Etiology of Childhood Bilateral Sensorineural Hearing Loss in Shandong Province, China.

Objectives The purpose of this study is to ascertain the etiology of bilateral sensorineural hearing loss (SNHL) in children aged ≤ 18 years living in Shandong province. Method Data were taken from a cross-sectional study, which was conducted between 2015 and 2017. The study included children aged ≤ 18 years, recruited from special schools for children with hearing loss and from hearing rehabilitation centers in Shandong province of China. Children were screened for bilateral SNHL through audiological testing. Clinical examination, genetic testing, and structured interviews were conducted for those children who were identified as having hearing loss to identify the potential cause. Results The etiology of bilateral SNHL in our sample was genetic in 874 (39.3%), acquired in 650 (29.3%), and unknown in 697 (31.4%) children. Among children with acquired SNHL, the cause was maternal viral infection in 75 (11.5%); perinatal factors in 238 (36.6%); meningitis, measles, and mumps in 146 (22.5%); and ototoxic exposure in 117 (18%) children. Among the children with genetic SNHL, only 44 (4.9%) were identified as having syndromic hearing loss, and the remainder (95.1%) were classified as nonsyndromic hearing loss. Conclusion The findings indicated that nearly 30% of bilateral SNHL in Shandong province could be preventable through immunization, early prenatal diagnosis, proper treatment of infections, and avoidance of prescription of ototoxic drugs. This finding emphasizes the need for programs aimed at improving the health services at primary and secondary levels of health care, which will in turn prevent childhood hearing loss.

Congenital Viral Infection: Traversing the Uterine-Placental Interface.

Why certain viruses cross the physical barrier of the human placenta but others do not is incompletely understood. Over the past 20 years, we have gained deeper knowledge of intrauterine infection and routes of viral transmission. This review focuses on human viruses that replicate in the placenta, infect the fetus, and cause birth defects, including rubella virus, varicella-zoster virus, parvovirus B19, human cytomegalovirus (CMV), Zika virus (ZIKV), and hepatitis E virus type 1. Detailed discussions include ( a) the architecture of the uterine-placental interface, ( b) studies of placental explants ex vivo that provide insights into the infection and spread of CMV and ZIKV to the fetal compartment and how these viruses undermine early development, and ( c) novel treatments and vaccines that limit viral replication and have the potential to reduce dissemination, vertical transmission and the occurrence of congenital disease.

Australian Paediatric Surveillance Unit Annual Report, 2016.

This report summarises the cases reported to the Australian Paediatric Surveillance Unit (APSU) of rare infectious diseases or rare complications of more common infectious diseases in children. During the calendar year 2016, there were approximately 1500 paediatricians reporting to the APSU and the monthly report card return rate was 90%. APSU continued to provide unique national data on the perinatal exposure to HIV, congenital rubella, congenital cytomegalovirus, neonatal and infant herpes simplex virus, and congenital and neonatal varicella. APSU contributed 10 unique cases of Acute Flaccid Paralysis (a surrogate for polio) - these data are combined with cases ascertained through other surveillance systems including the Paediatric Active Disease Surveillance (PAEDS) to meet the World Health Organisation surveillance target. There was a decline in the number of cases of juvenile onset Recurrent Respiratory Papillomatosis which is likely to be associated with the introduction of the National HPV Vaccination Program. The number of cases of severe complications of influenza was significantly less in 2016 (N=32) than in 2015 (N=84) and for the first time in the last nine years no deaths due to severe influenza were reported to the APSU. In June 2016 surveillance for microcephaly commenced to assist with the detection of potential cases of congenital Zika virus infection and during that time there were 21 confirmed cases - none had a relevant history to suspect congenital Zika virus infection, however, these cases are being followed up to determine the cause of microcephaly.

IUGR and infections.

Intra-uterine growth retardation (IUGR) is usually defined as impaired growth and development of the fetus and/or its organs during gestation. Infants are defined small for gestational age (SGA), following IUGR, when the birth weight is below the 10th percentile. Pre-natal congenital infections caused by T. gondii, rubella, cytomegalovirus (CMV), herpes simplex virus (HSV), varicella-zoster virus (VZV), and Treponema are associated with, and account for, approximately 5 to 15% of IUGR. On the other hand, SGA preterm infants are at increased risk of post-natal infection compared to their age-matched appropriately grown controls, in particular nosocomial infection, irrespective of the responsible pathogen. One possible mechanism is the retarded development in the immune system which has been described in association with IUGR. Indeed, SGA infants have a disproportionately small thymus and low leukocyte, lymphocyte and macrophage counts. However, immune therapies, including prophylactic intravenous immunoglobulins and GM-CSF have not proven to be effective in reducing the incidence of sepsis, and further research is required.

Emerging viral infections in neonatal intensive care unit.

Nosocomial infections are the most important cause of morbidity and mortality among neonates and mostly in infants admitted to neonatal intensive care units (NICU). The total number of neonates who develop nosocomial infections per admission varies from 6.2 to 30%. The role of nosocomial virus infections is generally neglected in the actual epidemiologic scenario mostly due to the lack of data in the medical literature. Based on a worldwide database of health care-associated outbreaks (http://www.outbreak-database.com) we performed an analysis of the incidence, type of pathogens and clinical features of neonatal viral outbreaks especially those reported in NICUs. We also describe, as an example of emerging virus in NICU, a Norovirus outbreak along with clinical presentation that varies from mild to moderate clinical symptoms like vomiting, gastric remainder, diarrhoea, abdominal distension or severe presentation like necrotizing enterocolitis. and measures implemented for terminating the outbreak. In conclusion, our study analyses the viral origins of nosocomial infections in NICU and underline that the role of viral agents in neonatal nosocomial infections needs to be further investigated even in diseases traditionally considered of bacterial origin like necrotizing enterocolitis.

Palivizumab prophylaxis in 'late preterm' newborns.

In the last decades the preterm birth rate rose more than 20%, largely because of an increase among deliveries of 'late preterm' infants, i.e. those born at 34 to 36 weeks gestational age. Late preterm infants are more susceptible to infection by pathogens, such as respiratory syncytial virus (RSV), possibly because of the immaturity of both the respiratory system and the immune system. As a consequence, similar risks of serious RSV illness have been observed in late preterm and preterm (born ≤ 32 wGA) infants, higher when compared with full-term infants. Prevention of RSV infection includes palivizumab, which is proven to be effective in reducing the overall hospitalization rate for RSV-induced bronchiolitis in preterm neonates. In order to maximize the cost-effectiveness of this preventive approach, the American Academy of Pediatrics (AAP) has suggested the administration of palivizumab to infants born between 32 0/7 and 34 6/7 wGA with at least one risk factor and born 3 months before or during RSV season. Because a variety of environmental and demographic traits may affect the severity of RSV epidemics in different Nations, a European risk scoring tool has been developed, based on the 'local' most important risk factors. Therefore, recommendations and guidelines must be modulated in each country, determining their appropriateness in the individual setting.

[Familial predisposition and microbial etiology in dilated cardiomyopathy]. / Familiäre Prädisposition und mikrobielle Atiologie bei dilatativer Kardiomyopathie.

Cardiomyopathies are an important and diverse group of heart muscle diseases in which the heart muscle itself is structurally or functionally abnormal and in which coronary artery disease, hypertension, valvular and congenital heart disease are absent or do not sufficiently explain the observed myocardial abnormality. This often results in severe heart failure accompanied by arrhythmias and/or sudden death. Clinical and morphological diversity of cardiomyopathies can reflect the broad spectrum of distinct underlying molecular causes or genetic heterogeneity. In many cases the disease is inherited and is termed familial dilated cardiomyopathy (FDC), which may account for up to 30% of dilated cardiomyopathies (DCM). FDC is principally caused by genetic mutations in FDC genes that encode for cytoskeletal, nuclear and sarcomeric proteins in the cardiac myocyte. In addition, modifying genes, lifestyle and additional factors were reported to influence onset of disease, disease progression, and prognosis. The individual patient's phenotype may reflect a summation and/or interaction of the underlying mutation(s) with other genetic or environmental factors. During the last years major advances have been made in the understanding of the molecular and genetic basis of this type of disease. Nevertheless, much more progress in the identification of underlying mutations, susceptibility genes and modifier genes is important and indispensable for the development of new etiology-orientated forms of therapy. A pivotal role for autoimmunity in a substantial proportion of patients with DCM is supported by the presence of organ-specific autoantibodies, inflammatory infiltrates and pro-inflammatory cytotoxic cytokines. Furthermore, familial occurrence of DCM goes ahead with the presence of autoantibodies and abnormal cytokine profiles in first-degree relatives with asymptomatic left ventricular enlargement. These relatives suffer from a higher risk for the development of DCM after years. This suggests the involvement of a disrupted humoral and cellular immunity early in the development of the disease. There is reasonable clinical and experimental evidence, that DCM in addition may occur as late stage of cardiac infection and inflammation. The large spectrum of clinical forms depends on several factors such as genetic determinants of the infective agent, the genetics, age and gender of the host, and the host immunocompetence. In general, infectious agents, including viruses such as entero-, cytomegalo-, and adenoviruses, bacteria such as Borrelia burgdorferi or Chlamydia pneumoniae, protozoa and even fungi can cause inflammatory heart disease leading to DCM. The infectious agents most often identified in DCM nowadays are parvovirus B19, human herpesvirus 3, and Epstein-Barr virus. Persistence of these viruses within the myocardium is associated with reduction of ejection fraction after 6 months. For patients with suspected inflammatory heart disease the immunohistochemical detection of inflammatory infiltrates is related to poor outcome. Many faces of inflammatory heart disease coexist where different phases of the disease progress simultaneously: phase 1 is dominated by viral infection itself, phase 2 by the onset of (probably) multiple autoimmune reactions, and phase 3 by the progression to cardiac dilatation. Further investigations with regard to the etiology of structural heart diseases should include an intensive clinical investigation of the given patient. A possible family history including a pedigree should be ascertained and with regard to a possible inflammatory or viral heart disease, endomyocardial biopsies should be investigated by polymerase chain reaction and immunohistochemistry.

Benefits and burden of the maternally-mediated immunological imprinting.

The ontogenetic development of both the immune and the nervous system entirely depend on external environmental signals that induce a lifelong learning process. The resulting collective immunological knowledge about the external world is transmitted in an epi-genetic fashion to the offspring, but only from the maternal and not the paternal side, with maternal IgG as the main transgenerational vector. As products of thymus-dependent responses, maternal IgG have undergone immune maturation by somatic hypermutations and are, therefore, acquired immunological phenotypes representing a great deal of the mother's immunological experience. During a limited neonatal imprinting period, maternal antibodies induce T cell-dependent idiotypic responses. These exert up to life-long determinative influences which may even be dominant over seemingly genetic predispositions. Such long-term immunological imprinting effects can be detected as (a) selection of the adult T and B cell repertoires, (b) anti-microbial protection by antigen-reactive antibodies (idiotypes) and anti-idiotypes, (c) allergen-specific suppression of IgE responsiveness by allergen-reactive IgG idiotype or corresponding anti-idiotype and (d) induction of autoimmune diseases by maternally-derived autoantibodies. Hence, immunological imprinting by maternal IgG antibodies will mostly be beneficial, but in case of autoantibodies can also be a burden for the initial development of the nascent immune system.

[Ultrasound findings in fetal infection]. / Sonographische Befunde bei materno-fetalen Infektionen.

Infections acquired in utero or during the birth process are a significant cause of fetal and neonatal mortality and an important contributor to early and later childhood morbidity. Advances in ultrasound, invasive prenatal procedures and molecular diagnostics have allowed in utero evaluation and given rise to more timely and accurate diagnosis in infected fetuses. Transplacental transmission of the infectious agent, even in subclinical maternal infection, may result in a severe congenital syndrome. Prenatal detection of infection is based on fetal sonographic findings and polymerase chain reaction to identify the specific agent. Nevertheless, most affected fetuses appear sonographically normal, but serial scanning may reveal evolving findings. Sonographic fetal abnormalities may be indicative of fetal infections, although they are generally not sensitive or specific. These include growth restriction, hydrops, ventriculomegaly, hydrocephaly, microcephaly, intracranial or hepatic calcifications, ascites, hepatosplenomegaly, echogenic bowel, placentomegaly, and abnormal amniotic fluid volume. When abnormalities are detected on ultrasound, a thorough fetal evaluation is recommended because of potential multiorgan involvement. The sonologist should understand the limitations of ultrasound. Patients should be counseled that ultrasound is not a sensitive test for fetal infection and that a normal fetal anatomy survey cannot reliably predict a favorable outcome.

[Aftereffects of congenital infections in infants].

Congenital infections are among the most pressing health care problems. Congenital infections are not reason of congenital malformation and perinatal mortality only, but also pathologies that can be revealed during first year of life. Frequency for congenital viral infection displayed from birth varies between 23% and 92%. The aim of the study was the investigation of inherent infection consequences (citomegaloviral infection, herpes infection and chlamidia) in children in different age groups. Under our observation were 81 children with congenital infections. Among them 29 were with citomegaloviral infection, 17 with herpes infection; 15 chlamidia infection and 22 infections mix (citomegalovirus + herpes, citomegalovirus + chlamidia and chlamidia + herpes). In all observed children neurological simptomatic such as neuro-reflectory hyperexcitability syndrom, hypertension-hydrocephalic syndrom, musculary dystonia syndrom, hydrocephaly, retardation of psychomotor development etc. were present. After birth the worst prevalent are pathologies of cardiovascular system: functional cardiopathy, carditis, congenital heart disease (among them multivalvular disease), affection of hepatobilliar system, organs of vision and hearing etc are present also.

Development of multiplex PCRs for detection of common viral pathogens and agents of congenital infections.

Potential causes of congenital infection include Toxoplasma gondii and viruses such as cytomegalovirus (CMV), enterovirus, hepatitis C virus, herpes simplex virus types 1 and 2 (HSV-1 and -2), human herpesvirus types 6, 7, and 8, lymphocytic choriomeningitis virus, parvovirus, rubella virus, and varicella-zoster virus. Testing for each of these agents using nucleic acid tests is time consuming and the availability of clinical samples such as amniotic fluid or neonatal blood is often limited. The aim of this study was to develop multiplex PCRs (mPCRs) for detection of DNA and RNA agents in the investigation of congenital infection and an mPCR for the viruses most commonly requested in a diagnostic virology laboratory (CMV, Epstein-Barr virus, enterovirus, HSV-1, HSV-2, and varicella-zoster virus). The assays were assessed using known pathogen-positive tissues (cultures, placentae, plasma, and amniotic fluid) and limits of detection were determined for all the agents studied using serial dilutions of plasmid targets. Nested PCR was performed as the most sensitive assay currently available, and detection of the amplicons using hybridization to labeled probes and enzyme-linked immunosorbent assay detection was incorporated into three of the four assays. This allowed detection of 10 to 10(2) copies of each agent in the samples processed. In several patients, an unexpected infection was diagnosed, including a case of encephalitis where HSV was the initial clinical suspicion but CMV was detected. In the majority of these cases the alternative agent could be confirmed using reference culture, serology, or fluorescence methods and was of relevance to clinical care of the patient. The methods described here provide useful techniques for diagnosing congenital infections and a paradigm for assessment of new multiplex PCRs for use in the diagnostic laboratory.

Insights into viral transmission at the uterine-placental interface.

During human gestation, viruses can cause intrauterine infections associated with pregnancy complications and fetal abnormalities. The ability of viruses to spread from the infected mother to the fetus arises from the architecture of the placenta, which anchors the fetus to the uterus. Placental cytotrophoblasts differentiate, assume an endothelial phenotype, breach uterine blood vessels and form a hybrid vasculature that amplifies the maternal blood supply for fetal development. Human cytomegalovirus - the major cause of congenital disease - infects the uterine wall and the adjacent placenta, suggesting adaptation for pathogen survival in this microenvironment. Infection of villus explants and differentiating and/or invading cytotrophoblasts offers an in vitro model for studying viruses associated with prenatal infections.

Paediatric infections: prevention of transmission and disease--implications for adults.

Congenital and neonatal viral infections usually display their acute manifestations in highly recognisable ways, for example, congenital rubella, cytomegalovirus (CMV), varicella, human immunodeficiency (HIV) and herpes simplex virus (HSV) infection. By contrast, congenital hepatitis B virus (HBV) infection may go undetected for years. Some of these are preventable, but what is not immediately apparent is that the long-term consequences are being prevented as well. The long-term consequences of congenital and neonatal infections include endocrine, immunological and cardiovascular disease, deafness, visual problems, intellectual handicap and cerebral palsy. With the survival of HIV-infected infants into adulthood the long-term consequences will soon be described. Maternally and neonatally transmitted HBV infection predisposes to carriage, liver cirrhosis and hepatocellular carcinoma in young adults. Neonatal HBV vaccination prevents adult cancer. Acquired viral infections may predispose to subsequent lung disease, malabsorption, fertility problems or neurological disability. In the prevention of acquired rubella, varicella, HBV, influenza, poliovirus, measles and hepatitis A, one should mention the added bonus of preventing secondary cases by preventing transmission from infants and children to other children and adults. Preventing paediatric HSV, HBV and HIV infection in females may even be preventing subsequent transmission to future generations. Turning to paediatric bacterial infections, vaccinating infants and young children against pertussis could not only prevent transmission to older children and adults but also break the cycle, which then transmits from adults back to infants and young children. There is evidence that disease in older age groups, including adults, has been prevented by virtue of herd immunity from paediatric vaccination, e.g. Neisseria meningitidis Group C and Streptococcus pneumoniae. The add-on benefits for other generations, including for adults, arising from the prevention of paediatric infections are considerable.

Pathogenesis and pathology of hematogenous infections of the fetus and newborn.

The earlier infections occur in intrauterine life the more severe are they. When the infection develops during embryogenesis, the lesions are much more serious, sometimes causing disruptions (malformations). At this time the organs are not completely formed and microorganisms may interfere with organogenesis to such an extent that the development of the functions necessary for viability become impaired. Infection acquired in utero may result in resorption of the embryo, abortion, stillbirth, neonatal death, intrauterine growth retardation (IUGR), or prematurity. The infected newborns commonly are apparently normal at birth but they may develop a late onset disease. Otherwise, neonates presenting symptomatology may derelop untoward sequelae.

[Virus infections in pregnancy--neonatal management]. / Virusinfektionen in der Schwangerschaft--neonatales Management.

We report on the most important viral infections in pregnancy. The importance of these infections is based on severe consequences for foetus, neonate and mother herself. New tests, e.g. direct virus detection assays, improved the security of diagnosis. We emphasize the management of viral infected neonates including own experiences.

Congenital infections.

Despite major medical advances, such as the introduction of the rubella vaccine and prolonged postnatal therapy of infants with congenital toxoplasmosis, intrauterine infections remain important causes of deafness, vision loss, and behavioral or neurologic disorders among children worldwide. This article describes the common pathogens causing intrauterine infections and summarizes the current status of diagnosis, treatment, and prevention.

The mechanisms of placental viral infection.

The placenta is a dynamic organ whose structure and function change throughout pregnancy. There is compelling evidence that the placenta plays an integral role in the vertical transmission of viruses, such as cytomegalovirus and human immunodeficiency virus, from the mother to the fetus. Although the sequelae of congenital viral infection (i.e., fetal anomalies, intrauterine fetal death, and persistent postnatal infection) may be devastating, very little is known about the passage of viruses across the placenta and the pathologic consequences of placental viral infection. We postulate that the syncytiotrophoblast, which forms a continuous barrier between the maternal and fetal circulation, is relatively resistant to viral infection. In support of this hypothesis, we observed that the susceptibility of trophoblast cells to infection by adenovirus and herpes simplex virus and the expression of viral receptors were reduced as trophoblast cells terminally differentiated into syncytiotrophoblast. Conversely, we observed that undifferentiated, extravillous trophoblast cells, which are susceptible to adenovirus infection, underwent pathologic changes (i.e., apoptosis) when infected by adenovirus in the presence of decidual lymphocytes (which were used to simulate the maternal immune response to viral infection). Based on these findings, we speculate that viral infection of extravillous trophoblast cells may negatively impact the process of placental invasion and predispose the mother and fetus to adverse reproductive outcomes that result from placental dysfunction.

[Significance of congenital mixed viral infection in the pathogenesis of retinopathy of prematurity]. / Znachenie vrozhdennoi smeshannoi virusnoi infektsii v patogeneze retinopatii nedonoshennykh.

Forty-three infants aged 1-5 months with somatic and neurological diseases, including congenital, 18 of these with retrolental fibroplasia (RF) and 25 without RF were examined. Control group consisted of 36 age-matched infants. Based on identification of viral antigens in urine precipitate cells, mixed viral infection was diagnosed in 100% patients and 16.6% healthy babies. Ophthalmotropic ECHO 11 and 19 viruses were detected in 100% patients with RF, 28% patients without RF, and 10% healthy babies, while rubella virus was identified in 83.3, 60, and 8.3%, respectively. The viruses were detected only in association with other enteroviruses: Coxsakie A, B, and entero 69-71. These viruses detected in infants with RF were as a rule present in their mothers. Maternal anamnesis was in all cases aggravated by high risk indicators of vertical transfer of toxigenic enteroviruses to the fetus. The results indicate that congenital mixed viral infection (association of ophthalmotropic ECHO and rubella viruses with toxigenic Coxsakie and entero 69-71 viruses) is involved in the pathogenesis of RF.