Viral Encephalitis after Hematopoietic Cell Transplantation: A Systematic Review.

Viral encephalitis is a rare but serious complication after hematopoietic cell transplantation (HCT). The nonspecific early signs and symptoms and rapid progression can make it difficult to diagnose and treat in a timely fashion. To better inform clinical decision making in post-HCT viral encephalitis, a systematic review of prior studies of viral encephalitis was performed, with the goal of characterizing the frequency of various infectious etiologies and their clinical course, including treatments and outcomes. A systematic review of studies of viral encephalitis was performed. Studies were included if they described a cohort of HCT recipients who were tested for at least 1 pathogen. Of 1613 unique articles initially identified, 68 met the inclusion criteria, with a total of 72,423 patients studied. A total of 778 cases of encephalitis were reported (1.1%). Human herpesvirus 6 (HHV-6) (n = 596), Epstein-Barr virus (n = 76), and cytomegalovirus (n = 33) were the most commonly reported causes of encephalitis, and HHV-6 encephalitis tended to occur the earliest, accounting for most cases prior to day +100 post-transplantation. Of 29,671 patients with available transplantation data, encephalitis was diagnosed in 282 of 4707 (6.0%) cord blood transplantation (CBT) recipients, in 372 of 24,664 (1.5%) non-CBT allogeneic HCT recipients, and in 5 of 300 (1.7%) autologous HCT recipients. Of the 282 CBT encephalitis cases, 270 (95.7%) were caused by HHV-6. Overall, 288 (37.0%) of the 778 patients with encephalitis died, and 75 deaths were attributable to encephalitis, with the time between diagnosis and death ranging from 3 to 192 days. Viral encephalitis occurs in approximately 1% of HCT recipients, and HHV-6 is the most common cause. Mortality following encephalitis in HCT recipients is high, indicating an urgent need for advancement in preventive and therapeutic strategies.

A Systematic Review of Human Challenge Trials, Designs, and Safety.

BACKGROUND: Few studies have assessed participant safety in human challenge trials (HCTs). Key questions regarding HCTs include how risky such trials have been, how often adverse events (AEs) and serious adverse events (SAEs) occur, and whether risk mitigation measures have been effective. METHODS: A systematic search of PubMed and PubMed Central for articles reporting on results of HCTs published between 1980 and 2021 was performed and completed by 7 October 2021. RESULTS: Of 2838 articles screened, 276 were reviewed in full. A total of 15 046 challenged participants were described in 308 studies that met inclusion criteria; 286 (92.9%) of these studies reported mitigation measures used to minimize risk to the challenge population. Among 187 studies that reported on SAEs, 0.2% of participants experienced at least 1 challenge-related SAE. Among 94 studies that graded AEs by severity, challenge-related AEs graded "severe" were reported by between 5.6% and 15.8% of participants. AE data were provided as a range to account for unclear reporting. Eighty percent of studies published after 2010 were registered in a trials database. CONCLUSIONS: HCTs are increasingly common and used for an expanding list of diseases. Although AEs occur, severe AEs and SAEs are rare. Reporting has improved over time, though not all papers provide a comprehensive report of relevant health impacts. We found very few severe symptoms or SAEs in studies that reported them, but many HCTs did not report relevant safety data. This study was preregistered on PROSPERO as CRD42021247218.

Tissue specific signature of HHV-6 infection in ME/CFS.

First exposure to various human herpesviruses (HHVs) including HHV-6, HCMV and EBV does not cause a life-threatening disease. In fact, most individuals are frequently unaware of their first exposure to such pathogens. These herpesviruses acquire lifelong latency in the human body where they show minimal genomic activity required for their survival. We hypothesized that it is not the latency itself but a timely, regionally restricted viral reactivation in a sub-set of host cells that plays a key role in disease development. HHV-6 (HHV-6A and HHV-6B) and HHV-7 are unique HHVs that acquire latency by integration of the viral genome into sub-telomeric region of human chromosomes. HHV-6 reactivation has been linked to Alzheimer's Disease, Chronic Fatigue Syndrome, and many other diseases. However, lack of viral activity in commonly tested biological materials including blood or serum strongly suggests tissue specific localization of active HHV-6 genome. Here in this paper, we attempted to analyze active HHV-6 transcripts in postmortem tissue biopsies from a small cohort of ME/CFS patients and matched controls by fluorescence in situ hybridization using a probe against HHV-6 microRNA (miRNA), miR-aU14. Our results show abundant viral miRNA in various regions of the human brain and associated neuronal tissues including the spinal cord that is only detected in ME/CFS patients and not in controls. Our findings provide evidence of tissue-specific active HHV-6 and EBV infection in ME/CFS, which along with recent work demonstrating a possible relationship between herpesvirus infection and ME/CFS, provide grounds for renewed discussion on the role of herpesviruses in ME/CFS.

Retrospective case analysis of antiviral therapies for HHV-6 encephalitis after hematopoietic stem cell transplantation.

Human herpesvirus 6 (HHV-6) is one of the most common causes of encephalitis in allogeneic hematopoietic stem cell transplant (HCT) recipients and is associated with significant morbidity and mortality. There are no FDA-approved treatments specifically for HHV-6 encephalitis; HHV-6 disease is typically treated with CMV antivirals. A review of antiviral medications used to treat HHV-6 encephalitis was conducted by aggregating data from case reports found on PubMed. Articles were included if they examined at least one HCT patient diagnosed with HHV-6 encephalitis and described their treatment course and outcome. Key data were abstracted from 123 cases described in 52 studies. The proportion of patients with encephalitis who died or developed sequelae was 63.6% among ganciclovir monotherapy recipients (n = 44), 55.3% among foscarnet monotherapy recipients (n = 47), and 37.5% among recipients of combination therapy with foscarnet and ganciclovir (n = 32). Logistic regression revealed that recipients of foscarnet (OR 4.286, 95% CI 1.235-14.877, P = .022) and ganciclovir (OR 5.625, 95% CI 1.584-19.975, P = .008) monotherapies were more likely to develop sequelae compared to recipients of combination therapy, respectively. In multivariate analyses, non-cord blood transplant was identified as an independent risk factor for developing sequelae after receiving ganciclovir monotherapy (OR 5.999, 95% CI 1.274-28.254, P = .023). There was no difference in mortality between patients who received combination therapy and those who received monotherapy. In conclusion, combination therapy with foscarnet and ganciclovir may reduce sequelae, but not mortality, secondary to HHV-6 encephalitis.