COVID-19: Distinctive Clinical Features of Critically Ill Patients (14 May 2020)

To date, I’ve given a general overview of coronaviruses, including SARS-CoV-2 (1 and 13 March 2020), a review of investigational therapeutics and vaccines currently being studied (23 March and 6 April), a discussion about the role of masks in providing protection from COVID-19 (6 April 2020), as well as a discussion of the virus’ transmissibility, viability on inanimate surfaces, and associated case fatality rate (14 April 2020), a discussion of SARS-CoV-2 antibodies and the potential role of antibody testing (20 April 2020), and a brief review of microbiocidal agents, with a focus on virucidal agents (29 April 2020). In this, my eighth COVID-19-themed post, I discuss some of the distinctive clinical features of critically ill COVID-19 patients and the challenges posed in their medical management. Note that unlike my prior posts, this update was written with those who provide healthcare for COVID-19 patients as the intended audience.

As of 11 May, the Centers for Disease Control (CDC) reported 1,324,488 U.S. cases of coronavirus disease (COVID-19), with 79,756 deaths, translating to an associated case fatality rate (CFR) of 6 percent (For an in-depth discussion of CFR, see my 14 April post). As the number of new cases continues to grow, it is increasingly apparent that there are distinct clinical features that are conserved among sicker COVID-19 patients. First among these is the rapid rate of progression from dyspnea to acute respiratory distress syndrome (ARDS). Dyspnea is a relatively late finding (median 6.5 days after the onset of symptoms), but for those patients who develop acute hypoxemic respiratory failure, progression can be swift (median 2.5 days after the onset of dyspnea). [JAMA. 2020;323(11):1061–1069] Anecdotally, it is not unusual for a mildly dyspneic patient to have an increasing supplemental oxygen requirement, progressing from nasal cannula to intubation within 24–48 hours. This typically occurs in older patients with underlying lung disease such as chronic obstructive pulmonary disease (COPD). Moreover, intubated patients may remain ventilator dependent for several weeks, with multiple attempts at weaning preceding eventual successful extubation. [JAMA. 2020;323(16):1574–1581] Interestingly, it is increasingly apparent that the ARDS seen in COVID-19 patients (CARDS) has features that are atypical for classic ARDS (e.g. sepsis-associated ARDS), which is characterized by pulmonary edema, shunt-related hypoxemia, and a reduction in the amount of aerated lung. (JAMA. Published online April 24, 2020) The net result is a reduction in the amount of aerated lung, for which a high level of positive end-expiratory pressure (PEEP) is employed to recruit collapsed lung units. In ARDS, low tidal volumes and permissive hypercapnia are typically used in order to avoid ventilator-induced lung injury (i.e. barotrauma). In contrast, at least a subset of patients with CARDS have interstitial lung disease (manifested by ground glass opacifications on CT) rather than pulmonary edema and retain relatively good compliance despite poor oxygenation. For these patients, targeting a lower PEEP (e.g. 8–10 cm H2O) is appropriate. COVID-19 patients with CARDS likely fall on a spectrum, and over time, some will progress to a more classic ARDS, perhaps resulting from ventilator-induced lung injury and ongoing infection. For these patients, a higher PEEP (≤15 cm H2O) and lower tidal volume (e.g. ≤6 ml/kg) are indicated. Additionally, prone ventilation appears to have benefit in the treatment of patients with CARDS. (Am J Respir Crit Care Med. 2020) This said, I am not an intensivist and an in-depth discussion of ventilator management of CARDS patients is beyond the scope of this post. However, the interested reader can find a more comprehensive discussion in any of the sources I’ve cited.

Another interesting, albeit incompletely understood, feature of critically ill COVID-19 patients is hypercoagulability. In addition to the hypercoagulable state common to critically ill patients (e.g. resulting from catheter-associated endothelial injury and from immobilization with consequent stasis of blood flow), there appear to be COVID-19-specific elements contributing to hypercoagulability, a condition referred to as COVID-19-associated coagulopathy (CAC), which is similar to but distinct from disseminated intravascular coagulation (DIC). (J Thromb Haemost. 2020) For example, autopsy specimens demonstrate direct invasion of the vascular endothelium by SARS-CoV-2, the virus that causes COVID-19. (Transl Res. 2020) Coagulation abnormalities associated with CAG include prolonged prothrombin time (PT), as well as elevated platelet counts, fibrinogen, D-dimer, von Willebrand factor (VWF), increased Factor VIII activity, and alterations in thromboelastography (TEG). (J Thromb Haemost. 2020) CAG is similar to DIC in that patients are critically ill, have an elevated D-dimer, and thrombocytopenia. However, whereas the major clinical finding associated with decompensated DIC is bleeding, CAG is associated with thrombosis. Moreover, the two differ with respect to fibrinogen and Factor VIII activity. The net effect is that venous thromboembolism, including deep vein thrombosis (DVT) and pulmonary embolism (PE), are common in critically ill COVID-19 patients. The incidence appears to be higher in men, especially those with obesity and other chronic comorbid medical conditions. (Histopathology. 2020 May 4 and Ann Intern Med. 2020 May 6) In addition to venous thromboembolic disease, COVID-19 patients also appear to be at increased risk for arterial thrombosis, including ischemic stroke (N Engl J Med. 2020 Apr 28) and limb ischemia. (J Vasc Surg. 2020 Apr 28) Because of the increased risk for thrombosis, prophylaxis with low molecular weight heparin or unfractionated heparin is generally recommended for patients with COVID-19. (https://www.uptodate.com/…/coronavirus-disease-2019-covid-1…)

In addition to the complications already described, critically ill COVID-19 patients also appear to be at increased risk of cardiovascular complications including myocardial injury, infarction, and arrhythmias. Although some of this reflects the prevalence of pre-existing heart disease in the most vulnerable patients, it is thought that the SARS-CoV-2 virus both indirectly (e.g. demand ischemia) and directly (e.g. inflammatory myocarditis) affects the heart and cardiovascular system. In several studies of hospitalized COVID-19 patients, the incidence of myocardial injury (as evinced by elevated cardiac biomarkers or electrocardiographic abnormalities) ranged from ~7–20 percent. (JAMA. 2020 Feb 7 and JAMA Cardiol. 2020 Mar 25) Moreover, the CFR appears to be higher in patients with underlying cardiovascular disease, approaching 10.5 percent, with 22.7 percent of fatal cases having pre-existing cardiovascular disease. (China CDC Weekly. 2020; 2:113) Arrhythmias have similarly been reported in patients with severe COVID-19, and in one cohort of 8,910 patients, a history of arrhythmia was 6.8 percent among patients who died as compared to 3.2 percent among survivors. (N Engl J Med. 2020 May 1) Sinus tachycardia is the commonest arrhythmia, but atrial fibrillation, atrial flutter, and ventricular tachycardia (including torsades de pointes) have also been described. Additionally, QTc interval prolongation has been described in COVID-19 patients prescribed hydroxychloroquine, especially those with electrolyte abnormalities or a reduced glomerular filtration rate. Consequently, the FDA cautions that hydroxychloroquine should be used for COVID-19 only when patients can be appropriately monitored in the hospital or are enrolled in a clinical trial with appropriate screening and monitoring. (https://www.fda.gov/…/hydroxychloroquine-or-chloroquine-cov…)

As I’ve mentioned previously, chronic comorbid medical conditions predispose COVID-19 patients to a more severe course and increase their risk of death. Therefore, it is not surprising that acute kidney injury (AKI) has been reported in more than a quarter of critically ill COVID-19 patients. [Lancet Respir Med. 2020 May;8(5):475–481 and BMJ. 2020;368:m1091. Epub 2020 Mar 26] Although this may derive in part from hemodynamic instability and cytokine storm, several studies suggest a role for viral-mediated renal cytotoxicity. In one postmortem series of 26 COVID-19 patients, coronaviruses were identified in seven of nine samples tested. (Kidney Int. 2020) In another autopsy series very recently published in the New England Journal of Medicine, researchers demonstrated organotropism of SARS-CoV-2 in kidneys, liver, heart, brain, and blood as well as the respiratory tract. (https://www.nejm.org/doi/pdf/10.1056/NEJMc2011400…) Although virus was found in all kidney compartments examined, there appeared to be preferential targeting of glomerular cells. The study authors speculate that renal tropism of SARS-CoV-2 is facilitated by the presence of certain proteins prevalent in kidney cells [i.e. angiotensin-converting enzyme 2 (ACE2), transmembrane serine protease 2 (TMPRSS2), and cathepsin L (CTSL)] Despite speculation that patients receiving angiotensin-converting enzyme inhibitors (ACE I) or angiotensin receptor blockers (ARB) may be at increased risk for adverse outcomes, there is no evidence that withholding ACE I or ARB reduces the severity of infection. Indeed, several studies suggest that these medications may attenuate the disease course or that withholding them may be associated with increased mortality. (Circ Res. 2020 Apr 17 and Hypertension. 2020 Apr 29)

As we enter the sixth month of the COVID-19 pandemic and continue to acquire experience and amass data, it is increasingly apparent that SARS-CoV-2 is organotropic, causing multi-system illness. This should not be surprising, as tissue tropism has been documented for other coronaviruses including severe acute respiratory syndrome virus (SARS-CoV-1) and Middle East respiratory syndrome corona virus (MERS-CoV) [J Pathol. 2004 Feb;202(2):157–63 and Virol J. 2015; 12: 218] Consequently, the best chance of recovery for a critically ill COVID-19 patient is afforded by a multidisciplinary team consisting not only of intensivists and infectious disease specialists, but hematologists, cardiologists, nephrologists, etc., working jointly to mitigate the pathological effects of the virus on individual organ systems; and because SARS-CoV-2 remains, in some respects, a novel coronavirus, innovative therapeutic approaches (such as prone ventilation) may pay dividends with respect to patient outcomes. What remains to be seen, however, is if there are any long-lasting sequelae of multi-organ involvement by the virus in COVID-19 patients.

Until my next update — regards.

Michael Zapor, MD, PhD, CTropMed, FACP, FIDSA
(14 May 2020)

Update (30 May 2020)