Description
Executive Summary
Authors Aruna Natarajan, MD, PhD, Robert Tamburro, MD, MSc, J. Matthew Craig, PhD, Sara Lin, PhD and Neil Aggarwal, MD
Background
Viral lower respiratory tract infections are generally more common and severe among infants and young children than in adults and include acute bronchiolitis and pneumonia, the mechanisms of which need elucidation. Currently there are neither objective markers of severity nor mechanism- based cures for these diseases which have disproportionately high mortality (influenza) and morbidity (RSV and rhinovirus) in infancy. Moreover, these infections may impact lung development and have far reaching pulmonary effects, both in the immediate post-viral period and further out into adulthood, that are only just beginning to be recognized.
The present COVID-19 pandemic with the remarkable sparing of young children from severe respiratory manifestations of SARS-CoV-2, further highlights the importance of interrogating and elucidating this field.
There are unique challenges to studying juvenile animal models and to understanding the development of immunity to viral insults in the early years which need attention. Further, the application of recent advances in single cell technologies and molecular techniques could enhance our understanding of the effects of respiratory virus infections, both on specific cellular subtypes of the developing lung and, more generally, on disease progression and outcome.
The Workshop- Gaps and Strategies
Recognizing these needs, a trans-NIH multidisciplinary workshop (supported by the National Heart, Lung, and Blood Institute (NHLBI) and the Eunice Kennedy Shriver National Institute of Child Health and Development (NICHD), and attended by the National Institute of Allergy and Infectious Diseases (NIAID)) was conducted on November 7 and 8, 2019. This workshop brought together immunologists, developmental lung biologists, infectious disease specialists, neonatologists, pediatric pulmonologists, critical care physician-scientists and viral epidemiologists to examine the scope and burden of disease, identify knowledge gaps and establish basic, translational and mechanistic clinical research direction.
Some of the areas of research need that gained consensus during and after the workshop among the participants included:
- Immunology and the Host Response- Research to elucidate immune cell trafficking to the lung and interactions with resident lung cells and structure were recommended, such as:
- The unique role of early exposures- e.g., B cell memory vaccine protectiveness
- The development of innate immunity and the role of early viral infections in setting immune tone and downstream cytokine responses
- The value of transcriptomics and proteomics in the nasal respiratory epithelium
- Metabolic effects of viral-induced respiratory insults
- The impact of bacterial super-infections on immunological memory
- Impact of Development on Viral Infections & Impact of Viral Infections on Lung Development
Much remains to be understood about lung development, repair of lung injury, and the molecular and metabolic mechanisms of adverse/productive healing in children and adults, including, but not limited to:- The differential response to viral injury in early and later life primarily related to immunity or to differences in structural susceptibility in the lung (or both, at different times)
- The development of epithelial barrier function and the impact of environmental pollutants on viral infections by studying lung organoids
- The impact of the young lung on the virus - e.g., viral evolution and viral resistance
- The unique host response in the young lung to antiviral therapies - using organ-on-chip technology
- Genomic, epigenomic and environmental effects of viral infections on respiratory structure and function, and trajectories of these effects
- Impact of viral infections in early life on response to viral infections in adulthood
- Translational correlates- In parallel with the above basic and mechanistic clinical questions, studies in non-human primates and humans were recommended, such as:
- The study of ‘immunological imprinting’ of viral infections from very early in life, conceptional or even pre-conceptional, through longitudinal cohorts and widespread testing for evidence of virus and/or immune response in mothers, babies, infants and young children
- Immunophenotyping combined with pulmonary phenotyping in juvenile non-human primate models
- The study of severe viral respiratory disease and biomarkers of severity with mechanistic implications for druggable pathways
- Clinical longitudinal studies for risk of future airway and parenchymal sequelae in a growing lung, and mitigation strategies
- Vaccine development as a ‘research probe’ to elucidate host antibody responses, mucosal immunity, systemic immunity and developmental correlates to protection
In summary, the members of the workshop reached a consensus on the above focus areas for future investigation to elucidate mechanisms of, and decrease morbidity and mortality from, pediatric viral lower respiratory tract infections.
Participants
| N. Ambalavanan, M.D. | The University of Alabama at Birmingham |
| Leonard B. Bacharier, M.D. | Washington University, St. Louis |
| Gustavo Nino Barrera, M.D. | Children’s National Hospital, Washington D.C. |
| Bria M. Coates, M.D. | Northwestern University Feinberg School of Medicine, Chicago |
| Hitesh Deshmukh, M.D., Ph.D. | Cincinnati Children’s Hospital |
| Melody Duvall, M.D., Ph.D. | Boston Children’s Hospital |
| Matthew Frieman, Ph.D. | University of Maryland |
| James Gern, M.D. | University of Wisconsin |
| Sarah Gilpin, Ph.D. | Harvard University |
| Thomas (Tom) Kepler, Ph.D. | Boston University |
| Michele Kong, MD | University of Alabama at Birmingham |
| Richard Locksley, MD | University of California San Francisco |
| Thomas (Tom) Mariani, PhD | University of Rochester |
| Fernando Martinez, M.D. | The University of Arizona |
| Sharon McGrath-Marrow, M.B.A.,M.D. | Johns Hopkins University School of Medicine |
| Ascuncion Mejias, M.D., Ph.D., MSCS | Ohio State University |
| Lisa Miller | University of California Davis |
| Joseph (Jay) Mizgerd, Sc.D. | Boston University |
| Wayne Morgan, M.D. | The University of Arizona |
| Peter Mourani, MD, | University of Colorado |
| Gloria Pryhuber, M.D. | University of Rochester |
| Octavio Ramilo, M.D. | Ohio State University |
| Adrienne Randolph, M.D., MSc | Harvard Medical School |
| Fariba Rezaee, M.D. | Cleveland Clinic |
| Jason Rock, Ph.D. | Boston University |
| Jeffrey (Jeff) Whitsett, MD | Cincinnati Children's Hospital |
| Sing Sing Way, M.D., Ph.D. | Cincinnati Children's Hospital |
| William Zacharias, M.D., PhD | Cincinnati Children's Hospital |
NIH Participants
| Neil Aggarwal, MD | NHLBI |
| Marishka Brown, PhD | NHLBI |
| James Kiley, PhD | NHLBI |
| Sonnie Kim, MS | NIAID |
| Marrah Lachowicz-Scroggins, PhD | NHLBI |
| Sara Lin, PhD | NHLBI |
| Valerie Maholmes, PhD | Eunice Kennedy Shriver NICHD |
| Aruna Natarajan, MD, PhD | NHLBI |
| Robert Tamburro, MD, MSc | Eunice Kennedy Shriver NICHD |