NIH researchers in Building 10 search for knowledge, therapies for COVID-19

Researchers at the NIH have joined those across the nation and the world in the search for a better understanding of COVID-19 and the therapies that may be used to care for those diagnosed and prevent others from infection. On the intramural campus, around 20 clinical trials are currently open and enrolling participants, nearly all of which will see patients and healthy volunteers in the Clinical Center. Some are digging deep by studying the DNA of people who have tested positive for COVID-19. Others are thinking long term to try to determine the extent to which natural immunity is protective against re-infection. And others still have one goal in mind – a vaccine. View a few of the promising studies, below:

Study aims to understand how COVID-19 causes disease

Two previously healthy patients, the same age, arrive at a hospital with COVID-19: one with fever and a cough that causes only mild discomfort while the other ends up in the ICU with respiratory failure and severe medical distress. Currently, there's no clear reason why these patients have different outcomes. NIH researchers are working to find out why people can react so differently to the same virus and determine treatment strategies to avoid the serious complications.

The NIH Clinical Center has unparalleled capacity to have a multidisciplinary team of infectious disease, pulmonary, cardiology and neurology experts use the most advanced techniques to understand disease processes. NIH launched a study, Cardiopulmonary Inflammation and Multi-System Imaging During the Clinical Course of COVID-19 Infection in Asymptomatic and Symptomatic Persons, in May 2020 which is using the full range of this advanced expertise to better understand COVID-19 and focus on advancing our ability to improve treatment and avoid short-term and long-term complications.

Multiple institutes are involved in this study: the National Institute of Allergy and Infectious Diseases, the National Heart, Lung, and Blood Institute (NHLBI), the National Institute of Diabetes and Digestive and Kidney Diseases, the National Institute of Neurological Disorders and Stroke, the National Institute of Arthritis and Musculoskeletal and Skin Diseases and the Critical Care Medicine Department of the Clinical Center. Critical Care Medicine focuses on life support and other intensive medical interventions, including running the hospital's intensive care unit.

"I am proud of the fact that we have been able to take advantage of experts in the intramural program who really want to do more, to understand more about this unique problem," said Dr. Anthony Suffredini, the principal investigator of the study and senior investigator at the Critical Care Medicine Department. "Ultimately, you have to have the patients here. Ultimately, you have to have the experience of looking at the patients, seeing what the trajectory of their disease is and seeing what the complications are also. That's what our hope is with this. And it can run in parallel and complement some of the other studies here. We have a lot of opportunities that we need to take advantage of."

COVID-19 is dramatically different from influenza and other viral diseases because it is highly transmissible and it affects multiple organs in different ways. There are few tools to predict which patients will develop severe disease and long-term consequences and which patients will have uneventful illnesses with few symptoms.

This research study will focus on inflammation in the body – with particular focus on the heart, lungs, kidneys and brain. Researchers are investigating how the viral load of COVID-19 stimulates the body's response and its impact on patient health outcomes. Researchers will use advanced radiology tools, like magnetic resonance imaging and computed tomography, to scan the body's organs and map the impact and recovery from the virus.

The study will recruit patients to be seen at the hospital who initially test positive for COVID-19 with no symptoms, patients with mild disease, patients with severe disease, and patients treated elsewhere who have recovered. Suffredini says they hope to enroll 75 patients treated at regional hospitals for their acute illness who can then enter the study in the recovery phase. In addition, his team has established a reliance agreement with the Washington Hospital Center to enroll their patients acutely (blood draws only, with less research imaging) and then have their follow up at the Clinical Center for recovery and convalescence.

Patients seen at the Clinical Center will receive state-of-the-art COVID-19 related care as outpatients or, if necessary for clinical care or research, as inpatients. NIH never charges for care or study medications.

- Donovan Kuehn

A time to ACTT: The Adaptive COVID-19 Treatment Trial

NIH's Dr. Richard Davey is leading an effort to find an effective treatment for the COVID-19. Davey is the medical director of the Special Clinical Studies Unit at the NIH Clinical Center and the deputy clinical director in the National Institute of Allergy and Infectious Diseases (NIAID). He's a seasoned research veteran and has been at the forefront of emerging infectious diseases in the early years of the human immunodeficiency virus, the 2009 H1N1 pandemic and the 2014-2016 Ebola virus disease outbreak. Together with colleagues in the Clinical Center Critical Care Medicine Department, he is leading the hospital's participation in the Adaptive COVID-19 Treatment Trial (ACTT) - three global clinical studies sponsored by NIAID's Division of Microbiology and Infectious Disease:

ACTT-1 began on Feb. 21, 2020 and ended on April 19, 2020. A total of 60 trial sites worldwide including the NIH Clinical Center enrolled 1,063 patients with respiratory compromise and showed that patients treated with remdesivir had a 31% faster time to recovery than those who received placebo. The preliminary results were recently published in the May issue of the New England Journal of Medicine. Remdesivir is a broad-spectrum antiviral that is not FDA approved to treat any diseases but that received emergency use authorization in the US for COVID-19 patients hospitalized with severe disease.

ACTT-2 began on May 26, 2020 and ended on July 30, 2020. The trial enrolled more than 1,030 COVID-19 patients also with evidence of lung infection, as indicated by a need for supplemental oxygen, abnormal chest X-rays, or illness requiring mechanical ventilation. Patients were treated with the combination of baricitinib and remdesivir or remdesivir and placebo. Baricitinib is an FDA-approved treatment for rheumatoid arthritis that works by suppressing the overreaction of the immune system. ACTT-2 is now in the data analysis phase.

ACTT-3 just recently started enrolling patients and will be comparing the clinical outcomes of a similar group of patients treated with remdesivir plus the immune system suppresser interferon beta-1a versus those treated with remdesivir and placebo.

Since the Clinical Center does not have an emergency room, the majority of the patients enrolled in the ACTT protocols at the Clinical Center were transferred from local hospitals to Building 10.  

"In terms of infection control, I was quite comfortable that, by working closely with the Hospital Epidemiology Service under Dr. Tara Palmore, we were able to implement very safe methods of caring for patients here at the Clinical Center," Davey said. 

Andrew Martin is one of the patients that was transferred to Building 10 and enrolled in the ACTT-1 study. In March 2020, Martin was rushed to the emergency room at Suburban Hospital with a fever, uncontrolled coughing, and shortness of breath. He was diagnosed with COVID-19, placed on low-dose supplemental oxygen and admitted. Two days later, his oxygen levels had a critical drop and he was moved to the intensive care unit. When his condition stabilized, he was presented with the option to join a clinical study of hydroxychloroquine and receive the treatment at home, or join the ACTT-1 study and receive treatment at the Clinical Center.

Martin explained, "I felt safer and more confident to be observed and treated for 10 days at the NIH Clinical Center than to be sent home to take hydroxychloroquine. Also, unlike the other study, the NIH covered all treatment costs for ACTT-1."

After being home for several months and feeling better, Martin's memory of his time in the hospital is still very foggy. "It all felt very surreal. Like I was watching everything from an out-of-body perspective," he added.

Despite their research and clinical care experience, Davey and colleagues in the Critical Care Medicine Department were surprised by how quickly their very stable-appearing COVID-19 patients, who were receiving low-level nasal oxygen, could deteriorate — often within 12-24 hours — to the point where they needed mechanical ventilation.

Davey emphasized, "That's a degree of rapidity that none of us truly had ever seen before."

This alarming observation in COVID-19 patients is also shared by many clinicians in hospitals around the world. Davey's team has treated the full spectrum of COVID-19 patients, from those whose disease was confined to their lungs to those who had multi-organ involvement including their kidneys and liver.

This is the first time that a medical treatment is being developed at this rapid pace, Davey emphasized. However, his planning and actions are guided by his primary concern for patient safety and to not push a treatment through with a substandard potential for therapeutic efficacy.

Despite his decades of leading clinical research studies, Davey said, "I've never been in a clinical trial network that was able to enroll so many patients so quickly. This speaks to both the leadership of NIAID in this regard and to the scope and urgency worldwide created by the COVID-19 pandemic." 

- Lester Davis

COVID-19: What's blood got to do with it?

Researchers are seeking to cure COVID-19 by collecting plasma from the blood of convalescent donors – patients who have recovered from the physical toll the virus can take.

At the protocol's root, the principle is simple: collect plasma from those who have recovered from the virus because that plasma contains antibodies that can attack the disease. The process is very similar to the work that was done roughly five years ago when fighting Ebola. However this treatment methodology has a higher chance for success when used with respiratory infections such as COVID-19.

The Clinical Center is uniquely well equipped for this kind of study. The hospital acquires detailed information about the donated plasma, such as antibody count, which is typically hard for blood banks to obtain. According to Dr. Kamille West, the principal investigator of the clinical trial, the Clinical Center has been able to set up partnerships to assist other hospitals who are often inundated with patients, by donating some high-quality samples to benefit their patients in need.

The study began enrollment in April, and there have been 155 donors to date. Most of the plasma is being saved specifically for COVID-19 patients at the NIH Clinical Center, but some is being shared with nearby hospitals that don't have adequate access to convalescent plasma in this global health crises. The plasma is frozen after collection and can last up to one year.

West explains how the process works: "When a person has a viral infection, the body's immune system may respond by making antibodies to fight against the virus. Antibodies are proteins that your immune system makes that can recognize and may kill the virus to help you to recover. If you recover from the infection, your blood is likely to have antibodies against the virus. Blood is made of liquid plasma and blood cells; the antibodies are found in the plasma. 

"If you give that plasma to patients who are very ill with the disease, the antibodies in the donor's plasma may help fight the virus in those patients," West added.

"Although promising, this plasma treatment has not yet been proven to always help patients with COVID-19. We think it might help, because in early studies, some patients have improved with this treatment," said West. "If we can get more information by studying the treatment, we can get a better idea of whether it is helpful for patients."

Many COVID-19 survivors who have signed up for the trial have come back to donate more than once, as the process is typically a good experience for the donors, and they can donate every 28 days. When a donor has blood drawn, the plasma is separated, and the red cells are returned to the patient's body. As a result, donors do not get very tired because of the limited blood loss. 

"We call our participants 'liquid gold donors' because of the color of the plasma (and because they are amazing)," West said. "Each donation will usually yield over 600mL of plasma. A treatment does is 200mL, so one donation can often treat as many as three patients."

One of the largest challenges is finding high-quality candidates for the research, West added. Contributors have to fit the profile, be appropriate for the study and be able to participate safely. The study is ongoing. If you or someone you know has recovered from COVID-19, consider applying to contribute to this study.

- Daniel Silber