Long COVID [post-acute sequelae of coronavirus disease 2019]: experimental drugs for cardiopulmonary complications

Abstract

KEYWORDS:

• SARS-CoV-2
• COVID-19
• Long COVID
• post-acute sequelae of coronavirus disease 2019
• renin-angiotensin-aldosterone system
• renin-angiotensin system
• ACE₂
• spike protein

1. Introduction

After recovery from the acute phase of coronavirus disease 2019 (COVID-19), a variable proportion of subjects may continue to present symptoms. Such a condition is generally referred to as ‘Long COVID,’ ‘post-acute sequelae of COVID-19,’ ‘chronic COVID-19,’ ‘post-COVID syndrome,’ or ‘post-COVID conditions.’ It is characterized by symptom clusters which occur or continue at a distance of at least 3 months after the acute infection [1]. Such constellation of symptoms is not explained by alternative diagnoses and exerts a significant impact on quality of life. In a meta-analysis of 54 clinical studies and 2 medical record databases, 6.2% of subjects experienced at least one of a predetermined set of 3 post-acute sequelae of COVID-19 symptom constellation (including fatigue, neurocognitive dysfunction, and respiratory symptoms) [1]. More specifically, the fatigue, respiratory, and cognitive clusters occur in 51.0%, 60.4%, and 35.4% of Long COVID cases, respectively [2]. Importantly, post-acute sequelae of COVID-19 is not associated with active viral infection and transmissibility.

In the wide spectrum of Long COVID manifestations, symptoms are representative of conditions involving different organs and systems including the cardiovascular, pulmonary, renal, gastrointestinal, vascular, musculoskeletal, neurological, and endocrine systems. The most frequent cardiopulmonary symptoms and complications are dyspnea, cough, pleuritic and chest pain, thromboembolic events, peripheral edema, dizziness, wheezing, syncope, postural orthostatic tachycardia syndrome, and cardiac dysrhythmias [3].

Unfortunately, the basic mechanisms of this syndrome are poorly understood. There is a paucity of high-quality data from clinical studies and trials allowing the generalizability of results on the correct management of persistent cardiopulmonary symptoms or complications of post-acute sequelae of COVID-19 [3,4]. Several drugs have been tested or are under scrutiny for the management of this syndrome. However, only few treatments for certain components of Long COVID have appeared to be candidates with supporting evidence. These include intravenous immunoglobulin (or BC007 to neutralize G protein-coupled receptor antibodies), oral anticoagulants, beta-blockers, pycnogenol (or sulodexide), Paxlovid, and naltrexone (or aripiprazole) to treat immune dysfunction, abnormal clotting, postural orthostatic tachycardia syndrome, endothelial dysfunction, viral persistence, and fatigue, respectively [5]. Moreover, some data suggest that coenzyme Q10 and D-ribose may be effective in patients with long COVID [5,6]. Nonetheless, most of the experimental drugs are used to treat individual symptoms of Long COVID (for cardiopulmonary complications: beta-blockers to treat postural orthostatic tachycardia syndrome, ivabradine to treat palpitations, aripiprazole and coenzyme Q10 for fatigue, apixaban for abnormal clotting, and sulodexide or pycnogenol to treat chest pain and improve microcirculation) or isolated organ dysfunction and there is significant heterogeneity across published and ongoing clinical studies in the characterization of Long COVID, diagnostic criteria, and ascertainment of outcomes (to verify that interventions are really effective). Furthermore, duration of interventions (ranging from few weeks to 12 months after diagnosis of Long COVID) is not a homogeneous feature [5,6].

As aforementioned, pathogenesis of post-acute sequelae of COVID-19 is poorly understood. There are multiple, potentially overlapping, hypothesized mechanisms for the explanation of pathophysiological insults and sequelae. They include a systemic inflammatory state, immune dysregulation, autoimmunity, microvascular clotting, and endothelial abnormalities [5].

However, the viral reservoir hypothesis might lead to additional treatment options worth to be explored (Figure 1, panel A). Anecdotal evidences for this hypothesis come from case reports and epidemiological data showing that 4% of recovered COVID-19 patients have viral RNA in their feces [7] and that a course of antivirals is associated with resolution of symptoms [8]. The presence of viral RNA does not necessarily indicate an intact virus as Long COVID might be a response to viral remnants. Notably, viral RNA or viral fragments, in the form of Spike proteins, can persist in many organs [9]. This suggests the possibility of persistent circulating Spike proteins [9].

Figure 1. The viral reservoir hypothesis (panel a, circulating Spike proteins promoting the imbalance between angiotensin II and angiotensin_1–7) with preexisting ACE₂ deficiency as phenotype at increased risk of Long COVID (panel c) when compared with normal levels of ACE₂ receptors (panel b); the potential pharmacological modulation to reduce angiotensin II accumulation is also depicted (panel d); see text for details. Note: Legend: ACE₂ = angiotensin converting enzyme 2 receptor.

A retrospective pilot study which examined plasma samples from adults who developed acute COVID-19 or post-acute sequelae of COVID-19 detected severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Spike proteins predominantly in Long COVID patients up to 12 months after diagnosis [10]. Moreover, the virus and the Spike protein have been found several months after infection, in various other study models [9–12].

The pivotal role of a dysregulated renin–angiotensin system (RAS) in the pathogenesis of the complications of COVID-19 is well recognized [13]. More specifically, the interaction between the Spike proteins of SARS-CoV-2 and the angiotensin converting enzyme 2 (ACE₂) receptors causes an imbalance between angiotensin II (Ang II) and angiotensin 1–7 (Ang_1,7) [13]. Of note, accumulation of Ang II favors a pro-inflammatory and pro-thrombotic state [13]. Similarly, circulating SARS-CoV-2 Spike proteins after the acute phase of COVID-19 may systematically interact with ACE₂ receptors expressed by a variety of cells, thereby promoting ACE₂ internalization and degradation [13] (Figure 1, panel A). These reactions may be associated with the pathological features of post-acute sequelae of COVID-19 (including platelet aggregation, thrombosis, and inflammation) [13] (Figure 1). Furthermore, older age and preexisting comorbidities, including chronic obstructive pulmonary disease (COPD), diabetes, and ischemic heart disease, are significantly associated with an increased risk of persistent symptoms of 3 months or more after the acute phase of COVID-19 infection [14]. Remarkably, all these conditions are associated with RAS dysregulation and ACE₂ deficiency and it is likely that phenotypes with ACE₂ deficiency in receptor activity are at increased risk of Long COVID (Figure 1, panel C) [13].

Thus, compounds with insurmountable inhibition of ACE₂, blocking or attenuating the binding of the viral Spike protein to the pocket of the ACE₂ receptor (without the inactivation of the crucial catalytic function of ACE₂), may have the potential to attenuate the cardiopulmonary sequelae of Long COVID (Figure 1, panel D) [13].

2. Expert opinion

While much of the attention on the COVID-19 pandemic was directed at the treatment and prevention of the disease, several reports addressed individuals with debilitating symptoms long after the initial infection. To date, unanimous accepted clinical diagnostic criteria for post-acute sequelae of COVID-19 are still lacking. Nonetheless, this syndrome is an emerging public health concern and the Chronic Disease Center included in the new Classification of Disease, Tenth Revision, Clinical Modification (ICD-10) the unspecified post-COVID conditions (U09.9).

Several experimental drugs are being investigated as potential pharmacological strategies to attenuate or resolve the Long COVID syndrome. However, how useful are the results of clinical studies in the pharmacological treatment of cardiopulmonary complications for a large group of patients with post-acute sequelae of COVID-19 remains to be determined. As highlighted by a systematic review including 6 published trials and 54 trial registration records, there is significant heterogeneity in the characterization of long COVID and definition of primary outcomes, and some studies lack internal and external validity, thus limiting their generalizability [6].

There is an urgent need for a better comprehension of the pathology of this syndrome and for evidence-based strategies to support the treatment of patients. Following the acute illness, patients should be evaluated on the long term using standardized screening measures. Furthermore, accrued data show that patients who develop Long COVID may require rehabilitation services (including pulmonary and cardiac rehabilitation; https://www.who.int/). In this context, the development of a trial platform evaluating the underlying pathophysiology, symptoms, and health impacts of post-acute sequelae of COVID-19 remains mandatory to map and prioritize interventions (including drug treatments and rehabilitation), tailored to individual patient needs [15].

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.