To the Editor:
Despite intensive research efforts, the search for new therapeutic options for sepsis
has yielded no result (1). However, the ongoing coronavirus disease (COVID-19) pandemic
shows that effective therapeutic options for the distinct subgroup of viral sepsis
due to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection can
be found within months (2). What can sepsis researchers learn from the way COVID-19
is studied?
Heterogeneity
In clinical practice, recognition of the wider sepsis syndrome can improve awareness
and timely initiation of treatment. However, when looking for new therapeutic options
in a research setting, this broad approach may be less desirable. One of the questionable
tenets of sepsis research has been whether the host response in sepsis represents
a “final common pathway” irrespective of the source of infection or causative pathogens
(1). This would justify looking at the broader sepsis population in research, with
the added benefit of having larger study cohorts. However, most believe that the host
response is just too complex and that a “final common pathway” may simply not exist
(1). The resultant heterogeneity within the sepsis population is therefore considered
to be a major limiting factor in finding specific sepsis therapies (1, 3). Extensive
efforts have thus been made to reveal homogeneous sepsis subgroups (1, 3, 4).
Shared and distinct gene expression profiles are found when pulmonary and abdominal
sepsis are compared (3), suggesting that part of the heterogeneity in the sepsis population
could be explained by the infection site or invading pathogen. Several other studies
that aim to find homogeneous sepsis subgroups through various methods show different
distributions of infectious etiology across the newly formed subgroups, again implying
that infecting organisms are associated with differences in the host response (3).
One study even states, “we examined only datasets of patients with bacterial sepsis
at admission, because the clustering algorithms may otherwise have been overwhelmed
by the differing host responses to different types of infections” (4).
In contrast to the many different causative microorganisms and arguably differing
host responses in sepsis, early COVID-19 studies show comparable gene expression profiles
in their populations, such as the upregulation of chemokines and neutrophils (2, 5).
This is possibly one of the key reasons why there have already been positive randomized
trials with therapeutic options for COVID-19 (2). Despite mixed results in sepsis
trials, dexamethasone treatment resulted in lowering of 28-day mortality in COVID-19,
particularly in patients who received respiratory support (2). Perhaps focusing on
a single site of infection or infective agent took away much of the heterogeneity.
Researchers in the field of sepsis may learn from this and adapt current research
paradigms and trial designs in such a way that stratification per infection type is
possible and statistically meaningful.
Outcome Measures
Outcome measures for sepsis clinical trials have been frequently discussed. Trials
using novel therapeutic options have failed to demonstrate a benefit in general outcomes
such as rates of ICU admission or mortality (1). In 2005, the International Sepsis
Forum proposed that sepsis researchers should widen the breadth of outcome measures
that are used in clinical trials (6). Mortality is an attractive outcome measure,
but other patient-centered benefits such as quality of life and long-term morbidity
should not be overlooked. The International Sepsis Forum colloquium provided additional
clinically relevant possibilities to show the benefits of a treatment (6). Nevertheless,
the literature on new therapeutics for sepsis continues to be dominated by the search
for short-term mortality benefits.
For COVID-19, the World Health Organization (WHO) recognized that a core set of outcome
measures was needed to investigate this new disease and compare outcomes globally.
Experts who proposed the outcome measures for sepsis in 2005 also did so for COVID-19
in 2020 (7). This time, a minimal common outcome measures set was used globally.
Another advantage of focusing on a more defined disease state, such as SARS-CoV-2
infection, in contrast to all-cause sepsis, is that site-specific outcome measures
can be used. For instance, the Murray score to assess lung injury (7) or diffusion
capacity to assess pulmonary function (8) are valuable outcomes that could potentially
be improved by certain treatments. Obviously, it does not make sense to assess pulmonary
function as an outcome in all sepsis patients.
Global Collaboration
Just weeks after the COVID-19 outbreak in Wuhan, China, the WHO coordinated a global
research roadmap (9). Experts from various fields agreed on key questions and strategies
to accelerate research. The WHO launched a COVID-19 Data Platform to collect global
data through a predefined case report form (CRF) (9). When patient data was collected
with this CRF anywhere around the world, the same variables were documented, and the
criteria for COVID-19 diagnosis (e.g., PCR or computed tomography scan) were available.
The CRF was widely adopted and created a unique opportunity for global collaborative
efforts, with minimal missing data or different inclusion criteria.
Furthermore, global genomic alliances are providing insights into how clinical and
immunological manifestations of infection, and its natural variability, are governed
by human genetics. In this case, global collaborations help find specific individuals
prone or resistant to disease, who are especially interesting when trying to elucidate
pathophysiological mechanisms.
Besides the use of a standardized data collection, COVID-19 research further profiled
itself through the use of popular messaging platforms such as Slack (10). In the United
States, a group of researchers created a Slack forum to coordinate research projects
across the country, providing yet another opportunity to have comparable study results.
Pitfalls
The COVID-19 pandemic created much urgency with researchers worldwide. So far, we
have outlined positive aspects of the COVID-19 research field from which sepsis researchers
can learn (Table 1). Inevitably, this urgency also created pitfalls. The pressure
to quickly perform and publish new studies led to acceptance of flexibility in protocols
and trial design, shorter turnaround times for peer review at medical journals, and
omission of extensive testing in preclinical animal models. Although these practices
speed up the research process, one should be aware that they can also lower the standard
of medical research, as is evident by the retraction of several papers in prominent
medical journals over the past months.
Table 1.
Key Aspects of COVID-19 Research from Which Sepsis Researchers Can Learn
Aspect
Message
Heterogeneity
COVID-19 is more homogenous than sepsis, and that has probably been helpful with identifying
effective treatments. Sepsis researchers should therefore consider smaller/more homogenous
subgroups for study.
Outcome measures
Widespread use of core outcome sets facilitates comparison and pooling across studies.
Examples of core outcomes are as follows (7):• Organ dysfunction• Biochemical parameters•
Radiological findings• Duration of intervention• Quality of life• Resource use
Examining homogenous subgroups facilitates additional outcome measures (e.g., severity
of lung injury) that would not be relevant to an all-cause sepsis population.
Global collaboration
Global data platforms with a standardized case report form can facilitate pooling
of sepsis research.
National or global coordination of large research projects can streamline sepsis research.
Popular messaging platforms can be excellent tools to aid trial coordination.
Definition of abbreviation: COVID-19 = coronavirus disease.