Novel Human Parechovirus 3 Diversity, Recombination, and Clinical Impact Across 7 Years: An Australian Story.

BACKGROUND: A novel human parechovirus 3 Australian recombinant (HPeV3-AR) strain emerged in 2013 and coincided with biennial outbreaks of sepsis-like illnesses in infants. We evaluated the molecular evolution of the HPeV3-AR strain and its association with severe HPeV infections. METHODS: HPeV3-positive samples collected from hospitalized infants aged 5-252 days in 2 Australian states (2013-2020) and from a community-based birth cohort (2010-2014) were sequenced. Coding regions were used to conduct phylogenetic and evolutionary analyses. A recombinant-specific polymerase chain reaction was designed and utilized to screen all clinical and community HPeV3-positive samples. RESULTS: Complete coding regions of 54 cases were obtained, which showed the HPeV3-AR strain progressively evolving, particularly in the 3' end of the nonstructural genes. The HPeV3-AR strain was not detected in the community birth cohort until the initial outbreak in late 2013. High-throughput screening showed that most (>75%) hospitalized HPeV3 cases involved the AR strain in the first 3 clinical outbreaks, with declining prevalence in the 2019-2020 season. The AR strain was not statistically associated with increased clinical severity among hospitalized infants. CONCLUSIONS: HPeV3-AR was the dominant strain during the study period. Increased hospital admissions may have been from a temporary fitness advantage and/or increased virulence.

Using a bedside test to detect genetic susceptibility to aminoglycoside-induced hearing loss: Has the future arrived?

Aminoglycosides are among the most commonly prescribed antibiotics in hospitalised Australian adults and children. A proportion of individuals with an underlying genetic predisposition to aminoglycoside-induced hearing loss (AIHL) can develop bilateral sensorineural hearing loss that is immediate and profound after just a single standard dose of an aminoglycoside. A recent publication described the use of a rapid point-of-care test (POCT) in a neonatal nursery in the United Kingdom for real-time detection of infants at risk of AIHL, in whom exposure to aminoglycosides could then be avoided. This proof of concept study should provide a catalyst for further development of similar assays that would be suitable for Australia's genetically diverse population. The barriers to mitigating the impact of AIHL on Australian children are not primarily technical, but involve a lack of data on the prevalence of the MT-RNR1 mutations in our current neonatal and paediatric populations and intensive care nurseries.

Impact of renin-angiotensin-aldosterone system inhibition on mortality in critically ill COVID-19 patients with pre-existing hypertension: a prospective cohort study.

BACKGROUND: The influence of renin-angiotensin-aldosterone system (RAAS) inhibitors on the critically ill COVID-19 patients with pre-existing hypertension remains uncertain. This study examined the impact of previous use of angiotensin-converting enzyme inhibitors (ACEi) and angiotensin receptor blockers (ARB) on the critically ill COVID-19 patients. METHODS: Data from an international, prospective, observational cohort study involving 354 hospitals spanning 54 countries were included. A cohort of 737 COVID-19 patients with pre-existing hypertension admitted to intensive care units (ICUs) in 2020 were targeted. Multi-state survival analysis was performed to evaluate in-hospital mortality and hospital length of stay up to 90 days following ICU admission. RESULTS: A total of 737 patients were included-538 (73%) with pre-existing hypertension had received ACEi/ARBs before ICU admission, while 199 (27%) had not. Cox proportional hazards model showed that previous ACEi/ARB use was associated with a decreased hazard of in-hospital death (HR, 0.74, 95% CI 0.58-0.94). Sensitivity analysis adjusted for propensity scores showed similar results for hazards of death. The average length of hospital stay was longer in ACEi/ARB group with 21.2 days (95% CI 19.7-22.8 days) in ICU and 6.7 days (5.9-7.6 days) in general ward compared to non-ACEi/ARB group with 16.2 days (14.1-18.6 days) and 6.4 days (5.1-7.9 days), respectively. When analysed separately, results for ACEi or ARB patient groups were similar for both death and discharge. CONCLUSIONS: In critically ill COVID-19 patients with comorbid hypertension, use of ACEi/ARBs prior to ICU admission was associated with a reduced risk of in-hospital mortality following adjustment for baseline characteristics although patients with ACEi/ARB showed longer length of hospital stay. Clinical trial registration The registration number: ACTRN12620000421932; The date of registration: 30, March 2020; The URL of the registration: https://www.australianclinicaltrials.gov.au/anzctr/trial/ACTRN12620000421932 .

Parechovirus infection in infants: Evidence-based parental counselling for paediatricians.

AIM: Human parechovirus (HPeV) is an increasingly recognised cause of severe illness and central nervous system infection in infants. Medium- to long-term neurodevelopmental outcomes post-HPeV infection remain unknown. This study aims to assess neurodevelopmental outcomes for children hospitalised as infants with HPeV infection in their second and third years of life. METHODS: This prospective cohort study followed children hospitalised with HPeV in Brisbane, Queensland during the 2017/2018 outbreak. Serial application of Ages and Stages Questionnaire (ASQ) was used to assess developmental progress in the second and third years of life. Data from clinical follow-up, audiology and neuroradiology were included. RESULTS: In the second year of life, 63% (n = 29) of children showed some or significant concerns for developmental delay. This had largely been ameliorated by the third year of life when only 30% (n = 14) reported developmental concerns. Prematurity and apnoeas were associated with developmental concerns at 27-36 months of age. Communication was the most common domain of concern. CONCLUSIONS: The majority of infants hospitalised with HPeV infection in 2017-2018 showed normalisation of developmental progress by 27-36 months of age. Further investigation into more subtle neurological impairments in later childhood is required. These results can help guide clinicians in counselling parents during the acute illness and in planning appropriate follow-up.

Paediatric intensive care admissions during the 2015-2016 Queensland human parechovirus outbreak.

AIM: The human parechovirus (HPeV) has emerged as a pathogen causing sepsis-like presentations in young infants, but there is a lack of data on HPeV presentations requiring intensive care support. We aimed to characterise the clinical presentation, disease severity, management and outcome of a population-based cohort of children with microbiologically confirmed HPeV infection requiring admission to paediatric intensive care units (PICUs) in Queensland, Australia during a recent outbreak. METHODS: This was a multicentre retrospective study of children admitted to PICU between 1 January 2015 and 31 December 2016 with confirmed HPeV infection. RESULTS: Thirty infants (median age 20 days) with HPeV genotype 3 were admitted to PICU, representing 16% of all children with HPeV admitted to hospital and 6.4% of non-elective PICU admissions in children <1 year of age. Children requiring PICU admission were younger than children admitted to hospital (P = 0.001). Apnoea, haemodynamic instability with tachycardia and seizures represented the main reasons for PICU admission. Eleven children (37%) required mechanical ventilation for a median duration of 62 h, 22 (73%) received fluid boluses and 7 (23%) were treated with vasoactive agents for a median duration of 53 h. Median length of stay was 2.62 days. A total of 24 children (80%) fulfilled sepsis criteria, 14 (47%) severe sepsis and 7 (23%) septic shock criteria. Eight (27%) had abnormal brain magnetic resonance imaging. No patient died. CONCLUSIONS: We confirm that HPeV infection is an important cause of sepsis-like syndrome in infants with substantial associated morbidity. Optimal management and long-term outcomes require further investigation.

Early-onset group B streptococcal disease in a risk factor-based prevention setting: A 15-year population-based study.

BACKGROUND: Intrapartum chemoprophylaxis reduces early-onset group B streptococcal disease (EOGBSD) in newborns. Some guidelines advise that intrapartum antibiotics should be offered following universal antenatal screening for GBS carriage and others recommend intrapartum antibiotics based on clinical risk factors alone. Since 1999, Queensland guidelines have recommended a risk factor-based approach. We examined trends in EOGBSD rates over time in Queensland in the setting of these guidelines and whether management of cases reflected the recommendations. METHODS: A state-wide retrospective search of pathology databases, allowing near-complete, population-based case identification, was conducted to detect live-born infants from January 2000 to December 2014 with GBS cultured from blood or cerebrospinal fluid within seven days of age. A nested audit of EOGBSD cases comparing two epochs, 2000-2010 and 2011-2014, was performed to determine patient characteristics and guideline adherence for each case. RESULTS: Mean incidence of EOGBSD in Queensland from 2000 to 2014 was 0.33 per 1000 live births (SD± 0.08) with no changing trend over time. The case-mortality rate in the 2011-2014 epoch was 1.2% compared to 11.9% in 2000-2004 (odds ratio (OR) 0.09, 95% confidence interval (CI) 0.002-0.67). The proportion of EOGBSD cases who were preterm infants decreased from 29.8% to 13.3% (OR 0.36, 95% CI 0.14-0.84). Of cases with risk factors in the 2011-2014 epoch, 46% received intrapartum antibiotics compared to 25% in 2000-2004 (OR 2.49, 95% CI 0.86-7.58, P = 0.09). CONCLUSIONS: EOGBSD incidence rate in Queensland remained low during 2000-2014. However, both the 2011-2014 case-mortality rate and the proportion of preterm cases significantly decreased. Missed opportunities for intrapartum chemoprophylaxis remain.

Human Parechovirus 3 in Infants: Expanding Our Knowledge of Adverse Outcomes.

BACKGROUND: Human parechovirus particularly genotype 3 (HPeV3) is an emerging infection affecting predominantly young infants. The potential for neurologic sequelae in a vulnerable subset is increasingly apparent. A review of 2 epidemics of human parechovirus (HpeV) infection in 2013 and in 2015 in Queensland, Australia, was undertaken, with an emphasis on identifying adverse neurodevelopmental outcome. METHODS: All hospitalized cases with laboratory-confirmed HPeV infection between October 2013 June 2016 were identified. Clinical, demographic, laboratory and imaging data were collected and correlated with reported developmental outcome. RESULTS: Laboratory-confirmed HPeV infections were identified in 202 patients across 25 hospitals; 86.6% (n = 175) were younger than 3 months 16.3% (n = 33) received intensive care admission. Of 142 cerebrospinal fluid samples which were HPeV polymerase chain reaction positive, all 89 isolates successfully genotyped were HPeV3. Clinical information was available for 145 children; 53.1% (n = 77) had follow-up from a pediatrician, of whom 14% (n = 11) had neurodevelopmental sequelae, ranging from hypotonia and gross motor delay to spastic quadriplegic cerebral palsy and cortical visual impairment. Of 15 children with initially abnormal brain magnetic resonance imaging, 47% (n = 7) had neurodevelopmental concerns, the remainder had normal development at follow-up between 6 and 15 months of age. CONCLUSIONS: This is the largest cohort of HPeV3 cases with clinical data and pediatrician-assessed neurodevelopmental follow-up to date. Developmental concerns were identified in 11 children at early follow-up. Abnormal magnetic resonance imaging during acute infection did not specifically predict poor neurodevelopmental in short-term follow-up. Continued follow-up of infants and further imaging correlation is needed to explore predictors of long-term morbidity.

Pertussis toxin IgA testing over-diagnoses recent pertussis infection.

The importance of pertussis toxin (PT) IgA testing in the diagnosis of recent pertussis infection remains unclear. The contribution of PT IgA to the diagnosis of recent pertussis was reviewed in two separate analyses. Firstly, an evaluation of two new automated assays [DiaSorin Liaison (DL), Italy] for PT IgG and PT IgA provided an opportunity to assess the contribution of PT IgA testing to PT IgG results. Secondly, a retrospective review of results from the PT IgA assay currently in use [Sullivan Nicolaides Pathology (SNP) PT IgA] was performed from 2013 to 2015 (n=63,474). For both the DL and SNP assays, the combination of PT IgG and PT IgA resulted in reduced specificity as compared to PT IgG results alone. For DL assays, an algorithm restricting DL PT IgA testing to samples with equivocal PT IgG results, demonstrated superior specificity to routinely testing both assays. The retrospective review indicated that only a minority of patients had a SNP PT IgA response without an accompanying rise in SNP PT IgG. There was also evidence of an age-related increase in the prevalence of isolated positive SNP PT IgA results which did not appear to be associated with recent pertussis infection. In general, PT IgA appears to contribute little diagnostic value to an accurate PT IgG assay in a community-based, Australian population. Reflex testing of PT IgA in the context of equivocal PT IgG results may be worthwhile if laboratory workflow permits.

Corynebacterium diphtheriae and the returned tropical traveler.

BACKGROUND: In Western countries, nontoxigenic Corynebacterium diphtheriae is known to cause skin and soft tissue infections (SSIs), upper respiratory tract infections, and occasionally invasive disease. Its role as a skin pathogen in returned travelers from tropical destinations where the organism is endemic is often forgotten. A retrospective analysis of a large Australian private pathology laboratory's experience with C. diphtheriae was performed to identify how frequently overseas travel was associated with C. diptheriae infection/colonization. METHODS: All C. diphtheriae isolates cultured from 2002 to 2012 were reviewed. Recorded clinical information regarding recent travel, country, and cause of infection was assessed. Antibiotic susceptibility was verified on all isolates. RESULTS: In all there were 72 patients who had C. diphtheriae isolated on clinical specimens, and information about prior travel was available for 63. Seventy percent of these were healthy individuals with an SSI and history of recent travel to a tropical nation. Ninety-seven percent had associated copathogens. Two isolates were penicillin resistant. There was uniform susceptibility to cephalothin, clindamycin, erythromycin, and vancomycin, with 14% resistance to trimethoprim/sulfamethoxazole and 4% resistance to tetracycline. Only one isolate was a toxigenic strain. CONCLUSION: The majority of C. diphtheriae isolated were from SSIs in otherwise healthy travelers returning from tropical destinations, rather than classical risk groups. Clinicians and laboratories need to be aware of this potential source of C. diphtheriae infection due to rare toxigenic strains.

Development and validation of an Australian in-house anti-pertussis toxin IgG and IgA enzyme immunoassay.

AIMS: Although anti-pertussis toxin (PT) immunoglobulin G (IgG) is considered one of the most specific serological markers for Bordetella pertussis infection, there are few commercial kits available in Australia. We aimed to present the process of development, quality control and on-going clinical validation of an anti-PT IgG and IgA enzyme immunoassay (EIA) in use since 1999, and discuss the application of such tests in the diagnosis of B. pertussis infections. METHODS: A total of 1311 serum samples were used during multiple clinical validations from 1998 to 2010. The samples were drawn from healthy adults, children, patients with other respiratory infections, and patients with confirmed pertussis. Assay reproducibility, accuracy and precision criteria conformed to National Pathology Accreditation Advisory Council (NPAAC) guidelines. RESULTS: Using the World Health Organization clinical and/or laboratory definition of a definite case as the comparative standard, sensitivity was 84% [95% confidence interval (CI) 75-93] and specificity was 98% (95%CI: 90-100) for anti-PT IgG. Sensitivity was 72% (95%CI 64-80) and specificity was 98% (95%CI 90-100) for anti-PT IgA. There was minimal background positivity in either healthy adults or children using the established cut-offs. There was no appreciable effect of immunisation or cross reactions with other respiratory pathogens. CONCLUSION: Serological evaluation of various populations enabled the development of an anti-PT IgG and IgA EIA assay which was suitable for the diagnosis of acute infection in convalescent samples from clinically confirmed cases. Repeated evaluations of population-based cut-offs are required for in-house assays to ensure they remain clinically relevant. The subsequent validation of the cut-offs with WHO international standards has been published in a recent prospective study.

Prospective evaluation of an Australian pertussis toxin IgG and IgA enzyme immunoassay.

Serological diagnosis of recent pertussis infection is an important part of both clinical assessment and epidemiological documentation of this disease. Standardization of serological testing and interpretation remains challenging despite international efforts to improve it. Currently, determining the anti-pertussis toxin (PT) IgG titer is recommended as the most accurate serological test in Europe and the United States, while Australia relies predominantly on measurement of Bordetella pertussis IgA antibody responses. Using B. pertussis PCR and the WHO clinical case definition as reference standards, the diagnostic utility of in-house anti-PT IgG and anti-PT IgA assays was evaluated prospectively in an Australian community-based cohort (n = 327). Patients provided up to four consecutive serum samples to document the kinetics of antibody response and decay. Previously validated cutoffs for positivity were converted to international units by using WHO-approved reference sera. At currently used cutoffs, both anti-PT IgG (>94 IU/ml) and anti-PT IgA (>20 IU/ml) assays had good specificity (80% [95% confidence interval {95% CI}, 68 to 88%] and 87% [95% CI, 77 to 94%]), but anti-PT IgG assay was consistently more sensitive than anti-PT IgA assay across a range of cutoffs (60 to 79% [95% CI, 53 to 84%] versus 41 to 62% [95% CI, 34 to 69%]). The combination of anti-PT IgG and anti-PT IgA assays performed no better than anti-PT IgG assay alone. The anti-PT IgA response in children under 12 years of age was poor. The accuracy of serology was optimal between 2 and 8 weeks after symptom onset. Cutoffs of >94 IU/ml for anti-PT IgG and >20 IU/ml for anti-PT IgA correlated well with recent pertussis infection and were consistent with recent recommendations from the EU Pertstrain group. Anti-PT IgG assay was superior to anti-PT IgA assay as the test of choice for the diagnosis of pertussis from a single sample.

Infant botulism in Australia: availability of human botulinum antitoxin for treatment.

We report the first Australian case of treatment of infant botulism with a human botulinum antitoxin developed in the United States by the California Department of Public Health. Our patient's clinical improvement was rapid, and although the product is expensive, cost-analysis supports the economical viability of its use. In future cases of suspected infant botulism, we recommend that Australian clinicians promptly obtain and administer this antitoxin to their patient.

Pertussis in infants: how to protect the vulnerable?

In terms of adverse outcomes, infants remain the group most vulnerable to severe pertussis disease. Adult household contact is thought to be the main source of transmission to infants. This study reviews exposure history, vaccination status, admission outcome and quality of discharge coding of hospitalised infants with pertussis at a tertiary paediatric hospital. We identified cases between 1997 and 2006 from 2 sources: hospital discharge coding and positive Bordetella pertussis results from the hospital laboratory database. We assessed the completeness of each of these sources, compared with the dataset of all identified cases. We identified 55 hospitalised infants with pertussis. The 35 cases (64%) less than 3 months of age had greater risk of Intensive Care Unit admission, higher mortality, and were more likely to have parents as an identified source. On admission, only 5 cases (9%) were more than 2 weeks overdue for their previous scheduled pertussis vaccination. Discharge coding was more sensitive for identifying cases than the laboratory database. Nine cases (16%) had incorrect discharge coding. Even infants up to date for pertussis vaccine can have severe disease requiring hospitalisation. Immunising parents planning to have, or who have had, a newborn baby may help to prevent pertussis in infants.

Influenza A associated morbidity and mortality in a Paediatric Intensive Care Unit.

This paper reports the clinical features and outcome of all children with a laboratory proven diagnosis of influenza A virus infection admitted to a major Paediatric Intensive Care Unit (PICU) in 2003. Eight of the 22 patients with influenza A virus infection (A/Fujian/411/2002-like type) presented with encephalopathy and three of the 22 patients died. This can be compared with 44 admissions and seven (16%) deaths of patients with influenza virus admitted in the same PICU in the preceding 15 years. In the present cohort, four (18%) of the 22 patients, including one child who died, should have received influenza vaccine according to the current Australian immunisation recommendations. We have no documented evidence that any of the 22 children received influenza vaccination. During the 2003 influenza season there was an increased number of children admitted to our PICU with influenza A infection and an increased number of deaths compared with previous years. Influenza infection causes significant morbidity and mortality in young children, most of whom are not currently recommended for annual influenza vaccination.