While COVID 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)?
Coronavirus disease 2019 (COVID-19) is caused by the severe acute respiratory syndrome corona virus-2 (SARS CoV-2).2–5 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.2–5
COVID-19 is commonly referred to as a novel coronavirus 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.6
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
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 need for more knowledge
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 treatment (remdesivir) and a vaccine (mRNA-1273).3 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.7 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.
Current data and principles
Much has also been learned about the natural history of the COVID-19 illness. The virus has a high enough basic reproduction number (R0) to be significantly contagious. The R0 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 R0 values for COVID-19 range from 1.4 to 5.7. In comparison, the COVID-19 R0 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 (R0 values range from 0.9 to 2.1), but are substantially lower than the R0 values for measles, one of the most infectious of all human viruses (R0 values range from 12 to 18).8
The Ro 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 community (or herd) immunity. Due to its very high Ro 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 Justin Lessler, PhD, associate professor of epidemiology at Johns Hopkins University. 9 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.10 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.10 Much has also been learned about risk factors for the seriousness of the illness as reflected in Table 1.11
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.12 That means that 90% of the individuals who were hospitalized, admitted to the ICU, or died (Table 1) 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 Table 1. 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 (Table 2).
There are some caveats concerning the data in Table 1, 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 Table 2, 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.
What strategies have been employed?
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 quarantine 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 isolation 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 Taiwan, Iceland, and Sweden 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 flattening the curve. 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.9 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.
Might risk stratification be the answer?
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 White House guidelines announced on April 16th13 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 convalescent serum) 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.”9 He has also been quoted as saying, “Ultimately, the showstopper will be obviously a vaccine.”9 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 World Health Organization’s Regional Office for Europe reported that 95% of those who died in Europe were 60 years of age or older.14 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 R0) 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 passivity immunity, as opposed to active immunity, 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.”15
This article was originally published in the Journal of Psychiatric Practice and has been adapted with permission from Lippincott Williams & Wilkins.
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.
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.
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