Author: Bill Stamey, M.D.

A neurologist trained in movement disorders, Dr. Stamey has no relevant financial or nonfinancial relationships to disclose. His artistic rendering is by Emily Stamey. Maine PD News receives no outside funding. www.mainepdnews.org

Something we should all read

As the state is trying to slowly reopen I highly recommend you read “The Risks – Know Them – Avoid Them” by Erin Bromage, Ph.D.   This essay covers the risk of contracting the SARS-CoV-2 virus in various situations, and is written in clear language.  Though I have touched on many of these points in my writing, I am impressed with this collection of thoughts and information to consider before venturing out into the grocery, the restaurant, a park, work, a public restroom, or church.  These mental tools will help to protect you from COVID-19. I wish everyone would read and understand what is being said in this article by a well-credentialed expert.  Dr. Bromage is an associate professor of biology at the University of Massachusetts Dartmouth, and teaches courses in immunology and infectious disease, including one on the SARS-CoV-2 virus.  Please do yourself a favor and read this heavily circulated discussion.  At the time I referenced it today, the link had nearly 13 million views. 

PD and the risk of COVID-19

Recent publications have indicated that people with PD are not at increased risk of the complications of COVID-19 compared with others of the same age (1-3). Advanced age itself seems to be a risk factor for severe disease.  However, this week a paper was accepted for publication in the journal Movement Disorders which reports that people who have had PD for an average of 12 years or more may be more likely to become seriously ill or die after catching SARS-CoV-2 virus that causes COVID-19 (4).  The statement is based on a small case series of 10 people with PD, average age 78.  The report was written in collaboration with two European academic movement disorders centers. 

The Parkinson and Movement Disorders Unit in Padua, Italy reports a catchment of 1022 patients with PD from the province, which also had 3407 cases of COVID-19 in the general population.  Among the infected were two women with advanced PD, both nursing home residents.  One of the women was asymptomatic aside from a limited fever, and the other died from respiratory complications of COVID-19. 

The Parkinson’s Foundation Centre of Excellence at King’s College Hospital in London, UK has a catchment of 4000 PD patients, and reported eight cases of COVID-19 among that cohort: six men and two women, all with advanced disease.  Most of these patients required additional levodopa while sick with COVID-19.   Anxiety, orthostatic hypotension, cognitive impairment, and psychosis worsened during the infection.  Fatigue was the dominant complaint. Three of these patients died from COVID-19 pneumonia. 

 The authors noted that people with advanced therapies such as infusions of levodopa (the dopamine pump), or deep brain stimulation seemed to be high risk.   The risk among people with advanced disease likely relates to worse overall health condition in people who have advanced in both disease and age.  In advanced PD muscles are susceptible to rigidity (stiffness) and this can include the ones associated with breathing. At baseline some patients have trouble clearing secretions, trouble coughing, an impaired cough reflex, or shortness of breath.  When regular exercise is halted, these issues may worsen, making one less able to fight off COVID-19. 

SARS-CoV-2 is a member the coronavirus family.  In 1992 it was shown that some people with PD had antibodies to much more benign strains of coronavirus in the cerebrospinal fluid (CSF) (5), which raised the question of whether an infection might trigger or cause PD.  Some researchers have questioned whether coronaviruses might infect cells high in the nasal passage, cause the loss of the sense of smell (anosmia), and then enter the brain. SARS-CoV-2 binds to angiotensin-converting enzyme 2 (ACE2) receptors, which are present on dopamine neurons, and are reduced significantly in PD.  There has been no evidence to date of direct infection of the brain of PD patients.  

Please take precautions and avoid infection. I think the preceding paragraph is interesting, but far from anything more than associations. And, we should be careful not to draw strong conclusions on the basis of such a small case series. It seems more likely that those who have poor health (including advanced PD) generally are at higher risk of complications of COVID-19, rather than some facet of PD that makes COVID-19 more dangerous. I will monitor for any more reports of COVID-19 in the PD population worldwide.

REFERENCES

  1. Helmich RC, Bloem BR. The Impact of the COVID-19 Pandemic on Parkinson’s Disease: Hidden Sorrows and Emerging Opportunities. J Parkinsons Dis. 2020;10(2):351-354.
  2. Stoess, et al. Editorial: MOVEMENT DISORDERS IN THE WORLD OF COVID-19. Mov Disord. 2020.
  3. Papa, et al. Impact of the COVID-19 pandemic on Parkinson’s disease and movement disorders. Mov Disord. 2020
  4. Antonini, et al., Outcome of Parkinson’s Disease patients affected by COVID-19. Mov Disord. 2020, doi: 10.1002/mds.28104 
  5. Fazzini E, Fleming J, Fahn S. Cerebrospinal fluid antibodies to coronavirus in patients with Parkinson’s disease. Move Disord 1992;7(2):153-158

COVID-19 update, flattening the curve on April 27, 2020

Today the Maine CDC is reporting a total of 1023 cases since testing began on March 12, 2020.  Congregate living facilities have accounted for 26% of the total.  In Maine there have been only eight new cases since yesterday.  The current doubling rate of the epidemic is 19 days, which has improved from a doubling rate of 14 days on April 17.  The state reports 549 people have recovered from COVID-19, and there was one more death overnight, bringing the total number of deaths since testing began to 51. More than half of deaths have come from long term care facilities.  Over the last 10 days, Maine has averaged 2.2 deaths per day.

The results covered include Maine residents who met criteria for testing, but probably exclude many others who have, or have had, COVID-19 because they were never tested.  It is likely that the actual number of cases in Maine is closer to 3-4 times as many as this total.  And, it is likely that 25% are asymptomatic carriers capable of spreading disease.  During this outbreak, that would mean that roughly, about 1000 people in Maine have, or currently are infected and don’t know it. 

Among the total number of positive cases of Maine residents, 244 have been healthcare workers (24% of the total number of cases), including people who work in congregate care facilities.  

In the last ten days the daily average number of new cases in Maine has been 20 people (down from a 10-day average of 30 on 4/17/20, which was down from the prior 10-day average of 32-the peak during this epidemic so far).  As the average number of new cases has gone down, so has the number of active cases, which peaked at 446 on 4/17/20.  The total number of active cases currently is 423. 

Numbers are trending in the right direction, all the result of efforts to flatten the curve.  It has meant stopping a lot of business, changing the way people get groceries, asking people to use social distancing, wearing masks or face covers, and many other steps.  People are frustrated and want to go back to normal, to restart the economy, to at least make a paycheck. The dollar amount in stimulus from the federal government across this nation is staggering: the CARES Act for example, amounted to 2.2 trillion dollars.  There is also a fringe of our society that think this is all some sort of hoax.  It is not.

There have always been conspiracy theorists.  Now they have the internet, and a lot of mixed signals, even from the highest offices of government.  To be clear, household cleaners and disinfectants should not be taken internally unless you want to die.  Ultraviolet light inside the body can be a fast way to cause cancer.  Hydroxychloroquine is a potentially dangerous drug, and anyone telling you to try it without a medical license is committing malpractice, even if that person is the president.  There is a saying in medicine: when you don’t know what you don’t know, you’re dangerous.  

We have to be cautious.  Because we are so painfully far from adequate testing, we do not know who is an asymptomatic carrier, who is sick and does not know it yet (but is probably contagious), and who is immune.  We don’t want to reopen businesses as they were before with the likelihood of thousands of infected people in our state.  That would mean a rapid growth of the epidemic, and a much worse situation. 

Leaders in our state are trying to figure out how to slowly and safely open back up for business.   The economy might climb out of this slump, but it has to be done the right way.  Doctors are also trying to catch up on patients who have not been seen in the last several weeks. To do these things successfully we need everyone to be very COVID-19 aware.  Wear a face cover in public, wash your hands, practice social distancing, and do not touch your face unless your hands and face are clean. The virus is still here. It is dangerous and for some, deadly. And, it is not just a risk for older people, though they seem the hardest hit. All age groups have been infected, 36% of those sick enough to be tested have been under age 50 in Maine. Our numbers are small relative to many other states. Across the nation we currently stand at 985,433 cases and 55,952 deaths. The U.S. has more cases than any other country by a wide margin, over four times as many cases as Spain, the country next after us. This weekend there were reports in the Washington Post of people in their 30s having strokes due to COVID-19. Medical journals have reported many different systemic illnesses associated with this disease. It is serious. Act accordingly. Also have faith that we will get through this. I hope we are all paying attention and learning. We need leaders who understand science, who value experts, who know what they don’t know.

Note that URL links are to sites with changing data tracking the outbreak and represent data at time of this post.

Note also that if you cannot see a graphic associated with this post, it can be viewed on a desktop computer.

Are you ready to meet virtually?

As you must have noticed, medical offices and hospitals during the time of COVID-19 have postponed or canceled most non-urgent visits, tests, and procedures.  This has meant a massive backup in patient care and we have tried to reach many people by telephone.  Phones are not ideal for movement disorders, however.  It helps for us to see your tremor, dyskinesia, or what have you.  Fortunately, the Center for Medicare and Medicaid Services has approved virtual appointments with video.  This means that if you have a smart phone, tablet, laptop, or a computer with a camera, you can probably have a virtual office visit with your healthcare provider from own home. 

I am not sure what platform every office in the state is using.  MaineHealth (including my practice recently) is using Zoom, an app (application) that you can download onto your device.  I am sure many of you are familiar with this, as it is being used all over the country for other types of virtual meetings (offices, families, and so on). I understand that some Parkinson’s support groups are even meeting by Zoom.  If you are not familiar with this app, it is free (on the end user side) and very easy to download.  On iphones visit the App Store, on Android phones visit the Play Store, and if using a desktop computer go to https://zoom.us/download   to download the software.

We are not sure when we will be back to normal office scheduling, and there is still a risk of contracting the SARS-CoV-2 virus that causes COVID-19 in our state, especially when people congregate.   In order to avoid a second wave of cases we are planning on trying to gradually reintroduce safe office encounters, but it is going to come along in stages, and there may be a long delay.  One thing we want to avoid at my office right now is a group larger than ten people, or a failure of social distancing, which would occur if all five doctors starting booking full appointment days in the clinic again. A video “telehealth” appointment is a good way to see your provider for now without that risk.  And, that technology is likely here to stay.  The genie is out of the bottle, so to speak. Further, becoming comfortable with this software would mean that you too could visit love ones with the computer or your phone.  So, put aside your computer discomfort, embrace the future, and get ready to meet virtually. 

COVID-19 update: flattening the curve by the numbers

Yesterday in Maine the total number of confirmed COVID-19 cases as counted since the beginning of testing on March 12th had risen to 796.  Healthcare workers in Maine represented 173 of these cases (22%). Per the Maine CDC 333 Mainers had recovered, and unfortunately, the death count had risen to 27.  Thus, the total number of Maine residents with confirmed active COVID-19 infections was 436, down 5 cases from the day prior.  The overall trend in active cases however, had been otherwise steadily increasing since testing began. 

On April 5 I wrote that on that the total number of confirmed cases had tripled over the prior 10 days. I wondered what the next 10 days would look like, and was hopeful that additional restrictions put in place by the governor would help prevent us from having a rapid exponential rise during an upcoming week, predicted by Dr. Anthony Fauci of the NIH and Surgeon General Jerome Adams to be very bad week in our country.  When the doubling time of an epidemic begins to shrink, the total number of cases rises rapidly (as in New York City, for example). 

Consider this example of very rapid exponential growth.  If you have 1 case, but the number of cases doubles every day, then that number will increase as follows from the first to the last day of the month:  1, 2, 4, 8, 16, 32, 64, 128, 256, 512, 1024, 2048, 4096, 8192, 16,384, 32,768, 65,536, 131,072, 262,144, 524,288, 1,048,576, 2,097,152, 4,194,304, 8,388,608, 16,777,216, 33,554,432, 67,108,864, 134,217,728, 268,435,456, 536,870,912.

We don’t have that many people in our country, let alone our state, but I hope you get the message.  Rapid exponential growth rates are scary in epidemics.   If we had a steady doubling time of even 10 days, then a month from now the total number of confirmed cases would grow to 796 to 6,368.   The current doubling time of the total number confirmed cases in Maine is about 2 weeks.  This is manageable currently, and a reason for optimism, but if we hold at that number, it would still mean that in a month the total number of confirmed cases would rise to 3,184.  I doubt that will happen because the doubling time is getting longer instead of shorter, and the average number of daily cases over the last few weeks has been much more consistent (instead of growing).

To go back to my April 5 post, and the question I posed, in Maine from April 5 to the 15th the number of cases grew from 470 to 770, a growth not of 3 times as many cases as we had seen in the prior 10 days, but 1.6 times as many, a good sign.  The rate of increase was actually slightly slower over the period leading to the 15th than it had been for the prior 10 days.  One simple way to see this is to compare the daily number of cases.   During the 10 days leading up to April 5, the number of new cases averaged 32.6 daily. Over the next ten days the number of new cases rose by an average of 30 daily.   If we hold at an average of 30 cases daily then we can expect 300 new cases every 10 days.   In one month we would increase to 1696 cases.  We are hopeful in Maine however, that we may be approaching a peak and we might see the numbers of new cases dropping.  I am hopeful we will see stability in the numbers of cases at congregate living facilities, which have seen an increase in the past week.  The numbers outside of those facilities have actually looked better.

The avoidance of a rapid expansion is no doubt helped a great deal by social distancing, executive orders by the governor, strong leadership at the Maine CDC, and the tireless effort of healthcare workers across the state.  Maine Responds volunteers have grown rapidly in numbers, and a variety of strategies have been used to triage testing-given that there is still such a short supply. To paraphrase Maine CDC Director Dr. Nirav Shah in his daily COVID-19 briefing yesterday afternoon, all of these efforts have raised the line above which the health system would have been overwhelmed: in other words, in addition to flattening the curve, we are raising the bar.  Good job Maine.     

This is not to say any of this is easy, or that it is not hurting people and businesses.  There have been many changes.  Over the last week and a half Mainers have had to stand in lines to get into grocery stores, and U.S. citizens have been asked to wear cloth face covers in public, to mention a couple of the changes. These, and other steps were put in place to slow the spread of the SARS-CoV-2 virus so that health systems would not be overwhelmed, and so that Maine people would all be protected.

Due to these efforts, and numbers discussed above, the Institute for Health Metrics and Evaluation (IHME) modeling has downgraded the severity of projections for Maine, and is now forecasting a total number of deaths at 63, rather than the 364 projected a week and a half ago. Any reduction in that number is a very good thing. Projected resource demands have dropped also, and per the IHME we should have passed our peak a few days ago. If we keep at it, we may scrape through, but still need to tread carefully.

Reopening businesses and relaxing restrictions can be dangerous.  We can estimate that the number of people we have confirmed with tests represents about 20-25% of all infections.  It is also estimated that  another 25% are asymptomatic carriers capable of spreading disease.  Since we do not have widespread testing yet, we don’t know who is a carrier, who has immunity, and who is on the way to getting sick.  We do not yet have a reliable treatment, a cure, or a vaccine.   We need to find a way through this without suffering the devastation seen in other parts of the country. 

The U.S. leads the world in confirmed cases (671,425)  by a wide margin, representing about a third of the over 2 million cases worldwide, and 3.5 times the number of cases in Spain, which is the next country after us.  To see a graphic of the top several countries by cases, and to get a sense of the unfortunate lead the U.S. has over other countries, Bangor Daily News has been keeping a lot of data, and updating daily.

We are not out of the woods, and we do not know what the coming months will look like. We have reason to be grateful in Maine because through leadership and clear communication in medicine, public health, and government, we have been able to work together and make the best of a bad situation.

Note, if you cannot see a graphic at the top of this article on a handheld device, please view the article on a computer.

All URLs verified at time of publishing. Remember that these sites are changing and updating numbers, thus may not reflect the same values I have listed if viewed at another time.

What about a COVID-19 vaccine?

Labs around the world are trying to develop a vaccine to stop the rapidly spreading novel coronavirus that causes COVID-19 (coronavirus infectious disease 2019), because this potentially deadly virus is unknown to the human immune system, making us completely vulnerable.   As of the writing of this post on April 10, 2020, the Johns Hopkins University of Medicine Coronavirus Resource Center indicates 1,619,495 cases of COVID-19 worldwide, along with 97,200 deaths.  Also as of today, in the U.S. there have been 466,396 cases (doubling in the last 10 days), and 16,703 deaths.    It is a serious pandemic, and we still do not know how this will end.

Know thine enemy

Coronaviruses were detected in the 1960s, and were probably around a long time before that.  This family of viruses can infect people and/or animals, and may cause epidemics of community-acquired upper respiratory tract infections (URI), or sometimes diarrhea.  The coronavirus subfamily can be divided into four genera: alpha, beta, gamma, and delta.  The human coronavirus (HCoV) genera taught when I attended medical school were the alpha coronaviruses (HCoV-229E and HCoV-NL63) and beta coronaviruses (HCoV-HKU1, HCoV-OC43). 

Until 2002 coronaviruses were thought of as generally benign.  Consider the quote from the 1996 Medical Virology textbook I still have, which described the typical coronavirus infection this way: “The illness lasts about a week and is of no real consequence.” It was known back then that coronaviruses tended to cause colds mainly in the winter and early spring.  In human volunteers whose nasal passages were swabbed with these viruses,incubation took 2-5 days, and in about half symptoms would develop, and virus would be shed for about a week. (1) Prior to 2002 it was thought that infection with the “benign” human coronaviruses would result in a form of immunity to reinfection, but that this would last only 2-3 years.  Thus, people would be reinfected every few years.    

Starting in 2002 the beta genera of coronaviruses were joined by new deadly members. 

SARS was caused by SARS-CoV (severe acute respiratory syndrome coronavirus), which began November 2002 in China, and by 2003 was responsible for the infection of 8098 people, and claimed 774 lives.  There was a massive containment strategy in the east, (and in the few cases that made it to the U.S.).  SARS seemed to have vanished from the human population since 2003.  

MERS was and is caused by MERS-CoV (Middle East respiratory syndrome coronavirus), and erupted in the Arabian Peninsula in 2012.  Though the initial outbreak was contained, the virus has since been endemic to camels, occasionally infecting humans (zoonotic transmission), and these “super-seeders” then spread the disease in local outbreaks.  From 2012 – November 2019 MERS has caused 2494 cases, and claimed 858 lives. 

The virus that causes COVID-19 is a type of coronavirus called SARS-CoV-2 (severe acute respiratory syndrome coronavirus-2).  It is the newest member of the coronavirus family, and is thought to have jumped from a species of bat (likely sold in a seafood market in Wuhan City, China), to the human species.   As yet there is only one serotype of SARS-CoV-2 reported in the literature.  

Serotypes are groups within a single species of microorganisms, such as viruses, which share distinctive surface structures.  These surface structures are usually proteins or glycoproteins that the virus uses to infect certain cell types in the body. Think of them like keys that fit into certain locks.  These proteins are important, because the human immune system also recognizes them. They tend to be very specific to the virus only.  If your immune system encounters some of these proteins, it knows they do not belong, and therefore the virus particles are invaders.  In the case of people who have survived an infection, the immune system has targeted these structures, usually by making antibodies.  Antibodies, as discussed in the last post, are part of our defense against viruses.  Direct infection and recovery seems to be the most effective way to gain immunity against an infection, but in the case of COVID-19, the risk associated with having an infection is high.  It would be better to have a vaccine.

How do vaccines work?

In the case of a virus with a single serotype, all of those viruses are essentially identical.  When infected with the virus, the immune system makes antibodies against that serotype, remembers that target, and therefore creates immunity. When there is more than one serotype, surface structures vary: one way for a virus to evade detection. 

In terms of vaccine production, having a single serotype is a good thing.  SARS-CoV-2 appears to only have one serotype.  A modern approach is to put the protein of interest in a vaccine.  Researchers often use the spike protein, which is what allows the virus to enter the cell it infects.  If you can inject that protein the immune system may make antibodies that block the spike protein on the virus of interest. Thus, the virus cannot infect the cell, and the vaccinated person will be protected. This is the basis of the hepatitis B virus (HBV) and the human papillomavirus (HPV) vaccines.  With the HPV vaccine the protein is made in a yeast cell (via genetic engineering), and is identical to the protein on the surface of the virus-pretty clever.   There are a variety of strategies that can be used to induce an immune response against a certain viral glycoprotein.  

Vector vaccines (the basis of the dengue and Ebola vaccines) use a harmless virus such as an adenovirus, which is altered in the lab to contain a gene that codes for a surface protein such as the spike protein.   The vector vaccine cannot replicate, but for a short time causes expression of the protein and thus, the immune response.

RNA vaccines are faster and cheaper to produce, and safer than traditional vaccines.  RNA vaccines take advantage of a process that cells already use.  Under normal circumstances cells use their own DNA as a template to make messenger RNA (mRNA) molecules, which are then translated to build proteins. An RNA vaccine contains a  mRNA strand that codes for a disease-specific molecule, such as a spike protein.  Once inside the body’s cells, the viral protein will be made, placed on the surface of a cell, and recognized as foreign by the immune system.  This will cause an immune response.    

There are DNA vaccines as well.   The problem is in selecting the right protein or glycoprotein target.  The spike protein may be an excellent and effective target, which will usually produce neutralizing antibodies.  Sometimes the wrong protein is chosen and a binding antibody is made, which may be ineffective, or even harmful. This is why animal models are needed, and why research and development is so slow.

Historically, it has taken an average of 10 years for a vaccine to go from development to use. (3) However, the U.S. Department of Health and Human Services took steps on March 30 to speed up development and manufacturing of vaccines to prevent COVID-19. And, the World Health Organization has developed a blueprint for disease models in lab animals.

The Coalition for Epidemic Preparedness Innovation (CEPI) is an international nongovernmental organization funded by the Wellcome Trust, the Bill and Melinda Gates Foundation, the European Commission, and eight countries (Australia, Belgium, Canada, Ethiopia, Germany, Japan, Norway, and the United Kingdom). CEPI supports development of vaccines against five epidemic pathogens on the World Health Organization (WHO) priority list, including COVID-19.

The genetic sequence of SARS-CoV-2 was published January 11, 2020, by Chinese scientists. In what must be record speed, the first COVID-19 vaccine candidate started human trials March 16, 2020. As of this week there are 115 vaccine candidates across 19 countries, and the U.S. leads with 46%. (2) In clinical development are:

Moderna began clinical testing of its mRNA-based vaccine in mid-March. The plan was to enroll 45 healthy adult volunteers in Seattle, Washington age 18 to 55. 

There are other licensed vaccines based on recombinant proteins and existing large-scale production capacity already in place for those vaccines. It might possible to scale up production for a similar SARS-CoV-2 vaccine quickly. Most of the candidates seem to induce neutralizing antibodies against the viral spike protein, which would prevent viral uptake by the human ACE2 receptor.

CanSino has moved its trial into phase II with 500 people as of today, after only three weeks in phase I with 108 healthy volunteers in the city of Wuhan.

Conclusion

These are just a few thoughts about vaccines. This is not an area in which I work, but one which is of course very interesting to all of us. I’m sure there will be a lot to come, and I hope the vaccine trials are successful and safe for those human volunteers, who have my deep admiration.

REFERENCES

  1. Wege, et al. The biology and pathogenesis of coronaviruses. Curr Top Microbiol Immunol. 1982;99:165-200.
  2. Le, et al, The COVID-19 vaccine development landscape. Nature Reviews Drug Discovery. doi: 10.1038/d41573-020-00073-5 https://www.nature.com/articles/d41573-020-00073-5
  3. Pronker, et al. Risk in Vaccine Research and Development Quantified. PLOS ONE https://doi.org/10.1371/journal.pone.0057755

Convalescent serum for COVID-19

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 20th 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.

When will the curve reach a peak in Maine?

That is something we would like to know on the medicine/public health side so that we can plan how to respond with vital resources and people to care for patients.  It would also give most of us a sense of relief to know that there is an end to this crisis here in Maine, and around the world.

To figure out when an epidemic with peak, we have to consider multiple factors.  There were early reports from China that wave of COVID-19 peaked at about 8-9 weeks. If that is true, it may have been due to excessive containment strategies, rather than a natural cycle of the outbreak. South Korea also was able to control the outbreak through a concerted effort to test huge numbers of people, track down contacts, isolate, quarantine, and the society was engaged in the ethos and practice of social distancing. It is less clear around the world whether the same period of time will occur, though according to news reports it appears Italy may be in a plateau, with a stable number of new cases over the last few days. I don’t think the duration of the outbreak is a universal number, though with infectious disease epidemics we often do see periods of time which seem to be the “season” for that disease, such as the range of time we see seasonal influenza. The SARS-CoV-2 virus that causes COVID-19 is a novel virus, and it spreads rapidly in populations. There are many unanswered questions about this pandemic.

One simple place to start in trying to determine the time a wave of a new epidemic will take is with the incubation period (the time from exposure to illness).  We know the incubation period is between 2 and 14 days, and the average time that symptoms develop in those affected is 5 days.  Using just this, we should be able to estimate that effective flattening of the curve would take up to two weeks to occur (if as many people as possible are social distancing, for example).  In other words, if we were able to completely separate all of the people in our state, it would take two weeks to see no new cases.  A virus needs a host to spread, and can’t do that if there is no one else around.  The problem is that complete isolation is not possible.

Complicating matters, there are many other factors at play, such as the stability of the population size.  Many cases of COVID-19 have been associated with travel, and we are seeing an influx of non-residents and residents coming back from out of state locations (more below). Although on March 16 educational facilities closed, and on March 25 non-essential services closed, essential workers are still in contact with people, in some cases, a lot of people.   Other factors include resources, the ability of health systems to withstand a surge of patients, what the size of that surge might be, and whether the percentage of healthcare workers who become ill is stable (17% of cases overall as of 4/3/20 when it was reported last), to name a few. 

There are many people in our state who are trying to model the pandemic within our regional outbreak.  You can be certain that every hospital system is trying to do this.  Dr. Nirav Shah, Director of the Maine CDC has said during his daily briefings recently that they are tracking various models, though none should be treated as completely predictive. 

“The modeling tools are only as good as the assumptions we put in, and then on the other side, how well Maine people follow those assumptions.”   

Nirav Shah, M.D.

The Institute for Health Metrics and Evaluation (IHME), part of the University of Washington, and the recent recipient of a 10-year, $279-million investment by the Bill & Melinda Gates Foundation, is tracking the COVID-19 outbreak across the U.S. and making models of how the outbreaks are projected to increase and peak in every state.  April 1, 2020 the IHME reportedly projected that Maine’s health care system might become overwhelmed by April 25, based on the concurrent trajectory of the outbreak, and social distancing and business restrictions in place at the time.  April 2 Governor Janet Mills’ Stay Healthy at Home mandate took effect.  There was however, much public concern about the influx of people coming in from out of state, including from hot spots such as the state of New York, the current epicenter of the epidemic in the U.S.  

A common facet in the history of epidemics is that those in the center of an outbreak flee.   However, this invariably spreads the epidemic while exhausting resources. Another commonality is a less than welcoming response by those in the receiving territory. 

On April 3 Governor Mills issued an Executive Order Mandating Quarantine Restrictions on Travelers Arriving in Maine to Protect Public Health and Safety which required that travelers arriving in Maine, regardless of state of residency, self-quarantine for 14 days.

“The Order directs the Maine Department of Transportation, the Maine Turnpike Authority, and others to post this guidance at all major points of entry into the State, exempts individuals who are providing essential services as defined by Governor Mills’ March 24 Executive Order.” 

Mills further instructed visitors not to travel to Maine if they are displaying symptoms of COVID-19 and advised them not to travel to Maine if they are traveling from cities or regions identified as COVID-19 hot spots. 

“To deter travel, the Order also suspends lodging operations, including hotels, motels, bed and breakfasts, inns, and short-term rentals such as those available through VRBO Airbnb, RV parks and campgrounds, and all public and private camping facilities as well as online reservations effective April 5, 2020 at 12:00 p.m.” 

There are some exceptions, such as vulnerable populations: children in emergency placements, persons at risk of domestic violence, and homeless individuals as permitted by the state, accommodations for health care workers, or other workers deemed necessary to support public health, public safety, or critical infrastructure.

The IHME projections for Maine as of 4/3/20 indicated hospitals would hit peak resource usage on 4/17/20, involving 1,179 beds (118 more than available), and 179 ICU beds (with a shortfall predicted).  Per Dr. Shah as of 4/3/20 at his weekday press briefing, there are 272 ICU beds in the state, but availability is a number which changes daily, based on more than just COVID-19 (we still have seasonal influenza, community acquired pneumonia, and many patients with chronic lung diseases in Maine).  IHME predicted we would need 143 ventilators for COVID-19 patients at peak.  Dr. Shah reported we have about 348 ventilators in the state, along with just under 200 “alternative” ventilators designed for medical procedures such as surgery.  IHME projects that by 4/15/20 deaths related to COVID-19 will peak at 12 per day in Maine.  Sadly, it is projected that by June we will see a total of 364 deaths due to this epidemic in our state.  That number appears to be flat through August.  That is of course, with assumption of only be one wave of this outbreak. 

While these numbers are frightening, they pale in comparison to some other parts of our country. In the U.S. 9,458 people have died from COVID-19, and over a third of the 331,234 cases in the U.S. as of this writing, are in New York. Over 60% of the states have case numbers in the thousands. New Jersey has over 37,000 cases, and several states have over 10,000. There are only 7 states in the continental U.S. with fewer cases than Maine: Nebraska, West Virginia, Montana, South Dakota, North Dakota, Wyoming, and Alaska, (in that order). We have fared better as a group of less densely populated states. Maine has the willingness of Mainers to pitch in to the effort. We need everyone on board with that effort.

We have still seen an unacceptable number of cases and should have had more testing a long time ago. The entire country is in that position. I will say again that we don’t really know how many people are sick. We, like the majority of the country are only able to test people who meet a narrow set of criteria. Many people have been, or still are sick at home with what is probably COVID-19, but have not qualified for testing. The CDC states that probably 25% of all of those infected are asymptomatic, but capable of spreading disease. It is imperative that we markedly increase testing.

Today in Maine there are 470 cases of confirmed COVID-19, and 86 people have been hospitalized.  There have been 10 deaths since the start of the outbreak, and all but one county, Piscataquis, have had cases. It is not time to relax. We could still overwhelm our hospitals. Take a close look at the graph. The number of cases has more than tripled in the last 10 days. What might that look like in 10 more days? We must flatten the curve. If we approached this pandemic the way experts have recommended, we could crush the curve.

Though our nation has the highest number of cases in the world, this is going to get better. On the other side of the peak is a downslope. We just need to continue to stay home, practice social distancing, wear cloth masks in public, wash our hands, to not touch our faces, and to help each other get through this. We are going to have to flexible, and we will likely come out of this a changed nation. May we all learn from this. May we be better prepared in the future. May we never allow our government to weaken the CDC and our defenses against infectious disease again. May we again learn to let the experts in science and medicine do their jobs. We are better and smarter than this.

Making cloth face coverings, instructions from the CDC

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.

CDC recommends wearing a cloth face cover in public

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.