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.Peer Reviewe

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.Peer Reviewe

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

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.Peer Reviewe

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

<p><b>Introduction</b>: 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.</p> <p><b>Areas covered</b>: 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).</p> <p><b>Expert commentary</b>: 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.</p