18 June 2020

Maybe COVID-19 isn’t that mysterious after all

COVID-19 Research

There’s a natural tendency when something catastrophic happens to expect there to be an extraordinary cause.

COVID-19 had killed nearly 400,000 people worldwide as of early June. The virus grounded around 94% of flights, put ICUs into overdrive, forced nations into lockdown and swung a wrecking ball into the global economy.

Understandably, people are hungry for information about the microbial monster that’s upending their lives.

There’s a sense of breathlessness and urgency in the COVID-19 pre-prints streaming out of servers such as medRxiv and SSRN and there are emails flying around between critical care specialists announcing the more alarming features of the virus.

The media tends to highlight the fact that this virus is “strange”, “unusual”, “mysterious” and “weird as hell”.

But the pathophysiology of COVID-19 – the disease mechanisms that make it so lethal – is nothing new; we’ve seen this before in patients with influenza pneumonia, SARS and acute respiratory distress syndrome (ARDS).

At least, that’s what some experts are saying.

Others, however, insist that there is something weird and distinct about COVID-19’s effect on the lungs and the body.

Look at the cytokine storm in the lungs, they say. Check out the funny microthrombi and microangiopathy in the alveoli. Look at the cardiovascular complications – the blood clots, strokes and pulmonary embolisms.

How about those strange chilblain-like lesions on the toes of patients with COVID-19? Oh, and don’t forget the children who had recovered from COVID-19 only to get a secondary inflammatory response similar to Kawasaki disease. How weird is that?

But is it possible we are over-emphasising how special COVID-19’s disease mechanisms are because we’re seeing more patients with viral pneumonia than we’ve ever seen before and thus more rare complications than we’ve ever come across?

Assistant Professor Corey Hardin has been working in the ICU at Massachusetts General Hospital in the US. Since March, the ICU has increased its capacity five-fold to treat around 400 patients with COVID-19 in need of critical care.

Hospital-wide there have been thousands of coronavirus presentations, with a 20% death rate. They’ve now passed the peak and currently have around 40 patients with COVID-19 in ICU.

As a pulmonary and ICU specialist at Harvard Medical School, Professor Hardin has considerable experience treating and researching end-stage pneumonia.

He’s been working in the trenches of this war against coronavirus, but unlike some of his colleagues he doesn’t think the pathophysiology and clinical features are all that different to other severe respiratory diseases.

COVID-19, influenza and bacteria can all cause Acute Respiratory Disease Syndrome. “The details differ but it’s the same thing – ARDS,” he says.

Autopsies show that COVID-19 causes diffuse alveolar damage – a key feature of ARDS. The treatments for ARDS work as expected for patients with COVID-19.

“Clinically and pathologically, COVID-19 patients have ARDS,” he says. The vast majority of severe COVID-19 pneumonia cases meet the 2012 Berlin definition for ARDS.

The enormity of the 2020 pandemic has focused the research community’s attention on what sets this coronavirus apart from other diseases.

“The COVID-19 pandemic has been a catastrophic event,” says Professor Hardin. “In the US, 100,000 people have died. There’s a tendency to want to transfer that drama to the virus. But thinking of COVID-19 as a unique virus tempts us to move away from what we know works. We think we have to start all over.

“COVID-19 is a devastating illness – but it’s a devastating illness we’ve seen before. There’s an awful lot that we know about how to treat ARDS successfully. We should keep our heads and not abandon what we know.”

Dealing with COVID-19 is less about cracking some grand medical mystery, it’s really a mundane operational challenge of trying to treat more patients than hospitals are built to help at once, he says.

“We know how to treat this illness,” he says.

Once you start thinking along these lines, the research being published about the difference between COVID-19 and other diseases starts to look a little less exciting.

For instance, there was a paper published in the New England Journal of Medicine in May that reported the histological differences between the lungs of seven patients who died from COVID-19, seven patients who died from influenza A(H1N1) and 10 uninfected, age-matched controls.

The influenza and COVID-19-affected lungs both showed diffuse alveolar damage with perivascular T-cell infiltration. There was widespread thrombosis with microangiopathy in the pulmonary vessels in patients with COVID-19.

“Alveolar capillary microthrombi were nine times as prevalent in patients with COVID-19 as in patients with influenza,” the researchers reported. “In lungs from patients with COVID-19, the amount of new vessel growth — predominantly through a mechanism of intussusceptive angiogenesis — was 2.7 times as high as that in the lungs from patients with influenza.”

These differences were all reported as statistically significant.

In the accompanying editorial, Professor Hardin politely praised the researchers on their “intriguing” findings but pointed out that the differences between the two diseases found in the study could be illusory.

The lungs affected by influenza appeared to be at a more advanced stage of diffuse alveolar damage than the patients with COVID-19, which “complicates any direct comparison”, says Professor Hardin.

Additionally, “none of the patients with COVID-19 had been intubated… whereas the majority of patients with influenza had been intubated and treated with ventilator settings that we would now consider not to be lung protective,” he says.

“The sample size of the study was also small, which is particularly problematic in a heterogeneous condition such as ARDS.

“These data are therefore unable to define differences specific to COVID-19 and H1N1 influenza. The investigators’ conclusion that ‘vascular angiogenesis distinguished the pulmonary pathobiology of COVID-19 from that of equally severe influenza virus infection’ has to be considered speculative.”

Even if the central finding of the paper – that COVID-19 is associated with greater blood vessel growth than H1N1 influenza – is true, “it isn’t really that interesting” from a clinical perspective, says Professor Hardin.

This piece of knowledge could have some future value as a way of defining ARDS subtypes, but “if it wasn’t about COVID-19, it wouldn’t be covered in NEJM,” he says.

Another way that researchers have tried to single out COVID-19 has been through the role of ACE2 receptors, he says.

SARS-CoV-2 gains entry to cells in the human body by binding to the ACE2 receptors. ACE2 receptors are found all over the body, so this has led to theories about the virus wreaking havoc in different organs – i.e. ‘COVID-toes’, ‘COVID-brain’, says Professor Hardin.

Patients with COVID-19 can develop strange symptoms such as strokes, blood clots, a red or purple rash on their toes, hypoxia without breathlessness, and delirium.

“It gets tempting to think these are unique features of COVID-19 but we see these strange presentations in critically ill patients, albeit rarely,” says Professor Hardin. “Severe illnesses can cause weird things to happen to the body.”

It’s hard to say whether these are unique clinical features of COVID-19 or whether these are rare, but expected, complications of viral pneumonia that hospitals are seeing much more frequently because of the high numbers of severely ill patients, he says.

Another feature of COVID-19 that seems to set it apart is the inflammatory response in a small number of children weeks after recovering from the disease. This Kawasaki-like disease was described as a “baffling ailment” and a “mysterious new syndrome” by The New York Times.

But Professor Hardin has poured cold water on the idea that this makes COVID-19 special too. “In some sense, that’s not surprising,” he says.

Viral infections do rarely lead to these kinds of delayed inflammatory reactions in a small number of people, he says.

Another COVID-19 feature is the higher level of thrombosis in the lungs of severely ill patients.

“There have been some poor quality studies on this,” says Professor Hardin.

Some hospitals are now using blood thinners such as low-molecular weight heparin to treat COVID-19, particularly in patients with higher D-dimer levels. (This prophylaxis is recommended by Australia’s National COVID-19 Clinical Evidence Taskforce for adults with moderate COVID-19 without contraindications such as risk of major bleeding.)

Elevated D-dimer levels have been shown to be connected to higher mortality from COVID-19 and correlate to higher levels of thrombosis in the lungs.

At Massachusetts General Hospital, however, doctors don’t routinely prescribe blood thinners for patients with COVID-19 because the medication can cause bleeding complications, says Professor Hardin.

“If there are positives and negatives to a treatment, it’s not ethical to flip a coin,” he says. “We’ll have to wait for trials.”

Another suggestion is that COVID-19 is more likely to cause myocarditis than other viral pneumonias.

“The cardiac arrest thing is interesting,” says Professor Hardin. “I’m not sure it’s true.”

“We’ve seen a few cases of myocarditis in patients with COVID-19 at Massachusetts General Hospital and some arrythmias. But you’d expect this. Some patients with ARDS have myocarditis.”

To make a call on this, researchers will have to disentangle the effect of COVID-19 from the effect of medications, because hydroxychloroquine is also known to cause cardiac complications, he says.

 

OUTLIER OPINION?

So is Professor Hardin’s just an outliner opinion, or do other experts also see a lack of novelty in the pathophysiology of COVID-19?

Professor Wendy Cooper, a pulmonary pathologist at Royal Prince Alfred Hospital in Sydney and fellow of Royal Australian College of Pathologists, also hasn’t found the histopathology of COVID-19 all that surprising or unusual.

“The pattern in COVID-19 is very much what you see in influenza,” says Professor Cooper.

“The pattern is not new, it’s not novel. Fatal COVID-19 cases have the same that pattern that we see in other severe respiratory illnesses, where you get acute lung injury, you get the clinical ARDS, and histologically what we see down the microscope is the acute lung injury pattern, diffuse alveolar damage and that’s common to fatal viral pneumonias including influenza and the previous SARS outbreak.”

Unfortunately, a lot more people reach the end-stages of viral pneumonia when infected with COVID-19 than influenza, but, once they are there, the disease does seem to go down a similar path as end-stage influenza, she says.

The recent NEJM paper shows that there are similar disease patterns in both end-stage COVID-19 and influenza, including diffuse alveolar damage, microthrombi and new blood vessel growth (angiogenesis).

“It’s just in this study they found more of these disease processes in the COVID-19 patient group,” she says.

These differences could be real, but they could also just be reflecting study biases.

Many experts are sticking to the narrative that COVID-19 is strange and different based on its epidemiology, clinical features and treatment – but this isn’t necessarily in conflict with the idea that end-stage COVID-19 looks very similar to end-stage influenza or SARS in terms of its histopathology, says Professor Cooper.

“It can be both,” she says. “It can be quite different at the epidemiological level but in the patients who get to hospital who are in intensive care and who die, COVID-19 is very similar to other severe viral infections.”

Jeremy Brown is a professor of respiratory infection at the University College London Hospital, where 470 patients with COVID-19 have been admitted over the past few months.

He’s currently working in the ward where COVID-19 patients who are struggling to get air into their lungs are given the less-invasive CPAP instead of ventilation.

“COVID-19 is quite an unusual disease,” says Professor Brown. “Now, it may be the other diseases occasionally are similar, but there are very rare cases of that.”

The C-reactive protein levels (a marker for the inflammatory response) are much higher in COVID-19 than influenza, he says. Patients with COVID-19 often have C-reactive protein levels of 100 to 200, which is closer to the levels seen in bacterial pneumonia than influenza pneumonia, where patients usually only have C-reactive protein levels of 40 to 60.

“Now, it may be that in severe viral influenza, the C-reactive protein will go up to those sorts of levels, but they are very rare cases of influenza,” says Professor Brown.

 

SAME SAME BUT DIFFERENT

Patients with COVID-19 pneumonia often have extensive shadowing and infiltrates on both sides of the lungs.

This is sometimes seen in cases of severe viral pneumonia but it’s rare, however it’s standard for COVID-19, he says.

Another clinical feature that is unique to COVID-19 is that patients are very hypoxic, but often don’t feel terribly breathless.

“Normally with pneumonia this hypoxia and the infiltrates in the lung, get better within two to five days,” he says. “But in COVID-19, it goes on for a week, two weeks, three weeks, sometimes longer. The ones in intensive care being ventilated, their lungs are very extensively affected for a month or so.”

The activation in the coagulation pathway appears to be very marked in COVID-19 cases, leading to blood clots in the legs, pulmonary artery and the small lung blood vessels – much more so than in other infectious lung diseases, says Professor Brown.

“We’ve been assuming the microthrombi in the organs are causing some of the problems that the patients are getting,” he says. “It’s not normal to see that. Most cases of viral pneumonia are very mild. It’s only the very rare cases of normally severe influenza that you get that.”

Dr Daman Langguth, a clinical immunologist and immunopathologist and allergist a The Wesley Hospital in Brisbane, says there are some signs that COVID-19 is different to other respiratory diseases, as it has a higher propensity for kickstarting deadly inflammatory responses and coagulation pathways.

“You will have seen reports of young people having strokes, losing limbs, having skin ischemia, having clots to their lung or clots in their legs and DVT and PEs. And so, clearly the disease is more than just a cold,” he says.

“Usually, we do not get that degree of endothelial involvement and we do not get that degree of pulmonary oedema,” he says.

The vast numbers of COVID-19 cases could be leading to higher numbers of unusual complications, however. “Until someone gets really good data and compares the effects of different viral pneumonias, I’m not sure we’ll ever really know.”

Associate Professor Robert Stevens is a critical care specialist at The Johns Hopkins Hospital in Baltimore. He says COVID-19 is probably more heterogeneous and complex than other viral pneumonias, but he accepts that his personal perception “could be tainted by the fact that there’s a large number of cases”.

“I think we should acknowledge that possibility,” he says. “Right now, in my hospital, we have more than 100 COVID patients, one-third of whom are in intensive care.”

COVID-19 has a large variability in its effect on patients, ranging from life threatening multi system organ failure to asymptomatic cases.

“So, the question is really, how do we explain such a variability in the way that people respond to the virus?” Professor Stevens says. “There’s got to be some underlying biology that’s driving this extremely variable phenotypes.”

 

AN ACADEMIC DEBATE?

In some respects, the debate around whether COVID-19’s disease mechanisms are really all that mysterious is an academic one. It depends entirely on what you’re comparing.

If you take a case of deadly influenza pneumonia and compare that against the worst form of COVID-19 pneumonia, the disease processes look fairly similar.

But if you take a random sample of severe influenza cases and compare that to a random sample of severe COVID-19 cases, differences start to look quite stark in terms of severity and frequency of complications.

By doing these kinds of analyses, it forces us to examine what we already know about how to combat severe respiratory infections.

But it also just clicks us into a slow, analytical thinking mode, which is a good antidote to the panic-publishing and medical gossip we’ve seen become an increasing problem during this  pandemic.

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