Masks and Distancing Won't Be Enough to Prevent School Outbreaks, Latest Science Suggests
The likely dominant mode of aerosol transmission cannot be ignored in school settings.
Never has the prospect of "back to school" seemed so ominous as it does in 2020. As the number of COVID-19 cases climb steadily in nearly every state, the prospect of in-person classes are filling students, parents, and faculty alike with a corresponding sense of dread.
The notion that children are immune or resistant to SARS-CoV-2 is demonstrably untrue.
The decision to resume classes at primary, secondary, and collegiate levels is not one that should be regarded lightly, particularly as coronavirus cases skyrocket across the United States.
What should be a measured, data-driven discussion that weighs risks and benefits has been derailed by political talking points. President Trump has been steadily advocating for an unfettered return to the classroom, often through imperative "OPEN THE SCHOOLS!!!" tweets. In July, Secretary of Education Betsy DeVos threatened to withhold funding from schools that did not reopen for full-time, in-person classes, despite not having the authority to do so. Like so many public health issues, opening schools in the midst of a generational pandemic has been politicized to the point that the question of whether it is safe to do so has been obscured and confounded. However, this question still deserves to be examined based on evidence.
What We Know About Kids and COVID-19
Some arguments for returning to in-person education have focused on the fact that children and young adults are less susceptible to severe disease. In some cases, people have stated that children cannot be infected, pointing to countries that have resumed in-person education with no associated outbreaks. However, those countries had extremely low community transmission and robust testing and surveillance.
The notion that children are immune or resistant to SARS-CoV-2 is demonstrably untrue: children can be infected, they can become sick, and, in rare cases, they can die. Children can also transmit the virus to others, especially if they are in prolonged proximity to them. A Georgia sleepaway camp was the site of at least 260 cases among mostly children and teenagers, some as young as 6 years old. Children have been shown to shed infectious virus in their nasal secretions and have viral loads comparable to adults. Children can unquestionably be infected with SARS-CoV-2 and spread it to others.
The more data emerges, the more it appears that both primary and secondary schools and universities alike are conducive environments for super-spreading. Mitigating these risks depends heavily on individual schools' ability to enforce reduction measures. So far, the evidence demonstrates that in most cases, schools are unable to adequately protect students or staff. A school superintendent from a small district in Arizona recently described an outbreak that occurred among staff prior to in-person classes resuming. Schools that have opened so far have almost immediately reported new clusters of cases among students or staff.
This is because it is impossible to completely eliminate risk even with the most thoughtful mitigation measures when community transmission is high. Risk can be reduced, but the greater the likelihood that someone will be exposed in the community, the greater the risk they might pass the virus to others on campus or in the classroom.
There are still many unknowns about SARS-CoV-2 transmission, but some environments are known risks for virus transmission: enclosed spaces with crowds of people in close proximity over extended durations. Transmission is thought to occur predominantly through inhaled aerosols or droplets containing SARS-CoV-2, which are produced through common school activities such as breathing, speaking, or singing. Masks reduce but do not eliminate the production of these aerosols. Implementing universal mask-wearing and physical distancing guidelines will furthermore be extraordinarily challenging for very young children.
Smaller particle aerosols can remain suspended in the air and accumulate over time. In an enclosed space where people are gathering, such as a classroom, this renders risk mitigation measures such as physical distancing and masks ineffective. Many classrooms at all levels of education are not conducive to improving ventilation through low-cost measures such as opening windows, much less installing costly air filtration systems.
As a risk reduction measure, ventilation greatly depends on factors like window placement, window type, room size, room occupancy, building HVAC systems, and overall airflow. There isn't much hard data on the specific effects of ventilation on virus transmission, and the models that support ventilation rely on assumptions based on scant experimental evidence that doesn't account for virologic parameters.
There is also no data about how effective air filtration or UV systems would be for SARS-CoV-2 transmission risk reduction, so it's hard to say if this would result in a meaningful risk reduction or not. We don't have enough data outside of a hospital setting to support that ventilation and/or filtration would significantly reduce risk, and it's impractical (and most likely impossible in most schools) to implement hospital ventilation systems, which would likely require massive remodeling of existing HVAC infrastructure. In a close contact situation, the risk reduction might be minimal anyway since it's difficult to avoid exposure to respiratory aerosols and droplets a person is exhaling.
You'd need to get very low rates in the local community to open safely in person regardless of other risk reduction measures, and this would need to be complemented by robust testing and contact tracing capacity.
Efforts to resume in-person education depend heavily on school health and safety plans, which often rely on self-reporting of symptoms due to insufficient testing capacity. Self-reporting is notoriously unreliable, and furthermore, SARS-CoV-2 can be readily transmitted by pre-symptomatic individuals who may be unaware that they are sick, making testing an essential component of any such plan. Primary and secondary schools are faced with limited access to testing and no funds to support it. Even in institutions that include a testing component in their reopening plans, this is still too infrequent to support the full student body returning to campus.
Economic Conflicts of Interest
Rebecca Harrison, a PhD candidate at Cornell University serving on the campus reopening committee, is concerned that her institution's plan places too much faith in testing capacity and is over-reliant on untested models. Harrison says that, as a result, students are being implicitly encouraged to return to campus and "very little has been done to actively encourage students who are safe and able to stay home, to actually stay home."
Harrison also is concerned that her institution "presumably hopes to draw students back from the safety of their parents' basements to (re)join the residential campus experience ... and drive revenue." This is a legitimate concern. Some schools may be actively thwarting safety plans in place to protect students based on financial incentives. Student athletes at Colorado State have alleged that football coaches told them not to report COVID-19 symptoms and are manipulating contact tracing reports.
Public primary and secondary schools are not dependent on student athletics for revenue, but nonetheless are susceptible to state and federal policies that tie reopening to budgets. If schools are forced to make decisions based on a balance sheet, rather than the health and safety of students, teachers, and staff, they will implement health and safety plans that are inadequate. Schools will become ground zero for new clusters of cases.
Looking Ahead: When Will Schools Be Able to Open Again?
One crucial measure is the percent positivity rate in the local community, the number of positive tests based on all the tests that are done. Some states, like California, have implemented policies guiding the reopening of schools that depend in part on a local community's percent positivity rate falling under 8 percent, among other benchmarks including the rate of new daily cases. Currently, statewide, test positivity is below 7%, with an average of 3 new daily cases per 1000 people per day. However, the California department of health acknowledges that new cases per day are underreported. There are 6.3 million students in the California public school system, suggesting that at any given time, there could be nearly 20,000 students who might be contagious, without accounting for presymptomatic teachers and staff. In the classroom environment, just one of those positive cases could spread the virus to many people in one day despite masks, distancing, and ventilation.
You'd need to get very low rates in the local community to open safely in person regardless of other risk reduction measures, and this would need to be complemented by robust testing and contact tracing capacity. Only with rapid identification and isolation of new cases, followed by contact tracing and quarantine, can we break chains of transmission and prevent further spread in the school and the larger community.
None of these safety concerns diminish the many harms associated with the sudden and haphazard way remote learning has been implemented. Online education has not been effective in many cases and is difficult to implement equitably. Young children, in particular, are deprived of the essential social and intellectual development they would normally get in a classroom with teachers and their peers. Parents of young children are equally unprepared and unable to provide full-time instruction. Our federal leadership's catastrophic failure to contain the pandemic like other countries has put us in this terrible position, where we must choose between learning or spreading a deadly pathogen.
Blame aside, parents, educators, and administrators must decide whether to resume in-person classes this fall. Those decisions should be based on evidence, not on politics or economics. The data clearly shows that community transmission is out of control throughout most of the country. Thus, we ignore the risk of school outbreaks at our peril.
[Editor's Note: Here's the other essay in the Back to School series: 5 Key Questions to Consider Before Sending Your Child Back to School.]
Questions remain about new drug for hot flashes
In May, a new drug, Fezolinetant, was approved by the FDA to treat hot flashes associated with menopause.
Vascomotor symptoms (VMS) is the medical term for hot flashes associated with menopause. You are going to hear a lot more about it because a company has a new drug to sell. Here is what you need to know.
Menopause marks the end of a woman’s reproductive capacity. Normal hormonal production associated with that monthly cycle becomes erratic and finally ceases. For some women the transition can be relatively brief with only modest symptoms, while for others the body's “thermostat” in the brain is disrupted and they experience hot flashes and other symptoms that can disrupt daily activity. Lifestyle modification and drugs such as hormone therapy can provide some relief, but women at risk for cancer are advised not to use them and other women choose not to do so.
Fezolinetant, sold by Astellas Pharma Inc. under the product name Veozah™, was approved by the Food and Drug Administration (FDA) on May 12 to treat hot flashes associated with menopause. It is the first in a new class of drugs called neurokinin 3 receptor antagonists, which block specific neurons in the brain “thermostat” that trigger VMS. It does not appear to affect other symptoms of menopause. As with many drugs targeting a brain cell receptor, it must be taken continuously for a few days to build up a good therapeutic response, rather than working as a rescue product such as an asthma inhaler to immediately treat that condition.
Hot flashes vary greatly and naturally get better or resolve completely with time. That contributes to a placebo effect and makes it more difficult to judge the outcome of any intervention. Early this year, a meta analysis of 17 studies of drug trials for hot flashes found an unusually large placebo response in those types of studies; the placebo groups had an average of 5.44 fewer hot flashes and a 36 percent reduction in their severity.
In studies of fezolinetant, the drug recently approved by the FDA, the placebo benefit was strong and persistent. The drug group bested the placebo response to a statistically significant degree but, “If people have gone from 11 hot flashes a day to eight or seven in the placebo group and down to a couple fewer ones in the drug groups, how meaningful is that? Having six hot flashes a day is still pretty unpleasant,” says Diana Zuckerman, president of the National Center for Health Research (NCHR), a health oriented think tank.
“Is a reduction compared to placebo of 2-3 hot flashes per day, in a population of women experiencing 10-11 moderate to severe hot flashes daily, enough relief to be clinically meaningful?” Andrea LaCroix asked a commentary published in Nature Medicine. She is an epidemiologist at the University of California San Diego and a leader of the MsFlash network that has conducted a handful of NIH-funded studies on menopause.
Questions Remain
LaCroix and others have raised questions about how Astellas, the company that makes the new drug, handled missing data from patients who dropped out of the clinical trials. “The lack of detailed information about important parameters such as adherence and missing data raises concerns that the reported benefits of fezolinetant very likely overestimate those that will be observed in clinical practice," LaCroix wrote.
In response to this concern, Anna Criddle, director of global portfolio communications at Astellas, wrote in an email to Leaps.org: “…a full analysis of data, including adherence data and any impact of missing data, was submitted for assessment by [the FDA].”
The company ran the studies at more than 300 sites around the world. Curiously, none appear to have been at academic medical centers, which are known for higher quality research. Zuckerman says, "When somebody is paid to do a study, if they want to get paid to do another study by the same company, they will try to make sure that the results are the results that the company wants.”
Criddle said that Astellas picked the sites “that would allow us to reach a diverse population of women, including race and ethnicity.”
A trial of a lower dose of the drug was conducted in Asia. In March 2022, Astellas issued a press release saying it had failed to prove effectiveness. No further data has been released. Astellas still plans to submit the data, according to Criddle. Results from clinical trials funded by the U.S. goverment must be reported on clinicaltrials.gov within one year of the study's completion - a deadline that, in this case, has expired.
The measurement scale for hot flashes used in the studies, mild-moderate-severe, also came in for criticism. “It is really not good scale, there probably isn’t a broad enough range of things going on or descriptors,” says David Rind. He is chief medical officer of the Institute for Clinical and Economic Review (ICER), a nonprofit authority on new drugs. It conducted a thorough review and analysis of fezolinestant using then existing data gathered from conference abstracts, posters and presentations and included a public stakeholder meeting in December. A 252-page report was published in January, finding “considerable uncertainty about the comparative net health benefits of fezolinetant” versus hormone therapy.
Questions surrounding some of these issues might have been answered if the FDA had chosen to hold a public advisory committee meeting on fezolinetant, which it regularly does for first in class medicines. But the agency decided such a meeting was unnecessary.
Cost
There was little surprise when Astellas announced a list price for fezolinetant of $550 a month ($6000 annually) and a program of patient assistance to ease out of pocket expenses. The company had already incurred large expenses.
In 2017 Astellas purchased the company that originally developed fezolinetant for $534 million plus several hundred million in potential royalties. The drug company ran a "disease awareness” ad, Heat on the Street, hat aired during the Super Bowl in February, where 30 second ads cost about $7 million. Industry analysts have projected sales to be $1.9 billion by 2028.
ICER’s pre-approval evaluation said fezolinetant might "be considered cost-effective if priced around $2,000 annually. ... [It]will depend upon its price and whether it is considered an alternative to MHT [menopause hormone treatment] for all women or whether it will primarily be used by women who cannot or will not take MHT."
Criddle wrote that Astellas set the price based on the novelty of the science, the quality of evidence for the drug and its uniqueness compared to the rest of the market. She noted that an individual’s payment will depend on how much their insurance company decides to cover. “[W]e expect insurance coverage to increase over the course of the year and to achieve widespread coverage in the U.S. over time.”
Leaps.org wrote to and followed up with nine of the largest health insurers/providers asking basic questions about their coverage of fezolinetant. Only two responded. Jennifer Martin, the deputy chief consultant for pharmacy benefits management at the Department of Veterans Affairs, said the agency “covers all drugs from the date that they are launched.” Decisions on whether it will be included in the drug formulary and what if any copays might be required are under review.
“[Fezolinetant] will go through our standard P&T Committee [patient and treatment] review process in the next few months, including a review of available efficacy data, safety data, clinical practice guidelines, and comparison with other agents used for vasomotor symptoms of menopause," said Phil Blando, executive director of corporate communications for CVS Health.
Other insurers likely are going through a similar process to decide issues such as limiting coverage to women who are advised not to use hormones, how much copay will be required, and whether women will be required to first try other options or obtain approvals before getting a prescription.
Rind wants to see a few years of use before he prescribes fezolinetant broadly, and believes most doctors share his view. Nor will they be eager to fill out the additional paperwork required for women to participate in the Astellas patient assistance program, he added.
Safety
Astellas is marketing its drug by pointing out risks of hormone therapy, such as a recent paper in The BMJ, which noted that women who took hormones for even a short period of time had a 24 percent increased risk of dementia. While the percentage was scary, the combined number of women both on and off hormones who developed dementia was small. And it is unclear whether hormones are causing dementia or if more severe hot flashes are a marker for higher risk of developing dementia. This information is emerging only after 80 years of hundreds of millions of women using hormones.
In contrast, the label for fezolinetant prohibits “concomitant use with CYP1A2 inhibitors” and requires testing for liver and kidney function prior to initiating the drug and every three months thereafter. There is no human or animal data on use in a geriatric population, defined as 65 or older, a group that is likely to use the drug. Only a few thousand women have ever taken fezolinetant and most have used it for just a few months.
Options
A woman seeking relief from symptoms of menopause would like to see how fezolintant compares with other available treatment options. But Astellas did not conduct such a study and Andrea LaCroix says it is unlikely that anyone ever will.
ICER has come the closest, with a side-by-side analysis of evidence-based treatments and found that fezolinetant performed quite similarly and modestly as the others in providing relief from hot flashes. Some treatments also help with other symptoms of menopause, which fezolinetant does not.
There are many coping strategies that women can adopt to deal with hot flashes; one of the most common is dressing in layers (such as a sleeveless blouse with a sweater) that can be added or subtracted as conditions require. Avoiding caffeine, hot liquids, and spicy foods is another common strategy. “I stopped drinking hot caffeinated drinks…for several years, and you get out of the habit of drinking them,” says Zuckerman.
LaCroix curates those options at My Meno Plan, which includes a search function where you can enter your symptoms and identify which treatments might work best for you. It also links to published research papers. She says the goal is to empower women with information to make informed decisions about menopause.
A company in England has made a test that picks out the compounds from breath that reveal if people have liver disease.
Every year, around two million people worldwide die of liver disease. While some people inherit the disease, it’s most commonly caused by hepatitis, obesity and alcoholism. These underlying conditions kill liver cells, causing scar tissue to form until eventually the liver cannot function properly. Since 1979, deaths due to liver disease have increased by 400 percent.
The sooner the disease is detected, the more effective treatment can be. But once symptoms appear, the liver is already damaged. Around 50 percent of cases are diagnosed only after the disease has reached the final stages, when treatment is largely ineffective.
To address this problem, Owlstone Medical, a biotech company in England, has developed a breath test that can detect liver disease earlier than conventional approaches. Human breath contains volatile organic compounds (VOCs) that change in the first stages of liver disease. Owlstone’s breath test can reliably collect, store and detect VOCs, while picking out the specific compounds that reveal liver disease.
“There’s a need to screen more broadly for people with early-stage liver disease,” says Owlstone’s CEO Billy Boyle. “Equally important is having a test that's non-invasive, cost effective and can be deployed in a primary care setting.”
The standard tool for detection is a biopsy. It is invasive and expensive, making it impractical to use for people who aren't yet symptomatic. Meanwhile, blood tests are less invasive, but they can be inaccurate and can’t discriminate between different stages of the disease.
In the past, breath tests have not been widely used because of the difficulties of reliably collecting and storing breath. But Owlstone’s technology could help change that.
The team is testing patients in the early stages of advanced liver disease, or cirrhosis, to identify and detect these biomarkers. In an initial study, Owlstone’s breathalyzer was able to pick out patients who had early cirrhosis with 83 percent sensitivity.
Boyle’s work is personally motivated. His wife died of colorectal cancer after she was diagnosed with a progressed form of the disease. “That was a big impetus for me to see if this technology could work in early detection,” he says. “As a company, Owlstone is interested in early detection across a range of diseases because we think that's a way to save lives and a way to save costs.”
How it works
In the past, breath tests have not been widely used because of the difficulties of reliably collecting and storing breath. But Owlstone’s technology could help change that.
Study participants breathe into a mouthpiece attached to a breath sampler developed by Owlstone. It has cartridges are designed and optimized to collect gases. The sampler specifically targets VOCs, extracting them from atmospheric gases in breath, to ensure that even low levels of these compounds are captured.
The sampler can store compounds stably before they are assessed through a method called mass spectrometry, in which compounds are converted into charged atoms, before electromagnetic fields filter and identify even the tiniest amounts of charged atoms according to their weight and charge.
The top four compounds in our breath
In an initial study, Owlstone captured VOCs in breath to see which ones could help them tell the difference between people with and without liver disease. They tested the breath of 46 patients with liver disease - most of them in the earlier stages of cirrhosis - and 42 healthy people. Using this data, they were able to create a diagnostic model. Individually, compounds like 2-Pentanone and limonene performed well as markers for liver disease. Owlstone achieved even better performance by examining the levels of the top four compounds together, distinguishing between liver disease cases and controls with 95 percent accuracy.
“It was a good proof of principle since it looks like there are breath biomarkers that can discriminate between diseases,” Boyle says. “That was a bit of a stepping stone for us to say, taking those identified, let’s try and dose with specific concentrations of probes. It's part of building the evidence and steering the clinical trials to get to liver disease sensitivity.”
Sabine Szunerits, a professor of chemistry in Institute of Electronics at the University of Lille, sees the potential of Owlstone’s technology.
“Breath analysis is showing real promise as a clinical diagnostic tool,” says Szunerits, who has no ties with the company. “Owlstone Medical’s technology is extremely effective in collecting small volatile organic biomarkers in the breath. In combination with pattern recognition it can give an answer on liver disease severity. I see it as a very promising way to give patients novel chances to be cured.”
Improving the breath sampling process
Challenges remain. With more than one thousand VOCs found in the breath, it can be difficult to identify markers for liver disease that are consistent across many patients.
Julian Gardner is a professor of electrical engineering at Warwick University who researches electronic sensing devices. “Everyone’s breath has different levels of VOCs and different ones according to gender, diet, age etc,” Gardner says. “It is indeed very challenging to selectively detect the biomarkers in the breath for liver disease.”
So Owlstone is putting chemicals in the body that they know interact differently with patients with liver disease, and then using the breath sampler to measure these specific VOCs. The chemicals they administer are called Exogenous Volatile Organic Compound) probes, or EVOCs.
Most recently, they used limonene as an EVOC probe, testing 29 patients with early cirrhosis and 29 controls. They gave the limonene to subjects at specific doses to measure how its concentrations change in breath. The aim was to try and see what was happening in their livers.
“They are proposing to use drugs to enhance the signal as they are concerned about the sensitivity and selectivity of their method,” Gardner says. “The approach of EVOC probes is probably necessary as you can then eliminate the person-to-person variation that will be considerable in the soup of VOCs in our breath.”
Through these probes, Owlstone could identify patients with liver disease with 83 percent sensitivity. By targeting what they knew was a disease mechanism, they were able to amplify the signal. The company is starting a larger clinical trial, and the plan is to eventually use a panel of EVOC probes to make sure they can see diverging VOCs more clearly.
“I think the approach of using probes to amplify the VOC signal will ultimately increase the specificity of any VOC breath tests, and improve their practical usability,” says Roger Yazbek, who leads the South Australian Breath Analysis Research (SABAR) laboratory in Flinders University. “Whilst the findings are interesting, it still is only a small cohort of patients in one location.”
The future of breath diagnosis
Owlstone wants to partner with pharmaceutical companies looking to learn if their drugs have an effect on liver disease. They’ve also developed a microchip, a miniaturized version of mass spectrometry instruments, that can be used with the breathalyzer. It is less sensitive but will enable faster detection.
Boyle says the company's mission is for their tests to save 100,000 lives. "There are lots of risks and lots of challenges. I think there's an opportunity to really establish breath as a new diagnostic class.”