COVID-19 and Long-Term Outcomes: Lessons from Other Critical Care Illnesses and Potential Mechanisms

Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a novel coronavirus that is currently causing a pandemic and has been termed coronavirus disease (COVID-19). The elderly or those with preexisting conditions like diabetes, hypertension, coronary heart disease, chronic obstructive pulmonary disease, cerebrovascular disease, or kidney dysfunction are more likely to develop severe cases when infected. Patients with COVID-19 admitted to the ICU have higher mortality than non-ICU patients. Critical illness has consistently posed a challenge not only in terms of mortality but also in regard to long-term outcomes of survivors. Patients who survive acute critical illness including, but not limited to, pulmonary and systemic insults associated with acute respiratory distress syndrome, pneumonia, systemic inflammation, and mechanical ventilation, will likely suffer from post-ICU syndrome, a phenomenon of cognitive, psychiatric, and/or physical disability after treatment in the ICU. Post-ICU morbidity and mortality continue to be a cause for concern when considering large-scale studies showing 12-month mortality risks of 11.8-21%. Previous studies have demonstrated that multiple mechanisms, including cytokine release, mitochondrial dysfunction, and even amyloids, may lead to end-organ dysfunction in patients. We hypothesize that COVID-19 infection will lead to post-ICU syndrome via potentially similar mechanisms as other chronic critical illnesses and cause long-term morbidity and mortality in patients. We consider a variety of mechanisms and questions that not only consider the short-term impact of the COVID-19 pandemic but its long-term effects that may not yet be imagined.

Keywords: SARS-CoV-2; amyloids; chronic critical illness; cytokine storm; mitochondrial dysfunction.

Figure 1.

Potential mechanisms of end-organ dysfunction (EOD) after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. (1) SARS-CoV-2 infects the lung via airborne transmission and causes symptoms of viral lung infection, including pneumonia. (2) SARS-CoV-2 infection of the lung leads to an uncontrolled pro-inflammatory response, mitochondrial dysfunction, and possibly release of cytotoxic amyloids (Aβ). Whether, how much, or in what way these three mechanisms interact to cause EOD is currently unclear but is hypothesized as a source of future investigation. (3) Varying end-organs are reported to suffer effects secondary to SARS-CoV-2 infection (outlined in Table 1). Whether any (or multiple) of the mechanisms in (2) are involved is unclear but are hypothesized as a source of future investigation. These end-organs include the (a) cardiovascular system, (b) endocrine system, (c) gastrointestinal system, (d) respiratory system, (e) brain/central nervous system, and (f) renal system. Numerous question marks are present as it is currently unclear which of these established mechanisms in critical illness are concurrently present in the long-term sequelae of COVID-19 infection or if their mechanisms overlap and/or act synergistically.

Figure 2.

Potential mechanisms of amyloid-mediated cytotoxicity after SARS-CoV-2 infection. (1) SARS-CoV-2 infects the lung via airborne transmission and causes symptoms of viral lung infection, including pneumonia. Based on studies on bacterial pneumonia, we suggest that one mechanism of EOD is the release of cytotoxic Aβ. (2) Aβ generated after bacterial infection is transmissible and can propagate between cells of the same type. Whether it is transmissible between different cell types is unclear but is hypothesized as a source of future investigation. (3) Prior studies have established that Aβ generated after a bacterial infection has damaging effects on the (a) endothelium, (b) lungs, and (c) brain via direct cytotoxicity (a and b) or decreases in long-term potentiation and increased cognitive dysfunction (c). (4) Whether Aβ generated after bacterial infection (or SARS-CoV-2 infection) has damaging effects on the (d) heart, (e) gastrointestinal system, and (f) kidneys is unclear but is hypothesized as a source of future investigation. (5) Other potential effects of Aβ generated after bacterial infection (or SARS-CoV-2 infection) are outside the scope of this review and are unclear but are hypothesized as a source of future investigation. CD = cognitive dysfunction; CT = cytotoxicity; LTP = long-term potentiation.