Simon Murray, MD

Polymerase chain reaction (PCR) testing for 

 is currently the most effective frontline test to detect exposure and infection. A positive test, taken from a nasal sample, is presumptive evidence of disease. But a negative test does not rule out infection for a variety of reasons. As many as 25% of the nasal swab tests are likely false negatives.

Causes of false-negative tests include improper collection, improper handling or storage, the prolonged time between collection and testing, or laboratory error.

Since the PCR swab test gives us no information about a person’s immunity to infection, we have been anxiously waiting for a method to test for antibodies to the virus. From experience with other infectious agents, we know that the presence of IgG antibodies indicates that immunity exists, and a presumption can often be made that the patient cannot be re-infected.

If this were, in fact, the case with SARS-CoV-2, we could send people with antibodies back to work, expecting that they will be protected. Unfortunately, not all enzyme-linked immunoassay (ELISA) tests are alike in their ability to reliably predict immunity.

Abbott Labs has been at the forefront of developing an ELISA test for COVID-19. The company has been reluctant to disclose much about its technology on the grounds that plans for deployment are still not finalized.

 it had received emergency clearance from the US Food and Drug Administration (FDA) to begin shipping the first point-of-care diagnostic test for the SARS-CoV-2 virus. The platform, called ID NOW, is the size of a toaster and can provide results in as little as 13 minutes. The ID NOW platform had been used to detect influenza and strep and was designed to be used by point-of-care providers.

By redesigning software and integrating different reagents, ID NOW was repurposed to test for SARS-CoV-2. Abbott said it could produce about 50,000 tests a day, with the eventual ability to produce 1.5 million tests a month. Initially, the tests were deploying only to areas with the highest concentration of COVID-19 cases.

A week later, Abbott announced it had developed an ELISA test, the m2000 SARS-CoV-2 assay, to be used in large laboratories. The company expects to produce about 4 million tests a month.

 the launch of its third test for COVID-19, a serology test to be run on its laboratory-based Architect i1000 and i2000 instruments. More than 2000 of these machines are in use in the United States. The test will cost about $5. Abbott expects to process 100-200 tests per hour. According to published reports, the number of true positives will be almost 100% within 14 days after the onset of symptoms. Remarkably, Abbott claims the false-negative rate is 99% after 14 days. It is unclear whether the test detects only IgG, or both IgG and IgM immunoglobulins.

Abbott tested its device on a few thousand patients, but when applied to millions of patients in the real world, we will see how it performs.

Another critical question is, what does a positive test tell us? Typical ELISA tests provide results for 2 distinct immunoglobulins, IgM and IgG. Typically, the IgM antibody is the first one detected. It usually rises and falls quickly, followed by a rise in IgG, which is believed to confer immunity. It may remain elevated for years, or months as in the case of influenza.

I spoke recently to Elliot A. Krauss, MD, chair of the Department of Pathology at Penn Medicine Princeton Medical Center, who expressed some concerns about the test, specifically that it didn’t undergo the same scrutiny as a test would in normal times; it was released as part of an FDA agency process that allows companies to produce and market tests without an explicit Emergency Use Authorization, although the company says it plans to file for one. As such, the test may cross-react with other common forms of coronavirus that cause the common cold.

Secondly, we don’t know which antigen is being detected by the ELISA. We know the critical antigens necessary to penetrate human cells are the s, or spike, and n antigen. There are several other antigens on the virus, some of which may be insignificant, or not enough to produce immunity, but may give rise in IgG.

Third, we don’t yet know whether the presence of IgG does, in fact, confer immunity and, if so, for how long.

Lastly, ELISA is a screening test. It casts a wide net and picks up many unrelated proteins. A positive ELISA must be confirmed by another method. Lyme disease is a prime example of a disease that causes the ELISA to be positive in many cases where there is no Lyme disease present.

Krauss had several questions about the value of the test in clinical practice. He mentioned that the University of Pennsylvania is also close to developing an antibody test, as well as other large manufacturers like Siemens and BD.

After testing positive via the ELISA test, are we going to allow teachers to return to school and doctors to return to work before we are certain they are indeed immune with no possibility of being infectious?

Krauss said it will take some time to have these questions answered.

Once again, it comes down to getting a vaccine that works, or the development of herd immunity. It is likely that the test will prove to be valuable epidemiologically and will help us better understand the natural history. It will take some time to see the real value.

For now, we will need to do both the test for active infection and the serologic test and not let the results determine whether or not to give up what we are doing. Over time we will learn the best utility of the ELISA. SARS-CoV-2 is here to stay. Most importantly, what we learn here can help us prepare for future pandemics that are undoubtedly going to affect us.

Simon Murray, MD, is an internist based in Princeton, NJ. The piece reflects his views, not necessarily those of the publication.

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Can positive ELISA test results better interpret for how much longer social distancing must continue?

Finally, an ELISA for COVID-19

ACE inhibition or angiotensin receptor blockers (ARBs)

There has been some dissent lately about the role angiotensin-converting enzyme plays in the COVID-19 infections. The chemistry can be quite confusing, making it easy to see why it has caused controversy.

 A very elegant system exists in humans to regulate blood pressure when there are sudden drops in renal blood flow or reduced sodium excretion, which could lead to hypotension. The system is called the renin-angiotensin system (RAS), which keeps us from fainting when we stand up quickly or when we are dehydrated.

Angiotensinogen is a protein formed in the liver and activated when renin, an enzyme secreted by the kidney in response to a drop in renal blood flow, cleaves it. The resulting protein is called Angiotensin 1, which has no known function except as an intermediary in the process of maintaining blood pressure. Angiotensin 1 is converted by angiotensin-converting enzyme-1 or ACE1 in the lung into angiotensin II.

Angiotensin II can act on the adrenal to produce the hormone aldosterone, which increases sodium retention and promotes potassium excretion. Angiotensin II will bind a specific receptor in the heart, lung, and blood vessels called the AT1 receptor. There are 3 other receptors—AT2, AT3, AT4&mdash;but their roles remain unknown.

Once bound to AT1, angiotensin II causes vasoconstriction, fluid and sodium retention, stimulation of aldosterone, and cardiac stimulation. Free, unbound angiotensin II has direct proinflammatory properties in lung tissue.

There is a second angiotensin-converting enzyme called ACE2 that had remained rather obscure in literature until 2002 when it turned out to be the point of entry for 

The 2 angiotensin-converting enzymes, ACE1 and ACE2, are analogs of each other and structurally very similar. ACE2 protein exists as a soluble form but mainly resides on the epithelial surface of the lung, intestine, and heart. Not much was known about ACE2 until the SARS epidemic, but much has been learned since.

ACE2 plays a counterregulatory role in the classical RAS and causes vasodilation, reduction in sodium, and reduced levels of angiotensin II. It does so by reducing angiotensin II levels and converting angiotensin II into angiotensin (1,7), which are vasodilators. 

ACE2 levels are generally 200 times higher than ACE1 levels.

It also has a negative effect on aldosterone. The 2 proteins ACE1 and ACE2 each have very different actions on the RAS.

Chronic overactivity of the RAS is felt to be one cause of hypertension. It became logical to look for drugs to interfere with this system. In the late 70’s and 1980’s a class of drugs were developed called angiotensin-converting enzyme inhibitors after the discovery that cobra snakes have a large amount of angiotensin in their venom. The way that cobra snakes kill their prey is by causing shock from hypotension.

ACE inhibitors block the conversion of angiotensin 1 to angiotensin II by inhibiting ACE1. The inhibitors were not felt to have any role in blocking ACE2. But a few years later, the second class of drugs was developed, which blocked the action of angiotensin II further upstream at by preventing angiotensin II from binding to specific receptor sites on the blood vessel and heart.

These are ARBS, which have been shown to reduce the symptoms of congestive heart failure, lower blood pressure and protect the kidney from high blood pressure. They are often the first-line drugs used to treat these conditions.

And I said before: the role of ACE2 remained obscure until 2002, prior to the discovery that it binds SARS virus avidly and served as the point of entry of the virus into the cells that 

Why is this important? We know that SARS-COV-2 is bound to ACE2 and serves as a portal of entry of the SARS-COV2 virus into cells—just as it was for the SARS and probably the MERS viruses. Theoretically, anything with increased ACE2 levels could make patients more susceptible to infection with coronavirus, and make their cases more severe.

described the observation that Chinese patients who had high blood pressure or diabetes and who were taking ACE inhibitors and ARBS had worse outcomes, with more severe infections and more deaths.

The article implied that ARBS and ACE inhibitors elevated ACE2 levels and that increased ACE2 facilitated more viral penetration into lung tissue. The paper concluded that taking these medicines could increase the number and severity of infections. The authors suggested that people should stop taking these medications. On face value, it seemed like a logical conclusion.

For several days after publication, there was a firestorm of confusion about whether or not to take ACE inhibitors or ARBs. 

The European Society of Cardiology and several leading American cardiology societies 

. They suggested that patients should continue their medications and that there was no proof that the COVID-19 infection was adversely affected by inhibition of the RAS. There is evidence that these medicines might make infections better.

It is complicated, but it has already been demonstrated that 

 when the patients were taking ACE inhibitors.

 article consider that the patients who did worse either had diabetes, hypertension, or obesity? That triad is part of the metabolic syndrome and would make any sick person worse, because the metabolic syndrome can produce the “cytokine storm” that generates damage to lung tissue.

I was drawn into this debate by several patients who had the quickly popularizing article. A few days later, when institutions refuted the findings, I saw more controversy stir.

This episode is an example of the ongoing issue we have during this pandemic—in which public announcements or declarations on the virus are later retracted. People in authority are making statements and decisions without certain and evidenced knowledge. The most present fact in this debate is that story is rapidly developing.

Of course, as we see the virus rapidly spread and take more lives, it is understandable to see people react quickly, rather than rationally.

Healthcare professionals and researchers interested in responding to this piece or contributing to MD Magazine® can reach the editorial staff 

A study’s proposed findings of increased coronavirus risk shows how presenting half of a fact can influence our care during a pandemic.

ACE Inhibitors & ARBs: Wading Into the Unknown of COVID-19

 This opinion column represents the author’s perspective and may not necessarily reflect the current status of the COVID-19 situation, which is rapidly evolving. This column, posted in early February 2020, captured the uncertainty of the beginning of the novel coronavirus pandemic. See the most up-to-date COVID-19 coverage 

 from the US Centers for Disease Control and Prevention (CDC), 

 has caused the deaths of 10,000-25,000 Americans, hospitalized 180,000, and sickened 19 million so far in the 2019-2020 season.

 about 900 people worldwide. There have been only a handful of cases in the United States, with no deaths reported. So why is the public so panicked over this outbreak?

>>> Clinical news for the connected physician. 

Sign up here to receive daily medical insights and news, straight to your inbox.

Novel coronavirus (2019-nCoV) has some obvious differences from the flu virus. The first difference is that we do not understand how the virus will transform itself via mutations to become more contagious in the future. The outbreak is similar to the severe acute respiratory syndrome (SARS) virus, which was initially transmitted from animals to humans and believed to have originated from civet cats and bats. Coronavirus, like the SARS virus, typically causes zoonotic infections, being transmitted from animals to humans. One way that these viruses are suspected of getting into the human population is when they are eaten as exotic foods, or taken as medicines, typically found in Asian countries like China. In many ways, the Coronavirus and SARS virus are similar.

"They likely had a common ancestor in the bat population,” Stanley Perlman, a virologist at the University of Iowa who is part of the Coronavirus Study Group, a subset of the International Committee on the Taxonomy of Viruses, 

. “However, over time the virus mutated and may have infected other animals, and eventually mutated into a form that could be spread from 1 human to another, but we don't completely understand the process of viral transmission yet.”

The CDC believes it has identified human-to-human transmission of the novel coronavirus between a married couple in Illinois, but are not sure how it occurred. On the other hand, we clearly understand the transmission patterns of the flu. There are hundreds of zoonotic infections that have the potential to mutate into other forms capable of causing human-to-human transmission.

The second difference is that we have therapies for flu, albeit imperfect therapies, but antiviral drugs that do work to shorten the duration of the illness. Antivirals can provide prophylaxis for those at greatest risk and can treat symptoms. There are some antiviral drugs with activity against this version of coronavirus, but they have not been approved. Recently scientists in China 

 that combining the antiviral drug remdesivir with chloroquine has been highly effective at killing the virus.

Third, patients infected with the flu virus generally become contagious about 1 day prior to developing symptoms, and remain infectious for another 5 days. We are not sure when patients exposed to coronavirus become infectious or how long infected patients remain contagious, so isolation strategies are difficult to develop. To be cautious, we have chosen long periods of isolation. The Chinese government has tried to isolate large populations of people to contain the virus. Entire cities have been quarantined, leading to widespread shortages of everyday goods like food, medicines, bandages, and water, triggering social panic.

The idea that large cities could be quarantined is a frightening prospect for many people and, the fact is, in today's world, it just does not work. The Chinese have built large hospitals to quarantine people who are suspected of being infectious or exposed to the virus. This has added to the public fear surrounding the disease.

The fact remains that this strain of coronavirus is not highly contagious; it behaves very similarly to other infectious viruses by targeting mainly the weak and/or immunocompromised portions of the population. For most of us, contracting coronavirus infection will lead to a flu-like syndrome, and the majority of patients will most likely survive—very similar to the majority of people who get flu.

There is a certain unspoken factor adding complexity to this outbreak: The fact that it originated in China. There is a good deal of anti-Chinese sentiment in the United States and around the world. Airlines refuse to travel to China and refuse Chines passangers, Chinese tourists are barred from entering certain countries, Western businesses have closed, and ex-pats have returned home. Some of this reflects a certain attitude of fear that the Chinese government hasn’t been honest or upfront about reporting details about the outbreak. Chinese citizens have been prohibited from traveling to some countries. I have even heard cases of Americans avoiding Asian people unless they are wearing masks out of fear that they will contract coronavirus.

All of this is, of course, absurd and, frankly, xenophobic at best—and racist at worst. The fact is, a Chinese visitor visiting the United States at this time is 10,000 times more likely to die from influenza than an American visiting China is of dying from coronavirus. In any case, wearing masks affords little protection against coronavirus since the virus is small enough to penetrate the microfibers of most masks. This strain of coronavirus appears to be far less contagious than the flu.

The fact is, influenza is an illness that is far more deadly but also far more familiar to us. The current coronavirus outbreak, which originated in China, serves as a surrogate for a good deal of xenophobia and fear of the country itself.

The views expressed are the authors and not reflective of the publication or its owners.

The newest virus scare has killed one-tenth as many patients as influenza this season, yet public concern fixates on the smaller issue.

The Fear of the Coronavirus, and the Reality of the Flu

After reviewing hundreds of medical charts over the course of my career in internal medicine, I can say with certainty that records often contain a great many errors, usually the result of less-than-perfect dictation or faulty copy and pasting.

Most of the errors are trivial, fortunately, and some can actually be quite humorous.

Here’s a sampling of some of these “doctor bloopers” I have heard about over the years:

The baby was delivered, the cord clamped and cut, and handed to the pediatrician, who breathed and cried immediately.

Rectal exam revealed a normal size thyroid. 

The patient lives at home with his mother, father, and pet turtle, who is presently enrolled in day care three times a week.

The patient was to have a bowel resection. However, he took a job as stockbroker instead.

On the second day the knee was better and on the third day it had completely disappeared.

 “The patient has been depressed ever since she began seeing Dr. Murray in 1983.”

The patient will need disposition, and therefore we will get Dr. Murray to dispose of him.

The patient's past medical history has been remarkably insignificant with only a 40-pound weight gain in the past 3 days.

The patient experienced sudden onset of severe shortness of breath with acute pulmonary edema at home while having sex, which gradually deteriorated in the emergency room.

The patient left the hospital feeling much better except for her original complaints.

She stated that she had been constipated for most of her life until 1989 when she got a divorce.

Discharge status: Alive but without my permission.

Since she can’t get pregnant with her husband, I thought you might like to work her up.

Occasional, constant infrequent headaches. (

We saw your patient today, who is still under our car for physical therapy.

Large brown stool ambulating in the hall. (

Patient has 2 teenage children, but no other abnormalities.

You really can’t make this stuff up. You just have to laugh. Happy New Year to everyone!

If you know of any other funny chart entries, we’d like to know. Send an email to 

Doctors are prone to workplace gaffes like anyone else. Here's a list of the funniest ones yet.

Simon Murray, MD

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