Respiratory Syncytial Virus Infection: A Tool For Assessing Clinical Severity
Respiratory syncytial virus (RSV) is a major cause of acute respiratory tract infection (ARTI) and the primary reason for hospitalization among infants, leading to substantial health and socioeconomic challenges. Ranging from mild cold-like symptoms to severe lower respiratory tract infection (LRTI), RSV infection carries significant morbidity and mortality, particularly in low- and middle-income countries (LMICs). While most children are infected with RSV by age 2, reinfections tend to be milder. Hospitalized infants, even those without preexisting health issues, may exhibit severe symptoms due to underlying conditions like prematurity or heart disease.
Measuring RSV disease severity has been attempted using various clinical parameters such as hospitalization duration, need for respiratory support, and admission to pediatric intensive care units. Current assessment methods rely heavily on physical signs and symptoms, as laboratory data and pulmonary function tests are rarely applied. Multiple scoring systems exist for RSV, including those for bronchiolitis, symptom-based pretest probability determination, and complex systems considering different clinical factors. However, these existing scores often prove cumbersome and time-consuming for practical use, particularly in busy healthcare settings with limited resources. Additionally, many current scoring systems lack robust validation and generalizability.
To address these challenges, this study aimed to create a user-friendly clinical severity score tailored specifically for RSV infection in children. The RSV-CLASS (Clinical Assessment Severity Score) was developed and validated using data collected from RSV-infected hospitalized children across multiple winter seasons. The goal was to provide a practical and reliable tool for assessing RSV disease severity in both clinical and research environments.
Study Methods
Over six winter seasons between November 2014 and March 2020, a total of 2,121 children under the age of 3, who showed respiratory symptoms at the pediatric outpatient department of the University Hospital Heidelberg in Germany, were routinely screened for respiratory syncytial virus (RSV) infection. This screening followed hospital guidelines to identify children at high risk of severe respiratory syncytial virus infection and to prevent the virus’s spread to vulnerable patient groups within the hospital.
The participating children had their baseline and clinical information collected, including the main reasons for admission and their respiratory symptoms. A nasopharyngeal swab was taken from each child to confirm RSV infection. For the seasons between 2014 and 2017, an FTD 21 multiplex real-time polymerase chain reaction (RT-PCR) was used, and for the seasons between 2017 and 2020, the Real Star® RSV RT-PCR Kit 3.0 was employed. A comparison of the two testing methods was done for the winter season of 2015/2016, and a positive respiratory syncytial virus result was indicated by a CT value of <35 for both assays.
The RT-PCR tests were conducted at the Center of Infectious Diseases, Virology, Heidelberg University Hospital, using a Light Cycler®480 Instrument II from Roche Life Science, following the manufacturer’s instructions. In total, 91 samples (40.6%) tested positive for RSV using the monoplex assay, and 88 samples (39.3%) tested positive using the multiplex assay out of 224 samples tested.
Results
The study examined data from six consecutive winter seasons involving children below the age of 3 years who were hospitalized due to respiratory symptoms and confirmed respiratory syncytial virus infection. Out of a total of 713 eligible children, 362 RSV-positive children (50.8%) were used to develop the RSV-CLASS (cohort A), while 351 RSV-positive children (49.2%) were used to validate the previously developed RSV-CLASS (cohort B). The characteristics of the children from both cohorts are shown in Table 1. More than half of the patients in each cohort were male (52.2% in cohort A and 56.1% in Cohort B) and presented to the pediatric outpatient department with a median age of 3.9 months (cohort A) and 3.5 months (cohort B), with the majority being under 6 months old.
During the winter seasons 2014–2017 (cohort A), a significant portion (83.4%) of patients were diagnosed with lower respiratory tract infections (LRTIs). Within this group, bronchiolitis accounted for 40.3% (n=146), bronchitis for 30.6% (n=111), and pneumonia for 12.4% (n=45) of cases. Similarly, in winter seasons 2017/2018 to 2019/2020 (cohort B), 83.2% (n=292) of children were diagnosed with LRTIs as their primary admission diagnosis. Other admission diagnoses in cohort A included croup (n=2, 0.6%), rhinitis with feeding difficulties (n=10, 2.8%), and upper respiratory tract infections (URTI) grouped together (n=25, 6.9%). Non-respiratory diagnoses included fever of unknown origin (n=2, 0.6%), gastroenteritis (n=4, 1.1%), general discomfort (n=5, 1.4%), febrile convulsions (n=7, 1.9%), and other conditions (n=5, 1.4%). Similarly, from 2017 to 2020, 12.8% (n=45) and 4.0% (n=14) of patients in cohort B were admitted with URTIs or non-respiratory diagnoses, respectively.
Conclusion
In summary, respiratory syncytial virus (RSV) is a prominent cause of acute respiratory tract infections in young children, often leading to severe lower respiratory tract infections (LRTIs) necessitating hospitalization. Despite its prevalence and diverse clinical presentations, a validated tool for systematically assessing disease severity is lacking. This study aimed to develop and validate a straightforward disease severity score for respiratory syncytial virus infection in children – the RSV-CLASS.
Over six winter seasons, data from more than 700 RSV-infected children were collected and analyzed using rigorous statistical methods to predict severe LRTIs. The final RSV-CLASS includes four items: cough, tachypnea, rales, and wheezing, each assigned one point. The score’s development and validation were robust, with a high area under the curve (AUC) indicating its accuracy.
The study population represented the full spectrum of RSV infections, with most patients being under 6 months old and a balance of genders. Admission diagnoses covered various presentations of RSV infection, including mild cases, upper respiratory tract infections (URTIs), and more severe LRTIs such as bronchiolitis and pneumonia.
Strengths of the RSV-CLASS include its large sample size, prospective design, and comprehensive data collection. The score’s simplicity and wide applicability make it suitable for both clinical and research settings, aiding in evidence-based decision-making for respiratory syncytial virus infection management.
While the RSV-CLASS provides a valuable tool for assessing disease severity, certain limitations should be considered, such as potential interobserver variation and the need for external validation. In conclusion, the RSV-CLASS offers a validated means of assessing RSV infection severity, aiding healthcare practitioners in effectively managing cases and guiding treatment decisions.
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