Congenital Chagas disease: progress toward implementation of pregnancy-based screening.

PURPOSE OF REVIEW: Lack of recognition of congenital Chagas disease in infants of mothers from endemic regions who are living in countries nonendemic for Trypanosoma cruzi infection suggests a high rate of underdiagnosis. Pregnancy is the optimal access point for identifying Chagas disease in at-risk mothers and their infants. In this review, we update progress toward implementation of pregnancy-based screening for congenital Chagas disease in nonendemic settings. RECENT FINDINGS: International organizations have updated recommendations for diagnosis, treatment and prevention of congenital Chagas disease. Reports of successful implementation of pregnancy-based screening at some centers provide a model for optimizing diagnosis of congenital Chagas disease. Screening family members of index patients may identify additional T. cruzi-infected persons. Promising tests to augment current diagnostic modalities for maternal and congenital Chagas disease are in development. Universal or risk-based screening would be cost-effective. More healthcare providers are now aware that treatment of congenital Chagas disease is curative and are promoting efforts to make pregnancy-based screening for congenital Chagas disease a standard of care. SUMMARY: Ongoing efforts to implement routine pregnancy-based screening for congenital Chagas disease in nonendemic regions will mutually benefit infants, their mothers and family members and can prevent potentially fatal Chagas cardiomyopathy.

A Phase 2, Randomized, Control Trial of Group B Streptococcus (GBS) Type III Capsular Polysaccharide-tetanus Toxoid (GBS III-TT) Vaccine to Prevent Vaginal Colonization With GBS III.

BACKGROUND: Group B Streptococcus (GBS) frequently colonizes pregnant women and can cause sepsis and meningitis in young infants. If colonization was prevented through maternal immunization, a reduction in perinatal GBS disease might be possible. A GBS type III capsular polysaccharide (CPS)-tetanus toxoid conjugate (III-TT) vaccine was evaluated for safety and efficacy in preventing acquisition of GBS colonization. METHODS: Healthy, nonpregnant women aged 18-40 years and screened to be GBS III vaginal and rectal culture negative were randomized to receive III-TT conjugate or tetanus diphtheria toxoid vaccine in a multicenter, observer-blinded trial. GBS vaginal and rectal cultures and blood were obtained bimonthly over 18 months. Serum concentrations of GBS III CPS-specific antibodies were determined using enzyme-linked immunosorbent assay. RESULTS: Among 1525 women screened, 650 were eligible for the intent-to-treat analysis. For time to first acquisition of vaginal GBS III, vaccine efficacy was 36% (95% confidence interval [CI], 1%-58%; P = .044), and for first rectal acquisition efficacy was 43% (95% CI, 11% to 63%; P = .014). Two months post-immunization, geometric mean concentrations of serum GBS type III CPS-specific immunoglobulin G were 12.6 µg/mL (95% CI, 9.95 to 15.81) in GBS III-TT recipients, representing a 4-fold increase from baseline in 95% of women, which persisted. Both vaccines were well tolerated. CONCLUSIONS: GBS CPS III-TT conjugate vaccine significantly delayed acquisition of vaginal and rectal GBS III colonization. In addition to its use for maternal immunization to passively protect infants with maternally derived antibodies, a multivalent vaccine might also serve to reduce fetal and neonatal exposure to GBS. CLINICAL TRIALS REGISTRATION: NCT00128219.

Addressing the Challenges of Chagas Disease: An Emerging Health Concern in the United States.

Chagas disease is an emerging health concern in the United States. US health care providers have an unparalleled opportunity to respond to the challenges this infection poses and to provide state-of-the-art care for patients with Chagas disease. Most of the approximately 300,000 persons with Trypanosoma cruzi infection living in the United States have chronic, asymptomatic infection acquired in endemic regions in Latin America. Congenital infection is often asymptomatic and, even when symptomatic, has no features that distinguish it from other congenitally transmitted infections. Health care providers and the public have limited awareness of this infection. Recognizing risk groups and performing targeted diagnostic testing for at-risk infants, children, and adults are a health priority because early treatment can effect cure and avert the life-threatening cardiac manifestations of Chagas disease. Two medications for treatment, benznidazole and nifurtimox, are available through the Centers for Disease Control and Prevention. Although challenges exist, informed health care providers can greatly reduce the effects of Chagas disease in the United States.

Immune Responses to Invasive Group B Streptococcal Disease in Adults.

Immunization of nonpregnant adults could help prevent invasive group B Streptococcus (GBS) infections, but adult immune responses have not been investigated. We defined capsular polysaccharide (CPS) and pilus island (PI) surface antigen distribution and expression and immune responses to GBS infection in nonpregnant adults. Prospective surveillance from 7 hospitals in Houston, Texas, USA, identified 102 adults with GBS bacteremia; 43% had skin/soft tissue infection, 16% bacteremia without focus, and 12% osteomyelitis. CPS-specific IgG was determined by ELISA and pilus-specific IgG by multiplex immunoassay. CPS types were Ia (24.5%), Ib (12.7%), II (9.8%), III (16.7%), IV (13.7%), and V (12.7%); 9.8% were nontypeable by serologic methods. Pili, expressed by 89%, were most often PI-2a. CPS and pilus-specific IgG increased during convalescence among patients with strains expressing CPS or PI. All GBS expressed CPS or PI; 79% expressed both. Increased antibodies to CPS and PI during recovery suggests that GBS bacteremia in adults is potentially vaccine preventable.

Maternal antibody at delivery protects neonates from early onset group B streptococcal disease.

BACKGROUND: Further reduction in the group B streptococcal (GBS) disease burden in neonates in the United States awaits an additional prevention strategy, such as maternal immunization. METHODS: We performed a prospective, multicenter, case-control study of 33 mothers delivering neonates with early onset GBS infection (cases), and 99 age- and ethnicity-matched mothers colonized with the same capsular polysaccharide (CPS) types delivering healthy neonates (controls). Relative risk and absolute risk were calculated for early onset disease associated with concentrations of type Ia, III, or V CPS-specific antibody in maternal serum. RESULTS: For GBS types Ia and III, maternal CPS-specific antibody concentrations of ≥ 0.5 µg/mL were associated with a relative risk of approximately 0.1 (95% confidence intervals [CIs], .01-.74 and 0-.72, respectively; P = .02 for each), corresponding to a 90% risk reduction (by logistic regression). For type V, the relative risk was 0.3 (95% CI, .01-3.1), corresponding to a 70% risk reduction. By Bayesian modeling, the risk of early onset disease would decrease by 70% if maternal CPS-specific antibody concentrations for these 3 GBS types were ≥ 1 µg/mL. CONCLUSIONS: Maternal CPS-specific antibody serum concentrations of ≥ 1 µg/mL at the time of delivery appear to protect most neonates from early onset GBS type Ia and III disease.

Safety and immunogenicity of tetanus diphtheria and acellular pertussis (Tdap) immunization during pregnancy in mothers and infants: a randomized clinical trial.

IMPORTANCE: Maternal immunization with tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis (Tdap) vaccine could prevent infant pertussis. OBJECTIVE: To evaluate the safety and immunogenicity of Tdap immunization during pregnancy and its effect on infant responses to diphtheria and tetanus toxoids and acellular pertussis (DTaP) vaccine. DESIGN, SETTING, AND PARTICIPANTS: Phase 1-2, randomized, double-blind, placebo-controlled, clinical trial conducted from 2008 to 2012. Forty-eight pregnant women aged 18 to 45 years received Tdap (n = 33) or placebo (n = 15) at 30 to 32 weeks' gestation, with crossover immunization postpartum. INTERVENTIONS: Tdap vaccination at 30 to 32 weeks' gestation or postpartum. MAIN OUTCOMES AND MEASURES: Primary outcomes were maternal and infant adverse events, pertussis illness, and infant growth and development until age 13 months. Secondary outcomes were antibody concentrations in pregnant women before and 4 weeks after Tdap immunization or placebo, at delivery and 2 months' postpartum, and in infants at birth, at 2 months, and after the third and fourth doses of DTaP. RESULTS: No Tdap-associated serious adverse events occurred in women or infants. Injection site reactions after Tdap immunization were reported in 26 (78.8% [95% CI, 61.1%-91.0%]) and 12 (80% [95% CI, 51.9%-95.7%]) pregnant and postpartum women, respectively (P > .99). Systemic symptoms were reported in 12 (36.4% [ 95% CI, 20.4%-54.9%]) and 11 (73.3% [95% CI, 44.9%-92.2%]) pregnant and postpartum women, respectively (P = .03). Growth and development were similar in both infant groups. No cases of pertussis occurred. Significantly higher concentrations of pertussis antibodies were measured at delivery in women who received Tdap during pregnancy vs postpartum (eg, pertussis toxin antibodies: 51.0 EU/mL [95% CI, 37.1-70.1] and 9.1 EU/mL [95% CI, 4.6-17.8], respectively; P < .001) and in their infants at birth (68.8 EU/mL [95% CI, 52.1-90.8] and 14.0 EU/mL [95% CI, 7.3-26.9], respectively; P < .001) and at age 2 months (20.6 EU/mL [95% CI, 14.4-29.6] and 5.3 EU/mL [95% CI, 3.0-9.4], respectively; P < .001). Antibody responses in infants born to women receiving Tdap during pregnancy were not different following the fourth dose of DTaP. CONCLUSIONS AND RELEVANCE: This preliminary assessment did not find an increased risk of adverse events among women who received Tdap vaccine during pregnancy or their infants. For secondary outcomes, maternal immunization with Tdap resulted in high concentrations of pertussis antibodies in infants during the first 2 months of life and did not substantially alter infant responses to DTaP. Further research is needed to provide definitive evidence of the safety and efficacy of Tdap immunization during pregnancy. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00707148.

Variation in reported neonatal group B streptococcal disease incidence in developing countries.

Group B Streptococcus (GBS) is a leading cause of neonatal sepsis in developed countries. Its burden in the developing world is less clear. Studies reporting neonatal GBS disease incidence from developing countries were identified from 5 literature databases. Studies were assessed with respect to case finding and culture methods. Only 20 studies were identified. The GBS incidence ranged 0-3.06 per 1000 live births with variation within and between geographic regions. All but 1 study identified GBS cases within a hospital setting, despite the potential for births in the community. Possible case under-ascertainment was only discussed in 2 studies. A higher GBS incidence was reported when using automated culture methods. Prospective, population-based surveillance is urgently needed in developing countries to provide an accurate assessment of the neonatal GBS disease burden. This will be crucial for the design of interventions, including novel vaccines, and the understanding of their potential to impact mortality from neonatal sepsis.

Invasive Group B Streptococcal Disease In Childhood.

Invasive group B streptococcal disease in childhood is uncommon and occupies a unique clinical niche. We present 10 children, 1-17 years of age, with invasive group B streptococcal disease from 2010 to 2020. Seven had conditions predisposing to infection and 3 had no identifiable risk factors. With appropriate consideration of pathogenesis, source control, and treatment, all children recovered.

Group B Streptococcal Cellulitis-Adenitis Syndrome in Infants: Insights From 24 Years of Experience.

This series of 28 infants with group B streptococcal (GBS) cellulitis-adenitis from a single institution over 24 years offers insights important to the early recognition, spectrum of findings, and optimal management of this rare manifestation of invasive GBS disease.

Intraorbital and intracranial extension of sinusitis: comparative morbidity.

OBJECTIVES: We hypothesized that intracranial extension of sinusitis carries greater morbidity than extension confined to the orbit and that presenting features can raise suspicion for intracranial extension. STUDY DESIGN: A retrospective review (1997 to 2006) identified 118 children with sinusitis complicated by intracranial extension or intraorbital extension. Presenting features and infecting organisms were compared using χ(2) or Fisher exact tests. Outcomes included duration of hospitalization, length of therapy and sequelae. RESULTS: Thirty-three children had intracranial extension and 85 had intraorbital extension. Children with intracranial extension were older (11.4 versus 7.6 years; P ≤ .001), had more preadmission encounters (1.9 versus 1.3; P = .012), longer headache duration (9.5 versus 2.8 days; P = .009), and presented more often with vomiting (73% versus 28%; P < .001) than those with intraorbital extension. Children with intracranial extension also were hospitalized (26 versus 10 days; P < .001) and treated (36 versus 24 days; P = .001) longer. Four children (3%) had persistent sequelae. CONCLUSIONS: Children with intracranial extension are hospitalized and treated longer than those with intraorbital extension of sinusitis but persistent sequelae are uncommon. Prolonged headache and protracted vomiting at presentation should alert caregivers to consider intracranial extension.

Chagas Disease: Implementation of Screening to Benefit Mother and Infant.

Pregnancy-based screening would identify women with Chagas disease, allowing for treatment of Trypanosoma cruzi-infected women and infants to prevent potentially fatal Chagas cardiomyopathy.

Two Cases of Cronobacter Sakazakii Meningitis in Infants: The Importance Of Early Advanced Brain Imaging and Public Health Reporting.

We report 2 infants hospitalized with Cronobacter sakazakii meningitis. Each infant had exposure to powdered infant formula at home. Both infants survived, but 1 infant had a subdural empyema drained and developed left sensorineural hearing loss. Early advanced brain imaging is recommended in infants with C. sakazakii meningitis. Reporting to state and federal public health officials may help identify outbreaks.

Evaluation and Management of Congenital Chagas Disease in the United States.

Chagas disease is underappreciated as a health concern in the United States. Approximately 40 000 women of childbearing age living in the United States have chronic Chagas disease. Most of them are unaware that they have an infection that is transmissible to their offspring. The estimated US maternal-to-infant transmission rate of Trypanosoma cruzi is 1% to 5%. Ten percent to 40% of neonates with congenital T cruzi infection have clinical signs consistent with a congenital infection but no findings are unique to Chagas disease. If left untreated, 20% to 40% of infants with Chagas disease will later develop potentially fatal cardiac manifestations. Molecular testing can confirm the diagnosis in neonates. Treatment is well tolerated in infancy and usually results in cure. Screening of at-risk women during pregnancy can identify maternal infection and allow early assessment and treatment for congenital T cruzi infection.

Serocorrelates of protection against infant group B streptococcus disease.

Group B streptococcus (GBS) is a leading cause of young infant mortality and morbidity globally, with vaccines being developed for over four decades but none licensed to date. A serocorrelate of protection against invasive disease in young infants is being considered to facilitate vaccine early licensure, followed by demonstration of efficacy assessed postlicensure. In this Review, we synthesise the available scientific evidence to define an immune correlate associated with GBS disease risk reduction on the basis of studies of natural infection. We summarise studies that have investigated GBS serum anticapsular or anti-protein antibodies, and studies measuring the association between antibody function and disease risk reduction. We highlight how knowledge on the development of correlates of protection from existing vaccines could be harnessed to facilitate GBS vaccine development. These lessons include aggregation of serocorrelates of protection for individual serotypes, understanding the relationship between immunity derived from natural exposure of adults and vaccine-induced immunity, or using extrapolation of protection from in-vitro immunoassay results. We also highlight key considerations for the assessment of the role of antibodies to derive a serocorrelate of risk reduction in future seroepidemiological studies of GBS disease.

Group B streptococcal conjugate vaccine: a timely concept for which the time has come.

Invasive disease due to group B Streptococcus (GBS) has been recognized as a threat to the health of pregnant women and their infants for almost half a century. Development of GBS vaccine candidates has progressed at an exemplary pace given lack of sponsorship by manufacturers. A trivalent or pentavalent vaccine will be required, and decisions must be made as to the criteria by which efficacy will be determined and the population in whom efficacy will be assessed. Concerns regarding durability of conjugate vaccine-derived immunity, pregnant women as a possible target group and regulatory issues required for licensing must be resolved if the prospect of impacting GBS disease burden through immunization is to become a reality.