Inward Bound - The T'ai Chi Corner

Inward Bound - The T'ai Chi Corner
thelivyjr
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AXIOS

WHO: Data suggests it's "very rare" for coronavirus to spread through asymptomatics


Marisa Fernandez

8 JUNE 2020

Contact tracing data from around the globe suggests that while there are instances of asymptomatic coronavirus patients transmitting the virus to others, they are not "a main driver" of new infections, World Health Organization officials said at a press conference Monday.

Why it matters:

Evidence early on suggested that person-to-person transmission among people who didn't experience symptoms could lead to outbreaks that would be difficult to control.

Young people and healthy people who did not experience symptoms were also suspected to be potential carriers to more vulnerable populations.

The big picture:

The WHO is now relying on data obtained through contact tracing, said Maria Van Kerkhove, head of the emerging diseases and zoonosis unit.

“We have a number of reports from countries who are doing very detailed contact tracing."

"They’re following asymptomatic cases."

"They’re following contacts."

"And they’re not finding secondary transmission onward."

"It’s very rare."


In the press conference Monday, Kerkhove said there are fewer asymptomatic patients than previously thought.

"(I)f you actually go back and say how many of them are truly asymptomatic, we find out that many have really mild disease, very mild disease, they’re not quote unquote COVID symptoms, meaning they may not have developed fever yet."

Between the lines:

Don't treat these statements as a permission to treat a lack of symptoms as a "get out of social distancing" free card.

Infected people can be contagious well before experiencing symptoms.

"Some modeling studies suggest 40-60% of spread is from people when they didn’t have symptoms," tweeted Ashish Jha, incoming dean at the Brown School of Public Health.

Singapore's coronavirus task force also said Monday that it believes half of the country's new COVID-19 cases are asymptomatic based on testing data, Reuters reports.

Van Kerkhove later tweeted a statement that cited a June summary by the WHO on symptomatic, pre-symptomatic and asymptomatic transmission:

"Comprehensive studies on transmission from asymptomatic individuals are difficult to conduct, but the available evidence from contact tracing reported by Member States suggests that asymptomatically-infected individuals are much less likely to transmit the virus than those who develop symptoms."

The bottom line:

These statements are a reminder of just how little we understand about this virus.

https://www.axios.com/who-coronavirus-a ... 50764.html
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thelivyjr wrote: Tue Jun 09, 2020 1:40 p "A strong country cannot be composed of weak people."

- Sun Lu Tang, January 15, 1915

News-Medical

Using Qigong to manage COVID-19 in older adults


By Dr. Liji Thomas, MD

May 25, 2020

A recent study published in The American Journal of Geriatric Psychiatry in May 2020 reports on the possible usefulness of the integrative practice called Qigong to prevent and manage COVID-19 in older adults.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that caused the COVID-19 pandemic that first began in Wuhan, China, has now spread to over 188 countries and territories, with a staggering 5.4 million cases and over 344,000 deaths so far.

Disease trends show that the disease is more severe in older people as well as individuals suffering from pre-existing medical conditions.

Alternative Remedies for COVID-19

In the absence of an effective vaccine or specific therapeutic drug, researchers are exploring a host of possibilities, from drugs that block inflammatory pathways like tocilizumab to antivirals like remdesivir.

However, practitioners of complementary and alternative medicine are not to be left behind.

Traditional Chinese Medicine (TCM) and Qigong are reported to have been valuable in controlling the spread of the pandemic in China.

The National Health Commission of China has recommended the Chinese herbal decoction Qingfei Paidu for mild to moderate COVID-19.


The same herbs were used in conjunction with Western medicine to treat severe COVID-19 disease.

In field hospitals set up to isolate patients with mild disease, rather than practice home quarantine, patients were treated with Ba Duan Jin Qigong under the tutelage of TCM practitioners.

This was both a valuable means of exercise and a therapeutic approach.

COVID-19 is a viral infection which, however, becomes severe due to both immunosuppression and the cytokine storm syndrome.

Patients with severe disease may rapidly develop severe respiratory difficulty.

Once they recover, they may need rehabilitative management, including training of the respiratory muscles, whole-body exercise, and mental rehabilitation.

What is Qigong?

Qigong is a Chinese word formed of two characters, Qi and Gong.

The first denotes the energy that underlies all human life processes, and Gong refers to the practice of developing control over this energy.

In TCM, Qi is involved in virtually every process of health and disease.

There are different types, such as defensive Wei Qi and organ-specific Qi, that is in charge of the function of each organ.

Qi moves through channels called meridians, running over the surface of the trunk and the limbs, and extending to the internal organs.

The practice of Qigong is, therefore, a mind-body integrative skill, meant to train the practitioner to regulate body, breath, and mind.

The operative techniques are adjustment of the posture and body movements, through gentle and smooth movements aimed at relaxation.

Another technique that forms part of Qigong is breath regulation, aimed at producing slow, long, and deep breaths.


Abdominal breathing and breathing with phonation, or while making audible sounds, are both commonly used Qigong respiratory components.

Finally, mind regulation is an integral part of Qigong, via focused attention and visualization, similar to meditation.

Though its roots go back to ancient times, the first modern Qigong institute came up in China in 1945.

Qigong is suitable for the elderly because of its smooth and gentle movements.

It could be widely applied in geriatric medicine, to treat painful musculoskeletal disorders, strengthen muscle, and achieve pain relief.

Its mental calming effects could help deal with psychosomatic disorders as well as mood disorders and even cognitive impairment.

Qigong can be practiced as dynamic or passive techniques, with each having its specific benefits.

Qigong in Respiratory Infections - Mechanisms

In TCM, respiratory infections are thought to be due to external pathogens that throw off the balance between good and evil.

Defensive Wei Qi is thought to fight against them, this being the embodiment of immunity.

Thus the strength of Wei Qi in relation to the exogenous pathogens decides the course of the disease and the outcome.

In older people, the organ function declines, and chronic medical conditions set in, causing their energy to decline.

This is thought of as a deficiency of Qi and blood.

TCM practitioners say that Qigong may help prevent and promote recovery from respiratory infections in such conditions because of its regulatory function in the human body, including Wei Qi.


Some of the possible mechanisms for the benefits of Qigong in this setting include:

• Reduction in stress due to meditation-induced physiological changes, such as decreased levels of stress hormones, reducing reactivity to negative thoughts, and regulating the level of reactivity of the hypothalamus-pituitary-adrenal axis and the autonomic nervous system.

It could also change the function of various brain areas related to inflammation and stress and enhance a feeling of control.

• Strengthening respiratory muscles, especially the diaphragm

• Reducing inflammation via lower IL-6 and increased IL-10 levels, which are pro-inflammatory and anti-inflammatory, respectively

• Enhanced immune function by increasing the number and activity of both specific and nonspecific immune cells

Qigong in Respiratory Infections – Clinical Proof

Some studies show that Qigong can reduce the incidence of respiratory infections for two years after this exercise, and the incidence only went down afterward.

Another study reports that Qigong, as practiced by swimmers, was linked to a significant reduction in colds and flu.

The more frequent the practice, the fewer were the symptoms.

For those who already have an acute respiratory infection, Qigong may shorten the total duration of infection.

Qigong in Respiratory Infections – Rehabilitation

After recovering from a severe respiratory infection, respiratory muscles may be weakened.

Limited research shows a possible role of Qigong in the rehabilitation of other lung diseases associated with respiratory impairment.


For instance, in chronic obstructive pulmonary disease (COPD), Qigong could improve lung function and exercise capability, as well as the quality of life.

Further research is necessary, given often conflicting findings.

Learning and Practicing Qigong

Videos alone are not a reliable source of Qigong instruction.

A medical consultation should be held before beginning any new form of exercise, including Qigong.

The current study recommends three forms of Qigong for use in elderly patients with respiratory disease.

These are Ba Duan Jin, Liu Zi Jue, and abdominal breathing, with their low intensity, smooth movement, and ease of learning, without a large range of movement or the need for wide-open spaces.

Taking the small amount of research into consideration, the authors say, “Qigong may be potentially useful for the prevention, treatment, and rehabilitation of respiratory infections, including COVID-19."

"The elderly, in particular, could benefit from Qigong during the ongoing pandemic.”

Journal reference:

• Feng, F. et al. (2020). Qigong for the Prevention, Treatment, and Rehabilitation of COVID-19 Infection in Older Adults. The American Journal of Geriatric Psychiatry. https://doi.org/10.1016/j.jagp.2020.05.012.

https://www.sciencedirect.com/science/a ... via%3Dihub

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News-Medical

Dead virus fragments are causing COVID-19 reinfection false positives


By Angela Betsaida B. Laguipo, BSN

May 4, 2020

The coronavirus disease (COVID-19) has ravaged across the globe, infecting a staggering 3.5 million people, and taking over 251,000 lives.

One of the most significant concerns in this global pandemic is the possibility of reinfection as previous reports in South Korea and Japan show people testing positive with the coronavirus again.

Now, a team of South Korean researchers has revealed that reports of recovered coronavirus patients testing positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection a second time round are due to testing errors and not actually reinfection.


Dead virus fragments

The country’s infectious disease experts said that dead-virus fragments were most likely cause positive results for SARS-CoV-2 infection among 260 people who have recovered from the disease.

The tests even showed the presence of these fragments even weeks after making full recoveries.

Oh Myoung-don, who spearheads the central clinical committee for emerging disease control in South Korea, said there was little reason to believe the cases had emerged from reactivation of the virus or reinfection.

“The tests detected the ribonucleic acid of the dead virus,” Dr. Oh, who is also a hospital doctor at the Seoul National University, explained.

The conventional test used to detect SARS-CoV-2 is the polymerase chain reaction test or PCR test.

However, there are technical limitations to the test.

It cannot distinguish whether the virus in the patient is alive or dead.


“PCR testing that amplifies genetics of the virus is used in Korea to test COVID-19, and relapse cases are due to technical limits of the PCR testing."

"The respiratory epithelial cell has a half-life of up to three months, and RNA virus in the cell can be detected with PCR testing one to two months after the elimination of the cell,” Dr. Oh explained.

So far, there were more than 260 people who tested positive again in South Korea.

These patients have recovered and were declared virus-free.

The new report confirmed a previous assessment of the Korean Centers for Disease Control and Prevention that patients who tested positive again had little or no contagiousness at all.

This means that they cannot transmit the virus to others, based on virus culture cells that all failed to find live viruses in recovered patients.

The resurgence of the virus

The reports of reinfection in the country have sparked panic, as South Korea has already flattened the curve after extensive mass testing and isolation of cases.

It is one of the countries that have controlled the spread of the virus without resorting to restrictions and lockdowns.


Though many measures have contributed to South Korea’s success in containing the virus spread, two measures were critical in its ability to flatten the curve – extensive testing and a national system for effectively tracking infected persons.

Being able to trace those who are positive with the virus, and their contacts can help isolate cases immediately before they even transmit the virus to others.

Virus resurgence is a problem not only in South Korea but also in other countries who had successfully flattened the curve.

In some countries, such as Japan, they see a sudden spike of new cases due to the premature lifting of restrictions.

Governments need to impose a “new normal” across industries to prevent a second wave of the outbreak.


In South Korea, health officials reported only ten new infections every day for the past 11 days.

During the initial stages of the pandemic, the country has been leading with high infection rates, until its health measures helped “flatten the curve.”

Its total case toll reached 10,801, with 252 deaths.

In comparison, many countries reported spikes of confirmed cases.

The United States has reported a whopping 1.18 million confirmed cases and more than 68,000 deaths.

Spain and Italy follow with more than 218,000 and 211,000 confirmed cases, respectively.

The United Kingdom has reported more than 191,000 cases and 28,809 deaths.

The UK has the second-highest death toll, next to Italy, with 29,079 deaths.

The death rate of Italy is 13.7 percent, the UK is 15.1 percent, while Spain has a fatality rate of 11.6 percent.

Sources:

• The Korean Herald - http://www.koreaherald.com/view.php?ud=20200429000724

• COVID-19 Dashboard by the Center for Systems Science and Engineering (CSSE) at Johns Hopkins University (JHU)- https://gisanddata.maps.arcgis.com/apps ... 7b48e9ecf6

https://www.news-medical.net/news/20200 ... tives.aspx
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SCIENCE ALERT

Antibiotics Found to Cause Immune System Damage And Reduce Brain Cell Growth


DAVID NIELD

26 MAY 2016

Two new international studies have shed further light on some of the harmful side effects associated with antibiotics – including damage to the immune system, and memory problems caused by a lack of growth in new brain cells.

The findings serve as a reminder that while antibiotics can be powerful allies for the human body in the fight against disease, they can also do more harm than good if used in the wrong situations (one of many reasons you should always follow the advice of your doctor).


Both studies found that the way antibiotics kill off microbes in the gut can cause health issues, due to the way the delicate chemical mixes in our bodies can be thrown out of balance by the medication.

The first study, led by researchers from the Memorial Sloan Kettering Cancer Centre in New York, involved 857 patients receiving hematopoietic stem cell transplants – a treatment typically used to tackle blood and bone marrow cancers.

Antibiotics are usually given in these cases to prevent or treat infections linked to the transplants, but the researchers found that patient health varied depending on the types of antibiotics used.

They tested 12 of the most common types of antibiotics, finding that two combinations in particular – piperacillin and tazobactam, and imipenem and cilastatin – led to a higher risk of a life-threatening inflammatory condition called graft-versus-host disease (GVHD).

The hypothesis is that the 'mass exodus' these particular antibiotics caused in the patients' gut microbiomes harmed the body's immune system in some way.

Similar results were observed when the researchers tried the same tests on mice.

The second study, led by a team from the Max-Delbrueck-Centre for Molecular Medicine in Germany, investigated the effects of broad-spectrum antibiotics – those that kill off many different types of microbes – on mice.

They noticed a slowdown in brain cell development in the hippocampus, which is the part of the brain responsible for memory and controlling the nervous system.

These mice performed poorly on memory tests, and were also found to have fewer monocytes (white blood cells that fight off viruses) in their bodies.

When the course of antibiotics was stopped, the mouse brains were able to rebound to their former state, according to the researchers.

Scientists involved in both studies have emphasised that there's more work to be done, and further tests to be run before we understand exactly what this means for the way we use these antibiotics in the future.

For the time being, though, it's a good reminder that these drugs should always be carefully used – and not overused in any circumstances.

The first study is published in Science Translational Medicine, and the second appears in Cell Reports.

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THE NEW ENGLAND JOURNAL OF MEDICINE

Editorial

Hydroxychloroquine for the Prevention of Covid-19 — Searching for Evidence


Myron S. Cohen, M.D.

June 3, 2020

DOI: 10.1056/NEJMe2020388

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus that causes coronavirus disease 2019 (Covid-19), has generated a worldwide pandemic.

The interruption of its spread depends on a combination of pharmacologic and nonpharmacologic interventions.

Initial SARS-CoV-2 prevention includes social distancing, the use of face masks, environmental hygiene, and hand washing.1

Although the most important pharmacologic interventions to prevent SARS-CoV-2 infection are likely to be vaccines, the repurposing of established drugs for short-term prophylaxis is another, more immediate option.

Some researchers have promoted chloroquine and hydroxychloroquine for the treatment and prevention of illness from a variety of microorganisms, including SARS-CoV.2

Hydroxychloroquine can inhibit replication of SARS-CoV-2 in vitro.3

Some observational studies have suggested benefits of hydroxychloroquine for the treatment of Covid-19, whereas other treatment reports have described mixed results.
4

Boulware et al. now report in the Journal the results of a randomized trial testing hydroxychloroquine as postexposure prophylaxis for Covid-19.5

This is described by the investigators as a “pragmatic” trial in which participants were recruited through social media and almost all data were reported by the participants.

Adults who described a high-risk or moderate-risk exposure to someone with Covid-19 in their household or an occupational setting were provided hydroxychloroquine or placebo (by mail) within 4 days after the reported exposure, and before symptoms would be expected to develop.

The authors enrolled 821 participants; an illness that was considered to be consistent with Covid-19 developed in 107 participants (13.0%) but was confirmed by polymerase-chain-reaction assay in less than 3% of the participants.

The incidence of a new illness compatible with Covid-19 did not differ significantly between participants receiving hydroxychloroquine (49 of 414 [11.8%]) and those receiving placebo (58 of 407 [14.3%]).

Although participant-reported side effects were significantly more common in those receiving hydroxychloroquine (40.1%) than in those receiving placebo (16.8%), no serious adverse reactions were reported.

This trial has many limitations, acknowledged by the investigators.

The trial methods did not allow consistent proof of exposure to SARS-CoV-2 or consistent laboratory confirmation that the symptom complex that was reported represented a SARS-CoV-2 infection.

Indeed, the specificity of participant-reported Covid-19 symptoms is low,6 so it is hard to be certain how many participants in the trial actually had Covid-19.

Adherence to the interventions could not be monitored, and participants reported less-than-perfect adherence, more notably in the group receiving hydroxychloroquine.

In addition, those enrolled in the trial were younger (median age, 40 years) and had fewer coexisting conditions than persons in whom severe Covid-19 is most likely to develop,7 so enrollment of higher-risk participants might have yielded a different result.

The trial design raises questions about the expected prevention benefits of hydroxychloroquine.

Studies of postexposure prophylaxis are intended to provide an intervention in the shortest possible time to prevent infection.

In a small-animal model of SARS-CoV-2 infection,8 prevention of infection or more severe disease was observed only when the experimental antiviral agent was given before or shortly after exposure.

In the current trial, the long delay between perceived exposure to SARS-CoV-2 and the initiation of hydroxychloroquine (≥3 days in most participants) suggests that what was being assessed was prevention of symptoms or progression of Covid-19, rather than prevention of SARS-CoV-2 infection.

Drugs for the prevention of infections must have an excellent safety profile.

When hydroxychloroquine was initially promoted as a possible solution to SARS-CoV-2 infection, the safety of the drug was emphasized.2

Under closer scrutiny, however, the potential for cardiac toxic effects and overall adverse outcomes have been emphasized, especially in persons with underlying coexisting conditions that increase the risk of severe Covid-19.9

Boulware et al. report frequent mild side effects of hydroxychloroquine, but cardiac toxic effects could not be assessed.


So, what are we to do with the results of this trial?

The advocacy and widespread use of hydroxychloroquine seem to reflect a reasonable fear of SARS-CoV-2 infection.

However, it would appear that to some extent the media and social forces — rather than medical evidence — are driving clinical decisions and the global Covid-19 research agenda.
10

On June 1, 2020, ClinicalTrials.gov listed a remarkable 203 Covid-19 trials with hydroxychloroquine, 60 of which were focused on prophylaxis.

An important question is to what extent the article by Boulware et al. should affect planned or ongoing hydroxychloroquine trials.

If postexposure prophylaxis with hydroxychloroquine does not prevent symptomatic SARS-CoV-2 infection (with recognition of the limitations of the trial under discussion), should other trials of postexposure prophylaxis with hydroxychloroquine continue unchanged?

Do the participants in these trials need to be informed of these results?

Do these trial results with respect to postexposure prophylaxis affect trials of preexposure prophylaxis with hydroxychloroquine, some of which are very large (e.g., the Healthcare Worker Exposure Response and Outcomes of Hydroxychloroquine [HERO-HCQ] trial, involving 15,000 health care workers; ClinicalTrials.gov number, NCT04334148. opens in new tab)?

The results reported by Boulware et al. are more provocative than definitive, suggesting that the potential prevention benefits of hydroxychloroquine remain to be determined.


This editorial was published on June 3, 2020, at NEJM.org.

References

1. Cohen MS, Corey L. Combination prevention for COVID-19. Science 2020;368:551-551.

2. Rolain J-M, Colson P, Raoult D. Recycling of chloroquine and its hydroxyl analogue to face bacterial, fungal and viral infections in the 21st century. Int J Antimicrob Agents 2007;30:297-308.

3. Yao T-T, Qian J-D, Zhu W-Y, Wang Y, Wang G-Q. A systematic review of lopinavir therapy for SARS coronavirus and MERS coronavirus — a possible reference for coronavirus disease-19 treatment option. J Med Virol 2020;92:556-563.

4. Hernandez AV, Roman YM, Pasupuleti V, Barboza JJ, White CM. Hydroxychloroquine or chloroquine for treatment or prophylaxis of COVID-19: a living systematic review. Ann Intern Med 2020 May 27 (Epub ahead of print).

5. Boulware DR, Pullen MF, Bangdiwala AS, et al. A randomized trial of hydroxychloroquine as postexposure prophylaxis for Covid-19. N Engl J Med. DOI: 10.1056/NEJMoa2016638.

6. Tostmann A, Bradley J, Bousema T, et al. Strong associations and moderate predictive value of early symptoms for SARS-CoV-2 test positivity among healthcare workers, the Netherlands, March 2020. Euro Surveill 2020;25(16):2000508-2000508.

7. Wu Z, McGoogan JM. Characteristics of and important lessons from the coronavirus disease 2019 (COVID-19) outbreak in China: summary of a report of 72 314 cases from the Chinese Center for Disease Control and Prevention. JAMA 2020 February 24 (Epub ahead of print).

8. Sheahan TP, Sims AC, Zhou S, et al. An orally bioavailable broad-spectrum antiviral inhibits SARS-CoV-2 in human airway epithelial cell cultures and multiple coronaviruses in mice. Sci Transl Med 2020;12:12-12(541):eabb5883-eabb5883.

9. Magagnoli J, Narendran S, Pereira F, et al. Outcomes of hydroxychloroquine usage in United States veterans hospitalized with Covid-19. April 16, 2020 (https://www.medrxiv.org/content/10.1101 ... 20065920v2. opens in new tab). preprint.

10. Sayare S. He was a science star. Then he promoted a questionable cure for COVID-19. New York Times Magazine. May 12, 2020 (https://www.nytimes.com/2020/05/12/maga ... quine.html. opens in new tab).

https://www.nejm.org/doi/full/10.1056/N ... ?query=TOC
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THE NEW ENGLAND JOURNAL OF MEDICINE

Medicine and Society

The Untold Toll — The Pandemic’s Effects on Patients without Covid-19


Lisa Rosenbaum, M.D.

June 11, 2020

N Engl J Med 2020; 382:2368-2371

DOI: 10.1056/NEJMms2009984

In late March, Zoran Lasic, an interventional cardiologist at Jamaica Hospital Medical Center and Lenox Hill Hospital in New York, was finishing afternoon clinic when he was approached by a nurse colleague seeking his advice.

Her husband — a 56-year-old whose father died of sudden cardiac arrest at 55 — had been feeling chest pressure.


The pressure radiated down his arms and occasionally to his neck and, the previous day, had been accompanied by dyspnea and diaphoresis, making him worried enough to call an ambulance.

The emergency medical technicians did an electrocardiogram, said it looked OK, and told him to call his primary care doctor.

He did, and he was advised that given New York’s Covid-19 outbreak, it was not a good time to go to the hospital.

Now, a day later, his colleague asked Lasic, what should they do?

Nearly apoplectic, Lasic advised urgent coronary angiography, which he performed a few hours later.


The man had a thrombus extending from his proximal-to-midleft anterior descending artery and became hemodynamically unstable during the procedure.

Nevertheless, revascularization was successful, and he was discharged the following day with preserved left ventricular function.

Lasic, describing a precipitous decline across the New York region in patients presenting with acute coronary syndromes, worries that others won’t be so lucky.

“I think the toll on non-Covid patients will be much greater than Covid deaths,” he said.


As the coronavirus pandemic focuses medical attention on treating affected patients and protecting others from infection, how do we best care for people with non–Covid-related disease?

For some, new risks may warrant reconsideration of usual standards of care.

For others, the need to protect caregivers and preserve critical care capacity may factor into decisions.

And for everyone, radical transformation of the health care system will affect our ability to maintain high-quality care.

As Michael Grossbard, chief of hematology at New York University’s Langone Hospital, told me, “Our practice of medicine has changed more in 1 week than in my previous 28 years combined.”

Cancer care, which often involves immunosuppressive therapy, tumor resection, and inpatient treatment, has been disproportionately affected by Covid-19.

Like other oncologists I spoke with, Grossbard, who primarily treats lymphoma, has been tasked with revising chemotherapy protocols to minimize both the frequency of chemotherapy visits and the degree of immunosuppression.


For example, though patients with low-grade lymphoma typically receive maintenance therapy, it will not be recommended for now because it requires an office visit, worsens immunosuppression, and improves progression-free but not overall survival.

Other protocol modifications have arisen because of cancellations of elective surgeries.

For instance, some patients with solid tumors, such as breast and rectal cancers, are being offered systemic therapy before, rather than after, surgery.

Many modifications may not affect long-term outcomes.

Eric Winer, a breast oncologist at Dana-Farber Cancer Institute, believes, for instance, that giving antihormonal therapy to women with hormone-receptor–positive breast tumors and delaying surgery probably won’t alter overall survival, though this approach hasn’t been formally tested in Stage I disease.

But even when there’s greater uncertainty about treatment modifications, Winer has been impressed by many patients’ graceful acceptance.

I spoke to Ms. C., a 40-year-old patient of Winer who was recently diagnosed with inflammatory breast cancer.

Treatment typically involves 4 to 6 months of chemotherapy followed by surgical excision, though as Ms. C. said, “When you have cancer, your first reaction is ‘Just get it out of my body now.’”

But as she and Winer watched Covid-19 decimate Italy, they began discussing what the evolving situation would mean for her.

She’d started receiving an anthracycline, which heightened her risk of infection, and was supposed to have surgery in May.

When we spoke, it wasn’t clear whether or when her surgery would proceed, but she and Winer had agreed that if it was postponed, she would resume targeted systemic therapy.

She seemed to take this uncertainty in stride, partly because the hallmark rash of inflammatory breast cancer disappeared after she began receiving Herceptin (trastuzumab) a few months ago.

“I literally saw my cancer shrink,” she told me, “and I’m so thankful we are where we are now, as opposed to 25 years ago.”

Suspending other aspects of cancer care will have graver consequences.

David Ryan, chief of oncology at Massachusetts General Hospital (MGH), told me that three patient groups worry him most.

The first are the subgroup of patients with lymphoma for whom CAR-T therapy is potentially curative.


More than half these patients receive therapy in clinical trials, many of which have been paused amid society-wide shutdowns; even if enrollment could continue, there’s concern about the need for ICU care in a resource-constrained system.

A related concern is for patients requiring bone marrow transplants, given their high risk of infection and potential need for ICU care.

Finally, and most wrenching to Ryan, are patients with refractory tumors who are nearing the end of life, but for whom an experimental targeted therapy may hold promise; Ryan would otherwise offer these patients enrollment in an early-phase trial.


One recent analysis suggests that such enrollment is associated with clinical benefit in nearly 20% of patients,1 and participation allows patients to have some hope in their dying days and to feel like they’re “giving back” to the scientific community.

The individual toll, as clinical trials slow to a crawl, is mirrored by a societal one.

As Ryan, who sent me an email message while serving a volunteer shift in the hospital’s Covid unit, lamented, “There’s no question that clinical research in cancer will be set back by at least a year as we all drop what we’re doing to take care of the surge of patients.”


Protecting Our Patients, Preserving Ourselves

Another distressing trade-off is that between patients’ needs for procedures and the need to protect caregivers from infection and preserve hospital capacity.

A cardiologist friend, for example, told me about a woman in her 70s with some cardiac risk factors who developed chest pressure and shortness of breath.

She was reluctant to go to the hospital, and when she presented (at a highly regarded institution), she needed urgent intubation.

When chest radiography revealed bilateral interstitial edema, she became a “Covid rule-out” and was transferred to the ICU.

As her team awaited the Covid test results, her troponin level climbed, causing increasing concern about an acute coronary syndrome.

Though this suspicion would usually prompt more urgent coronary angiography, the uncertainty about Covid status delayed the procedure.

When the Covid result came back negative, she underwent urgent coronary angiography, which revealed an acute coronary occlusion.

By then, however, she had developed progressive cardiogenic shock, and she ultimately died.

Though physicians must often make judgments amid uncertainty, we typically focus on the patient’s risk, not our own.

In an infectious disease epidemic, our calculus must incorporate our own exposure risk — and how exposure would limit our ability to care for future patients.

The agony and complexity of these decisions is currently compounded by shortages of personal protective equipment (PPE).

Ajay Kirtane, an interventional cardiologist at Columbia who has coauthored recommendations for cardiac catheterization laboratories during the pandemic,2 told me that “People are being told to do procedures with inadequate protection.”

Though these recommendations aim to minimize both staff exposure and resource utilization, Kirtane recognizes the potential consequences of caution.

“One of the yet-to-be-told stories of the Covid-19 pandemic is the recognition that the (necessary) proscriptions on the performance of less urgent cases has led to collateral damage to so many patients with medical conditions that truly couldn’t wait.”

Although canceling procedures such as elective hernia repairs and knee replacements is relatively straightforward, for many interventions the line between urgent and nonurgent can be drawn only in retrospect.

As Brian Kolski, director of the structural heart disease program at St. Joseph Hospital in Orange County, California, told me, “A lot of procedures deemed ‘elective’ are not necessarily elective.”

Two patients in his practice whose transthoracic aortic valvular replacements were postponed, for example, died while waiting.

“These patients can’t wait 2 months,” Kolski said.

“Some of them can’t wait 2 weeks.”


Rather than a broad moratorium on elective procedures, Kolski believes we need a more granular approach.

“What has been the actual toll on some of these patients?” he asked.

Mr. R., a 75-year-old man with advanced heart failure, is another of Kolski’s patients for whom the toll has been great.

Because he had progressive volume overload and delirium, Kolski referred him to a hospital for an LVAD workup in early March.

Then, as his wife, Ms. R., told me, “the world went wonky, and everything went down the toilet.”

Having begun admitting patients with coronavirus, the hospital told the couple it was kicking everyone else out.

“They are telling me my husband has 6 to 12 months to live without this procedure,” Ms. R. said, “and now they are canceling it on us.”


They were then quarantined at home — 2 hours away from the hospital — with no plan in place.

Mr. R.’s health quickly deteriorated again, but his wife had been advised to keep him out of the hospital.

When they finally had a video visit on April 9, he’d become so ill that the heart failure physician didn’t recognize him.

Mr. R. was promptly admitted, and the LVAD was placed.

Though Ms. R. is relieved, ongoing challenges include her husband’s persistent delirium, a visitor policy that allows her to be at the bedside only intermittently, and the need for nearby lodging that they can’t afford.

As painful as these stories are, the degree of uncertainty renders calculated risk–benefit analyses impossible.

Should hospitals schedule LVAD placements when ICU and ventilator capacity may soon be exceeded?

Is a patient with severe aortic stenosis more likely to die from his underlying valvular disease or from a valve-replacement hospitalization that leaves him with coronavirus infection?

How many times can you expose a cath-lab team to patients with Covid-19–associated myocarditis, which can mimic an acute coronary syndrome, before so many staff members are infected that no one remains to treat patients with real myocardial infarction?

No one knows the answers to these questions because modern medicine has never faced them before.

Indeed, as Robert Yeh, an interventional cardiologist and health services researcher at Boston’s Beth Israel Deaconess Medical Center, emphasized, “there perhaps has never been a greater gap between what we need to know urgently and what is actually knowable.”

From policy questions, such as how long to postpone elective procedures, to treatment decisions, such as whether to treat Covid-19 with investigational therapies, the stakes of “failing to understand the universe we don’t pursue” have increased.

Referring to the global reduction in patients presenting with acute coronary syndromes, Yeh worries that our emphasis on social mitigation measures makes people who truly need care afraid to seek it.

Equally worrisome is how we treat people with myocardial infarction who do reach the hospital.

Concern about proceduralists’ exposure has led some physicians to advocate using thrombolytics rather than the standard revascularization strategy, but Yeh asks, “Are we protecting ourselves at the cost of worse patient outcomes?”

Yeh and his colleagues plan to attempt to answer some of these questions empirically, but as we await epidemiologic data, he cautioned against dismissing anecdotes emerging from around the world in the name of scientific purity.

Right now, he emphasized, “the sum total of what we hear from our colleagues at other institutions is the best data we have.”

Trade-offs We Don’t Have to Make

Ms. D. is a 51-year-old ICU nurse who was recently diagnosed with breast cancer and underwent lumpectomy in late February; unfortunately, the margins were not clear.

When she then learned in early March that she carried the BRCA2 mutation, she discussed with her surgeon either further excision and intense monitoring or bilateral mastectomy.

Ms. D chose the latter but wanted some time to process the decision.

With “Covid barreling in,” however, she was urged not to delay.

Pathology studies then revealed cancer in the contralateral breast.

Though Ms. D. was relieved to have the procedure over with, the rush was hard.

“I wished I had time to say goodbye to my breasts,” she recalled.

Harder still was follow-up.

Ms. D. was discharged with bilateral axillary drains, which she removed herself, as was “strongly recommended.”

But the most difficult moment was the postsurgical multidisciplinary meeting, which would typically be a discussion of treatment options with the team who’d be caring for her, followed by an opportunity to learn about social and emotional support resources.

For Ms. D., this meeting instead happened more quickly over the phone, without the visual cues we rely on to signal that we may be overwhelmed or confused.

She knows she received lifesaving care.

Indeed, sidelined by her illness while watching her nurse colleagues risk their lives on the front lines, she jokes that cancer saved her life.

But the lack of face-to-face interaction, compounded by the unavailability of typical support systems, has made it difficult to cope.

“Cancer is so emotionally loaded,” she told me, “You need some love."

"The human part is falling by the wayside.”

Humanity absent sound medical judgment is meaningless.

But though the pandemic may force difficult choices, my sense from both doctors and patients is that making these decisions thoughtfully and transparently helps patients feel cared for.

Under some circumstances, simply hewing to medicine’s foundational principles will suffice.

For example, when I asked Brian Bergmark, a colleague and interventional cardiologist at Brigham and Women’s Hospital, about whether our cath lab would use thrombolytics in lieu of the usual revascularization strategy for acute coronary syndromes, he said his group would maintain the standard of care as long as possible: “We still have the capacity to provide the right therapy for the right disease for the right patient.”

But what should we do when capacity limitations necessitate delays?

Hugh Auchincloss, a thoracic surgeon at MGH, who, like many surgeons, has had to delay some cases, notes that patients may “think that a bunch of administrators and bureaucrats are issuing blanket proclamations about their care.”

Auchincloss emphasizes how important it is for patients to know that he has personally reviewed their cases and postponed only those he has deemed nonurgent.

Having spoken to all his patients facing delays, he said that despite the difficulty of these conversations, patients are reassured knowing that their doctor has made a personal judgment.

These caring gestures probably assume greater importance in pandemic circumstances.

The common fear of “bothering the doctor” is magnified amid images of doctors risking their lives on the front lines.

Even Ms. C., the woman with inflammatory breast cancer, felt guilty asking Winer, her oncologist, how Covid might affect her care.

“I felt very selfish bringing it up,” she told me.

“The whole world is going through this crisis, and here I am thinking about my own situation."

"But I am also facing life and death.”

Yet despite not knowing whether her mastectomy will proceed, Ms. C. feels as cared for as ever.

She trusts Winer.

He articulated a clear rationale for alternative therapies, and he and his nurse practitioner leave her feeling as if, for her, they have all the time in the world.

Perhaps the greatest challenge, then, is an invisible one: How do we help people who are afraid to seek care to begin with?

To date, much public health messaging regarding Covid has focused on social distancing, hand hygiene, PPE for health care workers, and the need for increased testing.

Yet as we begin to observe fewer admissions for common emergencies such as heart attack and stroke,3,4 the need for vigilance about viral transmission need not detract from an equally important message: Covid or no Covid, we are still here to care for you.

This article was published on April 17, 2020, at NEJM.org.

References

1. Chakiba C, Grellety T, Bellera C, Italiano A. Encouraging trends in modern phase 1 oncology trials. N Engl J Med 2018;378:2242-2243.

2. Welt FGP, Shah PB, Aronow HD, et al. Catheterization laboratory considerations during the coronavirus (COVID-19) pandemic: from ACC’s Interventional Council and SCAI. J Am Coll Cardiol 2020 March 16 (Epub ahead of print).

3. Sheth K. Hospital admissions for strokes appear to have plummeted, a doctor says, a possible sign people are afraid to seek critical help. Washington Post. April 9, 2020 (https://www.washingtonpost.com/national ... story.html. opens in new tab).

4. Garcia S, Albaghdadi MS, Meraj PM, et al. Reduction in ST-segment elevation cardiac catheterization laboratory activations in the United States during COVID-19 pandemic. J Am Coll Cardiol 2020 April 9 (Epub ahead of print).

https://www.nejm.org/doi/full/10.1056/N ... _article_3
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THE NEW ENGLAND JOURNAL OF MEDICINE

Perspective

Putting the Public Back in Public Health — Surveying Symptoms of Covid-19


Andrew T. Chan, M.D., M.P.H., and John S. Brownstein, Ph.D.

June 5, 2020

DOI: 10.1056/NEJMp2016259

To address the unprecedented challenge posed by the Covid-19 pandemic, much of the world — including an estimated 90% of Americans — was locked down and socially distanced.

Large gatherings were prohibited, most schools and nonessential businesses were closed, and people were asked to stay at home or shelter in place.

But as many parts of the United States see a slow decrease in Covid-19 cases, restrictions are gradually being lifted, particularly as the pandemic’s devastating economic and social consequences mount.

Although decisions to gradually reopen societies are ultimately based on a complex calculus of political, economic, and public health considerations, it’s clear that there is a high unmet need for better estimates of communities’ burden of Covid-19 to guide such decision making.

Fortunately, some mobile symptom-surveillance tools can be used for predictive modeling to address this critical priority.

To date, most projections of the Covid-19 burden have been based on incidence calculated from Covid-19 testing, hospitalizations, and deaths.

However, such estimates are severely limited.

First, such data are not uniformly collected on a national scale and rely on a patchwork of variable efforts by regional and local public health authorities.

There are also substantial delays in reporting and aggregating data and stark discrepancies in how cases and deaths are counted.


Second, despite advances in diagnostics, the availability of testing for infection continues to be limited.

This limitation leads to wide variation in the severity of symptoms and the underlying risk profiles used to qualify people for testing in different states and localities.

Thus, confirmed incidence based only on Covid-19–positive tests may depend on these factors rather than reflecting true underlying prevalence in a population.

Third, hospitalizations and death rates largely capture more severe cases of Covid-19.

Increasing quantities of data are highlighting the importance of identifying asymptomatic or minimally symptomatic persons who may not seek medical care, since they may account for a significant proportion of community spread.

Finally, although antibody-based testing is receiving increasing attention, we don’t yet know how reliable, accurate, or widely available such assays will be, nor what implications the results will have, including whether positive results will indicate immunity to reinfection.


To address this knowledge gap, new and cost-efficient participatory syndromic-surveillance tools have been developed that can be used in real time to rapidly address critical near-term needs.

These tools work by capturing data on reported symptoms using mobile technology such as phone apps or Internet-based questionnaires, which often provide more timely signals of infectious disease transmission than more traditional sources.

For example, we have launched a Covid Symptom Study app (http://covid.joinzoe.com. opens in new tab), developed by Zoe Global with scientific input from Massachusetts General Hospital and King’s College London, that has been used by nearly 3.5 million people in the United States, the United Kingdom, and Sweden; it collects daily information about whether people feel well, and if not, about their symptoms and whether they have been tested for Covid-19.

This tool has also been configured to collect additional data on risk factors for and outcomes of Covid-19 that can be used for real-time epidemiologic studies, especially when embedded within existing population-based cohort studies.1

At Boston Children’s Hospital, we have adapted a Web- and text-message–based syndromic surveillance tool, FluNearYou (http://flunearyou.org. opens in new tab),2 designed to assess patterns of influenza incidence, into a tool for Covid-19 known as CovidNearYou (www.covidnearyou.org. opens in new tab).

This platform, which has now captured more than a million reports, is providing insights into Covid-19 symptomology and key demographic risk factors.

Syndromic data have been collected by others with the use of fitness trackers, continuous wearable devices, and smart thermometers, all validated to provide early insight into respiratory illness in the community.

With each of these tools, symptom data can be used to model population incidence of Covid-19 in the absence of widespread population testing.3

Since varied but complementary information is collected with the range of available tools, integrating their output could lead to more robust models.4

In the early phases of the pandemic, these estimates were used for real-time assessment of viral spread, including identification of new “hot spots” or regions at high risk for a heavy Covid-19 burden.5

Many of these tools also entail direct engagement with participants, providing opportunities for real-time communication of study results for public health messaging.

Although syndromic surveillance data play a role in deploying resources to meet surges in health care demand, they may be even more critical for guiding decision making regarding reopening economies and loosening stay-at-home orders.

For example, the current White House strategy calls for dependence on data regarding influenza-like and Covid-like illness as part of the gating criteria for easing social distancing guidelines.

These data, however, currently rely only on emergency department utilization, which may represent an underestimate, given the documented avoidance of in-person medical care and the explosion of telemedicine visits.

Thus, symptom information is vital to providing an earlier window into our progress against viral spread and can be used to complement traditional measures of the pandemic’s severity.

Electronically collected symptom data will be particularly important as a readily adaptable tool that can be applied widely in various populations as states move at variable paces to lift restrictions.

Data based on symptom burden have the advantages of avoiding confounding by differences in testing availability and being flexible and sensitive to detecting changes in response to public health recommendations and government mandates.

Nonetheless, crowd-sourced data from mobile apps have limitations.

The population providing the information will not perfectly reflect the broader population.

Although more than 80% of the U.S. population uses smartphones, there remain many important subgroups, such as older adults and socioeconomically disadvantaged people, whose lack of access to technology will be a barrier to participation.

Through the Covid Symptom Study app, we have specifically sought to enhance representation from racial and ethnic groups that are more vulnerable to Covid-19 by recruiting participants within ongoing studies such as the Black Women’s Health Study and the Multiethnic Cohort Study and by launching a Spanish-language app.1

In addition, as with any study that relies on voluntary contribution of data, people’s differential willingness to participate may reflect differences in underlying health-seeking behavior and anxiety regarding symptoms.

Moreover, several syndrome-surveillance platforms are already in use, which may lead to consumer confusion; it is thus important for data collectors to collaborate and standardize their platforms through such initiatives as the International Workshop on Participatory Surveillance.

Efforts to aggregate data should, however, recognize the potential for compounding limitations related to representativeness unless platforms are specifically adapted to reach different segments of the population.

Finally, the use of any platform that captures health information must balance concerns regarding privacy and data sharing.

Tools based on syndromic surveillance do not require identifying information that can be shared with insurers or public health authorities — a key feature distinguishing them from so-called contact-tracing apps, from which information about Covid-19 testing may be shared publicly, albeit in an anonymized form.

As we move forward with app-based syndromic surveillance, it will be critical to differentiate this work from efforts based on contact tracing and to offer output complementary to those efforts’ results.

Ultimately, we believe that digital syndromic surveillance as a method of “contactless tracing” holds substantial appeal for the future, beyond the immediate priority of reopening our society.

Although caseloads are decreasing, without a universal vaccine or highly effective treatment, we will continue to need to collect data on Covid-19 symptoms for the foreseeable future, particularly given concerns about a resurgence of cases after the summer.

These tools will also be valuable for other efforts, including recruiting volunteers for clinical trials, estimating risk of reinfection, and assessing vaccine efficacy on a population scale.

Thus, such mobile technology will remain an important weapon in our efforts to defeat Covid-19 and to better position ourselves to respond to the next pandemic.

This article was published on June 5, 2020, at NEJM.org.

Author Affiliations

From the Clinical and Translational Epidemiology Unit, the Division of Gastroenterology, and the Cancer Center, Massachusetts General Hospital and Harvard Medical School (A.T.C.), the Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health (A.T.C.), the Massachusetts Consortium for Pathogen Readiness (A.T.C., J.S.B.), the Computational Epidemiology Lab, Boston Children’s Hospital and Harvard Medical School (J.S.B.), and the Departments of Pediatrics and Biomedical Informatics, Harvard Medical School (J.S.B.) — all in Boston.

References

1. Chan AT, Drew DA, Nguyen LH, et al. The COronavirus Pandemic Epidemiology (COPE) consortium: a call to action. Cancer Epidemiol Biomarkers Prev 2020 May 5 (Epub ahead of print).

2. Smolinski MS, Crawley AW, Baltrusaitis K, et al. Flu near you: crowdsourced symptom reporting spanning 2 influenza seasons. Am J Public Health 2015;105:2124-2130.

3. Menni C, Valdes AM, Freidin MB, et al. Real-time tracking of self-reported symptoms to predict potential COVID-19. Nat Med 2020 May 11 (Epub ahead of print).

4. Brownstein JS, Chu S, Marathe A, et al. Combining participatory influenza surveillance with modeling and forecasting: three alternative approaches. JMIR Public Health Surveill

5. Drew DA, Nguyen LH, Steves CJ, et al. Rapid implementation of mobile technology for real-time epidemiology of COVID-19. Science 2020 May 5 (Epub ahead of print).

https://www.nejm.org/doi/full/10.1056/N ... article_23
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THE NEW ENGLAND JOURNAL OF MEDICINE

False Negative Tests for SARS-CoV-2 Infection — Challenges and Implications


Steven Woloshin, M.D., Neeraj Patel, B.A., and Aaron S. Kesselheim, M.D., J.D., M.P.H.

June 5, 2020

DOI: 10.1056/NEJMp2015897

There is broad consensus that widespread SARS-CoV-2 testing is essential to safely reopening the United States.

A big concern has been test availability, but test accuracy may prove a larger long-term problem.


While debate has focused on the accuracy of antibody tests, which identify prior infection, diagnostic testing, which identifies current infection, has received less attention.

But inaccurate diagnostic tests undermine efforts at containment of the pandemic.

Diagnostic tests (typically involving a nasopharyngeal swab) can be inaccurate in two ways.

A false positive result erroneously labels a person infected, with consequences including unnecessary quarantine and contact tracing.

False negative results are more consequential, because infected persons — who might be asymptomatic — may not be isolated and can infect others.


Given the need to know how well diagnostic tests rule out infection, it’s important to review assessment of test accuracy by the Food and Drug Administration (FDA) and clinical researchers, as well as interpretation of test results in a pandemic.

The FDA has granted Emergency Use Authorizations (EUAs) to commercial test manufacturers and issued guidance on test validation.1

The agency requires measurement of analytic and clinical test performance.

Analytic sensitivity indicates the likelihood that the test will be positive for material containing any virus strains and the minimum concentration the test can detect.

Analytic specificity indicates the likelihood that the test will be negative for material containing pathogens other than the target virus.

Clinical evaluations, assessing performance of a test on patient specimens, vary among manufacturers.

The FDA prefers the use of “natural clinical specimens” but has permitted the use of “contrived specimens” produced by adding viral RNA or inactivated virus to leftover clinical material.

Ordinarily, test-performance studies entail having patients undergo an index test and a “reference standard” test determining their true state.

Clinical sensitivity is the proportion of positive index tests in patients who in fact have the disease in question.

Sensitivity, and its measurement, may vary with the clinical setting.

For a sick person, the reference-standard test is likely to be a clinical diagnosis, ideally established by an independent adjudication panel whose members are unaware of the index-test results.

For SARS-CoV-2, it is unclear whether the sensitivity of any FDA-authorized commercial test has been assessed in this way.

Under the EUAs, the FDA does allow companies to demonstrate clinical test performance by establishing the new test’s agreement with an authorized reverse-transcriptase–polymerase-chain-reaction (RT-PCR) test in known positive material from symptomatic people or contrived specimens.

Use of either known positive or contrived samples may lead to overestimates of test sensitivity, since swabs may miss infected material in practice.1

Designing a reference standard for measuring the sensitivity of SARS-CoV-2 tests in asymptomatic people is an unsolved problem that needs urgent attention to increase confidence in test results for contact-tracing or screening purposes.

Simply following people for the subsequent development of symptoms may be inadequate, since they may remain asymptomatic yet be infectious.

Assessment of clinical sensitivity in asymptomatic people had not been reported for any commercial test as of June 1, 2020.

Two studies from Wuhan, China, arouse concern about false negative RT-PCR tests in patients with apparent Covid-19 illness.

In a preprint, Yang et al. described 213 patients hospitalized with Covid-19, of whom 37 were critically ill.2

They collected 205 throat swabs, 490 nasal swabs, and 142 sputum samples (median, 3 per patient) and used an RT-PCR test approved by the Chinese regulator.

In days 1 through 7 after onset of illness, 11% of sputum, 27% of nasal, and 40% of throat samples were deemed falsely negative.


Zhao et al. studied 173 hospitalized patients with acute respiratory symptoms and a chest CT “typical” of Covid-19, or SARS-CoV-2 detected in at least one respiratory specimen.

Antibody seroconversion was observed in 93%.3 RT-PCR testing of respiratory samples taken on days 1 through 7 of hospitalization were SARS-CoV-2–positive in at least one sample from 67% of patients.

Neither study reported using an independent panel, unaware of index-test results, to establish a final diagnosis of Covid-19 illness, which may have biased the researchers toward overestimating sensitivity.

In a preprint systematic review of five studies (not including the Yang and Zhao studies), involving 957 patients (“under suspicion of Covid-19” or with “confirmed cases”), false negatives ranged from 2 to 29%.4

However, the certainty of the evidence was considered very low because of the heterogeneity of sensitivity estimates among the studies, lack of blinding to index-test results in establishing diagnoses, and failure to report key RT-PCR characteristics.4

Taken as a whole, the evidence, while limited, raises concern about frequent false negative RT-PCR results.


If SARS-CoV-2 diagnostic tests were perfect, a positive test would mean that someone carries the virus and a negative test that they do not.

With imperfect tests, a negative result means only that a person is less likely to be infected.

To calculate how likely, one can use Bayes’ theorem, which incorporates information about both the person and the accuracy of the test (recently reviewed5).

For a negative test, there are two key inputs: pretest probability — an estimate, before testing, of the person’s chance of being infected — and test sensitivity.

Pretest probability might depend on local Covid-19 prevalence, SARS-CoV-2 exposure history, and symptoms.

Ideally, clinical sensitivity and specificity of each test would be measured in various clinically relevant real-life situations (e.g., varied specimen sources, timing, and illness severity).

Assume that an RT-PCR test was perfectly specific (always negative in people not infected with SARS-CoV-2) and that the pretest probability for someone who, say, was feeling sick after close contact with someone with Covid-19 was 20%.

If the test sensitivity were 95% (95% of infected people test positive), the post-test probability of infection with a negative test would be 1%, which might be low enough to consider someone uninfected and may provide them assurance in visiting high-risk relatives.

The post-test probability would remain below 5% even if the pretest probability were as high as 50%, a more reasonable estimate for someone with recent exposure and early symptoms in a “hot spot” area.

But sensitivity for many available tests appears to be substantially lower: the studies cited above suggest that 70% is probably a reasonable estimate.

At this sensitivity level, with a pretest probability of 50%, the post-test probability with a negative test would be 23% — far too high to safely assume someone is uninfected.


The graph shows how the post-test probability of infection varies with the pretest probability for tests with low (70%) and high (95%) sensitivity.

The horizontal line indicates a probability threshold below which it would be reasonable to act as if the person were uninfected (e.g., allowing the person to visit an elderly grandmother).

Where this threshold should be set — here, 5% — is a value judgment and will vary with context (e.g., lower for people visiting a high-risk relative).

The threshold highlights why very sensitive diagnostic tests are needed.

With a negative result on the low-sensitivity test, the threshold is exceeded when the pretest probability exceeds 15%, but with a high-sensitivity test, one can have a pretest probability of up to 33% and still, assuming the 5% threshold, be considered safe to be in contact with others.

The graph also highlights why efforts to reduce pretest probability (e.g., by social distancing, possibly wearing masks) matter.

If the pretest probability gets too high (above 50%, for example), testing loses its value because negative results cannot lower the probability of infection enough to reach the threshold.

We draw several conclusions.

First, diagnostic testing will help in safely opening the country, but only if the tests are highly sensitive and validated under realistic conditions against a clinically meaningful reference standard.

Second, the FDA should ensure that manufacturers provide details of tests’ clinical sensitivity and specificity at the time of market authorization; tests without such information will have less relevance to patient care.

Third, measuring test sensitivity in asymptomatic people is an urgent priority.


It will also be important to develop methods (e.g., prediction rules) for estimating the pretest probability of infection (for asymptomatic and symptomatic people) to allow calculation of post-test probabilities after positive or negative results.

Fourth, negative results even on a highly sensitive test cannot rule out infection if the pretest probability is high, so clinicians should not trust unexpected negative results (i.e., assume a negative result is a “false negative” in a person with typical symptoms and known exposure).

It’s possible that performing several simultaneous or repeated tests could overcome an individual test’s limited sensitivity; however, such strategies need validation.


Finally, thresholds for ruling out infection need to be developed for a variety of clinical situations.

Since defining these thresholds is a value judgement, public input will be crucial.

This article was published on June 5, 2020, at NEJM.org.

Author Affiliations

From the Center for Medicine in the Media, Dartmouth Institute for Health Policy and Clinical Practice, Lebanon, NH (S.W.); the Lisa Schwartz Program for Truth in Medicine, Norwich, VT (S.W.); the Program on Regulation, Therapeutics, and Law (PORTAL), Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston (S.W., A.K.); and Yale University, New Haven, CT (N.P.).

References

1. U.S. Food and Drug Administration. Emergency Use Authorization (EUA) information, and list of all current EUAs (https://www.fda.gov/emergency-preparedn ... horization. opens in new tab).

2. Yang Y, Yang M, Shen C, et al. Evaluating the accuracy of different respiratory specimens in the laboratory diagnosis and monitoring the viral shedding of 2019-nCoV infections. February 17, 2020 (https://www.medrxiv.org/content/10.1101 ... 20021493v2. opens in new tab). preprint.

3. Zhao J, Yuan Q, Wang H, et al. Antibody responses to SARS-CoV-2 in patients of novel coronavirus disease 2019. Clin Infect Dis 2020 March 28 (Epub ahead of print).

4. Arevalo-Rodriguez I, Buitrago-Garcia D, Simancas-Racines D, et al. False-negative results of initial RT-PCR assays for COVID-19: a systematic review. April 21, 2020 (https://www.medrxiv.org/content/10.1101 ... 20066787v1. opens in new tab). preprint.

5. Watson J, Whiting PF, Brush JE. Interpreting a covid-19 test result. BMJ 2020;369:m1808-m1808.

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THE NEW ENGLAND JOURNAL OF MEDICINE

Perspective

Waiting for Certainty on Covid-19 Antibody Tests — At What Cost?


Milton C. Weinstein, Ph.D., Kenneth A. Freedberg, M.D., Emily P. Hyle, M.D., and A. David Paltiel, Ph.D.

June 5, 2020

DOI: 10.1056/NEJMp2017739

Governments around the world and throughout the United States are beginning to “reopen their economies” in stages.

Some have been considering the use of serologic antibody testing to screen for possible immunity and to identify people who could return to the workplace with less severe mitigation measures1 or be assigned to higher-exposure tasks.

Although availability of antibody tests is lagging and successful mitigation has kept seroprevalence too low to rely fully on positive test results, at some point in the near future antibody testing will become a viable option.

This idea is not without its critics.


On April 24, for example, the World Health Organization (WHO) issued the following guidance: “At this point in the pandemic, there is not enough evidence about the effectiveness of antibody-mediated immunity to guarantee the accuracy of an ‘immunity passport’ or ‘risk-free certificate.’”2

The WHO is right to note the many uncertainties.

Do antibodies confer immunity and, if so, for how long?

How accurate is the antibody test?

What are the individual and collective harms that may be caused if persons with no actual immunity are certified for return to the workplace?


How great is the danger that people desperate to return to work may seek intentional exposure to the virus in the hope of developing antibodies?

But we believe that the WHO is dead wrong to suggest that we cannot act until we “guarantee” the accuracy of the immunity-certification process.

Demanding incontrovertible evidence may be appropriate in the rarefied world of scholarly scientific inquiry.

But in the context of a raging pandemic, we simply do not have the luxury of holding decisions in abeyance until all the relevant evidence can be assembled.

Failing to take action is itself an action that carries profound costs and health consequences.

For caregivers, acting on incomplete information is not a revolutionary idea.

Practicing medicine means relying on imperfect evidence to balance harms against benefits on a daily basis.

Physicians use tests offering less than 100% accuracy every day, knowing that there will always be false positives and false negatives.


When we judge that the likely benefits of acting on a correct diagnosis outweigh the possible harms of mistakenly acting on an incorrect diagnosis, we act.

We choose to perform appendectomies, for example, even though we rarely have irrefutable evidence that a patient’s appendix is inflamed.

Though we arrive at public health policies and clinical decisions by different avenues, in both domains we must often make choices with less-than-perfect evidence.

Many U.S. governors are opening up workplaces now without requiring evidence of immunity or prior infection.

Is this policy better than a more nuanced policy of requiring less virologic testing and mitigation for people who obtain a positive result from a serologic test — even an imperfect one — based on the unproven but likely premise that there is some immunity conferred by the presence of antibodies?


We don’t give penicillin to everyone with a sore throat; a throat culture is usually a prerequisite.

Even though throat cultures have false positives and false negatives, they are still useful.

Demands for guarantees are both particularly appealing and especially dangerous in times of crisis.

The Covid-19 pandemic throws the risk–benefit trade-off into relief so stark that many of us would rather turn away than confront it.


By soft-pedaling the less tangible, less emotionally salient considerations that figure into a decision, insisting on certainty permits policymakers to speak with persuasive, decisive clarity in the space of a tweet.

No need for “on the other hand” equivocation.

Those who believe that no economic benefit justifies the risk of spreading Covid-19 can find shelter in the solution of not reopening the economy until the entire population is covered by a completely effective vaccine or until a highly effective treatment is widely available.

At the other extreme is the solution arrived at by those who would reopen the economy without regard for the risks that individual workers would incur and impose on others.

A more reasoned, humane position is to take explicit stock of the benefits and harms.

Four independent pieces of information need to be weighed against one another in assessing serologic testing as a basis for returning people to work.

First is our understanding of the presence of SARS-CoV-2 antibodies in the population (prevalence).

Second is our understanding of the performance of serologic testing — both its ability to detect the presence of antibodies (test sensitivity) and its ability to confirm the absence of SARS-CoV-2 antibodies when they are truly absent (test specificity).

Third is our beliefs about whether and how antibodies confer immunity; if they do, what do we assume about the relationship between antibody level (titer) and the resultant degree and persistence of any immunity that is conferred?

Fourth is our belief about the relative magnitude of the two different kinds of harm that we could cause: the net harm of mistakenly releasing a susceptible, and potentially infectious, person into the workforce with minimal mitigation (false positive cost) and the net cost of failing to certify a truly immune person to rejoin the workforce (false negative cost).


The delicate balance to be struck among these four considerations can be described mathematically, but the bottom line is this: we have enough evidence and expert opinion to make an informed decision today.

And we can put the monitoring systems in place to learn from that decision so that we can make even better choices tomorrow.

In the world of randomized clinical trials, statisticians test scientific hypotheses by requiring a probability of less than 5% that the observed result could have occurred by chance.

This so-called type I error — and the associated mistake of approving a truly ineffective (or even dangerous) drug — is the enemy of the truth.

But reducing the risk of type I error places us unavoidably at greater risk of committing a type II error and failing to approve a truly effective drug.

In times of crisis, when the consequences of both action and inaction are so serious, it makes sense to take into account the benefits and harms of all possible errors and to be prepared to commit some type I errors in exchange for fewer type II errors and the opportunity to learn something important.

To be sure, there are problems with serologic testing.

Tests with poor quality control and unacceptably high error rates need to be culled out, as the Food and Drug Administration has begun to do.3

Persons receiving false positive test results may be mistakenly reassured that they are safe and may pay less attention to basic prevention (e.g., social distancing).

Tests with nontrivial false positive rates should not be used when the prevalence of the condition being tested for is too low, as it remains in most communities.


First-generation antibody tests for HIV had specificities in the range we currently see for Covid-19 antibody tests, but today HIV antibody tests are 99.5% specific.4

Soon, Covid-19 antibody tests could reach that level of accuracy.5

Important ethical questions need to be addressed regarding the implications of restricting work on the basis of health status.

Any public policy that distinguishes among citizens according to their Covid-19 serologic status has the potential to threaten rights of equal access to paid employment, undermine freedom to socialize and to travel, violate expectations of privacy, and exacerbate enforcement practices that discriminate against vulnerable groups.


The risks of reopening workplaces and the economy to individuals and communities are real; steps in that direction should be taken cautiously.

Antibody testing, made available to those in the workforce, will soon offer a scientifically valid way to better determine workplace access and mitigation strategies based on the risk that individuals may transmit the virus to or acquire the virus from coworkers.

But the costs of delaying any reopening until we are certain that no one returning to work will transmit Covid-19 are also real.

There is no such thing as a 100% safe bet.

Let’s not permit an unattainable ideal to be the enemy of a very good option that we currently have.

This article was published on June 5, 2020, at NEJM.org.

Author Affiliations

From the Department of Health Policy and Management, Harvard T.H. Chan School of Public Health (M.C.W.), and the Medical Practice Evaluation Center, Massachusetts General Hospital and Harvard Medical School (K.A.F., E.P.H.) — all in Boston; and the Public Health Modeling Unit, Yale School of Public Health, New Haven, CT (A.D.P.).

References

1. Walensky RP, Del Rio C. From mitigation to containment of the COVID-19 pandemic: putting the SARS-CoV-2 genie back in the bottle. JAMA 2020 April 17 (Epub ahead of print).

2. World Health Organization. “Immunity passports” in the context of COVID-19. April 24, 2020 (https://www.who.int/news-room/commentar ... f-Covid-19. opens in new tab).

3. Shah A, Shuren J. Insight into FDA’s revised policy on antibody tests: prioritizing access and accuracy. Silver Spring, MD: Food and Drug Administration, May 4, 2020. https://www.fda.gov/news-events/fda-voi ... d-accuracy. opens in new tab).

4. Alexander TS. Human immunodeficiency virus diagnostic testing: 30 years of evolution. Clin Vaccine Immunol 2016;23:249-253.

5. Cheng MP, Papenburg J, Desjardins M, et al. Diagnostic testing for severe acute respiratory syndrome-related coronavirus-2: a narrative review. Ann Intern Med 2020;172:726-734.

https://www.nejm.org/doi/full/10.1056/N ... ?query=TOC
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