<div class="section">
<a class="named-anchor" id="ab-joi190047-1">
<!--
named anchor
-->
</a>
<h5 class="section-title" id="d793470e680">Question</h5>
<p id="d793470e682">Are clinical sepsis phenotypes identifiable at hospital presentation
correlated with
the biomarkers of host response and clinical outcomes and relevant for understanding
the heterogeneity of treatment effects?
</p>
</div><div class="section">
<a class="named-anchor" id="ab-joi190047-2">
<!--
named anchor
-->
</a>
<h5 class="section-title" id="d793470e685">Findings</h5>
<p id="d793470e687">In this retrospective analysis using data from 63 858 patients
in 3 observational
cohorts, 4 novel sepsis phenotypes (α, β, γ
<i>,</i> and δ) with different demographics, laboratory values, and patterns of organ
dysfunction
were derived, validated, and shown to correlate with biomarkers and mortality. In
the simulations using data from 3 randomized clinical trials involving 4737 patients,
the outcomes related to the treatments were sensitive to changes in the distribution
of these phenotypes.
</p>
</div><div class="section">
<a class="named-anchor" id="ab-joi190047-3">
<!--
named anchor
-->
</a>
<h5 class="section-title" id="d793470e693">Meaning</h5>
<p id="d793470e695">Four novel clinical phenotypes of sepsis were identified that
correlated with host-response
patterns and clinical outcomes and may help inform the design and interpretation of
clinical trials.
</p>
</div><div class="section">
<a class="named-anchor" id="ab-joi190047-4">
<!--
named anchor
-->
</a>
<h5 class="section-title" id="d793470e699">Importance</h5>
<p id="d793470e701">Sepsis is a heterogeneous syndrome. Identification of distinct
clinical phenotypes
may allow more precise therapy and improve care.
</p>
</div><div class="section">
<a class="named-anchor" id="ab-joi190047-5">
<!--
named anchor
-->
</a>
<h5 class="section-title" id="d793470e704">Objective</h5>
<p id="d793470e706">To derive sepsis phenotypes from clinical data, determine their
reproducibility and
correlation with host-response biomarkers and clinical outcomes, and assess the potential
causal relationship with results from randomized clinical trials (RCTs).
</p>
</div><div class="section">
<a class="named-anchor" id="ab-joi190047-6">
<!--
named anchor
-->
</a>
<h5 class="section-title" id="d793470e709">Design, Settings, and Participants</h5>
<p id="d793470e711">Retrospective analysis of data sets using statistical, machine
learning, and simulation
tools. Phenotypes were derived among 20 189 total patients (16 552 unique patients)
who met Sepsis-3 criteria within 6 hours of hospital presentation at 12 Pennsylvania
hospitals (2010-2012) using consensus
<i>k</i> means clustering applied to 29 variables. Reproducibility and correlation
with biological
parameters and clinical outcomes were assessed in a second database (2013-2014; n = 43 086
total patients and n = 31 160 unique patients), in a prospective cohort study of sepsis
due to pneumonia (n = 583), and in 3 sepsis RCTs (n = 4737).
</p>
</div><div class="section">
<a class="named-anchor" id="ab-joi190047-7">
<!--
named anchor
-->
</a>
<h5 class="section-title" id="d793470e717">Exposures</h5>
<p id="d793470e719">All clinical and laboratory variables in the electronic health
record.</p>
</div><div class="section">
<a class="named-anchor" id="ab-joi190047-8">
<!--
named anchor
-->
</a>
<h5 class="section-title" id="d793470e722">Main Outcomes and Measures</h5>
<p id="d793470e724">Derived phenotype (α, β, γ
<i>,</i> and δ) frequency, host-response biomarkers, 28-day and 365-day mortality,
and RCT
simulation outputs.
</p>
</div><div class="section">
<a class="named-anchor" id="ab-joi190047-9">
<!--
named anchor
-->
</a>
<h5 class="section-title" id="d793470e730">Results</h5>
<p id="d793470e732">The derivation cohort included 20 189 patients with sepsis (mean
age, 64 [SD, 17]
years; 10 022 [50%] male; mean maximum 24-hour Sequential Organ Failure Assessment
[SOFA] score, 3.9 [SD, 2.4]). The validation cohort included 43 086 patients (mean
age, 67 [SD, 17] years; 21 993 [51%] male; mean maximum 24-hour SOFA score, 3.6 [SD,
2.0]). Of the 4 derived phenotypes, the α phenotype was the most common (n = 6625;
33%) and included patients with the lowest administration of a vasopressor; in the
β phenotype (n = 5512; 27%), patients were older and had more chronic illness and
renal dysfunction; in the γ phenotype (n = 5385; 27%), patients had more inflammation
and pulmonary dysfunction; and in the δ phenotype (n = 2667; 13%), patients had more
liver dysfunction and septic shock. Phenotype distributions were similar in the validation
cohort. There were consistent differences in biomarker patterns by phenotype. In the
derivation cohort, cumulative 28-day mortality was 287 deaths of 5691 unique patients
(5%) for the α phenotype; 561 of 4420 (13%) for the β phenotype; 1031 of 4318 (24%)
for the γ phenotype; and 897 of 2223 (40%) for the δ phenotype. Across all cohorts
and trials, 28-day and 365-day mortality were highest among the δ phenotype vs the
other 3 phenotypes (
<i>P</i> < .001). In simulation models, the proportion of RCTs reporting benefit,
harm, or
no effect changed considerably (eg, varying the phenotype frequencies within an RCT
of early goal-directed therapy changed the results from >33% chance of benefit
to
>60% chance of harm).
</p>
</div><div class="section">
<a class="named-anchor" id="ab-joi190047-10">
<!--
named anchor
-->
</a>
<h5 class="section-title" id="d793470e738">Conclusions and Relevance</h5>
<p id="d793470e740">In this retrospective analysis of data sets from patients with
sepsis, 4 clinical
phenotypes were identified that correlated with host-response patterns and clinical
outcomes, and simulations suggested these phenotypes may help in understanding heterogeneity
of treatment effects. Further research is needed to determine the utility of these
phenotypes in clinical care and for informing trial design and interpretation.
</p>
</div><p class="first" id="d793470e743">In this study, Sepsis-3 investigators use
electronic health record and trial data
from patients with sepsis within 6 hours of hospital presentation to define clinical
phenotypes that correlate with host-response patterns, sepsis biomarkers, mortality,
and treatment effects.
</p>