Therapeutic Phage Monitoring: A Review.

With the global rise in antimicrobial resistance, there has been a renewed interest in the application of therapeutic phages to treat bacterial infections. Therapeutic phage monitoring (TPM) is proposed as an essential element of phage therapy (PT) protocols to generate data and fill knowledge gaps regarding the in vivo efficacy of therapeutic phages, patients' immune responses to PT, and the wider ecological effects of PT. By monitoring phage concentrations in blood and tissues, together with immune responses and possible ecological changes during PT, TPM may enable the optimization of dosing and the implementation of precision medicine approaches. Furthermore, TPM can validate diagnostic surrogates of efficacy, direct research efforts, and establish quality assurance indicators for therapeutic phage products. Thus, TPM holds great potential for enhancing our understanding of the multidirectional phage-bacteria-host interactions and advancing "best practice" PT, ultimately improving patient care.

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.

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

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

Vaccines for COVID-19: The current state of play.

There is a strong consensus globally that a COVID-19 vaccine is likely the most effective approach to sustainably controlling the COVID-19 pandemic. An unprecedented research effort and global coordination has resulted in a rapid development of vaccine candidates and initiation of trials. Here, we review vaccine types, and progress with 10 vaccine candidates against SARS-CoV-2 - the virus that causes COVID-19 - currently undergoing early phase human trials. We also consider the many challenges of developing and deploying a new vaccine on a global scale, and recommend caution with respect to our expectations of the timeline that may be ahead.

Filling in the gaps.

The COVID-19 pandemic, and our response to it, has created many voids in our lives, with no-one spared of its effects. As a result, we have all looked for, and found ways to fill in the gaps. In the midst of the epidemic, with healthcare providers in New York City pushed to the extremes of what can be asked of them, they have found ways to bridge the gulf between how they were trained to practice medicine, and what they are being asked to do now.

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.

Low prevalence of Kingella kingae carriage in children aged 6-48 months in Sydney, Australia.

AIM: A prospective observational study was conducted to estimate the prevalence of oropharyngeal carriage of Kingella kingae in healthy Australian pre-school children. METHODS: Screening for carriage of K. kingae as well as Streptococcus pyogenes, Streptococcus pneumoniae, Streptococcus agalactiae, Staphylococcus aureus, Haemophilus influenzae, and K. kingae was undertaken using a single bacterial throat swab taken from well children aged 6 months to 4 years. Standard laboratory procedures were used for culture and identification of organisms. RESULTS: One hundred children were enrolled between October and December 2014 at the Children's Hospital at Westmead. Median age was 24.0 months (range 6.1-48.8 months); 52 children were male and 36 attended day-care facilities. Forty-one children had siblings aged less than 5 years and 67 children had siblings of any age. K. kingae oropharyngeal carriage was not detected in any of the children. Rates of carriage of other organisms were: 30% S. aureus, 21% H. influenzae, 2% S. pneumoniae and 2% S. pyogenes. Thirty-eight children were colonised with Kingella denitrificans. CONCLUSIONS: Our results suggest that prevalence of K. kingae carriage in pre-school children in Sydney is very low and support local and national guidelines that recommend flucloxacillin as empiric first-line therapy for children with osteoarticular infections. Studies conducted over the winter months and in other Australian centres could help answer outstanding questions regarding differences in carriage rates of K. kingae in children.

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.

Methicillin-resistant Staphylococcus aureus bacteraemia and epidural abscess in a neonate.

A 24-day-old boy presented with fever, irritability and poor feeding. Blood culture grew methicillin-resistant Staphylococcus aureus. Cerebrospinal fluid analysis showed pleocytosis, and methicillin-resistant Staphylococcus aureus grew from enrichment broth. Magnetic resonance imaging revealed an epidural abscess extending from C2-3 to T8-9. Staphylococcal infections of the central nervous system are uncommon in neonates. This case demonstrates the importance of performing a lumbar puncture in isolated staphylococcal bacteraemia. The case also highlights that cerebrospinal fluid pleocytosis may indicate a parameningeal focus of infection.

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.

Comparative B cell and antibody responses induced by adenoviral vectored and mRNA vaccines against COVID-19.

Both vector and mRNA vaccines were an important part of the response to the COVID-19 pandemic and may be required in future outbreaks and pandemics. However, adenoviral vectored (AdV) vaccines may be less immunogenic than mRNA vaccines against SARS-CoV-2. We assessed anti-spike and anti-vector immunity among infection-naïve Health Care Workers (HCW) following two doses of AdV (AZD1222) versus mRNA (BNT162b2) vaccine. 183 AdV and 274 mRNA vaccinees enrolled between April and October 2021. Median ages were 42 and 39 years, respectively. Blood was collected at least once, 10-48 days after vaccine dose 2. Surrogate virus neutralization test (sVNT) and spike binding antibody titres were a median of 4.2 and 2.2 times lower, respectively, for AdV compared to mRNA vaccinees (p<0.001). Median percentages of memory B cells that recognized fluorescent-tagged spike and RBD were 2.9 and 8.3 times lower, respectively for AdV compared to mRNA vaccinees. Titres of IgG reactive with human Adenovirus type 5 hexon protein rose a median of 2.2-fold after AdV vaccination but were not correlated with anti-spike antibody titres. Together the results show that mRNA induced substantially more sVNT antibody than AdV vaccine due to greater B cell expansion and targeting of the RBD. Pre-existing AdV vector cross-reactive antibodies were boosted following AdV vaccination but had no detectable effect on immunogenicity.