Invasive fungal disease and antifungal prophylaxis in children with acute leukaemia: a multicentre retrospective Australian cohort study.

Background: Invasive fungal disease (IFD) is a significant complication for children receiving treatment for leukaemia, contributing to morbidity and mortality. Recent regional paediatric epidemiological IFD data are lacking. Additionally uncertainty remains regarding the optimal prophylactic approach in this context. Methods: In a multi-centre Australian cohort study of children diagnosed with de novo acute leukaemia between 1st January 2017 and 30th June 2020, we characterised antifungal prophylaxis prescribing and IFD prevalence. Impact of antifungal prophylaxis was assessed using Kaplan Meier curves and Cox-proportional hazards regression adjusting for known IFD risk factors. Findings: A total of 434 children were included (47.2% female; median age 5.0 years, median follow-up 240 days). This cohort included 351 children with ALL (214 high-risk [HR-ALL]; 137 standard-risk [SR-ALL]), and 73 with AML. The prevalence of proven/probable IFD was 6.8% for AML, 14.0% for HR-ALL and 4.4% for SR-ALL. A mould was implicated as the causative pathogen in almost two thirds of cases. Antifungal prophylaxis was prescribed in 98.7% of chemotherapy cycles for AML, 56.7% for HR-ALL and 14.9% for SR-ALL. A mould-active agent was used in 77.4% of AML cycles and 21.2% of HR-ALL cycles. Mould-active prophylaxis was associated with a lower risk of IFD overall and increased IFD-free survival in AML. Interpretation: These data demonstrate the persistent high regional burden of IFD in children with HR-ALL, and the potential for mould-active prophylaxis to ameliorate this. Strategies to increase uptake of appropriate prophylaxis are required in this cohort. Funding: This study was supported by a Perth Children's Hospital Foundation grant (PCHF9973).

Challenges and considerations for antifungal prophylaxis in children with acute myeloid leukemia.

INTRODUCTION: Children receiving treatment for acute myeloid leukemia (AML) are at high risk of invasive fungal disease (IFD). Evidence from pediatric studies support the efficacy of antifungal prophylaxis in reducing the burden of IFD in children receiving therapy for AML, yet existing antifungal agents have specific limitations and comparative data to inform the optimal prophylactic approach are lacking. AREAS COVERED: This review summarizes the epidemiology of invasive fungal disease (IFD) and current antifungal prophylaxis recommendations for children with acute myeloid leukemia (AML). Challenges with currently available antifungal agents and considerations related to the changing landscape of AML therapy are reviewed. A keyword search was conducted to identify pediatric studies regarding IFD and antifungal prophylaxis in children with AML up to December 2023. EXPERT OPINION: Children undergoing treatment for AML are recommended to receive antifungal prophylaxis to reduce risk of IFD, with tolerability, pharmacokinetics, feasibility of administration, and drug interactions all factors that require consideration in this context. With increased use of novel targeted agents for AML therapy, together with the development of new antifungal agents, data from well-designed clinical studies to optimize prophylactic approaches will be essential to limit the burden of IFD in this vulnerable cohort.

Herpes simplex virus in infancy: Evaluation of national surveillance case capture.

AIM: As herpes simplex virus (HSV) in infancy is not a mandatory notifiable condition in Australia, completeness of ascertainment by the Australian Paediatric Surveillance Unit (APSU) has been difficult to evaluate to date. We evaluated case capture in Queensland (QLD) and Western Australia (WA) using statewide laboratory and clinical data and complementary surveillance data collected via the APSU. METHODS: HSV polymerase chain reaction positive results in infants (0-3 months) from 2007 to 2017 were obtained from statewide public pathology providers in QLD and WA. Clinical data were extracted from patient records and compared to APSU reported cases. RESULTS: A total of 94 cases of HSV disease in infancy (70 QLD; 24 WA) were identified from laboratory data sets, compared to 36 cases (26 QLD; 10 WA) reported to the APSU. In total there was 102 unique cases identified; 28 cases were common to both data sets (seven skin eye mouth (SEM) disease, 13 central nervous system (CNS) disease and eight disseminated disease). Active surveillance captured 35% (36/102) of cases overall including 74% (14/19) of CNS, 71% (10/14) of disseminated and 17% (12/69) of SEM disease cases, respectively. Surveillance reported cases had a higher case-fatality rate compared to those not reported (14% vs. 3%, P = 0.038). Neurological sequelae at discharge were comparable between the groups. CONCLUSION: Active surveillance captures one third of hospitalised HSV cases in QLD and WA, including the majority with severe disease. However, morbidity and mortality remain high. Future studies on HSV will rely on observational studies. Enhanced case ascertainment through combined laboratory and surveillance data is essential for better understanding and improving outcomes.

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.

Characterization of invasive Group B Streptococcus isolates from Western Australian infants, 2004-2020.

Background. Invasive Group B Streptococcus (GBS; Streptococcus agalactiae) remains a leading cause of infant morbidity and mortality. Intrapartum antibiotic prophylaxis (IAP) has been implemented in many countries with a reduction in early-onset disease, but an effective vaccine may further reduce the disease burden. Candidate vaccines targeting capsular polysaccharides and surface proteins are now in clinical trials.Methods. Using whole-genome sequencing and phenotypic antimicrobial susceptibility testing, we characterized sterile-site GBS isolates recovered from Western Australian infants between 2004 and 2020. Characteristics were compared between three time periods: 2004-2008, 2009-2015 and 2016-2020.Results. A total of 135 isolates were identified. The proportion of serotype III (22.7 % in Period 1 to 47.9 % in Period 3, P=0.04) and clonal complex 17 (13.6-39.6 %, P=0.01) isolates increased over time. Overall coverage of vaccines currently being trialled was >95 %. No isolates were penicillin resistant (MIC>0.25 mg l-1), but 21.5 % of isolates had reduced penicillin susceptibility (MIC>0.12 mg l-1) and penicillin MIC increased significantly over time (P=0.04). Clindamycin resistance increased over time to 45.8 % in the latest period.Conclusions. Based on comprehensive characterization of invasive infant GBS in Western Australia, we found that coverage for leading capsular polysaccharide and surface protein vaccine candidates was high. The demonstrated changes in serotype and molecular type highlight the need for ongoing surveillance, particularly with regard to future GBS vaccination programmes. The reduced susceptibility to IAP agents over time should inform changes to antibiotic guidelines.

International Pediatric COVID-19 Severity Over the Course of the Pandemic.

Importance: Multiple SARS-CoV-2 variants have emerged over the COVID-19 pandemic. The implications for COVID-19 severity in children worldwide are unclear. Objective: To determine whether the dominant circulating SARS-CoV-2 variants of concern (VOCs) were associated with differences in COVID-19 severity among hospitalized children. Design, Setting, and Participants: Clinical data from hospitalized children and adolescents (younger than 18 years) who were SARS-CoV-2 positive were obtained from 9 countries (Australia, Brazil, Italy, Portugal, South Africa, Switzerland, Thailand, UK, and the US) during 3 different time frames. Time frames 1 (T1), 2 (T2), and 3 (T3) were defined to represent periods of dominance by the ancestral virus, pre-Omicron VOCs, and Omicron, respectively. Age groups for analysis were younger than 6 months, 6 months to younger than 5 years, and 5 to younger than 18 years. Children with an incidental positive test result for SARS-CoV-2 were excluded. Exposures: SARS-CoV-2 hospitalization during the stipulated time frame. Main Outcomes and Measures: The severity of disease was assessed by admission to intensive care unit (ICU), the need for ventilatory support, or oxygen therapy. Results: Among 31 785 hospitalized children and adolescents, the median age was 4 (IQR 1-12) years and 16 639 were male (52.3%). In children younger than 5 years, across successive SARS-CoV-2 waves, there was a reduction in ICU admission (T3 vs T1: risk ratio [RR], 0.56; 95% CI, 0.42-0.75 [younger than 6 months]; RR, 0.61, 95% CI; 0.47-0.79 [6 months to younger than 5 years]), but not ventilatory support or oxygen therapy. In contrast, ICU admission (T3 vs T1: RR, 0.39, 95% CI, 0.32-0.48), ventilatory support (T3 vs T1: RR, 0.37; 95% CI, 0.27-0.51), and oxygen therapy (T3 vs T1: RR, 0.47; 95% CI, 0.32-0.70) decreased across SARS-CoV-2 waves in children 5 years to younger than 18 years old. The results were consistent when data were restricted to unvaccinated children. Conclusions and Relevance: This study provides valuable insights into the impact of SARS-CoV-2 VOCs on the severity of COVID-19 in hospitalized children across different age groups and countries, suggesting that while ICU admissions decreased across the pandemic in all age groups, ventilatory and oxygen support generally did not decrease over time in children aged younger than 5 years. These findings highlight the importance of considering different pediatric age groups when assessing disease severity in COVID-19.

A surge in human metapneumovirus paediatric respiratory admissions in Western Australia following the reduction of SARS-CoV-2 non-pharmaceutical interventions.

AIM: Western Australian laboratory data demonstrated a decrease in human metapneumovirus (hMPV) detections through 2020 associated with SARS-CoV-2-related non-pharmaceutical interventions (NPIs), followed by a subsequent surge in metropolitan region in mid-2021. We aimed to assess the impact of the surge in hMPV on paediatric hospital admissions and the contribution of changes in testing. METHODS: All respiratory-coded admissions of children aged <16 years at a tertiary paediatric centre between 2017 and 2021 were matched with respiratory virus testing data. Patients were grouped by age at presentation and by ICD-10 AM codes into bronchiolitis, other acute lower respiratory infection (OALRI), wheeze and upper respiratory tract infection (URTI). For analysis, 2017-2019 was utilised as a baseline period. RESULTS: hMPV-positive admissions in 2021 were more than 2.8 times baseline. The largest increase in incidence was observed in the 1-4 years group (incidence rate ratio (IRR) 3.8; 95% confidence interval (CI): 2.5-5.9) and in OALRI clinical phenotype (IRR 2.8; 95% CI: 1.8-4.2). The proportion of respiratory-coded admissions tested for hMPV in 2021 doubled (32-66.2%, P < 0.001), with the greatest increase in wheeze (12-75% in 2021, P < 0.001). hMPV test percentage positivity in 2021 was higher than in the baseline period (7.6% vs. 10.1% in 2021, P = 0.004). CONCLUSION: The absence and subsequent surge underline the susceptibility of hMPV to NPIs. Increased hMPV-positive admissions in 2021 can be partially attributable to testing, but test-positivity remained high, consistent with a genuine increase. Continued comprehensive testing will help ascertain true burden of hMPV respiratory diseases.

The Challenge of Diagnosing Invasive Pulmonary Aspergillosis in Children: A Review of Existing and Emerging Tools.

Invasive pulmonary aspergillosis remains a major cause of morbidity and mortality for immunocompromised children, particularly for patients with acute leukaemia and those undergoing haematopoietic stem cell transplantation. Timely diagnosis, using a combination of computed tomography (CT) imaging and microbiological testing, is key to improve prognosis, yet there are inherent challenges in this process. For CT imaging, changes in children are generally less specific than those reported in adults and recent data are limited. Respiratory sampling by either bronchoalveolar lavage or lung biopsy is recommended but is not always feasible in children, and serum biomarkers, including galactomannan, have important limitations. In this review we summarise the current paediatric data on available diagnostic tests for IPA and highlight key emerging diagnostic modalities with potential for future use.

The Impact of a Multifaceted Tertiary Pediatric Hospital's Antimicrobial Stewardship Service.

BACKGROUND: Antimicrobials are the most commonly prescribed drug class in children. Overuse through inappropriate prescribing is a key driver of antimicrobial resistance and is recognized as one of the top 10 threats to global health by the World Health Organization. METHODS: A prospective observational cohort study was performed following implementation of a multifaceted Antimicrobial Stewardship (AMS) program (January 2014 to December 2020). Data were collected on AMS and "handshake" ward rounds from patient information sources and directly from clinicians responsible for patient care. Primary outcomes include appropriateness of therapy (drug, dose, antimicrobial spectrum, duration and route), compliance with prescribing guidelines, antimicrobial expenditure, use of high-priority antimicrobials and duration of hospitalization. We compared outcomes across 3 time periods; January 2014-December 2015, January 2016-December 2017 and January 2018-December 2020. RESULTS: The appropriateness of individual antimicrobial orders improved across the study periods from 6111/7040 (79.4%) in the first 2 years following implementation of the AMS program to 17,819/19,229 (92.3%) in the latter period. Guideline compliance increased from 5426/7700 (70.5%) to 17,822/19,316 (92.3%). A reduction in overall antimicrobial expenditure (34% reduction, equivalent to $12.52 per bed day) and a decrease in antifungal expenditure (37% reduction, equivalent to $5.56 per bed day) was observed across the time periods. CONCLUSIONS: This study quantifies a comprehensive pediatric AMS program's sustained impact on reducing inappropriate antimicrobial use and expenditure and improving compliance with guidelines. The effectiveness of these interventions has been demonstrated and should be considered by institutions seeking to improve rational antimicrobial use in children.

Assessing the utility of routine viral surveillance performed in children undergoing autologous stem cell transplantation at a single centre.

We assessed the utility of routine viral surveillance for cytomegalovirus, Epstein-Barr virus and human adenovirus in children <16 years, undergoing autologous stem cell transplantation (ASCT) at a single centre over a 10-year period. A total of 85 ASCT were performed in 65 patients. Routine viral surveillance resulted in a high number of tests performed (median 20 tests per ASCT), without any clinically significant viral detections. These data support the limited clinical utility of routine viral surveillance in children undergoing ASCT. Adopting a clinically driven approach for viral testing is likely to be both cost-effective and safe.

Blinatumomab as bridging therapy in paediatric B-cell acute lymphoblastic leukaemia complicated by invasive fungal disease.

Invasive fungal disease (IFD) remains a challenging complication of treatment for paediatric acute leukaemia. Consensus fungal treatment guidelines recommend withholding chemotherapy to facilitate immune recovery in this setting, yet prolonged delays in leukaemia therapy increase risk of relapse. Blinatumomab, a bispecific T-cell engager targeting cells expressing CD19, has shown promise for treatment of relapsed/refractory B-cell acute lymphoblastic leukaemia (B-ALL) and is associated with reduced toxicity compared to conventional chemotherapy. With close monitoring of minimal residual disease, we demonstrate that children with B-ALL can receive repeated cycles of bridging blinatumomab whilst conventional chemotherapy is withheld during treatment and recovery from IFD.

Antifungal use in children with acute leukaemia: state of current evidence and directions for future research.

Invasive fungal disease (IFD) remains a common and serious complication in children treated for leukaemia. Antifungal prescription in children with leukaemia presents unique challenges, particularly due to variation in IFD risk between and within leukaemia treatment protocols, drug toxicities and interactions between antifungals and chemotherapeutic agents. With recent advances in the understanding of IFD epidemiology and large clinical trials in adults assessing antifungals for IFD treatment and prophylaxis, together with paediatric clinical and pharmacokinetic studies, there is a growing body of data to inform optimal antifungal use in children. A panel of infectious diseases and haematology-oncology clinicians with expertise in IFD management compiled a list of 10 key clinical questions following development of the 2021 Australia and New Zealand Mycology Antifungal Consensus Guidelines. A focused literature review was conducted to explore available evidence and identify gaps in knowledge to direct future research. With the changing epidemiology of IFD globally, the ongoing evolution of paediatric leukaemia treatment and the increasing availability of novel antifungal agents, advocacy for paediatric clinical studies will remain vital to optimize IFD prevention and treatment in children with leukaemia.

COVID-19 in children: I. Epidemiology, prevention and indirect impacts.

Children globally have been profoundly impacted by the coronavirus disease 2019 (COVID-19) pandemic. This review explores the direct and indirect public health impacts of COVID-19 on children. We discuss in detail the transmission dynamics, vaccination strategies and, importantly, the 'shadow pandemic', encompassing underappreciated indirect impacts of the pandemic on children. The indirect effects of COVID-19 will have a long-term impact beyond the immediate pandemic period. These include the mental health and wellbeing risks, disruption to family income and attendant stressors including increased family violence, delayed medical attention and the critical issue of prolonged loss of face-to-face learning in a normal school environment. Amplification of existing inequities and creation of new disadvantage are likely additional sequelae, with children from vulnerable families disproportionately affected. We emphasise the responsibility of paediatricians to advocate on behalf of this vulnerable group to ensure the longer-term effects of COVID-19 public health responses on the health and wellbeing of children are fully considered.

COVID-19 in children. II: Pathogenesis, disease spectrum and management.

The global disruption of the COVID-19 pandemic has impacted the life of every child either directly or indirectly. This review explores the pathophysiology, immune response, clinical presentation and treatment of COVID-19 in children, summarising the most up-to-date data including recent developments regarding variants of concern. The acute infection with SARS-CoV-2 is generally mild in children, whilst the post-infectious manifestations, including paediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2 (PIMS-TS) and 'long COVID' in children, are more complex. Given that most research on COVID-19 has focused on adult cohorts and that clinical manifestations, treatment availability and impacts differ markedly in children, research that specifically examines COVID-19 in children needs to be prioritised.

Examining the interseasonal resurgence of respiratory syncytial virus in Western Australia.

BACKGROUND: Following a relative absence in winter 2020, a large resurgence of respiratory syncytial virus (RSV) detections occurred during the 2020/2021 summer in Western Australia. This seasonal shift was linked to SARS-CoV-2 public health measures. We examine the epidemiology and RSV testing of respiratory-coded admissions, and compare clinical phenotype of RSV-positive admissions between 2019 and 2020. METHOD: At a single tertiary paediatric centre, International Classification of Diseases, 10th edition Australian Modification-coded respiratory admissions longer than 12 hours were combined with laboratory data from 1 January 2019 to 31 December 2020. Data were grouped into bronchiolitis, other acute lower respiratory infection (OALRI) and wheeze, to assess RSV testing practices. For RSV-positive admissions, demographics and clinical features were compared between 2019 and 2020. RESULTS: RSV-positive admissions peaked in early summer 2020, following an absent winter season. Testing was higher in 2020: bronchiolitis, 94.8% vs 89.2% (p=0.01); OALRI, 88.6% vs 82.6% (p=0.02); and wheeze, 62.8% vs 25.5% (p<0.001). The 2020 peak month, December, contributed almost 75% of RSV-positive admissions, 2.5 times the 2019 peak. The median age in 2020 was twice that observed in 2019 (16.4 vs 8.1 months, p<0.001). The proportion of RSV-positive OALRI admissions was greater in 2020 (32.6% vs 24.9%, p=0.01). There were no clinically meaningful differences in length of stay or disease severity. INTERPRETATION: The 2020 RSV season was in summer, with a larger than expected peak. There was an increase in RSV-positive non-bronchiolitis admissions, consistent with infection in older RSV-naïve children. This resurgence raises concern for regions experiencing longer and more stringent SARS-CoV-2 public health measures.

Re-examining Hepatitis B Postexposure Prophylaxis Following Pediatric Community-acquired Needle-stick Injury in an Era of a National Immunization Registry.

BACKGROUND: Long-term hepatitis B immunity has been demonstrated following the completion of the primary vaccination series in childhood. Some guidelines recommend a hepatitis B surface antibody (anti-HBs) directed approach following community-acquired needle-stick injury (CANSI) to inform hepatitis B postexposure prophylaxis (PEP) management. We assessed the utility of anti-HBs testing post-CANSI, as well as the costing of, and adherence to PEP at a pediatric hospital. METHODS: Children presenting to an Australian tertiary pediatric hospital post-CANSI (2014-2019) were identified retrospectively using medical and laboratory records. Immunization status was obtained from the Australian Immunisation Registry. RESULTS: Fifty-six children with CANSI were identified. Of those with immunization records, all had completed hepatitis B vaccinations (n = 52). At presentation, 44% (n = 23) had anti-HBs <10 IU/L, which was more likely in older (≥6 years, 68%) versus younger children (OR 4.59, P < 0.02). HBIG and hepatitis B vaccine adherence was 65% (15/23) and 78% (18/23), respectively. All children (n = 14) with anti-HBs ≥4 weeks postvaccination ±HBIG, demonstrated an anamnestic response. No hepatitis B infections were detected. Using completed immunizations versus anti-HBs levels as a marker of immunity to direct PEP resulted in a projected cost savings of AUD$ 4234. CONCLUSION: Anti-HBs levels <10 IU/L, despite previous vaccinations, were frequent in children post-CANSI, with many demonstrating an anamnestic response. Adherence to postexposure HBIG and hepatitis B vaccine was suboptimal using an anti-HBs directed approach. These data support re-evaluating PEP in an era of the national immunization registry; completion of hepatitis B vaccinations as a marker of immunity provides a practical approach, ensuring optimized care for pediatric CANSI.

Consensus guidelines for antifungal prophylaxis in haematological malignancy and haemopoietic stem cell transplantation, 2021.

Antifungal prophylaxis can reduce morbidity and mortality from invasive fungal disease (IFD). However, its use needs to be optimised and appropriately targeted to patients at highest risk to derive the most benefit. In addition to established risks for IFD, considerable recent progress in the treatment of malignancies has resulted in the development of new 'at-risk' groups. The changing epidemiology of IFD and emergence of drug resistance continue to impact choice of prophylaxis, highlighting the importance of active surveillance and knowledge of local epidemiology. These guidelines aim to highlight emerging risk groups and review the evidence and limitations around new formulations of established agents and new antifungal drugs. It provides recommendations around use and choice of antifungal prophylaxis, discusses the potential impact of the changing epidemiology of IFD and emergence of drug resistance, and future directions for risk stratification to assist optimal management of highly vulnerable patients.

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.