Safety and efficacy of favipiravir in COVID-19 patients with pneumonia. A randomized, double-blind, placebo-controlled study (FAVID).

PURPOSE: To design a randomized clinical trial to assess the efficacy and safety of favipiravir in patients with COVID-19 disease with pneumonia. METHODS: A randomized, double blind, placebo-controlled clinical trial of favipiravir in patients with COVID-19 pneumonia was conducted in three Spanish sites. Randomization 1:1 to favipiravir or placebo (in both groups added to the Standard of Care) was performed to treat the patients with COVID-19 pneumonia. The primary endpoint was "time to clinical improvement," measured as an improvement for ≥ two categories on a 7-point WHO ordinal scale in an up to 28 days' time frame. RESULTS: Forty-four patients were randomized (23 in the favipiravir group and 21 in the placebo group). The median time to clinical improvement was not different between the favipiravir and the placebo arms (10 days for both groups) and none of the secondary endpoints showed significant differences between arms. The proportion of adverse events (both serious and non-serious) was statistically different between the favipiravir group (68.29%) and the placebo group (31.7%) (p = 0.019), but there was insufficient statistical evidence to correlate the degree of severity of the events with the treatment group. CONCLUSIONS: Favipiravir administered for ten days to patients with COVID-19 and pneumonia did not improve outcomes compared with placebo. Although this is an underpowered negative study, efficacy results align with other randomized trials. However, in the present study, the non-serious adverse events were more frequent in the favipiravir group.

A retrospective case-control study to evaluate the use of beta-lactam desensitization in the management of penicillin-allergic patients: a potential strategy for Antimicrobial Stewardship Programs.

Introduction: Penicillin allergy labels (PAL) are common in the hospital setting and are associated with worse clinical outcomes. Desensitization can be a useful strategy for allergic patients when alternative options are suboptimal or not available. The aim was to compare clinical outcomes of patients with PAL managed with antibiotic desensitization vs. those who received alternative non-beta-lactam antibiotic treatments. Methods: A retrospective 3:1 case-control study was performed between 2015-2022. Cases were adult PAL patients with infection who required antibiotic desensitization; controls were PAL patients with infection managed with an alternative antibiotic treatment. Cases and controls were adjusted for age, sex, infection source, and critical or non-critical medical services. Results: Fifty-six patients were included: 14 in the desensitization group, 42 in the control group. Compared to the control group, desensitized PAL patients had more comorbidities, with a higher Charlson index (7.4 vs. 5; p = 0.00) and more infections caused by multidrug-resistant (MDR) pathogens (57.1% vs. 28.6%; p = 0.05). Thirty-day mortality was 14.3% in the desensitized group, 28.6% in the control group (p = 0.24). Clinical cure occurred in 71.4% cases and 54.8% controls (p = 0.22). Four control patients selected for MDR strains after alternative treatment; selection of MDR strains did not occur in desensitized patients. Five controls had antibiotic-related adverse events, including Clostridioides difficile or nephrotoxicity. No antibiotic-related adverse events were found in the study group. In multivariate analysis, no differences between groups were observed for main variables. Conclusion: Desensitization was not associated with worse clinical outcomes, despite more severe patients in this group. Our study suggests that antibiotic desensitization may be a useful Antimicrobial Stewardship tool for the management of selected PAL patients.

The balance between antibiotic resistance and fitness/virulence in Pseudomonas aeruginosa: an update on basic knowledge and fundamental research.

The interplay between antibiotic resistance and bacterial fitness/virulence has attracted the interest of researchers for decades because of its therapeutic implications, since it is classically assumed that resistance usually entails certain biological costs. Reviews on this topic revise the published data from a general point of view, including studies based on clinical strains or in vitro-evolved mutants in which the resistance phenotype is seen as a final outcome, i.e., a combination of mechanisms. However, a review analyzing the resistance/fitness balance from the basic research perspective, compiling studies in which the different resistance pathways and respective biological costs are individually approached, was missing. Here we cover this gap, specifically focusing on Pseudomonas aeruginosa, a pathogen that stands out because of its extraordinary capacity for resistance development and for which a considerable number of recent and particular data on the interplay with fitness/virulence have been released. The revised information, split into horizontally-acquired vs. mutation-driven resistance, suggests a great complexity and even controversy in the resistance-fitness/virulence balance in the acute infection context, with results ranging from high costs linked to certain pathways to others that are seemingly cost-free or even cases of resistance mechanisms contributing to increased pathogenic capacities. The elusive mechanistic basis for some enigmatic data, knowledge gaps, and possibilities for therapeutic exploitation are discussed. The information gathered suggests that resistance-fitness/virulence interplay may be a source of potential antipseudomonal targets and thus, this review poses the elementary first step for the future development of these strategies harnessing certain resistance-associated biological burdens.

Validation of circulating histone detection by mass spectrometry for early diagnosis, prognosis, and management of critically ill septic patients.

BACKGROUND: As leading contributors to worldwide morbidity and mortality, sepsis and septic shock are considered a major global health concern. Proactive biomarker identification in patients with sepsis suspicion at any time remains a daunting challenge for hospitals. Despite great progress in the understanding of clinical and molecular aspects of sepsis, its definition, diagnosis, and treatment remain challenging, highlighting a need for new biomarkers with potential to improve critically ill patient management. In this study we validate a quantitative mass spectrometry method to measure circulating histone levels in plasma samples for the diagnosis and prognosis of sepsis and septic shock patients. METHODS: We used the mass spectrometry technique of multiple reaction monitoring to quantify circulating histones H2B and H3 in plasma from a monocenter cohort of critically ill patients admitted to an Intensive Care Unit (ICU) and evaluated its performance for the diagnosis and prognosis of sepsis and septic shock (SS). RESULTS: Our results highlight the potential of our test for early diagnosis of sepsis and SS. H2B levels above 121.40 ng/mL (IQR 446.70) were indicative of SS. The value of blood circulating histones to identify a subset of SS patients in a more severe stage with associated organ failure was also tested, revealing circulating levels of histones H2B above 435.61 ng/ml (IQR 2407.10) and H3 above 300.61 ng/ml (IQR 912.77) in septic shock patients with organ failure requiring invasive organ support therapies. Importantly, we found levels of H2B and H3 above 400.44 ng/mL (IQR 1335.54) and 258.25 (IQR 470.44), respectively in those patients who debut with disseminated intravascular coagulation (DIC). Finally, a receiver operating characteristic curve (ROC curve) demonstrated the prognostic value of circulating histone H3 to predict fatal outcomes and found for histone H3 an area under the curve (AUC) of 0.720 (CI 0.546-0.895) p < 0.016 on a positive test cut-off point at 486.84 ng/mL, showing a sensitivity of 66.7% and specificity of 73.9%. CONCLUSIONS: Circulating histones analyzed by MS can be used to diagnose SS and identify patients at high risk of suffering DIC and fatal outcome.

The Intricate Role of Non-Coding RNAs in Sepsis-Associated Disseminated Intravascular Coagulation.

Disseminated Intravascular Coagulation (DIC) is a type of tissue and organ dysregulation in sepsis, due mainly to the effect of the inflammation on the coagulation system. Unfortunately, the underlying molecular mechanisms that lead to this disorder are not fully understood. Moreover, current biomarkers for DIC, including biological and clinical parameters, generally provide a poor diagnosis and prognosis. In recent years, non-coding RNAs have been studied as promising and robust biomarkers for a variety of diseases. Thus, their potential in the diagnosis and prognosis of DIC should be further studied. Specifically, the relationship between the coagulation cascade and non-coding RNAs should be established. In this review, microRNAs, long non-coding RNAs, and circular RNAs are studied in relation to DIC. Specifically, the axis between these non-coding RNAs and the corresponding affected pathway has been identified, including inflammation, alteration of the coagulation cascade, and endothelial damage. The main affected pathway identified is PI3K/AKT/mTOR axis, where several ncRNAs participate in its regulation, including miR-122-5p which is sponged by circ_0005963, ciRS-122, and circPTN, and miR-19a-3p which is modulated by circ_0000096 and circ_0063425. Additionally, both miR-223 and miR-24 were found to affect the PI3K/AKT pathway and were regulated by lncGAS5 and lncKCNQ1OT1, respectively. Thus, this work provides a useful pipeline of inter-connected ncRNAs that future research on their impact on DIC can further explore.

Evaluation of the host immune response assay SeptiCyte RAPID for potential triage of COVID-19 patients.

Tools for the evaluation of COVID-19 severity would help clinicians with triage decisions, especially the decision whether to admit to ICU. The aim of this study was to evaluate SeptiCyte RAPID, a host immune response assay (Immunexpress, Seattle USA) as a triaging tool for COVID-19 patients requiring hospitalization and potentially ICU care. SeptiCyte RAPID employs a host gene expression signature consisting of the ratio of expression levels of two immune related mRNAs, PLA2G7 and PLAC8, measured from whole blood samples. Blood samples from 146 adult SARS-CoV-2 (+) patients were collected within 48 h of hospital admission in PAXgene blood RNA tubes at Hospital del Mar, Barcelona, Spain, between July 28th and December 1st, 2020. Data on demographics, vital signs, clinical chemistry parameters, radiology, interventions, and SeptiCyte RAPID were collected and analyzed with bioinformatics methods. The performance of SeptiCyte RAPID for COVID-19 severity assessment and ICU admission was evaluated, relative to the comparator of retrospective clinical assessment by the Hospital del Mar clinical care team. In conclusion, SeptiCyte RAPID was able to stratify COVID-19 cases according to clinical severity: critical vs. mild (AUC = 0.93, p < 0.0001), critical vs. moderate (AUC = 0.77, p = 0.002), severe vs. mild (AUC = 0.85, p = 0.0003), severe vs. moderate (AUC = 0.63, p = 0.05). This discrimination was significantly better (by AUC or p-value) than could be achieved by CRP, lactate, creatine, IL-6, or D-dimer. Some of the critical or severe cases had "early" blood draws (before ICU admission; n = 33). For these cases, when compared to moderate and mild cases not in ICU (n = 37), SeptiCyte RAPID had AUC = 0.78 (p = 0.00012). In conclusion, SeptiCyte RAPID was able to stratify COVID-19 cases according to clinical severity as defined by the WHO COVID-19 Clinical Management Living Guidance of January 25th, 2021. Measurements taken early (before a patient is considered for ICU admission) suggest that high SeptiScores could aid in predicting the need for later ICU admission.

Alterations in leukocyte DNA methylome are associated to immunosuppression in severe clinical phenotypes of septic patients.

Introduction: Sepsis patients experience a complex interplay of host pro- and anti-inflammatory processes which compromise the clinical outcome. Despite considering the latest clinical and scientific research, our comprehension of the immunosuppressive events in septic episodes remains incomplete. Additionally, a lack of data exists regarding the role of epigenetics in modulating immunosuppression, subsequently impacting patient survival. Methods: To advance the current understanding of the mechanisms underlying immunosuppression, in this study we explored the dynamics of DNA methylation using the Infinium Methylation EPIC v1.0 BeadChip Kit in leukocytes from patients suffering from sepsis, septic shock, and critically ill patients as controls, within the first 24 h after admission in the Intensive Care Unit of a tertiary hospital. Results and discussion: Employing two distinct analysis approaches (DMRcate and mCSEA) in comparing septic shock and critically ill patients, we identified 1,256 differentially methylated regions (DMRs) intricately linked to critical immune system pathways. The examination of the top 100 differentially methylated positions (DMPs) between septic shock and critically ill patients facilitated a clear demarcation among the three patient groups. Notably, the top 6,657 DMPs exhibited associations with organ dysfunction and lactate levels. Among the individual genes displaying significant differential methylation, IL10, TREM1, IL1B, and TNFAIP8 emerged with the most pronounced methylation alterations across the diverse patient groups when subjected to DNA bisulfite pyrosequencing analysis. These findings underscore the dynamic nature of DNA methylation profiles, highlighting the most pronounced alterations in patients with septic shock, and revealing their close association with the disease.

Histone Citrullination Mediates a Protective Role in Endothelium and Modulates Inflammation.

NETosis is a key host immune process against a pathogenic infection during innate immune activation, consisting of a neutrophil "explosion" and, consequently, NET formation, containing mainly DNA, histones, and other nuclear proteins. During sepsis, an exacerbated immune host response to an infection occurs, activating the innate immunity and NETosis events, which requires histone H3 citrullination. Our group compared the circulating histone levels with those citrullinated H3 levels in plasma samples of septic patients. In addition, we demonstrated that citrullinated histones were less cytotoxic for endothelial cells than histones without this post-translational modification. Citrullinated histones did not affect cell viability and did not activate oxidative stress. Nevertheless, citrullinated histones induced an inflammatory response, as well as regulatory endothelial mechanisms. Furthermore, septic patients showed elevated levels of circulating citrullinated histone H3, indicating that the histone citrullination is produced during the first stages of sepsis, probably due to the NETosis process.

Comparative Analysis of Complicated Urinary Tract Infections Caused by Extensively Drug-Resistant Pseudomonas aeruginosa and Extended-Spectrum ß-Lactamase-Producing Klebsiella pneumoniae.

The objective was to compare clinical characteristics, outcomes, and economic differences in complicated urinary tract infections (cUTI) caused by extensively drug-resistant Pseudomonas aeruginosa (XDR P. aeruginosa) and extended-spectrum beta-lactamase-producing Klebsiella pneumoniae (ESBL-K. pneumoniae). A retrospective study was conducted at a tertiary care hospital. Patients with XDR P. aeruginosa and ESBL-K. pneumoniae cUTIs were compared. The primary outcome was clinical failure at day 7 and at the end of treatment (EOT). Secondary outcomes: 30- and 90-day mortality, microbiological eradication, and economic cost. Two-hundred and one episodes were included, of which 24.8% were bloodstream infections. Patients with XDR P. aeruginosa cUTI more frequently received inappropriate empirical therapy (p < 0.001). Nephrotoxicity due to antibiotics was only observed in the XDR P. aeruginosa group (26.7%). ESBL-K. pneumoniae cUTI was associated with worse eradication rates, higher recurrence, and higher infection-related readmission. In multivariate analysis, XDR P. aeruginosa was independently associated with clinical failure on day 7 of treatment (OR 4.34, 95% CI 1.71−11.04) but not at EOT, or with mortality. Regarding hospital resource consumption, no significant differences were observed between groups. XDR P. aeruginosa cUTI was associated with worse early clinical cures and more antibiotic side effects than ESBL-K. pneumoniae infections. However, no differences in mortality or in hospitalization costs were observed.

Antibiotic desensitization as a potential tool in antimicrobial stewardship programs: retrospective data analysis and systematic literature review.

OBJECTIVES: Antibiotic allergy labels (AAL) are related to worse therapeutic results. Strategies to improve the management of these patients, such as the implementation of antibiotic desensitization, are essential for Antimicrobial Stewardship Programs (ASP). The aim of our study is to evaluate the efficacy and safety of antibiotic desensitization procedures for the management of patients with AAL. METHODS: A retrospective study from 2015 to 2022 was performed to describe all antibiotic desensitization conducted in our institution, within the framework of ASP. A systematic literature review using electronic databases, such as PubMed, was also done to identify studies describing antibiotic desensitization between 2000 and 2022. RESULTS: Sixteen antibiotic desensitization protocols were carried out in our institution. In fourteen cases, the desensitization was successfully completed, and the antibiotic could be used to treat the infection. In the systematic review, twenty-two studies were included, with a total of 202 desensitization episodes . In 97% of them, the desensitization was completed successfully. No desensitization-related mortality was observed neither in our cohort nor in literature review. CONCLUSIONS: Antibiotic desensitization strategies should be considered a safe and effective tool that can be included in ASP for patients with a high risk of or confirmed allergy to penicillin.

A profile of delafloxacin in the treatment of adults with community-acquired bacterial pneumonia.

INTRODUCTION: Community-acquired bacterial pneumonia (CABP) is the most common infectious cause of hospital admission in adults, and poses a significant clinical and economic burden. At the same time, antimicrobial resistance is increasing worldwide with only a few new antibiotics developed in recent years. Delafloxacin is an anionic fluoroquinolone available in intravenous and oral formulations and with a broad spectrum of activity targeting Gram-positives, including methicillin-resistant Staphylococcus aureus (MRSA), gram-negative organisms, and atypical and anaerobic organisms. It also has a better adverse event profile compared to other fluoroquinolones. AREAS COVERED: This article reviews the current epidemiology of CABP, etiologic agents and current resistance rates, current treatment guidelines, characteristics of delafloxacin (chemistry, microbiology, PK/PD), clinical efficacy and safety in pneumonia and other indications, and regulatory affairs. EXPERT OPINION: Delafloxacin's susceptibility profile against respiratory pathogens, bioequivalent intravenous and oral formulations and favorable safety profile, support its use for the treatment of CABP. It could be useful as empirical treatment in countries with high rates of penicillin-resistant S. pneumoniae and in patients with suspected or documented pneumonia due to MRSA. In post-influenza staphylococcal bacterial pneumonia, MRSA could be also considered an important pathogen.

Comparison of Hospitalized Coronavirus Disease 2019 and Influenza Patients Requiring Supplemental Oxygen in a Cohort Study: Clinical Impact and Resource Consumption.

BACKGROUND: To compare clinical characteristics, outcomes, and resource consumption of patients with coronavirus disease 2019 (COVID-19) and seasonal influenza requiring supplemental oxygen. METHODS: Retrospective cohort study conducted at a tertiary-care hospital. Patients admitted because of seasonal influenza between 2017 and 2019, or with COVID-19 between March and May 2020 requiring supplemental oxygen were compared. Primary outcome: 30-day mortality. Secondary outcomes: 90-day mortality and hospitalization costs. Attempted sample size to detect an 11% difference in mortality was 187 patients per group. RESULTS: COVID-19 cases were younger (median years of age, 67; interquartile range [IQR] 54-78 vs 76 [IQR 64-83]; P < .001) and more frequently overweight, whereas influenza cases had more hypertension, immunosuppression, and chronic heart, respiratory, and renal disease. Compared with influenza, COVID-19 cases had more pneumonia (98% vs 60%, <.001), higher Modified Early Warning Score (MEWS) and CURB-65 (confusion, blood urea nitrogen, respiratory rate, systolic blood pressure, and age >65 years) scores and were more likely to show worse progression on the World Health Organization ordinal scale (33% vs 4%; P < .001). The 30-day mortality rate was higher for COVID-19 than for influenza: 15% vs 5% (P = .001). The median age of nonsurviving cases was 81 (IQR 74-88) and 77.5 (IQR 65-84) (P = .385), respectively. COVID-19 was independently associated with 30-day (hazard ratio [HR], 4.6; 95% confidence interval [CI], 2-10.4) and 90-day (HR, 5.2; 95% CI, 2.4-11.4) mortality. Sensitivity and subgroup analyses, including a subgroup considering only patients with pneumonia, did not show different trends. Regarding resource consumption, COVID-19 patients had longer hospital stays and higher critical care, pharmacy, and complementary test costs. CONCLUSIONS: Although influenza patients were older and had more comorbidities, COVID-19 cases requiring supplemental oxygen on admission had worse clinical and economic outcomes.

Aminoglycoside or Polymyxin Monotherapy for Treating Complicated Urinary Tract Infections Caused by Extensively Drug-Resistant Pseudomonas aeruginosa: A Propensity Score-Adjusted and Matched Cohort Study.

INTRODUCTION: Extensively drug-resistant (XDR) Pseudomonas aeruginosa (PA) infections are difficult to treat. We aimed to compare aminoglycosides or polymyxin monotherapy versus other antibiotic regimens (carbapenems, aztreonam, ceftazidime, cefepime, ceftolozane-tazobactam, or ceftazidime-avibactam) in complicated urinary tract infections (cUTI) caused by XDR-PA. METHODS: Study performed at a tertiary-care hospital from 2010 to 2019. All consecutive adult patients with XDR-PA urine cultures and diagnosed with cUTI were retrospectively reviewed. XDR phenotype was defined according to Magiorakos et al. A propensity score was used as a covariate in multivariate analyses and for matching. Primary outcome was early clinical failure and at end of treatment (EOT). Main secondary outcomes were 30- and 90-day mortality, microbiological clearance, and antibiotic-related side effects. RESULTS: Of the 465 episodes screened, 101 were included, 48% were treated with aminoglycoside or colistin monotherapy. Most XDR-PA were susceptible to colistin (100%) and amikacin (43%). Patients treated with antibiotic regimens other than aminoglycosides or polymyxin monotherapy were more likely to have hematologic malignancy (p < 0.001), higher SOFA score (p = 0.048), and bacteremia (p = 0.003). In multivariate models adjusted by propensity score, aminoglycoside or colistin monotherapy was not associated with worse outcomes. After propensity score matching, 28 episodes in each treatment group were matched. Adjusted ORs (95% CI) for early clinical failure and at EOT with aminoglycosides or polymyxin monotherapy were 0.53 (0.18-1.58) and 1.29 (0.34-4.83), respectively. Aminoglycoside or colistin monotherapy was not associated with higher 30-day (HR 0.93, 95% CI 0.17-5.08) or 90-day mortality (HR 0.68, 95% CI 0.20-2.31), nor with absence of microbiological clearance (OR 0.72, 95% CI 0.33-1.58). No statistically significant differences were found in terms of nephrotoxicity. Clostridioides difficile infection was observed only in the "other antibiotic regimens" group (n = 6, 11.3%). CONCLUSIONS: Aminoglycosides or polymyxin monotherapy showed good efficacy and safety profile in treating cUTI caused by XDR-PA. These results may be useful for antibiotic stewardship activities.

Role of non-coding RNAs as biomarkers of deleterious cardiovascular effects in sepsis.

The mechanisms occurring during sepsis that produce an increased risk of cardiovascular (CV) disease (CVD) are poorly understood. Even less information exists regarding CV dysfunction as a complication of sepsis, particularly for sepsis-induced cardiomyopathy. However, recent research has demonstrated that non-coding RNAs, including microRNAs, long non-coding RNAs, and circular RNAs, play a crucial role in genetic reprogramming, gene regulation, and inflammation during the development of CVD. Here we describe experimental findings showing the importance of non-coding RNAs mediating relevant mechanisms underlying CV dysfunction after sepsis, so contributing to sepsis-induced cardiomyopathy. Importantly, non-coding RNAs are critical novel regulators of CVD risk factors. Thus, they are potential candidates to improve diagnostics and prognosis of sepsis-induced cardiomyopathy and other CVD events occurring after sepsis and set the basis to design novel therapeutic strategies.

Risk Factors for Amoxicillin-Clavulanate Resistance in Community-Onset Urinary Tract Infections Caused by Escherichia coli or Klebsiella pneumoniae: The Role of Prior Exposure to Fluoroquinolones.

BACKGROUND: High rates of amoxicillin-clavulanate (AMC) resistance among Enterobacterales isolated from urinary tract infections (UTIs) were observed in our area. The aim of this study was to identify risk factors associated with AMC resistance in patients with community-onset UTI in emergency departments (EDs). METHODS: A retrospective study was performed of all ED patients with positive urine cultures for Escherichia coli or Klebsiella pneumoniae in a Spanish tertiary-care hospital. RESULTS: 330 urine cultures in all were included: 261 (79.1%) for E. coli and 69 (20.90%) for K. pneumonia. Rates of AMC resistance were 14.94% and 34.78%, respectively. UTI was clinically confirmed in 212 (64.24%) cases. Previous antimicrobial exposure was independently associated with AMC resistance development in E. coli and K. pneumoniae urinary isolates (OR = 2.94, 95% CI = 1.55-5.58). Analyses of infected patients revealed that previous exposure to fluoroquinolones (OR = 3.33, 95% CI = 1.10-10.12, p = 0.034) and to AMC (OR = 5.68, 95% CI = 1.97-16.44, p = 0.001) was significantly associated with isolation of AMC-resistant strains. CONCLUSIONS: Prior antibiotic exposure, particularly to AMC or fluoroquinolones, was the only independent risk factor associated with development of AMC resistance in E. coli and K. pneumoniae urinary isolates from patients attending the ED.

Circular RNAs in Sepsis: Biogenesis, Function, and Clinical Significance.

Sepsis is a life-threatening condition that occurs when the body responds to an infection that damages it is own tissues. The major problem in sepsis is rapid, vital status deterioration in patients, which can progress to septic shock with multiple organ failure if not properly treated. As there are no specific treatments, early diagnosis is mandatory to reduce high mortality. Despite more than 170 different biomarkers being postulated, early sepsis diagnosis and prognosis remain a challenge for clinicians. Recent findings propose that circular RNAs (circRNAs) may play a prominent role in regulating the patients' immune system against different pathogens, including bacteria and viruses. Mounting evidence also suggests that the misregulation of circRNAs is an early event in a wide range of diseases, including sepsis. Despite circRNA levels being altered in sepsis, the specific mechanisms controlling the dysregulation of these noncoding RNAs are not completely elucidated, although many factors are known to affect circRNA biogenesis. Therefore, there is a need to explore the molecular pathways that lead to this disorder. This review describes the role of this new class of regulatory RNAs in sepsis and the feasibility of using circRNAs as diagnostic biomarkers for sepsis, opening up new avenues for circRNA-based medicine.