Research Aimed at Understanding Long COVID

Infection with severe acute respiratory syndrome coronavirus 2, or SARS-CoV-2, can leave persistent and prolonged effects in multiple organ systems, causing breathing problems, fatigue, joint pain, brain fog, and heart palpitations, plus depression and other mood disorders.1,2 Survivors of the SARS epidemic and the Middle East respiratory syndrome, or MERS, outbreak have reported similar long-term effects.3–7

Scientists are investigating the reasons why some people are more susceptible than others to long-term effects of COVID-19. Research aims to answer questions like “Is viral RNA protein from SARS-CoV-2 stored somewhere in the body?”. Analyses of intestinal biopsies from people who had asymptomatic COVID-19 seem to suggest so—evidence of SARS-CoV-2 viral RNA and protein four months after infection were detected by immunofluorescence and PCR.8

Could viral RNA persist in the brain, and is this why some people report feelings described as brain fog—lost sense of time, mood changes, and forgetfulness? A prospective study of people with long COVID report that brain fog is the most common neurological symptom, affecting cognition and quality of life.1 It is possible that it may represent a mild form of post-COVID-19 encephalopathy, with symptoms like those seen in people who have experienced mild traumatic brain injury and in those with encephalomyelitis/chronic fatigue syndrome (ME/CFS).9–14

What is the role of genetics in long COVID? The COVID Human Genetic Effort is an international research cohort investigating the genetic and immunological factors that increase the risk of long COVID, in addition to other manifestations of COVID, such as multisystem inflammatory syndrome in children and COVID toes.15 The focus of this effort is to study people who had mild acute COVID-19 but are still having persistent fevers, dysautonomia, or other abnormal physiological presentations 12 weeks or more after their initial symptoms.2

To best manage people with long COVID, robust studies of the manifestations of this disease are important and will inform evidence-based multidisciplinary-care approaches and prioritize research in this area. The National Institutes of Health established a research initiative focused on the post-acute sequelae of SARS-CoV-2 Infection (PASC) to study a cohort of patients to determine how many people experience symptoms of long-term COVID and why.16

References

 

  1. Graham EL, Clark JR, Orban ZS, et al. Persistent neurologic symptoms and cognitive dysfunction in non-hospitalized Covid-19 “long haulers.” Ann Clin Transl Neurol. 2021;Mar 23: Epub ahead of print.
  2. Marx V. Scientists set out to connect the dots on long COVID. Nat Methods. 2021;Apr 28: Epub ahead of print.
  3. Ahmed H, Patel K, Greenwood DC, et al. Long-term clinical outcomes in survivors of severe acute respiratory syndrome and Middle East respiratory syndrome coronavirus outbreaks after hospitalisation or ICU admission: a systematic review and meta-analysis. J Rehabil Med. 2020;52:jrm00063.
  4. Hui DS, Joynt GM, Wong KT, et al. Impact of severe acute respiratory syndrome (SARS) on pulmonary function, functional capacity and quality of life in a cohort of survivors. Thorax. 2005;60:401-409.
  5. Lam MH, Wing YK, Yu MW, et al. Mental morbidities and chronic fatigue in severe acute respiratory syndrome survivors: long-term follow-up. Arch Intern Med. 2009;169:2142-2147.
  6. Lee SH, Shin HS, Park HY, et al. Depression as a mediator of chronic fatigue and post-traumatic stress symptoms in Middle East respiratory syndrome survivors. Psychiatry Investig. 2019;16:59-64.
  7. Moldofsky H, Patcai J. Chronic widespread musculoskeletal pain, fatigue, depression and disordered sleep in chronic post-SARS syndrome; a case-controlled study. BMC Neurol. 2011;11:37.
  8. Gaebler C, Wang Z, Lorenzi JCC, et al. Evolution of of antibody immunity to SARS-CoV-2. Nature. 2021;591:639-644.
  9. Liotta EM, Batra A, Clark JR, et al. Frequent neurologic manifestations and encephalopathy-associated morbidity in Covid-19 patients. Ann Clin Transl Neurol. 2020;7:2221-2230.
  10. Islam MF, Cotler J, Jason LA. Post-viral fatigue and COVID-19: lessons from past epidemics. Fatigue Biomed Health Behav. 2020;8:61-69.
  11. Townsend L, Dyer AH, Jones K, et al. Persistent fatigue following SARS-CoV-2 infection is common and independent of severity of initial infection. PLoS One. 2020;15:e0240784.
  12. Afari N, Buchwald D. Chronic fatigue syndrome: a review. Am J Psychiatry. 2003;160:221-236.
  13. Norrie J, Heitger M, Leathem J, et al. Mild traumatic brain injury and fatigue: a prospective longitudinal study. Brain Inj. 2010;24:1528-1538.
  14. Marshall M. The lasting misery of coronavirus long-haulers. Nature. 2020;585:339-341.
  15. Covid Human Genetic Effort. (www.covidhge.com/) Accessed 5/6/2021.
  16. National Institutes of Health (NIH). Explore COVID-19 funding opportunities from NIH. (https://covid19.nih.gov/funding/open-funding-opportunities) Accessed 5/6/2021.
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Updates in the Treatment and Prevention of COVID-19​

FDA Authorizes Lower Dose of Intravenous and Subcutaneous Dose of Casirivimab and Imdevimab Antibody Cocktail

The Food and Drug Administration authorized lower-dose (1200 mg) casirivimab and imdevimab monoclonal-antibody infusion therapy for nonhospitalized people with COVID-19 who have risk factors for disease progression. The Emergency Use Authorization (EUA) is supported by data from a phase 3 trial showing a consistent 70% reduced risk of hospitalization or death with either the lower dose or the higher dose (2400 mg) originally authorized. Subcutaneous administration of casirivimab and imdevimab was granted EUA based on scientific evidence to date regarding its safety and efficacy. Infusion-related reactions of grade 2 or higher have been observed in 0.2% of people who have received IV therapy; 12% of those treated subcutaneously have experienced injection-site reactions.

This antibody combination has shown efficacy in vitro against variants of concern identified in the United States with origins from Brazil (P.1/Gamma) and South Africa (B.1.351/Beta).

In May 2021, the definition of eligible patients for outpatient COVID-19 monoclonal antibody therapies was expanded to include more medical conditions and other factors, such as race or ethnicity, that increase the risk for severe disease.

Subcutaneous Administration of Casirivimab and Imdevimab Reduced the Risk of Symptomatic COVID-19 by 81% Among Household Contacts

Top-line results from a phase 3 trial showed that the combination of casirivimab and imdevimab reduced the risk of symptomatic infections by 81% among household contacts of SARS-CoV-2 infected individuals. The trial enrolled 1,505 individuals who did not have COVID-19 symptoms or anti-SARS-CoV-2 antibodies, but who lived in the same household as an individual who tested positive for SARS-CoV-2 within the prior 4 days. A single subcutaneous injection of casirivimab and imdevimab provided rapid protection to those with exposure to SARS-CoV-2 at home, with protection against symptomatic infections ranging from 72% in the first week to 93% in subsequent weeks. Individuals who developed symptomatic infections despite casirivimab and imdevimab therapy had a shorter duration of symptoms compared with those who received placebo (1 week vs 3 weeks, respectively). Infected individuals who received therapy also cleared the virus faster. Adverse events (AEs) occurred in 20% of patients receiving casirivimab and imdevimab and 29% of patients receiving placebo. Injection site reactions, all of which were grades 1-2, occurred in 4% of patients in the treatment group and 2% of placebo participants.

Casirivimab and Imdevimab Significantly Reduced Progression to Symptomatic COVID-19 in Recently Infected Asymptomatic Patients

In a phase 3 trial of 204 recently infected asymptomatic COVID-19 patients, subcutaneous administration of casirivimab and imdevimab reduced the overall risk of progressing to symptomatic COVID-19 by 31%, and by 76% after the third day. In addition to reducing the risk of symptomatic infections, the top-line results report that the combination of casirivimab and imdevimab shortened the total number of weeks patients experienced symptoms by 45% and reduced the viral burden by more than 90%. No patients withdrew from the trial due to AEs in either group. Casirivimab and imdevimab are investigational drugs with emergency use authorization for the treatment of individuals with mild-to-moderate COVID-19 who are at high-risk of progressing to severe COVID-19 or hospitalization. Casirivimab and imdevimab (REGEN-COV™) continues to be evaluated in clinical trials in multiple settings for COVID-19, including the open-label RECOVERY trial of hospitalized patients in the UK.

Johnson & Johnson COVID-19 Vaccine Administration Paused

The Centers for Disease Control and Prevention (CDC) and the Federal Drug Administration (FDA) are recommending a pause in the use of the Ad26.COV2.S vaccine developed by Johnson & Johnson (Janssen) as they review data involving 6 reported cases of a rare and severe type of blood clot in individuals after vaccination. The vaccine has been administered to more than 6.8 million individuals in the US. In all 6 reported cases, a type of blood clot called cerebral venous sinus thrombosis (CVST) occurred in combination with low platelet levels (thrombocytopenia). Treatment of CVST differs from other blood clots and administration of heparin may be dangerous in these patients. All 6 cases occurred among women aged 18 to 48 years and symptoms usually occurred 6 to 13 days after vaccination. People who develop severe headache, abdominal pain, leg pain, or shortness of breath within 3 weeks after vaccination should contact their healthcare provider.

References:

Regeneron Press Release. FDA Authorizes Lower 1,200 mg Intravenous and Subcutaneous Dose of REGEN-COV™ (Casirivimab and Imdevimab). Antibody Cocktail to Treat Patients with COVID-19. Available at: https://prnewswire.com/news-releases/fda-authorizes-lower-1-200-mg-intravenous-and-subcutaneous-dose-of-regen-cov-casirivimab-and-imdevimab-antibody-cocktail-to-treat-patients-with-covid-19–301305941

Regeneron Press Release. Phase 3 Prevention Trial Showed 81% Reduced Risk of Symptomatic SARS-CoV-2 Infections with Subcutaneous Administration of REGEN-COV™ (Casirivimab and Imdevimab). April 12, 2021. Available at: https://investor.regeneron.com/news-releases/news-release-details/phase-3-prevention-trial-showed-81-reduced-risk-symptomatic-sars

Regeneron Press Release. Phase 3 Treatment Trial in Recently Infected Asymptomatic Patients Showed REGEN-COV™ (Casirivimab and Imdevimab) Significantly Reduced Progression to Symptomatic COVID-19. April 12, 2021. Available at: https://investor.regeneron.com/news-releases/news-release-details/phase-3-treatment-trial-recently-infected-asymptomatic-patients

FDA Statement. Joint CDC and FDA Statement on Johnson & Johnson COVID-19 Vaccine. April 13, 2021. Available at: https://www.fda.gov/news-events/press-announcements/joint-cdc-and-fda-statement-johnson-johnson-covid-19-vaccine