Severe varicella in persons vaccinated with varicella vaccine (breakthrough varicella): a systematic literature review

Introduction: Varicella vaccines are highly effective at preventing disease, but varicella may occur among vaccinated persons (termed breakthrough varicella). Breakthrough varicella is generally mild, but severe cases have been reported. The objective of this review is to describe severe breakthrough varicella. Areas covered: We conducted a systematic review of articles published during 1974–2016. A total of 34 articles were included in our review: 21 described breakthrough varicella with disseminated varicella-zoster virus (VZV) infection with other organ involvement in addition to skin (none among two-dose vaccinees); 9 described hospitalized breakthrough varicella without mention of other organ involvement in addition to skin (of which 2 reported 4 two-dose vaccinees); and 4 described both. A total of 52–60 unique breakthrough varicella cases with disseminated VZV infection with other organ involvement in addition to skin reported with the following complications, not mutually exclusive: pneumonia (n = 8–9 cases), neurologic (n = 18–24 cases), hematologic (n = 10–11 cases), ocular (n = 5 cases), renal (n = 2 cases), hepatic (n = 3 cases), secondary infection with bacteremia or sepsis (n = 8 cases), and other complication (n = 4 cases). There were 6 cases of fatal breakthrough varicella. Expert commentary: With >31 million doses distributed annually worldwide since 2007, severe breakthrough varicella can occur but they appear to be uncommon

Influenza-associated deaths among children in the United States, 2003-2004

BACKGROUND: Although influenza is common among children, pediatric mortality related to laboratory-confirmed influenza has not been assessed nationally. METHODS: During the 2003-2004 influenza season, we requested that state health departments report any death associated with laboratory-confirmed influenza in a U.S. resident younger than 18 years of age. Case reports, medical records, and autopsy reports were reviewed, and available influenza-virus isolates were analyzed at the Centers for Disease Control and Prevention. RESULTS: One hundred fifty-three influenza-associated deaths among children were reported by 40 state health departments. The median age of the children was three years, and 96 of them (63 percent) were younger than five years old. Forty-seven of the children (31 percent) died outside a hospital setting, and 45 (29 percent) died within three days after the onset of illness. Bacterial coinfections were identified in 24 of the 102 children tested (24 percent). Thirty-three percent of the children had an underlying condition recognized to increase the risk of influenza-related complications, and 20 percent had other chronic conditions; 47 percent had previously been healthy. Chronic neurologic or neuromuscular conditions were present in one third. The mortality rate was highest among children younger than six months of age (0.88 per 100,000 children; 95 percent confidence interval, 0.52 to 1.39 per 100,000). CONCLUSIONS: A substantial number of influenza-associated deaths occurred among U.S. children during the 2003-2004 influenza season. High priority should be given to improvements in influenza-vaccine coverage and improvements in the diagnosis and treatment of influenza to reduce childhood mortality from influenza. Copyright © 2005 Massachusetts Medical Society.Link_to_subscribed_fulltex

TDP-43 represses cryptic exon inclusion in the FTD-ALS gene UNC13A.

A hallmark pathological feature of the neurodegenerative diseases amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) is the depletion of RNA-binding protein TDP-43 from the nucleus of neurons in the brain and spinal cord1. A major function of TDP-43 is as a repressor of cryptic exon inclusion during RNA splicing2-4. Single nucleotide polymorphisms in UNC13A are among the strongest hits associated with FTD and ALS in human genome-wide association studies5,6, but how those variants increase risk for disease is unknown. Here we show that TDP-43 represses a cryptic exon-splicing event in UNC13A. Loss of TDP-43 from the nucleus in human brain, neuronal cell lines and motor neurons derived from induced pluripotent stem cells resulted in the inclusion of a cryptic exon in UNC13A mRNA and reduced UNC13A protein expression. The top variants associated with FTD or ALS risk in humans are located in the intron harbouring the cryptic exon, and we show that they increase UNC13A cryptic exon splicing in the face of TDP-43 dysfunction. Together, our data provide a direct functional link between one of the strongest genetic risk factors for FTD and ALS (UNC13A genetic variants), and loss of TDP-43 function

Near Real-Time Surveillance for Influenza Vaccine Safety: Proof-of-Concept in the Vaccine Safety Datalink Project

The emergence of pandemic H1N1 influenza in 2009 has prompted public health responses, including production and licensure of new influenza A (H1N1) 2009 monovalent vaccines. Safety monitoring is a critical component of vaccination programs. As proof-of-concept, the authors mimicked near real-time prospective surveillance for prespecified neurologic and allergic adverse events among enrollees in 8 medical care organizations (the Vaccine Safety Datalink Project) who received seasonal trivalent inactivated influenza vaccine during the 2005/06–2007/08 influenza seasons. In self-controlled case series analysis, the risk of adverse events in a prespecified exposure period following vaccination was compared with the risk in 1 control period for the same individual either before or after vaccination. In difference-in-difference analysis, the relative risk in exposed versus control periods each season was compared with the relative risk in previous seasons since 2000/01. The authors used Poisson-based analysis to compare the risk of Guillian-Barré syndrome following vaccination in each season with that in previous seasons. Maximized sequential probability ratio tests were used to adjust for repeated analyses on weekly data. With administration of 1,195,552 doses to children under age 18 years and 4,773,956 doses to adults, no elevated risk of adverse events was identified. Near real-time surveillance for selected adverse events can be implemented prospectively to rapidly assess seasonal and pandemic influenza vaccine safety