The COVID-19 Pandemic of 2020 (Part 2)
Part 2. Safe Behavior in the Time of COVID-19. Some Atypical Effects of the Virus. Treatment and a Vaccine
The transmission of the virus, severe acute respiratory syndrome coronavirus 2 or SARS-CoV-2 is the mechanism of spread of the disease Covid-19.
Respiratory Spread
Because it is a respiratory virus an infected person has two ways to transmit the virus into the external environment. The first and dominant way is from the nasopharynx (mucus droplets) or mouth (mucus droplets from the nasopharynx or bronchial tubes entering the mouth) or from contaminated saliva in the mouth. This process can involve a cough or sneeze, which can eject virus–containing mucus over long distances, roughly 20 or more feet in large amounts and from talking or from breathing, but the latter over shorter distances, approximately five feet in the case of talking. The latter two routes, talking and breathing do not travel as far and the virus load is less, but they both are potentially able to transmit sufficient virus to spread the disease between unprotected individuals in close contact.
Masks and Social Distancing
The facts regarding spread led to two important means of decreasing transmission in the community, distancing and wearing masks. Six feet has been proposed as a rule for the minimum distance one should maintain, but the farther apart the better. Six feet is practical and probably would limit the spread from breathing and, perhaps, talking but under certain circumstances it is not enough. Wearing a mask is vital. Initially masks were downplayed but there are several studies showing the utility of masks in decreasing the spread of respiratory infections. Moreover, it is logical to conclude that an appropriate mask will decrease the emission of virus containing particles from the mouth and nose simply by its barrier function. In so doing, the dose of virus transmitted can be minimized. Although the virus is measured in nanometers, it usually is expelled in mucus droplets that are much larger and can be retained by a mask. With more sophisticated mask, such as used by healthcare workers, inhalation of viral contaminated particles is also decreased.
Hand Washing (Tactile Touching Spread)
The other major means of transmission is by touching with virus contaminated hands. The virus is acquired on the hands of an infected person because they touch their face, mouth, nose, or sneeze or cough into their hands among other routes to the hand. Virus particles on the hand can then be deposited on surfaces and objects and can be transmitted by a handshake or touching another person. Handshaking should never be done. Virus-containing particles can be deposited on objects and surfaces such as furniture, utensils, clothing, packages, and so forth. These are referred to in medical lingo as “fomites”, that is any inanimate objects containing infectious particles. These infectious particles, in this case viruses, are transmitted by the touch of a previously uninfected person and, once hands are contaminated, the transmission from hand to that persons mouth, nose, or eyes, the three major portals of entry of the virus. Thus, frequent hand-washing is the single most effective means to decrease virus spread. Hand-washing should follow any act that could increase the risk of spread by one’s hands. In the case of this pandemic, hands should be washed multiple times per day and certainly on returning home, after handling packages or mail, transferring items from one person to another, or any time that one’s hands are in a transaction that involves another person or fomites that have been exposed to another person. In this description, when one says another person, it is someone outside your domicile, not the person who has been isolated with you. As an important adjunct, disinfecting surfaces such as kitchen counters, door knobs, and light switches is useful.
Goggles
Goggles are very important for healthcare workers who may receive virus particles from spray while caring for patients, especially if placing or removing tubes from the trachea. In certain situations, such as unavoidable air travel, goggles should be considered. Although goggles are probably not useful when outdoors and maintaining distance, in a situation like an airplane or other prolonged stays in close quarters, use of mask, gloves, and disinfection of surfaces has not been enough to protect some travelers; the assumption has been that lack of eye protection might explain the transmission.
Gloves
Plastic, disposable gloves are useful in certain circumstances in which one is leaving the home and will encounter potentially contaminated surfaces. Once, however, the glove touches a contaminated, or potentially contaminated, surface, it should be treated like your bare hands. One cannot touch one’s face or another person with the potentially contaminated glove. Once the usefulness of the glove is over, it should be carefully discarded.
Crowds
It is simple logic that the more people one encounters, the greater the probability one of those persons is a carrier of the virus. Hence, the admonition to avoid crowded spaces. This advice has become particularly important since the finding that asymptomatic persons can transmit the virus. Hence, there is no way of knowing who is infected, unless they have been in quarantine for at least two weeks. The onset of the disease is usually four to six days after sufficient exposure but can be delayed up to two weeks and, hence, the duration of quarantine. Thus, restaurants, theaters, and other places in which multiple persons are in close proximity are a hazard for the foreseeable future, especially for seniors.
Shelter in Place
The best way to avoid contact with infected individuals, whether they are symptomatic or asymptomatic, is to shelter in place. This approach can be socially disruptive, especially for children and young persons who should be in school or out playing or interacting with friends. It is similarly challenging to adults, but their ability to deal with such a state should be better. This acceptance is especially true for adults who can work from home. For older adults, such an approach is very important because of the higher risk of hospitalization or death in seniors. Even if the individual has to leave the shelter for special, short periods of time, if done with great care, their risk of contact with an infected person is significantly decreased.
Virus distribution
The virus has been shown to be able to enter several tissues or organs besides the upper and lower respiratory tracts, the principal sites of the disease and its complications. There have been studies suggesting the receptor for the virus that allow it to enter the lungs may be present on other organs. The virus has been found in stool, and although thought to be inactivated, it has become an epidemiological tool for tracking areas that have a high density of cases by the virus load in sewage.
Exaggerated Inflammatory Reaction
The virus in some people causes an exaggerated immune reaction, which when invoked contributes to the severity of the disease. This reaction has been called “cytokine storm”. Cytokines are important proteins that play a role in the inflammatory and immune responses. When released in an exaggerated and uncoordinated way, they contributes to enhancing the severity of the illness, increasing fever, tissue swelling, causing effects on the lungs, heart and other organs, requiring hospitalization and special treatment to try to subdue the reaction. It can add, also, to inflammation and fluid accumulation in the lungs, impairing oxygen exchange and in many cases explaining the severity of the illness and contributing to death.
Hypercoaguability and the Antibody-Antigen Interaction
Another effect of Covid-19 is the propensity to intravascular clotting in large vessels, small vessels, veins and arteries. This hypercoaguable state may be driven by a natural occurring system called the complement pathway. This pathway is activated by the antibody interaction with an antigen on the virus. In this case, an antigen is a part of the microbe, a substance foreign to the body that is recognized as foreign and provokes a highly specific immune response resulting in an antibody made by lymphocytes, the latter cells a key part of the immune system. The purpose of the antibody is to inactivate the invading microbe. The antibody is highly specific for that antigen and it binds to the antigen, in the case of Covid-19 the SARS-CoV-2 virus antigen, and inactivates it by preventing its attachment to the host’s cell (cannot get in to infect), preventing its penetration of the host cell (cannot get in to infect) or coating the virus so that if it gets into the cell it cannot “uncoat” exposing its genome (RNA in the case of this virus) and replicate in the host’s cell. A virus is not a complete cell, cannot replicate; it is inert. To replicate and cause disease, it must invade an animal or plant cell and capture that cell’s machinery for RNA or DNA replication, depending on which type of virus it is, an RNA or DNA virus.
Antibody formation is a key normal reaction of one’s immune system to inactivate a viral, bacterial or other microbial threat. In the case of other microbes, such as bacteria, the antibody specifically attaches to the microbe and the other end of the antibody is recognized by white cells that are phagocytes or “eating” cells. They attach to the tail end of the antibody and ingest the antibody-coated bacterium. Once internalized the phagocyte has the internal cellular mechanisms to kill the bacterium. Interestingly, these intracellular mechanisms are two-fold and are analogous to disinfectants (Chlorox) or antibiotics. The intracellular release of “Chlorox” kills not only the bacteria or other microbes but also the ingesting white cell itself. These carcasses (dead cells) accumulate and contribute to the formation of pus. The ability of the body to generate microbe-ingesting cells is so great that they are replaced rapidly during an infection.
Returning to the question of why hypercoaguability in Covid-19, complement is a group of proteins that play a critical role in the normal immune response. However, activation of the complement pathway, can trigger the coagulation system and, some think, this event may be the mediator of the hypercoaguability seen in some Covid-19 patients. These clots may also be responsible not just for strokes and other thrombotic events, but for occluding small arteries serving the kidney, heart, or lungs and causing or contributing to damage or, even failure, of those organs.
Unusual Signs or Symptoms
The characteristic onset of fever, cough, chills, muscle aches, headache, shortness of breath after a few days may instead be less prominent than unusual early symptoms, which include sudden onset of trouble breathing, confusion, loss of taste (ageusia) or smell (anosmia) (possibly neural system mediated), rashes (especially in the multisystem inflammatory disease of children), inflamed heart muscle (myocarditis), gastrointestinal symptoms, especially nausea and diarrhea and other unusual events. Fever is frequently absent at onset. Unusual or atypical signs or symptoms occur in other viral respiratory diseases, but since the incidence is usually lower per unit time and, thus, these events are spread over long periods of time, general awareness is less. In this case several millions cases have occurred over a few months, making uncommon atypical events more apparent in a compressed time frame, coupled with the disease being under intense scrutiny world-wide.
Effect of age
The virus clearly has a gradient of severity from young to old. Approximately 2 percent of cases have occurred in those less than 18 years of age, which group makes up 23 percent of the population. The age-adjusted fatality rates is heavily weighted to seniors. Eighty percent of deaths in persons with Covid-19 have been in those over 65 years, whereas they make up 17 percent of the population. Nevertheless, severe illness and death can occur at any age.
The striking but, fortunately, thus far, very infrequent (approximately 100+ cases out of 1.5 million as of May 15, 2020), childhood syndrome called pediatric multisystem inflammatory disease is a severe disorder that presents with high, prolonged fever, characteristic skin rashes over chest abdomen or legs, lymph node enlargement, abdominal pain with diarrhea or vomiting, and cardiac involvement. These kids are, frequently, desperately ill, require hospital care, but most have recovered. It is unclear what the long-term effects, if any, will be. The disease is very similar to Kawasaki disease in children, which can be triggered by infectious agents. Studies are in process to see if SARS-CoV-2 is such a triggering agent or if this is disease in children is a mimic, only.
Co-Morbid Conditions Disease severity is related to age and, in part. that relationship is related to the increased prevalence of diseases and conditions in seniors that contribute to Covid- 19 morbidity and mortality. These conditions include diabetes, chronic lung 14 disease, heart disease, kidney disease and frailty. These diseases, also, increase severity of disease and the risk of death, independent of age. Obesity, especially, morbid obesity is another condition that exerts a negative effect on outcome, independent of age. Presumably, immunodeficiency would also be a risk comorbid state, the most common of which may be acquired as a result of chemotherapy,
immunotherapy, or radiation therapy.
Antivirals
Specific treatment of viral disease has been possible more recently, long after the introduction of antibacterial chemicals and, subsequently, antibiotics were discovered. It has been estimated that in the last five or six decades 50 newly identified viruses have been shown to cause human disease. Today, there are many effective antiviral compounds and some have been game changers. Examples of viruses for which useful therapy is available include herpes simplex virus (HSV), human immunodeficiency virus (HIV), hepatitis C virus (HCV), hepatitis B virus (HCV), varicella-zoster virus and influenza. The advances in treatment of several viral diseases have been very impactful: two examples are hepatitis C caused by HCV and acquired immunodeficiency syndrome caused by HIV.
In the case of Covid-19, existing antivirals have been ineffective. The possible exception is an antiviral, remdesivir, developed for the Ebola outbreak. Studies have suggested that it can shorten the duration of illness in mildly and moderately ill patients. At this time, it has not been shown to change the disease in severely affected individuals. It is administered intravenously, so it is basically a hospital treatment. In addition, the studies have been few and involved a small sample of patients. Studies in China have not supported its efficacy. In typical settings, more studies would be conducted before reaching a conclusion, so the urgency of the pandemic makes it difficult to be certain about its utility without further study. Given the circumstances, the FDA has given it emergency approval. A vast scientific network around the world is working to identify other more effective agents that might prevent severe disease and death, the most critical endpoints.
Active immunity: Vaccines
In all diseases, prevention is preferable to treatment. In Covid-19, the ability of a vaccine to generate immunity to the viral infection would be among the most profound achievements in medicine given the virus’s impact on human life and the world’s economy, educational systems, travel, and socialization.
Although there have been questioned raised about whether there are “protective antibodies” in response to the infection, the likelihood of an appropriate immune response is extraordinarily high. This effect of antibodies to SARS-CoV-2 has been validated cell culture and in animal models of the infection. The immune system has two major cooperating parts: the innate immune system and the adaptive immune system. The latter, the adaptive immune system, is composed of two parts: cellular immunity (mediated by cells, T lymphocytes) and humoral immunity (mediated by antibodies made by another type of lymphocyte, B lymphocytes). The cellular response (T lymphocytes) and the humoral (antibody) response, often, act cooperatively to provide a protective immune response. The immune response engendered by the natural virus or an engineered viral vaccine would be very similar, if the latter induced protection against the virus.
The attempt to develop a vaccine for a new organism, such as SARS-CoV-2, customarily, would be measured in many years, in part, because of the careful, stepwise attention to effectiveness and safety. Given the numerous crash programs underway and several programs in Phase 1 or 2 trials (e.g. U.S., U.K., China) it could be significantly less. But development depends on the as yet unknown hurdles: the Ebola vaccine took about four years; but, the chickenpox vaccine took approximately 20 years to achieve. Of course, a vaccine might be engineered but not work, that is provide protection against the agent for which it was developed. The vaccine, also, might produce too many side effects. Thus, vaccine testing goes in stages, starting with tolerability and effectiveness in small animals models of the viral infection (e.g. mice, hamsters) and moving eventually to non-human primates. After engineering a vaccine and showing it is both safe and results in protective antibodies that inactivates the virus in non-human primates, it may be ready to test in humans for efficacy. Human trials are usually broken down into three phases. Initially, under usual circumstances, the sponsor must submit an Investigational New Drug Application to the FDA. This application must describe the vaccine, its method of manufacture, quality control tests, information about the vaccines safety and ability to produce a protective immune response in animals, as well as the protocols to be used in human testing.
If approved, Phase 1 is used to determine dose and initial safety. In this phase, usually three doses of vaccine, estimated at lower, medium, and higher dose, based on the response to it in monkeys are injected into a small number of persons, perhaps 50 to 100 of an optimal age range, for example 18 to 50 years. From this experience, the dose that is best tolerated and produces the best antibody response is selected to test in Phase 2. Here many more persons (hundreds to a few thousand) are given the vaccine, broadening the age range and, perhaps, including persons with underlying conditions, such as obesity, diabetes, hypertension, to measure safety and tolerance and antibody response in a more diverse population. If safety and antibody production are shown to be very good, then, Phase 3 is entered. Here many (tens or more) thousands of patients are given the vaccine and they are tracked to see if the vaccine provided a significant reduction in the incidence of the disease. Ideally, this would include a comparable group, randomly assigned, who would be given an inactive version of the vaccine to use as a virtually identically composed (age, gender, other characteristics) comparison group. The FDA tracks progress very closely and can pause or end the trials if they deem the vaccine is not safe or not effective or some combination thereof. An important feature of this phase is that the sham or placebo treated group must get enough cases of the specific disease against which the vaccine is designed to permit the vaccine exposed group to show a significant reduction in the disease. If that dose not occur, the Phase 3 trial continues to assign patients randomly to each group. If successful, the sponsor must submit a Biologics License Application. A team of physicians, microbiologists, chemists, biostatisticians, and others assembled by the FDA reviews all data on safety and efficacy from the trials and determines if the risk to benefit assessment is sufficiently favorable to proceed to manufacturing. Often, there is another tier of review in which the FDA and sponsor present the data to a non-FDA panel of experts in the various relevant disciplines who provide additional advice to the FDA regarding safety and efficacy. This review includes inspection of the product labelling to be certain healthcare providers can have information regarding the vaccines proper use, risks and benefits, so as to be able to provide critical information to their patients.
After licensing the vaccine, the FDA provides oversight for manufacturing. It inspects manufacturing facilities, and oversees procedures, and conducts its own tests of potency and purity of each vaccine lot. Thereafter, in effect, Phase 4 involves following the results of the vaccine once it is on the market, tracking adverse events through an elaborate system referred to as the Vaccine Adverse Events Reporting System to get expanded information on its tolerability and safety.
In this case, some shortcuts may be invoked, but it is critical that those be modest and safety and effectiveness is assured.
Many laboratories in Europe, the United States and Asia are working full tilt to develop a vaccine. Vaccines have been engineered and given to monkeys with the apparent development of protective antibodies and without serious adverse events. There are several approaches one can use to engineer a vaccine: e.g. attenuated live virus, killed virus, or the subunit of a virus (a key virus antigen or other viral element that determines the virus’s ability to infect and, thus, can generate a protective immune response).
If successful, the next challenge is to manufacture, distribute, and administer the vaccine to hundreds of millions in the United States and other countries at a reasonable cost and regardless of ability to pay. In this case, manufacturing will occur in parallel with testing so if the vaccine is safe and effective, it can be rolled out without delay. It should be shared world-wide and provision made for vaccinating persons in poor countries unable to afford the vaccine. Our unwillingness to be collaborative and support the World Health Organization is mean spirited and short-sighted. Another country may get to the goal first or have a more effective vaccine. It is likely that more than one vaccine may be approved for use. It is, also, likely that different vaccines will be available in other countries working toward that end. This pandemic is, by definition, a global problem that we should be leading. As an aside, it would be better to remain and help strengthen WHO practices than to leave it.
An effective vaccine with a reasonable duration of effectiveness would be the best outcome possible. Another positive outcome, but less so, would be the virus mutating to a less virulent strain, as apparently happened in the 1918-1920 influenza pandemic. One, however, would not want the virus to mutate, remain virulent and no longer be responsive to the vaccine. RNA viruses, like influenza virus, have a very high propensity to mutate, making the influenza vaccine an educated guess as to what strains to protect against each year. The SARS-CoV-2 virus’s propensity to mutate critical structures relevant to antibody neutralization appears to be less than influenza virus. Thus far, experts feel this coronavirus is more stable. The SARS-CoV-2 vaccine should, also, work effectively in seniors for maximal effect, not a given.
A critical limb of the immune system, cellular immunity, mediated by T lymphocytes, weakens significantly with aging. If that limb is critical to the antibody response to the vaccine, seniors may not derive full benefit. However, even if that were the case, decreasing susceptibility of a great fraction of the population to the SARS-CoV-2 virus would be very good for seniors. Their risk of exposure would be greatly reduced by the mass of vaccinated, protected individuals. The inability of seniors to generate a strong cellular immune response is the reason the flu vaccine comes in two doses, the standard dose and quadruple the standard dose for seniors. This has proved to generate, safely, a better antibody response in seniors, and the level of protection is presumed to be better as a result, but there are no data to support that view. A similar approach of a higher dose coronavirus vaccine for seniors may be possible.
Opening Up for Seniors
Inevitably, in large part because of the devastating economic impact on (i) workers, tens of millions now unemployed, unable to pay rent or mortgage, buy food, (ii) business owners unable to meet payroll or rent, (iii) the closure of schools, colleges, universities, (iv) reduction of air travel, (v) closure of theaters and so many other examples of economic involution and financial disruption, worsened by an uncoordinated, unsupervised, and thus, less impactful federal response, the pressure to open up is very great.
R naught (R0) is the number of persons to whom an infected individual transmits the infection. Ideally, one would want the R0 to be less than 1. That is, one would want to have decreasing incidence of the disease, indicating the spread was below replacement levels. It is estimated that an R0 of ~1.5 represents the rate of spread in an average season of influenza in the U.S., whereas the R0 for SARS-CoV-2 is ~2.5. This degree of spread results in an exponential growth of cases, if the spread is not interrupted by the techniques described above: social distancing, masks, handwashing, sheltering in place and so forth.
Spread is complex because there appear to be superspreaders who account for a disproportionate number of new cases. Usually, this occurs in a crowed area, such as a church service. In addition, there is controversy regarding what fraction of the population is required to be immune (recovered from the disease and has protective antibodies) to provide herd immunity. Herd immunity is the fraction of a population that is required to be immune to markedly decrease the spread of the disease among non-immune individuals. Herd immunity is best achieved by vaccination, but can be achieved by spread of the infectious virus to some large fraction of the population, a fraction being debated. The latter pathway would be accompanied by horrific morbidity and mortality.
The forces for getting back to work are prevailing, understandably, but many persons will not work, will not shop, will not attend events requiring crowds or close contact, so the economic toll may be lessened with reopening but still profound until treatment, a vaccine, or natural events reduce the pandemics impact. Some institutions and businesses will not reopen. The concern of experts is by opening up, even if rational persons try to take steps to enhance distancing, wear masks, provide for handwashing or hand disinfectant, and invoke other protective actions, the result will be a rebound of cases with Ro >>1.0 returning. In many cases, reopening is occurring without an R0 <1.0, proposed as a marker for reopening.
If opening occurs, seniors should stay isolated for approximately three weeks to see the extent of the rebound in cases, if any. Seniors staying isolated will serve three purposes: first, it will allow determination if the disease is rebounding; second, their risk will be nil if sheltered in place; and, third, the hospitalization rate may increase, but with seniors, the most vulnerable to severe disease and death still sheltered in place, it may not exceed capacity. Seniors should continue to do what they are doing, assuming it is an optimal protocol: sheltering in place and all the other steps to avoid infection. The issue for seniors is that the risk to them of severe infection and death remains. It would not be good for them to “open up” until clear signs of being at R0 of <1 is in evidence. Even then it should be done with special care.
Widespread Testing and Contact Tracing
A critical step to suppressing R0 is widespread testing of asymptomatic and of course, symptomatic individuals, tracing their contacts and quarantining symptomatic individuals, not hospitalized, and at least all asymptomatic contacts deemed at medium or high-risk of exposure to the positive individual.
During this several week extended shelter in place of seniors, careful excursions to see one’s children or friends who have been sheltered, using all appropriate precautions, could be entertained. Thereafter, one can only use one’s best judgement and balance the need of the excursion with the risk. Public health officials may also provide guidance, but it should be considered as a senior, not an average person. Conditions such as diabetes, lung and heart disease, obesity, and frailty should also be factored in to the risk calculation.
Life in the 21st Century
This topic is outside the purpose of this commentary. Nevertheless, the changes in commerce, education, the arts, travel, medicine, public health, and government will be consequential. Many pundits are already predicting, how, life will change. One hopes government will take this opportunity to act with ingenuity and foresight to encourage and contribute to advances that enhance the life of its citizens, which should be centered on fostering equity.
Written June 2020