April 3, 2020 Johns Hopkins in Baltimore was given FDA approval to test a blood plasma therapy to treat COVID-19 patients.  The trial will use blood serum (a straw colored liquid left after the clotting of plasma), collected from recovered COVID-19 patients. This trial will evaluate convalescent serum as a preventive treatment for infection in people at high risk of contracting disease, and as a potential treatment for people critically ill with COVID-19. 

How does this work?

When we get better from an infection, we have made antibodies, and these tiny molecules protect us from reinfection at some point in the future.  Antibodies are found in the blood serum.  This therapy is therefore about harnessing the immune system of one person who has recovered from COVID-19 to help another person either prevent getting ill in the first place, or possibly recover from active infection.    

Passive antibody therapy occurs with administration of antibodies against a target such as a virus, to a person who is susceptible to that virus. This is done to prevent or treat the infectious disease the virus might cause. We could contrast that to active vaccination, which occurs when for example, a protein from a virus is injected into a person to provoke an immune response to that virus. Doing that takes time, and may vary depending on the biology of the person getting the vaccination. 

According to the Johns Hopkins based Health University News, Arturo Casadevall, M.D., Ph.D., Johns Hopkins Chair of Molecular Microbiology and Immunology has worked with physicians and scientists from around the United States “to establish a network of hospitals and blood banks that can collect, isolate, and process blood plasma from COVID-19 survivors.”  The FDA, which is allowing emergency authorization of convalescent plasma as an investigational new drug (IND), notes “it is possible that convalescent plasma that contains antibodies to SARS-CoV-2 (the virus that causes COVID-19) might be effective against the infection. Use of convalescent plasma has been studied in outbreaks of other respiratory infections, including the 2009-2010 H1N1 influenza virus pandemic, 2003 SARS-CoV-1 epidemic, and the 2012 MERS-CoV epidemic.”  (footnote 1, and 2)

The history of passive immunization

The concept of using convalescent plasma is not new.  Doctors have long recognized that with most illnesses there will be some people who do better than others.   In the case of an infectious disease outbreak the same is true. The question is why. 

Much of the answer has to do with the immune system, the body’s defense against infection.  It has been shown that some people mount a more robust, or more effective immune response, than other people who might succumb to the same infection.

The therapy proposed here goes back at least to the 1890s, when it was shown that serum from rabbits previously exposed to tetanus toxin could be used to prevent tetanus in other rabbits exposed to the toxin.  The technique was also shown to work with diphtheria toxin.  Building on this it was shown that increasing from small to larger doses of bacterial toxins such as those in diphtheria and tetanus could induce an animal to develop immunity against larger, lethal doses.  This led to mass production of serum in dairy cattle and horses for the treatment of diphtheria.  It also led to the concepts of active and passive immunization, and to the field of humoral (antibody) immunity.  Nobel prizes were awarded for these history-changing discoveries.

In the early part of the 20th century, physicians would often try to contain outbreaks of viral diseases such as measles, mumps, and polio by treating exposed people with convalescent serum. During the 1918 influenza pandemic, serum from recovered patients was used to treat some acutely ill influenza victims, and to treat people who had been exposed.  By the 1920s it became very common to treat pneumococcal pneumonia with serum form horses.  Over the next few decades clinical benefit was also seen with this technique in the treatment of Haemophilus influenza B, and meningococcus.  There were multiple related therapies over the years.

An expert in the field

Dr. Casadevall discussed how doctors of the early 20^th century used convalescent serum to prevent outbreaks of infectious disease on the Johns Hopkins Bloomberg School of Public Health podcast Public Health On Call.  He noted that the antibodies we make with our immune system during an infection are “why people only catch measles once, and (why) they’re protected for the rest of their lives.”  When an epidemic decades ago was starting, doctors “would find somebody who’s immune, somebody who’s recovered from the illness, ask him to donate blood, they would separate the blood and the serum, and then they would give small amounts of the serum to people who are vulnerable, that is, those who have been exposed, those who  are likely to have caught the disease.  And, it was quite effective.” 

Convalescent serum was used in 1934 for example, to stop an outbreak of measles in a Pennsylvania preparatory school.  In that case the serum taken from one recovered boy was used to treat 66 other boys who had been exposed.  Each boy was given only 5-10 mL of serum.   “When you have a disease like measles, approximately 25% of the kids will get it.  It’s one of the most infectious contagious diseases that we have. And…only 3 children developed measles, even though they expected numbers would have been a quarter of the 66 children,” (17 of them).  The 3 boys that had measles wound up having mild cases due to the treatment.  “When vaccines came on board in the 1960s this practice was both stopped and forgotten.”    

With COVID-19 many people are going to do well, and are going to make antibodies to the coronavirus. The plan is to use blood banking processes to prevent the spread of other diseases, and give small amounts of safe convalescent serum to healthcare workers, first responders, people caring for others with coronavirus at home.  Convalescent serum therapy is more effective for prevention than treatment.   However, it can be given after disease has already started, but there were some hard lessons learned decades back.  

When antibody therapy was used to treat streptococcal pneumonia doctors found if it was given in the first few days of symptoms good results were seen, though it seemed to have much less, or no value if given later than that. One speculation as to why has to do with the amount of antibody needed. To prevent disease people need very little antibody because the number of organisms infecting a person is usually very low. Alternatively, once disease has developed in a person and cells are making copies of the infectious agent (bacterium or virus), the number of particles in the body is very high, which would require more antibodies and thus, more serum.

Conclusion

Convalescent serum sounds very promising, especially as a protective strategy for those who have likely been exposed to the virus that causes COVID-19. It seems less likely to be helpful in those with fulminant disease.

Larger doses of convalescent plasma may be helpful. Shen, et al. reported in the March 27 issue of JAMA that doctors in China treated 5 critically ill patients on ventilators with laboratory-confirmed COVID-19 by giving convalescent plasma transfusion. There were improvements in the first week, and by 37 days after infusion, 3 had been discharged from the hospital, and 2 were in stable condition. This is interesting, because the fatality rate of COVID-19 patients on a ventilator is high. It is a hopeful sign.

Given all of these points, even if convalescent serum is helpful in limiting the spread of an outbreak, it is probably a stopgap measure.  There is a massive worldwide research effort aiming to give stronger therapies, such as drugs to inactivate coronavirus, monoclonal antibodies-which are usually superior to convalescent serum (think silver bullet versus shotgun), and vaccines.  The problem is the time it takes to develop these interventions. Convalescent serum may be a much faster option. That is probably why this is also being tried around the world.

FOOTNOTE 1:  The FDA has significant “Considerations for healthcare providers interested in obtaining COVID-19 Convalescent Plasma for Use under IND.” These include using COVID-19 convalescent plasma collected from recovered individuals if they are eligible to donate blood under the Code of Federal Regulations used by blood banks.  Evidence of COVID-19 should be documented by a laboratory test either by a diagnostic test (e.g., nasopharyngeal swab) at the time of illness, a positive serologic test for SARS-CoV-2 antibodies after recovery, if prior diagnostic testing was not performed at the time COVID-19 was suspected.   The donors must have either complete resolution of symptoms at least 28 days prior to donation, or complete resolution of symptoms at least 14 days prior to donation, and negative results for COVID-19 either from one or more nasopharyngeal swab specimens or by a molecular diagnostic test from blood.   In terms of recipients of the blood serum, the FDA requires laboratory confirmed COVID-19, with a severe or immediately life-threatening COVID-19 (specific criteria on the FDA website).  

FOOTNOTE 2: This study in Northern China in 2003 evaluated 99 convalescent serum samples from patients 35-180 days after the onset of symptoms. Anti-SARS antibodies were detected with three lab tests in 87 of the samples. Zhang, et al., A serological survey on neutralizing antibody titer of SARS convalscent sera. J Med Virol. 2005;77(2):147-50.

In the MPDN post yesterday, CDC recommends wearing a cloth face cover in public, I gave a link to CDC instructions for making a cloth face covering from a cotton T-shirt, along with a couple links to videos, etc. The CDC has added additional instructions which can be viewed online or downloaded as a .pdf. These instructions demonstrate how to construct three types of face coverings:

• Sewn Face Covering from fabric
• Quick Cut T-shirt Face Covering (no sew method)
• Bandanna Face Covering (no sew method)

To put on a face covering, grip the cover by the draw strings or elastic material used over the ears. It is okay to adjust to tightness around the nose, but try not to touch the material through which you will breathe. In general, try to limit touching the mask while wearing, and if you do so, use clean hands. Please keep in mind that any cloth face cover should be washed regularly, depending on use. It follows then that any material you select should be capable of being laundered and machine dried without damage or change to shape.

The CDC notes “individuals should be careful not to touch their eyes, nose, and mouth when removing their face covering and wash hands immediately after removing.”

There are many other sites that show instructions as well. I am not sure all are equal and would generally treat the CDC instructions as the standard, especially where safety features such as material and thickness are concerned. An article in The New York Times also included instructions for a simple cloth face cover. If I see any more interesting articles on this topic in the coming days I might add an addendum to this one.

Remember, the purpose of wearing a face cover in public is to limit the spread of the virus. Do your part, cover your face. We in the hospital and clinic have been masking for every patient encounter to protect you. Now, we all need to cover our faces in public for the time being.

Finally, I will say it again, wearing a cloth cover does not mean you should stand closer than 6 feet with other people. Keep doing that. Let’s crush the curve.

Friday, April 3 the CDC recommended:

“Everyone should wear a cloth face cover when they have to go out in public, for example to the grocery store or to pick up other necessities.  Cloth face coverings should not be placed on young children under age 2, anyone who has trouble breathing, or is unconscious, incapacitated or otherwise unable to remove the mask without assistance.” 

The CDC was clear that “the cloth face cover is meant to protect other people in case you are infected.”  More on that below.  The CDC also stated:

• Do NOT use a facemask meant for a healthcare worker
• Continue to keep about 6 feet between yourself and others. The cloth face cover is not a substitute for social distancing.

Dr. Jerome Adams, U.S. Surgeon General, gives a 46 second video about how to convert a simple winter scarf and two rubber bands into a face cover.   Also check here for more Q/A on cloth face coverings by the CDC.

This might seem to be a reversal of Dr. Adams’ February 29, 2020 tweet in response to Americans panic-buying all the surgical and N95 masks (specialized microfiltration respirator masks):

“Seriously people- STOP BUYING MASKS!  They are NOT effective in preventing general public from catching #Coronavirus, but if healthcare providers can’t get them to care for sick patients, it puts them and our communities at risk!”  

It is not, and he was right on more than one point.  If healthcare workers all get sick, there won’t be anyone left to care for the rest of the public.  If health systems fail, the epidemic curve steeply and broadly increases, and that is bad.  

He was also right that there was, and still is a big shortage of personal protective equipment (PPE) all over the country (and in many other nations). N95s are needed by medical personnel who perform procedures which might result in aerosolization of virus, such as intubation of people with COVID-19. N95s, or some other specific PPE are also worn by medical personnel in the presence of suspected and confirmed cases of COVID-19 generally, though I have heard from colleagues around the country who may be running out of those supplies. This places them at very high risk.

Paper surgical masks have a role also for medical personnel, and should not be worn by the general public. Take a moment to consider that when a surgeon and his or her team wear a mask, they are protecting the patient from their own respirations: respirations which contain droplets, droplets which might contain bacteria, viruses, or other pathogens. 

Dr. Adams was also right that with an airborne virus a paper surgical mask is not effective in preventing the general public from catching the virus.  This point is a complex thought contained in a tiny tweet.  A paper mask (even if you are wearing it correctly, and many people are not), will not prevent aerosolized particles from being inhaled because they are so tiny.  Even if you wear a face cover, stay away from sick people. 

Being in the proximity of a sick, coughing and/or sneezing person is the most likely way to catch this virus, because you will probably be exposed to high numbers of active virus particles, which means a better chance of getting some of them into your respiratory system.  It might also mean a more aggressive case of disease.  In medicine a general principle is that being exposed to higher numbers of infectious particles is usually a bad thing, and might explain why otherwise healthy medical personnel made up about 15% of cases in China (and a high number of cases in the U.S.).  It is common knowledge that droplets can travel much farther than 6 feet after a sneeze or a cough.  A very recent report demonstrated droplets up to 27 feet after a sneeze.  Click to see the video and read the report in JAMA.

The droplet range of 6 feet is meant for people who are not coughing or sneezing.  However, even breathing or speaking usually causes people to expire respiratory droplets.  And, louder talking requires more air, thus is likely to generate more droplets.  So… loud talkers, you know who you are (or at least everyone else does), it only makes sense to tell you to lower your voice for public safety.   And, go ahead and keep that in mind from now on. 

The most important consideration with wearing a cloth face cover in public is that you might not know you are infected, and still be able to spread the virus.   CDC authorities are reporting that asymptomatic carriers might make up about 25% of all infections. These are not people who qualify for testing under current federal or state guidelines.  These are not people who are even aware they have been infected.  Even among those who will become symptomatic, data shows they are shedding virus particles during the 48 hours prior to symptoms.  For these reasons wearing a cloth face cover in public can limit the spread of the virus. When wearing a face cover, put it on properly over your nose and mouth. Do not lower it to speak, and do not touch it a lot. Only touch your mask with clean hands. But please don’t forget, even if you wear a face cover, you should still stay at least 6 feet back from even seemingly well people.

Finally, there are many free patterns available on the internet if you want to make your own mask. One a friend gave me looks nice. You have to make sure there are enough layers and the right kind of material is used. It might surprise you to find out you may already have what you need. In 2006 the CDC posted a page about how to make an 8-layer thick cloth mask out of a Haines cotton T-shirt.

If you want to make a very strong DIY mask, a Maine physician posted this video about how to make a mask that contains a pocket, into which you can insert a HEPA filter cut from a vacuum bag.

According to the Maine CDC, there have been as of today 344 cases of COVID-19 (up 41 cases since yesterday) and a case has been detected in Hancock County, bringing the number of counties affected to 13 (though we should assume there is virus in every county).  Community spread is present in York and Cumberland Counties, where cases are the highest. The number of healthcare workers infected remains at 43.  Since the onset of testing 63 people have been hospitalized, and 80 people have recovered.  Two more people have died from COVID-19, both women in their 80s who were hospitalized, bringing the total to 7 deaths.  A second positive case at the Oxford homeless shelter has been detected. Authorities have been working to identify potential spread at that shelter.

Testing

Maine CDC has supplies to test another 4000 people at present, and there have been 8400 negative tests so far.  As mentioned yesterday, there is a new FDA-approved (Emergency Use Authorization (EUA)) rapid test (taking less than 15 minutes) being manufactured by Abbott Laboratories (based in Illinois with production in Scarborough, ME).  This test will be used in the existing Abbott ID NOW device, a small piece of medical equipment about the size of a toaster.  The availability of a rapid test will be helpful in reducing the amount of personal protective equipment (PPE) used by medical personnel. Dr. Nirav Shah today noted that this week we received our third and final distribution of PPE from the Strategic National Stockpile.

To that end, Maine will be taking possession of 15 Abbott Laboratories ID Now devices, 100 test kits, each able to perform 24 tests, therefore 2400 tests.  Several labs around the state also have these machines, which were designed for rapid diagnosis of other diseases.  As noted yesterday, Abbott can produce 50,000 test kits daily, though as below, it sounds as though the majority will not be allocated for Maine. Miles White, the outgoing CEO of Abbott, told CNBC on March 30, 2020 that in addition to the rapid tests, more tests are coming. “There’s still more, and there’s a need for more.  We have a collection of technologies and formats, we’ve got multiple R&D teams at work.  There are more tests coming, there are serology tests, antibody tests, we’re looking at automated versions of that…all of those are a matter of weeks to a couple of months away.  Those teams are working around the clock…” They are also reportedly working on ramping up production to much higher numbers of tests daily.   “For a while we’ll be allocating and prioritizing to high need areas.”

Vital resources

More and more hospitals are reporting to Maine CDC, and the numbers of vital resources are going up:

• 272 ICU beds, 124 available
• 348 ventilators, 271 available
• Alternative ventilators, approximately 128 available

Stay at home orders

Multiple governors around the country have instituted stay at home orders in the last few days. These orders are an effort to contain the outbreak in local communities, to prevent deaths, and to prevent an overwhelming surge of cases in hospitals and healthcare systems during this most severe pandemic the world has seen in the last 100 years.  I have read that some Mainers feel it is too soon to execute such an order. However, in medicine and epidemiology we know that this is precisely the time to act. And, we know that the numbers of seriously ill people with COVID-19 we are seeing today are people who contracted the disease an average of five days ago. Right now there are likely many more people who are infected but not yet showing signs of disease. There are also likely many asymptomatic carriers who are capable of spreading disease. Some experts have documented high levels of virus in the nasopharynx of people with no symptoms at all.

As an epidemic like this grows, it does so in an exponential fashion. For more on this please read my COVID-19 questions post. Looking at national trends on March 29, 2020 Dr. Anthony Fauci told CNN’s State of the Union audience that this pandemic could kill 100,000 to 200,000 Americans and infect millions. Many different authorities are making projections, and many are keeping track of the rapid spread of this pandemic. As it stands now Johns Hopkins notes that there are 190,740 cases in the U.S.  We are unfortunately the country with the highest number of reported cases worldwide.  Johns Hopkins further indicates a total number of positive tests worldwide of 887,067, with 44,264 deaths since the start of the pandemic.  Some cities such as New York and New Orleans are being particularly hard hit.  Stay at home orders and social distancing should be taken very seriously.   

Conclusion

Check the home page for links to other useful sites on the web. Know that people all over the world are working on this, and advances are happening daily. This is what science is for. And, caring for patients and constantly trying to improve how we do that is what doctors, nurses, and other healthcare workers are trained to do. We are not going to stop.

Please safely check on someone who might be isolated. Use social distancing, a telephone, texting, whatever works to say that you care. We need to stay connected in the ways that we can. Think about checking in on all of your loved ones. They might not be as strong as they seem. None of us has ever faced a worldwide crisis like this.  

Also, please keep up routines and sleep/wake schedule. Make sure you move your body in a healthy way daily with exercise, stretching, and other activities you enjoy.

Finally, I know many of these posts are about frightening topics. Try to also focus on something happy, meaningful, or beautiful to you. There is a reason we have poets, novelists, artists, and musicians. They center us, they bring us peace.  Know too that if you or someone you know is in a states of crisis, there is still help. Call your doctor’s office or call the Maine Crisis Hotline at 1-888-568-1112.

Today the Maine CDC reports there are 303 confirmed cases of COVID-19 in fulltime residents of Maine. Since the start of the outbreak there have been 68 recoveries, 57 patients have been hospitalized, and 5 deaths. Among positive cases, 43 are healthcare workers.  There is a current backlog of 600 tests to run, all patients in the lowest risk category. High risk patient tests are prioritized (more below).  

Positive cases are present in 12 Maine counties with 169 cases in Cumberland County, and 59 cases in York County.  Cases are represented by every decade of life, though over 87% of cases are in people 40 and up.  

Non-residents who test positive in Maine are not listed in the total above, but are instead recorded in their home states. Those numbers (as far as I can tell), are not available on the Maine CDC website.  From an epidemiology standpoint it makes sense to count the number in the state where the disease was contracted.  If presumably a case was contracted in Massachusetts, but the person traveled to Maine and was tested here, MA needs to know not just the number of cases they have generated, but also the identities of cases.  Knowing the identity allows public health officials to track contacts and hopefully limit spread.

From the opposite view, it is not clear to me how many cases we are counting who are Mainers with COVID-19 in other states.  Many Maine residents are currently in Florida for example.  A week ago Governor Mills advised people in other states to stay put, as the risk of encountering the virus would be higher with travel than staying in place.

As far as the numbers go, the total count of infected people in one place still matters.  If an infected person is present in a state where they did not contract the virus, it can be important for the logistics of disease management to count those people, especially if the numbers of sick people become significant. Think of it this way: if you needed to feed a certain number people at a dinner it wouldn’t matter how they got there. All that would matter would be how many plates to set and how much food to cook.  Managing a disease within a population can be the same way.  You need to know how many cases there are so that you can plan on resources like hospital beds, ICU space, ventilators, supplies, and people to care for those patients.

There is another reason to know the total number.  If you have an epidemic of an infectious disease it grows to some maximum number (the peak) before numbers of new cases start to drop off.   Consider the total number of infected cases like a number that needs to fit into a math problem.  If you know that for every person who has disease the overall size of the epidemic will expand in a certain way, then it becomes necessary to count those people.  With relatively small numbers like we are seeing now, I am hopeful that the difference is negligible.   A lot of effort in Maine is being put into predicting the growth of the epidemic and what that will mean in terms of resource and response. 

Maine CDC

At his daily media brief today Dr. Nirav Shah of the Maine CDC noted that overnight two women in their 80s passed away in the hospital.   He noted that two new pediatric patients (who are not school-aged) have been diagnosed.  One person who spent some time at the Oxford Street shelter tested positive.  Health officials are responding. 

The Maine CDC is continuing with a plan to send some samples to an outside commercial laboratory (LabCorp) as a response to the backlog of tests.  There is also an order for a new piece of equipment which should arrive in 1-2 weeks.  Once that new equipment arrives it will take several days to calibrate and integrate into the workflow.  See below for a new test.  

In terms of the mechanics of testing, Dr. Shah noted that the way these numbers are collected is that overnight the commercial laboratories and the state lab combine results.  When this occurs the PCP is contacted for more information about the patients with a positive result, including phone numbers.  The patient is contacted by the Maine CDC and is asked about every contact they have had in the last two weeks.  There is community transmission in many parts of the state. 

“What we know about disease transmission, is that it occurs in places of congregation.” 

Nirav Shah, M.D., Director of the Maine CDC

However, cell phone companies have been reporting to what extent people are straying from their homes (much lower), and traffic patterns have changed to reflect this.  It appears social distancing is occurring, and it is having a curve-flattening effect on the rate of new cases.  To be certain, number of cases is growing, but there are many factors at play.  We are not done seeing a rise in the rate of cases, and we need to take it very seriously. There is of course a concern that if numbers continue to grow we will see a large rise in the numbers before the outbreak peaks in Maine.  We don’t want to overwhelm health systems in our state. This brings us to supplies.    

Yesterday Maine received a third distribution from the federal stockpile, including 60,000 N95 masks and other PPE.  Maine CDC authorities are to soon distribute, primarily to hospitals.   

Vital resources currently in Maine

• 190 ICU beds, 90 available
• 330 ventilators, 262 available
• 89 alternative ventilators (primarily ventilators used in short term medical procedures such as surgeries that can be modified for use in COVID-19 patients)

If those numbers seem like a lot, they aren’t. The Maine CDC is asking hospitals to increase reporting, including available numbers of PPE, and other data.   “In any type of a situation, we have to know where were going, but in order to know where we are going we have to know where we are right now.”

A new COVID-19 test

In other news, Abbott labs has developed a new, FDA-approved rapid COVID-19 test which will give a positive results in 5 minutes, and a negative response in 13 minutes.  Production begins at the Scarborough facility tomorrow.  Abbott reports they will produce 50,000 tests daily, and will be working with the Trump administration in terms of distribution.

Stay Healthy at Home Mandate

Governor Janet Mills this afternoon announced “a series of substantial new mandates to protect public health and safety in the face of COVID-19, including a Stay Healthy at Home directive that requires people living in Maine to stay at home at all times unless for an essential job or an essential personal reason, such as obtaining food, medicine, health care, or other necessary purposes.” This new mandate will take effect 12:01 a.m. April 2, 2020 and will last until at least April 30, 2020 unless changed by the governor. 

In brief, essential businesses and operations that remain open will limit the number of customers in buildings at any one time, implement curb-side pickup, delivery options, and enforce U.S. CDC-recommended physical distancing requirements for their customers and employees in and around their facilities.  The mandate also prohibits the use of public transportation “unless for an essential reason or job that cannot be done from home and limiting the number of people traveling in private vehicles to persons within the immediate household unless transporting for essential activities.”  Classroom and other in-person instruction will not resume until at least May 1, 2020.  It is now mandated that when out of the home or at work at an essential business, “individuals shall maintain a minimum distance of six feet from other persons.”

Essential personal activities defined in the mandate “with relation to an individual, their family, household members, pets, or livestock” include obtaining necessary supplies for household consumption or use, medication or medical supplies, seeking medical or behavioral health, emergency services, providing care, traveling to and from an educational institution for purposes of receiving meals or instructional materials for distance learning, engaging in outdoor exercise activities, such as walking, hiking, running, or biking, “but, only in compliance with the social gathering restriction in Executive Order 14 and all applicable social distancing guidance published by the U.S. and Maine Centers for Disease Control and Prevention.”   For further details please read the mandate.

Conclusion

This is a virus, a deadly virus. For it to spread, it has to be spread from one person to the next. If we could all isolate for two weeks, it would be gone. Do your part, please stay home.

If you have a fever, new cough, shortness of breath, sore throat, or muscle aches, call your doctor’s office.  Watery diarrhea is also seen in a minority of cases, and a new loss of sense of smell or taste has been reported frequently in mild and severe cases. 

Over 80% of cases of COVID-19 are mild, but in high risk groups (people over 60, and people with serious underlying chronic diseases such as COPD, asthma, cardiovascular disease, diabetes, kidney disease, or immunocompromised state), risk of serious illness or death is higher than the general public.  

Mild symptoms

Generally speaking, for MILD symptoms, we encourage patients to monitor their own health at home.   This is in part to avoid spreading the disease, and in part to avoid overwhelming the hospitals in our state.  People with mild symptoms are not usually going to qualify for a COVID-19 screening test at this time because there are not enough tests.  Hopefully that will change soon.  Whatever the case, it is still cold and flu season also, and most tests are coming back positive. Those who come in for a test are also running the risk of exposure to the virus that causes COVID-19.

People with mild symptoms should isolate at home for 14 days as long as the symptoms remain mild (and at least three days free of fever without medications).   One should call back for medical advice if the symptoms become severe, and call ahead before going to the doctor or the emergency room.  Health workers need to know if there is a chance you might have this highly infectious disease. 

If symptoms remain mild, stay home, isolate in one room, use one bathroom that is not shared, avoid contact with others, and do not share plates or eating utensils.  Have someone else bring you groceries and medications. If you must leave the house for any reason, avoid public transportation and wear a mask. Do all that you can to avoid spreading this disease. Wherever you are, cover your mouth and nose with a tissue or your sleeve (not your hands) when coughing or sneezing.  Throw all used tissues in the trash.  Wash your hands with soap and water immediately after coughing, sneezing, or blowing you nose.  Wash hands often with soap and water for at least 20 seconds to avoid spreading virus to others.   If soap and water are not readily available, use an alcohol-based hand sanitizer that contains 60% alcohol. Always was hands if hands are visibly dirty with soap and water.  Here is one resource to go over these issues: CDC

If you are sick, stay hydrated, and get good nutrition. Please let your doctor’s office know, and ask loved ones to check on you by phone if you do not live with someone.

For people with SEVERE symptoms:

Call ahead to your local ER that you are coming in, or inform EMS of your symptoms and that you might have COVID-19.  Wear a mask immediately upon entering ER or ER registration.  If you have called EMS put on a mask prior to seeing them.

If you haven’t put your code status in writing, it is time

There is no easy way to say this.  We should all know our code status.  For the uninitiated, code status refers to whether you would want heroic measures to be taken if your heart stopped, or if you had serious problems breathing.  In other words, would you want chest compressions, possible shocks to restart or normalize your heart (cardioversion), or a tube down your throat to help you breathe (intubation), and be put on a machine (a ventilator) that would breath for you?  Many of you have thought this through and have an advance directive, POLST form, or similar document.  That is good, as long as it covers code status clearly, and it is available to EMS or the ER. 

Under Maine law, advance directive refers to any spoken or written instructions you have given about the health care you want should you become too ill to decide.  An advance directive will let others know what treatments or interventions you want, and those you do not.  Having decided these issues well before you become ill is helpful to medical personnel, helpful to you, and helpful to your loved ones by sparing them the burden of making tough end of life decisions.

In Maine, anyone 18 years of age or older may use the Maine Health Care Advance Directive Form, (click here to download the .pdf). This form can be canceled or changed at any time.  This document does not take away your rights as a patient.   Once you state your wishes in writing, please let your loved ones know what you want.  The ER and the intensive care unit (ICU) are not good places for surprises.  The key thing to medical personnel is what you want. Your doctor and local hospital should have copies too.  Most people keep the document with their code status handy, perhaps on a refrigerator door, along with a list of medications.  

In our lifetimes there has never been such a threat in our communities.   The percentage of those who experience serious illness or die is much higher in people over age 60.  About 20% of people of all ages with COVID-19 have a severe case requiring hospitalization, with about half of them winding up in an ICU.  About half of those patients wind up on a ventilator (5-10% of COVID-19 cases overall).  We can break the risk apart by age to some degree.  On March 21, 2020 I noted here in MPDN that the state of Washington that day had 1793 confirmed cases with 95 deaths (today the numbers have climbed to 4,896 cases and 195 deaths).  Deaths up to March 21 occurred as follows by age and (percentage):  60-69 (10%), 70-79 (23%), 80 and up (60%).  If a person winds up in the ICU and on a ventilator risk of dying is high, much moreso in older people.

A research letter to JAMA March 19, 2020 noted that at Evergreen Hospital in Kirkland, Washington a case series of 21 people with COVID-19 was admitted to the ICU (average age, 70 years with a range of 43-92 years).  Mechanical ventilation was used in 15 patients (71%) and acute respiratory distress syndrome (ARDS) developed in all of those patients.  As of March 17, 2020, death had occurred in 67%, and 24% of patients remained critically ill. 

In a summary of 72,314 cases from the Chinese Center for Disease Control and Prevention published in JAMA, 14% of cases were defined as severe, and 5% of cases as critical.  The case fatality rate for all ages was 2.3%, but 14.8% for patients over 80, and 8% for those 70-79 years of age.   Of note 3.8% of all cases were healthcare personnel, and 14.8% of them were classified as severe or critical.  Healthcare workers risk exposure to high inoculation of virus particles, especially while performing intubation and other invasive procedures.  All patients in this group who were listed as critical died from COVID-19. 

A study published in The Lancet Respiratory Medicine reported that of 52 critically ill patients (average age 59) at a Wuhan, China hospital 30 (81%) of 37 patients requiring mechanical ventilation had died by 28 days. The age of those patients was not given.

The point is that older people, especially those with chronic illnesses, do not have good outcomes with this disease, especially if they become critically ill.  Please consider your code status carefully. 

The following is a summary of questions I was asked by patients about COVID-19 this week. Please bear in mind that I am a neurologist.  My main concern in writing and posting this articles is to protect public health.  I hope this is helpful.  If you are not finding what you need here, try the Maine CDC COVID-19 FAQ page, or the CDC in Atlanta FAQ page.

Isn’t COVID-19 like the flu?

No, but it is easy to see why people might make the comparison.  COVID-19 and influenza are both respiratory illnesses that can be spread by droplets (coughs, sneezes, talking, dirty hands, dirty doorknobs, etc.).  However, COVID-19 is about twice as infectious as the current seasonal flu in the U.S.   

How do we know COVID-19 is more infectious than the flu?

One way to figure this out is the reproduction number, or R₀ – pronounced “R-naught.”  This basically tells us the number of people to whom an infected person will likely spread the disease.  It is a way to describe how contagious a disease is. When R₀ = 1 then and infected person will infect 1 other person. When the R₀  = 10, then an infected person will infect 10 other people, and so on.  Therefore, a lower number is better than a higher number. As we will see, it is possible to lower the number. When the R₀ is less than 1, the epidemic is likely to stop, because an infected person is unlikely to spread disease to anyone. 

The basic reproduction number of seasonal influenza is R₀= 1.3.  Thus, each infected person spreads the flu to about one other person (1.3 people, but let’s round down to keep it simple).  That person spreads it to another person, and so on.  The spread of seasonal influenza is usually person to person.  So far, the data with COVID-19 is that the R₀ = 2.2, close to twice as high: every person infected spreads it to two people, rounding down again, but it becomes person to people.   That is a real problem, because it means that if nothing stands in the way, the number of cases doubles when it spreads. Based on data from the Wuhan, China outbreak, that occurred about every week during the early stage of the epidemic. (1)  The spread might first go from 1 person, who spreads to 2 people, who spread to 2 each (4 more people), who spread to 8, and those 8 to another 16, to 32, to 64, to 128, to 256, to 512, to 1024, (keep doubling, and in ten more steps you have reached 1,048,576 new cases, and the aggregate  is about 1.5 million). However, there are even more factors that influence an “exponential growth curve.”

Wuhan, China is a city of 11 million people.  The city contains a large outdoor seafood market where the virus that causes COVID-19 is thought to have originated. There were several issues that fostered the growth of COVID-19.  It was the season of the Chinese Lunar New Year (the largest annual mass travel event worldwide).  There were huge crowds, people had come in from all over China, and all over the world.  In the City of Wuhan community spread first occurred in mid-December.   By mid-February, China reported over 77,000 cases.  However, people who traveled to Wuhan returned home, and flights left through the end of 2019 until at least the first week of March, many of them to the U.S., and bringing the virus with them. Remember that many people may not have had any symptoms during travel.  As of this am, Johns Hopkins reports there are 607,965 cases of COVID-19 affecting 177 countries.  There are 104,837 cases in the U.S. This is far worse, and far more rapid than influenza.  For a little more detail on R₀, see footnote 1.

But doesn’t the flu kill more people?

This flu season from October 1, 2019 until March 14, 2020, the CDC in Atlanta estimated 38 – 54 million flu infections in the U.S., with 400,000 – 730,000 hospitalizations, and 23,000 – 62,000 deaths.  (footnote 2)  By comparison, in the U.S. there have so far been 1,711 deaths from COVID-19. (footnote 3)  But, consider the fact that influenza had a six week lead on COVID-19.  We don’t yet know how bad this will be.  And, the case fatality rate (the number of people who will die from an illness as percentage of all those who are infected) is only about 0.1% for seasonal influenza.  In Wuhan, China the case fatality rate was 2.5% (25 times higher than seasonal influenza in the U.S.), and in most parts of the U.S. the case fatality rate appears closer to 1% (10 times higher). In some outbreaks the case fatality has been as high as 5% (50 times higher).   The bottom line is that COVID-19 is much more lethal than seasonal flu. This is why we are trying so hard to avoid it.   

Even if COVID-19 is more deadly than the flu, please make no mistake, you should get a flu vaccine every year unless there is a clear medical reason not to get one.  The numbers I have given for the flu should shock you.  We lose an average of 30,000 Americans to the flu annually (some years much worse).  You can do your part to stop the spread of the flu by getting your vaccine every year.  As I mentioned in the last post, older people should also get a pneumonia vaccine.  Stop the spread of infectious disease.  

Will this be over before Easter?

I don’t think so.  But there is reason to be hopeful that we will get this under control before summer.  All viral illnesses seem to have a “wave” during which they pass through a community or population.  Cases go up, peak, then come down.  China claims to have leveled off the rate of new cases not long after mid-February, with a current 81,996 cases.  I hope that is true.  China also claims 75,099 recovered cases.  Remember also that about 80% of cases are mild.   In the U.S., which is several weeks behind China, we are still reporting growth in the number of cases and have seen nearly 900 recoveries (among those tested).  If the wave of illness lasts about 8-9 weeks, we might see a decline in the rate of cases soon on the west coast.   However, like everything else about this, it is complicated.  It also requires social distancing to flatten the curve.  As above, this disease is very contagious.  Stay home, and avoid sick people. 

Are there parts of the country, or maybe parts of our state that will be able to go back to business soon?

It is possible.  A reasonable strategy might be to identify and isolate all cases in a community if the number is low (such as Montana).  This would mean finding all contacts of sick people and isolating them, and not allowing new cases in. The problem is that we don’t have enough tests yet to do mass screening.  So, the strategy is still social isolation.  Stay home.  

When will we have more tests?

A lot of work is being done.  I understand that vendors are coming online as fast as possible.  The most common test, the rt-PCR, requires a special reagent which is in short supply around the country.  This test checks swabs from the nasopharynx for viral RNA.  As far as I know, home test kits I have seen advertised are not yet FDA approved.   There may soon be a blood test.

Do people develop resistance to COVID-19?

We think so.  We are not yet sure, and there is not enough data to be sure.  There is data that people who have recovered produce antibodies against the virus.  Opinions around the globe are that it is likely that people will be immune to COVID-19 if they have recovered from a prior infection.  The director of Allergy and Infectious Disease at the NIH, had this to say to Trevor Noah on March 27, 2020:

“I feel really confident that if this virus acts like every other virus that we know, once you get infected, get better, clear the virus, then you’ll have immunity that will protect you against reinfection.” 

Anthony Facui, MD

Is there a vaccine?

Not yet, but people all over the world are working on it. We need a vaccine.  For more about why we need a vaccine, see footnote 4. 

Are there treatments for COVID-19?

There are currently no proven treatments.  The strategy is largely supportive at this point.  Fortunately, in the general population, 80% of cases are mild about 15% are moderate, and about 5% are severe, requiring mechanical ventilation.  As discussed in prior posts, the numbers are not the same if we break it apart by age.  Above age 60 the frequency of severe illness increases steeply.

What about hydroxychloroquine?

There has been some data to suggest it might be helpful, by making it less likely for the virus to bind to targeted cells in the lungs and GI tract.   But there is no proof that this works, or that it is even safe to take during this illness.  A drug for any condition should be tested and thoroughly vetted before use.    Hydroxychloroquine is needed for rheumatologic diseases however, and it is unethical to take drugs out of supply that are needed by other people.  Those who are selfishly attempting to take hydroxychloroquine prophylactically are doing so at a great cost to people with chronic disease.

What about ACE inhibitors and ARBs?

There is an association between angiotensin-converting enzyme 2 (ACE2) and SARS-CoV-2, the virus that causes COVID-19. (2)  ACE2 is a co-receptor for viral entry for SARS-CoV-2 (is needed to help the virus get in the cell), and it might be related to pathogenesis (the evolution of disease) of COVID-19. ACE2 is seen in the human lung, GI tract, heart, and kidney.  ACE inhibitors, which are normally prescribed to lower high blood pressure, might directly inhibit ACE2. The problem is that ACE2 is not inhibited by clinically prescribed ACEIs. (3)  And, there is concern that the use of ACEIs and ARBs (angiotensin receptor blockers) might actually increase expression of ACE2, and that might increase susceptibility to the virus.  We know from many animal and human studies that these drugs increase expression of ACE2 in the heart and brain, and there is limited evidence that the same might happen in the lungs.  Still, as we try to find something that might help COVID-19, experts have called for both the use and the cessation of ACEIs, ARBs.  The data is not there yet. 

What about antivirals?

There is no data yet. Some of the antivirals used to treat HIV look interesting, but the same can be said about safety and appropriate use here. 

What about plasma or serum from recovered people?

Data is being collected.  This is a very promising area, and a very old idea. For about a century we have used the technique of collecting antibodies from recovered patients to treat the acutely ill.  I have also read about trails harvesting specialized white blood cells from recovered people. 

  

FOOTNOTE 1: R₀ is not a fixed number.  Factors within a population such as whether vaccines are used (and to what degree), the status of nutrition in a population, whether people in a community have some resistance to this virus, or whether some other infections are going around all come to bear on how infectious something is.  That is why doctors, scientists, and epidemiologists discuss the effective R_0.   It is also why we ask you to take vaccines (see footnote 4 below).

FOOTNOTE 2:  The reason for the lack of certainty is put by the CDC as follows: “Because influenza surveillance does not capture all cases of flu that occur in the U.S., CDC provides these estimated ranges to better reflect the larger burden of influenza. These estimates are calculated based on CDC’s weekly influenza surveillance data and are preliminary.” 

FOOTNOTE 3: Sadly, the first death due to this infection in Maine occurred this week.  Worldwide, there have been 28,125 deaths due to COVID-19 as of this am, 3/28/20. 

FOOTNOTE 4: Measles is one of the most contagious infectious diseases and can cause explosive outbreaks. It has an R₀ of between 12-18 in the U.S.  The R₀ can be higher in completely susceptible populations.  Consider 1875, when measles arrived in the Fiji Islands. According to Hans Zinsser, in his excellent 1934 book Rats, Lice, and History, the King of the Fijis and his son returned home from a visit to Sydney, Australia, apparently bringing the infection back with them, and killing 40,000 people from a population of 150,000 (28% of the population).  This population was naïve to measles.  If a disease has been present for a while in a population, some immunity develops.  Those people, who have survived an infection are either not susceptible or partially susceptible.  It becomes much more complicated when most adults, but no small children are immune.  And, there are many other factors such as hygiene, nutrition, and medical care that play a role.  Such was the case with measles in the U.S. prior to the introduction of a safe and effective vaccine in 1968.  Measles used to infect 3-4 million children in the U.S., resulting in up to 500 deaths annually. (4)  There have been multiple measles outbreaks associated with unvaccinated children in the U.S. since then, though in 2019 we saw a 25 year high of over 1200 cases in 31 states.  This was fueled by the anti-vaccine movement and those claiming religious exemption. Epidemiologists calculate that we need to vaccinate 95% of kindergarteners to reach a community protection threshold adequate to protect those who are not able to be vaccinated due to medical concerns.  It is the ethical duty of all parents whose children can be vaccinated to do so in order to protect not just their own children, but those who are more vulnerable, and cannot have the vaccine. 

REFERENCES

1. Li, et al.  Early Transmission Dynamics in Wuhan, China, of Novel Coronavirus-Infected Pneumonia. NEJM 2020;382(13): 1199-1207.  
2. Zhou,  et al.  A pneumonia outbreak associated with a new coronavirus of probable bat origin.  Nature. 2020;579(7798):270-273.
3. Rice, et al.  Evaluation of angiotensin-converting enzyme (ACE), its homologue ACE2 and neprilysin in angiotensin peptide metabolism.  Biochem J. 2004;383(pt 1):45-51.
4. Kohl, K, Gelline, B. Measles as Metaphor-What Resurgence Means for the Future of Immunization.  JAMA 2020;323(10):914-915