoglobulin-like receptor-1) is an inhibitory cell surface receptor that has high affinity for an MHC class I homologue (UL18) encoded by human cytomegalovirus. We aimed to investigate whether reactivation of human cytomegalovirus affects the expression of LIR-1. We measured LIR-1 expression on peripheral blood lymphocytes from 13 lung-transplant recipients and established human cytomegalovirus load using PCR. Eight patients developed cytomegalovirus disease. The percentage of cells expressing LIR-1 increased in the patients who developed cytomegalovirus disease several weeks before viral DNA was detectable by PCR. Measurement of LIR-1 expression might allow early identification of cytomegalovirus disease in lung-transplant patients.

Increased Expression of Leukocyte Ig-Like Receptor-1 and Activating Role of UL18 in the Response to Cytomegalovirus Infection

NK and T cells are important for combating CMV infection. Some NK and T cells express leukocyte Ig-like receptor-1 (LIR-1), an inhibitory receptor recognizing MHC class I and the CMV-encoded homolog UL18. We previously demonstrated an early increase in LIR-1-expressing blood lymphocytes in lung-transplanted patients later developing CMV disease. We now show that NK and T cells account for the observed LIR-1 augmentation. Coincubation of PBMC from CMV-seropositive donors with virus-infected lung fibroblasts led to a T cell-dependent secretion of IFN-γ, produced mainly by LIR-1+ T cells and by NK cells. Cytokine production during coculture with fibroblasts infected with virus containing the UL18 gene was augmented compared with the UL18 deletion virus, suggesting a stimulatory role for UL18. However, purified UL18Fc proteins inhibited IFN-γ production of LIR-1+ T cells. We propose that cytokine production in the transplant induces NK and T cells to express LIR-1, which may predispose to CMV disease by MHC/LIR-1-mediated suppression. Although the UL18/LIR-1 interaction could inhibit T cell responses, this unlikely plays a role in response to infected cells. Instead, our data point to an activating role for viral UL18 during infection, where indirect intracellular effects cannot be excluded.

Incidence of CSF abnormalities in siblings of multiple sclerosis patients and unrelated controls.

Abstract We found that 19% (9/47) of healthy siblings of patients with clinically definite multiple sclerosis had an intrathecal immunological reaction with two or more 2 CSF-enriched oligoclonal bands (OCBs), in contrast to (4%) (2/50) unrelated healthy controls. Furthermore, in this group of nine healthy sibs the measles CSF IgG antibody titers were higher than that of the other sibs and that of controls. There were also differences in the serum titers for measles IgG antibody, which were higher in the group of all healthy sibs than in healthy volunteers, and (as with CSF titers) higher in the subgroup of healthy sibs with two or more 2 CSF-enriched OCBs than the other sibs. Thus a significant proportion of healthy siblings to MS patients have a partially hyperimmune condition similar to that occurring in MS, which in 19% manifested itself as an OCB reaction, in 9% as increased CSF measles IgG antibody titers, and in 21% as increased serum measles IgG antibody titers, these phenomena tending to occur in the same individuals. This condition is characterized by CSF-enriched OCBs with undefined specificity, although some increased antiviral reactivity is found both in the serum and CSF. While it needs further characterization, a genetic trait interacting with common infections is suggested. The recurrence risk of this condition is approximately five times higher than the 3–4% recurrence risk for manifest MS reported for sibs.

Varicella-Zoster Virus (VZV) Glycoprotein E Is a Serological Antigen for Detection of Intrathecal Antibodies to VZV in Central Nervous System Infections, without Cross-Reaction to Herpes Simplex Virus 1

ABSTRACT Herpes simplex virus 1 (HSV-1) and varicella-zoster virus (VZV) cause serious central nervous system (CNS) diseases that are diagnosed with PCR using samples of cerebrospinal fluid (CSF) and, during later stages of such infections, with assays of intrathecal IgG antibody production. However, serological diagnoses have been hampered by cross-reactions between HSV-1 and VZV IgG antibodies and are commonly reported in patients with herpes simplex encephalitis (HSE). In this study we have evaluated VZV glycoprotein E (gE) as a new antigen for serological diagnosis of VZV-induced CNS infections. Paired samples of CSF and serum from 29 patients with clinical diagnosis of VZV CNS infection (n = 15) or HSE (n = 14), all confirmed by PCR, were analyzed. VZV gE and whole VZV were compared as antigens in enzyme-linked immunosorbent assays (ELISAs) for serological assays in which the CSF/serum sample pairs were diluted to identical IgG concentrations. With the gE antigen, none of the HSE patients showed intrathecal IgG antibodies against VZV, compared to those shown by 11/14 patients using whole-VZV antigen (P < 0.001). In the patients with VZV infections, significantly higher CSF/serum optical density (OD) ratios were found in the VZV patients using the VZV gE antigen compared to those found using the whole-VZV antigen (P = 0.001). These results show that gE is a sensitive antigen for serological diagnosis of VZV infections in the CNS and that this antigen was devoid of cross-reactivity to HSV-1 IgG in patients with HSE. We therefore propose that VZV gE can be used for serological discrimination of CNS infections caused by VZV and HSV-1.

Serum and CSF measles antibody levels increase over time in patients with multiple sclerosis or clinically isolated syndrome

In general, measles virus (MV) immunoglobulin G (IgG) antibody titres decline over time. However, we found that serum and CSF MV antibody titres increased with age (slope=0.038, p<0.001 and slope=0.022, p=0.008), respectively, and disease duration (slope=0.031, p=0.002 and slope=0.032, p=0.005), respectively, in patients with multiple sclerosis (MS) or clinically isolated syndrome (CIS). The age dependency of serum antibody levels differed between patients and controls (slope=0.038 versus -0.004, p<0.001). The increasing MV antibody titres over time in MS/CIS patients support a general nonspecific stimulation of B cells and plasma cells that is not confined only to the CNS/CSF compartment.

The effect of live, attenuated measles vaccine and measles infection on measles antibody levels in serum and CSF of patients with multiple sclerosis or clinically isolated syndrome.

High occurrence of measles, rubella and varicella zoster antibodies has been used as a biomarker for MS (the MRZ test). We analyzed measles antibody titres with respect to measles infection/measles vaccination status in 166 patients with MS or clinically isolated syndrome. Fifty blood donors served as controls. Measles vaccination yielded CSF measles antibodies in fewer patients (62%) than measles infection did (87%, p=0.001) and yielded lower measles titres in both serum and CSF (p<0.001). Controls had lower CSF measles titres than patients with measles vaccination alone (p<0.001). Childhood vaccinations probably reduce the sensitivity of the MRZ diagnostic test for MS.

Frequent detection of cytomegalovirus and Epstein-Barr virus in cervical secretions from healthy young women.

To investigate asymptomatic shedding from the uterine cervix of five human herpes viruses: cytomegalovirus (CMV), Epstein–Barr virus (EBV), herpes simplex virus (HSV) type 1 and type 2 and varicella zoster virus (VZV), in young women.

Herpes simplex viruses

Understanding and Diagnosing HSV. Evolution of Herpes Simplex Virus Infections. Immune Evasion and HSV Vaccine. Natural Course of Herpes Simplex Virus Infection and Epidemiology. Pathogenesis. Diagnostics. Disease Manifestations of HSV and Treatment. Antiviral Treatment. Primary Gingivostomatitis and Recurrent Oral Infection. Herpes Virus Infections of the Skin. Acute and Recurrent Genital Herpes Virus Infection. Herpes Simplex Virus Infections of the Eye. Herpes Simplex Encephalitis. Herpes Simplex Meningo/Radiculo/Myelitis. Facial Paresis. Herpes Simplex Virus Infections of the Immunosuppressed Patient. Neonatal and Congenital Herpes Simplex Infection. Future Therapeutics. Future Outlook

Sequence analysis of human rhinovirus aspirated from the nasopharynx of patients with relapsing-remitting MS

Background Upper respiratory infections were reported to trigger multiple sclerosis relapses. A relationship between picornavirus infections and MS relapses was recently reported. Objective To evaluate whether human rhinovirus is associated with multiple sclerosis relapses and whether any particular strain is predominant. Method Nasopharyngeal fluid was aspirated from 36 multiple sclerosis patients at pre-defined critical time points. Reverse-transcriptase-PCR was performed to detect human rhinovirus-RNA. Positive amplicons were sequenced. Results We found that rhinovirus RNA was present in 17/40 (43%) of specimens obtained at the onset of a URTI in 19 patients, in 1/21 specimens during convalescence after URTI in 14 patients, in 0/6 specimens obtained in 5 patients on average a week after the onset of an “at risk” relapse, occurring within a window in time from one week before to three weeks after an infection, and in 0/17 specimens obtained after the onset of a “not at risk” relapse not associated with any infection in 12 patients. Fifteen specimens from healthy control persons not associated with URTI were negative. The frequency of HRV presence in URTI was similar to that reported for community infections. Eight amplicons from patients represented 5 different HRV strains. Conclusion We were unable to reproduce previous findings of association between HRV infections and multiple sclerosis relapses. HRV was not present in nasopharyngeal aspirates obtained during “at risk” or “not at risk” relapses. Sequencing of HRV obtained from patients during URTI did not reveal any strain with predominance in multiple sclerosis.