Vaccine value profile for cytomegalovirus.

Cytomegalovirus (CMV) is the most common infectious cause of congenital malformation and a leading cause of developmental disabilities such as sensorineural hearing loss (SNHL), motor and cognitive deficits. The significant disease burden from congenital CMV infection (cCMV) led the US National Institute of Medicine to rank CMV vaccine development as the highest priority. An average of 6.7/1000 live births are affected by cCMV, but the prevalence varies across and within countries. In contrast to other congenital infections such as rubella and toxoplasmosis, the prevalence of cCMV increases with CMV seroprevalence rates in the population. The true global burden of cCMV disease is likely underestimated because most infected infants (85-90 %) have asymptomatic infection and are not identified. However, about 7-11 % of those with asymptomatic infection will develop SNHL throughout early childhood. Although no licensed CMV vaccine exists, several candidate vaccines are in development, including one currently in phase 3 trials. Licensure of one or more vaccine candidates is feasible within the next five years. Various models of CMV vaccine strategies employing different target populations have shown to provide substantial benefit in reducing cCMV. Although CMV can cause end-organ disease with significant morbidity and mortality in immunocompromised individuals, the focus of this vaccine value profile (VVP) is on preventing or reducing the cCMV disease burden. This CMV VVP provides a high-level, comprehensive assessment of the currently available data to inform the potential public health, economic, and societal value of CMV vaccines. The CMV VVP was developed by a working group of subject matter experts from academia, public health groups, policy organizations, and non-profit organizations. All contributors have extensive expertise on various elements of the CMV VVP and have described the state of knowledge and identified the current gaps. The VVP was developed using only existing and publicly available information.

Virological Characteristics of Hospitalized Children With SARS-CoV-2 Infection.

BACKGROUND AND OBJECTIVES: In children with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, virological characteristics and correlation with disease severity have not been extensively studied. The primary objective in this study is to determine the correlation between SARS-CoV-2 viral load (VL) in infected children with age, disease severity, and underlying comorbidities. METHODS: Children <21 years, screened for SARS-CoV-2 at the time of hospitalization, who tested positive by polymerase chain reaction were included in this study. VL at different sites was determined and compared between groups. RESULTS: Of the 102 children included in this study, 44% of the cohort had asymptomatic infection, and children with >1 comorbidity were the most at risk for severe disease. VL in children with symptomatic infection was significantly higher than in children with asymptomatic infection (3.0 × 105 vs 7.2 × 103 copies per mL; P = .001). VL in the respiratory tract was significantly higher in children <1 year, compared with older children (3.3 × 107 vs 1.3 × 104 copies per mL respectively; P < .0001), despite most infants presenting with milder illness. Besides the respiratory tract, SARS-CoV-2 RNA was also detectable in samples from the gastrointestinal tract (saliva and rectum) and blood. In 13 children for whom data on duration of polymerase chain reaction positivity was available, 12 of 13 tested positive 2 weeks after initial diagnosis, and 6 of 13 continued to test positive 4 weeks after initial diagnosis. CONCLUSIONS: In hospitalized children with SARS-CoV-2, those with >1 comorbid condition experienced severe disease. SARS-CoV-2 VL in the respiratory tract is significantly higher in children with symptomatic disease and children <1 year of age.

Initial Guidance on Use of Monoclonal Antibody Therapy for Treatment of Coronavirus Disease 2019 in Children and Adolescents.

BACKGROUND: In November 2020, the US Food and Drug Administration (FDA) provided Emergency Use Authorizations (EUA) for 2 novel virus-neutralizing monoclonal antibody therapies, bamlanivimab and REGN-COV2 (casirivimab plus imdevimab), for the treatment of mild to moderate coronavirus disease 2019 (COVID-19) in adolescents and adults in specified high-risk groups. This has challenged clinicians to determine the best approach to use of these products. METHODS: A panel of experts in pediatric infectious diseases, pediatric infectious diseases pharmacy, pediatric intensive care medicine, and pediatric hematology from 29 geographically diverse North American institutions was convened. Through a series of teleconferences and web-based surveys, a guidance statement was developed and refined based on review of the best available evidence and expert opinion. RESULTS: The course of COVID-19 in children and adolescents is typically mild and there is no high-quality evidence supporting any high-risk groups. There is no evidence for safety and efficacy of monoclonal antibody therapy for treatment of COVID-19 in children or adolescents, limited evidence of modest benefit in adults, and evidence for potential harm associated with infusion reactions or anaphylaxis. CONCLUSIONS: Based on evidence available as of December 20, 2020, the panel suggests against routine administration of monoclonal antibody therapy (bamlanivimab, or casirivimab and imdevimab), for treatment of COVID-19 in children or adolescents, including those designated by the FDA as at high risk of progression to hospitalization or severe disease. Clinicians and health systems choosing to use these agents on an individualized basis should consider risk factors supported by pediatric-specific evidence and ensure the implementation of a system for safe and timely administration that does not exacerbate existing healthcare disparities.

Multicenter Interim Guidance on Use of Antivirals for Children With Coronavirus Disease 2019/Severe Acute Respiratory Syndrome Coronavirus 2.

BACKGROUND: Although coronavirus disease 2019 (COVID-19) is a mild infection in most children, a small proportion develop severe or critical illness. Data describing agents with potential antiviral activity continue to expand such that updated guidance is needed regarding use of these agents in children. METHODS: A panel of pediatric infectious diseases physicians and pharmacists from 20 geographically diverse North American institutions was convened. Through a series of teleconferences and web-based surveys, a set of guidance statements was developed and refined based on review of the best available evidence and expert opinion. RESULTS: Given the typically mild course of COVID-19 in children, supportive care alone is suggested for most cases. For children with severe illness, defined as a supplemental oxygen requirement without need for noninvasive or invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO), remdesivir is suggested, preferably as part of a clinical trial if available. Remdesivir should also be considered for critically ill children requiring invasive or noninvasive mechanical ventilation or ECMO. A duration of 5 days is appropriate for most patients. The panel recommends against the use of hydroxychloroquine or lopinavir-ritonavir (or other protease inhibitors) for COVID-19 in children. CONCLUSIONS: Antiviral therapy for COVID-19 is not necessary for the great majority of pediatric patients. For children with severe or critical disease, this guidance offers an approach for decision-making regarding use of remdesivir.

Multicenter Initial Guidance on Use of Antivirals for Children With Coronavirus Disease 2019/Severe Acute Respiratory Syndrome Coronavirus 2.

BACKGROUND: Although coronavirus disease 2019 (COVID-19) is mild in nearly all children, a small proportion of pediatric patients develop severe or critical illness. Guidance is therefore needed regarding use of agents with potential activity against severe acute respiratory syndrome coronavirus 2 in pediatrics. METHODS: A panel of pediatric infectious diseases physicians and pharmacists from 18 geographically diverse North American institutions was convened. Through a series of teleconferences and web-based surveys, a set of guidance statements was developed and refined based on review of best available evidence and expert opinion. RESULTS: Given the typically mild course of pediatric COVID-19, supportive care alone is suggested for the overwhelming majority of cases. The panel suggests a decision-making framework for antiviral therapy that weighs risks and benefits based on disease severity as indicated by respiratory support needs, with consideration on a case-by-case basis of potential pediatric risk factors for disease progression. If an antiviral is used, the panel suggests remdesivir as the preferred agent. Hydroxychloroquine could be considered for patients who are not candidates for remdesivir or when remdesivir is not available. Antivirals should preferably be used as part of a clinical trial if available. CONCLUSIONS: Antiviral therapy for COVID-19 is not necessary for the great majority of pediatric patients. For those rare cases of severe or critical disease, this guidance offers an approach for decision-making regarding antivirals, informed by available data. As evidence continues to evolve rapidly, the need for updates to the guidance is anticipated.

Clinical Diagnostic Testing for Human Cytomegalovirus Infections.

Human cytomegalovirus (HCMV) infections are among the most common complications arising in transplant patients, elevating the risk of various complications including loss of graft and death. HCMV infections are also responsible for more congenital infections worldwide than any other agent. Congenital HCMV (cCMV) infections are the leading nongenetic cause of sensorineural hearing loss and a source of significant neurological disabilities in children. While there is overlap in the clinical and laboratory approaches to diagnosis of HCMV infections in these settings, the management, follow-up, treatment, and diagnostic strategies differ considerably. As yet, no country has implemented a universal screening program for cCMV. Here, we summarize the issues, limitations, and application of diagnostic strategies for transplant recipients and congenital infection, including examples of screening programs for congenital HCMV that have been implemented at several centers in Japan, Italy, and the United States.

Neonatal herpes simplex virus infections.

Neonatal herpes simplex virus (HSV) is an uncommon but devastating infection in the newborn, associated with significant morbidity and mortality. The use of PCR for identification of infected infants and acyclovir for treatment has significantly improved the prognosis for affected infants. The subsequent use of suppressive therapy with oral acyclovir following completion of parenteral treatment of acute disease has further enhanced the long-term prognosis for these infants. This review article will discuss the epidemiology, risk factors and routes of acquisition, clinical presentation, and evaluation of an infant suspected to have the infection, and treatment of proven neonatal HSV disease.

Clinical Predictors of Sensorineural Hearing Loss and Cognitive Outcome in Infants with Symptomatic Congenital Cytomegalovirus Infection.

The objective of this study was to determine newborn clinical findings predictive of adverse clinical outcomes in infants with symptomatic congenital cytomegalovirus infection. Of 160 infants, significantly more children with central nervous system involvement had sensorineural hearing loss (P = 0.0007) and an IQ ≤70 (P < 0.0001) compared with infants with transient findings or only a petechial rash.

Comparison of saliva PCR assay versus rapid culture for detection of congenital cytomegalovirus infection.

As part of the CMV and Hearing Multicenter Screening (CHIMES) study, 72,239 newborns were screened for cytomegalovirus by rapid culture and real-time PCR of saliva samples. Of the 266 infants with congenital cytomegalovirus infection, discordance between rapid culture and PCR was observed in 14 children, and 13 were identified only by PCR, demonstrating the superiority of the PCR assay.

Preventing herpes simplex virus in the newborn.

Genital herpes simplex virus (HSV) infections are very common worldwide. Approximately 22% of pregnant women are infected genitally with HSV, and most of them are unaware of this. The most devastating consequence of maternal genital herpes is HSV disease in the newborn. Although neonatal HSV infections remain uncommon, due to the significant morbidity and mortality associated with the infection, HSV infection in the newborn is often considered in the differential diagnosis of ill neonates. This review summarizes the epidemiology and management of neonatal HSV infections and discusses strategies to prevent HSV infection in the newborn.

Management of neonatal herpes simplex virus infection and exposure.

Neonatal herpes simplex virus (HSV) infections are rare but are associated with significant morbidity and mortality. Advances in diagnostic modalities to identify these infants, as well as the development of safe and effective antiviral therapy, have revolutionised the management of affected infants. This review will summarise the epidemiology of neonatal HSV infections and discuss the management of infants with HSV exposure and infection.

Neonatal herpes simplex virus infections.

Neonatal herpes simplex virus infections are uncommon, but because of the morbidity and mortality associated with the infection they are often considered in the differential diagnosis of ill neonates. The use of polymerase chain reaction for diagnosis of central nervous system infections and the development of safe and effective antiviral therapy has revolutionized the diagnosis and management of these infants. Initiation of long-term antiviral suppressive therapy in these infants has led to significant improvement in morbidity. This article summarizes the epidemiology of neonatal herpes simplex virus infections and discusses clinical presentation, diagnosis, management, and follow up of infants with neonatal herpes disease.

Maternal and neonatal herpes simplex virus infections.

Genital herpes infections are extremely common worldwide and ~22% of pregnant women are infected with herpes simplex virus. Eighty percent of those affected with genital herpes are unaware of being infected. The most devastating consequence of maternal genital herpes is neonatal herpes disease. Fortunately, neonatal herpes simplex infections are uncommon but due to the morbidity and mortality associated with the infection are often considered in the differential diagnosis of ill neonates. The use of polymerase chain reaction assay for diagnosis of central nervous system infections and the development of safe and effective antiviral therapy have revolutionized the diagnosis and management of these infants. Most recently, the initiation of long-term antiviral suppressive therapy in these infants has led to significant improvement in morbidity. This review will summarize the epidemiology of maternal and neonatal herpes infections and discuss clinical presentation, diagnosis, management, and follow-up of infants with neonatal herpes disease.

Neonatal herpes disease following maternal antenatal antiviral suppressive therapy: a multicenter case series.

OBJECTIVE: The goal was to describe herpes simplex virus (HSV) disease in neonates whose mothers received suppressive acyclovir therapy for HSV infection. STUDY DESIGN: A multicenter case series of 8 infants who developed neonatal HSV disease following maternal antiviral suppressive therapy during pregnancy. RESULTS: Eight infants were identified from New Jersey (5), Maine (1), New York (1), and Texas (1) between 2005 and 2009. All 6 mothers of infants infected with HSV who were screened prenatally for group B Streptococcus were positive; 1 mother was not tested and the other had bacterial vaginosis and genital human papillomavirus infection. Six mothers had a first clinical episode of genital HSV infection during this pregnancy; mothers with a prior history of genital HSV had no clinically recognized outbreak during the pregnancy. Perinatal transmission of HSV occurred in 7 infants (despite suppressive therapy until the day of delivery in 5 instances). Seven of 8 patients were born at term; 6 infants were male. In 7 of 8 cases, HSV was diagnosed by 8 days of age. Five infants had skin, eye, and mucous membrane disease, 2 had central nervous system disease (without and with disseminated disease), and one had intrauterine/disseminated disease. CONCLUSIONS: Although maternal antiviral suppressive therapy is an increasingly wide practice, physicians caring for neonates should be aware that suppressive therapy does not prevent neonatal HSV disease, which can have an atypical clinical presentation and drug resistance.