#COVID19 assay update: "Test performance evaluation of SARS-CoV-2 serological assay"

"This is a preliminary report of work that has not been certified by peer review. This should not be relied on to guide clinical practice or health-related behavior and should not be reported in news media as established information."

Ran across a link to this recent R&D paper (39 pg PDF) over at Naked Capitalism. Interesting, in light of my prior rants on lab QA issues.

ABSTRACT
Background
Serological tests are crucial tools for assessments of SARS-CoV-2 exposure, infection and potential immunity. Their appropriate use and interpretation require accurate assay performance data.

Method
We conducted an evaluation of 10 lateral flow assays (LFAs) and two ELISAs to detect anti SARS-CoV-2 antibodies. The specimen set comprised 130 plasma or serum samples from 80 symptomatic SARSCoV-2 RT-PCR-positive individuals; 108 pre-COVID-19 negative controls; and 52 recent samples from individuals who underwent respiratory viral testing but were not diagnosed with Coronavirus Disease 2019 (COVID-19). Samples were blinded and LFA results were interpreted by two independent readers, using a standardized intensity scoring system.

Results
Among specimens from SARS-CoV-2 RT-PCR-positive individuals, the percent seropositive increased with time interval, peaking at 81.8-100.0% in samples taken >20 days after symptom onset. Test specificity ranged from 84.3-100.0% in pre-COVID-19 specimens. Specificity was higher when weak LFA bands were considered negative, but this decreased sensitivity. IgM detection was more variable than IgG, and detection was highest when IgM and IgG results were combined. Agreement between ELISAs and LFAs ranged from 75.8-94.8%. No consistent cross-reactivity was observed.

Conclusion
Our evaluation showed heterogeneous assay performance. Reader training is key to reliable LFA performance, and can be tailored for survey goals. Informed use of serology will require evaluations covering the full spectrum of SARS-CoV-2 infections, from asymptomatic and mild infection to severe disease, and later convalescence. Well-designed studies to elucidate the mechanisms and serological correlates of protective immunity will be crucial to guide rational clinical and public health policies.

"Well-designed studies to elucidate the mechanisms and serological correlates of protective immunity will be crucial to guide rational clinical and public health policies."

Important, vitally necessary work. This particular effort focuses on qualitative ("positive/negative") screens via which to detect the presence (or absence) of Novel Coronavirus antibodies--possible markers of immunity for those having been exposed to the pathogen (even if subsequently remaining asymptomatic).

Suffice it to observe again than bioassay accuracy does not come quickly or on the cheap (gotta love their poignantly euphemistic "heterogeneous assay performance" admission). Moreover, after a test method is validated and approved at the R&D level, ongoing vigilant QA remain necessary at the production bench level. Neither is that cheap. Concurrent best-practice minimization of false positives and false negatives (the "sensitivity" vs "specificity" thing) is no cakewalk.

We remain seriously behind the curve on effective screening at scale for the current pandemic crisis.

STATnews article:

Many states are far short of Covid-19 testing levels needed for safe reopening, new analysis shows

More than half of U.S. states will have to significantly step up their Covid-19 testing to even consider starting to relax stay-at-home orders after May 1, according to a new analysis by Harvard researchers and STAT.

The analysis shows that as the U.S. tries to move beyond its months-long coronavirus testing debacle — faulty tests, shortages of tests, and guidelines that excluded many people who should have been tested to mitigate the outbreak — it is at risk of fumbling the next challenge: testing enough people to determine which cities and states can safely reopen and stay open. Doing so will require the ability to catch reappearances of the coronavirus before it again spreads uncontrollably…

UPDATE FROM SCIENTIFIC AMERICAN

Scientists have long warned that the rate of emergence of new infectious diseases is accelerating—especially in developing countries where high densities of people and animals increasingly mingle and move about...

POTUS TODAY

President Trump: "The testing itself is going really well. No complaints." pic.twitter.com/dVSUWNOCiB

— The Hill (@thehill) April 27, 2020

APR 28TH UPDATE

 

YASCHA MOUNK, associate professor at Johns Hopkins University

America is still behind on testing for COVID-19. Although Trump promised almost two months ago that anyone who wanted a test could get one, the U.S. has still conducted only about 5.4 million. The country needs to increase its testing rate at least threefold to reopen safely.

America is also behind on test and trace. Some countries, such as South Korea, now have robust systems in place to inform people that they have been exposed to the coronavirus, and need to self-isolate. But implementing such a system requires two things the United States sorely lacks: widespread trust in the government and a coordinated response from the White House.

In the absence of a federal strategy, some states, such as New York and Massachusetts, are trying to develop their own test-and-trace systems. But without help from Washington, they will likely lack both the resources to build a comprehensive system and the ability to persuade a large majority of their residents to sign up for an app that tracks their movements. Even if, against the odds, they should succeed in both these tasks, they face another obvious obstacle: Viruses don’t respect state lines.

If he were truly interested in limiting the damage to America’s economy, and opening up the country, Trump would be laser-focused on remedying these problems. Instead, the president has doubled down on culture wars and quack cures.

Early last week, Trump fanned the flames of the irresponsible protests against stay-at-home orders that are now being staged in cities across the country. A few days later, he vowed to “suspend immigration” to the United States. Then he suggested that scientists look into the possibility of injecting patients with bleach.

For all his blustering demands to get the country back to normal, the president is failing to take the steps that are required to reopen the economy without a horrific death toll. And for all the ingenuity shown by individual governors, the absence of a coordinated federal strategy may prove impossible to overcome…

Yeah. Interesting Atlantic article.

A SAD DAY HERE

Two years ago today, my younger daughter Danielle succumbed to her severe pancreatic cancer, 20 years after we lost her elder sister Sissy to an unrelated cancer.

Sigh...
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More to come...

Presidential COVID19 update

UV gro-light exposure and Lysol ingestion.
Problem solved

PRESIDENT TRUMP [4-23-2020 White House COVID19 briefing]:

"So supposing we hit the body with a tremendous whether it’s ultraviolet or just very powerful light and I think you said that hasn’t been checked but you’re gonna test it.

And then I said supposing you bring the light inside the body which you can do either through the skin or ah in some other way and I think you said you’re gonna test that too.
Sounds interesting. Right?

And then I see the disinfectant where it knocks it out in a minute one minute and is there a way we can do something like that by injection inside or or almost a cleaning cause you see it gets in the lungs and it does a tremendous number on the lungs so it would be interesting to check that. So that you’re gonna have to use medical doctors with but it sounds sounds interesting to me."

Quacksalver-in-Chief

YouTube clip here.

He shortly thereafter lamely claimed he was just being "sarcastic," trolling the press. Like that's appropriate for the top national executive amid an epidemiological crisis.

HOPKINS DATA SITE

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"Give Me Liberty, or Give Me #COVID19!"

OK, FreeDumb Fighters, how about we give you BOTH?

Be careful what you ask for.

How long before the Bundys' World Branch Stupidian Playtriots recall themselves to active duty?

UPDATE: SIGNS YOU MAY BE A #COVIDIOT

No caption necessary

Below, NY mass grave, COVID16 victims' bodies stacked 3 high in plain wood coffins.

No more "Freedom & Liberty" for these folks.

UPDATE

The Body Collectors of the Coronavirus Pandemic
As the death toll from COVID-19 rises, the funeral homes and hospital morgues of New York City are struggling to keep up.

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More to come...

#Covid19 Venting

APRIL 21ST UPDATE: Criminally negligent, lethal lab QA failure at the CDC.

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Many #Covid19 patients are reported to have to be on ICU ventilators for 7 to 14 days (or longer).

I can hardly imagine.

I've only been intubated and on an ICU ventilator once, for just part of a day. Don't want to ever go there again. As I recounted in a prior post:

UPDATE
SAVR the experience. 

Up at 3:45 a.m., after a difficult, anxious, short night's sleep. No foods of liquids allowed. Ugh. Off to Concord, arriving at the Cardiovascular Institute at 5:23. Preregistered, straight up to “Short Stay” on the 2nd floor to begin pre-op prep. First (after vitals and a bunch of Consent signatures), neck-to-ankles full-frontal body shave (“OMG! I’m a Foster Farms Thighs & Breasts Valu-Pack!"), then blood draws and chest x-rays. IV insertions next (both arms), and EKG telemetry hookups follow forthwith.

Quick discussions ensue informing my wife and sister as to where to go to wait and what to expect in the way of surgery progress notifications. The anesthesiologist comes by to introduce herself and chat reassuringly. My cardiac surgeon stops by to warmly greet and further encourage me. Cardiac staffers would subsequently remark, on multiple occasions, “boy, did you ever get the A-Team!”

All good to hear. My anxiety is pretty minimal, all things considered, but it would not be true to claim there wasn’t any. I guess I’ll wake up. Or not.

More prep — lost of stuff going on all around me in tandem — and then it’s off to the OR.

They sidle my gurney up aside the operating table, which has a large stainless steel hump on it. I’m instructed to slide over on to it, with my upper-mid back positioned over the hump. It’s uncomfortable…

That’s the last thing I remember until waking up several hours later in Cardiac ICU (it seemed like mere minutes). Eventually the intubation is removed, I and have episodic bouts of harsh coughing. Right away they push me to begin using the spirometer. Pre-op I’d been pinning it at 2,500, no sweat. Now I can barely get it to move.

In short order I start intractable bouts of rather harsh, persistent hiccups from my irritated windpipe, some of which last 2-3 hours at a time through Saturday. Nothing works to abate it. They finally resort to two sequential IM doses of thorazine, which knock me out.

I will never EVER do thorazine again. You can just forget it. The most vivid adverse side effect was my mouth feeling like the surface of planet Mercury. Bone dry. By Saturday evening I was totally exhausted...

I simply cannot fathom being vented for a week or two (or longer). Ugh.

Given the emerged exigent clinical picture thus far, were I to come down ill with Covid19 seriously enough to end up ICU'd and vented, I wouldn't be thrilled about my survival odds.

UPDATE

WaPo article about a doc who now does nothing but Covid19 pt intubations for vents.

One more (April 15th):

The new coronavirus kills by inflaming and clogging the tiny air sacs in the lungs, choking off the body’s oxygen supply until it shuts down the organs essential for life.

But clinicians around the world are seeing evidence that suggests the virus also may be causing heart inflammation, acute kidney disease, neurological malfunction, blood clots, intestinal damage and liver problems. That development has complicated treatment for the most severe cases of covid-19, the illness caused by the virus, and makes the course of recovery less certain, they said…

UPDATE:

The Next Coronavirus Nightmare Is What Happens After the ICU
For many coronavirus patients lucky enough to make it off a ventilator, getting out of the ICU is only half the battle.

Decades of research shows many of the sickest ICU patients will never return to their former selves. An ailment called Post-Intensive Care Syndrome (PICS) causes cognitive, physical, and psychological problems in up to 80 percent of all critical-care survivors. About a third never return to work.

Now physicians say they are witnessing many of these effects in COVID-19 survivors, at a scale they’ve never seen before. And some are not sure we’re ready for the influx of ICU survivors this crisis will bring…

UPDATE, SCIENCE MAGAZINE

How does coronavirus kill? Clinicians trace a ferocious rampage through the body, from brain to toes

On rounds in a 20-bed intensive care unit (ICU) one recent day, physician Joshua Denson assessed two patients with seizures, many with respiratory failure and others whose kidneys were on a dangerous downhill slide. Days earlier, his rounds had been interrupted as his team tried, and failed, to resuscitate a young woman whose heart had stopped. All shared one thing, says Denson, a pulmonary and critical care physician at the Tulane University School of Medicine. “They are all COVID positive.”

As the number of confirmed cases of COVID-19 surges past 2.2 million globally and deaths surpass 150,000, clinicians and pathologists are struggling to understand the damage wrought by the coronavirus as it tears through the body. They are realizing that although the lungs are ground zero, its reach can extend to many organs including the heart and blood vessels, kidneys, gut, and brain…

Lordy Mercy. Read all of it.

ERRATUM: CUCKOO FOR COVID19

Comment in my Facebook feed.

Okeee-Dokeee, then.
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Flatten the #COVID19 curve, yeah, but "raise the line" as well.

Easier said than done midstream in a pandemic.

That's all great as far as it goes. A comment I left on Facebook relating to this topic:

The abiding historical, and speculative future problem is one of deciding what constitutes “sufficient” capacity? In a capitalist private market your executive priority is to fill the hospital beds, the airplane seats, the hotel rooms, etc. Spare capacity is toxic to the bottom line.

The “free market” that Trump otherwise loudly loves has been doing what it’s intended to do.

Recall how Trump peevishly said “I’m a businessman,“ and that he could just snap his fingers and get all the resources he needed at will. But, a “just in time” public health pandemic response infrastructure simply doesn’t exist on call. Like just about everything else, this escapes him.

Interesting interview with Science Magazine's Jon Cohen on PBS this morning:

ON DECK

apropos of my recent rants about lab QA and Covid19 "testing," seems there are R&D QA issues with the fast-tracked "antibody / immunity" assays as well. Stay tuned.
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Science denialism and the pandemic

Ran across this NPR Living On Earth piece on my iPhone. Listened to it, and grabbed the the mp3 podcast link for you.

 Science denial and the pandemic 

Dr. Naomi Oreskes.

"I think there are two things that we need to do here in the United States. The first is I think we need to rebuild our scientific institutions and in the process of rebuilding them as institutions, we can also rebuild trust. We've had 30 years in this country of decreasing support for scientific institutions, particularly federal scientific agencies, like the CDC, like the US Geological Survey, like NOAA and in the process of cutting back the budgets from Of these organizations, we've also seen these organizations subjected to a lot of hostility, a lot of criticism by political forces in Washington, DC, if we roll the clock back and think about the 1950s, when I was born, and when money was flowing into science, it wasn't just that the government was putting money into science. It was also that the government was telling us a story about why science mattered. So if you think about Dwight Eisenhower and the early years of the space program, or john Kennedy and Lyndon Johnson, who carried the space program forward, why did the American people believe in the importance of the Apollo program, it's because we were told a story, a good story, a true story, about how science could help build America, how to build our economy, how it could help build our educational systems, and how we could do cool things like put men on the moon. So I think we need to recapture that commitment to science and to scientific institutions and to scientists. The other thing though, that I think is equally important is to rebuild trust in government because the bashing of science has been linked in a very specific and direct way to a general argument against the government, particularly the argument against so-called big government. And this is something that began in the United States under Ronald Reagan, who's admired by many people and was an excellent president in certain ways but he did something that I considered to have been deeply, deeply damaging. And it's summarized by his slogan is that “the government's not the solution to our problems the government is the problem. For 40 years, we have heard that argument made by political leaders on the conservative side of the spectrum, so much so that a lot of ordinary people don't understand why we even have a CDC, the Centers for Disease Control, much less why we really need to count on them now in this current moment. And so that's about rebuilding trust in government and governance and making the point that sometimes we actually do need big government. We don't want the government telling us what to do with our lives on a day to day basis. But we do want the government to be there for us when we need it and it won't be there for us. We can't just say, oh, suddenly there's a crisis, suddenly we have to have government. No. If you want the government to be there when you need it. Well, it's got to be developed in advance..."

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A million+ #COVID19 cases and rapidly increasing

A grim milestone.

5.1% aggregate death rate.

On my iPhone at 3:41 EDT. The U.S. now accounts for nearly one-fourth of global cases. That proportion will only increase, likely for several more weeks. Data source, Johns Hopkins.

UPDATE: 24 HOURS LATER

Fatality rate now 5.4%

Below, April 4th, same time.

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A Boston physician writes in The New Yorker,

This disease is different from what we typically see, and its severity has unsettled even our most experienced doctors. One man arrived and had to be intubated immediately; his blood-oxygen level, thirty-eight per cent, was the lowest any of us had ever seen. (Greater than ninety-five per cent is normal; eighty per cent is alarming.) We have seen other patients with levels in the sixties or seventies. Another patient’s levels plummeted to below twenty per cent in the few seconds it took us to connect him to a ventilator. Not long ago, one of our physicians started wearing a new fitness tracker that purports to measure stress levels; when it recognizes high stress, it vibrates and displays messages, like “Relax” and “Take a break.” During a recent shift, it buzzed almost continuously…

APRIL 3RD UPDATE: A HOSPITALIST REFLECTS

For many patients, a diagnosis of covid-19 carries with it a deep unease associated with the worst of maladies. It is not pneumonia, or diabetes, or even a heart attack; it is H.I.V. and cancer. They’ve heard the gruesome statistics on the news—the high death rates, the rapid rise in cases, the dwindling supply of needed resources. And there are few symptoms as troubling for patients as shortness of breath. With the coronavirus, the anxiety of labored breathing is exacerbated by the fact that it must be suffered alone, without friends and family and with limited contact with doctors. Among the cruellest aspects of covid-19 is the intense isolation that it inflicts…

I am sympathetic to those concerned about the widespread economic and social disruption created by aggressive social distancing, and to the political and business leaders asking whether it’s all worth it. But I think that if they saw what I see—the fear, the tears, the gasping for air, the destruction of bodies and psyches wrought by the virus, the daily contortions that doctors, nurses, and hospitals must make to provide even basic care—they, too, would understand that social distancing is the only option. They would feel what I feel: that we cannot return to normal during a time when thousands of Americans, of all ages and backgrounds, cannot breathe, and there aren’t enough people or supplies to help them...

MEANWHILE, BACK IN THE WHITE HOUSE

Donald Trump takes repeated emphatic (increasingly strident) pains to disclaim any responsibility for his initially indifferent, dismissively negligent reaction to the COVID19 pandemic: "It came from out of nowhere. No one could have foreseen it."

Right. Facts are inconvenient things.

Box 6: What Would the 1918 Influenza Pandemic Look Like Today?
In the worst pandemic in recorded history, the 1918 influenza pandemic, the novel virus infected approximately one-third of the global population over a period of 2 years, ultimately leading to 50 to 100 million deaths world-wide. One might imagine that the death rate would be lower today due to the advent of modern medical equipment and procedures that did not exist in 1918, but the global population is now approximately 4 times greater than in 1918. This growth, however, is disproportionately higher in low- and middle-income countries, often the ones with developing health systems. Many—predominantly in Africa, Southeast Asia, Latin America, and the Middle East—have experienced population growths of 1,000% or more since 1918. Crowded urban areas provide prime conditions for the spread of respiratory diseases, and urbanization is increasing globally, including the emergence of 47 “mega-cities” (populations over 10 million). By comparison, London was the world’s largest city in 1918, at approximately 5 million people. Additionally, global travel has increased by orders of magnitude compared to 1918. Even then, shipping and population movement (including World War I) played an important role in global spread of the disease, but today, humans can fly anywhere in the world in less than 1 incubation period, meaning that global transmission can be expected to be even faster.

In 1918, the global case fatality ratio is estimated to have been 2.5%, but it was considerably greater in low- and middle-income countries, with some estimates exceeding 10%. Today, some high-income countries would be expected to fare much better because of modern health care, but the case fatality in countries with limited access to healthcare could be as bad as or worse than 1918. Simple arithmetic would suggest the possibility of 100 to 400 million deaths if a 1918-like pandemic were to occur today, but unprepared or under-resourced health systems could further exacerbate disease transmission through nosocomial spread and an inability to promptly diagnose and render care, a particular concern for developing health systems. During the 2003 SARS epidemic, 72% and 55% of presumed and confirmed cases in Toronto and Taiwan, respectively, occurred as a result of healthcare transmission. A similar nosocomial outbreak in which healthcare facilities became amplifiers of the epidemic, this time of MERS, happened in South Korea in 2015. [Page 47 of 83]

Hat tip to Dr. Naomi Oreskes.

UPDATE

ERRATUM

Citizens who lost health coverage in past 2 weeks due to economic collapse:

USA 3,500,000

Australia 0
Belgium 0
Canada 0
Chile 0
Denmark 0
Finland 0
France 0
Germany 0
Greece 0
Hungary 0
Italy 0
Japan 0
New Zealand 0
Norway 0
Portugal 0
S Korea 0
Spain 0
Sweden 0
Turkey 0
UK 0

Hat tip to a good Facebook friend.
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