Updated April 9, 2020
1. How is the virus spreading?
In terms of transmission, Covid-19 is a super-SARS -- it spreads
in all the same ways SARS spreads, and more. It is spread primarily from
symptomatic people to others who are in close contact through respiratory
droplets, by direct contact with infected persons, or by contact with contaminated
objects and surfaces (fomites). Covid-19 can sometimes spread from asymptomatic
people, and this is an area we need to learn much more about. Spread by
aerosolization appears limited to medical procedures and unique settings which
can create superspreading events such
as choir practice.
2. How contagious is the virus (the R0, or basic reproductive rate)?
High. It was 14 (a single infected person infecting an average
of 14 others) on the Diamond Princess cruise ship. The best current estimate is
that that the R0 is between 2-2.5, roughly twice that of seasonal influenza. Some studies
have reported higher estimates, including this look at 11 countries in Europe which had initial
reproduction numbers of 3.8. Even with physical distancing measures, the R0 was
still 1.4, indicating continued spread. It appears very difficult to get this
below 1, although several countries have done so. This is what it will take to
end the pandemic.
3. How common is spread from contaminated surfaces?
We know contact transmission is possible, as documented in this description of transmission via a seat in church. It is
probably more common in health care facilities (as was the case with SARS) and
cruise ships, which have more frequently touched surfaces.
4. How effective is increasing ventilation at reducing risk?
We don't know how effective this is, but it is not likely to be high.
Still, the World Health Organization recommends increased ventilation in all phases of a pandemic
because simulation studies show that increasing the ventilation rate would
reduce influenza transmission, specifically aerosol transmission and perhaps to
a lesser extent, large respiratory droplet transmission or indirect contact
transmission.
5. How much spread is from asymptomatic cases?
There is some, but most Covid-19 infections are not spread this
way. Studies have shown that between 6% and 13% of cases
were attributed to presymptomatic or asymptomatic transmission. This means it
will be harder but not impossible to control (though may make complete
elimination virtually impossible until there is a vaccine), and we need to
adapt control measures to account for presymptomatic and asymptomatic spread.
6. How sensitive are PCR assays -- what is the false-negative
rate from properly collected nasopharyngeal, or NP, samples?
This is one area where we don't yet know the answer. A lot
depends on how well the sample was taken, how much virus the patient was
shedding at that time, and the quality of the test.
An FDA document for
LabCorp's Emergency Use Authorization of RT-PCR boasts near 100% "positive
agreement" and "negative agreement" for both upper respiratory
and lower respiratory samples. In literature from China's experience, sensitivity for NP swab
PCR-based testing has been as low as 60% and as high as 85% testing.
Specificity has been higher than sensitivity. The CDC's fact sheet for health
care providers that accompanies testing kits does contain information about
false negative tests; however, it does not report a sensitivity or specificity.
CDC guidance for labs states: "FDA Sensitivity Evaluation: The analytical sensitivity
of the test will be further assessed by evaluating an FDA-recommended reference
material using an FDA developed protocol if applicable and/or when
available."
7. Is serology accurate, and what is the time course of antibody
response?
Serology for Covid-19 is likely accurate if done well. The
median time for seroconversion (antibody response) has been shown to be around
11 days for total antibody, 12 days for IgM (generally the first antibody made
in response to infection), and 14 days for IgG (the most common and generally
long-lasting antibody that fights off viral infection). Antibodies were present
in less than 40% of patients within one week of symptom onset, and in almost
100% of patients after 15 days. At eight days after symptom onset, the
sensitivity of serology may rise above that of PCR. In samples from patients
during days 8 to 14 after onset, the sensitivities of antibody (90%), IgM (73%)
and IgG (54%) were all higher than that of RNA test (54%). Among samples from
patients in later phase (day 15-39 since onset), the sensitivities of antibody,
IgM and IgG were 100%, 94% and 80%, respectively. More importantly, we
still don't know whether antibodies protect against repeat infection, whether
they reflect a lack of the potential to infect others, and, if they are
protective, how long that protection lasts.
8. Can an accurate, rapid point-of-care test be
developed?
Many rapid point-of-care tests which detect IgM/IgG have been
created and are starting to be used. These tests take between 2 and 20 minutes
to obtain results. The first approval for
this type of testing in the United States was for Cellex Inc.'s rapid serology
tester, approved on April 1. In
addition, rapid RT-PCR tests (e.g., Cepheid GeneXpert Xpress SARS-CoV-2)
provide rapid (30 minute) PCR RNA testing where the GeneXpert Xpress machine is
available and if test kits are available. The Abbott ID NOW test is a rapid
test that can provide positive results in as little as 5 minutes and is most
suitable for office and urgent care clinics which need timely results but don't
require high throughput, but is not yet widely available. (This machine is
approved for use outside of clinical laboratories). Shortages of sampling and
laboratory supplies are one of the many limiting factors to expanding testing
in the United States.
9. How deadly is the virus?
Reported case fatality rates vary greatly from country to country (range 0-17%),
but are strongly age dependent in all settings. Using data available on April
6, mortality starts to rise sharply in those aged
over 60 years (globally) and over age 65 in the U.S., which hasn't reported
60-65 year-olds separately (6.5%), and is highest in those over age 80
(>20%). China, which initially saw a case fatality rate greater than 10%,
now has a CFR of 0.7% as its epidemic winds down. Most models anticipate
that the global case fatality rate will ultimately be determined to be to near
or just below 1%.
10. Which are the most vulnerable groups we
need to protect? Which underlying diseases increase risk the most?
Groups at highest risk include the elderly (beginning at age 60) and people with
the following conditions: chronic lung disease (including moderate or severe
asthma); serious heart disease; immunocompromised status (including HIV);
chronic kidney disease (especially those dependent on dialysis); liver disease;
diabetes mellitus (type 1 or 2); and severe obesity (BMI greater than 40). Also
at higher risk are people living in congregate settings (e.g., nursing homes,
prisons). There are concerns about the risk level of pregnant/peripartum women and
newborns as well as the homeless;
however, there is currently insufficient data to determine risk.
11. Do different types of virus cause different levels of severity?
SARS-CoV-2 is mutating at a
rate as expected for similar RNA viruses. None of the mutations detected so far
are associated with significant change in virus behavior or virulence, but
information continues to emerge, and it is possible that some of the
differences seen in different areas could reflect subtle genetic changes in the
virus.
12. Is the virus changing genetically in
important ways as it spreads?
This requires a more in-depth evaluation -- stay tuned.
13. What treatments work to decrease the severity of Covid-19 disease?
We are still trying to find out. If there are effective
anti-viral treatments, not only can patients' lives be saved, but the duration
of intensive care stay can be reduced. This would allow more patients to be
treated and reduce the risk to health care workers, and contacts and health
care workers could potentially receive preventive treatment to reduce spread.
There are multiple ongoing trials to evaluate several classes of therapeutics,
including the Solidarity clinical trial coordinated by the World Health Organization, with
preliminary results expected by early May. The Solidarity trial is assessing
four different treatment options, including antivirals (remdesivir,
lopinavir/ritonavir), antimalarials (chloroquine, hydroxychloroquine), and
Interferon beta-1a (used to treat multiple sclerosis).
14. Can a preventive medication be identified to be given to
contacts of patients with Covid-19 as is done for influenza with oseltamivir (Tamiflu) in nursing homes and
other areas?
As with potential treatments, there is yet no conclusive data to
report, but effective prophylaxis would help greatly until a vaccine is
developed. More than 60 clinical trials for Covid-19 preventive medications are registered
on the NIH ClinicalTrials.gov website
and are currently recruiting or planned among household and community contacts,
health care workers and rheumatology patients. Some candidates include
chloroquine, hydroxychloroquine, azithromycin, remdesivir, lopinavir/ritonavir,
bacille Calmette-Guerin (BCG) vaccine, zinc, vitamin D, inhaled nitrous oxide,
and intranasal IFNα.
15. Is there any role for steroid treatment of patients with severe pneumonia caused by
SARS-CoV-2?
One recent study in February 2020 found that Covid-19 patients would obtain minimal if any benefit
from corticosteroid treatment, and might more likely be harmed by it. An Expert Consensus Statement from the Chinese Thoracic Society cited in The Lancet calls for individual risk benefit
consensus and consideration of low-dose short courses in severe Covid-19
pneumonia (except those already using corticosteroids for another chronic
condition). A non-randomized comparison of 26 pneumonia patients given low-dose
methylprednisolone had faster improvement in lung function and resolution of
chest computed tomography findings. Six clinical trials registered ClinicalTrials.gov are currently planned or recruiting participants.
Control
16. What works to change behavior, including hand-washing and cough
hygiene? Telling people what to do gives
leaders a sense they are doing something, but does it actually work?
We can only know and improve our messaging by objectively
monitoring how people respond, but there is limited evidence of what is
happening today. A 2017 Cochrane Review of interventions to improve handwashing among health
workers found moderate evidence to support placement of alcohol-based hand rub
and providing performance feedback; there was low certainty of evidence for
multimodal strategies including increasing the availability of alcohol‐based
hand hygiene products, education for staff, reminders, performance feedback,
administrative support and staff involvement. A 2012 systematic review of community handwashing was associated with
reduction of influenza and respiratory infection in both wealthy and
low/middle-income countries, but there was no impact shown within households
where an index case was already present.
17. What works to limit spread? For example, will school closures make a
difference?
We don't know. Non-pharmaceutical interventions (NPIs) are important given the lack of pharmaceutical
interventions or a vaccine, but we lack understanding of the effectiveness of individual measures, which
makes balancing benefits against potential harms difficult, particularly in resource-limited settings. Combined home, school and workplace interventions might
have the biggest impact on transmission dynamics. Since most children don't
appear to get seriously ill if infected (unlike with influenza), they may not
be common sources of infection -- and school closures may (or may not) have
limited value. Early travel restrictions are useful in the early stages of the epidemic but other measures are needed to mitigate later local spread. The
situation in the US may prove to be a place to learn in order to provide measure-specific data, as different
communities are enacting different policies at different times.
18. What are the most important ways to protect health care
workers and patients in health facilities?
This is a crucial area where we must learn more. As evidence on environmental and airborne transmission and transmission from pre- and
asymptomatic people accumulates, measures to prevent transmission in healthcare settings that differ from current recommendations are being called for. Although suggested approaches
largely based on experience during other epidemics and studies on other pathogens are likely relevant to Covid-19, concrete data on
the relative importance of measures that recognize the unique features of this
pathogen and this pandemic, including resource limitations, are lacking.
19. How can creation of a safe and effective vaccine be accelerated?
Safety concerns from experiences with other coronavirus vaccines
necessitate rigorous safety monitoring and multiple time, cost, scale and distribution issues must be overcome, multiple vaccine candidates are being investigated concurrently. A globally collaborative system can absorb the increased financial risk associated
with using a pandemic paradigm to rapidly develop multiple vaccines; this approach
has been used to launch the first phase I trial of a candidate vaccine in the US.
We need to get good data from everywhere on what is being done
and what works. As we continue to get better answers to all of these questions,
we'll be better able to fight World War C against our viral enemy.
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