Australian Paediatric Surveillance Unit (APSU) Annual Surveillance Report 2019

Roberts J.A., Hobday L.K., Ibrahim A., Aitken T., Thorley B.R.

Australia conducts surveillance for cases of acute flaccid paralysis (AFP) in children less than 15 years as recommended by the World Health Organization (WHO) as the main method to monitor its polio-free status. Cases of AFP in children are notified to the Australian Paediatric Surveillance Unit or the Paediatric Active Enhanced Disease Surveillance System and faecal specimens are referred for virological investigation to the National Enterovirus Reference Laboratory. In 2015, no cases of poliomyelitis were reported from clinical surveillance and Australia reported 1.2 non-polio AFP cases per 100,000 children, meeting the WHO performance criterion for a sensitive surveillance system. Two non-polio enteroviruses, enterovirus A71 and coxsackievirus B3, were identified from clinical specimens collected from AFP cases. Australia complements the clinical surveillance program with enterovirus and environmental surveillance for poliovirus. Two Sabin-like polioviruses were isolated from sewage collected in Melbourne in 2015, which would have been imported from a country that uses the oral polio vaccine. The global eradication of wild poliovirus type 2 was certified in 2015 and Sabin poliovirus type 2 will be withdrawn from oral polio vaccine in April 2016. Laboratory containment of all remaining wild and vaccine strains of poliovirus type 2 will occur in 2016 and the National Enterovirus Reference Laboratory was designated as a polio essential facility. Globally, in 2015, 74 cases of polio were reported, only in the two remaining countries endemic for wild poliovirus: Afghanistan and Pakistan. This is the lowest number reported since the global polio eradication program was initiated.

Bao J., Thorley B., Elliott E.J., McIntyre P., Britton P.N.

We have identified a previously unrecognised cluster of a newly recognised condition – acute flaccid myelitis (AFM) – among acute flaccid paralysis (AFP) cases identified by the Australian Paediatric Active Enhanced Disease Surveillance Network (PAEDS) 2007–2017. In the 12 months before and after detection of enterovirus D68 (EV-D68) from a single AFP case in April 2016, 24 of 97 notified cases of AFP were found to be clinically compatible with AFM; of these 24 cases, ten, clustered in early 2016, met magnetic resonance imaging (MRI) criteria for AFM. Detection of emerging enteroviruses requires collection of respiratory, cerebrospinal fluid and stool specimens, and should be routine practice for all AFP cases.

Hull B., Hendry A., Dey A., Brotherton J., Macartney K., Beard F.

This eleventh national annual immunisation coverage report focuses on data for the calendar year 2017 derived from the Australian Immunisation Register (AIR) and the National Human Papillomavirus (HPV) Vaccination Program Register. This is the first report to include data on HPV vaccine course completion in Aboriginal and Torres Strait Islander (Indigenous) adolescents. ‘Fully immunised’ vaccination coverage in 2017 increased at the 12-month assessment age reaching 93.8% in December 2017, and at the 60-month assessment age reaching 94.5%. ‘Fully immunised’ coverage at the 24-month assessment age decreased slightly to 89.8% in December 2017, following amendment in December 2016 to require the fourth DTPa vaccine dose at 18 months. ‘Fully immunised’ coverage at 12 and 60 months of age in Indigenous children reached the highest ever recorded levels of 93.2% and 96.9% in December 2017. Catch-up vaccination activity for the second dose of measles-mumps-rubella-containing vaccine was considerably higher in 2017 for Indigenous compared to non-Indigenous adolescents aged 10–19 years (20.3% vs. 6.4%, respectively, of those who had not previously received that dose). In 2017, 80.2% of females and 75.9% of males aged 15 years had received a full course of three doses of human papillomavirus (HPV) vaccine. Of those who received dose one, 79% and 77% respectively of Indigenous girls and boys aged 15 years in 2017 completed three doses, compared to 91% and 90% of non-Indigenous girls and boys, respectively. A separate future report is planned to present adult AIR data and to assess completeness of reporting.

Nunez C., Morris A., Teutsch S., McGregor S., Brotherton J., Novakovic D., Rawlinson W., Jones C., Thorley B., Elliott E.

Beard F.H., Hendry A.J., Macartney K.

McRae J.E., Quinn H.E., Saravanos G.L., McMinn A., Britton P.N., Wood N., Marshall H., Macartney K.

Introduction The Paediatric Active Enhanced Disease Surveillance (PAEDS) network is a hospital-based active surveillance system employing prospective case ascertainment for selected serious childhood conditions, particularly vaccine preventable diseases and potential adverse events following immunisation (AEFI). PAEDS data is used to better understand these conditions, inform policy and practice under the National Immunisation Program, and enable rapid public health responses for certain conditions of public health importance. PAEDS enhances data available from other Australian surveillance systems by providing prospective, detailed clinical and laboratory information on children with selected conditions. This is the third annual PAEDS report, and presents surveillance data for 2016. Methods Specialist nurses screened hospital admissions, emergency department records, laboratory and other data, on a daily basis in 5 paediatric tertiary referral hospitals in New South Wales, Victoria, South Australia, Western Australia and Queensland to identify children with the conditions under surveillance. Retrospective data on some conditions was also captured by an additional hospital in the Northern Territory. Standardised protocols and case definitions were used across all sites. Conditions under surveillance in 2016 included acute flaccid paralysis (AFP) (a syndrome associated with poliovirus infection), acute childhood encephalitis (ACE), influenza, intussusception (IS; a potential AEFI with rotavirus vaccines), pertussis, varicella-zoster virus infection (varicella and herpes zoster), invasive meningococcal and invasive Group A streptococcus diseases. Most protocols restrict eligibility to hospitalisations; Emergency Department (ED) only presentations are also included for some conditions. Results In 2016, there were 673 cases identified across all conditions under surveillance. Key outcomes of PAEDS included: contribution to national AFP surveillance to reach World Health Organization (WHO) reporting targets; identification of the leading infectious causes of acute encephalitis which included human parechovirus, influenza, enteroviruses, Mycoplasma pneumoniae, and bacterial meningo-encephalitis; demonstration of high influenza activity with vaccine effectiveness (VE) analysis demonstrating some protection offered through vaccination. All IS cases associated with vaccine receipt were reported to the relevant state health department. Varicella and herpes zoster case numbers increased from previous years associated with suboptimal vaccination in up to 40% of cases identified. Pertussis surveillance continued in 2016 with the addition of test negative controls captured for estimating vaccine effectiveness. Surveillance for invasive meningococcal disease showed predominance for serotype B in absence of immunisation, and new invasive group A streptococcus surveillance captured severe disease in children.   Conclusions PAEDS continues to provide unique policy-relevant data on serious paediatric conditions using hospital-based sentinel surveillance. Keywords: paediatric, surveillance, child, hospital, vaccine preventable diseases, adverse event following immunisation, acute flaccid paralysis, encephalitis, influenza, intussusception, pertussis, varicella zoster virus, meningococcal, group A streptococcus.

Bartlett A.W., Hall B.M., Palasanthiran P., McMullan B., Shand A.W., Rawlinson W.D.

Australian national surveillance data was used to assess recognition, sequelae, and antiviral therapy for congenital cytomegalovirus (CMV) cases.Data from congenital CMV cases reported through the Australian Paediatric Surveillance Unit born January 1999 to December 2016 were described and Chi-square tests used to characterise trends and associations in case reporting, maternal CMV serology testing, and antiviral therapy. Descriptive analyses for hearing loss and developmental delay were reported for cases born ≥2004, following introduction of universal neonatal hearing screening.There were 302 congenital CMV cases (214 symptomatic, 88 asymptomatic). Congenital CMV was suspected in 70.6% by 30 days of age, with no differences across birth cohorts. Maternal CMV serology testing was associated with maternal illness during pregnancy but not birth cohort. There was increasing antiviral use for symptomatic cases, being used in 14% born 1999-2004, 19.6% born 2005-2010, and 44.4% born 2011-2016 (p < 0.001). For those born ≥2004, hearing loss was reported in 42.1% of symptomatic and 26.6% of asymptomatic cases; while developmental delay was reported in 16.9% of symptomatic and 1.3% of asymptomatic cases.There appears to be under-reporting and under-recognition of congenital CMV despite increasing use of antiviral therapy. Universal newborn CMV screening should be considered to facilitate follow-up of affected children and targeted linkage into hearing and developmental services, and to provide population-level infant CMV epidemiology to support research and evaluation of antiviral and adjunctive therapies.

Zurynski Y., Deverell M., Phu A., Booy R., Elliott E.

Machalek D.A., Garland S.M., Brotherton J.M., Bateson D., McNamee K., Stewart M., Rachel Skinner S., Liu B., Cornall A.M., Kaldor J.M., Tabrizi S.N.

A quadrivalent human papillomavirus vaccination program targeting females aged 12-13 years commenced in Australia in 2007, with catch-up vaccination of 14-26 year olds through 2009. We evaluated the program's impact on HPV prevalence among women aged 18-35 in 2015.HPV prevalence among women aged 18-24 and 25-35 was compared with prevalence in these age groups in 2005-2007. For women aged 18-24, we also compared prevalence with that in a postvaccine study conducted in 2010-2012.For the 2015 sample, Vaccination Register-confirmed 3-dose coverage was 53.3% (65.0% and 40.3% aged 18-24 and 25-35, respectively). Prevalence of vaccine HPV types decreased from 22.7% (2005-2007) and 7.3% (2010-2012), to 1.5% (2015) (P trend < .001) among women aged 18-24, and from 11.8% (2005-2007) to 1.1% (2015) (P = .001) among those aged 25-35.This study, reporting the longest surveillance follow-up to date, shows prevalence of vaccine-targeted HPV types has continued to decline among young women. A substantial fall also occurred in women aged 25-35, despite lower coverage. Strong herd protection and effectiveness of less than 3 vaccine doses likely contributed to these reductions.

Bartlett A.W., McMullan B., Rawlinson W.D., Palasanthiran P.

Congenital CMV is one of the commonest congenital infections and a recognised cause of sensorineural hearing loss and neurodevelopmental impairment. Ninety percent are clinically inapparent at birth but are reported to be at risk of developing such abnormalities throughout childhood, the extent of which requires further elucidation.A systematic literature review was conducted using Medline and Embase databases, manual citation review, and personal libraries for articles reporting primary data on hearing and neurodevelopmental outcomes for children with asymptomatic congenital CMV. PROSPERO registration number CRD42015025407.Thirty-seven of 480 articles identified between 1969 and 2016 met the eligibility criteria. Twenty-nine of these contributed primary data on hearing outcomes and 20 on neurodevelopmental outcomes (12 of the 37 studies contributed data on both). Cumulative incidence of sensorineural hearing loss with follow-up to at least 5 years was 7% to 11%, which is more than healthy controls but less than children with symptomatic congenital CMV (34%-41%). The onset, course, and severity of hearing loss was variable with no reliable virological prognostic marker. In comparison to controls, children with asymptomatic congenital CMV did not perform worse than controls in neurodevelopmental assessments and performed better than children with symptomatic congenital CMV.Studies show children with asymptomatic congenital CMV are at increased risk of developing hearing loss but perform equally well on neurodevelopmental assessments when compared with healthy controls. There is no reliable virological marker to determine which infants will develop sequelae. Regular follow-up until school entry is supported by the literature.

Martin N., Durrheim D., Khandaker G., Butler M., Jones C.

James S.H., Kimberlin D.W.

Herpes simplex virus types 1 (HSV-1) and 2 (HSV-2) are highly prevalent viruses capable of establishing lifelong infection. Genital herpes in women of childbearing age represents a major risk for mother-to-child transmission (MTCT) of HSV infection, with primary and first-episode genital HSV infections posing the highest risk. The advent of antiviral therapy with parenteral acyclovir has led to significant improvement in neonatal HSV disease mortality. Further studies are needed to improve the clinician's ability to identify infants at increased risk for HSV infection and prevent MTCT, and to develop novel antiviral agents with increased efficacy in infants with HSV infection.

Khandaker G., Zurynski Y., Jones C.

To describe the epidemiology of congenital rubella infections notified to the Australian Paediatric Surveillance Unit (APSU) from 2004 to 2013 and compare that with previously published APSU data for 1993–2003. Active national surveillance for congenital rubella infection has been conducted through the APSU since 1993. Monthly reporting by child health clinicians according to pre-defined case criteria triggers requests for clinicians to provide de-identified clinical, epidemiological, and laboratory information. Data were extracted for cases reported between January 2004 and December 2013 and compared with previous years. Five cases of confirmed congenital rubella infection were identified during the reporting period. All five infants had defects consistent with congenital rubella syndrome (CRS). Four of the infants were born in Australia during the study period, and all were born to mothers born overseas. Three of the five mothers had not had rubella vaccination, and in two vaccination status was unknown, although both were from countries without routine rubella immunization programmes. Since 1993, there have been 57 notifications of congenital rubella infection to the APSU; 40 of these infants were born between January 1993 and December 2013, of whom 34 had confirmed CRS. Congenital rubella infection in Australia is predominantly among children born to unimmunized immigrant mothers. Migrant women born in rubella endemic countries without routine immunization remain an important group to target for vaccination. Rubella-susceptible women, especially those in the early stages of pregnancy, should also carefully consider the risks of travelling to rubella endemic countries.

Tjon Pian Gi R.E., San Giorgi M.R., Slagter-Menkema L., van Hemel B.M., van der Laan B.F., van den Heuvel E.R., Dikkers F.G., Schuuring E.M.

Desai S., Smith T., Thorley B.R., Grenier D., Dickson N., Altpeter E., Sabbe M., Elliott E., Zurynski Y.

Coordes A., Grund D., Mainka A., Olze H., Hanitsch L., von Bernuth H., Dommerich S.

ZusammenfassungDie rezidivierende Larynxpapillomatose (RLP) wird in 90 % der Fälle durch die humanen Papillomviren (HPV) 6 und 11 verursacht. Unklar ist, ob Rezidive durch Neuinfektion oder Ausbreitung infizierter Zellen entstehen. Symptomatische und z. T. kurative Therapie ist die laserchirurgische bzw. konventionelle mikrochirurgische Abtragung. Die Operation zielt auf die Linderung der Atemnot und Verbesserung der Stimme. Im Krankheitsverlauf werden Patienten, insbesondere Kinder, durch Stimmprobleme, wiederholte operative Abtragungen, pulmonale Manifestationen und psychologische Traumata beeinträchtigt. Die Impfung mit Gardasil 9 (Merck & Co., Rahway, NJ, USA) beugt Neuinfektionen mit HPV 6, 11, 16, 18, 31, 33, 45, 52 und 58 vor und induziert Impfantigen-spezifische Antikörper und CD4+-T-Helferzellen. Die RLP ist nach aktueller Studienlage durch eine prophylaktische Impfung vermeidbar. Die Behandlung ist mit dem allgemeinen Impfrisiko verbunden (EMA-Zulassung: Mädchen, Jungen ab 9 Jahren). Studien zeigen zudem, dass der Impfstoff nach Entfernung HPV-assoziierter Neoplasien/Papillome Rezidiven vorbeugt. Die Erweiterung der Impfempfehlung für die Rezidivprophylaxe HPV-assoziierter Erkrankungen und als prophylaktische Impfung bei Männern würde zusätzlich die Anwendbarkeit und Herdenimmunität fördern. Für seltene und therapieresistente Fälle mit laryngotrachealer Beteiligung ist die systemische Therapie mit Bevacizumab (Avastatin; Genentech, San Francisco, CA, USA), einem VEGF-Antikörper, eine vielversprechende adjuvante Therapiemöglichkeit.

Dikkers F.G., Seedat R.Y., San Giorgi M.R.

Recurrent respiratory papillomatosis (RRP) is a condition caused by human papillomavirus (HPV) that occurs in both children and adults, characterized by recurrent growths of intraluminal papillomas in the airway, usually in the larynx. Patients present with dysphonia (both roughness and breathiness), coughing, and eventually airway obstruction. The most common causative HPV types are HPV6 and HPV11. RRP has a significant adverse effect on quality of life. In the absence of a curative treatment, patients have to undergo frequent surgical procedures. Some patients require more than a 100 procedures. Several adjuvant therapies have been proposed to reduce the severity of disease and the number of surgical interventions. The introduction of vaccines against HPV6 and HPV11 can reduce the incidence of RRP.

Morris A., Elliott E., Madden S.

The aim of this study was to collect prospective national data on early-onset eating disorders (EOEDs) in children in Australia to document changes in clinical presentations, medical complications, management, and incidence since initially described in 2002-2005.Each month pediatricians reported children aged 5-13 years newly diagnosed with an eating disorder to the Australian Paediatric Surveillance Unit and provided de-identified clinical data.Between 2016 and 2018, 184 children were confirmed with EOED with a minimum estimated national incidence of 2.79 per 100,000 children aged 5-13 years (95% confidence interval [CI] 2.40-3.23), nearly double the previously recorded incidence. The mean age at diagnosis was 12.2 years; 43(24%) were boys who were younger than girls (11.85 vs. 12.33 years; p = .03). All had food avoidance. Common symptoms included fear of weight gain 140 (76%), preoccupation with body weight 134 (73%), and misperception of body size 116 (63%). Bradycardia was present in 83 (45%) and 117 (64%) who required hospital admission. The Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, Text Revision (DSM-5) criteria for anorexia nervosa were met for 144 (78%).Children with eating disorders continue to present with severe illness. Near doubling in incidence in just over a 10-year period highlights the need for increased clinical resourcing and comparable international data.The incidence of new presentations of eating disorders in children aged 5-13 years has nearly doubled since a similar study was conducted over 10 years ago. Children were unwell for an average of 8 months before diagnosis; approximately 80% had a clear diagnosis of anorexia nervosa and 64% needed hospital admission due to medical complications. This highlights the need for improvements in education and clinical resources for this age group.

King R.E., Bilger A., Rademacher J., Ward-Shaw E.T., Hu R., Lambert P.F., Thibeault S.L.

Recurrent respiratory papillomatosis (RRP), caused by laryngeal infection with low-risk human papillomaviruses, has devastating effects on vocal communication and quality of life. Factors in RRP onset, other than viral presence in the airway, are poorly understood. RRP research has been stalled by limited preclinical models. The only known papillomavirus able to infect laboratory mice, Mus musculus papillomavirus (MmuPV1), induces disease in a variety of tissues. We hypothesized that MmuPV1 could infect the larynx as a foundation for a preclinical model of RRP. We further hypothesized that epithelial injury would enhance the ability of MmuPV1 to cause laryngeal disease, because injury is a potential factor in RRP and promotes MmuPV1 infection in other tissues. In this report, we infected larynges of NOD scid gamma mice with MmuPV1 with and without vocal fold abrasion and measured infection and disease pathogenesis over 12 weeks. Laryngeal disease incidence and severity increased earlier in mice that underwent injury in addition to infection. However, laryngeal disease emerged in all infected mice by week 12, with or without injury. Secondary laryngeal infections and disease arose in nude mice after MmuPV1 skin infections, confirming that experimentally induced injury is dispensable for laryngeal MmuPV1 infection and disease in immunocompromised mice. Unlike RRP, lesions were relatively flat dysplasias and they could progress to cancer. Similar to RRP, MmuPV1 transcript was detected in all laryngeal disease and in clinically normal larynges. MmuPV1 capsid protein was largely absent from the larynx, but productive infection arose in a case of squamous metaplasia at the level of the cricoid cartilage. Similar to RRP, disease spread beyond the larynx to the trachea and bronchi. This first report of laryngeal MmuPV1 infection provides a foundation for a preclinical model of RRP.

Teutsch S.M., Nunez C.A., Morris A., Eslick G.D., Khandaker G., Berkhout A., Novakovic D., Brotherton J.M., McGregor S., King J., Egilmezer E., Booy R., Jones C.A., Rawlinson W., Thorley B., et. al.

For 27 years, national prospective data on selected rare childhood diseases have been collected monthly by the Australian Paediatric Surveillance Unit (APSU) from paediatricians and other clinical specialists who report cases in children aged up to 16 years. We report here the annual results of APSU surveillance in 2020 for ten rare communicable diseases and complications of communicable diseases, namely: acute flaccid paralysis (AFP); congenital cytomegalovirus (CMV) infection; neonatal herpes simplex virus (HSV) infection; perinatal exposure to human immunodeficiency virus (HIV); paediatric HIV infection; severe complications of seasonal influenza; juvenile onset recurrent respiratory papillomatosis (JoRRP); congenital rubella syndrome; congenital varicella syndrome; and neonatal varicella infection. We describe the results for each disease in the context of the total period of study, including demographics, clinical characteristics, treatment and short-term outcomes. Despite challenges presented by the coronavirus disease 2019 (COVID-19) pandemic in 2020, more than 1,400 paediatricians reported regularly to the APSU and an overall monthly reporting rate of > 90% was achieved. The minimum AFP target of 1 case per 100,000 children aged less than 15 years was achieved and there were few cases of vaccine-preventable diseases (JoRRP, rubella, varicella). However, high cases of congenital CMV, neonatal HSV and perinatal exposure to HIV persist. There were no severe complications of seasonal influenza reported for the first time in 13 years. This is consistent with other surveillance data reporting a decline of influenza and other communicable diseases in 2020, and likely reflects the wider effects of public health measures to reduce transmission of SARS-CoV-2 in the Australian community.

Syrjänen S., Syrjänen K.

Squamous cell papilloma (SCP) in the upper aero-digestive tract is a rare disease entity with bimodal age presentation both at childhood and in adults. It originates from stratified squamous and/or respiratory epithelium. Traditionally, SCPs have been linked to chemical or mechanical irritation but, since the 1980s, they have also been associated with human papillomavirus (HPV) infection. Approximately 30% of the head and neck SCPs are associated with HPV infection, with this association being highest for laryngeal papillomas (76–94%), followed by oral (27–48%), sinonasal (25–40%), and oropharyngeal papillomas (6–7%). There is, however, a wide variation in HPV prevalence, the highest being in esophageal SCPs (11–57%). HPV6 and HPV11 are the two main HPV genotypes present, but these are also high-risk HPVs as they are infrequently detected. Some 20% of the oral and oropharyngeal papillomas also contain cutaneous HPV genotypes. Despite their benign morphology, some SCPs tend to recur and even undergo malignant transformation. The highest malignant potential is associated with sinonasal inverted papillomas (7–11%). This review discusses the evidence regarding HPV etiology of benign SCPs in the upper aero-digestive tract and their HPV-related malignant transformation. In addition, studies on HPV exposure at an early age are discussed, as are the animal models shedding light on HPV transmission, viral latency, and its reactivation.

Meites E., Stone L., Amiling R., Singh V., Unger E.R., Derkay C.S., Markowitz L.E.

Abstract Background Juvenile-onset recurrent respiratory papillomatosis (JORRP) is a rare and serious disease caused by human papillomavirus (HPV) presumably acquired during vaginal delivery. HPV vaccination of females through age 26 years, recommended in the United States since 2006, can prevent HPV transmission. We assessed trends in JORRP cases before and after HPV vaccine introduction in the United States. Methods Case-patients were identified from 26 pediatric otolaryngology centers in 23 U.S. states. Demographics and clinical history were abstracted from medical records. Case-patients were grouped by year of birth, and birth-cohort incidences were calculated using number of births from either national or state-level natality data from the 23 states. We calculated incidence rate ratios (IRR) and 95% confidence intervals (CI) in 2-year intervals. Results We identified 576 U.S. JORRP case-patients born in 2004–2013. Median age at diagnosis was 3.4 years (interquartile range: 1.9, 5.5). Number of identified JORRP case-patients declined from a baseline of 165 born in 2004–2005 to 36 born in 2012–2013. Incidence of JORRP per 100 000 births using national data declined from 2.0 cases in 2004–2005 to 0.5 cases in 2012–2013 (IRR = 0.2, 95% CI = .1–.4); incidence using state-level data declined from 2.9 cases in 2004–2005 to 0.7 cases in 2012–2013 (IRR = 0.2, 95% CI = .1–.4). Conclusions Over a decade, numbers of JORRP case-patients and incidences declined significantly. Incidences calculated using national denominator data are likely underestimates; those calculated using state-level denominator data could be overestimates. These declines are most likely due to HPV vaccination. Increasing vaccination uptake could lead to elimination of this HPV-related disease.