Gregory Valentine

Zika Virus-Associated Microcephaly and Eye Lesions in the Newborn

On February 1, 2016, Zika virus (ZIKV) was designated as a Public Health Emergency of International Concern by the director of the World Health Organization. Zika virus has spread to numerous countries throughout the Americas, affecting up to an estimated 1.3 million people since the first reports from Brazil in early 2015. Although ZIKV infections are self-limiting, fetal microcephaly and ophthalmic anomalies have been associated with ZIKV infection as a possible result of perinatal transmission. The causal link between maternal ZIKV infection and newborn microcephaly and eye lesions has not been proven beyond doubt and is currently debated. We discuss the possibility of causality by ZIKV using Kochs postulates and the more appropriate Bradford Hill criteria. In this review, we summarize and consolidate the current literature on newborn microcephaly and eye lesions associated with ZIKV infection and discuss current perspectives and controversies.

Zika virus epidemic: an update

ABSTRACT Introduction: Zika Virus (ZIKV), previously the cause of only rare and sporadic human infections, is now considered a Public Health Emergency of International Concern. Over the past two years, ZIKV has become a pandemic encompassing much of the Americas. ZIKV is now proven to cause microcephaly and ophthalmic anomalies in the newborn. Hydrops fetalis, developmental delay, and other anomalies are increasingly being attributed to ZIKV infection in fetuses and neonates. Sequelae of congenital infection and rapid spread of ZIKV throughout the Americas has catapulted Zika virus concerns to the forefront of the medical community. Areas covered: This review seeks to consolidate ZIKV epidemiology, diagnostic testing methods, CDC screening recommendations, and preventive strategies including potential vaccines. Expert commentary: Many unknowns still exist regarding ZIKV infections and its long-term effects in neonates. In addition, further studies need to evaluate if genomic differences that have occurred from the African to the Asian lineage of the virus have led to increased virulence of the virus. The authors believe that all pregnant women with fetuses showing microcephaly and/or intracranial calcifications should be tested for ZIKV infection if they cannot recall their sexual partner travel history. This change from the current CDCs recommendations could increase substantially the number of pregnant women and neonates, screened for ZIKV.

Clinical assessment and brain findings in a cohort of mothers, fetuses and infants infected with ZIKA virus

BACKGROUND: Congenital Zika virus (ZIKV) infection can be detected in both the presence and absence of microcephaly and manifests as a number of signs and symptoms that are detected clinically and by neuroimaging. However, to date, qualitative and quantitative measures for the purpose of diagnosis and prognosis are limited. OBJECTIVES: Main objectives of this study conducted on fetuses and infants with confirmed congenital Zika virus infection and detected brain abnormalities were (1) to assess the prevalence of microcephaly and the frequency of the anomalies that include a detailed description based on ultrasound and magnetic resonance imaging in fetuses and ultrasound, magnetic resonance imaging, and computed tomography imaging postnatally, (2) to provide quantitative measures of fetal and infant brain findings by magnetic resonance imaging with the use of volumetric analyses and diffusion‐weighted imaging, and (3) to obtain additional information from placental and fetal histopathologic assessments and postnatal clinical evaluations. STUDY DESIGN: This is a longitudinal cohort study of Zika virus–infected pregnancies from a single institution in Colombia. Clinical and imaging findings of patients with laboratory‐confirmed Zika virus infection and fetal brain anomalies were the focus of this study. Patients underwent monthly fetal ultrasound scans, neurosonography, and a fetal magnetic resonance imaging. Postnatally, infant brain assessment was offered by the use of ultrasound imaging, magnetic resonance imaging, and/or computed tomography. Fetal head circumference measurements were compared with different reference ranges with <2 or <3 standard deviations below the mean for the diagnosis of microcephaly. Fetal and infant magnetic resonance imaging images were processed to obtain a quantitative brain volumetric assessment. Diffusion weighted imaging sequences were processed to assess brain microstructure. Anthropometric, neurologic, auditory, and visual assessments were performed postnatally. Histopathologic assessment was included if patients opted for pregnancy termination. RESULTS: All women (n=214) had been referred for Zika virus symptoms during pregnancy that affected themselves or their partners or if fetal anomalies that are compatible with congenital Zika virus syndrome were detected. A total of 12 pregnant patients with laboratory confirmation of Zika virus infection were diagnosed with fetal brain malformations. Most common findings that were assessed by prenatal and postnatal imaging were brain volume loss (92%), calcifications (92%), callosal anomalies (100%), cortical malformations (89%), and ventriculomegaly (92%). Results from fetal brain volumetric assessment by magnetic resonance imaging showed that 1 of the most common findings associated with microcephaly was reduced supratentorial brain parenchyma and increased subarachnoid cerebrospinal fluid. Diffusion weighted imaging analyses of apparent diffusion coefficient values showed microstructural changes. Microcephaly was present in 33.3–58.3% of the cases at referral and was present at delivery in 55.6–77.8% of cases. At birth, most of the affected neonates (55.6–77.8%) had head circumference measurements >3 standard deviations below the mean. Postnatal imaging studies confirmed brain malformations that were detected prenatally. Auditory screening results were normal in 2 cases that were assessed. Visual screening showed different anomalies in 2 of the 3 cases that were examined. Pathologic results that were obtained from 2 of the 3 cases who opted for termination showed similar signs of abnormalities in the central nervous system and placental analyses, including brain microcalcifications. CONCLUSION: Congenital microcephaly is not an optimal screening method for congenital Zika virus syndrome, because it may not accompany other evident and preceding brain findings; microcephaly could be an endpoint of the disease that results from progressive changes that are related to brain volume loss. Long‐term studies are needed to understand the clinical and developmental relevance of these findings.

Chronic Granulomatous Disease Presenting as Hemophagocytic Lymphohistiocytosis: A Case Report

Chronic granulomatous disease (CGD) is a primary immunodeficiency characterized by recurrent infections and a dysregulated inflammatory response. Infection-triggered hemophagocytic lymphohistiocytosis (HLH), which manifests itself as pathologic hyperactive inflammation, has been observed in subjects with CGD. However, there have been no reports of HLH as the initial presentation with subsequent diagnosis of CGD. Furthermore, the primary therapeutic strategy for HLH focuses on immunosuppressive therapies, which limits immune-mediated tissue damage. With immunodeficiency, this therapeutic strategy may worsen the outcome. This article discusses an 8-week-old Hispanic male who presented with fever of unknown origin. The initial diagnostic evaluation demonstrated pathologic hyperactive inflammation, meeting the HLH-2004 diagnostic criteria without an identified infectious etiology. Immunosuppressive therapy was initiated, with subsequent disseminated candida septic shock and sepsis-induced multisystem organ failure. Additional evaluations ultimately established the diagnosis of CGD. We transitioned to an immune-enhancing strategy with granulocyte and immunoglobulin infusions, and intensified antifungal therapies. These interventions ultimately led to the clearance of the fungal infection and the resolution of the hyperactive inflammatory state. This case represents the first reported case of HLH as the presenting finding leading to the subsequent diagnosis of CGD. It serves as a reminder that both immunodeficiency and inflammatory disorders may share features of pathologic hyperactive inflammation and highlights the conundrum that clinicians face when treating HLH in the setting of an unresolved infection. In this case report, we demonstrate that immune-enhancing therapies may aid in the control and the clearance of the infection, thus paradoxically decreasing the pathologic hyperactive inflammatory response.

Relationships Between Perinatal Interventions, Maternal-Infant Microbiomes, and Neonatal Outcomes

The human microbiome acquires its vastness and diversity over a relatively short time period during development. Much is unknown, however, about the precise prenatal versus postnatal timing or its sources and determinants. Given early evidence of a role for influences during pregnancy and early neonatal and infant life on the microbiome and subsequent metabolic health, research investigating the development and shaping of the microbiome in the fetus and neonate is an important arena for study. This article reviews the relevant available literature and future questions on what shapes the microbiome during early development and mechanisms for doing so.

Timing of Gestational Exposure to Zika Virus is Associated with Postnatal Growth Restriction in a Murine Model

BACKGROUND: Vertical transmission of Zika virus leads to infection of neuroprogenitor cells and destruction of brain parenchyma. Recent evidence suggests that the timing of infection as well as host factors may affect vertical transmission. As a result, congenital Zika virus infection may only become clinically apparent in the postnatal period. OBJECTIVE: We sought to develop an outbred mouse model of Zika virus vertical transmission to determine if the timing of gestational Zika virus exposure yields phenotypic differences at birth and through adolescence. We hypothesized that later gestational inoculations would only become apparent in adolescence. STUDY DESIGN: To better recapitulate human exposures, timed pregnant Swiss‐Webster dams (n = 15) were subcutaneously inoculated with 1 × 104 plaque‐forming units of first passage contemporary Zika virus HN16 strain or a mock injection on embryonic day 4, 8, or 12 with bioactive antiinterferon alpha receptor antibody administered in days preceding and proceeding inoculation. The antibody was given to prevent the robust type I interferon signaling cascade that make mice inherently resistant to Zika virus infection. At birth and adolescence (6 weeks of age) offspring were assessed for growth, brain weight, and biparietal head diameters, and Zika virus viral levels by reverse transcription–polymerase chain reaction or in situ hybridization. RESULTS: Pups of Zika virus–infected dams infected at embryonic days 4 and 8 but not 12 were growth restricted (P < .003). Brain weights were significantly smaller at birth (P = .01) for embryonic day 8 Zika virus–exposed offspring. At 6 weeks of age, biparietal diameters were smaller for all Zika virus–exposed males and females (P < .05), with embryonic day 8–exposed males smallest by biparietal diameter and growth‐restriction measurements (weight >2 SD, P = .0007). All pups and adolescent mice were assessed for Zika virus infection by reverse transcription–polymerase chain reaction. Analysis of all underweight pups reveled 1 to be positive for neuronal Zika virus infection by in situ hybridization, while a second moribund animal was diffusely positive at 8 days of age by Zika virus infectivity throughout the brain, kidneys, and intestine. CONCLUSION: These findings demonstrate that postnatal effects of infection occurring at single time points continue to be detrimental to offspring in the postnatal period in a subset of littermates and subject to a window of gestational susceptibility coinciding with placentation. This model recapitulates frequently encountered clinical scenarios in nonendemic regions, including the majority of the United States, where travel‐related exposure occurs in short and well‐defined windows of gestation. Our low rate of infection and relatively rare evidence of congenital Zika syndrome parallels human population‐based data.

A 3-Week-Old With an Isolated “Blueberry Muffin” Rash

A 3-week-old infant presents to the hospital with 1 week of a “blueberry muffin” skin rash. Our panel of experts discusses diagnostic considerations. A 3-week-old boy, former 39-week term infant, presented to the emergency department with a rash. One week before presentation, he developed dark, purple papules on his forehead, which then spread to the abdomen and inguinal regions. Throughout this time, he was eating well, gaining weight, developing appropriately, and was afebrile without cough, congestion, or rhinorrhea. On presentation, the patient was well appearing with normal vital signs. His weight was 4.83 kg (86th percentile for age), his length was 56 cm (47th percentile for age), and his head circumference was 37 cm (62nd percentile for age). On skin examination, there were scattered purpuric papules and macules on the scalp, forehead, trunk, abdomen, and inguinal region. Initial laboratory studies were remarkable only for mild anemia. Our expert panel examines the case, offers a differential for a child with a “blueberry muffin” rash, and makes diagnostic considerations.A 3-week-old boy, former 39-week term infant, presented to the emergency department with a rash. One week before presentation, he developed dark, purple papules on his forehead, which then spread to the abdomen and inguinal regions. Throughout this time, he was eating well, gaining weight, developing appropriately, and was afebrile without cough, congestion, or rhinorrhea. On presentation, the patient was well appearing with normal vital signs. His weight was 4.83 kg (86th percentile for age), his length was 56 cm (47th percentile for age), and his head circumference was 37 cm (62nd percentile for age). On skin examination, there were scattered purpuric papules and macules on the scalp, forehead, trunk, abdomen, and inguinal region. Initial laboratory studies were remarkable only for mild anemia. Our expert panel examines the case, offers a differential for a child with a blueberry muffin rash, and makes diagnostic considerations.

Refractory seizures in a term neonate due to pyridoxine dependent epilepsy

A 4-day-old former 38-week term neonate was transferred to the NICU from a community emergency center (EC) due to concern for seizure activity. She was born at term via emergent Cesarean section for chorioamnionitis. The mother was group B streptococcus (GBS) positive and treated with clindamycin less than 4 hours before delivery. A blood culture was obtained which was negative. The baby did not receive postnatal antibiotics and was discharged home on the second day of life. On the third day of life, the mother witnessed an episode of whole body cyanosis with “stiffening of the arms and legs with jerking movements.” This prompted the parents to take the patient to the EC. At the community EC, the patient had respiratory distress with continued episodes of desaturations necessitating intubation. Rapid respiratory syncytial virus and influenza testing were negative. Patient also noted to exhibit upper and lower extremity flexion and extension concerning for seizure activity that transiently improved with Ativan 0.05 mg/kg. Blood cultures were obtained, and intravenous (IV) ampicillin and gentamicin were started. The patient was transferred to our level 4 NICU where electroencephalogram (EEG) showed multifocal sharp wave transients and depressed background activity in all regions. Antiepileptic treatment with Keppra 30 mg/kg/day divided three times a day was started. The blood cultures from the outside EC later grew Bacillus species in both aerobic and anaerobic culture bottles, but these had been considered a contaminant by the microbiology lab and were therefore discarded. Blood and cerebrospinal fluid (CSF) cultures obtained after treatment did not grow any pathogens, however there was a mild CSF leukocytosis (White Blood Cell 36). As no definitive bacteria were identified, the infant was treated for presumed meningitis with 14 days of IV vancomycin and cefotaxime. Magnetic resonance imaging (MRI) of the brain on day of life 4 showed multiple foci of restricted diffusion in the bilateral frontal lobes, right temporal lobe and bilateral pareito-occipital regions concerning for septic emboli or venous thrombosis (Figure 1A, B). A subsequent MRA/MRV was normal. Due to concern for hyper-coagulable state causing these MRI findings, hematology was consulted. After extensive testing, the results returned within normal limits. An echocardiogram also did not show any abnormalities. The patient’s seizure activity continued to worsen throughout the hospitalization despite increasing Keppra to 100 mg/ kg/day and adding phenobarbital up to 8 mg/kg/day. The patient’s anti-epileptic drugs (AEDs) were ultimately escalated to include versed drip. EEG showed numerous right hemispheric electroclinical seizures (Figure 2). The patient had pyridoxine challenges on day of life 17 and day of life 28. Neither challenge produced an immediate change in clinical or electrographic seizures (Figure 3). After the second challenge, pyridoxine 50 mg/day was continued for 3 days with improvement in EEG (Figure 4). However, clinical improvement was believed to be related to changes in AEDs or improvement in meningitis rather than pyridoxine supplementation and pyridoxine was discontinued. Notably, repeat MRIs demonstrated improvement in the parietal-occipital lesions (Figure 1C, D) and repeat infectious work-ups including blood and CSF cultures remained negative. CSF