Sepsis in multimorbidity: a domain-based framework for systemic vulnerability and precision care.

Introduction

Sepsis is a life-threatening condition characterized by a dysregulated inflammatory response to infection, which can progress to multiple organ dysfunction and death ( 1 , 2 ). Its clinical and social relevance has increased in recent decades due to the growing prevalence of chronic comorbidities worldwide, such as diabetes mellitus, heart failure, chronic obstructive pulmonary disease (COPD), and chronic kidney disease ( 1 , 3 , 4 ). These conditions not only predispose individuals to a higher risk of developing sepsis but also complicate its clinical course and increase associated mortality ( 5–7 ).

The infections most frequently leading to sepsis are pneumonia and urinary tract infections. Sociodemographic factors such as advanced age, White race, low educational attainment, limited income, and smoking are also associated with increased incidence of sepsis ( 1 , 2 ).

The underlying pathophysiology can be linked to persistent systemic inflammation and immune dysfunction observed in patients with chronic diseases, which compromise the host’s ability to mount an effective response against infections. Additionally, endothelial dysfunction in vascular diseases facilitates progression toward organ failure, a hallmark of sepsis ( 1 , 2 ).

Chronic diseases substantially increase the risk of sepsis. Among the most strongly associated are chronic lung disease, peripheral artery disease, chronic kidney disease, prior myocardial infarction ( 1 , 8 ), diabetes mellitus, stroke, deep vein thrombosis, coronary artery disease, hypertension, atrial fibrillation, and dyslipidemia ( 1 , 3 , 4 ). The risk rises proportionally with the number of comorbidities present ( 1 ).

These findings underscore the need for interventions aimed at rigorous control of chronic comorbidities and preventive strategies against infections as essential components to reduce the clinical and systemic burden of sepsis ( 1 , 3 , 4 ).

This review seeks to analyze the complex interplay between sepsis and chronic diseases, integrating epidemiological, pathophysiological, and immunological perspectives to provide an updated map of systemic vulnerability. The overarching goal is to elucidate how comorbidities modulate immune responses and clinical trajectories in sepsis, thereby identifying factors that may guide personalized therapeutic interventions.

Sepsis is one of the leading causes of morbidity and mortality worldwide, and its impact is exacerbated by multimorbidity. Metabolic comorbidities such as type 2 diabetes mellitus and obesity; cardiovascular conditions such as heart failure; pulmonary disorders such as COPD; renal diseases such as chronic kidney disease; as well as cancer, HIV, and severe mental illness, substantially influence the incidence, severity, and outcomes of sepsis. These comorbidities condition higher risks of hospitalization, complications, and mortality ( 9 , 10 ). Nosocomial sepsis adds an additional burden, with high incidence in intensive care units (ICUs) and neonatal units and mortality rates exceeding 50% among critically ill patients ( 11–13 ). In parallel, survivors often experience persistent neurological and psychosocial sequelae, highlighting that sepsis is not merely an acute event but also a determinant of long-term vulnerability. This epidemiological landscape demonstrates that multimorbidity amplifies both the risk and the global burden of sepsis and emphasizes the urgent need for integrated strategies of prevention, surveillance, and management tailored to heterogeneous risk profiles ( 14 , 15 ).

Immunological and pathophysiological bases of sepsis in the context of comorbidity

Dysfunctional immune response in sepsis

Sepsis begins when invading microorganisms such as bacteria, viruses, or fungi release pathogen-associated molecular patterns (PAMPs), which are recognized by innate immune receptors, particularly Toll-like receptors (TLRs) expressed on monocytes, macrophages, and dendritic cells. In parallel, tissue injury releases endogenous danger signals (damage-associated molecular patterns, DAMPs), which activate the same signaling pathways ( 6 , 16 , 17 ). This stimulation promotes the translocation of NF-κB into the nucleus, triggering the transcription of proinflammatory genes ( 5–7 , 18 ).

As a result, there is a massive release of proinflammatory cytokines such as IL-1β, TNF- α , and IL-6, together with chemokines that recruit neutrophils to the site of infection ( 5 , 17 ). Under physiological conditions, this response is self-limiting and promotes resolution. In sepsis, however, it becomes dysregulated and persistent, driving systemic inflammation, endothelial dysfunction, and increased capillary permeability, which clinically manifest as hypotension, edema, and multiorgan failure ( 5 , 7 , 16 ).

Neutrophils, as the first effector cells, release neutrophil extracellular traps (NETs), composed of DNA and antimicrobial proteins, that serve to immobilize pathogens. However, excessive NET formation activates coagulation and damages the endothelium, promoting microthrombosis, hypoperfusion, and progressive organ dysfunction ( 5 , 7 , 16 ).

At the same time, there is accelerated depletion of T and B lymphocytes, as well as dendritic cells, through apoptosis. This immunosuppressive phenomenon reduces host defense capacity, favoring secondary infections, viral reactivation, and prolongation of critical illness ( 5 , 7 , 16 , 19 ).

Neurologically, microglial activation and neuroinflammation compromise the integrity of the blood–brain barrier, leading to septic encephalopathy. Clinically, this manifests as delirium, altered consciousness, and, in severe cases, coma ( 20–22 ).

The baseline timing of cytokine surge, peak NETosis/leak, and the subsequent immunosuppressive window is summarized in Figure 1 .

Malnutrition, immunoparalysis, and post-sepsis musculoskeletal vulnerability

To orient disease-specific discussions, Table 1 consolidates how prevalent chronic comorbidities map onto five pathobiological domains—immunity/inflammation, endothelium, barriers/microbiota, neuroaxis, and immunometabolism—and highlights exemplar biomarkers with bedside implications.

Nutritional status has been shown to play a pivotal role in sepsis outcomes. In septic patients admitted to ICUs, the prevalence of malnutrition has been reported as 42.8% when assessed by height indices and 33.3% when assessed by body weight ( 23 ). In ICU-based sepsis studies, 100% of patients evaluated exhibited hypoalbuminemia within the first days of hospitalization, while 93.3% demonstrated zinc deficiency. Additionally, 35% showed severe lymphocytopenia (<500 lymphocytes/mm 3 ) on the first day of admission, a finding consistent with functional immunoparalysis; during clinical evolution, increases in serum zinc levels were accompanied by progressive recovery of lymphocyte counts ( 23–25 ). Similarly, among adults with sepsis, a higher 28-day survival rate was observed in patients who achieved caloric intake above 89% of daily requirements by day 7, and higher levels of HLA-DR expression on monocytes at day 1 were associated with better clinical prognosis. However, malnutrition did not alter mortality in patients with established immunosuppression, defined by low HLA-DR expression ( 25 ).

These findings can be better understood in light of the profound metabolic response triggered by sepsis. The hypermetabolic and catabolic stress response accelerates nutritional deterioration early in the disease course, thereby aggravating immune dysfunction, organ failure, and overall clinical complexity ( 26 , 27 ). Sustained activation of the neuroendocrine stress axis and inflammatory signaling increases energy expenditure, insulin resistance, and preferential protein catabolism, while mitochondrial dysfunction and impaired cellular bioenergetics limit efficient substrate utilization and contribute to organ dysfunction ( 27 , 28 ). In this context, nutritional deterioration is not merely a consequence of reduced intake, but also a manifestation of sepsis-induced immunometabolic reprogramming and anabolic resistance, with activation of proteolytic pathways that promote progressive muscle wasting and negative nitrogen balance ( 28 , 29 ).

Objective nutritional risk has also emerged as an adverse prognostic signal in sepsis. In a large multicenter cohort, moderate and severe malnutrition defined by objective nutritional indices were associated with higher 30-day mortality, and this signal remained evident even among mechanically ventilated patients ( 30 ). However, the benefit of nutritional support is unlikely to depend on calorie delivery alone and should instead be understood within individualized strategies aligned with metabolic phase, illness severity, gastrointestinal tolerance, and recovery potential ( 31 , 32 ). Thus, malnutrition may influence not only acute trajectories but also the pace of physical recovery and long-term vulnerability among survivors ( 31 , 33 , 34 ).

Beyond the acute phase, malnutrition converges with sarcopenia and broader musculoskeletal decline as part of a syndrome of post-sepsis vulnerability. A meta-analysis found that sarcopenia at admission was associated with increased early mortality in sepsis, and this adverse signal persisted after discharge at 3–6 months and at 1 year ( 35 ). Likewise, pre-existing low muscle mass independently predicted worse 1-year outcomes in critically ill patients with sepsis, suggesting that muscle depletion may be more strongly linked to long-term vulnerability than to in-hospital survival alone ( 36 ). An emerging osteometabolic dimension may further shape survivorship trajectories: through an osteoimmunologic framework, systemic inflammation, immobilization, endocrine dysregulation, and altered calcium–vitamin D homeostasis may shift bone remodeling toward resorption while impairing osteoblast activity and skeletal repair ( 37–39 ). Observational data suggests a bidirectional relationship in which lower bone mineral density is associated with increased future risk of infection and sepsis, whereas sepsis itself may increase subsequent risk of osteoporosis and fracture ( 40–42 ). Although this area remains less developed than the evidence on sarcopenia, it reinforces the concept that malnutrition, muscle loss, and bone fragility converge within a common network of systemic vulnerability and deserve greater consideration in longitudinal prognostic assessment and structured post-sepsis follow-up ( 43 , 44 ).

Metabolic and endocrine comorbidities

Diabetes mellitus

Type 2 diabetes mellitus (T2DM) is associated with a significantly higher risk of infection and sepsis, with studies reporting a 2- to 6-fold increased risk compared to non-diabetic individuals ( 14 , 15 ), along with elevated morbidity and mortality rates ( 45–47 ). Increased colonization with resistant pathogens, particularly methicillin-resistant Staphylococcus aureus (MRSA), has been documented. Over a 25-year period, diabetes was present in 17% of hospitalized patients with sepsis and represented the most common comorbidity among those who developed complications and died after a septic episode ( 9 , 10 , 47 ).

From a pathophysiological perspective, T2DM creates an altered immunometabolic environment that promotes sepsis progression. Chronic low-grade inflammation, mediated by IL-6, TNF- α , and IL-1β, activates pathways such as NF-κB and JNK, driving endothelial dysfunction, insulin resistance, and leukocyte trafficking alterations ( 48–50 ). This state translates into an increased risk of acute kidney injury (AKI), secondary to hypoperfusion, endothelial inflammation, and preexisting susceptibility, while the association with acute respiratory distress syndrome (ARDS) remains controversial ( 51 , 52 ).

T2DM also induces specific immunological alterations, including neutrophil dysfunction, humoral immune defects, and abnormal T-cell responses, which reduce antimicrobial efficacy and facilitate severe infections ( 53–55 ). Although colonization with resistant pathogens, particularly MRSA, is more frequent in this group, this finding is considered secondary compared with the overall impact of poor glycemic control ( 10 , 45–47 ). Interestingly, recent studies suggest that chronic exposure to hyperglycemia may generate immune adaptations that, in certain contexts, are associated with lower mortality among septic diabetic patients. However, this observation is preliminary and requires further validation ( 56 , 57 ).

Therapeutically, hypoglycemic agents such as insulin, metformin, and thiazolidinediones have shown, in some studies, a potential to reduce the incidence and mortality of sepsis. Nevertheless, current evidence remains insufficient to establish definitive recommendations regarding their specific use or the optimal glycemic control targets during the septic course ( 48 , 58 ).

Obesity and the obesity paradox

Obesity and its relationship with sepsis represent an area of growing clinical and pathophysiological interest. This highly prevalent condition among critically ill patients has been consistently associated with an increased risk of severe infections and sepsis development ( 59–63 ). The association is not explained solely by adipose tissue mass but also by the immunometabolic dysfunction inherent to obesity and the frequent coexistence of comorbidities such as T2DM, hypertension, cardiovascular disease, and renal failure. However, its impact on sepsis mortality has given rise to a controversial phenomenon known as the “obesity paradox” ( 59 , 60 ).

This paradox refers to the observation that obese patients with sepsis exhibit lower short- and long-term mortality compared with those of normal or low body weight. Although associated with improved survival, this does not necessarily translate into early functional recovery: obese patients often experience longer hospitalizations and, in some cases, prolonged mechanical ventilation or ICU stays, which may reflect extended survival at the cost of higher complication burdens ( 59 , 61 , 62 ).

From a pathophysiological standpoint, several mechanisms have been proposed to explain this differential response. First, the greater energy reserves provided by adipose tissue may offer an adaptive advantage during the hypercatabolic phase of sepsis by sustaining cellular metabolism, nutritional stability, and partial preservation of immune function under prolonged stress. Additionally, obese patients display an attenuated inflammatory response during early sepsis, with lower levels of cytokines such as IL-6 and TNF-α, potentially mitigating the damage induced by the initial inflammatory storm ( 60 , 63 ). Adipose tissue also acts as an immunomodulatory organ, capable of sequestering lipopolysaccharide (LPS) and other bacterial products, thereby buffering their systemic impact ( 64 , 65 ).

Hormonally, adipocytes in obese individuals secrete leptin and adiponectin at elevated concentrations. Leptin plays a central role in immune modulation, activating T lymphocytes (particularly CD4 + T cells) and macrophages, and promoting Th1/Th17-driven inflammatory responses, whereas adiponectin exerts anti-inflammatory effects, attenuating macrophage activation and regulating metabolic homeostasis through pathways involving SIRT1 and AMPK ( 63 , 66 ). Another relevant factor is the hyperactivity of the renin–angiotensin–aldosterone system (RAAS), common in obesity. While RAAS contributes to hypertension, its activation may provide hemodynamic advantages during sepsis, such as more effective responses to endogenous vasoconstrictors and reduced vasopressor requirements, facilitating circulatory stability in critical phases ( 59 , 61 , 62 ).

Nonetheless, this supposed adaptive advantage does not eliminate the clinical risks associated with obesity. Obesity increases susceptibility to more severe and difficult-to-manage infections—particularly of the skin, soft tissues, and surgical sites—due to impaired barrier function, chronic inflammation, and compromised lymphatic drainage. Furthermore, obesity induces significant alterations in the pharmacokinetics and pharmacodynamics of antimicrobials, including increased volume of distribution, altered hepatic metabolism, and modified renal clearance. These changes may reduce therapeutic efficacy and increase the risk of suboptimal exposure or cumulative toxicity ( 67–69 ).

The coexistence of cardiovascular, renal, and metabolic comorbidities, combined with insulin resistance, dyslipidemia, and persistent systemic inflammation, heightens the risk of multiple organ dysfunction and thromboembolic complications. This profile explains why obesity can simultaneously act as a source of adaptive reserve and a driver of organ dysfunction ( 59–63 ).

Therefore, the therapeutic approach to obese patients with sepsis should be individualized and multidisciplinary. It is essential to adjust antimicrobial and sedative dosing, closely monitor cardiovascular and respiratory function, and continuously evaluate nutritional and metabolic status. Early rehabilitation strategies and secondary prevention after recovery from the septic episode should also be prioritized ( 59–63 ).

Building on Figure 1 and Table 2 summarizes how common comorbidities deform key immune and hemostatic trajectories in sepsis (cytokines, NETosis, monocyte HLA-DR, and absolute lymphocytes), linking curves to practical bedside notes.

Cardiovascular comorbidities

Heart failure with reduced ejection fraction (HFrEF)

In patients with sepsis, the coexistence of HFrEF exacerbates cardiovascular dysfunction through converging immunometabolic mechanisms. Sepsis can induce or decompensate heart failure via mitochondrial dysfunction, oxidative stress, cardiomyocyte apoptosis, and sustained systemic inflammation. Recently, a specific gene signature— GNMT, SEMA4B, FURIN, RNASE2, BEX1, and EPHX2 —with an area under the curve (AUC) greater than 0.9 has been identified, characterizing a shared immunopathological response between sepsis and HFrEF. This activation reflects structural injury, impaired myocardial contractility, and persistence of antigenic stimuli, compromising functional reserve under septic stress ( 70 ).

This immunometabolic dysfunction is also mirrored in the downregulation of immune checkpoints such as PD-1 and CTLA-4, observed in both murine models and human cardiac tissue. The loss of immunoregulatory mechanisms facilitates persistent antigenic activation, perpetuating systemic inflammation and directly contributing to myocardial damage. This dysfunctional environment not only compromises cardiac function during the acute septic phase but is also associated with worse long-term outcomes after hospitalization ( 70 ).

Consequently, the 90-day readmission rate after discharge reaches 30.2% in patients with HFrEF, compared with 22.5% in those without heart failure, representing a relative increase of 15% ( 71 , 72 ). This vulnerability extends beyond the acute episode, negatively impacting prognosis, hospital stay, and health-care costs ( 71 , 73 , 74 ), thereby contributing to a substantial clinical and economic burden ( 75 ).

The underlying pathophysiology explains this adverse association: ventricular dysfunction limits the heart’s functional reserve, impairing its ability to adapt to the increased metabolic and fluid demands induced by sepsis ( 71 , 73 , 74 ). In this context, aggressive fluid administration—central to the initial management of septic shock—can precipitate volume overload, exacerbate congestion, and decompensate cardiac function in HFrEF patients ( 75–78 ).

Additional risk arises from the frequent requirement for vasopressors and inotropes to maintain tissue perfusion and blood pressure during septic shock. However, agents such as dopamine have been linked to higher risks of arrhythmias and adverse cardiovascular events, whereas norepinephrine has demonstrated a more favorable profile in terms of efficacy and safety ( 79–82 ). The presence of HFrEF further increases the likelihood of critical complications, including arrhythmias requiring cardioversion, pulmonary edema necessitating ventilatory support, and acute kidney injury requiring renal replacement therapy, either due to hypoperfusion or cardiorenal syndrome ( 79 , 83 , 84 ). In this setting, the chronic use of β -blockers must be carefully evaluated. Current evidence supports their continuation in the absence of acute hemodynamic instability, without associations with higher mortality or clinical deterioration ( 73 ).

Moreover, HFrEF is characterized by immune dysfunction that impairs the inflammatory response and hinders infection control, thereby promoting multiorgan deterioration ( 73 , 75 , 85 ). This convergence of cardiovascular and immune dysfunction defines a high-risk clinical phenotype in which sepsis acts as a trigger for systemic decompensation, marked by persistent hemodynamic instability, susceptibility to nosocomial infections, and poor organ recovery even after resolution of the acute episode ( 73 ).

Cerebrovascular disease and sepsis

Sepsis induces multifactorial neurological dysfunction characterized by ischemic and hemorrhagic cerebrovascular complications, which may occur during both the acute and delayed phases, substantially contributing to morbidity and mortality. A retrospective study analyzing 278 cranial CT scans in critically ill patients with suspected sepsis found that 10.8% presented significant acute cerebral findings. Among these, 7.2% corresponded to major cerebrovascular events, with a predominance of intracranial hemorrhages (80%) over ischemic strokes (20%). In addition, 4.3% showed diffuse parenchymal injury, mainly attributable to post–cardiac arrest hypoxia ( 86 , 87 ).

The frequency of these findings was significantly higher in patients with deep coma (Glasgow ≤8), reaching 13.4%, compared with 4.4% in those with milder neurological compromise. Incidence also varied by clinical setting, being highest among patients from cardiac or nephrology ICUs (16.3%) compared with those from pulmonary (4.9%) or surgical units (6.1%) ( 86 , 87 ).

Sepsis affects the central nervous system through complex pathophysiological mechanisms that extend beyond septic encephalopathy. Generalized endothelial dysfunction, inflammation-induced coagulopathy, cerebral vasoplegia, and impaired autoregulation of perfusion contribute to severe neurological events. At the microvascular level, capillary thrombosis, endothelial leakage, and glial cell activation exacerbate cerebral edema and perpetuate regional hypoperfusion. New-onset atrial fibrillation (AF) during sepsis, observed in up to 25% of critically ill patients, represents an adverse prognostic marker. Its occurrence reflects acute cardiovascular dysfunction, systemic inflammation, and dysregulated neurohumoral activation, particularly in patients with structural heart disease. This state amplifies thromboembolic and neurological risks, warranting careful consideration of the balance between anticoagulation and hemostatic safety, integrating factors such as hepatorenal function, inflammatory status, and hematologic profile ( 86–88 ).

In a retrospective study of patients with septic shock and AF, therapeutic anticoagulation was not associated with a significant reduction in clinically evident strokes or with an increase in major hemorrhages. However, it was linked to reduced in-hospital mortality, possibly due to prevention of subclinical embolic phenomena and modulation of disseminated intravascular coagulation ( 86 , 87 ). Notably, this benefit coexisted with significant declines in hemoglobin levels among anticoagulated patients, necessitating interventions such as transfusions or therapeutic adjustments, reinforcing the need for close monitoring ( 89 , 90 ).

Sepsis is increasingly recognized as a systemic trigger for cerebrovascular events, even in the post-acute period. In a cohort of over 120,000 septic patients, 0.5% experienced stroke within the following year, with associated risk factors including valvular heart disease, heart failure, chronic kidney disease, lymphoma, peripheral vascular disease, pulmonary disorders, and coagulopathy. Each additional point on a composite risk index was associated with a 43% increase in stroke probability, with the highest risk seen in younger patients without prior vascular history ( 89 , 90 ).

This risk extends beyond the immediate post-sepsis period. A meta-analysis including more than 800,000 patients confirmed a robust association between sepsis and higher long-term stroke incidence, particularly among those with comorbidities such as diabetes mellitus, hypertension, and chronic kidney disease. These findings underscore the need for secondary prevention strategies, early neurological screening, and long-term surveillance in sepsis survivors ( 89 , 90 ).

Pulmonary comorbidities

Chronic obstructive pulmonary disease (COPD)

Chronic obstructive pulmonary disease (COPD) is an independent risk factor that increases mortality, complications, and health-care resource utilization in patients with sepsis ( 12 , 91 , 92 ). Large cohort studies have shown that septic patients with COPD have higher 28-day mortality, greater need for invasive and noninvasive ventilation, higher SOFA and APACHE II scores, as well as increased ICU admissions and longer hospital stays ( 12 , 91–93 ).

The link between COPD and sepsis is mediated by a complex interaction among chronic pulmonary inflammation, mucociliary dysfunction, and both local and systemic immune alterations. The innate immune response is impaired in these patients: alveolar macrophage phagocytosis is reduced, neutrophil activity is dysregulated, and antimicrobial peptide production is diminished. These changes facilitate chronic bacterial colonization and heightened susceptibility to invasive infections, particularly by Haemophilus influenzae , Streptococcus pneumoniae , and Pseudomonas aeruginosa ( 12 , 92 , 93 ).

Prolonged corticosteroid use, common in COPD exacerbations, adds an additional layer of immunosuppression and increases the risk of severe respiratory infections and sepsis. This vulnerability is compounded by the frequent coexistence of comorbidities such as heart failure, pulmonary hypertension, and diabetes mellitus, which worsen systemic outcomes ( 12 , 92 , 93 ).

Population-based studies have demonstrated that COPD patients who develop sepsis have significantly higher rates of hospitalization for pneumonia, more frequent recurrence of acute exacerbations, and greater medium-term mortality, even after hospital discharge, compared with COPD patients without sepsis ( 91 , 93 ).

This pathological combination not only intensifies the acute infectious episode but also accelerates long-term respiratory and systemic decline ( 12 , 92 , 93 ). From a pathophysiological perspective, dysregulated inflammation in COPD is amplified during sepsis, with excessive release of proinflammatory cytokines, increased pulmonary capillary permeability, and elevated risk of acute respiratory distress syndrome (ARDS). This inflammatory storm prolongs organ dysfunction, hampers clinical recovery, and increases the risk of ventilatory failure, tracheostomy, and long-term dependence on oxygen or home ventilation ( 91 , 93 ).

Furthermore, chronic hypoxia inherent to COPD can negatively modulate mitochondrial function and the immunometabolic response, thereby exacerbating sepsis-induced immunosuppression. In this setting, infection resolution may be impaired, leading to higher incidence of nosocomial infections and broader-spectrum antibiotic requirements ( 12 , 92 , 93 ).

In COPD patients, sepsis is strongly associated with an increased burden of respiratory and systemic sequelae. Survivors experience higher rates of severe exacerbations, hospitalizations, emergency visits, pneumonia, and severe pneumonia, as well as higher overall mortality. These findings indicate that sepsis represents a clinical inflection point, worsening the natural course of COPD and amplifying post-sepsis disease burden ( 91 , 94 ).

Renal comorbidities

Chronic kidney disease (CKD)

Chronic kidney disease (CKD) is a frequent and highly relevant comorbidity in patients with sepsis, exerting an adverse impact on both short- and long-term outcomes. Sepsis-induced acute kidney injury (AKI) is a common complication, with incomplete recovery in nearly 47% of cases at hospital discharge or within 90 days, thereby accelerating progression to advanced CKD stages, increasing the need for renal replacement therapy (RRT), and elevating mortality ( 95–97 ).

Intermediate and advanced stages of AKI (stages 0C and ≥1) are associated with adjusted hazard ratios of up to 3.25 for major adverse renal events and death, underscoring the importance of stratified assessment of renal injury in the septic context ( 95 , 97 , 98 ).

From a pathophysiological perspective, the septic kidney is exposed to multiple insults: dysregulated systemic inflammation, endothelial dysfunction, heterogeneous hypoperfusion, altered renal microcirculation, and mitochondrial dysmetabolism ( 95 , 99 , 100 ). These mechanisms converge to produce acute tubular injury, cellular apoptosis, and loss of glomerular autoregulation ( 101–103 ), in a scenario characterized by “flow–function dissociation,” where renal blood flow may be preserved or even increased, but effective utilization of oxygen and nutrients remains impaired ( 95 , 97 , 98 ).

In patients with preexisting CKD, reduced renal functional reserve increases vulnerability to septic insult. This is further compounded by baseline proinflammatory status, acid–base disturbances, and mineral–bone abnormalities that impair immune responses and promote multiorgan dysfunction. These patients also display blunted febrile responses, greater bacterial dissemination, and reduced efficacy of antimicrobial therapy ( 95 , 97 , 98 ).

Initial resuscitation strategies in this population demand particular caution with fluid administration: volumes exceeding 27 mL/kg have been linked to longer hospital stays, higher need for mechanical ventilation, hemodynamic complications, and increased costs, without clear benefit in reducing vasopressor use or ICU admission ( 95 , 97 , 98 ). Fluid overload contributes to pulmonary edema, renal venous hypertension, and further glomerular deterioration ( 104 ).

Another challenge lies in scoring systems such as SOFA or qSOFA, which do not adequately adjust for baseline renal function or consider variability in prior glomerular filtration rate, leading to potential underestimation of severity and delays in critical interventions ( 105–107 ).

Accordingly, there is a pressing need to incorporate stratification models that integrate prior renal parameters, tubular injury biomarkers such as NGAL and KIM-1, and dynamic real-time renal monitoring tools ( 95 , 99 , 100 ). Their implementation would allow early identification of CKD patients at risk of progressive deterioration, optimization of nephroprotective measures, improved selection of timing and modality of RRT, and ultimately a reduction in sepsis-related morbidity and mortality ( 105–107 ).

Oncological and HIV comorbidities

Solid and hematologic malignancies

Sepsis is a frequent and critical complication in patients with malignancies and represents one of the leading causes of ICU admission. Up to 20% of critically ill patients have some form of cancer, with a tenfold higher risk of sepsis compared with the general population. Thirty-day mortality in this group remains high—around 40%—although it has declined in recent decades owing to advances in life support and clinical management strategies ( 108–110 ).

Hematologic malignancies such as acute leukemia, non-Hodgkin lymphoma, and multiple myeloma are the most common among septic oncology patients, with a significant proportion presenting with neutropenia at ICU admission. This condition, resulting from either the malignancy itself or chemotherapy, combined with functional defects in neutrophils, severely impairs host defense, hindering infection control and increasing the likelihood of multiple organ failure ( 108–110 ).

The most common infections are pneumonia, followed by abdominal infections, skin and soft tissue infections, and catheter-associated infections. Gram-negative bacilli predominate, with increasing antimicrobial resistance in nosocomial infections, further complicating management ( 108–110 ).

Prognostic factors influencing mortality include renal dysfunction, the severity of organ failure assessed by scores such as SOFA, the need for advanced life support (mechanical ventilation, continuous renal replacement therapy), and reduced adherence to standardized sepsis protocols. Biomarkers such as B-type natriuretic peptide and the neutrophil-to-lymphocyte ratio have demonstrated utility in outcome prediction ( 108–110 ).

Improving survival in this population requires not only effective infection control but also comprehensive care that accounts for tumor activity, functional status, and early definition of goals of care and appropriate levels of support ( 108–110 ).

HIV/AIDS

The introduction of combination antiretroviral therapy (cART) transformed HIV infection into a controllable chronic condition, yet sepsis remains a frequent and life-threatening complication with substantial morbidity and mortality ( 111 , 112 ). The incidence of sepsis reaches up to 1,000 cases per 100,000 people with HIV, compared with 150–300 in the general population. This disparity persists even among patients with undetectable viral loads, due to residual immunosuppression, chronic opportunistic infections, and non-AIDS comorbidities such as COPD, liver disease, chronic kidney disease, and malignancies ( 112–114 ).

Hospital mortality among HIV-positive patients with sepsis is markedly higher, ranging from 55 to 58% at 6 months, compared with 27% in HIV-negative patients, reflecting both the clinical severity and the diagnostic and therapeutic challenges imposed by immune dysfunction ( 114 , 115 ). Precipitating infections include not only common bacterial pathogens (Gram-negative bacilli) but also opportunistic organisms such as Mycobacterium tuberculosis, Pneumocystis jirovecii, Cryptococcus neoformans, and Candida spp., whose atypical presentations may delay diagnosis ( 108 , 112–114 ).

From an immunological standpoint, HIV-positive patients exhibit an altered inflammatory response that directly influences sepsis progression. Classical biomarkers such as C-reactive protein (CRP) and procalcitonin (PCT) tend to be lower than in immunocompetent individuals, potentially masking infection severity. Conversely, persistently elevated interleukin-10 (IL-10)—an anti-inflammatory cytokine—suggests a shift toward a regulatory or tolerogenic immune response, characteristic of “immunoparalysis” observed in late sepsis and advanced immunodeficiency ( 112–114 ).

This immune imbalance translates into more aggressive clinical trajectories, with higher frequency of multiple organ dysfunction, prolonged vasopressor support, mechanical ventilation, and renal replacement therapy. Despite advances in critical care and the availability of cART, sepsis remains an independent predictor of both early and late mortality in HIV patients, even among those with partial immune recovery ( 112–114 ).

Clinical management of sepsis in HIV requires a multidisciplinary approach that integrates general sepsis protocols with immunocompromised-specific considerations. Early recognition, immediate initiation of broad-spectrum antimicrobials covering both common bacterial and opportunistic pathogens, and rational use of diagnostics for coinfections and reactivations are essential. Continuous evaluation of immune status—including viral load, CD4 + count, and latent coinfections—is critical to guiding therapy ( 112–114 ).

A particularly controversial issue is whether to initiate or reintroduce cART during the acute critical phase: while some studies suggest potential benefits from continuation, others warn of the risk of immune reconstitution inflammatory syndrome (IRIS). Currently, no definitive consensus exists ( 112–114 ).

Neuropsychiatric comorbidities

Severe mental illness (SMI)

Patients with severe mental illness (SMI)—including schizophrenia, bipolar disorder, and major depressive disorder—exhibit an unexpected clinical course in the setting of sepsis and septic shock. Although these conditions are generally associated with greater vulnerability and reduced access to health-care services, current evidence suggests lower mortality rates once hospitalized for sepsis compared with the general population without such disorders ( 116 , 117 ).

A meta-analysis evaluating data from more than 2 million patients found substantially lower unadjusted hospital mortality among individuals with SMI, with an odds ratio (OR) of 0.61 (95% CI: 0.58–0.65), corresponding to nearly a 40% relative reduction in the risk of death during hospitalization for sepsis ( 116 , 118 ).

A large multicenter study in France including nearly 188,000 patients diagnosed with septic shock reported lower 90-day mortality in those with SMI. Mortality was 32.2% in schizophrenia versus 45.5% in controls, 32.9% in bipolar disorder versus 45.3, and 41.4% in major depression versus 47.1%. These differences persisted after multivariable adjustment for age, sex, and comorbidities, with adjusted hazard ratios of 0.70 for schizophrenia and bipolar disorder and 0.85 for major depression ( 116–118 ).

In contrast, a Mendelian randomization study suggested that major depression may be modestly associated with increased risk of developing sepsis (OR 1.13; 95% CI: 1.02–1.26), pointing to heightened susceptibility to infection ( 116 , 117 ). However, no significant associations were found between schizophrenia or bipolar disorder and sepsis onset, nor between any of these psychiatric conditions and sepsis-related mortality. These findings reinforce the notion that prior psychiatric history does not necessarily translate into higher risk of death once sepsis is established ( 116–118 ).

Several clinical and biological hypotheses have been proposed to explain this phenomenon. First, SMI patients admitted to ICUs are often younger and, in many cohorts, include a higher proportion of women—factors that may confer biological advantages. In addition, comorbidity profiles and treatment patterns differ significantly. Chronic use of antipsychotics, mood stabilizers, and certain antidepressants may modulate inflammatory and immune pathways. Some psychotropic medications are thought to exert immunomodulatory effects through dopamine, serotonin, and glucocorticoid receptors, thereby altering systemic inflammatory responses ( 116–118 ).

Moreover, atypical immune profiles in individuals with SMI—characterized by chronic glial activation, altered cytokine levels including IL-6, IL-10, and TNF- α , and changes in neuroendocrine signaling—may attenuate the hyperinflammatory response typical of severe sepsis. This could translate into reduced endothelial dysfunction, less cytokine-mediated tissue injury, and greater metabolic adaptability during septic shock, although these mechanisms remain speculative and require experimental validation ( 116–118 ).

Another contributing factor may be earlier recognition and treatment during acute episodes due to frequent contact with health-care services or assisted living facilities, which could enable more timely interventions against severe infections.

Taken together, these findings challenge the traditional paradigm associating SMI with poorer clinical outcomes. In the specific context of sepsis, patients with SMI appear to have a relative survival advantage, suggesting the presence of immunological or pharmacological protective mechanisms that remain incompletely understood ( 116–118 ).

Aggravating clinical contexts

Nosocomial infections and hospital-acquired sepsis

Hospital-acquired sepsis represents a substantial proportion of cases managed in inpatient settings. A meta-analysis of 51 studies estimated that 23.6% of patients with sepsis developed the infection during hospitalization. In ICUs, 24.4% of sepsis episodes with organ dysfunction originated in the hospital, and nearly half (48.7%) were of nosocomial origin ( 119–121 ).

Incidence rates are particularly high: 9.3 cases of hospital-acquired sepsis with organ dysfunction per 1,000 hospitalized patients have been reported, rising to 56.5 per 1,000 in ICUs. In neonatal intensive care units (NICUs), this figure exceeds 250 per 1,000 admissions. Mortality is equally alarming: in ICU-acquired sepsis with organ dysfunction, case fatality rates reach 52.3% ( 119–121 ).

These findings confirm that nosocomial sepsis constitutes a critical public health problem, exerting a disproportionate impact on critically ill patients and neonates. Variability across studies in both incidence and mortality highlights the urgent need to strengthen epidemiological surveillance, standardize clinical and microbiological definitions, and implement sustainable infection prevention and control strategies, with particular emphasis on ICUs and NICUs ( 119–121 ).

Discussion

This review portrays sepsis amid chronic multimorbidity as a systems-level disorder arising from convergent axes of immune dysregulation, endothelial injury, barrier failure, and neuroendocrine maladaptation. The accumulation of chronic conditions—particularly type 2 diabetes mellitus, heart failure, COPD, chronic kidney disease, cerebrovascular disease, obesity, cancer, HIV, and severe mental illness—not only increases the likelihood of developing sepsis but also reshapes its clinical trajectory toward greater organ dysfunction and higher mortality. Mechanistically, a background of low-grade inflammation and impaired innate/adaptive immunity primes the host for an exaggerated early inflammatory surge with microvascular injury and immunothrombotic activity, followed by a phase of pronounced immunosuppression that sustains secondary infections and multi-organ failure. These convergent axes are synthesized in our proposed integrative model ( Figure 2 ).

The marked heterogeneity observed at the bedside reflects shifting contributions of hyperinflammation and immunosuppression across time and across comorbidity profiles, in patterns that mirror the pathobiological domains summarized in Figure 1 . These differences influence tolerance to resuscitation strategies, propensity to specific infection phenotypes, and pharmacokinetic/pharmacodynamic behavior of antimicrobials and sedatives, arguing against uniform protocols. Heart failure constrains fluid and vasoactive choices; obesity modifies antimicrobial distribution, metabolism, and clearance; COPD adds defective alveolar macrophage function and chronic colonization that predispose to severe pneumonia and ARDS; chronic kidney disease introduces flow–function dissociation, venous congestion, and reduced antimicrobial efficacy; and oncology/HIV contexts complicate recognition and timing because neutropenia, opportunistic pathogens, and atypical biomarker patterns (e.g., low CRP/PCT with elevated IL-10) can mask severity. Intriguingly, severe mental illness has been associated with lower adjusted mortality once sepsis is established, a signal that may reflect pharmacologic or neuroimmune modulation and warrants mechanistic clarification within a precision-sepsis framework.

The current evidence base carries important limitations. Much of it derives from observational, hospital-based cohorts that vary in sepsis definitions, organ-dysfunction scoring, and comorbidity ascertainment, limiting causal inference and generalizability. Neutral results from many immunomodulatory trials likely reflect imprecise patient selection and suboptimal timing within biologically heterogeneous populations rather than a lack of therapeutic potential. Standard bedside scores such as SOFA and qSOFA insufficiently adjust for baseline organ function (notably renal reserve) or for comorbidity-specific physiology, which risks misclassification and delayed intervention. These constraints underscore the need for endotyping approaches that integrate clinical features with immune, endothelial, barrier, and organ-specific biomarkers to guide more accurate selection and timing of therapies.

Clinical implications flow directly from this perspective. Moving toward precision management means aligning interventions with mechanism and phenotype—operationalized in Table 3 —by tailoring fluids and vasoactives in patients with limited cardiac or renal reserve; coupling early broad antimicrobial coverage to timely de-escalation, with dose optimization in obesity and chronic kidney disease; and incorporating immune and organ monitoring (e.g., HLA-DR expression or tubular injury biomarkers such as NGAL and KIM-1, where available) to anticipate trajectories. Post-sepsis recovery should likewise be structured with attention not only to cognitive, cardiovascular, respiratory, and renal sequelae, but also to nutritional status, muscle loss, frailty, and emerging osteometabolic vulnerability, all of which may shape long-term functional recovery and survivorship trajectories and are aligned with the patient-specific care pathways outlined in Table 3 .

In parallel, health-system priorities must include the prevention of nosocomial sepsis—especially in ICUs and NICUs, where incidence and mortality remain disproportionate—by strengthening surveillance, standardizing clinical/microbiological definitions, and enforcing sustainable infection-prevention bundles. Family- and patient-engagement programs can improve knowledge, preparedness, and escalation behaviors without materially increasing anxiety, even if effects on mortality are modest; the co-design of multimodal education, peer networks, and structured follow-up offers a scalable route to support recovery and continuity of care ( 122–124 ) ( Table 2 ).

Future work should emphasize prospective, biomarker-informed endotyping; adaptive trials that test mechanism-matched interventions (e.g., immune-restorative strategies in low HLA-DR phenotypes, antithrombotic/anti-NET approaches in microthrombosis-dominant endotypes, decongestive resuscitation in heart-failure/CKD profiles); dose-finding PK/PD studies in obesity and kidney disease; and longitudinal cohorts quantifying post-sepsis neurocognitive and cardiometabolic outcomes by comorbidity profile, alongside evaluation of structured rehabilitation packages. Clarifying the observed survival signal in severe mental illness and the roles of psychotropic agents and neuroimmune pathways may open novel therapeutic avenues.

Activation of five pathobiological domains across ten chronic comorbidities and their contribution to sepsis vulnerability. Across ten prevalent comorbidities, the activation of five domains—immunity, inflammation, endothelium, barriers, and neuroaxis—to depict shared mechanisms that heighten susceptibility to severe infection and organ failure. “Immunity” denotes impaired innate and adaptive responses that blunt pathogen recognition and clearance; “inflammation” reflects persistent signaling (e.g., NF-κB/JAK–STAT) and immunothrombosis; “endothelium” captures loss of vascular integrity, increased permeability, and procoagulant activation; “barriers” refers to epithelial/mucosal disruption, dysbiosis, and tight-junction failure enabling microbial translocation; and “neuroaxis” indicates neuroendocrine/autonomic dysregulation that fosters immunosuppression and hemodynamic instability. Cells shaded green indicate substantial activation of a given domain within the comorbidity, whereas gray denotes minimal or indirect involvement. By consolidating these signals, the matrix offers a concise, clinically oriented view of systemic vulnerability that supports risk stratification and the design of targeted preventive and therapeutic strategies.

Conclusion

Sepsis in the setting of multimorbidity is best characterized as a state of systemic vulnerability arising from convergent axes of immune dysregulation, endothelial injury, barrier failure, and neuroendocrine maladaptation. Common comorbidities—type 2 diabetes and obesity, heart failure and cerebrovascular disease, COPD, chronic kidney disease, cancer and HIV, and severe mental illness—not only increase the incidence of sepsis but reshape its clinical trajectory: an early hyperinflammatory phase with immunothrombosis and microvascular injury is followed by immunoparalysis with secondary infections and multiorgan failure. This framework explains the marked bedside heterogeneity, the disproportionate impact of nosocomial sepsis (particularly in ICUs and NICUs), and the substantial burden of neurocognitive and cardiometabolic sequelae among survivors, underscoring the need for integrated strategies spanning prevention, surveillance, and recovery. At the recovery stage, structured follow-up should also consider nutritional risk, sarcopenia, frailty, and bone health as potentially relevant determinants of long-term prognosis after sepsis.

Clinically, progress toward precision sepsis requires aligning interventions with mechanism and phenotype: titrated resuscitation and vasoactive therapy in patients with limited cardiac or renal reserve; pharmacokinetic/pharmacodynamic optimization of antimicrobials in obesity and chronic kidney disease with timely de-escalation; and immune and organ monitoring (e.g., monocyte HLA-DR, NGAL/KIM-1) to anticipate trajectories. At the health-system level, strengthening bundles for prevention of hospital-acquired sepsis and structuring multidisciplinary post-sepsis follow-up are priorities. Important evidence gaps persist due to heterogeneity of definitions and imprecise patient selection and timing. Prospective endotyping and adaptive trials that test mechanism-matched therapies (anti-NET/antithrombotic strategies for microthrombosis-dominant endotypes, decongestive resuscitation in heart-failure/CKD profiles, immune-restorative approaches in low-HLA-DR phenotypes), together with dose-finding PK/PD studies and longitudinal cohorts quantifying neurocognitive and cardiometabolic outcomes, are needed. Framing sepsis through the lens of multimorbidity is essential to reduce mortality and long-term burden and to enable genuinely personalized care.

Edited by: Baiqiang Li , Nanjing University, China

Reviewed by: Kun Zheng , Peking Union Medical College Hospital (CAMS), China

Wensheng Lu , Guangxi Academy of Medical Sciences and the People’s Hospital of Guangxi Zhuang Autonomous Region, China

Author contributions

JS-T: Data curation, Methodology, Conceptualization, Resources, Validation, Writing – original draft, Investigation, Software. HN-C: Investigation, Resources, Methodology, Validation, Writing – original draft, Data curation, Software. AG-P: Methodology, Investigation, Resources, Software, Formal analysis, Writing – original draft. WO: Software, Formal analysis, Resources, Methodology, Writing – original draft, Investigation. MM: Methodology, Validation, Writing – original draft, Resources, Formal analysis, Investigation. CN: Formal analysis, Data curation, Writing – original draft, Software, Resources, Investigation. DP: Investigation, Resources, Software, Formal analysis, Validation, Writing – original draft. JV: Formal analysis, Resources, Data curation, Writing – original draft, Investigation. LS: Methodology, Formal analysis, Resources, Validation, Data curation, Visualization, Investigation, Software, Writing – original draft. AL-C: Methodology, Visualization, Investigation, Validation, Writing – review & editing. JI-C: Funding acquisition, Writing – review & editing, Project administration, Methodology, Validation, Visualization, Investigation, Conceptualization, Supervision.

Conflict of interest

The author(s) declared that this work was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Generative AI statement

The author(s) declared that Generative AI was not used in the creation of this manuscript.

Any alternative text (alt text) provided alongside figures in this article has been generated by Frontiers with the support of artificial intelligence and reasonable efforts have been made to ensure accuracy, including review by the authors wherever possible. If you identify any issues, please contact us.

Publisher’s note

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

References

1. Wang HE Shapiro NI Griffin R Safford MM Judd S Howard G . Chronic medical conditions and risk of Sepsis . PLoS One . ( 2012 ) 7 : e48307 . doi: 10.1371/journal.pone.0048307 , 23118977 PMC3485139

2. Schoevaerdts D Sibille F-X Gavazzi G . Infections in the older population: what do we know? Aging Clin Exp Res . ( 2021 ) 33 : 689 – 701 . doi: 10.1007/s40520-019-01375-4 , 31656032

3. CDC . Risk Factors for Sepsis . Atlanta, Georgia: Sepsis ; ( 2025 ). Available online at: https://www.cdc.gov/sepsis/risk-factors/index.html (Accessed June 14, 2025).

4. Wang HE Moore JX Donnelly JP Levitan EB Safford MM . Risk of acute coronary heart disease after Sepsis hospitalization in the REasons for geographic and racial differences in stroke (REGARDS) cohort . Clin Infect Dis Off Publ Infect Dis Soc Am . ( 2017 ) 65 : 29 – 36 . doi: 10.1093/cid/cix248 , 28369197 PMC5849104

5. Cao M Wang G Xie J . Immune dysregulation in sepsis: experiences, lessons and perspectives . Cell Death Discov . ( 2023 ) 9 : 465 . doi: 10.1038/s41420-023-01766-7 , 38114466 PMC10730904

6. Giamarellos-Bourboulis EJ Aschenbrenner AC Bauer M Bock C Calandra T Gat-Viks I . The pathophysiology of sepsis and precision-medicine-based immunotherapy . Nat Immunol . ( 2024 ) 25 : 19 – 28 . doi: 10.1038/s41590-023-01660-5 , 38168953

7. Rubio I Osuchowski MF Shankar-Hari M Skirecki T Winkler MS Lachmann G . Current gaps in sepsis immunology: new opportunities for translational research . Lancet Infect Dis . ( 2019 ) 19 : e422 – 36 . doi: 10.1016/S1473-3099(19)30567-5 , 31630991

8. Yende S Iwashyna TJ Angus DC . Interplay between sepsis and chronic health . Trends Mol Med . ( 2014 ) 20 : 234 – 8 . doi: 10.1016/j.molmed.2014.02.005 , 24636941 PMC4016696

9. Delano MJ Ward PA . The immune system’s role in sepsis progression, resolution, and long-term outcome . Immunol Rev . ( 2016 ) 274 : 330 – 53 . doi: 10.1111/imr.12499 27782333 PMC5111634

10. Frydrych LM Fattahi F He K Ward PA Delano MJ . Diabetes and Sepsis: risk, recurrence, and ruination . Front Endocrinol . ( 2017 ) 8 : 271 . doi: 10.3389/fendo.2017.00271 , 29163354 PMC5670360

11. Zaragoza R Ramírez P López-Pueyo MJ . Nosocomial infections in intensive care units . Enferm Infecc Microbiol Clin . ( 2014 ) 32 : 320 – 7 . doi: 10.1016/j.eimc.2014.02.006 , 24661994

12. La Via L Sangiorgio G Stefani S Marino A Nunnari G Cocuzza S . The global burden of sepsis and septic shock . Epidemiologia (Basel) . ( 2024 ) 5 : 456 – 78 . doi: 10.3390/epidemiologia5030032 39189251 PMC11348270

13. Osman AH Darkwah S Kotey FCN Odoom A Hotor P Dayie NTKD . Reservoirs of nosocomial pathogens in intensive care units: a systematic review . Environ Health Insights . ( 2024 ) 18 : 3239 . doi: 10.1177/11786302241243239 PMC11141231 38828046

14. Kim EJ Ha KH Kim DJ Choi YH . Diabetes and the risk of infection: a national cohort study . Diabetes Metab J . ( 2019 ) 43 : 804 – 14 . doi: 10.4093/dmj.2019.0071 , 31701687 PMC6943267

15. Carey IM Critchley JA DeWilde S Harris T Hosking FJ Cook DG . Risk of infection in type 1 and type 2 diabetes compared with the general population: a matched cohort study . Diabetes Care . ( 2018 ) 41 : 513 – 21 . doi: 10.2337/dc17-2131 , 29330152

16. Jarczak D Kluge S Nierhaus A . Sepsis—pathophysiology and therapeutic concepts . Front Med . ( 2021 ) 8 : 628302 . doi: 10.3389/fmed.2021.628302 , 34055825 PMC8160230

17. van der Poll T Shankar-Hari M Wiersinga WJ . The immunology of sepsis . Immunity . ( 2021 ) 54 : 2450 – 64 . doi: 10.1016/j.immuni.2021.10.012 34758337

18. Saavedra-Torres JS Pinzón-Fernández MV Ocampo-Posada M Nati-Castillo HA Jiménez Hincapie LA Cadrazo-Gil EJ . Inflammasomes and signaling pathways: key mechanisms in the pathophysiology of sepsis . Cells . ( 2025 ) 14 : 930 . doi: 10.3390/cells14120930 , 40558557 PMC12191029

19. Saavedra-Torres JS Pinzón-Fernández MV Nati-Castillo HA Cadena Correa V Lopez Molina LC Gaitán JE . Immunodynamic disruption in sepsis: mechanisms and strategies for personalized immunomodulation . Biomedicine . ( 2025 ) 13 : 2139 . doi: 10.3390/biomedicines13092139 , 41007702 PMC12467355

20. Moraes CA Zaverucha-do-Valle C Fleurance R Sharshar T Bozza FA d’Avila JC . Neuroinflammation in Sepsis: molecular pathways of microglia activation . Pharmaceuticals . ( 2021 ) 14 : 416 . doi: 10.3390/ph14050416 , 34062710 PMC8147235

21. Schütze S Drevets DA Tauber SC Nau R . Septic encephalopathy in the elderly – biomarkers of potential clinical utility . Front Cell Neurosci . ( 2023 ) 17 : 8149 . doi: 10.3389/fncel.2023.1238149 , 37744876 PMC10512712

22. Mazeraud A Righy C Bouchereau E Benghanem S Bozza FA Sharshar T . Septic-associated encephalopathy: a comprehensive review . Neurotherapeutics . ( 2020 ) 17 : 392 – 403 . doi: 10.1007/s13311-020-00862-1 , 32378026 PMC7283452

23. Kosałka K Wachowska E Słotwiński R . Disorders of nutritional status in sepsis – facts and myths . Przeglad Gastroenterol . ( 2017 ) 12 : 73 – 82 . doi: 10.5114/pg.2017.68165 , 28702094 PMC5497135

24. Manzoli TF Delgado AF Troster EJ de Carvalho WB Antunes ACB Marques DM . Lymphocyte count as a sign of immunoparalysis and its correlation with nutritional status in pediatric intensive care patients with sepsis: a pilot study . Clin Sao Paulo Braz . ( 2016 ) 71 : 644 – 9 . doi: 10.6061/clinics/2016(11)05 , 27982165 PMC5108166

25. Hung K-Y Chen Y-M Wang C-C Wang Y-H Lin C-Y Chang Y-T . Insufficient nutrition and mortality risk in septic patients admitted to ICU with a focus on immune dysfunction . Nutrients . ( 2019 ) 11 : 367 . doi: 10.3390/nu11020367 , 30744171 PMC6412372

26. Iskander KN Osuchowski MF Stearns-Kurosawa DJ Kurosawa S Stepien D Valentine C . Sepsis: multiple abnormalities, heterogeneous responses, and evolving understanding . Physiol Rev . ( 2013 ) 93 : 1247 – 88 . doi: 10.1152/physrev.00037.2012 , 23899564 PMC3962548

27. Wasyluk W Zwolak A . Metabolic alterations in Sepsis . J Clin Med . ( 2021 ) 10 : 2412 . doi: 10.3390/jcm10112412 , 34072402 PMC8197843

28. Paul SN Nessel I Puthucheary Z Henson SM . Sepsis and the immunometabolic inflammatory response . Npj Metab Health Dis . ( 2026 ) 4 : 4 . doi: 10.1038/s44324-025-00095-w , 41629610 PMC12865009

29. Pang X Zhang P Chen X Liu W . Ubiquitin-proteasome pathway in skeletal muscle atrophy . Front Physiol . ( 2023 ) 14 : 1289537 . doi: 10.3389/fphys.2023.1289537 , 38046952 PMC10690626

30. Baek MS Kwon YS Kang SS Shim D Yoon Y Kim JH . Association of malnutrition status with 30-day mortality in patients with sepsis using objective nutritional indices: a multicenter retrospective study in South Korea . Acute Crit Care . ( 2024 ) 39 : 127 – 37 . doi: 10.4266/acc.2023.01613 , 38476065 PMC11002609

31. Bear DE Wandrag L Merriweather JL Connolly B Hart N Grocott MPW . The role of nutritional support in the physical and functional recovery of critically ill patients: a narrative review . Crit Care . ( 2017 ) 21 : 226 . doi: 10.1186/s13054-017-1810-2 , 28841893 PMC6389279

32. Grillo-Ardila CF Tibavizco-Palacios D Triana LC Rugeles SJ Vallejo-Ortega MT Calderón-Franco CH . Early enteral nutrition (within 48 h) for patients with Sepsis or septic shock: a systematic review and Meta-analysis . Nutrients . ( 2024 ) 16 : 1560 . doi: 10.3390/nu16111560 , 38892494 PMC11174497

33. Daud M Ullah F Uzair M Siddiq A Siddiq U Riaz FB . Malnutrition and its influence on Sepsis outcomes in elderly patients . Cureus . ( 2024 ) 16 : e63433 . doi: 10.7759/cureus.63433 , 39077281 PMC11284507

34. Petrucci M Gemma S Carbone L Piccioni A Della Polla DA Simeoni B . ICU-acquired weakness: from pathophysiology to management in critical care . Emerg Care Med . ( 2025 ) 2 : 4 . doi: 10.3390/ecm2010004

35. Liu W Hu C Zhao S . Sarcopenia and mortality risk of patients with Sepsis: a meta-analysis . Int J Clin Pract . ( 2022 ) 2022 : 4974410 . doi: 10.1155/2022/4974410 , 35685536 PMC9159150

36. Darden N Sharma S Wu X Mancini B Karamchandani K Bonavia AS . Long-term clinical outcomes in critically ill patients with sepsis and pre-existing low muscle mass: a retrospective cohort study . BMC Anesthesiol . ( 2023 ) 23 : 313 . doi: 10.1186/s12871-023-02274-y , 37715183 PMC10503077

37. Weitzmann MN . The role of inflammatory cytokines, the RANKL/OPG Axis, and the immunoskeletal interface in physiological bone turnover and osteoporosis . Scientifica . ( 2013 ) 2013 : 125705 . doi: 10.1155/2013/125705 , 24278766 PMC3820310

38. Epsley S Tadros S Farid A Kargilis D Mehta S Rajapakse CS . The effect of inflammation on bone . Front Physiol . ( 2020 ) 11 : 511799 . doi: 10.3389/fphys.2020.511799 , 33584321 PMC7874051

39. Kim T Kim H . Pathophysiology and therapeutic management of bone loss in patients with critical illness . Pharmaceuticals . ( 2023 ) 16 : 1718 . doi: 10.3390/ph16121718 , 38139844 PMC10747168

40. Zhang X Man K-W Li GH-Y Tan KC Kung AW-C Cheung C-L . Osteoporosis is a novel risk factor of infections and sepsis: a cohort study . EClinicalMedicine . ( 2022 ) 49 : 101488 . doi: 10.1016/j.eclinm.2022.101488 , 35747178 PMC9189871

41. Lee Y-F Tsou H-K Leong P-Y Wang Y-H Wei JC-C . Association of sepsis with risk for osteoporosis: a population-based cohort study . Osteoporos Int . ( 2021 ) 32 : 301 – 9 . doi: 10.1007/s00198-020-05599-3 , 32827276

42. Orford NR Saunders K Merriman E Henry M Pasco J Stow P . Skeletal morbidity among survivors of critical illness . Crit Care Med . ( 2011 ) 39 : 1295 – 300 . doi: 10.1097/CCM.0b013e318211ff3d , 21336120

43. Wu Q Huang Q Xu Z Hou C Wang C . Comprehensive review of Sepsis-related skeletal muscle atrophy: mechanisms, diagnosis and therapeutic strategies . J Inflamm Res . ( 2025 ) 18 : 17879 – 94 . doi: 10.2147/JIR.S554850 , 41458356 PMC12741264

44. Torres JSS Tamayo-Giraldo FJ Bejarano-Zuleta A Nati-Castillo HA Quintero DA Ospina-Mejía MJ . Sepsis and post-sepsis syndrome: a multisystem challenge requiring comprehensive care and management—a review . Front Med . ( 2025 ) 12 : 737 . doi: 10.3389/fmed.2025.1560737 , 40265185 PMC12011779

45. Cervantes-García E García-González R Reséndiz-Albor A Salazar-Schettino PM . Infections of diabetic foot ulcers with methicillin-resistant Staphylococcus aureus . Int J Low Extrem Wounds . ( 2015 ) 14 : 44 – 9 . doi: 10.1177/1534734614564053 , 25573977

46. Costantini E Carlin M Porta M Brizzi MF . Type 2 diabetes mellitus and sepsis: state of the art, certainties and missing evidence . Acta Diabetol . ( 2021 ) 58 : 1139 – 51 . doi: 10.1007/s00592-021-01728-4 , 33973089 PMC8316173

47. Carrillo-Larco RM Anza-Ramírez C Saal-Zapata G Villarreal-Zegarra D Zafra-Tanaka JH Ugarte-Gil C . Type 2 diabetes mellitus and antibiotic-resistant infections: a systematic review and meta-analysis . J Epidemiol Community Health . ( 2022 ) 76 : 75 – 84 . doi: 10.1136/jech-2020-216029 , 34326183 PMC8666814

48. Chaudhury A Duvoor C Dendi VSR Kraleti S Chada A Ravilla R . Clinical review of antidiabetic drugs: implications for type 2 diabetes mellitus management . Front Endocrinol (Lausanne) . ( 2017 ) 8 : 6 . doi: 10.3389/fendo.2017.00006 28167928 PMC5256065

49. Rohm TV Meier DT Olefsky JM Donath MY . Inflammation in obesity, diabetes, and related disorders . Immunity . ( 2022 ) 55 : 31 – 55 . doi: 10.1016/j.immuni.2021.12.013 35021057 PMC8773457

50. Tsalamandris S Antonopoulos AS Oikonomou E Papamikroulis GA Vogiatzi G Papaioannou S . The role of inflammation in diabetes: current concepts and future perspectives . Eur Cardiol . ( 2019 ) 14 : 50 – 9 . doi: 10.15420/ecr.2018.33.1 31131037 PMC6523054

51. Kaur A Sharma GS Kumbala DR . Acute kidney injury in diabetic patients: a narrative review . Medicine (Baltimore) . ( 2023 ) 102 : e33888 . doi: 10.1097/MD.0000000000033888 , 37233407 PMC10219694

52. Venot M Weis L Clec’h C Darmon M Allaouchiche B Goldgran-Tolédano D . Acute kidney injury in severe sepsis and septic shock in patients with and without diabetes mellitus: a multicenter study . PLoS One . ( 2015 ) 10 : e0127411 . doi: 10.1371/journal.pone.0127411 , 26020231 PMC4447271

53. Trandafir M-F Savu OI Gheorghiu M . The complex immunological alterations in patients with type 2 diabetes mellitus on hemodialysis . J Clin Med . ( 2024 ) 13 : 3687 . doi: 10.3390/jcm13133687 , 38999253 PMC11242658

54. Daryabor G Atashzar MR Kabelitz D Meri S Kalantar K . The effects of type 2 diabetes mellitus on organ metabolism and the immune system . Front Immunol . ( 2020 ) 11 : 1582 . doi: 10.3389/fimmu.2020.01582 , 32793223 PMC7387426

55. Berbudi A Rahmadika N Tjahjadi AI Ruslami R . Type 2 diabetes and its impact on the immune system . Curr Diabetes Rev . ( 2020 ) 16 : 442 – 9 . doi: 10.2174/1573399815666191024085838 , 31657690 PMC7475801

56. Shomali N Mahmoudi J Mahmoodpoor A Zamiri RE Akbari M Xu H . Harmful effects of high amounts of glucose on the immune system: an updated review . Biotechnol Appl Biochem . ( 2021 ) 68 : 404 – 10 . doi: 10.1002/bab.1938 , 32395846

57. Lee H Kim M-J Lee I-K Hong C-W Jeon J-H . Impact of hyperglycemia on immune cell function: a comprehensive review . Diabetol Int . ( 2024 ) 15 : 745 – 60 . doi: 10.1007/s13340-024-00741-6 , 39469566 PMC11512986

58. Lee DSU Lee H . Adherence and persistence rates of major antidiabetic medications: a review . Diabetol Metab Syndr . ( 2022 ) 14 : 12 . doi: 10.1186/s13098-022-00785-1 35033161 PMC8761325

59. Yeo HJ Kim HL So MW Park JM Kim D Cho WH . Obesity paradox of sepsis in long-term outcome: the differential effect of body composition . Intensive Crit Care Nurs . ( 2025 ) 87 : 103893 . doi: 10.1016/j.iccn.2024.103893 , 39608164

60. Arabi YM Dara SI Tamim HM Rishu AH Bouchama A Khedr MK . Clinical characteristics, sepsis interventions and outcomes in the obese patients with septic shock: an international multicenter cohort study . Crit Care . ( 2013 ) 17 : R72 . doi: 10.1186/cc12680 , 23594407 PMC3672731

61. Kalani C Venigalla T Bailey J Udeani G Surani S . Sepsis patients in critical care units with obesity: is obesity protective? Cureus . ( 2020 ) 12 : e6929 . doi: 10.7759/cureus.6929 32190482 PMC7067368

62. Pepper DJ Sun J Welsh J Cui X Suffredini AF Eichacker PQ . Increased body mass index and adjusted mortality in ICU patients with sepsis or septic shock: a systematic review and meta-analysis . Crit Care . ( 2016 ) 20 : 181 . doi: 10.1186/s13054-016-1360-z , 27306751 PMC4908772

63. Wacharasint P Boyd JH Russell JA Walley KR . One size does not fit all in severe infection: obesity alters outcome, susceptibility, treatment, and inflammatory response . Crit Care . ( 2013 ) 17 : R122 . doi: 10.1186/cc12794 , 23786836 PMC4057102

64. Trim WV Lynch L . Immune and non-immune functions of adipose tissue leukocytes . Nat Rev Immunol . ( 2022 ) 22 : 371 – 86 . doi: 10.1038/s41577-021-00635-7 34741167

65. Aida XM-U Ivan T-V Juan GJ-R . Adipose tissue immunometabolism: unveiling the intersection of metabolic and immune regulation . Rev Investig Clin Organo Hosp Enfermedades Nutr . ( 2024 ) 76 : 65 – 79 . doi: 10.24875/RIC.23000231 38718804

66. Taylor EB . The complex role of adipokines in obesity, inflammation, and autoimmunity . Clin Sci Lond Engl . ( 2021 ) 135 : 731 – 52 . doi: 10.1042/CS20200895 , 33729498 PMC7969664

67. Miura SI Matsuo Y Seumatsu Y . Renin-angiotensin-aldosterone system and its relation to hypertension . Hypertens Res . ( 2025 ) 48 : 2209 – 17 . doi: 10.1038/s41440-025-02229-5 40437114

68. Cabandugama PK Gardner MJ Sowers JR . The renin angiotensin aldosterone system in obesity and hypertension: roles in the Cardiorenal metabolic syndrome . Med Clin North Am . ( 2017 ) 101 : 129 – 37 . doi: 10.1016/j.mcna.2016.08.009 , 27884224 PMC5125542

69. Manrique C Lastra G Gardner M Sowers JR . The renin angiotensin aldosterone system in hypertension: roles of insulin resistance and oxidative stress . Med Clin North Am . ( 2009 ) 93 : 569 – 82 . doi: 10.1016/j.mcna.2009.02.014 , 19427492 PMC2828938

70. Lang Y Liang T Li F . Integrated multi-omics analysis and predictive modeling of heart failure using sepsis-related gene signature . PLoS One . ( 2025 ) 20 : e0326212 . doi: 10.1371/journal.pone.0326212 , 40526611 PMC12173235

71. Epstein AM Jha AK Orav EJ . The relationship between hospital admission rates and rehospitalizations . N Engl J Med . ( 2011 ) 365 : 2287 – 95 . doi: 10.1056/NEJMsa1101942 22168643

72. Dhaliwal JS Dang AK . Reducing hospital readmissions . In: StatPearls . Treasure Island (FL) : StatPearls Publishing ; ( 2025 ). Available online at: http://www.ncbi.nlm.nih.gov/books/NBK606114/ (Accessed June 13, 2025). 39163436

73. Arfaras-Melainis A Polyzogopoulou E Triposkiadis F Xanthopoulos A Ikonomidis I Mebazaa A . Heart failure and sepsis: practical recommendations for the optimal management . Heart Fail Rev . ( 2020 ) 25 : 183 – 94 . doi: 10.1007/s10741-019-09816-y , 31227942

74. Mohamoud A Abdallah N Wardhere A Teeri S Ismayl M . Sepsis and septic shock outcomes and 90-day readmissions in heart failure with reduced ejection fraction: a national readmission database study . Curr Probl Cardiol . ( 2024 ) 49 : 102696 . doi: 10.1016/j.cpcardiol.2024.102696 , 38852912

75. Jones TW Smith SE Van Tuyl JS Newsome AS . Sepsis with preexisting heart failure: Management of Confounding Clinical Features . J Intensive Care Med . ( 2021 ) 36 : 989 – 1012 . doi: 10.1177/0885066620928299 , 32495686 PMC7970342

76. Macdonald S . Fluid resuscitation in patients presenting with sepsis: current insights . Open Access Emerg Med . ( 2022 ) 14 : 633 – 8 . doi: 10.2147/OAEM.S363520 , 36471825 PMC9719278

77. Zampieri FG Bagshaw SM Semler MW . Fluid therapy for critically ill adults with sepsis: a review . JAMA . ( 2023 ) 329 : 1967 – 80 . doi: 10.1001/jama.2023.7560 , 37314271

78. King J Chenoweth CE England PC Heiler A Kenes MT Raghavendran K . Early Recognition and Initial Management of Sepsis in Adult Patients . Ann Arbor (MI) : Michigan Medicine University of Michigan . ( 2023 ). Available online at: http://www.ncbi.nlm.nih.gov/books/NBK598311/ (Accessed June 13, 2025) 38109324

79. Overgaard CB V D . Inotropes and vasopressors . Circulation . ( 2008 ) 118 : 1047 – 56 . doi: 10.1161/CIRCULATIONAHA.107.728840 18765387

80. Becerra AF Amanamba U Lopez JE Blaker NJ Winchester DE . The current use of vasoactive agents in cardiogenic shock related to myocardial infarction and acute decompensated heart failure . Am Heart J Plus Cardiol Res Pract . ( 2025 ) 52 : 100524 . doi: 10.1016/j.ahjo.2025.100524 , 40170689 PMC11960524

81. Bozkurt B . Contemporary pharmacological treatment and management of heart failure . Nat Rev Cardiol . ( 2024 ) 21 : 545 – 55 . doi: 10.1038/s41569-024-00997-0 , 38532020

82. Auty R . Pharmacological management of chronic heart failure in adults: a review of the literature . Malawi Med J J Med Assoc Malawi . ( 2004 ) 16 : 22 – 6 . PMC3345495 27528985

83. Mergoum AM Rhone AR Larson NJ Dries DJ Blondeau B Rogers FB . A guide to the use of vasopressors and inotropes for patients in shock . J Intensive Care Med . ( 2025 ) 40 : 726 – 38 . doi: 10.1177/08850666241246230 38613381

84. Jentzer JC Coons JC Link CB Schmidhofer M . Pharmacotherapy update on the use of vasopressors and inotropes in the intensive care unit . J Cardiovasc Pharmacol Ther . ( 2015 ) 20 : 249 – 60 . doi: 10.1177/1074248414559838 25432872

85. Fan D Wu R . Mechanisms of the septic heart: from inflammatory response to myocardial edema . J Mol Cell Cardiol . ( 2024 ) 195 : 73 – 82 . doi: 10.1016/j.yjmcc.2024.08.003 , 39142438 PMC13104036

86. Pohlan J Nawabi J Witham D Schroth L Krause F Schulze J . Cerebrovascular events in suspected Sepsis: retrospective prevalence study in critically ill patients undergoing full-body computed tomography . Front Neurol . ( 2022 ) 13 : 811022 . doi: 10.3389/fneur.2022.811022 , 35614926 PMC9125158

87. Allam S Na J Moon J Desai Y Messner C Potenza R . Bleeding, stroke, and mortality risk of patients with septic shock receiving anticoagulation for atrial fibrillation . Heart Rhythm . ( 2025 ) 22 : 2774 – 83 . doi: 10.1016/j.hrthm.2024.12.001 39647561

88. Stösser S Isakeit J Bode FJ Bode C Petzold GC . Sepsis in patients with large vessel occlusion stroke-clinical characteristics and outcome . Front Neurol . ( 2022 ) 13 : 902809 . doi: 10.3389/fneur.2022.902809 35903123 PMC9315268

89. Arero AG Vasheghani-Farahani A Tigabu BM Arero G Ayene BY Soltani D . Long-term risk and predictors of cerebrovascular events following sepsis hospitalization: a systematic review and meta-analysis . Front Med . ( 2022 ) 9 : 1065476 . doi: 10.3389/fmed.2022.1065476 , 36507522 PMC9732021

90. Shao IY Elkind MSV Boehme AK . Risk factors for stroke in patients with Sepsis and bloodstream infections . Stroke . ( 2019 ) 50 : 1046 – 51 . doi: 10.1161/STROKEAHA.118.023443 , 30896327 PMC6476655

91. Chen C-H Lai C-C Wang Y-H Wang C-Y Wang H-C Yu C-J . The impact of sepsis on the outcomes of COPD patients: a population-based cohort study . J Clin Med . ( 2018 ) 7 : 393 . doi: 10.3390/jcm7110393 , 30373237 PMC6262552

92. Chen Y Lu L Li X Liu B Zhang Y Zheng Y . Association between chronic obstructive pulmonary disease and 28-day mortality in patients with sepsis: a retrospective study based on the MIMIC-III database . BMC Pulm Med . ( 2023 ) 23 : 435 . doi: 10.1186/s12890-023-02729-5 , 37946194 PMC10633936

93. Søgaard M Madsen M Løkke A Hilberg O Sørensen HT Thomsen RW . Incidence and outcomes of patients hospitalized with COPD exacerbation with and without pneumonia . Int J Chron Obstruct Pulmon Dis . ( 2016 ) 11 : 455 – 65 . doi: 10.2147/COPD.S96179 , 27042038 PMC4780743

94. Lai C-C Wang Y-H Wang C-Y Wang H-C Yu C-J Chen L . Comparative effects of angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers on the risk of pneumonia and severe exacerbations in patients with COPD . Int J Chron Obstruct Pulmon Dis . ( 2018 ) 13 : 867 – 74 . doi: 10.2147/COPD.S158634 , 29563786 PMC5846309

95. Flannery AH Li X Delozier NL Toto RD Moe OW Yee J . Sepsis-associated acute kidney disease and Long-term kidney outcomes . Kidney Med . ( 2021 ) 3 : 507 – 514.e1 . doi: 10.1016/j.xkme.2021.02.007 , 34401718 PMC8350838

96. Venkataraman R Kellum JA . Sepsis: update in the management . Adv Chronic Kidney Dis . ( 2013 ) 20 : 6 – 13 . doi: 10.1053/j.ackd.2012.10.013 , 23265591

97. Rice DM Ratliff PD Judd WR Kseibi SA Eberwein KA . Assessing the impact of CKD on outcomes in septic shock patients receiving standard vs reduced initial fluid volume . Am J Emerg Med . ( 2020 ) 38 : 2147 – 50 . doi: 10.1016/j.ajem.2020.07.055 , 33046295

98. Akcan Arikan A Ostermann M Goldstein SL Kellum JA . Sepsis criteria and kidney function: eliminating sex, age and economic status biases . Nat Rev Nephrol . ( 2025 ) 21 : 565 – 75 . doi: 10.1038/s41581-025-00973-y , 40506504

99. Yang H Chen Y He J Li Y Feng Y . Advances in the diagnosis of early biomarkers for acute kidney injury: a literature review . BMC Nephrol . ( 2025 ) 26 : 115 . doi: 10.1186/s12882-025-04040-3 , 40045274 PMC11884078

100. Brozat JF Harbalioğlu N Hohlstein P Abu Jhaisha S Pollmanns MR Adams JK . Elevated serum KIM-1 in Sepsis correlates with kidney dysfunction and the severity of multi-organ critical illness . Int J Mol Sci . ( 2024 ) 25 : 5819 . doi: 10.3390/ijms25115819 , 38892009 PMC11172102

101. He J Chen Y Li Y Feng Y . Molecular mechanisms and therapeutic interventions in acute kidney injury: a literature review . BMC Nephrol . ( 2025 ) 26 : 144 . doi: 10.1186/s12882-025-04077-4 40121405 PMC11929251

102. Hanif MO Rout P Ramphul K . Acute Renal Tubular Necrosis . In: StatPearls . Treasure Island (FL) : StatPearls Publishing ; ( 2025 ). Available online at: http://www.ncbi.nlm.nih.gov/books/NBK507815/ (Accessed October 7, 2025) 29939592

103. Havasi A Borkan SC . Apoptosis and acute kidney injury . Kidney Int . ( 2011 ) 80 : 29 – 40 . doi: 10.1038/ki.2011.120 21562469 PMC4625984

104. Hsieh Y-T Lee T-Y Kao J-S Hsu H-L Chong C-F . Treating acute hypertensive cardiogenic pulmonary edema with high-dose nitroglycerin . Turk J Emerg Med . ( 2018 ) 18 : 34 – 6 . doi: 10.1016/j.tjem.2018.01.004 , 29942881 PMC6009803

105. Castello LM Gavelli F . Sepsis scoring systems: mindful use in clinical practice . Eur J Intern Med . ( 2024 ) 125 : 32 – 5 . doi: 10.1016/j.ejim.2024.05.015 , 38782628

106. Oduncu AF Kıyan GS Yalçınlı S . Comparison of qSOFA, SIRS, and NEWS scoring systems for diagnosis, mortality, and morbidity of sepsis in emergency department . Am J Emerg Med . ( 2021 ) 48 : 54 – 9 . doi: 10.1016/j.ajem.2021.04.006 , 33839632

107. Reddy V Reddy H Gemnani R Kumar S Acharya S . Navigating the complexity of scoring Systems in Sepsis Management: a comprehensive review . Cureus . ( 2024 ) 16 : e54030 . doi: 10.7759/cureus.54030 , 38481909 PMC10932875

108. Lemiale V Pons S Mirouse A Tudesq J-J Hourmant Y Mokart D . Sepsis and septic shock in patients with malignancies: a Groupe de Recherche Respiratoire en Réanimation Onco-Hématologique study . Crit Care Med . ( 2020 ) 48 : 822 – 9 . doi: 10.1097/CCM.0000000000004322 , 32317596

109. Hong G Ju H Oh DK Lee SY Park MH Lee H . Clinical characteristics and prognostic factors of sepsis in patients with malignancy . Sci Rep . ( 2025 ) 15 : 7078 . doi: 10.1038/s41598-025-87457-y , 40016348 PMC11932214

110. Nates JL Pène F Darmon M Mokart D Castro P David S . Septic shock in the immunocompromised cancer patient: a narrative review . Crit Care . ( 2024 ) 28 : 285 . doi: 10.1186/s13054-024-05073-0 , 39215292 PMC11363658

111. The HIV-CAUSAL Collaboration . The effect of combined antiretroviral therapy on the overall mortality of HIV-infected individuals . AIDS Lond Engl . ( 2010 ) 24 : 123 – 37 . doi: 10.1097/QAD.0b013e3283324283 PMC2920287 19770621

112. Barbier F Mer M Szychowiak P Miller RF Mariotte É Galicier L . Management of HIV-infected patients in the intensive care unit . Intensive Care Med . ( 2020 ) 46 : 329 – 42 . doi: 10.1007/s00134-020-05945-3 , 32016535 PMC7095039

113. Japiassú AM Amâncio RT Mesquita EC Medeiros DM Bernal HB Nunes EP . Sepsis is a major determinant of outcome in critically ill HIV/AIDS patients . Crit Care . ( 2010 ) 14 : R152 . doi: 10.1186/cc9221 , 20698966 PMC2945136

114. Silva JM dos Santos SDS . Sepsis in AIDS patients: clinical, etiological and inflammatory characteristics . J Int AIDS Soc . ( 2013 ) 16 : 17344 . doi: 10.7448/IAS.16.1.17344 , 23374857 PMC3564973

115. Gao Q Wang T Tan S Tian Y Zhang A . Outcomes and risk factors in HIV-positive patients with sepsis: a retrospective study . Eur J Med Res . ( 2025 ) 30 : 494 . doi: 10.1186/s40001-025-02753-7 , 40537837 PMC12178050

116. Lakbar I Leone M Pauly V Orleans V Srougbo KJ Diao S . Association of severe mental illness and septic shock case fatality rate in patients admitted to the intensive care unit: a national population-based cohort study . PLoS Med . ( 2023 ) 20 : e1004202 . doi: 10.1371/journal.pmed.1004202 , 36913434 PMC10042353

117. Yang R Xiang H Zheng T . Causal associations between severe mental illness and sepsis: a Mendelian randomization study . Front Psych . ( 2024 ) 15 : 1341559 . doi: 10.3389/fpsyt.2024.1341559 , 38532990 PMC10964346

118. Lakbar I Maakaron E Leone M Delamarre L Yon DK Tran B . Severe mental illness and mortality in sepsis and septic shock: a systematic review and meta-analysis . Mol Psychiatry . ( 2024 ) 29 : 3857 – 64 . doi: 10.1038/s41380-024-02603-8 , 38769373

119. Markwart R Saito H Harder T Tomczyk S Cassini A Fleischmann-Struzek C . Epidemiology and burden of sepsis acquired in hospitals and intensive care units: a systematic review and meta-analysis . Intensive Care Med . ( 2020 ) 46 : 1536 – 51 . doi: 10.1007/s00134-020-06106-2 , 32591853 PMC7381455

120. Le Gall JR Alberti C Brun Buisson C . Epidemiology of infection and sepsis in intensive care unit patients . Bull Acad Natl Med . ( 2004 ) 188 : 1115 – 25 . 15787068

121. Machado FR Cavalcanti AB Bozza FA Ferreira EM Angotti Carrara FS Sousa JL . The epidemiology of sepsis in Brazilian intensive care units (the Sepsis PREvalence assessment database, SPREAD): an observational study . Lancet Infect Dis . ( 2017 ) 17 : 1180 – 9 . doi: 10.1016/S1473-3099(17)30322-5 , 28826588

122. Haines KJ Quasim T McPeake J . Family and support networks following critical illness . Crit Care Clin . ( 2018 ) 34 : 609 – 23 . doi: 10.1016/j.ccc.2018.06.008 , 30223998

123. Raman S English A O’Keefe M Harley A Steele M Minogue J . Designing support structures post sepsis in children: perspectives of the Queensland paediatric sepsis program . Front Pediatr . ( 2021 ) 9 : 759234 . doi: 10.3389/fped.2021.759234 , 34869116 PMC8636900

124. Mackintosh NJ Davis RE Easter A Rayment-Jones H Sevdalis N Wilson S . Interventions to increase patient and family involvement in escalation of care for acute life-threatening illness in community health and hospital settings . Cochrane Database Syst Rev . ( 2020 ) 2020 : CD012829 . doi: 10.1002/14651858.CD012829.pub2 , 33285618 PMC8406701

Glossary

angiotensin-converting enzyme inhibitor

atrial fibrillation

acquired immunodeficiency syndrome

acute kidney injury

AMP-activated protein kinase

Acute Physiology and Chronic Health Evaluation II

airway pressure release ventilation

acute respiratory distress syndrome

area under the curve

blood–brain barrier

brain-expressed X-linked protein 1

B-type natriuretic peptide

cluster of differentiation 4-positive T lymphocyte

confidence interval

chronic kidney disease

chronic obstructive pulmonary disease

C-reactive protein

creatinine clearance

computed tomography

cytotoxic T-lymphocyte–associated protein 4

damage-associated molecular patterns

deep vein thrombosis

epoxide hydrolase 2

furin (proprotein convertase subtilisin/kexin type 3)

guideline-directed medical therapy

glycine N-methyltransferase

heart failure

heart failure with reduced ejection fraction

human immunodeficiency virus

human leukocyte antigen–DR

intensive care unit

intensive care units

infectious diseases

interleukin-1β

interleukin-6

interleukin-10

immune reconstitution inflammatory syndrome

inferior vena cava

Janus kinase–signal transducer and activator of transcription

c-Jun N-terminal kinase

kidney injury molecule-1

lipopolysaccharide

methicillin-resistant Staphylococcus aureus

mineralocorticoid receptor antagonist

neutrophil extracellular trap–mediated cell death

neutrophil extracellular traps

neutrophil gelatinase-associated lipocalin

neonatal intensive care unit

neutrophil-to-lymphocyte ratio

nucleotide-binding oligomerization domain

N-terminal pro–B-type natriuretic peptide

odds ratio

pathogen-associated molecular patterns

procalcitonin

programmed cell death protein 1

pneumocystis jirovecii pneumonia

pharmacokinetics/pharmacodynamics

renin–angiotensin–aldosterone system

ribonuclease A family member 2

renal replacement therapy

sodium–glucose cotransporter 2 inhibitor

sirtuin 1

severe mental illness

Sequential Organ Failure Assessment

type 2 diabetes mellitus

tuberculosis

therapeutic drug monitoring

Toll-like receptor

tumor necrosis factor-α

T helper 1

T helper 17

venous excess ultrasound

volume of distribution

combination antiretroviral therapy

quick Sequential Organ Failure Assessment