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An Illustrated Primer on COVID-19 Therapy: part 1
“…but they all had an evasive tremor in their voices and an uncertainty in their eyes that belied their words.”
- Gabriel García Márquez
With early data illustrating upwards of 1 in 5 COVID-19 patients developing acute respiratory distress syndrome [ARDS], there is understandable alarm around the absence of definitive therapies. Nevertheless, a handful of pharmacotherapies have been proposed and/or recommended for critically-ill COVID-19 patients including:
-antivirals such as oseltamivir, ganciclovir, lopinavir/ritonavir and remdesivir
The above are in addition to classical, supportive therapies such as oxygenation, ventilation and rational fluid management in the intensive care unit [ICU]. While this short, two-part, summary is inarguably incomplete and should not supplant clinical judgement regarding individual patient pathophysiology, it is meant to remind the clinician of the relatively sparse evidence base upon which many of these therapeutic recommendations are founded.
This is a polemical matter, no doubt, and could be an entire review on its own. The current World Health Organization [WHO] recommendations are to withhold routine administration of corticosteroids for viral pneumonia unless there is another reason to administer them [e.g. COPD exacerbation, septic shock]. Further, the WHO recommendation resonates with a recent review by Russell and colleagues in The Lancet arguing against the indiscriminate use of corticosteroids in COVID-19.
As Russell et al. note, corticosteroids suppress inflammation, and pulmonary inflammation is well-documented in both influenza and coronavirus pneumonias; consequently, there is some pathophysiological rationale for deploying corticosteroids in COVID-19. Yet, in totality, the data from MERS-CoV, SARS-CoV and influenza provide no clear benefit for corticosteroids with a few signals for harm [e.g. delayed clearance of viremia, increased ICU length-of-stay and mortality].
Though, in a thoughtful rebuttal, Shang and colleagues remark that the data summarized by both Russell and the WHO are better interpreted as ‘inconclusive’ and that these data should not completely preclude the administration of ‘low-dose, short-duration’ corticosteroids in COVID-19 [i.e. ≤ 0.5–1 mg/kg per day methylprednisolone or equivalent for less than one week]. Unfortunately, however, it is unclear from their brief correspondence which COVID-19 patients in the ICU should be considered candidates. For further information on ‘cytokine storm’ and patient selection for anti-inflammation, see the section on tocilizumab in part 2.
Further underscoring the contentious nature of corticosteroids, the recently-published Surviving Sepsis Campaign [SSC] guidelines for COVID-19 suggest using corticosteroids in mechanically-ventilated patients only when ARDS is present. The authors remark:
“The majority of our panel support a weak recommendation [i.e. suggestion] to use steroids in the sickest patients with COVID-19 and ARDS. However, because of the very low-quality evidence, some experts on the panel preferred not to issue a recommendation until higher quality direct evidence is available.”
Lopinavir/ritonavir is an antiviral used, most commonly, in HIV. Lopinavir is a protease inhibitor, which also plays a role in the coronavirus life cycle, while ritonavir acts as a lopinavir booster by inhibiting CYP3A-mediated metabolism of lopinavir. There is older evidence supporting the use of lopinavir/ritonavir in the original SARS-CoV outbreak and this provided foundation for investigation in SARS-CoV-2 [i.e. the virus that leads to COVID-19]. Unfortunately, a very recent randomized controlled trial published in New England Journal of Medicine failed to find favourable effects for lopinavir/ritonavir as monotherapy in severe COVID-19. Further, those treated with lopinavir/ritonavir exhibited more adverse events.
Intravenous remdesivir was used in the first case report of COVID-19 in the United States without adverse events reported. Remdesivir is a nucleotide analog inhibitor of RNA-dependent RNA polymerases with activity against RNA viruses [e.g. Ebola, SARS-CoV and MERS-CoV]. More specifically, remdesivir is an adenosine analogue, which incorporates into nascent viral RNA chains and results in pre-mature termination. Remdesivir is not FDA approved as of March 2020 and is for investigational use only; the dosing protocol is as follows: 200 mg IV loading dose on day 1 followed by 100 mg IV daily for 9 days.
Chloroquine and hydroxychloroquine have the same mechanism of action against coronaviruses, though in vitro data implies that hydroxychloroquine may be more potent. The mechanisms of these drugs are manifold and include inhibition of viral cell binding, endosomal membrane fusion, and post-translational modification of viral proteins. Further, chloroquine is a well-known modulator of the immune system [e.g. down-regulation of pro-inflammatory cytokines]. For example, chloroquine inhibits interleukin-1 beta, interleukin-6 [IL-6], tumour necrosis factor-alpha, interferon-alpha amongst others.
Initial clinical data for chloroquine and hydroxychloroquine were favourable and typically the latter is better tolerated. Further, some very early, observational data from a small number of patients suggested that the addition of azithromycin supplements the anti-viral effects of chloroquine, though more recent data is less encouraging. The National Institute of Health [NIH] has recently terminated a trial on hydroxychloroquine in critically-ill adults with COVID-19 for futility and recommends against its use.
Figure 1: Illustration summarizing potential COVID-19 therapies - see text for details; by @_carlemd_
Most importantly, the European Society of Cardiology has released the following statement:
“…speculation about the safety of ACEI or ARB treatment in relation to COVID-19 does not have a sound scientific basis or evidence to support it.”
There are conflicting hypotheses around the angiotensin system in the setting of SARS-CoV-2 infection. Firstly, there are two angiotensin converting enzymes [ACE] to know about:
-ACE, which converts angiotensin I to the vasoconstrictor angiotensin II and
-ACE2, which converts angiotensin II to the vasodilator angiotensin 1-7.
ACE is the more familiar enzyme because of drugs that inhibit its function [e.g. captopril]. The product of ACE, angiotensin II, is a potent vasoconstrictor acting upon angiotensin receptors. Additionally, there are well-known drugs that block the angiotensin receptor [e.g. valsartan].
The lesser known enzyme is ACE2, which degrades the vasoconstrictor angiotensin II into the vasodilator angiotensin 1-7. Accordingly, ACE2 acts as a counterbalance to ACE.
In 2020, ACE2 will become as recognized as its better-known ACE cousin because ACE2 acts as the binding protein for SARS-CoV and SARS-CoV2. Previous investigation has shown that chronic therapy with angiotensin receptor blockers [i.e. ARBs like valsartan] upregulates ACE2 and this led some to be wary of ARBs in the time of coronavirus. However, others have – more convincingly – argued that the upregulation of ACE2 by ARBs is – somewhat paradoxically – beneficial during SARS-CoV-2 infection. This is because stimulated angiotensin receptors by angiotensin II results in increased pulmonary vascular permeability [i.e. pulmonary edema]. Accordingly, downregulation of ACE2 by binding of SARS-CoV-2 leaves angiotensin II unopposed – allowing it to exacerbate lung injury. Therefore, ARBs may be advantageous because they 1. Upregulate ACE2 which degrades angiotensin II and 2. Directly block the action of angiotensin II at the angiotensin receptor [see figure 2]!
For the aforementioned reasons, and also because of direct binding and neutralization of SARS-CoV-2, others have suggested directly administering soluble ACE2.
Figure 2: Simplified illustration demonstrating hypothetical benefit of ARB in SARS-CoV-2. ARB both directly blocks the angiotensin receptor from angiotensin II and upregulates ACE2 which degrades angiotensin II. Thus the potential injurious pulmonary effects of angiotensin II are mitigated. Note that SARS-CoV-2 decreases ACE2 which promotes the activity of angiotensin II.
Avoiding non-steroidal anti-inflammatory medications in COVID-19 is largely based on a few anecdotal cases of worsening disease with NSAID administration and a tweet by a French health minister. Three days prior to the tweet, The Lancet released this speculative letter claiming that the upregulation of ACE2 by ARBs, thiazolidinediones and ibuprofen could exacerbate SARS-CoV-2 infection. Yet, if the aforementioned hypothesis on ACE2 is correct, then the upregulation of ACE2 may be helpful! Of interest, supporting the 'ACE2-up-regulation may be beneficial' hypothesis is this recent study associating ACEI/ARB use in COVID-19 patients with reduced mortality.
The World Health Organization is not endorsing the notion that NSAIDs are risky based on current evidence.
Dr. Kenny is the cofounder and Chief Medical Officer of Flosonics Medical; he also the creator and author of a free hemodynamic curriculum at heart-lung.org