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.

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.

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.

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. 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.

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.

Antifungal prescribing in neonates: Using national point prevalence survey data from Australia.

We describe contemporary antifungal use in neonates, with point-prevalence survey data from the National Antimicrobial Prescribing Survey across Australian hospitals from 2014 to 2018. There were 247 antifungal prescriptions in 243 neonates in 20 hospitals, median age six days (range 0-27 days). In 219/247 prescriptions (89%) antifungals were prescribed as prophylaxis. Topical (oral) nystatin was the most frequently prescribed in 233/247 prescriptions (94%), followed by fluconazole 11/227 (4%), with substantial variation in dosing for both. Two of 243 neonates (0.8%) had invasive fungal infection. Nystatin use dominates current antifungal prescribing for Australian neonates, in contrast to other countries, and invasive fungal infection is rare. LAY SUMMARY: Novel nationwide surveillance found newborn infants in Australian hospitals commonly receive antifungal medications, mostly oral nystatin. This is given mainly to prevent rather than treat infection, which is rare. There is substantial unexplained variation in dosing of antifungal drugs nationally.

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.

Antibiotic appropriateness and guideline adherence in hospitalized children: results of a nationwide study.

BACKGROUND: Information on the nature and appropriateness of antibiotic prescribing for children in hospitals is important, but scarce. OBJECTIVES: To analyse antimicrobial prescribing and appropriateness, and guideline adherence, in hospitalized children across Australia. PATIENTS AND METHODS: We analysed data from the National Antimicrobial Prescribing Survey (NAPS) from 2014 to 2017. Surveys were performed in hospital facilities of all types (public and private; major city, regional and remote). Participants were admitted children <18 years old. Risk factors associated with inappropriate prescribing were explored using logistic regression models. RESULTS: Among 6219 prescriptions for 3715 children in 253 facilities, 19.6% of prescriptions were deemed inappropriate. Risk factors for inappropriate prescribing included non-tertiary paediatric hospital admission [OR 1.37 (95% CI 1.20-1.55)] and non-major city hospital location [OR 1.52 (95% CI 1.30-1.77)]. Prescriptions for neonates, immunocompromised children and those admitted to an ICU were less frequently inappropriate. If a restricted antimicrobial was prescribed and not approved, the prescription was more likely to be inappropriate [OR 12.9 (95% CI 8.4-19.8)]. Surgical prophylaxis was inappropriate in 59% of prescriptions. CONCLUSIONS: Inappropriate antimicrobial prescribing in children was linked to specific risk factors identified here, presenting opportunities for targeted interventions to improve prescribing. This information, using a NAPS dataset, allows for analysis of antimicrobial prescribing among different groups of hospitalized children. Further exploration of barriers to appropriate prescribing and facilitators of best practice in this population is recommended.

Penicillin - getting prescribing right for children.

Penicillins are commonly prescribed to children. Recommendations in the product information may not be the most appropriate doses for children and may list clinical indications that are preferably treated with other antibiotics Reputable guidelines, for example Therapeutic Guidelines: Antibiotic, offer up-to-date advice on optimal choice, route, dosage and duration of oral penicillins in children In most instances, the child's weight should be used to calculate the dose in mg per kg without exceeding the maximum adult dose When prescribing higher weight-based doses of amoxicillin or flucloxacillin, check the volume of oral liquid required to complete a treatment course to ensure adequate supply

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.

High prevalence of developmental concern amongst infants at 12 months following hospitalised parechovirus infection.

AIM: The human parechovirus (HPeV) is an increasingly recognised cause of sepsis and central nervous system infection in young infants for which there are limited long-term outcome data. We aimed to assess neurodevelopmental outcome and quality of life in infants following hospitalised HPeV infection. METHODS: This cohort study was a 12-month follow-up of infants who were hospitalised with confirmed HPeV infection at the Sydney Children's Hospitals Network during an outbreak in Sydney in 2013. Telephone interviews were conducted with parents/guardians. We administered standardised questionnaires, including: Ages and Stages Questionnaire (ASQ), Liverpool Outcome Score-follow-up, Pediatric Quality of Life Inventory(PedsQL) Infant scales and Short-Form health survey (SF-12). RESULTS: We followed up 46 of 79 infants (58%) aged between 12 and 16 months who had been hospitalised with HPeV infection; 19% showed significant concern in developmental attainment (ASQ3 score <2 standard deviation below population mean), and 50% showed some concern (<1 standard deviation below mean). ASQ3 developmental outcome was associated with the presence of neurodevelopmental sequelae (lower total Liverpool Outcome Score) and poorer health-related quality of life (HRQOL) in physical functioning (PedsQL physical component score), but not overall HRQOL (total PedsQL score) or parental HRQOL (SF-12 scores). No significant associations were identified between clinical or laboratory features during acute hospitalisation and adverse outcome on ASQ3. CONCLUSIONS: A high proportion of infants show developmental concern at 12-month follow-up post-hospitalisation with HPeV infection. Clinical features during hospitalisation were not associated with adverse outcomes at 12 months. These results suggest that careful follow-up of young infants hospitalised with HPeV disease may be warranted.

Outcomes of multisite antimicrobial stewardship programme implementation with a shared clinical decision support system.

Background: Studies evaluating antimicrobial stewardship programmes (ASPs) supported by computerized clinical decision support systems (CDSSs) have predominantly been conducted in single site metropolitan hospitals. Objectives: To examine outcomes of multisite ASP implementation supported by a centrally deployed CDSS. Methods: An interrupted time series study was conducted across five hospitals in New South Wales, Australia, from 2010 to 2014. Outcomes analysed were: effect of the intervention on targeted antimicrobial use, antimicrobial costs and healthcare-associated Clostridium difficile infection (HCA-CDI) rates. Infection-related length of stay (LOS) and standardized mortality ratios (SMRs) were also assessed. Results: Post-intervention, antimicrobials targeted for increased use rose from 223 to 293 defined daily doses (DDDs)/1000 occupied bed days (OBDs)/month (+32%, P < 0.01). Conversely, antimicrobials targeted for decreased use fell from 254 to 196 DDDs/1000 OBDs/month (-23%; P < 0.01). These effects diminished over time. Antimicrobial costs decreased initially (-AUD$64551/month; P < 0.01), then increased (+AUD$7273/month; P < 0.01). HCA-CDI rates decreased post-intervention (-0.2 cases/10 000 OBDs/month; P < 0.01). Proportional LOS reductions for key infections (respiratory from 4.8 to 4.3 days, P < 0.01; septicaemia 6.8 to 6.1 days, P < 0.01) were similar to background LOS reductions (2.1 to 1.9 days). Similarly, infection-related SMRs (observed/expected deaths) decreased (respiratory from 1.1 to 0.75; septicaemia 1.25 to 0.8; background rate 1.19 to 0.90. Conclusions: Implementation of a collaborative multisite ASP supported by a centrally deployed CDSS was associated with changes in targeted antimicrobial use, decreased antimicrobial costs, decreased HCA-CDI rates, and no observable increase in LOS or mortality. Ongoing targeted interventions are suggested to promote sustainability.

Sepsis-like disease in infants due to human parechovirus type 3 during an outbreak in Australia.

BACKGROUND: Infections with human parechoviruses (HPeVs) are associated with a wide range of clinical presentations in children, ranging from mild or asymptomatic infections to severe sepsis-like presentations or meningoencephalitis. METHODS: We reviewed medical records of infants admitted to 5 hospitals in New South Wales, Australia, during an outbreak of HPeV-3 infection. Data were collected on clinical presentation, laboratory markers, and outcome of infants with HPeV infection confirmed by reverse transcription polymerase chain reaction. RESULTS: We identified 118 infected infants. Most presented with an acute sepsis-like syndrome with high fever, tachycardia, poor perfusion, and severe irritability. Other common features were erythrodermic rash, abdominal distension, edema, and hepatitis. The age range of infants was 4 days to 9.5 months; 75% were <2 months old, including all but 1 of the 30 infants (25%) admitted to intensive care units (ICUs), who as a group, were significantly younger than infants not admitted to ICUs. Only 4% of evaluable cerebrospinal fluid samples had pleocytosis, but HPeV was detected in 95%. Brain magnetic resonance imaging on a small number of children demonstrated white matter changes and diffusion restriction. Sequencing of the VP1 gene confirmed HPeV-3 in all samples tested. All children recovered without ongoing complications at last follow-up. CONCLUSIONS: We report the largest series of HPeV-3 infection in infants, and the first outbreak in Australia. Infants presented with a severe sepsis-like syndrome with a high rate of ICU admissions, but all recovered from the acute infection without complications. Long-term sequelae are unknown.

Parechovirus Genotype 3 Outbreak among Infants, New South Wales, Australia, 2013-2014.

From October 2013 through February 2014, human parechovirus genotype 3 infection was identified in 183 infants in New South Wales, Australia. Of those infants, 57% were male and 95% required hospitalization. Common signs and symptoms were fever >38°C (86%), irritability (80%), tachycardia (68%), and rash (62%). Compared with affected infants in the Northern Hemisphere, infants in New South Wales were slightly older, both sexes were affected more equally, and rash occurred with considerably higher frequency. The New South Wales syndromic surveillance system, which uses near real-time emergency department and ambulance data, was useful for monitoring the outbreak. An alert distributed to clinicians reduced unnecessary hospitalization for patients with suspected sepsis.

Prescribing azithromycin.

Azithromycin is a broad-spectrum macrolide antibiotic with a long half-life and excellent tissue penetration. It is primarily used for the treatment of respiratory, enteric and genitourinary infections and may be used in preference to other macrolides for some sexually transmitted and enteric infections. Azithromycin has additional immunomodulatory effects and has been used in chronic respiratory inflammatory diseases for this purpose. Potential major adverse effects include cardiovascular arrhythmias and hearing loss. Macrolide resistance is also a problem, as are interactions with commonly prescribed drugs.

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.

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.