Sheldon H. Preskorn, MD

 written to help psychiatrists and other health care providers better understand the range of severity of illness that the coronavirus disease 2019 (COVID-19) virus can cause so that they can better explain the facts (as we know them today) to their patients and their families.

The mortality rate reported for COVID-19 has declined since the earliest days of the pandemic. This is partly due to better knowledge about the infection and better protocols that have been developed to treat the more serious forms of the illness. However, arguably the greatest decline in mortality rates is the result of being better able to identify who has been infected with the virus. This increase in identification of infections has increased the size of the denominator, while the numerator has remained relatively unchanged.

Equation 1. Calculation of mortality rate

“Cases” refers to individuals who have been infected with the Sudden Acute Respiratory Syndrome Coronavirus 2 (SARS CoV-2).

The calculation of the mortality rate is illustrated in 

, cases of COVID-19 initially were determined by the number of individuals who sought medical attention because of fever, cough, respiratory distress, or other flu-like symptoms and had no other potential causes for these symptoms including not having the seasonal influenza.

 Thus, it was a symptomatic diagnosis, just as it the case with most psychiatric diagnoses. Using this definition of a case, the denominator was smaller than the actual number infected, with the degree of underestimation being a function of how many individuals were infected but either were asymptomatic, did not have sufficient symptoms to seek medical attention, or for some other reason did not seek out care. The degree of underestimation would result in proportional overestimation of the mortality rate based on the 

Case example: A floating, unintentional laboratory experiment

Cruise ships can function as naturalistic research experiments with more controls than is true in clinical practice. The following summary, based on the original report published by 

, details such an example. In May 2020, a trio of Australian physicians and health researchers who traveled on an expeditionary cruise to the Antarctic Peninsula published a report about their experiences in the medical journal 

. Two of the authors, Alvin J. Ing, MBBS (Hons 1 Syd), MD FRACP, and Christine Cocks, were passengers on the cruise, and Jeffrey Green, MD, was a ship physician for this expedition.

In mid-March, the ship departed Ushuaia, Argentina, for a planned 21-day cruise of the Antarctic Peninsula to explore a route similar to the one taken by British explorer Ernest Shackleton in 1915-1917.

No one was allowed on board who had transited through then known hot spots (eg, China, Macau, Hong Kong, Taiwan, Japan, South Korea, or Iran) in the 3 weeks preceding the cruise.

 = 217) were screened for COVID-19 symptoms and body temperature as a condition of boarding.

Multiple hand hygiene stations were positioned throughout the ship, especially in the dining area.

Everyone had daily temperatures taken, which were reviewed by the ship’s 2 physicians.

The first recorded fever occurred in a passenger on day 8.

Isolation protocols were immediately initiated after this discovery. All passengers were confined to their cabins and all were issued surgical masks.

Full personal protective equipment was used for contact with any febrile patients, and N95 masks were worn for any contact between the ship staff and passengers.

By day 14, 5 additional passengers and 4 crew members developed fever, mild cough, and lethargy.

On day 17, one of these passengers, a 68-year-old man who had been a lifelong nonsmoker and had no comorbid medical conditions, deteriorated and required urgent evacuation to a hospital.

Subsequently, 7 additional passengers required medical evacuation: a 70-year-old woman with chronic obstructive pulmonary disease on day 20; a 65-year-old woman with no known comorbid conditions and 2 crew members on day 21; a 68-year-old male (after 15 days of cabin isolation) on day 24, and one of the two ship physicians on day 27.

All the evacuated patients tested positive using reverse transcription polymerase chain reaction (RT-PCR) tests to detect SARS CoV-2 RNA in respiratory specimens.

On Day 20, all 217 individuals onboard were tested with RT-PCR;

128 (59%) tested positive for SARS CoV-2. Of those that tested negative for SARS CoV-19, some were later found to have SARS CoV2 antibodies indicating prior infection.

Of the individuals who tested positive, 104 individuals (81%) were asymptomatic at the time of testing. The other individuals who tested positive (about 1 out of 5) were symptomatic at the time of testing. Of those 24 symptomatic individuals, 16 (two-thirds of the group) had only fever and mild symptoms, while 8 (one-third of the group) had to be medically evacuated. Four of those individuals required intubation and ventilation, and 1 of them died (mortality rate = 0.8% based on 1/128). He was a 50-year-old crew member with no known comorbid medical illness (personal communication, Ing 2020).

: When a population is small (as was true for this cruise ship with about 100 positive individuals), the confidence interval for a rare adverse event (ie, death, which was < 1 out of 100) is large. In such instances, a general rule for estimating the 95% confidence interval is that the upper and lower boundaries would be 3 times higher and 3 times lower, respectively, compared to what was observed. Hence, the estimate of the 95% confidence interval for the mortality rate in this case would be between 2.4% and 0.27% (ie, 0.8% multiplied by and divided by 3, respectively).

Difference in mortality rates based on symptoms versus on the total infected

In the example of the cruise ship, the mortality rate would have been calculated as 4% when the presence of symptoms was required to define a case (ie, 1 death among 24 symptomatic individuals) versus 0.8% when laboratory evidence of infection was sufficient to define a case (1 death among 128 infected cases). The result is a 5-fold difference in the calculated mortality rate depending on whether it was calculated based on symptomatic cases versus all infected cases.

The difference in practice would likely be even greater because mildly symptomatic cases may be missed in clinical practice because asymptomatic patients may not present for medical attention or because their symptoms might be attributed to a common cold or a mild flu-like syndrome. The number of infected individuals on the ship may also have been underestimated, since all 89 individuals who tested negative for actively shedding virus did not have antibody testing. It is possible that some of those who tested negative for actively shedding the virus may have been infected but the virus had already been cleared via an immune response before testing.

While the availability of reliable and valid laboratory tests is a great advance over the early symptomatic-based diagnosis (readers may want to think about the implications for symptomatic diagnosis in psychiatry), the tests can only determine if an individual is actively shedding virus. Obviously, a negative test does not tell us whether the individual will become infected in the future (even within an hour of having the test done) nor does it tell us if the individual has already been infected and has mounted a sufficient immune response to have eradicated the virus. (The first column in this series1 discussed this issue in more detail, along with the need for other reliable and valid tests to identify a history of an eradicated infection that will hopefully convey immunity against the virus—perhaps lifelong as with measles or perhaps much shorter as with seasonal influenza.)

The number of participants in this naturalistic experiment was small, which means that the 95% confidence interval for a mortality rate of 0.8% would be large as previously discussed. However, this caveat does not change the basic observation that the initial mortality rate, by virtue of being based on symptomatic cases, would be several times higher than the true mortality rate with a virus such as SARS CoV-2 because it can produce many mild and even asymptomatic cases.

The mortality rate observed on this ship is consistent with rates observed in the low-risk population discussed in the 

 This population has a low risk of developing an illness that requires hospitalization (

) and a low risk of death (below 1% but nevertheless not zero; 

) from infection with the SARS CoV-2 virus. In contrast, nearly 35% of those who die will be 85 years of age or older. The individuals younger than 85 who die will most likely have comorbid medical illnesses (

For these reasons, it is extremely important to protect high-risk populations via social distancing, the use of masks, and limited contact with anyone nonessential to the health and well-being of these individuals. The experience from this cruise ship also illustrates 2 important factors to consider when endeavoring to protect the vulnerable population. First, there is long incubation period between infection and the development of symptoms (8 days or more). Second, a high number of individuals who are infected are not symptomatic (more than 80% in the case of the experience on this ship).

The media can inform the population, but they can also hype topics to increase audience ratings to drive their revenue as has clearly been the case with COVID-19 reporting (in the author’s opinion). The most recent, egregious example is the focus on increasing numbers of cases, which is directly relevant to the discussion in this series of columns. What the media has not adequately explained (in the author’s opinion) is the nuanced understanding that a rising number of cases may not necessarily be bad but rather could be a positive development—if the cases occur in the low-risk and not the high-risk population and morbidity and mortality remain low. As explained in the second column in this series

 a higher number of low-risk cases could bring us closer to the number needed to achieve community (ie, “herd”) immunity.

Achieving such immunity is an important consideration because a reliable, safe, and effective vaccine has not been developed.While there is hope that a safe and effective vaccine may be available by late this year or early next year, the historical track record suggests it may be years before one is successfully produced for the world population. The reasons for caution relative to vaccines involve many facets, and a full discussion of this issue is beyond the scope of this column. One reason for caution is that vaccines may promote an antibody response that may alone be sufficient to prevent the illness, but it may be that a T cell (lymphocyte) response is also necessary to prevent the illness and that such a response may not occur with some vaccines. In addition, people have to be willing to receive the vaccine. Meanwhile, a recent 

found that 49% of Americans reported that they would be agreeable to vaccination against COVID-19 if such a vaccine becomes available, but 31% were not sure and 20% said they would not be vaccinated.

 Of course, these responses may change as the public becomes more familiar with the illness and more is known about the efficacy and safety of any vaccine.

With that said, there are several important concerns about a strategy of letting the virus propagate through the low-risk population while protecting the vulnerable population. First is the question of how feasible it will be to accomplish this dual goal. For example, grandparents want to see their grandchildren, but the grandchildren may be asymptomatic even though they are shedding the virus. Protecting the vulnerable populations will also be difficult if the current problem of compliance with wearing masks to decrease the spread of the virus in the United States continues.

Second, a small percentage of the low-risk population may be at risk for serious infections, and even death, for reasons that have not yet been identified, or at least not in the public domain. The mortality rate in what should be low-risk individuals is perhaps between 0.01% and 0.1% (

). However, the problem is that those numbers are so small that the 95% confidence intervals will be large, as previously discussed, so that it is difficult to calculate the rate with certainty.

While a difference between 0.01% and 0.1% may seem small, the issue is what such numbers mean in large populations. For example, a major issue is how to re-open schools. There are 72.7 million children 0 to 17 years of age in the United States (www.childstats.gov/americaschilrden/tables/tables/pop1/asp). If the mortality rate in this population is within the noted range, that would translate to between 7270 and 72,700 deaths of children 0 to 17 years of age (ie, the difference between a risk of 0.01% versus 0.1%).

Given these estimates, one must ask: What risk is acceptable (and to whom) to achieve community immunity and save more individuals in the higher risk groups? Or, should that even be a consideration? How does one balance risk when it comes to lives of young healthy individuals versus older and/or unhealthy individuals? These are the type of calculated decisions that Americans have not faced since perhaps World War II. Parenthetically, this discussion illustrates how important it is to know the mortality rate and provides a quite crude example of the type of mathematical modelling of a pandemic that is driving governmental decisions. Currently, it appears that every citizen is free to make these decisions (eg, to wear a mask or not) based on their understanding of the illness and their sense of community responsibility (because wearing a mask protects others more than the life of the person wearing the mask).

Third, little is known about whether and how long immunity lasts after a person has been infected and recovered (again highlighting the problems posed by a novel human pathogenic virus). The assumption is that immunity has occurred with recovery but even that remains to be proven. Beyond that, there is the potential problem that the virus may be able to mutate to overcome immunity. It should be kept in mind that all these caveats also apply to the development of a vaccine. Life is not always straightforward.

Finally, there is little known about whether there are after-effects of viral infection, such as shingles with herpes zoster. What has been established is that the virus can cause damage to other organs beyond the lungs in some (probably small) fraction of those infected. The virus attacks the circulatory system and, hence, can affect any organ in the body even though it probably does so relatively rarely.

The ship’s experience illustrates how difficult it is to stop the spread of the SARS CoV-2 virus unless social distancing and masks are used, especially since people can be are infectious long before they become symptomatic. In the case of the Antarctica cruise ship, SARS CoV-2 spread to the majority of the passengers and crew, even though the passengers were sheltering in their cabins and wearing masks as soon as the first individual developed symptoms.

This article was originally published in the 

and has been adapted here with permission from Lippincott Williams & Wilkins. The original version can be found online at www.psychiatricpractice.com.

s professor in the department of Psychiatry and Behavioral Sciences. The author notes that he has received grants/research support from or has served as a consultant, on the advisory board, or on the speaker’s bureau for Alkermes, BioXcel, Eisai, Janssen, National Institute of Mental Health, Sunovion, and Usona Institute. All clinical trial and study contracts were with and payments made to The University of Kansas Medical Center Research Institute, a research institute affiliated with The University of Kansas School of Medicine-Wichita.

1. Preskorn SH. Coronavirus disease 2019: The first wave and beyond. 

April 28, 2020. Accessed August 3, 2020. 

https://www.psychiatrictimes.com/view/coronavirus-disease-2019-first-wave-and-beyond

COVID-19: Protecting the Vulnerable and Opening the Economy

3. Ing AJ, Cocks C, Green JP. COVID-19: in the footsteps of Ernest Shackleton. Thorax. 2020;75:693-694. May 27, 2020. Accessed August 3, 2020. 

https://thorax.bmj.com/content/thoraxjnl/75/8/693.full.pdf

4. Neergaard L, Fingerhut H. AP-NORC poll: Half of Americans would get a COVID-19 vaccine. ABC News. May 27, 2020. Accessed August 3, 2020.

https://abcnews.go.com/Health/wireStory/ap-norc-poll-half-americans-covid-19-vaccine-70897024

5. Gupta A. Madhavan MV, Sehgal K, et al. Extrapulmonary manifestations of COVID-19. 

 2020;26:1017-1032. Accessed August 3, 2020. 

https://www.nature.com/articles/s41591-020-0968-3.pd

Articles

New data and an intriguing case example suggest the mortality rate may be decreasing. What does this mean for the days ahead? 

COVID-19: Has the Mortality Rate Declined?

What data are currently available about COVID-19 and how can they inform decisions? How successful are the strategies employed to date? How can we minimize damage from the pandemic? In this video, we learn about those concepts and more.

Coronavirus Disease 2019: The First Wave and Beyond

Dr Preskorn is Professor in the Department of Psychiatry and Behavioral Sciences at the University of Kansas School of Medicine-Wichita. The author notes that he has received grants/research support from or has served as a consultant on the advisory board or speaker’s bureau for Alkermes, BioXcel, Eisai, Janssen, National Institute of Mental Health, Sunovion, and Usona Institute. All clinical trial and study contracts were with and payments made to The University of Kansas Medical Center Research Institute, a research institute affiliated with The University of Kansas School of Medicine-Wichita.

Videos

This video presents Information that may help you and your patients deal with the pandemic.

Addressing Critical Questions About COVID-19

 can infect virtually everyone in the human population, based on data from China, the US, and Europe, only about 5% are susceptible to severe infection requiring admission to an intensive care unit (ICU) and/or causing a fatal outcome; this vulnerable population is identified by medical comorbidity and/or age. While 5% may initially seem like a small number, it nevertheless represents potentially 16.5 million people given a US population of 330 million. That is a tremendous number of people requiring ICU admission, potential deaths, and can easily overwhelm the US health care system, especially in hotspots. Nonetheless, it is important to consider the data for at-risk populations as part of mitigation strategies in attempts to re-open the country and the US economy.

This piece was written with the hope of helping mental health care practitioners understand the issues so that they can better explain the complexities of the current crisis to their patients. It is a personal synthesis of the implications of the extant literature in the public domain and to share thoughts on minimizing COVID-19’s damage. The piece will aim to address the following questions:

What are the 3 aspects of the race to minimize damage?

What data are currently available and how can they inform decisions?

How successful are the strategies employed to date?

Might risk stratification be a viable strategy to minimize the damage: impact of the illness and economic damage (which also can devastate and cost lives)?

 is caused by the severe acute respiratory syndrome corona virus-2 (SARS CoV-2).

 This virus, which jumped from an animal species (possibly a bat or an anteater) to humans in China in December 2019, causes a respiratory illness in humans that ranges in severity from no symptoms to cold-like symptoms to a severe, even fatal, respiratory illness.

 because of its recent emergence as a human pathogen. Due to its novel nature, humans had little to no immunity when it emerged as a human pathogen, and data were not available about the severity of the illness, the percentage of the population that could be affected, and whether risk factors could be identified for its severest forms. The concern was heightened by the fact that since 2002, 2 other novel coronaviruses (the SARS-CoV-1 and the Middle East respiratory syndrome [MERS] viruses) jumped from animals to man and caused serious, even highly fatal, illnesses. As it turned out, these earlier viruses had much higher fatality rates than COVID-19 infections: 10% for SARS-CoV-1 and 34% for MERS versus 2% for COVID-19’s SARS-CoV-2  and < 0.1% for seasonal flu.

However, it is important to keep a caveat in mind for the SARS-CoV-2 death rate. It is a general number for the whole population, but it varies widely based on subpopulations, as it is less than 1% in adults who are not of advanced age (ie, > 85 years) and those without certain specific serious comorbid medical conditions. When these two groups are excluded, most people who become infected with the SARS-CoV-2 virus have minimal to mild-moderate symptoms that do not require hospitalization. Thus, readers should keep in mind that COVID-19 fatality rate estimates are influenced by at least 2 factors: estimated rates will be higher based on the percentage of the population that has the risk factors of comorbid medical illness and/or is ≥ 85 years of age (eg, a nursing home populations versus the general population) and estimated rates may be substantially lower once sufficient results of antibody testing are available to determine the percentage of the population who have been asymptomatic or mildly symptomatic and have developed an antibody response.

Suffice it to say that COVID-19 did overwhelm the health care system in many countries and some areas of the US. Since there were no scientifically proven effective and safe treatments nor a vaccine in the earlier phases of this pandemic-and that those limitations continue as of  the writing of this article (April 20th), the response has been to try to limit the spread of the virus by good hygiene practices and social distancing. This has included orders to shelter in place, quarantining exposed individuals, and isolating infected people. This approach has resulted in shutdowns of major parts of the economy and sudden high unemployment, which has its own negative consequences.

The 3 components of the race are the pieces needed to address the previously noted unknown factors. We have needed and continue to need more knowledge about: 1- the nature of the disease and its treatment or prevention; 2 - how to best safeguard public health and avoid overwhelming the health care system; and 3- how to minimize the societal damage caused by the substantial disruption of the economy. These are 3 quite different dilemmas, and they require different expertise. To win the race, we need to balance risk in these different domains.

The good news is that we have learned a lot about the virus and the illness over the past 4 to 5 months. Within 2 weeks of the discovery of COVID-19, researchers at the 

National Institute of Allergy and Infectious Diseases

 determined how the virus enters human cells and, within 2 months, sites began Phase I trials of a potential mechanism-based 

 The problem is that treatment and vaccine trials historically take more than a year at the earliest to be successful. So, while these 2 possibilities are the most likely game changers, there will still be loss of lives and  negative economic fall-out. For this reason, there are 692 trials listed on clinicaltrials.gov examining the potential efficacy and safety of different treatments as of April 20th.

 Most-if not all-of these studies are examining the effect of already marketed drugs, because it takes many years to develop a completely new molecular entity specifically targeted for a given illness.

Much has also been learned about the natural history of the COVID-19 illness. The virus has a high enough basic reproduction number (R

 value refers to the expected number of cases directly generated by one case in a population where all individuals are susceptible to infection, as was the case for the world human population when this virus became a human pathogen. The R

 values for COVID-19 range from 1.4 to 5.7. In comparison, the COVID-19 R

 values are higher than reported for the 2 earlier coronaviruses (ie, SARS-CoV-1 and MERS) and higher than that for seasonal strains of influenza (R

 values range from 0.9 to 2.1), but are substantially lower than the R

 values for measles, one of the most infectious of all human viruses (R

 value can be used to estimate the fraction of the population that needs to be immune to the virus-whether by natural exposure or vaccination-to slow or stop the spread of the virus among nonimmune individuals. This fraction is referred to as 

 values, the threshold for effective community immunity for measles is 93% to 95% of the population being immune to the measles virus. For COVID-19, the threshold to achieve community immunity is estimated to be between 50% and 66%, according to 

, associate professor of epidemiology at Johns Hopkins University.

 Those figures are consistent with estimates that 50% to 70% of American and European populations will likely become infected with the SARS CoV-2 virus.

 Complicating this problem is that fact that somewhere between 25% and 50% of people infected with the virus are at least initially asymptomatic but nevertheless infectious to others based on data from the Centers for Disease Control and Prevention (CDC) and epidemiology studies in Iceland.

 Much has also been learned about risk factors for the seriousness of the illness as reflected in 

Clearly, age is an important risk factor but so also are comorbid medical illnesses, particularly pre-existing respiratory and cardiovascular disease, immunocompromised status, morbid obesity (ie, body mass index > 40), significant kidney or liver impairment, and/or diabetes. Age and these comorbid medical illnesses are correlated-that is, the older a person is, the more likely they have one or more of these comorbid illnesses. However, what is not known is whether age is simply a surrogate for having a comorbid illness or an independent risk factor. When younger people (< 55 years) have serious and even fatal outcomes, they most often have one or more of the medical illnesses listed, including severe asthma. In fact, almost 90% of all patients hospitalized for COVID-19 independent of age had one or more of the listed comorbid conditions.

 That means that 90% of the individuals who were hospitalized, admitted to the ICU, or died (

) had comorbid medical illness. When these individuals are removed, the likelihood of those 3 adverse outcomes drops dramatically, in some cases approaching zero. For these reasons, it is probably best to consider both age and medical status when stratifying risk; this was not done in 

. Age is likely mainly a surrogate for comorbid medical illness, but by age 85 and above, the vital capacity of many organs, such as forced vital capacity, a measure of lung function, has often declined to a significant degree. On the basis of this information, 5 potential severity levels can be identified (

There are some caveats concerning the data in 

, which represents cases from February 12 to March 16, 2020. First, early recognition and medical care have since improved substantially, which could produce a drop in these numbers even in vulnerable populations. Second and even more important, the data are based on approximately 2500 cases; more than 775,000 cases have now been reported, a number that almost undoubtedly includes more individuals at severity levels 0 or 1 because cases in the early days were first diagnosed on the basis of symptoms that would have been missed in these people. Because the number of cases is now so much higher, the CDC will be able to determine whether the larger numbers replicate the earlier findings shown in 

, which will give greater confidence in the results. Such an analysis has not yet been posted in the public domain, but this will likely happen and/or the results will be shared with policy makers.

The most widely adopted strategies have involved the epidemiological approach of encouraging good hygiene practices and social distancing, including orders to shelter in place and quarantine. (Parenthetically, the term 

 refers to the situation in which an individual has been in close contact with someone known to be actively shedding virus. Individuals in quarantine may be grouped together while following social distancing and they may use masks as an added precaution. The term 

 refers to the situation in which an individual is infected and is isolated from others to prevent further spread of the virus.) These strategies have met with varying degrees of success depending on the country, with smaller countries in terms of land mass and population generally doing better than large countries. Not all countries have taken these approaches, with 

 being perhaps the most notable exceptions. While those 3 countries have not experienced the same economic consequences as have occurred with the more restrictive policies elsewhere, it is too early to tell how they will do with the spread of the illness. Taiwan seems to being doing remarkably well, relying not on sheltering policies for the general population but instead case detection followed by establishing at-risk contacts and quarantining those individuals through the period of risk of developing illness and recovery using extensive testing for active infection and viral shedding.

The common phrase used to describe the goal of this epidemiological approach is 

. This term refers to reducing the height of the peak of the infection, which was critical in the earliest days of the infection when a steep peak could have catastrophic consequences by overwhelming the health care system and society. This approach was also a way of buying time to learn more about the disease and to find more effective ways to deal with it, ie, developing validated treatments and vaccines. Unfortunately, as previously mentioned, treatments and vaccines take time. There is also the possibility that COVID-19 might follow the same pattern of seasonal variation as seen with seasonal strains of influenza-the onset of spring will test this possibility.

This epidemiological approach has 2 potential downsides. The most obvious is its profound effect on the economy. The other is whether it simply delays-but does not meaningfully prevent-the spread of the virus. Prescribers can consider the analogy with immediate versus delayed or extended-release formulations of drugs. While the latter produce a lower peak level, they may have the same area under the curve (AUC)-in pharmacokinetics, the same AUC means that the amount of drug absorbed is essentially the same for the 2 formulations (ie, they are bioequivalent). In the case of the spread of the virus, it might mean that the total number of infected people will be the same but that the infections will be spread out over a longer interval. While this approach is good in terms of not overwhelming health care resources, it could prolong the economic impact, which is not without adverse consequences; it can also delay the time when sufficient community immunity will have been acquired in order to eradicate the infection and protect the vulnerable subset of the population susceptible to serious adverse outcomes. As previously mentioned, the estimate is that 50% to 66% of the population will need to have immunity to substantially reduce the spread to those who are not immune and possibly even eradicate the current version of the virus.

 This last caveat concerning the current version of the virus is included because some viruses mutate enough that they are no longer recognized by the immune system; an example of such are the seasonal strains of influenza, which is why new vaccines are produced before the start of the flu season.

Based on what it is now known, a small percentage of the population (5% to 10%) is at risk for a serious infection, which occurs at severity levels 3 and 4. Moreover, the vulnerable population can be identified and can shelter until the current version of this virus is essentially eradicated.

During the preceding 4 months, 2 approaches have generally been suggested to deal with the current crisis: 1- continue the epidemiological approach focused on slowing the rate of the infection and its most serious health consequences and 2- relax the most rigorous social restrictions to end the economic suffering. The 

 recommend a phased movement from a shelter-in-place approach to a gradual reduction in social restrictions and an opening up of the economy. Such opening would be based on regions meeting specific criteria in terms of their ability to contain the virus, coupled with vigorous monitoring for outbreaks, followed by case monitoring, quarantining of exposed individuals, isolation of infected individuals, and increased use of testing for active disease as well as for immunity (ie, the presence of sufficient titers of antibodies against the virus in the blood). This approach has been quite successful in smaller countries such as Taiwan. Testing for antibodies will also help estimate how far the country is from developing effective community immunity.

However, these guidelines do not take the data outlined earlier into consideration, which suggest that individuals younger than 85 years without specific comorbid illnesses have little risk of developing a serious illness from the current form of this virus. In this population, more rapid movement through the phases of lifting restrictions and opening up the economy seems possible, while continuing to practice good hygiene and social distancing, and simultaneously-and perhaps even more vigorously-focusing on sheltering the vulnerable population until the critical threshold for community immunity has been reached, whether through natural exposure alone or with the addition of vaccination.

This approach would have several benefits. First, it would more quickly restore the economy and thus help the entire population avoid the profound adverse societal and health effects of a serious recession or depression. Second, it would increase community immunity, which would drive down the risk for everyone, including those most susceptible to serious adverse outcomes. Third, those who develop immunity could donate antibody enriched serum (what has been called 

) to vulnerable individuals with serious adverse outcomes, which could potentially provide effective treatment while the development and testing of vaccines proceed.

However, there are also downsides to this approach. First, it assumes that immunity to the COVID-19 virus will develop. Anthony Fauci, MD, the director of the National Institute of Allergies and Infectious Diseases, has been quoted as saying that he would be “willing to bet anything that people who recover are really protected against reinfection.”

 He has also been quoted as saying, “Ultimately, the showstopper will be obviously a vaccine.”

 Both statements seem almost truisms and necessary conditions to resolve this situation. Second, this approach involves risk but so, too, does either of the first two alternatives; the risk with this proposed approach is arguably more calculated and nuanced. Third, individuals who are younger than 20 years old (or as old as the data indicate have minimal risk of serious adverse outcomes) and without comorbid medical illness will undoubtedly have contact with older individuals, but that is also true for the other 2 approaches. Therefore, public awareness of the need to exercise heightened concern for the vulnerable population must be understood and acted upon rather than taking a one size fits all approach, which is the approach that has been taken so far. That approach has led to many younger and healthy individuals incorrectly believing that they have the same risk as the vulnerable population and, at the same time, has diminished the understanding of the need for heightened concern for the population that is at high risk. To underscore this point, in their COVID-19 surveillance report for the week of April 6-12, 2020, the 

’s Regional Office for Europe reported that 95% of those who died in Europe were 60 years of age or older.

 However, even that finding probably over focuses on age as a surrogate for comorbid medical illness, ie, whether the patient is under or over 60 years old.

Although a tremendous amount has been learned, much still remains unknown. First and foremost, we need to determine how many individuals in different regions of the country have been infected. That information should increasingly become available over the next weeks to months as antibody testing is undertaken. As discussed, that information will help determine both the infectivity of the virus (its basic reproduction number or R

) and its fatality rate. A second major question is whether the antibodies that are produced convey immunity to reinfection, and, if so, how long that immunity lasts. Another key question is how much of a role cell-mediated processes play in the development of immunity. This will also determine if giving convalescent plasma enriched with antibodies from recovered individuals will help treat individuals experiencing a moderate to more severe infection, which is known as 

, which refers to the production of antibodies by the immune system of an infected individual.

Moreover, there may be other risk and protective factors yet to be identified. A key question concerns the critical aspects of the host-pathogen interaction. For example, is the sudden acute respiratory syndrome due to an excessive inflammatory response in some individuals (eg, a cytokine storm)? And, there is the question of vaccine efficacy. Some vaccines are highly effective and their use has resulted in illnesses essentially being eradicated. In contrast, the helpfulness of the seasonal flu vaccine varies from year to year and individual to individual.

This list of unanswered questions is not exhaustive but gives a perspective on the types of additional knowledge that is needed to combat the SARS-CoV-2 virus. The answers to these questions will be forthcoming, but this process will take time. In that interval, hopefully this information will help to mitigate the damage done by the virus, whether directly as a result of the infection or indirectly due to its effects on the economy.

The future is not as clear as anyone would like. This article reviewed the great progress that has been made to date in understanding COVID-19 and possible pathways for moving forward. Perhaps the words Winston Churchill used in speaking of the Allied victory in the Battle of Egypt describe the current war with COVID-19 as succinctly as possible: “Now this is not the end. It is not even the beginning of the end. but it is, perhaps, the end of the beginning.”

 and has been adapted with permission from Lippincott Williams & Wilkins.

 is Professor in the Department of Psychiatry and Behavioral Sciences at the University of Kansas School of Medicine-Wichita. The author notes that he has received grants/research support from or has served as a consultant on the advisory board or speaker’s bureau for Alkermes, BioXcel, Eisai, Janssen, National Institute of Mental Health, Sunovion, and Usona Institute. All clinical trial and study contracts were with and payments made to The University of Kansas Medical Center Research Institute, a research institute affiliated with The University of Kansas School of Medicine-Wichita.

The author acknowledges Garold Minns, MD, Dean of the University of Kansas School of Medicine-Wichita and an expert on infectious diseases, for his review of this article.

1. Preskorn SH. Mental healthcare providers dealing with coronavirus disease 2019 (COVID-19): what is the definition of a case, how is that changing, and what kinds of tests are available? J Psychiatr Pract. Epub April 8, 2020.

2. Corman VM, Muth D, Niemeyer D, et al. Hosts and sources of endemic human coronaviruses. Adv Virus Res. 2018;100:163–188.

3. National Institute of Allergy and Infectious Diseases (NIAID). Coronaviruses. Bethesda, MD: NIAID; Updated April 9, 2020. Available at: 

www.niaid.nih.gov/diseases-conditions/coronaviruses

4. Wikipedia. Severe Acute Respiratory Syndrome. Available at: 

https://en.wikipedia.org/wiki/Severe_acute_respiratory_syndrome. 

5. Wikipedia. Coronavirus. Available at: 

https://en.wikipedia.org/wiki/Coronavirus

6. Worldometer Website. Coronavirus (COVID-19) Mortality Rate. Available at: Worldometers.info/coronavirus/coronavirus-death-rate. Accessed April 20, 2020.

7. National Institutes of Health. ClinicalTrials.gov website. Available at: 

https://www.clinicaltrials.gov/ct2/results?cond=COVID-19

8. Wikipedia. Basic Reproduction Number. Available at: 

https://en.wikipedia.org/wiki/Basic_reproduction_number

9. Bruggeman L. As some leaders weigh pursuit of ‘herd immunity’ from coronavirus, experts warn risks are too high. ABC News. April 9, 2020. Available at: 

https://abcnews.go.com/Health/leaders-weigh-pursuit-herd-immunity-experts-warn-risks/story?id=70072952. 

10. Hjelmgaard K. Iceland has tested more of its population for coronavirus than anywhere else. Here’s what it learned. USA Today. April 10, 2020. www.usatoday.com/story/news/world/2020/04/10/coronavirus-covid-19-small-nations-iceland-big-data/2959797001. Accessed April 20, 2020.

11. CDC COVID-19 Response Team. Severe outcomes among patients with Coronavirus Disease 2019 (COVID-19)-United States, February 12–March 16, 2020. MMWR Morb Mortal Wkly Rep. 2020;69:343-346. Available at: 

https://www.cdc.gov/mmwr/volumes/69/wr/mm6912e2.htm

12. Garg S, Kim L, Whitaker M, et al. Hospitalization rates and characteristics of patients hospitalized with laboratory-confirmed Coronavirus Disease 2019 - COVID-NET, 14 States, March 1–30, 2020. MMWR Morb Mortal Wkly Rep. 2020;69:458–464. Available at: 

www.cdc.gov/mmwr/volumes/69/wr/mm6915e3.htm

13. Healthcare Fact Sheet. President Donald J. Trump Is Beginning the Next Phase In Our Fight Against Coronavirus: Guidelines for Opening Up America Again. April 16, 2020. Available at: 

www.whitehouse.gov/briefings-statements/president-donald-j-trump-beginning-next-phase-fight-coronavirus-guidelines-opening-america

14. World Health Organization Regional Office for Europe. COVID-19 weekly surveillance report: data for the week of 6-12 April, 2020. Available at: 

www.euro.who.int/en/health-topics/health-emergencies/coronavirus-covid-19/weekly-surveillance-report

15. Winston Churchill. Address at the The Lord Mayor’s Luncheon, Mansion House, November 10, 1942. Available at: 

www.churchill-society-london.org.uk/EndoBegn.html

Guidance for mental health care practitioners to better explain the complexities of the current crisis to their patients.

) and the media coverage concerning it have created great concern among both the general population and health care providers. This distress is likely to be further amplified in those who have significant psychiatric illnesses, including but not limited to anxiety disorders, major depression, bipolar disorder, and psychotic illnesses. Mental health care providers are therefore likely to encounter patients with questions and concerns about this illness. I hope that this article will help clinicians answer their patients’ questions and concerns.

In the interest of brevity, the article will focus on the following questions:

1. What is the definition of a case and how is that changing?

2. What types of tests are available and what types of tests are coming?

3. How will the availability of these tests impact probabilities of serious risk including fatalities?

4. What is likely to happen after the first wave of COVID-19?

Readers should keep in mind a number of caveats as context for this piece. First, it is being written as of April 9, 2020, with total US deaths now exceeding 14696. Changes are occurring rapidly so that this article may be dated in a short time. Nevertheless, the information is timely for practitioners now. To help keep it current, the references include links to websites from credible sources that are being continuously updated, so that readers can go to those sources for additional current information even months after this column has been published.

Second, I am a physician specializing in psychiatry and clinical pharmacology rather than infectious diseases, virology, or other related medical and laboratory specialties. However, I did 2 years of anatomical pathology during which I studied viral diseases. After that, I completed my general medical internship followed by my psychiatry residency. Subsequently, I have spent 40 year as an academic physician with an emphasis on all phases of drug development research, and I have read the current literature on COVID-19.

Coronaviruses are a large family of viruses that are so named because of the crown-like spikes observed on their surface when viewed by electron microscopy. There are hundreds of coronaviruses, most of which circulate among animals, including pigs, camels, bats, and cats. Sometimes those viruses jump to humans-called a 

Seven coronaviruses are known to cause human disease. Four of these human coronaviruses (HCoVs)-HCoV-229E, HCoV-OC43, HCoV-NL63, and HCoV-HKU1-usually cause a mild to moderate upper respiratory illness (eg, the common cold) in people. These 4 viruses continually circulate in the human population and cause respiratory infections in adults and children worldwide.

However, 3 more recent coronaviruses can cause severe acute respiratory syndrome (SARS) with more serious outcomes in people, including death. These 3 viruses and the diseases associated with them are: SARS-CoV (now more commonly called SARS-CoV-1), which emerged in late 2002 and disappeared by 2004; Middle East respiratory syndrome (MERS) virus, which emerged in 2012 and remains in circulation in camels; and SARS-CoV-2 which emerged in December 2019 in China and causes the COVID-19.

Challenges of defining and testing COVID-19 cases

The first definition of COVID-19 was based solely on signs and symptoms of the infection (principally fever, cough, and shortness of breath) and ruling out other possible causes, particularly negative tests for influenza. This approach is still common but has been enhanced by a test to detect active shedding of the COVID-19 virus in respiratory specimens, mainly via upper nasal swabs. These tests use real time Reverse Transcriptase (RT)-Polymerase Chain Reaction (PCR) Diagnostics Panels.

 A real-time RT-PCR is a diagnostic laboratory test that is used to measure the amount of a specific type of RNA, such as the RNA associated with the COVID-19 virus, as a means of detecting the presence of that virus. It involves 

 and then amplification of specific DNA targets using a 

. The use of these tests moves the diagnosis from one based on symptoms and exclusions to one that confirms the individual is shedding COVID-19 virus.

There are, however, several limitations to these tests. First, they have been and still are in limited supply in many areas of this country, although that situation is improving. Second, a negative test in someone who is asymptomatic is of limited value, because the individual could be too early in the disease process to test positive (the incubation period can be from 2 to 14 days after becoming infected) or, more importantly, because the asymptomatic individual may not have been exposed to the virus at the time of the testing but could be exposed even later that day and subsequently become positive. Therefore, for both reasons, the test is generally reserved for individuals who are meaningfully symptomatic. In other words, a negative test does not mean that an individual is safe going forward. An exception to the general rule is to test even asymptomatic individuals who have been in close contact with an active COVID-19 patient. Testing such individuals may detect the presence of virus before they become symptomatic-this is important since some people will never become symptomatic but they can still infect others.

Some individuals who become infected have either no symptoms or only mild symptoms (as high as 20% and 50%, respectively, in individuals under 20 years of age with no significant comorbid medical conditions such as lung or cardiac disease, immunodeficiency conditions, and morbid obesity). Conversely, the risk of serious infection goes up with age (> 65 years) and/or with comorbid medical conditions including respiratory and cardiovascular disease, immunocompromised status, morbid obesity (ie, body mass index > 40), significant kidney or liver impairment, and/or diabetes. It is very important, however, to be aware that asymptomatic and mildly symptomatic individuals can still spread the disease (termed 

). Therefore, precautions need to be taken when younger individuals are in the same home as those who are at high risk for serious and potentially fatal infections.

Another type of test is currently in development that will detect antibodies against COVID-19.

 Several groups in this country and around the world are developing these tests, and some companies have begun to sell them. This test would be positive in patients who have had the virus even if they were asymptomatic. In addition, these are individuals who may be immune to the current form of COVID-19 and thus could be able to return to work and be a COVID-19 “blocker,” an individual who would not spread the disease.

With that said, this disease is new and knowledge is being accumulated rapidly. Currently, it is not known how long people who never become symptomatic can continue to shed virus, nor is it known how long immunity-if developed-will last.

When the disease was diagnosed only by the presence of symptoms and the absence of other causes, only individuals with symptoms-and often mainly those with moderate to severe symptoms-were in the denominator, which would increase the apparent fatality rate. As the antibody test becomes available, it can identify individuals who were infected but were either asymptomatic or whose symptoms were so mild that they did not come to medical attention. Those cases will now be added to the denominator and thus will bring down the apparent fatality rate. How much it will drop remains to be seen. Currently, the population-wide fatality rate has been estimated to be as low as 0.05% to 1%, but the fatality rate can be as high as 8% in elderly patients in nursing homes.

The COVID-19 pandemic is circling the globe. Having started in the northern hemisphere, it is now moving into the southern hemisphere. Over the coming months, it could die out or it could mutate to a new form that is either more or less virulent. If such a mutation occurs, it is possible that those who become immune to the first version of the virus will not be immune to the next version, which is what is referred to as 

. There could also be additional subsequent waves. This is, of course, a common pattern for influenza and certainly was the case for the 

 that lasted from January 1918 to December 1920 with 3 waves.

 However, numerous efforts are underway to develop safe and effective vaccines. Those vaccines would first be focused on the current form of COVID-19, but they would then shift to other variant versions of COVID-19 if they emerge as second or subsequent wave(s).

Fortunately, pharmacological treatments are available that can be critical to the treatment of seriously ill patients with COVID infections. These patients often develop secondary bacterial infections, for which antibiotics can play an important role. Also, intravenous fluids are often critical to prevent cardiovascular collapse. The virus produces inflammatory reactions and may cause a cytokine storm, and anti-inflammatory treatments, including corticosteroids and antihistamines, may be used to combat these conditions. In addition, oxygen and ventilator support can be critical in saving lives in desperately ill patients.

In addition to these treatment options, as of March 28, 2020, there were 202 studies to test the effectiveness of various treatments for COVID-19 and/or related serious coronavirus infections listed on the 

 These studies are being conducted in 9 regions of the world, with China (71 trials), Europe (44 trials), and the US (22 trials) leading the list. The drugs being studied are mainly, if not exclusively, already marketed for other indications and run the gamut from antimalarial, antiviral, and anti-inflammatory drugs to herbal agents and antibodies. While there is a rationale for studying each of these agents, clinical trials must be conducted to determine their efficacy and safety for COVID-19. The reason that most, if not all, of the drugs being studied are already marketed is that their approval provides evidence of safety at least in patients with the illness for which the drug was approved, but the safety profile even of these agents may be different in individuals with COVID-19. In addition to these treatments, as previously noted, efforts are underway to develop safe and effective vaccines.

A detailed discussion of each of the treatments being considered in these trials is beyond the scope of this article. The point for you and for your conversations with your patients is the recognition that effective treatments for some of the complications of COVID-19 are available now and that a substantial effort is underway to find additional treatments.

The goal of this article was to provide information that you can share with your patients who may be understandably fearful about COVID-19, focusing on topics that may be of foremost concern to them. It is important to discuss the risk posed by COVID-19 as realistically as possible, as the risk is less than one might imagine from current news reports, especially for younger patients who are not immunocompromised and do not have significant respiratory or cardiovascular disease. It will also help patients to understand the nature of the tests that are available or soon will be available, which will allow an assessment of where an individual is in the disease process. It is also important for our patients to realize that effective treatments are available for the various consequences of COVID-19 and, in addition, that active research is underway to establish the efficacy and safety of other possible treatments and to develop safe and effective vaccines. Most important at this stage is to explain the rationale for and the importance of the guidance from the Centers for Disease Control and Prevention on protecting oneself and the population at large by practicing good hygiene (eg, frequent handwashing) and social distancing to reduce the chances of becoming infected and/or infecting others. Interested readers can find a wealth of additional information on COVID-19 and other coronaviruses on the websites

The author acknowledges Garold Minns, MD, Dean of The University of Kansas School of Medicine-Wichita and an expert on infectious diseases, for his review of this column.

 and has been adapted here with permission from Lippincott Williams & Wilkins. The original version can be found online at 

 is Professor in the Department of Psychiatry and Behavioral Sciences. The author notes that 

he has received grants/research support from or has served as a consultant, on the advisory board, or on the speaker’s bureau for Alkermes, BioXcel, Eisai, Janssen, National Institute of Mental Health, Sunovion, and Usona Institute. All clinical trial and study contracts were with and payments made to The University of Kansas Medical Center Research Institute, a research institute affiliated with The University of Kansas School of Medicine-Wichita. 

What is the nature of the virus turning the world upside down? Dr Sheldon Preskorn shares critical clinical information to better understand the virus, testing, and what might the future hold as we look to turn the corner in this pandemic.

Author | Sheldon H. Preskorn, MD

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