Invasive fungal disease in children with solid tumors: An Australian multicenter 10-year review.

Invasive fungal disease (IFD) occurs less frequently during treatment for solid compared to hematological malignancies in children, and risk groups are poorly defined. Retrospective national multicenter cohort data (2004-2013) were analyzed to document prevalence, clinical characteristics, and microbiology of IFD. Amongst 2067 children treated for solid malignancy, IFD prevalence was 1.9% overall and 1.4% for proven/probable IFD. Of all IFD episodes, 42.5% occurred in patients with neuroblastoma (prevalence 7.0%). Candida species comprised 54.8% of implicated pathogens in proven/probable IFD. In children with solid tumors, IFD is rare, and predominantly caused by yeasts.Routine prophylaxis may not be warranted.

Are serious games seriously good at preparing students for clinical practice?: A randomized controlled trial.

PURPOSE: Serious games (SGs) have great potential for pediatric medical education. This study evaluated the efficacy of a SG in improving learner satisfaction, knowledge, and behavior. MATERIALS AND METHODS: This was an investigator-blinded randomized controlled trial (RCT) comparing a SG against two controls: (i) adaptive tutorial (AT), and (ii) low-stimulus control (LSC). SG is a highly immersive role-playing game in a virtual hospital. AT delivers interactive web-based lessons. LSC is paper-based clinical practice guidelines. Metropolitan senior medical students at UNSW were eligible. A total of 154 enrolled and were block randomized to one intervention. Participants had access to one intervention for 8 weeks which taught pediatric acute asthma and seizure assessment and management. Satisfaction was assessed with Likert-scale responses to 5 statements and 2 free-text comments. Knowledge was assessed with 10 multiple-choice questions (MCQs). Clinical behavior was assessed during a 30-point simulated clinical management scenario (CMS). Primary analysis was performed on a modified intention-to-treat basis and compared: (1) SG vs. AT; and (2) SG vs. LSC. RESULTS: A total of 118 participants were included in the primary analysis (modified intention-to-treat model). No significant differences in MCQ results between the SG and control groups. SG group outperformed the LSC group in the CMS, with a moderate effect (score out of 30: 20.8 (3.2) vs. 18.7 (3.2), respectively, d = 0.65 (0.2-1.1), p = 0.005). No statistically significant difference between SG and AT groups in the CMS (score: 20.8 (3.2) vs. 19.8 (3.1), respectively, d = 0.31 (-0.1 to 0.8), p = 0.18). A sensitivity analysis (per-protocol model) was performed with similar outcomes. CONCLUSIONS: This is the first investigator-blinded RCT assessing the efficacy of a highly immersive SG on learner attitudes, knowledge acquisition, and performance in simulated pediatric clinical scenarios. The SG demonstrated improved translation of knowledge to a simulated clinical environment, particularly compared to LSC. SGs show promise in pediatric medical education.

High activation levels maintained in receptor-binding domain-specific memory B cells in people with severe coronavirus disease 2019.

The long-term health consequences of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection are still being understood. The molecular and phenotypic properties of SARS-CoV-2 antigen-specific T cells suggest a dysfunctional profile that persists in convalescence in those who were severely ill. By contrast, the antigen-specific memory B-cell (MBC) population has not yet been analyzed to the same degree, but phenotypic analysis suggests differences following recovery from mild or severe coronavirus disease 2019 (COVID-19). Here, we performed single-cell molecular analysis of the SARS-CoV-2 receptor-binding domain (RBD)-specific MBC population in three patients after severe COVID-19 and four patients after mild/moderate COVID-19. We analyzed the transcriptomic and B-cell receptor repertoire profiles at ~2 months and ~4 months after symptom onset. Transcriptomic analysis revealed a higher level of tumor necrosis factor-alpha (TNF-α) signaling via nuclear factor-kappa B in the severe group, involving CD80, FOS, CD83 and TNFAIP3 genes that was maintained over time. We demonstrated the presence of two distinct activated MBCs subsets based on expression of CD80hi TNFAIP3hi and CD11chi CD95hi at the transcriptome level. Both groups revealed an increase in somatic hypermutation over time, indicating progressive evolution of humoral memory. This study revealed distinct molecular signatures of long-term RBD-specific MBCs in convalescence, indicating that the longevity of these cells may differ depending on acute COVID-19 severity.

Clinical management and outcomes of acute febrile illness in children attending a tertiary hospital in southern Ethiopia.

BACKGROUND: The management of febrile illnesses is challenging in settings where diagnostic laboratory facilities are limited, and there are few published longitudinal data on children presenting with fever in such settings. We have previously conducted the first comprehensive study of infectious aetiologies of febrile children presenting to a tertiary care facility in Ethiopia. We now report on clinicians' prescribing adherence with guidelines and outcomes of management in this cohort. METHODS: We consecutively enrolled febrile children aged 2 months and under 13 years, who were then managed by clinicians based on presentation and available laboratory and radiologic findings on day of enrolment. We prospectively collected outcome data on days 7 and 14, and retrospectively evaluated prescribing adherence with national clinical management guidelines. RESULTS: Of 433 children enrolled, the most common presenting syndromes were pneumonia and acute diarrhoea, diagnosed in 177 (40.9%) and 82 (18.9%), respectively. Antibacterial agents were prescribed to 360 (84.7%) of 425 children, including 36 (34.0%) of 106 children without an initial indication for antibacterials according to guidelines. Antimalarial drugs were prescribed to 47 (11.1%) of 425 children, including 30 (7.3%) of 411 children with negative malaria microscopy. Fever had resolved in 357 (89.7%) of 398 children assessed at day 7, and in-hospital death within 7 days occurred in 9 (5.9%) of 153 admitted patients. Among children with pneumonia, independent predictors of persisting fever or death by 7 days were young age and underweight for age. Antibacterial prescribing in the absence of a guideline-specified indication (overprescribing) was more likely among infants and those without tachypnea, while overprescribing antimalarials was associated with older age, anaemia, absence of cough, and higher fevers. CONCLUSION: Our study underscores the need for improving diagnostic support to properly guide management decisions and enhance adherence by clinicians to treatment guidelines.

Identification, Management, and Outcomes of Combination Antiretroviral Treatment Failure in Adolescents With Perinatal Human Immunodeficiency Virus Infection in Asia.

BACKGROUND: Combination antiretroviral therapy (cART) failure is a major threat to human immunodeficiency virus (HIV) programs, with implications for individual- and population-level outcomes. Adolescents with perinatally acquired HIV infection (PHIVA) should be a focus for treatment failure given their poorer outcomes compared to children and adults. METHODS: Data (2014-2018) from a regional cohort of Asian PHIVA who received at least 6 months of continuous cART were analyzed. Treatment failure was defined according to World Health Organization criteria. Descriptive analyses were used to report treatment failure and subsequent management and evaluate postfailure CD4 count and viral load trends. Kaplan-Meier survival analyses were used to compare the cumulative incidence of death and loss to follow-up (LTFU) by treatment failure status. RESULTS: A total 3196 PHIVA were included in the analysis with a median follow-up period of 3.0 years, of whom 230 (7.2%) had experienced 292 treatment failure events (161 virologic, 128 immunologic, 11 clinical) at a rate of 3.78 per 100 person-years. Of the 292 treatment failure events, 31 (10.6%) had a subsequent cART switch within 6 months, which resulted in better immunologic and virologic outcomes compared to those who did not switch cART. The 5-year cumulative incidence of death and LTFU following treatment failure was 18.5% compared to 10.1% without treatment failure. CONCLUSIONS: Improved implementation of virologic monitoring is required to realize the benefits of virologic determination of cART failure. There is a need to address issues related to accessibility to subsequent cART regimens, poor adherence limiting scope to switch regimens, and the role of antiretroviral resistance testing.

Invasive fungal disease in children with acute myeloid leukaemia: An Australian multicentre 10-year review.

BACKGROUND: Invasive fungal disease (IFD) is a common and important complication in children with acute myeloid leukaemia (AML). We describe the epidemiology of IFD in a large multicentre cohort of children with AML. METHODS: As part of the retrospective multicentre cohort TERIFIC (The Epidemiology and Risk factors for Invasive Fungal Infections in immunocompromised Children) study, proven/probable/possible IFD episodes occurring in children with primary or relapsed/refractory AML from 2003 to 2014 were analysed. Crude IFD prevalence, clinical characteristics, microbiology and treatment were assessed. Kaplan-Meier survival analysis was used to estimate 6-month survival. RESULTS: There were 66 IFD episodes diagnosed in 63 children with AML. The majority (75.8%) of episodes occurred in the context of primary AML therapy. During primary AML therapy, the overall prevalence was 20.7% (95% CI 15.7%-26.5%) for proven/probable/possible IFD and 10.3% (95% CI 6.7%-15.0%) for proven/probable IFD. Of primary AML patients, 8.2% had IFD diagnosed during the first cycle of chemotherapy. Amongst pathogens implicated in proven/probable IFD episodes, 74.4% were moulds, over a third (37.9%) of which were non-Aspergillus spp. Antifungal prophylaxis preceded 89.4% of IFD episodes, most commonly using fluconazole (50% of IFD episodes). All-cause mortality at 6 months from IFD diagnosis was 16.7% with IFD-related mortality of 7.6% (all in cases of proven IFD). CONCLUSIONS: IFD is a common and serious complication during paediatric AML therapy. Mould infections, including non-Aspergillus spp. predominated in this cohort. A systematic approach to the identification of patients at risk, and a targeted prevention strategy for IFD is needed.

Impact of climate change and biodiversity collapse on the global emergence and spread of infectious diseases.

The reality of climate change and biodiversity collapse is irrefutable in the 21st century, with urgent action required not only to conserve threatened species but also to protect human life and wellbeing. This existential threat forces us to recognise that our existence is completely dependent upon well-functioning ecosystems that sustain the diversity of life on our planet, including that required for human health. By synthesising data on the ecology, epidemiology and evolutionary biology of various pathogens, we are gaining a better understanding of factors that underlie disease emergence and spread. However, our knowledge remains rudimentary with limited insight into the complex feedback loops that underlie ecological stability, which are at risk of rapidly unravelling once certain tipping points are breached. In this paper, we consider the impact of climate change and biodiversity collapse on the ever-present risk of infectious disease emergence and spread. We review historical and contemporaneous infectious diseases that have been influenced by human environmental manipulation, including zoonoses and vector- and water-borne diseases, alongside an evaluation of the impact of migration, urbanisation and human density on transmissible diseases. The current lack of urgency in political commitment to address climate change warrants enhanced understanding and action from paediatricians - to ensure that we safeguard the health and wellbeing of children in our care today, as well as those of future generations.

Fetal therapies for cytomegalovirus: What we tell prospective parents.

Congenital CMV is the most common congenital infection in the developed world. Infection results in congenital disease ranging from asymptomatic infection to severe neurodevelopmental impairment, and occasionally fetal or neonatal death. Fetal infection can occur through maternal-fetal transmission during primary maternal infection or maternal reactivation or re-infection. Awareness among maternal health care providers and parents is low. The prevention of maternal CMV infection currently relies on hygiene measures, with no effective CMV vaccine or prophylactic therapies. No licensed treatment options are available to prevent maternal-fetal transmission or fetal disease. Hyperimmunoglobulin and valaciclovir have been investigated for prevention of maternal-fetal transmission or fetal treatment, with some evidence supporting consideration of maternal administration of hyperimmunoglobulin or valaciclovir therapy in certain circumstances. This article outlines the clinical evidence regarding proven preventative behavioral measures and experimental hyperimmunoglobulin and valaciclovir therapies, that is structured around common questions asked by pregnant women about CMV infection. It is aimed to help maternity health care providers counsel prospective parents about congenital CMV disease and the preventative and therapeutic strategies currently available.

Invasive fungal infections in children with acute lymphoblastic leukaemia: Results from four Australian centres, 2003-2013.

BACKGROUND: Invasive fungal infections (IFI) are an important complication of acute lymphoblastic leukaemia (ALL) treatment. Our study describes the prevalence and outcomes of IFI in children with ALL. METHODS: IFI episodes in children with primary or relapsed ALL, identified for The Epidemiology and Risk Factors for Invasive Fungal Infections in Immunocompromised Children study, were analysed. IFI were classified according to European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group criteria with a 'modified-possible' category included. RESULTS: A total of 123 IFI episodes in 119 patients with ALL were included. A proven, probable, possible and modified-possible IFI was diagnosed in 56 (45.5%), 22 (17.9%), 39 (31.7%) and six (4.9%) episodes, respectively. The prevalence was 9.7% (95% confidence interval [CI] 8-11.4%) overall and 23.5% (95% CI 14.5-32.5%) for relapsed/refractory ALL. For non-relapsed ALL, the IFI prevalence was significantly higher for children with high-risk compared to standard-risk ALL (14.5% vs 7.3%, P = .009), and IFI were more common during induction, consolidation and delayed intensification phases. Mould infections occurred more frequently than non-mould infections. Thirteen children (10.9%) died within 6 months of IFI diagnosis with five deaths (4.2%) attributable to an IFI. CONCLUSIONS: IFI is more common in children with high-risk ALL and in relapsed disease. Overall survival was encouraging, with IFI contributing to very few deaths.

Epidemiology of invasive fungal infections in immunocompromised children; an Australian national 10-year review.

BACKGROUND: A thorough understanding of local and contemporary invasive fungal infection (IFI) epidemiology in immunocompromised children is required to provide a rationale for targeted prevention and treatment strategies. METHODS: Retrospective data over 10 years from four tertiary pediatric oncology and hematopoietic stem cell transplant (HSCT) units across Australia were analyzed to report demographic, clinical, and mycological characteristics of IFI episodes, and crude IFI prevalence in select oncology/HSCT groups. Kaplan-Meier survival analyses were used to calculate 180-day overall survival. RESULTS: A total of 337 IFI episodes occurred in 320 children, of which 149 (44.2%), 51 (15.1%), and 110 (32.6%) met a modified European Organization for Research and Treatment of Cancer (mEORTC) criteria for proven, probable, and possible IFI, respectively. There were a further 27 (8.0%) that met a "modified possible IFI" criteria. Median age at IFI diagnosis was 8.4 years. Crude mEORTC IFI prevalence in acute lymphoblastic leukemia, acute myeloid leukemia, solid tumor, and allogeneic HSCT cohorts was 10.6%, 28.2%, 4.4%, and 11.7%, respectively. Non-Aspergillus species represented 48/102 (47.1%) molds identified, and non-albicans Candida represented 66/93 (71.0%) yeasts identified. There were 56 deaths among 297 children who met mEORTC criteria, with 180-day overall survival for proven, probable, and possible IFIs of 79.7%, 76.2%, and 84.4%, respectively. CONCLUSION: Non-Aspergillus molds and non-albicans Candida contributed substantially to pediatric IFI in our study, with high IFI prevalence in leukemia and allogeneic HSCT cohorts. Inclusion of IFIs outside of European Organization for Research and Treatment of Cancer criteria revealed an IFI burden that would go otherwise unrecognized in published reports.

Hearing and neurodevelopmental outcomes for children with asymptomatic congenital cytomegalovirus infection: A systematic review.

INTRODUCTION: Congenital CMV is one of the commonest congenital infections and a recognised cause of sensorineural hearing loss and neurodevelopmental impairment. Ninety percent are clinically inapparent at birth but are reported to be at risk of developing such abnormalities throughout childhood, the extent of which requires further elucidation. METHODS: A systematic literature review was conducted using Medline and Embase databases, manual citation review, and personal libraries for articles reporting primary data on hearing and neurodevelopmental outcomes for children with asymptomatic congenital CMV. PROSPERO registration number CRD42015025407. RESULTS: Thirty-seven of 480 articles identified between 1969 and 2016 met the eligibility criteria. Twenty-nine of these contributed primary data on hearing outcomes and 20 on neurodevelopmental outcomes (12 of the 37 studies contributed data on both). Cumulative incidence of sensorineural hearing loss with follow-up to at least 5 years was 7% to 11%, which is more than healthy controls but less than children with symptomatic congenital CMV (34%-41%). The onset, course, and severity of hearing loss was variable with no reliable virological prognostic marker. In comparison to controls, children with asymptomatic congenital CMV did not perform worse than controls in neurodevelopmental assessments and performed better than children with symptomatic congenital CMV. CONCLUSIONS: Studies show children with asymptomatic congenital CMV are at increased risk of developing hearing loss but perform equally well on neurodevelopmental assessments when compared with healthy controls. There is no reliable virological marker to determine which infants will develop sequelae. Regular follow-up until school entry is supported by the literature.

Human immunodeficiency virus-infected young people in Australia: data from the Australian HIV Observational Database.

BACKGROUND: Individuals aged 13-24 years undergo vast physical, cognitive, social and psychological changes. Australian data regarding clinical outcomes of those diagnosed with HIV in this age are sparse. AIM: We aimed to describe demographic factors, virologic and clinical outcomes of individuals aged 13-24 years diagnosed with human immunodeficiency virus (HIV). METHODS: Patients diagnosed with HIV after 1997 in the Australian HIV Observational Database were divided into young adults, diagnosed at age <25 years (n = 223), and older adults (n = 1957). Demographic and clinical factors were compared between groups. RESULTS: Young adults had a median age at diagnosis of 22 years (inter quartile range (IQR) 20-24) and median age at treatment initiation of 24 years (IQR 22-26). They were more likely to be female than the older cohort (21.1 vs 10.8%; P < 0.001). Men who have sex with men was the most common exposure category in both groups. CD4 count at diagnosis was significantly higher in younger than older adults (median 460 vs 400 cells/mm3 , P = 0.006), whereas HIV viral load at diagnosis was lower (35 400 vs 61 659 copies/mL, P = 0.011). The rate of loss to follow up (LTFU) was higher in young adults (8.0 vs 4.3 per 100PY, P < 0.001). Young adults were more likely to have a treatment interruption compared to older adults (5.3 vs 4.0 per 100PY, P = 0.039). Rates of treatment switch, time to treatment change, and CD4 and viral load responses to treatment were similar between groups. CONCLUSIONS: Young adults were diagnosed with HIV at higher CD4 counts and lower viral loads than their older counterparts. LTFU and treatment interruption were more common highlighting the need for extra efforts directed towards retention in care and education regarding the risks of treatment interruptions.

Clinical, Genomic, and Immunological Characterization of RSV Surge in Sydney, Australia, 2022.

OBJECTIVES: The 2022 seasonal respiratory syncytial virus (RSV) epidemic in Sydney, Australia saw an unprecedented number of RSV detections. We aimed to characterize genomic and immunologic factors associated with the surge in RSV cases. METHODS: Whole genome sequences of RSV were generated from 264 RSV-infected infants and linked to case-matched clinical data from the 2022 southern hemisphere RSV season. We then performed an immunologic analysis of baseline RSV-specific humoral immunity in women of childbearing age before and throughout the coronavirus disease 2019 pandemic. RESULTS: Clinical analysis revealed a high burden of disease across patients of all health backgrounds. More than one-half of RSV-related health care visits by infants resulted in hospitalization, and one-quarter required high-flow respiratory support or a higher level of care. Viral phylogenetic analyses revealed that 2022 Sydney RSV sequences were closely related to viruses that had been circulating globally since 2017, including those detected in recent US outbreaks. Nonsynonymous mutations within the palivizumab and nirsevimab binding sites were detected at low frequencies. There was no difference in baseline RSV-neutralizing antibody titers between 2020 and 2022. CONCLUSIONS: Collectively, these findings suggest that neither the emergence of a novel RSV genotype nor hypothesized immune debt was associated with the surge of RSV cases and hospitalizations in 2022. Continued genomic and immunologic surveillance is required to further understand the factors driving outbreaks of RSV globally, and to inform guidelines for the rollout and ongoing use of recently developed immunotherapeutics and vaccines.

Estimating Prevalence and Infection Intensity of Soil-Transmitted Helminths Using Quantitative Polymerase Chain Reaction and Kato-Katz in School-Age Children in Angola.

Quantitative polymerase chain reaction (qPCR) is gaining recognition in soil-transmitted helminth (STH) diagnostics, especially for Strongyloides stercoralis and differentiating hookworm species. However, sample preservation and DNA extraction may influence qPCR performance. We estimated STH prevalence and infection intensity by using qPCR in schoolchildren from Huambo, Uige, and Zaire, Angola, and compared its performance with that of the Kato-Katz technique (here termed Kato-Katz). Stool samples from 3,063 children (219 schools) were preserved in 96% ethanol and analyzed by qPCR, of which 2,974 children (215 schools) had corresponding Kato-Katz results. Cluster-adjusted prevalence and infection intensity estimates were calculated by qPCR and Kato-Katz, with cycle threshold values converted to eggs per gram for qPCR. Cohen's kappa statistic evaluated agreement between qPCR and Kato-Katz. DNA extraction and qPCR were repeated on 191 (of 278) samples that were initially qPCR negative but Kato-Katz positive, of which 112 (58.6%) became positive. Similar prevalence for Ascaris lumbricoides (37.5% versus 34.6%) and Trichuris trichiura (6.5% versus 6.1%) were found by qPCR and Kato-Katz, respectively, while qPCR detected a higher hookworm prevalence (11.9% versus 2.9%). The prevalence of moderate- or high-intensity infections was higher by Kato-Katz than by qPCR. Agreement between qPCR and Kato-Katz was very good for A. lumbricoides, moderate for T. trichiura, and fair for hookworm. Strongyloides stercoralis prevalence was 4.7% (municipality range, 0-14.3%), and no Ancylostoma ceylanicum was detected by qPCR. Despite suboptimal performance, presumably due to fixative choice, qPCR was fundamental in detecting S. stercoralis and excluding zoonotic A. ceylanicum. Further evaluations on sample fixatives and DNA extraction methods are needed to optimize and standardize the performance of qPCR.

Knowledge, attitudes, practices and acceptability of a school preventive chemotherapy programme for schistosomiasis and soil-transmitted helminths control in Angola.

Schistosomiasis and soil-transmitted helminth (STH) control programs require target population engagement, assessed through knowledge, attitudes and practices (KAP) surveys. We report the results of a KAP survey of Angolan schoolchildren supported by a school preventive chemotherapy (PC) programme, without or with a school water, sanitation and hygiene (WASH) programme (PC+/WASH- and PC+/WASH+, respectively); and schoolchildren without a school PC or WASH program (PC-/WASH-). Schoolchildren from PC+/WASH- (N = 218), PC+/WASH+ (N = 250) and PC-/WASH- (N = 254) schools were interviewed. Descriptive statistics were used to report demographics and survey responses. Chi-square or Fisher's exact test was used to compare PC+/WASH- schoolchildren with (i) PC+/WASH+ and (ii) PC-/WASH- schoolchildren. A lower proportion of PC+/WASH- schoolchildren used latrines and a higher proportion practised open defecation at school compared with PC+/WASH+ schoolchildren. A lower proportion of PC+/WASH- schoolchildren always washed their hands after toileting and before meals at school compared with PC+/WASH+ schoolchildren. However, the PC+/WASH- schoolchildren reported better toileting and handwashing practices at school compared to PC-/WASH- schoolchildren. Over 90% of PC+ schoolchildren agreed with schistosomiasis and STH control and accepted schoolteacher PC delivery. Expanding the integration of both school PC and WASH programs will improve health behaviours relevant to reduce the risk of schistosomiasis and STHs in schoolchildren. This article is part of the theme issue 'Challenges and opportunities in the fight against neglected tropical diseases: a decade from the London Declaration on NTDs'.

Detection of dengue virus infection in children presenting with fever in Hawassa, southern Ethiopia.

Dengue fever is a mosquito-borne viral infection, with rising incidence globally. Eastern Ethiopia has had dengue fever outbreaks in recent years. However, the extent to which the infection contributes to hospital presentation among children with fever in southern Ethiopia is unknown. We examined 407 stored plasma samples collected to investigate the aetiology of fever in children aged at least 2 months and under 13 years presenting to the outpatient of the largest tertiary hospital in southern Ethiopia. We analyzed samples for dengue virus non-structural 1 antigen using enzyme-linked immunosorbent assay. The median (interquartile range) age of the 407 children examined was 20 (10-48) months, and 166 (40.8%) of the children were females. Of 407 samples analyzed, 9 (2.2%) were positive for dengue virus non-structural 1 antigen, of whom 2 were initially treated with antimalarial drugs despite having negative malaria microscopy, and 1 of the 8 patients had a persistent fever at the seventh day of follow-up time. The presence of active dengue virus infection in the study area highlights the need for studies at the community level as well as the integration of dengue diagnostics into fever-management strategies. Further research to characterize circulating strains is warranted.

School-based preventive chemotherapy program for schistosomiasis and soil-transmitted helminth control in Angola: 6-year impact assessment.

BACKGROUND: A school preventive chemotherapy (PC) program for soil-transmitted helminths (STHs) and schistosomiasis has operated in Huambo, Uige and Zaire provinces, Angola, since 2013 and 2014, respectively; complemented by a school water, sanitation and hygiene (WASH) program in a subset of schools from 2016. Conducted in 2021, this is the first impact assessment of the school program for the control of schistosomiasis and STHs. METHODOLOGY/PRINCIPAL FINDINGS: A two-stage cluster design was used to select schools and schoolchildren for parasitological and WASH surveys. The rapid diagnostic tests (RDTs), point of care circulating cathodic antigen (POC-CCA) and Hemastix, were used to estimate Schistosoma mansoni and Schistosoma haematobium prevalence, respectively. Kato Katz was used to detect STHs, and quantify STH and S. mansoni infections. Urine filtration was used to quantify S. haematobium infections. Prevalence, infection intensity, relative prevalence reduction and egg reduction rates were calculated for schistosomiasis and STHs. Cohen's Kappa co-efficient was used to assess agreement between RDTs and microscopy. Chi-square or Fisher's exact test was used to compare WASH indicators in WASH-supported and WASH-unsupported schools. Overall, 17,880 schoolchildren (599 schools) and 6,461 schoolchildren (214 schools) participated in the schistosomiasis and STH surveys, respectively. Prevalence of any schistosomiasis in Huambo was 29.6%, Uige 35.4%, and Zaire 28.2%. Relative reduction in schistosomiasis prevalence from 2014 for Huambo was 18.8% (95% confidence interval (CI) 8.6, 29.0), Uige -92.3% (95%CI -162.2, -58.3), and Zaire -14.0% (95%CI -48.6, 20.6). Prevalence of any STH in Huambo was 16.3%, Uige 65.1%, and Zaire 28.2%. Relative reduction in STH prevalence for Huambo was -28.4% (95%CI -92.1, 35.2), Uige -10.7% (95%CI -30.2, 8.8), and Zaire -20.9% (95%CI -79.5, 37.8). A higher proportion of WASH-supported schools had improved water sources, and toilet and handwashing facilities compared to WASH-unsupported schools. CONCLUSIONS/SIGNIFICANCE: The limited impact this school program has had in controlling schistosomiasis and STHs identifies the need for a comprehensive understanding of individual, community, and environmental factors associated with transmission, and consideration for a community-wide control program.

Severe COVID-19 represents an undiagnosed primary immunodeficiency in a high proportion of infected individuals.

Since the emergence of the COVID-19 pandemic in early 2020, a key challenge has been to define risk factors, other than age and pre-existing comorbidities, that predispose some people to severe disease, while many other SARS-CoV-2-infected individuals experience mild, if any, consequences. One explanation for intra-individual differences in susceptibility to severe COVID-19 may be that a growing percentage of otherwise healthy people have a pre-existing asymptomatic primary immunodeficiency (PID) that is unmasked by SARS-CoV-2 infection. Germline genetic defects have been identified in individuals with life-threatening COVID-19 that compromise local type I interferon (IFN)-mediated innate immune responses to SARS-CoV-2. Remarkably, these variants - which impact responses initiated through TLR3 and TLR7, as well as the response to type I IFN cytokines - may account for between 3% and 5% of severe COVID-19 in people under 70 years of age. Similarly, autoantibodies against type I IFN cytokines (IFN-α, IFN-ω) have been detected in patients' serum prior to infection with SARS-CoV-2 and were found to cause c. 20% of severe COVID-19 in the above 70s and 20% of total COVID-19 deaths. These autoantibodies, which are more common in the elderly, neutralise type I IFNs, thereby impeding innate antiviral immunity and phenocopying an inborn error of immunity. The discovery of PIDs underlying a significant percentage of severe COVID-19 may go some way to explain disease susceptibility, may allow for the application of targeted therapies such as plasma exchange, IFN-α or IFN-ß, and may facilitate better management of social distancing, vaccination and early post-exposure prophylaxis.

Burden and factors associated with schistosomiasis and soil-transmitted helminth infections among school-age children in Huambo, Uige and Zaire provinces, Angola.

BACKGROUND: Schistosomiasis and soil-transmitted helminths (STHs) contribute high disease burdens amongst the neglected tropical diseases (NTDs) and are public health problems in Angola. This study reports the prevalence, intensity and risk factors for schistosomiasis and STH infection in Huambo, Uige and Zaire provinces, Angola, to inform a school-based preventive chemotherapy program. METHODS: A two-stage cluster design was used to select schools and schoolchildren to participate in parasitological and water, sanitation and hygiene (WASH) surveys across Huambo, Uige, and Zaire provinces. Point-of-care circulating cathodic antigen and urinalysis rapid diagnostic tests (RDTs) were used to determine the prevalence of Schistosoma mansoni and S. haematobium, respectively. Kato-Katz was used to identify and quantify STH species and quantify and compare with RDTs for S. mansoni. Urine filtration was used to quantify and compare with RDTs for S. haematobium. Descriptive statistics were used for prevalence and infection intensity of schistosomiasis and STH infection. Performance of RDTs was assessed through specificity and Cohen's Kappa agreement with microscopy. A multivariate regression analysis was used to determine demographic and WASH factors associated with schistosomiasis and STH infection. RESULTS: A total 575 schools and 17,093 schoolchildren participated in the schistosomiasis survey, of which 121 schools and 3649 schoolchildren participated in the STH survey. Overall prevalence of S. mansoni was 21.2% (municipality range 0.9-74.8%) and S. haematobium 13.6% (range 0-31.2%), with an overall prevalence of schistosomiasis of 31.4% (range 5.9-77.3%). Overall prevalence of Ascaris lumbricoides was 25.1% (range 0-89.7%), hookworm 5.2% (range 0-42.6%), and Trichuris trichiura 3.6% (range 0-24.2%), with an overall prevalence of STH infection of 29.5% (range 0.8-89.7%). Ecological zone and ethnicity were factors associated with schistosomiasis and STH infection, with older age and female sex additional risk factors for S. haematobium. CONCLUSIONS: Most municipalities met World Health Organization defined prevalence thresholds for a schistosomiasis preventive chemotherapy program. A STH preventive chemotherapy program is indicated for nearly all municipalities in Uige and select municipalities in Huambo and Zaire. The association between ecological zone and ethnicity with schistosomiasis and STH infection necessitates further evaluation of home and school environmental, sociodemographic and behavioural factors to inform targeted control strategies to complement preventive chemotherapy programs.