Zika virus: a public health perspective.

PURPOSE OF REVIEW: Zika virus' impact on pregnancy became widely known in 2015 with a dramatic increase in the number of babies born with microcephaly in Recife, Brazil. A mosquito-borne virus resulting in congenital anomalies is unique, and Zika's ability to cause neurological defects on a large scale was a grim reminder of the Rubella epidemic in the 1950s. Over the past 2 years, studies have provided insight on how Zika virus (ZIKV) infects cells and causes disease, but much remains unknown about the long-term risks of Zika exposure on infant growth and development. RECENT FINDINGS: The impact of ZIKV on pregnancy extends beyond microcephaly and may only first be identified in infancy. The virus has a long latency in semen and can be transmitted sexually. Transplacental passage occurs through infection of Hofbauer cells in the trophoblast. A major difficulty in management of ZIKV disease is that most infections are asymptomatic and the diagnostic methods are not ideal, making both diagnosis and ascertainment of timing of infection problematic. Several different types of vaccines are in development. Large studies are ongoing to determine the risk and total spectrum of anomalies based on the timing of infection and other environmental exposures. SUMMARY: This review will summarize the epidemic, what we have learned, what we hope to learn, and current recommendations for care and management.

Zika Virus Infection in the Pregnant Woman.

Zika virus is a single-stranded RNA virus from the Flaviviridae family. Transmission is typically from the bite of an infected mosquito though mother-to-child, sexual and blood donation transmissions can occur. Although maternal symptoms are uncommon and rarely severe, the consequences of congenital infections are devastating. The emergence of congenital Zika syndrome is a world-wide public health crisis. The Centers for Disease Control and Prevention, ACOG, and SMFM have developed algorithms for screening and managing women exposure to and diagnosed with Zika virus infection. Prevention is the mainstay of infection control as there is currently no vaccine or therapy available.

First Autopsy of a Newborn with Congenital Zika Syndrome in Puerto Rico.

We report on the first autopsy performed on a neonate with congenital Zika syndrome in Puerto Rico. A term male was born to a mother with confirmed Zika virus infection; he had a prenatal diagnosis of microcephaly and multiple cerebral calcifications, among other anomalies, and a normal male karyotype (determined by amniocentesis). He required neonatal resuscitation at birth and died at 2 days ofage. At autopsy, his head circumference was only 1.5 standard deviations below the mean, not fulfilling the criteria for microcephaly. He presented scissor legs, clenched and hyperflexed hands, and multiple contractures (arthrogryposis). The central nervous system findings were consistent with Zika encephalopathy: ventriculomegaly, lissencephaly, and severe encephalic degeneration with numerous dystrophic calcifications, among other findings. These anomalies were most likely secondary to congenital ZV infection. Although prenatally diagnosed with microcephaly, he did not fulfill the criteria after birth, which fact indicates the need for reassessment of the definition of microcephaly as it applies to patients exposed prenatally to the ZV.

Progressive lesions of central nervous system in microcephalic fetuses with suspected congenital Zika virus syndrome.

OBJECTIVE: To describe the pattern and progression of central nervous system (CNS) lesions in microcephalic fetuses with suspected Zika virus (ZIKV) infection. METHODS: In this prospective study in Salvador, Brazil, we analyzed fetuses diagnosed with microcephaly and suspected ZIKV infection after a routine primary care ultrasound scan between July 2015 and February 2016 raised suspicion of fetal microcephaly. The pregnancies were followed with serial ultrasound scans until delivery at one of the three main referral centers for fetal abnormalities in Salvador, Brazil. Microcephaly was diagnosed when the head circumference was two or more SDs below the mean for gestational age and its relationship with ZIKV infection was defined according to the World Health Organization's criteria. All women were interviewed, to assess potential factors associated with fetal microcephaly. Serology test results for toxoplasmosis, cytomegalovirus, rubella, syphilis and human immunodeficiency virus (HIV) were recorded, as were previous routine ultrasound results. Signs/symptoms of infection during the pregnancy were noted. RESULTS: Of 60 cases of suspected ZIKV-related fetal microcephaly seen during the study period, eight were excluded due to serological evidence of other congenital infections or major ultrasound chromosomal markers. In the remaining 52 fetuses, microcephaly was diagnosed between 19 and 40 (median, 27.7; interquartile range, 23.4-32.0) weeks of gestation. The main ultrasound findings were: ventriculomegaly (65.4% of cases), cerebral calcifications (44.2%) and posterior fossa abnormalities (32.7%). 9.6% presented with arthrogryposis as an associated finding. Microcephaly was an isolated finding in four cases (7.7%). While ventriculomegaly was progressive in 41.2% of cases with this finding, the velocity of head circumference increase decreased progressively in almost all cases. Exanthematic disease was present in the majority (86.5%) of the women, 67.3% presenting in the first trimester of pregnancy. Additional lesions were detected after birth in 71.4% of the 35 cases with neonatal follow-up. CONCLUSIONS: The majority of cases of congenital ZIKV syndrome have other ultrasonographic findings in addition to microcephaly. ZIKV-related CNS anomalies present mainly as progressive CNS lesions and slowing rate of growth of the fetal head, and this seems to be evident only in the late second trimester, even when maternal infection occurs in the first trimester. Other ultrasound findings, such as ventriculomegaly, brain calcifications and posterior fossa destruction lesions, are also common in this congenital syndrome. Posterior fossa destruction lesions and arthrogryposis are an uncommon finding in other congenital infections, perhaps suggesting a novel severe congenital syndrome associated with fetal ZIKV. Copyright © 2016 ISUOG. Published by John Wiley & Sons Ltd.

Confirmed case of Zika virus congenital infection, Spain, March 2016.

We describe Zika virus (ZIKV) vertical transmission in an imported case in Spain, in a 17-week pregnant woman. ZIKV IgG, IgM and RNA were detected in serum in week 17. At 19 weeks, ultrasound scan revealed fetal malformations and ZIKV was detected in the amniotic fluid. Pregnancy was terminated at week 21; autopsy of the fetus revealed bilateral hydrocephalus, brain microcalcifications and arthrogryposis multiplex congenita. ZIKV was detected in the umbilical cord and brain tissue.

Congenital rubella with agenesis of the inferior cerebellar vermis and total anomalous pulmonary venous drainage.

Congenital rubella infection has been associated with a number of abnormalities including cardiac, central nervous system and placental complications. We present a case with multiple fetal abnormalities detected on prenatal ultrasound, and confirmed postnatally, that included a single umbilical artery, severe tricuspid regurgitation, micrognathia and agenesis of the inferior cerebellar vermis. Postnatal echocardiography additionally revealed unobstructed total anomalous pulmonary venous drainage (TAPVD) into the coronary sinus. Placental examination showed signs of placentitis, and polymerase chain reaction on neonatal serum was positive for rubella. Following a multidisciplinary team review, it was decided to provide only supportive care, and the infant died at 6 months of age owing to a respiratory tract infection. To our knowledge, TAPVD and agenesis of the inferior cerebellar vermis have not been reported previously in association with congenital rubella infection. This case illustrates how congenital infection may present in atypical ways and stresses the importance of considering congenital infection in the differential diagnosis of fetal anomalies when multiple features are present.

Investigation into the aetiology of runting and stunting syndrome in chickens.

Currently, the aetiology of runting and stunting syndrome (RSS) in chickens is unknown. The impact of RSS on weight gain and microscopic lesions in immunological organs and the duodenum, was investigated in 1-day-old commercial broilers at 12 days following exposure to RSS-contaminated litter. Furthermore, the presence of the viral nucleic acids of three astroviruses and one parvovirus was analysed by in situ hybridization from days 1 through 5 post exposure. A 70% decrease in weight was observed in the RSS-exposed group at the end of the experiments when compared with the unexposed controls. Lesions in the bursa of Fabricius and thymus were present in both groups but were significantly higher at the end of the study in the RSS-exposed group. In contrast, no significant difference in Harderian gland lesions was observed between the groups. Histological lesions in the duodenum were already present 24 h after exposure in the RSS-exposed group only, peaked at day 4 and declined until the end of the study. Results of the in situ hybridization studies clearly indicate replication of three astroviruses (chicken astrovirus, avian nephritis virus [ANV]-1, ANV-2) in the duodenum but not in other organs evaluated. Chicken astrovirus nucleic acids were detected on days 1 and 2 post exposure, while ANV-1 and ANV-2 nucleic acids were observed on several days during the period investigated. Surprisingly, no viral nucleic acid specific for the chicken parvovirus was observed. The results indicate that astroviruses probably play an important role during RSS due to the concurrence of viral RNA detection and lesions in the duodenum.

Epizootic of ovine congenital malformations associated with Schmallenberg virus infection.

Epizootic outbreaks of congenital malformations in sheep are rare and have, to the best of our knowledge, never been reported before in Europe. This paper describes relevant preliminary findings from the first epizootic outbreak of ovine congenital malformations in the Netherlands. Between 25 November and 20 December 2011, congenital malformations in newborn lambs on sheep farms throughout the country were reported to the Animal Health Service in Deventer. Subsequently, small ruminant veterinary specialists visited these farms and collected relevant information from farmers by means of questionnaires. The deformities varied from mild to severe, and ewes were reported to have given birth to both normal and deformed lambs; both male and female lambs were affected. Most of the affected lambs were delivered at term. Besides malformed and normal lambs, dummy lambs, unable to suckle, were born also on these farms. None of the ewes had shown clinical signs during gestation or at parturition. Dystocia was common, because of the lambs' deformities. Lambs were submitted for post-mortem examination, and samples of brain tissue were collected for virus detection. The main macroscopic findings included arthrogryposis, torticollis, scoliosis and kyphosis, brachygnathia inferior, and mild-to-marked hypoplasia of the cerebrum, cerebellum and spinal cord. Preliminary data from the first ten affected farms suggest that nutritional deficiencies, intoxication, and genetic factors are not likely to have caused the malformations. Preliminary diagnostic analyses of precolostral serum samples excluded border disease virus, bovine viral diarrhoea virus, and bluetongue virus. In December 2011, samples of brain tissue from 54 lambs were sent to the Central Veterinary Institute of Wageningen University Research, Lelystad. Real-time PCR detected the presence of a virus, provisionally named the Schmallenberg virus, in brain tissue from 22 of the 54 lambs, which originated from seven of eight farms that had submitted lambs for post-mortem examination. This Schmallenberg virus was first reported in Germany and seems to be related to the Shamonda, Aino, and Akabane viruses, all of which belong to the Simbu serogroup of the genus Orthobunyavirus of the family Bunyaviridae. These preliminary findings suggest that the Schmallenberg virus is the most likely cause of this epizootic of ovine congenital malformations, which is the first such outbreak reported in Europe.

Ulerythema ophryogenes, a rare and often misdiagnosed syndrome: analysis of an idiopathic case.

Keratosis pilaris (KP) is a follicular hyperkeratosis disorder which is frequently detected in the adult population (44%), mostly in female adolescents (80%). It is a genetic autodominant dermatosis with variable penetrance, but no specific gene association has been determined, even though association to the presence of chromosome 18p deletion has been reported in some cases. We report the case of a 51-year-old Caucasian woman affected by keratosis pilaris gradually progressing with age and with a story of multiple abortions. Standard karyotype and CGH array analyses did not reveal any genetic abnormality. Virological analyses detected the presence of HPV 36 DNA inside the dorsum biopsy, leading to hypothesize its involvement in the evolution of the lesion. Clinical history and patient examination led the diagnosis of an idiopathic case of Ulerythema ophryogenes. The analysis of more cases could be useful to verify the involvement of cutaneous HPV in the progression of the clinical manifestation of the KP variants.

Viral molecular characterization of the first congenital rubella syndrome case in Vietnam.

BACKGROUND: Rubella virus (RV) infection during the first trimester of pregnancy often leads to severe birth defects known as congenital rubella syndrome (CRS). METHODS: A premature newborn male was clinically diagnosed as CRS with cataracts, congenital heart defects, microcephaly, hepatosplenomegaly, and thrombocytopenia. The infection was confirmed serologically and molecularly. RESULTS: The RV was characterized and clustered with the 2B genotype. CONCLUSIONS: The integrated description of clinical features, serological and molecular data provide a baseline for diagnosis and control of rubella and CRS in Vietnam. This is the first report of molecular investigation of wildtype RV strain in Vietnam, thus contributing to the documentation of RV's worldwide distribution.

Different composition of intraocular immune mediators in Posner-Schlossman-Syndrome and Fuchs' Uveitis.

Posner-Schlossman-Syndrome (PSS) is clinically characterized by acute, recurrent, mild, unilateral uveitis anterior accompanied by elevated intraocular pressure (IOP). Fuchs´ Uveitis (FU) is a chronic, low-grade-inflammatory disorder, involving anterior uvea and vitreous. The clinical findings show remarkable similarities as well as differences. In our study, we determine the composition of immune mediators in aqueous humor of patients with PSS and FU and evaluate if immune mediators play a crucial role in specific viral intraocular inflammation and IOP rises. Aqueous humor samples from 81 uveitis patients (= eyes) presenting with either PSS or FU were collected at one time point. Local intraocular antibody synthesis to rubella virus was confirmed in 65 patients, whereas 16 were tested positively for human cytomegalovirus. Thirteen patients with PSS and 10 patients with FU were treated with glaucoma medications. Additionally, 11 cataract patients acted as control group. Immune mediator concentrations were measured by Bio-Plex Pro assay. We observed in both PSS (IFN-γ: 174.9 pg/mL; TNF-α: 25.1 pg/mL) and FU (IFN-γ: 25.4 pg/mL; TNF-α: 27.2 pg/mL) groups a significantly increased level of T-helper 1 immune mediators compared to controls (IFN-γ, TNF-α: 0 pg/mL) [median]. Notably, PSS patients (IL-1RA: 73.4 pg/mL; IL-8: 199.4 pg/mL; IL-10: 33.4 pg/mL; IP-10: 126350 pg/mL) showed a stronger and more active ocular inflammatory response, than FU patients (IL-1RA: 4.3 pg/mL; IL-8: 72.4 pg/mL; IL-10: 1.6 pg/mL; IP-10: 57400 pg/mL). Furthermore, a negative correlation between mediators and IOP was seen in the PSS group, potentially caused by acetazolamide-treatment. Our findings show that immune mediators play a crucial role in specific viral intraocular inflammation and influence IOP levels. Remarkable similarities but also significant differences of immune mediator concentrations are apparent in PSS compared to FU. High concentrations of IL-1RA, IL-8, IL-10, and IP-10 correlate with active inflammation in PSS, while FU may trigger chronic inflammation. Our data also substantiated a very similar composition of cytokines in those patients from the PSS group suffering from ocular hypertension and thus offers a potential explanation model for a negative correlation between mediators and IOP.

Chronic excretion of a norovirus in a child with cartilage hair hypoplasia (CHH).

We have demonstrated the long-term excretion of a stable recombinant norovirus in a patient with cartilage hair hypoplasia (CHH), with a T cell immunodeficiency, following bone marrow transplantation (BMT). The patient excreted an ARG320/1999/US-like recombinant norovirus (rGII-3) for 156 days during a period of immune reconstitution. The child was symptomatic during the period of virus shedding. It is not known if the child acquired the recombinant strain or if recombination occurred in vivo.

Detection of varicella-zoster virus in congenital varicella syndrome: a case report.

BACKGROUND: We studied the possibility of detecting varicella-zoster virus in formalin-fixed tissue samples from a still-born infant with congenital anomalies in order to verify the relationship with maternal varicella. CASE: A girl with hypoplasia of extremities, skin lesions, and microphthalmos was stillborn at 34 weeks' gestation. Her mother had had chickenpox between the 13th and 15th gestational weeks. Varicella-zoster virus DNA could be detected in formalin-fixed tissue samples of lungs, spleen, adrenal glands, bulbus oculi, and placenta by polymerase chain reaction (PCR). The method, with the use of primers from gene 29 encoding the major DNA-binding protein, proved to be highly sensitive. In addition, varicella-zoster virus DNA/antigens were localized in some organs by in situ hybridization/monoclonal antibodies. CONCLUSION: The PCR method should be included in the diagnosis of congenital varicella syndrome. The varicella-zoster virus can be detected in formalin-fixed tissue samples using this technique.

Ovine fetal malformations induced by in utero inoculation with Main Drain, San Angelo, and LaCrosse viruses.

The teratogenic potential of three bunyaviruses, two California serogroup bunyaviruses, LaCrosse virus and San Angelo virus, and a Bunyamwera serogroup member, Main Drain virus, in sheep was studied following in utero inoculation of ewes in early gestation. Although Main Drain virus appeared to be most teratogenic, all three viruses induced a range of lesions including arthrogryposis, hydrocephalus, fetal death, axial skeletal deviations, anasarca, and oligohydramnios. The teratogenic effects of these viruses are identical to those described in ovine infections by Cache Valley and Akabane viruses. Demonstration of a common bunyaviral tropism for fetal tissue infection that results in congenital brain and musculoskeletal malformations provides evidence that human in utero infection by bunyaviruses could result in similar malformations in human infants.

A congenital abnormality of calves, suggestive of a new type of arthropod-borne virus infection.

About 1000 calves with a congenital disease were born in Kagoshima prefecture, Japan, between October 1990 and October 1991, the peaks of the epidemic being in March and July 1991. Of 85 abnormal calves examined pathologically and serologically, 70 appeared to have been suffering from a viral disease. Of these 70 animals, 17 had lesions bearing some resemblance to those of the diseases produced by Akabane, Chuzan, Aino, bluetongue and bovine viral diarrhoea-mucosal disease viruses-diseases known to occur in Kagoshima-but serum samples contained no antibodies to these viruses or to infectious bovine rhinotracheitis virus. This suggested the occurrence of a new type of viral infection in southern Japan. Six of the 17 calves were born dead and the others manifested clinical signs such as weakness, difficulty in sucking, inability to stand, vertigo, opisthotonus, staggering and weak eyesight or blindness. They were of small size and showed domed head, scoliosis, arthrogryposis, maxillary retraction, sunken eye, cataracts, and irregularities and defects of the teeth. At necropsy, almost all cases showed hydranencephaly, and many had cerebral defects and cerebellar hypoplasia or agenesis. Both cerebral and cerebellar lesions were seen in six cases, two of which showed a hypoplastic defect of the brain stem. Histopathological examination of the affected organs revealed gliosis, loss of cerebral parenchyma resulting from dilation of the ventricles, perivascular cuffing with round cells such as lymphocytes and plasma cells, proliferation of blood vessels, thick-walled blood vessels in the brain stem, dilation of mesencephalic aqueducts, cerebellar cortical dysplasia, decreased nerve cells in the ventral horn of the spinal cord, and myodysplasia of skeletal muscle.

Congenital anomalies following maternal varicella infection during early pregnancy.

We report a typical case of congenital varicella syndrome following a maternal varicella infection during the 10th week of pregnancy. The presenting symptoms in the small gestational age baby were: cicatricial skin lesion, Horner's syndrome,dysphagia with resulting aspiration pneumonia and delayed developmental milestones. Serologic studies revealed persistence of varicella zoster virus IgG for at least 10 months. Although congenital varicella syndrome is rare, it should be kept in mind when counseling families where maternal varicella infection has occurred during the first 20 weeks of gestation. A maternal history of varicella infection, typical manifestations and serologic proof are crucial in the diagnosis of congenital varicella syndrome.

Cache Valley virus.

Cache Valley Virus (CVV) is a causative agent of a mosquito-borne disease syndrome of sheep and, possibly, of all ruminants, characterized by embryonic and fetal death, stillbirths, and multiple congenital malformations. CVV is endemic in Canada, Mexico, and the United States. Several related Bunyaviruses also may play a role in syndromes of congenital malformations and embryonic losses in North America.

Congenital varicella syndrome.

The fetal consequences of chickenpox complicating pregnancy depends on the period of gestation at which the infection is contracted. The extremely rare classical form of congenital varicella syndrome, resulting from maternal varicella infection in the first trimester of pregnancy, is being reported here. The unusual features in this baby are bilateral hypoplastic lower extremities, fracture of bones, a normal electroencephalogram and phantom hernias of the anterior abdominal wall.

Congenital varicella syndrome as an unusual cause of congenital malformation: report of one case.

Intrauterine infections with varicella-zoster virus following maternal varicella in early pregnancy and resulting in congenital malformations are rare. Herein we report a child with congenital varicella syndrome characterized by low birth weight, cicatricial scarring, hypoplasia of both lower extremities with joint contracture, congenital hip dislocation, corneal opacity, atresia of the sigmoid colon and a rarely associated cloaca anomaly. The varicella IgG remained positive after she was seven months old. Her mother developed chickenpox at the 14th week of gestation. The purpose of this article is to raise pediatricians' index of suspicion for congenital varicella syndrome when an infant is born with multiple congenital malformations with an apparent history of maternal varicella infection.