The Journal of Infectious Diseases

SUPPLEMENT ARTICLE

Sepsis Perspective 2020
Edward J. Septimus
Department of Population Medicine, Harvard Medical School, Boston Massachusetts, USA, and Department of Internal Medicine, Texas A&M College of Medicine, Houston, Texas, USA

Keywords.  sepsis; antimicrobial stewardship; sepsis surveillance biomarkers.

Sepsis is defined as a dysregulated immune response to infec- sepsis code for those beneficiaries in those calendar years rose
tion affecting millions of individuals per year and carries high from $17 792 657 303 to $22 439 794 212. The total cost of skilled

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morbidity and mortality rates even if appropriate care is pro- nursing facility care in the 90  days after an inpatient hospital
vided [1, 2]. In the United States, sepsis is considered the most discharge for Medicare Part A/B rose from $3 931 616 160 to
common cause of inpatient death, affecting 1.7 million adults $5 623 862 486 over that same interval.
per year and contributing to 270 000 deaths [3]. Globally, there Over the past 2 decades, the Surviving Sepsis Campaign
were an estimated 49 million cases of sepsis in 2017 [4]. Sepsis (SSC) has released several guidelines aimed at standardizing and
incidence and mortality rates varied significantly by region. improving the management of patients with severe sepsis and
Furthermore, sepsis can be difficult to accurately diagnose, is septic shock. These guidelines have helped raise sepsis aware-
a diverse clinical syndrome, and there is no reference standard ness and triggered numerous quality improvement initiatives
for diagnosis. Subjectivity in determining whether an infection around the world [10]. In 2013, the New York State Department
is present and whether organ dysfunction is due to infection can of Health began a mandatory state-wide initiative to improve
be challenging. early recognition and treatment of severe sepsis and septic
After hospitalization, survivors can be too ill to return to their shock [11]. The Centers for Medicare & Medicaid Services’
homes or work and may require ongoing care in venues such as SEP-1 measure has appropriately established sepsis as a national
skilled nursing facilities. In addition, cognitive impairment and priority for quality improvement. SEP-1 was first implemented
functional disability can be major consequences, adding signif- in October 2015 and requires hospitals to report their bundled
icantly to societal health care costs and productivity. Iwashyna performance rates to Centers for Medicare & Medicaid Services
et  al demonstrated that severe sepsis in this older population as part of the Inpatient Quality Reporting Program. This is a
was independently associated with substantial and persistent condition of payment, and results are publicly available.
new cognitive impairment and functional disability among While the Infectious Diseases Society of America (IDSA) sup-
survivors. The magnitude of these new deficits was significant, ports SSC and SEP-1 for making sepsis care a national priority,
likely resulting in a critical downturn in patients’ ability to live IDSA chose not to endorse the 2016 version of the SSC guide-
independently [5]. Rosendahl et al [6] documented the risk of lines. IDSA’s reasons included the guidelines’ failure to acknowl-
psychological symptoms in not just survivors, but also spouses. edge the uncertainty and subjectivity that frequently confound a
Sepsis also ranks in the top 10 of principal diagnoses leading diagnosis of sepsis, the guidelines’ conflation of sepsis and septic
to readmission. Multiple studies document up to a 26% risk of shock, overly aggressive recommendations for sustained com-
readmission. These readmissions were frequently due not just to bination therapy for gram-negative septic shock, and unclear
infection but also to other acute conditions and seemed to result guidance on measuring adherence to time-to-antibiotics [12].
in substantially increased morbidity and mortality rates [7, 8]. Several of these concerns also apply to SEP-1 but are amplified
Sepsis can also be very expensive to treat, with total inpatient by the powerful influence of national quality measures on clini-
hospital and skilled nursing facility admission counts, costs, cian prescribing and hospital behavior. IDSA recently published
and mortality rates increasing over time from calendar year a Position Paper outlining several recommendations aimed at
2012 to calendar year 2018 in Medicare beneficiaries [9]. The reducing the risk of unintended consequences of SEP-1 while
total cost of inpatient hospital admissions including an explicit maintaining focus on its evidence-based elements [13]. IDSA’s
core recommendation is to limit SEP-1 to septic shock, where the
evidence supports the benefit of immediate antibiotics. Prompt
 

Correspondence: Edward J. Septimus, 4257 Albans, Houston, TX 77005 (eseptimus@gmail.

com). empiric antibiotics are often appropriate for suspected sepsis
The Journal of Infectious Diseases®  2020;222(S2):S71–3 without shock, but IDSA believes there is too much heteroge-
© The Author(s) 2020. Published by Oxford University Press for the Infectious Diseases Society
of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.
neity and difficulty defining this population, uncertainty about
DOI: 10.1093/infdis/jiaa220 the presence of infection, and insufficient data on the necessity

Sepsis Perspective 2020  •  jid 2020:222 (Suppl 2) • S71

of immediate antibiotics to support a mandatory treatment The challenge is that many published trials on duration exclude
standard for all patients in this category. This position paper is critically ill patients. As they point out, potential challenges to
endorsed by the American College of Emergency Physicians, shorter duration of therapy in sepsis include source control,
Pediatric Infectious Diseases Society, Society for Healthcare treatment of multidrug-resistant organisms, and the alterations
Epidemiology of America, Society of Hospital Medicine, and in pharmacokinetic and pharmacodynamic discussed by Phe
Society of Infectious Disease Pharmacists. et  al [20]. McCreery et  al [22] discuss the current knowledge
In this supplement to The Journal of Infectious Diseases, we of sepsis in immunocompromised patients, the diagnostic and
offer 10 articles with the goal of presenting the science and com- therapeutic challenges, and the diverse microbial pathogens.
plexity on the diagnosis and treatment of sepsis. Shappell et al Finally, Winslow and Swenson [23] review unintended conse-
[14] summarize the strengths and weaknesses of common ap- quences of the current sepsis mandates. They highlight that the
proaches to sepsis surveillance. An objective surveillance defi- mandate to rapidly start broad-spectrum antimicrobial agents
nition is crucial in making meaningful comparisons, tracking within a specified time frame, especially for patients who are not

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quality improvement efforts and outcomes. Tawfik and col- in shock, can result in overuse of broad-spectrum antimicrobial
leagues [15] remind us of the complex interplay between therapy. This can lead to increased resistance, increased adverse
various parts of the immune response. These investigators de- effects, and increased risk of Clostridioides difficile. They cor-
veloped an immune profiling panel consisting of 16 biomarkers. rectly point out that unlike guidelines, mandates such as SEP-1
These biomarkers can be integrated into a molecular multiplex reduce the time clinicians have to review diagnostics and ther-
platform that will enable clinicians in the future to more pre- apeutic strategies appropriate for an individual patient that can
cisely manage critically ill patients. lead to overuse and misuse of broad-spectrum antibiotics.
Gilbert [16] reviews a commonly available biomarker, I believe the this supplement will provide a valuable resource
procalcitonin (PCT), and discusses PCT biology, interpreta- to the Infectious Diseases community.
tion of elevated serum PCT levels, and the advantages of meas-
uring serum PCT in septic patients. He also presents a list of Note

topics that need additional study. Eubank et al. [17] discuss Supplement sponsorship.  This supplement is sponsored
the role of rapid diagnostics in the diagnosis and treatment of by bioMérieux, the Gordon and Betty Moore Foundation and
patients with sepsis. They conclude that these advances hold Beckman Coulter.
tremendous promise in increasing diagnostic yield, decreasing Potential conflicts of interest.  Author certifies no potential
turnaround time, and improving outcomes when integrated conflicts of interest. The author has submitted the ICMJE Form
into robust antimicrobial stewardship programs. Weinberger for Disclosure of Potential Conflicts of Interest. Conflicts that
et al [18] review published articles assessing the evidence con- the editors consider relevant to the content of the manuscript
cerning time-to-antibiotics and mortality. As they point out, have been disclosed.
most of these relate to observational cohort studies that have
key limitations and biases. This article helps us understand the References
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