Nirsevimab: Alleviating the burden of RSV morbidity in young children.

Respiratory syncytial virus (RSV) is the leading cause of acute lower respiratory tract infections (LRTIs) and hospital admissions in early childhood. Recent advancements in novel preventive therapies, including extended half-life monoclonal antibodies and antenatal vaccination, have afforded new opportunities to significantly reduce the burden of this infection. Nirsevimab is a novel monoclonal antibody that provides sustained protection against RSV for at least 5 months among newborns and young children. It has received regulatory approval in numerous countries and is being implemented across various settings. Two pivotal Phase 3 trials (MELODY, HARMONIE) demonstrated significant reductions in RSV-associated LRTI hospitalisations following nirsevimab administration, with treatment efficacy of 62.1% and 83.2%. Emerging real-world data from early adopters of nirsevimab corroborates these findings. Studies from Spain, Luxembourg, France and the USA report effectiveness rates between 82% and 90% in preventing RSV-associated hospitalisations among infants entering their first RSV season. Current implementation strategies for nirsevimab have primarily focused on seasonal administration for all infants, aligned to local RSV seasons, and often include catch-up doses for those born before the season begins. Available cost-effectiveness analyses indicate that while nirsevimab offers significant potential public health benefits, its adoption must carefully consider economic factors such as treatment costs, implementation strategies tailored to local viral epidemiology, and logistics for vaccine delivery. Overall, nirsevimab presents a promising opportunity to alleviate the burden of severe RSV infections in young children. However, ongoing surveillance and refinements in implementation strategies are crucial to optimise its impact and ensure sustainability across diverse health-care settings.

ATAGI targeted review 2023: Vaccination for preventing influenza in Australia.

Abstract: Annual seasonal influenza epidemics cause substantial disease and economic burden worldwide. During the coronavirus disease 2019 (COVID-19) pandemic in 2020 and 2021, influenza activity significantly declined. However, influenza resurged in Australia following the relaxation of non-pharmaceutical interventions, with increased influenza virus circulation in early 2022 coinciding with the SARS-CoV-2 Omicron BA.2 variant wave. Together with other respiratory virus diseases, these disease impacts on the Australian population and healthcare system have re-emphasised the importance of influenza vaccination and control. We aim to provide an overview of the current seasonal influenza vaccination program in Australia and summarise evidence and considerations underpinning potential future immunisation strategies. Influenza causes disproportionately higher morbidity and mortality in young children and older adults. Other populations at elevated risk from influenza include Aboriginal and Torres Strait Islander peoples, pregnant women, and people with certain underlying medical conditions. All Australians aged ≥ 6 months are recommended to receive influenza vaccine every year. The National Immunisation Program (NIP) provides free vaccine for eligible at-risk populations. While approximately 70% of older adults had received influenza vaccine in 2022, coverage in other age groups remains suboptimal. There are several key unmet needs and challenges, but also potential strategies for enhancing the influenza vaccination program in Australia. Improved monitoring and evaluation, including the use of relevant linked datasets for such purposes, is imperative to better understand variations in coverage and vaccination impact in specific populations. Adoption of evidence-based strategies, such as culturally appropriate resources that consider the characteristics of diverse Australian populations, may also help to achieve higher vaccine coverage rates. Additionally, greater vaccine uptake across the population could be facilitated by expanding the NIP-eligible population where cost-effective, and adopting the use of more effective and different types of vaccines when available.

COVID-19 vaccines in 2023.

Most Australian adults now have hybrid immunity to the SARS-CoV-2 virus, referring to a combination of protection from previous vaccine doses and past infection. Protection from both vaccination and past infection wanes over time. Booster doses are recommended to ensure that those who are at increased risk of severe COVID-19 remain protected. The optimal timing of future booster doses to maintain adequate protection against severe illness is not yet known. Older age remains the most important risk factor for severe COVID-19, including in the current Omicron variant era. The original COVID-19 vaccines are monovalent vaccines based on the ancestral strain of the SARS-CoV-2 virus. Bivalent vaccines have been developed based on earlier Omicron subvariants (BA.1 or BA.4-5) and the ancestral strain. These provide enhanced protection against severe illness from Omicron compared with the original monovalent vaccines. Updated monovalent vaccines based on a more recent Omicron subvariant (XBB.1.5) have been developed. COVID-19 vaccines have an excellent safety record, and serious adverse events are extremely rare.

ATAGI Targeted Review 2022: Vaccination for prevention of herpes zoster in Australia.

Abstract: In November 2016, herpes zoster (HZ) vaccination for older adults, using the live-attenuated zoster vaccine (Zostavax; ZVL) was added to the Australian National Immunisation Program (NIP) with the aim of reducing morbidity from HZ and its complications, particularly for people at increased risk. Prior to the program, there were on average 5.6 cases of HZ per 1,000 persons annually in Australia, with highest risk of disease in older and in immunocompromised people. The burden of complications of HZ, such as post-herpetic neuralgia (PHN), was also highest in older and immunocompromised groups. No formal comprehensive program evaluation has been undertaken since program commencement. This review examined published literature and available vaccine administration data to summarise the evidence and considerations underpinning current use of HZ vaccines and potential future program directions in Australia. There have been modest reductions in the incidence of HZ and its complications since program introduction. However, five years into the program, challenges remain, including suboptimal vaccine coverage and significant safety concerns arising from inadvertent use of ZVL in immunocompromised people, who are contraindicated to receive this vaccine. This reduces opportunities to offset the burden of HZ-related disease. The recombinant subunit zoster vaccine (Shingrix; RZV), first registered in Australia in 2018, became available on the Australian market in June 2021. This vaccine has higher efficacy than ZVL and, as a non-live vaccine, can be used in both immunocompetent and immunocompromised people. RZV has potential to address the unmet needs of at-risk population groups. However, it has not yet demonstrated cost-effectiveness for inclusion as a funded vaccine under the NIP. The Australian HZ vaccination program has had limited effectiveness in meeting its aim in highest risk groups. Future options and challenges anticipated in using vaccination to reduce the burden of HZ and its complications are discussed in this review.

Disseminated varicella zoster virus infection following live attenuated herpes zoster vaccine: descriptive analysis of reports to Australia's spontaneous vaccine pharmacovigilance system, 2016-2020.

OBJECTIVES: To examine the reported incidence and features of disseminated varicella zoster virus (VZV) infection following live attenuated herpes zoster vaccine live (ZVL: Zostavax, Merck) in immunocompromised people in Australia. DESIGN AND SETTING: ZVL was funded in 2016 in Australia for people aged 70 years, with a catch-up programme for those 71-79 years. From 2016 to 2020, three deaths due to disseminated vaccine-strain VZV infection occurred following inadvertent ZVL administration in individuals with varying levels of immunocompromise. This descriptive study examined 4 years of national surveillance data reported to the Therapeutic Goods Administration's Adverse Event Monitoring System (AEMS). Denominator data for rates were from doses recorded in the Australian Immunisation Register. PARTICIPANTS: Individuals vaccinated between 1 November 2016 and 31 December 2020 who experienced adverse event(s) following immunisation (AEFI) after ZVL recorded in the AEMS. PRIMARY AND SECONDARY OUTCOME MEASURES: Rates and outcomes of confirmed (Oka strain positive) or probable disseminated VZV infection, and inadvertent administration of ZVL in immunocompromised individuals. RESULTS: 854 AEFI were reported from 1 089 966 doses of ZVL administered (78.4 per 100 000 doses). Of those, 14 were classified as confirmed (n=6, 0.55 per 100 000) or probable (n=8) disseminated VZV infection. The confirmed cases were all hospitalised, and most (5/6) were immunocompromised; three cases died. Thirty-seven individuals were reported as vaccinated despite a contraindication due to immunocompromise (3.4 per 100 000), with 12/37 (32%) hospitalised. CONCLUSIONS: Disseminated VZV is potentially life-threatening and occurs mostly in those with severe immunocompromise. Inadvertent administration of ZVL to immunocompromised individuals has occurred despite initial provider guidance and education. Multiple additional strategies to assist providers to identify contraindications have been implemented to prevent adverse outcomes.

General practitioner knowledge gaps regarding live attenuated zoster vaccination of immunocompromised individuals: An ongoing concern?

BACKGROUND AND OBJECTIVES: Live attenuated herpes zoster vaccine (Zostavax [CSL/Merck]) was included on the Australian National Immunisation Program from 1 November 2016 for adults aged 70 years, with a catch-up program for adults aged 71-79 years. The aim of this study was to assess the knowledge of Australian general practitioners (GPs) regarding Zostavax. METHOD: A national cross-sectional online survey was distributed to GPs by Healthed, a private health education provider. RESULTS: Of 605 GPs, 502 responded to the survey (response rate 83%). Eighty-nine per cent were aware that Zostavax is funded and recommended for adults aged 70-79 years. Approximately 10% incorrectly responded that immunocompromise is not a contraindication to Zostavax, and 8% were unsure. For five clinical scenarios assessing knowledge of Zostavax contraindications, the proportion of correct responses ranged 25-82%. DISCUSSION: While most GPs surveyed had good knowledge, notable gaps were identified. Further efforts are needed to promote awareness of recommendations, particularly for immunocompromised individuals. The availability of Shingrix, a non-live recombinant subunit zoster vaccine, in the private market provides an alternative, especially for immuncompromised patients.

Impact of Fever and Antipyretic Use on Influenza Vaccine Immune Reponses in Children.

BACKGROUND: Comparing postvaccination fever rates in pediatric influenza vaccine clinical trials is difficult due to variability in how fever is reported. The impact of vaccine-related fever and antipyretic use on trivalent influenza vaccine immunogenicity in children is also unclear. METHODS: In this pilot study, we used individual-level data provided by GlaxoSmithKline from 3 pediatric clinical trials of GlaxoSmithKline versus comparator trivalent influenza vaccine. We explored a primary study (NCT00764790), the largest trial involving young children (6-35 months, n = 3317), and further explored key findings in the 2 other trials (3-17 years, NCT00980005; 6 months to 17 years, NCT00383123). We analyzed postvaccination fever and antipyretic use, and their association with immunogenicity through use of multivariable regression. RESULTS: Postvaccination fever data were reanalyzed from the primary study using the Brighton Collaboration standardized definition (vaccine-related fever ≥38°C, measured by any route, reported after each dose). Rates were substantially lower after first (2.7%-3.4%) and second doses (3.3%-4.1%), than those published (6.2%-6.6%; combined dose data, any causality). A pooled immunogenicity analysis combining the 3 studies (n = 5902) revealed children with postvaccination fever had significantly higher adjusted geometric mean titers than those without fever (ratio, 1.21-1.39; P ≤ 0.01). Conversely those with antipyretic use had significantly lower adjusted geometric mean titers (ratio, 0.80-0.87; P < 0.0006), dependent on virus strain. CONCLUSIONS: Varying analyses and reporting methods can result in substantially different reported fever rates in studies. Standardized reporting of fever is needed to facilitate comparison between studies. Fever and antipyretic use may have important associations with influenza vaccine immunogenicity in children and need further prospective investigation.

The Spectrum and Burden of Influenza-Associated Neurological Disease in Children: Combined Encephalitis and Influenza Sentinel Site Surveillance From Australia, 2013-2015.

Background: There are few longitudinal studies of seasonal influenza-associated neurological disease (IAND) and none from the Southern Hemisphere. Methods: We extracted prospectively acquired Australian surveillance data from 2 studies nested within the Paediatric Active Enhanced Disease Surveillance (PAEDS) network: the Influenza Complications Alert Network (FluCAN) study and the Australian Childhood Encephalitis (ACE) study between 2013 and 2015. We described the clinical features and severity of IAND in children, including influenza-associated encephalitis/encephalopathy (IAE). We calculated the proportion of hospitalized influenza that is associated with IAND and IAE, and incidence of IAE. Results: Over 3 influenza seasons, we identified 54 cases of IAND at 2 tertiary children's hospitals from Australia that accounted for 7.6% of hospitalized influenza. These included 10 cases of IAE (1.4% hospitalized influenza). The mean annual incidence of IAE among Australian children (aged ≤14 years) was 2.8 per 1000000. The spectrum of IAND was broad and included IAE (n = 10) including distinct acute encephalopathy syndromes, simple febrile seizures (n = 14), other seizures (n = 16), acute ataxia (n = 4), and other subacute syndromes (transverse myelitis [n = 1], opsoclonus myoclonus [n = 1]). Two-thirds of children with IAND were aged ≤4 years; less than half had preexisting neurological disease or other risk factors for severe influenza. IAE caused death or neurological morbidity in half of cases. Conclusions: Seasonal influenza is an important cause of acute neurological disease in Australian children. The spectrum of seasonal IAND appears similar to that described during the 2009 H1N1 pandemic. IAE is associated with high morbidity and mortality.

Influenza vaccine efficacy in young children attending childcare: A randomised controlled trial.

AIM: Influenza causes a substantial burden in young children. Vaccine efficacy (VE) data are limited in this age group. We examined trivalent influenza vaccine (TIV) efficacy and safety in young children attending childcare. METHODS: A double-blind, randomised controlled trial in children aged 6 to <48 months was conducted with recruitment from Sydney childcare centres in 2011. Children were randomised to receive two doses of TIV or control hepatitis A vaccine. Efficacy was evaluated against polymerase chain reaction-confirmed influenza using parent-collected nose/throat swabs during influenza-like-illness. Safety outcomes were assessed during 6 months of follow-up. RESULTS: Fifty-seven children were allocated to influenza vaccine and 67 to control; all completed the study. The influenza attack rate was 1.8 vs 13.4% in the TIV and control groups, respectively; VE 87% (95%CI: 0-98%). For children aged 24 to <48 months, 0 vs 8 (18.6%) influenza infections occurred in the TIV and control groups respectively, giving a VE of 100% (16-100%). Efficacy was not shown in children 6 to <24 months, probably due to insufficient power. Injection site and systemic adverse events were mostly mild to moderate with no significant differences, apart from more mild diarrhoea following dose 2 in TIV recipients (11.8 vs 0%). CONCLUSIONS: Influenza vaccine appeared efficacious in the subgroup of children aged 24 to <48 months, although caution is required due to the small number of participants. There were no serious adverse events and most parents would vaccinate again. Influenza vaccination in a childcare setting could be valuable and a larger confirmatory study would be helpful.

Utility of early influenza diagnosis through point-of-care testing in children presenting to an emergency department.

AIM: Influenza causes a large burden of disease in children. Point-of-care testing (POCT) can rapidly diagnose influenza with the potential to reduce investigation and hospital admission rates, but information on its use in an Australian setting is limited. METHODS: Through a retrospective review of laboratory-confirmed influenza cases presenting at a paediatric emergency department (ED) in 2009, we evaluated children diagnosed by POCT versus standard testing (direct fluorescent antibody, polymerase chain reaction or viral culture) and assessed differences in investigations, admission requirements, length-of-stay (LOS) in ED/hospital and antibiotic/antiviral prescription. The rate of serious bacterial infection was examined. RESULTS: Compared with standard testing (n = 65), children diagnosed by positive POCT (n = 236) had a shorter median hospital LOS by 1 day (P = 0.006), increased antiviral prescription (odds ratio 3.31, P < 0.001) and a reduction in the time to influenza diagnosis (2.4 vs. 24.4 h, P < 0.001); however, a negative POCT result (n = 63) resulted in delayed diagnosis (44.0 h, P = 0.001). POCT did not decrease LOS in ED. Interpretation of reductions in admission and investigations with POCT may be limited by possible confounding. Approximately 4% of influenza patients had a serious bacterial infection; urinary tract infections were commonest (2.7%), but no cerebrospinal fluid cultures were positive. A single positive blood culture was seen among 332 immunocompetent influenza patients. CONCLUSIONS: Influenza diagnosis by POCT was quicker and reduced LOS of hospitalised children, whereas negative results delayed diagnosis. Negative POCT should not alter usual investigations if influenza remains suspected. A controlled prospective study during the influenza season is needed to clarify the direct benefits of POCT.

The manufacturing process should remain the focus for severe febrile reactions in children administered an Australian inactivated influenza vaccine during 2010.

Influenza vaccine safety is an ongoing issue. In 2010, inactivated trivalent influenza vaccines (TIVs), Fluvax(®) and Fluvax Junior(®) manufactured by CSL Biotherapies ('CSL'), Parkville, Australia, were associated with a marked increase in febrile seizures (FS) in children <5 years old. Extensive investigations initially failed to identify a root cause. The company's researchers recently published two papers outlining their latest findings. Cytokine responses to TIV were measured in paediatric whole blood assays (WBA); NF-κB activation was assessed using a HEK293 cell line reporter assay. CSL suggest that the combination of new influenza strains (H1N1 A/California/7/2009 and B/Brisbane/60/2008), increased complexes of viral RNA and lipid in the vaccine, and inherent sensitivities of some children <5 years old caused elevated inflammatory responses resulting in FS. Whilst the papers provide insight into pathogenesis, much remains unclear. The WBA were from only 10 'healthy' children, potentially affecting generalisability of the results and reliability of these in vitro tests in assessing future influenza vaccine safety. Increased fever rates (without FS) found in CSL TIV studies between 2005 and 2010 suggest a long-standing contribution to reactogenicity from the manufacturing process. More detailed comparisons with non-CSL vaccines would have helped elucidate the relative contribution of patient/strain factors and the manufacturing process. The focus remains on manufacturing process differences as the key causative factor of elevated febrile responses. Studies underway, of modified vaccines in young children, will determine whether reactogenicity issues have been successfully addressed and whether CSL TIV can be relicensed in children <5 years of age.

Australian vaccine preventable disease epidemiological review series: Influenza 2006 to 2015.

INTRODUCTION: Influenza is a major contributor to the preventable health burden of Australians each year. The National Immunisation Program provides influenza vaccine for those at highest risk of severe disease. This review of influenza epidemiology examines current data on influenza disease burden in Australia, in the context of several comparable countries having programs with much broader eligibility for influenza vaccine in children. METHODS: Influenza notifications (2006-2015), hospitalisations, and deaths (2006-2013) were sourced and age-specific rates calculated. Comparisons were made across age groups in the pre-pandemic, pandemic, and post-pandemic periods and by Indigenous and non-Indigenous status. RESULTS: The 2009 pandemic year and the 2012 non-pandemic season resulted in the highest rates of notification, hospitalisation and death. Influenza notification rates were 4.0 times higher and hospitalisation rates 2.1 times higher during 2011-2013 compared with 2006-2008. Death rates varied widely, but peaks corresponded to high-activity seasons. Influenza hospitalisation rates were highest among those aged <5 and ≥65 years, but influenza-attributable deaths were identified primarily in those aged ≥75 years. Significantly higher notification and hospitalisation rates were seen for all Indigenous people, but higher death rates were largely restricted to the 2009 pandemic year. CONCLUSIONS: Based on notifications, hospitalisations and deaths, burden of disease from influenza is highest at the extremes of life and is significantly higher among Indigenous people of all ages. This pattern of disease burden warrants consideration of widened eligibility for influenza vaccine under the National Immunisation Program to all Indigenous people and all children less than 5 years of age.

Comparing the use of, and considering the need for, lumbar puncture in children with influenza or other respiratory virus infections.

BACKGROUND: The clinical presentation of influenza in infancy may be similar to serious bacterial infection and be investigated with invasive procedures like lumbar puncture (LP), despite very limited evidence that influenza occurs concomitantly with bacterial meningitis, perhaps because the diagnosis of influenza is very often not established when the decision to perform LP is being considered. METHODS: A retrospective medical record review was undertaken in all children presenting to the Children's Hospital at Westmead, Sydney, Australia, in one winter season with laboratory-confirmed influenza or other respiratory virus infections (ORVIs) but excluding respiratory syncytial virus, to compare the use of, and reflect on the need for, the performance of invasive diagnostic procedures, principally LP, but also blood culture, in influenza and non-influenza cases. We also determined the rate of concomitant bacterial meningitis or bacteraemia. FINDINGS: Of 294 children, 51% had laboratory-confirmed influenza and 49% had ORVIs such as parainfluenza viruses (34%) and adenoviruses (15%). Of those with influenza, 18% had a LP and 71% had a blood culture performed compared with 6·3% and 55·5% in the ORVI group (for both P<0·01). In multivariate analysis, diagnosis of influenza was a strong independent predictor of both LP (P=0·02) and blood culture (P=0·05) being performed, and, in comparison with ORVIs, influenza cases were almost three times more likely to have a LP performed on presentation to hospital. One child with influenza (0·9%) had bacteraemia and none had meningitis. INTERPRETATION: Children with influenza were more likely to undergo LP on presentation to hospital compared with those presenting with ORVIs. If influenza is confirmed on admission by near-patient testing, clinicians may be reassured and less inclined to perform LP, although if meningitis is clinically suspected, the clinician should act accordingly. We found that the risk of bacterial meningitis and bacteraemia was very low in hospitalised children with influenza and ORVIs. A systematic review should be performed to investigate this across a large number of settings.

Esophageal subepithelial fibrosis and hyalinization are features of eosinophilic esophagitis.

BACKGROUND AND OBJECTIVE: Eosinophilic esophagitis (EE) is characterized by marked esophageal mucosal eosinophilia on histological examination. Although the clinical and histological features of EE are increasingly recognized, the overlap of clinical symptoms and histological findings with gastroesophageal reflux disease (GERD) can lead to diagnostic difficulty. In children with EE we sought to define the frequency of subepithelial fibrosis and define the clinical correlates of this feature. The specificity of this finding in EE was obtained by comparison with a matched group of children with GERD, to ascertain its usefulness as a histological aid in differentiating between the 2 diagnoses. PATIENTS AND METHODS: Comparison was made between 27 patients with EE and 24 patients with GERD, whose endoscopic biopsy specimens included subepithelial tissue. Demographic data, symptoms, endoscopic findings, and other histological findings were also compared. RESULTS: In contrast to patients with GERD, those with EE more commonly reported longer periods of symptoms (especially dysphagia) and were more likely to have endoscopic abnormalities. Subepithelial fibrosis was present in 89% of patients with EE and 37.5% of patients with GERD (P < 0.0001). The features of fibrosis in EE included uniformity and hyalinization, whereas the fibrosis in GERD was predominantly associated with lymphoid tissue. CONCLUSIONS: Subepithelial fibrosis commonly occurs in children with EE and is associated with increased age and length of symptoms. We propose that along with mucosal eosinophilic infiltration the presence of subepithelial fibrosis is a feature of EE.

Management of acute superior mesenteric artery occlusion.

BACKGROUND: This review examines the surgical management of acute superior mesenteric artery (SMA) occlusion and the impact of interventional radiology techniques. METHODS: Eight consecutive patients with SMA occlusion were treated at the Lismore Base Hospital, Lismore, NSW, Australia, from 1996 through to 2001 and of these, one patient was managed successfully with catheter-directed lytic therapy. The study group included five male and three female patients with a mean age of 71.3 (range 57-88) years. The records of these patients were reviewed to determine demographic characteristics, clinical features, predisposing factors and the duration of symptoms before intervention, management details and final outcome. RESULTS: Embolic phenomena due to atrial fibrillation were the most frequently identifiable cause of acute SMA occlusion, present in six of eight patients. Seven patients were managed with open surgery in the first instance and of these, four died. Three patients remain alive and well at a mean 2.8 years follow-up. Patient number eight developed acute SMA occlusion from embolism secondary to atrial fibrillation and was managed initially with SMA urokinase thrombolysis. This patient's pain was relieved 1 h after initiation of the procedure. Delayed films after 18 h from initiation of thrombolysis demonstrated re-opening of all the ileo-colic branches and at 6 weeks' follow-up the patient remains well with normal bowel function. CONCLUSIONS: There is a role for selective SMA cannulation and urokinase thrombolysis in the management of patients with acute SMA thrombosis.