September 17, 2020
Without reliable information, we rely on fear or luck.
“Face masks are the most important powerful public health tool we have. They are our best defense. I might even go so far as to say that this face mask is more guaranteed to protect me than the vaccine because the immunogenicity might only be 70% and if I don’t get an immune response, the vaccine is not going to protect me. This mask will.”Dr. Robert Redfield, Director of Center of Disease Control
“Epidemiologists say COVID-19 at least a four-to-five-year problem. Pausing in-person education that long would be devastating to colleges and their students. And even a one-year delay would be a substantial challenge. The virus isn’t going away. That’s why campuses need to reopen.”Jason Aoun,President of Northeastern University
1. Cases & Tests
3. Top 5 States in Cases, Deaths, Hospitalizations & Positivity
4. Nationwide C19 Trends
2. Steroids Can Be Lifesaving for C19 Patients (Link Only)
2. Were Lockdowns A Mistake? (Spoiler Alert: YES!!!) (Link Only)
A. The Pandemic As Seen Through Headlines
(In no particular order)
- The head of the United Nations calls the virus the world’s top security threat
- The U.S. says it plans to start distributing a vaccine within 24 hours of approval
- Bill Gates says Pfizer has the best chance of seeking emergency approval for a coronavirus vaccine by next month even though he thinks such an aggressive timeline is unlikely
- A small group of wealthy nations has bought more than half of the expected supply of the most promising coronavirus vaccines
- AstraZeneca’s trial illnesses may not be caused by COVID-19 vaccine
- Federal government unveils plans to make coronavirus vaccine free for all Americans
- Tens of thousands in China receiving experimental COVID-19 vaccines
- US virologists dispute Chinese whistleblower’s claim that COVID-19 is man made
- Twitter suspends Chinese virologist who says COVID-19 was made in Wuhan lab
- Death from COVID-19 very rare for Americans 21 and under
- US Attorney General Barr: A Nationwide COVID-19 lockdown would be ‘greatest intrusion on civil liberties’ since slavery
- Trump says CDC director got it all wrong on COVID-19 masks, vaccines
- ‘Recklessly endangering lives’: Trump slams Joe Biden for doubting vaccine
- Joe Biden calls for COVID-19 vaccine plan, admits he didn’t read Trump’s
- Houston Mayor Launches Study That Will Collect Blood Samples From Randomly Selected Homes
- NYC Is Opening Its Own Virus Testing Lab to Address Shortages
- NYC Mayor de Blasio unsure if NYC will be ‘back to normal’ by next summer
- NYC’s spring lockdown cut coronavirus transmission 70%, study claims
- Astonishing amount (nearly 50%) of NYC’s top earners are mulling a Big Apple exodus
- De Blasio said NYC would close off additional streets to vehicle traffic to allow restaurants to serve customers outdoors and would also extend the street closings from weekends to weekdays
- Connecticut shuts down a nursing home after an outbreak
- Hospitals in India scramble for oxygen as coronavirus cases top 5 million
- India reported 97,894 new coronavirus infections on Thursday, its highest one-day increase
- Myanmar races to build field hospital as coronavirus overwhelms health system
- India strikes deal with Russia for 100,000,000 doses of “Sputnik V” vaccine
- South Korea to secure coronavirus vaccines for 60% of population
- London may face “localized” lockdown
- South Africa plans to reopen its borders as it further eases restrictions
- Six months after locking down the country to curb the spread of the virus, Nepal is starting to welcome back trekkers and mountaineers
- Israeli reporters quarantine after a White House event
- US’s international reputation declined over handling of coronavirus
- Science says: Colleges should all reopen (with precautions)
- The University of Michigan is seeking a court order to end a strike by graduate students demanding more protection from the virus
- All students at the University of Colorado Boulder, which has an enrollment of about 35,000, were advised to quarantine for two weeks by the county’s health department on Tuesday after a surge of cases tied to the university
- The University of Arizona, with about 45,000 students, asked students living on or near campus to quarantine this week and next, with the exception of attending classes, after a major spike in cases
- Grand Valley State University’s 21,000 students in Allendale, Mich., were also ordered to “stay in place” for two weeks by the county health department
- Students in Indonesia collect, trade plastic trash to get internet access for online learning
- Alarming spike in stillbirths may be result of COVID-19 lockdown
- OECD says global economic slump not as bad as previously feared
- US retail sales climb 0.6% as COVID-19 recovery slows
- New Zealand has entered its first recession in a decade, economic data showed Thursday
- France fast-tracks citizenship for foreign virus fighters
- Airport in Rome is world’s first to earn 5-star ‘COVID-19’ safety rating
- 7 People Die From a Wedding They Didn’t Attend
- Many COVID-19 patients still have lung issues months after recovering
- Majority of Young Americans Live with Parents for First Time Since Great Depression
- US woman may face jail for spreading COVID-19 during bar crawl in Germany
- Cops drag anti-masker out of South Dakota school board meeting
- ‘Maskless flash mob’ marches through Target shouting ‘Take off that mask’
- City of Anaheim Asks CA Gov. Newsom to Re-open Disney After $100 Million Shortfall
- Kentucky theme park is allowing families to rent out the entire space
- Fauci says Broadway will see a ‘gradual return to normal’ through 2021
- Backlash After UK Policing Minister Encourages People To Spy On Neighbors For “COVID Contraventions”
- Big Ten votes to play football in 2020, reversing decision
- Hollywood rethinks movie release schedule as ‘Tenet’ stumbles at box office
- Student claims roach-infested college (University of Michigan) gave one roll of toilet paper to quarantiners
- US retailers roll out foreign toilet paper amid COVID-19 pandemic
- Senate bill proposes maintaining daylight-saving time all year
- Maskless party at ‘Jersey Shore’ house overwhelms local police
B. Numbers & Trends
Note: Unless otherwise noted, (i) all cases/deaths are confirmed cases/deaths that have been reported, (ii) all numbers reported in this update are as of the end of the most recent reporting period, and (iii) all changes reflect changes since the preceding day.
1. Cases & Tests
- Total Cases = 30,026,460
- New Cases = 308,318
- New Cases (7 day average) = 282,843 (+3,753) (+1.3)
- Second highest number of new cases
- Record high 7 day average of new cases
- 7 day average of new cases has been steadily increasing since 9/10
- 1,130,000+ cases every 4 days (based on 7 day average)
US Cases & Testing:
- Total Cases = 6,828,301
- New Cases = 40,154
- Percentage of New Global Cases = 13.0%
- New Cases (7 day average) = 38,987 (+701) (+1.8%)
- Total Number of Tests = 94,338,929
- Percentage of positive tests (7 day average) = 6.2%
- Although the 7 day average of new cases is 43.8% lower than the 2nd peak on 7/25, the 7 day average has been trending higher since 9/12
- 7 day average of new cases has increased 3,770 (7.1%) since 9/12
- Total Deaths = 944,707
- New Deaths = 6,220
- New Deaths (7 day average) = 5,342 (+1) (+0.02%)
- 7 day average of new deaths has been trending higher since 9/13
- Total Deaths = 201,348
- New Deaths = 1,151
- Percentage of Global New Deaths = 18.5%
- New Deaths (7 day average) = 873 (-8) (-0.9%)
- Although the 7 day average of new deaths is 25.8% lower than the 2nd peak on 8/4, the 7 day average has been increasing since 9/8
- 7 day average of new deaths has increased 123 (18.5%) since 9/8
3. Top 5 States in Cases, Deaths, Hospitalizations & Positivity (9/16)
- Arkansas count includes 139 “probable” cases and deaths that have happened over the past several months
- A total of 33 states have positivity rates in excess of 5.00%, which is the rate the WHO recommends the rate remain below 5% for at least two weeks before governments consider reopening
4. Nationwide C19 Trends
- Average hospitalizations (30,278) are trending toward the lows reached on June 20 (27,967)
- The increase in daily cases are likely due to the rise in college cases.
- Several states recently updated their death counts to include “probable” cases and deaths that have happened over the past several months
Source: Worldometer and The Covid Tracking Project
C. New Scientific Findings & Research
1. Sticky Webs of DNA Released From Immune Cells May Drive Lung Pathology in Severe C19
Neutrophil extracellular traps (NETs), composed of DNA (blue), Cit-H3 (red), and MPO (green), in the lung of a patient who succumbed to COVID-19. Credit: © 2020 Radermecker et al. Originally published in Journal of Experimental Medicine. https://doi.org/10.1084/jem.20201012
- Sticky webs of DNA released from immune cells known as neutrophils may cause much of the tissue damage associated with severe C19 infections, according to two new studies published on September 14, 2020, in the Journal of Experimental Medicine (JEM). The research, conducted by independent groups in Belgium and Brazil, suggests that blocking the release of these DNA webs could be a new therapeutic target for the management of severe forms of C19.
- While many people infected with the coronavirus experience relatively mild symptoms, some patients mount an excessive inflammatory response that can damage the lungs and cause acute respiratory distress syndrome (ARDS), leading to low blood oxygen levels and, potentially, patient death.
- An early indicator of severe C19 is an increased number of circulating neutrophils, a type of white blood cell. Neutrophils can catch and kill invading microbes by unwinding their DNA and extruding it from the cell to form sticky webs known as neutrophil extracellular traps (NETs). NETs can also damage surrounding tissue, however, and could therefore cause some of the lung pathology associated with severe C19.
Image shows the release of NETs composed of DNA (blue) and the proteins MPO (green) and Cit-H3 (red) from neutrophils isolated from a C19 patient.
- In one of the new studies, a research team from Liege University’s GIGA Institute led by Thomas Marichal, Cécile Oury, and Philippe Delvenne examined the lungs of patients who had succumbed to C19 and found large numbers of NETs dispersed throughout the organ. The researchers saw many NETs in the airway compartment, where they often appeared to almost completely obstruct the small bronchioles and alveoli that mediate gas exchange. NETs were also formed at sites of inflammation located in the interstitial compartment between the alveoli and blood vessels, and could even be seen in the blood vessels themselves near tiny blood clots known as micro-thrombi that can restrict blood flow through the lungs and are a common pathological feature of severe C19 patients.
- “NETs can form a platform for the adhesion of platelets and other blood-clotting factors, but whether NETs actually contribute to the formation of C19-associated pulmonary micro-thrombi will require further investigation,” says Thomas Marichal. “Altogether, our study supports the idea that targeting NETs in C19 patients may help the clinical management of severe forms of C19 by alleviating thrombotic events, excessive tissue-damaging inflammation, fibrosis, and airway obstruction.”
- In the second study, a team of researchers led by Fernando Queiroz Cunha, Flavio Protasio Veras, and Thiago Mattar Cunha at the University of São Paulo also identified increased numbers of NETs in the lungs of severe C19 patients and found that NET formation was elevated in C19 patients’ blood plasma as well. Moreover, the researchers determined that the coronavirus can trigger the release of NETs by infecting neutrophils and replicating inside of them. NETs released from coronavirus-infected neutrophils induce the death of lung cells grown in the lab, the researchers found, but cell death is prevented if NET release is inhibited or the NETs are degraded by an enzyme that chews up DNA.
- “Our study supports the use of inhibitors of NET synthesis or promoters of NET fragmentation as a strategy to ameliorate the organ damage associated with severe C19,” says Fernando Queiroz Cunha.
2. T cells take the lead in controlling Coronavirus and reducing C19 disease severity
- Ever since the coronavirus first appeared, researchers have been trying to understand whether sometimes the immune system does more harm than good during the acute phase of C19. The latest study by researchers at La Jolla Institute for Immunology clearly argues in favor of the immune system.
- Their work, published in the Sept. 16, 2020, online issue of Cell, confirms that a multi-layered, virus-specific immune response is important for controlling the virus during the acute phase of the infection and reducing COVID-19 disease severity, with the bulk of the evidence pointing to a much bigger role for T cells than antibodies. A weak or uncoordinated immune response, on the other hand, predicts a poor disease outcome. The findings suggest that vaccine candidates should aim to elicit a broad immune response that include antibodies, helper and killer T cells to ensure protective immunity.
- “Our observations could also explain why older C19 patients are much more vulnerable to the disease,” says senior author Shane Crotty, Ph.D., who co-led the study with Alessandro Sette, Dr. Biol.Sci., both professors in LJI’s Center for Infectious Disease and Vaccine Research. “With increasing age, the reservoir of T cells that can be activated against a specific virus declines and the body’s immune response becomes less coordinated, which looks to be one factor making older people drastically more susceptible to severe or fatal C19.”
- Adds Sette, “What we didn’t see was any evidence that T cells contribute to a cytokine storm, which is more likely mediated by the innate immune system.”
- When the coronavirus (or any other virus) infiltrates the body, the innate immune system is first on the scene and launches a broad and unspecific attack against the intruder. It releases waves of signaling molecules that incite inflammation and alert the immune system’s precision forces to the presence of a pathogen.
- Within days, the so-called adaptive immune system tools up and moves with pinpoint precision against the virus, intercepting viral particles and killing infected cells.
- The adaptive immune system consists of three branches: antibodies; helper T cells (Th), which assist B cell to make protective antibodies; and killer T cells (CTL), which seek out virus-infected cells and eliminate them.
- For their latest study, the researchers collected blood samples from 50 C19 patients and analyzed all three branches of the adaptive immune system–coronavirus specific antibodies, helper and killer T cells–in great detail.
- “It was particularly important to us to capture the whole range of disease manifestation from mild to critically ill so we could identify differentiating immunological factors,” says co-first author and infectious disease specialist Sydney Ramirez, M.D., Ph.D., who spearheaded the sample collection.
- What the team found was that similar to their previous study all fully recovered individuals had measurable antibody, helper and killer T cell responses, while the adaptive immune response in acute C19 patients varied more widely with some lacking neutralizing antibodies, others helper or killer T cells or any combination thereof.
- “When we looked at a combination of all of our data across all 111 measured parameters we found that in general, people who mounted a broader and well-coordinated adaptive response tended to do better. A strong coronavirus specific T cell response, in particular, was predictive of milder disease,” says co-first author and postdoctoral research Carolyn Moderbacher, Ph.D. “Individuals whose immune response was less coordinated tended to have poorer outcomes.”
- The effect was magnified when the researchers broke down the dataset by age. “People over the age of 65 were much more likely to have poor T cell responses, and a poorly coordinated immune response, and thus have much more severe or fatal C19,” says Crotty. “Thus, part of the massive susceptibility of the elderly to C19 appears to be a weak adaptive immune response, which may be because of fewer naïve T cells in the elderly.”
- Naïve T cells are inexperienced T cells that have not met their viral match yet and are waiting to be called up. As we age, the immune system’s supply of deployable naïve T cells dwindles and fewer cells are available to be activated to respond to a new virus. “This could either lead to a delayed adaptive immune response that is unable to control a virus until it is too late to limit disease severity or the magnitude of the response is insufficient,” says Moderbacher.
- In line with what other research teams had found before, antibodies don’t seem to play an important role in controlling acute C19. Instead, T cells and helper T cells in particular are associated with protective immune responses. “This was perplexing to many people,” says Crotty, “but controlling a primary infection is not the same as vaccine-induced immunity, where the adaptive immune system is ready to pounce at time zero.”
- If a vaccination is successful, vaccine-induced antibodies are ready to intercept the virus when it shows up at the doorstep. In contrast, in a normal infection the virus gets a head start because the immune system has never seen anything like it. By the time the adaptive immune system is ready to go during a primary infection, the virus has already replicated inside cells and antibodies can’t get to it.
- “Thus, these findings indicate it is plausible T cells are more important in natural coronavirus infection, and antibodies more important in a C19 vaccine,” says Crotty, “although it is also plausible that T cell responses against this virus are important in both cases.”
3. Scientists studying treatments that target the coronavirus in the nose that might help prevent C19
- C19 can ravage the body, targeting the lungs, heart and blood vessels. To curb this wide-ranging attack, scientists are focusing on another part of the body: the nose.
- Studies suggest the coronavirus gains its foothold by infecting certain nasal cells. As a result, the nose has emerged as a key battleground in the war against C19. Slowing or stopping that nasal invasion might ultimately be powerful enough to change the course of the pandemic, some scientists suspect.
- So far, no such therapies exist. But people who study the nose and its contents bring fresh perspectives about the early stages of C19 infections. Scientists are developing and testing ways to prevent the virus from settling in to prime nasal real estate. These include a nose spray that smothers and inactivates a key viral protein, disinfectants that are commonly used before sinus surgeries, and even dilute baby shampoo misted up the nose.
- “I’m a nose person,” says Andrew Lane, an otolaryngologist and rhinology specialist at Johns Hopkins School of Medicine. But to most people, noses don’t usually spark a lot of interest, he says. “Now it’s the center of people’s attention.”
- This nasal gazing makes perfect sense. “The nose is a place where the virus is setting up shop,” Lane says. In a recent study, he and colleagues measured levels of a protein on human cells called ACE2 that’s thought to be one of the ways the virus can infect the cells. Among a collection of human tissues taken from the noses and throats of people, the upper back part of the nasal cavity, known as the olfactory epithelium, was packed with ACE2. (This spot is also where smell cells dwell; the coronavirus infections there have been linked to loss of smell.
- “You would just see this incredibly bright signal coming from the olfactory epithelium,” Lane says. That ACE2 signal suggests that those cells might be key entry ports that allow the virus to move into the rest of the body, and even perhaps back out again to infect other people, the researchers report in the Sept. 1 European Respiratory Journal.
- In the upper, back part of a person’s nasal cavity, certain cells contain lots of ACE2 (red), a protein that can allow entry to the virus that causes C19. Here, cells’ nuclei are shown in blue and olfactory nerve cells, which don’t seem to have ACE2, are green.
- To interrupt the infection in the nose, some scientists are turning to specialized immune proteins found in camels, llamas and alpacas. Called nanobodies, these proteins help fight off invaders in the body, but are smaller and thought to be hardier than their human antibody kin. In lab studies of proteins and cells in dishes, biochemist Aashish Manglik and cell biologist Peter Walter, both at the University of California, San Francisco, have shown that custom-designed nanobodies can smother the spike protein that the coronavirus can use to break into cells (SN: 2/3/20).
- The researchers haven’t yet tested the nanobodies in people. But their preliminary results suggest that, once neutralized with nanobodies, the virus “cannot enter human cells,” Walter says. “It cannot establish that beachfront in the nasal cavity.” These nanobodies were stable when dried and aerosolized, the researchers found, suggesting that they could be made into a nose spray. The most recent results, which haven’t been peer-reviewed, were posted August 17 at bioRxiv.org. The team hopes to begin tests in laboratory animals and eventually, in humans. Walter and Manglik hold patents on the specially designed nanobodies.
- A simpler approach would be to wash away or kill the virus in the nose. Some doctors have begun looking at iodine — the basis of a common antiseptic that can treat wounds and disinfect skin before surgeries. In a June 10 review article in Ear, Nose & Throat Journal, researchers describe evidence that suggests a dilute solution called povidone-iodine might safely eradicate the coronavirus in the nasal cavity and throat.
- Early hints that this rinse might work come from studies of the virus in lab dishes, including a paper published June 16 in the Journal of Prosthodontics. And a clinical trial is under way at the University of Kentucky in Lexington with health care workers using povidone-iodine nose sprays and gargles preventively before, during and after shifts.
- Other researchers are turning to an even more low-tech solution: a mixture of soap and salt. Saline rinses can remove bacteria and allergens from the nasal cavity and ease symptoms of allergies, sinus infections and colds. A current clinical trial is designed to look for effects of baby shampoo mixed with a salt solution on the symptoms and possible spreading of coronavirus in people who have C19. The soapy solution might be able to wash viruses out of the nose, or pop their protective outer layer and inactivate them, says Justin Turner, a nasal and sinus surgeon and rhinologist who is among the researchers running the trial at Vanderbilt University in Nashville.
- “We know that the virus is very sensitive to soaps and surfactants,” Turner says. Washing hands with soap, for example, is a good way to eliminate the coronavirus. “It seems like it could be reasonable to recommend that for the nose as well,” Turner says.
- During the trial, C19 patients with mild to moderate symptoms, but not sick enough to be hospitalized, will either do nothing special to their nose, rinse it with saline several times a day or rinse it with saline plus a small amount of baby shampoo. In the clinical trial, which began May 1, Turner and colleagues are tracking around 100 people’s symptoms and the amount of virus in their noses, a measurement that might indicate whether someone is more or less contagious. An early look at 45 patients shows that people who did the nose rinses, either saline alone or saline with soap, got rid of their headaches and nose congestion about a week earlier than the people who didn’t use rinses. Those interim results appear online September 11 in the International Forum of Allergy & Rhinology.
- It’s possible that nose rinses might “stir up the virus and facilitate its spread,” Lane cautions. But the idea of a nose rinse holds promise, and is worth testing, he says. This work, and other studies that target the nose are gaining momentum. “Everybody is thinking the same way, and I think there’s a lot of merit to it,” Lane says. “Nip it in the bud, and stop it before it gets a hold.”
4. Startlingly New Images of Coronavirus Infected Cells – Ready to Spread C19 Virus
A higher power magnification image shows the structure and density of the coronavirus virions (red) produced by human airway epithelia.
- The University of North Carolina School of Medicine lab of Camille Ehre, PhD, generated high-powered microscopic images showing startlingly high coronavirus viral loads on human respiratory surfaces, ready to spread infection in infected individuals and to others.
- The UNC School of Medicine laboratory of Camille Ehre, PhD, Assistant Professor of Pediatrics, produced striking images in respiratory tract cultures of the infectious form of the coronavirus produced by infected respiratory epithelial cells. The New England Journal of Medicine featured this work in its “Images in Medicine” section.
- Ehre, a member of the UNC Marsico Lung Institute and the UNC Children’s Research Institute, captured these images to illustrate how intense the coronairus infection of the airways can be in very graphic and easily understood images. Her lab conducted this research in collaboration with the labs of Ralph Baric, PhD, the William R. Kenan Distinguished Professor of Epidemiology at the UNC Gillings School of Public Health, who holds a joint faculty appointment at the UNC Department of Microbiology and Immunology, and Richard Boucher, MD, the James C. Moeser Eminent Distinguished Professor of Medicine and Director of the Marsico Lung Institute at the UNC School of Medicine.
- In a laboratory setting, the researchers inoculated the coronavirus into human bronchial epithelial cells, which were then examined 96 hours later using scanning electron microscopy.
The coronavirus virions (red).
- The images, re-colorized by UNC medical student Cameron Morrison, show infected ciliated cells with strands of mucus (yellow) attached to cilia tips (blue). Cilia are the hair-like structures on the surface of airway epithelial cells that transport mucus (and trapped viruses) from the lung. A higher power magnification image shows the structure and density of coronavirus virions (red) produced by human airway epithelia. Virions are the complete, infectious form of the virus released onto respiratory surfaces by infected host cells.
- This imaging research helps illustrate the incredibly high number of virions produced and released per cell inside the human respiratory system. The large viral burden is a source for spread of infection to multiple organs of an infected individual and likely mediates the high frequency of C19 transmission to others. These images make a strong case for the use of masks by infected and uninfected individuals to limit coronavirus transmission.
D. Vaccines & Testing
1. Synthetic biologists have created a slow-growing version of the coronavirus to give as a vaccine
- In the 1950s, Albert Sabin was searching for an improved polio vaccine. To that end, his lab infected the brains of mice, chimpanzees, and monkeys with the virus that causes the disease. They wanted to see if the pathogen would change and if weakened forms might arise.
- They eventually isolated versions of the polio virus that could still infect people but didn’t cause paralysis. Sabin’s so-called attenuated strains became the famous oral polio vaccine given on a sugar cube to billions of children.
- Now, researchers say, synthetic biology has led to a way to create a weakened form of the pandemic coronavirus that causes C19. Although the idea remains a long-shot in the vaccine race, an attenuated coronavirus could be formulated into inexpensive nose drops for use around the world.
- The startup company behind the new version of the coronavirus, called Codagenix, is working with Serum Institute of India, based in Pune, which bills itself as the world’s largest vaccine maker. Plans are for the first volunteers to sniff up the synthetically designed virus starting in November, in initial human safety tests in the UK.
- The most advanced covid vaccine candidates, including those from AstraZeneca and Moderna Pharmaceuticals, expose a person to only one part of the virus, the crown-shaped “spike” that gives it its name, in order to generate antibodies.
- The potential advantage of a vaccine using an attenuated live strain is that the body will encounter—and be able to react to—the entire virus. People will “catch” it through their nose, and it will even grow inside them. In theory, that could prompt the formation of not just antibodies but also T cells and specialized forms of immunity in the nasal passage, leading to broader protection.
- It might seem scary to imagine getting infected by the coronavirus on purpose, but attenuated-virus vaccines are common. The kids’ flu vaccine FluMist has a weakened influenza virus in it. And Serum Institute sells 750,000 doses a year of vaccines using live measles. The only disease ever successfully eradicated from the globe, smallpox, was wiped out with shots of a live virus.
- “If you want to complete the immunological response, then you need to mimic the course of the disease,” says Rajeev Dhere, a director at Serum Institute. “This can only be done with live attenuated vaccine.”
Re-creating the virus
- In the past, finding an attenuated strain to use as a vaccine was a painstaking process, says Stanley Plotkin, who advises Codagenix and was involved in early polio studies. That’s because it’s been done by growing a virus in cells from other species and waiting for a weaker strain to appear by chance. That can take 10 years. Sometimes a suitably behaving strain is never found.
- A new, rational approach emerged in 2002. That is when Eckard Wimmer, a virologist at Stony Brook University, caused a sensation by creating infectious polio virus starting from only genetic instructions. It was the “first creation of life in a test tube,” according to the newspaper headlines, and a possible bioterror threat, too.
- Some called Wimmer’s demonstration irresponsible. But the technology for generating viruses from data also allows researchers to get creative, since the procedure lets them rewrite the viral genes in any way they want. “That is where synthetic biology, genome editing, comes in. You can take evolution, which took years to occur, down to days,” says Farren Isaacs, a biologist at Yale University. “Unfortunately, the pandemic is creating an opportunity for this technology.”
- Instead of creating dangerous germs, by 2008 Wimmer and J. Robert Coleman, then a member of his lab and now the CEO of Codagenix, had started showing how they could use synthetic biology to design weakened versions of polio using a strategy they called “synthetic attenuated-virus engineering” or, more colorfully, “death by a thousand cuts.”
- To understand how they do it, it’s necessary to know that genes work using a three-letter code. To make proteins, a cell looks to these three-letter “codons” to determine which amino acid to add next to a protein it is building. But it turns out the genetic code has redundancy. There are 64 codons that can be spelled with the genetic alphabet, but only 20 amino acids to make. For instance, four codons code for the same amino acid, serine.
- The way evolution has handled that redundancy matters, too. All life uses the same rules, but depending on whether you are a bacterium, a human, or a starfish, you will have a preference for using certain codons or pairs of codons.
- Viruses, which hijack cells to copy their proteins, have, predictably, evolved a taste for the same codons that human cells prefer. But evolution’s choices can be reversed in the laboratory, in a process Codagenix calls “deoptimization.” Coleman says the company has made versions of the coronavirus whose genes are peppered with 240 mutations that endow it with some of the worst-performing codons.
- The result: the engineered virus looks exactly the same on the outside but has a “virtual brake pedal” inside, causing it to replicate much less quickly. The coronavirus can usually make 100 million copies of itself inside a cell in about a day, but Coleman says the deoptimized version will copy itself half as well in the lab. Inside a person, it could be less efficient by a factor of up to 1,000, giving the immune system time to respond.
- Some scientists don’t see a role for a live vaccine in the C19 fight. “This is a stupid easy virus to vaccinate against,” says Michael Farzan, a specialist at the Scripps Research Institute. He says the virus exposes its most important vulnerability, the spike protein, in a way that makes it a ready target for antibodies, which other vaccines can generate. “You only need live attenuated viruses when you don’t have a safer one. In this case it brings a risk that is unnecessary. There’s no need to have a live virus multiplying inside you.”
- Serum Institute, which sells vaccines mostly in the developing world, is working to manufacture four potential coronavirus vaccines, including front-runners from Oxford University and Novavax, a US biotech company. These are in advanced stages of testing, but there is no guarantee they will work, and there could be supply shortfalls.
- Dhere calls the live vaccine something of a backup plan for the Serum Institute. Such vaccines are made using old, well-established technology, and can be delivered without a needle. “The oral polio vaccine is so successful around the world because it’s a few drops in the mouth of a child. You don’t need a big medical paraphernalia,” he says. “So we felt that during a pandemic, the simplest version of a vaccine is the one that could reach billions of doses. When it goes to a mass scale, we think intranasal will be the best approach.”
- What are the risks? An attenuated virus can still be dangerous for people with compromised immune systems. Another risk is that a weakened virus can “revert” to its more dangerous form. “We always get the question if it will revert,” says Coleman.
- That does occur with polio. In recent decades, more outbreaks have been caused by vaccine strains than by wild virus. According to Plotkin, that’s because only “relatively few” mutations distinguished Sabin’s vaccine strains from wild polio, and the attenuated virus (which does multiply inside people and even spreads between them) can eventually mutate back to its original form.
- By contrast, the “deoptimized” coronavirus has several hundred genetic changes. The chances of evolution finding a way to undo even a fraction of them are mathematically minuscule. “I think it’s impossible,” says Dhere.
- Rather than the vaccine strain reverting to the dangerous form, Dhere says bigger risk is that the wild coronavirus will mutate in ways that render certain vaccines less effective. The coronavirus hasn’t been changing very substantially so far: in fact, it’s been remarkably stable. Yet if the spike protein were to change, the main candidate vaccines could become less effective because they only target that molecule.
- An attenuated live vaccine—because it includes all the parts of the virus—might not have that problem. “We don’t want to be chasing the virus if it changes,” he says. But if it does, “we’ll still have a vaccine that’s still 99% similar.”
2. New at-home coronavirus test can produce results in 15 minutes
- A new C19 test that can produce results in 15 minutes with the help of a smartphone app could become the first test that can be performed at home without involving a laboratory.
- Biotech company Cellex partnered with Gauss, a computer vision startup, to develop the rapid-response test which uses artificial intelligence to provide the results, Axios reported.
- The antigen test involves taking a nasal swab to both nostrils then placing it in a small vial filled with a buffer solution. Four droplets are then taken from the vial and placed on a test cassette.
- Lines will develop with varying degrees of intensity depending on how much — if any — of the virus is present in the sample, similar to a pregnancy test.
- The test is then scanned with a smartphone through an app, which will use AI to inform users if they tested positive or negative — all within 15 minutes, Axios explained.
- “By embedding advanced computer vision algorithms within a thoughtfully-designed user experience, we can enable consumers to perform a rapid test in their own homes just as well as a trained operator or a laboratory instrument — simply by using their smartphone cameras,” Gauss CEO Siddarth Satish said in a statement.
- If the FDA approves the diagnostic, it would be the first C19 test that can be done to completion at home.
- Cellex CEO James Li said the test has 90% sensitivity and nearly 100% specificity.
- Test sensitivity is the ability to correctly identify positive cases and test specificity is the ability to correctly identify negative cases — meaning the rapid-test is not always 100% accurate in detecting those with C19 but is almost always accurate in determining when a person is not infected.
- “What is important for C19 pandemic management is that this is a tool that will allow people to self-monitor and self-isolate,” he told Axios.
- The test is expected to be submitted to the FDA for Emergency Use Authorization later this year.
3. Further evidence that PCR tests are too sensitive
- Making a diagnosis used to be a well understood and practised procedure: take a history from someone presenting with symptoms, examine them and do some tests to arrive at an overall diagnosis. It requires substantial training and experience to put this into practice. William Osler, known as one of the founders of modern medicine, often directed his trainees to ‘listen to the patient, he/she is telling you the diagnosis’.
- With C19, however, clinical diagnosis is seemingly a secondary consideration in the face of mass testing. All you require is a positive PCR test; no symptoms, no signs, no other diagnostic proof. But our limited understanding of mass testing and PCR suggests this might not suffice.
- Detection of viruses using Polymerase Chain Reaction (PCR) is helpful so long as its accuracy can be understood: it offers the capacity to detect RNA in minute quantities, but whether that RNA represents infectious virus is another matter. RT-PCR uses enzymes called reverse transcriptase to change a specific piece of genetic material called RNA into a matching piece of genetic DNA. The test then amplifies this DNA exponentially; millions of copies of DNA can be made from a single viral RNA strand.
- A fluorescent signal is attached to the DNA copies, and when the fluorescent signal reaches a certain threshold, the test is deemed positive. The number of cycles required before the fluorescence threshold is reached gives an estimate of how much virus is present in the sample. This measure is called the cycle threshold (Ct). The higher the cycle number, the less RNA there is in the sample; the lower the level, the greater the amount in the initial sample.
- In a recent BMJ rapid response, doctors in Wales set out these problems when using the PCR test when there is low viral circulation in the population. Routine testing found 26 low-level positive results for the coronavirus. The number of cycles required to reach the threshold in these patients ranged from 36 to 43. Nineteen of these weakly positive tests were repeated, and all 19 were negative on repeat testing.
- The importance of the cycle threshold is shown in a Canadian study of 96 samples from coronavirus infected patients that reported live virus was only detected when the cycle threshold was less than 24. The difference in a threshold might not look like much, but samples can differ by more than a million more copies of viral RNA per millilitre. Some of the testing threshold used is attempting to detect one viral copy in the sample, which further exacerbates the problems.
- Out of the 19 individuals who tested positive, one had been PCR positive three months earlier and was also antibody positive. The immune system works to neutralise the virus and prevent further infection. The infectious stage lasts about a week. Inactivated RNA, however, degrades slowly: it can be detected weeks after infectiousness has gone. In one case, RT-PCR continued to pick up fragments of RNA until the 63rd day after symptom onset. The duration of faecal shedding of viral RNA in one patient was up to 47 days from symptom onset.
- PCR detection of viruses is helpful so long as its limitations are understood; while it detects RNA in minute quantities, caution needs to be applied to the results as it often does not detect the infectious virus. This detection problem is ubiquitous for RNA viruses detection. SARS-CoV, MERS, Influenza Ebola and Zika viral RNA can also be detected long after the disappearance of the infectious virus.
- Why does this matter? Because when it comes to C19, insufficient attention has been paid to how PCR results actually relate to disease. The harms of false-positive results can be substantial: operations can be delayed or cancelled; patients are kept in hospital, just in case; further testing is required; in some cases, it drives local lockdowns. The results of our recent systematic review on viral infectiousness indicate that cycle thresholds are essential to understand who is infectious, and consequently, the extent of any outbreak and for controlling transmission.
- When it comes to dealing with this ongoing pandemic, it is clear that C19 – and our limited understanding of it – is testing our decision-making skills to the limit when it comes to diagnosing infections. And without a better understanding of what test results really show us, it seems that while coronavirus is at a low prevalence in our communities, mass testing might cause more harm than good if the nuances of test threshold are not understood.
4. Fast coronavirus tests: what they can and can’t do
- The United States leads the world in C19 deaths but lags behind many countries — both large and small — in testing capacity. That could soon change.
- At the end of August, the FDA granted emergency-use approval to a new credit-card-sized testing device for the coronavirus that costs US$5, gives results in 15 minutes and doesn’t require a laboratory or a machine for processing. The United States is spending $760 million on 150 million of these tests from health-care company Abbott Laboratories, headquartered in Abbott Park, Illinois, which plans to ramp up production to 50 million per month in October.
- The tests detect specific proteins — known as antigens — on the surface of the virus, and can identify people who are at the peak of infection, when virus levels in the body are likely to be high. Proponents argue that this could be a game changer. Antigen tests could help to keep the pandemic at bay, because they can be rolled out in vast numbers and can spot those who are at greatest risk of spreading the disease. These tests are also a key element in the testing strategies of other countries, such as India and Italy.
- Antigen assays are much faster and cheaper than the gold-standard tests that detect viral RNA using a technique called the polymerase chain reaction (PCR). But antigen tests aren’t as sensitive as the PCR versions, which can pick up minuscule amounts of the the coronavirus.
- This difference raises some concerns among specialists, who worry that antigen tests will miss infectious people and result in outbreaks in countries that have largely controlled coronavirus transmission. Others view the lower sensitivity as an attribute, because some people who receive positive PCR test results are infected, but are no longer able to spread the virus to others. So antigen tests could shift the focus to identifying the most infectious people.
- At present, antigen tests are administered by trained professionals, but some companies are developing versions that are simple enough to be used at home — similar to pregnancy tests.
- “Making the tests faster, cheaper, easier is definitely the goal — and I think the antigen test is the way to get there,” says Martin Burke, a chemist at the University of Illinois at Urbana-Champaign, who is co-developing rapid tests, including antigen-based assays. “This is by no means the perfect solution, it’s just the fastest thing we could get going now,” he says.
What tests are there and how do they work?
- Tests for C19 fall into two categories: diagnostic tests such as PCR and antigen assays, which detect parts of the coronavirus, and antibody tests that sense molecules that people produce when they have been infected by the virus. Antibodies can take several days to develop after an infection and often stay in the blood for weeks after recovery, so antibody tests have limited use in diagnosis (see ‘Catching C19’).
- The high-sensitivity PCR tests are almost 100% accurate in spotting infected people, when they are administered properly. But such tests generally require trained personnel, specific reagents and expensive machines that take hours to provide results.
- Countries such as South Korea and New Zealand have succeeded in boosting PCR-based testing, but scaling up these tests has proved difficult elsewhere. The United States, for example, has seen a slow and poorly coordinated response to outbreaks, faulty tests from the Centers for Disease Control and Prevention (CDC) and problems with the supply chain. All of this has hindered efforts to collect and process samples for PCR, pushing waiting times to days or even weeks. These delays, along with a lack of tests, have contributed to the rampant spread of C19 across the country, which by 16 September had seen almost 200,000 deaths from the disease.
- A typical antigen test starts with a health-care professional swabbing the back of a person’s nose or throat — although companies are developing kits that use saliva samples, which are easier and safer to collect than a swab. The sample is then mixed with a solution that breaks the virus open and frees specific viral proteins. The mix is added to a paper strip that contains an antibody tailored to bind to these proteins, if they’re present in the solution. A positive test result can be detected either as a fluorescent glow or as a dark band on the paper strip.
- Antigen tests give results in less than 30 minutes, don’t have to be processed in a lab and are cheap to produce. Yet that speed comes with a cost in sensitivity. Whereas a typical PCR test can detect a single molecule of RNA in a microlitre of solution, antigen tests need a sample to contain thousands — probably tens of thousands — of virus particles per microlitre to produce a positive result1. So, if a person has low amounts of virus in their body, the test might give a false-negative result.
- When used on people who were positive for Coronavirus in a standard PCR test, Abbott’s antigen assay correctly spotted the virus in 95–100% of cases if the samples were collected within a week of the onset of symptoms. But that proportion dropped to 75% if samples were taken more than a week after people first showed symptoms. The sensitivity — or the rate of detecting infections correctly — of the other antigen tests used in the United States is between 84% and 98% if a person is tested in the week after showing symptoms.
- Companies and academic research labs are also rolling out other tests that are faster, cheaper and more user-friendly than standard PCR assays, although they are not being produced on the same scale as antigen tests. Some of these other tests use the gene-editing tool CRISPR to zero in on genetic snippets of the coronavirus. Others are quicker variants of the PCR test that use different reagents, meaning they’re not limited by the same supply-chain problems. Saliva-based PCR tests, for example, are being used as screening tools in universities and for professional basketball teams.
Which tests tell whether someone is infectious?
- Although the PCR method can test whether someone is infectious, it also detects people who have the virus but are not likely to spread it.
- Antigen-based testing, by contrast, could help to rapidly identify people who have high levels of virus — those who are most likely to be infectious to others — and isolate them from the community, says Marion Koopmans, a virologist at the Erasmus University Medical Centre in Rotterdam, the Netherlands. “The question is, what is the safe limit? Because the moment you get that wrong, the whole idea implodes,” she says. It’s still unclear what viral load is the threshold below which a person is no longer contagious, says Koopmans, who is working with the World Health Organization (WHO) to determine a standard to validate rapid tests. “It would be very worrying if everyone does that on their own, using different criteria,” she says.
- Viral load peaks early in the Coronavirus infections and then gradually declines, with tiny amounts of virus RNA staying in someone’s nose or throat for weeks or possibly months2. And although there are not enough data to equate different viral levels with how infectious people are, there is evidence that individuals are unlikely to spread the virus about eight to ten days after showing symptoms3.
- “If you’re at risk of transmitting the virus to somebody else, you’re going to have plenty of viral particles — those would certainly show up in antigen tests,” says Michael Mina, an infectious-disease immunologist at the Harvard T. H. Chan School of Public Health in Boston, Massachusetts, who has been a vocal proponent of antigen tests.
- There are challenges at the start of the infection, when people have low levels of the virus. The answer, says Mina, is frequent testing — done multiple times per week. This could quickly identify infected people, even if the assays are less sensitive than a PCR-based test, because the amount of virus in their noses and throats rises within hours, he says.
- Mina and his colleagues have used statistical models to assess this strategy. In a preprint updated on 8 September, they suggest that testing people twice a week with a relatively insensitive test could be more effective at curbing the spread of the Coronavirus than are more-accurate tests done once every two weeks. Another study that modelled different scenarios for safely reopening university campuses reported similar findings4.
- To slow outbreaks, the focus should be on identifying those who are at risk of spreading the coronavirus to other people, rather than on spotting anyone who is infected with it, some experts say.
- When used as a screening tool to frequently assess as many people as possible, rapid antigen tests could be “a game changer”, says Rebecca Lee Smith, an epidemiologist at the University of Illinois.
How do countries plan to use antigen tests?
- At the beginning of April, as coronavirus outbreaks raged across the world, India had tested only about 150,000 people — one of the lowest testing rates per capita worldwide. On 21 August, the country conducted more than one million coronavirus tests in a single day. It reached that milestone after Indian authorities began using antigen assays to boost testing capacity.
- Delhi was the first Indian state to begin using rapid antigen tests, in June. By mid-July, the number of cases there had decreased and the daily death counts had plateaued, suggesting that the tests might have played some part in controlling the spread of the virus. Epidemiologist K. Srinath Reddy, president of the Public Health Foundation of India, a non-profit organization in New Delhi, says that the Delhi example is interesting, but not clear-cut: he notes that the government started to lift lockdown restrictions in August, which led to a surge in infections. “Rapid antigen tests have picked up the increased number of cases, but whether they have been successful in limiting the spread of COVID, we’ll only know in the next couple of months,” Reddy says.
- So far, India has approved the use of three antigen tests for screening large numbers of people, whether or not they have symptoms. One of the kits was evaluated by the Indian Council of Medical Research (ICMR) and the All India Institute of Medical Sciences, which found that the test detected infections between 51% and 84% of the time. Guidance from the ICMR says that people who have a negative result from an antigen test should also get a PCR test if they show symptoms, to rule out the possibility that the rapid test missed an infection.
- The WHO and the US CDC have also advised getting a PCR test if people showing symptoms test negative with a rapid antigen test. The US FDA has so far granted emergency use authorization for four antigen tests, each of which has a higher sensitivity than those used in India. The 150 million tests bought from Abbott will be used in schools and “other special needs populations”, according to the Department of Health and Human Services. The FDA, however, has authorized antigen-based tests only for people who have had symptoms for 12 days or fewer. Tests must be prescribed by a physician and administered by a health-care professional.
- Other countries are also considering the use of rapid antigen tests to meet targets. In July, the Philippine Society for Microbiology and Infectious Diseases issued temporary guidelines for clinicians and health-care workers, saying that antigen tests could be used as an alternative to PCR for diagnosing a coronavirus infection during the first week in people with symptoms. But it also recommends that all negative results should be confirmed with a PCR-based assay, says Edsel Salvaña, an infectious-diseases expert at the University of the Philippines Manila, who is advising Philippine officials on rapid testing.
- Antigen-based tests are being used in some of Italy’s major airports to screen people who arrive from four Mediterranean countries considered to have a high risk of infection. Negative results do not have to be confirmed with a PCR test. The Italian health minister, Roberto Speranza, has announced plans to use antigen tests to screen passengers at all of the country’s airports, and a group of experts has urged the Italian government to use the rapid tests in schools and universities.
- But others don’t think rapid antigen tests are a good idea. When trying to contain small outbreaks, such as those happening in Italy, public-health authorities should use assays that are highly accurate, because missing even just one positive individual could lead to a steep increase in the total number of cases, says Andrea Crisanti, a microbiologist at the University of Padua.
- Some researchers worry that there won’t be enough antigen tests available to greatly expand their use. “Rapid tests right now are for the happy few,” Koopmans says. “If we want to take these assays responsibly forward, we should talk about whether they can be produced to levels that would make them globally available.”
Could antigen assays be used at home like pregnancy tests?
- Several experts have promoted the idea of developing an antigen test that is cheap and simple enough to use at home, without a health-care worker administering it.
- Burke says what’s needed is something as easy as a pregnancy test. “You just spit into a tube, put a piece of paper in it and you get the result within minutes,” Burke says. “Testing should become a part of life: in the morning you take your cereals, your vitamins, and you quickly check your status,” he says.
- A few companies are developing simple paper-strip antigen tests. But drug regulators have not yet approved them for emergency use. “We don’t have a lot of real-life experience with these tests, and a lot of the validations have only been done in the laboratory,” Salvaña says.
- Beyond concerns about costs and availability, researchers worry that, with an over-the-counter test, people who get positive results might not follow up with public-health authorities, so their contacts won’t be traced. Another risk would be people “gaming the system”, Smith says — for example, getting someone else to take their test — so they can be sure of a negative result and avoid quarantine. Without incentives such as freely available tests and a living salary for those who have to isolate, testing and self-isolation could become a luxury reserved for wealthier people, others have argued.
- Another concern is that people will get a false sense of security from tests that have only limited accuracy. “There’s a big risk that the moment these tests become widely available, people will just use them and say, ‘It’s negative, so I’m clear,’” Koopmans says.
- Even when testing negative, people should continue to wash their hands, wear masks and avoid gathering in big groups, she says. Testing, she adds, “cannot replace the basic control measures that need to be in place to keep this virus controlled”.
5. Could Breathalyzers Make Covid Testing Quicker and Easier?
- 6 months into battling the C19 pandemic, it’s clear that the US still needs better testing. Backlogs have caused unbearably long wait times for results, and the coming flu season might further encumber test processing. But what if our coronavirus-carrying breath could be harnessed to detect C19? That’s the hope of some researchers at Ohio State University and Northeastern University, who are developing C19 breathalyzer devices.
- Most people know breathalyzers as the handheld tools toted by police officers for determining alcohol intoxication; but scientists wield them too—just not for sobriety tests. Researchers have explored using them, and similar devices, to analyze exhaled breath for indicators of diabetes, certain cancers, respiratory diseases, and many other conditions.
- Now, researchers like Ohio State University engineering professor Perena Gouma say a similar approach might work for C19 and could offer key advantages over the current gold standard, polymerase chain reaction (PCR) tests based on throat or nose swabs. A breathalyzer needs no reagents nor laboratory processing and could provide rapid results. This kind of test “is noninvasive and nonintrusive,” Gouma says. “You can deploy it wherever, whenever.” While there aren’t any on the market yet for C19 testing, her lab and others are conducting trials on people and hope to gain approval from the Food and Drug Administration for broader use.
- Gouma has been studying breath analysis, sensors, and diagnostic devices for years. In 2017, she invented a breath-monitoring device aimed at early detection of the flu by primarily targeting the exhaled chemical compound isoprene. Building on this work, she’s now developed a prototype C19 breathalyzer that uses ceramic sensors to detect volatile organic compounds in a person’s breath that she believes act as C19 biomarkers, or disease indicators. Since this work is still unpublished, Gouma won’t say specifically which gaseous molecules her device looks for, only that she and her collaborators came to their conclusions about the likely indicators for C19 after studying the medical literature on other coronavirus diseases and their related biomarkers.
- The breathalyzer’s sensors incorporate nanomaterials with high affinity for these biomarkers, meaning the sensors respond only to the target chemical compounds. When users exhale into a disposable mouthpiece attached to the device, the presence of these chemicals in their breath triggers a change in electrical resistance, which the device measures in order to give a reading.
- The results take only 15 seconds, Gouma says, and can be transmitted wirelessly or read directly on the device. About a minute later, the breathalyzer is ready for another go. “With this technology, you can monitor the next day and the day after,” Gouma says. “Nothing prevents you from knowing your state of health at any time.”
- While the breathalyzer could be used in hospitals or other health care settings, it wouldn’t require specialized training or health care workers to operate, so people at theaters, airports, schools, and other places could also use it, Gouma says. “I envision ubiquitous use of the breathalyzer. That’s what we strive for,” she says.
- Development of her breathalyzer received support from a National Science Foundation grant in June. Earlier this summer, Gouma began running a clinical study to test the device at the Ohio State Wexner Medical Center, which included people who had C19 and those who did not. Additional testing is underway that involves participants from various C19 testing sites around Columbus, Ohio. Gouma plans to seek FDA emergency-use authorization for the breathalyzer—which, during public health emergencies, permits use and distribution of certain medical products without full approval.
- Earlier this year, Nian Sun, a Northeastern University engineering professor, made the switch from studying gas sensors that detect lung cancer biomarkers to sensors targeting the novel coronavirus. With an NSF grant received in June, Sun and his colleagues have developed a handheld breathalyzer outfitted with electrochemical sensors made to catch viral particles from the air, including from exhaled breath.
- The sensors contain tiny imprinted cavities that exactly match the shape and size of the spike proteins protruding from the surface of the coronavirus virus. “We make a mold for the specific virus,” Sun says. Like a key going into a lock, the virus’ spike proteins, and only those proteins, fit within the sensors’ cavities. Hydrogen bonds provide electromagnetic force that binds the airborne viral particles to the sensors’ imprints, triggering an increase in measurable electrical resistance. The more particles there are, the higher the resistance.
- The breathalyzer designed by Nian Sun’s lab uses electrochemical sensors made to catch viral particles from the air, including from exhaled breath.
- The user blows into a one-way airflow disposable tube, and LEDs on the device indicate results. A red light means the virus has been detected, green indicates a negative reading, and yellow is borderline, possibly requiring another exhale or further testing, Sun says. Sun says false positives would be unlikely, since the sensors won’t engage any other type of virus. “This kind of sensor has extremely high specificity,” he says. “We can even differentiate different [Coronavirus] strains.”
- The prototype, which measures only a few inches in length and width, produces results in just one or two seconds, which can then be wirelessly transmitted. “This device doesn’t need any special training [to operate] and does not need any special reagents, so it’s pretty straightforward,” Sun says.
- Testing the sensors in the lab has involved using frozen, inactivated Coronavirus viruses. Now, pending approval from the institutional review boards at potential testing sites—a requirement for research involving people—Sun and his colleagues hope to soon test the breathalyzer among patients from Massachusetts General Hospital and Northeastern student, faculty, and staff volunteers. Part of the testing will involve comparing breathalyzer results against results from nasal swab tests, Sun says. He, too, plans to apply for FDA emergency-use authorization for his device.
- But breath analysis can be complex. Our every exhale swirls with hundreds of compounds originating from the mouth, gut bacteria, food, and ingested medications, says Raed Dweik, chair of the Cleveland Clinic Respiratory Institute. Even our environment comes out in the breath. “When patients come to me [after] driving on the highway, I can detect diesel exhaust on their breath,” he says. In other words, he continues, “there are challenges for breath analysis, because the breath does not only have what you’re looking for, it has a lot more.”
- For example, says Dweik, once while he was conducting a study, he detected a certain compound in 100 percent of the hospital patients’ breath samples that was absent from the breath of all the healthy participants in the control group. That might look like the compound was a signifier of a disease, but after digging deeper, the researchers traced it to a hospital cleaning solution not used in the clinic where controls were evaluated. “So you have to be really careful when you do breath,” Dweik says. “You see a lot of people publishing papers or making claims about how breath is great, but if you look deeper into their data you realize they have not controlled for the environment.”
- Dweik, who has studied breath-based diagnosis of liver disease, kidney failure, and other diseases, hasn’t specifically reviewed either Gouma’s or Sun’s breathalyzers. But he says he’s cautiously optimistic about C19 breathalyzers but enthusiastic about their potential. “The potential is huge,” Dweik says, but he emphasizes that “breath testing, or any test, has to be done accurately.”
- Beyond detecting C19, Cristina Davis, a UC Davis engineering professor and chair, thinks analyzing breath could also help determine if a Covid patient’s immune system will overreact to the infection, leading the body’s own defenses to damage itself, potentially fatally. “Some even seemingly healthy people have [this] issue come up,” says Davis. “So why is that? And can we see something in their breath that would allow us to predict that this patient is going to have more problems than another patient?”
- Davis and her collaborators are collecting and analyzing breath aerosols from people who have C19 using previously developed palm-sized devices that capture breath condensates. Larger molecules such as cytokines and eicosanoids—signaling molecules linked to inflammation and other processes—can also be found in breath aerosols, Davis says. By analyzing the condensates using mass spectrometry, Davis hopes to pinpoint which concentrations of these molecules could indicate a likely immune system overreaction. To correlate, she’ll compare these levels against study participants’ pulmonary function testing, which determines how well the lungs are working, and eventual outcomes—including how ill people become. Should she find a correlation between these molecules and people who wind up with severe immune reactions, Davis says, this technology could help predict which future C19 patients should be closely monitored for inflammation problems.
- To participate in the test, patients exhale into a disposable mouthpiece connected to the device, and their breath condenses into a liquid that can then be poured into a vial and stored in the freezer until it’s collected for analysis. Participants in her team’s study, being conducted by the UC Davis School of Medicine and the VA Northern California Health Care System, can provide breath samples at C19 testing sites or if they’re admitted to the hospital. The collection devices can also be sent home with people who don’t require hospitalization.
- Yet even though these new devices offer some intriguing possibilities, PCR probably isn’t going anywhere soon. “PCR and other traditional detection assays, they’re pretty good,” notes Davis. “I think that breath analysis can play a role. In my mind I don’t see it replacing those traditional measures; I see it as being something that can augment.”
- Other experts even think that C19 detection technologies might be used in combination. “I think it’s really good to have complementary tests that work in different environments,” says Heather Walker, facility manager of the University of Sheffield’s Biological Mass Spectrometry Facility. She says that PCR is reliable but slow and that a rapid, nimble testing method, like a breathalyzer, could be great for, say, testing passengers before they board an airplane.
- Different types of C19 tests can also reveal different kinds of information. “Certainly with breath analysis you would expect a change in metabolism if you had the virus,” Walker says, which would correspond to a change in the compounds expelled in breath. “But you wouldn’t necessarily be looking for antibodies to see if somebody had had the virus already and had recovered.” (Antibody tests are usually done using a blood draw.)
- So, when could Covid breathalyzers be available? That could depend on FDA approvals and on manufacturing capabilities for large-scale production, among other factors. Should she receive an emergency-use authorization, Ohio State’s Gouma hopes to begin deploying the devices as soon as this fall. At Northeastern, Sun says he and his colleagues are working to obtain a manufacturing partner for the device, and they’ll also still need FDA approval.
- Perhaps our breath, a culprit in spreading C19, will ultimately be used to our advantage. “I think that the time is now when breath analysis and minimally invasive diagnostics and monitoring can really help the world,” Davis says.
E. Improved & Potential Treatments
1. An Experimental Drug Reduces Hospitalizations by 72%
- A single infusion of an experimental drug markedly reduced levels of the coronavirus in newly infected patients and lowered the chances that they would need hospitalization, the drug’s maker announced on Wednesday.
- The drug is a monoclonal antibody, a manufactured copy of an antibody produced by a patient who recovered from C19. Many scientists hope that monoclonal antibodies will prove to be powerful treatments for C19, but they are difficult and expensive to manufacture, and progress has been slow.
- The announcement, by Eli Lilly, was not accompanied by detailed data; independent scientists have not yet reviewed the results, nor have they been published in a peer-reviewed journal. The findings are the interim results of an ongoing trial.
- More than 450 newly diagnosed patients received the monoclonal antibody or a placebo infusion. Some 1.7% of those who got the drug were hospitalized, compared with 6% of those who received a placebo — a 72% reduction in risk, Eli Lilly reported.
- Levels of the coronavirus plummeted among participants who received the drug, and their symptoms were fewer, compared with those who got the placebo.
- The treatments so far shown to help coronavirus patients — the antiviral drug remdesivir and the steroid dexamethasone — are intended only for hospitalized patients. Those with mild to moderate disease have had to wait and hope for the best.
- Dr. Myron Cohen, director of the Institute for Global Health and Infectious Diseases at the University of North Carolina at Chapel Hill, said he was impressed. The clinical trial appears to be rigorous, and the results are “really compelling.”
- Other companies, too, are developing monoclonal antibodies to combat the coronavirus, he noted: “This is the opening of a door.”
- Dr. Rajesh T. Gandhi, an infectious disease specialist at Massachusetts General Hospital, applauded Eli Lilly for studying people with mild to moderate disease. “That’s where more than 80% of patients are,” he said.
- Dr. Gandhi said it was encouraging that the drug seemed to have lowered amounts of the virus in the respiratory tract, and said it might mean that patients could be made less infectious. But that would be difficult to demonstrate, requiring enormous trials, he added.
- While the data so far are “tantalizing,” Dr. Gandhi said, he wanted more detail and anticipated the completion of the study, which will include more patients.
- Monoclonal antibodies are used to treat diseases from cancer to arthritis to eczema. But they are expensive and extremely difficult to manufacture.
- To make its monoclonal antibody, researchers at Eli Lilly gathered blood plasma from people who had survived infections with the coronavirus, retrieving and testing thousands of antibodies from the plasma to find the ones that seemed most powerful.
- Next the scientists determined that antibody’s genetic sequence and inserted DNA with that sequence into E. coli bacteria, turning them into tiny antibody factories. The bacteria were grown in huge stainless steel vats under aseptic conditions in a sterile room; the bacterial soup must be constantly monitored to ensure that it has not been contaminated by other microbes.
- Once the vat is teeming with bacteria and brimming with antibodies, workers remove the soup and concentrate the antibodies for use as a drug. They ship the new drug to a plant for packaging and labeling, all the while maintaining aseptic conditions and keeping the antibodies chilled.
- The process takes two to four weeks. The high cost of the monoclonal antibody results from the conditions that must be maintained to make such large quantities safely, Dr. Adams said.
- The study will eventually enroll 800 patients of all ages and in all risk categories at sites across the United States. So far the research has proceeded with unusual speed.
- Working feverishly, researchers at Eli Lilly needed just 6 months from isolating the antibody to enrolling the first patients on June 17.
- “It was an all-out effort,” said Dr. Daniel Skovronsky, the company’s chief scientific officer.
- Eli Lilly is also testing the drug in nursing homes to see if it prevents infections in residents and staff members.
- In addition to constantly measuring the amount of the coronavirus in blood, the investigators also sought to understand whether the pathogen was mutating to avoid antibodies.
- They found that the virus was changing, to some extent: 8% of the viruses had mutated in participants getting the drug, compared with 6% in those receiving the placebo. (Presumably, the virus also was trying to dodge the natural antibodies that placebo patients were making on their own.)
- The investigators expected that their drug might produce a reduction in the amount of virus in patients’ nasal passages. They did not anticipate a sharp reduction in patients who needed hospitalization.
- “This is the first time we have ever seen anything of this magnitude,” Dr. Skovronsky said.
- The antibody drug did not produce significant side effects, he said. Patients received a single infusion, providing antibodies that should last about a month.
- There is good news regarding a vaccine in these findings. If monoclonal antibodies had not worked, then the finding may have cast doubt on the notion that the virus could be stopped with antibodies.
- On the other hand, the results — if they are proven accurate — do not guarantee that a vaccine will work. Eli Lilly’s monoclonal antibody is a temporary treatment; a vaccine is designed to elicit long-lasting natural antibodies and thus immunity.
- Like other companies, Eli Lilly has been manufacturing large quantities of its drug — 100,000 doses — in the hope that it turns out to be effective.
- The company will be discussing its data with the FDA, Dr. Skovronsky said, along with the possibility of obtaining an emergency use authorization allowing Eli Lilly to market the drug.
- If the findings hold up, there will be comfort for the public in knowing there is something doctors can do to head off dire illness, Dr. Cohen said.
- “For my wife and I, who are older and fatter — we are waiting for drugs like this so we can see our grandchildren,” he added.
F. Concerns & Unknowns
1. The lasting misery of coronavirus long-haulers
- The lung scans were the first sign of trouble. In the early weeks of the coronavirus pandemic, clinical radiologist Ali Gholamrezanezhad began to notice that some people who had cleared their C19 infection still had distinct signs of damage. “Unfortunately, sometimes the scar never goes away,” he says.
- Gholamrezanezhad, at the University of Southern California in Los Angeles, and his team started tracking patients in January using computed tomography (CT) scanning to study their lungs. They followed up on 33 of them more than a month later, and their as-yet-unpublished data suggest that more than one-third had tissue death that has led to visible scars. The team plans to follow the group for several years.
- These patients are likely to represent the worst-case scenario. Because most infected people do not end up in hospital, Gholamrezanezhad says the overall rate of such intermediate-term lung damage is likely to be much lower — his best guess is that it is less than 10%. Nevertheless, given that 28.2 million people are known to have been infected so far, and that the lungs are just one of the places that clinicians have detected damage, even that low percentage implies that hundreds of thousands of people are experiencing lasting health consequences.
- Doctors are now concerned that the pandemic will lead to a significant surge of people battling lasting illnesses and disabilities. Because the disease is so new, no one knows yet what the long-term impacts will be. Some of the damage is likely to be a side effect of intensive treatments such as intubation, whereas other lingering problems could be caused by the virus itself. But preliminary studies and existing research into other coronaviruses suggest that the virus can injure multiple organs and cause some surprising symptoms.
- People with more severe infections might experience long-term damage not just in their lungs, but in their heart, immune system, brain and elsewhere. Evidence from previous coronavirus outbreaks, especially the severe acute respiratory syndrome (SARS) epidemic, suggests that these effects can last for years.
- And although in some cases the most severe infections also cause the worst long-term impacts, even mild cases can have life-changing effects — notably a lingering malaise similar to chronic fatigue syndrome.
- Many researchers are now launching follow-up studies of people who had been infected with the coronavirus. Several of these focus on damage to specific organs or systems; others plan to track a range of effects. In the United Kingdom, the Post-Hospitalisation C19 Study (PHOSP-COVID) aims to follow 10,000 patients for a year, analysing clinical factors such as blood tests and scans, and collecting data on biomarkers. A similar study of hundreds of people over 2 years launched in the United States at the end of July.
- What they find will be crucial in treating those with lasting symptoms and trying to prevent new infections from lingering. “We need clinical guidelines on what this care of survivors of C19 should look like,” says Nahid Bhadelia, an infectious-diseases clinician at Boston University School of Medicine in Massachusetts, who is setting up a clinic to support people with C19. “That can’t evolve until we quantify the problem.”
- In the first few months of the pandemic, as governments scrambled to stem the spread by implementing lockdowns and hospitals struggled to cope with the tide of cases, most research focused on treating or preventing infection.
- Doctors were well aware that viral infections could lead to chronic illness, but exploring that was not a priority. “At the beginning, everything was acute, and now we’re recognizing that there may be more problems,” says Helen Su, an immunologist at the National Institute of Allergy and Infectious Diseases in Bethesda, Maryland. “There is a definite need for long-term studies.”
- The obvious place to check for long-term harm is in the lungs, because C19 begins as a respiratory infection. Few peer-reviewed studies exploring lasting lung damage have been published. Gholamrezanezhad’s team analysed lung CT images of 919 patients from published studies1, and found that the lower lobes of the lungs are the most frequently damaged. The scans were riddled with opaque patches that indicate inflammation, that might make it difficult to breathe during sustained exercise. Visible damage normally reduced after two weeks1. An Austrian study also found that lung damage lessened with time: 88% of participants had visible damage 6 weeks after being discharged from hospital, but by 12 weeks, this number had fallen to 56% (see go.nature.com/3hiiopi).
- Lung scans from a 50-year-old show that damage from C19 (red) can improve with time — but many patients have lasting symptoms (above).
- Symptoms might take a long time to fade; a study2 posted on the preprint server medRxiv in August followed up on people who had been hospitalized, and found that even a month after being discharged, more than 70% were reporting shortness of breath and 13.5% were still using oxygen at home.
- Evidence from people infected with other coronaviruses suggests that the damage will linger for some. A study published in February recorded long-term lung harm from SARS, which is caused by SARS-CoV-1. Between 2003 and 2018, Peixun Zhang at Peking University People’s Hospital in Beijing and his colleagues tracked the health of 71 people who had been hospitalized with SARS. Even after 15 years, 4.6% still had visible lesions on their lungs, and 38% had reduced diffusion capacity, meaning that their lungs were poor at transferring oxygen into the blood and removing carbon dioxide from it.
- C19 often strikes the lungs first, but it is not simply a respiratory disease, and in many people, the lungs are not the worst-affected organ. In part, that’s because cells in many different locations harbour the ACE2 receptor that is the virus’s major target, but also because the infection can harm the immune system, which pervades the whole body.
- Some people who have recovered from C19 could be left with a weakened immune system. Many other viruses are thought to do this. “For a long time, it’s been suggested that people who have been infected with measles are immunosuppressed in an extended period and are vulnerable to other infections,” says Daniel Chertow, who studies emerging pathogens at the National Institutes of Health Clinical Center in Bethesda, Maryland. “I’m not saying that would be the case for COVID, I’m just saying there’s a lot we don’t know.” SARS, for instance, is known to decrease immune-system activity by reducing the production of signalling molecules called interferons.
- Su and her colleagues hope to enrol thousands of people worldwide in a project called the COVID Human Genetic Effort, which aims to find genetic variants that compromise people’s immune systems and make them more vulnerable to the virus. They plan to expand the study to those with long-term impairment, hoping to understand why their symptoms persist and to find ways to help them. “Someone who has prolonged problems, beyond what would be normally seen, they would be of interest to study,” says Su.
- The virus can also have the opposite effect, causing parts of the immune system to become overactive and trigger harmful inflammation throughout the body. This is well documented in the acute phase of the illness, and is implicated in some of the short-term impacts. For instance, it might explain why a small number of children with C19 develop widespread inflammation and organ problems.
- This immune over-reaction can also happen in adults with severe C19, and researchers want to know more about the knock-on effects after the virus has run its course. “It seems there’s a lag there for it to get hold of the person and then cause this severe inflammation,” says Adrienne Randolph, a senior associate in critical-care medicine at Boston Children’s Hospital. “But then the thing is that, long term, when they recover, how long does it take the immune system to settle back to normality?”
Heart of the matter
- An over-reactive immune system can lead to inflammation, and one particularly susceptible organ is the heart. During the acute phase of C19, about one-third of patients show cardiovascular symptoms, says Mao Chen, a cardiologist at Sichuan University in Chengdu, China. “It’s absolutely one of the short-term consequences.”
- One such symptom is cardiomyopathy, in which the muscles of the heart become stretched, stiff or thickened, affecting the heart’s ability to pump blood. Some patients also have pulmonary thrombosis, in which a clot blocks a blood vessel in the lungs. The virus can also injure the wider circulatory system, for instance, by infecting the cells lining blood vessels.
- Lung damage (opaque white patch, lower left) can persist for weeks after the initial infection.
- “My major concern is also the long-term impact,” says Chen. In some patients, he says, the risk to the cardiovascular system “lingers for a long time”. Chen and his colleagues reviewed data from before the pandemic for a study6 published in May, noting that people who have had pneumonia are at increased risk of cardiovascular disease 10 years later — although the absolute risk is still small. Chen speculates that an over-reactive immune system, and the resulting inflammation, might be involved. However, there is little information on long-term cardiovascular harms from SARS or the related disease Middle Eastern respiratory syndrome (MERS), let alone from the Coronavirus.
- Studies are now starting. At the beginning of June, the British Heart Foundation in London announced six research programmes, one of which will follow hospitalized patients for six months, tracking damage to their hearts and other organs. Data-sharing initiatives such as the CAPACITY registry, launched in March, are compiling reports from dozens of European hospitals about people with COVID-19 who have cardiovascular complications.
- Similar long-term studies are needed to understand the neurological and psychological consequences of COVID-19. Many people who become severely ill experience neurological complications such as delirium, and there is evidence that cognitive difficulties, including confusion and memory loss, persist for some time after the acute symptoms have cleared. But it is not clear whether this is because the virus can infect the brain, or whether the symptoms are a secondary consequence — perhaps of inflammation.
- One of the most insidious long-term effects of COVID-19 is its least understood: severe fatigue. Over the past nine months, an increasing number of people have reported crippling exhaustion and malaise after having the virus. Support groups on sites such as Facebook host thousands of members, who sometimes call themselves “long-haulers”. They struggle to get out of bed, or to work for more than a few minutes or hours at a time. One study7 of 143 people with COVID-19 discharged from a hospital in Rome found that 53% had reported fatigue and 43% had shortness of breath an average of 2 months after their symptoms started. A study of patients in China showed that 25% had abnormal lung function after 3 months, and that 16% were still fatigued.
- Paul Garner, a infectious-disease researcher at the Liverpool School of Tropical Medicine, UK, has experienced this at first hand. His initial symptoms were mild, but he has since experienced “a roller coaster of ill health, extreme emotions and utter exhaustion”. His mind became “foggy” and new symptoms cropped up almost every day, ranging from breathlessness to arthritis in his hands.
- These symptoms resemble chronic fatigue syndrome, also known as myalgic encephalomyelitis (ME). The medical profession has struggled for decades to define the disease — leading to a breakdown of trust with some patients. There are no known biomarkers, so it can only be diagnosed based on symptoms. Because the cause is not fully understood, it is unclear how to develop a treatment. Dismissive attitudes from doctors persist, according to some patients.
- People reporting chronic fatigue after having COVID-19 describe similar difficulties. In the forums, many long-haulers say they have received little or no support from doctors — perhaps because many of them showed only mild symptoms, or none at all, and were never hospitalized or in danger of dying. It will not be easy to establish the links between COVID-19 and fatigue with certainty, says Randolph. Fatigue does not seem to be limited to severe cases. It is common in people who had mild symptoms and who therefore might not have been tested for the virus.
- The only way to find out whether the coronavirus is behind these symptoms is to compare people known to have had the virus with those who have not, says Chertow, to see how often fatigue manifests and in what form. Otherwise there is a risk of lumping together people whose fatigue has manifested for different reasons, and who might need distinct treatments.
- Chertow says he is not aware of such a study for C19, but they have been done for other diseases. Following the Ebola epidemic in West Africa in 2014–16, US researchers collaborated with the Ministry of Health in Liberia to perform a long-term follow-up study9 called Prevail III. The study identified six long-term impacts from Ebola, ranging from joint pain to memory loss. Bhadelia, who treated hundreds of people with Ebola during the outbreak, says that these post-viral symptoms had not previously been recognized. Usually, she says, “we don’t stick around past the acute stage. We don’t look at the long tail of recovery. It’s important to do that, because it tells you more about the virus and its pathophysiology.”
- The situation is clearer for people who have been severely ill with COVID-19, especially those who ended up on ventilators, says Chertow. In the worst cases, patients experience injury to muscles or the nerves that supply them, and often face “a really long-fought battle on the order of months or up to years” to regain their previous health and fitness, he says. He and his colleagues are now recruiting people with COVID-19 from across the severity spectrum for a long-term follow-up study, assessing their brains, lungs, hearts, kidneys and inflammation responses while they are acutely ill, then during recovery a few weeks later, and again after 6–12 months (see go.nature.com/3mfqqxc).
- Once again, there is evidence from SARS that coronavirus infection can cause long-term fatigue. In 2011, Harvey Moldofsky and John Patcai at the University of Toronto in Canada described 22 people with SARS, all of whom remained unable to work 13–36 months after infection10. Compared with matched controls, they had persistent fatigue, muscle pain, depression and disrupted sleep. Another study11, published in 2009, tracked people with SARS for 4 years and found that 40% had chronic fatigue. Many were unemployed and had experienced social stigmatization.
- It is not clear how viruses might do this damage, but a 2017 review12 of the literature on chronic fatigue syndrome found that many patients have persistent low-level inflammation, possibly triggered by infection.
- If COVID-19 is such a trigger, a wave of psychological effects “may be imminent”, write a group of researchers led by Declan Lyons, a psychiatrist at St Patrick’s Mental Health Services in Dublin13. The ME Association, a UK-based charity, says it has received many reports of previously healthy people whose energy levels have not returned to normal after becoming infected with the virus, and expects to see new cases of chronic fatigue syndrome. In many countries, the pandemic shows no sign of waning, and health systems are already at capacity responding to acute cases. Nevertheless, researchers say it is crucial to start digging into the long-term effects now.
- But the answers will not come quickly. “The problem is,” says Gholamrezanezhad, “to assess long-term consequences, the only thing you need is time.”
2. How C19 can damage the brain
- The woman had seen lions and monkeys in her house. She was becoming disoriented and aggressive towards others, and was convinced that her husband was an impostor. She was in her mid-50s — decades older than the age at which psychosis typically develops — and had no psychiatric history. What she did have, however, was C19. Hers was one of the first known cases of someone developing psychosis after contracting the disease.
- In the early months of the C19 pandemic, doctors struggled to keep patients breathing, and focused mainly on treating damage to the lungs and circulatory system. But even then, evidence for neurological effects was accumulating. Some people hospitalized with C19 were experiencing delirium: they were confused, disorientated and agitated. In April, a group in Japan published the first report of someone with C19 who had swelling and inflammation in brain tissues. Another report described a patient with deterioration of myelin, a fatty coating that protects neurons and is irreversibly damaged in neurodegenerative diseases such as multiple sclerosis.
- “The neurological symptoms are only becoming more and more scary,” says Alysson Muotri, a neuroscientist at the University of California, San Diego, in La Jolla.
- The list now includes stroke, brain haemorrhage and memory loss. It is not unheard of for serious diseases to cause such effects, but the scale of the C19 pandemic means that thousands or even tens of thousands of people could already have these symptoms, and some might be facing lifelong problems as a result.
- Yet researchers are struggling to answer key questions — including basic ones, such as how many people have these conditions, and who is at risk. Most importantly, they want to know why these particular symptoms are showing up.
- Although viruses can invade and infect the brain, it is not clear whether the coronavirus does so to a significant extent. The neurological symptoms might instead be a result of overstimulation of the immune system. It is crucial to find out, because these two scenarios require entirely different treatments. “That’s why the disease mechanisms are so important,” says Benedict Michael, a neurologist at the University of Liverpool, UK.
- As the pandemic ramped up, Michael and his colleagues were among many scientists who began compiling case reports of neurological complications linked to C19.
- In a June paper, he and his team analysed clinical details for 125 people in the United Kingdom with C19 who had neurological or psychiatric effects. Of these, 62% had experienced damage to the brain’s blood supply, such as strokes and haemorrhages, and 31% had altered mental states, such as confusion or prolonged unconsciousness — sometimes accompanied by encephalitis, the swelling of brain tissue. Ten people who had altered mental states developed psychosis.
- Not all people with neurological symptoms have been seriously ill in intensive-care units, either. “We’ve seen this group of younger people without conventional risk factors who are having strokes, and patients having acute changes in mental status that are not otherwise explained,” says Michael.
- A similar study1 published in July compiled detailed case reports of 43 people with neurological complications from C19. Some patterns are becoming clear, says Michael Zandi, a neurologist at University College London and a lead author on the study. The most common neurological effects are stroke and encephalitis. The latter can escalate to a severe form called acute disseminated encephalomyelitis, in which both the brain and spinal cord become inflamed and neurons lose their myelin coatings — leading to symptoms resembling those of multiple sclerosis. Some of the worst-affected patients had only mild respiratory symptoms. “This was the brain being hit as their main disease,” says Zandi.
- Less common complications include peripheral nerve damage, typical of Guillain–Barré syndrome, and what Zandi calls “a hodgepodge of things”, such as anxiety and post-traumatic stress disorder. Similar symptoms have been seen in outbreaks of severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS), also caused by coronaviruses. But fewer people were infected in those outbreaks, so less data are available.
How many people?
- Clinicians don’t know how common these neurological effects are. Another study6 published in July estimated their prevalence using data from other coronaviruses. Symptoms affecting the central nervous system occurred in at least 0.04% of people with SARS and in 0.2% of those with MERS. Given that there are now 28.2 million confirmed cases of C19 worldwide, this could imply that between 10,000 and 50,000 people have experienced neurological complications.
- But a major problem in quantifying cases is that clinical studies have typically focused on people with C19 who were hospitalized, often those who required intensive care. The prevalence of neurological symptoms in this group could be “more than 50%”, says neurobiologist Fernanda De Felice at the Federal University of Rio de Janeiro in Brazil. But there is much less information about those who had mild illness or no respiratory symptoms.
- That scarcity of data means it is difficult to work out why some people have neurological symptoms and others do not. It is also unclear whether the effects will linger: C19 can have other health impacts that last for months, and different coronaviruses have left some people with symptoms for years.
Infection or inflammation?
- The most pressing question for many neuroscientists, however, is why the brain is affected at all. Although the pattern of disorders is fairly consistent, the underlying mechanisms are not yet clear, says De Felice.
- Finding an answer will help clinicians to choose the right treatments. “If this is direct viral infection of the central nervous system, these are the patients we should be targeting for remdesivir or another antiviral,” says Michael. “Whereas if the virus is not in the central nervous system, maybe the virus is clear of the body, then we need to treat with anti-inflammatory therapies.”
- Getting it wrong would be harmful. “It’s pointless giving the antivirals to someone if the virus is gone, and it’s risky giving anti-inflammatories to someone who’s got a virus in their brain,” says Michael.
- There is clear evidence that the coronavirus can infect neurons. Muotri’s team specializes in building ‘organoids’ — miniaturized clumps of brain tissue, made by coaxing human pluripotent stem cells to differentiate into neurons.
- In a May preprint7, the team showed that the coronavirus could infect neurons in these organoids, killing some and reducing the formation of synapses between them. Work by immunologist Akiko Iwasaki and her colleagues at Yale University School of Medicine in New Haven, Connecticut, seems to confirm this using human organoids, mouse brains and some post-mortem examinations, according to a preprint published on 8 September8. But questions remain over how the virus might reach people’s brains.
- Because loss of smell is a common symptom, neurologists wondered whether the olfactory nerve might provide a route of entry. “Everyone was concerned that this was a possibility,” says Michael. But the evidence points against it.
- A team led by Mary Fowkes, a pathologist at the Icahn School of Medicine at Mount Sinai in New York City, posted a preprint in late May9 describing post mortems in 67 people who had died of C19. “We have seen the virus in the brain itself,” says Fowkes: electron microscopes revealed its presence. But virus levels were low and were not consistently detectable. Furthermore, if the virus was invading through the olfactory nerve, the associated brain region should be the first to be affected. “We’re simply not seeing the virus involved in the olfactory bulb,” says Fowkes. Rather, she says, infections in the brain are small and tend to cluster around blood vessels.
- Michael agrees that the virus is hard to find in the brain, compared with other organs. Tests using the polymerase chain reaction (PCR) often do not detect it there, despite their high sensitivity, and several studies have failed to find any virus particles in the cerebrospinal fluid that surrounds the brain and spinal cord (see, for example, ref. 10)10. One reason might be that the ACE2 receptor, a protein on human cells that the virus uses to gain entry, is not expressed much in brain cells10.
- “It seems to be incredibly rare that you get viral central nervous system infection,” Michael says. That means many of the problems clinicians are seeing are probably a result of the body’s immune system fighting the virus.
- Still, this might not be true in all cases, which means that researchers will need to identify biomarkers that can reliably distinguish between a viral brain infection and immune activity. That, for now, means more clinical research, post mortems and physiological studies.
- De Felice says that she and her colleagues are planning to follow patients who have recovered after intensive care, and create a biobank of samples including cerebrospinal fluid. Zandi says that similar studies are beginning at University College London. Researchers will no doubt be sorting through such samples for years. Although the questions they’re addressing have come up during nearly every disease outbreak, C19 presents new challenges and opportunities, says Michael. “What we haven’t had since 1918 is a pandemic on this scale.”
G. Back to School!?
1. C19 complications killed 121 Americans under age 21 through July (0.077% of all deaths)
- A true saving grace of the pandemic is that C19 poses far less risk to children than to adults, particularly older adults. But in rare cases, it has made children and young adults severely sick or even been fatal.
- In a new report that analyzed fatal C19 cases in Americans under age 20, researchers found that some of the same patterns of deaths in older populations carried over to younger populations: There was a disproportionate burden among children and young adults with underlying health conditions and those who were Latinx, Black, or American Indian or Alaska Native.
- The report also found that 18- to 20-year-olds accounted for nearly half of the 121 deaths in the group during the time period studied — mid-February to the end of July — adding to the evidence that younger children generally are less likely to get seriously ill from C19. Still, 10% of fatal cases occurred in children under 1 year old.
- The report, from researchers at the Centers for Disease Control and Prevention and state and local health departments, was published Tuesday in the CDC’s Morbidity and Mortality Weekly Report.
- Overall, of the 121 people under 21 who died from C19 complications, 45% were Latinx, 29% were Black, 14% were white, and 4% were American Indian or Alaska Native. Seventy-five percent of the fatal cases were among children and young adults with existing medical problems, most commonly chronic lung diseases like asthma, obesity, neurologic or developmental conditions, or heart conditions.
- The tally of deaths include 15 that stemmed from what’s been named multisystem inflammatory syndrome in children, or MIS-C. It’s a rare but serious condition that typically develops two to four weeks after a case of C19 and involves severe inflammation affecting a range of organs. So far, doctors think it’s most likely to occur in children older than 5. Most kids recover, but a few cases have been fatal.
- In accounting for the differences in death rates by race and ethnicity, the researchers pointed to the challenges minority groups often face getting care. The groups are also “disproportionately represented among essential workers unable to work from their homes, resulting in higher risk for exposure to the coronavirus with potential secondary transmission among household members, including infants, children, adolescents, and young adults,” the researchers wrote. “In addition, disparities in social determinants of health, such as crowded living conditions, food and housing insecurity, wealth and educational gaps, and racial discrimination, likely contribute to racial and ethnic disparities in C19 and MIS-C incidence and outcomes”
- Overall, the 121 deaths of people under 21 accounted for just 0.08% of all C19 deaths in the country through July, the researchers reported. But they warned that the incidence of cases among children could change as day cares and schools reopen and children started having contact with more people. [NOTE: According to the CEC report, during February 12–July 31, a total of 391,814 cases of confirmed or probable C19 or MIS-C in persons aged <21 years were reported. At 121 deaths, the overall case fatality rate was 0.03%. For those without pre-exisiting conditions, the case fatality rate was 0.008%.
- Read the CDC study here:
2. College athletes show signs of possible heart injury after C19
- Amid growing concerns that a bout of C19 might damage the heart, a small study is reporting signs of an inflammatory heart condition in college athletes who had the infection.
- More than two dozen male and female competitive athletes at Ohio State University underwent magnetic resonance imaging of their hearts in the weeks to months after a positive test for the coronavirus. The images indicated swelling in the heart muscle and possible injury to cells in four of the athletes, or 15%, researchers report online September 11 in JAMA Cardiology. That could mean the athletes had myocarditis, an inflammation of the heart muscle most frequently caused by viral infections.
- Heart images of eight additional athletes showed signs of possible injury to cells without evidence of swelling. It’s more difficult to interpret whether these changes in the heart tissue are due to coronavirus infection, says Saurabh Rajpal, a cardiologist at the Ohio State University Wexner Medical Center in Columbus. One limitation of the research is the lack of images of the athletes’ hearts prior to the illness for comparison, Rajpal and his colleagues write.
- None of the 26 athletes in the study, who play football, soccer, basketball, lacrosse or run track, were hospitalized due to C19. Twelve of the 26, including two of the four with signs of inflamed hearts, reported mild symptoms during their infection, such as fever, sore throat, muscle aches and difficulty breathing.
- It will take more research to confirm the study’s findings and understand what they could mean for these young hearts. For now, the results suggest the heart may be at risk of injury, and serve as a reminder that after having C19 — even with mild or no symptoms — young people need to pay close attention to how they are feeling when they return to exercise, says Rajpal. If they have symptoms like chest pain, shortness of breath or an abnormal heartbeat, he says, they should see a doctor.
- It’s been apparent since early in the pandemic that C19 can be worse in patients who already have heart problems (SN: 3/20/20). More recently, studies have reported on what the infection might do to the heart. For example, researchers assessed 100 German adult patients who’d recovered from C19, one third of whom needed to be hospitalized. Cardiac MRIs revealed signs of heart inflammation in 60 of these patients after their infection.
- Those signals of heart inflammation could mean that the patients had developed myocarditis, which is estimated to occur in approximately 22 out of 100,000 people annually around the world. Patients with myocarditis can experience chest pain, shortness of breath, fatigue or a rapid or irregular heartbeat. The heart can recover from myocarditis, but in rare cases, the condition can damage the heart muscle enough to lead to heart failure.
- For athletes diagnosed with myocarditis, the recommendation is to stop participating in sports for three to six months to give the heart time to heal, as animal evidence suggests that vigorous exercise when the heart is still inflamed worsens the injury. With a break from sports, young athletes can expect to recover from myocarditis. But the condition is taken seriously: A 2015 study estimated that 10 percent of sudden cardiac deaths in NCAA athletes were due to myocarditis. When the Big Ten Conference, which includes Ohio State, announced in August that it was postponing its football season, one of the reported reasons was concerns about COVID-related myocarditis. [NOTE: Under pressure, The Big Ten voted to resume the football season in October.]
- This new study of college athletes and C19 “is really a step in the right direction,” says Meagan Wasfy, a sports cardiologist at Massachusetts General Hospital. “We need more data like this.” But it’s hard to draw firm conclusions from the findings, she says. Cardiac MRI usually is used to confirm a diagnosis of myocarditis in combination with other clinical signs, including symptoms, blood test results that signal inflammation, high levels of a protein called troponin I that indicates stress on the heart and abnormal findings in an electrocardiogram.
- In the study, while some athletes had signs of possible myocarditis in imaging, their troponin I levels were normal, and their electrocardiograms didn’t look unusual. Wasfy sees a few possible explanations. Had the athletes been tested when they were first infected, those other clinical signs might have shown up. Perhaps the other indications had returned to normal by the time the cardiac MRI and other tests were performed. In that case, the MRI is a “ghost” of that prior inflammation and stress, she says.
- Another possibility is that the coronavirus is impacting the heart muscle in a way that cardiologists aren’t accustomed to, absent some of the usual signs of inflammation and stress. Without those indicators of myocarditis, it’s hard to say if the heart had this condition, she says.
- Some might argue that the imaging signs could be chalked up to differences between the hearts of competitive athletes and those of the more sedentary. Wasfy thinks that’s less likely, but cardiologists “certainly have a lot of work to do to define what the prevalence of these [imaging] findings is at baseline” in healthy athletes.
- To expand on the study, Rajpal and his colleagues plan to take heart scans of more athletes, repeat cardiac MRIs in the athletes already imaged, and scan athletes who did not have C19 to compare their images with those who have.
- Sweden just recorded the fewest daily cases of C19 since the pandemic’s peak in March — all without a single lockdown.
- The Scandinavian country, intensely criticized for not shutting down businesses and mandating masks nationwide, now has one of the lowest number of C19 cases in Europe.
- Its rolling seven-day average stood at 108 on Tuesday, its lowest number since March 13, The Daily Mail reported.
- Just 1.2% of Sweden’s 120,000 tests last week were positive for the virus, data from their national health agency shows, according to The Guardian.
- “According to the European Centre for Disease Prevention and Control (ECDC), the Scandinavian country’s 14-day cumulative total of new cases was 22.2 per 100,000 inhabitants on Tuesday, against 279 in Spain, 158.5 in France, 118 in the Czech Republic, 77 in Belgium and 59 in the UK, all of which imposed lockdowns this spring,” the UK paper wrote.
- “We don’t have the resurgence of the disease that many countries have,” Anders Tegnell, the country’s chief epidemiologist and architect of its no-lockdown strategy, told broadcaster France-24 in an interview. “In the end, we will see how much difference it will make to have a strategy that’s more sustainable, that you can keep in place for a long time, instead of the strategy that means that you lock down, open up and lock down over and over again.”
- “Sweden has gone from being the country with the most infections in Europe to the safest one,” Tegnell last week told the Italian newspaper Corriere della Sera.
- “What we see now is that the sustainable policy might be slower in getting results, but it will get results eventually,” Tegnell said. “And then we also hope that the result will be more stable.”
- Tegnell has long taken a hard line, saying last month he saw “no point” in mandating masks in public across the country. “With numbers diminishing very quickly in Sweden, we see no point in wearing a face mask in Sweden, not even on public transport,” Anders Tegnell said, according to Fortune.
- “That Sweden has come down to these levels is very promising,” Tegnell told reporters in Stockholm last month. “The curves are going down and the curves for the seriously ill are beginning to approach zero.”
I. Projections & Our (Possible) Future
1. C19 will cause outbreaks year-round until herd immunity is reached, after which it will become seasonal in countries with temperate climates
- Thanks to the sniffling noses, coughs, and colds that accompany the colder months of the year, we are all too familiar with the seasonal patterns of some respiratory viruses. A new review published in Frontiers in Public Health suggests that C19 will likely follow suit and become seasonal in countries with temperate climates, but only when herd immunity is attained. Until that time, C19 will continue to circulate across the seasons. These conclusions highlight the absolute importance of public health measures needed just now to control the virus.
- Senior author of the study Dr. Hassan Zaraket, of the American University of Beirut in Lebanon, warns that “C19 is here to stay and it will continue to cause outbreaks year-round until herd immunity is achieved. Therefore, the public will need to learn to live with it and continue practicing the best prevention measures, including wearing of masks, physical distancing, hand hygiene and avoidance of gatherings.”
- Collaborating author Dr. Hadi Yassine, of Qatar University in Doha, affirms and states that there could be multiple waves of C19 before herd immunity is achieved.
- We know that many respiratory viruses follow seasonal patterns, especially in temperate regions. For instance, influenza and several types of coronaviruses that cause common cold are known to peak in winter in temperate regions but circulate year-round in tropical regions. The authors reviewed these seasonal viruses, examining the viral and host factors that control their seasonality as well as the latest knowledge on the stability and transmission of the coronavirus.
- The researchers explain that virus survival in the air and on surfaces, people’s susceptibility to infections and human behaviors, such as indoor crowding, differ across the seasons due to changes in temperature and humidity. These factors influence transmission of respiratory viruses at different times of the year.
- However, in comparison to other respiratory viruses such as the flu, C19 has a higher rate of transmission (R0), at least partly due to circulation in a largely immunologically naïve population.
- This means that unlike the flu and other respiratory viruses, the factors governing seasonality of viruses cannot yet halt the spread of C19 in the summer months. But, once herd immunity is attained through natural infections and vaccinations, the R0 should drop substantially, making the virus more susceptible to seasonal factors.
- Such seasonality has been reported for other coronaviruses, including those that emerged more recently such as NL63 and HKU1, which follow the same circulation pattern like influenza.
- “This remains a novel virus and despite the fast-growing body of science about it there are still things that are unknown. Whether our predictions hold true or not remains to be seen in the future. But we think it’s highly likely, given what we know so far, C19 will eventually become seasonal, like other coronaviruses,” adds Zaraket.
- Dr. Yassine states that “the highest global C19 infection rate per capita was recorded in the Gulf states, regardless of the hot summer season. Although this is majorly attributed to the rapid virus spread in closed communities, it affirms the need for rigorous control measures to limit virus spread, until herd immunity is achieved”.
J. Practical Tips & Other Useful Information
1. New Apple Watch can measure blood oxygen, a vital metric for people with C19
- Apple’s new Apple Watch Series 6 goes all-in on health care, including a new feature to measure blood oxygen level — a vital sign that’s been helpful monitoring C19, among other things. Other gadgets that do this, called pulse oximeters, have been around for ages, and have become something of a hot commodity during the coronavirus pandemic.
- The small devices usually clip onto your finger and painlessly check your blood to determine how well your lungs are working, but Apple Watch Series 6 will build it right into the smartwatch.
- When doctors pointed out that people with the coronavirus frequently arrive at the hospital with abnormally low oxygen levels, sales of pulse oximeters skyrocketed, especially after an op-ed piece in The New York Times recommended using them to detect a condition called “silent hypoxia,” which can indicate a coronavirus infection.
- However, questions and controversy still surround the at-home use of pulse oximeters, especially when used to monitor for C19. It’s still not entirely clear if pulse oximeters can help detect a coronavirus infection or whether their widespread use can help curb the spread of C19 overall.
- A pulse oximeter is a small medical device that measures heart rate and blood oxygen saturation. It’s usually clipped to your finger, but it can also attach to your ear, nose, toe or forehead. On Apple Watches, it’s the sensor on the underside of the watch, the part that goes against the top of your wrist, that takes the measurement.
- Some pulse oximeters are battery powered and provide real-time results on a small LED display on the device itself. Others connect with a wire to a separate vital sign monitor that records even more precise information about your heart rhythm, body temperature and blood pressure using other sensors connected to your body.
How pulse oximeters measure heart rate and oxygen
- A pulse oximeter measures your blood oxygen saturation and heart rate by shining a light through your skin and detecting both the color and movement of your blood cells. Oxygenated blood cells are bright red — deoxygenated cells are dark red.
- The pulse oximeter compares the number of bright red cells to dark red cells to calculate your oxygen saturation as a percentage. So, for example, a reading of 99% means only 1% of the blood cells in your bloodstream have been depleted of oxygen.
- Every time your heart beats, it pushes your blood through your body in a quick pulse (which is why “pulse” is another word for “heart rate”). A pulse oximeter, using light, detects this movement and calculates your heart rate in beats per minute, or BPM, basically the same way every Apple Watch since the first one does.
What’s a healthy oxygen level and heart rate?
- According to the Mayo Clinic, a normal pulse oximeter oxygen level reading is between 95% and 100%, and anything less than 90% is considered dangerously low, or hypoxic. Some doctors have reported C19 patients entering the hospital with oxygen levels at 50% or below.
- A normal resting heart rate is between 60 and 100 BPM. Typically, lower is better, as a slower heart rate is usually an indication of a strong cardiovascular system.
Can a pulse oximeter detect C19?
- Not exactly. Although many doctors report that patients with C19 are presenting with dangerously low blood oxygen levels, C19 isn’t the only disease that can cause such a problem. Chronic lung diseases, like COPD, asthma and other non-C19 lung infections can also result in a low oxygen count.
- A low oxygen reading by itself is not enough to diagnose C19, but your doctor would want to know about it, especially if you notice the level decreasing over time. And if you’ve been diagnosed with C19, your doctor may want you to monitor your oxygen level to determine whether your condition is worsening or improving.
How accurate are over-the-counter pulse oximeters?
- Like with any electronic equipment, not all pulse oximeters are created equal. A 2016 study of low-cost pulse oximeters concluded several inexpensive consumer-grade devices provided highly inaccurate readings.
- Some pulse oximeters have been cleared by the FDA, which means they should meet FDA standards for accuracy. Note that there is a distinction between “FDA-approved” and “FDA-cleared,” with “cleared” being the less rigorous of the two. That said, Class II medical devices like pulse oximeters are usually “cleared” rather than “approved.”
- You can look for pulse oximeters on the FDA-cleared list by visiting the FDA’s Premarket Notification website and searching for “pulse oximeter” in the Device Name field, with or without a manufacturer’s name.
How much should I spend on a standalone pulse oximeter?
- In the 2016 study that found most low-cost pulse oximeters to be relatively inaccurate, “low-cost” was defined as costing less than $50. Pulse oximeters that have been cleared by the FDA tend to range in price from around $50 to $60 to well into the hundreds and even thousands of dollars.
- Where can I buy a pulse oximeter if I don’t get an Apple Watch 6?
- Standalone pulse oximeters are on sale online — start here. You can also look at stores such as Walmart, Amazon and eBay and most brick-and-mortar drug stores, grocery stores and big box stores.
2. A Common Snake Oil Reemerges for the Coronavirus
- To the silver salesmen, moms must have seemed like an ideal demographic. Last year, Candy Keane, a 44-year-old lifestyle blogger in Florida, heard about colloidal silver—silver particles suspended in liquid—from a mom’s group she’s part of. A company called My Doctor Suggests was sending out free samples of its products, including colloidal-silver solution, lozenges, lotion, and soap, to bloggers who might be willing to review the products online.
- Keane spoke with Doug Godkin, the vice president of My Doctor Suggests, who she says assured her that taking the silver was as harmless as taking a vitamin, and that the solution could help with all kinds of ailments. She remembers him saying it would be safe to drink up to a bottle a day.
- Keane thought the silver might clear up some white splotches that had spread across her skin. She tried all the products and sipped the metallic-tasting “silver solution” daily. While they didn’t seem to do much, they didn’t make anything worse, either. She wrote up her results, such as they were, in a blog post. When she later read an (erroneous) online claim that silver can kill the coronavirus as it enters the mouth, she let her 5-year-old son eat the rest of the lozenges—he liked their sweet taste.
- Before I called her, Keane hadn’t realized that in April, a federal court in Utah shut down My Doctor Suggests for allegedly fraudulently promoting their colloidal-silver products as a treatment for C19. Godkin and My Doctor Suggests’s founder, a self-proclaimed naturopathic doctor named Gordon Pedersen, released videos and podcasts in which they suggested that colloidal silver could protect against the coronavirus because “the silver can isolate and eliminate that virus.” Pedersen has no medical license, and he has been cited in the past for the unauthorized practice of medicine. (Godkin declined to comment, and lawyers for Godkin and Pedersen did not return requests for comment. A spokesperson for Pedersen has previously said that “all the statements he has made are supported by scientific documents.”)
- Pedersen’s efforts may have been halted, but he’s far from the only one selling this substance. The state of Missouri recently filed suit against the televangelist Jim Bakker for promoting a “Silver Solution” for the coronavirus on his show. And last month, the U.S. Food and Drug Administration went to court to stop an Oklahoma company called N-Ergetics from allegedly touting colloidal silver as a cure for everything from the coronavirus to yeast infections. (“Jim Bakker is being unfairly targeted by those who want to crush his ministry and force his Christian television program off the air,” Jay Nixon, Bakker’s attorney and the former governor of Missouri, said in a statement. “Bakker did not claim or state that Silver Solution was a cure for C19.” And in a statement to the Tulsa World, N-Ergetics said, “To the best of our knowledge, we are in compliance.”)
- What’s happening here seems deeper than snake-oil salesmen foisting useless potions on people. All of these silver peddlers are tapping into a real interest in the stuff. Colloidal silver enjoys a devout following online among people who believe it can cure a number of diseases. Before the site was shut down, demand for My Doctor Suggests’s products was surging, and Pedersen was paying a separate company an average of $10,000 a week to fulfill orders.
- Unlike Pedersen’s or Bakker’s, though, most colloidal-silver brewers are homespun operations in which people make the silver themselves or buy it in small quantities from a trusted source. Devotees say its effects have been nearly miraculous for various ailments, including suspected C19 cases. They flock to Facebook groups to discuss the best ways to prepare the solution and share success stories.
- Though topical silver can be used in wound care, almost all mainstream scientists say colloidal silver doesn’t do much of anything—except, in extreme cases, turn a person’s skin blue. Most doctors would say these individuals’ positive experiences are most likely the result of a placebo effect, or of the disease resolving on its own. According to the National Center for Complementary and Integrative Health, silver has “no known function or benefits in the body when taken by mouth.”
- Nevertheless, people’s deep faith in colloidal silver speaks to how the uncertainty of C19 has fueled a desire for alternative remedies. Crises such as the current pandemic are a prime time for sham cures, fraud experts told me, because people are isolated, afraid, and willing to do whatever it takes to protect themselves.
- More so now than normally, people feel let down and ripped off by medical professionals. There’s no proven treatment for the coronavirus, and advice about how to stave it off seems to shift from week to week. Some people now look at “natural” remedies such as silver and think, At least this won’t hurt me.
- In April, Alyss H. had spent weeks gasping for breath, and she was desperate for relief. Alyss, a 34-year-old who lives in Oklahoma City, had been following the spread of the novel coronavirus since it was first identified in China in December. (She asked me to use only her first name and last initial to protect her family’s privacy.) She learned about the R0 number, and understood that quarantines were a possibility in the United States. She was worried about her family.
- Her nightmare, it seemed, had come true. Alyss had body aches, a bad sore throat, and a persistent burning in her chest, and antibiotics weren’t working. She started researching colloidal silver in medical journals, and she began corresponding on Facebook with a British man, Jim Ryan, who appeared to have a lot of information on the subject.
- She followed the instructions for making colloidal silver the way Ryan suggested. She placed two strands of silver wire in a flask of water on top of a hot plate set to 160 degrees. She hooked a battery to the silver, and kept the wire submerged until the water turned urine yellow. This process, Ryan said, releases the silver particles into the water. Then, Alyss drank the water, making sure to keep it in her mouth for a few minutes and sloshing it under her tongue.
- Two days later, she told me, she felt better. She still drinks about 20 milliliters of colloidal silver two or three times daily—five times a day if she’s feeling sick. Alyss seems to understand why the FDA is cracking down on colloidal-silver manufacturers. But, she said, what other options are there? She’s still not sure whether she had C19, but doctors sent her home to convalesce alone for weeks. “My recommendation is to fight it,” she said. “Fight it with everything you have.” Including silver.
- Ryan, the man who taught her about the silver, has been into colloidal silver for more than two decades. A 48-year-old tattoo artist and a helicopter pilot from Devon, Ryan blasted me with a torrent of silver’s glories during our phone call. “It doesn’t actually kill the virus,” he explained, sounding like a rapid-fire Ozzy Osbourne. “It literally stops, it prevents the bacteria or the virus from doing its job, which is to cause that chest infection that leads to pneumonia.”
- He and others I interviewed wanted to let me know that the infamous “blue man”—Paul Karason, who appeared on the Today show in 2008 with violet skin from a supposed silver overdose—was actually drinking too much of it, and in the wrong formulation, and for decades. But, they were sure to add, he didn’t get sick.
- Ryan, too, used a colloidal-silver solution on himself and his daughter when they had what he thought was C19. “It turns COVID into a mere sniffle,” he assured me.
- Perhaps expectedly, doctors push back against this idea. David Gorski, a surgical oncologist at the Karmanos Cancer Institute and the managing editor of the pseudoscience-debunking blog Science-Based Medicine, told me via email that Ryan and others are simply confusing correlation and causation. “Without a placebo or no-treatment control, there’s no way of knowing if the person would have gotten better anyway,” he said. “This is particularly true for a disease with such a variable level of severity as C19, which can range from asymptomatic to mild symptoms to life-threatening.”
- Still, there’s an element of seeing-for-yourself-ness among the silver stans. Ryan emphasized that he likes to research “both sides of the coin” and to question official narratives. His daughter is unvaccinated. He and others said they did months of research before they jumped into the silver world. They had this sense that there was a body of information that experts don’t want you to know, and they were lucky to have figured it out.
- In central Wisconsin, Dawn Louise—who also didn’t want me to use her full name for privacy reasons—says she found success using colloidal silver for her Lyme disease and shingles. When her 40-year-old daughter started having C19 symptoms recently, with plummeting oxygen and shortness of breath, Dawn gave some to her. In 48 hours, Dawn told me, her daughter could breathe again.
- When I told Dawn that Pedersen and others had been shut down because they were considered fraudulent, she wasn’t surprised at all—nor was she daunted. In her mind, it was a sign that the substance works, but there wasn’t an opportunity for Big Pharma to capitalize on it. “They don’t want that found out, the truth that it actually does work,” she said. “They want to get their patent on it so they can make it a prescription.”
- C19 is a brand-new, deadly condition about which little is known, which can appear to strike at random, and which has no cure. “It’s very fear-arousing,” Michael Goldstein, a sociologist and a complementary- and alternative-medicine expert at UCLA, told me. That kind of situation primes people to seek out unconventional remedies, to try to regain some of the power that’s been stripped away by a scary new menace. Or as Alyss put it to me, “we all wanted to have control in our lives, and it felt like a possibility to have control.”
- People who are into untested treatments such as colloidal silver—or even ever-so-slightly-more-evidence-based treatments such as Reiki or acupuncture—are commonly derided as crackpots. But in many cases, experts say, they are drawn to these New Age-y cures because of bad experiences they’ve had with conventional medicine. “Most people don’t start by going to some kind of alternative provider,” Goldstein said. “They start by going to the doctor, and they find that whatever the doctor has to offer doesn’t really help them in a way that they want to be helped. So that skepticism is one of the things that leads people to say, Well, the next time I have this problem, I’m going to go to a chiropractor or an acupuncturist.”
- This is especially true when people are weighing what seems like a safe medication—and silver does seem safe, to them—against the deadly consequences of certain prescription drugs, such as opioids. Though few responsible doctors would prescribe opioids for C19, President Donald Trump has recently encouraged people to take the antimalarial hydroxychloroquine. When a man in Arizona tried to take a fish-tank cleaner with a similar name, he died.
- Some experts warn that untested remedies such as colloidal silver may, too, become more damaging once a coronavirus vaccine becomes available. If people begin rejecting the vaccine in favor of “alternative” treatments, it will greatly reduce our ability to reach herd immunity and reopen society. “One of the things that I will be monitoring is whether or not some of that group that plans to refuse the vaccine is doing so because they think that other treatments—alternative treatments—will get the job done,” Matthew Motta, a political-science professor at Oklahoma State University, told me. “That to me is potentially very scary.”
- Compared with prescription drugs, silver might seem more “natural” to some people, Maria Chao, the associate director of research at the University of California San Francisco’s Osher Center for Integrative Medicine, told me. People tend to be drawn to such organic-seeming cures because they see illness as a violation of the natural, healthy state of the world, according to Alan Levinovitz, a religion professor at James Madison University and the author of the recent book Natural, about people’s faith in nature. “Naturalness represents that which is good, and that which will return us to health,” Levinovitz told me.
- Simmering a pair of silver wires and drinking the resulting mixture also serves as a kind of ritual, and rituals can help us feel better about things when little else can. (Just think of all the “morning ritual” literature out there.) “It’s about symbolic empowerment,” Levinovitz said. “These are rituals that people can do when they’ve lost confidence in an establishment.”
- And why wouldn’t they have lost confidence in conventional medicine? Pharmaceutical companies actually did lie about the addictive nature of prescription opioids. People get rushed to hospitals, only to face confounding, towering bills later. Less nefariously, but still significantly, some public-health experts were telling us not to wear masks as recently as a month ago. The internet brims with misinformation, such as the kind Keane, the blogger, stumbled on, about what can and cannot kill the coronavirus.
- None of this means that unscrupulous silver scammers shouldn’t go unpunished, or that even more people should consider taking colloidal silver for C19. But it should, perhaps, help us understand why people believe in something dubious at a time when there isn’t much to believe in.
- At one point in our interview about colloidal silver, Chao, a professor who has multiple advanced degrees from Columbia University, admitted that while she doesn’t know when she would ever actually take silver, “I have a bottle of it in my medicine cabinet.”
K. Johns Hopkins COVID-19 Update
September 16, 2020
1. Cases & Trends
- The WHO C19 Dashboard reports 29.36 million cases and 930,260 deaths as of 5:45am EDT on September 16.
- Globally, at least 11 countries are reporting test positivity greater than 15%, at least 3 times higher than the WHO’s 5% benchmark. Of these countries, 4 are reporting test positivity greater than 30%: Argentina (51.6%), Mexico (47.4%), Oman (38.9%)*, and Bolivia (32.5%). Additionally, a number of these countries are reporting increasing trends, which indicates that testing capacity is not sufficient to accurately capture the existing level of community transmission. Beyond the countries reporting high test positivity, a number of countries currently reporting increasing incidence are also reporting increasing test positivity. Several in Europe are reporting increased test positivity, including the Czech Republic, France, Hungary, Italy, Norway, Spain, and the UK. While a number of these countries have sufficiently low test positivity, including some less than 3%, the increasing trends have persisted over the past several weeks, which is concerning.
- In the US, test positivity has increased sharply over the past several days as well, up from 4.8% to 6.1% (a 27% increase) from September 10 to September 13—the most recent data available—which is the highest average reported in the US since August 12. Notably, the testing volume in the US decreased sharply over that time as well, falling below 600,000 tests per day for the first time since mid-June. Additionally, C19 incidence has increased in the US over the past several days, so it will be important to continue monitoring test positivity to determine if this could be the early stage of a longer-term trend.
- As we have addressed previously, test positivity data is not available for many countries, so it is likely that additional countries are facing similar challenges.
- The US CDC reported 6.54 million total cases and 194,092 deaths. The US is averaging 35,752 new cases and 772 deaths per day, both slight increases over the past several days. If the US continues at its current pace, it could reach 200,000 cumulative C19 deaths in the next 8 days. In total, 21 states (no change) are reporting more than 100,000 cases, including California with more than 700,000 cases; Florida and Texas with more than 600,000; New York with more than 400,000; and Arizona, Georgia, and Illinois with more than 200,000.
- The Johns Hopkins CSSE dashboard reported 6.61 million US cases and 195,926 deaths as of 10:30am EDT on September 16.
2. US CDC REPORTING & GUIDANCE
- Reports have emerged over the past week that publications in the CDC’s Morbidity Mortality Weekly Report (MMWR) journal have been subject to review by political appointees. The initial report was made by Politico and then supported by other media outlets. This is a departure from the traditional scientific review process, and has raised concerns by some experts that the involvement of political appointees could jeopardize the impartiality of the information contained in the articles. The MMWR is a key source of information for outside experts, including state and local public health officials and clinicians. Some experts also expressed concern that political involvement, or the appearance of political involvement, in CDC reporting could further undermine confidence in health and regulatory agencies and officials, which could be particularly problematic in terms of establishing confidence in a future vaccine.
- HHS Assistant Secretary for Communications, Michael Caputo, said that the effort was designed to increase scrutiny over CDC reporting, but he also accused the CDC reports of including “political content” in their reports, as opposed to strictly technical information and evidence-based guidance. Mr. Caputo has himself recently faced controversy for a video posted on his personal Facebook page in which he levied a series of accusations against CDC scientists, including that they were engaging in acts of “sedition.” It is not clear exactly whether or how the review by government officials outside of the CDC ultimately changed the content of individual reports.
3. US K-12 SCHOOLS
- US school districts are employing a wide array of approaches to provide educational opportunities, whether in person or remote, to students. According to Burbio, more than 60% of public schools in the US have decided to begin the academic year with remote learning. While some schools had planned to bring students back in person, at least in some capacity, a renewed increase in C19 cases has forced several districts to return to remote learning plans. School superintendents point to students attending parties before the start of school as one reason for the rise in cases. Coupled with staff shortages, school districts have few choices other than to pursue remote learning. Plans to return students physically to class have not been fully abandoned; many schools are looking at the possibility of delayed return to in-person learning in October or January. Parents counting on the return of their children to school have been disappointed that in-person learning will not occur on schedule, but many agree that the safety of students and staff are paramount under the current circumstances.
- Above the school district level, state-level interventions to support in-person learning are also highly varied across the US. In Rhode Island, the state government has initiated a school testing program that offers free diagnostic testing to students, teachers, and staff. This program is separate from the normal state testing program. Rhode Island Health Director Dr. Nicole Alexander-Scott reported that the school testing program would be able to run 5,000 tests per day. Meanwhile, Florida Governor Ron DeSantis declared that school testing data is considered confidential by the government and has not encouraged schools to independently report their data. However, many school districts have decided to continue publishing their case data in the interest of transparency for students, staff, and the community. While open and transparent data sharing practices are important for controlling C19 in communities, the lack of standardization for reporting across school districts could complicate response efforts.
4. US COLLEGES & UNIVERSITIES
- On a per capita basis, college towns are accounting for many of the country’s most severe outbreaks. According to data published by USA Today on September 11, 19 of the top 25 local outbreaks in the US were in college towns. Harrisonburg, Virginia—home to James Madison University—topped the list with more than 1,500 cases per 100,000 population over the previous 2 weeks. The school suspended in-person classes and sent students home in order to reduce the number of people on campus after detecting more than 500 cases within the first week of classes.
- Universities continue to issue suspensions and other punishments for students who violate university C19 policies or public health guidelines. Virginia Tech has now issued more than 40 interim suspensions to students and removed some students from campus housing. Oxford, Mississippi, home to the University of Mississippi (Ole Miss), has issued more than 60 citations since August to people for violations of local social distancing restrictions. Transmission around college campuses is not limited to students and staff. In Oxford, 26 residents in a long-term care facility for veterans “died in connection with” C19 in the past month. Although it is likely not possible to link students directly to individual cases and deaths in the local community in most instances, transmission between the university population and local public is inevitable.
5. US PEDIATRIC TESTING
- Since the onset of the pandemic, SARS-CoV-2 testing has been a challenge in the US. Following the summer resurgence, the US appeared to be recovering in terms of testing capacity, with the national-level test positivity settling in at approximately 5%—in line with the WHO’s benchmark. Notably, however, national testing volume has decreased drastically over the past several days—dropping from 800,000 tests per day to fewer than 600,000 in just 4 days—and test positivity has sharply increased. But the national trends do not tell the entire story. One problem in particular, lies in testing availability for pediatric patients. This barrier is especially problematic as the school year starts and children across the country resume in-person classes. Many public testing sites are not able to provide tests for children (or have an age cutoff that excludes younger children), and many pediatricians do not offer testing or have limited testing supplies, making it difficult for parents and guardians to identify testing locations that will accept their children. As it becomes increasingly clear that children can be infected and transmit the virus it is critical that health systems and public health agencies incorporate pediatric patients into their testing strategies.
6. US ELECTION & VOTING
- The US presidential election is less than 50 days away, and it is clear that this election will be like no other in history. Election experts anticipate an increase in the use of mail-in voting in many parts of the country, as many people are concerned about the risk of SARS-CoV-2 transmission at polling locations. States vary widely in how they are addressing the need or desire to vote by mail during the pandemic, as opposed to in person, as well as their readiness to implement vote-by-mail programs. According to Ballotpedia, at least 35 states have adapted voting regulations regarding absentee or mail-in voting in response to C19. Efforts to increase access to mail-in voting in some states have been challenged in court, with outcomes of these lawsuits varying from state to state. In addition to voters in the US, US citizens currently living in other countries may also face challenges to the normal absentee voting process. In Hong Kong, for example, government officials warned that standard mail to the US could take several months to arrive, so individuals might need to use couriers or other services in order to request, receive, and return ballots on time. Additionally, the US Postal Service (USPS) has suspended international mail service to more than 40 countries and territories due to C19.
- In addition to voting, presidential and other campaigns are navigating restrictions imposed to contain C19. As we covered previously, the Democratic and Republican National Conventions incorporated a variety of changes, including remote speeches and delegate voting. The Presidential debate schedule and format have been finalized, although the location of several debates has already changed due to C19 concerns. As the election season continues, both presidential candidates, President Donald Trump and former Vice President Joe Biden, are ramping up their campaign schedules.
- Notably, the two candidates are taking different approaches to campaign events, including rallies. Earlier this week, President Trump held his first indoor rally since June. The event, held in Nevada (which prohibits indoor gatherings of more than 50 people), drew thousands of people. Many attendees did not wear masks or practice appropriate physical distancing, prompting the local government to issue a fine of $3,000 to the company hosting the event for violating state C19 restrictions. Conversely, Joe Biden and running mate Senator Kamala Harris continue to host remote events or smaller in-person events rather than large rallies. These events reportedly maintain strict adherence to mask use and social distancing recommendations or requirements.
7. CORONAVIRUS RESEARCH
- The FDA is collaborating with researchers in the UK, Saudi Arabia, and Singapore to conduct a study of SARS-CoV, SARS-CoV-2, and MERS-CoV clinical specimens in order to better characterize coronavirus evolution, virulence, and immunity. The research could provide critical insight for vaccine and therapeutic development and identify biomarkers for disease severity and progression as well as enhanced immunity or protection. Additionally, the study aims to research the potential for these coronaviruses to develop antiviral resistance. As part of the study, the researchers will develop and evaluate in vitro models for coronavirus infections, including “organs-on-chips,” and validate them against animal and human in vivo responses to support advanced MCM screening efforts. The study is scheduled to run through 2023 and projected to cost US$5.4 million.
8. VACCINE CLINICAL TRIALS
- Following news that Phase 3 clinical trials for the AstraZeneca/Oxford University vaccine will resume in the UK after pausing to evaluate a serious adverse event in one of the participants, US regulatory authorities are evaluating the available data to determine whether or not to proceed with the clinical trials. Reportedly, there is considerable concern among senior officials at the NIH, and the agency is awaiting tissue samples for evaluation. One senior agency researcher indicated that an assessment could take a month or longer to determine whether it is appropriate to continue the clinical trials in the US. Regulatory officials and experts at the NIH may compare tissue samples to those from US trial participants or request additional data from the UK researchers and safety monitoring board.
- In the UK, researchers at Imperial College London and Oxford University are reportedly initiating a study to determine if candidate SARS-CoV-2 vaccines could potentially be inhaled rather than injected. Previous studies for other vaccines have found that nasal formulations require lower doses compared to intramuscular injection, which could increase the number of doses available, particularly early on as production capacity is scaling up. Additionally, many people prefer nasal sprays to injections. The study will include 30 participants and test vaccines developed by both universities.
9. DIVERSITY & ETHICS IN CLINICAL TRIALS
- One of the major challenges facing clinical trials in the midst of the C19 pandemic is ensuring appropriate inclusion and diversity among participants. Certain populations, including racial and ethnic minorities and incarcerated individuals, have faced a disproportionate burden during the pandemic, but there are concerns among researchers and health experts that clinical trial subjects are not sufficiently representative of the affected population. As we covered earlier this week, Pfizer, Inc., recently announced its intent to expand the study population for the Phase 3 trials of its candidate vaccine, in part to improve the diversity among the participants. Despite awareness campaigns, some trials—for vaccines and other investigational drugs—continue to struggle to enroll racial and ethnic minorities, which can hinder efforts to effectively evaluate candidate vaccines’ efficacy through clinical trials.
- While incarcerated individuals represent a high-risk population, both for infection and severe disease and death, it is difficult to include these individuals in clinical trials. From an ethical perspective, there is concern that these individuals, due to the control and restrictions associated with their incarceration, may not be able to fully consent to be included in clinical trials.
- Pharmaceutical company Eli Lilly announced preliminary findings from a study that indicates that baricitinib, a drug typically used to treat rheumatoid arthritis, could provide treatment benefit for hospitalized C19 patients when administered in conjunction with remdesivir. The study was conducted under the Adaptive C19 Treatment Trial (ACTT-2), which is administered by the US National Institute of Allergy and Infectious Disease (NIAID). According to a press release issued by Eli Lilly, the study was randomized, double-blinded, and placebo-controlled and included more than 1,000 hospitalized C19 patients. Participants received either baricitinib in conjunction with remdesivir or remdesivir treatment alone.
- The patients who received baricitinib exhibited a statistically significant decrease of 1 day in their time to hospital discharge. Additional analysis is ongoing, including for safety and mortality. Based on the data, Eli Lilly intends to discuss the possibility of an Emergency Use Authorization. Eli Lilly is also conducting a Phase 3 clinical trial for the drug—”baricitinib versus background therapy”—in the US and multiple countries in Europe, Asia, and Latin America. While this preliminary data is promising, additional study is needed to better characterize the treatment benefits of baricitinib as well as its safety profile. Like numerous previous examples during the C19 pandemic, early results from clinical trials are being published first in press release form rather than in peer-reviewed publications, and we have not yet been able to locate the underlying data and analysis that supports the press release.