A systematic review and meta-analysis of HHV-6 and mortality after hematopoietic cell transplant.

Human herpesvirus-6B (HHV-6B) reactivation has been associated with non-relapse mortality (NRM) and overall mortality (OM) following allogeneic hematopoietic stem cell transplant (HCT). We performed a systematic review and meta-analysis to better quantify the association. Studies were included if they systematically tested a cohort of HCT recipients for HHV-6 infection or reactivation and described mortality for patients with and without HHV-6B. Random effects models were used to assess the pooled effect of HHV-6B positivity on each outcome of interest. Bayesian aggregation was additionally performed if models included 10 or fewer studies. Eight studies were included in the NRM analysis, which demonstrated a significant association between HHV-6 detection and NRM (pooled effect: 1.84; 95% CI: 1.29-2.62) without significant heterogeneity (I2 = 0.0%, p = 0.55). A Bayesian aggregation of the raw data used to construct the NRM random effects model supported these findings (95% credible interval: 0.15-1.13). Twenty-five studies were included in OM analysis, which showed a significant positive association (pooled effect: 1.37; 95% CI: 1.07-1.76), though considerable heterogeneity was observed (I2 = 36.7%, p < 0.05). HHV-6 detection is associated with NRM and OM following HCT. Randomized trials are warranted to evaluate if preventing or treating HHV-6B reactivation improves outcomes.

Engineered Skin Substitutes in Dermatologic Surgery: A Systematic Review.

BACKGROUND: Artificial skin substitutes are a flexible alternative to autografting in Mohs micrographic surgery (MMS), but the characteristics and clinical outcomes of skin substitutes are not well defined. OBJECTIVE: Summarize clinical data of skin substitutes in MMS for cutaneous malignancy. METHODS: A MEDLINE/Embase/Web of Science search was conducted. Articles with original data on outcomes after skin substitute use in MMS for cutaneous malignancy were included. Articles not in English or without original data were excluded. Bias was assessed using the Oxford CEBM Levels of Evidence Table. Outcomes were synthesized using weighted averages. This study was prospectively registered in PROSPERO. RESULTS: Of 1,007 articles, 40 met eligibility for inclusion. In total, 898 patients who underwent MMS and received a skin substitute were included. Xenografts were most commonly used ( n = 613). Semi-synthetic grafts (∼$<1/cm 2 ) and xenografts (∼$10/cm 2 ) are most affordable. Overall, outcomes were excellent for all skin substitutes, with a small proportion of patients experiencing correctable complications. CONCLUSION: Skin substitutes are highly effective in MMS, with enormous potential. While the data demonstrate positive outcomes, they predominately draw from small, retrospective studies or case reports. There is also a scarcity of data comparing skin substitutes with each other or controls. Prospective studies are recommended.

Two years of a pilot virtual melanoma education program for adolescents in Texas: Assessing knowledge gaps and demographic disparities.

A formal melanoma primary prevention program was developed for a target audience of grade-school adolescents near Houston, Texas, focusing on skin cancer education and promoting long-term sun safety habits. Upon application of a multivariable regression model, adolescents of Black, non-Hispanic race, male gender, and lower grade levels were independent predictors of lower baseline skin cancer prevention knowledge. These findings reveal potential areas to prioritize when addressing knowledge gaps in the adolescent community.

Immunopathogenic Insights on Preferential Human Herpesvirus-6 Reactivation in Drug Rash With Eosinophilia and Systemic Symptoms: A Scoping Review.

INTRODUCTION: Human herpesvirus-6 (HHV-6) is a ubiquitous lymphotropic betaherpesvirus that can reactivate in drug rash with eosinophilia and systemic symptoms (DRESS). Despite recent publications advancing our understanding of HHV-6 in DRESS, the exact role of HHV-6 in disease pathogenesis remains unclear. METHODS: A scoping review with the PubMed query "(HHV 6 AND (drug OR DRESS OR DIHS)) OR (HHV6 AND (drug OR DRESS OR DIHS))" was conducted in accordance with PRISMA guidelines. Articles containing original data on at least one DRESS patient with HHV-6 testing were included. RESULTS: Our search returned a total of 373 publications, of which 89 met eligibility criteria. HHV-6 reactivation occurred in 63% of DRESS patients (n = 748), which was significantly more often than other herpesviruses. HHV-6 reactivation was associated with worse outcomes and greater severity in controlled studies. Case reports have demonstrated sometimes fatal HHV-6-related multi-organ involvement. Temporally, HHV-6 reactivation typically occurs 2 to 4 weeks after DRESS onset and has been linked to markers of immunologic signaling, such as OX40 (CD134), an HHV-6 entry receptor. Efficacy of antiviral or immunoglobulin treatment has only been demonstrated anecdotally, and steroid use may affect HHV-6 reactivation. CONCLUSION: HHV-6 is implicated in DRESS more than in any other dermatologic condition. It is still unclear whether HHV-6 reactivation is cause or consequence of DRESS dysregulation. Similar pathogenic mechanisms precipitated by HHV-6 in other contexts may be relevant in DRESS. Future randomized controlled studies to assess effects of viral suppression on clinical outcomes is needed.

Epstein-Barr Virus and Human Herpesvirus-6 Reactivation in Acute COVID-19 Patients.

Beyond their pulmonary disease, many COVID-19 patients experience a complex constellation of characteristics, including hyperinflammatory responses, autoimmune disorders, and coagulopathies. However, the pathogenesis of these aspects of COVID-19 is obscure. More than 90% of people are latently infected with the lymphotropic herpesviruses Epstein-Barr Virus (EBV) and/or Human Herpesvirus-6 (HHV-6). Some of the inflammatory features of COVID-19 resemble clinical syndromes seen during EBV and HHV-6 infection, and these latent viruses can be reactivated by inflammatory mediators. We hypothesized that EBV and HHV-6 reactivation might be a common feature of early COVID-19, particularly in patients with more inflammation. We tested for EBV and HHV-6 reactivation in 67 patients acutely hospitalized with COVID-19 using previously validated quantitative PCR assays on the plasma. In our cohort, we found that 15/67 (22.4%) patients had detectable EBV and 3/67 (4.5%) had detectable HHV-6. This frequency of activation is somewhat more than the frequency reported for some healthy cohorts, such as blood donors and other healthy control cohorts. There was no association between EBV or HHV-6 and markers indicative of more inflammatory disease. We conclude that EBV and HHV-6 activation at about day 7 of hospitalization occurred in a modest fraction of our cohort of COVID-19 patients and was not associated with high levels of inflammation. In the modest fraction of patients, EBV and HHV-6 reactivation could contribute to some features of acute disease and pre-disposition to post-acute sequelae in a subset of patients.

Topical hedgehog inhibitors for basal cell carcinoma: how far away are we?

INTRODUCTION: The standard treatment of basal cell carcinoma (BCC) consists of conventional excision or Mohs micrographic surgery. However, surgical excision is not feasible in specific cases, particularly in patients with several BCCs such as those with Gorlin syndrome or individuals receiving immunosuppression after solid-organ transplantation. Additionally, the geriatric population may not be appropriate candidates for surgery. Thus, alternative therapies are needed for these populations. AREAS COVERED: Hedgehog (Hh) inhibitors are approved and effective but are currently available only in oral formulations. These agents such as vismodegib and sonidegib are associated with short-lived responses as well as significant adverse effects including myalgias, dysgeusia, and alopecia. Patidegib and itraconazole are two topical Hh inhibitors agents emerging as alternatives to oral Hh inhibiton for difficult-to-treat BCCs. These agents exhibit limited systemic absorption, leading to improved tolerability; however, an optimal formulation is needed to maximize efficacy and is currently being investigated. EXPERT OPINION: Ongoing and recent clinical studies on topical Hedgehog inhibitors show great promise for the development of an agent with a high therapeutic index and limited adverse effects. If patidegib continues to show clinical efficacy in randomized controlled trials, it may become a universal therapy for all subtypes of difficult-to-treat BCC.

Unique Challenges to Diagnosing Human Herpesvirus-6 (HHV-6) Encephalitis Following Post-Hematopoietic Stem Cell Transplant: A Case and Brief Review.

A patient with an ultimate diagnosis of human herpesvirus-6 (HHV-6) encephalitis developed central nervous system (CNS) symptoms 13 days after undergoing myeloablative haploidentical allogeneic hematopoietic stem cell transplant (HSCT). Due to the patient's body habitus, magnetic resonance (MR) imaging was not obtained until the onset of retrograde amnesia on day +24. MR imaging and other clinical findings eliminated all skepticism of HHV-6 encephalitis and HHV-6 antivirals were initiated on day +28, leading to gradual recovery. This case demonstrates some of the factors that may complicate the diagnosis of post-alloHSCT HHV-6 encephalitis. Because HHV-6 encephalitis and viremia can occur without warning, a single negative study should not exclude future development, especially if CNS symptoms are present. Acute graft-versus-host disease and cord blood transplantation are both significant risk factors for HHV-6 encephalitis. Human leukocyte antigen (HLA) mismatch, engraftment complications, or certain HLA alleles have also been associated with HHV-6 encephalitis. Chromosomally integrated HHV-6 must also be ruled out to prevent inappropriate and potentially harmful administration of antivirals. Due to the severe short- and long-term sequelae of HHV-6 encephalitis, appropriate treatment should be administered as soon as possible.