Summary The number of infants infected with HIV is declining with the rise in interventions for the elimination of paediatric HIV infection, but the number of uninfected infants exposed to HIV ...through their HIV-infected mothers is increasing. Interest in the health outcomes of HIV-exposed, uninfected infants has grown in the past decade, with several studies suggesting that these infants have increased mortality rates, increased infectious morbidity, and impaired growth compared with HIV-unexposed infants. However, heterogeneous results might reflect the inherent challenges in studies of HIV-exposed, uninfected infants, which need large populations with appropriate, contemporaneous comparison groups and repeated HIV testing throughout the period of breastfeeding. We review the effects of HIV exposure on mortality, morbidity, and growth, discuss the immunological abnormalities identified so far, and provide an overview of interventions that could be effective in this susceptible population. As the number of infants infected with HIV declines, the health needs of HIV-exposed, uninfected infants should be prioritised further, to ensure that post-2015 Sustainable Development Goals are achieved.
IMPORTANCE: In communities with high rates of coronavirus disease 2019, reports have emerged of children with an unusual syndrome of fever and inflammation. OBJECTIVES: To describe the clinical and ...laboratory characteristics of hospitalized children who met criteria for the pediatric inflammatory multisystem syndrome temporally associated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (PIMS-TS) and compare these characteristics with other pediatric inflammatory disorders. DESIGN, SETTING, AND PARTICIPANTS: Case series of 58 children from 8 hospitals in England admitted between March 23 and May 16, 2020, with persistent fever and laboratory evidence of inflammation meeting published definitions for PIMS-TS. The final date of follow-up was May 22, 2020. Clinical and laboratory characteristics were abstracted by medical record review, and were compared with clinical characteristics of patients with Kawasaki disease (KD) (n = 1132), KD shock syndrome (n = 45), and toxic shock syndrome (n = 37) who had been admitted to hospitals in Europe and the US from 2002 to 2019. EXPOSURES: Signs and symptoms and laboratory and imaging findings of children who met definitional criteria for PIMS-TS from the UK, the US, and World Health Organization. MAIN OUTCOMES AND MEASURES: Clinical, laboratory, and imaging characteristics of children meeting definitional criteria for PIMS-TS, and comparison with the characteristics of other pediatric inflammatory disorders. RESULTS: Fifty-eight children (median age, 9 years interquartile range {IQR}, 5.7-14; 20 girls 34%) were identified who met the criteria for PIMS-TS. Results from SARS-CoV-2 polymerase chain reaction tests were positive in 15 of 58 patients (26%) and SARS-CoV-2 IgG test results were positive in 40 of 46 (87%). In total, 45 of 58 patients (78%) had evidence of current or prior SARS-CoV-2 infection. All children presented with fever and nonspecific symptoms, including vomiting (26/58 45%), abdominal pain (31/58 53%), and diarrhea (30/58 52%). Rash was present in 30 of 58 (52%), and conjunctival injection in 26 of 58 (45%) cases. Laboratory evaluation was consistent with marked inflammation, for example, C-reactive protein (229 mg/L IQR, 156-338, assessed in 58 of 58) and ferritin (610 μg/L IQR, 359-1280, assessed in 53 of 58). Of the 58 children, 29 developed shock (with biochemical evidence of myocardial dysfunction) and required inotropic support and fluid resuscitation (including 23/29 79% who received mechanical ventilation); 13 met the American Heart Association definition of KD, and 23 had fever and inflammation without features of shock or KD. Eight patients (14%) developed coronary artery dilatation or aneurysm. Comparison of PIMS-TS with KD and with KD shock syndrome showed differences in clinical and laboratory features, including older age (median age, 9 years IQR, 5.7-14 vs 2.7 years IQR, 1.4-4.7 and 3.8 years IQR, 0.2-18, respectively), and greater elevation of inflammatory markers such as C-reactive protein (median, 229 mg/L IQR 156-338 vs 67 mg/L IQR, 40-150 mg/L and 193 mg/L IQR, 83-237, respectively). CONCLUSIONS AND RELEVANCE: In this case series of hospitalized children who met criteria for PIMS-TS, there was a wide spectrum of presenting signs and symptoms and disease severity, ranging from fever and inflammation to myocardial injury, shock, and development of coronary artery aneurysms. The comparison with patients with KD and KD shock syndrome provides insights into this syndrome, and suggests this disorder differs from other pediatric inflammatory entities.
At birth, neonates are particularly vulnerable to infection and transplacental transfer of immunoglobulin G (IgG) from mother to fetus provides crucial protection in the first weeks of life. ...Transcytosis of IgG occurs
binding with the neonatal Fc receptor (FcRn) in the placental synctiotrophoblast. As maternal vaccination becomes an increasingly important strategy for the protection of young infants, improving our understanding of transplacental transfer and the factors that may affect this will become increasingly important, especially in low-income countries where the burden of morbidity and mortality is highest. This review highlights factors of relevance to maternal vaccination that may modulate placental transfer-IgG subclass, glycosylation of antibody, total maternal IgG concentration, maternal disease, infant gestational age, and birthweight-and outlines the conflicting evidence and questions that remain regarding the complexities of these relationships. Furthermore, the intricacies of the Ab-FcRn interaction remain poorly understood and models that may help address future research questions are described.
The neonatal period and early infancy are times of increased vulnerability to infection. The immune system of infants undergoes rapid changes and a number of factors can influence the maturation and ...function of the early infant immune system, amongst these factors are maternal infections and immunity. Infants who are HIV-exposed, but uninfected show important immune alterations, which are likely to be associated with the increased morbidity and mortality observed in these infants. Maternally derived antibodies are crucial in early life to protect infants from infection during the time when their own immune system is becoming more experienced and fully mature. However, maternal antibodies can also interfere with the infant's own antibody responses to primary vaccination. Preterm infants are particularly vulnerable to infection, having not had the opportunity to benefit from the transplacental transfer of maternal antibodies in late pregnancy. In addition, further differences have been observed in the innate and adaptive immune system between preterm and term infants. Here, we focus on maternal influences on the infant immune system, using HIV and maternal vaccination as examples and finish by considering how prematurity impacts infant immune responses to vaccination.
The current antituberculosis vaccine, BCG, was derived in the 1920s, yet the mechanisms of BCG-induced protective immunity and the variability of protective efficacy among populations are still not ...fully understood. BCG challenges the concept of vaccine specificity, as there is evidence that BCG may protect immunized infants from pathogens other than
- resulting in heterologous or nonspecific protection. This review summarizes the up-to-date evidence for this phenomenon, potential immunological mechanisms and implications for improved childhood vaccine design. BCG induces functional changes in infant innate and adaptive immune compartments, encouraging their collaboration in the first year of life. Understanding biological mechanisms beyond heterologous BCG effects is crucial to improve infant protection from infectious diseases.
Summary Maternal immunisation has the potential to substantially reduce morbidity and mortality from infectious diseases after birth. The success of tetanus, influenza, and pertussis immunisation ...during pregnancy has led to consideration of additional maternal immunisation strategies to prevent group B streptococcus and respiratory syncytial virus infections, among others. However, many gaps in knowledge regarding the immunobiology of maternal immunisation prevent the optimal design and application of this successful public health intervention. Therefore, we did an innovative landscape analysis to identify research priorities. Key topics were delineated through review of the published literature, consultation with vaccine developers and regulatory agencies, and a collaborative workshop that gathered experts across several maternal immunisation initiatives—group B streptococcus, respiratory syncytial virus, pertussis, and influenza. Finally, a global online survey prioritised the identified knowledge gaps on the basis of expert opinion about their importance and relevance. Here we present the results of this worldwide landscape analysis and discuss the identified research gaps.
Paramedics respond to acute medical and trauma emergencies in the community and transport patients to emergency departments (ED). In some cases, paramedics are not only attending calls for mental ...health and psychosocial care but are also connecting individuals with more appropriate services to address their needs. This study qualitatively explores to what extent there are promising practices to be learned from paramedic services that are connecting patients to mental health and psychosocial programming. The study is organised as follows. In terms of the methods, we conducted a critical ethnographic case study of mental health and psychosocial care within paramedic services in Ontario, Canada. Interviews were conducted with frontline paramedics (n = 31), paramedic services management (n = 5), educators at paramedic college programmes (n = 5) and Base Hospital physicians/directors (n = 5). Work observations were also performed in three paramedic services, with multiple crews across different shifts (n ~90 hr). The study findings outline three promising practices: diversion programmes that transfer patients to a destination other than the ED; crisis response teams that attend calls identified as involving mental health and community paramedicine programmes including referral programmes. We outline the social, political and economic conditions in which these programmes were established and are provided. We also describe the conditions required to enable connecting patients to non‐ED supports. The benefits of implementing specific programming for mental health‐related calls within paramedic services are discussed, as well as the importance of reaching beyond the prehospital and mental healthcare system to comprehensively and preventatively address mental health needs. Tensions are explored related to running programmatic interventions for mental health by paramedic services. We conclude by noting some public policy‐level challenges including the need to focus more broadly on prevention and address the social determinants of health to aid the de‐escalation of distress.
Transplacental antibody transfer from mother to fetus provides protection from infection in the first weeks of life, and the four different subclasses of IgG (IgG1, IgG2, IgG3, and IgG4) have diverse ...roles in protection against infection. In this study, we evaluated concentrations and transplacental transfer ratios of the IgG subclasses in a healthy UK-based cohort of mother-cord pairs, and investigated associations with maternal, obstetric, and fetal factors. In agreement with previous studies, we found a strong association between maternal and cord IgG for all subclasses. We report a transfer efficiency hierarchy of IgG1>IgG3>IgG4=IgG2 in our study population, and our review of the literature demonstrates that there is no consensus in the hierarchy of subclass transfer, despite the commonly made statement that the order is IgG1>IgG4>IgG3>IgG2. We report additional data regarding negative associations between elevated maternal IgG concentrations and maternal/cord transfer ratios, finding an effect on IgG1, IgG2, and IgG3 subclasses. Levels of IgG subclasses were the same between venous and arterial blood samples from the umbilical cord, but there was a significantly higher level of total IgG in arterial blood. We found no correlation between placental FcRn protein levels and IgG transfer in our cohort, suggesting that IgG is the main determinant of observed differences in transplacental transfer ratios at term. Neonatal IgG1 and IgG4 levels were increased with later gestation at delivery, independent of any increase in transplacental transfer, indicating that the benefit of later gestation is through accumulation of these subclasses in the fetus. Neonatal IgG2 levels and transfer ratios were reduced in rhesus-negative pregnancies, suggesting that administered anti-D antibodies may compete for transplacental transfer of this subclass. Maternal influenza vaccination resulted in elevated maternal and neonatal levels of IgG4, whereas maternal Tdap vaccination had no impact on neonatal levels of the subclasses, nor transfer. However, within Tdap vaccinated pregnancies, later gestation at Tdap vaccination was associated with higher transplacental transfer. Our study provides information regarding levels and transfer of IgG subclasses in healthy term pregnancies and demonstrates the importance of recording detailed clinical information in studies of antibody transfer, including parity, ethnicity, and timing of maternal vaccine delivery.
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