Long-term SARS-CoV-2 shedding was observed from the upper respiratory tract of a female immunocompromised patient with chronic lymphocytic leukemia and acquired hypogammaglobulinemia, according to a Case Study: Prolonged infectious SARS-CoV-2 shedding from an asymptomatic immunocompromised cancer patient.
A COVID-19 patient whose immune system had been weakened by treatment for leukemia shed SARS-CoV-2 for up to 70 days, much longer than typical COVID-19 patients, NIAID scientists and colleagues report in Cell. SARS-CoV-2 is the virus that causes COVID-19. The finding could help inform treatment and testing considerations for COVID-19 patients with weakened immune systems
the report says shedding of infectious SARS-CoV-2 was observed up to 70 days, and genomic and subgenomic RNA up to 105 days past initial diagnosis.
The infection was not cleared after a first treatment with convalescent plasma, suggesting limited impact on SARS-CoV-2 in the upper respiratory tract within this patient. Several weeks after a second convalescent plasma transfusion, SARS-CoV-2 RNA was no longer detected.
We observed marked within-host genomic evolution of SARS-CoV-2, with continuous turnover of dominant viral variants. However, replication kinetics in Vero E6 cells and primary human alveolar epithelial tissues were not affected.
Our data indicate that certain immunocompromised patients may shed infectious virus for longer durations than previously recognized. Detection of subgenomic RNA is recommended in persistently SARS-CoV-2 positive individuals as a proxy for shedding of infectious virus.
credit: National Institute of Allergy and Infectious Diseases (NIAID)
Study identifies potential approach to treat severe respiratory distress in patients with COVID-19
Early data from a clinical study suggest that blocking the Bruton tyrosine kinase (BTK) protein provided clinical benefit to a small group of patients with severe COVID-19.
Colorized scanning electron micrograph of an apoptotic cell (green) heavily infected with SARS-COV-2 virus particles (purple), isolated from a patient sample. Image captured at the NIAID Integrated Research Facility (IRF) in Fort Detrick, MarylandNIAID
Researchers observed that the off-label use of the cancer drug acalabrutinib, a BTK inhibitor that is approved to treat several blood cancers, was associated with reduced respiratory distress and a reduction in the overactive immune response in most of the treated patients.
The findings were published June 5, 2020, in Science Immunology. The study was led by researchers in the Center for Cancer Research at the National Cancer Institute (NCI), in collaboration with researchers from the National Institute of Allergy and Infectious Diseases (NIAID), both part of the National Institutes of Health, as well as the U.S. Department of Defense’s Walter Reed National Military Medical Center, and four other hospitals nationally.
These findings should not be considered clinical advice but are being shared to assist the public health response to COVID-19. While BTK inhibitors are approved to treat certain cancers, they are not approved as a treatment for COVID-19. This strategy must be tested in a randomized, controlled clinical trial in order to understand the best and safest treatment options for patients with severe COVID-19.
The BTK protein plays an important role in the normal immune system, including in macrophages, a type of innate immune cell that can cause inflammation by producing proteins known as cytokines. Cytokines act as chemical messengers that help to stimulate and direct the immune response. In some patients with severe COVID-19, a large amount of cytokines are released in the body all at once, causing the immune system to damage the function of organs such as the lungs, in addition to attacking the infection. This dangerous hyperinflammatory state is known as a “cytokine storm.” At present, there are no proven treatment strategies for this phase of the illness. The study was developed to test whether blocking the BTK protein with acalabrutinib would reduce inflammation and improve the clinical outcome for hospitalized patients with severe COVID-19.
This prospective off-label clinical study included 19 patients with a confirmed COVID-19 diagnosis that required hospitalization, as well as with low blood-oxygen levels and evidence of inflammation. Of these patients, 11 had been receiving supplemental oxygen for a median of two days, and eight others had been on ventilators for a median of 1.5 (range 1-22) days.
Within one to three days after they began receiving acalabrutinib, the majority of patients in the supplemental oxygen group experienced a substantial drop in inflammation, and their breathing improved. Eight of these 11 patients were able to come off supplemental oxygen and were discharged from the hospital. Although the benefit of acalabrutinib was less dramatic in patients on ventilators, four of the eight patients were able to come off the ventilator, two of whom were eventually discharged. The authors note that the ventilator patient group was extremely clinically diverse and included patients who had been on a ventilator for prolonged periods of time and had major organ dysfunction. Two of the patients in this group died.
Blood samples from patients in the study showed that levels of interleukin-6 (IL-6), a major cytokine associated with hyperinflammation in severe COVID-19, decreased after treatment with acalabrutinib. Counts of lymphocytes, a type of white blood cell, also rapidly improved in most patients. A low lymphocyte count has been associated with worse outcome for patients with severe COVID-19. The researchers also tested blood cells from patients with severe COVID-19 who were not in the study. In comparison with samples from healthy volunteers, they found that these patients with severe COVID-19 had higher activity of the BTK protein and greater production of IL-6. These findings suggest that acalabrutinib may have been effective because its target, BTK, is hyperactive in severe COVID-19 immune cells.
The results of this study were used to inform the trial design of the CALAVI (acalabrutinib) randomized, controlled clinical trial, sponsored by AstraZeneca, which will examine the safety and efficacy of acalabrutinib in patients with severe COVID-19.
A clinical trial to evaluate the safety and effectiveness of hydroxychloroquine for the treatment of adults hospitalized with coronavirus disease 2019 (COVID-19) has begun, with the first participants now enrolled in Tennessee.
Colorized scanning electron micrograph of an apoptotic cell (green) heavily infected with SARS-COV-2 virus particles (purple), isolated from a patient sample. Image captured and color-enhanced at the NIAID Integrated Research Facility (IRF) in Fort Detrick, Maryland.NIAID
The Outcomes Related to COVID-19 treated with hydroxychloroquine among In-patients with symptomatic Disease study, or ORCHID Study, is being conducted by the Prevention and Early Treatment of Acute Lung Injury (PETAL) Clinical Trials Network of the National Heart, Lung, and Blood Institute (NHLBI), part of the National Institutes of Health.
The first participants have enrolled in the trial at Vanderbilt University Medical Center, Nashville, one of dozens of centers in the PETAL Network. The blinded, placebo-controlled randomized clinical trial aims to enroll more than 500 adults who are currently hospitalized with COVID-19 or in an emergency department with anticipated hospitalization. All participants in the study will continue to receive clinical care as indicated for their condition. Those randomized to the experimental intervention will also receive hydroxychloroquine.
“Effective therapies for COVID-19 are urgently needed,” said James P. Kiley, director, Division of Lung Diseases, NHLBI. “Hydroxychloroquine has showed promise in a lab setting against SARS-CoV-2, the virus that causes COVID-19 and preliminary reports suggest potential efficacy in small studies with patients. However, we really need clinical trial data to determine whether hydroxychloroquine is effective and safe in treating COVID-19.”
While COVID-19 usually presents as an acute respiratory infectious illness, it can damage multiple organ systems, including heart, lung, and blood. Most adults with COVID-19 experience fever, cough, and fatigue and then recover within one to three weeks. However, some develop severe illness, typically manifesting as pneumonia and respiratory failure, with continued progression to acute respiratory distress syndrome and death. Currently, no therapies have been demonstrated to prevent the progression of COVID-19 to severe illness, but several medicines available in the United States have been proposed as potential therapies.
Hydroxychloroquine is used to treat malaria and rheumatoid conditions such as arthritis. In various studies, the drug has demonstrated antiviral activity, an ability to modify the activity of the immune system, and has an established safety profile at appropriate doses, leading to the hypothesis that it may also be useful in the treatment of COVID-19. The drug is not without risks as even short term use can cause cardiac arrythmias, seizures, dermatological reactions, and hypoglycemia.
“Many U.S. hospitals are currently using hydroxychloroquine as first-line therapy for hospitalized patients with COVID-19 despite extremely limited clinical data supporting its effectiveness,” said Wesley Self, M.D., M.P.H., emergency medicine physician at Vanderbilt University Medical Center and PETAL Clinical Trials Network investigator leading the ORCHID trial. “Thus, data on hydroxychloroquine for the treatment of COVID-19 are urgently needed to inform clinical practice.”
COVID-19 cases were first identified in December 2019 in Wuhan, Hubei Province, China. As of April 8, 2020, the World Health Organization (WHO) has reported more than 1.3 million cases of COVID-19 and more than 79,000 deaths worldwide, and the Centers for Disease Control and Prevention has reported more than 395,000 confirmed COVID-19 cases and 12,700 deaths in the United States.
ORCHID participants will be randomly assigned to receive hydroxychloroquine 400 mg twice daily for two doses (day one), then 200 mg twice daily for the subsequent eight doses (days two to five) or a placebo twice daily for five days.
NIH also recently launched a trial to study Remdesivir as a possible treatment for COVID-19. That clinical trial is sponsored by the National Institute of Allergy and Infectious Diseases (NIAID) [NCT04280705]. These two trials will provide data on the effectiveness and safety of each agent versus placebo in the urgent race to find effective therapies for treating COVID-19.
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