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BACKGROUND: Kikuchi disease (KD) is a rare and generally benign condition of uncertain etiology that presents with nonspecific symptoms including fever and cervical lymphadenopathy. Clinical presentations can vary. Here, we present an atypical case of KD in a 10-year-old girl, as well as an updated literature review of the clinical presentation, laboratory features and management of KD in children. METHODS: Studies (published up until February 2020) were identified through searches of PubMed using the following search items: Kikuchi-Fujimoto disease or histiocytic necrotizing lymphadenitis or Kikuchi disease. Our primary search resulted in 1117 publications. A total of 34 publications with a total of 670 patients were included in the final analysis. RESULTS: All children present with lymphadenopathy. Almost all (96.3%) have cervical lymphadenopathy. Fever is recorded in the majority of children (77.1%). Analysis of laboratory features found that the majority of children have leukopenia (56.0%) and a raised erythrocyte sedimentation rate (56.0%). Over 30% have a raised C-reactive protein and anemia. Other features such as leukocytosis, thrombocytopenia and antinuclear antibodies positivity are less common. KD is mostly self-limiting, but steroids, hydroxychloroquine and intravenous immunoglobulin are used in protracted courses. Their efficacy has yet to be established in clinical trials. CONCLUSIONS: The presentation of KD is variable, and there is no specific set of symptoms or laboratory features that reliably establishes the diagnosis. Thus, histopathology is crucial. Definitive evaluation and establishment of effective treatments will require future prospective research studies for a more comprehensive description of the clinical course and effects of treatment. Given the rarity of the disease, this will have to be performed in collaborative consortia.

Background It has been demonstrated that human milk from mothers who have been infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) contains antibodies against the virus, which could play an important role in protecting the recipient infant against coronavirus disease 2019 (COVID-19). Seroconversion is measured frequently around the world, but the milk conversion rate is unknown. Research Aims To determine (1) the prevalence and (2) the dynamics of immunoglobulin A (IgA) antibodies against SARS-CoV-2 in human milk amongst lactating mothers in the Netherlands. Methods In this large prospective cohort study, lactating mothers ( N = 2312) were included between October 12, 2020 and February 24, 2021. Enzyme-linked immunosorbent assay was used to determine levels of IgA antibodies in human milk and immunoglobulin G (IgG) antibodies in serum against the ectodomain of the SARS-CoV-2 spike protein. Results A total of 691 (30.6%) participants had SARS-CoV-2 specific antibodies in human milk and/or serum. Of these participants, 524 (23.1%) had IgA antibodies against SARS-CoV-2 in human milk, and 356 (15.7%) had IgG antibodies against SARS-CoV-2 in serum. A total of 199 (8.8%) participants had antibodies in both human milk and serum. SARS-CoV-2 specific IgA antibodies in human milk remain present at least 10 months after a polymerase chain reaction confirmed infection. Conclusion The prevalence of IgA antibodies against SARS-CoV-2 in human milk was 23.1% in our cohort. This high prevalence of antibodies in human milk might lead to passive immunity in many breastfed infants and may serve as protection against COVID-19.

Supplemental Digital Content is available in the text, Objective: Cross-sectional studies, including one from our NOVICE cohort [Neurological Visual and Cognitive performance in children with treated perinatally acquired HIV (PHIV) compared with matched HIV-negative controls], have revealed that the brains of children with PHIV have lower white matter and grey matter volumes, more white matter hyperintensities (WMH) and poorer white matter integrity. This longitudinal study investigates whether these differences change over time. Methods: We approached all NOVICE participants to repeat MRI after 4.6 ± 0.3 years, measuring total white matter and grey matter volume, WMH volume and white matter integrity, obtained by T1-weighted, fluid-attenuated inversion recovery (FLAIR) and diffusion tensor imaging (DTI), respectively. We compared rates of change between groups using multivariable linear mixed effects models, adjusted for sex and age at enrolment. We investigated determinants of developmental deviation, and explored associations with cognitive development. Results: Twenty out of 31 (65%) PHIV-positive, and 20 out of 37 (54%) HIV-negative participants underwent follow-up MRI. Groups did not significantly differ in terms of age and sex. Over time, we found no statistically different changes between groups for white matter and WMH volumes, and for white matter integrity (P > 0.1). Total grey matter volume decreased significantly less in PHIV [group∗time 10 ml, 95% confidence interval −1 to 20, P = 0.078], but this difference in rate of change lost statistical significance after additional adjustment for height (group∗time 9 ml, 95% confidence interval −2 to 20, P = 0.112). We found no HIV-associated determinants for potential reduced grey matter pruning, nor associations with cognitive development. Conclusion: While using long-term antiretroviral treatment, structural brain development of adolescents growing up with perinatally acquired HIV appears largely normal.

Young people perinatally infected with HIV (pHIV) are at risk of a lowered health-related quality of life (HRQOL). Previous evaluation of the NeurOlogical, VIsual and Cognitive performance in HIV-infected Children (NOVICE)-cohort showed no difference in HRQOL between pHIV and matched HIV-uninfected controls (HIV-), yet a higher percentage of pHIV had impaired HRQOL. The aim of this study is to compare the change over time in HRQOL of pHIV to HIV- over a 5-year period. We used the Pediatric Quality of Life Inventory (PedsQL)™ 4.0 to repeat HRQOL assessment. High PedsQL scores indicate good HRQOL. Fifteen/33 (45.5%) pHIV and 17/37 (45.9%) HIV- completed both assessments. At the first assessment, the mean age was 13.1 years (range 8.0–18.4). PHIV scored higher than HIV- on Emotional functioning and on Total scale score. After five years, the mean age was 17.6 years (range 12.1–22.8). PHIV scored higher than HIV- on all scales, except Social functioning. PHIV did not differ significantly from the Dutch norm on either time-point. LMEM showed no difference in change over time for any of the PedsQL scales. In this study, young people with pHIV receiving high-quality health care, including monitoring of HRQOL, remain to experience a good HRQOL.

Syphilis is caused by a spirochaete bacterium called Treponema pallidum. Vertical transmission of spirochaetes can lead to congenital infection of the fetus in pregnant women who are inadequately treated or not treated at all, causing various clinical manifestations including stillbirth and neonatal death, cutaneous and visceral manifestations, or asymptomatic infection. We present a severe case of syphilis in a 3-month-old boy with skin lesions, portal hypertension, and anaemia. Because the mother was tested negative for syphilis antibodies at 16 weeks of gestation, a diagnosis of congenital syphilis was initially not considered. This case shows that transmission of T pallidum can still occur in high-income countries with a high rate of antenatal screening. Early recognition might be hampered if physicians do not consider congenital syphilis as a possible diagnosis. Congenital syphilis should be considered in any severe and diagnostically challenging infectious disease case, even in the context of negative antenatal screening.

OBJECTIVES Rotavirus vaccination has 87% to 100% effectiveness against severe rotavirus acute gastroenteritis (AGE) in healthy infants in high-income countries. Little is known whether infants with medical risk conditions (MRCs) are equally protected and if the vaccine is equally well tolerated. We conducted a quasi-experimental prospective multicenter before-after cohort study to assess the vaccine effectiveness (VE) and safety profile of the human rotavirus vaccine (HRV) among MRC infants that required prolonged or frequent postnatal care. METHODS The Netherlands has no national rotavirus immunization program, but HRV was implemented in routine care for MRC infants in 13 Dutch hospitals. Participants in the before and after cohort, HRV unvaccinated and vaccinated, respectively, were followed for occurrence of (rotavirus) AGE. VE of at least 1 dose was estimated by using time-to-event analysis for severe rotavirus AGE. Vaccine-related serious adverse event (AEs) after HRV were retrieved systematically from medical charts. Solicited AEs after vaccinations were prospectively collected and compared between vaccination time points with or without HRV. RESULTS In total, 1482 high-risk infants with MRC were enrolled, including 631 in the before and 851 in the after cohorts; 1302 infants were premature (88.3%), 447 were small for gestational age (30.2%), and 251 had at least 1 congenital disorder (17.0%). VE against severe rotavirus AGE was 30% (95% confidence interval [CI]: −36% to 65%). Overall, the observed number of rotavirus hospitalizations was low and not significantly different between the cohorts (2 and 2, respectively). The rate of vaccine-related serious AE was 0.24 per 100 vaccine doses. The adjusted risk ratio for any AE after HRV vaccination compared with other routine vaccinations was 1.09 (95% CI: 1.05 to 1.12) for concomitant administration and 0.91 (95% CI: 0.81 to 0.99) for single HRV administration. Gastrointestinal AEs were 10% more frequent after HRV. CONCLUSIONS In contrast to previous findings among healthy term infants, in routine use, HRV offered limited protection to vulnerable medical risk infants. HRV is generally well tolerated in this group in single administration, but when coadministered with routine vaccines, it is associated with higher risk of (mostly gastrointestinal) AE. Our study highlights the importance of studying vaccine performance in subgroups of medically vulnerable infants.

COVID-19 patients produce circulating and mucosal antibodies. In adults, specific saliva antibodies have been detected. Nonetheless, seroprevalence is routinely investigated, while little attention has been paid to mucosal antibodies. We therefore assessed SARS-CoV-2-specific antibody prevalence in serum and saliva in children in the Netherlands. We assessed SARS-CoV-2 antibody prevalence in serum and saliva of 517 children attending medical services in the Netherlands (irrespective of COVID-19 exposure) from April to October 2020. The prevalence of SARS-CoV-2 spike (S), receptor binding domain (RBD), and nucleocapsid (N)-specific IgG and IgA were evaluated with an exploratory Luminex assay in serum and saliva and with the Wantai SARS-CoV-2 RBD total antibody enzyme-linked immunosorbent assay in serum. Using the Wantai assay, the RBD-specific antibody prevalence in serum was 3.3% (95% confidence interval [CI]. 1.9 to 5.3%). With the Luminex assay, we detected heterogeneity between antibodies for S, RBD, and N antigens, as IgG and IgA prevalence ranged between 3.6 and 4.6% in serum and between 0 and 4.4% in saliva. The Luminex assay also revealed differences between serum and saliva, with SARS-CoV-2-specific IgG present in saliva but not in serum for 1.5 to 2.7% of all children. Using multiple antigen assays, the IgG prevalence for at least two out of three antigens (S, RBD, or N) in serum or saliva can be calculated as 3.8% (95% CI, 2.3 to 5.6%). Our study displays the heterogeneity of the SARS-CoV-2 antibody response in children and emphasizes the additional value of saliva antibody detection and the combined use of different antigens. IMPORTANCE Comprehending humoral immunity to SARS-CoV-2, including in children, is crucial for future public health and vaccine strategies. Others have suggested that mucosal antibody measurement could be an important and more convenient tool to evaluate humoral immunity compared to circulating antibodies. Nonetheless, seroprevalence is routinely investigated, while little attention has been paid to mucosal antibodies. We show the heterogeneity of SARS-CoV-2 antibodies, in terms of both antigen specificity and differences between circulating and mucosal antibodies, emphasizing the additional value of saliva antibody detection next to detection of antibodies in serum.

HIV is an independent risk factor of cardiovascular disease (CVD), therefore, perinatally HIV-infected (PHIV) children potentially have a greater CVD risk at older age. Lipoprotein(a) (Lp(a)) is an established risk factor for CVD in the general population. To evaluate a potential increased CVD risk for PHIV children, we determined their lipid profiles including Lp(a). In the first substudy, we assessed the lipid profiles of 36 PHIV children visiting the outpatient clinic in Amsterdam between 2012 and 2020. In the second substudy, we enrolled 21 PHIV adolescents and 23 controls matched for age, sex and ethnic background on two occasions with a mean follow-up time of 4.6 years. We assessed trends of lipid profiles and their determinants, including patient and disease characteristics, using mixed models. In the first substudy, the majority of PHIV children were Black (92%) with a median age of 8.0y (5.7–10.8) at first assessment. Persistent elevated Lp(a) levels were present in 21/36 (58%) children (median: 374 mg/L (209–747), cut off = 300). In the second substudy, the median age of PHIV adolescents was 17.5y (15.5–20.7) and of matched controls 16.4y (15.8–19.5) at the second assessment. We found comparable lipid profiles between groups. In both studies, increases in LDL-cholesterol and total cholesterol were associated with higher Lp(a) levels. A majority of PHIV children and adolescents exhibited elevated Lp(a) levels, probably associated with ethnic background. Nonetheless, these elevated Lp(a) levels may additionally contribute to an increased CVD risk.

Background Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines are being administered around the world; however, lactating women were excluded from SARS-CoV-2 vaccine trials. Therefore, knowledge about the effect of vaccination in this specific group is limited. This information is essential to empower lactating women to make a well-informed decision on their choice for vaccination. After natural infection, SARS-CoV-2 specific antibodies are present in human milk, which might offer protection for her newborn. The dynamics of these antibodies in human milk following vaccination remain to be elucidated. Research Aim To determine the effect of vaccination with BNT162b2 on the levels of SARS-CoV-2 specific IgA in human milk. Methods In this prospective longitudinal study, we included lactating women who received the BNT162b2 vaccine. Human milk samples were collected prior to vaccination and 3, 5, 7, 9, 11, 13, and 15 days after both vaccine doses. Samples were analyzed using enzyme-linked immunosorbent assay against the spike protein of SARS-CoV-2. Results In total, 366 human milk samples from 26 lactating women were analyzed. A biphasic response was observed, with SARS-CoV-2 specific immunoglobulin A (IgA) starting to increase between day 5 and 7 after the first dose of the vaccine. After the second dose, an accelerated IgA antibody response was observed. Conclusion After vaccination with the mRNA-based BNT162b2 vaccine, a SARS-CoV-2 specific antibody response was observed in human milk. The presence of SARS-CoV-2 specific IgA after vaccination is important as antibodies are transferred via human milk, and thereby might provide protection to infants against COVID-19.

Background Human milk contains antibodies against Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) following Coronavirus Disease 2019 (COVID-19). These antibodies may serve as protection against COVID-19 in infants. However, the evolution of these human milk antibodies over time is unclear. Research Aim To elucidate the evolution of immunoglobulin A (IgA) against SARS-CoV-2 in human milk after a SARS-CoV-2 infection. Methods This longitudinal follow-up study included lactating mothers ( N = 24) who had participated in the COVID MILK study. To assess the evolution of SARS-CoV-2 antibodies, serum and human milk samples were collected 14–143 days after the onset of clinical symptoms related to COVID-19. Enzyme-Linked ImmunoSorbent Assay was used to detect antibodies against the ectodomain of the SARS-CoV-2 spike protein. Results SARS-CoV-2 antibodies remain present up to 5 months (143 days) in human milk after onset of COVID-19 symptoms. Overall, SARS-CoV-2 IgA in human milk seems to gradually decrease over time. Conclusion Human milk from SARS-CoV-2 convalescent lactating mothers contains specific IgA antibodies against SARS-CoV-2 spike protein up to at least 5 months post-infection. Passive viral immunity can be transferred via human milk and may serve as protection for infants against COVID-19.

Human parechovirus (PeV-A), one of the species within the Picornaviridae family, is known to cause disease in humans. The most commonly detected genotypes are PeV-A1, associated with mild gastrointestinal disease in young children, and PeV-A3, linked to severe disease with neurological symptoms in neonates. As PeV-A are detectable in stool and nasopharyngeal samples, entry is speculated to occur via the respiratory and gastro-intestinal routes. In this study, we characterized PeV-A1 and PeV-A3 replication and tropism in the intestinal epithelium using a primary 2D model based on human fetal enteroids. This model was permissive to infection with lab-adapted strains and clinical isolates of PeV-A1, but for PeV-A3, infection could only be established with clinical isolates. Replication was highest with infection established from the basolateral side with apical shedding for both genotypes. Compared to PeV-A1, replication kinetics of PeV-A3 were slower. Interestingly, there was a difference in cell tropism with PeV-A1 infecting both Paneth cells and enterocytes, while PeV-A3 infected mainly goblet cells. This difference in cell tropism may explain the difference in replication kinetics and associated disease in humans.

OBJECTIVES: The incidence of neonatal herpes simplex virus (nHSV) infections is monitored periodically in the Netherlands, yet management and outcome is unknown. Comprehensive national guidelines are lacking. We aim to describe management and outcome in the last decade to explore current diagnostic and therapeutic challenges. We aim to identify possible variability in management of patients with a suspected nHSV infection. METHODS: We conducted a retrospective case series of management and outcome of nHSV infections at 2 tertiary care center locations in the Netherlands. RESULTS: An nHSV infection was diagnosed in 1% (12 of 1348) of patients in whom polymerase chain reaction for HSV was performed. Of the patients with nHSV infection, 3 of 12 died, and 4 of 9 (44%) survivors suffered neurologic sequelae. Neurologic symptoms at presentation were seen in only 2 of 8 patients with nHSV encephalitis. A cerebral spinal fluid analysis was performed in 3 of 6 patients presenting with skin lesions. Only 3 of 6 patients with neurologic symptoms received suppressive therapy. nHSV infection was diagnosed in 8 of 189 (4%) patients who were empirically treated. CONCLUSIONS: Management of nHSV infection, particularly when presented with skin lesions, is inconsistent. Many infants without a HSV infection are exposed to antiviral medication. There is substantial interhospital variation in diagnostic and therapeutic management of a suspected infection. Comprehensive guidelines need to be developed to standardize management of suspected nHSV infection.

ObjectiveWe aim to give an overview of the available evidence on brain structure and function in PHIV-infected patients (PHIV+) using long-term combination antiretroviral therapy (cART) and how differences change over time.MethodsWe conducted an electronic search using MEDLINE, Embase, and PsycINFO. We used the following selection criteria: cohort and cross-sectional studies that reported on brain imaging differences between PHIV+ of all ages who used cART for at least six months before neuroimaging and HIV-negative controls. Two reviewers independently selected studies, performed data extraction, and assessed quality of studies.ResultsAfter screening 1500 abstracts and 343 full-text articles, we identified 19 eligible articles. All included studies had a cross-sectional design and used MRI with different modalities: structural MRI (n = 7), diffusion tensor imaging (DTI) (n = 6), magnetic resonance spectroscopy (n = 5), arterial spin labeling (n = 1), and resting-state functional neuroimaging (n = 1). Studies showed considerable methodological limitations and heterogeneity, preventing us to perform meta-analyses. DTI data on white matter microstructure suggested poorer directional diffusion in cART-treated PHIV+ compared with controls. Other modalities were inconclusive.ConclusionEvidence may suggest brain structure and function differences in the population of PHIV+ on long-term cART compared with the HIV-negative population. Because of a small study population, and considerable heterogeneity and methodological limitations, the extent of brain structure and function differences on neuroimaging between groups remains unknown.

Background Fatigue is common among adults living with human immunodeficiency virus (HIV) as well as children with a chronic disease (CCD). Fatigue can have disastrous effects on health status, including health related quality of life (HRQOL). Even so, fatigue is underexplored in children and adolescents perinatally infected with HIV (PHIV+) in the Netherlands. The objective of this observational study is to explore fatigue in PHIV+ and its association with their HRQOL. Methods We measured HRQOL and fatigue using the Pediatric Quality of Life Inventory™ (PedsQL 4.0) and the PedsQL Multidimensional Fatigue Scale (MFS). The PedsQL MFS encompasses three subscales: general fatigue, sleep/rest fatigue and cognitive fatigue, and a total fatigue score. We compared outcomes of PHIV+ children and adolescents in the Amsterdam University Medical Centre with three groups: 1) HIV-uninfected controls (HIV-) matched for age, sex, region of birth, socioeconomic status and adoption status, 2) CCD, and 3) the general Dutch population. Within the PHIV+ group we explored associations between fatigue and HRQOL. Results We enrolled 14 PHIV+ (median age 10.2 years [IQR 9.2–11.4]) and 14 HIV-. Compared to CCD, PHIV+ significantly reported less general fatigue (mean difference 13.0, 95% CI 1.3 to 24.8). PHIV+ did not score significantly different on any of the other PedsQL MFS scales compared to HIV-, CCD or the general Dutch population. PHIV children scored relatively low on the cognitive fatigue scale in comparison to HIV-uninfected matched controls, CCD and the general population, although these differences did not reach significance. Among PHIV+, a lower score on total fatigue, general fatigue and cognitive fatigue was associated with a lower HRQOL score. Conclusions The results of this study suggest that PHIV children and adolescents do not experience more symptoms of fatigue than their healthy peers. However, PHIV children and adolescents may be more likely to experience cognitive fatigue. Fatigue in PHIV also appears to be associated with children’s HRQOL. Further research should confirm these exploratory findings.

Enteroviruses (EVs) are highly prevalent viruses world-wide, causing a wide range of diseases in both children and adults. Insight in the global prevalence of EVs is important to define their clinical significance and total disease burden, and assists in making therapeutic decisions. While many studies have been conducted to describe epidemiology of EVs in specific (sub)populations and patient cohorts, little effort has been made to aggregate the available evidence. In the current study, we conducted a search in the PubMed and Embase (Ovid) databases to identify articles reporting EV prevalence and type distribution. We summarized the findings of 153 included studies. We found that EVs are highly prevalent viruses in all continents. Enterovirus B was the most detected species worldwide, while the other species showed continent-specific differences, with Enterovirus C more detected in Africa and Enterovirus A more detected in Asia. Echovirus 30 was by far the most detected type, especially in studies conducted in Europe. EV types in species Enterovirus B—including echovirus 30—were often detected in patient groups with neurological infections and in cerebrospinal fluid, while Enterovirus C types were often found in stool samples.

BACKGROUND: The Dutch fever without an apparent source (FWS) guidelines were published to timely recognize and treat serious infections. We determined the adherence to the Dutch FWS guidelines and the percentage of serious infections in infants younger than 3 months of age. Second, we identified which clinical criteria, diagnostic tests, and management were associated with nonadherence to the guidelines. METHODS: A retrospective cohort study was performed in 2 Dutch teaching hospitals. We assessed the charts of all infants with FWS who presented at the emergency departments from September 30, 2017, to October 1, 2019. Diagnostic and therapeutic decisions were compared with the recommendations, as published in the Dutch guidelines. Infants were categorized into the nonadherence group in case 1 or more recommendations were not adhered to. RESULTS: Data on 231 infants were studied; 51.5% of the cases adhered to the Dutch guidelines and 16.0% suffered from a serious infection. The percentage of infants with a serious infection was higher in the adherence compared with the nonadherence group. We observed no relevant differences in clinical outcomes. Univariate regression analysis showed that an abnormal white blood cell count was associated with nonadherence (OR 0.4, P = 0.049). Not obtaining a urine and blood culture and not starting intravenous antibiotic treatment were the most frequent reasons for nonadherence to the guidelines. CONCLUSIONS: Our study indicates that there was nonadherence in a large proportion of FWS cases. The guidelines may need to be adjusted to increase adherence.

Cerebral white matter hyperintensities (WMH) persist in children and adults living with HIV, despite effective combination antiretroviral therapy (cART). As age and principal routes of transmission differ between children (perinatally) and adults (behaviorally), comparing the characteristics and determinants of WMH between these populations may increase our understanding of the pathophysiology of WMH. From separate cohorts of 31 children (NOVICE) and 74 adults (AGEhIV), we cross-sectionally assessed total WMH volume and number of WMH per location (periventricular vs. deep) using fluid-attenuated inversion recovery (FLAIR) MRI images. WMH were either periventricular when within 10mm of the lateral ventricles, or deep otherwise. We assessed patient- or HIV-related determinants of total WMH volume (adjusted for intracranial volume) and location of WMH using logistic regression, while stratifying on children and adults. At enrollment, median age of participants was 13.8 years (IQR 11.4–15.9) for children and 53.4 years (IQR 48.3–60.8) for adults and 27/31 children (87%) and 74/74 adults (100%) had an HIV RNA viral load

The development of gene therapies for central nervous system disorders is challenging because it is difficult to translate preclinical data from current in vitro and in vivo models to the clinic. Therefore, we developed induced pluripotent stem cell (iPSC)-derived cerebral organoids as a model for recombinant adeno-associated virus (rAAV) capsid selection and for testing efficacy of AAV-based gene therapy in a human context. Cerebral organoids are physiological 3D structures that better recapitulate the human brain compared with 2D cell lines. To validate the model, we compared the transduction efficiency and distribution of two commonly used AAV serotypes (rAAV5 and rAAV9). In cerebral organoids, transduction with rAAV5 led to higher levels of vector DNA, transgenic mRNA, and protein expression as compared with rAAV9. The superior transduction of rAAV5 was replicated in iPSC-derived neuronal cells. Furthermore, rAAV5-mediated delivery of a human sequence-specific engineered microRNA to cerebral organoids led to a lower expression of its target ataxin-3. Our studies provide a new tool for selecting and deselecting AAV serotypes, and for demonstrating therapeutic efficacy of transgenes in a human context. Implementing cerebral organoids during gene therapy development could reduce the usage of animal models and improve translation to the clinic., Graphical Abstract, Induced pluripotent stem cell-derived cerebral organoids are an innovative human model of the brain that could improve translation of gene therapy to the clinic. Depla et al. demonstrate the application of cerebral organoids as a preclinical model for AAV capsid selection and testing efficacy of therapeutic transgenes.

Human parechoviruses (HPeV) of the species Parechovirus A are highly prevalent disease-causing pathogens in children worldwide. HPeVs are capable of causing severe disease in adults as well, but the prevalence in adults may be much lower. The aim of our present study was to determine the prevalence of HPeV in clinical samples from adults sent in for diagnostic procedures in a tertiary hospital in the Netherlands. From a total of 10,645 samples obtained from 6175 patients, 20 samples from 11 patients (0.18%) tested positive for HPeV by RT-PCR. Two patients were positive for HPeV-1, two for HPeV-3, and one for HPeV-6. Six HPeVs could not be typed. Eight of the 11 HPeV-positive patients were immunocompromised. Due to comorbidity, we were unable to attribute the patients’ clinical symptoms to the HPeV infection. The HPeV prevalence in adults found in this study is low compared to HPeV prevalence in children. This may be largely explained by the high seropositivity rates in adults, although there could be other mechanisms involved. Electronic supplementary material The online version of this article (10.1007/s00705-020-04547-0) contains supplementary material, which is available to authorized users.

Background Since the outbreak of COVID-19, many put their hopes in the rapid development of effective immunizations. For now patient isolation, physical distancing and good hygiene are the sole measures for prevention. Processed breast milk with antibodies against SaRS-CoV-2 may serve as additional protection. We aimed to determine the presence and neutralization capacity of antibodies against SaRS-CoV-2 in breastmilk of mothers who have recovered from COVID-19. Methods This prospective case control study included lactating mothers, recovered from (suspected) COVID-19 and healthy controls. Serum and breastmilk was collected. To assess the presence of antibodies in breastmilk and serum, we used multiple complementary assays, namely ELISA with the SARS-CoV-2 spike protein, SARS-CoV-2 receptor binding domain (RBD) and with the SARS-CoV-2 nucleocapsid (N) protein for IgG and bridging ELISA with the SARS-CoV-2 RBD and N protein for total Ig. To assess the effect of pasteurization breastmilk was exposed to Holder Pasteurization and High Pressure Pasteurization. Results Breastmilk contained antibodies against SARS-CoV-2 using any of the assays in 24 out of 29 (83%) proven cases, in six out of nine (67%) suspected cases and in none of the 13 controls. In vitro neutralization of SARS-CoV-2 clinical isolate virus strain was successful in a subset of serum (13%) and milk samples (26%). Although after pasteurization of the milk SARS-CoV-2 antibodies were detected with both methods of pasteurization, virus neutralizing capacity of those antibodies was only retained with the HPP approach. Conclusion Breastmilk of mothers who recovered from COVID-19 contains significant amounts of IgA against SARS-CoV-2, both before and after pasteurization. Key Points Question Does breastmilk of mothers who have recovered from coronavirus disease 2019 (COVID-19) contain antibodies against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)? Findings We provide multiple lines of evidence on the presence of a variety of antibodies against SARS-CoV-2, with no such antibodies present in the controls. These antibodies are capable of neutralizing a clinical isolate of SARS-CoV-2 in vitro. We furthermore show that high pressure pasteurization hardly affects antibody levels and efficacy. Meaning Breastmilk, obtained from mothers who have recovered from COVID-19, may serve as a safe and widely applicable preventive strategy for vulnerable high risk populations

Enteroviruses (EVs) are highly prevalent viruses worldwide. Recombination is known to occur frequently in EVs belonging to species Enterovirus A, Enterovirus B, and Enterovirus C. Although many recombinant vaccine-derived poliovirus (VDPV) strains have been reported, our knowledge on recombination in non-polio EVs in the species Enterovirus C is limited. Here, we combined a dataset consisting of 11 newly generated full-length Enterovirus C sequences and 180 publicly available sequences to study recombination dynamics in non-polio EVs. To identify recombination patterns, maximum likelihood phylogenetic trees of different genomic regions were constructed, and segregation analyses were performed. Recombination was observed between members of the same 3DPol cluster, but was rarely observed between members of different clusters. We hypothesize that this restriction may have arisen through their different compartmentalization in respiratory and enteric tracts related to differences in cellular tropisms so that the opportunity to recombine may not be available.

Human coronaviruses (CoVs) are increasingly recognized as important respiratory pathogens associated with a broad range of clinical diseases. We sought to increase the insight into clinically relevant CoV infections by monitoring antigen concentrations in six confirmed CoV-positive patients using a newly developed assay for rapid detection of CoV OC43 infections. Antigen positivity lasted 3 to 6 days in secondary infections and 13 days in primary infection. CoV infections are clinically diverse, are common, and cannot be diagnosed from clinical symptoms alone. Keywords: Human coronavirus, point-of-care test, rapid antigen test, rapid detection, respiratory tract infection

Background Laboratory testing for respiratory tract infections (RTIs) is not routinely performed in primary care. Their etiology is usually unknown, and although RTIs are mainly of viral origin, the contribution of different respiratory viruses is uncertain. Our study aims to increase our insight into the epidemiology of respiratory viruses in primary care and to evaluate the accuracy of the general practitioner's (GP's) clinical diagnosis of influenza virus infection. Methods We prospectively recruited patients who presented with RTI symptoms at a primary care facility in Amsterdam, the Netherlands, during the 2015-2016 winter season. Demographic and clinical characteristics of patients were summarized using a questionnaire. Nasopharyngeal swabs were collected and tested with a multiplex polymerase chain reaction assay detecting 14 respiratory viruses. Results One or more respiratory viruses were present in 42.5% of the patients (n = 353). The most frequently detected viruses were rhinovirus (11.6%), human coronavirus (8.8%), and influenza A virus (7.6%). Sensitivity of GP's clinical diagnosis for influenza virus infection was 52.6% and specificity was 78.3%. Conclusions Despite the use of a sensitive polymerase chain reaction, a respiratory virus could be detected in less than half of the patients visiting the GP with RTI symptoms. It is difficult to clinically distinguish influenza from other causes of RTIs. Correct etiological diagnosis of RTIs is needed because it contributes to differential diagnosis, might give direction to development of specific antiviral therapies and vaccines, reduce unnecessary prescription of antibiotics, and clarifies the clinical spectrum of the different respiratory viruses.

Supplemental Digital Content is available in the text., Background: Human parechoviruses (HPeVs) are common pathogens in young children, and in the Netherlands, HPeV1, HPeV3 and HPeV4 are the most frequently detected genotypes. HPeV3 in particular has been associated with severe disease in young infants below 3 months of age while the other genotypes more often infect older children and elicit mild symptoms. We investigated if maternal neutralizing antibodies (nAbs) against HPeV1, HPeV3 and HPeV4 protect young Dutch infants from severe disease related to HPeV infection. Methods: We conducted a prospective case–control study of Dutch mother–infant pairs. Thirty-eight HPeV-infected infants and their mothers were included as cases, and 65 HPeV-negative children and their mothers as controls. Results: In control infants, we observed nAb seropositivity rates of 41.4%, 33.3% and 27.6%, with median nAb titers of 1:16, 1:12 and 1:8, against HPeV1, HPeV3 and HPeV4, respectively. In control mothers, nAb seropositivity rates were 84.6%, 55.4% and 60.0% with median nAb titers of 1:128, 1:32 and 1:45 against HPeV1, HPeV3 and HPeV4, respectively. The HPeV3 nAb seroprevalence was significantly lower in HPeV3-infected infants and their mothers (0.0% with P < 0.05 and 10.0% with P < 0.001, respectively). In contrast, no differences in nAb seroprevalence against HPeV1 or HPeV4 could be detected between case and control infants or mothers. Conclusions: Our results suggest that young Dutch infants are protected against severe disease related to HPeV1 and HPeV4 by maternal nAbs, but less so against HPeV3 explaining the distinct age distributions and disease severity profiles of children infected with these HPeV genotypes.

Enteroviruses (EVs) are among the most commonly detected viruses infecting humans worldwide. Although the prevalence of EVs is widely studied, the status of EV prevalence in sub-Saharan Africa remains largely unknown. The objective of our present study was therefore to increase our knowledge on EV circulation in sub-Saharan Africa. We obtained 749 fecal samples from a cross-sectional study conducted on Malawian children aged 6 to 60 months. We tested the samples for the presence of EVs using real time PCR, and typed the positive samples based on partial viral protein 1 (VP1) sequences. A large proportion of the samples was EV positive (89.9%). 12.9% of the typed samples belonged to EV species A (EV-A), 48.6% to species B (EV-B) and 38.5% to species C (EV-C). More than half of the EV-C strains (53%) belonged to subgroup C containing, among others, Poliovirus (PV) 1-3. The serotype most frequently isolated in our study was CVA-13, followed by EV-C99. The strains of CVA-13 showed a vast genetic diversity, possibly representing a new cluster, 'F'. The majority of the EV-C99 strains grouped together as cluster B. In conclusion, this study showed a vast circulation of EVs among Malawian children, with an EV prevalence of 89.9%. Identification of prevalences for species EV-C comparable to our study (38.5%) have only previously been reported in sub-Saharan Africa, and EV-C is rarely found outside of this region. The data found in this study are an important contribution to our current knowledge of EV epidemiology within sub-Saharan Africa.

Background: Paediatric data on CNS penetration of antiretroviral drugs are scarce. Objectives: To evaluate CNS penetration of antiretroviral drugs in HIV-infected children and explore associations with neurocognitive function. Patients and methods: Antiretroviral drug levels were measured in paired CSF and blood samples of clinically stable HIV-infected children between 8 and 18 years old on long-term combined ART. Plasma drug concentrations were corrected for protein binding. We evaluated CNS penetration using CSF/plasma ratios and compared CSF concentrations with the IC50 as a surrogate marker for effectiveness. Blood-brain barrier permeability was assessed for possible confounding. Associations with neurocognitive function were explored using linear regression analysis. Results: Median CSF/plasma ratios (IQR) were: lopinavir 0.059 (0.024-0.157, n = 7), efavirenz 0.681 (0.555-0.819, n = 12), tenofovir 0.021 (0.020-0.024, n = 4), lamivudine 0.464 (0.331-0.607, n = 17), emtricitabine 0.365 (0.343-0.435, n = 3), nevirapine 1.203 (n = 1), zidovudine 0.718 (0.711-1.227, n = 5) and abacavir 1.344 (0.670-2.450, n = 10). CSF concentrations were below the IC50 for tenofovir (100%), emtricitabine (100%), abacavir (50%) and zidovudine (17%). Lamivudine, lopinavir, efavirenz and nevirapine concentrations were all above the IC50. All participants were virologically suppressed in blood and CSF. CSF drug concentrations were not associated with blood-brain barrier permeability or neurocognitive function. Conclusions: We showed adequate CSF concentrations of lamivudine, lopinavir, efavirenz and nevirapine, and potential suboptimal CSF concentrations of tenofovir, abacavir and emtricitabine in long-term treated HIV-infected children. None the less, the use of combined antiretroviral drugs led to adequate viral suppression.

Despite effective combination anti-retroviral therapy (cART), perinatally HIV infected (PHIV) adolescents still experience cognitive complications. We previously reported higher cerebral blood flow (CBF) in basal ganglia and white matter (WM) in PHIV children compared to matched controls. In healthy children CBF is associated with cognitive domains. To determine longitudinal changes in CBF and its impact on cognitive complications, we measured CBF—using arterial spin labeling—in 21 PHIV adolescents and 23 controls matched for age, sex and socio-economic status twice with a mean follow-up of 4.6 years. We explored associations between CBF changes and WM micro- and macrostructural markers and cognitive domains using linear mixed models. The median age at follow-up was comparable between PHIV adolescents 17.4y (IQR:15.3–20.7) and controls 16.2y (IQR:15.6–19.1). At baseline, PHIV had higher CBF in the caudate nucleus and putamen. CBF development was comparable in gray matter (GM), WM and subcortical regions in both groups. In our cohort, we found that over time an increase of GM CBF was associated with an increase of visual motor function (p = 0.043) and executive function (p = 0.045). Increase of CBF in the caudate nucleus, putamen and thalamus was associated with an increase processing speed (p = 0.033, 0.036, 0.003 respectively) and visual motor function (p = 0.023, 0.045, 0.003 respectively). CBF development is relatively normal in PHIV adolescents on cART. CBF decline is associated with cognitive impairment, irrespective of HIV status.

Key Points This meta-analysis evaluates the diagnostic accuracy of rapid tests for the detection of respiratory viruses. Sensitivity of tests varied considerably, but specificity was high. Although newly developed tests seem more sensitive, high quality evaluations of these tests are lacking., Rapid diagnosis of respiratory virus infections contributes to patient care. This systematic review evaluates the diagnostic accuracy of rapid tests for the detection of respiratory viruses. We searched Medline and EMBASE for studies evaluating these tests against polymerase chain reaction as the reference standard. Of 179 studies included, 134 evaluated rapid tests for influenza viruses, 32 for respiratory syncytial virus (RSV), and 13 for other respiratory viruses. We used the bivariate random effects model for quantitative meta-analysis of the results. Most tests detected only influenza viruses or RSV. Summary sensitivity and specificity estimates of tests for influenza were 61.1% and 98.9%. For RSV, summary sensitivity was 75.3%, and specificity, 98.7%. We assessed the quality of studies using the Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2) checklist. Because of incomplete reporting, the risk of bias was often unclear. Despite their intended use at the point of care, 26.3% of tests were evaluated in a laboratory setting. Although newly developed tests seem more sensitive, high-quality evaluations of these tests are lacking.

Background Inappropriately high levels of antibiotics are still prescribed in primary health care for respiratory tract infections (RTIs). Access to diagnostic point-of-care tests (POCTs) for RTIs might reduce this over-prescription. Objective The purpose of our study was to determine the diagnostic performance and clinical feasibility of a recently developed diagnostic POCT for respiratory viruses, the mariPOC®, in a Dutch primary healthcare setting. Methods In patients with RTI symptoms presenting to a family practice during the 2015–2016 winter season, we determined the test’s sensitivity and specificity relative to polymerase chain reaction (PCR) testing performed in a laboratory. The clinical feasibility of the POCT was evaluated by interviewing general practitioners (GPs). Results One or more respiratory viruses were detected in 54.9% of the patients (n = 204). For influenza A virus (n = 24), sensitivity of the POCT was 54.2% and specificity was 98.9%; for influenza B virus (n = 18), sensitivity was 72.2% and specificity 99.5%; and for respiratory syncytial virus (RSV) (n = 12), sensitivity was 50.0% and specificity 100%. In samples with higher viral load, sensitivity was 85.7% for influenza A, 78.6% for influenza B and 85.7% for RSV. The availability of a diagnostic test for respiratory viruses was appreciated by both patients and GPs. Conclusions Our study shows that diagnostic POCTs for respiratory viruses might contribute to a precise and evidence-based diagnosis of RTIs and could positively influence prescription of antibiotics by GPs. However, before implementation in primary healthcare, diagnostic accuracy of the POCT needs improvement and it is impact on clinical decision making should be further assessed.

Background Enterovirus D68 (EV-D68) has caused major outbreaks of severe respiratory illness worldwide since 2010. Aim Our aim was to evaluate EV-D68 circulation in the Netherlands by conducting a serosurvey of EV-D68 neutralising antibodies (nAb) among the Dutch general population. Methods We screened 280 sera from children and adults in the Netherlands and used two independent sets of samples collected in the years 2006 and 2007 and in the years 2015 and 2016, time points before and after the first EV-D68 upsurge in 2010. Neutralisation capacity of the sera was tested against the prototype Fermon EV-D68 strain isolated in 1962 and against a recent EV-D68 strain (genotype B3) isolated in France in 2016. Results Regardless of the time of serum collection, we found remarkably high overall seropositivity (94.3–98.3%) for nAb against both EV-D68 strains. Geometric mean titres increased in an age-dependent manner. Conclusions Our data suggest that EV-D68 has been circulating in the Netherlands for decades and that the enterovirus surveillance does not accurately capture the prevalence of this clinically relevant pathogen.

Supplemental Digital Content is available in the text, Clinical signs and symptoms of central nervous system (CNS) infections in neonates are often nonspecific. Therefore, cerebrospinal fluid (CSF) analysis is performed to diagnose CNS infections. Data on combined microbiological results and their correlation with biochemical characteristics in CSF and blood in infants younger than 90 days are limited. This study provides an overview of microbiological test results, CSF- and hematological characteristics among infants with a clinically suspected CNS infection. This retrospective study included infants younger than 90 days, with a clinically suspected CNS infection who underwent a diagnostic lumbar puncture between January 2012 and January 2014. Data on the presence of microbiological pathogens in CSF, CSF inflammation markers (white blood cell [WBC] counts, protein levels and glucose CSF/serum ratio) and blood inflammatory responses (WBC count, C-reactive protein [CRP], neutrophil percentage) were collected by reviewing patient files. We included data from 576 infants (median age 12.5 days, interquartile range, 6–27 days) of whom 383 (66.5%) were born prematurely. In total, 16 bacterial pathogens (3.0%) and 21 viruses (5.5%) were detected in CSF. Escherichia coli was detected in 5 cases (1.0%), Enterovirus was detected in 12 cases (3.1%). Leucocytosis in CSF was associated with identification of a pathogen in CSF. Increased CRP was associated with the identification of a bacterial pathogen in CSF. Bacterial or viral pathogens were only identified in a small proportion of infants with a clinically suspected CNS infection. Leucocytosis in CSF was associated with CNS infection in infants. An increased CRP was indicative of bacterial meningitis.

Parechovirus A is a species in the Parechovirus genus within the Picornaviridae family that can cause severe disease in children. Relatively little is known on Parechovirus A epidemiology and pathogenesis. This review aims to explore the Parechovirus A literature and highlight the differences between Parechovirus A genotypes from a pathogenesis standpoint. In particular, the curious case of Parechovirus-A3 and the genotype-specific disease association will be discussed. Finally, a brief outlook on Parechovirus A research is provided.

Background HIV-associated cognitive deficiency in perinatally HIV-infected (PHIV) children has been studied in Western countries in a population of which an increasing proportion has been internationally adopted. Studies often lack an appropriate internationally adopted HIV-uninfected control group, potentially confounding the relationship between HIV and cognitive functioning. This study aims to further elucidate the association between treated HIV infection and cognitive development by addressing the background of international adoption. Methods We cross-sectionally studied the impact of HIV on cognition by comparing PHIV children and HIV- uninfected controls, matched for age-, sex-, ethnicity-, socioeconomic status (SES)- and adoption status. We used a standardized neuropsychological test battery to measure intelligence (IQ), and the cognitive domains of processing speed, working memory, executive function, learning ability and visual-motor function and compared outcomes using lineair regression models, adjusted for IQ. We determined cognitive profiles and cognitive impairment by using multivariate normative comparison (MNC) and explored associations with HIV disease- and treatment-related factors. Results We enrolled fourteen PHIV children (mean age 10.45 years [1.73 SD], 93% adopted from sub-Saharan Africa at a median age of 3.3 years [IQR 2.1–4.2]) and fifteen HIV- uninfected controls. Groups did not clinically nor statistically differ in age, sex, ethnicity, SES, region of birth, adoption status and age at adoption. PHIV scored consistently lower on all cognitive domains and MNC outcomes. Compared to controls, PHIV children had a significant lower IQ (mean 81 [SD 11] versus mean 97 [SD 15], p = 0.005), and a poorer cognitive profile by MNC (Hotelling’s T2 mean -4.36 [SD 5.6] versus mean 0.16 [SD 4.5], p = 0.021), not associated with HIV disease- and treatment-related factors. Two PHIV (14%) and one control (7%) were classified as cognitively impaired (p = 0.598). Conclusions Findings indicate treated HIV-infection to be independently associated with lower IQ and poorer cognitive profiles in PHIV children, irrespective of a background of international adoption.

Parechoviruses (PeVs) are highly prevalent viruses worldwide. Over the last decades, several studies have been published on PeV epidemiology in Europe, Asia and North America, while information on other continents is lacking. The aim of this study was to describe PeV circulation in a cohort of children in Malawi, Africa. A total of 749 stool samples obtained from Malawian children aged 6 to 60 months were tested for the presence of PeV by real-time PCR. We performed typing by phylogenetic and Basic Local Alignment Search Tool (BLAST) analysis. PeV was found in 57% of stool samples. Age was significantly associated with PeV positivity (p = 0.01). Typing by phylogenetic analysis resulted in 15 different types, while BLAST typing resulted in 14 different types and several indeterminate strains. In total, six strains showed inconsistencies in typing between the two methods. One strain, P02-4058, remained untypable by all methods, but appeared to belong to the recently reclassified PeV-A19 genotype. PeV-A1, -A2 and -A3 were the most prevalent types (26.8%, 13.8% and 9.8%, respectively). Both the prevalence and genetic diversity found in our study were remarkably high. Our data provide an important contribution to the scarce data available on PeV epidemiology in Africa. Electronic supplementary material The online version of this article (10.1007/s00705-018-04131-7) contains supplementary material, which is available to authorized users.

Non-polio enteroviruses (NPEV) and parechoviruses (PeV) are widespread pathogens that cause significant morbidity. Surveillance is based on culturing or genotyping of virus strains found in clinical samples. Sero-surveillance, by measuring neutralising antibodies (nAb) through virus neutralisation assays (VNA), could provide additional information as it offers a more comprehensive overview of exposure to circulating types in the general population. In our study we evaluated Intravenous immunoglobulins (IVIG) to generate sero-surveillance data. We performed VNA of nineteen NPEV and PeV with Dutch IVIG batches from two different time points (2010 and 2017) and an IVIG batch from Vietnam (2011). We compared our findings with geno- and sero-surveillance data and evaluated changes over time and between the two countries. Our findings show a good correlation with what is known from geno-surveillance data. The highest nAb titres were found against strains from Enterovirus B, while we did not observe nAb titres against strains belonging to Enterovirus C. In conclusion, we demonstrated that sero-surveillance by means of IVIG can be used to obtain insight into circulation of EV and PeV genotypes. This is of particular interest for public health, to evaluate changes over time and population susceptibility to emerging genotypes.

Noncirrhotic portal hypertension (NCPH) has been reported in HIV-infected adults. Antiretroviral drugs, as well as genetic and thrombophilic predisposition, have been suggested as possible etiologic factors. Clinical data were collected from 6 HIV-infected patients attending the Infectious Diseases Departments at respectively Emma Children's Hospital Academic Medical Centre in Amsterdam, The Thai Red Cross AIDS Research Centre, Bangkok, Imperial College Healthcare NHS Trust, London who were diagnosed with NCPH. All underwent extensive blood analysis, liver ultrasound, liver elastography, esophagogastroduodenoscopy and percutaneous needle liver biopsy for histological evaluation. We describe 6 perinatally HIV-infected adolescents, all female, who developed NCPH after prolonged exposure during childhood to a didanosine-containing antiretroviral regimen. Histology and electron microscopy showed periportal fibrosis and mitochondrial damage as key findings in their liver biopsies. One of these 6 patients required surgical intervention, the remainder have been managed conservatively to date. Thus, symptomatic NCPH may present in adolescence after perinatally acquired HIV-1 infection. In this case series, risk factors included female sex and prolonged exposure to antiretroviral regimens that included the nucleoside-analogue didanosine in childhood

Purpose: Despite combination antiretroviral therapy (cART), perinatal HIV-infection can cause decreased gray and white matter volume, microstructural white matter injury, and retinal structural abnormalities. As neuroretinal tissue is directly connected to the brain, these deficits may have a shared pathogenesis. We aimed to assess associations between neuroretinal thickness and cerebral injury in cART-treated perinatally HIV-infected children and healthy controls.Methods: This cross-sectional observational study included 29 cART-treated perinatally HIV-infected children and 35 matched healthy controls. All participants underwent 3.0 Tesla magnetic resonance imaging (MRI), determining gray and white matter volumes from T1-weighted sequences, and white matter diffusivity using diffusion tensor imaging (DTI). Regional individual and total neuroretinal layer thickness was quantified using spectral-domain optical coherence tomography. We explored associations between retinal and cerebral parameters using multivariable linear regression analysis.Results: In HIV-infected children, lower foveal and pericentral neuroretinal thickness was associated with damaged white matter microstructure, in terms of lower fractional anisotropy and higher mean and radial diffusivity. In healthy controls only, neuroretinal thickness was associated with gray and white matter volume.Conclusions: Decreased neuroretinal thickness is associated with microstructural white matter injury, but not with lower cerebral volume in HIV-infected children. This suggests that HIV-induced retinal thinning and microstructural white matter injury may share a common pathogenesis, and longitudinal assessment of neuroretinal alterations in parallel with MRI and neuroinflammatory markers may further our insight into the pathogenesis of HIV-induced cerebral injury in children.