Adeno-associated virus type 2 in US children with acute severe hepatitis.

As of August 2022, clusters of acute severe hepatitis of unknown aetiology in children have been reported from 35 countries, including the USA1,2. Previous studies have found human adenoviruses (HAdVs) in the blood from patients in Europe and the USA3-7, although it is unclear whether this virus is causative. Here we used PCR testing, viral enrichment-based sequencing and agnostic metagenomic sequencing to analyse samples from 16 HAdV-positive cases from 1 October 2021 to 22 May 2022, in parallel with 113 controls. In blood from 14 cases, adeno-associated virus type 2 (AAV2) sequences were detected in 93% (13 of 14), compared to 4 (3.5%) of 113 controls (P < 0.001) and to 0 of 30 patients with hepatitis of defined aetiology (P < 0.001). In controls, HAdV type 41 was detected in blood from 9 (39.1%) of the 23 patients with acute gastroenteritis (without hepatitis), including 8 of 9 patients with positive stool HAdV testing, but co-infection with AAV2 was observed in only 3 (13.0%) of these 23 patients versus 93% of cases (P < 0.001). Co-infections by Epstein-Barr virus, human herpesvirus 6 and/or enterovirus A71 were also detected in 12 (85.7%) of 14 cases, with higher herpesvirus detection in cases versus controls (P < 0.001). Our findings suggest that the severity of the disease is related to co-infections involving AAV2 and one or more helper viruses.

Systematic review with meta-analysis of active herpesvirus infections in patients with COVID-19: Old players on the new field.

OBJECTIVES: Herpesviruses are ubiquitous and after primary infection they establish lifelong latency. The impairment of maintaining latency with short-term or long-term consequences could be triggered by other infection. Therefore, reactivation of herpesviruses in COVID-19 patients represents an emerging issue. DESIGN AND METHODS: This study provided the first systematic review with meta-analysis of studies that evaluated active human herpesvirus (HHV) infection (defined as the presence of IgM antibodies or HHV-DNA) in COVID-19 patients and included 36 publications collected by searching through PubMed, SCOPUS, and Web of science until November 2022. RESULTS: The prevalence of active EBV, HHV6, HSV, CMV, HSV1, and VZV infection in COVID-19 population was 41% (95% CI =27%-57%), 3% (95% CI=17%-54%), 28% (95% CI=1%-85%), 25% (95% CI=1%-63%), 22% (95% CI=10%-35%), and 18% (95% CI=4%-34%), respectively. There was a 6 times higher chance for active EBV infection in patients with severe COVID-19 than in non-COVID-19 controls (OR=6.45, 95% CI=1.09-38.13, p=0.040), although there was no difference in the prevalence of all evaluated active herpesvirus infections between COVID-19 patients and non-COVID-19 controls. CONCLUSIONS: Future research of herpesvirus and SARS-CoV-2 coinfections must be prioritized to define: who, when and how to be tested, as well as how to effectively treat HHVs reactivations in acute and long COVID-19 patients.

Pityriasis Rosea after COVID-19 Infection.

Dear Editor, Pityriasis rosea (PR) is a common, self-limited erythematous papulosquamous dermatosis that mainly affects young adults. It is believed to represent a delayed reaction to viral infections and is usually associated with endogenous systemic reactivation of human herpesvirus (HHV) 6 and / or 7 (1). A 46-year-old man presented to our Department with a two-week history of skin rash associated with mild pruritus. He described the appearance of an erythematous centrally scaled lesion at the right part of his abdomen, followed by the spreading of red oval mildly scaling lesions on the trunk, neck, and proximal parts of the upper extremities, which showed in the physical examination (Figure 1, a and b). He was otherwise healthy and taking no medications. Six weeks prior to the appearance of the initial skin lesion, the patient had coronavirus disease 2019 (COVID-19) infection with mild clinical presentation (fever up to 38 °C lasting for four days and mild headache) and with symptoms of post COVID-19 syndrome (excessive tiredness). He denied oropharyngeal lesions. Potassium hydroxide, syphilis, and laboratory tests were within normal limits. Within two weeks of topical betamethasone dipropionate treatment, the lesions disappeared completely. In addition to reactivation of HHV-6 or HHV-7, PR can be triggered by some drugs (like angiotensin-converting enzyme inhibitors alone or in combination with hydrochlorothiazide, sartans plus hydrochlorothiazide, allopurinol, nimesulide, and acetyl salicylic acid (2) and vaccines (such as smallpox, poliomyelitis, influenza, human papillomavirus, diphtheria, tuberculosis, hepatitis B, pneumococcus, and yellow fever vaccines) (3). There is a growing number of published cases that link PR to COVID-19 infection, with PR appearing either in the acute phase of COVID-19 or, as in our patient, in the post COVID-19 period (4-9). Unlike in our patient, oropharyngeal lesions were observed in approximately 16% of patients with typical PR (10). It has been suggested that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) induces reactivation of other viruses, such as HHV-6, HHV-7, varicella zoster virus, and Epstein-Barr virus (5). PR has also been reported to follow COVID-19 vaccination (11). As our patient did not receive a COVID-19 vaccine, we cannot evaluate the latter based on the present case. We speculate that PR could be a delayed skin manifestation of COVID-19 infection, triggered either by SARS-CoV-2 immediately or indirectly by the reactivation of other viruses such as HHV-6 or HHV-7. However, the etiopathogenetic mechanisms remain largely unknown and further studies are needed in order to clarify the correlation between SARS-CoV-2 and PR.

Primary Human Herpes Virus-6 Causing Recalcitrant Pyrexia after Pilocytic Astrocytoma Resection.

INTRODUCTION: Human herpes virus-6 (HHV-6) is a ubiquitous virus but can lead to deleterious clinical manifestations due to its predilection for the pediatric central nervous system. Despite significant literature describing its common clinical course, it is rarely considered as a causative agent in CSF pleocytosis in the setting of craniotomy and external ventricular drainage device. Identification of a primary HHV-6 infection allowed for timely treatment with an antiviral agent along with earlier discontinuation of antibiotic regimen and expedited placement of a ventriculoperitoneal shunt. CASE PRESENTATION: A two-year-old girl presented with 3 months of progressive gait disturbance and intranuclear ophthalmoplegia. Following craniotomy for removal of 4th ventricular pilocytic astrocytoma and decompression of hydrocephalus, she suffered a prolonged clinical course due to persistent fevers and worsening CSF leukocytosis despite multiple antibiotic regimens. The patient was admitted to the hospital during the COVID-19 pandemic and isolated with her parents in the intensive care unit with strict infection control measures. FilmArray Meningitis/Encephalitis (FAME) panel ultimately detected HHV-6. Clinical confirmation of HHV-6-induced meningitis was proposed given improvement in CSF leukocytosis and fever reduction following the initiation of antiviral medications. Pathologic analysis of brain tumor tissue failed to show HHV-6 genome positivity, suggesting a primary peripheral etiology of infection. CONCLUSION: Here, we present the first known case of HHV-6 infection detected by FAME following intracranial tumor resection. We propose a modified algorithm for persistent fever of unknown origin which may decrease symptomatic sequelae, minimize additional procedures, and shorten length of ICU stay.

Reactivation of herpesviruses during COVID-19: A systematic review and meta-analysis.

To provide a comprehensive systematic review and meta-analysis regarding the cumulative incidence (incidence proportion) of human herpesvirus (HHV) reactivation among patients with coronavirus disease 2019 (COVID-19), we searched PubMed/MEDLINE, Web of Science, and EMBASE up to 25 September 2022, with no language restrictions. All interventional and observational studies enrolling patients with confirmed COVID-19 and providing data regarding HHV reactivation were included. The random-effects model was used in the meta-analyses. We included information from 32 studies. HHV reactivation was considered a positive polymerase chain reaction result taken at the time of COVID-19 infection. Most of the included patients were severe COVID-19 cases. The pooled cumulative incidence estimate was 38% (95% Confidence Intervals [CI], 28%-50%, I2  = 86%) for herpes simplex virus (HSV), 19% (95% CI, 13%-28%, I2  = 87%) for cytomegalovirus (CMV), 45% (95% CI, 28%-63%, I2  = 96%) for Epstein-Barr virus (EBV), 18% (95% CI, 8%-35%) for human herpesvirus 6 (HHV-6), 44% (95% CI, 32%-56%) for human herpesvirus 7 (HHV-7), and 19% (95% CI, 14%-26%) for human herpesvirus 8 (HHV-8). There was no evidence of funnel plot asymmetry based on visual inspection and Egger's regression test for the results of HSV (p = 0.84), CMV (p = 0.82), and EBV (p = 0.27) reactivation. In conclusion, the identification of HHV reactivation in severe COVID-19 patients is helpful in the management of patients as well as the prevention of complications. Further research is required to elucidate the interaction between HHVs and COVID-19. Systematic review registration: PROSPERO CRD42022321973.

Persistent SARS-CoV-2 Infection, EBV, HHV-6 and Other Factors May Contribute to Inflammation and Autoimmunity in Long COVID.

A novel syndrome called long-haul COVID or long COVID is increasingly recognized in a significant percentage of individuals within a few months after infection with SARS-CoV-2. This disorder is characterized by a wide range of persisting, returning or even new but related symptoms that involve different tissues and organs, including respiratory, cardiac, vascular, gastrointestinal, musculo-skeletal, neurological, endocrine and systemic. Some overlapping symptomatologies exist between long COVID and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Very much like with long ME/CFS, infections with herpes family viruses, immune dysregulation, and the persistence of inflammation have been reported as the most common pattern for the development of long COVID. This review describes several factors and determinants of long COVID that have been proposed, elaborating mainly on viral persistence, reactivation of latent viruses such as Epstein-Barr virus and human herpesvirus 6 which are also associated with the pathology of ME/CFS, viral superantigen activation of the immune system, disturbance in the gut microbiome, and multiple tissue damage and autoimmunity. Based on these factors, we propose diagnostic strategies such as the measurement of IgG and IgM antibodies against SARS-CoV-2, EBV, HHV-6, viral superantigens, gut microbiota, and biomarkers of autoimmunity to better understand and manage this multi-factorial disorder that continues to affect millions of people in the world.

Saliva antibody-fingerprint of reactivated latent viruses after mild/asymptomatic COVID-19 is unique in patients with myalgic-encephalomyelitis/chronic fatigue syndrome.

Background: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a chronic disease considered to be triggered by viral infections in a majority of cases. Symptoms overlap largely with those of post-acute sequelae of COVID-19/long-COVID implying common pathogenetic mechanisms. SARS-CoV-2 infection is risk factor for sustained latent virus reactivation that may account for the symptoms of post-viral fatigue syndromes. The aim of this study was first to investigate whether patients with ME/CFS and healthy donors (HDs) differed in their antibody response to mild/asymptomatic SARS-CoV-2 infection. Secondly, to analyze whether COVID-19 imposes latent virus reactivation in the cohorts. Methods: Anti-SARS-CoV-2 antibodies were analyzed in plasma and saliva from non-vaccinated ME/CFS (n=95) and HDs (n=110) using soluble multiplex immunoassay. Reactivation of human herpesviruses 1-6 (HSV1, HSV2, VZV, EBV, CMV, HHV6), and human endogenous retrovirus K (HERV-K) was detected by anti-viral antibody fingerprints in saliva. Results: At 3-6 months after mild/asymptomatic SARS-CoV-2 infection, virus-specific antibodies in saliva were substantially induced signifying a strong reactivation of latent viruses (EBV, HHV6 and HERV-K) in both cohorts. In patients with ME/CFS, antibody responses were significantly stronger, in particular EBV-encoded nuclear antigen-1 (EBNA1) IgG were elevated in patients with ME/CFS, but not in HDs. EBV-VCA IgG was also elevated at baseline prior to SARS-infection in patients compared to HDs. Conclusion: Our results denote an altered and chronically aroused anti-viral profile against latent viruses in ME/CFS. SARS-CoV-2 infection even in its mild/asymptomatic form is a potent trigger for reactivation of latent herpesviruses (EBV, HHV6) and endogenous retroviruses (HERV-K), as detected by antibody fingerprints locally in the oral mucosa (saliva samples). This has not been shown before because the antibody elevation is not detected systemically in the circulation/plasma.

Herpesvirus and neurological manifestations in patients with severe coronavirus disease.

BACKGROUND: Certain clinical manifestations of coronavirus disease (COVID-19) mimic those associated with human herpesvirus (HHV) infection. In this study, we estimated the prevalence of herpesvirus in patients with COVID-19 and determined if coinfection is associated with poorer outcomes and neurological symptoms. METHODS: We analyzed samples of 53 patients diagnosed with COVID-19. The samples were evaluated for the presence of alphaherpesviruses, betaherpesviruses, and gammaherpesviruses, and the viral loads were quantified using quantitative polymerase chain reaction (qPCR) method. RESULTS: Among the patients, in 79.2% had detection at least one type of herpesvirus. HHV-6 (47.2%), cytomegalovirus (43.3%), and HHV-7 (39.6%) showed the highest detection rates. Patients with a high severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) load were more likely to show herpes simplex virus 1 detection (p = 0.037). Among patients coinfected with SARS-CoV-2 and HHVs, 26.4% showed central nervous system-associated neurological symptoms and herpetic manifestations. A statistically significant association was observed between neurological changes and HHV-6 detection (p = 0.034). CONCLUSIONS: The findings showed a high prevalence of herpesvirus in patients with COVID-19. Furthermore, even though SARS-CoV-2 and HHV coinfection was not associated with poorer outcomes, the findings demonstrated the association between neurological symptoms and HHV-6 detection.

Presence and clinical impact of human herpesvirus-6 infection in patients with moderate to critical coronavirus disease-19.

Human herpesvirus-6 (HHV-6) may cause serious diseases in immunocompromised individuals. SARS-CoV-2/HHV-6 coinfection has been emphasized in previous works, mostly case reports, small series, or epidemiological studies, but few are known about its real clinical outcomes. Here we present a real-world pilot study aiming to understand the frequency and the clinical impact of HHV-6 coinfection in moderate to critically ill patients hospitalized due to COVID-19. SARS-CoV-2 and HHV-6 were evaluated in nasopharyngeal samples at the hospital admission of suspected COVID-19 patients. From 173 consecutive cases, 60 were SARS-CoV-2 positive and 13/60 (21.7%) were HHV-6 positive after identified as the HHV-6B species by a Sanger sequencing. The SARS-CoV-2+/HHV-6+ group was younger but not significant for cardiovascular diseases, diabetes, obesity, and cancer, but significant among therapeutic immunosuppressed patients (as systemic lupus erythematosus and kidney transplant patients). In the medical records, only sparse data on cutaneous or neurological manifestations were found. Biochemical and hematological data showed only a trend towards hyperferritinemic status and lymphopenia. In conclusion, despite the impressive high frequency of HHV-6 coinfection in SARS-CoV-2 positive cases, it did not impact general mortality. We suggest larger future prospective studies to better elucidate the influence of HHV-6 reactivation in cases of COVID-19, designed to specific assessment of clinical outcomes and viral reactivation mechanisms.

The Spontaneous Course of Human Herpesvirus 6 DNA-Associated Myocarditis and the Effect of Immunosuppressive Intervention.

INTRODUCTION: This study investigated the spontaneous clinical course of patients with endomyocardial biopsy (EMB)-proven lymphocytic myocarditis and cardiac human herpesvirus 6 (HHV6) DNA presence, and the effectiveness of steroid-based intervention in HHV6-positive patients. RESULTS: 756 heart failure (HF) patients underwent an EMB procedure to determine the underlying cause of unexplained HF. Low levels of HHV6 DNA, detectable by nested PCR only, were found in 10.4% of the cases (n = 79) of which 62% (n = 49) showed myocardial inflammation. The spontaneous course of patients with EMB-proven HHV6 DNA-associated lymphocytic myocarditis (n = 26) showed significant improvements in the left ventricular ejection fraction (LVEF) and clinical symptoms, respectively, in 15/26 (60%) patients, 3-12 months after disease onset. EMB mRNA expression of components of the NLRP3 inflammasome pathway and protein analysis of cardiac remodeling markers, analyzed by real-time PCR and MALDI mass spectrometry, respectively, did not differ between HHV6-positive and -negative patients. In another cohort of patients with ongoing symptoms related to lymphocytic myocarditis associated with cardiac levels of HHV6-DNA copy numbers <500 copies/µg cardiac DNA, quantified by real-time PCR, the efficacy and safety of steroid-based immunosuppression for six months was investigated. Steroid-based immunosuppression improved the LVEF (≥5%) in 8/10 patients and reduced cardiac inflammation in 7/10 patients, without an increase in cardiac HHV6 DNA levels in follow-up EMBs. CONCLUSION: Low HHV6 DNA levels are frequently detected in the myocardium, independent of inflammation. In patients with lymphocytic myocarditis with low levels of HHV6 DNA, the spontaneous clinical improvement is nearby 60%. In selected symptomatic patients with cardiac HHV6 DNA copy numbers less than 500 copies/µg cardiac DNA and without signs of an active systemic HHV6 infection, steroid-based therapy was found to be effective and safe. This finding needs to be further confirmed in large, randomized trials.

Roseola Infantum During the COVID-19 Pandemic.

INTRODUCTION: Roseola infantum is always considered to be among the differential diagnosis of young patients with fever and leukopenia whom to be strictly isolated with the preliminary diagnosis of COVID-19 until otherwise proven during the pandemic. RESULTS: Human herpes virus-6 (HHV-6) polymerase chain reaction (PCR) blood test was performed in 4 of 7 patients with a clinical diagnosis of roseola infantum and all found to be HHV-6 PCR positive. The most striking laboratory finding in all patients was leukopenia. HHV-6 PCR tests were found to be positive. Severe acute respiratory syndrome coronavirus-2 testing were found to be negative in all patients. CONCLUSION: During the peak of the pandemic, children continued to present with fever because of viral infections other than COVID-19.

Pityriasis Rosea-like eruptions following COVID-19 mRNA-1273 vaccination: A case report and literature review.

Pityriasis rosea (PR) is a self-limited disease with exanthematous papulosquamous rashes mostly associated with reactivation of human herpesvirus (HHV)-6 or HHV-7. PR-like eruptions, which occur along with peripheral eosinophilia, interface dermatitis, and eosinophils on histopathology, may result from medications or vaccinations. Previously, PR-like eruptions had been noted following vaccination for influenza or other vaccines. During this pandemic, acute COVID-19 infection has been related to PR or PR-like eruptions in several cases. Various COVID-19 vaccines associated with PR-like eruptions were rarely reported. Herein, we report a case of cutaneous PR-like eruptions following COVID-19 mRNA-1273 vaccination.

Insights into the knowledge of complex diseases: Environmental infectious/toxic agents as potential etiopathogenetic factors of systemic sclerosis.

Systemic sclerosis (SSc) is a connective tissue disease secondary to three cardinal pathological features: immune-system alterations, diffuse microangiopathy, and fibrosis involving the skin and internal organs. The etiology of SSc remains quite obscure; it may encompass multiple host genetic and environmental -infectious/chemical-factors. The present review focused on the potential role of environmental agents in the etiopathogenesis of SSc based on epidemiological, clinical, and laboratory investigations previously published in the world literature. Among infectious agents, some viruses that may persist and reactivate in infected individuals, namely human cytomegalovirus (HCMV), human herpesvirus-6 (HHV-6), and parvovirus B19 (B19V), and retroviruses have been proposed as potential causative agents of SSc. These viruses share a number of biological activities and consequent pathological alterations, such as endothelial dysfunction and/or fibroblast activation. Moreover, the acute worsening of pre-existing interstitial lung involvement observed in SSc patients with symptomatic SARS-CoV-2 infection might suggest a potential role of this virus in the overall disease outcome. A variety of chemical/occupational agents might be regarded as putative etiological factors of SSc. In this setting, the SSc complicating silica dust exposure represents one of the most promising models of study. Considering the complexity of SSc pathogenesis, none of suggested causative factors may explain the appearance of the whole SSc; it is likely that the disease is the result of a multifactorial and multistep pathogenetic process. A variable combination of potential etiological factors may modulate the appearance of different clinical phenotypes detectable in individual scleroderma patients. The in-deep investigations on the SSc etiopathogenesis may provide useful insights in the broad field of human diseases characterized by diffuse microangiopathy or altered fibrogenesis.

iciHHV-6 in a Patient With Multisystem Inflammatory Syndrome in Children.

Multisystem inflammatory syndrome in children (MIS-C) is a serious, sometimes life-threatening late complication of coronavirus disease 2019 (COVID-19) with multiorgan involvement and evidence of immune activation. The pathogenesis of MIS-C is not known, nor is the pathogenesis of the severe organ damage that is the hallmark of MIS-C. Human herpesvirus 6 (HHV-6), the virus responsible for roseola, is a ubiquitous herpesvirus that causes close to universal infection by the age of 3 years. HHV-6 remains latent for life and can be activated during inflammatory states, by other viruses, and by host cell apoptosis. HHV-6 has been associated with end-organ diseases, including hepatitis, carditis, and encephalitis. In addition, ∼1% of people have inherited chromosomally integrated human herpesvirus 6 (iciHHV-6), which is HHV-6 that has been integrated into chromosomal telomeric regions and is transmitted through the germ line. iciHHV-6 can be reactivated and has been associated with altered immune responses. We report here a case of MIS-C in which an initial high HHV-6 DNA polymerase chain reaction viral load assay prompted testing for iciHHV-6, which yielded a positive result. Additional research may be warranted to determine if iciHHV-6 is commonly observed in patients with MIS-C and, if so, whether it may play a part in MIS-C pathogenesis.

COVID-19, HHV6 and MOG antibody: A perfect storm.

BACKGROUND: Serious neurological complications of SARS-CoV-2 are increasingly being recognized. CASE: We report a novel case of HHV6 myelitis with parainfectious MOG-IgG in the setting of COVID-19-induced lymphopenia and hypogammaglobulinemia. The patient experienced complete neurological recovery with gancyclovir, high dose corticosteroids, and plasma exchange. To our knowledge, this is the first case of HHV6 reactivation in the central nervous system in the setting of COVID19 infection and the first case of MOG-IgG myelitis in the setting of SARS-CoV-2 and HHV6 coinfection. CONCLUSION: Patients with neurological manifestations in the setting of COVID19-related immunodeficiency should be tested for opportunistic infections including HHV6. Viral infection is a known trigger for MOG-IgG and therefore this antibody should be checked in patients with SARS-CoV-2 associated demyelination.

High incidence of Epstein-Barr virus, cytomegalovirus, and human-herpes virus-6 reactivations in critically ill patients with COVID-19.

BACKGROUND: Systemic reactivation of herpesviruses may occur in intensive care unit (ICU) patients and is associated with morbidity and mortality. Data on severe Coronavirus disease-19 (COVID-19) and concomitant reactivation of herpesviruses are lacking. METHODS: We selected patients admitted to ICU for confirmed COVID-19 who underwent systematic testing for Epstein-Barr virus (EBV), cytomegalovirus (CMV) and human-herpes virus-6 (HHV-6) DNAemia while in the ICU. We retrospectively analysed frequency, timing, duration and co-occurrence of viral DNAemia. RESULTS: Thirty-four patients were included. Viremia with EBV, CMV, and HHV-6 was detected in 28 (82%), 5 (15%), and 7 (22%) patients, respectively. EBV reactivation occurred early after ICU admission and was associated with longer ICU length-of-stay. CONCLUSIONS: While in the ICU, critically ill patients with COVID-19 are prone to develop reactivations due to various types of herpesviruses.