During recent years, in-hospital mortality to sepsis has substantially declined (1). However, this decrease in mortality has not translated into improved long-term outcomes, nor has it resulted in expedited patient recoveries. Instead, the improvement in short-term survival in the sepsis population has been matched by a growing number of sepsis survivors that develop chronic critical illness (CCI). These patients not only exhibit physical and cognitive deficits that persist beyond their initial hospitalization, but routinely succumb to late complications of sepsis (2, 3). In fact, recent studies demonstrate that over a third of patients diagnosed with sepsis are dead within a year and that another one-third have not returned to independent living within 6 months (3). CCI patients are often assumed by the clinician to be chronically immunosuppressed, but clinical data to support this are lacking. To date, there have been no studies that examined whether patients with prolonged recoveries after sepsis demonstrate a greater degree of immune suppression as compared with patients who experience a more rapid recovery (RAP).
Host protective immunity has been studied in various patient populations with diverse methodologies being used to assess a patient's immune status. Some of these methodologies are clinically based, measuring outcomes such as the incidence of secondary infections occurring after admission, whereas others focus on biological measures, including gene expression patterns, biomarker profiles, specific cell counts, and immune functional assays (4–6). Most of these studies, however, fail to link biomarkers of immunosuppression with poor clinical outcomes such as increased long-term mortality and development of nosocomial infections after sepsis. Thus, we attempted to quantify immune suppression in two different populations of sepsis survivors using clinical outcomes, specifically the incidence of postsepsis secondary infections, as well as biological measures to suggest altered host immunity. We hypothesize that all postsepsis patients will show clinical and biomarker evidence of immune suppression when compared with healthy age-matched controls. Furthermore, we hypothesize that patients who develop CCI after sepsis will exhibit more severe or persistent alterations in biomarkers to suggest greater impairment in protective immunity, which places these patients at risk for subsequent infections and, perhaps, results in increased long-term mortality. Ultimately, our goal was to determine whether RAP from sepsis is associated with biomarker evidence to suggest restoration of host protective immunity, or conversely, whether those with CCI exhibit persistent immune suppression and increased incidence of secondary infections.
PATIENTS AND METHODS
Study Site and Patients
This prospective observational cohort study was approved by the Institutional Review Board of the University of Florida (UF) and was performed between April 2016 and April 2017 at UF Health Shands Hospital, a 996-bed academic quaternary-care referral center. The study was registered with clinicaltrials.gov (NCT02276417) and conducted by the Sepsis and Critical Illness Research Center at UF, whose study design and protocols have previously been published (7).
Over the 1-year period during which the study was conducted, 85 surgical intensive care unit (ICU) patients were enrolled who were either admitted with, or subsequently developed sepsis during their hospitalization. Patient enrollment and classification is outlined in Figure 1.
Screening for sepsis was carried out using the Modified Early Warning Signs-Sepsis Recognition System (MEWS-SRS), which quantifies derangements in vital signs, white blood cell count, and mental status (8). All patients eligible for inclusion in the study were enrolled within 12 h of sepsis protocol onset on a delayed waiver of consent, which was approved by our Institutional Review Board. If written informed consent could not be obtained from the patient or their legally assigned representative within 96 h of study enrollment, the patient was removed from the study and all collected biologic samples and clinical data were destroyed. All patients with sepsis were managed using a standardized, evidence-based protocol that emphasizes early goal-directed fluid resuscitation as well as other time-appropriate interventions such as administration of broad-spectrum antibiotics. Emperic antibiotics were chosen based on current hospital antibiograms in conjunction with the suspected source of infection (9). Antimicrobial therapy was then narrowed based on culture and sensitivity data. If a patient did not improve on this standardized empiric antibiotic regimen, a consult was placed to infectious disease for alternative recommendations.
Inclusion and Exclusion Criteria
Patients eligible for participation in the study met the following inclusion criteria: admission to the surgical or trauma ICU; age at least18 years; clinical diagnosis of sepsis, severe sepsis, or septic shock with this being the patient's first septic episode; and entrance into our sepsis clinical management protocol.
Patients were excluded if any of the following were present: refractory shock (i.e., patients expected to die within the first 24 h); an inability to achieve source control (i.e., irreversible disease states such as unresectable dead bowel); presepsis expected lifespan less than 3 months; patient/family not committed to aggressive management; severe CHF (NYHA Class IV); Child-Pugh Class C liver disease or preliver transplant; known HIV with CD4+ count less than 200 cells/mm3; organ transplant recipient or use of chronic corticosteroids or immunosuppressive agents; pregnancy; institutionalized patients; chemotherapy or radiotherapy within 30 days; severe traumatic brain injury (i.e., evidence of neurological injury on CT scan and a GCS <8); spinal cord injury resulting in permanent sensory and/or motor deficits; or inability to obtain informed consent.
Patients were diagnosed with sepsis, severe sepsis, or septic shock using the definitions established by the Society of Critical Care Medicine, the European Society of Intensive Care Medicine, the American College of Chest Physicians, the American Thoracic Society, and the Surgical Infection Society (SCCM/ESICM/ACCP/ATS/SIS) 2001 International Sepsis Definitions Conference (10). CCI was defined as an ICU length of stay (LOS) at least 14 days with evidence of persistent organ dysfunction, measured using components of the Sequential Organ Failure Assessment (SOFA) score at 14 days (i.e., cardiovascular SOFA ≥ 1, or score in any other organ system ≥ 2) (11). Patients with an ICU LOS less than 14 days would also qualify for CCI if they were discharged to another hospital, a long-term acute care facility, or to hospice, and demonstrated evidence of organ dysfunction at the time of discharge. Those patients experiencing death within 14 days of sepsis onset were excluded from the clinical and biomarker analyses. Any patient who did not meet criteria for CCI or early death was classified as RAP. As there is no consensus definition for CCI, we focused on combining key elements established by previous definitions reported in the literature, including the requirement for prolonged intensive care and the presence of persistent organ dysfunction. However, our definition was modified to include a more broad classification of organ dysfunction, as previous definitions relied heavily on the presence of respiratory failure requiring mechanical ventilation.
Primary Clinical Outcomes
Primary outcomes included incidence and overall number of secondary infections per patient during the index hospitalization, secondary infections corrected for the time at risk (i.e., secondary infections per 100 hospital person days), discharge disposition, and all-cause 30-day and 6-month mortality. Immunosuppression was determined clinically, by the presence of a secondary infection, because these patients are prima facie immunocompromised. This concept is supported by a recent study, which demonstrated the genomic response of patients who acquire secondary infections after sepsis is consistent with that of immune suppression (6). As previously described, secondary infections were defined as any probable or microbiologically confirmed bacterial, yeast, fungal, or viral infection requiring treatment with antimicrobials and occurring at least 48 h after sepsis protocol onset during the index hospitalization (6, 12, 13). Coexisting infections, that is, those occurring within the first 48 hafter sepsis diagnosis, were not included because these were felt to represent simultaneous infections independent of the primary sepsis event. Viral titers were not routinely measured; therefore, subclinical viral infections are not presented in this analysis.
Selection of Biomarkers
In routine laboratory analyses, absolute lymphocyte counts (ALCs) have been used as an indicator of immune suppression because lower ALCs are linked to the reactivation of latent viruses as well as recurrent bacterial infections requiring hospital admission (14–16). In addition, monocytic human leukocyte antigen-DR (mHLA-DR) expression on CD14+ blood monocytes has been found to correlate with mortality in severe sepsis patients and susceptibility to secondary infections in neurosurgical patients (17, 18). Elevated levels of sPD-L1, the soluble form of the transmembrane receptor PD-L1, has been associated with decreased activation of T cells and T-cell apoptosis in cancer (19, 20).
Sample Collection and Laboratory Analyses
Serial blood samples were collected from hospitalized septic patients at 12 h—1, 4, 7, 14, 21, and 28 days after sepsis protocol initiation. Blood samples were also collected from 20 healthy controls, which were age-, race-, and sex-matched to the sepsis population. For septic patients, complete blood counts with differential were performed by the Clinical and Diagnostic Laboratories at UF Health Shands Hospital for determination of ALCs. Plasma levels of sPD-L1 were determined by ELISA (R&D Systems, Minneapolis, Minn).
mHLA-DR expression was determined using fluorescence quantification with the Quantibrite HLA-DR/Monocyte system (BD Biosciences, San Jose, Calif) following the manufacturer's instructions. Fluorescent beads were used to quantitate the number of binding antibodies per CD14+ cell. Fluorescence was determined using a Becton–Dickinson LSR II Flow Cytometer (BD Biosciences).
Data are presented as frequency and percentage for categorical variables, or mean and SD, or median and 25th/75th percentiles for continuous variables. Fisher exact test and the Kruskal–Wallis test were used for comparison of categorical and continuous variables, respectively. The number of secondary infections per 100 hospital person days and the number of secondary infections per patient were modeled using a Poisson model with overdispersion. Six-month survival and incidence of secondary infection curves were plotted for both the CCI and RAP groups using the Kaplan–Meier method.
The effect of time and group on laboratory results were modeled using generalized estimating equations (GEE) with Poisson variance assumption and log link, which incorporated time, group, and the interaction of the two variables into the model. The fitted mean functions are plotted with 95% pointwise confidence bands. The means of the laboratory results for each group at distinct time points have been added to all plots.
Univariate and multivariate logistic regression models using HLA-DR, sPDL1, and ALC at 24 h after sepsis onset were constructed to predict clinical trajectory (CCI and early death vs. RAP), as well as the incidence of secondary infection. Adjusted and unadjusted odds ratios (ORs) and the area under the receiver-operating characteristics (AUC) curve values with 95% confidence intervals (95% CIs) were reported. All significance tests were two-sided, with P ≤ 0.05 considered statistically significant. These statistical analyses were performed using SAS 9.4 (SAS Institute Inc, Cary, NC) and R 3.4.0 (Foundation for Statistical Computing, Vienna, Austria).
Patient Demographics and Sepsis Characteristics
Demographics of the overall cohort and the individual RAP and CCI groups appear in Table 1. Of the 88 patients enrolled, 3 died within the first 14 days of sepsis onset (3%), 35 patients progressed to CCI (40%), and 50 patients experienced RAP (57%). Between the CCI and RAP groups, there were no significant differences in patient age, race, number of comorbidities, or hospital transfer status. However, patients with CCI showed greater physiological derangement within 24 h after sepsis onset, as indicated by their APACHE II scores (P < 0.001). Only 40% of the entire cohort was admitted for either sepsis or an infectious-related complication, whereas the majority of surgical patients enrolled in the study were admitted for noninfectious etiologies, a planned surgical procedure, or severe traumatic injury.
Sepsis characteristics of the two cohorts of interest, that is, RAP and CCI, appear in Table 2. In comparison to patients who experience RAP, CCI patients were twice as likely to develop hospital-acquired sepsis (sepsis onset ≥48 h after hospital admission) and 3 times as likely to present in septic shock (P < 0.001 and P = 0.008, respectively). With regard to primary sepsis diagnosis, CCI patients demonstrated a predisposition toward pneumonia, whereas RAP patients were more likely to present with necrotizing soft tissue infections or urosepsis. Notably, the incidence of intra-abdominal infections did not significantly differ between groups, nor did the number of surgical source control procedures performed.
Patient Outcomes and Clinical Evidence of Immune Suppression
Patient outcomes are presented in Table 3. A striking number of CCI patients acquired a secondary infection (25 patients, or 71%), with a mean onset of 12 days. In contrast, only a small percentage (6%) of RAP patients developed a secondary infection (P < 0.001). Within the CCI cohort, the mean number of secondary infections per patient was 1.11, in comparison to 0.06 in the RAP group (P < 0.001). Even after adjusting for time at risk (i.e., hospital LOS), the difference in the incidence of secondary infections between CCI and RAP groups remained statistically significant (P < 0.001). The most commonly observed secondary infection was pneumonia (n = 11), followed by intra-abdominal infections (n = 10), surgical site infections (n = 6), urinary tract infections (n = 4), and reactivation of latent viruses (n = 4). Of the intra-abdominal infections, the most common etiologies were intra-abdominal abscesses, anastomotic leaks, and Clostridium difficile colitis. Although the etiology of secondary infections did not significantly differ between groups, there was a trend toward increasing viral, fungal, and surgical site infections in the CCI group, without a single patient in the RAP group experiencing one of these infections (Table 3).
Notably, most RAP patients who developed a secondary infection were likely to present with these infections within the first 10 days of sepsis onset, but thereafter, the incidence of secondary infections slowed, reaching a plateau. Conversely, in the CCI group, there was a continued sharp rise in the incidence of secondary infections until approximately 20 days after sepsis diagnosis, at which point the curve stabilized (Fig. 2).
In addition to the frequency of secondary infections, discharge dispositions between the two groups were examined. To determine significant differences between groups, the four patients who met the criteria for CCI based on their discharge disposition and an ICU LOS less than 14 days were excluded. After excluding these individuals, we found that CCI patients were still more likely to be discharged to “poor” discharge dispositions, as compared with patients with RAP, the majority of which (92%) were discharged to home or to a rehabilitation facility.
Not only were CCI patients more likely to require a higher level of care due to presumed functional impairment, but these patients also exhibited a statistically significant increase in 30-day and 6-month mortality (P = 0.015 and P = 0.002, respectively) (Table 3 and Fig. 3). A striking 26% of CCI patients had succumbed within 6 months after their initial sepsis event, with 11% dying within the first 30 days. Comparatively, 96% of RAP patients were alive 6 months.
Characteristics of Patients With Secondary Infections
A subgroup analysis was performed to examine differences in the characteristics of patients who developed secondary infections and those who did not (Table 4). On average, patients who acquired secondary infections after sepsis were older (62 ± 16 yr vs. 55 ± 16 yr, P = 0.044), had more comorbidities (4.9 vs. 3.4, P = 0.025), and were more likely to present in septic shock, demonstrating greater measurable organ dysfunction within 24 h (APACHE II scores of 21 ± 8 vs. 15 ± 7, P = 0.003). Furthermore, these patients had significantly longer hospital and ICU LOS (P < 0.001), and were more likely to present with intra-abdominal sepsis as their primary sepsis diagnosis, whereas patients who did not develop secondary infections showed a predilection for necrotizing soft tissue infections.
Commonly identified etiologies of secondary infections within the surgical sepsis population included Gram-negative bacteria (34.5%), followed by Gram-positive bacteria (25.6%), fungi (15.5%), and viral infections (5.2%). Causative organisms were often either resistant or opportunisitic pathogens such as Candida spp., Pseudomonas aeruginosa, Enterobacter spp., Klebsiella spp., Staphylococcus aureus, Escherichia coli, and Herpes Simplex Virus (HSV) (Table 5).
Biological Evidence of Immune Suppression
All sepsis patients demonstrated biomarker evidence to suggest impaired host immunity, with CCI patients displaying the greatest alterations in these biomarkers. In comparison to matched healthy controls, sepsis patients had lower ALCs, particularly within the first 4 days postsepsis event. Based on GEE model results, there were significant estimated differences in the slope for ALC over time between the CCI and RAP groups (P = 0.036), with RAP patients demonstrating accelerated restoration of their ALCs (Fig. 4A). In contrast, CCI patients experienced a more gradual increase in cell count, with ALCs often remaining suppressed out to 28 days (Fig. 4A). HLA-DR expression was also dramatically reduced in all sepsis patients at every time point when compared with healthy controls (Fig. 4B). GEE model analyses, used to examine the CCI and RAP groups, revealed that HLA-DR, over time, was significantly lower in CCI patients. Likewise, significant differences in HLA-DR were found at 14 and 21 days when examining means between groups at individual time points using nonparametric rank-sum tests (P < 0.05). Concentrations of sPD-L1 were markedly elevated in the sepsis population when compared with healthy controls. Among sepsis survivors, RAP patients demonstrated a decline of sPD-L1 toward normal range, whereas sPD-L1 remained persistently elevated in CCI patients (P < 0.05) (Fig. 4C). Subanalysis of patients admitted with sepsis versus those who acquired sepsis after another injury such as trauma or a planned surgery, revealed no significant differences between the two groups with respect to the above biomarkers.
Univariate logistic regression model analyses revealed that all biomarkers were relatively poor at predicting the development of CCI at 24 h with AUCs of 0.536 (95% CI, 0.405–0.666), 0.637 (95% CI, 0.512–0.762), and 0.654 (95% CI, 0.516–0.792) for HLA-DR, sPD-L1, and ALC, respectively (Fig. 5A). When combined, the multivariate model yielded an AUC of 0.652 (95% CI, 0.513–0.790). None of the unadjusted or adjusted ORs were significant. Similar results were observed for the outcome of secondary infections (Fig. 5B). Clinical scoring, using patient APACHE II scores obtained at 24 h, only slightly improved the performance of the prediction models with AUCs of 0.748 (95% CI, 0.638–0.858) and 0.699 (95% CI, 0.583–0.815) for predicting CCI and secondary infections, respectively.
An increasing number of patients survive the exaggerated inflammatory phase of their initial septic insult, but often develop protracted hospital courses and ongoing organ dysfunction. These chronically critically ill patients are presumed to enter a prolonged immunosuppressive state, during which they are at increased risk for secondary infections and resulting mortality (21, 22). This immunosuppressive state may occur as a result of chronic antigenic stimulation and T-cell exhaustion, but requires further investigation (23). Although there is sufficient evidence to confirm immune suppression in those who die of sepsis and multiple organ failure, there is a relative paucity of data surrounding immune suppression in sepsis survivors, particularly those who develop CCI (24). Rather, most studies, to date, have focused on characterizing the immunological phenotype of sepsis survivors as compared with nonsurvivors, with the goal of identifying biomarkers to predict mortality to sepsis.
Our study shows that all sepsis survivors, regardless of their clinical trajectory, exhibit impairment in host immunity, with biomarker alterations to suggest ongoing immunosuppression persisting out to a month after the initial septic insult. This immune suppression is manifested, clinically, by increased susceptibility to secondary infections during the index hospitalization after sepsis onset, with one-third of sepsis survivors (33%) developing a secondary infection. Strikingly, the nosocomial infection rate observed in postsepsis patients is almost 3 times higher than the current reported rate of health care-associated infections observed in adults and children in ICUs across the United States (13%) (25). However, it is important to note that CCI patients accounted for the majority of subjects (89%) with secondary infections. One may assume this is due to their prolonged hospital and ICU LOS, which increase their exposure to highly virulent and resistant pathogens, and hence their risk of nosocomial infections. However, we found that differences between the mean secondary infections occurring in the CCI versus RAP population, when adjusted for hospital days, remained statistically significant (3.5 secondary infections per 100 hospital person days vs. 0.3, P < 0.001), suggesting an alternative explanation for the increased incidence of nosocomial infections in these patients.
One plausible explanation for the increased susceptibility to secondary infections in sepsis survivors is ongoing immune dysfunction, which is consistent with our previously proposed syndrome of persistent inflammation, immunosuppression, and catabolism (26–29). In the present study, we show that all septic patients demonstrate reduced ALCs and HLA-DR expression and increased sPD-L1 concentrations, which persist for weeks to months after sepsis onset. Compared with healthy individuals, the ALCs of CCI patients remained suppressed over time, whereas ALCs increased dramatically in the RAP group. Similarly, expression of HLA-DR in the septic population, measured by antibodies bound per cell, was one-third to one-half of that seen in healthy controls, suggesting greater monocyte deactivation in these patients (30). There is also evidence to support a blunted adaptive immune response in septic patients, as indicated by their increased plasma concentrations of sPD-L1, which ultimately leads to the downregulation of T cells (31). Of the sepsis population, those who developed CCI had significantly higher sPD-L1 concentrations and lower HLA-DR expression, most notable around 2 weeks after sepsis onset. These findings support a greater and a more prolonged impairment of both innate and adaptive immunity in the CCI group.
The immune suppression observed in the CCI group is not only reflected by deviations in quantifiable biomarkers such as the ALC, sPD-L1 concentrations, and HLA-DR expression, but is also clinically supported by these patients’ increased susceptibility to secondary infections and all-cause mortality at 6 months. The pairing of physiological biomarkers of immunosuppression with clinical data to support immune suppression makes this study unique because previous studies have often looked at these entities in isolation of one another, or have looked at the relationship between these biomarkers and outcomes such as in-hospital mortality or multiple organ failure. Therefore, this is the first study to link the physiological and clinical data to support immune suppression with clinical outcomes such as CCI and secondary infections. With the research paradigm evolving to a bench-to-bedside-to-bench format, studies of this nature which will be increasingly relevant to ensure the applicability of future translational research.
With regard to the broader context of this research, our study challenges previous immune deficiency thresholds used to predict the risk of nosocomial sepsis. These thresholds include neutropenia (absolute neutrophil count <500 cells/mm3), monocyte deactivation (HLA-DR expression <30% or <8,000–12,000 molecules per cell), lymphopenia (ALC < 1,000 cells/mm3), and hypogammaglobulinemia (IgG < 500 mg/dL) (32). Refuting any of the above has significant clinical implications because several of these thresholds are used as criteria for enrollment into current clinical trials. One ongoing clinical trial is evaluating immunomodulatory therapies, specifically GM-CSF, to decrease ICU acquired infections (NCT02361528). In this clinical trial, HLA-DR expression levels of less than 8,000 molecules per cell at day 3 of sepsis onset are used to determine sepsis-associated immunosuppression. However, this is problematic because our data suggest that a single measurement of HLA-DR, especially at the time of sepsis diagnosis, is a poor early predictor of outcomes such as the development of CCI and secondary infections, which represent the clinical manifestations of underlying immune suppression. In fact, HLA-DR levels of patients who rapidly recover versus those who progress to CCI and are at increased risk for nosocomial infections cannot be reliably distinguished until 7 to 14 days after sepsis onset, which is significantly longer than the collection time during which HLA-DR is measured in current clinical trials. Taken together, these findings raise the question as to whether these biomarkers of immune suppression can be used early in a patient's clinical course after sepsis to stratify patients into presumed clinical trajectories. Our data suggest that biomarkers obtained within the first 12 to 24 h will not aid in early prediction of CCI or secondary infections for this surgical sepsis cohort, although the utility of these biomarkers at later time points, or in sepsis with other origins, has yet to be determined. It is clear that additional studies will be required to assess the robustness of current biomarker thresholds being used to enroll sepsis patients in clinical trials, which are assumed to be linked to poor clinical outcomes.
Although these biomarkers could not distinguish between RAP and CCI patients at early time points, specifically within the first 24 h of sepsis diagnosis, there are significant differences in the overall trends between CCI and RAP patients, which mirrors their clinical trajectories. The divergence of these two patient populations, with respect to their clinical outcomes and immunologic phenotype, demonstrates there are key underlying differences present in host protective immunity. Whether these differences supersede a patient's sepsis diagnosis or arise as a product of sepsis, it has yet to be determined. However, the similarities in patient demographics and biomarkers, at baseline, suggest perhaps that these immunologic changes are triggered by sepsis, with more persistent immunologic alterations coinciding with increasing sepsis severity. Still, this hypothesis remains speculative, and further studies that include functional assays will be needed to fully assess the immunologic phenotype of these patient populations.
There are a number of limitations to this study that require comment. First, our study is limited to sepsis occurring within the surgical ICU population, so the results may not be applicable when extrapolated to the overall community. In addition, surgical patients are prone to recurrent inflammatory insults, which may lead to persistent immune dysregulation, predisposing them to develop CCI with resulting immune suppression. This study is also centered around the inpatient experience, and does not include postdischarge data following the index hospitalization, so infections occurring after hospital discharge are not accounted for in this analysis. Blood sampling is also confined to the inpatient setting, making it difficult to obtain samples at later time points, particularly in the RAP group as many of these patients were discharged. Undoubtedly, further long-term studies that involve collection of blood samples during later time points with a larger study cohort, including possible outpatient follow-up, may be required to reliably determine long-term differences in immune status between groups. Another limitation worth noting is the selection of the control population for this study. Septic ICU patients were compared with healthy age, race, and sex-matched controls rather than noninfected ICU patients, as there was concern that admission to the ICU for nonsepsis events such as severe traumatic injury generates a highly heterogeneous group of patients with varying organ injury that would likely minimize detectable differences in the experimental group. Finally, the recently established sepsis-3 definitions were not used to classify patients in the study because the use of qSOFA and operationalizing sepsis-3 remains controversial, and because CMS continues to use the old definitions, complicating the ability of physician–scientists to fully embrace sepsis-3.
Despite these limitations, we were able to conclude the following: postsepsis patients, for the most part, are immunosuppressed; and in comparison to those who rapidly recover, patients who develop CCI experience greater and more prolonged impairment of host protective immunity, as evidenced by their increased susceptibility to secondary infections, lower ALCs and mHLA-DR expression, and marked elevations in sPD-L1.
The authors thank all clinicians and support staff of the Sepsis and Critical Illness Research Center at UF Shands Health engaged in ongoing sepsis and inflammation research, and thank Bridget Baisden, Jillianne Brakenridge, Ruth Davis, Jennifer Lanz, and Ashley McCray for their invaluable work and contributions to this project.
1. Kaukonen KM, Bailey M, Suzuki S, Pilcher D, Bellomo R. Mortality related to severe sepsis and septic shock
among critically ill patients in Australia and New Zealand, 2000–2012. JAMA
2014; 311 13:1308–1316.
2. Iwashyna TJ, Ely EW, Smith DM, Langa KM. Long-term cognitive impairment and functional disability among survivors of severe sepsis. JAMA
2010; 304 16:1787–1794.
3. Yende S, Austin S, Rhodes A, Finfer S, Opal S, Thompson T, Bozza FA, LaRosa SP, Ranieri VM, Angus DC. Long-term quality of life among survivors of severe sepsis: analyses of two international trials. Crit Care Med
2016; 44 8:1461–1467.
4. Budde K, Matz M, Durr M, Glander P. Biomarkers of over-immunosuppression
. Clin Pharmacol Ther
2011; 90 2:316–322.
5. Fraser DR, Dombrovskiy VY, Vogel TR. Infectious complications after vehicular trauma in the United States. Surg Infect (Larchmt)
2011; 12 4:291–296.
6. van Vught LA, Klein Klouwenberg PM, Spitoni C, Scicluna BP, Wiewel MA, Horn J, Schultz MJ, Nurnberg P, Bonten MJ, Cremer OL, et al. Incidence, risk factors, and attributable mortality of secondary infections in the intensive care unit after admission for sepsis. JAMA
2016; 315 14:1469–1479.
7. Loftus TJ, Mira JC, Ozrazgat-Baslanti T, Ghita GL, Wang Z, Stortz JA, Brumback BA, Bihorac A, Segal MS, Anton SD, et al. Sepsis and Critical Illness Research Center investigators: protocols and standard operating procedures for a prospective cohort study of sepsis in critically ill surgical patients. BMJ Open
2017; 7 7:e015136.
8. Croft CA, Moore FA, Efron PA, Marker PS, Gabrielli A, Westhoff LS, Lottenberg L, Jordan J, Klink V, Sailors RM, et al. Computer versus paper system for recognition and management of sepsis in surgical intensive care. J Trauma Acute Care Surg
2014; 76 2:311–317.
9. Fitousis K, Moore LJ, Hall J, Moore FA, Pass S. Evaluation of empiric antibiotic use in surgical sepsis. Am J Surg
2010; 200 6:776–782.
10. Levy MM, Fink MP, Marshall JC, Abraham E, Angus D, Cook D, Cohen J, Opal SM, Vincent JL, Ramsay G, et al. 2001 SCCM/ESICM/ACCP/ATS/SIS International Sepsis Definitions Conference. Crit Care Med 31 (4):1250–1256, 2003.
11. Ferreira FL, Bota DP, Bross A, Melot C, Vincent JL. Serial evaluation of the SOFA score to predict outcome in critically ill patients. JAMA
2001; 286 14:1754–1758.
12. Calandra T, Cohen J. International Sepsis Forum Definition of Infection in the ICUCC. The international sepsis forum consensus conference on definitions of infection in the intensive care unit. Crit Care Med
2005; 33 7:1538–1548.
13. Garner JS, Jarvis WR, Emori TG, Horan TC, Hughes JM. CDC definitions for nosocomial infections, 1988. Am J Infect Control
1988; 16 3:128–140.
14. Ong DSY, Bonten MJM, Spitoni C, Verduyn Lunel FM, Frencken JF, Horn J, Schultz MJ, van der Poll T, Klein Klouwenberg PMC, Cremer OL. Epidemiology of multiple herpes viremia in previously immunocompetent patients with septic shock
. Clin Infect Dis
2017; 64 9:1204–1210.
15. Prescott HC, Langa KM, Iwashyna TJ. Readmission diagnoses after hospitalization for severe sepsis and other acute medical conditions. JAMA
2015; 313 10:1055–1057.
16. Walton AH, Muenzer JT, Rasche D, Boomer JS, Sato B, Brownstein BH, Pachot A, Brooks TL, Deych E, Shannon WD, et al. Reactivation of multiple viruses in patients with sepsis. PLoS One
2014; 9 2:e98819.
17. Asadullah K, Woiciechowsky C, Docke WD, Egerer K, Kox WJ, Vogel S, Sterry W, Volk HD. Very low monocytic HLA-DR
expression indicates high risk of infection—immunomonitoring for patients after neurosurgery and patients during high dose steroid therapy. Eur J Emerg Med
1995; 2 4:184–190.
18. Ditschkowski M, Kreuzfelder E, Rebmann V, Ferencik S, Majetschak M, Schmid EN, Obertacke U, Hirche H, Schade UF, Grosse-Wilde H. HLA-DR
expression and soluble HLA-DR
levels in septic patients after trauma. Ann Surg
1999; 229 2:246–254.
19. Dong H, Strome SE, Salomao DR, Tamura H, Hirano F, Flies DB, Roche PC, Lu J, Zhu G, Tamada K, et al. Tumor-associated B7-H1 promotes T-cell apoptosis: a potential mechanism of immune evasion. Nat Med
2002; 8 8:793–800.
20. Norde WJ, Maas F, Hobo W, Korman A, Quigley M, Kester MG, Hebeda K, Falkenburg JH, Schaap N, de Witte TM, et al. PD-1/PD-L1 interactions contribute to functional T-cell impairment in patients who relapse with cancer after allogeneic stem cell transplantation. Cancer Res
2011; 71 15:5111–5122.
21. Hotchkiss RS, Monneret G, Payen D. Sepsis-induced immunosuppression
: from cellular dysfunctions to immunotherapy. Nat Rev Immunol
2013; 13 12:862–874.
22. Otto GP, Sossdorf M, Claus RA, Rodel J, Menge K, Reinhart K, Bauer M, Riedemann NC. The late phase of sepsis is characterized by an increased microbiological burden and death rate. Crit Care
2011; 15 4:R183.
23. Hotchkiss RS, Monneret G, Payen D. Immunosuppression
in sepsis: a novel understanding of the disorder and a new therapeutic approach. Lancet Infect Dis
2013; 13 3:260–268.
24. Boomer JS, To K, Chang KC, Takasu O, Osborne DF, Walton AH, Bricker TL, Jarman SD 2nd, Kreisel D, Krupnick AS, et al. Immunosuppression
in patients who die of sepsis and multiple organ failure. JAMA
2011; 306 23:2594–2605.
25. Klevens RM, Edwards JR, Richards CL Jr, Horan TC, Gaynes RP, Pollock DA, Cardo DM. Estimating health care-associated infections and deaths in U.S. hospitals, 2002. Public Health Rep
2007; 122 2:160–166.
26. Gentile LF, Cuenca AG, Efron PA, Ang D, Bihorac A, McKinley BA, Moldawer LL, Moore FA. Persistent inflammation
: a common syndrome and new horizon for surgical intensive care. J Trauma Acute Care Surg
2012; 72 6:1491–1501.
27. Mira JC, Gentile LF, Mathias BJ, Efron PA, Brakenridge SC, Mohr AM, Moore FA, Moldawer LL. Sepsis pathophysiology, chronic critical illness, and persistent inflammation
syndrome. Crit Care Med
2017; 45 2:253–262.
28. Rosenthal MD, Moore FA. Persistent inflammation
, and catabolism
: evolution of multiple organ dysfunction. Surg Infect (Larchmt)
2016; 17 2:167–172.
29. Vanzant EL, Lopez CM, Ozrazgat-Baslanti T, Ungaro R, Davis R, Cuenca AG, Gentile LF, Nacionales DC, Cuenca AL, Bihorac A, et al. Persistent inflammation
, and catabolism
syndrome after severe blunt trauma. J Trauma Acute Care Surg
2014; 76 1:21–29. discussion 29-30.
30. Volk HD, Reinke P, Krausch D, Zuckermann H, Asadullah K, Muller JM, Docke WD, Kox WJ. Monocyte deactivation—rationale for a new therapeutic strategy in sepsis. Intensive Care Med
1996; 22 (Suppl. 4):S474–S481.
31. Frigola X, Inman BA, Lohse CM, Krco CJ, Cheville JC, Thompson RH, Leibovich B, Blute ML, Dong H, Kwon ED. Identification of a soluble form of B7-H1 that retains immunosuppressive activity and is associated with aggressive renal cell carcinoma. Clin Cancer Res
2011; 17 7:1915–1923.
32. Carcillo JA. Critical illness stress-induced immune suppression. In: Intensive Care Medicine: Annual Update 2007. Edited by Vincent J-L. New York: Springer Science & Business Media, 2007.