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Response to Commentary

Ten Accomplishments from VA Research on COVID-19

As the United States emerges from the pandemic with hopes of a return to a more normal life, it is an opportune time to reflect on the challenges and successes of the past year. VA has performed admirably during the COVID-19 pandemic, demonstrating the value of an integrated system and a coordinated, national response: we closed our community living centers to visitors early and instituted universal screening, avoiding the dramatic spread seen in private nursing homes; we surged staff where needed, preventing our hospitals from being overwhelmed and allowing VA to take in non-Veterans in hot spots; we pivoted quickly to telehealth; and as documented in this issue, we distributed vaccine quickly and efficiently to our staff and patients while maintaining high levels of trust in VA.

For the VA research enterprise, which spans more than 100 medical centers, the pandemic delivered a trio of challenges: local shutdowns interrupted access to labs and participant recruitment; clinician researchers were pulled into patient care; and researchers dove into solving COVID-19 questions without supplemental COVID-19 funds flowing to research. Despite these challenges, research teams across VA pivoted to address the numerous questions surrounding this novel pathogen. Below we outline just a few of our major efforts and accomplishments.

1. Clinical Trials of Vaccines and COVID- 19 Therapies: Early in the pandemic, VA entered into partnerships with the National Institutes of Health (NIH), the Food and Drug Administration (FDA) and the Centers for Disease Control (CDC). Under NIH’s Accelerating COVID-19 Therapeutics and Vaccines (ACTIV) initiative, VA continues to participate in both outpatient (ACTIV-2) and inpatient (ACTIV-3) platform trials. Under what was then called Operation Warp Speed, VA enrolled more than 1,500 Veterans in trials of five different vaccines and VA sites are continuing to participate in ongoing therapy trials. VA also funded intramural clinical trials of potential new therapeutics such as degarelix, a testosterone suppressant. Facilitating these trials required a substantial effort by the Office of Research & Development (ORD) as we devised new and streamlined processes for Central Institutional Review Board (IRB) review, and processed multiple new agreements with participating agencies and industry partners. ORD was able to accelerate these steps because of efforts we had undertaken to make the clinical trial start-up process more efficient, including establishing a Partnered Research Program Office to assist external partners and obtaining approval to rely upon commercial IRBs. We also tapped into the existing research infrastructure within VA: our 59 enrollment sites for the Million Veteran Program and the network of 5 coordinating centers and 10 enrollment sites for the VA Cooperative Studies Program.


2. Real World Evidence: As part of an FDA Evidence Accelerator collaboration involving multiple health systems, VA researchers worked with the Pharmacy Benefits Management office to use national EHR data to examine the real-world effectiveness of potential COVID-19 therapies in use in VA. Efforts began with hydroxychloroquine (soon shown to not be effective) but proceeded to compare real-world findings to treatments that had been examined in treatment trials: prophylactic anticoagulation (lowers risk of death in hospitalized patients);¹ remdesivir (of limited value) and steroids (analysis underway). Other studies by independent teams have examined effects of aspirin and alpha-blockers.


3. Risk Modeling and Risk Prediction: As illustrated in accompanying articles, VA’s EHR data on 9 million Veterans and nearly 250,000 cases across the United States provided one of the richest databases to examine factors associated with getting infected or developing severe COVID-19. Such analyses helped clarify the role of race, ethnicity and comorbidity in risk of infection with COVID-19 and of developing severe disease among Veterans.


4. Rapid Evidence Synthesis: Our Evidence Synthesis Program produces rapid reviews of emerging COVID literature to assist our clinical partners and created a website, VA-ESP | COVID-19 Reviews, compiling an average of 500 similar reviews from around the world per month.


5. Genomic Insights into COVID: The Million Veterans Program platform, with genomic information on more than 800,000 enrolled subjects, 33,000 of whom were infected with COVID-19, provides a laboratory to identify possible targets for new therapies. A recent paper using Mendelian randomization examined over 1,000 potential protein targets for COVID-19 therapies and highlighted one that is most promising.²


6. COVID-19 and Community Living Centers: Research in VA community living centers identified the need for a lower temperature threshold to detect COVID-19 among older patients,³ and more recently has documented the steep decline in infections post vaccination.


7. COVID-19 and Mental Health: Given the high prevalence of mental health conditions in Veterans and the stresses imposed by the pandemic, ORD launched multiple “rapid response” studies aimed at detecting early signals of how patients with PTSD, SUD, and other conditions have fared. Some results were counterintuitive. Patients with serious mental illness or recent homelessness recovered more quickly than healthier controls from the early stress of the pandemic;⁴ patients with PTSD fared relatively well during the quarantine period.


8. Long-term Outcomes of COVID-19: As we pass one year since the first wave, evidence is increasing about long-term consequences in patients who have recovered from COVID-19. A VA-DoD partnership has enrolled COVID-19-infected patients in a long-term follow-up study to examine how immunologic and serologic changes correlate with disease progression and recovery. VA EHR data have already provided compelling information on long-term outcomes; among recovered patients, mortality risk remains elevated up through six months as does incidence of conditions involving pulmonary, cardiac, and neurologic systems.⁵ A recently launched 2-year follow-up study will expand on this work with symptom surveys and analyses in specific high-risk groups. Research is working closely with clinical partners as VA plans how to care for patients with “long COVID.”


9. Deferred and Disrupted Care:  Not all  effects of the pandemic are directly due to the virus. The massive economic dislocations, social isolation, and disrupted health care of the pandemic affected nearly everyone and proved especially hard on the most vulnerable. National and VA analyses suggest the excess total mortality in 2020 compared to previous years exceeds that attributed directly to COVID-19.⁶ While some may be late effects of COVID-19 or undetected infection, at least one cause of death – overdoses – seems clearly to have increased outside VA. In contrast, despite dire predictions, the rate of suicides does not seem to have risen. With patients deferring a variety of acute and elective care, HSR&D has launched several research opportunities to examine outcomes in greater detail, including a national study comparing VA mortality to national benchmarks during the pandemic.


10. Assessing Vaccine Acceptance and Vaccine Effectiveness: Despite success in vaccination efforts, up to one-third of Veterans have not yet received or decided to get the vaccine. QUERI and HSR&D are supporting efforts to examine the causes of vaccine hesitancy and develop interventions. At the same time, researchers at White River Junction are conducting an FDA-funded study to assess vaccine effectiveness in the VA population.

The pandemic will have both positive and negative enduring effects on VA research. Some pre-existing work suffered major disruptions, which will mean more money and time to complete the research. Absent supplemental funding for COVID-19 research, ORD funding for other projects was tighter than previous years. The urgency of the pandemic, however, accelerated the transformation of VA research from a collection of research centers into a more unified research enterprise with even tighter connections to VA care. COVID-19 also forced us to test more efficient processes for rigorous peer review of time-sensitive research proposals. Beginning this summer, VA research will launch an enterprise-building initiative to institutionalize lessons learned to ensure that the system emerges from the pandemic better able to meet Veterans’ needs across the full range of health conditions.

References

1. Rentsch CT, Beckman JA, Tomlinson L, et al. “Early Initiation of Prophylactic Anticoagulation for Prevention of Coronavirus Disease 2019 Mortality in Patients Admitted to Hospital in the United States: Cohort Study.” BMJ 2021 Feb 11; 372:n311.
2. Gaziano L, Giambartolomei C, Pereira AC, et al. “Actionable Druggable Genome-wide Mendelian Randomization Identifies Repurposing Opportunities for COVID-19,” Nature Medicine 2021; 27(4):668-76.
3. Rudolph J, Halladay C, Barber M, et al. “Temperature in nursing home residents systematically tested for SARS-CoV-2,” Journal of the American Medical Directors Association 2020; 21(7):895-9.
4. Wynn JK, McCleery A, Novacek D, et al. “Clinical and Functional Effects of the COVID-19 Pandemic and Social Distancing on Vulnerable Veterans with Psychosis or Recent Homelessness,” Journal of Psychiatric Research 2021; 138:42-9.
5. Al-Aly Z, Xie Y, Bowe B. “High-dimensional Characterization of Post-acute Sequalae of COVID-19,” Nature 2021.
6. Ahmad FB, Anderson RN. “The Leading Causes of Death in the US for 2020,”JAMA. Published online March 31, 2021. doi:10.1001/jama.2021.5469