Treatment of Sedation, Hypertension, Secondary Infection, and Coagulopathy in Severe COVID-19

In the past week the NIH has announced a number of new COVID-19 clinical trials. The first trial is ACTT-3. This trial builds upon the first Remdesivir trial (ACTT-1) and will test the combination of Remdesivir with Interferon-beta-1a which has pleiotropic effects on the immune system. In addition, two antibody trials, ACTIV-2 and ACTIV-3, were announced by the NIH . These trials will test Eli Lily’s new antibody therapy LY-CoV555 in non-hospitalized and hospitalized patients respectively. Interestingly, the ACTIV-2 trial hopes to administer antibody therapy early in mild and moderate patients to test whether the therapy reduces later disease progression and complications. Eli Lily has also announced a new trial of their own for this antibody that will focus on nursing homes. Utilizing mobile research units, Lily will enroll elderly patients and staff in nursing homes with positive COVID-19 cases. Of note, they will enroll individuals with both positive and negative testing to test whether administration to a population reduces severity and transmission of SARS-CoV-2. The final trial announcement is the ACTIV-4 trial, which unlike the other ACTIV trial will instead focus on blood thinners. The specifics of this trial still remain unknown, but treating the coagulopathy in severe COVID-19 patients is at the forefront of managing the disease.

This week, I wanted to focus on therapies often used in conjunction with main COVID-19 therapies to treat a number of secondary pathologies that develop with disease. The first therapy class are sedatives for COVID-19 patients. The Food and Drug Administration (FDA) has granted an emergency use authorization (EUA) to Propoven 2% emulsions (propofol) to maintain sedation in severe COVID-19 patients. Profol is one of the most common drugs used for sedation and is commonly administered when a patient is intubated. However, some concern has been raised about the therapy since previously propofol has been shown to increase expression of ACE2 in human pulmonary artery endothelial cells in both a concentration-dependent and time-dependent manner (Cao L, et al. 2020). The effects of increased expression of the viral entry path remains unknown but there is a possibility for it to have deleterious effects. Thus, there has been a proposal for use of other sedation medications such as midazolam and dexmedetomidine to be studied and considered for COVID-19 patients, which have less known effects on ACE2 and blood pressure (Sohn JT, 2020). Of note, the EUA of a sedative therapy was greatly needed due to the large number of COVID-19 patients requiring  intubation; however, moving forward different sedative treatments should be tested and compared as this often overlooked therapy could change the overall course of disease.

With a large proportion of the population being hypertensive, high blood pressure has become a grave concern in treating COVID-19. Initially, there was high trepidation behind treating  COVID-19 with hypertensive medications since many of these therapies theoretically increase ACE2 expression. However, COVID-19 has been associated with hypertension as both a risk-factor and secondary pathology emphasizing the pressing need for hypertensive treatment. As such, there is larger risk posed to COVID-19 patients by not treating their hypertension (Vaduganathan M, et al. 2020). At this time, the discontinuation of Renin-Angiotensin-Aldosterone System inhibitors is not recommended by the American College of Cardiology, American Heart Association, and Heart Failure Society of America as no study has found detrimental effects in COVID-19 whereas hypertension poses a clear threat.

Another pathology that develops often in severe COVID-19 patients is secondary pneumonias. These secondary infections pose a dangerous threat and often occur in patients with COVID-19 associated cytokine storms. There has been a wide variety of proposals on how best to treat this secondary bacterial infection in addition to the viral SARS-CoV-2 infection, with some topics including phage therapy and antibiotics (Manohar P, et al. 2020). As seen in a Tocilizumab Phase II trial, the anti-IL6 antibody reduced mortality in severe COVID-19 patients, but led to a larger proportion of patients developing secondary superinfections. While these superinfections did not affect mortality, these superinfections may become more common as other anti-inflammatory therapies in clinical trials for COVID-19 may find an increased prevalence as well. 

Finally, as one of the most prevalent pathologies, coagulopathy is a large concern in patients. A number of autopsy studies have reported systemic clotting in patients who have died from COVID-19 with increased neutrophil counts, neutrophil nets, and clotting factors in these patients. In clinical practice, these patients are often seen with increased D-dimer and fibrinogen with the severity of coagulopathy associated with the severity of disease (Kander T, 2020). Often times, coagulopathy is treated with an anticoagulant such as heparin, with the Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis providing specific clinical guidelines on different anticoagulant regimen (Spyropoulos AC, et al. 2020). However, in many cases of COVID-19, heparin does not appear to be sufficient/beneficial for COVID-19 related coagulopathy. Excitingly, there has been the recent announcement of the ACTIV-4 trial which will study different antithrombotics in COVID-19 such as heparin as mentioned in the first paragraph.

COVID-19 is a pressing disease with a majority of the trials focused on treating the viral SARS-CoV-2 infection and immunological hyperactivation in severe COVID-19. However, it is just as critical to thoroughly study treatment of secondary COVID-19 related pathologies such as hypertension and coagulopathy.