ABSTRACT
The Zika virus (ZIKV) can be vertically transmitted, causing congenital Zika syndrome (CZS) in fetuses. ZIKV infection in early gestational trimesters increases the chances of developing CZS. This syndrome involves several pathologies with a complex diagnosis. In this work, we aim to identify biological processes and molecular pathways related to CZS and propose a series of putative protein and metabolite biomarkers for CZS prognosis in early pregnancy trimesters. We analyzed serum samples of healthy pregnant women and ZIKV-infected pregnant women bearing nonmicrocephalic and microcephalic fetuses. A total of 1090 proteins and 512 metabolites were identified by bottom-up proteomics and untargeted metabolomics, respectively. Univariate and multivariate statistical approaches were applied to find CZS differentially abundant proteins (DAP) and metabolites (DAM). Enrichment analysis (i.e., biological processes and molecular pathways) of the DAP and the DAM allowed us to identify the ECM organization and proteoglycans, amino acid metabolism, and arachidonic acid metabolism as CZS signatures. Five proteins and four metabolites were selected as CZS biomarker candidates. Serum multiomics analysis led us to propose nine putative biomarkers for CZS prognosis with high sensitivity and specificity.
Subject(s)
Pregnancy Complications, Infectious , Zika Virus Infection , Zika Virus , Pregnancy , Female , Humans , Zika Virus Infection/diagnosis , Zika Virus/genetics , Pregnancy Complications, Infectious/diagnosis , Pregnancy Complications, Infectious/pathology , Multiomics , BiomarkersABSTRACT
BACKGROUND: There are limited data on how coronavirus disease 2019 (COVID-19) severity, timing of infection, and subsequent vaccination impact transplacental transfer and persistence of maternal and infant antibodies. METHODS: In a longitudinal cohort of pregnant women with polymerase chain reaction-confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, maternal/infant sera were collected at enrollment, delivery/birth, and 6 months. Anti-SARS-CoV-2 spike immunoglobulin (Ig)G, IgM, and IgA were measured by enzyme-linked immunosorbent assay. RESULTS: Two-hundred fifty-six pregnant women and 135 infants were enrolled; 148 maternal and 122 neonatal specimens were collected at delivery/birth; 45 maternal and 48 infant specimens were collected at 6 months. Sixty-eight percent of women produced all anti-SARS-CoV-2 isotypes at delivery (IgG, IgM, IgA); 96% had at least 1 isotype. Symptomatic disease and vaccination before delivery were associated with higher maternal IgG at labor and delivery. Detectable IgG in infants dropped from 78% at birth to 52% at 6 months. In the multivariate analysis evaluating factors associated with detectable IgG in infants at delivery, significant predictors were 3rd trimester infection (odds ratio [OR] = 4.0), mild/moderate disease (OR = 4.8), severe/critical disease (OR = 6.3), and maternal vaccination before delivery (OR = 18.8). No factors were significant in the multivariate analysis at 6 months postpartum. CONCLUSIONS: Vaccination in pregnancy post-COVID-19 recovery is a strategy for boosting antibodies in mother-infant dyads.
Subject(s)
COVID-19 , Mothers , Pregnancy , Infant, Newborn , Female , Infant , Humans , SARS-CoV-2 , Immunoglobulin A , Immunoglobulin G , Immunoglobulin M , Antibodies, ViralABSTRACT
INTRODUCTION: Congenital Zika syndrome (CZS) is a recently described disease. Our main objective was to evaluate and monitor, over 3 years, the ophthalmoscopic findings in children exposed to zika virus (ZIKV) during gestation. METHODS: This prospective observational study was conducted in Rio de Janeiro, Brazil, between April 2016 and May 2019. We evaluated two groups with exanthema serving as a proxy for viremia: (i) children whose mothers had exanthema during pregnancy and (ii) children who had microcephaly without maternal exanthema during pregnancy. We performed indirect ophthalmoscopy at recruitment and every 6 months thereafter. We also tested the association between ocular findings with maternal exanthema, microcephaly, CZS and maternal infection confirmed by reverse transcriptase quantitative polymerase chain reaction and gender. RESULTS: Of the 72 children included, 16 (22.2%) had optic nerve and/or retinal lesions. All 16 had CZS and 15 (93.7%) had microcephaly (14 at birth and 1 postnatally). The child with postnatally acquired microcephaly was born to a mother without exanthema during pregnancy. Fifty-six (77.8%) of the 72 children were followed for a median time of 24 months and none exhibited differences between admission and follow-up examinations. After logistic regression, only microcephaly at birth was associated with eye abnormalities (odds ratio, 77.015; 95% confidence interval, 8.85-670.38; p < 0.001). CONCLUSION: We observed that there was no progression of the lesions over the follow-up period. We also showed that the eye findings were associated only with microcephaly at birth. Attention should be paid to all children born during a ZIKV epidemic, regardless of maternal exanthema and/or microcephaly at birth.
Subject(s)
Exanthema , Microcephaly , Zika Virus Infection , Zika Virus , Infant, Newborn , Female , Pregnancy , Child , Humans , Zika Virus/genetics , Zika Virus Infection/diagnosis , Zika Virus Infection/epidemiology , Microcephaly/epidemiology , Follow-Up Studies , Brazil/epidemiology , Exanthema/etiology , MothersABSTRACT
Hereditary hyperferritinemia-cataract syndrome (HHCS) is a rare, frequently misdiagnosed, autosomal dominant disease caused by mutations in the FTL gene. It causes bilateral pediatric cataract and hyperferritinemia without iron overload. The objective of this case series, describing three Brazilian families, is to increase awareness of HHCS, as well as to discuss possible phenotypic interactions with concurrent mutations in HFE, the gene associated with autosomal recessive inheritance hereditary hemochromatosis. Whole-exome sequencing was performed in eight individuals with HHCS from three different families, as well as one unaffected member from each family for trio analysis-a total of eleven individuals. Ophthalmological and clinical genetic evaluations were conducted. The likely pathogenic variant c.-157G>A in FTL was found in all affected individuals. They presented slowly progressing bilateral cataract symptoms before the age of 14, with a phenotype of varied bilateral diffuse opacities. Hyperferritinemia was present in all affected members, varying from 971 ng/mL to 4899 ng/mL. There were two affected individuals with one concurrent pathogenic variant in HFE (c.187C>G, p.H63D), who were also the ones with the highest values of serum ferritin in our cohort. Few publications describe individuals with pathogenic mutations in both FTL and HFE genes, and further studies are needed to assess possible phenotypic interactions causing higher values of hyperferritinemia.
Subject(s)
Cataract , Hyperferritinemia , Iron Metabolism Disorders , Humans , Brazil , Pedigree , Iron Metabolism Disorders/pathology , Cataract/pathology , MutationABSTRACT
INTRODUCTION: The increasing burden of non-communicable diseases and limited public financing are major challenges facing health care systems in Latin America. Although COVID-19 severely impacted the Brazilian health care system, it is crucial to further characterize the degree of disruption caused to public health efforts, in order to address and manage long term effects of this pandemic. We therefore quantified the demand for preventive and treatment services from the Brazilian Unified Health System (Sistema Único de Saúde/SUS) in 2020 to evaluate potential repercussions of COVID-19 in this setting. METHODS: Using the SUS database, we compared preventative and treatment services rendered in 2020 to the same services rendered from 2017 to 19. We also evaluated the frequency of respiratory infection (RI) diagnoses during the pandemic, relative to the preceding years. RESULTS: Compared to 2017-19, in 2020 non-urgent medical appointments decreased 1.4-fold (p = 0.0017), dental consultations 2.8-fold (p = 0.05), and immunization coverage 1.5 fold (p = 0.0005). The number of RI visits to SUS ambulatory care units in 2020 was 4.2 times higher than in preceding years (p = 0.0014), with a peak of 280,898 diagnoses in July 2020. CONCLUSION: The COVID-19 pandemic appears to have led to a dramatic decline in preventative and treatment services provided by SUS to the Brazilian population. Our findings may aid decision-makers in formulating policies to increase the availability of outpatient services in the aftermath of the pandemic. Counter measures will be critical to avoid a resurgence in vaccine-preventable diseases and complications stemming from non-communicable, chronic health conditions.
Subject(s)
COVID-19 , Pandemics , Brazil/epidemiology , Humans , Pandemics/prevention & control , SARS-CoV-2 , Vaccination CoverageABSTRACT
BACKGROUND: X-linked agammaglobulinemia (XLA) is an Inborn Errors of Immunity (IEI) characterized by pan-hypogammaglobulinemia and low numbers of B lymphocytes due to mutations in BTK gene. Usually, XLA patients are not susceptible to respiratory tract infections by viruses and do not present interstitial lung disease (ILD) such as bronchiolitis obliterans (BO) as a consequence of acute or chronic bacterial infections of the respiratory tract. Although many pathogenic variants have already been described in XLA, the heterogeneous clinical presentations in affected patients suggest a more complex genetic landscape underlying this disorder. CASE PRESENTATION: We report two pediatric cases from male siblings with X-Linked Agammaglobulinemia and bronchiolitis obliterans, a phenotype not often observed in XLA phenotype. The whole-exome sequencing (WES) analysis showed a rare hemizygous missense variant NM_000061.2(BTK):c.1751G>A(p.Gly584Glu) in BTK gene of both patients. We also identified a gain-of-function mutation in TGFß1 (rs1800471) previously associated with transforming growth factor-beta1 production, fibrotic lung disease, and graft fibrosis after lung transplantation. TGFß1 plays a key role in the regulation of immune processes and inflammatory response associated with pulmonary impairment. CONCLUSIONS: Our report illustrates a possible role for WES in patients with known inborn errors of immunity, but uncommon clinical presentations, providing a personalized understanding of genetic basis, with possible implications in the identification of potential treatments, and prognosis for patients and their families.
Subject(s)
Agammaglobulinemia , Bronchiolitis Obliterans , Genetic Diseases, X-Linked , Agammaglobulinaemia Tyrosine Kinase/genetics , Agammaglobulinemia/complications , Agammaglobulinemia/diagnosis , Agammaglobulinemia/genetics , Child , DNA Mutational Analysis , Genetic Diseases, X-Linked/diagnosis , Genetic Diseases, X-Linked/genetics , Humans , Male , Mutation , SiblingsABSTRACT
OBJECTIVE: The aim of this study was to investigate the role of middle cerebral artery (MCA) Doppler measurements for the prediction of abnormal neonatal outcomes in pregnancies affected by Zika virus (ZIKV). METHODS: Secondary analysis of a prospective cohort of pregnant women diagnosed with ZIKV infection from September 2015 to December 2016 at a single regional referral center. Ultrasonography with measurements of MCA peak systolic velocity (PSV), PSV multiples of the median (MoM) for gestational age, and pulsatility index (PI) were collected. The primary outcome was a composite abnormal neonatal outcome. MCA Doppler values of normal and abnormal neonatal outcomes were compared with Wilcoxon rank sum test. The predictive value of MCA Dopplers for development of abnormal neonatal outcome was calculated by logistic regression. RESULTS: One-hundred twenty-seven ZIKV-positive pregnancies with MCA Doppler measurements and known neonatal outcomes were included. Of the 132 neonates, 66 (50%) had an abnormal neonatal outcome. Lower MCA PSV (p = 0.027) and PSV MoM (p = 0.008) were associated with abnormal neonatal outcomes. There was no significant difference in MCA PI. Abnormal neonatal outcomes had lower MCA PSV by 5.36 cm/s (95% confidence interval [CI]: 0.95-9.77, p = 0.018) and lower MCA PSV MoM by 0.13 (95% CI: 0.05-0.22, p = 0.002). MCA PSV of 30 cm/s had a 65% predicted probability of an abnormal neonatal outcome (95% CI: 51-79%). CONCLUSION: In ZIKV-infected pregnancies, lower MCA PSV and PSV MoM measurements were seen with abnormal neonatal outcomes. This may represent a physiologic response to fetal ZIKV infection. Evaluation of MCA Dopplers may be of clinical utility in the surveillance of ZIKV-affected pregnancies. KEY POINTS: · Significantly lower MCA PSV is associated with abnormal neonatal outcomes in ZIKV pregnancies.. · Lower MCA PSV may reflect the underlying neuropathology of ZIKV exposure on the fetus.. · There is potential utility for MCA Doppler evaluation in antepartum surveillance of ZIKV pregnancies..
Subject(s)
Zika Virus Infection , Zika Virus , Blood Flow Velocity , Female , Humans , Infant, Newborn , Middle Cerebral Artery/diagnostic imaging , Middle Cerebral Artery/physiology , Pregnancy , Pregnant Women , Prospective Studies , Ultrasonography, Doppler , Ultrasonography, Prenatal , Zika Virus Infection/complications , Zika Virus Infection/diagnostic imagingABSTRACT
BACKGROUND: Zika virus (ZIKV) is associated with severe congenital abnormalities and laboratory diagnosis of antenatal infection is difficult. Here we evaluated ZIKV neutralizing antibody (nAb) kinetics in infants born to mothers with PCR-confirmed ZIKV infection during pregnancy. METHODS: Neonates (nâ =â 98) had serum specimens tested repeatedly for ZIKV nAb over the first 2 years of life using virus neutralization test (VNT). ZIKV neonatal infection was confirmed by RT-PCR in blood or urine and/or presence of ZIKV IgM antibodies, and results were correlated with infant clinical features. RESULTS: Postnatal laboratory evidence of ZIKV vertical transmission was obtained for 60.2% of children, while 32.7% exhibited clinical abnormalities. Congenital abnormalities were found in 37.3% of children with confirmed ZIKV infection and 31.0% of children without confirmed infection (Pâ =â .734). All but 1 child displayed a physiologic decline in ZIKV nAb, reflecting maternal antibody decay, despite an early ZIKV-IgM response in one-third of infants. CONCLUSIONS: Infants with antenatal ZIKV exposure do not develop ZIKV nAb despite an early IgM response. Therefore, ZIKV VNT in children is not useful for diagnosis of congenital infection. In light of these findings, it remains to be determined if children infected in utero are potentially susceptible to reinfection.
Subject(s)
Antibodies, Neutralizing/blood , Antibodies, Viral/blood , Infectious Disease Transmission, Vertical , Pregnancy Complications, Infectious , Zika Virus Infection/diagnosis , Zika Virus/immunology , Biomarkers , Female , Humans , Immunoglobulin M , Infant , Infant, Newborn , Kinetics , Male , Polymerase Chain Reaction , Pregnancy , Zika Virus/genetics , Zika Virus/isolation & purification , Zika Virus Infection/congenitalABSTRACT
BACKGROUND: There are limited data on the natural history of antenatal Zika virus (ZIKV) exposure in twin pregnancies, especially regarding intertwin concordance of prenatal, placental, and infant outcomes. METHODS: This prospective cohort study included twin pregnancies referred to a single institution from September 2015 to June 2016 with maternal ZIKV. Polymerase chain reaction (PCR) testing of maternal, placental, and neonatal samples was performed. Prenatal ultrasounds were completed for each twin, and histomorphologic analysis was performed for each placenta. Abnormal neonatal outcome was defined as abnormal exam and/or abnormal imaging. Two- to three-year follow-up of infants included physical exams, neuroimaging, and Bayley-III developmental assessment. RESULTS: Among 244 pregnancies, 4 twin gestations without coinfection were identified. Zika virus infection occurred at 16-33 weeks gestation. Zika virus PCR testing revealed discordance between dichorionic twins, between placentas in a dichorionic pair, between portions of a monochorionic placenta, and between a neonate and its associated placenta. Of the 8 infants, 3 (38%) had an abnormal neonatal outcome. Of 6 infants with long-term follow-up, 3 (50%) have demonstrated ZIKV-related abnormalities. CONCLUSIONS: Neonatal PCR testing, placental findings, and infant outcomes can be discordant between co-twins with antenatal ZIKV exposure. These findings demonstrate that each twin should be evaluated independently for vertical transmission.
Subject(s)
Pregnancy Complications, Infectious/diagnosis , Pregnancy, Twin , Zika Virus Infection/diagnosis , Adult , Female , Humans , Infant , Infant, Newborn , Infectious Disease Transmission, Vertical , Placenta/virology , Polymerase Chain Reaction , Pregnancy , Pregnancy Complications, Infectious/virology , Prospective Studies , Ultrasonography, Prenatal , Young Adult , Zika Virus/pathogenicity , Zika Virus Infection/transmission , Zika Virus Infection/virologyABSTRACT
BACKGROUND: Zika-exposed infants with microcephaly (proportional or disproportional) and those who are small for gestational age without microcephaly should be closely followed, particularly their growth trajectories. They are at high risk of adverse outcomes in the first year of life.Antenatal Zika virus (ZIKV) exposure may lead to adverse infant outcomes including microcephaly and being small for gestational age (SGA). ZIKV-exposed infants with a diagnosis of microcephaly (proportional [PM] or disproportional [DM]) or SGA at birth were evaluated with anthropometric measurements and health outcomes. METHODS: Infants had laboratory-confirmed ZIKV exposure in Brazil. PM, DM, or SGA classification was based on head circumference and weight. First-year growth parameters and clinical outcomes were recorded with analyses performed. RESULTS: Among the 156 ZIKV-exposed infants, 14 (9.0%) were SGA, 13 (8.3%) PM, 13 (8.3%) DM, and 116 (74.4%) were neither SGA nor had microcephaly (NSNM). High rates of any neurologic, ophthalmologic, and hearing abnormalities were observed for PM (100%), DM (100%), and SGA (42.9%) vs NSNM infants (18.3%; P <.001); odds ratio [OR], 3.4 (95% confidence interval [CI], 1.1-10.7) for SGA vs NSNM. Neuroimaging abnormalities were seen in 100% of PM and DM and in 42.9% of SGA vs NSNM infants 16%; (P <.001); OR 3.9 (95% CI, 1.2-12.8) for SGA vs NSNM. Growth rates by z score, particularly for microcephaly infants, were poor after birth but showed improvement beyond 4 months of life. CONCLUSIONS: ZIKV-exposed infants with microcephaly (PM and DM) had similarly high rates of adverse outcomes but showed improvement in growth measurements beyond 4 months of life. While SGA infants had fewer adverse outcomes compared with microcephaly infants, notable adverse outcomes were observed in some; their odds of having adverse outcomes were 3 to 4 times greater compared to NSNM infants.Zika-exposed infants with microcephaly, irrespective of being proportional or disproportional, and those who are small for gestational age without microcephaly should be closely followed, particularly their growth trajectories. They are at high risk of adverse outcomes in the first year of life.
Subject(s)
Microcephaly , Pregnancy Complications, Infectious , Zika Virus Infection , Zika Virus , Brazil/epidemiology , Female , Gestational Age , Humans , Infant , Microcephaly/epidemiology , Pregnancy , Pregnancy Complications, Infectious/epidemiology , Zika Virus Infection/complications , Zika Virus Infection/epidemiologyABSTRACT
There are limited data on amniocentesis as a diagnostic tool for congenital Zika syndrome. Here we report on a prospective cohort of 16 women with suspected Zika virus infection in a highly endemic area, and discuss the role of amniocentesis in the prenatal diagnosis of fetal Zika infection.
Subject(s)
Amniocentesis , Fetal Diseases/diagnosis , Pregnancy Complications, Infectious/diagnosis , Zika Virus Infection/congenital , Zika Virus Infection/diagnosis , Female , Humans , Infectious Disease Transmission, Vertical , Pregnancy , Prospective StudiesABSTRACT
BACKGROUND: Zika virus (ZIKV) infection gained public health concern after the 2015 outbreak in Brazil, when microcephaly rates increased in babies born from infected mothers. It was demonstrated that ZIKV causes a congenital Zika virus syndrome, including various alterations in the development of the central nervous system. Although the infection of cells from the nervous system has been well documented, less is known in respect of ZIKV ability to infect immune cells. Herein, we investigated if peripheral blood mononuclear cells (PBMCs), freshly-isolated from healthy donors, could be infected by ZIKV. METHODS: PBMCs from healthy donors were isolated and cultured in medium with ZIKV strain Rio-U1 (MOI = 0.1). Infection was analyzed by RT-qPCR and flow cytometry. RESULTS: We detected the ZIKV RNA in PBMCs from all donors by RT-qPCR analysis. The detection of viral antigens by flow cytometry revealed that PBMC from more than 50% the donors were infected by ZIKV, with CD3+CD4+ T cells, CD3-CD19+ B cells and CD3+CD8+ T cells being, respectively, the most frequently infected subpopulations, followed by CD14+ monocytes. Additionally, we observed high variability in PBMC infection rates among different donors, either by numbers or type infected cells. CONCLUSIONS: These findings raise the hypothesis that PBMCs can act as a reservoir of the virus, which may facilitate viral dissemination to different organs, including immune-privileged sites.
Subject(s)
Leukocytes, Mononuclear/virology , Zika Virus Infection/virology , Zika Virus/isolation & purification , Antigens, CD19/genetics , Antigens, CD19/immunology , B-Lymphocytes/immunology , Brazil , CD8-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/virology , Cells, Cultured , Humans , Leukocytes, Mononuclear/immunology , Monocytes/immunology , Monocytes/virology , Real-Time Polymerase Chain Reaction , Zika Virus/genetics , Zika Virus/physiology , Zika Virus Infection/diagnosis , Zika Virus Infection/genetics , Zika Virus Infection/immunologyABSTRACT
BACKGROUND: Zika Virus (ZIKV), member of Flaviviridae family and Flavivirus genus, has recently emerged as international public health emergency after its association with neonatal microcephaly cases. Clinical diagnosis hindrance involves symptom similarities produced by other arbovirus infections, therefore laboratory confirmation is of paramount importance. DISCUSSION: The most reliable test available is based on ZIKV RNA detection from body fluid samples. However, short viremia window periods and asymptomatic infections diminish the success rate for RT-PCR positivity. Beyond molecular detection, all serology tests in areas where other Flavivirus circulates proved to be a difficult task due to the broad range of cross-reactivity, especially with dengue pre-exposed individuals. CONCLUSION: Altogether, lack of serological diagnostic tools brings limitations to any retrospective evaluation. Those studies are central in the context of congenital infection that could occur asymptomatically and mask prevalence and risk rates.
Subject(s)
Zika Virus Infection/diagnosis , Adult , Antibodies, Viral/analysis , Body Fluids/chemistry , Humans , Infant , Infant, Newborn , Microcephaly , Pathology, Molecular , Zika Virus Infection/bloodSubject(s)
Brain/diagnostic imaging , Child Development , Zika Virus Infection , Brazil , Child Language , Cognition , Developmental Disabilities/virology , Female , Humans , Infant , Longitudinal Studies , Neuroimaging , Neuropsychological Tests , Pregnancy , Pregnancy Complications, Infectious , Zika Virus , Zika Virus Infection/congenitalSubject(s)
Lymphoproliferative Disorders/epidemiology , Wiskott-Aldrich Syndrome/epidemiology , Adolescent , Adult , Child , Child, Preschool , France/epidemiology , Humans , Lymphoproliferative Disorders/genetics , Lymphoproliferative Disorders/therapy , Middle Aged , Registries , Stem Cell Transplantation , Wiskott-Aldrich Syndrome/genetics , Wiskott-Aldrich Syndrome/therapy , Wiskott-Aldrich Syndrome Protein/genetics , Young AdultABSTRACT
BACKGROUND: Congenital Zika virus (ZIKV) infection leads to severe newborn abnormalities, but its long-term impact on childhood immunity is not well understood. This study aims to investigate the serum proteomics in children exposed to ZIKV during pregnancy to understand potential immunological consequences during early childhood. METHODS: The study included ZIKV-exposed infants (ZEI) at birth (n = 42) and children exposed to ZIKV (ZEC) at two years of age (n = 20) exposed to ZIKV during pregnancy, as well as healthy controls. Serum proteomic analysis was performed on these groups to assess inflammation and immune profiles. Additionally, antibody titres against two common childhood vaccines, DTaP and MMR, were measured in healthy controls (n = 50) and ZEC (n = 92) to evaluate vaccine-induced immunity. FINDINGS: Results showed elevated inflammation in ZEI with birth abnormalities. Among ZEC, despite most having normal clinical outcomes at two years, their serum proteomics indicated a bias towards Th1-mediated immune responses. Notably, ZEC displayed reduced anti-Diphtheria toxin and anti-Clostridium tetani IgG levels against DTaP and MMR vaccines. They also exhibited lower antibody titres particularly against Th2-biased DTaP vaccines, but not Th1-biased MMR vaccines. INTERPRETATION: In conclusion, the study highlights the long-term immunological consequences of congenital ZIKV exposure. Heightened inflammation was observed in ZEI with abnormalities at birth, while ZEC maintained a chronic Th1-biased immune profile. The impaired response to Th2-biased vaccines raises concerns about lasting effects of ZIKV exposure on immune responses. Consequently, there is a need for continued longitudinal clinical monitoring to identify potential immune-related complications arising from prenatal exposure to ZIKV. FUNDING: This work was partially funded by the National Institute of Allergy and Infectious Diseases (NIAID) and National Institute of Dental and Craniofacial Research (NIDCR).
Subject(s)
Inflammation , Zika Virus Infection , Zika Virus , Humans , Zika Virus Infection/immunology , Zika Virus Infection/blood , Female , Zika Virus/immunology , Pregnancy , Male , Inflammation/immunology , Child, Preschool , Infant , Proteomics/methods , Antibodies, Viral/blood , Antibodies, Viral/immunology , Infant, Newborn , Pregnancy Complications, Infectious/immunology , Pregnancy Complications, Infectious/virologyABSTRACT
Up to 25% of pediatric cataract cases are inherited. There is sparse information in the literature regarding the cost of whole-exome sequencing (WES) for suspected hereditary pediatric cataracts. Molecular diagnosis of suspected hereditary pediatric cataracts is important for comprehensive genetic counseling. We performed a partial economic evaluation with a mixed costing analysis, using reimbursement data and microcosting approach with a bottom-up technique to estimate the cost of using WES for genetic diagnosis of suspected hereditary pediatric cataracts from the perspective of the Brazilian governmental health care system. One hundred and ten participants from twenty-nine families in Rio de Janeiro (RJ) were included. Costs of consumables, staff and equipment were calculated. Two scenarios were created: (1) The reference scenario included patients from RJ with suspected hereditary pediatric cataracts plus two family members. (2) The alternative scenario considered other genetic diseases, resulting in 5,280 exams per month. Sensitivity analysis was also performed. In the reference scenario, the total cost per exam was 700.09 United States dollars (USD), and in the alternative scenario, the total cost was 559.23 USD. The cost of WES alone was 527.85 USD in the reference scenario and 386.98 USD in the alternative scenario. Sensitivity analysis revealed that the largest costs were associated with consumables in both scenarios. Economic evaluations can help inform policy decisions, especially in middle-income countries such as Brazil.
ABSTRACT
Background: Prenatally transmitted viruses can cause severe damage to the developing brain. There is unexplained variability in prenatal brain injury and postnatal neurodevelopmental outcomes, suggesting disease modifiers. Discordant outcomes among dizygotic twins could be explained by genetic susceptibly or protection. Among several well-recognized threats to the developing brain, Zika is a mosquito-borne, positive-stranded RNA virus that was originally isolated in Uganda and spread to cause epidemics in Africa, Asia, and the Americas. In the Americas, the virus caused congenital Zika syndrome and a multitude of neurodevelopmental disorders. As of now, there is no preventative treatment or cure for the adverse outcomes caused by prenatal Zika infection. The Prenatal Infection and Neurodevelopmental Genetics (PING) Consortium was initiated in 2016 to identify factors modulating prenatal brain injury and postnatal neurodevelopmental outcomes for Zika and other prenatal viral infections. Methods: The Consortium has pooled information from eight multi-site studies conducted at 23 research centers in six countries to build a growing clinical and genomic data repository. This repository is being mined to search for modifiers of virally induced brain injury and developmental outcomes. Multilateral partnerships include commitments with Children's National Hospital (USA), Instituto Nacional de Salud (Colombia), the Natural History of Zika Virus Infection in Gestation program (Brazil), and Zika Instituto Fernandes Figueira (Brazil), in addition to the Centers for Disease Control and Prevention and the National Institutes of Health. Discussion: Our goal in bringing together these sets of patient data was to test the hypothesis that personal and populational genetic differences affect the severity of brain injury after a prenatal viral infection and modify neurodevelopmental outcomes. We have enrolled 4,102 mothers and 3,877 infants with 3,063 biological samples and clinical data covering over 80 phenotypic fields and 5,000 variables. There were several notable challenges in bringing together cohorts enrolled in different studies, including variability in the timepoints evaluated and the collected clinical data and biospecimens. Thus far, we have performed whole exome sequencing on 1,226 participants. Here, we present the Consortium's formation and the overarching study design. We began our investigation with prenatal Zika infection with the goal of applying this knowledge to other prenatal infections and exposures that can affect brain development.
ABSTRACT
Zika virus (ZIKV) infections during pregnancy can result in Congenital Zika Syndrome (CZS), a range of severe neurological outcomes in fetuses that primarily occur during early gestational stages possibly due to placental damage. Although some placentas can maintain ZIKV persistence for weeks or months after the initial infection and diagnosis, the impact of this viral persistence is still unknown. Here, we aimed to investigate the immunological repercussion of ZIKV persistence in term placentas. As such, term placentas from 64 pregnant women diagnosed with Zika in different gestational periods were analyzed by ZIKV RT-qPCR, examination of decidua and placental villous histopathology, and expression of inflammation-related genes and IFNL1-4. Subsequently, we explored primary cultures of term decidual Extravillous Trophoblasts (EVTs) and Term Chorionic Villi (TCV) explants, as in vitro models to access the immunological consequences of placental ZIKV infection. Placenta from CZS cases presented low IFNL1-4 expression, evidencing the critical protective role of theses cytokines in the clinical outcome. Term placentas cleared for ZIKV showed increased levels of IFNL1, 3, and 4, whether viral persistence was related with a proinflammatory profile. Conversely, upon ZIKV persistence placentas with decidual inflammation showed high IFNL1-4 levels. In vitro experiments showed that term EVTs are more permissive, and secreted higher levels of IFN-α2 and IFN-λ1 compared to TCV explants. The results suggest that, upon ZIKV persistence, the maternal-skewed decidua contributes to placental inflammatory and antiviral signature, through chronic deciduitis and IFNL upregulation. Although further studies are needed to elucidate the mechanisms underlying the decidual responses against ZIKV. Hence, this study presents unique insights and valuable in vitro models for evaluating the immunological landscape of placentas upon ZIKV persistence.
ABSTRACT
Gene therapy (GT) has emerged as a promising treatment option for disorders in the hematopoietic system, particularly primary immunodeficiencies (PID). Hematopoietic stem cells (HSCs) have gained attention due to their ability to support long-term hematopoiesis. In this study, we present a summary of research evaluating the most effective method of gene editing in HSCs for translational medicine. We conducted a systematic literature search in various databases, including Cochrane, LILACs, SciELO, and PubMed (MEDLINE), covering the period from January 1989 to June 10, 2023. The aim of this study was to identify articles that assessed the efficiency of gene editing in HSCs and clinical trials focusing on PID. Our research protocol was registered with the International Prospective Register of Systematic Reviews (PROSPERO; registration number CRD42022349850). Of the 470 studies identified in our search, 77 met the inclusion criteria. Among these, 61 studies were included in strategy 1 (gene therapy using HSC [GT-HSC]) of the systematic review (SR). We performed a meta-analysis on 17 of these studies. In addition, 16 studies were categorized under strategy 2 (clinical trials for PID). While clinical trials have demonstrated the potential benefits of GT-HSC, the safety and efficacy of gene editing still pose significant challenges. Various viral and nonviral approaches for gene delivery have been explored in basic and clinical research, with viral vectors being the most commonly used method in HSC therapeutics. Although promising, recent technologies such as CRISPR/Cas are not yet ready for efficient long-term restoration of the immune system as a whole.