COVID-19 – CMO Update and Overview – 9th Edition

Date of data extraction: May 7, 2020.

Given the fast-changing situation, this overview has been updated on a regular basis.

New If you read the previous edition, new/amended content can be quickly found via the small green box markers. To quickly locate material of specific interest, the table of contents at the beginning of this report has direct links to the respective sections.

Much is still unknown about the 2019 novel coronavirus (SARS-CoV-2). This document, created by Achim Regenauer, Chief Medical Officer PartnerRe, is intended only as a general overview and to help identify the most relevant and state-of-the-art knowledge with relevance to insurance. Opinions expressed are those of the author. Over the coming weeks and months, a much clearer picture of this virus and its impact is likely to emerge. We hope you find this information useful.

 


Terminology

  1. The virus: SARS-CoV-2 (similar usage to the term “HIV virus”)
  2. The disease: COVID-19 (similar usage to the term “AIDS”)

Table of contents

 

New Updated personal assessment of the author

Current pandemic situation

The SARS-CoV-2 pandemic shows a globally diverse pattern:

  • Several Asian countries have achieved successful lockdowns, though some are now experiencing a second ‘wave’ of new infections.
  • In many European countries implemented lockdowns are efficient at slowing the spread.
  • Healthcare systems in multiple world regions, North America and Europe included, are heavily challenged.
  • There are also many countries, for example in the Middle East and Africa, where SARS-CoV-2 testing remains at very low levels.

Developing and low-income countries from temperate zones and the southern hemisphere report low numbers of confirmed COVID-19 cases. This is also due to a lack of testing, and potentially also to the virus’ assumed seasonality; although this remains controversial, it increasingly looks as if SARS-CoV-2 is transmitted less efficiently in warmer and more humid climates.

Globally, it has to be assumed that the number of asymptomatic infections is at least as high as the number of confirmed SARS-CoV-2 infections, which now stands at over 3.7 million. SARS-CoV-2 is now so widespread that a spontaneous disappearance of this virus is highly unlikely.

Non-pharmaceutical containment measures

Due to the long incubation and testing periods for COVID-19, it takes several weeks to assess the success of any containment measures. Positive indications are, however, now emerging from Western Europe. Even stronger non- pharmaceutical (containment plus digital monitoring of quarantine measures and tracing of individuals), as taken for example by China, Singapore, Taiwan and South Korea, have yielded positive results, although secondary outbreaks are now being reported. It remains unclear what will happen in these countries, nor indeed in any country imposing containment measures, once the measures are loosened.

An aggravating factor for all containment measures is the newly confirmed fact that SARS-CoV-2 is particularly concentrated, and therefore particularly contagious, in pre-symptomatic carriers.

Some governments are now testing SARS-CoV-2 mobile apps for instant contact tracing. Though issues exist, including pre-symptomatic contagion, if rapidly and widely deployed, such apps could help to contain the spread of the virus. If apps were to be supplemented with regular large-scale testing of population groups, it may even be possible to dispense with most other containment measures.

Often overlooked, and showing the need for international solutions, is the fact that even if outbreaks are contained in one global region, other regions may continue to be a source of recurrent outbreaks.

Testing

Important progress has been made in the field of diagnostic tests. Serological tests, blood tests that detect antibodies against SARS-CoV-2, are now available. These tests can identify who currently has the virus and who has already survived (knowingly and unknowingly) a SARS-CoV-2 infection. These tests also enable large epidemiological studies – now initiated – which can advise governments on the best way forward to control outbreaks. Unfortunately, false positive results are an issue due to cross-reactions from previous colds caused by less harmful coronaviruses. Research continues to find a way to solve this issue.

The fast-growing presence of rapid on-site-testing needs to be viewed with care. These tests detect the virus itself in the acute phase of COVID-19 or antibodies produced to fight it. However, their validity is still a concern; these tests could therefore currently also complicate the management of the pandemic.

Pharmaceutical measures

Last but by no means least, success is expected soon as regards a pharmaceutical response. The U.S. Food and Drug Administration has issued an emergency use authorization for the investigational antiviral drug Remdesivir for the treatment of severe COVID-19, and it is looking increasingly likely that more (antiviral) drugs will be approved in coming months.

Vaccine development is also running at a high pace, although this remains at an early phase. Approval of a vaccine before November/December 2020 is only speculative.

COVID-19 disease

It has been observed that a significant proportion of older patients with a severe form of COVID-19 and pre-damaged vessels, suffer from an overreacting immune system together with elevated blood clotting activity and vessel inflammation. This explains the increased incidence in severe forms of COVID-19 of brain impairments (stroke), heart impairments (myocarditis or heart attacks), liver and kidney impairments, and ultimately multiorgan dysfunction with lethal outcome1. These observations are increasing understanding of COVID-19 and its progression.

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Where it all started

Novel zoonotic coronavirus SARS-CoV-2 was first identified during an outbreak of pneumonia in Wuhan City, Hubei Province, China in November 2019. On January 9, 2020, the WHO announced that this is a new strain of coronavirus not previously identified in humans. On March 11, the WHO declared this to be a pandemic. The virus is now rapidly spreading in Europe, Asia and North America, with cases now in many countries in Africa, the Middle East and Latin America. ‘Super-spreading events’ – individuals infecting an unusually high number of others at gatherings – have played a role in many of the most heavily impacted countries, effectively turbo-charging the spread of the virus.

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New Epidemiologic situation

New infection numbers currently lag reality by approximately 8 to 10 days due to incubation and reporting times. The genuine current situation is therefore likely to be higher than the reported infection number doubling times of 2 to 10 days.

Since December 31, 20192and as of May 7, 2020 – 3,717,797 confirmed cases of COVID-19 (according to the applied case definition in the impacted countries) with 263,878 deaths have been reported globally. The table below lists the countries most affected, respectively most tested, for SARS-CoV-2 infections3.

CountryConfirmed casesDeathsConfirmed casesDeaths
Current week2-weeks prior (April 23, 2020)
United States1,228,60373,318840,89546,704
Spain220,32525,857208,38921,717
Italy214,45729,684187,32725,085
United Kingdom202,35930,076133,49518,100
France174,22425,809119,15121,340
Germany168,1627,275150,6485,315
Russia165,9291,625
Turkey131,7443,58498,6742,376
Iran101,6506,41885,9965,391
China83,9704,63382,7984,632

Note: Case Fatality Rate (CFR) is the ratio of deaths to the total number of people diagnosed with the disease over a certain time period. For more information and discussion points relating to the CFR, see section ‘How lethal is COVID-19?’

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What are coronaviruses?

Coronaviruses are a large family of viruses.

  • Some cause illness in humans (e.g. the common cold, Severe Acute Respiratory Syndrome (SARS) and Middle East Respiratory Syndrome (MERS)).
  • Others are common to different animal species including camels, cattle, cats and bats.
  • Rarely, animal coronaviruses can infect humans and then spread between humans, such as with:
    • SARS 2002/3. Note, it took over a year to halt the spread of this virus. Any ongoing transmission is mostly secondary in the hospital setting.
    • MERS 2012. Note, despite rigorous control measures, isolated outbreaks of MERS-CoV are still occurring. Again, any ongoing transmission is mostly secondary in the hospital setting.
    • SARS-CoV-2. A new strain of coronavirus not previously identified in humans (the topic of this overview). In contrast to SARS and MERS, the mean transmission is occurring via close person-to-person contact, a factor more likely to initiate a pandemic, as has occurred.
  • The coronavirus is named (‘corona’, Latin for ‘crown’) after the crownlike spikes (spike proteins, or S-proteins) that protrude from its surface. SARS-CoV-2 usually enters the patient`s body through the mucous cells of the nose, mouth or eyes. The virus then attaches to cells in the airway (throat) that produce a receptor protein called Angiotensin-converting enzyme 2 (ACE2). The interplay between the coronavirus’ spike protein (as a ‘key’) and the patient’s ACE2 receptor protein (as a ‘lock and hold’) is pivotal for achieving infection. Equally, blocking this interplay is pivotal for successful vaccination (see section, ‘Vaccine development’).

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New Viral shedding and infectivity

  • Viral shedding refers to the expulsion and release of virus progeny (RNA), mostly by exhaled droplets from the respiratory tract of infected individuals, but also via an individual’s stools. Over the course of the infection, the virus has been identified by RT-PCR testing (see section, ‘How is the virus detected?’) in respiratory tract specimens 1-2 days before the onset of symptoms and can persist for up to 8 days in moderate cases and for longer periods (up to 37 days) in more severe cases, peaking in the second week after infection.
  • The viral load is the quantity of SARS-CoV-2 in a given amount of patient tissue. It can be a useful marker for assessing disease severity and prognosis: a recent study indicated that viral loads in severe cases were up to 60 times higher than in mild cases. It is also an indicator of the chance of contagion to others (higher viral load, higher chance of contagion to others).
  • It should be noted, however, that detection of viral RNA does not equate with infectivity. Confirmation of infectivity further requires labor-intensive sample virus isolation and culturing.

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Primary routes of transmission

This section describes the main SARS-CoV-2 transmission paths about which quite a lot is now known. It is important to note, however, that the minimum infectious viral ‘dose’ required for each transmission route to initiate COVID-19 is not yet understood.

Four transmission category routes can be identified:

1. Symptomatic transmission: direct transmission via aerosols from an infected symptomatic individual through close and direct contact. Epidemiological records from China reported that up to 85%4 of human-to-human transmission occurred in family clusters5.

  • The primary route is via coughing or sneezing: in one study, viable SARS-CoV-2 virus was detected in aerosols in largely stable amounts for 3 hours6,7 after aerosolization, although the heavier droplets containing the virus as produced from coughing and sneezing are likely to fall out of the air faster.
  • Face-to-face contact with an infected individual in the transmittable phase, within 1 meter and for more than 15 minutes8; talking can generate aerosol clouds filled with SARS-CoV-29.
  • Direct physical contact with an individual infected with COVID-19 and in the transmittable phase.

2. Pre-symptomatic transmission: direct transmission from an infected individual before the source individual experiences noticeable symptoms.

  • Infected individuals begin to transmit the virus 1 to 2.5 days (mean) before the onset of COVID-19 symptoms.
  • The steepest increase in viral load and therefore the most contagious period unfortunately occurs during the incubation period and shortly after the onset of first symptoms10.
  • The incubation period is currently assumed to be approximately 5-6 days, but there are some outliers, including rare claims of up to 27 days.
  • These characteristics help to explain the fast-spreading nature of this pandemic.
  • Initial studies, though based on small numbers, indicate that this transmission route has been underestimated – pre-symptomatic transmission may be responsible for 10-45% of transmissions11.
  • Pre-symptomatic transmission from individuals to other individuals occurs in many types of respiratory infections, such as varicella (chickenpox) which is highly contagious several days before the classic rash erupts.

3. New Asymptomatic transmission: direct human-to-human transmission from individuals who never experience any noticeable symptoms. The combination of pre-symptomatic and cryptic asymptomatic transmission could explain the rapid spread of SARS-CoV-2 around the globe. This group can only be identified by widespread testing, but even with that, at any point in time it is not possible to distinguish asymptomatic from pre-symptomatic individuals. Furthermore, asymptomatic individuals have (retrospectively) recalled experiencing minor symptoms such as fatigue or muscle pain. A recent survey of small international SARS-CoV-2 testing studies estimated that approximately 40% of infections are asymptomatic12. Before large-scale antibody testing (serological surveys, see section ‘How is the SARS-CoV-2 virus detected?’) is carried out, and given the low viral load of such individuals, this transmission route is assumed not to be a driver of this pandemic.

The latest reports from China indicate that the large majority (80%) of SARS-CoV-2 infections are asymptomatic13.

4. Environmental transmission: transmission via contact with contaminated objects/surfaces and foodstuffs. There are some preliminary indications14 that object contamination, e.g. of door handles, toilets and sinks, may play a minor role, though this has now been disputed by other studies. On a positive note, even in the preliminary study, the virus was successfully decontaminated (no longer detectable) after routine cleaning. In terms of how long SARS-CoV-2 remains viable on surfaces, no viable virus was detected after 4 hours on copper, 24 hours on cardboard, and 72 hours on plastic and stainless steel15. At over 30°C, the survival duration of SARS-CoV-2 is shortened16. It should be noted that all these findings relate to laboratory-based investigations which do not correspond fully to real-world conditions. Environmental transmission remains speculative and is not the main driver of this pandemic.

Also relating to transmission:

  • Pre-symptomatic and asymptomatic transmission17 complicate screening and containment measures18.
  • An indication of the risk of infection from social contact is given by the secondary attack rate, defined as the probability that an infection occurs among susceptible people within a specific group (e.g. household or close colleagues).
    • According to initial reports, the secondary attack rate of SARS-CoV-2 is estimated to be between 1% and 5%, and even as high as 35%, though supporting studies remains scarce19 and include only small sample numbers20.
    • Several reports have noted secondary attack rates for households of approximately 15%21.
    • Older ages (≥60 years) are the most vulnerable to household transmission22.
  • While the minimum quantity of infectious SARS-CoV2 virus particles required for infection is still unknown, numerous studies indicate that close and prolonged contact is required. The risk is highest in enclosed environments; household, long-term care facilities and public transport. Casual, short interactions are not the main driver of the pandemic.
  • Higher rates of infection in enclosed and connected environments is in keeping with the high infection rates observed in megacities and crowded areas23.
  • Not everybody infected with SARS-CoV-2 will fall ill. Three early studies from different settings (the Diamond Princess cruise ship outbreak, returnees and a contact-based case search) reported manifestation index values (the percentage of infected persons who became ill with symptoms) of 51%24, 69%25 and 81%26 respectively.

Transmission is fairly high and certainly easier than for SARS. The vast majority suffer a mild, if not an asymptomatic course of the disease.

The main transmission routes are symptomatic and then pre-symptomatic transmission. Transmission via pre-symptomatic infected individuals and favored by an unusually long incubation period is now known to be a major transmission route, and explains the rapid spread of SARS-CoV-2 around the world. The role of asymptomatic transmission is still controversially discussed.

Transmission of e.g. measles or varicella is more than 5 to 10 times higher27.

As far as the duration of infectivity to others is concerned, most experts assume that this begins 2.5 days before the onset of symptoms. The end of the infectivity period, however, cannot yet be determined with certainty, but patients appear to no longer be infectious during the second week after the onset of symptoms.

The shedding of reproducible SARS-CoV-2 viruses from samples of pharynx and sputum appears to last for up to 37 days, but this does not directly equate to infectivity.

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Pandemic course

For risk monitoring, epidemiologists primarily use R0 – the basic reproduction number – as the parameter to describe the transmission potential of an infectious disease outbreak. This parameter is dependent on factors including the infectivity, susceptibility of the population and population density.

  • R0=1: the number of cases is stable, the disease is endemic
  • R0 >1: the number of cases is increasing, it will eventually become an epidemic
  • R0 <1: the number of cases is decreasing
  • SARS had a R0 of <1 to 2.75. Seasonal influenza has an R0 of 2 to 3
  • SARS-CoV-2: An accurate R0 is difficult to assess, as this parameter depends upon a number of criteria, which may also vary by country. Most experts, however, agree on an R0 of 2-328, which is higher than SARS. An R0 of 2.2 is now often quoted.
  • New The basic R0 is often mixed up with the effective reproduction number, Re (sometimes also called Rt), a measure for monitoring the course of a given pandemic at a specific time.
  • New Re reduces over time as a population becomes increasingly immunized and with effective lockdown/containment measures and new behaviors (e.g. social distancing).

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How long will the SARS-CoV-2 pandemic last (herd immunity)?

Herd immunity occurs when a significant proportion of the population (‘herd’) are immune either by infection or by vaccination. The higher the number of immune individuals in a population, the lower the likelihood that a susceptible (respectively unvaccinated) person will come into contact with the virus; the chain of infection is effectively broken.

  • The time it takes to achieve this will be strongly dependent on the time it takes for the widespread application of effective vaccines; experts are anticipating at least another 12 months (see section, ‘Vaccine development’).
  • The herd immunity threshold is the proportion of a population that needs to be immune (either via natural infection or vaccination) for an infectious disease to become stable in that population.
  • An important measure used in infectious disease control and immunization and eradication programs, the threshold value is strongly dependent on the transmission potential, as measured by the R0 value. The following formula is used: Herd immunity threshold = 1-1/R0.
  • An R0 of 2.2 is currently assumed. The herd immunity threshold for SARS-CoV-2 is therefore approximately 60%.
  • Once the herd immunity threshold is surpassed, R0 becomes <1 and the number of cases of infection will fall.
  • Any protection from a natural infection of COVID-19 may, however, only be short-lived and incomplete, as shown by the ongoing circulation of the four human coronaviruses responsible for common colds29.
  • It is, however, highly unlikely that SARS-CoV-2 will disappear completely once the threshold is surpassed, rather it will enter into regular circulation with smaller ongoing regional outbreaks in the years after the pandemic.
  • The future course of the pandemic will also depend on how long immunity lasts. For those who were infected and recovered, does the magnitude of their antibody response play a role? Is there any cross immunity acquired from other coronavirus infections (common colds)? Even vaccines may have a limited time effectiveness.
  • Longitudinal serological studies (large-scale testing for antibodies against SARS-CoV-2, see section ‘How is the SARS-CoV-2 virus detected?’) will provide information on the extent and duration of immunity, and will help assess the pandemic’s dynamics over the coming months and years.

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Who is at risk?

  • The first instructive statistics were given by the Chinese Center for Disease Control and Prevention (China CDC)30: SARS-CoV-2 mostly affected the age range of 30 to 79 years (87%), 1% were aged 9 years or younger, 1% were aged 10 to 19 years, and 3% were aged 80 years and older.
  • New Children have not been the focus of studies as they are rarely tested.
  • New In the meantime, there is growing evidence31 that infection rates in children are in fact not lower than the population average, but rather are only lower for symptomatic COVID-19 disease32. A recent study found no significant difference in the viral loads of infected children and adults. Children may therefore often act as asymptomatic transmitters.
  • Older people and those with chronic underlying diseases such as heart and lung conditions and cancer, are at particular risk33. In the US, nearly 90% of intensive-care cases had at least one underlying condition34,35. The health of the immune system plays a key role here, as it declines with age (and smoking status). Patients with cancer or autoimmune conditions are usually treated with immunosuppressive drugs, putting them at further risk.
  • The severity of COVID-19 and mortality36 seem to be higher if several risk factors for atherosclerotic diseases exist – such as smoking, morbid obesity, diabetes and hypertension, also known as metabolic syndrome.
  • Other risk groups are health care workers and close contacts, e.g. family members, coming into contact with infected persons.

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Genomics – insights and differences compared to past pandemics

COVID-19 affects different people differently. Much of this discrepancy cannot be explained by differences in healthcare or conventional risk factors. Numerous project groups are collecting and comparing DNA from COVID-19 patients to try to identify any genetic risk factors. The hope is that the results will provide insights into who is at unusually high or low risk, and to help direct potential drugs and vaccines.

The following points show the wide scope of genomic research applications:

  • Genome sequencing delivers the highest possible resolution information of the SARS-CoV-2 genome, potentially transforming the management of this disease. Both SARS-CoV-2 and COVID-19 patient genomes are subject to ongoing research.
  • Genome sequencing37 of SARS-CoV-2 completed on January 29 suggests that the virus originated from a single source within a very short time period and was rapidly detected.
  • The analysis of genomic data related to the overall molecular structure of SARS-CoV-2 shows that the backbone of the virus’ genome most closely resembles that of a bat coronavirus discovered shortly after the initial COVID-19 outbreak. This indicates the most likely source of the virus and dispels any rumors of genetic manipulation38.
  • Genome sequencing can show how the SARS-CoV-2 virus is changing from host to host and across geographies, allowing researchers to build a phylogenetic tree of the mutation history (essentially a family tree of the virus). This will enable researchers to track the virus’ spread within and between populations over time, and to help identify ‘hot spots’ and ‘super spreaders’, and even to determine how effective non-pharmaceutical interventions have been.
  • New As with all viruses, SARS-CoV-2 mutates constantly and does not have the same capability as human cells to correct these ‘errors’. However, from over 10,000 genetic sequences39, it is known that to date, SARS-CoV-2 has only a limited propensity to diversify40, i.e. has a much lower mutation rate than the influenza virus. All analyzed samples are closely related with only a few mutations relative to a common ancestor, originating in Wuhan, China41. None of these mutations are associated with significant change in the virus’ behavior or virulence.
  • Genome sequencing will have more to give, as it will be extremely important for the development of diagnostics and vaccines, and for designing therapies. To date, over 500 patents have been issued for vaccines and therapeutic agents, such as antibodies, cytokines and nucleic acids, which could help to prevent or treat SARS-CoV-2 infections42.
    • New As mentioned above, the manifestation of COVID-19 seems to be selective, at least to some extent; not all infected individuals actually become ill and others who were seemingly healthy and even relatively young, die from the disease. This indicates that genetic predisposition could play a role. Prior research has shown that some gene variants can put people at higher risk of certain infectious diseases. Mutations in the receptor-binding domain of the spike protein (S-protein) and host cell surface protein – the angiotensin-converting enzyme 2 (ACE2) – are of interest here (see section, ‘What are coronaviruses?’).
    • New Other publications have suggested that interleukin-6, HLA antigens and blood groups may be risk factors in COVID-19 severity and outcomes43.
    • Large national and international (genetic) biobanks are planning to add COVID-19 health data from participants to their data sets to try to identify protective or susceptible DNA variants44.
  • Scientific communication is now faster than during past pandemics45 as scientists share more information using preprints via biomedical preprint servers or Twitter or Slack. This will expedite knowledge exchange and transfer.
  • New To date, more than 1000 studies addressing various aspects of COVID-19 are registered on ClinicalTrials.gov, including more than 600 interventional studies and randomized clinical trials (RCTs). However, few of these will be sufficiently powered to detect a difference in mortality. With such high interest, preliminary results from some have already been reported46. Ideally, scientific studies of COVID-19 risk factors for transmission and severity should investigate the interaction of the two genomes of the SARS-CoV-2 virus and infected COVID-19 patients, along with other exogenic environmental factors and emerging ‘big data’ types.

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Digital technologies – insights and differences compared to past pandemics

In contrast to past pandemics, there is now a wide variety of digital tools (e.g. the internet of things, artificial intelligence, big data analytics and blockchain technology) to facilitate and reinforce various approaches to combat the SARS-CoV-2 pandemic. A few examples illustrate the range of options47:

  • Live updates for the various online databases disclosing confirmed COVID-19 cases.
  • Thermal imaging to identify individuals with elevated temperature at screening points (e.g. airports and borders).
  • Real-time tracking of infected and at-risk vicinity individuals (as in e.g. South Korea and China).
  • Screening for suspected cases based on artificial intelligence algorithms instead of expensive testing via throat swabs following exposure to confirmed COVID-19 cases or travel history.
  • Modeling of disease spread and preparedness.
  • Tele-medicine consultations with imaging data (CT scans).
  • Collaborating with pharmacies and blockchain providers to deliver patients’ medication to the doorstep (e.g. as done in China).

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Statistical modelling

  • All model projections should be viewed with some reservation as they are based on as-yet uncertain assumptions. The specific case definitions and clinical criteria for diagnostic evaluation also differ by country.
  • Furthermore, data on pre-symptomatic and asymptomatic infections are essential in modelling the risk posed by SARS-CoV-248, but are still mostly unknown.
  • Statistical modelling will likely play a central role for many governments in deciding when and to what extent non-pharmaceutical interventions should be loosened, as there is as yet no empirical evidence for the impact of such interventions.

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What are the symptoms of COVID-19 and their development over time?

  • Unfortunately, the clinical picture is unspecific and offers a wide spectrum of clinical severity, which complicates timely detection. The main symptoms include a dry cough, fatigue, headaches, muscle pain, runny nose, fever, sore throat and, at advanced stages, shortness of breath.
  • The only specific (other symptoms are unspecific in medical terms) symptom displayed in some countries by up to 70% of COVID-19 patients is a sudden and temporary loss of smell and taste49. This indicates that SARS-CoV-2 targets the central nervous system and infects neurons in the nasal passage.
  • Furthermore, no clinical criteria and biomarkers are available by now to help differentiate individuals more likely to progress to severe illness, though this is in development, see section ‘Genomics – insights and differences compared to past pandemics’.
  • Pneumonia appears to be the most frequent manifestation of infection, characterized primarily by fever, cough, dyspnea and bilateral infiltrates on chest imaging. Headache, sputum production and diarrhea are less common.
  • Patients can present with a spectrum of disease ranging from mild respiratory illnesses, particularly in younger adults or children, to severe disease (including respiratory failure, septic shock or other organ failure requiring intensive care).
  • Patients usually seek medical care on day 2-4 after the onset50 of symptoms because this is when they develop shortness of breath and early pneumonia. For those who suffer from a severe form, day 7 is mostly critical. After day 1151, most patients who survive are on their way to recovery.
  • The majority of patients who have recovered from COVID-19 pneumonia52 showed the greatest severity of lung disease on CT scans at approximately 10 days after the initial onset of symptoms. Chest CT scan signs of improvement began at approximately 14 days after the initial onset of symptoms.

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New Patient recovery

  • Due to a lack of supporting data, it is not yet clear whether COVID-19 patients fully recover. It seems that an inflammatory response is likely to play an important role here, as disclosed by a considerable increase in various inflammatory markers in the blood of COVID-19 patients which may correlate with a worse prognosis53.
  • New In some (severe?) cases a cytokine storm (uncontrolled overreaction of the immune system) can lead to brain impairment (encephalopathy), heart impairment (myocarditis), liver and kidney impairment, and ultimately to multiorgan dysfunction54.
  • There are some indications that severe COVID-19 forms have a reduced general condition for at least four weeks, with feelings of fatigue, shortness of breath, reduced exercise tolerance and even restricted lung function and long-term breathing problems due to the scarring of lung tissue (possibly to lung fibrosis)55,56.
  • In the UK there have been observations that 50% of patients admitted to hospital required no further medical support, 45% needed some form of low level medical or social input for recovery, and 5% required more focused, ongoing, intense rehabilitation57.
  • Approximately 20% of patients suffering a severe form of COVID-19 may develop cardiac injury (e.g. inflammation of the heart muscle) associated with higher risk of in-hospital mortality58.
  • It is realistic to assume that the virus’ neuro-virulence (e.g. affecting the nerve cells for smell and taste) may leave long-lasting ‘sequels’ affecting the brain and behavior59. By now, it is too early to quantify these sequels.
  • New SARS-CoV-2 appears to cause blood vessel wall inflammation leading to thrombosis formations, potentially resulting in stroke or heart attack. Last week, US news reports of several young stroke patients with only mild or even asymptomatic COVID-1960 are a cause for concern and require further investigation.

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New Who is immune to SARS-CoV-2?

SARS-CoV-2 causes a robust immune activation and survivors generally generate antibodies to the virus60.

  • Could immunity to coronaviruses that cause the common cold be beneficial? Unfortunately, such immunity is short-lived, even for those developing high levels of antibodies.
  • New SARS-CoV-2 closely followed SARS-CoV-1 (SARS) and MERS, so could recovered SARS and MERS patients have immunity to SARS-CoV-2? This question remains unanswered, but in view of the low number of infected SARS and MERS individuals, is not so critical. Furthermore, the immunity of patients who have survived one of these two coronavirus infections is known to wane, although it is detectable for in excess of 1 year after hospitalization61.
  • Generally, immunity to a virus is complex as it is based on both antibody responses (via so-called B cells) and T cell responses (no antibodies involved, only special immune cells). T cell responses are very sophisticated to measure, and the importance of each response type is currently unknown.
  • It remains unknown as to whether SARS-CoV-2 antibodies protect against a repeat infection62, or if they prevent the infection of others. If they are protective, it remains unknown as to how long that protection lasts.
  • New A Chinese study of hospitalized, severe COVID-19 survivors showed that about 90% had functional, virus-neutralizing antibodies and that approximately 50% had strong T-lymphocyte responses63. This finding, however, might not be representative of mild or asymptomatic cases.

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How is the SARS-CoV-2 virus detected?

There is currently no centralized global database for COVID-19 testing data. The frequency of testing of suspected SARS-CoV-2 cases varies by country depending on available resources and healthcare system laboratories. This heavily impacts Case Fatality Rate (CFR) reporting (see section, ‘How lethal is COVID-19? (CFR)’). High testing rates, as for example in South Korea and Germany, can explain relatively low CFRs (higher CFR denominators).

Antigen testing (throat swabs) – early stage of COVID-19:

  • The current main form of testing, a combined viral nose and throat swab and a 5ml serum tube.
  • The assays in current use require designing small pieces of DNA that match sections of the viral genome obtained from the swab of the back wall of the throat. This test is very reliable in the first week after onset of symptoms and less reliable in the second week due to the decreasing amount of virus in the throat (see bullet point below). The WHO has appointed SARS-CoV-2 referral laboratories for testing – capabilities remain limited due to the required sophisticated technologies. These diagnostic tests are based on a genome-based standard technology known as reverse-transcriptase polymerase chain reaction, or RT-PCR. Results are at best available in about 4 hours. Another significant hindrance for wide-scale screening is the cost – currently up to USD 250 to run per individual, depending on procedures and the volume of tests that a laboratory performs.
  • RT-PCR picks up viral genetic material only if there’s a lot of it. Early in an infection, before someone starts to feel really sick, and for those who remain asymptomatic, there’s often not enough RNA material for such tests (the amount of virus produced by the body changes throughout the course of the illness) and they can therefore deliver false negative results. The same issue is true for the second week after the onset of symptoms due to a decreasing amount of virus in the throat. RT-PCR testing is most reliable in the first week after the onset of symptoms, though this does not mean per se that this patient is infectious.
  • Other issues with RT-PCR testing indicate that results should be interpreted in the context of an individual’s clinical and other data, e.g:
    • Widely shared reports of a group of approximately 90 COVID-19 patients in South Korea who had recovered, tested negative on discharge from hospital, but who were then PCR positive again. It appears that towards the end of the course of COVID-19, the PCR is sometimes positive and sometimes negative. It’s a matter of chance. Therefore, the results do not signify reinfection64.
    • Some false negative test results have also been reported due to intermittent viral shedding or incorrect sampling or transportation (unsuitable viral transport medium).
    • And very often ignored: the results of the PCR test do not indicate the amount of viable SARS-CoV-2. What’s found may not be viable.
  • With regard to the rapidly evolving outbreak, healthcare systems need in the short term to be able to carry out high-volume testing with the capability to reliably detect the spread of the virus. Many countries that are massively ramping up their testing capacities are experiencing a bottleneck as supply can no longer keep up with the production of the necessary chemical reagents.

Antibody testing (serologic) – late stage of COVID-19:

  • The next step for monitoring the spread of the virus will follow a different, more convenient and significantly more effective diagnostic65 approach: a blood test that identifies antibodies against the SARS-CoV-2 virus. Antibody tests are known as ‘serologic’ tests. First studies indicate that antibodies against SARS-CoV-2 begin to form around day 10 after the onset of symptoms (not of infection) and peak around week 3 (‘seroconversion’)66 when there is a strong antibody production67. There are two types of antibodies: Immunoglobulin M (IgM – generally the first antibody made after 12 days in response to an infection), and Immunoglobulin G (IgG – the most common and generally long-lasting (more mature, more specific to SARS-CoV-2) antibody made after 14 days to fight off a viral infection). In the near future, epidemiologists will focus on weekly surveys of seroconversion rates in the population, providing a more accurate picture of the rate of spread of SARS-CoV-2.
  • Many research68 groups have been working on developing serologic tests that are able to detect the antibodies independently of whether an individual suffered or is suffering from an asymptomatic, mild or severe form of COVID-19. These tests (Immuno ELISA) have carried out validation studies over recent weeks with well characterized sera (blood samples from infected individuals) in order to be reliable for general use in medicine and epidemiological investigations. Laboratories are set to introduce these tests (as automated immunoassays – high-throughput testing) to enable mass screening of parts of the population within coming months69.
  • But there are some caveats:
    • New Emerging evidence suggests that at least some COVID-19 patients with very mild or almost asymptomatic infections have very low levels of antibodies, or even no detectable antibody. This complicates serologic testing and the interpretation of results.
    • Coinfections of SARS-CoV-2 and other respiratory pathogens are quite frequent – e.g. for a group of patients with respiratory symptoms in California, 21% of nasopharyngeal swab specimens that tested positive for SARS-CoV-2 also tested positive for other respiratory pathogens (cross reactions due to earlier, harmless coronaviruses)70,71.
    • Therefore, positive serologic tests on SARS-CoV-2 have to be confirmed in a second step that excludes cross reactions via a neutralizing antibody stimulation test.
    • Even then, it is not yet clear if antibodies indicate an immunity against SARS-CoV-272 (see section, ‘Who is immune to SARS-CoV-2?’).
    • Another unknown which is valid for most infections, is that the strength of the antibody response correlates to the severity of infection.

Widely available validated tests for antibodies will be a game changer. Health authorities will use these serologic tests73 to investigate the immune status of the population (so-called ‘serosurveys’). The results will influence important decisions by public health measures, such as the reopening of public institutions and loosening of containment measures. By testing healthcare workers, clinics could specifically assign doctors and nurses with positive antibody tests to care for patients with COVID-19. Such tests could also be used to identify convalescent individuals whose blood serum would be suitable for the treatment of an active infection.

Rapid tests

  • An increasing number of rapid diagnostic tests potentially suitable for COVID-19 at point of care are in development, mainly in Asia. These tests could support early identification of those with COVID-19.
  • Some directly detect the SARS-CoV-2 virus (antigen tests), others indirectly detect the virus via the body’s immune response (antibody tests).
  • These so-called rapid tests utilize a range of specimens including serum, plasma or finger-prick whole blood.
  • Some function similarly to a pregnancy test and should show a result within 10 minutes74 (known as lateral flow tests).
  • However, there is little information on the reliability and diagnostic performance of the tests as regards positive or negative results. It can be expected, however, that these tests will become more accurate in the medium-term.

The gold-standard for SARS-CoV-2 testing is the RT-PCR test, which is complex and confined to special laboratories, although in many countries testing capacity has been ramped up. Unfortunately, the test is fairly expensive and does not reliably detect the virus during its incubation period.

Blood tests detecting SARS-CoV-2 antibodies (serologic tests) are now available for clinical application. Though issues exist, these will make screening more effective and also shed more light on COVID-19’s epidemiology.

A variety of rapid tests that should show a result within several minutes, either detecting the antigen or antibodies (including lateral flow tests) against SARS-CoV-2, are currently being developed. The sensitivity and specificity of these tests is not yet clear, i.e. numerous false positive and negative results may be produced.

COVID-19 reporting will in the near future be mainly based on three parameters:

  • Confirmed COVID-19 cases (via RT-PCR testing).
  • Deaths due to COVID-19.
  • Infected (including asymptomatic) COVID-19 cases (from serologic testing).

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Population %s of SARS-CoV-2 infection

In the absence of serologic tests (see section, ‘How is the SARS-CoV-2 virus detected?’), hard figures are scarce and discussions continue. To give some examples:

  • Iceland currently has one of the highest testing rates in the world, testing approximately 1 in every 25 people, including those with symptoms and all new arrivals since February. Testing is now available to all residents. From random testing, approximately 6% have tested positive (RT-PCR)75.
  • A large-scale screening of the entire Italian village of Vo (population 3,300) indicated that, as of March 16, more than 3% of residents tested positive (RT-PCR)76.
  • A first small-scale serologic study in the region of Helsinki, Finland, indicated that the number of SARS-CoV-2 infections may be many times higher than the confirmed cases: the sampling was of 442 men and women between the ages of 15 and 90 who had given a blood sample for reasons other than an infection. The range of positive results was between 0.7 and 3.4%77.
  • A first (preprint) study conducted after the lockdown in Wuhan reported an infected percentage (seroprevalence) of 19% in Wuhan55.
  • Within the next few months, much more information on this can be expected as serologic tests become increasingly available and larger epidemiological studies are published.

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How morbid is COVID-19?

  • There is a potentially large number of asymptomatic or only minor symptomatic (including pre-symptomatic) individuals whose infection is not being detected – this has a clear impact on the statistics. One indication of these ‘missing numbers’ is given in a report78 that states that 18% of the Diamond Princess cruise ship passengers who tested positive for SARS-CoV-2 showed no symptoms during or after the quarantine period79. Other publications are assuming that up to 50% remain asymptomatic without a general feeling of illness80. The discrepancy and uncertainty is related to the fact that it is often difficult to distinguish asymptomatic from mild cases.
  • Diverse patterns of COVID-19 infection will be reported by country over the next few months, reflecting differences81 in age structure, monitoring, healthcare-seeking behavior and varied environmental factors.
  • There seem to be 3 major patterns of the clinical course of the infection:
    • 81% have mild cold82 symptoms or mild pneumonia83, allowing a higher chain of transmission through populations.
    • 14% are severe cases.
    • 5% are critical cases needing intensive care unit (ICU) treatment due to complications such as acute respiratory distress syndrome (ARDS), acute respiratory injury, septic shock and acute renal injury. There are first reports84 that more than 50 to 66% of critically ill patients require invasive breathing support85, a clear strain for hospital critical care resources.
  • There is, however, still a scarcity86 of data for the clinical course of COVID-19. Reports regarding associated long-term complications are logically not yet available.

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New What is the mechanism of SARS-CoV-2, why it is so virulent?

  • New The exact mechanism (pathogenesis) of COVID-19 remains unclear. However, it appears that there are two distinct immune responses: one that is triggered by the presence of the virus and which aims to eliminate it, and an impaired protective immune response with out of control inflammation that propagates the virus and causes massive tissue destruction.
  • New SARS-CoV-2 enters the body through the mucous membranes, principally the nasal and larynx mucosa, and then descends, in some (?) patients, to the lungs through the respiratory tract. SARS-CoV-2 binds to its target using the angiotensin-converting enzyme 2 (ACE2) receptor on human cells which are predominantly expressed in the lungs, intestine and vessels87.
  • New Most infections cause only mild respiratory or common cold-like symptoms (without shortness of breath) and patients seem to completely recover.
  • New Once COVID-19 is established in the lungs with massive viral replication, a viral pneumonia evolves. At this stage (moderate form) most patients with COVID-19 need to be hospitalized for close observation and management for monitoring hypoxia (insufficient oxygen supply). If hypoxia ensues, it is likely that patients will progress to requiring mechanical ventilation.
  • New A minority of COVID-19 patients will proceed, sometimes very quickly, into a severe phase of the illness, which manifests as an extra-pulmonary systemic hyperinflammation syndrome. Immune cells then release cytokines generating a so-called pro-inflammatory cytokine storm (tumour necrosis factor [TNF], IL-6, and IL-1β), which in turn increases blood flow to the affected tissues so that more immune cells can reach them. The immune cells also kill other host cells, if necessary, to stop the infection spreading. This ultimately elicits an acute respiratory distress syndrome (ARDS), septic shock, vascular hyperpermeability, activation of blood coagulation and multi-organ injury. Damage to other organs, such as the heart, kidneys, liver and central nervous system (brain), is discernable.
  • The release of these cytokines, known as a cytokine storm, is known to occur with other viruses, such as with Spanish flu and HIV88.
  • Some researchers consider that SARS-CoV-2 might target the nervous system through the olfactory bulb, causing the known symptoms of sudden loss of smell and/or taste. The hypothesis is that the virus can then rapidly spread to the central nerve system (brain) causing breathing problems and potential death89.
  • It is still unclear as to why this disease is so fatal for some patients and more like a cold for others. Research remains focused on those who develop a severe form of COVID-19. Insight and better understanding is expected from genome research.

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Timing of COVID-19 disease progression

  • The report, “WHO-China Joint Mission on Coronavirus Disease 2019”, states that on average (median) the disease course is 2 weeks for mild cases and 3-6 weeks for severe cases. For deaths, most died approximately 3 weeks after being infected.
  • There is still a lack of detailed studies on the progression of COVID-19. Initial indications, mainly from Chinese studies90,91 are as follows:
Initial indication of COVID-19 progressionLength of time
Illness onset* to fever1 day
Illness onset to cough1 day
Illness onset to dyspnea7 days
Illness onset to sepsis9 days
lllness onset to ICU** admission12 days
Illness onset to death18-21 days
Illness onset to hospital discharge25 days
Duration of viral shedding after illness onset20 days
Duration of mechanical ventilation (much longer than non-COVID-19 patients)2-3 weeks

*: Onset of symptoms.
**: Intensive care unit.

  • Generally, it can be assumed that mild COVID-19 cases last approximately 2 weeks, and that severe and critical cases last 3-6 weeks92.
  • For patients who have died, the time from onset of illness to death ranges from 2-8 weeks.

The clinical course pattern of SARS-CoV-2 infection is dominated by a mild or even asymptomatic form which lasts for approximately 2 weeks. However, even mild forms can quickly develop into severe forms lasting for up to 6 weeks or to death. More precise studies on the progression patterns of COVID-19 can be expected only in the medium-term.

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How lethal is COVID-19? (CFR)

The mortality of infectious agents in an epidemic is usually expressed as a case fatality rate (CFR), being the ratio of deaths to the total number of people diagnosed with the disease over a certain time period. A problem arises here, as many cases are mild or asymptomatic, and are therefore not diagnosed. As serologic tests are carried out, these individuals will become part of the CFR denominator. Until this time, the CFR is only an estimate and is likely to change over time.

  • Italy, for example, has a high CFR of approximately 13.8%. Contributory factors include the fact that Italy currently tests all suspicious causes of death for SARS-CoV-2, thus increasing the CFR numerator. In addition:
    • The longer the outbreak continues, the more the CFR will increase within a 3-week window (time from illness onset to death)
    • Demographic structure (elderly population)
    • Hospitals with MRSA contamination
    • Overstrained healthcare staff
    • Too few ventilators
    • Social structure – multiple generations living together
    • High smoking rates.
  • Impact of underlying conditions. 94% of hospitalized patients in the US who died had an underlying condition/s. Among COVID-19 patients admitted to the ICU, 32% had diabetes, 29% had heart disease and 21% had chronic lung disease including asthma, COPD and emphysema. Similar results were reported in China and Italy. In addition, 37% had other chronic conditions including hypertension or a history of cancer93.
  • The table below shows a range of (to date) CFR values.
CountryCFR* as per May 7, 2020
United States6.0%
Spain11.7%
Italy13.8%
France14.8%
Germany4.3%
China5.5%
Iran6.3%
United Kingdom14.9%
Turkey2.7%
Russia1.0%

*CFR: Case Fatality Rate. The ratio of deaths to the total number of people diagnosed with the disease over a certain time period.

  • To compare these CFR values with previous pandemics:
    • A normal flu season has a CFR of 0.1%.
    • Previous major influenza pandemics, e.g. 1957 and 1968, had CFRs of 0.8-1.2%. Spanish flu had a CFR of 2.0%.
    • SARS had a CFR of 9-10%, MERS had a CFR of 36% – both coronavirus epidemics had lower transmissibility but higher mortality than COVID-19.

In view of significant under-recording of cases, the lethality of COVID-19 is lower than published and reliable estimations remain difficult to make.

The CFR also varies considerably between countries, ranging from 1% to around 15%. It is heavily dependent on patient age, associated comorbidities, the availability of isolation facilities, intensive care units and ventilators, and on the general ‘surge capacity’ of the healthcare system.  

Historically, the CFR and transmissibility develop inversely: there seems to be an adaption of the virus to the host that makes transmission easier and more effective (contagious), but that results in less deaths – Spanish flu, however, was the exception.

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How will the infection be treated?

No specific treatments are available for COVID-19 and considerable uncertainty exists. The mainstay of management is therefore optimized supportive care to relieve symptoms and support organ function in more severe illness.

  • Even mechanical ventilation of critically ill COVID-19 patients remains controversial94: ventilation over long periods can lead to additional lung damage due to the high pressure at which oxygen is pushed into the lungs. This may explain the high mortality rate of ventilated COVID-19 patients (approximately 50%).
  • There are no specific antivirals available, but China is currently running more than 80 clinical trials on potential treatments for COVID-1995.
  • The fastest approach to finding an effective antiviral is to test existing drugs used for other infections, such as Chloroquine (Malaria), Arbidol (Influenza), Remdesivir (SARS, Ebola), Favipiravir (Ebola) and Oseltamivir (Influenza). If any one of these proves efficacious against COVID-19, a fast-track regulatory approval can be expected96. A good review of this can be found in the British Medical Journal97. The WHO recently launched a mega-trial across multiple countries called SOLIDARITY. The trial will investigate the impact on the mortality of critically ill COVID-19 patients of the four most promising antiviral treatments (Remdesivir, Chloroquine, lopinavir and Ritonavir with/without interferon-beta). The first results will be announced soon98.
  • Remdesivir is considered the most likely to be effective. This drug inserts a missense mutation into the genome sequence of the SARS-CoV-2 virus. This mutation is said to interrupt the reproduction of the virus. Large international trials of this drug are underway. The U.S. Food and Drug Administration has now issued an emergency use authorization for Remdesivir for the treatment of severe COVID-19.
  • Antivirals typically need to be given very early on in an infection as they are most effective before large-scale viral replication begins. For COVID-19, this is a considerable challenge in terms of preventing spread, as there are so many asymptomatic and mild cases. It is likely that the first clinical applications of antivirals will be administered to critically ill patients as a last resort, and whereby knowledge on efficacy and side effects will also be gained.

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Vaccine development

  • As humans have not previously been confronted with SARS-CoV-2, there is no natural protection from the immune system.
  • No vaccine is currently available for COVID-19, but many research groups99, supported by new technologies, are working on this. Even before regulatory approval, which requires evidence of both the safety (e.g. to rule out the risk of enhanced disease) and efficacy of a new vaccine, the new candidate has to run through clinical trials which usually take place in four phases (including a pre-clinical phase).
  • New The centerpiece of vaccine research is the spike protein (S-protein) on the surface of the SARS-CoV-2 virus. With this, the virus docks onto the surface and enters a host cell. This protein is also responsible for the ‘fitness’ (virulence) of SARS-CoV-2 and is therefore the target of the immune system’s neutralizing antibodies; these antibodies may be the starting point for development of prophylactic and therapeutic agents to prevent, treat and control the spread of COVID-19100. Studies have fortunately shown that mutation rates for this protein are quite stable, making this ‘site’ an ideal target immunogen for vaccine candidates101. Most of the vaccines in development are not therefore using the whole virus – but are using RNA-coding of the viral S-proteins.
  • New More than 100 vaccine candidates102,103,104,105 are in development and 2 phase-1 studies of a mRNA vaccine by the US National Institutes of Health (NIH) are underway, as is an Adenovirus study on an already applied vaccine for Ebola.
  • New Traditional vaccine development takes over 10 years on average. Ebola achieved an accelerated 5-year timescale. The current scale and speed of vaccine development for SARS-CoV-2 is unprecedented. Successes will hopefully be reported, but it is realistic to expect that first applications, even if approval processes by authorities are accelerated, will not be available within the next 12 to 18 months, but likely before the second wave of this pandemic.
  • Despite high expectations and hopes for a SARS-CoV-2 vaccine, there are several caveats:
    • It is not guaranteed that a vaccine will be 100% effective and give lasting protection.
    • Production capacity will not meet the huge demand. Production facilities tend to be tailored to specific vaccines, as vaccine development is already a complex and high-risk field.
    • Distribution and administration of the new vaccine will require considerable time.
    • Vaccinating a large proportion of the population will take considerable time.
    • It is highly likely that more than one dose of the vaccine will be needed to achieve (even temporary) immunity.
    • With regard to the mRNA technology, it should be noted that this is new and has not yet led to a vaccine approved for human application.
  • The Bacillus Calmette-Guerin (BCG) vaccine – first developed for tuberculosis- is now being studied in several clinical trials around the world as a potential vaccine for SARS-CoV-2; at least six countries are running studies that involve giving front-line health workers and elderly people the BCG vaccine to find out whether it provides any protection against SARS-CoV-2. This follows several epidemiological COVID-19 studies that have reported a significantly reduced COVID-19 mortality correlated with the respective country’s BCG vaccine administration106.
    • Though the exact mechanism for these off-target effects of the BCG vaccine isn’t clear, it’s believed that the vaccine can cause a nonspecific immune response boost. However, since many of the abovementioned correlation studies have some methodological flaws, the likelihood of this being effective is not high.

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Medical prevention of SARS-CoV-2 infections

There is currently no known or approved prophylaxis (preventative treatment or action) other than non-pharmaceutical interventions for COVID-19. Healthcare staff are particularly at risk. In the absence of a vaccine, other strategies aiming to reduce the development of COVID-19 in the population or in select risk groups are now being investigated107. Such an approach, as widely used against HIV, is called pre-exposure prophylaxis (PrEP). Several trials108 are in progress including mostly healthcare staff and prophylactically applying e.g malaria drugs.

Another similar approach is the short-term application of a drug that might prevent COVID-19 or lessen at least its impact in individuals who have already been exposed to the SARS-CoV-2 virus. This is called postexposure prophylaxis (PEP) – a kind of ‘test and treat’ strategy of infected patients. Studies are underway with a malaria drug and other antivirals109.

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How can I protect myself?

General measures for prevention of viral respiratory infections if there is a concern of contracting COVID-19 include:

  • Handwashing for at least 20 seconds. An alcohol-based hand sanitizer may be used if soap is unavailable.
  • Individuals should avoid touching their eyes, nose and mouth with unwashed hands.
  • Limit travelling to areas impacted by COVID-19 and avoid contact with sick people, in particular those with a cough.
  • Avoid social gatherings.
  • Try to avoid close (<1.8 m) contact with persons suspected of having the virus.
  • A face mask should be worn inside if social distancing cannot be maintained. Simple surgical face masks could prevent transmission of human coronaviruses and influenza viruses from symptomatic individuals by shortening the travel distance of infectious droplets and aerosols110. Due to their scarcity, FFP2 (N95) respirator masks (currently sold out) and FFP3 (N99) masks should be reserved for health care personnel and those living with an individual with confirmed COVID-19.

Handwashing, no handshaking and general preventive measures (in particular social distancing) are key. Wearing facemasks where social distance is not feasible is useful.

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Efficacy of non-pharmaceutical interventions111,112

As there is currently no vaccine (pharmaceutical intervention) or known/approved prophylaxis for COVID-19, the best way to prevent widespread infection is for the population to avoid exposure to the virus (non-pharmaceutical intervention). International health authorities are not currently coordinating risk-commensurate measures, partly perhaps as there is no hard data from epidemiological studies or international recommendations that corroborate more drastic measures.

Many governments – e.g. in Asia and Europe (e.g. Italy, France, Spain, Germany and Austria)– are now implementing measures such as school closures, restricted social gathering, limiting population movement and quarantining of hot spots at the scale of cities or regions (often referred to as lockdown or mitigation, see table below). This is mainly encouraged by the success of consistent, severe non-pharmaceutical measures as taken in China, South Korea, Taiwan and Singapore. Less severe strategies – such as home isolation of suspected cases, home quarantine of those living in the same household as suspected cases and social distancing of the elderly and others at most risk of developing a severe form of the disease – are less promising and at best a means of intervention in case of secondary outbreaks.

Some large telecommunication companies are sharing aggregated (time and space) mobility data with governments and health authorities, as in Germany, to give an approximation of population-level mobility to help measure social distancing, in compliance with EU laws113. In Germany, for example, it has been shown that containment measures reduced population-level mobility by approximately 40% within the first week. However, two weeks later, with unchanged containment measures, the mobility restriction was only 27% of pre-lockdown levels114.

Though their effectiveness remains unknown due to the lack of historical examples and data for entire populations, the more stringent non-pharmaceutical interventions now being widely implemented should slow or even stop the spread of COVID-19 to avoid a rapid and steep peak in COVID-19 cases in favor of slower growth to relieve the pressure on hospitals, healthcare workers, intensive care units and ventilators.

The experience from China and South Korea has shown that suppression is possible, at least for a fairly short time period. However, it remains to be seen if it is possible long term to maintain this suppression and to manage the associated social and economic costs.

If strong containment measures remain in place for sufficient time and are adhered to, the curve of COVID-19 cases will flatten, and although unlikely, could also peter out. However, as long as there is no vaccine available and no basic immunity in the population, once the measures have been loosened or lifted, it will become key, if an outbreak returns, for authorities to be vigilant and to promptly apply stringent contact tracing and quarantining to avoid a second and potentially longer lockdown115.

Non-Pharmaceutical InterventionsWhy? When?Examples
Laissez faireHerd immunityUK, Sweden (both subsequently changed from this approach)
Travel restrictionsEarly phase
Isolation of suspected casesFormer contact to COVID-19
Quarantine of healthy contactsEarly phase
Tracking by scouts – only effective if daily new cases < 200
Singapore
Social distancingAirborne aerosols
Face masksAustria
Stay at homeWide rangeRisk groups vs. all
Voluntary vs. Mandatory
Closure of educational systemsEarly phaseLess social contact of the young.
Workplace – home offices or closureWide rangeLess social contact of the 20-59 age group116.
Mass gatheringsSoccer, religious events, carnivals, parties
Cordon sanitaireBuildings; residential areas
Digital trackingSmartphone; credit cardSouth Korea

 

There appears to be some evidence that countries have taken an average of about three weeks to act (with substantial variations between European and Asian countries, and by size of country, a factor that needs to be taken into account when assessing the efficacy of measures and timing of relaxation of measures) and that even stringent interventions do not show immediate results; these taking over three weeks on average to contain the spread of COVID-19.

As the transmission of SARS-CoV-2 occurs rapidly and very often before symptoms manifest, it is unlikely that this pandemic will be contained solely by non-pharmaceutical interventions. Mathematical models117 suggest that, in practice, traditional contact tracing can only improve on this to a certain extent; it is too slow and cannot be scaled up once the epidemic grows beyond the early phase due to limited personnel, lag-time of reporting of positive tests and pre-symptomatic transmissions. Contact tracing apps could help in some aspects: a recent model-based publication118 showed how a contact-tracing app disclosing memory of proximity contacts and immediately alerting contacts of positive cases might potentially achieve epidemic control without a comprehensive and long-lasting lockdown if used by at least 60% of a population. However, several issues exist (e.g. apps cannot detect the use of other protective measures such as facemasks) and a significant number of false positive alerts has to be assumed.

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Positive signs of how well equipped we are to handle a pandemic

Given the many advances made since previous pandemics, societies are now far better equipped to handle even a severe pandemic. For example:

  • The SARS-CoV-2 genome was decoded within two weeks of the virus’ identification and a diagnostic test119 was developed.
  • We can expect much more progress from genomics (see section on genomics above) and digital technologies (see section, ‘Digital technologies – insights and differences compared to past pandemics’).
  • Highly stringent containment measures, as implemented in China, South Korea, Singapore and Taiwan, appear to have been effective.
  • The vast majority of COVID-19 cases are mild.
  • Science, global and national health authorities can now more easily communicate with the public and exchange timely data, experience and information via the internet.
  • Vaccine prototypes are already being tested.
  • Numerous antiviral drugs, efficacy of drugs approved for other virus diseases, and vaccine candidates are underway.

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Contributor

Dr. Achim Regenauer, Chief Medical Officer, PartnerRe

Editor: Dr. Sara Thomas, PartnerRe.

This article is for general information, education and discussion purposes only. It does not constitute legal or professional advice of PartnerRe or its affiliates.

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30https://jamanetwork.com/journals/jama/fullarticle/2762130
31https://www.medrxiv.org/content/10.1101/2020.03.03.20028423v1
32https://zoonosen.charite.de/fileadmin/user_upload/microsites/m_cc05/virologie-ccm/dateien_upload/Weitere_Dateien/analysis-of-SARS-CoV-2-viral-load-by-patient-age.pdf
33https://www.imperial.ac.uk/media/imperial-college/medicine/sph/ide/gida-fellowships/Imperial-College-COVID19-symptom-progression-11-03-2020.pdf?utm_source=share&utm_medium=ios_app&utm_name=iossmf; https://www.medscape.com/viewarticle/926698; and https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(20)30566-3/fulltext
34https://www.cdc.gov/mmwr/volumes/69/wr/mm6913e2.htm?s_cid=mm6913e2_e&deliveryName=USCDC_921-DM24524
35https://www.medscape.com/viewarticle/928531
36https://onlinelibrary.wiley.com/doi/abs/10.1002/oby.22831; https://www.nih.gov/news-events/news-releases/nida-director-outlines-potential-risks-people-who-smoke-use-drugs-during-covid-19-pandemic
37https://www.nextbigfuture.com/2020/02/coronavirus-is-bat-coronavirus-with-sars-receptor-and-likely-joined-in-a-lab.html
38https://directorsblog.nih.gov/2020/03/26/genomic-research-points-to-natural-origin-of-covid-19/; WHO press conference 28 April 2020
39https://www.sciencemag.org/news/2020/02/completely-new-culture-doing-research-coronavirus-outbreak-changes-how-scientists
40https://www.aerzteblatt.de/archiv/36927/SARS-Virus-Nur-geringe-Neigung-zur-Mutation
41https://www.gisaid.org/epiflu-applications/next-sars-cov2-app/
42https://www.sciencedaily.com/releases/2020/03/200312101037.htm
43https://blogs.cdc.gov/genomics/2020/04/21/the-public-health-impact/
44https://www.sciencemag.org/news/2020/03/how-sick-will-coronavirus-make-you-answer-may-be-your-genes#
45https://www.sciencemag.org/news/2020/02/completely-new-culture-doing-research-coronavirus-outbreak-changes-how-scientists
46https://jamanetwork.com/journals/jama/fullarticle/2765696?guestAccessKey=4811e168-311d-4a52-b080-0a3ee047359b&utm_source=silverchair&utm_medium=email&utm_campaign=article_alert-jama&utm_content=olf&utm_term=050420
47https://www.nature.com/articles/s41591-020-0824-5
48Not expanded upon here as this is not the expertise of the author.
49https://www.the-scientist.com/news-opinion/lost-smell-and-taste-hint-covid-19-can-target-the-nervous-system-67312
50https://www.bmj.com/content/368/bmj.m606?utm_source=twitter&utm_medium=social&utm_term=hootsuite&utm_content=sme&utm_campaign=usage
51https://www.ucsf.edu/news/2020/02/416671/how-new-coronavirus-spreads-and-progresses-and-why-one-test-may-not-be-enough
52https://pubs.rsna.org/doi/10.1148/radiol.2020200370
53https://www.medrxiv.org/content/10.1101/2020.04.14.20065680v1
54https://www.medscape.com/viewarticle/928929
55Professor Drosten, Podcast, March 27. Charité University Hospital Berlin.
56https://www.sciencemag.org/news/2020/04/survivors-severe-covid-19-beating-virus-just-beginning#
57https://www.sciencemediacentre.org/expert-comment-on-treatment-and-recovery-post-covid-infection/
58https://jamanetwork.com/journals/jamacardiology/fullarticle/2763524
59https://www.sciencedirect.com/science/article/pii/S088915912030489X
60https://www.nejm.org/doi/full/10.1056/NEJMc2009787?query=RP&page=1&sort=oldest
61https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(20)30985-5/fulltext
62https://www.statnews.com/2020/04/20/everything-we-know-about-coronavirus-immunity-and-antibodies-and-plenty-we-still-dont/
63https://www.jimmunol.org/content/181/8/5490
64https://www.nature.com/articles/s41586-020-2196-x_reference.pdf
65https://www.the-scientist.com/news-opinion/how-sars-cov-2-tests-work-and-whats-next-in-covid-19-diagnostics-67210
66https://www.thelancet.com/journals/laninf/article/PIIS1473-3099(20)30235-8/fulltext
67https://wwwnc.cdc.gov/eid/article/26/7/20-0841_article
68https://globalbiodefense.com/headlines/singapore-first-to-test-out-covid-19-serological-assay-in-outbreak-contact-tracing/
69Professor Drosten, Podcast, 25 March. Charité University Hospital Berlin.
70Professor Drosten, Podcast, 8 April. Charité University Hospital Berlin.
71https://www.jwatch.org/fw116555/2020/04/15/covid-19-hydroxychloroquine-hypoxic-pneumonia-timing?query=pfw&jwd=000020109420&jspc=IM
72https://www.sciencemediacentre.org/expert-reaction-to-announcement-by-roche-of-its-new-serology-test-for-covid-19-antibodies/
73https://www.sciencemag.org/news/2020/03/new-blood-tests-antibodies-could-show-true-scale-coronavirus-pandemic#
74Professor Kekule, Die Zeit, 26 March.
75https://www.politico.com/news/2020/03/27/coronavirus-global-guide-152375
76https://www.repubblica.it/salute/medicina-e-ricerca/2020/03/16/news/coronavirus_studio_il_50-75_dei_casi_a_vo_sono_asintomatici_e_molto_contagiosi-251474302/?ref=RHPPTP-BH-I251454518-C12-P3-S2.4-T1
77https://thl.fi/en/web/thlfi-en/-/number-of-people-with-coronavirus-infections-may-be-dozens-of-times-higher-than-the-number-of-confirmed-cases
78https://www.bloomberg.com/news/articles/2020-03-14/a-fifth-of-virus-cruise-cases-asymptomatic-study-says
79Another study reported a 51% manifestation index: https://www.eurosurveillance.org/content/10.2807/1560-7917.ES.2020.25.10.2000180
80https://www.weforum.org/agenda/2020/03/people-with-mild-or-no-symptoms-could-be-spreading-covid-19/; https://www.zmescience.com/medicine/iceland-testing-covid-19-0523/; https://www.repubblica.it/salute/medicina-e-ricerca/2020/03/16/news/coronavirus_studio_il_50-75_dei_casi_a_vo_sono_asintomatici_e_molto_contagiosi-251474302/?ref=RHPPTP-BH-I251454518-C12-P3-S2.4-T1
81https://www.imperial.ac.uk/media/imperial-college/medicine/sph/ide/gida-fellowships/Imperial-College-COVID19-symptom-progression-11-03-2020.pdf?utm_source=share&utm_medium=ios_app&utm_name=iossmf
82https://www.jwatch.org/fw116437/2020/03/10/covid-19-can-look-common-cold-researchers-say
83https://jamanetwork.com/journals/jama/fullarticle/2762130
84https://www.bloomberg.com/news/articles/2020-02-23/coronavirus-patients-long-ventilator-stays-strain-hospitals
85Professor Drosten, Podcast, 18 March. Charité University Hospital Berlin.
86https://www.ncbi.nlm.nih.gov/books/NBK554776/
87https://www.jhltonline.org/article/S1053-2498(20)31473-X/fulltext
88https://www.nature.com/articles/d41586-020-01056-7
89https://www.the-scientist.com/news-opinion/lost-smell-and-taste-hint-covid-19-can-target-the-nervous-system-67312
90https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(20)30566-3/fulltext
91https://www.thelancet.com/action/showPdf?pii=S1473-3099%2820%2930243-7
92https://www.who.int/docs/default-source/coronaviruse/who-china-joint-mission-on-covid-19-final-report.pdf
93https://www.cdc.gov/mmwr/volumes/69/wr/mm6913e2.htm?s_cid=mm6913e2_w
94https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7129706/ and https://www.linkedin.com/pulse/over-80-covid-patients-placed-ventilators-new-york-have-colangelo/?trackingId=twCl8vi%2FRVm884hmSkMQGw%3D%3D
95https://www.nature.com/articles/d41586-020-00444-3
96For a good overview, see https://www.bmj.com/content/368/bmj.m1252
97https://www.bmj.com/content/368/bmj.m1252
98https://www.sciencemag.org/news/2020/03/who-launches-global-megatrial-four-most-promising-coronavirus-treatments
99https://www.pharmaceutical-technology.com/analysis/coronavirus-mers-cov-drugs/; and
https://www.nih.gov/news-events/news-releases/nih-clinical-trial-investigational-vaccine-covid-19-begins
100https://www.sciencedirect.com/science/article/pii/S1471490620300570
101https://www.biorxiv.org/content/10.1101/2020.04.27.064774v1.full.pdf
102https://jamanetwork.com/journals/jama/fullarticle/2762510
103https://www.who.int/blueprint/priority-diseases/key-action/novel-coronavirus-landscape-ncov-21march2020.PDF?ua=1
104https://www.bloomberg.com/news/articles/2020-04-13/who-says-70-vaccines-in-the-works-with-three-leading-candidates
105https://www.nature.com/articles/d41573-020-00073-5
106https://www.medrxiv.org/content/10.1101/2020.04.01.20049478v1.full.pdf; and https://www.medrxiv.org/content/10.1101/2020.03.24.20042937v1
107https://www.sciencemag.org/news/2020/04/trials-drugs-prevent-coronavirus-infection-begin-health-care-workers#
108https://clinicaltrials.gov/ct2/show/NCT04334928
109https://clinicaltrials.gov/ct2/show/NCT04304053
110https://www.nature.com/articles/s41591-020-0843-2
111https://www.imperial.ac.uk/mrc-global-infectious-disease-analysis/news–wuhan-coronavirus/
112https://www.sciencemediacentre.org/expert-reaction-to-mrc-centre-for-global-infectious-disease-analysis-report-9-impact-of-non-pharmaceutical-interventions-npis-to-reduce-covid-19-mortality-and-healthcare-demand/
113https://science.sciencemag.org/content/368/6487/145.2.full
114https://www.spiegel.de/panorama/corona-lockdown-deutsche-sind-immer-mehr-unterwegs-a-c8a6b940-600d-47c5-bf40-2ce4c26b9a7a
115https://www.statnews.com/2020/03/25/coronavirus-experts-craft-strategies-to-relax-lockdowns/
116https://www.maths.cam.ac.uk/features/cambridge-perspectives-julia-gog-and-bbc-pandemic-project
117https://www.ncbi.nlm.nih.gov/pubmed/32119825?dopt=Abstract; https://www.ncbi.nlm.nih.gov/pubmed/17183638?dopt=Abstract
118https://science.sciencemag.org/content/early/2020/03/30/science.abb6936
119https://www.who.int/emergencies/diseases/novel-coronavirus-2019/technical-guidance/laboratory-guidance

Additional sources (selection)

https://www.cdc.gov/coronavirus/2019-ncov/index.html
https://www.ecdc.europa.eu/en/current-risk-assessment-novel-coronavirus-situation
https://theconversation.com/r0-how-scientists-quantify-the-intensity-of-an-outbreak-like-coronavirus-and-its-pandemic-potential-130777
https://jamanetwork.com/journals/jama/pages/coronavirus-alert
https://www.bmj.com/coronavirus
https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(20)30374-3/fulltext
https://www.ecdc.europa.eu/en/geographical-distribution-2019-ncov-cases
https://www.nejm.org/coronavirus

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