The cohort included children with impaired immune systems and serious infection requiring intensive care. Malignancy was the most common underlying condition, accounting for 56.5% of cases, and 76.1% of the patients had septic shock. Sepsis and septic shock were classified using the 2024 Phoenix Sepsis Score criteria.

The researchers used multivariate analysis to identify factors associated with mortality and receiver operating characteristic curve analysis to assess the score’s ability to distinguish survivors from nonsurvivors. For every one-point increase in the maximum score during the first 24 hours, the adjusted odds of death increased substantially. The study reported an adjusted odds ratio of 8.20 per point, with a 95% confidence interval of 1.35–49.69 and a p-value of 0.022.

This was the strongest independent prognostic association identified in the analysis. The confidence interval was wide, indicating substantial uncertainty around the estimated size of the association, an important limitation given the retrospective design and cohort size of 92 patients. The investigators also explored a Phoenix Sepsis Score threshold of 8 or higher.

These values describe performance in the study population only. The researchers characterized the threshold as exploratory, and their results do not establish that a score of 8 can be applied as a universal clinical rule or that the score itself causes changes in outcomes. The findings support further evaluation of the Phoenix Sepsis Score as a prognostic marker in immunocompromised children with sepsis and septic shock, but external validation is required.

Because the study was retrospective and confined to one pediatric intensive care unit in Thailand, the results do not establish performance in other hospitals, patient populations or healthcare settings. The clearest supported conclusion is that higher maximum Phoenix Sepsis Scores were strongly associated with mortality in this high-risk cohort, while the proposed cutoff of 8 remains an exploratory finding awaiting validation in independent populations.

Subject of Research: Prognostic performance of the Phoenix Sepsis Score in immunocompromised children with sepsis and septic shock

Article Title: Phoenix Sepsis Score as a prognostic tool for mortality in immunocompromised children with sepsis and septic shock: a six-year study from a Thai referral center

Article References: Menorath, P., Niamsanit, S., Nanthavongsa, S., Uppala, R., Sitthikarnkha, P., & Sriruengrat, D. (2026). Phoenix Sepsis Score as a prognostic tool for mortality in immunocompromised children with sepsis and septic shock: a six-year study from a Thai referral center. BMC Infectious Diseases. https://doi.org/10.1186/s12879-026-14456-3

Image Credits: AI Generated

DOI: 10.1186/s12879-026-14456-3

Keywords: Phoenix Sepsis Score, pediatric sepsis, septic shock, immunocompromised children, mortality prediction, prognosis, pediatric intensive care, Thailand, retrospective cohort, risk stratification, Phoenix, Sepsis

The research team, led by Youjia Hao and colleagues in the Department of Critical Care Medicine at Beijing Jishuitan Hospital, Capital Medical University, systematically searched PubMed, EMBASE, Web of Science, and the Cochrane Library from inception to January 2025. They included prospective studies reporting resistin levels in relation to mortality or disease severity in sepsis. After rigorous screening, eighteen studies encompassing 2,197 sepsis patients made it into the final analysis. The review was registered with PROSPERO under CRD42025639277, ensuring methodological transparency from the outset.

Resistin itself has an intriguing biology. Originally named for its proposed role in insulin resistance, the molecule is now recognized as a potent driver of inflammation. Unlike adipose-derived resistin in rodents, human resistin circulates largely from immune cells, and it amplifies the release of tumor necrosis factor and interleukin-6 while promoting endothelial dysfunction. In the context of sepsis, where a dysregulated host response to infection cascades into organ failure, resistin’s rise seems to mirror the intensity of that inflammatory storm.

The meta-analysis quantified this relationship using standardized mean differences, a statistical measure that allows comparison across studies employing different laboratory assays. Resistin levels were significantly higher in non-survivors than in survivors, with a pooled standardized mean difference of 0.83 and a 95 percent confidence interval spanning 0.31 to 1.36. Patients with septic shock, the most severe form of sepsis characterized by profound circulatory collapse, showed even more striking elevations compared to those without shock, with a standardized mean difference of 1.34 and a confidence interval of 0.62 to 2.05. Compared with healthy controls, sepsis patients overall displayed substantially elevated resistin, yielding a standardized mean difference of 1.99 with a confidence interval of 1.63 to 2.35.

When the researchers arranged these findings along the spectrum of disease, a stepwise gradient emerged. Healthy controls occupied the lowest rung, followed by patients with non-shock sepsis, then those with septic shock, and finally non-survivors at the top. This ordered pattern suggests that resistin is not merely a binary flag of infection but a quantitative readout of inflammatory burden, potentially offering clinicians a way to gauge how far along the severity curve a patient sits at the moment of admission.

The team also assessed resistin’s diagnostic accuracy using areas under the receiver operating characteristic curve, a metric that ranges from 0.5, equivalent to random guessing, to 1.0, representing perfect discrimination. The pooled AUC for predicting mortality was 0.68 with a confidence interval of 0.64 to 0.73. In adult patients specifically, the pooled AUC rose to 0.70 with a confidence interval of 0.65 to 0.75. These values indicate moderate discriminatory power, meaning resistin alone cannot reliably sort survivors from non-survivors but may contribute meaningful prognostic information when combined with clinical scoring systems.

However, the analysis was not without caveats. Substantial heterogeneity pervaded the main pooled analyses, reaching an I-squared value of 89 percent, a statistical signal that the included studies varied considerably in their populations, assays, and timing of measurement. The 95 percent prediction intervals for sepsis-related mortality, 28-day mortality, and septic shock all included zero, indicating that the direction of the effect in future studies remains uncertain. Subgroup and meta-regression analyses were conducted to explore potential effect modifiers, but the authors acknowledge that these exploratory tools cannot fully resolve the underlying variability.

The authors conclude that admission resistin levels may be associated with disease severity and adverse outcomes in sepsis, but they are careful to emphasize that clinical utility remains unproven. Their recommendation is unambiguous: large, multicenter prospective studies are needed before resistin can be integrated into routine prognostic assessment. In the interim, the molecule joins a growing list of inflammatory biomarkers, including procalcitonin and interleukin-6, whose prognostic value in sepsis is promising but not yet definitive.

For a condition that kills swiftly and often silently, any tool that sharpens early risk stratification carries enormous clinical weight. Resistin’s stepwise rise across the sepsis spectrum offers a compelling biological narrative, one that aligns with the broader understanding of sepsis as a crescendo of immune dysregulation. Whether this cytokine will earn a place beside lactate and procalcitonin in the emergency department or intensive care unit remains to be seen, but this meta-analysis provides the strongest synthesis to date of its prognostic signal.

The study, published open access under a Creative Commons license, received no specific funding and involved no competing interests. As sepsis continues to challenge clinicians worldwide, biomarkers like resistin represent a frontier where laboratory science meets bedside decision-making, and the coming years of multicenter validation will determine whether this inflammatory messenger becomes a standard component of the sepsis prognostic toolkit.

Subject of Research: The prognostic value of resistin in patients with sepsis: a systematic review and meta-analysis

Article Title: The prognostic value of resistin in patients with sepsis: a systematic review and meta-analysis

Article References: Hao, Y., Bai, Y., Zhang, L., Cui, Z., Liu, C., & Wang, H. (2026). The prognostic value of resistin in patients with sepsis: a systematic review and meta-analysis. BMC Infectious Diseases. https://doi.org/10.1186/s12879-026-14293-4

Image Credits: AI Generated

DOI: 10.1186/s12879-026-14293-4

Keywords: resistin, sepsis, biomarker, meta-analysis, septic shock, mortality, inflammation, BMC Infectious Diseases, prognostic, value, patients, systematic

Sepsis is among the most common and deadliest medical emergencies in the United States, affecting an estimated 1.7 million Americans each year. It arises when the body’s response to an infection turns against its own tissues and organs, triggering a cascade of inflammation that can lead to widespread organ dysfunction. Septic shock represents the most severe form of this syndrome. In these patients, the inflammatory response causes blood vessels to dilate excessively, and blood pressure falls so low that blood and oxygen can no longer reach vital organs such as the brain, kidneys, and heart in sufficient quantities. Without rapid intervention, the result is often multi-organ failure and death. Septic shock contributes to an estimated one in three hospital deaths nationwide, making it one of the most consequential conditions in modern medicine.

The standard approach to septic shock involves two parallel strategies. Clinicians administer antibiotics and control the source of the infection, while simultaneously using medications called vasopressors to constrict blood vessels and raise blood pressure to a level that keeps organs perfused. First-line vasopressors are agents related to adrenaline, such as norepinephrine, which act on receptors that tighten blood vessels and support cardiac output. But when these first-line drugs are not enough, physicians turn to a second agent: vasopressin, a naturally occurring hormone that raises blood pressure through a different mechanism, constricting vessels via vasopressin receptors rather than adrenergic ones. Vasopressin is also, notably, an expensive infusion, and its use consumes significant hospital resources.

What has never been clear is when to add it. Some critical care clinicians begin vasopressin relatively early, as soon as a patient’s blood pressure starts to become difficult to control on norepinephrine alone. Others wait, reserving the drug for patients who require higher doses of the first-line agents before escalation. Both strategies have coexisted in intensive care units around the world, guided by physiological reasoning rather than direct comparative evidence. “For years, clinicians have known what medications to use for septic shock, but there has been little evidence about when to add vasopressin after initial vasopressor therapy,” said Ithan D. Peltan, MD, principal investigator of the study and an Intermountain Health critical care physician and researcher.

The new findings come from the Vasopressin for Septic Shock Pragmatic (VASSPR) Trial, which evaluated the two treatment strategies across 13 Intermountain Health hospitals in Utah and Idaho between February 2024 and July 2025. The trial enrolled 3,959 adults with septic shock, making it one of the largest studies of its kind in the field. Rather than randomizing individual patients, the investigators used a hospital-level design, comparing periods in which hospitals recommended starting vasopressin earlier against periods in which they recommended waiting until a patient’s shock potentially worsened. Researchers then evaluated outcomes over the following 28 days.

The result was striking in its simplicity: no meaningful differences between the groups. Survival, the amount of time patients spent alive and out of the hospital, and other measures of recovery were similar regardless of when vasopressin treatment was initiated. The trial did observe slightly higher rates of cardiogenic shock in the early-treatment group, a finding that may reflect physiological differences in how the two strategies affect the heart, but the researchers determined that this difference had no meaningful impact on patient-centered outcomes such as survival and recovery.

“The question wasn’t whether vasopressin works. We already know it can help raise blood pressure in patients with septic shock. The question is when it should be added to other vasopressors,” Dr. Peltan explained. “This trial directly answers a common bedside question that affects thousands of patients every year: is it safe to wait to see if a patient’s sepsis gets worse before giving them costly infusions they may not need? Our study found that it is.”

The implications extend beyond the specific question of vasopressin timing. Sepsis is a leading cause of intensive care unit admissions and one of the most expensive conditions treated in U.S. hospitals, costing billions of dollars to treat annually. If hospitals can safely adopt a more conservative approach to escalation, waiting to confirm that a patient truly needs a second vasopressor before starting it, the savings in medication costs, infusion equipment, and nursing workload could be substantial, all without compromising patient outcomes. In an era of intense pressure on hospital resources, evidence that supports restraint is a rare and valuable commodity.

“In healthcare, findings that show a treatment doesn’t need to be used earlier are often just as important as findings that support a new therapy,” said Dr. Peltan. “Our study suggests that hospitals can take a more conservative approach, helping deliver effective care while using resources wisely.” Researchers say the findings will help inform future clinical practice guidelines and provide physicians with greater confidence when making treatment decisions for patients with septic shock, replacing habitual variation between institutions with a shared, evidence-based standard.

Beyond its clinical findings, the VASSPR trial is also an example of an important advancement in how health systems conduct research. By embedding large-scale clinical trials within routine patient care, researchers can answer important questions efficiently in real-world settings, enrolling broad patient populations at a fraction of the cost and time required by traditional trials. The infrastructure developed for the study is already being used to launch additional clinical trials within Intermountain Health, designed to address the challenging questions that physicians and nurses encounter daily at the bedside. “Trials like this one have the potential to make meaningful changes and guide us on difficult questions that are hard to answer with traditional clinical trials,” said Dr. Peltan. For the hundreds of thousands of patients who develop septic shock each year, that means the evidence base guiding their care is finally catching up with the urgency of their condition.

Subject of Research: Timing of vasopressin initiation for the treatment of septic shock

Article Title: New study finds escalating treatment earlier for patients with life-threatening septic shock doesn’t improve survival or recovery

Article References: New study finds escalating treatment earlier for patients with life-threatening septic shock doesn’t improve survival or recovery. (n.d.). Original publication

Image Credits: AI Generated

DOI: Not provided

Keywords: septic shock, sepsis, vasopressin, vasopressors, critical care, randomized controlled trial, VASSPR trial, Intermountain Health, JAMA, blood pressure, intensive care, clinical guidelines

The research team, led by Yunfeng Chen and Yunyun Rui of the Department of Ultrasound at Nanjing Gaochun People’s Hospital in China, assembled a cohort of 3,000 patients with acute appendicitis treated between January 2020 and December 2025. The primary cohort of 2,000 patients from Nanjing Gaochun People’s Hospital was split into a training set of 1,400 patients and an internal testing set of 600, while an independent external validation cohort of 1,000 patients was drawn from The Fourth Affiliated Hospital of Soochow University. Roughly six percent of patients across the cohorts developed septic shock, defined according to the Sepsis-3 consensus criteria as sepsis requiring vasopressor therapy to maintain a mean arterial pressure of at least 65 mmHg together with a serum lactate level above 2 mmol/L despite adequate fluid resuscitation. Crucially, the outcome was restricted to shock occurring before surgery or during conservative treatment, so the model predicts the natural progression of the infection rather than complications of the operation itself.

The pathophysiological rationale behind the model is elegant. The transition from a localized appendiceal infection to systemic shock is fundamentally rooted in the breakdown of local anatomical barriers, which triggers a cascade of immune hyperactivation, systemic inflammation, and metabolic decompensation. High-resolution abdominal ultrasound can capture direct morphological evidence of this destructive process: distinct sonographic features of the inflamed appendix can indicate irreversible transmural necrosis, which acts as the primary gateway for massive bacterial and endotoxin translocation into the systemic circulation. The researchers reasoned that combining these local imaging features with systemic immunological profiles derived from blood tests could yield a comprehensive multimodal predictive landscape that no single biomarker could provide.

Technically, the study began with a pool of 35 baseline variables extracted from electronic medical records, spanning demographics, vital signs, detailed appendiceal sonographic morphology, and extensive preoperative laboratory parameters. From the initial blood samples obtained within 24 hours of admission and strictly before surgery, the team mathematically derived four integrated indices designed to quantify the crosstalk between systemic immunity and metabolic nutrition. The Systemic Immune-Inflammation Index, or SII, is calculated by multiplying the peripheral platelet count by the absolute neutrophil count and dividing by the absolute lymphocyte count. The C-Reactive Protein to Albumin Ratio divides the serum CRP concentration by the serum albumin level. The Prognostic Nutritional Index sums the serum albumin level with five times the total peripheral lymphocyte count, and the Glucose-to-Lymphocyte Ratio divides the fasting blood glucose level by the absolute lymphocyte count. Rather than analyzing isolated cell counts, these composite indices reflect the delicate systemic equilibrium among aggressive hyperinflammation, host immune surveillance, and baseline metabolic reserves.

To distill this high-dimensional feature space into a parsimonious model, the researchers applied a two-step feature selection process exclusively within the training cohort. All continuous variables were Z-score standardized, and the Least Absolute Shrinkage and Selection Operator, or LASSO, regression with 10-fold cross-validation was used to address the severe multicollinearity among raw inflammatory markers, whose variance inflation factors exceeded 5 in the initial pool. Subsequent multivariable logistic regression identified six independent predictors: the Systemic Immune-Inflammation Index, the C-Reactive Protein to Albumin Ratio, the Glucose-to-Lymphocyte Ratio, the Prognostic Nutritional Index, periappendiceal fluid, and the sonographic loss of the submucosal echogenic layer. Notably, the final six predictors showed minimal correlation with one another, with a maximum Spearman coefficient of just 0.15 and variance inflation factors all below 2.0, ensuring minimal information redundancy in the optimal model.

Eight supervised machine learning algorithms were then constructed on these six variables, including Random Forest, eXtreme Gradient Boosting, Support Vector Machine, Logistic Regression, Decision Tree, K-Nearest Neighbors, LightGBM, and Naive Bayes. The Random Forest model demonstrated the highest discriminative performance, achieving an area under the receiver operating characteristic curve of 0.914 in the training set. Because septic shock was relatively uncommon, the team applied inverse-frequency class weights during model training and additionally evaluated the area under the precision-recall curve, which was 0.421 in the training cohort, 0.356 in the internal testing cohort, and 0.331 in the external validation cohort, supporting the model’s discriminatory ability after accounting for the low prevalence of the outcome. A sensitivity analysis using a uniform 48-hour prediction horizon yielded consistent discrimination across all three cohorts, with areas under the curve of 0.902, 0.886, and 0.878 respectively.

Validation was rigorous and three-tiered. After the final model was locked, it was applied directly to the internal testing and external validation cohorts without any refitting, feature selection, hyperparameter tuning, or recalibration. Calibration plots closely tracked the ideal 45-degree reference line across all three cohorts, with calibration intercepts near zero and slopes of 1.00, indicating generally good agreement between predicted and observed risks. Decision curve analysis demonstrated that using the model to guide clinical interventions yields a superior net clinical benefit compared to default treat-all or treat-none strategies across a broad spectrum of threshold probabilities. Importantly, the model significantly outperformed conventional clinical scoring systems: in the external validation cohort, the Random Forest achieved an area under the curve of 0.914 compared with 0.671 for qSOFA and 0.575 for the Alvarado score, with DeLong tests confirming the differences were highly significant.

To demystify the black-box nature of the algorithm, the researchers employed the SHapley Additive exPlanations, or SHAP, framework, which provides both a global perspective on feature importance and a local interpretation of individual patient predictions. The SHAP analysis identified the Systemic Immune-Inflammation Index as the paramount contributor to the model, followed by the loss of the submucosal echogenic layer, the C-Reactive Protein to Albumin Ratio, the Glucose-to-Lymphocyte Ratio, and the Prognostic Nutritional Index. Elevated systemic inflammatory indices combined with ultrasound signs of local anatomical destruction significantly increased the predicted probability of shock, while a robust immuno-nutritional status indicated by higher Prognostic Nutritional Index values exerted a substantial protective effect. The authors emphasize that these SHAP values reflect the contribution of predictors to model predictions and do not establish causality or statistical interaction between features.

The immunological interpretation of these findings is compelling. During early sepsis, peripheral neutrophils are massively recruited and activated, releasing reactive oxygen species and forming neutrophil extracellular traps, while platelets act as critical immune effectors by interacting with neutrophils to promote microvascular thrombosis, a hallmark of septic shock pathogenesis. Concurrently, sepsis induces rapid apoptosis of lymphocytes, leading to a state of profound adaptive immunosuppression. An elevated Systemic Immune-Inflammation Index therefore mirrors the lethal combination of hyperinflammation, microcirculatory dysfunction, and immune paralysis. Similarly, the C-Reactive Protein to Albumin Ratio quantifies the acute-phase response against hepatic synthetic function, serving as a sensitive barometer for the intensity of the systemic inflammatory cytokine storm, while an elevated Glucose-to-Lymphocyte Ratio reflects severe stress hyperglycemia coupled with infection-induced lymphopenia.

The sonographic predictors bridge the gap between systemic blood profiles and localized anatomical pathology. The submucosa of the appendix is rich in vascular and lymphatic networks, and the sonographic obliteration of this echogenic layer strongly indicates severe transmural ischemia, purulent micro-abscess formation, and impending or established gangrene. This irreversible structural destruction implies complete failure of the local mucosal barrier, providing a direct anatomical gateway for massive quantities of intestinal flora and endotoxins to translocate into the portal and systemic circulation. Periappendiceal fluid, the second ultrasound feature, similarly reflects local disease severity. The authors caution, however, that the present analysis does not establish a causal pathway, biological interaction, or synergistic effect between these systemic and local features, since formal interaction analyses were not performed.

To facilitate point-of-care clinical translation, the optimized model has been deployed as a publicly accessible web-based dynamic calculator built with the R Shiny package. Clinicians can input individualized patient profiles and obtain a real-time probability of septic shock, and the interface generates a patient-specific SHAP waterfall plot quantitatively detailing the exact contribution of each clinical and sonographic feature to the final prediction. Two representative clinical scenarios illustrate the tool’s capacity for personalized risk stratification: a low-risk patient with a predicted septic shock probability of 2.0 percent and a high-risk patient with a predicted probability of 59.0 percent.

Despite the promising results, several limitations warrant attention. The retrospective design carries a potential risk of selection bias, although strict consecutive enrollment and multicenter validation substantially mitigate this concern. The model relies on baseline parameters obtained strictly upon hospital admission, so the dynamic trajectories of these immune-inflammatory indices over time were not captured, which might provide additional prognostic insights during the initial resuscitation phase. Specialized immunological cytokines such as Interleukin-6 and Tumor Necrosis Factor-alpha were not routinely measured in the emergency setting and were therefore unavailable for inclusion. The limited number of positive events may also have contributed to uncertainty in the performance estimates, particularly in the external validation cohort, where the confidence interval for the Brier score was wider.

The authors conclude that this multicenter study developed and externally validated an interpretable machine learning model for early risk stratification of septic shock in acute appendicitis, and that the publicly accessible calculator may support individualized risk assessment. However, they stress that prospective impact evaluation is required to determine whether its clinical implementation facilitates earlier resuscitation or improves patient outcomes. Future studies incorporating dynamic biomarker monitoring and advanced multi-omics profiling are warranted to further refine this predictive framework. For now, the study stands as a vivid demonstration of how routine blood tests and bedside ultrasound, fused through transparent machine learning, may transform the early triage of a common surgical emergency.

Subject of Research: Machine learning model predicts septic shock in acute appendicitis using immune indices and ultrasound

Article Title: Systemic immune dysregulation and local barrier failure as predictors of septic shock in acute appendicitis: a large-scale multicenter interpretable machine learning study

Article References: Chen, Y., & Rui, Y. (2026). Systemic immune dysregulation and local barrier failure as predictors of septic shock in acute appendicitis: a large-scale multicenter interpretable machine learning study. Frontiers in Cellular and Infection Microbiology, 16, Article 1935756. https://doi.org/10.3389/fcimb.2026.1935756

Image Credits: AI Generated

DOI: 10.3389/fcimb.2026.1935756

Keywords: machine learning, septic shock, acute appendicitis, ultrasound, immune inflammation, predictive medicine, clinical decision support, Systemic, immune, dysregulation, local, barrier

Candida auris is a yeast species first identified in Japan in 2009 and has since spread to dozens of countries, earning a place on public health watchlists because of its unusual combination of traits. Unlike most Candida species, it persists on skin and hospital surfaces for weeks, resists routine disinfection, spreads between patients in intensive care units, and frequently shows reduced susceptibility to the antifungal drugs that clinicians rely on. Compounding the problem, the organism is notoriously difficult to identify in the laboratory: conventional biochemical methods often misidentify it as Candida haemulonii or other related species, which means accurate detection typically requires matrix-assisted laser desorption/ionization time-of-flight mass spectrometry, known as MALDI-TOF MS, or molecular sequencing. Misidentification delays both appropriate treatment and the infection control measures needed to contain outbreaks.

The Palestinian study included 36 patients with laboratory-confirmed C. auris infection treated at the tertiary care hospital. The mean age of the cohort was 54 years, with a standard deviation of 19.9 years, and 69 percent of the patients were female. The overwhelming majority, 89 percent, required intensive care unit admission, and their median ICU stay was strikingly long at 32 days, with an interquartile range of 18 to 58 days. This prolonged critical care exposure reflects both the severity of the underlying illnesses that predispose patients to invasive fungal infection and the persistent, difficult-to-eradicate nature of C. auris itself, which can colonize patients for weeks and complicate every subsequent hospitalization.

The researchers documented the invasive medical devices that characterize this patient population and that serve as classic gateways for fungal entry. Central venous catheters were present in 81 percent of patients, urinary catheters in 75 percent, and mechanical ventilation in 72 percent. These figures align with the international understanding of C. auris as a pathogen that exploits breaches in natural barriers and indwelling hardware in critically ill patients. The anatomical distribution of infection mirrored this device burden: the urinary tract was involved in 56 percent of cases, the respiratory tract in 50 percent, the bloodstream in 33 percent, and wounds in 17 percent, with some patients harboring the organism at multiple sites simultaneously.

The clinical trajectory of these infections was severe. Septic shock, the life-threatening circulatory collapse that represents the most extreme manifestation of sepsis, developed in 89 percent of the cohort. This extraordinary rate underscores how C. auris infection tends to emerge in patients already fighting for their lives, often superimposed on bacterial infections, organ failure, and prolonged ventilatory support. Distinguishing the specific contribution of the fungus to a patient’s deterioration from that of their underlying condition remains one of the central diagnostic challenges in invasive candidiasis, and the high septic shock rate in this cohort illustrates the grim context in which these infections typically declare themselves.

Treatment patterns revealed notable prescribing choices that the authors flag as potential stewardship targets. Definitive antifungal therapy consisted of azoles in 50 percent of patients, amphotericin B in 44 percent, and echinocandins in only 14 percent. This distribution is significant because international treatment guidelines generally recommend echinocandins, such as anidulafungin, caspofungin, or micafungin, as first-line agents for invasive Candida infections, including C. auris, due to their favorable efficacy and safety profile. The comparatively low echinocandin use and the prominent reliance on azoles, a class to which many C. auris strains exhibit reduced susceptibility, raise questions about antifungal stewardship practices, drug availability, cost constraints, and local susceptibility patterns that the authors suggest warrant further investigation.

The central outcome of the study was stark: all-cause in-hospital mortality reached 50 percent. On univariate analysis using Fisher’s exact test, two factors emerged as more frequent among non-survivors. Respiratory tract isolation of C. auris carried a crude odds ratio of 8.2, with a 95 percent confidence interval of 1.4 to 47.3 and a p-value of 0.008, while septic shock was also significantly associated with death, with a p-value of 0.034. The wide confidence interval around the odds ratio reflects the small sample size and the inherent imprecision of estimates drawn from 36 patients. The authors are careful to emphasize that these are exploratory, hypothesis-generating findings and should not be interpreted as independent predictors or causal relationships, since univariate comparisons cannot disentangle confounding factors such as illness severity, mechanical ventilation, or concurrent bacteremia.

From a methodological standpoint, the study followed the Strengthening the Reporting of Observational Studies in Epidemiology, or STROBE, framework and received ethical approval from the An-Najah National University Institutional Review Board, with a waiver of informed consent granted because of the retrospective design and the use of de-identified data. Laboratory confirmation relied on the hospital’s microbiology diagnostics, and susceptibility considerations were framed in terms of minimum inhibitory concentrations as defined by the Clinical and Laboratory Standards Institute. The retrospective cohort design, while efficient for characterizing a rare and recently emerged pathogen, carries limitations including reliance on documentation quality, the absence of a comparison group, and the possibility that some C. auris isolates were colonization rather than true infection, a distinction that even experienced clinicians find difficult in this population.

The significance of this work extends beyond a single institution. C. auris has been reported across the Middle East and globally, but granular clinical data from many regional health systems remain sparse, and this cohort provides a rare quantitative window into how the pathogen behaves in a tertiary hospital serving the Palestinian population. The 50 percent mortality figure sits within, though at the higher end of, the range reported in international literature, where mortality for invasive C. auris infection often falls between 30 and 60 percent depending on the population and the proportion of bloodstream infections. The heavy representation of urinary and respiratory tract isolates in this cohort, rather than predominantly bloodstream infection, may reflect local diagnostic and sampling practices as well as the patient mix.

The authors conclude that prospective, multicenter studies are needed to confirm these observations, define risk factors with adequate statistical power, and inform evidence-based antifungal stewardship and infection control policies in the region. In the meantime, the study delivers a clear message for clinicians and hospital epidemiologists: C. auris is established in this healthcare setting, it strikes patients who are already among the most vulnerable, and survival depends on early laboratory detection, judicious device management, rapid escalation to appropriate antifungal therapy, and rigorous adherence to the contact precautions and environmental disinfection protocols that are the only proven tools for interrupting its transmission within hospitals. As this pathogen continues its global expansion, cohorts like this one from previously underrepresented settings will be essential for building the collective evidence base needed to confront it.

Subject of Research: Clinical characteristics and in-hospital mortality of Candida auris infection in a Palestinian tertiary hospital cohort

Article Title: Candida auris infection in a palestinian tertiary hospital: 36-patient retrospective cohort with high mortality

Article References: Abutaha, M., Hattab, S., dweik, H., Mlitat, A., Najjar, N., Ayesh, B., Taha, A. A., & Sabatin, A. (2026). Candida auris infection in a palestinian tertiary hospital: 36-patient retrospective cohort with high mortality. BMC Infectious Diseases. https://doi.org/10.1186/s12879-026-14648-x

Image Credits: AI Generated

DOI: 10.1186/s12879-026-14648-x

Keywords: Candida auris, fungal infection, antimicrobial resistance, in-hospital mortality, intensive care unit, septic shock, antifungal stewardship, Palestine, retrospective cohort, nosocomial infection, echinocandins, infection control

The core problem is deceptively straightforward. Fluid administration remains a cornerstone of resuscitating circulatory shock, yet only a subset of critically ill patients actually increases their stroke volume after a fluid bolus. For everyone else, the extra volume does nothing for the heart and everything for the wrong places: it pools in the lungs as pulmonary oedema, distends the systemic veins, and quietly damages organs through congestion. The traditional triggers for giving more fluid — hypotension, low urine output, a low central venous pressure — have been repeatedly discredited as predictors of who will benefit. What has emerged instead is a physiology-based framework in which each bolus must be justified twice over: once by evidence that the heart is preload responsive, and once by evidence that the body can absorb the added volume without harm.

Echocardiography occupies a unique position in this framework because it answers several clinically decisive questions within minutes at the bedside. It can identify pericardial tamponade, severe left or right ventricular dysfunction, acute cor pulmonale, major valvular disease, and septic cardiomyopathy. It can estimate whether additional fluid is likely to augment stroke volume, and it can detect signs that a patient is unlikely to tolerate more volume. But the review is emphatic about two caveats. First, a single snapshot is insufficient: echocardiography enables effective haemodynamic monitoring only when assessments are performed serially and frequently, because critically ill patients can deteriorate or improve within hours. Second, in the most severe or haemodynamically complex patients, echocardiography cannot replace continuous cardiac output monitoring, which clinical guidelines still recommend. The two tools are complementary rather than interchangeable — continuous monitors provide high-frequency haemodynamic trends, while echocardiography delivers anatomical and functional information, including valvular regurgitation, right ventricular function, and venous congestion patterns such as the Venous Excess Ultrasound score, that pulse-contour or thermodilution devices simply cannot see.

Static echocardiographic measurements — chamber size, inferior vena cava dimensions, diastolic indices — remain clinically valuable, but mostly because they describe the haemodynamic context rather than predict the effect of a future bolus. A small, hyperdynamic left ventricle may suggest fluid responsiveness, whereas a dilated, poorly contractile ventricle should raise immediate concern about fluid intolerance. The inferior vena cava is the most widely used bedside index because it is rapidly obtainable, yet its behaviour is confounded by spontaneous inspiratory effort, tidal volume, positive end-expiratory pressure, abdominal pressure, obesity, and even probe position. Reported diagnostic performance varies so widely across studies and ventilation conditions that IVC metrics should never be used in isolation to decide on fluid administration. Diastolic indices such as the E/e’ ratio and left atrial size are better understood as markers of filling pressure and fluid tolerance than as predictors of responsiveness — observational studies link an elevated E/e’ to higher left-sided filling pressures and poorer fluid tolerance, but its ability to predict whether stroke volume will rise has never been established in original research.

The real strength of echocardiography in fluid management lies in tracking changes in stroke volume surrogates during a controlled preload-modifying manoeuvre, and the workhorse measurement here is the left ventricular outflow tract velocity-time integral, or LVOT VTI. Pulsed-wave Doppler interrogation of the outflow tract yields a surrogate that can be measured repeatedly at the bedside; although absolute stroke volume calculation requires accurate LVOT diameter measurement, relative changes in VTI are more reproducible for serial decision-making. The technique is not without pitfalls. Subaortic VTI is susceptible to variability in angle correction, sample volume positioning, and signal quality, and small measurement errors can meaningfully distort the calculated change in cardiac output during a responsiveness test. This is formalised through the concept of the least significant change — the smallest change exceeding inherent measurement variability that can be interpreted as a true haemodynamic shift rather than random noise. For transthoracic LVOT VTI, studies estimate the least significant change at roughly 10 to 15 percent, which substantially overlaps with the diagnostic thresholds of around 5 to 10 percent commonly used for the end-expiratory occlusion test and the mini-fluid challenge. Some changes classified as diagnostic by these tests may therefore approach, or even fall within, the measurement noise of the technique itself — a sobering caveat that argues for averaged, repeated measurements and, in selected settings where the expected VTI change is small, for transoesophageal echocardiography with its greater image stability, balanced against its invasiveness.

Against this backdrop, one strategy stands out as the best validated: passive leg raising combined with real-time LVOT VTI measurement. Passive leg raising works by transferring venous blood from the legs and splanchnic circulation to the central compartment, producing a reversible endogenous fluid challenge without administering a single millilitre of intravenous fluid. When paired with real-time VTI monitoring, it achieves a pooled sensitivity of around 85 percent and a specificity of around 91 percent when preload responsiveness is assessed with any cardiac output monitoring technique, and it remains applicable in spontaneously breathing patients, mechanically ventilated patients, and those with arrhythmias — situations where most other dynamic indices fail. The procedural details matter enormously. The manoeuvre should move the patient from semi-recumbent to supine while simultaneously elevating the legs, preferably using the bed mechanism rather than manual lifting, with minimal patient stimulation and real-time capture of the maximal haemodynamic response. The response must be assessed with VTI rather than heart rate or blood pressure, which are insensitive and non-specific markers of preload-induced changes. VTI should be averaged over three to five cardiac cycles in sinus rhythm and up to ten to twelve cycles in arrhythmia. The commonly used threshold is a VTI increase of at least 10 to 12 percent within one minute of leg elevation, though some studies have used 15 percent. Passive leg raising is contraindicated or unreliable in intra-abdominal hypertension, elevated intracranial pressure, and morbid obesity, where the manoeuvre may fail to generate an effective preload challenge.

Two alternatives extend the approach when passive leg raising is impractical. The mini-fluid challenge administers a small bolus of 100 to 150 millilitres while the operator immediately reassesses LVOT VTI, achieving a sensitivity of roughly 82 percent and specificity of 83 percent; its main drawback is that some fluid is still given to non-responders, and repeated testing can cumulatively contribute to overload. The end-expiratory occlusion test, which transiently interrupts the ventilator circuit at end-expiration to increase cardiac preload without delivering fluid, performs even better on paper — sensitivity around 86 percent and specificity around 91 percent — but requires controlled mechanical ventilation without significant spontaneous effort, close bedside coordination, and real-time Doppler acquisition during a short time window. Respiratory variation in LVOT VTI, once a mainstay of ventilated patients, has fared worse: its specificity drops markedly in the largest multicentre cohort compared with earlier small studies, and its usefulness collapses under lung-protective ventilation, arrhythmias, right ventricular dysfunction, or altered thoraco-pulmonary compliance — which is precisely why contemporary practice increasingly favours functional tests over passive respiratory variation alone.

The most consequential conceptual shift in the review is the move from fluid responsiveness to fluid tolerance. A patient may still show a positive preload-responsiveness test while simultaneously exhibiting worsening lung ultrasound B-lines, venous Doppler abnormalities, right ventricular overload, or elevated filling pressures — a coexistence of responsiveness and congestion that identifies exactly the patients in whom the risk-benefit balance of a bolus is most uncertain. The evidence here is still maturing. In preload-responsive, fluid-tolerant patients undergoing cardiac surgery, a substantial proportion developed transient venous congestion within minutes of a fluid bolus, and this congestion was associated with worse renal outcomes; remarkably, it could be predicted before fluid administration by the change in portal vein pulsatility index induced by passive leg raising. Yet other studies temper the concept: one multicentre observational study found that fluid challenge did not worsen venous congestion in most fluid responders, suggesting the coexistence may be less common than often assumed. The review also distinguishes left-sided intolerance, marked by pulmonary congestion, elevated E/e’, and B-lines, from right-sided intolerance, marked by systemic venous congestion, right ventricular dilatation, septal dyskinesia, and VExUS abnormalities — phenotypes that frequently coexist but carry different management implications. Acute right ventricular dilatation signals poor fluid tolerance, whereas chronic enlargement from cor pulmonale may represent an adaptive baseline state, making the time course of ventricular change critical to interpretation.

What does this mean at the bedside? The authors propose a pragmatic sequence: first identify the dominant mechanism of shock and rule out major structural or obstructive causes; second, select the appropriate functional test, with passive leg raising plus LVOT VTI as the default when feasible; third, simultaneously assess fluid tolerance using lung ultrasound, right ventricular findings, filling-pressure surrogates, and venous congestion markers; and finally, re-evaluate after each intervention rather than assuming persistent benefit from repeated boluses. When fluid is inappropriate, alternatives exist — optimising vasopressor dosing, adding inotropic support, or, in carefully selected cases, adjusting positive end-expiratory pressure or lightening sedation, though the latter measures are highly context-dependent and can precipitate patient self-inflicted lung injury or pendelluft in patients with existing lung injury. The framework aligns with a broader movement toward stepwise, personalised fluid management rather than automatic repetition of boluses during shock resuscitation.

The honest bottom line is that physiological appeal has so far outrun outcome evidence. Most studies are single-centre, use heterogeneous populations and thresholds, and rely on surrogate haemodynamic endpoints rather than patient-centred outcomes such as mortality, organ failure, or length of stay. No randomised trial has yet shown that an echocardiography-guided approach to fluid therapy improves these outcomes, and operator skill remains a major determinant of reliability — a limitation that tempers enthusiasm for indiscriminate bedside use and reinforces the need for structured training, ideally aligned with the PRICES consensus statement on critical care echocardiography research. Future priorities include outcome-focused trials, standardised training pathways for Doppler-based measurements, and deeper integration of cardiac, lung, and venous ultrasound so that haemodynamic efficacy and congestion are interpreted together rather than in parallel silos. Until that evidence arrives, the review’s central message stands: echocardiographic findings should inform bedside fluid decisions, not dictate them — and the clinically relevant question is no longer simply whether stroke volume can rise, but whether the expected haemodynamic benefit outweighs the risk of pulmonary or systemic congestion.

Subject of Research: Echocardiography-guided fluid resuscitation and fluid tolerance assessment in critically ill adults

Article Title: Echocardiography-guided fluid resuscitation in critical illness: from fluid responsiveness to fluid tolerance

Article References: Attou, R., Jaafari, A., Mansour, S., El Mallouli, M., Redant, S., Gallerani, A., & Khelifa, H. (2026). Echocardiography-guided fluid resuscitation in critical illness: from fluid responsiveness to fluid tolerance. Frontiers in Anesthesiology, 5, Article 1894770. https://doi.org/10.3389/fanes.2026.1894770

Image Credits: AI Generated

DOI: 10.3389/fanes.2026.1894770

Keywords: echocardiography, fluid resuscitation, fluid responsiveness, fluid tolerance, critical care, passive leg raising, LVOT VTI, venous congestion, septic shock, hemodynamic monitoring, intensive care, lung ultrasound

The patient arrived at the emergency department of the 900th Hospital of the PLA Joint Logistic Support Force in Fuzhou, China, in September 2025 with two days of left-sided abdominal pain, fever of 39 degrees Celsius, and confusion. His blood pressure had collapsed to 76/45 mmHg, his heart raced at 123 beats per minute, and laboratory results revealed a lactate of 5.4 mmol/L — a marker of profound tissue oxygen starvation — alongside a procalcitonin level of 78.34 ng/mL, indicating overwhelming bacterial sepsis. Computed tomography showed free air in the abdominal cavity and fecal ascites, the signature of a ruptured bowel. Surgeons found an 0.8-centimeter perforation on the sigmoid colon and performed an emergency partial colectomy with colostomy.

What followed was a cascade that the case authors, led by Jiewei Liu, Wei Zhang, and Hua Chen, describe as unprecedented. Postoperatively, the man remained in refractory septic shock and received intravenous hydrocortisone at 200 milligrams daily for three days — a standard, guideline-endorsed measure for septic shock that supports blood pressure when fluids and vasopressors fail. He stabilized briefly, was extubated on postoperative day 4, but fever returned the next day. Drainage fluid cultures grew only the bacterium Proteus mirabilis, and a serum 1,3-β-D-glucan test — a common fungal screening assay — came back negative. Based on the suspicion of intra-abdominal candidiasis, a frequent complication after fecal peritonitis, clinicians added micafungin, an echinocandin antifungal.

That choice would prove fatal. Echinocandins, which inhibit fungal cell wall synthesis, have no meaningful activity against Mucorales — the order of molds that includes Rhizopus, Mucor, and Lichtheimia, the causative agents of mucormycosis. For eight days the patient received ineffective antifungal coverage while the infection advanced silently. On postoperative day 10, dark brown fluid began draining from his abdominal tubes, and an emergency second laparotomy revealed the source: a 6.0 by 8.0-centimeter full-thickness rupture on the posterior wall of his stomach and a spleen that had turned ischemic and necrotic. Surgeons removed the entire stomach and spleen, but it was too late.

Histopathology delivered the definitive answer on postoperative day 13. Microscopic examination of the gastric and splenic tissue revealed broad, ribbon-like, aseptate hyphae branching at right angles — the pathognomonic appearance of Mucorales — invading blood vessel walls and triggering thrombosis, the hallmark of angioinvasive mucormycosis. The gastric specimen showed full-thickness hemorrhagic infarction with fungal elements throughout the mucosa, while the spleen exhibited acute inflammation, fungal invasion, and infarction. Liposomal amphotericin B, the gold-standard first-line agent for mucormycosis, was initiated immediately upon diagnosis, but the patient succumbed to refractory shock and systemic capillary leak syndrome the same day.

The most striking finding, however, was what the pathologists did not see. Multiple-level serial sections of the resected sigmoid colon — the original site of perforation — contained no fungal elements whatsoever, a result confirmed independently by two pathologists reviewing all hematoxylin-eosin-stained slides. In classic primary gastrointestinal mucormycosis, ingested spores germinate on injured intestinal mucosa and invade contiguously, so the primary bowel lesion is almost always fungus-laden. Here, the colon was sterile while the stomach and spleen were overrun. The authors conclude that the fungi reached these organs through the bloodstream — a hematogenous dissemination pathway never before documented in comparable visceral perforation cases.

To explain how the fungi selectively colonized the gastric and splenic vasculature, the authors point to the CotH3–GRP78 virulence axis, a molecular interaction well characterized in laboratory and animal studies. Mucorales hyphae express CotH3, a surface adhesin from the CotH family of proteins, which binds GRP78 (glucose-regulated protein 78 kDa), a receptor on the surface of human endothelial cells lining blood vessels. Stress-induced hyperglycemia, lactic acidosis from severe sepsis, and exogenous glucocorticoids each independently upregulate endothelial GRP78 expression. In this patient, all three factors converged within days, potentially creating a transient

The diagnostic delays documented in this case reflect a broader and well-recognized blind spot in the management of postoperative intra-abdominal sepsis. Serum 1,3-β-D-glucan, the fungal biomarker used in this patient, is validated primarily for the detection of invasive Candida and certain mold species, but it is consistently negative in mucormycosis because Mucorales possess cell walls whose glucan content differs structurally from that of the fungi the assay was designed to detect. Peritoneal fungal cultures perform similarly poorly, since Mucorales are fastidious in culture, grow slowly on standard media, and are frequently killed by routine specimen processing. The result is a diagnostic landscape in which a patient can harbor a rapidly advancing angioinvasive mold infection while every routinely ordered test returns reassuringly negative results. The authors argue that this reality should lower the threshold for surgical re-exploration and tissue biopsy in deteriorating postoperative patients, because histopathology remains the only reliably definitive diagnostic modality for intra-abdominal mucormycosis.

The therapeutic pitfall highlighted by the case is equally instructive. Micafungin and the other echinocandins inhibit β-1,3-glucan synthase, an enzyme essential to the cell wall architecture of Candida and Aspergillus species, but Mucorales are intrinsically resistant to this class because their cell wall composition and target enzyme structure differ sufficiently to confer no meaningful susceptibility. Empirical echinocandin coverage is a rational and widely endorsed strategy for patients with fecal peritonitis at risk of candidemia, which makes the eight-day window of ineffective therapy in this case less a failure of individual judgment than a predictable consequence of a common ICU protocol colliding with an uncommon pathogen. The authors emphasize that once mucormycosis enters the differential — particularly in a deteriorating patient with unexplained visceral infarction — the empirical regimen should be escalated promptly to liposomal amphotericin B, the agent with the most established activity against Mucorales, rather than waiting for microbiological or histological confirmation that may arrive too late.

The immunological dimension of the case also merits careful interpretation. The authors are explicit that three days of stress-dose hydrocortisone should be understood as one potential contributing factor within a broader state of sepsis-associated immune dysfunction, not as a standalone cause. Critical illness itself induces profound immune perturbations, including impaired neutrophil chemotaxis and phagocytosis, monocyte deactivation, and lymphocyte exhaustion, and these defects are compounded by the metabolic and hormonal stress of major abdominal surgery. Glucocorticoids add a further layer by suppressing phagocyte function and, as the authors note, upregulating endothelial GRP78 expression, which may enhance the ability of circulating Mucorales spores and hyphal fragments to adhere to and invade blood vessel walls. The convergence of these mechanisms within a matter of days may explain how a previously immunocompetent host became permissive to an infection classically reserved for the chronically immunosuppressed.

The CotH3–GRP78 axis, invoked by the authors to explain the selective pattern of organ involvement, has emerged in recent years as the central molecular paradigm of Mucorales pathogenesis. CotH3 is a surface protein expressed by Rhizopus, Mucor, and related genera that functions as a ligand for GRP78, a host stress-response chaperone normally resident in the endoplasmic reticulum but translocated to the endothelial cell surface under conditions of hyperglycemia, acidosis, iron overload, and glucocorticoid exposure. Binding of CotH3 to endothelial GRP78 triggers invasion of the vessel wall, endocytosis of the fungal element, and subsequent thrombosis, producing the hemorrhagic infarction that characterizes angioinvasive disease. The distribution of GRP78 expression across vascular beds may partly account for the preferential involvement of the gastric and splenic circulation observed in this patient, although the authors present this as a biologically plausible framework rather than a definitively proven mechanism in this specific case.

The hematogenous route of dissemination, confirmed by the complete absence of fungal elements in the resected sigmoid colon, carries important implications for how clinicians conceptualize postoperative fungal sepsis. In classic gastrointestinal mucormycosis, ingested spores colonize injured mucosa and spread contiguously through the bowel wall, so the primary lesion is invariably fungus-laden and the disease tends to remain anatomically localized until late stages. By contrast, a bloodstream route implies that fungal elements seeded distant organs early and silently, potentially before any localizing signs appeared, and that the visible gastric rupture and splenic infarction were downstream consequences of vascular invasion rather than the leading edge of the infection. This distinction matters prognostically, because hematogenous dissemination is associated with a higher fungal burden, more extensive vascular thrombosis, and a narrower window for effective surgical and antifungal intervention.

For clinicians managing postoperative patients with fecal peritonitis, the case suggests several practical considerations. Unexplained deterioration after apparent source control, particularly when accompanied by signs of visceral ischemia such as rising lactate, new organ dysfunction, or dark drainage fluid, should prompt consideration of angioinvasive fungal infection even in the absence of traditional risk factors. Imaging findings of gastric wall thickening or splenic hypoperfusion in this context warrant urgent surgical consultation rather than watchful waiting. And when tissue is obtained, the pathology laboratory should be alerted to the possibility of mucormycosis, since the broad, aseptate, right-angle branching hyphae that define the infection can be distinguished from Aspergillus and other septate molds only by careful morphological assessment. The authors conclude that early re-laparotomy for histopathological biopsy, rather than reliance on negative cultures and biomarkers, is the decisive step in refractory cases of this kind.

Subject of Research: Hematogenous dissemination of Mucorales causing fatal gastric perforation and splenic infarction in an immunocompetent adult after brief stress-dose glucocorticoid therapy

Article Title: Case report: Fatal hematogenous gastrosplenic mucormycosis in an immunocompetent adult following sigmoid perforation, septic shock, and short-term stress glucocorticoids

Article References: Liu, J., Zhang, W., & Chen, H. (2026). Case report: Fatal hematogenous gastrosplenic mucormycosis in an immunocompetent adult following sigmoid perforation, septic shock, and short-term stress glucocorticoids. Frontiers in Fungal Biology, 7, Article 1940494. https://doi.org/10.3389/ffunb.2026.1940494

Image Credits: AI Generated

DOI: 10.3389/ffunb.2026.1940494

Keywords: mucormycosis, Mucorales, gastric perforation, splenic infarction, septic shock, glucocorticoids, liposomal amphotericin B, echinocandins, CotH3, GRP78, immunocompetent host, intra-abdominal sepsis

The research, led by Amr A. Amin of Umm Al-Qura University in Makkah, Saudi Arabia, together with colleagues at Ain-Shams University in Cairo, focused on two single-nucleotide polymorphisms in the IL-10 gene on chromosome 1, designated rs1518111 and rs1554286. Rather than treating each variant in isolation, the team reconstructed how the two SNPs are inherited together as haplotypes and diplotypes—paired combinations of haplotypes on the two copies of chromosome 1. This multilocus approach matters because nearby variants that travel together, a phenomenon known as linkage disequilibrium, can obscure or exaggerate the apparent effect of any single variant when analyzed alone.

The study enrolled consecutive adults meeting the Sepsis-3 criteria in the intensive care units of a tertiary care medical center between August 2023 and September 2025. Blood and 24-hour urine samples were collected within 24 hours of sepsis confirmation, and genotyping was performed using TaqMan allelic discrimination assays with rigorous quality control: blinded laboratory staff, negative controls, and replicate testing of random sample subsets with complete concordance. Of the 492 patients, 84—about 17 percent—progressed to septic shock, defined as persistent hypotension requiring vasopressors to maintain a mean arterial pressure of at least 65 mmHg together with a serum lactate above 2 mmol/L despite adequate fluid resuscitation.

The genetic findings were striking. The two variants showed near-complete linkage disequilibrium, with a D′ of 1.00 and an r² of 0.903, meaning they are almost always inherited as a single block. When the researchers grouped patients by diplotype and adjusted for age, sex, admission white blood cell count, and baseline SOFA score, a clear pattern emerged. Patients homozygous for the variant T-A haplotype carried roughly 6.3-fold higher odds of progressing to septic shock compared with the heterozygous reference configuration, while those homozygous for the wild-type C-G haplotype showed dramatically lower odds—an adjusted odds ratio of 0.28, indicating a strongly protective profile. The allele frequency data underscore the disparity: among patients who developed shock, the minor allele frequency at both loci reached 0.785, compared with roughly 0.3 in patients whose sepsis remained hemodynamically stable.

Crucially, the genetic risk profile was not an abstract statistical construct—it tracked directly with measurable physiology. Homozygous variant carriers at either locus had the highest concentrations of IL-10 in both serum and urine, with median serum levels exceeding 214 pg/mL versus roughly 165 pg/mL in wild-type carriers, and they also exhibited significantly lower systolic and diastolic blood pressures. Heterozygous carriers, by contrast, resembled the wild-type group on both counts, a pattern consistent with a recessive mode of inheritance. Septic shock patients overall showed elevated serum IL-10 (median 193.9 pg/mL versus 169.4 pg/mL) and urinary IL-10 (20.8 versus 17.2 pg/mL) compared with non-shock patients, suggesting a coordinated counter-regulatory immune response spanning both systemic and renal compartments.

The biology behind this pattern is complex and, at first glance, paradoxical. Interleukin-10 is essential for reining in the inflammatory cascade during infection, preventing the collateral tissue destruction caused by unchecked cytokine amplification. But excessive or prolonged IL-10 expression can push patients into immunoparalysis—a state of immune suppression that may heighten susceptibility to secondary infections and mortality. The new findings hint that inherited variation within the IL-10 locus may tilt patients toward one end of this immunological spectrum, predisposing some individuals to an exaggerated anti-inflammatory response that coincides with hemodynamic deterioration. The authors are careful to note that the association between genotype, cytokine levels, and low blood pressure does not establish causation; the cross-sectional cytokine measurements cannot determine whether elevated IL-10 preceded, accompanied, or resulted from the onset of shock.

The team also explored whether these biomarkers could discriminate which patients would deteriorate. Serum IL-10 alone performed best among individual markers, achieving an area under the receiver operating characteristic curve of 0.851; at a threshold of 210 pg/mL it detected 95.2 percent of septic shock cases with 69.6 percent specificity and a negative predictive value of 98.6 percent. A combined clinical-genetic model integrating serum IL-10, admission white blood cell count, and diplotype category pushed the AUC to 0.889 (95 percent confidence interval, 0.820–0.958), with the same high sensitivity and 72.5 percent specificity. Urinary IL-10 and white blood cell count alone were more modest, with AUCs of 0.736 and 0.744 respectively.

Important caveats temper the enthusiasm. The performance estimates were derived and evaluated within the same cohort, without bootstrap correction, cross-validation, or external validation, so they likely represent an optimistic ceiling. The study was also single-center, and allele frequencies and linkage disequilibrium patterns can vary substantially across ancestries—a particular concern given that Middle Eastern populations remain underrepresented in genomic reference resources, a gap the authors cite as motivation for their work. IL-10 was measured at only a single early time point, precluding analysis of cytokine trajectories, and the panel did not include other established inflammatory and perfusion markers such as IL-6, procalcitonin, monocyte HLA-DR, or serial lactate. The authors also observed deviations from Hardy–Weinberg equilibrium within the non-shock reference group, which they interpreted cautiously given that disease-associated cohorts frequently deviate from HWE because of risk-allele enrichment.

Notably, this is not the first time rs1518111 has surfaced in the team’s work. An earlier study, conducted in a completely independent cohort recruited between 2016 and 2018, linked the same variant and paired serum and urinary IL-10 measurements to sepsis-associated acute kidney injury. The recurrence of rs1518111 across two clinically distinct severe-sepsis phenotypes strengthens the rationale for continued investigation, even though the two outcomes are not interchangeable and cannot be assumed to share a common causal pathway.

For now, the message is one of promise rather than prescription. The authors explicitly caution that IL-10 genotyping should not yet be used to guide vasopressor selection or any bedside treatment decisions, and they emphasize that their combined model is hypothesis-generating pending validation in larger, multicenter, multi-ethnic cohorts with serial biomarker measurements and functional studies of the implicated variants. If those efforts succeed, the vision is compelling: a rapid genetic and biochemical fingerprint, obtainable within the first day of ICU admission, that flags which sepsis patients carry the highest risk of circulatory collapse—turning septic shock from a sudden catastrophe into a foreseeable event that clinicians can anticipate, monitor, and perhaps preempt.

Subject of Research: Association of IL-10 gene haplotypes and diplotypes with septic shock susceptibility, cytokine expression, and hemodynamic dysfunction in critically ill patients

Article Title: IL-10 diplotype and septic shock: Genotype–Phenotype associations with hemodynamic dysfunction and IL-10 expression

Article References: Amin, A. A., Althubiti, M., Fatani, S. H., Mufti, A. H., Azher, Z. A., Malibari, G. M., & Bogari, N. M. (2026). IL-10 diplotype and septic shock: Genotype–Phenotype associations with hemodynamic dysfunction and IL-10 expression. Frontiers in Molecular Biosciences, 13, Article 1958117. https://doi.org/10.3389/fmolb.2026.1958117

Image Credits: AI Generated

DOI: 10.3389/fmolb.2026.1958117

Keywords: sepsis, septic shock, interleukin-10, IL-10 gene polymorphisms, haplotype, diplotype, linkage disequilibrium, genetic association study, biomarkers, hemodynamic dysfunction, cytokine expression, critical care

The mechanics of the new study are worth unpacking, because they illustrate both the ingenuity and the limits of modern observational research. The investigators assembled a cohort of patients with septic shock who were all receiving norepinephrine at 0.25 micrograms per kilogram per minute, the lowest norepinephrine dose recommended by the Surviving Sepsis Campaign guidelines, together with vasopressin. They then divided these patients into two groups according to when vasopressin was started relative to that norepinephrine threshold: an ultra-early group of 744 patients in whom vasopressin began within zero to three hours, and an early group of 293 patients in whom it began between three and six hours. After rigorous statistical adjustment, the ultra-early strategy was associated with a five percent absolute reduction in 28-day mortality, with a 95 percent confidence interval spanning minus 6.8 to minus 3.2 percent.

Secondary outcomes reinforced the mortality signal in a biologically coherent way. Patients treated ultra-early needed less renal replacement therapy, accumulated less fluid balance, and experienced fewer medically treated arrhythmias — findings that echo earlier observational and randomized work. Equally important, the researchers found no differences between the two strategies in mesenteric or digital ischemia or in coagulation disorders, addressing one of the principal safety concerns that has historically limited enthusiasm for vasopressin. Because high doses of any vasopressor can compromise blood flow to the gut, fingers, and heart, the absence of excess ischemic complications in the ultra-early group is a reassuring, if preliminary, signal.

Methodologically, the study leaned on a validated statistical framework known as cloning, censoring, and weighting, which attempts to mimic the structure of a randomized trial within observational data. Each eligible patient was duplicated into two artificial clones, one assigned to each treatment strategy, and clones were artificially censored the moment their actual care deviated from the assigned strategy. Inverse-probability-of-censoring weights were then applied to correct the selection bias introduced by that artificial censoring. The authors also conducted subgroup analyses according to lactate level, norepinephrine infusion rate at time zero, use of invasive mechanical ventilation, severity score, and baseline corticosteroid use, and they separately examined patients whose care adhered to international sepsis guidelines. Ultra-early vasopressin was consistently associated with lower mortality across these strata.

Still, the editorialists emphasize that the study should not be read as a head-to-head comparison of ultra-early versus early vasopressin initiation. The investigators defined time zero as the first hour in which norepinephrine infusion reached the 0.25 microgram per kilogram per minute threshold before vasopressin was started, and the time required to reach that threshold almost certainly varied enormously between patients, reflecting profound clinical differences in disease trajectory and resuscitation. The analysis is therefore better understood as an emulation of treatment strategies applied after patients had already reached a specified norepinephrine dose, rather than a true comparison of when vasopressin should first enter the therapeutic sequence.

Deeper limitations temper the enthusiasm. Observational studies, however sophisticated their statistics, cannot fully account for unmeasured confounding, and the timing of a treatment strategy is notoriously difficult to pin down in retrospective data. The authors of the emulation acknowledged that time-varying covariates were included in the censoring model but were not used for post-treatment outcome adjustment, a subtle asymmetry that could bias effect estimates. These caveats do not invalidate the findings, but they explain why Leone and Russell, along with the broader critical care community, remain unwilling to declare vasopressin a mortality-lowering therapy on the strength of observational evidence alone.

The physiological rationale for early vasopressin, however, is compelling and increasingly well understood. In septic shock, profound vasoplegia — the loss of vascular tone — triggers three overlapping compensatory pathways: the sympathetic response, which floods the circulation with norepinephrine acting on alpha-1 and beta-1 adrenergic receptors; the hypothalamic-pituitary vasopressinergic response, which releases vasopressin acting on V1a and V1b receptors, the latter amplifying the corticosteroid response; and the renin-angiotensin system, which generates angiotensin II acting on type 1 receptors. Sepsis simultaneously drives the release of nitric oxide, a potent vasodilator that further undermines vascular tone. Treating this complex, dynamic hemodynamic derangement with norepinephrine alone addresses only the adrenergic component, which is precisely why multimodal vasopressor strategies have gained theoretical and practical appeal.

Multimodal approaches — combining vasopressin with norepinephrine — typically allow lower doses of each individual agent, potentially reducing adverse effects such as organ ischemia and tachyarrhythmias. They may also counteract vascular hyporesponsiveness, a phenomenon in which prolonged exposure to high catecholamine levels decreases the density of adrenergic receptors on vascular smooth muscle membranes, blunting the effectiveness of further norepinephrine escalation. Experimental work assessing the cumulative effect of norepinephrine and vasopressin in isolated blood vessels has demonstrated synergy between the two drugs at low norepinephrine doses, a synergy that attenuates at high norepinephrine doses and under septic shock-like conditions. This dose-dependent interaction provides a mechanistic explanation for why very early vasopressin, introduced before norepinephrine requirements climb, might offer the greatest benefit.

The disconnect between observational promise and randomized trial reality has several plausible explanations, as the editorial outlines. First, randomized trials of vasopressin may have enrolled patients too late in the disease course, missing the window in which early efficacy effects are most pronounced. Second, randomized trials are generally far smaller than observational cohorts, limiting their statistical power to detect modest mortality differences. Third, the restoration of macro-hemodynamic targets in trials may have driven excessive vasopressor dosing, increasing adverse effects and potentially offsetting any survival benefit; a personalized, tissue-perfusion-focused hemodynamic strategy may prove safer and more effective. Finally, 28-day mortality is a challenging primary endpoint because a host of coincident acute and chronic health and treatment variables influence it. Alternative endpoints, such as vasopressor-free days, have been explored — notably in a randomized trial of selepressin, a selective V1a agonist, which failed to improve that composite outcome — and novel intermediate outcomes, including the reduction of patients progressing to refractory septic shock, may offer more sensitive measures of treatment effect in future trials.

Where does this leave clinicians today? The editorial concludes that adjunctive vasopressor use in septic shock has evolved from desperate, last-resort deployment in refractory cases toward ultra-early, multimodal strategies, and the new emulation study reinforces the plausibility that very early vasopressin introduction could reduce mortality. But the accumulating observational evidence, however consistent, does not constitute high-grade evidence sufficient to change practice. Until large, multicenter, robust randomized controlled trials demonstrate both the efficacy and the safety of vasopressin in septic shock — whether initiated ultra-early, early, or later — guidelines will continue to recommend vasopressin only for patients who do not respond adequately to norepinephrine. Future trial designs, the editorialists suggest, could incorporate predictive biomarkers to identify patients most likely to benefit and could test the simultaneous introduction of several vasopressors early in the disease course. For now, the message is one of disciplined patience: a promising signal, a sound physiological foundation, and an urgent need for definitive randomized evidence.

Subject of Research: Timing of adjunctive vasopressin initiation in septic shock

Article Title: Toward very early vasopressin use in septic shock: observational data accumulate but trial evidence still lacking

Article References: Leone, M., & Russell, J. A. (2026). Toward very early vasopressin use in septic shock: observational data accumulate but trial evidence still lacking. Intensive Care Medicine. https://doi.org/10.1007/s00134-026-08640-x

Image Credits: AI Generated

DOI: 10.1007/s00134-026-08640-x

Keywords: septic shock, vasopressin, norepinephrine, target trial emulation, observational study, vasoplegia, Surviving Sepsis Campaign, randomized controlled trials, multimodal vasopressor therapy, critical care, hemodynamics, mortality

The underlying condition, neutropenic septic shock, is among the most feared complications of cancer treatment. Chemotherapy does not distinguish between malignant cells and the rapidly dividing cells of the bone marrow, so it often wipes out neutrophils, the white blood cells that form the body’s first line of defense against bacterial and fungal invasion. When an infection takes hold in a neutropenic child, it can progress with terrifying speed. Bacterial toxins and the resulting inflammatory cascade damage blood vessels, causing them to dilate and leak, while the myocardium itself becomes depressed by circulating inflammatory mediators. Blood pressure falls, organs are starved of oxygen, and despite aggressive fluid resuscitation and escalating doses of vasopressor medications, the circulation may simply refuse to respond. This state, known as refractory septic shock, carries a high mortality risk and historically has been viewed as a relative contraindication to ECMO support.

The hesitation is understandable. VA ECMO involves cannulating large blood vessels, typically the jugular vein and carotid artery in the neck or the femoral vessels in the groin, and diverting blood through an external circuit where a membrane oxygenator removes carbon dioxide and adds oxygen before a pump returns the blood to the arterial system. This provides both cardiac and respiratory support, effectively taking over the work of the failing heart. But the machine requires systemic anticoagulation to prevent clotting in the circuit, and anticoagulation in a patient with no neutrophils, disseminated intravascular coagulation, and fragile bone marrow is a recipe for catastrophic bleeding. Critics have also worried that ECMO cannulation could seed infection in an already septic, immunocompromised patient, and that children with cancer have such poor prognoses that the enormous resource investment is not justified.

The Seoul team challenged those assumptions with a carefully reasoned selection strategy. Their retrospective single-center study included only patients who met three criteria: refractory septic shock that could not be stabilized with conventional therapy, an anticipated potential for hematologic recovery, meaning the bone marrow was expected to rebound and produce neutrophils again, and the absence of uncontrolled malignancy or prior hematopoietic stem cell transplantation. This third criterion is crucial, because it distinguishes between a transient, potentially reversible state of immunosuppression and a permanent or progressive one. Chemotherapy-induced neutropenia, the authors emphasize, is often temporary. If the marrow can be given time, sometimes just a few days, the neutrophil count recovers and the immune system can begin fighting the infection on its own. ECMO, in this framework, is not a cure but a bridge, buying the body time to reach that recovery point.

The four patients in the study had a median age of 13.0 years, and all underwent peripheral VA ECMO cannulation. What makes the outcomes striking is the timing of hematologic recovery relative to extracorporeal support. In every case, neutrophil recovery occurred before, during, or shortly after the ECMO run, confirming that the team’s selection criteria had correctly identified children whose bone marrow was poised to rebound. All four patients were successfully weaned from ECMO after a median support duration of just 5.0 days, a relatively short run that suggests the mechanical support was used precisely as intended, as a temporary bridge across the most dangerous phase of shock rather than a prolonged dependence. Every patient survived to hospital discharge, and none showed neurologic injury, a critical measure in pediatric critical care where hypoxic brain damage is a common and devastating consequence of prolonged circulatory collapse.

The study is equally candid about its complications, and one case in particular carries an important technical lesson. In a single patient, the team attempted to place a distal perfusion catheter, a small cannula inserted downstream of the arterial cannulation site to restore blood flow to the limb on the cannulated side. Peripheral femoral arterial cannulation can compromise perfusion of the leg because the ECMO circuit diverts blood away from the distal vessels. In this patient, the catheter could not be placed at all, because severe vasoconstriction and small-caliber vessels made the procedure technically infeasible. The child subsequently developed severe limb ischemia, the death of tissue deprived of blood flow, and ultimately required amputation. This complication underscores that in septic children, whose vasculature is clamped down by both shock physiology and vasopressor drugs, limb protection strategies must be planned before cannulation, and alternative cannulation sites or techniques should be considered when distal perfusion is not achievable.

Encouragingly, no life-threatening hemorrhagic or neurologic complications were observed in any of the four patients, despite the traditional fears about anticoagulation in this population. The authors attribute this in part to a restrictive anticoagulation strategy, meaning the team deliberately kept heparin dosing and anticoagulation targets conservative, accepting a higher risk of circuit clotting in exchange for a lower risk of bleeding in a patient population already prone to coagulopathy. Modern heparin-bonded circuits and careful monitoring make such strategies increasingly feasible. The combination of peripheral cannulation, restrictive anticoagulation, and strict patient selection appears to have been central to the favorable outcomes, and the authors highlight timely multidisciplinary decision-making as a fourth pillar, bringing pediatric intensivists, hematologists, oncologists, surgeons, and ECMO specialists to the bedside together rather than serially.

The significance of this work lies less in its size than in its proof of concept. Four patients is a small sample, and the retrospective, single-center design means the results cannot be generalized without caution. Centers with different resources, patient mixes, or ECMO volumes might see different outcomes. Nevertheless, the study provides concrete evidence against the reflexive exclusion of neutropenic children from ECMO candidacy. Previous literature has been sparse and largely discouraging, with many centers citing bleeding and infection concerns as reasons to withhold extracorporeal support from immunocompromised patients. By demonstrating that a structured selection process, one that hinges on the reversibility of the neutropenia and the absence of uncontrolled disease, can identify children who not only tolerate ECMO but survive it with good neurologic outcomes, the Seoul group has shifted the conversation from whether to support these patients to how to select and manage them.

The broader implications reach into how pediatric intensive care units approach the immunocompromised child in extremis. As survival from childhood cancer continues to improve, the population of children receiving intensive chemotherapy grows, and with it the number who will encounter life-threatening infections during periods of profound neutropenia. The concept of ECMO as a bridge to hematologic recovery reframes the technology in a way that aligns with modern transplant and oncology practice, where temporary mechanical support is routinely used to bridge patients to recovery or definitive therapy. The key insight is that the neutropenia itself is not the barrier; the barrier is whether the marrow will recover. When clinicians can answer that question with reasonable confidence, the calculus of offering ECMO changes fundamentally.

For now, the authors’ conclusions remain measured. VA ECMO, they write, may be a viable rescue therapy for carefully selected pediatric patients with chemotherapy-induced neutropenic septic shock in whom hematologic recovery is anticipated. The emphasis on careful selection is not hedging but the heart of the finding. The four survivors in this study were chosen precisely because their disease was controlled, their marrow was expected to rebound, and their shock was refractory but not yet irreversible. Larger multicenter studies will be needed to define the optimal timing of cannulation, the best anticoagulation protocols, and the long-term outcomes of these children. But for families and clinicians confronting the bleakest moments of pediatric septic shock, the message from Seoul is one of cautious hope: with the right patient, the right timing, and a disciplined multidisciplinary team, the heart-lung machine can carry a child through the storm until their own immune system returns to fight.

Subject of Research: VA ECMO as rescue therapy for chemotherapy-induced neutropenic septic shock in children

Article Title: Venoarterial extracorporeal membrane oxygenation for chemotherapy-induced neutropenic septic shock in children: a single-center experience

Article References: Lee, W. Y., Lee, K. H., Kang, H. M., Yoo, J. W., Chung, N.-G., & Lee, I. K. (2026). Venoarterial extracorporeal membrane oxygenation for chemotherapy-induced neutropenic septic shock in children: a single-center experience. BMC Pediatrics. https://doi.org/10.1186/s12887-026-07709-2

Image Credits: AI Generated

DOI: 10.1186/s12887-026-07709-2

Keywords: VA ECMO, septic shock, neutropenia, chemotherapy, pediatrics, critical care, extracorporeal membrane oxygenation, refractory shock, limb ischemia, anticoagulation, bone marrow recovery, pediatric intensive care