Disease Burden and Inpatient Management of Children with Acute Respiratory Viral Infections during the Pre-COVID Era in Germany: A Cost-of-Illness Study.

Respiratory viral infections (RVIs) are common reasons for healthcare consultations. The inpatient management of RVIs consumes significant resources. From 2009 to 2014, we assessed the costs of RVI management in 4776 hospitalized children aged 0-18 years participating in a quality improvement program, where all ILI patients underwent virologic testing at the National Reference Centre followed by detailed recording of their clinical course. The direct (medical or non-medical) and indirect costs of inpatient management outside the ICU ('non-ICU') versus management requiring ICU care ('ICU') added up to EUR 2767.14 (non-ICU) vs. EUR 29,941.71 (ICU) for influenza, EUR 2713.14 (non-ICU) vs. EUR 16,951.06 (ICU) for RSV infections, and EUR 2767.33 (non-ICU) vs. EUR 14,394.02 (ICU) for human rhinovirus (hRV) infections, respectively. Non-ICU inpatient costs were similar for all eight RVIs studied: influenza, RSV, hRV, adenovirus (hAdV), metapneumovirus (hMPV), parainfluenza virus (hPIV), bocavirus (hBoV), and seasonal coronavirus (hCoV) infections. ICU costs for influenza, however, exceeded all other RVIs. At the time of the study, influenza was the only RVI with antiviral treatment options available for children, but only 9.8% of influenza patients (non-ICU) and 1.5% of ICU patients with influenza received antivirals; only 2.9% were vaccinated. Future studies should investigate the economic impact of treatment and prevention of influenza, COVID-19, and RSV post vaccine introduction.

Successful Treatment of Complicated Influenza A(H3N2) Virus Infection and Rhabdomyolysis with Compassionate Use of IV Zanamivir.

In 2019, EMA licensed intravenous (IV) zanamivir for severe influenza virus infection in children over 6 months as well as adults. Prior to that, it was possible via a compassionate use program. We present successful compassionate use of IV zanamivir in a 14-year-old female with severe influenza A(H3N2) and multi-organ failure, who had failed oral oseltamivir. Her illness was complicated by acute respiratory distress syndrome and rhabdomyolysis requiring extracorporeal membrane oxygenation and hemofiltration. Considering the broad safety margins with neuraminidase inhibitors, an adult dose of 600 mg IV BID was administered in this 60 kg patient. Influenza virus was cleared rapidly and undetectable on day 13. Creatine kinase (CK) values were dropping from 38,000 to 500 within nine days. Given the recent licensure of IV zanamivir, multi-center prospective observational studies in pediatric Intensive Care Unit patients would be beneficial to guide the most appropriate use of IV zanamivir in this vulnerable age group.

Linking digital surveillance and in-depth virology to study clinical patterns of viral respiratory infections in vulnerable patient populations.

To improve the identification and management of viral respiratory infections, we established a clinical and virologic surveillance program for pediatric patients fulfilling pre-defined case criteria of influenza-like illness and viral respiratory infections. The program resulted in a cohort comprising 6,073 patients (56% male, median age 1.6 years, range 0-18.8 years), where every patient was assessed with a validated disease severity score at the point-of-care using the ViVI ScoreApp. We used machine learning and agnostic feature selection to identify characteristic clinical patterns. We tested all patients for human adenoviruses, 571 (9%) were positive. Adenovirus infections were particularly common and mild in children ≥1 month of age but rare and potentially severe in neonates: with lower airway involvement, disseminated disease, and a 50% mortality rate (n = 2/4). In one fatal case, we discovered a novel virus: HAdV-80. Standardized surveillance leveraging digital technology helps to identify characteristic clinical patterns, risk factors, and emerging pathogens.

Incidence, Disease Severity, and Follow-Up of Influenza A/A, A/B, and B/B Virus Dual Infections in Children: A Hospital-Based Digital Surveillance Program.

Influenza virus (IV) coinfection, i.e., simultaneous infection with IV and other viruses, is a common occurrence in humans. However, little is known about the incidence and clinical impact of coinfection with two different IV subtypes or lineages ("dual infections"). We report the incidence, standardized disease severity, and follow-up of IV dual infections from a hospital-based digital surveillance cohort, comprising 6073 pediatric patients fulfilling pre-defined criteria of influenza-like illness in Berlin, Germany. All patients were tested for IV A/B by PCR, including subtypes/lineages. We assessed all patients at the bedside using the mobile ViVI ScoreApp, providing a validated disease severity score in real-time. IV-positive patients underwent follow-up assessments until resolution of symptoms. Overall, IV dual infections were rare (4/6073 cases; 0.07%, incidence 12/100,000 per year) but showed unusual and/or prolonged clinical presentations with slightly above-average disease severity. We observed viral rebound, serial infection, and B/Yamagata-B/Victoria dual infection. Digital tools, used for instant clinical assessments at the bedside, combined with baseline/follow-up virologic investigation, help identify coinfections in cases of prolonged and/or complicated course of illness. Infection with one IV does not necessarily prevent consecutive or simultaneous (co-/dual) infection, highlighting the importance of multivalent influenza vaccination and enhanced digital clinical and virological surveillance.

Cost of Respiratory Syncytial Virus-Associated Acute Lower Respiratory Infection Management in Young Children at the Regional and Global Level: A Systematic Review and Meta-Analysis.

BACKGROUND: Respiratory syncytial virus (RSV) is a major cause of acute lower respiratory infection (ALRI) in young children aged <5 years. METHODS: We aimed to identify the global inpatient and outpatient cost of management of RSV-ALRI in young children to assist health policy makers in making decisions related to resource allocation for interventions to reduce severe morbidity and mortality from RSV in this age group. We searched 3 electronic databases including Global Health, Medline, and EMBASE for studies reporting cost data on RSV management in children under 60 months from 2000 to 2017. Unpublished data on the management cost of RSV episodes were collected through collaboration with an international working group (RSV GEN) and claim databases. RESULTS: We identified 41 studies reporting data from year 1987 to 2017, mainly from Europe, North America, and Australia, covering the management of a total of 365 828 RSV disease episodes. The average cost per episode was €3452 (95% confidence interval [CI], 3265-3639) and €299 (95% CI, 295-303) for inpatient and outpatient management without follow-up, and it increased to €8591(95% CI, 8489-8692) and €2191 (95% CI, 2190-2192), respectively, with follow-up to 2 years after the initial event. CONCLUSIONS: Known risk factors (early and late preterm birth, congenital heart disease, chronic lung disease, intensive care unit admission, and ventilator use) were associated with €4160 (95% CI, 3237-5082) increased cost of hospitalization. The global cost of inpatient and outpatient RSV ALRI management in young children in 2017 was estimated to be approximately €4.82 billion (95% CI, 3.47-7.93), 65% of these in developing countries and 55% of global costs accounted for by hospitalization. We have demonstrated that RSV imposed a substantial economic burden on health systems, governments, and the society.

Partnering for enhanced digital surveillance of influenza-like disease and the effect of antivirals and vaccines (PEDSIDEA).

BACKGROUND: Standardised clinical outcome measures are urgently needed for the surveillance of influenza and influenza-like illness (ILI) based on individual patient data (IPD). OBJECTIVES: We report a multicentre prospective cohort using a predefined disease severity score in routine care. PATIENTS/METHODS: The Vienna Vaccine Safety initiative (ViVI) Disease Severity Score ("ViVI Score") was made available as an android-based mobile application to three paediatric hospitals in Berlin and Athens between 2013 and 2016. Healthcare professionals assessed ILI patients at the point of care including severity, risk factors and use of antibiotics/antivirals/vaccines. RT-PCR for influenza A/B viruses was performed at the Hellenic Pasteur Institute and the Robert Koch Institute. PCR testing was blinded to severity scoring and vice versa. RESULTS: A total of 1615 children aged 0-5 years (54.4% males) were assessed at the three sites. The mean age was 1.7 years (SD 1.5; range 0-5.9). The success rate (completion of the scoring without disruption to the ER workflow) was 100%. ViVI Disease Severity Scores ranged from 0 to 35 (mean 13.72). Disease severity in the Berlin Cohort was slightly higher (mean 15.26) compared to the Athens Cohorts (mean 10.86 and 11.13). The administration of antibiotics was most prevalent in the Berlin Cohort, with 41.2% on antibiotics (predominantly cefuroxime) as opposed to only 0.5% on neuraminidase inhibitors. Overall, Risk-adjusted ViVI Scores were significantly linked to the prescription of both, antibiotics and antivirals. CONCLUSIONS: The Risk-adjusted ViVI Score enables a precision medicine approach to managing ILI in multicentre settings. Using mobile applications, severity data will be obtained in real time with important implications for the evaluation of antiviral/vaccine use.

Can we distinguish respiratory viral infections based on clinical features? A prospective pediatric cohort compared to systematic literature review.

Studies have shown that the predictive value of "clinical diagnoses" of influenza and other respiratory viral infections is low, especially in children. In routine care, pediatricians often resort to clinical diagnoses, even in the absence of robust evidence-based criteria. We used a dual approach to identify clinical characteristics that may help to differentiate infections with common pathogens including influenza, respiratory syncytial virus, adenovirus, metapneumovirus, rhinovirus, bocavirus-1, coronaviruses, or parainfluenza virus: (a) systematic review and meta-analysis of 47 clinical studies published in Medline (June 1996 to March 2017, PROSPERO registration number: CRD42017059557) comprising 49 858 individuals and (b) data-driven analysis of an inception cohort of 6073 children with ILI (aged 0-18 years, 56% male, December 2009 to March 2015) examined at the point of care in addition to blinded PCR testing. We determined pooled odds ratios for the literature analysis and compared these to odds ratios based on the clinical cohort dataset. This combined analysis suggested significant associations between influenza and fever or headache, as well as between respiratory syncytial virus infection and cough, dyspnea, and wheezing. Similarly, literature and cohort data agreed on significant associations between HMPV infection and cough, as well as adenovirus infection and fever. Importantly, none of the abovementioned features were unique to any particular pathogen but were also observed in association with other respiratory viruses. In summary, our "real-world" dataset confirmed published literature trends, but no individual feature allows any particular type of viral infection to be ruled in or ruled out. For the time being, laboratory confirmation remains essential. More research is needed to develop scientifically validated decision models to inform best practice guidelines and targeted diagnostic algorithms.

Influenza and other respiratory viruses: standardizing disease severity in surveillance and clinical trials.

INTRODUCTION: Influenza-Like Illness is a leading cause of hospitalization in children. Disease burden due to influenza and other respiratory viral infections is reported on a population level, but clinical scores measuring individual changes in disease severity are urgently needed. Areas covered: We present a composite clinical score allowing individual patient data analyses of disease severity based on systematic literature review and WHO-criteria for uncomplicated and complicated disease. The 22-item ViVI Disease Severity Score showed a normal distribution in a pediatric cohort of 6073 children aged 0-18 years (mean age 3.13; S.D. 3.89; range: 0 to 18.79). Expert commentary: The ViVI Score was correlated with risk of antibiotic use as well as need for hospitalization and intensive care. The ViVI Score was used to track children with influenza, respiratory syncytial virus, human metapneumovirus, human rhinovirus, and adenovirus infections and is fully compliant with regulatory data standards. The ViVI Disease Severity Score mobile application allows physicians to measure disease severity at the point-of care thereby taking clinical trials to the next level.

Innovative Digital Tools and Surveillance Systems for the Timely Detection of Adverse Events at the Point of Care: A Proof-of-Concept Study.

INTRODUCTION AND OBJECTIVE: Regulatory authorities often receive poorly structured safety reports requiring considerable effort to investigate potential adverse events post hoc. Automated question-and-answer systems may help to improve the overall quality of safety information transmitted to pharmacovigilance agencies. This paper explores the use of the VACC-Tool (ViVI Automated Case Classification Tool) 2.0, a mobile application enabling physicians to classify clinical cases according to 14 pre-defined case definitions for neuroinflammatory adverse events (NIAE) and in full compliance with data standards issued by the Clinical Data Interchange Standards Consortium. METHODS: The validation of the VACC-Tool 2.0 (beta-version) was conducted in the context of a unique quality management program for children with suspected NIAE in collaboration with the Robert Koch Institute in Berlin, Germany. The VACC-Tool was used for instant case classification and for longitudinal follow-up throughout the course of hospitalization. Results were compared to International Classification of Diseases , Tenth Revision (ICD-10) codes assigned in the emergency department (ED). RESULTS: From 07/2013 to 10/2014, a total of 34,368 patients were seen in the ED, and 5243 patients were hospitalized; 243 of these were admitted for suspected NIAE (mean age: 8.5 years), thus participating in the quality management program. Using the VACC-Tool in the ED, 209 cases were classified successfully, 69 % of which had been missed or miscoded in the ED reports. Longitudinal follow-up with the VACC-Tool identified additional NIAE. CONCLUSION: Mobile applications are taking data standards to the point of care, enabling clinicians to ascertain potential adverse events in the ED setting and during inpatient follow-up. Compliance with Clinical Data Interchange Standards Consortium (CDISC) data standards facilitates data interoperability according to regulatory requirements.