Hybrid capture shotgun sequencing detected unexpected viruses in the cerebrospinal fluid of children with acute meningitis and encephalitis.

PURPOSE: Investigation of undiagnosed cases of infectious neurological diseases, especially in the paediatric population, remains a challenge. This study aimed to enhance understanding of viruses in CSF from children with clinically diagnosed meningitis and/or encephalitis (M/ME) of unknown aetiology using shotgun sequencing enhanced by hybrid capture (HCSS). METHODS: A single-centre prospective study was conducted at Sant Joan de Déu University Hospital, Barcelona, involving 40 M/ME episodes of unknown aetiology, recruited from May 2021 to July 2022. All participants had previously tested negative with the FilmArray Meningitis/Encephalitis Panel. HCSS was used to detect viral nucleic acid in the patients' CSF. Sequencing was performed on Illumina NovaSeq platform. Raw sequence data were analysed using CZ ID metagenomics and PikaVirus bioinformatics pipelines. RESULTS: Forty episodes of M/ME of unknown aetiology in 39 children were analysed by HCSS. A significant viral detection in 30 CSF samples was obtained, including six parechovirus A, three enterovirus ACD, four polyomavirus 5, three HHV-7, two BKV, one HSV-1, one VZV, two CMV, one EBV, one influenza A virus, one rhinovirus, and 13 HERV-K113 detections. Of these, one sample with BKV, three with HHV-7, one with EBV, and all HERV-K113 were confirmed by specific PCR. The requirement for Intensive Care Unit admission was associated with HCSS detections. CONCLUSION: This study highlights HCSS as a powerful tool for the investigation of undiagnosed cases of M/ME. Data generated must be carefully analysed and reasonable precautions must be taken before establishing association of clinical features with unexpected or novel virus findings.

Virus detection of measles-negative cases in Gyeonggi Province, South Korea, from 2017 to 2019.

To investigate viruses in measles-negative cases, 221 measles-suspected samples collected in Gyeonggi Province, South Korea were tested using a real-time PCR assay. Rubella virus was not detected. However, 11 cases of parvovirus B19 (5.0%), 47 cases of human herpesvirus 6 (21.3%), 25 cases of human herpesvirus 7 (11.3%), and one case of co-infection with parvovirus B19 and human herpesvirus 7 were confirmed, as were eight cases of co-infection with human herpesvirus 6 and human herpesvirus 7. This study showed that parvovirus B19, human herpesvirus 6, and human herpesvirus 7 should be considered by physicians for the diagnosis of measles-suspected patients.

Herpesvirus infections in adenoids in patients with chronic adenotonsillar disease.

Adenoids and tonsils have gained interest as a new in vivo model to study local immune functions and virus reservoirs. Especially herpesviruses are interesting because their prevalence and persistence in local lymphoid tissue are incompletely known. Our aim was to study herpesvirus and common respiratory virus infections in nonacutely ill adenotonsillar surgery patients. Adenoid and/or palatine tonsil tissue and nasopharyngeal aspirate (NPA) samples were collected from elective adenoidectomy (n = 45) and adenotonsillectomy (n = 44) patients (median age: 5, range: 1-20). Real-time polymerase chain reaction was used to detect 22 distinct viruses from collected samples. The overall prevalence of herpesviruses was 89% and respiratory viruses 94%. Human herpesviruses 6 (HHV6), 7 (HHV7), and Epstein-Barr virus (EBV) were found, respectively, in adenoids (33%, 26%, 25%), tonsils (45%, 52%, 23%), and NPA (46%, 38%, 25%). Copy numbers of the HHV6 and HHV7 genome were significantly higher in tonsils than in adenoids. Patients with intra-adenoid HHV6 were younger than those without. Detection rates of EBV and HHV7 showed agreement between corresponding sample types. This study shows that adenoid and tonsil tissues commonly harbor human herpes- and respiratory viruses, and it shows the differences in virus findings between sample types.

[Lymphadenitis possibly due to human herpesvirus 7 during methotrexate therapy for rheumatoid arthritis].

A 75-year-old woman who was treated with methotrexate (MTX) for rheumatoid arthritis was admitted to our hospital because of fever and loss of appetite. Physical examination revealed exanthems in the upper limbs and systemic lymphadenopathy. Her blood test showed elevated levels of serum lactate dehydrogenase (LDH) and soluble interleukin-2 receptor (sIL-2R). Lymph node biopsy indicated atrophic follicles, interfollicular hyperplasia, and infiltration of macrophages phagocytosing nuclear debris and T-lymphocytes. This suggested lymphadenitis associated with viral infection. Human herpesvirus 7 (HHV-7) DNA was detected in the lymphoid tissue using polymerase chain reaction. The patient was successfully treated with MTX discontinuation and short-term administration of dexamethasone. Her symptoms improved, and LDH and sIL-2R levels were normalized. Human herpesvirus reactivates in patients with immunodeficiency on MTX administration. To the best of our knowledge, this is a valuable case of lymphadenitis considered to have been caused by HHV-7.

Human Herpesvirus-6 and -7 in the Brain Microenvironment of Persons with Neurological Pathology and Healthy People.

During persistent human beta-herpesvirus (HHV) infection, clinical manifestations may not appear. However, the lifelong influence of HHV is often associated with pathological changes in the central nervous system. Herein, we evaluated possible associations between immunoexpression of HHV-6, -7, and cellular immune response across different brain regions. The study aimed to explore HHV-6, -7 infection within the cortical lobes in cases of unspecified encephalopathy (UEP) and nonpathological conditions. We confirmed the presence of viral DNA by nPCR and viral antigens by immunohistochemistry. Overall, we have shown a significant increase (p < 0.001) of HHV antigen expression, especially HHV-7 in the temporal gray matter. Although HHV-infected neurons were found notably in the case of HHV-7, our observations suggest that higher (p < 0.001) cell tropism is associated with glial and endothelial cells in both UEP group and controls. HHV-6, predominantly detected in oligodendrocytes (p < 0.001), and HHV-7, predominantly detected in both astrocytes and oligodendrocytes (p < 0.001), exhibit varying effects on neural homeostasis. This indicates a high number (p < 0.001) of activated microglia observed in the temporal lobe in the UEP group. The question remains of whether human HHV contributes to neurological diseases or are markers for some aspect of the disease process.

Summary of the 11th International Conference on Human Herpesviruses-6A, -6B, and -7.

The 11th International Conference on Human Herpesviruses (HHV)-6A, -6B, and -7 was held in Quebec City, from 23 to 26 June 2019. It attracted 144 basic, translational, and clinical scientists from 20 countries. Important new information was presented regarding: the mechanisms of chromosomal integration for HHV-6A and -6B; the biology of inherited chromosomally integrated HHV-6A and -6B; animal models for, and animal viruses with similarities to, HHV-6A, -6B, and -7; established and possible disease associations, including provocative new information suggesting these viruses may be one trigger of Alzheimer's disease, and new treatment strategies. In this review, we summarize presentations that were of particular interest. The full text of the Abstracts cited in the manuscript is available in the online Supporting Information Materials.

Pityriasis rosea during omalizumab treatment for chronic spontaneous urticaria.

Pityriasis rosea (PR) is an exanthematous disease whose etiology is related to reactivation of herpes human herpesviruses 6 (HHV-6) and 7 (HHV-7). We observed two cases of PR arising during omalizumab therapy for chronic spontaneous urticaria (CSU). Here we report for the first time PR occurring during omalizumab treatment. After PR diagnosis, viral serology was performed. Data in literature about omalizumab mechanism of action, PR and HHV-6/7 infection were analyzed in order to identify possible correlations. In both our cases IgM against HHV-6 and HHV-7 were negative. The first patient presented altered IgG titers for both viruses (1:160 and 1:80, respectively) while only HHV-6 IgG (1:320) were detected in the second patient. From data in literature, we consider it presumable that apoptotic immune cells due to omalizumab immunomodulation could release viral proteins produced from integrated DNA. This could elicit cutaneous cross-reactivity and PR onset. In conclusion, we think there is a link between omalizumab therapy and PR occurring in patients with CSU. Our case history is too small to draw firm conclusions. Data collection of similar cases could be helpful to improve our knowledge.

Reactivation of human herpesviruses 6 and 7 in Kawasaki disease.

Objectives: Kawasaki disease (KD) is one of the most common childhood vasculitides. Some serological studies have suggested an etiological relationship between KD and human herpesvirus (HHV)-6 or HHV-7. However, primary or reactivated HHV-6 and -7 has not been fully investigated in patients with KD. Methods: Twenty-three patients with KD were prospectively enrolled in this study. Peripheral blood was collected in the acute and convalescence phases, and HHV-6 and -7 viral loads were measured by real-time PCR. Results: In the acute phase, HHV-6 and -7 DNA was detected in 7 (30%) patients each, compared to 13 (57%) and 9 (39%) patients in the convalescence phase, respectively. HHV-6 and -7 DNA loads were significantly higher in the convalescence phase than in the acute phase. Significant increases in HHV-6 and -7 DNA loads were not observed in disease control patients. Taking into account HHV-6 and -7 serostatus, reactivation of HHV-6 and -7 was observed in 7 and 9 patients, respectively. KD patients with HHV-6 reactivation showed higher C-reactive protein levels and more frequently required steroid therapies than patients without reactivation. Conclusion: HHV-6 and -7 reactivation is frequent in KD patients. HHV-6 reactivation might exacerbate the severity of KD.

Summary of the 10th International Conference on Human Herpesviruses-6 and -7 (HHV-6A, -6B, and HHV-7).

The 10th International Conference on Human herpesviruses-6 and -7 (HHV-6A, HHV-6B, and HHV-7) was held at the Freie Universität, Berlin, Germany from July 23-26, 2017. It attracted more than 130 basic, translational and clinical scientists from 19 countries. Important new information was presented regarding: the biology of HHV-6A and -6B; the biology and epidemiology of inherited chromosomally integrated HHV-6A and -6B; improved diagnostic tests; animal models for and animal viruses with similarities to HHV-6A, -6B, and -7; established and possible disease associations; and new treatment strategies. Here, we summarize work presented at the meeting that is of particular interest.

Pityriasis Rosea during Pregnancy: Major and Minor Alarming Signs.

BACKGROUND: Pityriasis rosea (PR) is a self-limiting exanthematous disease associated with human herpesvirus (HHV)-6 and/or HHV-7 reactivation. In pregnant women, PR may be associated with pregnancy complications. OBJECTIVE: To determine relevant risk factors in the development of negative pregnancy outcome in PR. METHODS: Between 2005 and 2017 at the Department of Dermatology, University of Genoa, we recruited 76 women who developed PR during pregnancy. In 60 patients without known risk factors for intrauterine fetal death (30 with pregnancy complications and 30 without) we analyzed the pregnancy week of PR onset, presence of enanthem and of constitutional symptoms, PR body surface area involvement, age, and in 50 patients (20 with pregnancy complications and 30 without), the viral load of HHV-6 and HHV-7 (copies/mL). RESULTS: In logistic regression analysis, early onset of PR (p = 0.0017) and enanthem (p = 0.0392) proved to be significantly associated with pregnancy complications. HHV-6 viral load (copies/mL) (p < 0.0001), constitutional symptoms (p < 0.001), and PR body surface area involvement (p < 0.004) were also significantly associated with pregnancy complications. CONCLUSION: The onset of PR before week 15 and enanthem may be considered major risk factors that should alarm the dermatologist. Constitutional symptoms and involvement of > 50% of the body area may be considered minor risk factors.

Encephalitis associated with human herpesvirus-7 infection in an immunocompetent adult.

BACKGROUND: Primary Human herpesvirus-7 (HHV-7) infection usually occurs during childhood and causes several clinical manifestations: mainly exanthem subitum (roseola infantum), followed by a lifelong latent state with possible reactivation in case of immunodeficiency. Nevertheless, some considerably different approaches exist regarding the natural history of HHV-7 and the possible consequences of HHV-7 infection in immunocompetent adults. In particular, little is known about its pathogenic role in central nervous system (CNS) disease in nonimmunosuppressed adults. Specifically, in case of encephalitis, it is important to distinguish between infectious encephalitis and postinfectious encephalomyelitis for the management of patients CASE PRESENTATION: We describe here a case of encephalitis associated to human herpesvirus-7 with associated polymyeloradiculopathy in an immunocompetent patient which may contribute to the delineation of the approach to a patient profile with a similar clinical presentation and evolution to those presented in the literature. CONCLUSIONS: This case may alert clinicians to consider this specific etiology in the differential diagnosis of encephalopathy in patients with suspected infectious encephalitis who do not respond to acyclovir or in patients who develop acute polymyeloradiculopathy, considering that HHV-7 may be a pathological factor and that a timely diagnosis is crucial for the early administration of specific treatment.

Summary of the 9th international conference on human herpesviruses 6 and 7 (HHV-6A, HHV-6B, and HHV-7).

The 9th International Conference on Human herpesviruses 6 and 7 (HHV-6A, HHV-6B, and HHV-7) was held at Harvard Medical School in Boston, Massachusetts from November 9 to 11, 2015. Important new information was presented regarding: the biology of these viruses, particularly HHV-6A and HHV-6B; the biology and epidemiology of inherited chromosomally integrated HHV-6A/B; improved diagnostic tests; animal models for studying HHV-6 and HHV-7, and animal viruses with similarities to HHV-6 and HHV-7; established and possible disease associations; and new approaches to treatment. Here, we summarize work of particular interest. J. Med. Virol. 88:2038-2043, 2016. © 2016 Wiley Periodicals, Inc.

Detection frequency of human herpesviruses-6A, -6B, and -7 genomic sequences in central nervous system DNA samples from post-mortem individuals with unspecified encephalopathy.

In this autopsy-based study, human herpesvirus-6 (HHV-6) and -7 (HHV-7) genomic sequence frequency, HHV-6 variants, HHV-6 load and the expression of HHV-6 antigens in brain samples from the individuals, with and without unspecified encephalopathy (controls), using nested and real-time polymerase chain reactions, restriction endonuclease, and immunohistochemical analysis were examined. GraphPad Prism 6.0 Mann-Whitney nonparametric and chi-square test and Fisher's exact test were used for statistical analysis. The encephalopathy diagnoses were shown by magnetic resonance imaging made during their lifetime and macro- and microscopically studied autopsy tissue materials. Widespread HHV-6 and/or HHV-7 positivity was detected in the brain tissue of various individuals with encephalopathy, as well as in controls (51/57, 89.4 % and 35/51, 68.6 %, respectively; p = 0.009). Significantly higher detection frequency of single HHV-6 and concurrent HHV-6 + HHV-7 DNA was found in pia mater meninges, frontal lobe, temporal lobe, and olfactory tract DNAs in individuals with encephalopathy compared to the control group. HHV-6 load and higher frequency of the viral load >10 copies/10(6) cells significantly differed in samples from individuals with and without encephalopathy. The expression of HHV-6 antigens was revealed in different neural cell types with strong predominance in the encephalopathy group. In all HHV-6-positive autopsy samples of individuals with and without encephalopathy, HHV-6B was revealed. Significantly higher detection frequency of beta-herpesvirus DNA, more often detected HHV-6 load >10 copies/10(6) cells, as well as the expression of HHV-6 antigens in different brain tissue samples from individuals with encephalopathy in comparison with control group indicate on potential involvement of these viruses in encephalopathy development.

A fatal case of DRESS induced by strontium ranelate associated with HHV-7 reactivation.

We report the first case of drug rash with eosinophilia and systemic symptoms (DRESS) following strontium ranelate (SR) treatment associated with systemic human HHV-7 reactivation. DRESS syndrome is a severe adverse drug-induced reaction presenting as a diffuse maculopapular skin rash with fever, hematological abnormalities (leukocytosis, eosinophilia, and/or atypical lymphocytosis), and multiorgan involvement. In our patient, diagnosis of DRESS was confirmed by the presence of six of the seven diagnostic criteria established in 2006 by the Japanese Research Committee on Severe Cutaneous Adverse Drug Reaction: maculopapular skin rash developing at least 3 weeks after starting therapy with a limited number of drugs, prolonged clinical symptoms after discontinuation of the causative drug, lymphadenopathy, fever, leukocyte abnormalities, and liver abnormalities. The diagnostic criteria of human herpesvirus (HHV)-6 reactivation have not been fulfilled in our patient, but a HHV-7 active infection was demonstrated by the presence of HHV-7 DNA and IgM in the patient's serum. In fact, in some DRESS instances, reactivation of HHVs other than HHV-6 may be detected, including HHV-7, Epstein-Barr virus (EBV), and cytomegalovirus (CMV). Our case underlines that not only HHV-6 but also HHV-7 systemic reactivation may be associated with a more severe and even fatal course of this syndrome.

Viral infections in acute graft-versus-host disease: a review of diagnostic and therapeutic approaches.

BACKGROUND: While immunosuppressive therapy for acute graft-versus-host disease (aGVHD) advances, viral reactivation has been found to be an increasingly common complication in these patients. Dermatologists may often be consulted on inpatient services for evaluation. OBJECTIVE: We investigated the literature for the role of viral infections in aGVHD and review the current evidence regarding management. METHODS: Articles in the public domain regarding aGVHD, cytomegalovirus, Epstein-Barr virus, varicella zoster virus, hepatitis viruses, parvovirus B19, and respiratory viruses were included. RESULTS: Dermatologic findings vary between different viral antigens, and some infections may be a marker for the development of aGVHD or worsen prognosis. LIMITATIONS: The heterogeneous cohorts of the studies reviewed often preclude direct comparison between results. CONCLUSION: The relationship between viral reactivation and aGVHD may be bidirectional and is worthy of further exploration. Additional studies are needed to determine appropriate prophylaxis and treatment.

Quantitative polymerase chain reaction for detection of human herpesvirus-7 infection in umbilical cord blood donors.

OBJECTIVE: Umbilical cord blood (UCB) has been a reasonable alternative to granulocyte colony-stimulating factor-mobilized peripheral blood or bone marrow, as a source of hematopoietic stem cells with a lower risk of graft-versus-host disease. In immunocompromised hosts after transplantation, the risk of viral infection in adults, especially with beta-herpesviruses such as human herpesvirus-7 (HHV-7), may be increased. This virus in immunocompromised patients can be reactivated from latency and converted to an active phase. Therefore, light-upon-extension real-time polymerase chain reaction (PCR) was developed to assess the prevalence and load of HHV-7 in the plasma and buffy coat of donors. METHODS: About 825 UCB samples under standard protocol from donors were collected. Then, DNA from plasma and buffy coat was extracted and quantitative real-time PCR was performed with light-upon-extension primers. RESULTS: Overall, HHV-7 was detected in 3.64% (30/825) of UCB donors. HHV-7 DNA was detected in 26 (3.2%) buffy coat samples (latent infection), and only 4 (0.48%) of them were positive for HHV-7 DNA in plasma samples (active infection); the mean HHV-7 viral load was 1.31 × 10(1) copies/mL in latent infection, and 1.94 × 10(5) copies/mL in active infection. CONCLUSIONS: We suggest that real-time PCR in plasma and buffy coat could be a useful method to detect active and latent HHV-7 infection in UCB donors and determine its role in subsequent transmission events.

Human herpesvirus 7 meningitis in an adolescent with normal immune function: A case report.

BACKGROUND: Human herpesvirus type 7 (HHV-7) is a less common herpes virus that usually causes mild, self-limiting illnesses. However, in recent years, there have been increasing reports of HHV-7 causing serious central nervous system infections, especially meningitis. The pathogenesis and clinical features of HHV-7 meningitis, particularly in adolescents with normal immune function, remain incompletely studied. Therefore, the purpose of this report is to share a case of HHV-7 meningitis in an immunocompetent adolescent with a view to deepening our understanding of the disease. CASE SUMMARY: A 12-year-old female was admitted with fever, headache, and vomiting. 4 d before admission, the patient developed a fever without obvious induction, with a temperature up to 39.5 °C, no convulsions, accompanied by chills, headaches, fatigue, and no muscle aches. The patient was treated with fever reduction, which could be reduced to 38 °C; repeated high fever, accompanied by vomiting 7-8 times; and no abdominal pain or diarrhea. The patient was diagnosed with "acute suppurative tonsillitis" in a local hospital, and the blood routine was generally normal. The patient was given symptomatic support treatment such as "ceftriaxone sodium" and antiemetic rehydration for 2 d, and his condition did not improve. The patient's physical examination showed pharyngeal congestion, bilateral tonsil grade I hypertrophy, regression of purulent secretions, and cervical resistance. Ocular B-ultrasound: Opacity of the vitreous body and edema of the optic disc in both eyes. Optical coherence tomography examination showed that the macular fovea was generally normal in both eyes, with edema of the optic disc. DNA virus monitoring results: HHV-7. We gave ganciclovir antiviral therapy, dexamethasone anti-inflammatory treatment, mannitol to reduce cranial pressure, omeprazole to protect gastrointestinal mucosa, and calcium and potassium supplementation. CONCLUSION: This study reports a case of HHV-7 meningitis in an adolescent with normal immune function. Through comprehensive analysis of the clinical manifestations, laboratory tests, and treatment methods of the patient, it is found that early identification and antiviral treatment are essential for the outcome of the disease. This case suggests that despite normal immune function, adolescents may still suffer from herpes virus type 7 meningitis, so clinicians should be vigilant and take effective treatment measures in time.