Hospital Employees Response Ante COVID-19 Listed Early Symptoms (HERACLES): A clinical study to examine the dynamics of the host-response to viral infection including COVID-19 in healthcare workers

Why is it important to detect viral infection presymtomatically?

The novel coronavirus disease (COVID-19) is currently causing a pandemic
affecting 197 countries up to now. To date, the World Health Organization (WHO)
has reported 413,467 confirmed cases and 18,433 confirmed deaths. Controlling a
viral outbreak like the current one requires early detection of the infection,
before the infected individual passes on the virus. Ideally the detection
should occur at the pre-symptomatic stage before symptom onset, when viral
titers may be undetectable but high enough to make an individual contagious.
Earlier diagnosis of COVID-19 would be extremely relevant in the containment of
the outbreak, as an infected person is already contagious before onset of
symptoms as described for influenza. Pre-symptomatic spread of COVID-19 is
currently topic of investigation.

If it would be possible to identify infected persons before showing symptoms,
this may help to contain a future outbreak if COVID-19 re-enters our country in
the future. It may even have more value if a unknown viral pathogen will emerge
in the future that is very contagious before symptoms arise. Before pathogen
specific PCR tests are developed and available on a large scale, a test that is
able to detect any pre-symptomatic virus may make the difference between the
ability to contain the virus or not before it spreads globally. So, a future
outbreak could be prevented with rapid early detection when the causing agent
is still unknown or rapid molecular viral diagnostics are still under
development.

In addition, healthcare workers are at the front line in the battle against
this outbreak, and it is at these crucial times when large percentages of
hospital staff are potentially exposed, raising the question of whether they
should go into quarantine. As the outbreak proceeds it becomes impractical to
base isolation on potential exposure. Healthcare workers, unaware of their own
infection, can inadvertently put their patients and co-workers at risk of
infection, especially if the virus is contagious at a pre-symptomatic or early
symptomatic stage. Identifying this individual as early as possible, isolating
them from the environment and providing them with pre-emptive treatment if
applicable, may be able to help to combat the outbreak.

In addition, managing an outbreak demands careful allocation of resources. Most
antivirals are known to be most effective when applied in a very early stage in
the disease, when the viral load is still low. If it would be possible to
assess how likely a person is exhibit severe infection symptoms at this stage,
it would help to make an informed decision on the expected risks and benefits
of treatment in this individual and from a population perspective the need to
allocate resources.

In this study we aim to evaluate whether the levels of TRAIL and/or IP-10,
alone or in combination, are a sign of viral infection at a stage before
symptoms arise. We will assess the diagnostic value of the biomarkers alone
and/or in combination, using various cutoffs, to evaluate the potential value
in different situations in clinical practice and/or when new outbreaks arise.

We will perform a prospective cohort study. Healthcare workers without symptoms
of respiratory tract infection (RTI), who have a high risk of infection due to
exposure to viral RTI patients will be followed up for two to four weeks during
the COVID-19 pandemic. Blood samples will be taken six times to measure the
biomarkers TRAIL and IP-10 using ImmunoXpert (Index test), and within 2 days
after symptoms occur the presence and type of viral infection will be
determined by PCR using a respiratory sample (reference test).

This study is designed to examine the dynamics of the host response to COVID-19
infection. Patients participating in the study do not receive any
investigational drug nor any experimental examination or procedure. The
participants are exposed to the minimal risk associated with the collection of
a venous blood sample (Phlebotomy) and with an additional, non-invasive nasal
swab sampling.

The risk of standard phlebotomy may include infection, discomfort, pain or
subcutaneous bleeding which may be caused by venous rupture. The risk in nasal
swab sampling may include mainly discomfort or limited pain. The described
procedures are very common in the clinical practice and are widely performed.
In addition, the medical staff that will perform these procedures is highly
qualified and experienced in performing these tests.

The participants in the study are not expected to have any direct benefit
following their enrollment to the study. Study results will not affect the
diagnosis, prognosis, or treatment of the participants. Still, by participating
in the study, the subjects contribute to investigation of the host response to
COVID-19 infection, with the goal of establishing host biomarker dynamics that
are useful in managing the COVID-19 outbreak and future outbreaks.