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Frequently Asked Questions on Symptoms and Clinical Manifestations of COVID-19

Sharon R. Lewin, AO, FRACP, PhD, FAHMS
Vikramjit Mukherjee, MD
Lynora Saxinger, MD, FRCPC, CTropMed
Released: July 8, 2020

Questions & Answers

Other than the oxygen levels, what are the most important markers of disease severity in COVID-19?

Short Answer: It’s complicated.

Vikramjit Mukherjee, MD (5/28/2020):

We have observed 3 broad indicators of progression to severe disease: respiratory failure, hemodynamics, and renal failure. COVID-19 pneumonia and COVID-19 acute respiratory distress syndrome (ARDS) start as a hypoxic respiratory failure. Many of our patients present with an ST-elevation myocardial infarction equivalent, but catheter results demonstrate clean coronaries and mild cardiac ischemia. However, the cardiac profile is a bit different compared with conventional viruses. We also observe transaminitis and renal failure in patients who progress to severe disease.

Many of our patients quickly progress to multiorgan failure. In New York, we are seeing children with a multisystem inflammatory response—or Kawasaki-like profile—and a Kawasaki-like profile affecting adults as well, which is new to us.

Which clinical manifestations of COVID-19 have surprised you the most?

Short Answer: Cytokine storm and renal failure

Vikramjit Mukherjee, MD (5/28/2020):

The first surprising manifestation has been the cytokine storm that patients experience. For example, a patient comes into the ICU with COVID-19 pneumonia and is improving on the ventilator for the first 3 or 4 days when suddenly the cytokine storm results in high heart rates, high respiratory rates, vasodilatation, vasoplegia, and shock. These patients have extremely elevated C-reactive protein and inflammatory markers. Despite our efforts to blunt the cytokine storm and to provide supportive care, many of our patients died due to these complications. This is something that I personally had never faced before, and the lack of answers that we could provide to patients’ questions in this setting were quite humbling.

The second surprising complication was the high incidence of renal failure that we saw in our ICU population—it was much higher than what we had expected to see. We expected COVID-19 to present as respiratory failure, viral pneumonia, and ARDS; we were equipped with ventilators, negative-pressure rooms, and other equipment to deal with that. However, when approximately 40% of our patients began requiring renal replacement therapy, our resources to respond to this had to evolve very quickly. At one point, 130 of our 300 ICU patients were on dialysis—some remain on dialysis—and many of them were on regular dialysis, which in the ICU is very resource intensive in terms of machines and equipment and nursing care. Therefore, in late March/early April, we switched to a peritoneal dialysis model, which has enabled us to provide renal replacement therapy to a large proportion of our ICU population.

Be very careful about the renal failure that accompanies COVID-19. These were completely healthy patients who did not have any chronic kidney disease who entered into renal failure requiring urgent renal replacement therapy. For the inevitable second wave, we will ensure that we can provide enough renal replacement therapy options, and we will continue to assess potential therapeutic tools to suppress the cytokine storm.

Do we know why patients with COVID-19 have hypercoagulability?

Short Answer: Not yet.

Vikramjit Mukherjee, MD (12/18/2020):

Hypercoagulability is a major challenge that we face daily when treating patients with COVID-19. We know that SARS-CoV-2 infection activates all 3 arms of Virchow’s triad, including abnormalities of blood flow, vascular injury, and abnormalities within the circulating blood.[Becker 2020] We know the SARS-CoV-2 spike protein invades angiotensin converting-enzyme 2 receptors on the endothelium, causing endothelial inflammation and promoting hypercoagulation.[Ackermann 2020; Varga 2020] In addition, the virus causes activation of the coagulation cascade through many autoimmune mechanisms. Hence, almost all patients with COVID-19 have an elevated risk for clot formation, both venous and arterial.[Tang 2020]

Vikramjit Mukherjee, MD (5/28/2020):

Autopsies suggest that many patients who have died from COVID-19 may have died of venous thromboembolism.[Deshpande 2020] Unexpectedly, COVID-19 is a very prothrombotic disease process, and we were seeing clots in the legs and, very frequently, in the lungs and venous systems of patients despite prophylactic or therapeutic anticoagulation. Many patients also develop arterial clots, strokes, and myocardial infarctions in the absence of normal risk factors. Therefore, hypercoagulability is a major concern in patients with COVID-19. Ongoing studies of autopsy data assessing patient anticoagulation profiles will provide more information on this phenomenon.

We now know that inflammation and endothelial damage are associated with forming clots, and the hyperinflammatory state that accompanies COVID-19 probably makes that worse. In addition, autopsy data have revealed microthrombi in the lung, likely due to inflammation.[Ackermann 2020] Therefore, I would hypothesize that inflammation plays a role in the hypercoagulability of COVID-19.

Based on the high thrombotic risk, when do you begin administration of anticoagulation therapy?

Short Answer: It’s complicated.

Vikramjit Mukherjee, MD (12/18/2020):

At this time, we closely examine patients daily for clot formation. If an objective clot is found, such as a deep vein thrombosis or pulmonary embolism, we treat them per standard institutional protocols. In the absence of clots, we monitor D-dimer levels every 48 hours. If D-dimer exceeds a threshold of 3000 ng/mL or if it is increasing rapidly (> 1000 ng/mL per day), we initiate heparin anticoagulation therapy. Knowing that this approach is not evidence based, we are piloting a trial to assess the utility of a monitoring approach. We are learning more about the risks and benefits; if the patient starts bleeding, we take a more moderate approach.

Vikramjit Mukherjee, MD (5/28/2020):

As mentioned, patients with COVID-19 are prothrombotic. Many of our patients are so sick in the ICU, and infection control parameters for administering a chest CT are often quite laborious. Therefore, we have started therapeutic anticoagulation based on patients’ D-dimer profiles. Almost all patients have been started on prophylactic anticoagulation with enoxaparin or heparin, but if D-dimer levels increase to 4000 ng/mL or higher (an arbitrarily chosen level), or if we have evidence of an objective clot, we begin therapeutic anticoagulation with either enoxaparin or heparin.

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