Comparison of the levels of human herpesvirus 6 (HHV‐6) DNA and cytokines in the cerebrospinal fluid and serum of children with HHV‐6 encephalopathy

Primary human herpesvirus‐6 (HHV‐6) infection is a common cause of acute sporadic encephalopathy in Japanese children. Occasionally, HHV‐6 is not detected in the cerebrospinal fluid (CSF) of patients with encephalopathy, for example, in those with focal viral encephalitis, such as herpes simplex viral encephalitis. This indicates that HHV‐6 encephalopathy is caused by an indirect mechanism, although this is not fully understood. HHV‐6 DNA, cytokines (interleukin (IL)‐1β, IL‐6, IL‐8, IL‐10, IL‐12 p70, tumor necrosis factor‐α, interferon‐γ), and matrix metalloproteinase‐9 were quantitated in both the CSF and serum of 13 patients with HHV‐6 encephalopathy during the acute phase of the disease. HHV‐6 DNA was detected in the CSF of seven patients with HHV‐6 encephalopathy. The viral DNA concentration was significantly higher in serum than in CSF (mean 1.64 × 10⁴ vs. 5.70 × 10¹ copies/ml; P = 0.003). The lack or low level of viral DNA in the CSF samples suggests that direct invasion of the central nervous system by HHV‐6 is not the main cause of encephalopathy. Additionally, the IL‐10 concentration was significantly higher in serum than in CSF (P < 0.001), whereas there was no significant difference in IL‐6 levels between the CSF and serum samples. Interestingly, the IL‐8 concentration was significantly higher in CSF than in serum (P = 0.038). The distribution of these cytokines differed between CSF and serum. The high CSF concentration of IL‐8 could play an important role in the pathogenesis of encephalopathy. J. Med. Virol. 82:1410–1415, 2010. © 2010 Wiley‐Liss, Inc.     

Viral serologies in patients with chronic fatigue and chronic fatigue syndrome

Chronic fatigue syndrome (CFS) is an illness characterized by disabling fatigue associated with complaints of fevers, sore throat, myalgia, lymphadenopathy, sleep disturbances, neurocognitive difficulties, and depression. A striking feature of CFS is its sudden onset following an acute, presumably viral, illness and the subsequent recurrent “flu-like” symptoms. It has been speculated that both CFS and debilitating chronic fatigue (CF) that does not meet strict criteria for CFS may be the direct or indirect result of viral infections. We therefore tested 548 chronically fatigued patients who underwent a comprehensive medical and psychiatric evaluation for antibodies to 13 viruses. Our objectives were to compare the seroprevalence and/or geometric mean titer (GMT) of antibodies to herpes simplex virus 1 and 2, rubella, adenovirus, human herpesvirus 6, Epstein-Barr virus, cytomegalovirus, and Coxsackie B virus, types 1–6 in patients with CF to healthy control subjects. Other goals were to determine if greater rates of seropositivity or higher GMTs occurred among subsets of patients with CFS, fibromyalgia, psychiatric disorders, a self-reported illness onset with a viral syndrome, and a documented temperature >37°C on physical examination. Differences in the seroprevalence or GMTs of antibodies to 13 viruses were not consistently found in those with CF compared with control subjects, or in any subsets of patients including those with CFS, an acute onset of illness, or a documented fever. These particular viral serologies were not useful in evaluating patients presenting with CF. © 1996 Wiley-Liss, Inc.     

IgG subclasses and DNA detection of HHV‐6 and HHV‐7 in healthy individuals

Human herpesvirus 6 (HHV‐6) and 7 (HHV‐7) are common opportunistic agents in immunocompromised hosts, although infection with HHV‐6 and HHV‐7 can also be observed in immunocompetent hosts. Despite similar biology and epidemiology, this study evaluated differences in the IgG subclass distribution associated with HHV‐6 and HHV‐7 in seropositive, healthy persons. The identified subclasses were also compared with the detection of HHV‐6 and HHV‐7 DNA. For these assays, sera, plasma, and saliva samples were obtained from 40 healthy blood donors in Argentina who were seropositive for both HHV‐6 and HHV‐7. HHV‐6 and HHV‐7 DNA were detected in saliva and plasma samples using nested PCR, and specific IgG subclasses were determined using immunofluorescent assays of sera samples. HHV‐7 DNA was detected in 90% of all plasma samples and in 100% of saliva samples. In contrast, HHV‐6 DNA was not detected in any of the plasma samples, and it was detected in only 6 of 40 saliva samples. Determination of IgG subclass distributions showed that HHV‐6 was restricted to IgG1, whereas HHV‐7 IgG subclasses included two groups, one restricted only to IgG1 and the other to IgG1 and IgG3. These results demonstrate the differences between HHV‐6 and HHV‐7 DNA range detection in saliva and plasma samples, as well as the IgG subclass patterns for each virus type, in healthy persons in Argentina. J. Med. Virol. 82:1679–1683, 2010. 2010 Wiley‐Liss, Inc.     

Serological evidence that activation of ubiquitous human herpesvirus‐6 (HHV‐6) plays a role in chronic idiopathic/spontaneous urticaria (CIU)

Acute infection with viral pathogens in the herpesviridae family can trigger acute urticaria, and reactivation of herpesviridae is associated with cutaneous urticarial‐like syndromes such as drug‐induced hypersensitivity syndrome/drug reaction with eosinophilia and systemic symptoms (DRESS). Reactivation of latent herpesviridae has not been studied systematically in chronic idiopathic/spontaneous urticaria (CIU). This review proposes that CIU is an inflammatory disorder with autoimmune features (termed ‘CVU’ for chronic viral urticaria), based on serology consistent with the hypothesis that reactivation of a latent herpesvirus or ‐viruses may play a role in CIU. Serology obtained from a cohort of omalizumab (Xolair)‐dependent patients with severe CIU was consistent with previous HHV‐6 infection, persistent viral gene expression and replication. CIU patients also exhibited serological evidence of increased immune response to HHV‐4 (Epstein–Barr virus, or EBV) but not all CIU patients were infected with EBV. These observations, combined with case reports of CIU response to anti‐viral therapy, suggest that HHV‐6, possibly interacting with HHV‐4 in cutaneous tissues, is a candidate for further prospective study as a co‐factor in CIU.     

Possible mechanisms of the formation of chronic fatigue syndrome in the clinical picture of multiple sclerosis

A frequent manifestation of multiple sclerosis (MS) is chronic fatigue syndrome, which can be defined as a subjective decrease in the level of physical and/or mental energy. Chronic fatigue syndrome can be divided into asthenia (fatigue at rest), pathological fatigability (fatigue on physical loading), and fatigue on the background of deterioration of other symptoms (exacerbation of MS). There are both central and peripheral mechanisms for the formation of fatigue. The combination of fatigue and affective disturbances, especially depression and sleep disorders (insomnia, restless legs syndrome) is common in MS and may provide evidence that they share common mechanisms — decreases in the activity of the serotoninergic and noradrenergic systems. An important component in the formation of chronic fatigue syndrome consists of endocrine and autoimmune factors, the latter having a greater effect on asthenia than on pathological fatigue. Further studies of the pathogenetic mechanisms of the formation of asthenia and pathological fatigue and clarification of their differential diagnostic signs should allow not only a better understanding of the nature of this syndrome, but also better selection of individual treatment. __________ Translated from Zhurnal Nevrologii i Psikhiatrii imeni S. S. Korsakova, Multiple Sclerosis, Supplement, No. 3, pp. 87–91, 2006.     

Relationships between self‐consistency,trauma‐centred identity,and post‐traumatic adjustment

Background: Post‐traumatic stress disorder (PTSD) models suggest that trauma‐centred self‐change is motivated by self‐consistency. Aim: The objective of this study was to investigate the relationships between self‐consistency, trauma‐centred identity, and PTSD symptoms. Method: University students (n = 134) completed measures of trauma‐centred identity (Centrality of Events Scale), self‐consistency, and post‐traumatic stress symptoms (Impact of Events Scale—Revised, Centre for Epidemiological Studies—Depression Scale). Results: A significant positive correlation was found between trauma‐centred identity and post‐traumatic symptoms. However, self‐consistency was not related to post‐traumatic symptoms or trauma‐centred identity. Given the relationship between depressive symptoms and self‐consistency, the correlations were also conducted controlling for depression. When the effects of depressive symptoms were partialled out, both self‐consistency and trauma‐centred identity were positively correlated with intrusion symptoms. Discussion and Conclusion: The implications for PTSD models, which suggest self‐change is motivated by self‐consistency, are discussed and implications for clinical treatments are considered.     

Randomized clinical trial to evaluate the efficacy and safety of valganciclovir in a subset of patients with chronic fatigue syndrome

There is no known treatment for chronic fatigue syndrome (CFS). Little is known about its pathogenesis. Human herpesvirus 6 (HHV‐6) and Epstein–Barr virus (EBV) have been proposed as infectious triggers. Thirty CFS patients with elevated IgG antibody titers against HHV‐6 and EBV were randomized 2:1 to receive valganciclovir (VGCV) or placebo for 6 months in a double‐blind, placebo‐controlled trial. Clinical endpoints aimed at measuring physical and mental fatigue included the Multidimensional Fatigue Inventory (MFI‐20) and Fatigue Severity Scale (FSS) scores, self‐reported cognitive function, and physician‐determined responder status. Biological endpoints included monocyte and neutrophil counts and cytokine levels. VGCV patients experienced a greater improvement by MFI‐20 at 9 months from baseline compared to placebo patients but this difference was not statistically significant. However, statistically significant differences in trajectories between groups were observed in MFI‐20 mental fatigue subscore (P = 0.039), FSS score (P = 0.006), and cognitive function (P = 0.025). VGCV patients experienced these improvements within the first 3 months and maintained that benefit over the remaining 9 months. Patients in the VGCV arm were 7.4 times more likely to be classified as responders (P = 0.029). In the VGCV arm, monocyte counts decreased (P < 0.001), neutrophil counts increased (P = 0.037) and cytokines were more likely to evolve towards a Th1‐profile (P < 0.001). Viral IgG antibody titers did not differ between arms. VGCV may have clinical benefit in a subset of CFS patients independent of placebo effect, possibly mediated by immunomodulation and/or antiviral effect. Further investigation with longer treatment duration and a larger sample size is warranted. J. Med. Virol. 85:2101–2109, 2013. © 2013 The Authors. Journal of Medical Virology Published by Wiley Periodicals, Inc.     

Differential diagnosis of chronic fatigue syndrome and major depressive disorder

The goal of this study was to identify variables that successfully differentiated patients with chronic fatigue syndrome, major depressive disorder, and controls. Fifteen participants were recruited for each of these three groups, and discriminant function analyses were conducted. Using symptom occurrence and severity data from the Fukuda et al. (1994) definitional criteria, the best predictors were postexertional malaise, unrefreshing sleep, and impaired memory-concentration. Symptom occurrence variables only correctly classified 84.4% of cases, whereas 91.1% were correctly classified when using symptom severity ratings. Finally, when using percentage of time fatigue reported, postexertional malaise severity, unrefreshing sleep severity, confusion-disorientation severity, shortness of breath severity, and self-reproach to predict group membership, 100% were classified correctly. We appreciate the financial assistance provided by the National Institute of Allergy and Infectious Diseases (grant nos. AI36295 and AI49720).     

Extended B cell phenotype in patients with myalgic encephalomyelitis/chronic fatigue syndrome: a cross‐sectional study

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a heterogeneous condition of unknown aetiology characterized by multiple symptoms including fatigue, post‐exertional malaise and cognitive impairment, lasting for at least 6 months. Recently, two clinical trials of B cell depletion therapy with rituximab (anti‐CD20) reported convincing improvement in symptoms. A possible but undefined role for B cells has therefore been proposed. Studies of the relative percentages of B cell subsets in patients with ME/CFS have not revealed any reproducible differences from healthy controls (HC). In order to explore whether more subtle alterations in B cell subsets related to B cell differentiation exist in ME/CFS patients we used flow cytometry to immunophenotype CD19⁺ B cells. The panel utilized immunoglobulin (Ig)D, CD27 and CD38 (classical B cell subsets) together with additional markers. A total of 38 patients fulfilling Canadian, Centre for Disease Control and Fukuda ME/CFS criteria and 32 age‐ and sex‐matched HC were included. We found no difference in percentages of classical subsets between ME/CFS patients and HC. However, we observed an increase in frequency (P < 0·01) and expression (MFI; P = 0·03) of CD24 on total B cells, confined to IgD⁺ subsets. Within memory subsets, a higher frequency of CD21⁺CD38^– B cells (>20%) was associated with the presence of ME/CFS [odds ratio: 3·47 (1·15–10·46); P = 0·03] compared with HC, and there was a negative correlation with disease duration. In conclusion, we identified possible changes in B cell phenotype in patients with ME/CFS. These may reflect altered B cell function and, if confirmed in other patient cohorts, could provide a platform for studies based on clinical course or responsiveness to rituximab therapy.     

Eosinophil cationic protein serum levels and allergy in chronic fatigue syndrome

Chronic fatigue syndrome (CFS) is a syndrome of uncertain etiopathogenesis characterized by disabling fatigue associated with a variable number of somatic and/or neuropsychologic symptoms. In patients with CFS, several immunologic abnormalities can be detected, including a higher prevalence of allergy. The aim of this study was to determine whether CFS patients, well studied for their allergy profile, show signs of eosinophil activation, as detectable by the measurement in serum of eosinophil cationic protein (ECP) levels. In 35 consecutive CFS outpatients (diagnosis based on the Centers for Disease Control case definition), ECP was measured in serum by a competitive enzyme immunoassay (ECP-FEIA kit, Kabi Pharmacia Diagnostics, Uppsala, Sweden). Fourteen disease-free subjects with no history of CFS or allergy were selected as controls. ECP serum levels were significantly higher in CFS patients than in controls (18.0±11.3 μg/1 vs 7.3 ± 2.1 μg/1; P < 0.01). In the CFS population, the prevalence of RAST positivity to one or more allergens was 77%, while no control showed positive RAST. Twelve of the 14 CFS patients with increased ECP serum levels were RAST-positive. However, CFS RAST-positive patients had no significantly higher ECP serum levels than CFS RAST-negative patients (19.3 ± 12.4 μg/1 vs 13.6 ± 3.7 μg/1; P = 0.4). This is the first report of increased serum levels of ECP in CFS. On the basis of the available data, it is discussed whether eosinophil activation has a pathogenetic role in CFS or is linked to the frequently associated allergic condition, or, finally, whether a common immunologic background may exist for both atopy and CFS.     

Prevalence of HHV‐6 integrated chromosomally among children treated for acute lymphoblastic or myeloid leukemia in the Czech Republic

Chromosomal integration of human herpesvirus 6 (HHV‐6) is a novel situation found in a small percentage of individuals. While active HHV‐6 infection is treatable using antivirals, the abnormally high level of HHV‐6 DNA found in chromosomal integration of HHV‐6 (CI‐HHV‐6) is not affected by such drugs. Stored DNA samples taken originally for detection of fusion genes and minimal residual disease from 339 pediatric patients treated for leukemia in the Czech Republic between the years 1995–2007 were tested retrospectively. Using real‐time quantitative PCR technology, the quantity of HHV‐6 DNA detected was normalized to 100,000 human genome equivalents as assessed by quantitation of the albumin gene. HHV‐6 DNA was detected in 107 samples from 91 patients (26.8%). In the majority of samples (99) only a minute level of normalized viral copies (NVCs) (median 1.84 NVCs) was detected. A high viral load of approximately 100,000 NVCs was detected in 5 patients (1.5%; median 140,150 NVCs), in all of whom were confirmed subsequently CI‐HHV‐6 by a detection of HHV‐6 DNA in hair follicles or in the nails. In all but one patient with HHV‐6 variant B, variant A of the virus was detected. None of the patients with CI‐HHV‐6 had complications attributable to HHV‐6 infection. The prevalence of CI‐HHV‐6 in childhood leukemia does not differ from that published for other patients or healthy populations. Where high levels of HHV‐6 DNA are present, CI‐HHV‐6 should be confirmed as soon as possible so that potentially toxic but ineffective antiviral treatment can be stopped. J. Med. Virol. 81:258–263, 2009. © 2008 Wiley‐Liss, Inc.     

Mesothelial‐to‐mesenchymal transition in the pathogenesis of post‐surgical peritoneal adhesions

Peritoneal adhesions (PAs) are fibrotic bands formed between bowel loops, solid organs, and the parietal peritoneum, which may appear following surgery, infection or endometriosis. They represent an important health problem with no effective treatment. Mesothelial cells (MCs) line the peritoneal cavity and undergo a mesothelial‐to‐mesenchymal transition (MMT) under pathological conditions, transforming into myofibroblasts, which are abundant in peritoneal fibrotic tissue. The aim of this study was to investigate if peritoneal MCs undergo a MMT contributing to the formation of post‐surgical adhesions. Biopsies from patients with PAs were analysed by immunohistochemistry, immunofluorescence, and quantitative RT‐PCR. A mouse model of PAs based on ischaemic buttons was used to modulate MMT by blocking the transforming growth factor‐beta (TGF‐β) pathway. The severity of adhesions and MMT‐related marker expression were studied. We observed myofibroblasts derived from the conversion of MCs in submesothelial areas of patients with PAs. In addition, MMT‐related markers were dysregulated in adhesion zones when compared to distant normal peritoneal tissue of the same patient. In animal experiments, blockage of TGF‐β resulted in molecular reprogramming of markers related to the mesenchymal conversion of MCs and in a significant decrease in the severity of the adhesions. These data indicate for the first time that MMT is involved in PA pathogenesis. This finding opens new therapeutic strategies to interfere with adhesion formation by modulating MMT with a wide range of pharmacological agents. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.     

Chronic fatigue syndrome,fibromyalgia, and related illnesses: a clinical model of assessment and intervention

A clinically informative behavioral literature on chronic fatigue syndrome (CFS) and fibromyalgia (FM) has emerged over the past decade. The purpose of this article is to (a) define these conditions and their less severe counterparts, i.e., unexplained chronic fatigue (UCF) and chronic widespread pain; (b) briefly review the behavioral theory and intervention literature on CFS and FM; and (c) describe a user‐friendly clinical model of assessment and intervention for these illnesses. The assessments described will facilitate understanding of the somewhat unusual and puzzling somatic presentations that characterize these patients. Using an individualized cognitive‐behavioral approach the mental health clinician can offer significant help to these often stigmatized and medically underserved patients. © 2010 Wiley Periodicals, Inc. J Clin Psychol 66:1–25, 2010.