Objectives To evaluate how UK guidelines for individual health conditions consider coexisting multiple long term conditions and to propose improvements to guideline development processes so that guidelines appropriately account for and consider coexisting multiple long term conditions.Design Analysis and recommendations from review of single condition guidelines.Setting Clinical guidelines developed by the National Institute for Health and Care Excellence (NICE), UK, 1 January 2013 to 31 December 2024.Population 56 clinical guidelines developed by NICE covering a broad range of long term conditions.Main outcome measures The extent to which guideline recommendations consider multiple long term conditions and coexisting conditions, distinguishing between concordant conditions (those affecting the same organ system as the index condition) and discordant conditions (those affecting different systems).Results All but one of the NICE guidelines (n=55, 98%) included some advice on managing the index condition in the presence of coexisting conditions, and 50 (89%) guidelines offered general guidance on tailoring care. Only 11 (20%) guidelines, however, explicitly referred to multiple long term conditions, and none included a dedicated section on multiple long term conditions or how care should be adapted in this context. 19 (34%) guidelines featured sections looking at specific coexisting conditions or coexisting conditions generally. Coverage of coexisting conditions varied widely across categories of conditions, with mental health guidelines dealing with the most coexisting conditions (median 10, interquartile range (IQR) 4.5-14.75) in contrast with guidelines on cancer and eye disease covering the fewest conditions (median 3, 1-4.5; median 3, 2.25-2.75, respectively). Of the 397 possible concordant pairings, 120 (30%) were referenced, whereas of the 3859 possible discordant pairings, 259 (7%) were referenced, indicating greater coverage of same system combinations. Data on the composition of guideline committees showed wide variation in size, disciplinary diversity, inclusion of generalist clinicians (eg, general practitioners, general physicians, or others with no single specialty focus), and public contributors, although lived experience of multiple long term conditions was rarely specified.Conclusions Despite widespread acknowledgement of coexisting or multiple long term conditions, NICE guidelines are predominantly condition specific and offer limited tailored support for the care of multiple long term conditions. Recommendations rarely considered common condition clusters or the cumulative effect of multiple long term conditions. Structured improvements, such as clearer guidance on adapting care, broader cross condition referencing, and more transparent inclusion of lived experience could enhance the relevance and usability of guidelines for clinicians managing patients with multiple long term conditions.

Abstract Background Reliably distinguishing infection from sterile inflammation is a major clinical challenge. Uncertainty can lead to unnecessary courses of antibiotics, fueling antimicrobial resistance and adverse effects. Calprotectin, a biomarker released by activated immune cells, may inform decision-making. Methods This prospective, observational, single-centre study recruited patients with suspected infection who provided blood samples on enrolment from the Emergency Department (ED) and Intensive Care Unit (ICU) of a central London university hospital. A separate longitudinal study with five days’ blood sampling was performed in patients undergoing elective major non-cardiac surgery, in whom infection was adjudicated according to the Standardised Endpoints in Perioperative Medicine (StEP) initiative. Diagnostic adjudication was performed blinded to calprotectin. The primary outcome was the ability of calprotectin to diagnose infection. Secondary outcomes included a comparison to C-reactive protein (CRP). Results 427 patients were included, of whom 186 (44%) were female. Of 245 ED patients, 71 (29%) had active cancer and 56 (23%) were on immunosuppressants. The median calprotectin level in the no-infection group was 1.97 mg/L (IQR 1.02–3.39), compared to 2.76 (IQR 1.65–5.08) mg/L in low-probability infection, 2.63 mg/L (IQR 1.83–5.23) in high-probability infection, and 2.64 mg/L (IQR 1.49–4.45) in patients with confirmed infection. Ordinal regression analysis found no meaningful association between calprotectin levels and infection, or bacterial infection. Logistic regression showed an unadjusted AUC of 0.53 (95%-CI 0.45–0.62) for calprotectin and a binary outcome of infection compared to an AUC of 0.63 (95%-CI 0.55–0.71) for CRP. Similar results were seen in a sensitivity analysis excluding patients with cancer or immunosuppression. In 98 ICU patients, neither calprotectin nor CRP showed a meaningful association with an adjudicated diagnosis of infection or ICU death. In the peri-operative cohort, calprotectin levels remained elevated over 5 days, but with no difference between patients developing or not developing infection. Conclusion Calprotectin showed only limited ability to differentiate infection from inflammation across ED, ICU, and elective surgery patients. Excluding patients with cancer or immunosuppression did not alter the overall findings.

OBJECTIVE:A definition of refractory septic shock is necessary to guide diagnosis, management, prognostication, research, and future guidelines for this most severe form of the disease. We sought to achieve consensus on clinical criteria that would be used to define refractory septic shock. DESIGN:Review of literature, expert panel position statements, and Delphi rounds with an international expert group. SETTING:Consensus was defined as having at least 75% of panellists in agreement or disagreement on the three highest or lowest levels of a 7-point Likert scale or based on responses to single- or multiple-choice questions, respectively. SUBJECTS:A panel of multinational, multiprofessional and multidisciplinary critical care experts assembled by the Society of Critical Care Medicine and the European Society of Intensive Care Medicine (57 invitations and 56 participants). MEASUREMENTS AND MAIN RESULTS:A five-round Delphi process was conducted for consensus and stability. The steering committee proposed 34 statements, and five of them were rejected by panel experts after round 2. Among 29 statements selected from eight domains, consensus was reached for 13. The panel agreed on the need for a comprehensive consensus set of clinical criteria for refractory septic shock. Markers of organ dysfunction (75%, 2 rounds), tissue perfusion (91.1%, 2 rounds) including lactate (94.6%, 2 rounds) and capillary refill time (76.8%, 2 rounds), assessment of fluid-responsiveness after initial resuscitation (92.9%, 5 rounds), and use of vasoactive drugs at norepinephrine equivalents greater than 0.5 µg/kg/min (75.0%, 3 rounds), were selected as clinical criteria of refractory septic shock. The use of critical care ultrasound (CCUS) (92.9%, 3 rounds) was the single diagnostic modality that reached a consensus-based agreement. CONCLUSIONS:A consensus for 13 criteria to frame the definition of refractory septic shock was reached. Refractory septic shock is characterised by persistently elevated lactate concentrations and or prolonged capillary refill time in patients with septic shock who are fluid unresponsive, require a norepinephrine base equivalent dose greater than 0.5 micrograms per kilogram per minute, and undergo CCUS assessment when mixed shock is suspected.

Sepsis is associated with immunosuppression, predisposing patients to secondary infections. Many treatments routinely used for infections have immunomodulatory effects, including antibiotics. We therefore assessed the immunomodulatory effects of beta-lactam antibiotics on monocyte and lymphocyte immunophenotype. Peripheral blood mononuclear cells isolated from Emergency Department patients with bacterial infection were incubated with narrow-spectrum (amoxicillin and cefuroxime) or broad-spectrum (piperacillin-Tazobactam and meropenem) beta-lactam antibiotics at low and high concentrations. We compared the effects of antibiotics with and without an additional stimulus, LPS for 24 h or anti-CD3/CD28 beads for 72 h to evaluate the effect on monocyte and lymphocyte phenotype respectively. Using spectral flow cytometry, we evaluated functional markers associated with immune activation and reproducible phenotypes consistent with sepsis-induced immunosuppression. Beta-lactams, at higher-dose, were associated with increased monocyte CCR2 and decreased CD14 expression. Cefuroxime, meropenem and piperacillin had additional effects, causing a reduced monocyte HLA-DR, NOX-2, CLIP, and NF-κB expression with increased CD80. Beta-lactam exposure was associated with increased CD4+ lymphocyte viability, whilst amoxicillin had additional effects including reduced PD-1 expression and proliferation, and increased IL-7R expression. Changes to immune cell phenotype were minimal in CD8+ lymphocytes, at lower antibiotic doses, or in unstimulated cells. Beta-lactam antibiotics have immunomodulatory effects in vitro, including changes consistent with sepsis-induced immunosuppression at clinically relevant doses. Further work is required to determine the mechanisms underpinning these observations and clinical implications, which may have significant clinical implications on the type and duration of antibiotics administered, and highlight the need for therapeutic antibiotic monitoring.

Studies on the global burden of sepsis confirm its major mortality, morbidity, and societal impact, with 85% of cases and deaths occurring in low-income and middle-income countries. Importantly, these analyses have blurred the boundaries between sepsis, defined as a dysregulated host response to infection causing life-threatening organ dysfunction, and endemic and emerging infectious diseases, such as malaria, leptospirosis, tuberculosis, and gastroenteric illnesses, which often follow clinical trajectories distinct from those of so-called standard sepsis. Framing these disease-specific deaths within the broader context of sepsis highlights the unacceptably high mortality from preventable and treatable endemic infectious diseases in resource-limited settings. However, important differences remain. Sepsis management focuses on early diagnosis, timely intervention, organ support, and, increasingly, patient stratification and precision-targeted therapies. In contrast, endemic and emerging infectious diseases often involve lengthy and complex courses before hospital admission and require disease-specific diagnostic and therapeutic approaches. In this Personal View, we discuss how this conceptual overlap affects estimates of disease burden, interpretation of pathophysiological mechanisms, therapeutic decision making, and the development of precision medicine strategies. We propose applying disease-specific stratification to endemic and emerging infectious diseases to distinguish milder cases from life-threatening forms associated with organ dysfunction (sepsis from an endemic and emerging infectious disease [SEEID]). Early recognition and diagnosis of SEEIDs are essential, and expert disease-specific guidance is urgently needed, particularly given the scarcity of randomised clinical trials evaluating treatment strategies for these conditions.

Critical illness is characterised by activation of the sympathetic nervous system which plays an important adaptive role in maintaining cardiovascular stability and organ perfusion. However, excessive sustained adrenergic stimulation may become maladaptive, contributing to tachyarrhythmias, myocardial injury, immune dysregulation, metabolic derangements, and organ dysfunction. This state-of-the-art review evaluates the role of ß-blocker therapy as a potential strategy to modulate or counteract the adrenergic response in critically ill patients. Current data suggest that their use remains highly context-dependent and controversial. There are established benefits in selected scenarios, including acute myocardial infarction, tachyarrhythmias, hypertensive emergencies, thyroid storm, and prevention of variceal bleeds. In contrast, evidence is limited or conflicting in septic shock, traumatic brain injury, acute heart failure, burns and other critical care syndromes. Concerns include impairment of compensatory cardiovascular responses, reduction of cardiac output, hypotension, and compromised organ perfusion. Furthermore, the safety and efficacy of ß-blockade appear to depend on the type and dose of ß-blocker, patient phenotype, timing of initiation, hemodynamic reserve, and whether therapy represents continuation of chronic treatment, withdrawal and re-initiation, or de novo initiation during acute illness. This review highlights major gaps in knowledge, including the absence of reliable indicators to identify patients most likely to benefit, uncertainty regarding optimal treatment targets and monitoring strategies, and limited randomised evidence in heterogeneous ICU populations. A phenotype-driven, physiology-guided approach that accounts for hemodynamic status, sympathetic spectrum and timing of ß-blocker therapy is likely required to optimise outcomes.

Many intensive care unit patients develop hyperglycaemia, and this is associated with an increased risk of adverse outcomes. Landmark randomised controlled trials (RCTs) suggest the impact of lowering blood glucose to the healthy, age-adjusted fasting range, hereafter called tight glucose control, depends on the accuracy of the glucose control protocol and the nutritional strategy. In the context of early parenteral nutrition, a condition that induces severe, iatrogenic hyperglycaemia, tight glucose control significantly reduced morbidity and mortality compared to tolerating severe hyperglycaemia. In the absence of early parenteral nutrition, hyperglycaemia was less severe; tight glucose control, applied with a computerised protocol that avoided severe hypoglycaemia, did not impact mortality nor the duration of ICU dependency as primary endpoint in a large multicentre RCT, but was associated with a less pronounced benefit on selected morbidity outcomes. Conversely, tight glucose control, using a protocol that considerably increased the risk of severe hypoglycaemic events, concomitantly increased mortality; nevertheless, the cause of excess mortality in this trial remains unproven and other mechanisms may have contributed as well. Altogether, evidence suggests that severe and iatrogenic hyperglycaemia and hypoglycaemia should both be avoided. From a pathophysiologic point of view, tight glucose control may be superior in selected settings if it can be applied with a validated protocol that avoids severe hypoglycaemia. In the absence of such a protocol, the increased risk of severe hypoglycaemia may offset any benefit of preventing hyperglycaemia, and tolerating intermediate blood glucose targets is likely the default setting. In the paper, we suggest specific blood glucose targets that differ according to the clinical context. Future research should aim at strategies that further optimise the quality of blood glucose control and study whether these improve patient-centred outcomes, and investigate whether specific patient populations benefit from individualised targets.

BACKGROUND:The ratio of arterial oxygen partial pressure to fraction of inspired oxygen (PaO2/FiO2, hereafter P/F ratio) is a key component of the Sequential Organ Failure Assessment (SOFA) score. It reflects the severity of hypoxaemic respiratory failure. The ongoing revision of the SOFA score requires data-driven cutoffs for P/F ratio as well as rational criteria for respiratory support. In this study, we aimed to determine the optimal P/F ratio cutoffs for determining respiratory failure categories in the revised SOFA score and examined whether advanced respiratory support should be a prerequisite for the most severe categories. METHODS:We used the database of the intensive care unit of Kuopio University Hospital, Finland, for cutoff derivation and the eICU database, a multicenter U.S. intensive care registry, for external validation. We identified cutoffs most discriminative for hospital mortality using the log-rank statistic test with the Contal and O'Quigley method. In external validation, these cutoffs were compared with those in the current respiratory SOFA score. RESULTS:Optimal cutoffs were identified as follows: P/F ratio > 40 kPa (normal), 30-40 kPa (mild impairment), 20-30 kPa (moderate impairment), 10-20 kPa (severe impairment), and ≤ 10 kPa (critical impairment). These cutoffs resulted in clear separation of the severity categories (chi-square for log-rank statistic 356.9). They outperformed the current respiratory SOFA score cutoffs in the validation cohort (AUROC 0.615, 95% CI 0.607-0.622 vs. AUROC 0.610, 95% CI 0.603-0.618, p < 0.001). Advanced respiratory support was associated with higher mortality, but its inclusion as a prerequisite improved discrimination only in the moderately impaired respiratory function category, not in the severely or critically impaired categories. CONCLUSION:P/F ratio cutoffs using 10 kPa (75 mmHg) intervals were identified to be optimal for distinguishing stages of respiratory failure severity. The impact of respiratory support on P/F ratio-mortality associations suggests the need to calibrate any P/F ratio-based score by support level, but optimal calibration methods require further study. EDITORIAL COMMENT:In this study, the cut-off values for the partial pressure of arterial oxygen to the fraction of inspired oxygen (P/F ratio) were investigated in a large Finnish intensive care database and validated externally with the US intensive care registry. The aim was to support a revision of the cut-off values for the P/F ratio in the Sequential Organ Failure Assessment (SOFA) score. The results showed that incremental changes in the P/F ratio of 10 kPa are better than 13 kPa and emphasize the need for critical assessment of the current SOFA score.

Deeper understanding of the temporal immune response architecture in sepsis may enable effective therapeutic interventions. Here, we investigated longitudinal immune response programs in critically ill patients with sepsis, as compared with elective cardiac surgery patients. Although transcriptomic profiles obtained at four clinical time points between admission and recovery or death showed substantial overlap, pseudotime analysis revealed a trajectory comprising three sepsis temporal immune states (STImS1-3). Weighted gene co-expression network analysis and immunophenotypic and cytokine profiles identified distinct programs associated with each STImS, and corresponding hub genes mapped to putative immunomodulatory targets, including interleukin 6 blockade, iron chelation, and anthracyclines. STImS1 was characterized by the strongest innate immune responses, elevated resistance programs, variable disease tolerance programs, and enrichment of low-resilience features, including mortality-associated signatures. In contrast, STImS3 was enriched for adaptive immune responses. Thus, clinical time and immune response trajectory are partially decoupled in sepsis, illustrating the need to align therapeutic intervention with the temporal immune state in sepsis.

Sepsis-induced immunosuppression is a phenomenon characterized by the development of several changes in immunophenotype which predispose to secondary infections and increased mortality risk. Immunomodulatory therapies have yet to reproducibly demonstrate benefit in large clinical trials. We propose that several changes consistent with an immunosuppressive phenotype in sepsis represent either adaptive changes or epiphenomenon, rather than direct drivers of outcome in infection and sepsis. We therefore conducted a prospective observational study of patients presenting with infections with a spectrum of illness severity, to evaluate canonical features of monocyte and lymphocyte immunosuppression using flow cytometry. Several features consistent with immunosuppression in sepsis are observed in mild infections and non-infectious acute conditions. These features may be better understood as markers along a continuum of illness severity rather than distinct features of critical illness. Monocyte HLA-DR and co-stimulatory molecules (CD80 and CD86), and an increase in soluble PD-L1, discriminate between critically ill patients, patients with mild infection, and patients with non-infectious illness. In contrast, CD4+ and CD8+ lymphocyte phenotype did not discriminate between patient groups. Immunotherapies targeting lymphocyte function may only be effective if simultaneously augmenting monocyte antigen presentation and co-stimulatory pathways. Combination immunotherapy in sepsis requires evaluation.

Therapeutic modulation of sepsis-induced immune dysfunction by targeting lymphocyte dysfunction with recombinant IL-7 (rIL-7) and anti-PD-1 (e.g. nivolumab) has shown promise in preclinical and early clinical studies. Prior to conducting large randomized controlled trials, an in-depth understanding of the changes induced by rIL-7 or nivolumab (and their differences) in patients with sepsis is imperative. We performed a prospective observational cohort study including patients admitted to the intensive care unit with sepsis and characterized their T lymphocyte phenotype using flow cytometry. The ability of T lymphocytes to respond to a stimulus (using anti-CD3/CD28 beads) and the effect of rIL-7 or nivolumab on T lymphocyte immunophenotype ex vivo was assessed. In a cohort of 55 patients, CD4+ and CD8+ T lymphocyte PD-1 was higher and IL-7R lower compared with healthy volunteers. In a subset of 24 intensive care unit patients in whom in-depth immunophenotype was characterized, ex vivo response of lymphocytes to anti-CD3/CD28 beads was reduced compared with healthy volunteers, simultaneously inducing features consistent with immune activation and immunosuppression. rIL-7 was associated with a greater spectrum of changes compared with nivolumab. The response to rIL-7 and nivolumab was influenced by anti-CD3/CD28 bead costimulation. rIL-7 and nivolumab elicited distinct T lymphocyte responses ex vivo, and the changes were influenced by T lymphocyte activation. It needs to be determined if similar changes occur in vivo, which may influence the choice of immunomodulatory therapy in sepsis.

Pragmatic trials test the effectiveness of an intervention within real-life clinical practice, prioritising applicability and generalisability. By contrast, explanatory trials evaluate the efficacy of an intervention under optimal conditions and in well-defined populations, aiming to minimise bias and confounding and to maximise the treatment effect. The majority of large-scale, multicentre academic ICU studies are overall pragmatic in nature but have repeatedly failed to demonstrate outcome differences against control populations. This relates in part to the marked heterogeneity of ICU populations, often with enrolment based on syndromic categories such as sepsis, acute respiratory distress syndrome, shock and acute kidney injury with significant inter-individual biological variability. Any beneficial treatment effects in specific, often unidentified, subsets are diluted or cancelled out by no effect or even harm in others. A second important factor underlying the lack of intervention effect is suboptimal performance of the trials, particularly poor protocol adherence, which undermines the likelihood of showing benefit, particularly when reliant on intention-to-treat analyses. In this article we discuss these issues and provide some suggestions for improvement.

IntroductionReduced monocyte HLA-DR expression, a hallmark of immunosuppression in sepsis, is associated with infectious complications and mortality. Therapeutic strategies, including IFN-γ, have been used to restore monocyte HLA-DR and immune function, but have not consistently improved clinical outcomes. Therefore, we conducted an iterative series of experiments to re-examine the core assumptions and address the key gaps in the current understanding.MethodsWe conducted a prospective cohort study of patients admitted to the intensive care unit (ICU) with sepsis (n = 55, 36% mortality) to characterize the dynamics of monocyte HLA-DR expression and associated functional pathways. Flow cytometry was used to evaluate monocyte phenotype, and lipopolysaccharide (LPS) stimulation was used to assess monocyte functional capacity. We examined canonical monocyte pathways and identified those that were responsive to LPS stimulation and/or modulated by IFN-γ ex vivo. We evaluated monocyte HLA-DR expression in the peripheral blood and inflamed tissues of healthy volunteers following intradermal administration of UV-killed E. coli.ResultsMonocyte HLA-DR expression was significantly lower in patients than in healthy volunteers, particularly in non-survivors. Monocyte phenotypes evolved discordantly over time, some markers trended toward healthy levels, while others diverged, with no consistent distinction between survivors and non-survivors. Intracellular trafficking of membrane HLA-DR on bacterial phagocytosis contributes to the reduced surface HLA-DR expression. Compared to healthy volunteers, monocytes from ICU patients had a significantly lower expression of proteins associated with antigen presentation and co-stimulation, cytokines, phagocytosis, and a blunted response to LPS. IFN-γ increased the levels of proteins involved in antigen presentation, but their expression remained significantly lower than that in healthy controls. Healthy volunteers demonstrated compartment-specific and temporally distinct regulation of monocyte HLA-DR in circulation versus that in inflamed tissue.ConclusionReduced monocyte HLA-DR expression in sepsis reflects broad disruptions across multiple pathways, explaining the limited efficacy of therapeutic interventions. Further insights into the mechanisms governing therapeutic modulation of monocyte HLA-DR and immune function are required to identify patients who are most likely to benefit from intervention.

Sepsis is defined as a dysregulated host response to infection that leads to life-threatening organ dysfunction. The infectious insult triggers a dysregulated immune response that variably activates and suppresses multiple body system functions. Susceptibility to either developing or succumbing to sepsis is influenced by pathogen load and virulence; site of infection; host factors, including genetics, biological variability, comorbidities, immunosuppression, and extremes of age; and a wide range of external influences, such as social deprivation and local environment. Increasing appreciation of the underlying pathobiology has identified differing biological signatures with variable temporal evolution. This variability highlights the requirement to individualise treatment with targeted interventions guided by rapidly accessible biomarkers. Although improved outcomes have been obtained with better prevention, early recognition, and treatment, sepsis is a major cause of global mortality and morbidity. All populations having the benefits currently enjoyed by a privileged few is imperative. This Seminar aims to unravel the complexity of the condition, describing epidemiology and pathophysiology, evolving fundamental shifts, patient management, current challenges, and future developments.

Encephalopathy is a common complication of sepsis, occurring in up to 70