The increasing healthcare burden of enteric fever in a low-incidence setting.

OBJECTIVES: Enteric fever carries appreciable morbidity in non-endemic settings, particularly in returned travelers. This study aimed to characterize the healthcare burden of enteric fever in a low-incidence setting and to identify risk factors and opportunities for preventative interventions. METHODS: Analysis of a retrospective case series from a tertiary pediatric center (2015-2019), augmented by public health notification and microbiological laboratory data (2018-2019), from Western Sydney, Australia, a region with frequent travel links to South Asia. RESULTS: Eighty-nine (89) patients were diagnosed with enteric fever, including 43 children with complete demographic and travel data. Enteric fever cases increased over time (by 4.9 % per year) and incidence was three times higher in the pediatric population (<15 years old) compared to adults. Travel to India and visiting friends and relatives (VFR) travel were risk factors. Few children received enteric fever vaccination prior to travel, as pre-travel advice most commonly was not sought. CONCLUSIONS: Children visiting relatives in high-incidence countries are increasingly at risk for enteric fever, particularly when travelling to South Asia. Targeted health advice to travelers visiting friends and relatives is warranted to mitigate the healthcare burden of enteric fever in low-incidence settings.

Risk factors for mortality in severe COVID-19: Exploring the interplay of immunomodulatory therapy and coinfection.

Patients with severe clinical manifestations of coronavirus disease 2019 (COVID-19) present particular diagnostic and management challenges to critical care physicians, including identifying and responding to concurrent bacterial and fungal coinfections. This study evaluates risk factors for in-hospital mortality in patients admitted to the intensive care unit with severe COVID-19 during circulation of the B.1.617.2 (Delta) variant, including the impact of immunomodulators and bacterial and/or fungal coinfection. This retrospective cohort study enrolled patients with severe COVID-19. A Cox proportional hazard ratio analysis identified risk factors for in-hospital mortality. Outcomes were also compared between patients receiving and not receiving immunomodulatory therapy alongside standard care. Ninety patients admitted to the intensive care unit were enrolled. On multivariate analysis, the greatest risk factors for in-hospital mortality were invasive mechanical ventilation (hazard ratio (HR) = 15.27; 95% confidence interval (CI) 3.29-71.0; P < 0.001), elevated body mass index (HR = 1.07 per unit; 95% CI 1.02-1.13; P = 0.007) and older age (HR = 1.53 per decade; 95% CI 1.05-2.24; P = 0.028). Bacterial and/or fungal coinfection occurred at equal frequency in patients receiving and not receiving immunomodulatory therapy. However, in patients receiving immunomodulators, coinfection carried a significantly higher mortality risk (63.0%) compared with those without coinfection (15.4%; P = 0.038). Mortality from severe COVID-19 is significantly higher in older patients and those with elevated body mass index and requiring mechanical ventilation. Immunomodulatory therapy necessitates vigilance towards evolving coinfection in the intensive care setting.

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.

Epidemiology, Modern Diagnostics, and the Management of Mucorales Infections.

Mucormycosis is an uncommon, yet deadly invasive fungal infection caused by the Mucorales moulds. These pathogens are a WHO-assigned high-priority pathogen group, as mucormycosis incidence is increasing, and there is unacceptably high mortality with current antifungal therapies. Current diagnostic methods have inadequate sensitivity and specificity and may have issues with accessibility or turnaround time. Patients with diabetes mellitus and immune compromise are predisposed to infection with these environmental fungi, but COVID-19 has established itself as a new risk factor. Mucorales also cause healthcare-associated outbreaks, and clusters associated with natural disasters have also been identified. Robust epidemiological surveillance into burden of disease, at-risk populations, and emerging pathogens is required. Emerging serological and molecular techniques may offer a faster route to diagnosis, while newly developed antifungal agents show promise in preliminary studies. Equitable access to these emerging diagnostic techniques and antifungal therapies will be key in identifying and treating mucormycosis, as delayed initiation of therapy is associated with higher mortality.

Clinical and Epidemiologic Profile of Invasive Pneumococcal Disease in Australian Children Following the Relaxation of Nonpharmaceutical Interventions Against SARS-COV-2.

A global resurgence of invasive pneumococcal disease (IPD) has been noted in children. We provide a detailed clinical and epidemiological analysis of IPD in Australian children following relaxation of nonpharmaceutical interventions against coronavirus disease 2019, revealing significant morbidity and mortality-even in vaccinated children without known predisposing risk factors. Almost half of the IPD cases were caused by serotypes not covered by the 13-valent pneumococcal conjugate vaccine.

Acute bacterial lymphadenitis in children: a retrospective, cross-sectional study.

Acute bacterial lymphadenitis is a common childhood condition, yet there remains considerable variability in antibiotic treatment choice, particularly in settings with low prevalence of methicillin-resistant Staphylococcus aureus such as Europe and Australasia. This retrospective cross-sectional study reviewed children presenting with acute bacterial lymphadenitis to a tertiary paediatric hospital in Australia between 1 October 2018 and 30 September 2020. Treatment approaches were analysed with respect to children with complicated versus uncomplicated disease. A total of 148 children were included in the study, encompassing 25 patients with complicated disease and 123 with uncomplicated lymphadenitis, as defined by the presence or absence of an associated abscess or collection. In culture-positive cases, methicillin-susceptible S. aureus (49%) and Group A Streptococcus (43%) predominated, while methicillin-resistant S. aureus was seen in a minority of cases (6%). Children with complicated disease generally presented later and had a prolonged length of stay, longer durations of antibiotics, and higher frequency of surgical intervention. Beta-lactam therapy (predominantly flucloxacillin or first-generation cephalosporins) formed the mainstay of therapy for uncomplicated disease, while treatment of complicated disease was more variable with higher rates of clindamycin use.    Conclusion: Uncomplicated lymphadenitis can be managed with narrow-spectrum beta-lactam therapy (such as flucloxacillin) with low rates of relapse or complications. In complicated disease, early imaging, prompt surgical intervention, and infectious diseases consultation are recommended to guide antibiotic therapy. Prospective randomised trials are needed to guide optimal antibiotic choice and duration in children presenting with acute bacterial lymphadenitis, particularly in association with abscess formation, and to promote uniformity in treatment approaches. What is Known: • Acute bacterial lymphadenitis is a common childhood infection. • Antibiotic prescribing practices are highly variable in bacterial lymphadenitis. What is New: • Uncomplicated bacterial lymphadenitis in children can be managed with single agent narrow-spectrum beta-lactam therapy in low-MRSA prevalence settings. • Further trials are needed to ascertain optimal treatment duration and the role of clindamycin in complicated disease.

Arthropod-Borne Flaviviruses in Pregnancy.

Flaviviruses are a diverse group of enveloped RNA viruses that cause significant clinical manifestations in the pregnancy and postpartum periods. This review highlights the epidemiology, pathophysiology, clinical features, diagnosis, and prevention of the key arthropod-borne flaviviruses of concern in pregnancy and the neonatal period-Zika, Dengue, Japanese encephalitis, West Nile, and Yellow fever viruses. Increased disease severity during pregnancy, risk of congenital malformations, and manifestations of postnatal infection vary widely amongst this virus family and may be quite marked. Laboratory confirmation of infection is complex, especially due to the reliance on serology for which flavivirus cross-reactivity challenges diagnostic specificity. As such, a thorough clinical history including relevant geographic exposures and prior vaccinations is paramount for accurate diagnosis. Novel vaccines are eagerly anticipated to ameliorate the impact of these flaviviruses, particularly neuroinvasive disease manifestations and congenital infection, with consideration of vaccine safety in pregnant women and children pivotal. Moving forward, the geographical spread of flaviviruses, as for other zoonoses, will be heavily influenced by climate change due to the potential expansion of vector and reservoir host habitats. Ongoing 'One Health' engagement across the human-animal-environment interface is critical to detect and responding to emergent flavivirus epidemics.

Emergent Omicron BR.2.1 sublineage of SARS-CoV-2 in New South Wales, Australia: a subvariant with high fitness but without increased disease severity.

OBJECTIVES: To describe the epidemiology and impact of Omicron BR.2.1, an emergent SARS-CoV-2 Omicron BA.2.75 sublineage displaying high fitness compared to other cocirculating subvariants in New South Wales, Australia. METHODS: From September 01 to November 26, 2022, 4971 SARS-CoV-2 consensus genomes from unique patients were generated, and correlated with international travel and reinfection history, and admission to the intensive care unit. RESULTS: BR.2.1 became the predominant variant by late November, and was responsible for a significantly higher proportion of community-acquired cases during the study period (55.1% vs 38.4%, P < 0.001). Reinfections (defined as occurring between 6 and 24 weeks after a prior diagnosis of COVID-19) were significantly higher among BR.2.1 compared to non-BR.2.1 infected persons (17.0% vs 6.0%, P < 0.001). BR.2.1 cases were also significantly younger compared to non-BR.2.1 (median age 48 years (interquartile range [IQR] 32) vs 53 years (IQR 32), P = 0.004). The proportion of patients admitted to the intensive care unit with BR.2.1 was not significantly higher than other subvariants (2.3% vs 2.0%, P = 0.717). CONCLUSION: Having emerged locally within New South Wales, BR.2.1 caused a significant number of SARS-CoV-2 reinfections, but with disease severity comparable with other currently circulating lineages. Given its rapid rise in prevalence, BR.2.1 has the potential to become established internationally.

Tracking the clonal dynamics of SARS-CoV-2-specific T cells in children and adults with mild/asymptomatic COVID-19.

Children infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) develop less severe coronavirus disease 2019 (COVID-19) than adults. The mechanisms for the age-specific differences and the implications for infection-induced immunity are beginning to be uncovered. We show by longitudinal multimodal analysis that SARS-CoV-2 leaves a small footprint in the circulating T cell compartment in children with mild/asymptomatic COVID-19 compared to adult household contacts with the same disease severity who had more evidence of systemic T cell interferon activation, cytotoxicity and exhaustion. Children harbored diverse polyclonal SARS-CoV-2-specific naïve T cells whereas adults harbored clonally expanded SARS-CoV-2-specific memory T cells. A novel population of naïve interferon-activated T cells is expanded in acute COVID-19 and is recruited into the memory compartment during convalescence in adults but not children. This was associated with the development of robust CD4+ memory T cell responses in adults but not children. These data suggest that rapid clearance of SARS-CoV-2 in children may compromise their cellular immunity and ability to resist reinfection.

Prompt control of a Serratia marcescens outbreak in a neonatal intensive care unit informed by whole-genome sequencing and comprehensive infection control intervention package.

Objective: This report describes a cluster of patients infected by Serratia marcescens in a metropolitan neonatal intensive care unit (NICU) and a package of infection control interventions that enabled rapid, effective termination of the outbreak. Design: Cross-sectional analytical study using whole-genome sequencing (WGS) for phylogenetic cluster analysis and identification of virulence and resistance genes. Setting: NICU in a metropolitan tertiary-care hospital in Sydney, Australia. Patients: All neonates admitted to the level 2 and level 3 neonatal unit. Interventions: Active inpatient and environmental screening for Serratia marcescens isolates with WGS analysis for identification of resistance genes as well as cluster relatedness between isolates. Planning and implementation of a targeted, multifaceted infection control intervention. Results: The cluster of 10 neonates colonized or infected with Serratia marcescens was identified in a metropolitan NICU. Two initial cases involved devastating intracranial infections with brain abscesses, highlighting the virulence of this organism. A targeted and comprehensive infection control intervention guided by WGS findings enabled termination of this outbreak within 15 days of onset. WGS examination demonstrated phylogenetic linkage across the cluster, and genomic unrelatedness of later strains identified in the neonatal unit and elsewhere. Conclusions: A comprehensive, multipronged, infection control package incorporating close stakeholder engagement, frequent microbiological patient screening, environmental screening, enhanced cleaning, optimization of hand hygiene and healthcare worker education was paramount to the prompt control of Serratia marcescens transmission in this neonatal outbreak. WGS was instrumental in establishing relatedness between isolates and identification of possible transmission pathways in an outbreak setting.

Pulmonary Cryptococcosis.

Pulmonary cryptococcosis describes an invasive lung mycosis caused by Cryptococcus neoformans or Cryptococcus gattii complex. It is often a high-consequence disease in both immunocompromised and immunocompetent populations, and may be misdiagnosed as pulmonary malignancy, leading to a delay in therapy. Epidemiology follows that of cryptococcal meningoencephalitis, with C. gattii infection more common in certain geographic regions. Diagnostic tools include histopathology, microscopy and culture, and the detection of cryptococcal polysaccharide antigen or Cryptococcus-derived nucleic acids. All patients with lung cryptococcosis should have a lumbar puncture and cerebral imaging to exclude central nervous system disease. Radiology is key, both as an adjunct to laboratory testing and as the initial means of detection in asymptomatic patients or those with non-specific symptoms. Pulmonary cryptococcomas (single or multiple) may also be associated with disseminated disease and/or cryptococcal meningitis, requiring prolonged treatment regimens. Optimal management for severe disease requires extended induction (amphotericin B and flucytosine) and consolidation therapy (fluconazole) with close clinical monitoring. Susceptibility testing is of value for epidemiology and in regions where relatively high minimum inhibitory concentrations to azoles (particularly fluconazole) have been noted. Novel diagnostic tools and therapeutic agents promise to improve the detection and treatment of cryptococcosis, particularly in low-income settings where the disease burden is high.

Emerging Genotype IV Japanese Encephalitis Virus Outbreak in New South Wales, Australia.

The detection of a new and unexpected Japanese encephalitis virus (JEV) outbreak in March 2022 in Australia, where JEV is not endemic, demanded the rapid development of a robust diagnostic framework to facilitate the testing of suspected patients across the state of New South Wales (NSW). This nascent but comprehensive JEV diagnostic service encompassed serological, molecular and metagenomics testing within a centralised reference laboratory. Over the first three months of the outbreak (4 March 2022 to 31 May 2022), 1,061 prospective samples were received from 878 NSW residents for JEV testing. Twelve confirmed cases of Japanese encephalitis (JE) were identified, including ten cases diagnosed by serology alone, one case by metagenomic next generation sequencing and real-time polymerase chain reaction (RT-PCR) of brain tissue and serology, and one case by RT-PCR of cerebrospinal fluid, providing an incidence of JE over this period of 0.15/100,000 persons in NSW. As encephalitis manifests in <1% of cases of JEV infection, the population-wide prevalence of JEV infection is likely to be substantially higher. Close collaboration with referring laboratories and clinicians was pivotal to establishing successful JEV case ascertainment for this new outbreak. Sustained and coordinated animal, human and environmental surveillance within a OneHealth framework is critical to monitor the evolution of the current outbreak, understand its origins and optimise preparedness for future JEV and arbovirus outbreaks.

Monkeypox: A clinical update for paediatricians.

The global spread of human monkeypox disease, a zoonotic infection related to smallpox and endemic to West and Central Africa, presents serious challenges for health systems. As of July 2022, 14 533 cases have been reported world-wide, leading to designation as a Public Health Emergency of International Concern. Monkeypox disease is spread from animals to humans through infected lesions or fluids; human-human transmission occurs through fomites, droplets or direct contact. Illness is usually self-limiting, but severe disease can occur in specific groups - particularly children, and people who are immunocompromised or pregnant. Clinical presentation may include fever, lymphadenopathy and skin rash, but the rash may occur without other symptoms. Complications can include secondary bacterial infection of skin lesions, vision loss from corneal involvement, pneumonia, sepsis and encephalitis. Diagnosis of monkeypox requires consideration of epidemiological, clinical and laboratory findings, with sensitive history-taking, to elicit close contacts, critical. Supportive management is usually sufficient, but treatment options (where required) include antivirals and vaccinia immune globulin. A paucity of safety data for relevant antivirals may limit their use. There are two types of monkeypox vaccines: a replication-competent vaccinia vaccine, the use of which is logistically and clinically complex, and a replication-deficient modified vaccinia Ankara virus vaccine. Preparedness of health systems for addressing the current outbreak is constrained by historic underfunding for research, and compounded by stigma and discrimination against cases and affected communities. Key challenges in halting transmission include improving vaccine equity and countering discrimination against men who have sex with men to aid diagnosis and treatment.

Emergence of Japanese encephalitis in Australia: a diagnostic perspective.

The unprecedented emergence of Japanese encephalitis (JE) in mainland Australia represents an outbreak of high clinical and public health significance. JE is a zoonosis spread by mosquitoes and is one of the most important causes of endemic viral encephalitis in South-East Asia and the Indian subcontinent. While occasional cases of human Japanese encephalitis virus (JEV) infection have occurred in far north Australia, its detection in pigs and the substantial number of locally acquired human cases across multiple jurisdictions in early 2022 prompted the declaration of this outbreak as a Communicable Disease Incident of National Significance. Laboratory testing for JEV is complex, and most cases are diagnosed by serology, for which interpretation is difficult. This review provides a comprehensive outline of currently available methods for JEV diagnosis including serology, nucleic acid amplification testing, virus isolation, sequencing and metagenomics. The relative advantages and disadvantages of the diagnostic tests are presented, as well as their value in clinical and public health contexts. This review also explores the role of mosquito, veterinary and human surveillance as part of the laboratory response to JEV. As JEV may become endemic in Australia, a collaborative and coordinated One Health approach involving animal, human and environmental health is required for optimal disease response and control.

Paediatric neurocysticercosis in high income countries.

BACKGROUND: Neurocysticercosis (NCC) is an unusual cause of seizures in high income settings. It typically presents as an afebrile seizure in a previously well child and can occur years after migration or travel. METHODS: Children diagnosed with neurocysticercosis from 01 July 2005 to 30 June 2020 were identified from the electronic medical records of a tertiary children's hospital in Australia. Additionally, a 10-year compilation of case reports of paediatric NCC in high income settings was performed by medline search (publication years 2011-2021). Diagnosis and treatment of neurocysticercosis were reviewed with reference to diagnostic criteria of Del Brutto et al., and the 2017 Infectious Diseases Society of America treatment guidelines. RESULTS: Over a fifteen-year period, eight children were diagnosed with NCC at our hospital in Sydney, Australia. Seizures and history of travel to or migration from South Asia were the two most frequently occurring findings. Children diagnosed after 2016 all received antiparasitic therapy. Outcomes were generally favorable, though long-term epilepsy resulted in some cases. Compiled case reports from high income settings revealed migration and travel exposures commensurate with local demographic patterns, and treatment approaches conforming with 2017 Infectious Diseases Society of America guidelines. CONCLUSIONS: Clinicians should be aware of NCC as a differential diagnosis in children from endemic areas presenting with unprovoked seizures as misdiagnosis can occur. Expert review of neuroimaging facilitates diagnosis and can avert unnecessary neurosurgery. In Australia, India was a key exposure country for NCC, reflecting its endemic burden of disease and local travel and migration patterns.

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.