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Approach for defining human adenovirus infection and disease for central review adjudication in clinical studies
Brian T Fisher1,2, Jesse Blumenstock1, Craig L K Boge1
1Division of Infectious Diseases, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
Insights
Standardized definitions for human adenovirus (HAdV) infection and disease in pediatric hematopoietic cell transplant (HCT) recipients are crucial. This study developed and tested definitions to improve consistent reporting and clinical trial outcomes.
Area of Science:
- Medical Virology
- Pediatric Hematology/Oncology
- Infectious Diseases
Background:
- Pediatric allogeneic hematopoietic cell transplant (allo-HCT) recipients face significant risks from human adenovirus (HAdV) infections.
- Distinguishing HAdV infection from HAdV disease is critical for patient management and research, necessitating standardized definitions.
Purpose of the Study:
- To develop and refine standardized case definitions for HAdV infection and disease in pediatric allo-HCT recipients.
- To establish criteria for classifying HAdV events by degree of certainty (possible, probable, proven).
Main Methods:
- A multidisciplinary expert working group developed initial definitions for HAdV infection and disease.
- Definitions were iteratively refined based on clinical and virological data from 81 patients.
- Final definitions were independently applied by two central review committees (CRCs) to 20 pediatric allo-HCT recipients with HAdV detection.
Main Results:
- Iterative refinement led to updated HAdV infection and disease definitions.
- Independent application of definitions by CRCs showed consistency in event counts but some variation in certainty levels.
- The process demonstrated feasibility for consistent outcome assignment in HAdV studies.
Conclusions:
- Developed definitions are feasible for consistent HAdV infection/disease outcome assignment in pediatric allo-HCT studies.
- Further refinement is needed to enhance reproducibility and guide clinical assessment of improvement or worsening.
Background:
Pediatric allogeneic hematopoietic cell transplant (allo-HCT) recipients are at risk for morbidity and mortality from human adenovirus (HAdV). HAdV can be detected in an asymptomatic state, referred to as infection or with signs or symptoms of illness, referred to as disease. Standardized case definitions are needed to distinguish infection from disease and allow for consistent reporting in both observational cohort studies and therapeutic clinical trials.
Methods:
A working group of experts in virology, transplant infectious disease, and HCT was assembled to develop HAdV infection and disease definitions with the degree of certainty (i.e., possible, probable, and proven). Definitions were further refined through an iterative process and independently applied by two central review committees (CRCs) to 20 pediatric allo-HCT recipients with at least one HAdV-positive PCR.
Results:
Initial HAdV infection and disease definitions were developed and updated through an iterative process after reviewing clinical and virological details for 81 subjects with at least one positive HAdV PCR detected in a clinical specimen. Independent application of final definitions to 20 HAdV positive allo-HCT recipients by two CRCs yielded similar number of HAdV infection or disease events but with variation of degree of certainty for some events.
Conclusions:
Application of definitions by a CRC for a study of HAdV infection and disease is feasible and can provide consistency in the assignment of outcomes. Definitions need further refinement to improve reproducibility and to provide guidance on determining clinical improvement or worsening after initial diagnosis of HAdV infection or disease.
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