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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

What are the latest in-hospital mortality trends?

Short Answer: Mortality rates appear to be increasing but remain lower than March/April 2020

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

The published data thus far report reduced in-hospital COVID-19 morality as of June 2020 in England and as of August 2020 in New York City compared with the earlier months of the pandemic.[Dennis 2020; Horwitz 2020] In New York City, we are currently seeing an increase that I would classify as a new shift in the curve. Although we saw high rates of mortality back in March and April 2020, the curve dipped through the summer but it is slowly beginning to worsen again.[Johns Hopkins] There are many reasons behind this latest increase in mortality. With the onset of colder winter weather, we have seen increasing cases of COVID-19, as we expected. However, we are also seeing patients come in with more advanced disease. The case number and the mortality rates are still below what we observed in March and April, but our local experience is that it has worsened this fall and winter compared with the summer months.

Why does in-hospital COVID-19 mortality appear to be lower compared with mortality in March/April 2020?

Short answer: Better care and resources, not viral changes

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

Currently, there is no evidence from viral genomic studies to suggest that any change in the virus is associated with lower mortality. I think that treatment protocols have certainly improved, along with other factors. In my experience, patients are able to be admitted to ICUs earlier in the disease course compared with the spring, and we have more nurse staffing, more ICU space, and improved resources to combat COVID-19 acute respiratory distress syndrome.

We know that in non–COVID-19 diseases, ICU strain alone is a considerable determinant of outcomes. Now that our ICUs have more capacity than they had in March and April, we have more time and attention for our patients. Moreover, we have a better understanding of the virus now, and we are better equipped to predict clinical outcomes. We are also taking a more minimal approach to hypoxia by providing high-flow nasal cannula for intubation. Thus, our treatment algorithms have improved, and that is a big factor in mortality outcomes.

Is there any evidence supporting the appearance of COVID-19 pneumonia following an apparent recovery?

Short Answer: Viral pneumonia typically presents between Day 7 to Day 14 of infection

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

COVID-19 pneumonia is a viral pneumonia caused by SARS-CoV-2 infection of the lung parenchyma. The initial disease course of this viral pneumonia is well described. Following an exposure, disease symptoms present within 5-7 days, ranging widely from asymptomatic or presymptomatic to critical illness or death.[Li 2020] After Day 14, an aggravated host immune system can contribute to intensified disease symptoms, at which time steroids play a significant therapeutic role.[Zhou 2020] This immune activation phase is followed by either a full recovery or progression to ventilator dependence and, in some cases, death. That is the typical natural history of SARS-CoV-2 infection.

Pneumonia appearing much later in infection, such as Day 30, likely reflects one of 3 things: 1) a bacterial superinfection in lung tissue that has been damaged by the virus; 2) fibrotic acute respiratory distress syndrome driven by the host immune response that can occur weeks after the initial infection[Carsana 2020; Schaller 2020]; or 3) a rare instance of SARS-CoV-2 reinfection in a person who had recovered approximately 1 month prior.[Tillett 2020; Larson 2020] Although late onset or second occurrence of COVID-19 pneumonia has been described, it seems to be fairly rare.

Is myocarditis a complication of COVID-19?

Short answer: Myocarditis is common in patients with COVID-19

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

Myocarditis is common in patients with COVID-19, and we have seen a fair amount of it at my institution.[Puntmann 2020] Indeed, inflammation of the myocardium is common with many severe viral illnesses. In general, by the time of recovery from infection, most of the myocarditis has resolved. Although it is too early to understand the breadth of the consequences of COVID-19–related myocarditis, we have not seen a lot of postviral myocarditis cardiac dysfunction. In our experience, as the virus and inflammation resolve, the inflammation of the myocardium also seems to resolve. We await publication of data on potential long-term consequences of myocarditis caused by COVID-19.

What is your recommendation regarding moderate to vigorous exercise for patients who have recently recovered from COVID-19?

Short answer: Gradual return

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

We know that COVID-19 disease is a spectrum, including individuals who are completely asymptomatic, those with mild/moderate disease (lower respiratory infection without hypoxia), those with severe disease (pneumonia with hypoxia), and those with critical disease (requiring intubation, extracorporeal membrane oxygenation, etc). Following recovery, the degree of residual lung dysfunction will determine in how much exercise patients can partake. In general, I would suggest that they return to exercise gradually, only exerting themselves as much as they can tolerate without becoming hypoxic or dyspneic. For the very sick patients I see in the ICU who are left with significant fibrotic lung disease, their ability to participate in moderate or vigorous exercise will remain quite limited. We try to engage those patients in rehabilitation services before they resume normal activities.

Now that cases of SARS-CoV-2 reinfection have been confirmed, is disease severity similar, milder, or worse during the second vs the first infection?

Short Answer: Not yet known.

Sharon R. Lewin, AO, FRACP, PhD, FAHMS (10/14/20):

First, it is important to note that the number of confirmed reinfection reports is still quite small relative to the millions of people been infected with COVID-19 overall, so I think reinfection is still a rare occurrence, but it can happen. The reinfection cases that I have looked at closely have had varying clinical descriptions.

The first reported case was in Hong Kong. The individual in this case had a milder course following reinfection than with the first infection. In another early report from Nevada, the individual had a more severe course with the second vs the first infection, suggesting that either situation is possible. Currently, there are too few reinfection cases to provide clear insights into the clinical pattern.

We do know that mild infection or asymptomatic infection generally results in lower antibody levels vs more severe disease, and this could also be associated with lower neutralizing antibody levels, which may leave people at higher risk of reinfection, but we do not yet know how common this is at a population level.

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

Thankfully, reinfection seems to be relatively uncommon, and the few reinfections that have been reported in the literature were typically a milder form of disease.[Goldman 2020; To 2020] There are some exceptions, including one case report of a patient from Nevada who was hospitalized and required oxygen with his second infection.[Tillett 2020] Because COVID-19 is still new, we must await more data to better understand the scope of reinfection dynamics. At this time, it appears that most reinfections seem to be milder.

What is the difference between pneumonitis and COVID-19 infection on x-rays? Is there a distinction in how they look, and would you treat them differently if the symptoms were similar?

Short Answer: It’s complicated.

Lynora Saxinger, MD, FRCPC, CTropMed (9/15/20):

I think of “pneumonitis” as being a nonspecific term in that it basically describes parenchymal inflammation, and it can be infectious or inflammatory. Viral pneumonitis, bacterial pneumonitis, and inflammatory allergic pneumonitis can all look quite similar. I think radiologists evaluating high volumes of COVID-19 x-rays do tend to see patterns that would make them suggest COVID-19 over other conditions, but there is a high enough rate of nonspecific presentation that I would hesitate to make the call on the basis of plain film.

Early on, there was some suggestion that CT scan patterns were more specific and could be used as an adjunct to COVID-19 diagnosis if other measures were not available. But I think that that is less relevant in most settings now. I think now COVID-19 testing is more available, and the radiation burden of CT is probably not justified as a diagnostic approach. Therefore, if someone tested positive for SARS-CoV-2, I would look at their x-ray and take the stance that observed changes could be caused by COVID-19 and treat accordingly.

Are signs and symptoms of COVID-19 in infants and children different than those seen in adults?

Short Answer: Yes.

Vikramjit Mukherjee, MD (7/8/2020):

We do know that COVID-19 presents differently in the pediatric population compared with the adult population. There is a higher incidence of asymptomatic or presymptomatic infection in children,[He 2021] and the outcomes of symptomatic disease are less severe than in adults.[Götzinger 2020] We also know that case-fatality rates and infection-fatality rates have been estimated to increase significantly with age, meaning that children are much less likely to die of COVID-19 than adults, more so an older patient.[Verity 2020] Presentation of COVID-19 in children also appears different than that typically seen in adults, with more gastrointestinal symptoms reported in children.[Zimmerman 2020] Cases of a multisystem inflammatory syndrome in children (MIS-C) associated with COVID-19 have been reported, including a series of cases in New York.[CDC MIS-C] A case definition has been put forward by the CDC, which involves fever, inflammation, a severe illness requiring hospitalization, multisystem organ involvement affecting at least 2 organs, a recent or current SARS-CoV-2 infection or exposure, and no other plausible diagnoses. Some patients may present with a Kawasaki-like illness.[Verdoni 2020] The pathophysiology of this syndrome is not well understood.

Are we likely to see long-term health complications in people who have recovered from COVID-19?

Short Answer: Yes.

Vikramjit Mukherjee, MD (7/8/2020):

COVID-19 remains a novel illness, and our understanding of its longer-term effects is incomplete. Significant numbers of COVID-19 patients who have survived acute illness have been left with serious clinical sequelae, including renal failure, neurologic manifestations, and significant fibrotic lung disease.[Hirsch 2020; Zubair 2020; George 2020] Patients and their families endure considerable emotional and financial stress, which will also play out in the months and years to come.

Does a patient with a previous moderate COVID-19 illness with a persistent cough, occasional shortness of breath, and a negative chest x-ray require further investigation?

Short Answer: Possibly.

Vikramjit Mukherjee, MD (7/8/2020):

Follow-up of patients with previous COVID-19 illness must be done on a case-by-case basis. Patients who have experienced significant lung disease from COVID-19 may well have a residual cough 2-3 months later. If the patient is also febrile, if shortness of breath is worsening, if the cough is worsening, or if there is mucopurulence, then the patient should seek medical help. If the cough is improving and there are no features of an active infection, the patient can be monitored at home.

Can a chest x-ray demonstrate persistent infiltrate in patients with COVID-19 pneumonia that has clinically resolved?

Short Answer: Yes.

Vikramjit Mukherjee, MD (7/8/2020):

In patients who have experienced COVID-19 pneumonia but have since improved clinically—meaning that fever has disappeared and shortness of breath and other symptoms have improved—a chest x-ray can take weeks to months to show complete resolution. In severe cases, it may never resolve, and the patient can be left with end-stage lung disease fibrotic pattern. If the patient has improved clinically and has had 2 negative polymerase chain reaction tests, you should be reassured that persistent infiltrate on chest x-ray is a sequela of previous infection. Bacterial superinfection, viral pneumonia, and fibrotic acute respiratory distress syndrome should be considered.

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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