Associations between COVID-19 and hospitalisation with respiratory and non-respiratory conditions: a record linkage study.

OBJECTIVES: To assess associations between SARS-CoV-2 infection and the incidence of hospitalisation with selected respiratory and non-respiratory conditions in a largely SARS-CoV-2 vaccine-naïve population . DESIGN, SETTING, PARTICIPANTS: Self-control case series; analysis of population-wide surveillance and administrative data for all laboratory-confirmed COVID-19 cases notified to the Victorian Department of Health (onset, 23 January 2020 - 31 May 2021; ie, prior to widespread vaccination rollout) and linked hospital admissions data (admission dates to 30 September 2021). MAIN OUTCOME MEASURES: Hospitalisation of people with acute COVID-19; incidence rate ratios (IRRs) comparing incidence of hospitalisations with defined conditions (including cardiac, cerebrovascular, venous thrombo-embolic, coagulative, and renal disorders) from three days before to within 89 days of onset of COVID-19 with incidence during baseline period (60-365 days prior to COVID-19 onset). RESULTS: A total of 20 594 COVID-19 cases were notified; 2992 people (14.5%) were hospitalised with COVID-19. The incidence of hospitalisation within 89 days of onset of COVID-19 was higher than during the baseline period for several conditions, including myocarditis and pericarditis (IRR, 14.8; 95% CI, 3.2-68.3), thrombocytopenia (IRR, 7.4; 95% CI, 4.4-12.5), pulmonary embolism (IRR, 6.4; 95% CI, 3.6-11.4), acute myocardial infarction (IRR, 3.9; 95% CI, 2.6-5.8), and cerebral infarction (IRR, 2.3; 95% CI, 1.4-3.9). CONCLUSION: SARS-CoV-2 infection is associated with higher incidence of hospitalisation with several respiratory and non-respiratory conditions. Our findings reinforce the value of COVID-19 mitigation measures such as vaccination, and awareness of these associations should assist the clinical management of people with histories of SARS-CoV-2 infection.

Efficacy of a Cell-Culture-Derived Quadrivalent Influenza Vaccine in Children.

BACKGROUND: Cell-culture-derived influenza vaccines may enable a closer antigenic match to circulating strains of influenza virus by avoiding egg-adapted mutations. METHODS: We evaluated the efficacy of a cell-culture-derived quadrivalent inactivated influenza vaccine (IIV4c) using a Madin-Darby canine kidney cell line in children and adolescents 2 to less than 18 years of age. During three influenza seasons, participants from eight countries were enrolled in an observer-blinded, randomized clinical trial comparing IIV4c with a noninfluenza vaccine (meningococcal ACWY). All the participants received a dose of a trial vaccine. Children 2 to less than 9 years of age without previous influenza vaccination who were assigned to the IIV4c group received a second dose on day 29; their counterparts who were assigned to the comparator group received placebo. Participants were followed for at least 180 days for efficacy and safety. The presence of influenza virus in nasopharyngeal swabs from participants with influenza-like illness was confirmed by reverse-transcriptase-polymerase-chain-reaction assay and viral culture. A Cox proportional-hazards model was used to evaluate the efficacy of IIV4c as measured by the first occurrence of laboratory-confirmed type A or B influenza (primary end point). RESULTS: Between 2017 and 2019, a total of 4514 participants were randomly assigned to receive IIV4c or the meningococcal ACWY vaccine. Laboratory-confirmed influenza occurred in 175 of 2257 participants (7.8%) in the IIV4c group and in 364 of 2252 participants (16.2%) in the comparator group, and the efficacy of IIV4c was 54.6% (95% confidence interval [CI], 45.7 to 62.1). Efficacy was 80.7% (95% CI, 69.2 to 87.9) against influenza A/H1N1, 42.1% (95% CI, 20.3 to 57.9) against influenza A/H3N2, and 47.6% (95% CI, 31.4 to 60.0) against influenza B. IIV4c showed consistent vaccine efficacy in subgroups according to age, sex, race, and previous influenza vaccination. The incidences of adverse events were similar in the IIV4c group and the comparator group. CONCLUSIONS: IIV4c provided protection against influenza in healthy children and adolescents across seasons, regardless of previous influenza vaccination. (Funded by Seqirus; EudraCT number, 2016-002883-15; ClinicalTrials.gov number, NCT03165617.).

Community-wide, contemporaneous circulation of a broad spectrum of human rhinoviruses in healthy Australian preschool-aged children during a 12-month period.

Human rhinovirus (HRV) replication triggers exacerbation of asthma and causes most acute respiratory illnesses (ARIs), which may manifest as influenza-like illness. The recent assignment of 60 previously unknown HRV types to a third HRV species, Human rhinovirus C, raised questions about the prevalence of these picornavirus types in the community, the extent of HRV diversity at a single site, and whether the HRVs have an equally diverse clinical impact on their hosts. We quantified HRV diversity, and there was no clinical impact attributable to HRV species and genotypes among a community population of preschool-aged children with ARI who provided respiratory samples during 2003. All HRV species were represented among 138 children with ARI, and 74 distinct HRV types were cocirculating. Fever accompanied 32.8% of HRV-positive ARI cases. HRVs were less likely than DNA viruses to be codetected with another virus, suggesting virus interference at the community level, demonstrated by the inverse correlation between influenza virus detection and HRV detection.

Comparison of three methods for ascertainment of contact information relevant to respiratory pathogen transmission in encounter networks.

BACKGROUND: Mathematical models of infection that consider targeted interventions are exquisitely dependent on the assumed mixing patterns of the population. We report on a pilot study designed to assess three different methods (one retrospective, two prospective) for obtaining contact data relevant to the determination of these mixing patterns. METHODS: 65 adults were asked to record their social encounters in each location visited during 6 study days using a novel method whereby a change in physical location of the study participant triggered data entry. Using a cross-over design, all participants recorded encounters on 3 days in a paper diary and 3 days using an electronic recording device (PDA). Participants were randomised to first prospective recording method. RESULTS: Both methods captured more contacts than a pre-study questionnaire, but ascertainment using the paper diary was superior to the PDA (mean difference: 4.52 (95% CI 0.28, 8.77). Paper diaries were found more acceptable to the participants compared with the PDA. Statistical analysis confirms that our results are broadly consistent with those reported from large-scale European based surveys. An association between household size (trend 0.14, 95% CI (0.06, 0.22), P < 0.001) and composition (presence of child 0.37, 95% CI (0.17, 0.56), P < 0.001) and the total number of reported contacts was observed, highlighting the importance of sampling study populations based on household characteristics as well as age. New contacts were still being recorded on the third study day, but compliance had declined, indicating that the optimal number of sample days represents a trade-off between completeness and quality of data for an individual. CONCLUSIONS: The study's location-based reporting design allows greater scope compared to other methods for examining differences in the characteristics of encounters over a range of environments. Improved parameterisation of dynamic transmission models gained from work of this type will aid in the development of more robust decision support tools to assist health policy makers and planners.

Modelling strategic use of the national antiviral stockpile during the CONTAIN and SUSTAIN phases of an Australian pandemic influenza response.

OBJECTIVE: To define optimum use of the national antiviral stockpile during the early phases of the response to pandemic influenza in Australia, to inform the 2008 revision of the Australian Health Management Plan for Pandemic Influenza. METHODS: A mathematical model was used to compare strategic uses of antiviral agents for treatment and post-exposure prophylaxis to limit transmission until availability of a strain-specific vaccine. The impact of provision of pre-exposure prophylaxis to healthcare workers (HCWs) on the ability to control the epidemic was also assessed. RESULTS: Optimal constraint of epidemic growth was achieved by intensive ascertainment of contacts of cases for post-exposure prophylaxis for as long as feasible. While pre-exposure prophylaxis of healthcare workers utilised a substantial proportion of the stockpile, this did not impede disease control or the ability to treat cases. Absolute delays to outbreak depended on both the intervention strategy and the growth rate of the epidemic. As vaccination was only effective when introduced before explosive growth, this timing was critical to success. CONCLUSIONS AND IMPLICATIONS: Liberal distribution of antiviral drugs to limit disease spread for as long as is feasible represents optimal use of these agents to constrain epidemic growth. In reality, additional non-pharmaceutical control measures are likely to be required to control transmission until vaccines can definitively contain pandemic influenza outbreaks.

Parent-collected respiratory specimens--a novel method for respiratory virus and vaccine efficacy research.

Population-based respiratory research and vaccine efficacy studies have previously required clinic or home visits when a subject had an acute respiratory illness. This method may mean parents are unwilling to enroll their child or report an illness of interest. We conducted a community-based cohort study into respiratory illnesses in 234 pre-school aged children using parent-collected specimens. Between January 2003 and January 2004 there were 563 specimens collected from 730 identified illnesses and these were tested using a panel of respiratory virus polymerase chain reaction (PCR) assays; 409 (73%) were positive for any virus. Specimens were not more likely to be positive when collected by a healthcare worker parent, when they included a throat swab, or when a very good collection technique was reported. A delay from illness onset to specimen collection of up to 5 days did not appear to impact on sensitivity of virus identification, but a delay of six or more days with minor delays in testing saw positivity fall. Combined with daily symptom diary completion and PCR testing, parent-collected specimens are an efficient and acceptable method for the conduct of future vaccine efficacy studies and other community-based respiratory virus research.

The cost of community-managed viral respiratory illnesses in a cohort of healthy preschool-aged children.

BACKGROUND: Acute respiratory illnesses (ARIs) during childhood are often caused by respiratory viruses, result in significant morbidity, and have associated costs for families and society. Despite their ubiquity, there is a lack of interdisciplinary epidemiologic and economic research that has collected primary impact data, particularly associated with indirect costs, from families during ARIs in children. METHODS: We conducted a 12-month cohort study in 234 preschool children with impact diary recording and PCR testing of nose-throat swabs for viruses during an ARI. We used applied values to estimate a virus-specific mean cost of ARIs. RESULTS: Impact diaries were available for 72% (523/725) of community-managed illnesses between January 2003 and January 2004. The mean cost of ARIs was AU$309 (95% confidence interval $263 to $354). Influenza illnesses had a mean cost of $904, compared with RSV, $304, the next most expensive single-virus illness, although confidence intervals overlapped. Mean carer time away from usual activity per day was two hours for influenza ARIs and between 30 and 45 minutes for all other ARI categories. CONCLUSION: From a societal perspective, community-managed ARIs are a significant cost burden on families and society. The point estimate of the mean cost of community-managed influenza illnesses in healthy preschool aged children is three times greater than those illnesses caused by RSV and other respiratory viruses. Indirect costs, particularly carer time away from usual activity, are the key cost drivers for ARIs in children. The use of parent-collected specimens may enhance ARI surveillance and reduce any potential Hawthorne effect caused by compliance with study procedures. These findings reinforce the need for further integrated epidemiologic and economic research of ARIs in children to allow for comprehensive cost-effectiveness assessments of preventive and therapeutic options.

Burden of acute sore throat and group A streptococcal pharyngitis in school-aged children and their families in Australia.

OBJECTIVE: The objective of this study was to determine the incidence, transmission, carriage, and risk factors for group A streptococcal pharyngitis in school-aged children and their families. METHODS: A 16-month, prospective, family-based cohort study was undertaken from August 2001 through December 2002 in Melbourne, Australia. A total of 202 families (853 people) with at least 1 child aged 3 to 12 years were randomly selected from 3 primary care practices across suburban Melbourne to collect surveillance data for acute group A streptococcal pharyngitis, including serology for index and secondary cases and intermittent carriage data. Cohort retention was 97% for 16 months. RESULTS: The incidence of acute sore throat, group A streptococcal swab-positive pharyngitis, and serologically confirmed group A streptococcal pharyngitis was 33, 13, and 8 per 100 child-years, respectively, for school-aged children (5-12 years) and 60, 20, and 15 per 100 family-years, respectively. Sore throat was less common in adults than children, but adults with sore throat were as likely as children to have group A streptococcal culture-positive or serologically proven pharyngitis. In families who had a primary case, 43% had at least 1 secondary case, and in family members who were at risk, 13% contracted a secondary case. The spring, summer, and winter carriage rates for children were 13%, 8%, and 16%, respectively, and for adults the rate was 2% across all seasons. CONCLUSIONS: Group A streptococcal pharyngitis is still common, and the peak incidence occurs in school-aged children. However, the incidence in adults is higher than expected, and the number of secondary cases in families may be an important factor when considering the potential benefits of treatment.

Community epidemiology of human metapneumovirus, human coronavirus NL63, and other respiratory viruses in healthy preschool-aged children using parent-collected specimens.

OBJECTIVES: The purpose of this work was to assess the impact of recently described human metapneumovirus and human coronavirus NL63 compared with other respiratory viruses by using sensitive molecular techniques in a cohort of healthy preschool-aged children. We also aimed to assess the use of parent collection to obtain an adequate respiratory specimen from acutely unwell children in the community. PATIENTS AND METHODS: The community epidemiology and burden of human metapneumovirus and other respiratory viruses (influenza A, influenza B, respiratory syncytial virus, parainfluenza viruses, adenoviruses, and picornaviruses) were examined in a cohort of 234 preschool-aged children from Melbourne, Australia, over a 12-month period by using polymerase chain reaction testing. Parents collected a daily symptom diary for the duration of the study and were taught to collect a combined nose-throat swab and complete an impact diary when the study child had an acute respiratory illness. RESULTS: The average incidence of acute respiratory illness was 0.48 per child-month for the duration of the study, with a winter peak. Of 543 illnesses with > or = 1 specimen returned, 33 were positive for human metapneumovirus (6.1%) and 18 for human coronavirus NL63 (3.3%). Of all of the viruses for which we tested, human metapneumovirus and human coronavirus NL63 were most strongly linked to child care attendance, occurring in 82% and 78% of infected children, respectively. Picornaviruses were the most commonly identified virus group (269 [49.5%]). Influenza virus and adenovirus illnesses had the greatest impact, with fever in more than three quarters and requiring, on average, > 1 local doctor visit per illness. CONCLUSIONS: Recently identified human metapneumovirus and human coronavirus NL63 are important pathogens in community-based illness in children, particularly in those who attend child care. Picornaviruses were detected in half of the nose-throat swabs collected during acute respiratory illness in children but resulted in milder illnesses; influenza and adenovirus caused the highest-impact illnesses. The use of parent-collected specimens should be considered for additional community-based epidemiologic studies and vaccine trials.

Missed opportunities to vaccinate a cohort of hospitalised elderly with pneumococcal and influenza vaccines.

This study examines missed opportunities for recommended influenza vaccine and 23-valent pneumococcal vaccine (23vPPV) among hospitalised elderly persons. 4772 inpatients aged > or = 65 years (cases of pneumonia and frequency-matched randomly selected cohort subjects) participated from two large tertiary Australian hospitals. For subjects unvaccinated with influenza vaccine (past year), 1110/1115 (99.6%) had visited either a doctor (99.4%, mean 11.2 visits) or the same hospital (52.0%, mean 1.5 visits). For those unvaccinated with 23vPPV (past 5 years), 1809/1813 (99.8%) had visited either a doctor (99.7%, mean 11.2 visits) or the same hospital (51.5%, mean 1.5 times) in the past year; 71% had been admitted to the same hospital in the past 5 years (mean 3.4 times). 2.3% of all subjects had vaccination status recorded. No unvaccinated subject was vaccinated during admission, despite approximately 40% reporting acceptability of vaccination if offered. Previous hospitalisation was a risk factor for being unvaccinated. Barriers to implementation of current vaccination policy in the hospital setting require formal evaluation in Australia.

The epidemiology of invasive group A streptococcal disease in Victoria, Australia.

OBJECTIVE: To estimate the incidence and severity of invasive group A streptococcal infection in Victoria, Australia. DESIGN: Prospective active surveillance study. SETTING: Public and private laboratories, hospitals and general practitioners throughout Victoria. PATIENTS: People in Victoria diagnosed with group A streptococcal disease notified to the surveillance system between 1 March 2002 and 31 August 2004. MAIN OUTCOME MEASURE: Confirmed invasive group A streptococcal disease. RESULTS: We identified 333 confirmed cases: an average annual incidence rate of 2.7 (95% CI, 2.3-3.2) per 100,000 population per year. Rates were highest in people aged 65 years and older and those younger than 5 years. The case-fatality rate was 7.8%. Streptococcal toxic shock syndrome occurred in 48 patients (14.4%), with a case-fatality rate of 23%. Thirty cases of necrotising fasciitis were reported; five (17%) of these patients died. Type 1 (23%) was the most frequently identified emm sequence type in all age groups. All tested isolates were susceptible to penicillin and clindamycin. Two isolates (4%) were resistant to erythromycin. CONCLUSION: The incidence of invasive group A streptococcal disease in temperate Australia is greater than previously appreciated and warrants greater public health attention, including its designation as a notifiable disease.

Validity of self-reported influenza and pneumococcal vaccination status among a cohort of hospitalized elderly inpatients.

Use of self-reported vaccination status is commonplace in assessing vaccination coverage for public health programs and individuals, yet limited validity data exist. We compared self-report with provider records for pneumococcal (23vPPV) and influenza vaccine for 4887 subjects aged>or=65 years from two Australian hospitals. Self-reported influenza vaccination status had high sensitivity (98%), positive predictive value (PPV) (88%) and negative predictive value (NPV) (91%), but low specificity (56%). Self-reported 23vPPV (previous 5 years) had a sensitivity of 84%, specificity 77%, PPV 85% and NPV 76%. Clinicians can be reasonably confident of self-reported influenza vaccine status, and for positive self-report for 23vPPV in this setting. For program evaluation, self-reported influenza vaccination coverage among inpatients overestimates true coverage by about 10% versus 1% for 23vPPV. Self-report remains imperfect and whole-of-life immunisation registers a preferable goal.

Prevention of community-acquired pneumonia among a cohort of hospitalized elderly: benefit due to influenza and pneumococcal vaccination not demonstrated.

Benefits from influenza and 23-valent pneumococcal polysaccharide (23vPPV) vaccines against invasive pneumococcal disease and laboratory confirmed influenza have been well documented. However, their effectiveness against pneumonia remains controversial for community-based elderly > or = 65 years. Using a case-cohort design we examined incremental VE of 23vPPV over and above influenza vaccine against hospitalization with community-acquired pneumonia (HCAP) in two large Australian hospitals. 1952 cases (ICD-10-AM codes for pneumonia: J10-J18) and 2927 randomly selected cohort subjects were studied. Vaccination status was confirmed by providers. Benefit against HCAP was not demonstrated in multivariate analysis for influenza vaccine compared with neither vaccine (RR 1.02, 95%CI 0.84-1.20) or for both vaccines compared with influenza vaccine (RR 0.98, 95%CI 0.81-1.18). The current program of funding these vaccines for the elderly is not having a discernable impact on HCAP in this setting.

Treatment of sore throat in light of the Cochrane verdict: is the jury still out?

There are few good-quality studies of the effectiveness of antibiotic treatment of proven group A streptococcal (GAS) pharyngitis in children; available data suggest that antibiotics may reduce symptom duration. While there is limited justification for antibiotic treatment of GAS pharyngitis to prevent acute rheumatic fever in non-Indigenous Australians, there is no justification for routine antibiotic treatment of all patients with sore throat. Two strategies are open to clinicians: not to treat GAS pharyngitis with antibiotics, in which case no investigations should be done; or to treat cases of sore throat with clinical features that suggest GAS, in which case diagnosis should be confirmed with a throat swab, and penicillin started while awaiting the result. Penicillin should be discontinued if the swab is negative, or continued for 10 days if it is positive for GAS. Surveillance of GAS infections and acute rheumatic fever is needed in Australia, as are further studies of effectiveness (including cost-effectiveness) of antibiotic treatment of proven GAS pharyngitis.