The Implication of Sphingolipids in Viral Infections.

Sphingolipids are involved in cell signaling and metabolic pathways, and their metabolites play a critical role in host defense against intracellular pathogens. Here, we review the known mechanisms of sphingolipids in viral infections and discuss the potential implication of the study of sphingolipid metabolism in vaccine and therapeutic development.

Risks and outcomes of adenovirus disease in pediatric hematopoietic stem cell transplant recipients-Comparison of current antiviral treatment options.

BACKGROUND: Adenovirus disease (ADVd) is a significant burden in pediatric hematopoietic stem cell transplant (HSCT) recipients. However, current knowledge of risk factors associated with poor clinical outcome and the effectiveness of antiviral therapy are not well understood. This study determined the relationship between transplant characteristics and risk of ADVd and also compared time to resolution of disease between pediatric patients who did and did not receive antiviral therapy. METHODS: We conducted a retrospective, single-center cohort study of pediatric patients undergoing HSCT at Duke University (2005-2016). Cases of ADVd were defined a priori using a classification tool. Cox proportional hazards (CPH) regression models were used to compare the hazard of ADVd between HSCT recipients differing by type of transplant and type of conditioning regimen. The hazard of time to resolution of ADVd by antiviral therapy (cidofovir, brincidofovir, both, or neither) was compared. RESULTS: Ninety-three of 830 subjects had ADVd post-HSCT (11.2%). Umbilical cord transplant (UCT) recipients had 2.30 (95% CI 1.57, 6.90, P = .002) higher hazard of developing ADVd compared to non-cord allogeneic transplants, and 6.30 higher (95% CI 2.70, 19.61, P < .001) hazard compared to autologous transplants. Subjects who did not receive antiviral therapy experienced earlier resolution of ADVd compared to subjects who received therapy, even after adjusting for subjects with disseminated disease (HR [95% CI]: 3.75 [1.57, 8.93], P = .003). CONCLUSIONS: Pediatric UCT recipients are at a higher risk for ADVd. Antiviral therapy was not associated with an earlier resolution of ADVd, even in patients with higher disease burden.

Viral meningoencephalitis in pediatric solid organ or hematopoietic cell transplant recipients: a diagnostic and therapeutic approach.

Neurologic complications, both infectious and non-infectious, are frequent among hematopoietic cell transplant (HCT) and solid organ transplant (SOT) recipients. Up to 46% of HCT and 50% of SOT recipients experience a neurological complication, including cerebrovascular accidents, drug toxicities, as well as infections. Defects in innate, adaptive, and humoral immune function among transplant recipients predispose to opportunistic infections, including central nervous system (CNS) disease. CNS infections remain uncommon overall amongst HCT and SOT recipients, compromising approximately 1% of total cases among adult patients. Given the relatively lower number of pediatric transplant recipients, the incidence of CNS disease amongst in this population remains unknown. Although infections comprise a small percentage of the neurological complications that occur post-transplant, the associated morbidity and mortality in an immunosuppressed state makes it imperative to promptly evaluate and aggressively treat a pediatric transplant patient with suspicion for viral meningoencephalitis. This manuscript guides the reader through a broad infectious and non-infectious diagnostic differential in a transplant recipient presenting with altered mentation and fever and thereafter, elaborates on diagnostics and management of viral meningoencephalitis. Hypothetical SOT and HCT patient cases have also been constructed to illustrate the diagnostic and management process in select viral etiologies. Given the unique risk for various opportunistic viral infections resulting in CNS disease among transplant recipients, the manuscript will provide a contemporary review of the epidemiology, risk factors, diagnosis, and management of viral meningoencephalitis in these patients.

Human In vitro Modeling Identifies Adjuvant Combinations that Unlock Antigen Cross-presentation and Promote T-helper 1 Development in Newborns, Adults and Elders.

Adjuvants are vaccine components that can boost the type, magnitude, breadth, and durability of an immune response. We have previously demonstrated that certain adjuvant combinations can act synergistically to enhance and shape immunogenicity including promotion of Th1 and cytotoxic T-cell development. These combinations also promoted protective immunity in vulnerable populations such as newborns. In this study, we employed combined antigen-specific human in vitro models to identify adjuvant combinations that could synergistically promote the expansion of vaccine-specific CD4+ cells, induce cross-presentation on MHC class I, resulting in antigen-specific activation of CD8+ cells, and direct the balance of immune response to favor the production of Th1-promoting cytokines. A screen of 78 adjuvant combinations identified several T cell-potentiating adjuvant combinations. Remarkably, a combination of TLR9 and STING agonists (CpG + 2,3-cGAMP) promoted influenza-specific CD4+ and CD8+ T cell activation and selectively favored production of Th1-polarizing cytokines TNF and IL-12p70 over co-regulated cytokines IL-6 and IL-12p40, respectively. Phenotypic reprogramming towards cDC1-type dendritic cells by CpG + 2,3-cGAMP was also observed. Finally, we characterized the molecular mechanism of this adjuvant combination including the ability of 2,3-cGAMP to enhance DC expression of TLR9 and the dependency of antigen-presenting cell activation on the Sec22b protein important to endoplasmic reticulum-Golgi vesicle trafficking. The identification of the adjuvant combination CpG + 2,3-cGAMP may therefore prove key to the future development of vaccines against respiratory viral infections tailored for the functionally distinct immune systems of vulnerable populations such as older adults and newborns.

Heterologous SARS-CoV-2 booster vaccine for individuals with hematological malignancies after a primary SARS-CoV-2 mRNA vaccine series.

Heterologous COVID-19 vaccine boosters have not been evaluated for patients with hematological malignancies. A Novavax booster was administered for 56 individuals with hematological malignancies who had received a primary COVID-19 series and prior boosters with mRNA vaccines only. Blood specimens were obtained at baseline (pre-vaccine), 28 days, and 168 days after vaccination with the Novavax booster. The median fold change of anti-Spike IgG was 1.02 (IQR 0.79, 1.3) between baseline and Day 28. Circulating Spike protein-specific B cells increased 1.4-fold at Day 28 (p < 0.05). Increases in antibody and T cell responses were modest without significance, with a waning of humoral and cellular responses at 168 days after vaccination.

Severe congenital neutropenia due to jagunal homolog 1 (JAGN1) mutation: a case report and literature review.

Severe congenital neutropenia caused by jagunal homolog 1 (JAGN1) mutation is a rare condition resulting from maturation arrest secondary to endoplasmic reticulum stress response from impaired neutrophil protein glycosylation. Here, we report a case of a 4-year-old boy who presented with a history of recurrent infections and manifestations, including recurrent intracranial hemorrhage. A review of similar cases reported in the literature indicates that a bleeding diathesis has not been previously described in these patients. We hypothesize that this newly described association of bleeding complications in this patient with JAGN1 mutation is secondary to defective glycosylation in the normal functioning of platelets or clotting factors. Recurrent infections with intracranial hemorrhage, new focal neurologic defects, or altered mental status in a child should warrant a suspicion for this immunodeficiency for the prompt initiation of treatment and prophylaxis for life-threatening infections or trauma.

Human in vitro modeling of adjuvant formulations demonstrates enhancement of immune responses to SARS-CoV-2 antigen.

Adjuvants can enhance vaccine immunogenicity, but their mechanism of action is often incompletely understood, hampering rapid applicability for pandemic vaccines. Herein, we characterized the cellular and molecular activity of adjuvant formulations available for pre-clinical evaluation, including several developed for global open access. We applied four complementary human in vitro platforms to assess individual and combined adjuvants in unformulated, oil-in-water, and liposomal delivery platforms. Liposomal co-formulation of MPLA and QS-21 was most potent in promoting dendritic cell maturation, selective production of Th1-polarizing cytokines, and activation of SARS-CoV-2 Spike-specific CD4+ and CD8+ T cells in a co-culture assay. Select formulations also significantly enhanced Spike antigen-specific humoral immunity in vivo. This study confirms the utility of the cumulative use of human in vitro tools to predict adjuvanticity potential. Thus, human in vitro modeling may advance public health by accelerating the development of affordable and scalable adjuvants for vaccines tailored to vulnerable populations.

Pediatric Infectious Diseases Milestones: A Step in the Right Direction to Evaluate Subspecialty Learners.

We share the work of the ACGME Pediatric Infectious Diseases Working Group in creating the Pediatric Infectious Diseases-Specific Milestones and discuss key considerations that lead to the reformation of competencies to better assess learners in Pediatric Infectious Diseases.

Raltegravir-associated Drug-Reaction With Eosinophilia and Systemic Symptoms Syndrome in a Pediatric Patient Without Characteristic Human Leukocyte Antigen B*57:01 or B*53:01 alleles.

We present the first published case of raltegravir-associated drug-reaction with eosinophilia and systemic symptoms (DRESS) syndrome in a child without characteristic human leukocyte antigen haplotypes HLA-B*57:01 or HLA-B*53:01. A 4-year-old African American female with perinatally acquired human immunodeficiency virus infection was hospitalized for DRESS after starting a raltegravir-based antiretroviral regimen.

A systematic review of the burden and risk factors of sudden infant death syndrome (SIDS) in Africa.

BACKGROUND: While sudden infant death syndrome (SIDS) has long been recognized as a leading preventable cause of infant mortality in high-income countries, little is known about the burden of SIDS in Africa. To address this knowledge gap, we conducted the first systematic review of SIDS-related publications in Africa. Our objective was to assess the prevalence of SIDS and its risk factors in Africa. METHODS: We systematically searched PubMed, Embase, Web of Science, Cochrane, and Google Scholar to identify studies published until December 26, 2020. Review authors screened titles and abstracts, and selected articles independently for full-text review. Risk of bias was assessed using the Newcastle Ottawa Scale (NOS) or a modification. Data on the proportion of infants who died of SIDS and reported prevalence of any risk factors were extracted using customized data extraction forms in Covidence. RESULTS: Our analysis rested on 32 peer-reviewed articles. Nine studies presented prevalence estimates on bedsharing and prone sleeping, suggesting near-universal bedsharing of infants with parents (range, 60 to 91.8%) and frequent use of the prone sleeping position (range, 26.7 to 63.8%). Eleven studies reported on the prevalence of SIDS, suggesting high rates of SIDS in Africa. The prevalence of SIDS ranged from 3.7 per 1000 live births in South Africa, 2.5 per 1000 live births in Niger, and 0.2 per 1000 live births in Zimbabwe. SIDS and other sudden infant deaths accounted for between 2.5 to 21% of infant deaths in South Africa and 11.3% in Zambia. CONCLUSIONS: Africa may have the highest global rate of SIDS with a high burden of associated risk factors. However, majority of the studies were from South Africa which limits generalizability of our findings to the entire continent. There is an urgent need for higher quality studies outside of South Africa to fill this knowledge gap. PROTOCOL REGISTRATION: Prospero Registration Number: CRD42021257261.