R01AI159684

Multi-Center Evaluation of the Threat of Established and Emerging Respiratory Viral Infections in Pediatric Transplant Recipients

Respiratory viral infections (RVI) have changed the world. RVI are a leading cause of infectious morbidity and mortality in children undergoing hematopoietic cell transplantation (HCT) and solid organ transplantation (SOT). RVI diagnosis by qualitative PCR screening is sensitive, but unfortunately does not distinguish disease from the presence of viral nucleic acid or predict risk for progression from upper to the more severe lower respiratory tract disease (LRTD).

In the COVID-19 era, many centers now use pre-transplant RVI screening, but the implications of detection in an asymptomatic host are unknown. Integrating quantitative viral load, viral sequencing, and/or host immune (T cell and antibody) responses could provide novel predictive tools to stratify the risk of developing an RVI and the progression to LRTD.

Our objective is to establish a comprehensive RVI diagnostic and disease progression predictive model in children undergoing transplantation. We propose a prospective multi-center epidemiologic study of 2000 pediatric transplant recipients, with a nested case-control immunologic and virologic substudy. This will be the largest study on RVI in any age group of HCT and SOT recipients. We will leverage the Pediatric Transplant ID Network (PIDTRAN), a consortium of 21 nationwide sites and the only group dedicated to pediatric transplant infectious diseases.

We will obtain pre-transplant blood and nasal samples in all 2000 transplant participants at enrollment and also blood at day +100 post-transplant.

In Aim 1, we will determine the prevalence of viral nucleic assay positivity using qualitative PCR and then perform quantitative PCR (QPCR) and viral sequencing (metagenomics) on positive specimens. We hypothesize that the quantity of respiratory viral nucleic acid or certain viral genotypes will identify patients at risk for RVI or disease progression.

In Aim 2, we will develop and validate an immunological classifier to predict the risk of RVI and progression to LRTD in a nested substudy focused on three major pediatric viruses: RSV, parainfluenza virus 3, and human metapneumovirus. We will characterize pre-transplant humoral and cellular immune responses in the subset of patients who develop those RVIs compared with pre-transplant immunologic and day +100 post-transplant immune responses from uninfected matched controls. The combination of host response and virologic data (QPCR and viral metagenomics) will also be compared between RVI cases who do or do not progress to LRTD to identify biomarkers. We hypothesize that patients with specific qualitative or quantitative antibody responses and/or specific T cell repertoires to RVI will have superior clinical outcomes.

Characterizing a comprehensive viral and host response pre-transplant, we will learn to predict who is at risk of RVI and LRTD and needs early intervention vs. delay of transplant, and when PCR positivity is indicative of potential disease. These results will allow us to generate novel evidence-based pediatric guidelines for personalized clinical management of children undergoing transplant, and also inform future antiviral and vaccine studies in these high-risk patient populations.

Arkansas Children's Research Institute

TO ASSIST PUBLIC AND PRIVATE NONPROFIT INSTITUTIONS AND INDIVIDUALS TO ESTABLISH, EXPAND AND IMPROVE BIOMEDICAL RESEARCH AND RESEARCH TRAINING IN INFECTIOUS DISEASES AND RELATED AREAS, TO CONDUCT DEVELOPMENTAL RESEARCH, TO PRODUCE AND TEST RESEARCH MATERIALS. TO ASSIST PUBLIC, PRIVATE AND COMMERCIAL INSTITUTIONS TO CONDUCT DEVELOPMENTAL RESEARCH, TO PRODUCE AND TEST RESEARCH MATERIALS, TO PROVIDE RESEARCH SERVICES AS REQUIRED BY THE AGENCY FOR PROGRAMS IN INFECTIOUS DISEASES, AND CONTROLLING DISEASE CAUSED BY INFECTIOUS OR PARASITIC AGENTS, ALLERGIC AND IMMUNOLOGIC DISEASES AND RELATED AREAS. PROJECTS RANGE FROM STUDIES OF MICROBIAL PHYSIOLOGY AND ANTIGENIC STRUCTURE TO COLLABORATIVE TRIALS OF EXPERIMENTAL DRUGS AND VACCINES, MECHANISMS OF RESISTANCE TO ANTIBIOTICS AS WELL AS RESEARCH DEALING WITH EPIDEMIOLOGICAL OBSERVATIONS IN HOSPITALIZED PATIENTS OR COMMUNITY POPULATIONS AND PROGRESS IN ALLERGIC AND IMMUNOLOGIC DISEASES. BECAUSE OF THIS DUAL FOCUS, THE PROGRAM ENCOMPASSES BOTH BASIC RESEARCH AND CLINICAL RESEARCH. SMALL BUSINESS INNOVATION RESEARCH (SBIR) PROGRAM EXPANDS AND IMPROVES PRIVATE SECTOR PARTICIPATION IN BIOMEDICAL RESEARCH. THE SBIR PROGRAM INTENDS TO INCREASE AND FACILITATE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, TO INCREASE SMALL BUSINESS PARTICIPATION IN FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION. THE SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM STIMULATES AND FOSTERS SCIENTIFIC AND TECHNOLOGICAL INNOVATION THROUGH COOPERATIVE RESEARCH AND DEVELOPMENT CARRIED OUT BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO FOSTER TECHNOLOGY TRANSFER BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION. RESEARCH CAREER DEVELOPMENT AWARDS SUPPORT THE DEVELOPMENT OF SCIENTISTS DURING THE FORMATIVE STAGES OF THEIR CAREERS. INDIVIDUAL NATIONAL RESEARCH SERVICE AWARDS (NRSAS) ARE MADE DIRECTLY TO APPROVE APPLICANTS FOR RESEARCH TRAINING IN SPECIFIED BIOMEDICAL SHORTAGE AREAS. IN ADDITION, INSTITUTIONAL NATIONAL RESEARCH SERVICE AWARDS ARE MADE TO ENABLE INSTITUTIONS TO SELECT AND MAKE AWARDS TO INDIVIDUALS TO RECEIVE TRAINING UNDER THE AEGIS OF THEIR INSTITUTIONAL PROGRAM.

93.855 - Allergy and Infectious Diseases Research

National Institute of Allergy and Infectious Diseases (NIAID) [HHS - NIH]

Little Rock, Arkansas 722023500 United States

Single Zip Code

NIH Research Project Grant (Parent R01 Clinical Trial Not Allowed) (PA-20-185)

Amendment Since initial award the End Date has been extended from 08/31/26 to 08/31/27 and the total obligations have increased 366% from $885,241 to $4,128,655.