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Residency training worldwide: a survey on similarities and differences

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IFCC Task Force – Young Scientists plans to survey on similarities and differences in Lab medicine residency training worldwide

by:

  • Claudia Imperiali. IFCC TF-YS member, Clinical Laboratory, Viladecans Hospital, Barcelona, Spain
  • Santiago Fares-Taie. TF-YS Chair, Laboratorio Bioquímico Mar del Plata, Argentina
  • Josep Miquel Bauçà-Rosselló. Expert Member, Qualifications Committee on Residency Exam for Chemists and Biochemists, Clinical Biochemistry, Hospital Universitari Son Espases, Palma de Mallorca, Spain

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Structure-guided Design of Novel SARS-CoV-2 Inhibitors

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As part of continued efforts to respond to the COVID-19 pandemic caused by SARS-CoV-2 virus, researchers have designed and synthesized two new inhibitors of the SARS-CoV-2 main protease – one of the best characterized drug targets among coronaviruses. Insights from their in vivo analyses suggest one of the novel inhibitors is a good candidate for further clinical studies. Therapies are urgently needed to fight the global COVID-19 pandemic. For viruses like HIV, effective drugs block the main virus protease – an enzyme that processes proteins critical to virus development. Here, informed by the structure of the SARS-CoV main protease, Wenhao Dai and colleagues designed two inhibitors, 11a and 11b. In cell culture, both inhibitors strongly inhibited the activity of the main SARS-CoV-2 protease, the authors report, showing good anti-viral activity. To elucidate the compounds’ mechanisms of inhibitory action, the authors determined the high-resolution crystal structure of 11a and 11b, respectively, bound to the main SARS-CoV-2 protease complex at 1.5-angstrom resolution. The two structures reveal a similar inhibitory mechanism, say the authors, in which both compounds occupy the substrate-binding pocket of the SARS-CoV-2 main protease. Compound 11a, however, had better pharmokinetic properties when tested in mice. It was selected for further investigation, including for toxicity, with intravenous drip dosing in Sprague-Dawley (SD) rats and Beagle dogs, where no obvious toxicity was observed for the period studied. The results of the tests in rats and dogs indicate that that this compound is a promising drug candidate for further clinical studies.

Foto: Gustavo Fring from Pexels

IFCC Survey on Impact of COVID-19 on Clinical Laboratories

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The current worldwide COVID-19 epidemic has had a significant impact on clinical laboratories globally and has highlighted the critical role of laboratory medicine in public health and patient care.

IFCC has responded by developing an IFCC Information Guide on COVID-19 (www.ifcc.org) as well as a Special Taskforce to provide guidelines to clinical laboratories around the world.

IFCC would now like to survey all colleagues in clinical laboratories in each country to understand how individual laboratories manage pre-analytical, analytical and post-analytical processes during the COVID-19 outbreak.

The questions raised are aimed at capturing what your laboratory is currently doing to mitigate the biohazards related to COVID-19. This survey has been developed with assistance of APFCB as well as IFCC Taskforce on COVID-19.

Please complete and distribute the following survey to all clinical colleagues in your country.

Requested completion extended to Friday 1st May 2020.

IFCC Survey now available in English, Spanish, Chinese, French

English: https://mysurvey.nus.edu.sg/EFM/se/543BE5C27BEEB457

Spanish: https://mysurvey.nus.edu.sg/EFM/se/543BE5C24A7682C1

Chinese: https://mysurvey.nus.edu.sg/EFM/se/543BE5C2696E93F8

French: https://mysurvey.nus.edu.sg/EFM/se/543BE5C26DDB9622

How does COVID-19 kill? Uncertainty is hampering doctors’ ability to choose treatments

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COVID-19 ravages the lungs of patients. Credit: Sergei Krasnoukhov/TASS/Getty

How does COVID-19 kill? Uncertainty over whether it is the virus itself — or the response by a person’s immune system — that ultimately overwhelms a patient’s organs, is making it difficult for doctors to determine the best way to treat patients who are critically ill with the coronavirus.

Clinical data suggest that the immune system plays a part in the decline and death of people infected with the new coronavirus, and this has spurred a push for treatments such as steroids that rein in that immune response. But some of these treatments act broadly to suppress the immune system, stoking fears that they could actually hamper the body’s ability to keep the viral infection in check.

“My greatest fear is that this gets taken to an extreme, where people are using whatever they can get their hands on to turn off the immune response,” says Daniel Chen, an immunologist and chief medical officer at IGM Biosciences in Mountain View, California. “You can’t knock down the immune system at a time when it’s battling an infection.”

Race for treatments

As coronavirus patients flood hospitals worldwide, physicians are wading through streams of incomplete data and preprints that have not been peer-reviewed, struggling to find ways to help their patients and sharing experiences on social media. Some doctors are trying cocktails of unproven therapies in a desperate bid to save lives.

“People are watching patients deteriorate before their eyes, and there’s a very strong motivation to reach for any therapy that you think could be effective,” says Kenneth Baillie, an intensive-care anaesthetist at the University of Edinburgh, UK. “When I feel powerless at the end of a bed, I feel the same.”

Some of the earliest analyses of coronavirus patients in China suggested that it might not be only the virus that ravages the lungs and kills; rather, an overactive immune response might also make people severely ill or cause death. Some people who were critically ill with COVID-19 had high blood levels of proteins called cytokines, some of which can ramp up immune responses. These include a small but potent signalling protein called interleukin-6 (IL-6). IL-6 is a call-to-arms for some components of the immune system, including cells called macrophages. Macrophages fuel inflammation and can damage normal lung cells as well. The release of those cytokines, known as a cytokine storm, can also occur with other viruses, such as HIV.

The ideal counter, then, would be a drug that blocks IL-6 activity and reduces the flow of macrophages into the lungs. Such drugs, known as IL-6 inhibitors, already exist for the treatment of rheumatoid arthritis and other disorders. One called Actemra (tocilizumab), made by the Swiss pharmaceutical firm Roche, has been approved in China to treat coronavirus patients, and researchers around the world are working furiously to test it and other drugs of this type.

Immune challenges

But globally there is not enough of the drug to go round, and many clinicians are turning to steroids, which more broadly dampen the immune system, says James Gulley, an immuno-oncologist at the National Cancer Institute in Bethesda, Maryland. IL-6 inhibitors may suppress only those immune responses that are governed by IL-6, allowing other immune responses that might help the body fight COVID-19 to continue. But steroids and some other therapies that act more generally might significantly reduce the body’s ability to fight infection overall. These drugs will not only suppress macrophages, but also immune cells called CD4 T cells, which are crucial for initiating immune responses, and also CD8 T cells, which are the body’s antiviral assassins, capable of destroying infected cells with more precision than macrophages. “When things get really bad, they’ll throw on steroids,” says Gulley. “I am a bit worried about where some people are going.”

Chen notes that although IL-6 levels are high in some acutely ill patients, viral loads are high as well, suggesting that the body is still fighting off an active viral infection. “You have to assume that there’s an ongoing antiviral immune response that is important to these patients,” he says. If so, then reducing CD4 and CD8 T cells could undermine that response.

Steroids and other immune suppressants are already being tested against coronavirus in clinical trials. In March, UK researchers launched the RECOVERY study, a randomized clinical trial that will evaluate the steroid dexamethasone and other potential treatments for COVID-19. This worries rheumatologist Jessica Manson at University College Hospital in London. Evidence from previous outbreaks caused by related coronaviruses suggests that steroids hold little benefit, and might even delay the time it takes for patients to rid themselves of the virus, she says. And the RECOVERY trial calls for giving the treatments before patients become critically ill and have no other recourse.

But Peter Horby, who studies infectious diseases at Oxford University in the UK and leader of the RECOVERY trial, notes that the trial will be using relatively low doses of steroid. “Higher doses are not routinely recommended, but the jury is out on lower doses,” he says. “And many authorities, including the World Health Organization, recommend a trial.”

Combination therapy

A combination of damage from both a virus and the immune response to it is not uncommon, says Rafi Ahmed, a viral immunologist at Emory University in Atlanta, Georgia. The effects of ‘hit-and-run’ viruses such as norovirus, which make people sick almost immediately after infection, are more probably due to the virus itself, he says. By contrast, people infected with viruses such as coronavirus do not show symptoms until several days after infection. By then, collateral damage from the immune response often contributes to the illness.

“It’s very hard to dissect what per cent of it is due to the virus itself, and what per cent is the immune response,” Ahmed says. “But it’s almost always a combination of the two.”

In the absence of an answer, Ahmed is hopeful that researchers will arrive at a combination therapy, such as an IL-6 inhibitor that does not completely suppress the immune system, combined with an antiviral drug that directly targets the virus. Other drugs that target the immune system are also being tested, including one called anakinra, which targets a signalling protein called IL-1, and may provide a way to reduce specific immune responses without hampering CD4 and CD8 T cells, says Chen.

But Baillie says that given the widespread use of steroids to treat people with coronavirus already, it is important to collect data on the practice. And although he is also concerned about suppressing immune responses in coronavirus patients, he notes that it is still possible that the practice could hold some benefit. “The only responsible thing to do is to use them in the context of a randomized clinical trial,” he says. “There’s no other way to know if a treatment is working.”

Nature 580, 311-312 (2020) doi: 10.1038/d41586-020-01056-7

Source: nature.com

How to Obtain a Nasopharyngeal Swab Specimen

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Authors: Francisco M. Marty, M.D., Kaiwen Chen, B.S., and Kelly A. Verrill, R.N.

Overview

Collection of specimens from the surface of the respiratory mucosa with nasopharyngeal swabs is a procedure used for the diagnosis of Covid-19 in adults and children.1-4 The procedure is also commonly used to evaluate patients with suspected respiratory infection caused by other viruses and some bacteria. This video describes the collection of nasopharyngeal specimens for detection of Covid-19, the illness caused by infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).

There are no specific contraindications for collecting specimens with nasopharyngeal swabs. However, clinicians should be cautious if the patient has had recent nasal trauma or surgery, has a markedly deviated nasal septum, or has a history of chronically blocked nasal passages or severe coagulopathy.

Preparation and Equipment

Nasopharyngeal swabs are specifically manufactured to have long, flexible shafts made of plastic or metal and tips made of polyester, rayon, or flocked nylon. In addition to nasopharyngeal swabs, you will need personal protective equipment (PPE), including a gown, nonsterile gloves, a protective mask, and a face shield, as described below. Make sure that all sample tubes have been labeled and that the appropriate requisition forms have been filled out before starting the procedure.

It is essential that you follow the pertinent respiratory and contact precautions specified by the Centers for Disease Control and Prevention (CDC) and by your own institution and that you put on the PPE correctly (Figure 1). If possible, you should put on and take off the PPE in the presence of an observer to make sure there are no breaks in technique that may pose a risk of contamination.

First, put on a protective gown, wash your hands with soap and water (or use an alcohol-based solution), and put on a pair of nonsterile gloves. Then put on a protective mask with a rating of N95 or higher, as recommended by the CDC. Finally, put on a face shield for face and eye protection.

Figure 1. Personal Protective Equipment.The clinician is shown wearing the PPE required during collection of a nasopharyngeal swab specimen.

Procedure

Masks are recommended for all patients suspected of having Covid-19 (Figure 2). Ask the patient to take off her mask and blow her nose into a tissue to clear excess secretions from the nasal passages. Remove the swab from the packaging. Tilt the patient’s head back slightly, so that the nasal passages become more accessible. Ask the patient to close her eyes to lessen the mild discomfort of the procedure. Gently insert the swab along the nasal septum, just above the floor of the nasal passage, to the nasopharynx, until resistance is felt (Figure 3).

Figure 2. Patient Wearing a Mask.Masks are recommended for all patients suspected of having Covid-19.

Figure 3. Obtaining the Nasopharyngeal Swab Specimen.

Insert the swab into the nostril, parallel to the palate. If you detect resistance to the passage of the swab, back off and try reinserting it at a different angle, closer to the floor of the nasal canal. The swab should reach a depth equal to the distance from the nostrils to the outer opening of the ear. The CDC recommends leaving the swab in place for several seconds to absorb secretions and then slowly removing the swab while rotating it. Your institution may also recommend rotating the swab in place several times before removing it. Ask the patient to reapply her mask.

Handling of the Specimen

Open the collection tube and insert the swab into the tube. Break the swab at the groove and discard what remains of the swab. Close the labeled collection tube and place it in a biohazard bag (Figure 4). Depending on institutional practices, you may instead return the sample to its original packaging for transport. Follow the CDC directions for direct processing of the swab specimen or placement of the swab in media with or without refrigeration.

Figure 4. Handling the Nasopharyngeal Swab Specimen.Shown is the swab in a collection tube placed in a biohazard bag.

Removing Personal Protective Equipment

Remove your PPE as shown in the video and described here or in accordance with the standards at your institution. First, remove your gown and gloves. Clean your hands with an alcohol-based solution or soap and water. Put on a new pair of gloves, and then remove your face shield and either dispose of it or clean and store it in accordance with the guidelines at your institution. Remove your gloves, rewash your hands, and put on another pair of gloves; then remove your mask and follow your institutional guidelines for disposal or reuse. Finally, remove the last pair of gloves and wash your hands.

https://www.infobioquimica.com/new/wp-content/uploads/2020/04/NEJMdo005746_download.mp4

Summary

This video demonstrates the collection of specimens from the surface of the respiratory mucosa with nasopharyngeal swabs for the diagnosis of Covid-19 in adults and in children. It is important to use approved PPE and the appropriate technique to minimize the possibility of spreading the virus.

Author Affiliations

From the Division of Infectious Diseases, Brigham and Women’s Hospital (F.M.M., K.C.), and the Division of Pediatric Oncology, Dana–Farber/Boston Children’s Cancer and Blood Disorders Center (K.A.V.) — both in Boston.

Address reprint requests to Dr. Marty at the Division of Infectious Diseases, Brigham and Women’s Hospital, 75 Francis St., PBB-A4, Boston, MA 02115, or at fmarty@bwh.harvard.edu.

Source: nejm.org

COVID and the convergence of three crises in Europe

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As the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic hits Europe, it converges and interacts with three global crises that will make it spread even further: governance, economics, and migration.1 Although these crises have different roots, all three reflect a lack of mechanisms to produce and protect essential public goods for an effective policy response. Understanding how these crises intersect and the scope of a potential transnational Europe-wide response is crucial.

Turning first to governance, the ongoing and devastating pandemic is exposing the limits of not only national preparedness and mitigation policies, but also transnational governance systems to organise and administer public goods, such as health-care support. As Italy’s outbreak accelerated, on Feb 26, 2020, the country’s leaders appealed for additional personal protective equipment and ventilators to the EU’s crisis hub, the Emergency Response Coordination Centre.2 Only by mid-March did EU member states begin sending supplies, by which point China was already providing medical experts, supplies and equipment.3

The second crisis is economic; the recession accompanying the coronavirus pandemic will lead to spikes in unemployment and lost income, especially among those countries who are already in precarious positions. A decade of austerity following the 2007–08 financial crisis has had devastating detrimental health and social effects,4, 5 and has rendered disadvantaged groups even more vulnerable to the socioeconomic impacts of the pandemic. To date, no EU-wide social protection shield or minimum social floor exists. Additionally, those who have the most economic difficulties may not be able to adhere to physical distancing effectively, as they seek to continue to work, worsening the risks of virus transmission. The public health systems in several EU countries—still with reduced capacity due to austerity measures—face important limitations in effectively responding to the pandemic.

Third, the migration crisis that started in 2015—and has rekindled in recent months—poses a major challenge. Attempts to settle asylum seekers and refugees across Europe have failed6 and revealed the limited solidarity within the EU. Border countries like Italy or Greece are struggling to handle the situation, partly due to the inadequate financial, technical, and institutional support from other European countries. The pandemic presents a further complication, as funds are being diverted away from refugee services,7 and some have blamed migrants for importing disease.8 Possible SARS-CoV-2 outbreaks in overcrowded, understaffed, and under-resourced refugee facilities could become health disasters.

What could an appropriate response to these converging crises look like? National strategies will not be enough, as dysfunctional responses to crises are partly caused by the lack of effective supranational mechanisms for providing public goods. As subnational borders, and then national borders began shutting down and the EU became the epicentre of the pandemic, supranational coordination, governance, and reciprocal distributive measures—eg, for the co-production of public goods—are needed more than ever. An effective and reciprocal distributive EU response mechanism must ensure that economic, social, technological, and health resources are shared more equally and in a spirit of solidarity among EU member states.

Sadly, so far there is widespread unwillingness to contribute to the equitable provision of public goods. Health is one of the sectors where resistance by EU members to transnational sovereignty has remained strongest,9 and countries pull back to serving unilateral, national-level interests at the cost of collective policy responses to shared challenges.

In the 21st century alone, Europe experienced the first SARS epidemic in 2003, a major financial meltdown in 2008, and a migration crisis in 2015. Yet, transnational mechanisms of crisis management and resolution remained ad hoc and limited.

One positive step is from the European Central Bank, which announced a no-limits commitment to protect European economies on March 19, 2020, by purchasing sovereign and corporate debt, among other measures.10 Such bold transnational action can be imitated in other areas, including the development of large-scale public investment projects, social cohesion policies, and redistributive measures to reach most-affected populations. After years of promoting fiscal austerity and economic deregulation, now is the time for European institutions to actively intervene to protect population health and wellbeing. Effective disease prevention and better social protection across the EU can only be achieved by the re-allocation of competences across different policy levels, and by implementing global solutions (including the International Labour Organization’s global Social Protection Floors recommendation, the Sustainable Development Goals, and rights-based approaches on migrants and refugees) that are already on the table.

References

  1. Gottlieb N Bozorgmehr K Trummer U Rechel B. Health policies and mixed migration – lessons learnt from the ‘refugee crisis’. Health Policy. 2019; 123: 805-808
  2. European Commission. Crisis management. https://ec.europa.eu/info/live-work-travel-eu/health/coronavirus-response/crisis-management_en
    Date accessed: March 22, 2020
  3. Braw E. The EU is abandoning Italy in its hour of need. Foreign Policy.
    https://foreignpolicy.com/2020/03/14/coronavirus-eu-abandoning-italy-china-aid/ Date: March 14, 2020 Date accessed: March 22, 2020
  4. Karanikolos M Mladovsky P Cylus J et al. Financial crisis, austerity, and health in Europe. Lancet. 2013; 381: 1323-1331
  5. Forster T Kentikelenis AE. Austerity and health in Europe: disentangling the causal links. Eur J Public Health. 2019; 29: 808-809
  6. Bozorgmehr K Wahedi K. Reframing solidarity in Europe: Frontex, frontiers, and the fallacy of refugee quota. Lancet Public Health. 2017; 2: e10-e11
  7. Kelly A Grant H Tondo L. NGOs raise alarm as coronavirus strips support from EU refugees. The Guardian, March 18, 2020 https://www.theguardian.com/global-development/2020/mar/18/ngos-raise-alarm-as-coronavirus-strips-support-from-eu-refugees Date accessed: March 22, 2020
  8. Hungary’s Orban blames foreigners, migration for coronavirus spread, France 24. https://www.france24.com/en/20200313-hungary-s-pm-orban-blames-foreign-students-migration-for-coronavirus-spread Date: March 13, 2020 Date accessed: March 22, 2020
  9. Greer SL Hervey TK Mackenbach JP McKee M. Health law and policy in the European Union. Lancet. 2013; 381: 1135-1144
  10. Arnold M. ECB to launch €750bn bond-buying programme. Financial Times, March 19, 2020 https://www.ft.com/content/711c5df2-695e-11ea-800d-da70cff6e4d3 Date accessed: March 22, 2020

Source: The Lancet

Why inequality could spread COVID-19

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Pandemics rarely affect all people in a uniform way. The Black Death in the 14th century reduced the global population by a third, with the highest number of deaths observed among the poorest populations.1 Densely populated with malnourished and overworked peasants, medieval Europe was a fertile breeding ground for the bubonic plague. Seven centuries on—with a global gross domestic product of almost US$100 trillion—is our world adequately resourced to prevent another pandemic?2 Current evidence from the coronavirus disease 2019 (COVID-19) pandemic would suggest otherwise. Estimates indicate that COVID-19 could cost the world more than $10 trillion,3 although considerable uncertainty exists with regard to the reach of the virus and the efficacy of the policy response. For each percentage point reduction in the global economy, more than 10 million people are plunged into poverty worldwide.3 Considering that the poorest populations are more likely to have chronic conditions, this puts them at higher risk of COVID-19-associated mortality. Since the pandemic has perpetuated an economic crisis, unemployment rates will rise substantially and weakened welfare safety nets further threaten health and social insecurity.

Working should never come at the expense of an individual’s health nor to public health. In the USA, instances of unexpected medical billings for uninsured patients treated for COVID-19 and carriers continuing to work for fear of redundancy have already been documented.4 Despite employment safeguards recently being passed into law in some high-income countries, such as the UK and the USA, low-income groups are wary of these assurances since they have experience of long-standing difficulties navigating complex benefits systems,4 and many workers (including the self-employed) can be omitted from such contingency plans. The implications of inadequate financial protections for lowwage workers are more evident in countries with higher levels of extreme poverty, such as India.

In recent pandemics, such as the Middle East respiratory syndrome, doctors were vectors of disease transmission due to inadequate testing and personal protective equipment.5 History seems to be repeating itself, with clinicians comprising more than a tenth of all COVID-19 cases in Spain and Italy. With a projected global shortage of 15 million health-care workers by 2030, governments have left essential personnel exposed in this time of need.

Poor populations lacking access to health services in normal circumstances are left most vulnerable during times of crisis. Misinformation and miscommunication disproportionally affect individuals with less access to information channels, who are thus more likely to ignore government health warnings.6 With the introduction of physical distancing measures, household internet coverage should be made ubiquitous. The inequitable response to COVID-19 is already evident. Healthy life expectancy and mortality rates have historically been markedly disproportionate between the richest and poorest populations. The full effects of COVID-19 are yet to be seen, while the disease begins to spread across the most fragile settings, including conflict zones, prisons, and refugee camps. As the global economy plunges deeper into an economic crisis and government bailout programmes continue to prioritise industry, scarce resources and funding allocation decisions must aim to reduce inequities rather than exacerbate them.

We declare no competing interests.

References

  1. Duncan CJ – Scott S. (2005). What caused the black death?.
    Postgrad Med J. 2005; 81: 315-320
  2. Roser M. The short history of global living conditions and why it matters that we know it. https://ourworldindata.org/a-history-of-global-living-conditions-in-5-charts
  3. International Food Policy Research Institute. How much will poverty increase because of COVID-19?. https://www.ifpri.org/blog/how-much-will-global-poverty-increase-because-covid-19
  4. Hoadley J. – Fuchs B. – Lucia K. Update on federal surprise billing legislation: new bills contain key differences. https://www.commonwealthfund.org/blog/2020/update-surprise-billing-legislation-new-bills-contain-key-differences
  5. Bedford J. – Enria D. – Giesecke J. – et al. COVID-19: towards controlling of a pandemic. Lancet. 2020; https://doi.org/10.1016/S0140-6736(20)30673-5
  6. Pirisi A. Low health literacy prevents equal access to care. Lancet. 2000; 3561828

Source: thelancet.com

Who Is Immune to the Coronavirus?

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Santi Palacios/Associated Press

By Marc Lipsitch

Among the many uncertainties that remain about Covid-19 is how the human immune system responds to infection and what that means for the spread of the disease. Immunity after any infection can range from lifelong and complete to nearly nonexistent. So far, however, only the first glimmers of data are available about immunity to SARS-CoV-2, the coronavirus that causes Covid-19.

What can scientists, and the decision makers who rely on science to inform policies, do in such a situation? The best approach is to construct a conceptual model — a set of assumptions about how immunity might work — based on current knowledge of the immune system and information about related viruses, and then identify how each aspect of that model might be wrong, how one would know and what the implications would be. Next, scientists should set out to work to improve this understanding with observation and experiment.

The ideal scenario — once infected, a person is completely immune for life — is correct for a number of infections. The Danish physician Peter Panum famously figured this out for measles when he visited the Faroe Islands (between Scotland and Iceland) during an outbreak in 1846 and found that residents over 65 who had been alive during a previous outbreak in 1781 were protected. This striking observation helped launch the fields of immunology and epidemiology — and ever since, as in many other disciplines, the scientific community has learned that often things are more complicated.

One example of “more complicated” is immunity to coronaviruses, a large group of viruses that sometimes jump from animal hosts to humans: SARS-CoV-2 is the third major coronavirus epidemic to affect humans in recent times, after the SARS outbreak of 2002-3 and the MERS outbreak that started in 2012.

Much of our understanding of coronavirus immunity comes not from SARS or MERS, which have infected comparatively small numbers of people, but from the coronaviruses that spread every year causing respiratory infections ranging from a common cold to pneumonia. In two separate studies, researchers infected human volunteers with a seasonal coronavirus and about a year later inoculated them with the same or a similar virus to observe whether they had acquired immunity.

In the first study, researchers selected 18 volunteers who developed colds after they were inoculated — or “challenged,” as the term goes — with one strain of coronavirus in 1977 or 1978. Six of the subjects were re-challenged a year later with the same strain, and none was infected, presumably thanks to protection acquired with their immune response to the first infection. The other 12 volunteers were exposed to a slightly different strain of coronavirus a year later, and their protection to that was only partial.

In another study published in 1990, 15 volunteers were inoculated with a coronavirus; 10 were infected. Fourteen returned for another inoculation with the same strain a year later: They displayed less severe symptoms and their bodies produced less of the virus than after the initial challenge, especially those who had shown a strong immune response the first time around.

No such human-challenge experiments have been conducted to study immunity to SARS and MERS. But measurements of antibodies in the blood of people who have survived those infections suggest that these defenses persist for some time: two years for SARS, according to one study, and almost three years for MERS, according to another one. However, the neutralizing ability of these antibodies — a measure of how well they inhibit virus replication — was already declining during the study periods.

These studies form the basis for an educated guess at what might happen with Covid-19 patients. After being infected with SARS-CoV-2, most individuals will have an immune response, some better than others. That response, it may be assumed, will offer some protection over the medium term — at least a year — and then its effectiveness might decline.

Other evidence supports this model. A recent peer-reviewed study led by a team from Erasmus University, in the Netherlands, published data from 12 patients showing that they had developed antibodies after infection with SARS-CoV-2. Several of my colleagues and students and I have statistically analyzed thousands of seasonal coronavirus cases in the United States and used a mathematical model to infer that immunity over a year or so is likely for the two seasonal coronaviruses most closely related to SARS-CoV-2 — an indication perhaps of how immunity to SARS-CoV-2 itself might also behave.

If it is true that infection creates immunity in most or all individuals and that the protection lasts a year or more, then the infection of increasing numbers of people in any given population will lead to the buildup of so-called herd immunity. As more and more people become immune to the virus, an infected individual has less and less chance of coming into contact with a person susceptible to infection. Eventually, herd immunity becomes pervasive enough that an infected person on average infects less than one other person; at that point, the number of cases starts to go down. If herd immunity is widespread enough, then even in the absence of measures designed to slow transmission, the virus will be contained — at least until immunity wanes or enough new people susceptible to infection are born.

At the moment, cases of Covid-19 have been undercounted because of limited testing — perhaps by a factor of 10 in some places, like Italy as of late last month. If the undercounting is around this level in other countries as well, then a majority of the population in much (if not all) of the world still is susceptible to infection, and herd immunity is a minor phenomenon right now. The long-term control of the virus depends on getting a majority of people to become immune, through infection and recovery or through vaccination — how large a majority depends on yet other parameters of the infection that remain unknown.

One concern has to do with the possibility of reinfection. South Korea’s Centers for Disease Control and Prevention recently reported that 91 patients who had been infected with SARS-CoV-2 and then tested negative for the virus later tested positive again. If some of these cases were indeed reinfections, they would cast doubt on the strength of the immunity the patients had developed.

An alternative possibility, which many scientists think is more likely, is that these patients had a false negative test in the middle of an ongoing infection, or that the infection had temporarily subsided and then re-emerged. South Korea’s C.D.C. is now working to assess the merit of all these explanations. As with other diseases for which it can be difficult to distinguish a new infection from a new flare-up of an old infection — like tuberculosis — the issue might be resolved by comparing the viral genome sequence from the first and the second periods of infection.

For now, it is reasonable to assume that only a minority of the world’s population is immune to SARS-CoV-2, even in hard-hit areas. How could this tentative picture evolve as better data come in? Early hints suggest that it could change in either direction.

It is possible that many more cases of Covid-19 have occurred than have been reported, even after accounting for limited testing. One recent study (not yet peer-reviewed) suggests that rather than, say, 10 times the number of detected cases, the United States may really have more like 100, or even 1,000, times the official number. This estimate is an indirect inference from statistical correlations. In emergencies, such indirect assessments can be early evidence of an important finding — or statistical flukes. But if this one is correct, then herd immunity to SARS-CoV-2 could be building faster than the commonly reported figures suggest.

Then again, another recent study (also not yet peer-reviewed) suggests that not every case of infection may be contributing to herd immunity. Of 175 Chinese patients with mild symptoms of Covid-19, 70 percent developed strong antibody responses, but about 25 percent developed a low response and about 5 percent developed no detectable response at all. Mild illness, in other words, might not always build up protection. Similarly, it will be important to study the immune responses of people with asymptomatic cases of SARS-CoV-2 infection to determine whether symptoms, and their severity, predict whether a person becomes immune.

The balance between these uncertainties will become clearer when more serologic surveys, or blood tests for antibodies, are conducted on large numbers of people. Such studies are beginning and should show results soon. Of course, much will depend on how sensitive and specific the various tests are: how well they spot SARS-CoV-2 antibodies when those are present and if they can avoid spurious signals from antibodies to related viruses.

Even more challenging will be understanding what an immune response means for an individual’s risk of getting reinfected and their contagiousness to others. Based on the volunteer experiments with seasonal coronaviruses and the antibody-persistence studies for SARS and MERS, one might expect a strong immune response to SARS-CoV-2 to protect completely against reinfection and a weaker one to protect against severe infection and so still slow the virus’s spread.

But designing valid epidemiologic studies to figure all of this out is not easy — many scientists, including several teams of which I’m a part — are working on the issue right now. One difficulty is that people with a prior infection might differ from people who haven’t yet been infected in many other ways that could alter their future risk of infection. Parsing the role of prior exposure from other risk factors is an example of the classic problem epidemiologists call “confounding” — and it is made maddeningly harder today by the fast-changing conditions of the still-spreading SARS-CoV-2 pandemic.

And yet getting a handle on this fast is extremely important: not only to estimate the extent of herd immunity, but also to figure out whether some people can re-enter society safely, without becoming infected again or serving as a vector, and spreading the virus to others. Central to this effort will be figuring out how long protection lasts.

With time, other aspects of immunity will become clearer as well. Experimental and statistical evidence suggests that infection with one coronavirus can offer some degree of immunity against distinct but related coronaviruses. Whether some people are at greater or lesser risk of infection with SARS-CoV-2 because of a prior history of exposure to coronaviruses is an open question.

And then there is the question of immune enhancement: Through a variety of mechanisms, immunity to a coronavirus can in some instances exacerbate an infection rather than prevent or mitigate it. This troublesome phenomenon is best known in another group of viruses, the flaviviruses, and may explain why administering a vaccine against dengue fever, a flavivirus infection, can sometimes make the disease worse.

Such mechanisms are still being studied for coronaviruses, but concern that they might be at play is one of the obstacles that have slowed the development of experimental vaccines against SARS and MERS. Guarding against enhancement will also be one of the biggest challenges facing scientists trying to develop vaccines for Covid-19. The good news is that research on SARS and MERS has begun to clarify how enhancement works, suggesting ways around it, and an extraordinary range of efforts is underway to find a vaccine for Covid-19, using multiple approaches.

More science on almost every aspect of this new virus is needed, but in this pandemic, as with previous ones, decisions with great consequences must be made before definitive data are in. Given this urgency, the traditional scientific method — formulating informed hypotheses and testing them by experiments and careful epidemiology — is hyper-accelerated. Given the public’s attention, that work is unusually on display. In these difficult circumstances, I can only hope that this article will seem out of date very shortly — as much more is soon discovered about the coronavirus than is known right now.

Marc Lipsitch (@mlipsitch) is a professor in the Departments of Epidemiology and Immunology and Infectious Diseases at Harvard T.H. Chan School of Public Health, where he also directs the Center for Communicable Disease Dynamics.

Report from the American Society for Microbiology COVID-19 International Summit, 23 March 2020: Value of Diagnostic Testing for SARS–CoV-2/COVID-19

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As we enter the second quarter of the COVID-19 pandemic, with testing for severe acute respiratory syndrome coronavirus 2 (SARS–CoV-2) increasingly available (though still limited and/or slow in some areas), we are faced with new questions and challenges regarding this novel virus. When to test? Whom to test? What to test? How often to test? And, what to do with test results? Since SARS–CoV-2 is a new virus, there is little evidence to fall back on for test utilization and diagnostic stewardship. Several points need to be considered to begin answering of these questions; specifically, what types of tests are available and under which circumstances are they useful? This understanding can help guide the use of testing at the local, regional, state, and national levels and inform those assessing the supply chain to ensure that needed testing is and continues to be available. Here, we explain the types of tests available and how they might be useful in the face of a rapidly changing and never-before-experienced situation. There are two broad categories of SARS–CoV-2 tests: those that detect the virus itself and those that detect the host’s response to the virus. Each will be considered separately.

Download PDF: mbio.asm.org/content/mbio/11/2/e00722-20.full.pdf

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