As I write this, both the US and the world are seeing an upsurge in COVID-19. There has been a 46% spike in hospitalized patients, and in the past seven days more than a half-million more Americans have contracted the coronavirus. According to the Johns Hopkins dashboard that tracks COVID-19 cases all over the world, as of today, the number of US cases is 9,982,054. And the number of deaths is 237,608. The daily totals have set new records: 103,369 new cases on November 8th, and 1,096 deaths. I cite Johns Hopkins data because it is generally thought to be the most accurate and timely data. All the same, there are holes in the data – it’s only as good as the sources, and some of the sources clearly may not report complete data.
This is the third spike in morbidity and mortality that the US has sustained since the pandemic hit us back in March of this year. About two weeks ago, epidemiologists predicted that the number of new cases per day would “soon reach 100,000.” That number was surpassed in just about a week. They also predicted that we would likely see another 100,000 fatalities by the end of the year. We’ll see how long it takes to reach that number.
In my previous Doc Gumshoe offering, I discussed the Great Barrington Declaration, which proposed limiting the measures currently being used to attempt to quell the infection rate to those persons most at risk, and greatly loosening the restrictions on the rest of the community, while herd immunity was allowed to do its work. This meant that a large enough fraction of the general population would contract COVID-19, but experience relatively mild cases and survive, contributing to herd immunity. I stated that I strongly disagreed with that position, and cited a few experts to support my position.
Several members of the Gumshoe congregation took issue with my response to that declaration. One parishioner went so far as to say that Dr Fauci (one of the experts I cited) should be locked up. Another, referring to the year and a half life expectancy (on average) of nursing home residents, said, “If they lose 6 months to a year of that (esp. with the quality of life being pretty low by this point) is that really that drastic compared to the economic fallout of never ending lockdowns?”
I strongly object to the notion that our society has to make a choice between combating the pandemic and supporting the economy (never mind that it’s not just nursing home patients that have contracted COVID-19 and perished). Without any doubt, the damages to the economy that the COVID-19 restrictions have caused are real and major. But the pandemic itself has serious economic consequences entirely independent of the restrictions. Even without the restrictions, many people would be loath to put themselves at risk of contracting the coronavirus. They would refrain from going to the movies or attending sports events; prefer doing a lot of their shopping on-line rather than going into crowded stores; postpone travelling on crowded buses, trains, or planes; and in general avoid putting themselves needlessly at risk from contagion. Most of the restrictions put in place by “authorities” of all types encourage careful behavior by the careful sector of the community, and attempt to require careful behavior from the not-so-careful remainder.
The rationale behind The Great Barrington Declaration assumes that the current restrictions also have the effect of interfering with the emergence of herd immunity. That would be a genuine concern if the only path to herd immunity were increasing the number of individuals in the community who had developed COVID-19 and recovered, thus having acquired a degree of immunity and no longer potentially transmitting the disease to others. But that is not the only path to herd immunity. The question about vaccines is not “if” but “when”. At some point there will be a vaccine. It will reduce the number of potential transmitters of the coronavirus. Herd immunity will be achieved though both avenues.
There continues to be a flood of interesting data and stimulating discussion related to COVID-19 that may have escaped the notice some of the Gumshoe tribe. In my previous piece I mentioned a few topics. Here are some:
The relationship between viral load and the severity of symptoms
This would appear to be fairly obvious – the poison is in the dose. A big dose will likely kill you, but a small dose won’t do much harm. That proposition is questionable with pathogens like viruses, which have the capacity to multiply rapidly, so that a tiny dose can quickly become an overwhelmingly large dose. Evidently, however, our natural immune systems are able to spot the invader and muster the resources to mount an effective battle against that invader. But it does depend on the size of the invading force.
An interesting perspective on that matter came from a very recent paper in The New England Journal of Medicine (Ghandi M. N Engl J Med 2020; 383:e101 DOI: 10.1056/NEJMp2026913). The paper cited examples of COVID-19 hot spots where large majorities of the individuals were infected by the coronavirus but did not develop any symptoms. On a closed Argentinean cruise ship, passengers were provided with surgical masks and the crew with N95 masks. Among those who were infected, the rate of asymptomatic infection was 81%, which was compared with a 20% rate of asymptomatic infection on a previous cruise ship where neither passengers nor crew had masks. Other examples included two US food processing plants, where all workers were issued masks each day and were required to wear them. A total of 500 persons were infected with the coronavirus in the two plants, but 95% of these were asymptomatic and the remaining 5% had mild to moderate symptoms. The CDC had estimated in mid-July of this year that about 40% of persons infected with the coronavirus would essentially be asymptomatic, but more recent evidence suggests that in settings where mask-wearing is universal, the observed rate of asymptomatic infections is closer to 80%.
These examples support the hypothesis that facial masking reduces the severity of disease among those individuals that do become infected, and also the concept that severity of symptoms is proportionate to the viral load or inocculum.
The authors of the paper speculate that widespread asymptomatic infection with SARS-CoV-2 would mimic a practice known as variolation. This was a process in which people were inoculated with material from a vesicle of a person with smallpox, with the intent of causing a mild infection and resulting in immunity. This practice was abandoned when the smallpox vaccine was introduced, making even the mild infections resulting from variolation unnecessary. Until a vaccine against the coronavirus becomes widely available, a near-universal use of face masks would not only decrease the proportion of severe or fatal COVID-19 cases, but would also increase the proportion of asymptomatic and mild cases, resulting in rising levels of immunity in the population. To quote from the paper,
“While we await the results of vaccine trials, however, any public health measure that could increase the proportion of asymptomatic SARS-CoV-2 infections may both make the infection less deadly and increase population-wide immunity without severe illnesses and deaths. Reinfection with SARS-CoV-2 seems to be rare, despite more than 8 months of circulation worldwide and as suggested by a macaque model. The scientific community has been clarifying for some time the humoral and cell-mediated components of the adaptive immune response to SARS-CoV-2 and the inadequacy of antibody-based seroprevalence studies to estimate the level of more durable T-cell and memory B-cell immunity to SARS-CoV-2. Promising data have been emerging in recent weeks suggesting that strong cell-mediated immunity results from even mild or asymptomatic SARS-CoV-2 infection, so any public health strategy that could reduce the severity of disease should increase population-wide immunity as well.”
Doc Gumshoe took the liberty of putting that last sentence in bold, because that’s the message in a nutshell.
The range of treatment options for COVID-19: no cures, but relief of symptoms
As you probably remember, about the time the coronavirus started to make headlines, the first drug that attracted attention – including my own – was Gilead’s remdesivir. About two weeks ago, October 22nd, the FDA approved remdesivir – now trade-named Veklury – for treatment of COVID-19 in patients requiring hospitalization. The terms of approval state that remdesivir should only be given in a hospital or a healthcare stetting capable of providing acute care comparable to acute hospital care. Remdesivir is the first drug to receive regular FDA approval for the treatment of COVID-19. The approval does not include the entire population that had been authorized for treatment with remdesivir under the previous Emergency Use Authorization, which included hospitalized pediatric patients less than 12 years of age.
The FDA approval was announced just a few days after an interim report on a large trial with remdesivir was made public. This was a study conducted by the World Health Organization (WHO). At 28 days, the death rate in patients being treated with remdesivir barely differed from that in other patients with COVID-19. And there were no advantages for remdesivir in the secondary outcomes – initiation of ventilation and duration of the hospital stay.
The trial was observational, rather than the double-blind placebo-controlled trial that is thought to give the most reliable results. From March 22 to October 4, WHO investigators compiled data from 405 hospitals in 30 countries, in a trial that comprised 11,266 adults: 2,750 receiving remdesivir, 954 were on hydroxychloroquine (HCQ), 1,411 on lopinavir, 651 on interferon plus lopinavir, 1,412 on interferon only, and 4,088 on standard care without any of the above. Within the study, HCQ was discontinued for futility on June 18 and lopinavir on July 4. Interferon was discontinued on October 16.
It was noted that the WHO study was based on data from many different settings around the world, and included a lot of different approaches to the care of hospitalized COVID-19 patients. In contrast, the FDA approval was largely based on the NIH Phase 3 trial showing that patients with mild, moderate, and severe disease who were treated with up to 10 days of remdesivir recovered about 5 days more quickly than those on placebo, and about 7 days sooner in those requiring oxygen at baseline.
In other words, not a cure, but significant relief of symptoms.
Two more possibilities
The first of these is Kaletra (from Abbvie), a drug widely used in AIDs patients, which combines two antiretrovirals, lopinavir and ritonavir. A nationwide clinical trial is now being launched. The plan is to enroll 600 volunteers with early COVID-19 symptoms to see whether daily doses of Kaletra will reduce the number of COVID-19 cases that become serious enough to require hospitalization.
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The hope is that reducing the severity of the symptoms will also reduce the morbidity that occurs when a patient is sick enough to need a ventilator or wind up in intensive care, and also reduce resource utilization and hospitalization.
In a previous trial in China, Kaletra did not show efficacy in the later stages of COVID-19, but did show some earlier benefit. In that trial, the drug was not introduced until day 13 of the onset of symptoms. The proposed US trial will start the drug in the first week after symptoms appear.
The trial is being led by Nathan Shapiro, professor of emergency medicine at Harvard Medical School and Beth Israel Deaconess Medical Center, along with investigators at Vanderbilt University and the University of Colorado.
Dr Shapiro was quoted as follows: “Is this a potential game-changer if we can intervene at this stage of the illness? Without a doubt. Whether this is the particular drug that will be the game-changer or if it’ll be a different drug, that’s the hypothesis that we’re testing, and we would look to test in sequence. If this drug doesn’t work, we would seek to bring in another.”
Another one is Regeneron’s monoclonal antibody (mAb), REGN-COV2, which was shown to decrease the viral load in COVID-19 patients. On October 28th, the company announced interim results from an ongoing Phase 2/3 trial in a subgroup of 524 outpatients. The study enrolled patients with a high viral load, comparing the mAb with usual care plus placebo. By day five of treatment, the patient cohort treated with REGN-COV2 experienced a greater than 10-fold reduction in viral load compared with patients receiving usual care plus placebo. The difference between the viral load reductions in the two groups was highly significant (P < 0.0001).
In the overall population of 799 patients, treatment with REGN-COV2 reduced COVID-19 medical visits in these outpatients by 57% compared with the placebo group (P = 0.024). In patients with one or more risk factors, the Regeneron mAb reduced medical visits by 72% (P = 0.0065). Medical visits were defined as hospitalizations, emergency room, urgent care visits and/or physician office/telemedicine visits.
REGN-COV2 is a combination of two monoclonal antibodies (REGN10933 and REGN10987) and was designed specifically to block infectivity of SARS-CoV-2, the guilty virus. The two potent, virus-neutralizing antibodies that form REGN-COV2 bind non-competitively to the critical receptor binding domain of the virus’s spike protein, which diminishes the ability of mutant viruses to escape treatment and protects against spike variants that have arisen in the human population.
It has been pointed out, however, that most patients in the trial were able to avoid medical visits whether they received the mAb or placebo. Although only 2.8% of the patients receiving the active agent required a medical visit, very few of the patients in the placebo cohort did either – only 6.5%.
In a comment about the possibility of treatment with monoclonal antibody agents, the Infectious Diseases Society of America noted that one of that type of therapy’s drawbacks is the high cost of creating the mAb, estimating that it would cost several thousand dollars per dose, and also that scaling production of mAbs to meet the needs during the pandemic would be difficult.
Whether AbbVie Kaletra or Regeneron’s REGN- COV2 make significant overall differences in the treatment of COVID-19 victims, they point in the right direction: treatment options that help these patients get over the disease. And, in addition to the benefit that those patients experience, there is also a benefit to the community – each COVID-19 survivor increases the level of herd immunity.
Those two drugs represent the tip of an iceberg of potential treatments. Not many years ago, there were no such things as antiviral drugs or monoclonal antibodies. The first antivirals were developed in the 1960s; before that viral diseases had to run their course since no drug treatment affected them. Now many viral diseases can be treated effectively with drugs, including AIDS. The first mAb was approved in 1986. Today, treatment with monoclonal antibodies is standards for many common diseases, especially autoimmune disorders such as rheumatoid arthritis. It is possible, and even probable, that existing antivirals can be repurposed to treat COVID-19. And it’s similarly possible-to-probable that mAbs can be used to subdue some of the COVID-19 symptoms caused by the patient’s own immune response. As clinicians and researchers learn more about the disease itself, it’s virtually certain that beneficial drug treatments will emerge.
The relationship between obesity and COVID-19 severity
As you certainly know, obesity is formally defined as a body mass index (BMI) greater than 30. BMI is a person’s weight in kilograms divided by the square of that person’s height in meters. The so-called “normal” BMI is between 18.5 and just under 25; “overweight” is 25.0 to just under 30, and over 30.0 counts as “obese.”
Obesity itself is divided into three classes: Class 1 is a BMI of 30 to <35; Class 2 is a BMI of 35 to < 40; Class 3 is BMI of 40 or higher. Class 3 obesity is sometimes termed as “morbid obesity,” implying that a BMI that high is a serious threat to health.
For example, a person whose height is 5 feet 10 inches and whose weight is 230 pounds is classified as obese, in Class 1, with a BMI of 33.0. If that same person gained another 20 pounds and tipped the scale at 250 pounds, he/she would be in Class 2, with a BMI of 35.9. And if he/she reached the 300 pound marker, that would put him/her in the morbidly obese category with a BMI of 43.0.
BMI does not take into account such matters as bone or muscle mass. A muscular heavy-boned male 5 feet 10 inches tall weighing 230 pounds might be a bit overweigh without being obese. And, of course, there are differences in the body composition of men and women. A person 5 feet 10 inches tall weighing 130 pounds would have a BMI of 18.7, just over the line into “normal” territory. In a woman, that might be considered slim and elegant, while a man of that height and weight would likely be thought a bit skinny.
And, it should be pointed out that overall life expectancy statistics favor BMIs in the “overweight” category, perhaps because low BMIs are sometimes indicators of a chronic illness, but also, perhaps, because the lines between those categories might be just a bit arbitrary.
However, genuine obesity is generally regarded as a threat to health, and the assumption is that the higher the BMI, the more serious the threat. The mechanisms through which obesity affects health are manifold and complex, but obesity goes hand in hand with diseases/conditions like diabetes and high blood pressure. And both diabetes and high blood pressure are the kinds of preconditions that would tend to make any infectious disease more difficult to treat.
But the specific connection between obesity and the severity of symptoms in persons infected with the coronavirus go beyond those common preconditions. For example, in meta-analysis published on August 26 in Obesity Reviews, an international team of researchers pooled data from scores of peer-reviewed papers capturing 399,000 patients. They found that people with obesity who were infected with SARS-CoV-2 were 113% more likely than people of healthy weight to land in the hospital, 74% more likely to be admitted to an ICU, and 48% more likely to die. (Popkin BM. Obesity Rev https://doi.org/10.1111/obr.13128)
Some of this may be due to the fact that obesity disproportionately affects certain minorities including persons of color and Hispanics, who, more often than the population at large, are likely to work and live in places where there is more exposure to the coronavirus. This is sometimes aggravated by more limited access to medical care than the general population.
However, there are also factors directly linked with obesity itself. One of these is purely mechanical. Large deposits of fat in the lower body compress the lungs, making it more difficult to breathe under the best of circumstances. The blood of people with obesity is more likely to form clots, clogging blood vessels throughout the body and depriving delicate tissues of oxygen. Excess weight also exacerbates the symptoms of asthma.
Fat, termed adipose tissue, also messes with the immune system. It emits hormones and other signals that tend to quell the body’s initial immune response, which then allows the virus to spread and multiply with no restraints. Eventually, the immune system will respond, but the delayed response often does more harm than good as an army of the immune infantry – the cytokines – swarm over the system, provoking uncontrolled inflammation everywhere they go. This constant inflammation hampers the immune system’s ability to generate a long-lived population of memory cells. These cells are the reservoir of the human body’s capacity to store information about past encounters with pathogens. They act as sentinels against future incursions and give orders to the immune system to summon up an army of antibodies.
An issue concerning obesity and COVID-19 is that vaccine developing and testing has not at this point looked carefully at that relationship. It is possible that vaccines that protect “normal weight” people from infections with the coronavirus, may fail to protect the obese. The effect of adipose tissue on the immune system may result in “pathogen amnesia” in obese individuals – the failure of the immune system to recognize and respond to pathogenic invasions. It is also possible, and even likely, that obese persons may require different dosage levels of a vaccine to become effective. Investigation of the effects of vaccines on obese individuals will no doubt be investigated eventually, but has not been at this point.
COVID-19 and neurologic symptoms
A significant percentage of hospitalized COVID-19 patients develop new neurologic disorders soon after the onset of symptoms. This was reported in a study published online in Neurology. The analysis included 4,491 COVID-19 patients hospitalized in New York City with severe acute respiratory distress between March 10, 2020, and May 20, 2020. (Frontera J. Neurology 10/05/20: https://doi.org/10.1212/WNL).
The researchers found that an average of 13.5% of these patients developed a new neurologic disorder in the first two days after symptom onset. These included toxic/metabolic encephalopathy (6.8%), seizure (1.6%), stroke (1.9%), and hypoxic/ischemic injury (1.4%). Neurologic disorders were more frequent among patients who were older, male, white, hypertensive, diabetic, and intubated. There were no reported cases of meningitis, encephalitis, or myelopathy/myelitis. COVID-19 patients with neurologic disorders had a 38% increased risk for in-hospital mortality and a 28% decreased likelihood of discharge to their homes.
In contrast with the relatively small percentage of hospitalized COVID-19 patients developing neurologic symptoms in New York City, the proportion of COVID-19 patients in Chicago who had neurologic manifestations was far greater. This was reported in a study which retrospectively analyzed the first 509 consecutive patients admitted with COVID‐19 to the Northwestern Medicine Healthcare system between March 5 and April 6. (Liotta E. Ann Clinical Translational Neurol. 10/05/20 https://doi.org/10.1002/acn3.51210)
Neurologic manifestations were present at symptom onset in 42.2% of 509 hospitalized COVID-19 patients, at hospitalization in 62.7%, and at anytime during the disease course in 82.3%. Myalgia (44.8%), headache (37.7%), encephalopathy (31.8%), and dizziness (29.7%) were the most frequent neurologic manifestations, followed by dysgeusia (15.9%) and anosmia (11.4%).
At least some of the differences between the New York City and Chicago reports can be accounted for by the outcome measures used in the respective studies. The Chicago study included myalgia (which is muscle pain), headache and dizziness among the neurologic manifestations. Disgeusia and anosmia are, respectively, the loss of the senses of taste and smell. These, by the way, are some of the COVID-19 symptoms that help to distinguish COVID-19 from other upper respiratory diseases.
Another key difference between the New York City and Chicago studies is that, whereas in New York the patients affected by neurologic disorders were older, the reverse was true in the Chicago cohort, where these manifestations were more likely to appear in younger patients. Again, that difference may in part be accounted for by the outcome measures used in the two studies. While the New York City study’s outcomes tended to be clear-cut neurologic disorders with potentially severe consequences, such as seizure, stroke, and ischemic injury, the Chicago study’s outcomes included several symptoms that were likely to be temporary.
Nevertheless, the evidence pointing to neurologic complications – another serious consequence of SARS-CoV-2 infection – is concerning.
The link between blood type and COVID-19 severity
The take-away here is that persons with A, B, or AB blood types are somewhat more likely to be infected by the coronavirus than patients with type O blood. This was reported in a Danish study. And another study, conducted in Vancouver, Canada, reported that patients with type A or AB more likely to experience more severe symptoms that did patients with type B or type O blood. Patients with these symptoms were more likely to require mechanical ventilation, renal support, and prolonged admission to intensive care units. There was no difference in the incidence of cytokine storms between the two groups.
In terms of the care and treatment of patients with COVID-19, those differences in susceptibility and the severity of symptoms in patients with differing blood types won’t, in all likelihood, make much difference. Care-givers will conduct treatment based on symptoms and not on blood type. However, those differences shed further light on the many ways that the coronavirus can impact our physiology. We see that in addition to the respiratory effects, there are cardiac, renal, sensory, muscular, neurologic effects, and no doubt others. The specific ways that the coronavirus messes with so many of our bodily functions are not yet fully understood, although there have been numerous suggestions that are being pursued.
One potential explanation of the way SARS-CoV-2 affects multiple bodily functions
This is merely a conjecture based on the observation that the coronavirus is able to disrupt so many different physiologic pathways simultaneously. We have mentioned a number of these: simultaneously dysregulating blood clotting and gastrointestinal function, damaging kidneys and lungs, perturbing neuronal processes and immunological function. That would indicate that a tiny RNA virus, incapable of even replicating itself independently, can perform a staggering array of disruptive cellular actions.
It has been suggested that the renin-angiotensin system (RAS) may be the coronavirus’s principal target. RAS acts to raise blood pressure and volume, which is not always a bad thing, since blood loss or dehydration can be addressed by this mechanism. But RAS is also a pervasive regulator of a great many tissue-level functions, ranging across the spectrum of bodily systems: glucose metabolism, cardiovascular functions, hypoxia sensing, neural crosstalk, inflammatory response, coagulation, and more. The body’s priority during stress or injury is to establish balance between physiologic responses and organ systems. RAS has evolved to become the master coordinator of these different but essential processes.
That conjecture points to a promising line of research – examining whether any of a number of drugs known to support the RAS has any effect on the coronavirus symptoms. At this point, have no knowledge of the results of any such research, but I’ll stay on the alert and inform the Gumshoe citizenry of whatever I learn.
Reassuring information about at least one worry
That worry being that antibody levels in persons who recover from COVID-19 tend to decline fairly rapidly, in the three to six month time frame after symptoms recede. Does this mean that COVID-19 survivors lose their immunity as the antibody levels drop? According to several immunologists and infectious disease specialists quoted in The NY Times on Wednesday, November 4th, the answer is “No!” Yes, the antibodies fade away, but cellular immunity persists. T-cells, having learned to recognize the intruder, will mount an attack, and even if the virus has established a beachhead, will fight the virus with enough force to minimize symptoms. And memory B-cells will signal the body to generate more antibodies, large numbers of which will be quickly recruited to attack the invading virus. The short take is that it’s not just the antibodies that constitute the immune response. Yes, the antibodies are the easiest to test, but the other sentinel cells persist and will protect us.
Late-breaking: Pfizer/BioNTech vaccine reported as being 90% effective
This was interim analysis of a Phase 3 study enrolling 43,538 participants, 94 of whom developed COVID-19. In an early analysis of the results so far, the companies reported that trial subjects who received two injections of the vaccine three weeks apart experienced more than 90% fewer cases of symptomatic COVID-19 than did those who received a placebo. The specific numbers of trial subjects in each arm who developed COVID-19 has not yet been revealed, but to substantiate the Pfizer/BioNTech claim that the vaccine was 90% effective, the split would have to be that about 9 in the vaccine group developed COVID-19 versus about 85 in the placebo group. Up to this point, no serious safety concerns have been observed.
The 90% efficacy reported with the Pfizer/BioNTech vaccine at this point exceeds expectations, which were that vaccines might be as much as 70% effective.
I emphasize that these are interim results. More will be known as further analysis is carried out, and as full study results are made public and scrutinized by outside experts. But, however you look at it, it’s good news.
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Doc Gumshoe is guessing that this particular document will not be his last discursion on COVID-19 and the villainous coronavirus. I hope to turn away from that subject in my next piece, but things keep coming up and I will attempt to keep you current. Many thanks for all your comments, and stay well. Michael Jorrin (aka Doc Gumshoe)
[ed. note: Michael Jorrin is a longtime medical writer (not a doctor), who I dubbed “Doc Gumshoe” many years ago — he writes health and medicine-focused columns for our readers a couple times a month, and though he does not generally cover investment ideas he has agreed to our trading restrictions. You can find his past columns here.]