As efforts to characterize the symptomology of infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and the subsequent development of coronavirus disease 2019 (COVID-19) move forward, so too have efforts to find and develop effective therapies.

A review published in Military Medical Research summarized the latest research progress of the epidemiology, pathogenesis, and clinical characteristics of COVID-19, and discussed the current treatment and scientific advancements that can be used to potentially combat the pandemic novel coronavirus.1

On January 7, 2020, Chinese scientists isolated and sequenced the genome of the virus. Based on this genome, the natural host origin is suspected to the bats, who might have transmitted it to humans through direct contact or consumption of unknown intermediate hosts. COVID-19 is an acute respiratory infectious disease that spreads through the respiratory tract by droplets, respiratory secretions, and direct contact. The virus has an estimated reproduction number around 2.2. Moreover, 2 strains have been discovered in China: L type (~70%) and S type (~30%); the L type derived from the S type and is thought to be evolutionarily more aggressive and contagious.1

The current gold standard for clinical diagnosis of COVID-19 is a nucleic acid detection of SARS-CoV-2 in nasal, throat, or other respiratory tract samples by real-time polymerase chain reaction testing and next-generation sequencing. Clinical symptoms of COVID-19 most commonly include cough, fever, and fatigue. The elderly population and those with underlying diseases (eg, diabetes, cardiovascular disease, chronic obstructive pulmonary disease, and hypertension) are most susceptible to infection and prone to serious outcomes, including the rapid development of acute respiratory distress syndrome, septic shock, cytokine storm, and coagulation dysfunction that could all lead to death.


Continue Reading

SARS-CoV-2 can also cause pneumonia (the staple sign of COVID-19), which exhibits strong infectivity; compared with other members of the coronavirus family such as SARS and Middle Eastern Respiratory Syndrome (MERS), SARS-CoV-2 has shown lower rates of morbidity and mortality.1,2 This may be the result of a more indolent course of infection, which allows for patients to be paucisymptomatic and obtain medical care before a critical level is reached.

SARS-CoV-2 spreads mainly through the respiratory tract binding with high affinity to the angiotensin-converting enzyme 2 (ACE2) receptor, the same receptor used by SARS-CoV.

However, several studies have also highlighted that the respiratory tract may only be the starting point for the effects of COVID-19 on the body. The ACE2 receptor is highly expressed in blood vessels, the kidneys, the neural cortex and brainstem, as well as the majority of the gastrointestinal tract.

This may help in explaining findings from a cohort of 52 patients who required stays in an intensive care unit: the most critical patients showed signs of organ function damage, including ARDS in 67%, pneumothorax in 2%, acute kidney injury in 29%, cardiac injury in 23%, and liver dysfunction in 29%.3 Moreover, in a study of 416 patients who required hospitalization due to COVID-19, 20% demonstrated signs of cardiac injury.3 Results of another study among 138 hospitalized patients with COVID-19 showed that 44% demonstrated a cardiac arrhythmia.4

Furthermore, 38% of a cohort of 184 patients with COVID-19 in a Dutch intensive care unit were found to have abnormal blood clotting as well as abnormally significantly elevated D-dimer levels.4 Researchers and physicians on the frontlines hypothesize that this may be the effect of the virus on the blood vessels or an indirect result of a cytokine storm as a result of interleukins released from the liver in response to the infection.

Several studies have evidenced what is currently a recognized constellation of gastroenterological (GI) symptoms as a result of infection with SARS-CoV-2.6,7,8,9 Reported symptoms include diarrhea and vomiting. In one cohort of 95 patients with COVID-19, researchers found that 61.1% patients had GI symptoms, and 11.6% of patients showed solely GI symptoms and did not have any imaging features of COVID-19 pneumonia.6 In a study of 73 hospitalized patients with SARS-CoV-2 infection, 53.42%, demonstrated SARS-CoV-2 RNA in stool samples.7

Moreover, researchers have examined the viral nucleocapsid protein in situ in the kidney postmortem and found that SARS-CoV-2 antigens accumulated in kidney tubules; they noted that this suggests SARS-CoV-2 infects the human kidney directly, and can cause acute kidney injury and contribute to viral spreading throughout the body.5 However, as with the effect on blood clotting, the noted acute kidney injury may be a consequence of the cytokine storm response to infection.5 Data from small subsets of patients with COVID-19, has also demonstrated that proteinuria and hematuria are common features of the disease and found in roughly 40% of patients on hospital admission.5

Due to the current lack of effective antiviral therapy against COVID-19, treatments are mainly focused on treating symptoms and providing respiratory support. Remdesivir (GS-5734) has broad-spectrum antiviral activity against several RNA viruses and has been reported to have successfully treated the first case of COVID-19 in the United States successfully.1

Chloroquine and hydroxycholorquine, medications used to treat malaria and rheumatologic diseases, and early data showed potent in vitro effects on SARS-CoV infection, and a potential in treating COVID-19 by suppressing the production and release of certain cytokines.1 However, data from several clinical trials have led to a recommendation by the Food and Drug Administration (FDA) against the public use of chloroquine and hydroxycholorquine.10 These treatments have also been associated with significant adverse events, particularly arrhythmias including ventricular fibrillation and ventricular tachycardia; also increased insulin levels and hemolysis in patients with glucose-6-phosphate dehydrogenase deficiency.10 Therefore the FDA recommended the use of these medications only under emergency use authorizations in the setting of clinical trials.

Preliminary in vitro data has shown the ability of remedesivir inhibit SARS-CoV-2. This has been followed up by several ongoing phase 3 clinical trials. The results of 2 such trials has demonstrated positive and clinically significant early findings as reported by Gilead and the National Institute of Allergy and Infectious Disease (NIAID). In a cohort of 1063 patients, results of the Adaptive COVID-19 Treatment Trial (conducted by Gilead and sponsored by NIAID) demonstrated that patients who received remdesivir had a recovery time that was 31% faster than those who received placebo (P < .001).11 The median time to recovery was 11 days for patients treated with remdesivir compared with 15 days for those who received placebo.11 Results also showed mortality rate of 8.0% for the group receiving remdesivir vs 11.6% for the placebo group (P = .059), thus suggesting a significant survival benefit.11

Related Articles

Gilead has also released preliminary results from another phase 3 clinical trial (SIMPLE) that compared a 5 day vs 10 day course of remdesivir for the treatment of hospitalized patients with severe COVID-19. In a press release, the company reported that “The study demonstrated that patients receiving a 10-day treatment course of remdesivir achieved similar improvement in clinical status compared with those taking a 5-day treatment course (odds ratio: 0.75 [95% CI 0.51 – 1.12] on Day 14). No new safety signals were identified with remdesivir across either treatment group.”12 Moreover, by day 14 post-treatment, 64.5% of patients in the 5-day group demonstrated clinical recovery and 60% were discharged, compared with 53.8% and 52.3%, respectively, of those in the 10-day group.12

The release also highlighted that an exploratory analysis found patients who received remdesivir earlier (within 10 days of symptom onset) had improved outcomes compared with those treated later: by day 14 post-treatment, 62% percent of patients who received early treatment with remdesivir were able to be discharged from the hospital, compared with 49% of patients who were treated >10 days after symptom onset.

Overall, researchers have concluded that, “Scientists have made progress in the characterization of the novel coronavirus and are working extensively on the therapies and vaccines against the virus.”1

Reference

  1. Guo Y, Cao Q, Hong Z, et al. The origin, transmission and clinical therapies on coronavirus disease 2019 (COVID-19) outbreak – an update on the status [published online March 13, 2020]. Military Medical Research. doi:10.1186/s40779-020-00240-0
  2. Raoult D, Zumla A, Locatelli F, Ippolito G, Kroeme G. Coronavirus infections: epidemiological, clinical and immunological features and hypotheses [published online February 3, 2020]. Cell Stress. doi:10.15698/cst2020.04.216
  3. Wadman M, Couzin-Frankel J, Kaiser J, Matacic C. How does coronavirus kill? Clinicians trace a ferocious rampage through the body, from brain to toes [published online April 17, 2020]. Science. doi:10.1126/science.abc3208
  4. Wang D, Hu B, Hu C. Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus–infected pneumonia in Wuhan, China [published online February 7, 2020] JAMA. doi:10.1001/jama.2020.1585.
  5. Perico L, Benigni A, Remuzzi G. Should COVID-19 concern nephrologists? Why and to what extent? The emerging impasse of angiotensin blockade [published online March 23, 2020]. Nephron. doi:10.1159/000507305
  6. Lin L, Jiang X, Zhang Z, et al. Gastrointestinal symptoms of 95 cases with SARS-CoV-2 infection [published online April 2, 2020]. Gut. doi:10.1136/gutjnl-2020-321013
  7. Xiao F, Tang M, Zheng X, Liu Y, Li X, Shan H. Evidence for gastrointestinal infection of SARS-CoV-2. Gastroenterology. 2020;158:1831-1833.
  8. Carvalho A, Alqusairi R, Adams A, et al. SARS-CoV-2 gastrointestinal infection causing hemorrhagic colitis [published online April 17, 2020]. The American Journal of Gastroenterology. doi:10.14309/ajg.0000000000000667
  9. Cheung KS, Hung IFN, Chan PPY, et al. Gastrointestinal manifestations of SARS-CoV-2 infection and virus load in fecal samples from the Hong Kong cohort and systematic review and meta-analysis [published online April 3, 2020]. Gastroenterology. doi:10.1053/j.gastro.2020.03.065
  10. United States Food and Drug Administration. FDA Drug Safety Communication: FDA cautions against use of hydroxychloroquine or chloroquine for COVID-19 outside of the hospital setting or a clinical trial due to risk of heart rhythm problems. Published online April 24, 2020. Accessed April 30, 2020.
  11. NIH clinical trial shows remdesivir accelerates recovery from advanced COVID-19 [news release]. National Institute of Allergy and Infectious Diseases; April 29, 2020.
  12. Gilead announces results from phase 3 trial of investigational antiviral remdesivir in patients with severe COVID-19 [news release]. Foster City, CA. Gilead; April 29, 2020.