- Grace C. Lee, Marcos I. Restrepo, Nathan Harper, Muthu Saravanan Manoharan, Alisha M. Smith, Justin A. Meunier, Sandra Sanchez-Reilly, Aamir Ehsan, Anne P. Branum, Caitlyn Winter, Lauryn Winter, Fabio Jimenez, Lavanya Pandranki, Andrew Carrillo, Graciela L. Perez, Antonio Anzueto, Hanh Trinh, Monica Lee, Joan M. Hecht, Celida Martinez, Raj T. Sehgal, Jose Cadena, Elizabeth A. Walter, Kimberly Oakman, Raymond Benavides, Jacqueline A. Pugh, Scott Letendre, Maristella Steri, Valeria Orrù, Edoardo Fiorillo, Francesco Cucca, Alvaro G. Moreira, Nu Zhang, Elizabeth Leadbetter, Brian K. Agan, Douglas D. Richman, Weijing He, Robert A. Clark, Jason F. Okulicz, Sunil K. Ahuja. Immunologic resilience and COVID-19 survival advantage. Journal of Allergy and Clinical Immunology, 2021; DOI: 10.1016/j.jaci.2021.08.021
In their Journal of Allergy and Clinical Immunology article, the researchers define immunologic resilience as the capacity to preserve or restore immune competence and control inflammation in the face of infection or other antigenic challenges. This capacity does not depend solely on age, they noted. In fact, the level of immunologic resilience that precedes COVID-19 and develops during the viral disease is a strong predictor of COVID-19 outcomes regardless of age, they wrote. An 18-year-old could have inferior immunologic resilience, resulting in a high risk of severe COVID-19, whereas an 80-year-old with robust resilience could manifest less severe COVID-19. However, with age, the proportion of individuals with capacity to preserve immunologic resilience declines, contributing to the greater burden of COVID-19 in older persons. Conceivably, durability of vaccines may wane in persons with inferior immunologic resilience, the researchers wrote.
The scientists developed novel metrics to monitor immunologic resilience and evaluated them in 522 patients with COVID-19 at Audie L. Murphy Memorial Veterans Hospital in San Antonio, a hospital of the U.S. Department of Veterans Affairs (VA). Each patient’s level of immunological resilience was assessed on the day of admission and then daily for varying durations. Patients whose infections did not require hospital admission were visited at home for assessments. For comparative purposes, the researchers evaluated metrics of immunologic resilience in 13,461 individuals without COVID-19.
The researchers quantified immunologic resilience through “immune health grades,” which are based on measures of infection-fighting T cells, and blood cell gene expression signatures. An immune health grade of I signifies the best immunity and a grade of IV the worst. The group also analyzed grades from large control groups of otherwise healthy adults.
“When the pandemic began, it became obvious that it would be very important for us to assess immune status from the day a patient is admitted all the way through the convalescence phase,” said the first author of the study, Grace C. Lee, PharmD, PhD, assistant professor, UT Health Science Center San Antonio and The University of Texas at Austin College of Pharmacy, and senior translational research scientist with the Foundation for Advancing Veterans’ Health Research. “We applied these immune metrics to every COVID-19 patient who came into the VA hospital. These metrics are highly prognostic. Metrics tracking inferior immunologic resilience predicted up to 19-times higher risk of dying within 30 days, which was the primary outcome of the study.
“Remarkably, irrespective of their COVID-19 status, men have inferior immunologic resilience, which may explain why they are predisposed to worse COVID-19 outcomes,” Dr. Lee said. She also noted that the large-scale analyses in the report were performed in collaboration with Col. Jason Okulicz, MD, U.S. Air Force infectious disease consultant, and investigators who follow a large aging cohort in Sardinia as well as datasets from the Framingham Heart Study.
Predicting need for advanced therapies
Co-first author Marcos Restrepo, MD, MSc, PhD, professor of medicine at the health science center and director of the medical intensive care unit in the South Texas Veterans Health Care System, said the immune health grades and overall concept of immunologic resilience accurately predicted most patient outcomes, which in addition to mortality included hospitalization, need for advanced respiratory support, and levels of SARS-CoV-2 in the nasopharynx.
“One reason this is important is that we are measuring immunologic resilience on the first day, before the patients receive therapy,” Dr. Restrepo said. “Moreover, the failure to show improvements in metrics of immunologic resilience during hospitalization is a prognosticator of worse outcomes.”
“The concept is a useful way to assess the severity levels of patients and understand their potential rate of progression and need for advanced therapies and longer hospitalizations,” said co-author Sandra Sanchez-Reilly, MD, professor of medicine at the health science center and associate chief of service for geriatrics and extended care in the South Texas Veterans Health Care System.
The converse is true, as well. Those who entered the hospital with the best immune health grades had shorter stays and non-progressive COVID-19, findings showed.
Refining the metrics
Non-COVID-19 studies in thousands of patients provided the framework for applying these metrics during the pandemic to VA patients and their families.
“We don’t normally assess the immunological status of people. If you went to your physician’s office today and said, ‘I need an immunological checkup,’ they wouldn’t know what to do for you,” said the senior author of the study, Sunil K. Ahuja, MD, professor of medicine at the UT Health Science Center San Antonio and director of the Veterans Health Administration Center for Personalized Medicine in the South Texas Veterans Health Care System.
“Based on prior work, we realized that we weren’t capturing immune status well with currently available immune metrics,” Dr. Ahuja said. “We therefore developed these novel measures. We studied these metrics in very large cohorts of patients with HIV, as well as in people who don’t have HIV. And those data suggested that these metrics of immunologic resilience are more precise, if you will, in assessment of immune status.”
For example, the immune health grades correlated well with inflammation as marked by interleukin-6, a protein produced at infection sites, Dr. Ahuja said.
The COVID-19 patients included mostly male U.S. veterans, many of whom were older and had other conditions, such as high blood pressure or diabetes.
Immunologic resilience metrics have value for “precision immune health monitoring across life span, irrespective of COVID-19 status,” the researchers wrote. Highlighting this point, a subset of the immunologic metrics that predicted mortality in patients with COVID-19 also associated with survival in persons without COVID-19.
“Measuring immunologic resilience as we did in our VA patients gave us a very panoramic view of how immune status contributed to infection and initial presentation of the disease, as well as insights during the recovery phase and how the immune abnormalities resolved,” Dr. Ahuja said. “This study is unique, and we believe it will help patients and clinical teams in the future, especially since immune health grades predicted COVID-19 outcomes independent of age, body mass index and coinfections such as cytomegalovirus.”
- Identification of novel metrics of immunologic resilience.
- Immune health grade I, the most protective immune status, was the most common (73%) among healthy adults in the non-COVID-19 populations studied, particularly among females.
- Immune health grades II and IV, less protective immune status, predominated (77%) among the 522 adults presenting with COVID-19.
- Immune health grade I was associated with 88% lower mortality, after controlling for age and gender.
- Grade I also was associated with reduced risk of hospitalization and respiratory failure, less inflammation, rapid clearance of SARS-CoV-2 from the nasopharynx and gene expression signatures correlating with survival.
- In non-COVID-19 populations, metrics of immunologic resilience correlated with resistance to progressive influenza or HIV infection, and lower mortality.
This work was supported by a collaboration between the U.S. Department of Veterans Affairs and the National Institutes of Health’s (NIH) National Institute of Allergy and Infectious Diseases (NIAID). The U.S. Department of Defense provided additional support. Pilot funding came from the Institute for the Integration of Medicine and Science (IIMS), which administers the NIH Clinical and Translational Science Award (CTSA) at the UT Health Science Center San Antonio. Other pilot funds from the health science center are through the Joe R. and Teresa Lozano Long School of Medicine and the Sam and Ann Barshop Institute for Longevity and Aging Studies through its San Antonio Claude D. Pepper Older Americans Independence Center.