Faculty Bibliography

Maternal colonization with Group B Streptococcus (GBS) is an important cause of stillbirth, prematurity, and serious infection and death in infants worldwide. Resource constraints limit prevention strategies in many regions. Maternal GBS vaccines in development could be a more accessible prevention strategy, but data on geographic variations in GBS clones are needed to guide development of a broadly effective vaccine. In the Dominican Republic (DR), limited data suggest that pregnant women experience GBS colonization at rates among the highest globally. We aimed to determine the prevalence of maternal rectovaginal GBS colonization and describe clonal characteristics of colonizing strains in the DR. A cross-sectional study assessed rectovaginal GBS colonization in 350 near-term pregnant women presenting for routine prenatal care at an urban tertiary center in the DR. Rectovaginal samples were tested with chromogenic Strep B Carrot Broth and cultured for confirmatory whole-genome sequencing. In a secondary analysis, participants' demographics and histories were assessed for association with GBS colonization. Rectovaginal GBS colonization occurred in 26.6% of women. Serotypes Ia, Ib, II, III, IV, and V were detected, with no one serotype predominating; serotype III was identified most frequently (21.5%). Virulent and emerging strains were common, including CC17 (15.1%) and ST1010 (17.2%). In this first characterization of maternal GBS serotypes in the DR, we found high rates of rectovaginal colonization including with virulent and emerging GBS strains. The serotypes observed here are all targeted by candidate hexavalent GBS vaccines, suggesting effective protection in the DR.

BACKGROUND:In 2018-2019, large outbreaks of measles occurred in Israel and in New York City, driven in part by travel of unimmunized children between the 2 communities. METHODS:A retrospective chart review was conducted for children tested for measles (March 2018-September 2019) at NYU Langone Health in New York, NY, and in Ramla subdistrict, Israel. Vaccination records were reviewed to determine vaccination status for measles, mumps, and rubella (MMR) at the time of measles testing and 1-year post-testing. RESULTS:A total of 264 children were tested for measles, and 102 (38.6%) had confirmed measles. Only 20 (19.6%) of measles-positive cases received a full 2-dose course of vitamin A. 82.4% of children with measles were ≥1 year at the time of diagnosis and fully eligible for MMR vaccine. Of the 100 measles-positive cases with available vaccine records, 63 were unvaccinated at testing, and 27 remained unimmunized against MMR 1 year later. At testing, measles-negative children were significantly more likely to have received MMR than measles-positive children (65.4% vs 37%, P < .01). One year later, 70.4% of measles-negative cases and only 57.1% of measles-positive cases had received MMR vaccine (P = .18). CONCLUSIONS:The majority of measles cases occurred in unimmunized children eligible for vaccination, and >25% of children in both measles-positive and -negative groups remained unimmunized for MMR 1-year post-outbreak. Our results suggest the need for novel, longitudinal vaccination strategies and increased awareness of the role of vitamin A.

We report the case of a 5-year-old male with B-cell acute lymphoblastic leukemia in remission, receiving maintenance chemotherapy, who presented with fever, emesis, diarrhea, headache, and lethargy. He developed rapidly progressive cytopenias and was found to have acute human granulocytic anaplasmosis as well as evidence of past infection with Babesia microti. The case highlights the need to maintain a broad differential for infection in children undergoing chemotherapy or other immunosuppressive therapies with possible or known tick exposure.

BACKGROUND:Group B Streptococcus (GBS) remains a leading cause of infant morbidity and mortality. A candidate vaccine targets six GBS serotypes, offering a potential alternative to intrapartum antibiotic prophylaxis to reduce disease burden. However, our understanding of the contributions of specific capsule types to GBS colonization and disease remains limited. METHODS:Using allelic exchange, we generated isogenic GBS strains differing only in the serotype-determining region in two genetic backgrounds, including the hypervirulent clonal complex (CC) 17. Using a murine model of vaginal co-colonization, we evaluated the roles of the presence of capsule and of expression of specific capsular types in GBS vaginal colonization fitness independent of other genetic factors. RESULTS:Encapsulated wild-type strains COH1 (CC17, serotype III) and A909 (non-CC17, serotype Ia), outcompeted isogenic acapsular mutants in murine vaginal co-colonization. COH1 wild-type outcompeted A909. Notably, expression of type Ia capsule conferred an advantage over type III capsule in both genetic backgrounds. CONCLUSIONS:Specific capsule types may provide an advantage in GBS vaginal colonization in vivo. However, success of certain GBS lineages, including CC17, likely involves both capsule and non-capsule genetic elements. Capsule switching in GBS, a potential outcome of conjugate vaccine programs, may alter colonization fitness or pathogenesis.

BACKGROUND:Starting in November 2020, the US Food and Drug Administration (FDA) has issued Emergency Use Authorizations (EUAs) for multiple novel virus-neutralizing monoclonal antibody therapies, including bamlanivimab monotherapy (now revoked), bamlanivimab and etesivimab, casirivimab and imdevimab (REGEN-COV), and sotrovimab, for treatment or postexposure prophylaxis of Coronavirus disease 2019 (COVID-19) in adolescents (≥12 years of age) and adults with certain high-risk conditions. Previous guidance is now updated based on new evidence and clinical experience. METHODS:A panel of experts in pediatric infectious diseases, pediatric infectious diseases pharmacotherapy, and pediatric critical care medicine from 18 geographically diverse US institutions was convened. Through a series of teleconferences and web-based surveys, a guidance statement was developed and refined based on a review of the best available evidence and expert opinion. RESULTS:The course of COVID-19 in children and adolescents is typically mild, though more severe disease is occasionally observed. Evidence supporting risk stratification is incomplete. Randomized controlled trials have demonstrated the benefit of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2)-specific monoclonal antibody therapies in adults, but data on safety and efficacy in children or adolescents are limited. Potential harms associated with infusion reactions or anaphylaxis are reportedly low in adults. CONCLUSIONS:Based on evidence available as of August 31, 2021, the panel suggests a risk-based approach to administration of SARS-CoV-2 monoclonal antibody therapy. Therapy is suggested for the treatment of mild to moderate COVID-19 in adolescents (≥12 years of age) at the highest risk of progression to hospitalization or severe disease. Therapeutic decision-making about those at moderate risk of severe disease should be individualized. Use as postexposure prophylaxis could be considered for those at the highest risk who have a high-risk exposure but are not yet diagnosed with COVID-19. Clinicians and health systems should ensure safe and timely implementation of these therapeutics that does not exacerbate existing healthcare disparities.

Pore-forming toxins (PFTs) are commonly produced by pathogenic bacteria, and understanding them is key to the development of virulence-targeted therapies. Streptococcus agalactiae, or group B Streptococcus (GBS), produces several factors that enhance its pathogenicity, including the PFT β-hemolysin/cytolysin (βhc). Little is understood about the cellular factors involved in βhc pore formation. We conducted a whole-genome CRISPR-Cas9 forward genetic screen to identify host genes that might contribute to βhc pore formation and cell death. While the screen identified the established receptor, CD59, in control experiments using the toxin intermedilysin (ILY), no clear candidate genes were identified that were required for βhc-mediated lethality. Of the top targets from the screen, two genes involved in membrane remodeling and repair represented candidates that might modulate the kinetics of βhc-induced cell death. Upon attempted validation of the results using monoclonal cell lines with targeted disruption of these genes, no effect on βhc-mediated cell lysis was observed. The CRISPR-Cas9 screen results are consistent with the hypothesis that βhc does not require a single nonessential host factor to mediate target cell death. IMPORTANCE CRISPR-Cas9 forward genetic screens have been used to identify host cell targets required by bacterial toxins. They have been used successfully to both verify known targets and elucidate novel host factors required by toxins. Here, we show that this approach fails to identify host factors required for cell death due to βhc, a toxin required for GBS virulence. These data suggest that βhc may not require a host cell receptor for toxin function or may require a host receptor that is an essential gene and would not be identified using this screening strategy.