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Background: Our inability to cure HIV/AIDS stems from the fact that HIV establishes and maintains cellular reservoirs where it shelters from the effects of combination antiretroviral therapy (cART) and host [...]

Background: Premature development of cardiovascular disease in children living with HIV‐1 (CLWH) may be associated with compromised gut barrier function, microbial translocation, immune activation, systemic inflammation and endothelial activation. Biomarkers of these pathways may provide insights into pathogenesis of atherosclerotic disease in CLWH. Methods: This was a cross‐sectional study of CLWH enrolled in the multicentre Early Pediatric Initiation‐Canadian Child Cure Cohort (EPIC4) who were on antiretroviral therapy (ART) with undetectable viral load. Plasma biomarkers of intestinal epithelial injury [intestinal fatty acid binding protein‐1 (IFABP)], systemic inflammation [tumour necrosis factor (TNF) and interleukin‐6 (IL‐6)] and endothelial activation [angiopoietin‐2 (Ang2), soluble vascular endothelial growth factor‐1 (sVEGFR1) and soluble endoglin (sEng)] were quantified by enzyme‐linked immunosorbent assay. Correlation and factor analysis of biomarkers were used to examine associations between innate immune pathways. Results: Among 90 CLWH, 16% of Ang2, 15% of sVEGFR1 and 23% of sEng levels were elevated relative to healthy historic controls. Pairwise rank correlations between the three markers of endothelial activation were statistically significant (ρ = 0.69, ρ = 0.61 and ρ = 0.65, P < 0.001 for all correlations). An endothelial activation index, derived by factor analysis of the three endothelial biomarkers, was correlated with TNF (ρ = 0.47, P < 0.001), IL‐6 (ρ = 0.60, P < 0.001) and intestinal fatty acid binding protein‐1 (ρ = 0.67, P < 0.001). Current or past treatment with ritonavir‐boosted lopinavir (LPV/r) was associated with endothelial activation (odds ratio = 5.0, 95% CI: 1.7–17, P = 0.0020). Conclusions: Endothelial activation is prevalent in CLWH despite viral suppression with combination ART and is associated with intestinal epithelial injury, systemic inflammation and treatment with LPV/r. [ABSTRACT FROM AUTHOR]

Objective: Dolutegravir is recommended worldwide as a first-line antiretroviral therapy (ART) for individuals living with HIV. A recent study reported increased rates of neural tube defects in infants of dolutegravir-treated women. This study examined rates of congenital anomalies in infants born to women living with HIV (WLWH) in Canada.Design: The Canadian Perinatal HIV Surveillance Programme captures surveillance data on pregnant WLWH and their babies and was analysed to examine the incidence of congenital anomalies.Setting: Paediatric HIV clinics.Population: Live-born infants born in Canada to WLWH between 2007 and 2017.Methods: Data on mother-infant pairs, including maternal ART use at conception and during pregnancy, are collected by participating sites.Main Outcome Measures: Congenital anomalies.Results: Of the 2423 WLWH, 85 (3.5%, 95% CI 2.85-4.36%) had non-chromosomal congenital anomalies. There was no evidence of a significant difference in rates of congenital anomalies between women who were on ART in their first trimester (3.9%, CI 1.7-7.6%) or later in the pregnancy (3.9%, 95% CI 2.6-5.6%). Four of the 80 (5.0%, 95% CI 1.4-12.3%) neonates born to WLWH on dolutegravir during the first trimester had congenital anomalies, none were neural tube defects (95% CI 0.00-3.10%).Conclusion: Despite recent evidence raising a safety concern, this analysis found no signal for increased congenital anomalies.Tweetable Abstract: Five percent of the infants of Canadian women living with HIV on dolutegravir at conception had congenital anomalies; none had neural tube defects. [ABSTRACT FROM AUTHOR]

Congenital infectious diseases, transmitted during the course of pregnancy, are estimated to affect nearly one in every hundred births worldwide. These infections may be associated with fetal and infant adverse health outcomes, due to congenital malformations caused by in utero transmission of the infectious organism itself (as is the case with cytomegalovirus, toxoplasmosis, syphilis and Zika virus), or due to chronic infection in the infant (as is the case with human immunodeficiency virus [HIV] and hepatitis B and C). In addition, children who are exposed, yet uninfected, may still suffer from the consequences of exposure to infectious pathogens or to the drugs given to treat pregnant women and prevent in utero transmission (as may be the case with HIV infection). [ABSTRACT FROM AUTHOR]

Objectives: While studies have demonstrated increased morbidity and mortality risk in infancy among children who are HIV-exposed and uninfected (CHEU), longitudinal data are limited. The objective of this study was to assess long-term risk of hospitalization among CHEU compared to children who are HIV-unexposed and uninfected (CHUU), and determine risk factors for hospitalization among CHEU., Design: Longitudinal cohort study (1988-2015) linking the Centre maternel et infantile sur le SIDA cohort (Montreal, Quebec) to administrative data from the Régie de l'assurance maladie du Québec (RAMQ), a universal health insurance provider in the province of Quebec., Methods: CHEU from the CMIS cohort were matched 1:3 by age, sex and postal code with CHUU controls from the RAMQ database. Incidence and causes of hospitalization between CHEU and CHUU were compared using Poisson regression., Results: 726 CHEU were matched to 2178 CHUU. Risk of first hospitalization was significantly higher among CHEU at 1 year (IRR 2.22, [1.86-2.66]), 5 years (IRR 1.62, [1.39-1.90]) and over the lifespan (IRR 1.55, [1.33-1.81]). Among CHEU, significant risk factors for hospitalization on univariate regression analysis included birth year before 2005, prematurity, small for gestational age (SGA), detectable maternal viral load (dVL) at delivery, and maternal hepatitis C co-infection. In the adjusted analysis, small for gestational age and dVL remained significant risk factors., Conclusions: CHEU had a higher rate of hospitalization than CHUU controls across their lifespan. Significant risk factors included SGA and detectable maternal dVL, suggesting a need enhanced pediatric care for these children., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Objective: To investigate the association between African ancestry and neutrophil counts among children living with HIV (CLWH). We also examined whether medications, clinical conditions, hospitalization, or HIV virologic control were associated with low neutrophil counts or African ancestry., Design: We conducted a secondary analysis of the Early Pediatric Initiation Canada Child Cure Cohort (EPIC4) Study, a multicenter prospective cohort study of CLWH across 8 Canadian pediatric HIV care centers., Methods: We classified CLWH according to African ancestry, defined as "African," "Caribbean," or "Black" maternal race. Longitudinal laboratory data (white blood cells, neutrophils, lymphocytes, viral load, and CD4 count) and clinical data (hospitalizations, AIDS-defining conditions, and treatments) were abstracted from medical records., Results: Among 217 CLWH (median age 14, 55% female), 145 were of African ancestry and 72 were of non-African ancestry. African ancestry was associated with lower neutrophil counts, white blood cell counts, and neutrophil-lymphocyte ratios. Neutrophil count <1.5 × 109/L was detected in 60% of CLWH of African ancestry, compared with 31% of CLWH of non-African ancestry (P < 0.0001), representing a 2.0-fold higher relative frequency (95% CI: 1.4-2.9). Neutrophil count was on average 0.74 × 109/L (95% CI: 0.45 to 1.0) lower in CLWH of African ancestry (P < 0.0001). Neither neutrophil count<1.5 × 109/L nor African ancestry was associated with medications, hospitalizations, AIDS-defining conditions, or markers of virologic control (viral load, sustained viral suppression, and lifetime nadir CD4)., Conclusions: In CLWH, African ancestry is associated with lower neutrophil counts, without clinical consequences. A flexible evaluation of neutrophil counts in CLWH of African ancestry may avoid unnecessary interventions., Competing Interests: The authors have no funding or conflicts of interest to disclose., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

A 2.5-month-old girl admitted for failure to thrive and severe pancytopenia was diagnosed with methylmalonic acidemia (MMA) secondary to transcobalamin II deficiency, an inborn error of vitamin B12 metabolism. Opportunistic Cytomegalovirus and Pneumocystis jirovecii pneumonia led to severe acute respiratory distress syndrome (ARDS) and immune reconstitution inflammatory syndrome (IRIS) after treatment initiation with vitamin B12 supplementation. In children with interstitial pneumonia-related ARDS, normal lymphocyte count should not delay invasive procedures required to document opportunistic infections. MMA can be associated with underlying lymphocyte dysfunction and vitamin B12 supplementation can fully reverse the associated immunodeficiency. IRIS may appear in highly treatment-responsive forms of pancytopenia in children and prompt treatment of dysregulated inflammation with high-dose corticosteroids should be initiated.

While children have experienced less severe coronavirus disease (COVID-19) after SARS-CoV-2 infection than adults, the cause of this remains unclear. The objective of this study was to describe the humoral immune response to COVID-19 in child vs. adult household contacts, and to identify predictors of the response over time. In this prospective cohort study, children with a positive SARS-CoV-2 polymerase chain reaction (PCR) test (index case) were recruited along with their adult household contacts. Serum IgG antibodies against SARS-CoV-2 S1/S2 spike proteins were compared between children and adults at 6 and 12 months after infection. A total of 91 participants (37 adults and 54 children) from 36 families were enrolled. Overall, 78 (85.7%) participants were seropositive for anti-S1/S2 IgG antibody at 6 months following infection; this was higher in children than in adults (92.6% vs. 75.7%) ( p = 0.05). Significant predictors of a lack of SARS-CoV-2 seropositivity were age ≥ 25 vs. < 12 years (odds ratio [OR] = 0.23, p = 0.04), presence of comorbidities (vs. none, adjusted OR = 0.23, p = 0.03), and immunosuppression (vs. immunocompetent, adjusted OR = 0.17, p = 0.02).

Background: Chronic/latent viral infections may accelerate immunological aging, particularly among people living with HIV (PLWH). We characterized chronic/latent virus infections across their lifespan and investigated their associations with leukocyte telomere length (LTL)., Methods: Participants enrolled in the CARMA cohort study were randomly selected to include n = 15 for each decade of age between 0 and >60 y, for each sex, and each HIV status. Cytomegalovirus (CMV), Epstein-Barr virus (EBV), human herpesvirus 8 (HHV-8), herpes simplex virus 1 (HSV-1), and HSV-2 infection were determined serologically; HIV, hepatitis C (HCV), and hepatitis B (HBV) were self-reported. LTLs were measured using monochrome multiplex qPCR. Associations between the number of viruses, LTL, and sociodemographic factors were assessed using ordinal logistic and linear regression modeling., Results: The study included 187 PLWH (105 female/82 male) and 190 HIV-negative participants (105 female/84 male), ranging in age from 0.7 to 76.1 years. Living with HIV, being older, and being female were associated with harbouring a greater number of chronic/latent non-HIV viruses. Having more infections was in turn bivariately associated with a shorter LTL. In multivariable analyses, older age, living with HIV, and the female sex remained independently associated with having more infections, while having 3-4 viruses (vs. 0-2) was associated with a shorter LTL., Conclusions: Our results suggest that persistent viral infections are more prevalent in PLWH and females, and that these may contribute to immunological aging. Whether this is associated with comorbidities later in life remains an important question.

Understanding the correlation between immune response and protection from COVID-19 will play a pivotal role in predicting the effectiveness of vaccines in children. We studied SARS-CoV-2 reinfection risk in children 12 months post-mild COVID-19. Children under 5 years old exhibited lower reinfection risk than older infected or vaccinated siblings during 12 months postimmunization., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

Despite success in managing HIV during pregnancy, challenges remain around sustained adherence with antiretroviral therapy (ART), and the suboptimal viral load (VL) suppression during the postpartum period. The objective of this study was to compare VL levels at delivery and during the postpartum period and assess factors associated with lack of viral suppression during the postpartum period in Canada. We combined data from two Canadian prospective cohorts, which included 286 HIV-positive women (352 pregnancies) who delivered between 2012 and 2020. Delivery VL, postpartum VL, and potential factors associated with an undetectable VL (<50 copies/mL), 2-18 weeks after delivery were assessed. To account for the correlation between multiple pregnancies from the same woman, generalized estimating equations were used to assess bivariate associations. Ninety-nine per cent of pregnant women were on ART during pregnancy compared to 93% during the postpartum period. Of those with available VL results ( n  = 214 pregnancies), 94% of women achieved an undetectable VL at delivery compared to 87% during the postpartum period. The postpartum period is a challenging time for ART use and VL control. Qualitative studies are needed to better understand these challenges and guide us in designing adequate interventions.

Objective: Our objective was to determine the frequency at which CD4 counts drop below 200 cells/mm 3 during pregnancy in women living with HIV and to identify factors associated with this., Methods: Data from 2005 to 2020 from two prospective Canadian cohorts of pregnant women living with HIV were extracted. As per national guidelines, women received antiretroviral therapy and CD4 counts were monitored once per trimester and at delivery., Results: Among 775 included cases, 72 (9.3%) had CD4 counts <200 cells/mm 3 at the first pregnancy visit. Of the 703 remaining pregnancies with CD4 counts ≥200 cells/mm 3 at the initial visit, 20 (2.8%) were associated with a drop to <200 cells/mm 3 . In univariate analysis, factors associated with this drop were coinfection with hepatitis B virus or hepatitis C virus (odds ratio [OR] 4.0, 95% confidence interval [CI] 1.52-10.50), lower first visit CD4 counts (OR 0.165, 95% CI 0.08-0.34), and baseline haemoglobin levels <11 g/dL (OR 2.89, 95% CI 1.04-8.00). In multivariable analysis, only CD4 count at first visit remained independently associated with this drop. A cut-off CD4 count ≤450 cells/mm 3 at the first pregnancy visit had a sensitivity of 100% to detect cases of CD4 drop to <200 cells/mm 3 ., Conclusion: A drop of CD4 count to <200 cells/mm 3 is uncommon during pregnancy in women living with HIV. Our results suggest that CD4 monitoring only once in pregnancy would be safe in women whose CD4 count is >450 cells/mm 3 at the first pregnancy visit., (© 2023 The Authors. HIV Medicine published by John Wiley & Sons Ltd on behalf of British HIV Association.)

Background: In North American countries, national guidelines have strongly recommended formula over breastmilk for people with human immunodeficiency virus (HIV) because of concern for HIV transmission. However, data from resource-limited settings suggest the risk is <1% among virally suppressed people. Information regarding breastfeeding experience in high-resource settings is lacking., Methods: A retrospective multisite study was performed for individuals with HIV who breastfed during 2014-2022 in the United States (8 sites) and Canada (3 sites). Descriptive statistics were used for data analysis., Results: Among the 72 cases reported, most had been diagnosed with HIV and were on antiretroviral therapy prior to the index pregnancy and had undetectable viral loads at delivery. Most commonly reported reasons for choosing to breastfeed were health benefits, community expectations, and parent-child bonding. Median duration of breastfeeding was 24 weeks (range, 1 day to 72 weeks). Regimens for infant prophylaxis and protocols for testing of infants and birthing parents varied widely among institutions. No neonatal transmissions occurred among the 94% of infants for whom results were available ≥6 weeks after weaning., Conclusions: This study describes the largest cohort to date of people with HIV who breastfed in North America. Findings demonstrate high variability among institutions in policies, infant prophylaxis, and infant and parental testing practices. The study describes challenges in weighing the potential risks of transmission with personal and community factors. Finally, this study highlights the relatively small numbers of patients with HIV who chose to breastfeed at any 1 location, and the need for further multisite studies to identify best care practices., Competing Interests: Potential conflicts of interest. A. W. reports research funding from NIH and GlaxoSmithKline; consulting fees for advisory board roles with GlaxoSmithKline, Seqirus, and Merck; and payment or honoraria from GlaxoSmithKline (for a podcast) and Merck (meeting presentation). I. B. reports grants or contracts with the Canadian Institutes for Health Research, NIH, Altona, Moderna, and Ferring; consulting fees from Pfizer; and a role with the Society of Obstetricians and Gynecologists of Canada. J. D. reports travel support from the American College of Obstetricians and Gynecologists for the national conference. A. P. reports support from NIAID (grant number K23AI155296) and royalties from UpToDate. K. K. reports meeting honoraria from Takeda Canada. L. A. reports grants or contracts from NIH and the Colorado Department of Public Health and Environment. L. R. reports consulting fees from the University of California, San Francisco Clinicians Consultation Center National Perinatal HIV Hotline. F. K. reports salary support from FRQS and research infrastructure support from the Quebec government (Ministère de la Santé et des Services Sociaux/Service de lutte contre infections transmissibles sexuellement et par le sang). All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Paediatric inflammatory multisystem syndrome (PIMS) is a rare condition temporally associated with SARS-CoV-2 infection. Using national surveillance data, we compare presenting features and outcomes among children hospitalized with PIMS by SARS-CoV-2 linkage, and identify risk factors for intensive care (ICU)., Methods: Cases were reported to the Canadian Paediatric Surveillance Program by a network of >2800 pediatricians between March 2020 and May 2021. Patients with positive versus negative SARS-CoV-2 linkages were compared, with positive linkage defined as any positive molecular or serologic test or close contact with confirmed COVID-19. ICU risk factors were identified with multivariable modified Poisson regression., Results: We identified 406 children hospitalized with PIMS, including 49.8% with positive SARS-CoV-2 linkages, 26.1% with negative linkages, and 24.1% with unknown linkages. The median age was 5.4 years (IQR 2.5-9.8), 60% were male, and 83% had no comorbidities. Compared to cases with negative linkages, children with positive linkages experienced more cardiac involvement (58.8% vs. 37.4%; p < 0.001), gastrointestinal symptoms (88.6% vs. 63.2%; p < 0.001), and shock (60.9% vs. 16.0%; p < 0.001). Children aged ≥6 years and those with positive linkages were more likely to require ICU., Conclusions: Although rare, 30% of PIMS hospitalizations required ICU or respiratory/hemodynamic support, particularly those with positive SARS-CoV-2 linkages., Impact: We describe 406 children hospitalized with paediatric inflammatory multisystem syndrome (PIMS) using nationwide surveillance data, the largest study of PIMS in Canada to date. Our surveillance case definition of PIMS did not require a history of SARS-CoV-2 exposure, and we therefore describe associations of SARS-CoV-2 linkages on clinical features and outcomes of children with PIMS. Children with positive SARS-CoV-2 linkages were older, had more gastrointestinal and cardiac involvement, and hyperinflammatory laboratory picture. Although PIMS is rare, one-third required admission to intensive care, with the greatest risk amongst those aged ≥6 years and those with a SARS-CoV-2 linkage., (© 2023. The Author(s), under exclusive licence to the International Pediatric Research Foundation, Inc.)

The management of adolescents living with HIV represents a particular challenge in the global response to HIV. The challenges specific to this age group include difficulties engaging and maintaining them in care, challenges with transition to adult care, and limited therapeutic options for treatment-experienced patients, all of which have been jeopardized by the COVID-19 pandemic. This paper summarizes some of the challenges in managing adolescents living with HIV, as well as some of the most recent and innovative therapeutic approaches in this population.

Introduction: COVID-19 features changed with the Omicron variant of SARS-CoV-2 in adults. This study aims to describe COVID-19 symptoms in children and adolescents during the Parental, Delta, and Omicron eras., Methods: A single-centre, prospective observational study was conducted on individuals aged 0-20 years attending the University Hospital of Padua (Italy) from April 2020 to December 2022. COVID-19 cases were defined by positive SARS-CoV-2 molecular detection and/or serology; patient/family symptoms and virological positivity were considered to determine the infection onset. Variables were summarized and compared using appropriate tests of descriptive statistics., Results: A total of 509 cases [46% female, median age eight years (IQR: 4-12)] were studied. Three-hundred-eighty-seven (76%), 52 (10%), and 70 (14%) subjects experienced COVID-19 during the Parental, Delta, and Omicron waves, respectively. All subjects developed an asymptomatic/mild COVID-19. Overall, the most frequent symptoms were fever (47%) and rhinitis (21%), which showed a significant increasing incidence from the Parental to Omicron waves ( p  < 0.001). Conversely, diarrhea was most common during the pre-Omicron eras ( p  = 0.03). Stratifying symptoms according to the age group, fever, rhinitis, and skin rashes were observed more frequently among infants/toddlers; conversely, fatigue was more common in children older than five years. The duration of symptoms was similar across different SARS-CoV-2 variants of concern (VOCs); conversely, the number of symptoms varied according to the age group ( p  < 0.0001)., Discussion: This study showed differences in COVID-19 clinical presentation among infants, children, and adolescents and confirmed Omicron infection is more likely to be associated with upper respiratory symptoms. However, further population-based studies are needed to support these findings. In addition, active surveillance will play a crucial role in assessing the disease severity of future VOCs., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2023 Di Chiara, Boracchini, Sturniolo, Barbieri, Costenaro, Cozzani, De Pieri, Liberati, Zin, Padoan, Bonfante, Kakkar, Cantarutti, Donà and Giaquinto.)

Objective: To evaluate the impact of type and timing of antiretroviral therapy (ART) on the risk of preterm delivery (PTD) and small-for-gestational age (SGA) birth among pregnant women and people living with HIV in Canada., Methods: Data for this retrospective cohort study were analyzed from the Canadian Perinatal HIV Surveillance Program from 1990 to 2020. The association between ART and risk of PTD (<37 weeks) and SGA birth (<10th percentile) was explored using mixed effects logistic regression and time-dependent Cox proportional hazards models., Results: Overall, there were 14.9% (654 of 4379) PTD and 18.5% (732 of 3947) SGA cases. A higher risk of PTD was observed with nonnucleoside reverse transcriptase inhibitor-(adjusted hazard ratio [aHR], 1.73; P = 0.019) and boosted protease inhibitor- (aHR, 186; P = 0.007) based regimens compared with integrase strand transfer inhibitor (INSTI)-based regimens. ART initiation prior to conception was associated with a lower risk of SGA birth compared with ART initiation after conception at 1 to 14 weeks (adjusted odds ratio [aOR], 0.69; P = 0.024) and > 14 weeks (aOR, 0.70; P = 0.005)., Conclusion: INSTI-based ART regimens were associated with lower risk of PTD compared with other regimens, and ART initiation before conception was associated with a lower risk of SGA birth. These findings, with overall safety data, should be considered when providing pregnancy counseling to people living with HIV., (© 2023 The Authors. International Journal of Gynecology & Obstetrics published by John Wiley & Sons Ltd on behalf of International Federation of Gynecology and Obstetrics.)

Introduction: The use of antiretroviral therapy drastically reduces vertical transmission of Human Immunodeficiency Virus. However, recent studies demonstrate associations between ART use during pregnancy and placental inflammation, particularly within protease inhibitor (PI)-based regimens. We sought to characterize placental macrophages, namely Hofbauer cells, according to the class of ART used during pregnancy., Methods: Using immunofluorescence and immunohistochemistry, placentas from 79 pregnant people living with HIV (PPLWH) and 29 HIV-uninfected people were analyzed to quantify the numbers and frequencies of leukocytes (CD45 + ) and Hofbauer cells (CD68 + and/or CD163 + ). PPLWH were stratified into three groups based on class of ART: non-nucleoside reverse transcriptase inhibitor (NNRTI)-based, integrase strand-transfer inhibitor (INSTI)-based, and PI-based regimens., Results: Placentas of PPLWH contained significantly more leukocytes and Hofbauer cells than controls. Multivariable analyses revealed that this increase in immune cells was associated with a predominantly CD163 + profile in all ART subgroups compared to the HIV-negative group. This was characterized by an increase in total CD163 + cells in the PI and INSTI subgroups, and a higher frequency of CD163 + cells and CD163 + /CD68 + ratio in the NNRTI and PI subgroups., Discussion: Placentas of PPLWH treated with any ART regimen during their entire pregnancy displayed a selection for CD163 + cells compared to the HIV-negative group, regardless of class of ART, suggesting that class of ART does not intrinsically affect selection of CD163+ and CD68 + Hofbauer cells. Further investigations into the role of Hofbauer cells in ART-associated placental inflammation are warranted to identify the mechanisms behind their potential involvement in maternal-fetal tolerance maintenance., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Targeted screening for congenital CMV infection (cCMV), which entails CMV testing of infants who fail newborn hearing screening (NBHS), has become common practice. However, this strategy misses nearly all infected infants with normal hearing at birth who are nonetheless at high risk of subsequent hearing loss and would benefit from timely cCMV diagnosis. The objective of this study was to identify expanded criteria predictive of cCMV to increase the scope and utility of targeted newborn CMV screening. In this retrospective study, 465 newborns were tested for cCMV at a single tertiary care center with a targeted screening program between 2014 and 2018. Twenty-two infants were diagnosed with cCMV, representing 0.2% of the 12,189 births over this period and 4.7% of the infants tested. The highest prevalence of cCMV infection was among infants tested because of primary maternal CMV infection (8/42, 19%), followed by failed initial NBHS (10/88, 11.4%), maternal HIV infection (3/137, 2.2%), and clinical suspicion alone (5/232, 2.2%). The symptoms with the highest prevalence of infection among all infants tested included an enlarged liver and/or spleen (33.3%) (3/9), followed by petechiae (33.3%), microcephaly (9.4%), direct hyperbilirubinemia (7.7%), thrombocytopenia (6%), and growth impairment (4.3%). In addition to CMV screening of newborns who fail the NBHS, these data suggest that certain clinical signs of cCMV-in particular: thrombocytopenia, growth impairment, and HIV exposure in pregnancy-should be additional criteria for expanded targeted newborn CMV screening, where universal screening is not yet the standard of care.

Background: Direct comparisons of paediatric hospitalizations for acute coronavirus disease 2019 (COVID-19) and multisystem inflammatory syndrome in children (MIS-C) can inform health system planning. We describe the absolute and relative hospital burden of acute paediatric COVID-19 and MIS-C in Canada., Methods: This national prospective study was conducted via the Canadian Paediatric Surveillance Program from March 2020-May 2021. Children younger than 18 years old and hospitalized for acute COVID-19 or MIS-C were included in the analysis. Outcomes included supplemental oxygen (low-flow oxygen or high-flow nasal cannula), ventilation (non-invasive or conventional mechanical), vasopressors, paediatric intensive care unit (PICU) admission, or death. Adjusted risk differences (aRD) and 95% confidence intervals (CI) were calculated to identify factors associated with each diagnosis., Results: Overall, we identified 330 children hospitalized for acute COVID-19 (including five deaths) and 208 hospitalized for MIS-C (including zero deaths); PICU admission was required for 49.5% of MIS-C hospitalizations versus 18.2% of acute COVID-19 hospitalizations (aRD 20.3; 95% CI, 9.9-30.8). Resource use differed by age, with children younger than one year hospitalized more often for acute COVID-19 (aRD 43.4% versus MIS-C; 95% CI, 37.7-49.1) and more children 5-11 years hospitalized for MIS-C (aRD 38.9% vs. acute COVID-19; 95% CI, 31.0-46.9)., Conclusion: While there were more hospitalizations and deaths from acute paediatric COVID-19, MIS-C cases were more severe, requiring more intensive care and vasopressor support. Our findings suggest that both acute COVID-19 and MIS-C should be considered when assessing the overall burden of severe acute respiratory syndrome coronavirus 2 in hospitalized children., Competing Interests: Competing interests CMH is the Director of Children’s Mental Health of Ontario, and the Director of Medical Affairs for the Canadian Paediatric Society and Canadian Paediatric Surveillance Program. MPM has received consulting fees from Sobin and Abbvie and payment for expert testimony from the Canadian Medical Protective Association. RAB has received honoraria and participated in advisory boards with SOBI, Roche, Amgen, and AbbVie. KB served as Past President of the Community Paediatrics Section of the Canadian Paediatric Society and has received royalties from Brush Education. TLB is an employee of the Public Health Agency of Canada (PHAC). KC is Chair of the Acute Care Committee of the Canadian Paediatric Society and is past-president of the Emergency Medicine Section of the Canadian Paediatric Society. EJD is Chair of the Scientific Research Committee and a director of Epilepsy Canada. She is also a member of Partners Against Mortality in Epilepsy and the advisory boards of Cardiol, Pendopharm and Stoke Therapeutics. CF is Chair of the Scientific Steering Committee for the Canadian Paediatric Surveillance Program, former Chair of the Specialty Committee in Paediatrics of the Royal College of Physicians and Surgeons of Canada, former president of the Canadian Paediatric Society, and member of the Executive as Secretary of the Canadian Critical Care Society. She has received reimbursement for travel expenses from Canadian Paediatric Society and the Royal College of Physicians and Surgeons of Canada. She has also received an honorarium for a presentation at a continuing education conference from the Université de Sherbrooke. SF is the President of the Association of Medical Microbiology and Infectious Disease Canada and has received consulting fees from Toronto Metropolitan University. RML has received honoraria for serving as a consultant to Sobi, Novartis, Sanofi, and Eli Lilly, as chair for data monitoring committees for Eli Lilly and Novartis, and from the Canadian Rheumatology Association. JP has received consultant fees from AbbVie, honoraria from AbbVie, AstraZeneca and Seegene, and he received respiratory virus testing materials from Seegene for his institution. He has participated in ad hoc advisory board meetings for AbbVie and Merck and is a voting member of the National Advisory Committee on Immunization. RP is a consultant for Verity Pharmaceuticals. MS is supported via salary awards from the BC Children’s Hospital Foundation and the Michael Smith Foundation for Health Research and has been an investigator on projects funded by GlaxoSmithKline, Merck, Moderna, Pfizer, Sanofi-Pasteur, Seqirus, Symvivo and VBI Vaccines. All funds have been paid to his institute, and he has not received any personal payments. MIS is an employee of the Public Health Agency of Canada. EH has participated in advisory board meetings of CSL-Behring and Takeda, data safety monitoring boards of Rocket Pharmaceutical and Jasper Therapeutics, and has patent applications with Immugenia and Immune Biosolutions. RS has received honoraria and served on an advisory board and as a consultant with Novartis, honoraria from Canadian Rheumatology Association, is a board member for Rheumatology for All, and her institution receives funding from Bristol Myers Squibb for a patient registry for which she is Principal Investigator. RSMY has received grant funding from CFI, CIHR, Genome Canada, PHAC and the COVID-19 Immunity Task Force, and The Arthritis Society; is a member of the Science and Industry Advisory Committee at Genome Canada and Medical Advisory Board at Kawasaki Disease Canada; and a member of a data safety monitoring board for a study on IL-1 inhibitors for Kawasaki Disease. FK has received honoraria for presentations given to the Association des Pédiatres du Québec and receives CMV testing kits from Altona Diagnostics. SKM has received honoraria for lectures from GlaxoSmithKline, was a member of ad hoc advisory boards for Pfizer Canada and Sanofi Pasteur, and is an investigator on an investigator led grant from Pfizer. DSF, OD, TET, MK, and MLT have no conflicts of interest to report.

Background: Limited data is available on raltegravir (RAL) pharmacokinetics during pregnancy and the value of therapeutic drug monitoring (TDM) in pregnancy is unknown. This study aims to describe RAL trough plasma concentrations (C trough ) during pregnancy and review the impact of RAL TDM on outcomes., Methods: Women from the prospective mother-infant HIV cohort of Mother and Children's Infectious Diseases Center who received RAL during their pregnancy between 2011-2020 were included. TDM reports were reviewed and C trough values estimated when possible, using historical RAL half-lives., Results: We included 76 pregnant women of which 47 underwent TDM. We observed a significant association between virological response and C trough ( p -value .034) with an increase of 0.1 mg/L corresponding to a 2.96 reduction in the risk of having a detectable viral load. The results indicated that in pregnant women a RAL C trough threshold of 0.04 mg/L has a higher specificity (75%) as compared to our current C trough target value of 0.02 mg/L (25%) and an acceptable sensitivity (77%). No significant differences were observed between C trough at each trimester. When comparing pregnancies with and without TDM, no statistically significant differences were observed in the virologic response during pregnancy and at delivery, or with the need for triple antiretroviral prophylaxis in newborns., Conclusions: An association between RAL C trough and viral load was observed and achieving a RAL C trough of 0.04 mg/L or greater is a predictor of virologic response in pregnant women. The impact of TDM in pregnancy, however, could not be demonstrated.

Background: Providing comprehensive infant feeding guidance to families affected by HIV is complex and requires a multidisciplinary approach. While exclusive formula feeding remains the preferred recommendation for infants born to women living with HIV (WLWH) in high-income countries, a more nuanced approach that may include the option of breastfeeding under certain circumstances is emerging in many resource-rich countries., Methods: The Canadian Pediatric & Perinatal HIV/AIDS Research Group (CPARG) hosted a Canadian Institute of Health Research-funded meeting in 2016 to develop consensus among multidisciplinary providers around counselling and recommendations for infant feeding. After presentations by adult and paediatric health care providers, basic scientists, and community-based researchers, a subgroup drafted summary evidence-informed recommendations. Along with revisions among CPARG members, a community review was performed by a convenience sample of WLWH who had given birth in the past 5 years from Ontario and Quebec. A legal review was also conducted to ensure understanding of the criminalization potential and concern of HIV transmission and exposure., Results: The Canadian consensus guidelines continue to support formula feeding as the preferred method of infant feeding as it eliminates any residual risk of postnatal vertical transmission. Formula should be made available for all infants born to mothers living with HIV for their first year of life. A comprehensive approach to counselling WLWH is outlined to assist providers to effectively counsel on current evidence to ensure WLWH are fully informed in their decision making. For women meeting criteria to and elect to breastfeed, frequent maternal virologic monitoring and follow-up is required of both mother and infant. Antiretroviral prophylaxis and monitoring are recommended for breastfed infants. The community review highlighted the importance of other supports and counselling needed for implementing effective formula feeding, aside from access to formula. The legal review provided clarifying language around child protection services involvement and the need to provide referral to legal resources or information upon request. Surveillance systems to monitor for cases of breastmilk transmission should be in place to improve gaps in care and develop further knowledge in this area., Conclusion: The Canadian infant feeding consensus guideline is designed to inform and enable better care for WLWH and their babies. Ongoing evaluation of these guidelines as new evidence emerges will be important., (© Association of Medical Microbiology and Infectious Disease Canada (AMMI Canada), 2023.)

Background: While treatment guidelines for HIV in adults have evolved rapidly with the advent of new antiretroviral (ARV) treatment, those for the prevention of vertical HIV transmission in pregnancy have evolved more slowly due to safety and efficacy concerns. Here we describe Canadian prescribing patterns for ARV treatments during pregnancy and compare them to perinatal HIV prescribing guidelines of the United States Department of Health and Human Services (HHS), that are commonly used in Canada and include recommendations for newly commercialized therapies., Methods: The Canadian Perinatal HIV Surveillance Program (CPHSP) captures annual medical data on mothers living with HIV and their infants from 23 sites across Canada. Women from this cohort who received an ARV treatment during pregnancy and who gave birth between 2004 and 2020 were included in the study. ARV treatments were designated as 'preferred/alternative' as per HHS HIV perinatal guidelines, or 'other than preferred/alternative'., Results: We identified 3673 pregnancies from 2720 women. The proportion of women that conceived while on ARV treatment increased from 29% in 2003 to 90% in 2020. Other than preferred/alternative ARV treatments were received in 1112 (30%) of pregnancies and this was significantly associated with having initiated ARV treatment before conception., Conclusion: In Canada during the study period, a high number of women were prescribed an other than preferred/alternative ARV treatment during pregnancy. Further optimization of ARV treatment in women of childbearing age living with HIV is warranted., (© 2022 The Authors. HIV Medicine published by John Wiley & Sons Ltd on behalf of British HIV Association.)

Perinatally infected children living with HIV (CLWH) face lifelong infection and associated inflammatory injury. Chitinase-like 3 protein-1 (CHI3L1) is expressed by activated neutrophils and may be a clinically informative marker of systemic inflammation in CLWH. We conducted a multi-centre, cross-sectional study of CLWH, enrolled in the Early Pediatric Initiation Canadian Child Cure Cohort Study (EPIC 4 ). Plasma levels of CHI3L1, pro-inflammatory cytokines, and markers of microbial translocation were measured by enzyme-linked immunosorbent assays. Longitudinal clinical characteristics (viral load, neutrophil count, CD4+ and CD8+ T-lymphocyte counts, and antiretroviral (ARV) regimen) were abstracted from patient medical records. One-hundred-and-five (105) CLWH (median age 13 years, 62% female) were included in the study. Seventy-seven (81%) had viral suppression on combination antiviral therapy (cART). The median CHI3L1 level was 25 μg/L (IQR 19-39). CHI3L1 was directly correlated with neutrophil count (ρ = 0.22, p = 0.023) and inversely correlated with CD4/CD8 lymphocyte ratio (ρ = -0.35, p = 0.00040). Children with detectable viral load had higher levels of CHI3L1 (40 μg/L (interquartile range, IQR 33-44) versus 24 μg/L (IQR 19-35), p = 0.0047). CHI3L1 levels were also correlated with markers of microbial translocation soluble CD14 (ρ = 0.26, p = 0.010) and lipopolysaccharide-binding protein (ρ = 0.23, p = 0.023). We did not detect differences in CHI3L1 between different cART regimens. High levels of neutrophil activation marker CHI3L1 are associated with poor virologic control, immune dysregulation, and microbial translocation in CLWH on cART.

Background: Children living with chronic comorbid conditions are at increased risk for severe COVID-19, though there is limited evidence regarding the risks associated with specific conditions and which children may benefit from targeted COVID-19 therapies. The objective of this study was to identify factors associated with severe disease among hospitalized children with COVID-19 in Canada., Methods: We conducted a national prospective study on hospitalized children with microbiologically confirmed SARS-CoV-2 infection via the Canadian Paediatric Surveillance Program (CPSP) from April 2020-May 2021. Cases were reported voluntarily by a network of >2800 paediatricians. Hospitalizations were classified as COVID-19-related, incidental infection, or infection control/social admissions. Severe disease (among COVID-19-related hospitalizations only) was defined as disease requiring intensive care, ventilatory or hemodynamic support, select organ system complications, or death. Risk factors for severe disease were identified using multivariable Poisson regression, adjusting for age, sex, concomitant infections, and timing of hospitalization., Findings: We identified 544 children hospitalized with SARS-CoV-2 infection, including 60·7% with COVID-19-related disease and 39·3% with incidental infection or infection control/social admissions. Among COVID-19-related hospitalizations (n=330), the median age was 1·9 years (IQR 0·1-13·3) and 43·0% had chronic comorbid conditions. Severe disease occurred in 29·7% of COVID-19-related hospitalizations (n=98/330 including 60 admitted to intensive care), most frequently among children aged 2-4 years (48·7%) and 12-17 years (41·3%). Comorbid conditions associated with severe disease included pre-existing technology dependence requirements (adjusted risk ratio [aRR] 2·01, 95% confidence interval [CI] 1·37-2·95), body mass index Z-scores ≥3 (aRR 1·90, 95% CI 1·10-3·28), neurologic conditions (e.g. epilepsy and select chromosomal/genetic conditions) (aRR 1·84, 95% CI 1·32-2·57), and pulmonary conditions (e.g. bronchopulmonary dysplasia and uncontrolled asthma) (aRR 1·63, 95% CI 1·12-2·39)., Interpretation: While severe outcomes were detected at all ages and among patients with and without comorbidities, neurologic and pulmonary conditions as well as technology dependence were associated with increased risk of severe COVID-19. These findings may help guide vaccination programs and prioritize targeted COVID-19 therapies for children., Funding: Financial support for the CPSP was received from the Public Health Agency of Canada., Competing Interests: Kevin Chan is Chair of the Acute Care Committee of the Canadian Paediatric Society, and served on the billing/finance committee of the Pediatric Section of the Ontario Medical Association. Catherine Farrell is Chair of the Scientific Steering Committee for the Canadian Paediatric Surveillance Program and a member of the Board of Directors of the Canadian Critical Care Society. She has received funding from Health Canada and the Canadian Institutes of Health Research, as well as an honorarium for a presentation at a continuing education conference from the Université de Sherbrooke. Sarah Forgie is the President of the Association of Medical Microbiology and Infectious Disease Canada, and received an honorarium for participation in the Senior Medical Advisory Committee at Ryerson Medical School. Fatima Kakkar has received salary support for a protected time from the FRQS Chercheur Boursieurs Program, and received honoraria for presentations given to the Association des Pédiatres du Québec. She has also served on the Quebec COVID-19 maternal-child health advisory committee and received grants from FRQS Reseau SIDA Maladies Infectieuses and Foundation of Stars. Charlotte Moore Hepburn is the Director of Children's Mental Health of Ontario, and the Director of medical affairs for the Canadian Paediatric Society and the Canadian Paediatric Surveillance Program. Shaun Morris has received honoraria for lectures from GlaxoSmithKline. He was a member of ad hoc advisory boards for Pfizer Canada and Sanofi Pasteur. Jesse Papenburg has received consultant fees from Merck, honoraria from Astra-Zeneca and Seegene, and is a voting member of the National Advisory Committee on Immunization. He is also site principal investigator for industry trials by MedImmune, Merck, Astra-Zeneca, and Sanofi, and is Medical Lead of the Study Steering Committee for AbbVie. Rupeena Purewal is a consultant for Verity Pharmaceuticals. Christina Ricci and Marina Salvadori are employees of the Public Health Agency of Canada. Manish Sadarangani has been an investigator on projects, unrelated to the current work, funded by GlaxoSmithKline, Merck, Moderna, Pfizer, Sanofi-Pasteur, Seqirus, Symvivo and VBI Vaccines. He is also Chair/Deputy Chair of Data Safety Monitoring Boards for two COVID-19 vaccine trials. Karina Top received a grant from GlaxoSmithKline to her institution outside the submitted work. No other competing interests were declared., (© 2022 The Authors.)

Background: The HIV care cascade is an indicators-framework used to assess achievement of HIV clinical targets including HIV diagnosis, HIV care initiation and retention, initiation of antiretroviral therapy, and attainment of viral suppression for people living with HIV., Methods: The HIV Care Cascade Research Development Team at the CIHR Canadian HIV Trials Network Clinical Care and Management Core hosted a two-day virtual workshop to present HIV care cascade data collected nationally from local and provincial clinical settings and national cohort studies. The article summarizes the workshop presentations including the indicators used and available findings and presents the discussed challenges and recommendations., Results: Identified challenges included (1) inconsistent HIV care cascade indicator definitions, (2) variability between the use of nested UNAIDS's targets and HIV care cascade indicators, (3) variable analytic approaches based on differing data sources, (4) reporting difficulties in some regions due to a lack of integration across data platforms, (5) lack of robust data on the first stage of the care cascade at the sub-national level, and (6) inability to integrate key socio-demographic data to estimate population-specific care cascade shortfalls., Conclusion: There were four recommendations: standardization of HIV care cascade indicators and analyses, additional funding for HIV care cascade data collection, database maintenance and analyses at all levels, qualitative interviews and case studies characterizing the stories behind the care cascade findings, and employing targeted positive-action programs to increase engagement of key populations in each HIV care cascade stage., (Copyright © 2022, Association of Medical Microbiology and Infectious Disease Canada (AMMI Canada).)

Introduction: Coagulopathy and thrombosis associated with SARS-CoV-2 infection are well defined in hospitalized adults and leads to adverse outcomes. Pediatric studies are limited., Methods: An international multicentered (n = 15) retrospective registry collected information on the clinical manifestations of SARS-CoV-2 and multisystem inflammatory syndrome (MIS-C) in hospitalized children from February 1, 2020 through May 31, 2021. This sub-study focused on coagulopathy. Study variables included patient demographics, comorbidities, clinical presentation, hospital course, laboratory parameters, management, and outcomes., Results: Nine hundred eighty-five children were enrolled, of which 915 (93%) had clinical information available; 385 (42%) had symptomatic SARS-CoV-2 infection, 288 had MIS-C (31.4%), and 242 (26.4%) had SARS-CoV-2 identified incidentally. Ten children (1%) experienced thrombosis, 16 (1.7%) experienced hemorrhage, and two (0.2%) experienced both thrombosis and hemorrhage. Significantly prevalent prothrombotic comorbidities included congenital heart disease (p-value .007), respiratory support (p-value .006), central venous catheter (CVC) (p = .04) in children with primary SARS-CoV-2 and in those with MIS-C included respiratory support (p-value .03), obesity (p-value .002), and cytokine storm (p = .012). Comorbidities prevalent in children with hemorrhage included age >10 years (p = .04), CVC (p = .03) in children with primary SARS-CoV-2 infection and in those with MIS-C encompassed thrombocytopenia (p = .001) and cytokine storm (p = .02). Eleven patients died (1.2%), with no deaths attributed to thrombosis or hemorrhage., Conclusion: Thrombosis and hemorrhage are uncommon events in children with SARS-CoV-2; largely experienced by those with pre-existing comorbidities. Understanding the complete spectrum of coagulopathy in children with SARS-CoV-2 infection requires ongoing research., (© 2022 Wiley Periodicals LLC.)

Background: There are limited data on outcomes of SARS-CoV-2 infection among infants (<1 year of age). In the absence of approved vaccines for infants, understanding characteristics associated with hospitalization and severe disease from COVID-19 in this age group will help inform clinical management and public health interventions. The objective of this study was to describe the clinical manifestations, disease severity, and characteristics associated with hospitalization among infants infected with the initial strains of SARS-CoV-2., Methods: This is a national, prospective study of infants with SARS-CoV-2 from April 8th 2020 to May 31st 2021 using the infrastructure of the Canadian Paediatric Surveillance Program. Infants <1 year of age with microbiologically confirmed SARS-CoV-2 infection from both inpatients and outpatients seen in clinics and emergency departments were included. Cases were classified as either: 1) Non-hospitalized patient with SARS-CoV-2 infection; 2) COVID-19-related hospitalization; or 3) non-COVID-19-related hospitalization (e.g., incidentally detected SARS-CoV-2). Case severity was defined as asymptomatic, outpatient care, mild (inpatient care), moderate or severe disease. Multivariable logistic regression was performed to identify characteristics associated with hospitalization., Results: A total of 531 cases were reported, including 332 (62.5%) non-hospitalized and 199 (37.5%) hospitalized infants. Among hospitalized infants, 141 of 199 infants (70.9%) were admitted because of COVID-19-related illness, and 58 (29.1%) were admitted for reasons other than acute COVID-19. Amongst all cases with SARS-CoV-2 infection, the most common presenting symptoms included fever (66.5%), coryza (47.1%), cough (37.3%) and decreased oral intake (25.0%). In our main analysis, infants with a comorbid condition had higher odds of hospitalization compared to infants with no comorbid conditions (aOR = 4.53, 2.06-9.97), and infants <1 month had higher odds of hospitalization then infants aged 1-3 months (aOR = 3.78, 1.97-7.26). In total, 20 infants (3.8%) met criteria for severe disease., Conclusions: We describe one of the largest cohorts of infants with SARS-CoV-2 infection. Overall, severe COVID-19 in this age group was found to be uncommon. Comorbid conditions and younger age were associated with COVID-19-related hospitalization amongst infants., Competing Interests: JP reports grants to his institution from MedImmune, Merck, Sanofi Pasteur and AbbVie, and speaker fees from AbbVie and AstraZeneca, all outside of the submitted work. MS is supported via salary awards from the BC Children’s Hospital Foundation, the Canadian Child Health Clinician Scientist Program and the Michael Smith Foundation for Health Research. MS has been an investigator on projects funded by GlaxoSmithKline, Merck, Pfizer, Sanofi-Pasteur, Seqirus, Symvivo and VBI Vaccines. All funds have been paid to his institute, and he has not received any personal payments. PPPR has been co-investigator on an investigator-led project funded by Pfizer that is unrelated to this study. RP is a consultant for Verity Pharmaceuticals. SKM is co-principal investigator on an investigator-led grant from Pfizer, has served on an ad-hoc advisory boards for Pfizer and Sanofi Pasteur, and has received speaker fees from GlaxoSmithKline, all unrelated to this study. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Objective: To identify risk factors for severe disease in children hospitalised for SARS-CoV-2 infection., Design: Multicentre retrospective cohort study., Setting: 18 hospitals in Canada, Iran and Costa Rica from 1 February 2020 to 31 May 2021., Patients: Children<18 years of age hospitalised for symptomatic PCR-positive SARS-CoV-2 infection, including PCR-positive multisystem inflammatory syndrome in children (MIS-C)., Main Outcome Measure: Severity on the WHO COVID-19 Clinical Progression Scale was used for ordinal logistic regression analyses., Results: We identified 403 hospitalisations. Median age was 3.78 years (IQR 0.53-10.77). At least one comorbidity was present in 46.4% (187/403) and multiple comorbidities in 18.6% (75/403). Eighty-one children (20.1%) met WHO criteria for PCR-positive MIS-C. Progression to WHO clinical scale score ≥6 occurred in 25.3% (102/403). In multivariable ordinal logistic regression analyses adjusted for age, chest imaging findings, laboratory-confirmed bacterial and/or viral coinfection, and MIS-C diagnosis, presence of a single (adjusted OR (aOR) 1.90, 95% CI 1.13 to 3.20) or multiple chronic comorbidities (aOR 2.12, 95% CI 1.19 to 3.79), obesity (aOR 3.42, 95% CI 1.76 to 6.66) and chromosomal disorders (aOR 4.47, 95% CI 1.25 to 16.01) were independent risk factors for severity. Age was not an independent risk factor, but different age-specific comorbidities were associated with more severe disease in age-stratified adjusted analyses: cardiac (aOR 2.90, 95% CI 1.11 to 7.56) and non-asthma pulmonary disorders (aOR 3.07, 95% CI 1.26 to 7.49) in children<12 years old and obesity (aOR 3.69, 1.45-9.40) in adolescents≥12 years old. Among infants<1 year old, neurological (aOR 10.72, 95% CI 1.01 to 113.35) and cardiac disorders (aOR 10.13, 95% CI 1.69 to 60.54) were independent predictors of severe disease., Conclusion: We identified risk factors for disease severity among children hospitalised for PCR-positive SARS-CoV-2 infection. Comorbidities predisposing children to more severe disease may vary by age. These findings can potentially guide vaccination programmes and treatment approaches in children., Competing Interests: Competing interests: None., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objectives: Rapid identification and isolation of SARS-CoV-2 cases are priorities in school and child care settings to prevent further outbreaks. The objective of this study was to compare the clinical presentation of SARS-CoV-2 infections among preschool (<5 years) versus school-aged (≥5 years) children diagnosed with SARS-CoV-2 infection, and, specifically, the probability of presenting with an isolated symptom, such rhinorrhea or sore throat., Methods: Retrospective study of children (≤18 years of age) diagnosed with SARS-CoV-2 in the outpatient COVID-19 clinic or the Emergency Department at the Centre Hospitalier Universitaire Sainte-Justine (Montreal, Quebec, Canada) February through May 2020., Results: Of 3,789 children tested, 105 (3%) were positive for SARS-CoV-2, and 104 included in the analysis (n=49 age <5 years and n=55 age ≥5 years). While fever was the most common presenting symptom across both age groups, in the absence of fever, the presence of a combination of two or more symptoms identified the majority (92%) of cases. Isolated single symptom presentations were uncommon (<5% of cases). Most importantly, not a single child in either age group presented with isolated rhinorrhea or sore throat., Conclusions: While there are differences in the clinical manifestations of COVID-19 in preschool- versus school-aged children, in both age groups, isolated rhinorrhea was not a manifestation of SARS-CoV-2 infection. These results could help further guide testing criteria and exclusion criteria in child care and school settings., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Canadian Paediatric Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Although sociodemographic factors have been linked with SARS-CoV-2 infection and hospitalizations in adults, there are little data on the association between sociodemographic characteristics and SARS-CoV-2-related hospitalization in children. The objective of this study was to determine the association between area-level material deprivation and incidence of hospitalization with SARS-CoV-2 among children., Methods: We conducted a retrospective cohort study of all children (0 to 17 years of age) with a PCR-confirmed SARS-CoV-2 infection March 1, 2020 through May 31, 2021 at a tertiary-care paediatric hospital, in Montreal, Canada. Data were collected through chart review and included age, sex, and postal code, allowing linkage to dissemination area-level material deprivation, measured with the Pampalon Material Deprivation Index (PMDI) quintiles. We examined the association between PMDI quintiles and hospitalization using Poisson regression., Results: During the study period, 964 children had a positive PCR-confirmed SARS-CoV-2 test and 124 were hospitalized. Children living in the most deprived quintile of PMDI represented 40.7% of hospitalizations. Incidence rate ratio of hospitalization for this group compared to the most privileged quintile was 2.42 (95%CI: 1.33; 4.41)., Conclusion: Children living in the most materially deprived areas had more than twice the rate of hospitalizations for COVID-19 than children living in most privileged areas. Special efforts should be deployed to protect children who live in disadvantaged areas, especially pending vaccination of younger children., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Canadian Paediatric Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Syphilis is an infection caused by Treponema pallidum spirochetes. The diagnosis of this sexually transmitted disease may be missed, partly due to the painless nature of genital ulcers in its primary stage. Women in Canada are screened for syphilis in their first trimester of pregnancy, but late pregnancy testing is not done in all provinces to date; therefore, undetected vertical transmission of syphilis may occur. This case emphasizes the importance of recognizing congenital syphilis in infants and young children with unexplained growth problems and biochemical and hematological abnormalities. Congenital syphilis remains a rare diagnosis, but in the context of increased syphilis rates in Canada during recent years, clinicians should consider this diagnosis in infants presenting with compatible clinical manifestations., Competing Interests: Competing interests: None.

Purpose of Review: There have been recent advances in the field of congenital CMV infection (cCMV) related to antiviral treatment of pregnant women and infants, the implementation of newborn CMV screening programs, and the frequency and diagnosis of complications among infected children. In addition, postnatal CMV infection (pCMV) is increasingly recognized as a potential cause of long-term sequelae in addition to acute complications among preterm infants, raising important questions related to treatment, and prevention., Recent Findings: High-dose valacyclovir appears to be safe and effective for the prevention of cCMV among women with first-trimester primary CMV infection. New studies reveal high rates of vestibular dysfunction and neuropsychiatric manifestations among children with cCMV. Some studies report associations between pCMV and long-term consequences, including neurodevelopmental delay and bronchopulmonary dysplasia, among very low birth weight infants, in addition to high risk of sepsis and death acutely, which has motivated efforts to eliminate the virus from breast milk by different methods., Summary: More long-term complications of cCMV are increasingly recognized among children previously thought to be asymptomatic. Although a preventive CMV vaccine may be achievable, strategies to reduce the burden of cCMV disease include maternal education about risk-reduction behaviors, antiviral treatment of pregnant women with primary infection, and newborn screening to allow timely, appropriate care. Similarly, although it remains unclear if pCMV causes long-term problems, there is growing interest in identifying and preventing disease from CMV infections among preterm infants., Competing Interests: Conflict of interest SG reports research funding and consulting fees from Moderna, Merck, GSK, VBI vaccines, and Altona Diagnostics. FK reports research funding Altona Diagnostics. ASC does not have existing conflicts of interest., (© The Author(s), under exclusive licence to Springer Nature Switzerland AG 2022, Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.)

Purpose: Childhood tuberculosis disease is difficult to diagnose and manage and is an under-recognised cause of morbidity and mortality. Reported data from Canada do not focus on childhood tuberculosis or capture key epidemiologic, clinical and microbiologic details. The purpose of this study was to assess demographics, presentation and clinical features of childhood tuberculosis in Canada., Methods: We conducted prospective surveillance from 2013 to 2016 of over 2700 paediatricians plus vertical tuberculosis programmes for incident tuberculosis disease in children younger than 15 years in Canada using the Canadian Paediatric Surveillance Program (CPSP)., Results: In total, 200 cases are included in this study. Tuberculosis was intrathoracic in 183 patients of whom 86% had exclusively intrathoracic involvement. Central nervous system tuberculosis occurred in 16 cases (8%). Fifty-one per cent of cases were hospitalised and 11 (5.5%) admitted to an intensive care unit. Adverse drug reactions were reported in 9% of cases. The source case, most often a first-degree relative, was known in 73% of cases. Fifty-eight per cent of reported cases were Canadian-born Indigenous children. Estimated study rates of reported cases (per 100 000 children per year) were 1.2 overall, 8.6 for all Indigenous children and 54.3 for Inuit children., Conclusion: Childhood tuberculosis may cause significant morbidity and resource utilisation. Key geographies and groups have very high incidence rates. Elimination of childhood tuberculosis in Canada will require well-resourced community-based efforts that focus on these highest risk groups., Competing Interests: Competing interests: JML holds the CIHR-GSK Chair in Pediatric Vaccinology at Dalhousie University., (© Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

Competing Interests: Intérêts concurrents : Krista Baerg déclare avoir reçu du financement du Chronic Pain Network. Elle a été présidente sortante de la section de la pédiatrie communautaire de la Société canadienne de pédiatrie et membre du conseil d’administration de la Saskatchewan Pain Society; elle a reçu des droits d’auteur de Brush Education. Kevin Chan est président du Comité des soins aigus de la Société canadienne de pédiatrie. Elizabeth Donner est présidente du comité de recherche scientifique et administratrice d’Épilepsie Canada. Elle est aussi membre de Partners Against Mortality in Epilepsy et de comités consultatifs pour Cardiol, Pendopharm et Stoke Therapeutics. Catherine Farrell est présidente du comité directeur scientifique du Programme canadien de surveillance pédiatrique, ancienne présidente du Comité de spécialité en pédiatrie du Collège royal des médecins et chirurgiens du Canada, ancienne présidente de la Société canadienne de pédiatrie, présidente du Comité d’éthique et membre du conseil d’administration de la Société canadienne de soins intensifs. Elle a reçu un remboursement de frais de déplacement de la Société canadienne de pédiatrie et du Collège royal des médecins et chirurgiens du Canada. Elle a aussi reçu des honoraires pour une présentation lors d’un symposium de formation continue à l’Université de Sherbrooke. Sarah Forgie est présidente de l’Association pour la microbiologie médicale et l’infectiologie Canada. Fatima Kakkar a reçu des honoraires pour des présentations données à l’Association des pédiatres du Québec. Thuy Mai Luu est directrice du Réseau canadien de suivi néonatal. Charlotte Moore Hepburn est directrice de Santé mentale pour enfants Ontario et directrice des affaires médicales pour la Société canadienne de pédiatrie et le Programme canadien de surveillance pédiatrique. Shaun Morris a reçu des honoraires de GlaxoSmithKline pour des conférences. Il a été membre d’un comité consultatif ad hoc pour Pfizer Canada. Jesse Papenburg a reçu des honoraires de consultation d’AbbVie et des honoraires d’AbbVie et de Seegene, et il a bénéficié de fournitures pour des tests de dépistage de virus respiratoires remis par Seegene pour son établissement. Il a participé à des réunions de comités consultatifs ad hoc pour AbbVie et il est membre ayant droit de vote du Comité consultatif national de l’immunisation. Rupeena Purewal est consultante pour Verity Pharmaceuticals. Manish Sadarangani est membre du comité consultatif d’Astra Zeneca. Marina Salvadori est une employée de l’Agence de la santé publique du Canada. Aucun autre intérêt concurrent déclaré.

Background: Risk factors for severe outcomes of SARS-CoV-2 infection are not well established in children. We sought to describe pediatric hospital admissions associated with SARS-CoV-2 infection in Canada and identify risk factors for more severe disease., Methods: We conducted a national prospective study using the infrastructure of the Canadian Paediatric Surveillance Program (CPSP). Cases involving children who were admitted to hospital with microbiologically confirmed SARS-CoV-2 infection were reported from Apr. 8 to Dec. 31 2020, through weekly online questionnaires distributed to the CPSP network of more than 2800 pediatricians. We categorized hospital admissions as related to COVID-19, incidental, or for social or infection control reasons and determined risk factors for disease severity in hospital., Results: Among 264 hospital admissions involving children with SARS-CoV-2 infection during the 9-month study period, 150 (56.8%) admissions were related to COVID-19 and 100 (37.9%) were incidental infections (admissions for other reasons and found to be positive for SARS-CoV-2 on screening). Infants (37.3%) and adolescents (29.6%) represented most cases. Among hospital admissions related to COVID-19, 52 (34.7%) had critical disease, 42 (28.0%) of whom required any form of respiratory or hemodynamic support, and 59 (39.3%) had at least 1 underlying comorbidity. Children with obesity, chronic neurologic conditions or chronic lung disease other than asthma were more likely to have severe or critical COVID-19., Interpretation: Among children who were admitted to hospital with SARS-CoV-2 infection in Canada during the early COVID-19 pandemic period, incidental SARS-CoV-2 infection was common. In children admitted with acute COVID-19, obesity and neurologic and respiratory comorbidities were associated with more severe disease., Competing Interests: Competing interests: Krista Baerg reports funding from the Chronic Pain Network. She also served as Past President of the Community Paediatrics Section of the Canadian Paediatric Society and on the Board of Directors for Saskatchewan Pain Society, and has received royalties from Brush Education. Kevin Chan is Chair of the Acute Care Committee of the Canadian Paediatric Society. Elizabeth Donner is Chair of the Scientific Research Committee and a director of Epilepsy Canada. She is also a member of Partners Against Mortality in Epilepsy and the advisory boards of Cardiol, Pendopharm and Stoke Therapeutics. Catherine Farrell is Chair of the Scientific Steering Committee for the Canadian Paediatric Surveillance Program, former Chair of the Specialty Committee in Pediatrics of the Royal College of Physicians and Surgeons of Canada, former President of the Canadian Paediatric Society, and Chair of the Ethics Committee and a member of the Board of Directors of the Canadian Critical Care Society. She has received reimbursement for travel expenses from Canadian Paediatric Society and the Royal College of Physicians and Surgeons of Canada. She has also received an honorarium for a presentation at a continuing education conference from the Université de Sherbrooke. Sarah Forgie is the President of the Association of Medical Microbiology and Infectious Disease Canada. Fatima Kakkar has received honoraria for presentations given to the Association des Pédiatres du Québec. Thuy Mai Luu is the Director of the Canadian Neonatal Follow-Up Network. Charlotte Moore Hepburn is the Director of Children’s Mental Health of Ontario, and the Director of medical affairs for the Canadian Paediatric Society and the Canadian Paediatric Surveillance Program. Shaun Morris has received honouraria for lectures from GlaxoSmithKline. He was a member of an ad hoc advisory board for Pfizer Canada. Jesse Papenburg has received consultant fees from AbbVie, honouraria from AbbVie and Seegene, and he received respiratory virus testing materials from Seegene for his institution. He has participated in ad hoc advisory board meetings for AbbVie and is a voting member of the National Advisory Committee on Immunization. Rupeena Purewal is a consultant for Verity Pharmaceuticals. Manish Sadarangani is a member of the advisory board of Astra Zeneca. Marina Salvadori is an employee of the Public Health Agency of Canada. No other competing interests were declared., (© 2021 CMA Joule Inc. or its licensors.)