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.

Risk Factors and Clinical Prognosis Associated With RSV-ALRI Intensive Care Unit Admission in Children <2 Years of Age: A Multicenter Study.

BACKGROUND: Respiratory syncytial virus (RSV) is the leading cause of acute lower respiratory infections (ALRIs) in children <2 years of age. Currently, there are limited data on risk factors for very severe RSV-ALRI requiring intensive care unit (ICU) admission. METHODS: We conducted a case-control study of children <2 years old admitted with RSV-ALRI to the Sydney Children's Hospital Network, comprising 2 large tertiary pediatric hospitals. Cases were children with laboratory-confirmed RSV-ALRI admitted to ICU, and controls were (1:2, matched on date of admission) children hospitalized with RSV-ALRI but not requiring ICU transfer. Data on risk factors were retrieved from the electronic medical record system. Adjusted odds ratios (aORs) with 95% confidence intervals (95% CI) associated with risk factors for ICU admission and the association with clinical and treatment factors were determined from logistic regression models. RESULTS: A total of 44 (44%) of 100 cases and 90 (48.1%) of 187 controls were male. Age <6 months and preterm births were associated with a 2.10-fold (95% CI: 1.14-3.79) and 2.35-fold (95% CI: 1.26-4.41) increased risk in ICU admissions, respectively. The presence of any chronic health condition was a significant risk factor for ICU admission. The clinical presentations on admission more commonly seen in cases were apnea (aOR: 5.01, 95% CI: 1.50-17.13) and respiratory distress (aOR: 15.91, 95% CI: 4.52-55.97). Cases were more likely to be hospitalized for longer duration and require respiratory support. CONCLUSIONS: Our results can be translated into a clinical risk algorithm to identify children at risk of very severe RSV disease.

Global guideline for the diagnosis and management of cryptococcosis: an initiative of the ECMM and ISHAM in cooperation with the ASM.

Cryptococcosis is a major worldwide disseminated invasive fungal infection. Cryptococcosis, particularly in its most lethal manifestation of cryptococcal meningitis, accounts for substantial mortality and morbidity. The breadth of the clinical cryptococcosis syndromes, the different patient types at-risk and affected, and the vastly disparate resource settings where clinicians practice pose a complex array of challenges. Expert contributors from diverse regions of the world have collated data, reviewed the evidence, and provided insightful guideline recommendations for health practitioners across the globe. This guideline offers updated practical guidance and implementable recommendations on the clinical approaches, screening, diagnosis, management, and follow-up care of a patient with cryptococcosis and serves as a comprehensive synthesis of current evidence on cryptococcosis. This Review seeks to facilitate optimal clinical decision making on cryptococcosis and addresses the myriad of clinical complications by incorporating data from historical and contemporary clinical trials. This guideline is grounded on a set of core management principles, while acknowledging the practical challenges of antifungal access and resource limitations faced by many clinicians and patients. More than 70 societies internationally have endorsed the content, structure, evidence, recommendation, and pragmatic wisdom of this global cryptococcosis guideline to inform clinicians about the past, present, and future of care for a patient with cryptococcosis.

Pediatric Cryptococcosis.

BACKGROUND: Seroprevalence studies have shown that 70% of children are exposed to Cryptococcus , the most common cause of meningitis in people living with human immunodeficiency virus (HIV), but reported pediatric disease prevalence is much lower than in adults. METHODS: PubMed and Ovid Global Health databases were searched with the terms "cryptococcosis," "cryptococcal meningitis," " Cryptococcus neoformans " or " Cryptococcus gattii ." All studies reporting pediatric specific data in the English language from 1980 up until December 2022 were included. RESULTS: One hundred sixty-eight publications were reviewed totaling 1469 children, with the majority reported from Africa (54.2%). Sixty-five percent (961) were HIV positive, 10% (147) were non-HIV immunocompromised and 19% (281) were immunocompetent. Clinical signs and symptoms were only reported for 458 children, with fever (64%), headache (55%) and vomiting (39%) being the most common. Most children (80%) suffered from meningoencephalitis. Lung involvement was rarely described in HIV-positive children (1%), but significantly more common in the non-HIV immunocompromised (36%) and immunocompetent (40%) groups ( P < 0.0001). Only 22% received the recommended antifungal combination therapy, which was significantly higher in immunocompetent children than those with HIV (39% vs. 6.8%; P < 0.0001). Overall mortality was 23%. A significant higher mortality was observed in children with HIV compared with immunocompetent children (32% vs. 16%; P < 0.001), but not compared with children with non-HIV immunosuppression (25). CONCLUSIONS: This is the largest review of pediatric cryptococcosis with new observations on differences in clinical presentation and outcome depending on the underlying condition. The lack of granular clinical data urges prospective clinical epidemiological studies for improved insight in the epidemiology, management and outcome of cryptococcosis in children.

Fatal Human Neurologic Infection Caused by Pigeon Avian Paramyxovirus-1, Australia.

Avian paramyxovirus type 1 (APMV-1) is a virus of birds that results in a range of outcomes, from asymptomatic infections to outbreaks of systemic respiratory and neurologic disease, depending on the virus strain and the avian species affected. Humans are rarely affected; those who are predominantly experience mild conjunctivitis. We report a fatal case of neurologic disease in a 2-year-old immunocompromised child in Australia. Metagenomic sequencing and histopathology identified the causative agent as the pigeon variant of APMV-1. This diagnosis should be considered in neurologic conditions of undefined etiologies. Agnostic metagenomic sequencing methods are useful in such settings to direct diagnostic and therapeutic efforts.

Invasive aspergillosis in adult patients in Australia and New Zealand: 2017-2020.

Background: New and emerging risks for invasive aspergillosis (IA) bring the need for contemporary analyses of the epidemiology and outcomes of IA, in order to improve clinical practice. Methods: The study was a retrospective, multicenter, cohort design of proven and probable IA in adults from 10 Australasian tertiary centres (January 2017-December 2020). Descriptive analyses were used to report patients' demographics, predisposing factors, mycological characteristics, diagnosis and management. Accelerated failure-time model was employed to determine factor(s) associated with 90-day all-cause mortality (ACM). Findings: Of 382 IA episodes, 221 (in 221 patients) fulfilled inclusion criteria - 53 proven and 168 probable IA. Median patient age was 61 years (IQR 51-69). Patients with haematologic malignancies (HM) comprised 49.8% of cases. Fifteen patients (6.8%) had no pre-specified immunosuppression and eleven patients (5.0%) had no documented comorbidity. Only 30% of patients had neutropenia. Of 170 isolates identified, 40 (23.5%) were identified as non-Aspergillus fumigatus species complex. Azole-resistance was present in 3/46 (6.5%) of A. fumigatus sensu stricto isolates. Ninety-day ACM was 30.3%. HM (HR 1.90; 95% CI 1.04-3.46, p = 0.036) and ICU admission (HR 4.89; 95% CI 2.93-8.17, p < 0.001) but not neutropenia (HR 1.45; 95% CI 0.88-2.39, p = 0.135) were associated with mortality. Chronic kidney disease was also a significant predictor of death in the HM subgroup (HR 3.94; 95% CI 1.15-13.44, p = 0.028). Interpretation: IA is identified in high number of patients with mild/no immunosuppression in our study. The relatively high proportion of non-A. fumigatus species complex isolates and 6.5% azole-resistance rate amongst A. fumigatus sensu stricto necessitates accurate species identification and susceptibility testing for optimal patient outcomes. Funding: This work is unfunded. All authors' financial disclosures are listed in detail at the end of the manuscript.

Inborn Errors of Immunity in Children With Invasive Pneumococcal Disease: A Multicenter Prospective Study.

BACKGROUND: In settings with universal conjugate pneumococcal vaccination, invasive pneumococcal disease (IPD) can be a marker of an underlying inborn error of immunity. The aim of this study was to determine the prevalence and characterize the types of immunodeficiencies in children presenting with IPD. METHODS: Multicenter prospective audit following the introduction of routinely recommended immunological screening in children presenting with IPD. The minimum immunological evaluation comprised a full blood examination and film, serum immunoglobulins (IgG, IgA and IgM), complement levels and function. Included participants were children in whom Streptococcus pneumoniae was isolated from a normally sterile site (cerebrospinal fluid, pleura, peritoneum and synovium). If isolated from blood, features of sepsis needed to be present. Children with predisposing factors for IPD (nephrotic syndrome, anatomical defect or malignancy) were excluded. RESULTS: Overall, there were 379 episodes of IPD of which 313 (83%) were eligible for inclusion and 143/313 (46%) had an immunologic evaluation. Of these, 17/143 (12%) were diagnosed with a clinically significant abnormality: hypogammaglobulinemia (n = 4), IgA deficiency (n = 3), common variable immunodeficiency (n = 2), asplenia (n = 2), specific antibody deficiency (n = 2), incontinentia pigmenti with immunologic dysfunction (n = 1), alternative complement deficiency (n = 1), complement factor H deficiency (n = 1) and congenital disorder of glycosylation (n = 1). The number needed to investigate to identify 1 child presenting with IPD with an immunologic abnormality was 7 for children under 2 years and 9 for those 2 years old and over. CONCLUSIONS: This study supports the routine immune evaluation of children presenting with IPD of any age, with consideration of referral to a pediatric immunologist.

Corrigendum to "Lower risk of multi-system Inflammatory Syndrome in Children (MIS-C) with the Omicron variant" [The Lancet Regional Health - Western Pacific 27 (2022) 100604].

[This corrects the article DOI: 10.1016/j.lanwpc.2022.100604.].

Analytical and Non-Analytical Variation May Lead to Inappropriate Antimicrobial Dosing in Neonates: An In Silico Study.

BACKGROUND: Therapeutic drug monitoring (TDM) of aminoglycosides and vancomycin is used to prevent oto- and nephrotoxicity in neonates. Analytical and nonanalytical factors potentially influence dosing recommendations. This study aimed to determine the impact of analytical variation (imprecision and bias) and nonanalytical factors (accuracy of drug administration time, use of non-trough concentrations, biological variation, and dosing errors) on neonatal antimicrobial dosing recommendations. METHODS: Published population pharmacokinetic models and the Australasian Neonatal Medicines Formulary were used to simulate antimicrobial concentration-time profiles in a virtual neonate population. Laboratory quality assurance data were used to quantify analytical variation in antimicrobial measurement methods used in clinical practice. Guideline-informed dosing recommendations based on drug concentrations were applied to compare the impact of analytical variation and nonanalytical factors on antimicrobial dosing. RESULTS: Analytical variation caused differences in subsequent guideline-informed dosing recommendations in 9.3-12.1% (amikacin), 16.2-19.0% (tobramycin), 12.2-45.8% (gentamicin), and 9.6-19.5% (vancomycin) of neonates. For vancomycin, inaccuracies in drug administration time (45.6%), use of non-trough concentrations (44.7%), within-subject biological variation (38.2%), and dosing errors (27.5%) were predicted to result in more dosing discrepancies than analytical variation (12.5%). Using current analytical performance specifications, tolerated dosing discrepancies would be up to 14.8% (aminoglycosides) and 23.7% (vancomycin). CONCLUSIONS: Although analytical variation can influence neonatal antimicrobial dosing recommendations, nonanalytical factors are more influential. These result in substantial variation in subsequent dosing of antimicrobials, risking inadvertent under- or overexposure. Harmonization of measurement methods and improved patient management systems may reduce the impact of analytical and nonanalytical factors on neonatal antimicrobial dosing.

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.

Individualized vancomycin dosing in infants: prospective evaluation of an online dose calculator.

BACKGROUND: Empiric vancomycin dosing regimens fail to achieve recommended target trough concentrations of 10-20 mg/L in the majority of infants. This study assessed the performance of a model-based dosing calculator (Vanc App) in achieving target vancomycin concentrations at first steady-state level. METHODS: This was a multicenter prospective study in four tertiary pediatric hospitals over an 18-month period. Infants aged 0-90 days with suspected Gram-positive sepsis requiring empiric vancomycin treatment were included if they did not meet any of the exclusion criteria: post-menstrual age (PMA) <25 weeks, weight <500 g, glycopeptide allergy, receiving extracorporeal membrane oxygenation, vancomycin use within the previous 72 h, and renal impairment. The Vanc App used a published population pharmacokinetic model to generate a dose based on the infant's PMA, weight, creatinine, and target vancomycin concentration. RESULTS: A total of 40 infants were included; 40% were female, median (range) weight was 2505 (700-4460) g and median (range) PMA was 37.4 (25.7-49.0) weeks. The median (range) vancomycin dose was 45 (24-79) mg/kg/day. All infants had trough vancomycin concentrations measured at steady-state (24-<48 hours) and 30 (75%) infants achieved target concentrations. Five infants had supratherapeutic (median 25, range 21-38 mg/L) and five had subtherapeutic (median 6, range <5-9 mg/L) concentrations. An area under the concentration-time curve (AUC0-24) of 400-650 mg/L.h was achieved in 33 (83%) infants. There were no infusion-related reactions or nephrotoxicity. CONCLUSION: Individualized intermittent vancomycin dosing using a model-based online calculator resulted in 75% and 83% of infants achieving target trough and AUC0-24, respectively, at first steady-state level. There were no vancomycin-related nephrotoxicity or infusion-related reactions.

Phage Therapy of Mycobacterium Infections: Compassionate Use of Phages in 20 Patients With Drug-Resistant Mycobacterial Disease.

BACKGROUND: Nontuberculous Mycobacterium infections, particularly Mycobacterium abscessus, are increasingly common among patients with cystic fibrosis and chronic bronchiectatic lung diseases. Treatment is challenging due to intrinsic antibiotic resistance. Bacteriophage therapy represents a potentially novel approach. Relatively few active lytic phages are available and there is great variation in phage susceptibilities among M. abscessus isolates, requiring personalized phage identification. METHODS: Mycobacterium isolates from 200 culture-positive patients with symptomatic disease were screened for phage susceptibilities. One or more lytic phages were identified for 55 isolates. Phages were administered intravenously, by aerosolization, or both to 20 patients on a compassionate use basis and patients were monitored for adverse reactions, clinical and microbiologic responses, the emergence of phage resistance, and phage neutralization in serum, sputum, or bronchoalveolar lavage fluid. RESULTS: No adverse reactions attributed to therapy were seen in any patient regardless of the pathogen, phages administered, or the route of delivery. Favorable clinical or microbiological responses were observed in 11 patients. Neutralizing antibodies were identified in serum after initiation of phage delivery intravenously in 8 patients, potentially contributing to lack of treatment response in 4 cases, but were not consistently associated with unfavorable responses in others. Eleven patients were treated with only a single phage, and no phage resistance was observed in any of these. CONCLUSIONS: Phage treatment of Mycobacterium infections is challenging due to the limited repertoire of therapeutically useful phages, but favorable clinical outcomes in patients lacking any other treatment options support continued development of adjunctive phage therapy for some mycobacterial infections.

Multinational consensus antimicrobial stewardship recommendations for children managed in hospital settings.

Children are entitled to receive antibiotic therapy that is based on evidence and best practice, but might be overlooked in hospital programmes designed to achieve antimicrobial stewardship [AMS]. This failure to include children could be because children make up small proportion of patients in most hospitals, and are cared for by specialised paediatric staff. We reviewed the evidence and consulted experts in three global regions to develop ten recommendations for good-practice in hospital AMS programmes for children. We performed a review of scientific research, published between Jan 1, 2007, and Oct 17, 2019, concerning AMS, and formed a multinational expert group comprising members from the USA, Canada, the UK, Belgium, Switzerland, Australia, and Aotearoa New Zealand to develop the recommendations. These recommendations aim to help health-care workers who care for children in these regions to deliver best-practice care. We surveyed health-care workers with expertise in antibiotic therapy for children across these regions, and found that the recommendations were considered both very important and generally feasible. These recommendations should be implemented in hospitals to improve antibiotic therapy for children and to stimulate research into future improvements in care.

COVID-19 in New South Wales children during 2021: severity and clinical spectrum.

OBJECTIVES: To describe the severity and clinical spectrum of coronavirus disease 2019 (COVID-19) in children during the 2021 New South Wales outbreak of the Delta variant of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). DESIGN, SETTING: Prospective cohort study in three metropolitan Sydney local health districts, 1 June - 31 October 2021. PARTICIPANTS: Children under 16 years of age with positive SARS-CoV-2 nucleic acid test results admitted to hospital or managed by the Sydney Children's Hospital Network (SCHN) virtual care team. MAIN OUTCOME MEASURES: Age-specific SARS-CoV-2 infection frequency, overall and separately for SCHN virtual and hospital patients; rates of medical and social reason admissions, intensive care admissions, and paediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2 per 100 SARS-CoV-2 infections; demographic and clinical factors that influenced likelihood of hospital admission. RESULTS: A total of 17 474 SARS-CoV-2 infections in children under 16 were recorded in NSW, of whom 11 985 (68.6%) received SCHN-coordinated care, including 459 admitted to SCHN hospitals: 165 for medical reasons (1.38 [95% CI, 1.17-1.59] per 100 infections), including 15 admitted to intensive care, and 294 (under 18 years of age) for social reasons (2.45 [95% CI, 2.18-2.73] per 100 infections). In an analysis that included all children admitted to hospital and a random sample of those managed by the virtual team, having another medical condition (adjusted odds ratio [aOR], 7.42; 95% CI, 3.08-19.3) was associated with increased likelihood of medical admission; in univariate analyses, non-asthmatic chronic respiratory disease was associated with greater (OR, 9.21; 95% CI, 1.61-174) and asthma/viral induced wheeze with lower likelihood of admission (OR, 0.38; 95% CI, 0.18-0.78). The likelihood of admission for medical reasons declined from infancy to 5-11 years, but rose again for those aged 12-15 years. Sex and Indigenous status did not influence the likelihood of admission. CONCLUSION: Most SARS-CoV-2 infections (Delta variant) in children were asymptomatic or associated with mild disease. Hospitalisation was relatively infrequent, and most common for infants, adolescents, and children with other medical conditions. More children were hospitalised for social than for medical reasons.

Disease and economic burden of infections in hospitalised children in New South Wales, Australia.

Objectives To describe the burden of disease and hospitalisation costs in children with common infections using statewide administrative data. Methods We analysed hospitalisation prevalence and costs for 10 infections: appendicitis, cellulitis, cervical lymphadenitis, meningitis, osteomyelitis, pneumonia, pyelonephritis, sepsis, septic arthritis, and urinary tract infections in children aged <18 years admitted to hospital within New South Wales, Australia, using an activity-based management administrative dataset over three financial years (1 July 2016-30 June 2019). Results Among 339 077 admissions, 28 748 (8.48%) were coded with one of the 10 infections, associated with a total hospitalisation cost of AUD230 905 190 and a per episode median length-of-stay of 3 bed-days. Pneumonia was the most prevalent coded infection (3.1% [n = 10 524] of all admissions), followed by appendicitis (1.61%; n = 5460), cellulitis (1.22%; n = 4126) and urinary tract infections (0.94%; n = 3193). Eighty per cent of children (n = 22 529) were admitted to a non-paediatric hospital. Mean costs were increased 1.18-fold per additional bed-day, 2.14-fold with paediatric hospital admissions, and 5.49-fold with intensive care unit admissions, which were both also associated with greater total bed-day occupancy. Indigenous children comprised 9.7% of children admitted with these infections, and mean per episode costs, and median bed-days were reduced compared with non-Indigenous children (0.84 [95% CI 0.78, 0.89] and 3 (IQR: 2,5) vs 2 (IQR: 2,4), respectively. Conclusions Infections in children requiring hospitalisation contributea substantial burden of disease and cost to the community. This varies by infection, facility type, and patient demographics, and this information should be used to inform and prioritise programs to improve care for children.

Computerized Clinical Decision Support Systems for the Early Detection of Sepsis Among Pediatric, Neonatal, and Maternal Inpatients: Scoping Review.

BACKGROUND: Sepsis is a severe condition associated with extensive morbidity and mortality worldwide. Pediatric, neonatal, and maternal patients represent a considerable proportion of the sepsis burden. Identifying sepsis cases as early as possible is a key pillar of sepsis management and has prompted the development of sepsis identification rules and algorithms that are embedded in computerized clinical decision support (CCDS) systems. OBJECTIVE: This scoping review aimed to systematically describe studies reporting on the use and evaluation of CCDS systems for the early detection of pediatric, neonatal, and maternal inpatients at risk of sepsis. METHODS: MEDLINE, Embase, CINAHL, Cochrane, Latin American and Caribbean Health Sciences Literature (LILACS), Scopus, Web of Science, OpenGrey, ClinicalTrials.gov, and ProQuest Dissertations and Theses Global (PQDT) were searched by using a search strategy that incorporated terms for sepsis, clinical decision support, and early detection. Title, abstract, and full-text screening was performed by 2 independent reviewers, who consulted a third reviewer as needed. One reviewer performed data charting with a sample of data. This was checked by a second reviewer and via discussions with the review team, as necessary. RESULTS: A total of 33 studies were included in this review-13 (39%) pediatric studies, 18 (55%) neonatal studies, and 2 (6%) maternal studies. All studies were published after 2011, and 27 (82%) were published from 2017 onward. The most common outcome investigated in pediatric studies was the accuracy of sepsis identification (9/13, 69%). Pediatric CCDS systems used different combinations of 18 diverse clinical criteria to detect sepsis across the 13 identified studies. In neonatal studies, 78% (14/18) of the studies investigated the Kaiser Permanente early-onset sepsis risk calculator. All studies investigated sepsis treatment and management outcomes, with 83% (15/18) reporting on antibiotics-related outcomes. Usability and cost-related outcomes were each reported in only 2 (6%) of the 31 pediatric or neonatal studies. Both studies on maternal populations were short abstracts. CONCLUSIONS: This review found limited research investigating CCDS systems to support the early detection of sepsis among pediatric, neonatal, and maternal patients, despite the high burden of sepsis in these vulnerable populations. We have highlighted the need for a consensus definition for pediatric and neonatal sepsis and the study of usability and cost-related outcomes as critical areas for future research. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): RR2-10.2196/24899.