Septic shock in the immunocompromised cancer patient: a narrative review.

Introduction

Acquired immunosuppression usually affects patients with all type of malignancies, stem cells and solid organ transplantation, those receiving immunosuppressive therapies, human immunodeficiency virus infection, and others. The 2021 annual US National Health Interview Survey showed that 6.6% of adults had an immunosuppressive condition or were taking immunosuppressive medications [ 1 ]. The approach and management of the immunocompromised cancer patient with septic shock may be different from that of the immunocompetent patient because of the underlying disease, the type and degree of immunosuppression, the stage and severity of the underlying condition, comorbidities, and therapies associated with high toxicity [ 2 , 3 ].

Immunocompromised hosts, especially those with cancer, have suffered from unconscious and conscious biases, including Intensive Care Unit (ICU) admission denials, delayed ICU admissions, time-limited ICU trials, and palliative ICU admissions [ 4 ]. In the late 1990s international guidelines, patients with malignancies had a lower priority for admission to the ICU [ 5 ]. The most recent guidelines for ICU admission, discharge, and triage, published in 2016 have addressed those issues, but differences persist [ 6 ]. While most of the Surviving Sepsis Campaign guidelines may apply to this population, gaps in knowledge still exist [ 7 ]. Therefore, there is a critical and unmet need for a better understanding of the unique challenges these patients offer regarding early recognition, differential diagnosis, and timely interventions. The purpose of this article is to review the current understanding, highlight the current and persistent issues, and propose a new paradigm to improve the outcomes of septic shock in cancer patients, those with solid tumors, hemato-oncologic malignancies, and hematopoietic stem cell transplantation (HSCT). The methodology for this narrative review involved a comprehensive and systematic search of the literature, guided by the expertise of an international panel of experts. The panel of experts collectively identified key topics, selected relevant studies, and synthesized findings to provide a thorough overview of current knowledge. Regular consensus consultations ensured the integration of diverse perspectives and the accuracy of the conclusions drawn.

Epidemiology

The incidence of cancer is increasing; the risk of developing sepsis is also on the rise despite a reduction in mortality. The risk of developing sepsis is ten times higher in cancer patients [ 8 ]. Given the world’s continuously growing population, currently surpassing eight billion, and the increased cancer survival rates, the number of individuals at augmented risk will rise [ 9 – 14 ]. In 2022, there were 19.98 million new cases and 9.74 million deaths globally, resulting in approximately 53.5 million prevalent cases over five years [ 15 – 17 ]. Since 1991, smoking reduction, better screening, and novel cancer therapies contributed to the 33% decline in cancer mortality in the USA [ 16 ].

Patients with cancers have higher morbidity than non-cancer patients, higher risk of infection, higher emergency room visits and higher rate of admission. A large epidemiological study of emergency services utilization in the USA (2006–2012) found that four million (4.2%) annual adult emergency room (ER) visits involved cancer diagnoses [ 18 ]. Sixty percent of cancer patients admitted to the hospital in the USA (2006–2012) had primarily severe infections or cardiorespiratory failure, compared to 16% of non-cancer patients. A smaller study also reported that cancer patients had a higher admission rate than non-cancer patients (47.6% vs. 13.6%) [ 19 ]. In the study by Rivera et al., the most common causes of infections were pneumonia, urinary tract infections, and septicemia [ 18 ]. In the study by Legrand et al., the four most frequent sources of infections were pneumonia (70.2%), abdomen (19.1%), skin and soft tissue infection (4.3%) and catheter-related infection (2.8%) [ 20 ]. Factors associated with higher hospitalization rates included male sex, older age, comorbidities, and lung cancer. Another study at a Comprehensive Cancer Center reported 387,306 adult cancer admissions in a 20-year period, of which 40.4% were surgical patients, 28.2% had hematologic malignancies, and 31.4% solid tumors [ 21 ]. Among these, 12.9% went to the ICU; 38.4% of those who died at discharge had infections as principal diagnosis (e.g., sepsis, pneumonia).

Although less often reported, data on cancer patients with sepsis are also available. Between 1979 and 2001, among 854 million patients hospitalized in the USA, 1.78 million patients had cancer and sepsis, equating to 1,465 sepsis cases per 100,000 cancer patients in the USA [ 15 ]. A 2011 state-wide (population 25.65 million) study of 2,713,776 hospital discharges found that 303,492 (14%) had cancer and 17,523 (5.8%) of them also had sepsis [ 22 ]. Similarly, a study of 2,901,019 patients in 409 US hospitals (2009–2014) reported a 6% sepsis occurrence and 15% overall mortality [ 23 ]. Another large study using the US National Readmission Database, encompassing over twenty-seven million hospitalizations, found that 4% of patients had sepsis, 15.1% had cancer, and 234,641 (5.7%) had both cancer and sepsis [ 2 ]. In the EPISEPSIS study of 206 French ICUs, 12.8% of severe sepsis admissions had metastatic cancer (7.5%) or hematological malignancies (5.3%) [ 24 ]. The global EPIC II study involving 13,796 ICU patients (51% infected) found that 17% had cancer (15.1% solid tumors, 2% hematological malignancies) [ 25 ]. Among these, infection rates were 74% for hematological patients, and 53.2% for those with solid tumors. The follow-up EPIC III study included 15,202 ICU patients, 16.7% of them had cancer (2.8% of those hematological) [ 26 ]. Similarly, 72.47% of the hematological patients and 49.85% of the solid tumor patients had an infection. Considering that, worldwide, not all cancers patients with sepsis are hospitalized, among those hospitalized, the review of three different studies performed at a high-volume cancer center demonstrated a 0.94% incidence of septic shock in solid and hematologic malignancies combined (1.68% including those not meeting Sepsis-3 criteria), and 1.44% in HSCT patients [ 27 – 29 ]. More recently, Liu et al. analyzed data from the National Inpatient Sample Database and found that among fourteen million patients hospitalized with sepsis between 2006 and 2014, the annual incidence rate increased at a higher rate in cancer patients [ 30 ]. They reported an increase in the annual incidence of 15.8% for Gram-negative bacteria (GNB), 7.4% for Gram-positive bacteria (GPB), 16.5% for anaerobes, and 11.6% for fungi. Whether or not those data reflect a real increase in incidence or better identification remains unclear.

Pathophysiology

Although not all cancer patients are immunosuppressed, the degree of immunosuppression is a crucial risk for sepsis and poor outcomes. The pathogenesis of sepsis is complex and depends on the type of infection and the host response involving the activation of the endothelium and complement, microvascular and coagulation dysfunction, and microbiome dysbiosis among others [ 31 – 34 ]. In cancer patients with sepsis, mortality and other complications are higher than in the general population, because of their intrinsic vulnerabilities and risk factors (Table 1 ). The affected pathways will influence development, progression and potentially outcome of sepsis. Table 1 Risk factors and comparative outcomes in cancer patients with sepsis Risk factor Description Impact on clinical outcomes Severity of immunosuppression Low levels of cluster of differentiation 4 (CD4) cells or intensive immunosuppressive treatments Increased mortality rates Comorbidities Conditions such as diabetes and chronic obstructive pulmonary disease Increased incidence of complications and mortality Age Advanced age of the patient Higher mortality rates due to weakened immune response and diminished physiological reserve Neutropenia Common in cancer patients and those undergoing chemotherapy Major risk factor for sepsis development and adverse clinical outcomes Organ dysfunction Measured by the Sequential Organ Failure Assessment (SOFA) scores Strong correlation with mortality Epithelial barrier dysfunction Facilitates bacterial translocation Risk factor for sepsis development Immunosuppressive drugs use Includes corticosteroids and biologic agents Increased risk of sepsis and adverse outcomes Renal dysfunction Need for renal replacement therapy Essential management to reduce mortality Intestinal dysfunction Increased intestinal permeability and microbial dysbiosis Contributes to sepsis progression Patient group Hospital mortality rate (%) Adverse events General immunocompromised patients 64.9–73.9 Increased incidence of severe complications, longer hospital stays Hematological malignancies 50–80 Associated with high mortality (e.g., coexisting tumor lysis syndrome, hemophagocytic lymphohistiocytosis) Human Immunodeficiency Virus (HIV) infected patients Risk of mortality 32% higher than in HIV negative patients [ 3 ] Major morbidity and mortality causes; complications from opportunistic infections Solid organ transplant recipients 7.8–20 Susceptibility to severe infections, extended hospital stays, organ function deterioration

The immune system includes rapid response, low-specificity innate immune system (complement system, phagocytic cells) and delayed response, high specificity adaptive immune system (B- and T-lymphocytes). Immunosuppression can come from the cancer, its therapy or both, Infection risks vary based on the immune defect type: for example, complement defects or inhibition (e.g., eculizumab, a C5 inhibitor) increase susceptibility to Neisseria and blood-borne pathogens, while defects in cell-mediated immunity increase the risk of opportunistic infections [ 35 ] (Table 2 ). The underlying immune status impacts the course of septic shock and the susceptibility to ICU-acquired complications [ 36 ]. The pathophysiology of cancer patients with sepsis is intertwined: both entities share common characteristics that result from a dysregulated immune system, raising the specter of their mutual impact on each other's course [ 37 ]. Few studies compare sepsis pathophysiology between immunocompromised hosts and those who are not, with various findings not always aligned with outcomes [ 38 ]. This may be because endotoxin effects are lymphocyte-independent, as shown in animal models, or because septic shock can induce acquired immunosuppression in previously non-immunosuppressed patients [ 34 , 39 ]. Comorbidities such as diabetes are not only a risk factor for infection and sepsis but also a risk factor of poor outcome [ 40 ]. Advanced age, malnutrition and frailty are also well-established risk factors of poor prognosis, due to a weakened immune response and diminished physiological reserve [ 41 ]. Table 2 Risk for specific pathogens according to the type of immunosuppression Immunologicdeficiency Neutrophils Monocytes/dendritic cells/ macrophages B lymphocytes T lymphocytes Humoral (antibody) immunity Anatomical Compression, obstruction, ulceration Diseases Acute leukemia; myelodysplastic syndrome; aplastic anemia; chemotherapy and drug-related neutropenia Hairy cell leukemia; aplastic anaemia; allogeneic bone marrow transplant; malignant histiocytosis; acute myeloid leukemia; chronic myeloid leukemia; solid tumors; hemophagocytic lymphohistocytosis Multiple myeloma; B-cell lymphoma; chronic lymphocytic leukemia T-cell leukemia; T-cell lymphoma; Hodgkin disease Multiple myeloma; chronic lymphoid leukemia Solid tumors Treatments Chemotherapy induced neutropenia Steroids; basiliximab; antithymocyte globulin; tacrolimus; mycophenolate mofetil; belatacept Chemotherapy; steroids; asplenia; rituximab; CAR-T cells; allogeneic bone marrow transplant Steroids;fludarabine; cyclophosphamide; methotrexate; azathioprine; alemtuzumab;; cyclosporine;mTOR inhibitors (sirolimus);tacrolimus; 2-chlorodeoxyadenosine; daratumumab; allogeneic bone marrow transplant; solid organ transplant Ibrutinib; rituximab; daratumumab; cyclophosphamide; hypogammaglobunemia induced CAR-T cells; allogeneic bone marrow transplant; solid organ transplant Chemotherapy-induced neutropenia Most frequently encountered infections Gram-negative bacteria Gram-positive bacteria Candida Aspergillus Nocardia Non-tuberculousmycobacteria Salmonella, Listeria, Legionella, Histoplasma, Brucella Herpes simplex virus, varicella zoster virus, parainfluenzavirus, respiratory syncytial virus Candida parapsilosis Staphylococcus aureus, Enterococcus faecalis, Pseudomonas aeruginosa Encapsulated bacteria (Streptococcus pneumoniae, Streptococcus pyogenes, Haemophilus influenzae) Giardia lamblia, Campylobacter, Salmonella Mycoplasma Enterovirus Recurrent infections Herpes simplex virus, Cytomegalovirus, Epstein-Barr virus Pneumocystis, Aspergillus, Cryptococcus Mycobacterial infection Skin candidiasis Diarrhea (rotaviruses, adenoviruses, Cryptosporidium, microsporidia,etc.) John Cunningham (JC) virus Encapsulated bacteria (S. pneumoniae,S pyogenes, H. influenzae) Mycoplasma, Ureaplasma urealyticum Other infections related to associated T-cell defects Gram-negative bacteria Gram-positive bacteria

Cancer patients, especially those with hematological malignancies, exhibit immune defects such as cytopenias, T-cell and B-cell suppression, and asplenia, all increasing the risk of sepsis and septic shock [ 42 , 43 ]. Neutropenia increases the risk of bacterial and fungal infections. Neutrophils may also sustain antimicrobial functional defects resulting in “functional neutropenia” despite preserved cell counts [ 44 – 46 ]. This is often due to chemotherapy or radiation-induced bone marrow failure but can also result from malignant infiltration of the bone marrow. Of note, in a recent meta-analysis on individual data by Georges et al., despite that neutropenia was associated with poor outcome, the association disappeared after granulocyte colony-stimulant factor (G-CSF) therapy [ 47 ]. The systemic immunity changes in cancer patients are characterized by the increase of immature and immunosuppressive myeloid cellular populations, lymphopenia, altered function of peripheral T cells, increased frequencies of suppressive lymphocyte populations, CD4 + regulatory T cells and regulatory B-cells, changes in neutrophil to lymphocyte ratio (NLR), among many other [ 48 ]. In sepsis neutrophils may have impaired chemotaxis and phagocytosis with promotion of neutrophil extracellular traps (NETs) in their interaction with platelets via the Toll-like 2 (TLR2) and TLR4 receptors, expansion of T regulatory cells, decrease CD4 and CD8 cells, immune exhaustion, and T cell apoptosis [ 49 ]. The inflammatory response in sepsis is acute and severe while in cancer patients it is chronic with low-grade inflammation (e.g., NLR is acutely increased in sepsis while less pronounced and chronic in cancer).

Immunosuppression in cancer is a broad term which is complex and poorly understood. In contrast to cancer patients, we can learn from other immunosuppressed patients such as solid organ transplant (SOT) patients where sepsis is also frequent and a common cause of death [ 50 , 51 ], although less often than with other immunosuppressed states. Two large retrospective analysis, one with about 30,000 ICU patients using the Sepsis-3 definition, and another with 903,816 sepsis hospitalizations (4.4% SOT), found that SOT patients presented a 14.4% lower 28-day mortality and OR 0.83 for hospital mortality (95% Confidence Interval, 0.79–0.87) compared to non-SOT septic patients, suggesting that immunosuppression alone may not always be associated with a worse outcome and other deleterious conditions may coexist [ 52 , 53 ].

The use of immunosuppressive drugs (e.g., corticosteroids or Bruton’s Tyrosine Kinase Inhibitors) is increasingly common in various diseases and in cancer patients. These drugs affect both innate and acquired immunity by diminishing phagocytosis and thereby the killing of bacterial and fungal pathogens, leading to systemic infections and significant defects in cell-mediated immunity during long-term treatment. These effects are dose-dependent and worsen with the combination of drugs [ 54 ]. Cytotoxic antineoplastic drugs affect all rapidly dividing cells, including bone marrow and gastrointestinal mucosa cells, making mucocutaneous barrier translocation a common source of bacterial infection in cancer patients. Antimetabolite agents (e.g., methotrexate, fluorouracil), often combined with corticosteroids, cause neutropenia and mucositis [ 55 ]. Alkylating agents (e.g., cyclophosphamide) cause bone marrow suppression, lower neutrophil, and lymphocyte counts, and increase the risk of infection. Anthracyclines (e.g., doxorubicin) also cause neutropenia and mucositis. Purine analogues (e.g., fludarabine) result in prolonged T-cell lymphopenia, exposing to infection from Staphylococcus , Streptococcus , GNB, Listeria , and Mycobacteria [ 56 ]. Anti-lymphocyte monoclonal antibodies (e.g., rituximab) deplete B lymphocytes, and alemtuzumab causes prolonged B- and T-cell lymphopenia, leading to a wide range of bacterial and non-bacterial infections [ 57 ]. Immune therapies (e.g., Anti-Tumor Necrosis Factor) affect both innate and acquired immune responses to microbial pathogens. Mycophenolate mofetil inhibits lymphocyte clonal expansion upon antigen exposure, while calcineurin inhibitors (cyclosporine and tacrolimus) primarily affect T-cells [ 58 ]. Anthracyclines can cause cardiotoxicity and long-term corticosteroid use can cause adrenal insufficiency. Altered gut microbiota diversity secondary to prolonged antimicrobial exposure is also a risk factor for bacteremia [ 59 , 60 ]. Endothelial stress secondary to cytotoxic chemotherapy could impair vasopressor response, although a study found no increased shock severity in cancer patients from chemotherapy exposure [ 61 ].

Evidence that immunosuppression affects severity of sepsis is conflicting and perspectives on the consequences of immunosuppression on the severity of sepsis may be changing. A recent multicenter retrospective study, comparing septic shock in non-cancer patients but on long-term immunosuppressive therapy to patients without immunosuppressive therapy, found no differences in ICU and 3-month mortality [ 62 ]. Another study found that in-hospital mortality was lower in patients taking immunosuppressive drugs than in patients not taking immunosuppressive drugs [ 63 ]. An experimental porcine study showed that immunosuppression from cyclosporine, methylprednisolone, and mycophenolate did not alter the hemodynamic response in septic shock. Plasma cytokines were similar, except for lower interleukin-6 and higher interleukin-10 levels in the immunosuppressed group [ 64 ].

Diagnostic challenges

The early recognition of clinical signs of sepsis is challenging in cancer patients because they may not display the same features as immunocompetent individuals. Corticosteroids can mask fever, whereas lymphoproliferative disorders and chemotherapy (e.g., cytosine arabinoside, dacarbazine, cyclophosphamide) can cause non-infectious fever. White blood cell count can either be high, e.g., after corticosteroids or granulocytic stimulants, or low, e.g., after chemotherapy. Due to a reduced inflammatory response, typical signs like redness, pain, heat, and swelling may be absent [ 65 , 66 ]. A low neutrophil count in the affected tissues may minimize the signs of infection which may worsen during recovery: e.g., acute respiratory distress syndrome may develop during neutropenia recovery in hematology malignancies with pneumonia [ 37 ].

Chest radiography, often first ordered for suspected lower respiratory tract infections, lacks sensitivity and specificity, making it difficult to detect new infiltrates and differentiate infection from inflammation (e.g., drug toxicity, radiation injury). Early chest computerized tomography (CT) has proven more effective than chest radiography [ 67 , 68 ]. A study found chest radiography of little value for early diagnosis of pulmonary infections on the first day of neutropenic fever, whereas low-dose CT detected pulmonary infiltrates in 80% of fungal pneumonia cases, with sensitivity, specificity, positive, and negative predictive values of 73%, 91%, 62%, and 94%, respectively [ 69 ]. However, international guidelines for community- and/or hospital-acquired pneumonias do not make any specific recommendation for patients with cancer [ 70 ].

Biomarkers, which present some limitations in the whole septic population, are even more difficult to interpret in cancer patients with sepsis [ 71 ]. Their levels are high in infectious and non-infectious conditions, e.g., mucositis, post-chemotherapy bone marrow depression, graft-versus-host disease, or by the tumor itself. C-reactive protein (CRP) is non-specific and may increase in extensive and metastatic cancers (renal, prostate, bladder), or after invasive procedures, radiation, or medications [ 72 ]. CRP concentrations are higher in case of neutropenia but its course over time does not depend on the presence of neutropenia [ 73 ]. CRP levels decrease in patients treated with tocilizumab, making it unreliable for detecting infections in this situation [ 74 ]. Baseline procalcitonin (PCT) levels are high in thyroid medullary carcinoma, lung cancer, and hepatocellular carcinoma, varying with disease stage, and higher in hematological malignancies than in solid tumors [ 75 ]. PCT lacks discriminatory value between GPB and GNB infections and between neutropenic and non-neutropenic patients [ 76 ].

Pro-adrenomedullin performs better than PCT in hematological patients, and the combination of both biomarkers to the Multinational Association of Supportive Care in Cancer (MASCC) index may be helpful [ 77 ]. PCT ≥ 1.5 ng/mL was predictive of septic shock with sensitivity and specificity of 84.0 and 90.7%. A MASCC score < 21 had a 46% sensitivity and 90% specificity in predicting bacteremia, and 68% and 90% in predicting septic shock, respectively [ 78 ]. PCT, CRP, and lipopolysaccharide-binding protein did not distinguish between systemic inflammatory response and infection but helped distinguish the presence of bacteremia in neutropenic patients [ 79 ]. In a condition of high prevalence of GNB in HSCT recipients, presepsin outperformed PCT and CRP for early diagnosis of GNB bloodstream infections in HSCT [ 80 ].

Other conditions that present with fever, multiorgan failure (including shock), and increase in inflammatory biomarker levels can resemble sepsis (Fig. 1 ). These mimickers include neutropenic enterocolitis (typhlitis), cytokine release syndrome (CRS) after CAR-T cell therapy or bispecific antibodies therapy, tumor lysis syndrome, hemophagocytic lymphohistiocytosis, or engraftment syndrome in HSCT, among others. Differential diagnosis of these syndromes with sepsis/septic shock can be challenging. Neutropenic enterocolitis is a dreadful condition seen after recent chemotherapy. It remains a diagnosis of exclusion that requires histological confirmation [ 81 ]. Thus, both clinical and microbiological infections are especially common during severe CRS and associated with poor outcome [ 82 , 83 ]. Therefore, one should aways entertain the diagnosis of sepsis and initiate immediately empirical antibiotic administration and specific therapy until securing a proper diagnosis. Fig. 1 Clinical vignettes: The need for a prompt admission to the ICU should be addressed for each vignette presented here

Management strategies

The management of septic shock in cancer patients should not depart from the strategy recommended for any septic shock and include four tenants: early recognition, early therapy (antibiotics, fluids, vasopressors, and source control), early ICU admission, and adjustment to the presumed cause of septic shock.

Early recognition should include a high degree of suspicion and awareness. The 2021 Surviving Sepsis Campaign guidelines recommend hospitals and health systems implement performance improvement programs, including sepsis screening for acutely ill, high-risk patients, and standard operating procedures for treatment [ 84 ]. The 2018 German guidelines for the management of sepsis in neutropenic cancer patients also encouraged screening criteria and performance improvement processes [ 85 ]. Many wearable devices such as smartwatches, fitness trackers, and medical devices patched to the body are available in the market. The combination of these devices and anomaly detection models have been used for early detection of COVID-19 infection in ambulatory settings [ 86 ]. At the same time, machine learning, artificial neural networks, decision trees, and other techniques have been used to improve early detection and management of sepsis and septic shock [ 87 ]. Although in the preliminary stages, their development is rapidly advancing and progressively integrated in our practice as part of the electronic health records clinical decision systems [ 88 ].

Early ICU admission is beneficial for septic patients with cancer [ 89 – 91 ]. Delayed ICU admission has been associated with worse outcomes [ 92 , 93 ]. Criteria alone are neither necessary nor sufficient to offer or decline ICU admission and vary across institutions, culture, and countries. It may be better to assess the potential for ICU admission based on the availability of technical support and clinician expertise. What happens in countries with limited resources is not well known. There is great variability among developing countries according to their size and healthcare systems (e.g., Ecuador versus West Africa-Nigeria or East Africa-Uganda) [ 94 – 96 ], and the availability of sepsis emergency medical services for early recognition, based on clinical signs that are easy to recognize, and simple and clear goal of care [ 97 ].

Addressing the suspected or confirmed source of septic shock should account for the type and duration of immunosuppression, prophylaxis given, geographic variations and the prevalence of MDRO, which have had a marked increase worldwide [ 98 ]. Recent epidemiologic data on the prevalence of MDRO colonization and infection highlight the role of contact precautions and isolation measures in limiting the emergence of MDRO. The prospective observational CIMDREA study demonstrated that cancer patients had a lower incidence rate of ICU-acquired MDRO colonization and/or infection [ 99 ]. Early antibiotic therapy and source control (e.g., removal of infected catheter) are particularly essential among patients with cancer and/or shock. In a study by Mokart et al. in neutropenic patients with severe sepsis, a delay of one hour between the first sign of sepsis in the ICU and the initiation of antibiotics was associated with an odds ratio of death of 10 [ 100 ]. In a recent observational study of 273,255 patients with community-onset sepsis, shorter time-to-antibiotics was associated with greater absolute mortality reduction among patients with metastatic cancer [ 101 ].

Recommendations for the antimicrobial treatment of neutropenic sepsis are consistent [ 102 – 105 ]. According to the ecology of the hospital, previous antibiotic exposure, and colonization, antibiotic treatment is based upon intravenous anti-pseudomonal cephalosporin or piperacillin-tazobactam or carbapenem. In critically ill patients, a combination therapy associating a beta-lactam with an aminoglycoside is safe [ 106 ] and has been associated with lower mortality [ 20 , 28 ]. Patients previously colonized by Methicillin-resistant Staphylococcus or Vancomycin-resistant Enterococcus or at elevated risk of carriage by resistant GBP should receive antibiotics that cover them. Vancomycin is the historical drug of choice for the treatment of MRSA, but linezolid, daptomycin and ceftaroline are also safe and efficient in this setting. Depending also on the clinical context, fungal and viral coverage could also be necessary [ 107 ]. Timely de-escalation with adequate antibiotics in neutropenic sepsis is safe and appropriate [ 108 ].

In the absence of specific data for cancer patients, fluid therapy and vasopressor administration should follow the recommendations for non-cancer patients [ 109 ]. A liberal red blood cell transfusion with a hemoglobin trigger of 9 g/dl was no more favorable than a restrictive strategy with a hemoglobin trigger of 7 g/dl in a population that included hematological malignancy and metastatic cancer [ 110 ]. However, a single center study in cancer patients with septic shock showed a survival trend favoring a liberal transfusion strategy when applied within the first 6 h of ICU admission [ 111 ] and a liberal transfusion strategy was associated with fewer major postoperative complications in patients having major cancer surgery compared with a restrictive strategy [ 112 ]. We need more studies to elucidate those discrepancies.

Prevention of infections is critical in high-risk oncology patients, and several organizations have developed evidence-based recommendations for antimicrobial prophylaxis that are beyond the scope of our review [ 113 ]. These range from the use of antibiotics (e.g., levofloxacin, trimethoprim/sulfamethoxazole, and cefpodoxime) to prevent bacterial infections in patients receiving treatments that cause neutropenia for over a week to the use of antifungals (e.g., fluconazole, posaconazole, voriconazole) in patients after stem cell transplant, acute myeloid leukemia. Antivirals (e.g., valacyclovir, acyclovir, letermovir, entecavir) are also added in these immunosuppressed groups to prevent herpes simplex, varicella zoster virus, cytomegalovirus, or hepatitis B virus [ 114 ].

Outcomes

Mortality in cancer patients with septic shock remains high but has declined over time [ 30 , 115 , 116 ] and may vary according to centers [ 117 , 118 ] and the immunodeficiency profile [ 119 ]. Three factors may be misconstrued as poor outcome: First, the use of Sepsis-3 criteria is associated with higher mortality (patients are sicker); second, there is admission selection bias (only the sicker patients or those expected to survive are admitted); third, cancer has become a chronic disease and more cancers at advanced stages are now admitted to the ICU. In 2019, Hensley et al. reported a 27.9% in-hospital mortality for septic cancer patients versus 19.5% for non-cancer septic patients [ 2 ]. A systematic review and meta-analysis by Nazer et al. found a mortality rate of 60% among septic cancer patients [ 120 ]. Kim et al. reported that among 322,526 patients hospitalized for septic shock (2009–2017), 13.6% had cancer, with 52% 30-day and 81.2% one-year mortality [ 121 ]. Two other studies using Sepsis-3 criteria found high mortality in cancer patients with septic shock [ 28 , 29 ]. Hematological patients had 67.7% 28-day and 80.6% 90-day mortality, while solid tumor patients had 69.4% and 77.1%, respectively. Studies using older criteria reported lower mortality rates, whereas mortality was higher when using Sepsis-3 definitions [ 122 ] (Table 3 ). Table 3 Studies reporting mortality in cancer patients with septic shock comprising study populations since 2004 Ref Year Country N Cancer type(s) Mortality 28–30 day 90-day In-hospital In-ICU 1-year [ 140 ] 2024 USA 132 Solid: 50%HM: 50% 80 (60.6) 57 (43.2) 110 (83.3) [ 141 ] 2022 Korea 897 Solid 237 (26.4) 1 [ 121 , 142 ] 2022 Korea 43,466 Solid: 87.7% HM 2 : 12.3% 22,639 (52.1) 35,338 (81.3) [ 29 ] 2022 USA 271 Solid 188 (69.4) 186 (68.6) 159 (58.7) [ 28 ] 2022 USA 459 HM 311 (67.8) 370 (80.6) 339 (73.9) 293 (63.8) [ 123 , 143 ] 2021 Jordan 1408 Solid: 67.8% HM: 32.2% 914 (64.9) 688 (48.9) [ 126 ] 2020 France 252 Solid: 52.8% HM: 47.2% 121 (48) 101 (40) [ 144 ] 2020 Korea 897 Solid 237 (26.4) [ 149 ] 2019 Korea 478 Solid 208 (43.5) [ 145 ] 2019 Saudi Arabia 100 Solid: 68% HM: 32% 76 (76) 61 (61) [ 150 ] 2019 Taiwan 11,825 Solid 8199 (69.3) [ 146 ] 2018 France 60 Solid: 35% HM: 65% 28 (47) [ 117 ] 2012 France 3437 Solid: 61.6% HM: 38.3% 2029 (59) [ 147 ] 2011 Mexico 82 Solid: 68% HM: 32% 34 (41.5) [ 115 ] 2008 France 148 Solid: 42.6% HM: 57.4% 78 (52.7) [ 148 ] 2008 Korea 50 HM 30 (60) 1 Number (%); 2 Hematological cancer, HM Hematological, ICU Intensive Care Unit

In cancer patients admitted to ICU with septic shock, different predictors have been identified: First, predictors of reduced survival include mechanical ventilation, illness severity, thrombocytopenia, positive cultures, elevated bilirubin, and high lactate level [ 123 ]. Increased mortality in hematologic cancer patients was associated with respiratory failure, higher Sequential Organ Failure Assessment (SOFA) score on admission, and high lactate levels [ 28 ]. The degree or organ dysfunction and neutropenia were not associated with increased mortality [ 124 , 125 ]. In solid tumor patients, mortality predictors included high lactate levels, metastatic stage, respiratory failure, and an Eastern Cooperative Oncology Group (ECOG) score of 3 or 4 [ 29 ]. Second, predictors of improved survival in hematological patients include higher albumin levels, the use of aminoglycoside, and G-CSF [ 28 ].

Reluctancy to ICU admission stems from the fact that the mortality in cancer patients admitted to the ICU with septic shock can be exceedingly high, raising questions about aligning ICU admission with goals of care and the decision to forgo life-sustaining therapy [ 28 , 29 , 126 ]. Recently, a study on the prognosis of patients with septic shock compared those with and without cancer and showed no difference, which is a similar ICU and hospital mortality [ 107 ]. A new paradigm is that ICU admission should not depend on the underlying immunosuppression and stage of cancer but on the degree of clinician expertise, technological support readily available and multi-discipline collaboration including telemedicine [ 127 ].

Besides the common determinants of death related to the underlying functional impairment and the extent of organ dysfunction, therapeutic strategies associated with improved survival include early recognition, early adequate antibiotic therapy and source control, early ICU admission. More debated issues are the inclusion of aminoglycosides, the place of liberal blood transfusion, and the addition of colony-stimulating factors [ 128 , 129 ].

It is important to note that evaluating the prognosis of cancer patients may require different criteria than those for non-cancer counterparts. Emphasis on hospital discharge and quality of life may be more appropriate measures in advanced cases not responding to cancer therapies [ 130 ]. Additionally, assessing the risk of ICU readmission and further adjusting the underlying hematology-oncology management, such as reducing therapy intensity, discontinuing treatment, and emphasizing patient-centered palliative care are also important considerations [ 131 , 132 ].

Gaps and future research directions

Because of their exclusion from epidemiological studies and clinical trials, the management of cancer patients follows the rules established for non-cancer patients. Efforts should be made to include more diverse populations in clinical trials to reduce the inappropriate extrapolation of potentially inapplicable results to underrepresented patient groups [ 133 ]. Poor clinical outcomes may be due to delay in therapy, inadequate therapy, or simply lack of data available regarding specific interventions in this population, rather than the shortfalls in medical care or healthcare systems.

Research priorities should include developing better diagnostic and prediction tools (e.g., use of artificial intelligence), better understanding of the pathophysiology of critical illness in cancer patients, optimizing diagnostic strategies, role of new immunotherapy agents (e.g., checkpoint inhibitors), treatment protocols (e.g., integration of machine learning models) [ 134 , 135 ] and new challenges for palliative care such as dealing with novel side effect profiles and coping with greater uncertainty regarding prognosis [ 132 ]. Identifying prognostic factors in addition to patient age, cancer type, disease stage, and prior treatment responses is also crucial for guiding ICU decisions and improving patient outcomes [ 109 ].

Implications for clinical practice and recommendations

Strategies to identify these patients early and application of unbiased ICU admission criteria are crucial for improving clinical outcomes [ 136 , 137 ]. Triage decisions should be based on intensive care needs rather than the malignancy or immunosuppression alone, and the management supported by a multidisciplinary team approach to provide comprehensive care. We propose a new paradigm that integrates innovative technologies and practices across the healthcare continuum of these complex patients (Fig. 2 ). An integrated system where risk assessment, active surveillance (e.g., wearable technologies), accurate sepsis prediction models through machine learning and artificial intelligence, precision medicine (e.g., metabolomics, proteomics), and others will complement the targeted management strategies [ 138 ]. Fig. 2 New Paradigm. Despite a rise in prevalence and severity of septic shock in immunosuppressed patients, survival has improved over time. An advanced stage of the disease should not deter from ICU admission, nor the use of novel technologies such as wearable devices, outreach programs, artificial intelligence, and machine learning models for early detection and diagnosis. Critical care should remain in line with values and preference of the patient supported by their family

To improve outcomes for cancer patients, it is crucial to promote awareness of the detrimental effects of failing to control infections in their initial stages. Developing strategies for earlier detection and avoiding misdiagnosis with non-infectious causes is essential. Early interventions by critical care teams, such as through critical care outreach programs, early warning systems, remote tele-ICU particularly when specialized ICU beds are sparse, and earlier admission to ICU, improve outcomes. Adequate management of antimicrobials is essential. Additionally, there is a need for more research into the ambulatory antimicrobial management of these patients, as well as further investigation into the accuracy of biomarkers and phenotype profile, the combined use of aminoglycosides, e.g., Combination-Lock01 study [ 139 ], the role of hematopoietic colony stimulating factors in cases of neutropenic sepsis or septic shock and optimal blood transfusion strategy.

Conclusion

Cancer incidence rates are rising, and so are the rates of septic shock among these patient populations. Malignancies are risk factors for sepsis and septic shock due to their impact on both innate and acquired immunity. Infection symptoms in cancer patients may be lacking, necessitating a high index of suspicion and early detection through more accurate and rapid methods. The sites of infections often depend on the cancer type. The types of organisms vary based on the type of immunosuppression, disease stage, duration, therapies, and local prevalence of MDRO. Mimickers of septic shock should always be on the differential. While cancers can be risk factors for poor outcomes, immunosuppressive therapies or immunotherapies might mitigate the immune response which deserves further investigation.

Septic shock is a medical emergency which imposes an immediate transfer to the ICU when there is a need for specific technical support and critical care expertise. Management of septic shock in immunosuppressed cancer patients should follow general sepsis management guidelines with additional considerations tailored to specifics inherent to cancers. Understanding and addressing the unique needs of cancer patients through a new paradigm, which includes the integration of innovative technologies into our healthcare system, targeted management strategies, and robust clinical practices, including early identification and diagnosis, coupled with early admission to ICUs that promote a multidisciplinary approach, is crucial for improving their prognosis and overall survival rates. No cancer patient should eschew ICU care solely because of their underlying disease.

Abbreviations

C- reactive protein

Cytokine release syndrome

Computerized tomography

Eastern Cooperative Oncology Group

Emergency room

Granulocyte colony stimulating factor

Gram-negative bacteria

Gram-positive bacteria

Hematopoietic stem cell transplantation

Intensive Care Unit

Multidrug-resistant organisms

Neutrophil extracellular trap

Neutrophil to lymphocyte ratio

Procalcitonin

Solid organ transplantation

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Author contributions

All authors collaborated to the conception of the manuscript, the redaction of the draft, tables and figures, editing and final approval of the manuscript. J.L.N. and P.R.B. put the manuscript together, and harmonized flow and balance of the whole project.

Funding

This work was supported by a discretionary fund from the Division of Pulmonary and Critical Care Medicine, Mayo Clinic, Rochester, MN, USA.

Availability of data and materials

Data sharing is not applicable to this article as no datasets were generated or analyzed during the current study.

Declarations

Ethical approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Competing interests

FP received lecture and consulting fees from Gilead. PC received honoraria for scientific collaboration from Pfizer, MSD, Gilead, and AbbVie, and advisory board fees from Alexion, Janssen, Sanofi and Gilead. PP received lecture fees from Gilead, Pfizer, Mundipharma, MSD and advisory board fees from Biocodex, Gilead. SD received lecture fees from Octapharm, OrphaSwiss, Alexion and advisory board fees from Alexion, Santersus, and Pantherna. The other authors declare no conflict of interest applicable to this work.

References

1. Martinson ML Lapham J Prevalence of Immunosuppression among US adults JAMA 2024 331 880 882 10.1001/jama.2023.28019 38358771 PMC10870224 Martinson ML, Lapham J. Prevalence of Immunosuppression among US adults. JAMA. 2024;331:880–2. 38358771 10.1001/jama.2023.28019 PMC10870224

2. Hensley MK Donnelly JP Carlton EF Prescott HC Epidemiology and outcomes of cancer-related versus non-cancer-related sepsis hospitalizations Crit Care Med 2019 47 1310 1316 10.1097/CCM.0000000000003896 31356477 PMC6815199 Hensley MK, Donnelly JP, Carlton EF, Prescott HC. Epidemiology and outcomes of cancer-related versus non-cancer-related sepsis hospitalizations. Crit Care Med. 2019;47:1310–6. 31356477 10.1097/CCM.0000000000003896 PMC6815199

3. Pyarali FF Iordanov R Palacio A Tamariz L Excess mortality risk from sepsis in patients with HIV—a meta-analysis J Crit Care 2020 59 101 107 10.1016/j.jcrc.2020.05.018 32590302 Pyarali FF, Iordanov R, Palacio A, Tamariz L. Excess mortality risk from sepsis in patients with HIV—a meta-analysis. J Crit Care. 2020;59:101–7. 32590302 10.1016/j.jcrc.2020.05.018

4. Lecuyer L Chevret S Thiery G Darmon M Schlemmer B Azoulay E The ICU trial: a new admission policy for cancer patients requiring mechanical ventilation Crit Care Med 2007 35 808 814 10.1097/01.CCM.0000256846.27192.7A 17235261 Lecuyer L, Chevret S, Thiery G, Darmon M, Schlemmer B, Azoulay E. The ICU trial: a new admission policy for cancer patients requiring mechanical ventilation. Crit Care Med. 2007;35:808–14. 17235261 10.1097/01.CCM.0000256846.27192.7A

5. Guidelines for intensive care unit admission discharge and triage Task force of the American college of critical care medicine society of critical care medicine Crit Care Med 1999 27 633 8 10199547 Guidelines for intensive care unit admission discharge and triage. Task force of the American college of critical care medicine society of critical care medicine. Crit Care Med. 1999;27:633–8. 10199547

6. Nates JL Nunnally M Kleinpell R Blosser S Goldner J Birriel B ICU admission, discharge, and triage guidelines: a framework to enhance clinical operations, development of institutional policies, and further research Crit Care Med 2016 44 1553 1602 10.1097/CCM.0000000000001856 27428118 Nates JL, Nunnally M, Kleinpell R, Blosser S, Goldner J, Birriel B, et al. ICU admission, discharge, and triage guidelines: a framework to enhance clinical operations, development of institutional policies, and further research. Crit Care Med. 2016;44:1553–602. 27428118 10.1097/CCM.0000000000001856

7. De Backer D Deutschman CS Hellman J Myatra SN Ostermann M Prescott HC Surviving Sepsis campaign research committee. Surviving sepsis campaign research priorities 2023 Crit Care Med 2024 52 268 296 10.1097/CCM.0000000000006135 38240508 De Backer D, Deutschman CS, Hellman J, Myatra SN, Ostermann M, Prescott HC, et al. Surviving Sepsis campaign research committee. Surviving sepsis campaign research priorities 2023. Crit Care Med. 2024;52:268–96. 38240508 10.1097/CCM.0000000000006135

8. Danai PA Moss M Mannino DM Martin GS The epidemiology of sepsis in patients with malignancy Chest 2006 129 1432 1440 10.1378/chest.129.6.1432 16778259 Danai PA, Moss M, Mannino DM, Martin GS. The epidemiology of sepsis in patients with malignancy. Chest. 2006;129:1432–40. 16778259 10.1378/chest.129.6.1432

9. National Cancer Institute. Annual report to the nation 2019: overall cancer statistics. https://seer.cancer.gov/report_to_nation/statistics.html Last accessed May 30, 2024.

10. National Cancer Institute-Cancer Statistics. https://www.cancer.gov/about-cancer/understanding/statistics . Accessed 30 May 2024.

11. Roser M, Ritchie H, Ortiz-Ospina E. World population growth. Our world in data 2019, University of Oxford. https://ourworldindata.org/world-population-growth . Accessed 30 May 2024.

12. Department of Economic and Social Affairs, Population Division, United Nations. World population Ageing 2015 Report. Accessed 30 May 2024.

13. Rozhok AI DeGregori J The evolution of lifespan and age-dependent cancer risk Trends Cancer 2016 2 552 560 10.1016/j.trecan.2016.09.004 28439564 PMC5400291 Rozhok AI, DeGregori J. The evolution of lifespan and age-dependent cancer risk. Trends Cancer. 2016;2:552–60. 28439564 10.1016/j.trecan.2016.09.004 PMC5400291

14. Weir HK Thompson TD Stewart SL White MC Cancer incidence projections in the United States between 2015 and 2050 Prev Chronic Dis 2021 18 E59 10.5888/pcd18.210006 34114543 PMC8220959 Weir HK, Thompson TD, Stewart SL, White MC. Cancer incidence projections in the United States between 2015 and 2050. Prev Chronic Dis. 2021;18:E59. 34114543 10.5888/pcd18.210006 PMC8220959

15. Cancer Today. International agency for research on cancer. World health organization. https://gco.iarc.who.int/today/en/dataviz/pie?mode=population&group_populations=0 . Accessed 30 May 2024.

16. Siegel RL Miller KD Wagle NS Jemal A Cancer statistics, 2023 CA Cancer J Clin 2023 73 17 48 10.3322/caac.21763 36633525 Siegel RL, Miller KD, Wagle NS, Jemal A. Cancer statistics, 2023. CA Cancer J Clin. 2023;73:17–48. 36633525 10.3322/caac.21763

17. Bray F Laversanne M Sung H Ferlay J Siegel RL Soerjomataram I Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries CA Cancer J Clin 2024 74 229 263 10.3322/caac.21834 38572751 Bray F, Laversanne M, Sung H, Ferlay J, Siegel RL, Soerjomataram I, et al. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2024;74:229–63. 38572751 10.3322/caac.21834

18. Rivera DR Gallicchio L Brown J Liu B Kyriacou DN Shelburne N Trends in adult cancer-related emergency department utilization: an analysis of data from the nationwide emergency department sample JAMA Oncol 2017 3 e172450 10.1001/jamaoncol.2017.2450 28859189 PMC5824316 Rivera DR, Gallicchio L, Brown J, Liu B, Kyriacou DN, Shelburne N. Trends in adult cancer-related emergency department utilization: an analysis of data from the nationwide emergency department sample. JAMA Oncol. 2017;3: e172450. 28859189 10.1001/jamaoncol.2017.2450 PMC5824316

19. Yang Z Yang R Kwak MJ Qdaisat A Lin J Begley CE Oncologic emergencies in a cancer center emergency department and in general emergency departments countywide and nationwide PLoS ONE 2018 13 e0191658 10.1371/journal.pone.0191658 29462166 PMC5819770 Yang Z, Yang R, Kwak MJ, Qdaisat A, Lin J, Begley CE, et al. Oncologic emergencies in a cancer center emergency department and in general emergency departments countywide and nationwide. PLoS ONE. 2018;13: e0191658. 29462166 10.1371/journal.pone.0191658 PMC5819770

20. Legrand M Max A Peigne V Mariotte E Canet E Debrumetz A Survival in neutropenic patients with severe sepsis or septic shock Crit Care Med 2012 40 43 49 10.1097/CCM.0b013e31822b50c2 21926615 Legrand M, Max A, Peigne V, Mariotte E, Canet E, Debrumetz A, et al. Survival in neutropenic patients with severe sepsis or septic shock. Crit Care Med. 2012;40:43–9. 21926615 10.1097/CCM.0b013e31822b50c2

21. Wallace SK Rathi NK Waller DK Ensor JE Jr Haque SA Price KJ Two decades of ICU utilization and hospital outcomes in a comprehensive cancer center Crit Care Med 2016 44 926 933 10.1097/CCM.0000000000001568 26765498 Wallace SK, Rathi NK, Waller DK, Ensor JE Jr, Haque SA, Price KJ, et al. Two decades of ICU utilization and hospital outcomes in a comprehensive cancer center. Crit Care Med. 2016;44:926–33. 26765498 10.1097/CCM.0000000000001568

22. Malik IA Cardenas-Turanzas M Gaeta S Borthakur G Price K Cortes J Sepsis and acute myeloid leukemia: a population-level study of comparative outcomes of patients discharged from texas hospitals Clin Lymphoma Myeloma Leuk 2017 17 e27 e32 10.1016/j.clml.2017.07.009 28844403 Malik IA, Cardenas-Turanzas M, Gaeta S, Borthakur G, Price K, Cortes J, et al. Sepsis and acute myeloid leukemia: a population-level study of comparative outcomes of patients discharged from texas hospitals. Clin Lymphoma Myeloma Leuk. 2017;17:e27–32. 28844403 10.1016/j.clml.2017.07.009

23. Rhee C Dantes R Epstein L Murphy DJ Seymour CW Iwashyna TJ Incidence and trends of sepsis in US hospitals using clinical vs claims data, 2009–2014 JAMA 2017 318 1241 1249 10.1001/jama.2017.13836 28903154 PMC5710396 Rhee C, Dantes R, Epstein L, Murphy DJ, Seymour CW, Iwashyna TJ, et al. Incidence and trends of sepsis in US hospitals using clinical vs claims data, 2009–2014. JAMA. 2017;318:1241–9. 28903154 10.1001/jama.2017.13836 PMC5710396

24. Brun-Buisson C Meshaka P Pinton P Vallet B EPISEPSIS: a reappraisal of the epidemiology and outcome of severe sepsis in French intensive care units Intensive Care Med 2004 30 580 8 10.1007/s00134-003-2136-x 14997295 Brun-Buisson C, Meshaka P, Pinton P, Vallet B. EPISEPSIS: a reappraisal of the epidemiology and outcome of severe sepsis in French intensive care units. Intensive Care Med. 2004;30:580–8. 14997295 10.1007/s00134-003-2136-x

25. Vincent JL Rello J Marshall J Silva E Anzueto A Martin CD International study of the prevalence and outcomes of infection in intensive care units JAMA 2009 302 2323 2329 10.1001/jama.2009.1754 19952319 Vincent JL, Rello J, Marshall J, Silva E, Anzueto A, Martin CD, et al. International study of the prevalence and outcomes of infection in intensive care units. JAMA. 2009;302:2323–9. 19952319 10.1001/jama.2009.1754

26. Vincent JL Sakr Y Singer M Martin-Loeches I Machado FR Marshall JC Prevalence and outcomes of infection among patients in intensive care units in 2017 JAMA 2020 323 1478 1487 10.1001/jama.2020.2717 32207816 PMC7093816 Vincent JL, Sakr Y, Singer M, Martin-Loeches I, Machado FR, Marshall JC, et al. Prevalence and outcomes of infection among patients in intensive care units in 2017. JAMA. 2020;323:1478–87. 32207816 10.1001/jama.2020.2717 PMC7093816

27. Bayraktar UD Shpall EJ Liu P Ciurea SO Rondon G de Lima M Hematopoietic cell transplantation-specific comorbidity index predicts inpatient mortality and survival in patients who received allogeneic transplantation admitted to the intensive care unit J Clin Oncol 2013 31 4207 4214 10.1200/JCO.2013.50.5867 24127454 PMC4878009 Bayraktar UD, Shpall EJ, Liu P, Ciurea SO, Rondon G, de Lima M, et al. Hematopoietic cell transplantation-specific comorbidity index predicts inpatient mortality and survival in patients who received allogeneic transplantation admitted to the intensive care unit. J Clin Oncol. 2013;31:4207–14. 24127454 10.1200/JCO.2013.50.5867 PMC4878009

28. Manjappachar NK Cuenca JA Ramírez CM Hernandez M Martin P Reyes MP Outcomes and predictors of 28-day mortality in patients with hematologic malignancies and septic shock defined by sepsis-3 criteria J Natl Compr Canc Netw 2022 20 45 53 10.6004/jnccn.2021.7046 34991066 Manjappachar NK, Cuenca JA, Ramírez CM, Hernandez M, Martin P, Reyes MP, et al. Outcomes and predictors of 28-day mortality in patients with hematologic malignancies and septic shock defined by sepsis-3 criteria. J Natl Compr Canc Netw. 2022;20:45–53. 34991066 10.6004/jnccn.2021.7046

29. Cuenca JA Manjappachar NK Ramírez CM Hernandez M Martin P Gutierrez C Outcomes and predictors of 28-day mortality in patients with solid tumors and septic shock defined by third international consensus definitions for sepsis and septic shock criteria Chest 2022 162 1063 1073 10.1016/j.chest.2022.05.017 35644244 PMC9808606 Cuenca JA, Manjappachar NK, Ramírez CM, Hernandez M, Martin P, Gutierrez C, et al. Outcomes and predictors of 28-day mortality in patients with solid tumors and septic shock defined by third international consensus definitions for sepsis and septic shock criteria. Chest. 2022;162:1063–73. 35644244 10.1016/j.chest.2022.05.017 PMC9808606

30. Liu MA Bakow BR Hsu TC Chen JY Su KY Asiedu EK Temporal trends in sepsis incidence and mortality in patients with cancer in the US population Am J Crit Care 2021 30 e71 e79 10.4037/ajcc2021632 34195781 Liu MA, Bakow BR, Hsu TC, Chen JY, Su KY, Asiedu EK, et al. Temporal trends in sepsis incidence and mortality in patients with cancer in the US population. Am J Crit Care. 2021;30:e71–9. 34195781 10.4037/ajcc2021632

31. Rubin RH Schaffner A Speich R Introduction to the Immunocompromised Host Society consensus conference on epidemiology, prevention, diagnosis, and management of infections in solid-organ transplant patients Clin Infect Dis 2001 33 Suppl 1 S1 4 10.1086/320896 11389514 Rubin RH, Schaffner A, Speich R. Introduction to the Immunocompromised Host Society consensus conference on epidemiology, prevention, diagnosis, and management of infections in solid-organ transplant patients. Clin Infect Dis. 2001;33(Suppl 1):S1-4. 11389514 10.1086/320896

32. Fernández S Palomo M Molina P Díaz-Ricart M Escolar G Téllez A Progressive endothelial cell damage in correlation with sepsis severity. Defibrotide as a contender J Thromb Haemost 2021 19 1948 1958 10.1111/jth.15343 33872468 Fernández S, Palomo M, Molina P, Díaz-Ricart M, Escolar G, Téllez A, et al. Progressive endothelial cell damage in correlation with sepsis severity. Defibrotide as a contender. J Thromb Haemost. 2021;19:1948–58. 33872468 10.1111/jth.15343

33. Wiersinga WJ van der Poll T Immunopathophysiology of human sepsis EBioMedicine 2022 86 104363 10.1016/j.ebiom.2022.104363 36470832 PMC9783164 Wiersinga WJ, van der Poll T. Immunopathophysiology of human sepsis. EBioMedicine. 2022;86: 104363. 36470832 10.1016/j.ebiom.2022.104363 PMC9783164

34. 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 10.1038/s41590-023-01660-5 38168953 Giamarellos-Bourboulis EJ, Aschenbrenner AC, Bauer M, Bock C, Calandra T, Gat-Viks I, et al. The pathophysiology of sepsis and precision-medicine-based immunotherapy. Nat Immunol. 2024;25:19–28. 38168953 10.1038/s41590-023-01660-5

35. Heesterbeek DAC Angelier ML Harrison RA Rooijakkers SHM Complement and bacterial infections: from molecular mechanisms to therapeutic applications J Innate Immun 2018 10 455 464 10.1159/000491439 30149378 PMC6784045 Heesterbeek DAC, Angelier ML, Harrison RA, Rooijakkers SHM. Complement and bacterial infections: from molecular mechanisms to therapeutic applications. J Innate Immun. 2018;10:455–64. 30149378 10.1159/000491439 PMC6784045

36. Azoulay E Russell L Van de Louw A Metaxa V Bauer P Povoa P Diagnosis of severe respiratory infections in immunocompromised patients Intensive Care Med 2020 46 298 314 10.1007/s00134-019-05906-5 32034433 PMC7080052 Azoulay E, Russell L, Van de Louw A, Metaxa V, Bauer P, Povoa P, et al. Diagnosis of severe respiratory infections in immunocompromised patients. Intensive Care Med. 2020;46:298–314. 32034433 10.1007/s00134-019-05906-5 PMC7080052

37. Gudiol C Albasanz-Puig A Cuervo G Carratalà J Understanding and managing sepsis in patients with cancer in the era of antimicrobial resistance Front Med 2021 8 636547 10.3389/fmed.2021.636547 PMC8044357 33869250 Gudiol C, Albasanz-Puig A, Cuervo G, Carratalà J. Understanding and managing sepsis in patients with cancer in the era of antimicrobial resistance. Front Med. 2021;8: 636547. 10.3389/fmed.2021.636547 PMC8044357 33869250

38. Jamme M Daviaud F Charpentier J Marin N Thy M Hourmant Y Time course of septic shock in immunocompromised and nonimmunocompromised patients Crit Care Med 2017 45 2031 2039 10.1097/CCM.0000000000002722 28937407 Jamme M, Daviaud F, Charpentier J, Marin N, Thy M, Hourmant Y, et al. Time course of septic shock in immunocompromised and nonimmunocompromised patients. Crit Care Med. 2017;45:2031–9. 28937407 10.1097/CCM.0000000000002722

39. Opal SM Cross AS The use of immunocompromised animals as models for human septic shock Shock 2005 24 Suppl 1 64 70 10.1097/01.shk.0000191335.93412.3e 16374375 Opal SM, Cross AS. The use of immunocompromised animals as models for human septic shock. Shock. 2005;24(Suppl 1):64–70. 16374375 10.1097/01.shk.0000191335.93412.3e

40. Delano MJ Ward PA Sepsis-induced immune dysfunction: can immune therapies reduce mortality? J Clin Invest 2016 126 23 31 10.1172/JCI82224 26727230 PMC4701539 Delano MJ, Ward PA. Sepsis-induced immune dysfunction: can immune therapies reduce mortality? J Clin Invest. 2016;126:23–31. 26727230 10.1172/JCI82224 PMC4701539

41. Nasa P Juneja D Singh O Severe sepsis and septic shock in the elderly: an overview World J Crit Care Med 2012 1 23 30 10.5492/wjccm.v1.i1.23 24701398 PMC3956061 Nasa P, Juneja D, Singh O. Severe sepsis and septic shock in the elderly: an overview. World J Crit Care Med. 2012;1:23–30. 24701398 10.5492/wjccm.v1.i1.23 PMC3956061

42. Williams MD Braun LA Cooper LM Johnston J Weiss RV Qualy RL Hospitalized cancer patients with severe sepsis: analysis of incidence, mortality, and associated costs of care Crit Care 2004 8 R291 R298 10.1186/cc2893 15469571 PMC1065011 Williams MD, Braun LA, Cooper LM, Johnston J, Weiss RV, Qualy RL, et al. Hospitalized cancer patients with severe sepsis: analysis of incidence, mortality, and associated costs of care. Crit Care. 2004;8:R291–8. 15469571 10.1186/cc2893 PMC1065011

43. Mirouse A Vigneron C Llitjos JF Chiche JD Mira JP Mokart D Sepsis and cancer: an interplay of friends and foes Am J Respir Crit Care Med 2020 202 1625 1635 10.1164/rccm.202004-1116TR 32813980 Mirouse A, Vigneron C, Llitjos JF, Chiche JD, Mira JP, Mokart D, et al. Sepsis and cancer: an interplay of friends and foes. Am J Respir Crit Care Med. 2020;202:1625–35. 32813980 10.1164/rccm.202004-1116TR

44. Martin S Baldock SC Ghoneim AT Child JA Defective neutrophil function and microbicidal mechanisms in the myelodysplastic disorders J Clin Pathol 1983 36 1120 1128 10.1136/jcp.36.10.1120 6311878 PMC498487 Martin S, Baldock SC, Ghoneim AT, Child JA. Defective neutrophil function and microbicidal mechanisms in the myelodysplastic disorders. J Clin Pathol. 1983;36:1120–8. 6311878 10.1136/jcp.36.10.1120 PMC498487

45. Reiné J Cooper K Sewell A Lyall J Thorbinson C Hincks E Neutrophil function is impaired in paediatric patients with malignancy and may be a useful clinical marker Clin Transl Oncol 2020 22 2121 2125 10.1007/s12094-020-02362-2 32410117 Reiné J, Cooper K, Sewell A, Lyall J, Thorbinson C, Hincks E, et al. Neutrophil function is impaired in paediatric patients with malignancy and may be a useful clinical marker. Clin Transl Oncol. 2020;22:2121–5. 32410117 10.1007/s12094-020-02362-2

46. Gurule NJ Malcolm KC Harris C Knapp JR O'Connor BP McClendon J Myelodysplastic neoplasm-associated U2AF1 mutations induce host defense defects by compromising neutrophil chemotaxis Leukemia 2023 37 2115 2124 10.1038/s41375-023-02007-7 37591942 PMC10539173 Gurule NJ, Malcolm KC, Harris C, Knapp JR, O’Connor BP, McClendon J, et al. Myelodysplastic neoplasm-associated U2AF1 mutations induce host defense defects by compromising neutrophil chemotaxis. Leukemia. 2023;37:2115–24. 37591942 10.1038/s41375-023-02007-7 PMC10539173

47. Georges Q Azoulay E Mokart D Soares M Jeon K Oeyen S Influence of neutropenia on mortality of critically ill cancer patients: results of a meta-analysis on individual data Crit Care 2018 22 326 10.1186/s13054-018-2076-z 30514339 PMC6280476 Georges Q, Azoulay E, Mokart D, Soares M, Jeon K, Oeyen S, et al. Influence of neutropenia on mortality of critically ill cancer patients: results of a meta-analysis on individual data. Crit Care. 2018;22:326. 30514339 10.1186/s13054-018-2076-z PMC6280476

48. Hiam-Galvez KJ Allen BM Spitzer MH Systemic immunity in cancer Nat Rev Cancer 2021 21 345 359 10.1038/s41568-021-00347-z 33837297 PMC8034277 Hiam-Galvez KJ, Allen BM, Spitzer MH. Systemic immunity in cancer. Nat Rev Cancer. 2021;21:345–59. 33837297 10.1038/s41568-021-00347-z PMC8034277

49. Arora J Mendelson AA Fox-Robichaud A Sepsis: network pathophysiology and implications for early diagnosis Am J Physiol Regul Integr Comp Physiol 2023 324 R613 R624 10.1152/ajpregu.00003.2023 36878489 PMC10085556 Arora J, Mendelson AA, Fox-Robichaud A. Sepsis: network pathophysiology and implications for early diagnosis. Am J Physiol Regul Integr Comp Physiol. 2023;324:R613–24. 36878489 10.1152/ajpregu.00003.2023 PMC10085556

50. Kutinova A Woodward RS Ricci JF Brennan DC The incidence and costs of sepsis and pneumonia before and after renal transplantation in the United States Am J Transplant 2006 6 129 139 10.1111/j.1600-6143.2005.01156.x 16433767 Kutinova A, Woodward RS, Ricci JF, Brennan DC. The incidence and costs of sepsis and pneumonia before and after renal transplantation in the United States. Am J Transplant. 2006;6:129–39. 16433767 10.1111/j.1600-6143.2005.01156.x

51. Adam R Karam V Delvart V O'Grady J Mirza D Klempnauer J Evolution of indications and results of liver transplantation in Europe. A report from the European liver transplant registry (ELTR) J Hepatol 2012 57 675 88 10.1016/j.jhep.2012.04.015 22609307 Adam R, Karam V, Delvart V, O’Grady J, Mirza D, Klempnauer J, et al. Evolution of indications and results of liver transplantation in Europe. A report from the European liver transplant registry (ELTR). J Hepatol. 2012;57:675–88. 22609307 10.1016/j.jhep.2012.04.015

52. Donnelly JP Locke JE MacLennan PA McGwin G Jr Mannon RB Safford MM Inpatient mortality among solid organ transplant recipients hospitalized for sepsis and severe sepsis Clin Infect Dis 2016 63 186 194 10.1093/cid/ciw295 27217215 PMC4928388 Donnelly JP, Locke JE, MacLennan PA, McGwin G Jr, Mannon RB, Safford MM, et al. Inpatient mortality among solid organ transplant recipients hospitalized for sepsis and severe sepsis. Clin Infect Dis. 2016;63:186–94. 27217215 10.1093/cid/ciw295 PMC4928388

53. Ackerman KS Hoffman KL Díaz I Simmons W Ballman KV Kodiyanplakkal RP Effect of sepsis on death as modified by solid organ transplantation Open Forum Infect Dis 2023 10 ofad148 10.1093/ofid/ofad148 37056981 PMC10086309 Ackerman KS, Hoffman KL, Díaz I, Simmons W, Ballman KV, Kodiyanplakkal RP, et al. Effect of sepsis on death as modified by solid organ transplantation. Open Forum Infect Dis. 2023;10:ofad148. 37056981 10.1093/ofid/ofad148 PMC10086309

54. Widdifield J Bernatsky S Paterson JM Gunraj N Thorne JC Pope J Serious infections in a population-based cohort of 86,039 seniors with rheumatoid arthritis Arthritis Care Res 2013 65 353 361 10.1002/acr.21812 22833532 Widdifield J, Bernatsky S, Paterson JM, Gunraj N, Thorne JC, Pope J, et al. Serious infections in a population-based cohort of 86,039 seniors with rheumatoid arthritis. Arthritis Care Res. 2013;65:353–61. 10.1002/acr.21812 22833532

55. Ota R Hata T Hirata A Hamada T Nishihara M Neo M Risk of infection from glucocorticoid and methotrexate interaction in patients with rheumatoid arthritis using biologics: a retrospective cohort study Br J Clin Pharmacol 2023 89 2168 2178 10.1111/bcp.15687 36755477 Ota R, Hata T, Hirata A, Hamada T, Nishihara M, Neo M, et al. Risk of infection from glucocorticoid and methotrexate interaction in patients with rheumatoid arthritis using biologics: a retrospective cohort study. Br J Clin Pharmacol. 2023;89:2168–78. 36755477 10.1111/bcp.15687

56. Ravandi F O'Brien S Infections associated with purine analogs and monoclonal antibodies Blood Rev 2005 19 253 273 10.1016/j.blre.2005.01.002 15963834 Ravandi F, O’Brien S. Infections associated with purine analogs and monoclonal antibodies. Blood Rev. 2005;19:253–73. 15963834 10.1016/j.blre.2005.01.002

57. Thursky KA Worth LJ Seymour JF Miles Prince H Slavin MA Spectrum of infection, risk and recommendations for prophylaxis and screening among patients with lymphoproliferative disorders treated with alemtuzumab* Br J Haematol 2006 132 3 12 10.1111/j.1365-2141.2005.05789.x 16371014 Thursky KA, Worth LJ, Seymour JF, Miles Prince H, Slavin MA. Spectrum of infection, risk and recommendations for prophylaxis and screening among patients with lymphoproliferative disorders treated with alemtuzumab*. Br J Haematol. 2006;132:3–12. 16371014 10.1111/j.1365-2141.2005.05789.x

58. Gea-Banacloche JC Opal SM Jorgensen J Carcillo JA Sepkowitz KA Cordonnier C Sepsis associated with immunosuppressive medications: an evidence-based review Crit Care Med 2004 32 S578 S590 10.1097/01.CCM.0000143020.27340.FF 15542967 Gea-Banacloche JC, Opal SM, Jorgensen J, Carcillo JA, Sepkowitz KA, Cordonnier C. Sepsis associated with immunosuppressive medications: an evidence-based review. Crit Care Med. 2004;32:S578–90. 15542967 10.1097/01.CCM.0000143020.27340.FF

59. Taur Y Xavier JB Lipuma L Ubeda C Goldberg J Gobourne A Intestinal domination and the risk of bacteremia in patients undergoing allogeneic hematopoietic stem cell transplantation Clin Infect Dis 2012 55 905 914 10.1093/cid/cis580 22718773 PMC3657523 Taur Y, Xavier JB, Lipuma L, Ubeda C, Goldberg J, Gobourne A, et al. Intestinal domination and the risk of bacteremia in patients undergoing allogeneic hematopoietic stem cell transplantation. Clin Infect Dis. 2012;55:905–14. 22718773 10.1093/cid/cis580 PMC3657523

60. Hakim H Dallas R Wolf J Tang L Schultz-Cherry S Darling V Gut microbiome composition predicts infection risk during chemotherapy in children with acute lymphoblastic leukemia Clin Infect Dis 2018 67 541 548 10.1093/cid/ciy153 29518185 PMC6070042 Hakim H, Dallas R, Wolf J, Tang L, Schultz-Cherry S, Darling V, et al. Gut microbiome composition predicts infection risk during chemotherapy in children with acute lymphoblastic leukemia. Clin Infect Dis. 2018;67:541–8. 29518185 10.1093/cid/ciy153 PMC6070042

61. Schnell D Besset S Lengliné E Maziers N Zafrani L Reuter D Impact of a recent chemotherapy on the duration and intensity of the norepinephrine support during septic shock Shock 2013 39 138 143 10.1097/SHK.0b013e3182810a0f 23324882 Schnell D, Besset S, Lengliné E, Maziers N, Zafrani L, Reuter D, et al. Impact of a recent chemotherapy on the duration and intensity of the norepinephrine support during septic shock. Shock. 2013;39:138–43. 23324882 10.1097/SHK.0b013e3182810a0f

62. Vaidie J Peju E Jandeaux LM Lesouhaitier M Lacherade JC Guillon A Long-term immunosuppressive treatment is not associated with worse outcome in patients hospitalized in the intensive care unit for septic shock: the PACIFIC study Crit Care 2023 27 340 10.1186/s13054-023-04626-z 37660107 PMC10475175 Vaidie J, Peju E, Jandeaux LM, Lesouhaitier M, Lacherade JC, Guillon A, et al. Long-term immunosuppressive treatment is not associated with worse outcome in patients hospitalized in the intensive care unit for septic shock: the PACIFIC study. Crit Care. 2023;27:340. 37660107 10.1186/s13054-023-04626-z PMC10475175

63. Oh SY Cho S Lee H Chang EJ Min SH Ryu HG Sepsis in patients receiving immunosuppressive drugs in Korea: analysis of the national insurance database from 2009 to 2013 Acute Crit Care 2015 30 249 257 Oh SY, Cho S, Lee H, Chang EJ, Min SH, Ryu HG. Sepsis in patients receiving immunosuppressive drugs in Korea: analysis of the national insurance database from 2009 to 2013. Acute Crit Care. 2015;30:249–57.

64. Kieslichova E Rocen M Merta D Kudla M Splichal I Cap J The effect of immunosuppression on manifestations of sepsis in an animal model of cecal ligation and puncture Transplant Proc 2013 45 770 777 10.1016/j.transproceed.2012.07.159 23498819 Kieslichova E, Rocen M, Merta D, Kudla M, Splichal I, Cap J, et al. The effect of immunosuppression on manifestations of sepsis in an animal model of cecal ligation and puncture. Transplant Proc. 2013;45:770–7. 23498819 10.1016/j.transproceed.2012.07.159

65. Guarana M Nucci M Nouér SA Shock and early death in hematologic patients with febrile neutropenia Antimicrob Agents Chemother 2019 63 e01250 e1319 10.1128/AAC.01250-19 31405857 PMC6811434 Guarana M, Nucci M, Nouér SA. Shock and early death in hematologic patients with febrile neutropenia. Antimicrob Agents Chemother. 2019;63:e01250-e1319. 31405857 10.1128/AAC.01250-19 PMC6811434

66. Rhee CK Kang JY Kim YH Kim JW Yoon HK Kim SC Risk factors for acute respiratory distress syndrome during neutropenia recovery in patients with hematologic malignancies Crit Care 2009 13 R173 10.1186/cc8149 19886984 PMC2811915 Rhee CK, Kang JY, Kim YH, Kim JW, Yoon HK, Kim SC, et al. Risk factors for acute respiratory distress syndrome during neutropenia recovery in patients with hematologic malignancies. Crit Care. 2009;13:R173. 19886984 10.1186/cc8149 PMC2811915

67. Claessens YE Debray MP Tubach F Brun AL Rammaert B Hausfater P Early chest computed tomography scan to assist diagnosis and guide treatment decision for suspected community-acquired pneumonia Am J Respir Crit Care Med 2015 192 974 982 10.1164/rccm.201501-0017OC 26168322 Claessens YE, Debray MP, Tubach F, Brun AL, Rammaert B, Hausfater P, et al. Early chest computed tomography scan to assist diagnosis and guide treatment decision for suspected community-acquired pneumonia. Am J Respir Crit Care Med. 2015;192:974–82. 26168322 10.1164/rccm.201501-0017OC

68. Gerritsen MG Willemink MJ Pompe E van der Bruggen T van Rhenen A Lammers JW Improving early diagnosis of pulmonary infections in patients with febrile neutropenia using low-dose chest computed tomography PLoS ONE 2017 12 e0172256 10.1371/journal.pone.0172256 28235014 PMC5325310 Gerritsen MG, Willemink MJ, Pompe E, van der Bruggen T, van Rhenen A, Lammers JW, et al. Improving early diagnosis of pulmonary infections in patients with febrile neutropenia using low-dose chest computed tomography. PLoS ONE. 2017;12: e0172256. 28235014 10.1371/journal.pone.0172256 PMC5325310

69. Self WH, Courtney DM, McNaughton CD, Wunderink RG, Kline JA. High discordance of chest x-ray and computed tomography for detection of pulmonary opacities in ED patients: implications for diagnosing pneumonia. Am J Emerg Med. 2013; 31:401–5. 10.1016/j.ajem.2012.08.041 PMC3556231 23083885

70. Torres A Niederman MS Chastre J Ewig S Fernandez-Vandellos P Hanberger H International ERS/ESICM/ESCMID/ALAT guidelines for the management of hospital-acquired pneumonia and ventilator-associated pneumonia: guidelines for the management of hospital-acquired pneumonia (HAP)/ventilator-associated pneumonia (VAP) of the European respiratory society (ERS), European society of intensive care medicine (ESICM), European society of clinical microbiology and infectious diseases (ESCMID) and asociación latinoamericana del tórax (ALAT) Eur Respir J 2017 50 1700582 10.1183/13993003.00582-2017 28890434 Torres A, Niederman MS, Chastre J, Ewig S, Fernandez-Vandellos P, Hanberger H, et al. International ERS/ESICM/ESCMID/ALAT guidelines for the management of hospital-acquired pneumonia and ventilator-associated pneumonia: guidelines for the management of hospital-acquired pneumonia (HAP)/ventilator-associated pneumonia (VAP) of the European respiratory society (ERS), European society of intensive care medicine (ESICM), European society of clinical microbiology and infectious diseases (ESCMID) and asociación latinoamericana del tórax (ALAT). Eur Respir J. 2017;50:1700582. 28890434 10.1183/13993003.00582-2017

71. Gradel KO Póvoa P Garvik OS Vinholt PJ Nielsen SL Jensen TG Longitudinal trajectory patterns of plasma albumin and C-reactive protein levels around diagnosis, relapse, bacteraemia, and death of acute myeloid leukaemia patients BMC Cancer 2020 20 249 10.1186/s12885-020-06754-z 32209087 PMC7092519 Gradel KO, Póvoa P, Garvik OS, Vinholt PJ, Nielsen SL, Jensen TG, et al. Longitudinal trajectory patterns of plasma albumin and C-reactive protein levels around diagnosis, relapse, bacteraemia, and death of acute myeloid leukaemia patients. BMC Cancer. 2020;20:249. 32209087 10.1186/s12885-020-06754-z PMC7092519

72. Shrotriya S Walsh D Bennani-Baiti N Thomas S Lorton C C-reactive protein is an important biomarker for prognosis tumor recurrence and treatment response in adult solid tumors: a systematic review PLoS ONE 2015 10 e0143080 10.1371/journal.pone.0143080 26717416 PMC4705106 Shrotriya S, Walsh D, Bennani-Baiti N, Thomas S, Lorton C. C-reactive protein is an important biomarker for prognosis tumor recurrence and treatment response in adult solid tumors: a systematic review. PLoS ONE. 2015;10: e0143080. 26717416 10.1371/journal.pone.0143080 PMC4705106

73. Póvoa P Souza-Dantas VC Soares M Salluh JF C-reactive protein in critically ill cancer patients with sepsis: influence of neutropenia Crit Care 2011 15 R129 10.1186/cc10242 21595932 PMC3218995 Póvoa P, Souza-Dantas VC, Soares M, Salluh JF. C-reactive protein in critically ill cancer patients with sepsis: influence of neutropenia. Crit Care. 2011;15:R129. 21595932 10.1186/cc10242 PMC3218995

74. Berman M Ben-Ami R Berliner S Anouk M Kaufman I Broyde A The effect of tocilizumab on inflammatory markers in patients hospitalized with serious infections. Case series and review of literature Life 2021 11 258 10.3390/life11030258 33804790 PMC8003879 Berman M, Ben-Ami R, Berliner S, Anouk M, Kaufman I, Broyde A, et al. The effect of tocilizumab on inflammatory markers in patients hospitalized with serious infections. Case series and review of literature. Life. 2021;11:258. 33804790 10.3390/life11030258 PMC8003879

75. El Haddad H Chaftari AM Hachem R Chaftari P Raad II Biomarkers of sepsis and bloodstream infections: the role of procalcitonin and proadrenomedullin with emphasis in patients with cancer Clin Infect Dis 2018 67 971 977 10.1093/cid/ciy331 29668936 El Haddad H, Chaftari AM, Hachem R, Chaftari P, Raad II. Biomarkers of sepsis and bloodstream infections: the role of procalcitonin and proadrenomedullin with emphasis in patients with cancer. Clin Infect Dis. 2018;67:971–7. 29668936 10.1093/cid/ciy331

76. Sakr Y Sponholz C Tuche F Brunkhorst F Reinhart K The role of procalcitonin in febrile neutropenic patients: review of the literature Infection 2008 36 396 407 10.1007/s15010-008-7374-y 18759057 Sakr Y, Sponholz C, Tuche F, Brunkhorst F, Reinhart K. The role of procalcitonin in febrile neutropenic patients: review of the literature. Infection. 2008;36:396–407. 18759057 10.1007/s15010-008-7374-y

77. Klastersky J Paesmans M The multinational association for supportive care in cancer (MASCC) risk index score: 10 years of use for identifying low-risk febrile neutropenic cancer patients Support Care Cancer 2013 21 1487 1495 10.1007/s00520-013-1758-y 23443617 Klastersky J, Paesmans M. The multinational association for supportive care in cancer (MASCC) risk index score: 10 years of use for identifying low-risk febrile neutropenic cancer patients. Support Care Cancer. 2013;21:1487–95. 23443617 10.1007/s00520-013-1758-y

78. Ahn S Lee YS Lim KS Lee JL Adding procalcitonin to the MASCC risk-index score could improve risk stratification of patients with febrile neutropenia Support Care Cancer 2013 21 2303 2308 10.1007/s00520-013-1787-6 23519568 Ahn S, Lee YS, Lim KS, Lee JL. Adding procalcitonin to the MASCC risk-index score could improve risk stratification of patients with febrile neutropenia. Support Care Cancer. 2013;21:2303–8. 23519568 10.1007/s00520-013-1787-6

79. Ratzinger F Haslacher H Perkmann T Schmetterer KG Poeppl W Mitteregger D Sepsis biomarkers in neutropaenic systemic inflammatory response syndrome patients on standard care wards Eur J Clin Invest 2015 45 815 823 10.1111/eci.12476 26046926 Ratzinger F, Haslacher H, Perkmann T, Schmetterer KG, Poeppl W, Mitteregger D, et al. Sepsis biomarkers in neutropaenic systemic inflammatory response syndrome patients on standard care wards. Eur J Clin Invest. 2015;45:815–23. 26046926 10.1111/eci.12476

80. Stoma I Karpov I Uss A Rummo O Milanovich N Iskrov I Diagnostic value of sepsis biomarkers in hematopoietic stem cell transplant recipients in a condition of high prevalence of gram-negative pathogens Hematol Oncol Stem Cell Ther 2017 10 15 21 10.1016/j.hemonc.2016.09.002 27793578 Stoma I, Karpov I, Uss A, Rummo O, Milanovich N, Iskrov I. Diagnostic value of sepsis biomarkers in hematopoietic stem cell transplant recipients in a condition of high prevalence of gram-negative pathogens. Hematol Oncol Stem Cell Ther. 2017;10:15–21. 27793578 10.1016/j.hemonc.2016.09.002

81. Sachak T Arnold MA Naini BV Graham RP Shah SS Cruise M Neutropenic enterocolitis: new insights into a deadly entity Am J Surg Pathol 2015 39 1635 1642 10.1097/PAS.0000000000000517 26414225 Sachak T, Arnold MA, Naini BV, Graham RP, Shah SS, Cruise M, et al. Neutropenic enterocolitis: new insights into a deadly entity. Am J Surg Pathol. 2015;39:1635–42. 26414225 10.1097/PAS.0000000000000517

82. Hill JA Li D Hay KA Green ML Cherian S Chen X Infectious complications of CD19-targeted chimeric antigen receptor-modified T-cell immunotherapy Blood 2018 4 131 121 130 10.1182/blood-2017-07-793760 PMC5755046 29038338 Hill JA, Li D, Hay KA, Green ML, Cherian S, Chen X, et al. Infectious complications of CD19-targeted chimeric antigen receptor-modified T-cell immunotherapy. Blood. 2018;4(131):121–30. 10.1182/blood-2017-07-793760 PMC5755046 29038338

83. Azoulay É Castro P Maamar A Metaxa V de Moraes AG Voigt L Outcomes in patients treated with chimeric antigen receptor T-cell therapy who were admitted to intensive care (CARTTAS): an international, multicentre, observational cohort study Lancet Haematol 2021 8 e355 e364 10.1016/S2352-3026(21)00060-0 33894170 Azoulay É, Castro P, Maamar A, Metaxa V, de Moraes AG, Voigt L, et al. Outcomes in patients treated with chimeric antigen receptor T-cell therapy who were admitted to intensive care (CARTTAS): an international, multicentre, observational cohort study. Lancet Haematol. 2021;8:e355–64. 33894170 10.1016/S2352-3026(21)00060-0

84. Evans L Rhodes A Alhazzani W Antonelli M Coopersmith CM French C Surviving sepsis campaign: international guidelines for management of sepsis and septic shock 2021 Crit Care Med 2021 49 e1063 e1143 10.1097/CCM.0000000000005337 34605781 Evans L, Rhodes A, Alhazzani W, Antonelli M, Coopersmith CM, French C, et al. Surviving sepsis campaign: international guidelines for management of sepsis and septic shock 2021. Crit Care Med. 2021;49:e1063–143. 34605781 10.1097/CCM.0000000000005337

85. Kochanek M Schalk E von Bergwelt-Baildon M Beutel G Buchheidt D Hentrich M Management of sepsis in neutropenic cancer patients: 2018 guidelines from the infectious diseases working party (AGIHO) and intensive care working party (iCHOP) of the German society of hematology and medical oncology (DGHO) Ann Hematol 2019 98 1051 1069 10.1007/s00277-019-03622-0 30796468 PMC6469653 Kochanek M, Schalk E, von Bergwelt-Baildon M, Beutel G, Buchheidt D, Hentrich M, et al. Management of sepsis in neutropenic cancer patients: 2018 guidelines from the infectious diseases working party (AGIHO) and intensive care working party (iCHOP) of the German society of hematology and medical oncology (DGHO). Ann Hematol. 2019;98:1051–69. 30796468 10.1007/s00277-019-03622-0 PMC6469653

86. Cheong SHR Ng YJX Lau Y Lau ST Wearable technology for early detection of COVID-19: a systematic scoping review Prev Med 2022 162 107170 10.1016/j.ypmed.2022.107170 35878707 PMC9304072 Cheong SHR, Ng YJX, Lau Y, Lau ST. Wearable technology for early detection of COVID-19: a systematic scoping review. Prev Med. 2022;162: 107170. 35878707 10.1016/j.ypmed.2022.107170 PMC9304072

87. Ocampo-Quintero N Vidal-Cortés P Del Río CL Fdez-Riverola F Reboiro-Jato M Glez-Peña D Enhancing sepsis management through machine learning techniques: A review Med Intensiva 2022 46 140 156 10.1016/j.medin.2020.04.003 35221003 Ocampo-Quintero N, Vidal-Cortés P, Del Río CL, Fdez-Riverola F, Reboiro-Jato M, Glez-Peña D. Enhancing sepsis management through machine learning techniques: A review. Med Intensiva. 2022;46:140–56. 35221003 10.1016/j.medin.2020.04.003

88. Ackermann K Baker J Green M Fullick M Varinli H Westbrook J Li L Computerized clinical decision support systems for the early detection of sepsis among adult inpatients: scoping review J Med Internet Res 2022 24 2 e31083 10.2196/31083 35195528 PMC8908200 Ackermann K, Baker J, Green M, Fullick M, Varinli H, Westbrook J, Li L. Computerized clinical decision support systems for the early detection of sepsis among adult inpatients: scoping review. J Med Internet Res. 2022;24(2): e31083. 35195528 10.2196/31083 PMC8908200

89. Lee DS Suh GY Ryu JA Chung CR Yang JH Park CM Effect of early intervention on long-term outcomes of critically ill cancer patients admitted to ICUs Crit Care Med 2015 43 1439 1448 10.1097/CCM.0000000000000989 25803653 Lee DS, Suh GY, Ryu JA, Chung CR, Yang JH, Park CM, et al. Effect of early intervention on long-term outcomes of critically ill cancer patients admitted to ICUs. Crit Care Med. 2015;43:1439–48. 25803653 10.1097/CCM.0000000000000989

90. Hourmant Y Mailloux A Valade S Lemiale V Azoulay E Darmon M Impact of early ICU admission on outcome of critically ill and critically ill cancer patients: a systematic review and meta-analysis J Crit Care 2021 61 82 88 10.1016/j.jcrc.2020.10.008 33157309 Hourmant Y, Mailloux A, Valade S, Lemiale V, Azoulay E, Darmon M. Impact of early ICU admission on outcome of critically ill and critically ill cancer patients: a systematic review and meta-analysis. J Crit Care. 2021;61:82–8. 33157309 10.1016/j.jcrc.2020.10.008

91. Hourmant Y Kouatchet A López R Mokart D Pène F Mayaux J Impact of early ICU admission for critically ill cancer patients: Post-hoc analysis of a prospective multicenter multinational dataset J Crit Care 2021 62 6 11 10.1016/j.jcrc.2020.10.022 33227593 Hourmant Y, Kouatchet A, López R, Mokart D, Pène F, Mayaux J, et al. Impact of early ICU admission for critically ill cancer patients: Post-hoc analysis of a prospective multicenter multinational dataset. J Crit Care. 2021;62:6–11. 33227593 10.1016/j.jcrc.2020.10.022

92. de Montmollin E Tandjaoui-Lambiotte Y Legrand M Lambert J Mokart D Kouatchet A Outcomes in critically ill cancer patients with septic shock of pulmonary origin Shock 2013 39 250 254 10.1097/SHK.0b013e3182866d32 23364436 de Montmollin E, Tandjaoui-Lambiotte Y, Legrand M, Lambert J, Mokart D, Kouatchet A, et al. Outcomes in critically ill cancer patients with septic shock of pulmonary origin. Shock. 2013;39:250–4. 23364436 10.1097/SHK.0b013e3182866d32

93. Doukhan L Bisbal M Chow-Chine L Sannini A Brun JP Cambon S Respiratory events in ward are associated with later intensive care unit (ICU) admission and hospital mortality in onco-hematology patients not admitted to ICU after a first request PLoS ONE 2017 12 e0181808 10.1371/journal.pone.0181808 28749989 PMC5531489 Doukhan L, Bisbal M, Chow-Chine L, Sannini A, Brun JP, Cambon S, et al. Respiratory events in ward are associated with later intensive care unit (ICU) admission and hospital mortality in onco-hematology patients not admitted to ICU after a first request. PLoS ONE. 2017;12: e0181808. 28749989 10.1371/journal.pone.0181808 PMC5531489

94. Okafor UV Challenges in critical care services in Sub-Saharan Africa: perspectives from Nigeria Indian J Crit Care Med 2009 13 25 27 10.4103/0972-5229.53112 19881176 PMC2772254 Okafor UV. Challenges in critical care services in Sub-Saharan Africa: perspectives from Nigeria. Indian J Crit Care Med. 2009;13:25–7. 19881176 10.4103/0972-5229.53112 PMC2772254

95. Firth P Ttendo S Intensive care in low-income countries–a critical need N Engl J Med 2012 367 1974 1976 10.1056/NEJMp1204957 23171093 Firth P, Ttendo S. Intensive care in low-income countries–a critical need. N Engl J Med. 2012;367:1974–6. 23171093 10.1056/NEJMp1204957

96. Estenssoro E Alegría L Murias G Friedman G Castro R Nin Vaeza N Organizational issues, structure, and processes of care in 257 ICUs in Latin America: a study from the Latin America intensive care network Crit Care Med 2017 45 1325 1336 10.1097/CCM.0000000000002413 28437376 Estenssoro E, Alegría L, Murias G, Friedman G, Castro R, Nin Vaeza N, et al. Organizational issues, structure, and processes of care in 257 ICUs in Latin America: a study from the Latin America intensive care network. Crit Care Med. 2017;45:1325–36. 28437376 10.1097/CCM.0000000000002413

97. Rello J Leblebicioglu H members of ESGCIP. Sepsis and septic shock in low-income and middle-income countries: need for a different paradigm Int J Infect Dis 2016 48 120 2 10.1016/j.ijid.2016.04.017 27117201 Rello J, Leblebicioglu H. members of ESGCIP. Sepsis and septic shock in low-income and middle-income countries: need for a different paradigm. Int J Infect Dis. 2016;48:120–2. 27117201 10.1016/j.ijid.2016.04.017

98. Multidrug-resistant organisms (MDRO) Management guidelines. Multidrug-resistant organisms (MDRO) Management guidelines | infection control | CDC. Accessed June 06 2024.

99. Kreitmann L Vasseur M Jermoumi S Perche J Richard JC Wallet F Relationship between immunosuppression and intensive care unit-acquired colonization and infection related to multidrug-resistant bacteria: a prospective multicenter cohort study Intensive Care Med 2023 49 154 165 10.1007/s00134-022-06954-0 36592202 Kreitmann L, Vasseur M, Jermoumi S, Perche J, Richard JC, Wallet F, et al. Relationship between immunosuppression and intensive care unit-acquired colonization and infection related to multidrug-resistant bacteria: a prospective multicenter cohort study. Intensive Care Med. 2023;49:154–65. 36592202 10.1007/s00134-022-06954-0

100. Mokart D Saillard C Sannini A Chow-Chine L Brun JP Faucher M Neutropenic cancer patients with severe sepsis: need for antibiotics in the first hour Intensive Care Med 2014 40 1173 1174 10.1007/s00134-014-3374-9 24966064 Mokart D, Saillard C, Sannini A, Chow-Chine L, Brun JP, Faucher M, et al. Neutropenic cancer patients with severe sepsis: need for antibiotics in the first hour. Intensive Care Med. 2014;40:1173–4. 24966064 10.1007/s00134-014-3374-9

101. Hechtman RK Kipnis P Cano J Seelye S Liu VX Prescott HC Heterogeneity of benefit from earlier time-to-antibiotics for sepsis Am J Respir Crit Care Med 2024 209 852 860 10.1164/rccm.202310-1800OC 38261986 PMC10995570 Hechtman RK, Kipnis P, Cano J, Seelye S, Liu VX, Prescott HC. Heterogeneity of benefit from earlier time-to-antibiotics for sepsis. Am J Respir Crit Care Med. 2024;209:852–60. 38261986 10.1164/rccm.202310-1800OC PMC10995570

102. Freifeld AG Bow EJ Sepkowitz KA Boeckh MJ Ito JI Mullen CA Clinical practice guideline for the use of antimicrobial agents in neutropenic patients with cancer: 2010 update by the infectious diseases society of America Clin Infect Dis 2011 52 e56 93 10.1093/cid/cir073 21258094 Freifeld AG, Bow EJ, Sepkowitz KA, Boeckh MJ, Ito JI, Mullen CA, et al. Clinical practice guideline for the use of antimicrobial agents in neutropenic patients with cancer: 2010 update by the infectious diseases society of America. Clin Infect Dis. 2011;52:e56-93. 21258094 10.1093/cid/cir073

103. Tam CS O'Reilly M Andresen D Lingaratnam S Kelly A Burbury K Turnidge J Slavin MA Worth LJ Dawson L Thursky KA Use of empiric antimicrobial therapy in neutropenic fever Internal Med J 2011 41 1b 90 101 10.1111/j.1445-5994.2010.02340.x 21272173 Tam CS, O’Reilly M, Andresen D, Lingaratnam S, Kelly A, Burbury K, Turnidge J, Slavin MA, Worth LJ, Dawson L, Thursky KA. Use of empiric antimicrobial therapy in neutropenic fever. Internal Med J. 2011;41(1b):90–101. 21272173 10.1111/j.1445-5994.2010.02340.x

104. Klastersky J de Naurois J Rolston K Rapoport B Maschmeyer G Aapro M ESMO guidelines committee. Management of febrile neutropaenia: ESMO clinical practice guidelines Ann Oncol 2016 27 111 118 10.1093/annonc/mdw325 27664247 Klastersky J, de Naurois J, Rolston K, Rapoport B, Maschmeyer G, Aapro M, et al. ESMO guidelines committee. Management of febrile neutropaenia: ESMO clinical practice guidelines. Ann Oncol. 2016;27:111–8. 10.1093/annonc/mdw325 27664247

105. Exceptional surveillance of neutropenic sepsis prevention and management in people with cancer (NICE guideline CG151) [Internet] 2020 London National Institute for Health and Care Excellence (NICE) 32040284 Exceptional surveillance of neutropenic sepsis. prevention and management in people with cancer (NICE guideline CG151) [Internet]. London: National Institute for Health and Care Excellence (NICE); 2020. 32040284

106. Lopez R Rello J Taccone FS Salem OBH Bauer PR Séguin A Aminoglycosides in immunocompromised critically Ill patients with bacterial pneumonia and septic shock: a post-hoc analysis of a prospective multicenter multinational cohort Shock 2020 54 731 737 10.1097/SHK.0000000000001553 32496415 Lopez R, Rello J, Taccone FS, Salem OBH, Bauer PR, Séguin A, et al. Aminoglycosides in immunocompromised critically Ill patients with bacterial pneumonia and septic shock: a post-hoc analysis of a prospective multicenter multinational cohort. Shock. 2020;54:731–7. 32496415 10.1097/SHK.0000000000001553

107. Kreitmann L Helms J Martin-Loeches I Salluh J Poulakou G Pène F ICU-acquired infections in immunocompromised patients Intensive Care Med 2024 50 332 349 10.1007/s00134-023-07295-2 38197931 Kreitmann L, Helms J, Martin-Loeches I, Salluh J, Poulakou G, Pène F, et al. ICU-acquired infections in immunocompromised patients. Intensive Care Med. 2024;50:332–49. 38197931 10.1007/s00134-023-07295-2

108. Mokart D Slehofer G Lambert J Sannini A Chow-Chine L Brun JP De-escalation of antimicrobial treatment in neutropenic patients with severe sepsis: results from an observational study Intensive Care Med 2014 40 41 49 10.1007/s00134-013-3148-9 24231857 Mokart D, Slehofer G, Lambert J, Sannini A, Chow-Chine L, Brun JP, et al. De-escalation of antimicrobial treatment in neutropenic patients with severe sepsis: results from an observational study. Intensive Care Med. 2014;40:41–9. 24231857 10.1007/s00134-013-3148-9

109. Azoulay E Schellongowski P Darmon M Bauer PR Benoit D Depuydt P The intensive care medicine research agenda on critically ill oncology and hematology patients Intensive Care Med 2017 43 1366 1382 10.1007/s00134-017-4884-z 28725926 Azoulay E, Schellongowski P, Darmon M, Bauer PR, Benoit D, Depuydt P, et al. The intensive care medicine research agenda on critically ill oncology and hematology patients. Intensive Care Med. 2017;43:1366–82. 28725926 10.1007/s00134-017-4884-z

110. Rygård SL Holst LB Wetterslev J Johansson PI Perner A TRISS trial group; scandinavian critical care trials group higher vs. lower haemoglobin threshold for transfusion in septic shock: subgroup analyses of the TRISS trial Acta Anaesthesiol Scand 2017 61 166 175 10.1111/aas.12837 27910086 Rygård SL, Holst LB, Wetterslev J, Johansson PI, Perner A. TRISS trial group; scandinavian critical care trials group higher vs. lower haemoglobin threshold for transfusion in septic shock: subgroup analyses of the TRISS trial. Acta Anaesthesiol Scand. 2017;61:166–75. 27910086 10.1111/aas.12837

111. Bergamin FS Almeida JP Landoni G Galas FRBG Fukushima JT Fominskiy E Liberal versus restrictive transfusion strategy in critically Ill oncologic patients: the transfusion requirements in critically Ill oncologic patients randomized controlled trial Crit Care Med 2017 45 766 773 10.1097/CCM.0000000000002283 28240687 Bergamin FS, Almeida JP, Landoni G, Galas FRBG, Fukushima JT, Fominskiy E, et al. Liberal versus restrictive transfusion strategy in critically Ill oncologic patients: the transfusion requirements in critically Ill oncologic patients randomized controlled trial. Crit Care Med. 2017;45:766–73. 28240687 10.1097/CCM.0000000000002283

112. de Almeida JP Vincent JL Galas FR de Almeida EP Fukushima JT Osawa EA Transfusion requirements in surgical oncology patients: a prospective, randomized controlled trial Anesthesiology 2015 122 29 38 10.1097/ALN.0000000000000511 25401417 de Almeida JP, Vincent JL, Galas FR, de Almeida EP, Fukushima JT, Osawa EA, et al. Transfusion requirements in surgical oncology patients: a prospective, randomized controlled trial. Anesthesiology. 2015;122:29–38. 25401417 10.1097/ALN.0000000000000511

113. Taplitz RA Kennedy EB Bow EJ Crews J Gleason C Hawley DK Antimicrobial prophylaxis for adult patients with cancer-related immunosuppression: ASCO and IDSA clinical practice guideline update J Clin Oncol 2018 36 3043 3054 10.1200/JCO.18.00374 30179565 Taplitz RA, Kennedy EB, Bow EJ, Crews J, Gleason C, Hawley DK, et al. Antimicrobial prophylaxis for adult patients with cancer-related immunosuppression: ASCO and IDSA clinical practice guideline update. J Clin Oncol. 2018;36:3043–54. 30179565 10.1200/JCO.18.00374

114. Bruno J and Tverdek FP. Antimicrobial prophylaxis in high-risk oncology patients. In oncologic critical care, Nates JL and Price KJ Editors. (Springer Nature Switzerland AG, ed. 1, 2020). Vol 1, chapter 14, Pages 153-167

115. Pène F Percheron S Lemiale V Viallon V Claessens YE Marqué S Temporal changes in management and outcome of septic shock in patients with malignancies in the intensive care unit Crit Care Med 2008 36 690 696 10.1097/CCM.0B013E318165314B 18431262 Pène F, Percheron S, Lemiale V, Viallon V, Claessens YE, Marqué S, et al. Temporal changes in management and outcome of septic shock in patients with malignancies in the intensive care unit. Crit Care Med. 2008;36:690–6. 18431262 10.1097/CCM.0B013E318165314B

116. Bouteloup M Perinel S Bourmaud A Azoulay E Mokart D Darmon M Outcomes in adult critically Ill cancer patients with and without neutropenia: a systematic review and meta-analysis of the Groupe de recherche en reanimation respiratoire du patient d'Onco-hematologie (GRRR-OH) Oncotarget 2017 8 1 1860 10.18632/oncotarget.12165 27661125 PMC5352103 Bouteloup M, Perinel S, Bourmaud A, Azoulay E, Mokart D, Darmon M. Outcomes in adult critically Ill cancer patients with and without neutropenia: a systematic review and meta-analysis of the Groupe de recherche en reanimation respiratoire du patient d’Onco-hematologie (GRRR-OH). Oncotarget. 2017;8(1):1860. 27661125 10.18632/oncotarget.12165 PMC5352103

117. Zuber B Tran TC Aegerter P Grimaldi D Charpentier J Guidet B Impact of case volume on survival of septic shock in patients with malignancies Crit Care Med 2012 40 55 62 10.1097/CCM.0b013e31822d74ba 21926606 Zuber B, Tran TC, Aegerter P, Grimaldi D, Charpentier J, Guidet B. Impact of case volume on survival of septic shock in patients with malignancies. Crit Care Med. 2012;40:55–62. 21926606 10.1097/CCM.0b013e31822d74ba

118. Biard L Darmon M Lemiale V Mokart D Chevret S Azoulay E Center effects in hospital mortality of critically Ill patients with hematologic malignancies Crit Care Med 2019 47 809 816 10.1097/CCM.0000000000003717 30889024 Biard L, Darmon M, Lemiale V, Mokart D, Chevret S, Azoulay E, et al. Center effects in hospital mortality of critically Ill patients with hematologic malignancies. Crit Care Med. 2019;47:809–16. 30889024 10.1097/CCM.0000000000003717

119. Tolsma V Schwebel C Azoulay E Darmon M Souweine B Vesin A Sepsis severe or septic shock: outcome according to immune status and immunodeficiency profile Chest 2014 146 1205 1213 10.1378/chest.13-2618 25033349 Tolsma V, Schwebel C, Azoulay E, Darmon M, Souweine B, Vesin A, et al. Sepsis severe or septic shock: outcome according to immune status and immunodeficiency profile. Chest. 2014;146:1205–13. 25033349 10.1378/chest.13-2618

120. Nazer L Lopez-Olivo MA Cuenca JA Awad W Brown AR Abusara A All-cause mortality in cancer patients treated for sepsis in intensive care units: a systematic review and meta-analysis Support Care Cancer 2022 30 10099 10109 10.1007/s00520-022-07392-w 36214879 PMC9549043 Nazer L, Lopez-Olivo MA, Cuenca JA, Awad W, Brown AR, Abusara A, et al. All-cause mortality in cancer patients treated for sepsis in intensive care units: a systematic review and meta-analysis. Support Care Cancer. 2022;30:10099–109. 36214879 10.1007/s00520-022-07392-w PMC9549043

121. Kim YJ Kim MJ Kim YJ Kim WY Short and long-term mortality trends for cancer patients with septic shock stratified by cancer type from 2009 to 2017: a population-based cohort study Cancers 2021 13 657 10.3390/cancers13040657 33562125 PMC7931033 Kim YJ, Kim MJ, Kim YJ, Kim WY. Short and long-term mortality trends for cancer patients with septic shock stratified by cancer type from 2009 to 2017: a population-based cohort study. Cancers. 2021;13:657. 33562125 10.3390/cancers13040657 PMC7931033

122. Le Borgne P Feuillassier L Schenck M Herbrecht JE Janssen-Langenstein R Simand C Comparison of short- and long-term mortality in patients with or without cancer admitted to the ICU for septic shock: a retrospective observational study Cancers 2022 14 3196 10.3390/cancers14133196 35804966 PMC9264783 Le Borgne P, Feuillassier L, Schenck M, Herbrecht JE, Janssen-Langenstein R, Simand C, et al. Comparison of short- and long-term mortality in patients with or without cancer admitted to the ICU for septic shock: a retrospective observational study. Cancers. 2022;14:3196. 35804966 10.3390/cancers14133196 PMC9264783

123. Awad WB Nazer L Elfarr S Abdullah M Hawari F A 12-year study evaluating the outcomes and predictors of mortality in critically ill cancer patients admitted with septic shock BMC Cancer 2021 21 709 10.1186/s12885-021-08452-w 34130642 PMC8207763 Awad WB, Nazer L, Elfarr S, Abdullah M, Hawari F. A 12-year study evaluating the outcomes and predictors of mortality in critically ill cancer patients admitted with septic shock. BMC Cancer. 2021;21:709. 34130642 10.1186/s12885-021-08452-w PMC8207763

124. Vandijck DM Depuydt PO Offner FC Nollet J Peleman RA Steel E Impact of organ dysfunction on mortality in ICU patients with hematologic malignancies Intensive Care Med 2010 36 1744 1750 10.1007/s00134-010-1903-8 20480137 Vandijck DM, Depuydt PO, Offner FC, Nollet J, Peleman RA, Steel E, et al. Impact of organ dysfunction on mortality in ICU patients with hematologic malignancies. Intensive Care Med. 2010;36:1744–50. 20480137 10.1007/s00134-010-1903-8

125. Mokart D Darmon M Resche-Rigon M Lemiale V Pène F Mayaux J Prognosis of neutropenic patients admitted to the intensive care unit Intensive Care Med 2015 41 296 303 10.1007/s00134-014-3615-y 25578678 Mokart D, Darmon M, Resche-Rigon M, Lemiale V, Pène F, Mayaux J, et al. Prognosis of neutropenic patients admitted to the intensive care unit. Intensive Care Med. 2015;41:296–303. 25578678 10.1007/s00134-014-3615-y

126. Camou F Didier M Leguay T Milpied N Daste A Ravaud A Long-term prognosis of septic shock in cancer patients Support Care Cancer 2020 28 1325 1333 10.1007/s00520-019-04937-4 31243586 Camou F, Didier M, Leguay T, Milpied N, Daste A, Ravaud A, et al. Long-term prognosis of septic shock in cancer patients. Support Care Cancer. 2020;28:1325–33. 31243586 10.1007/s00520-019-04937-4

127. Hradská K Popková T Skořupová M Mihályová J Jelínek T Lančová J Management of treatment-related infectious complications in high-risk hemato-oncological patients via telemedicine Cancer Manag Res 2022 14 1655 1661 10.2147/CMAR.S348923 35547597 PMC9081028 Hradská K, Popková T, Skořupová M, Mihályová J, Jelínek T, Lančová J, et al. Management of treatment-related infectious complications in high-risk hemato-oncological patients via telemedicine. Cancer Manag Res. 2022;14:1655–61. 35547597 10.2147/CMAR.S348923 PMC9081028

128. Smith TJ Bohlke K Lyman GH Carson KR Crawford J Cross SJ Recommendations for the use of WBC growth factors: american society of clinical oncology clinical practice guideline update J Clin Oncol 2015 33 3199 3212 10.1200/JCO.2015.62.3488 26169616 Smith TJ, Bohlke K, Lyman GH, Carson KR, Crawford J, Cross SJ, et al. Recommendations for the use of WBC growth factors: american society of clinical oncology clinical practice guideline update. J Clin Oncol. 2015;33:3199–212. 26169616 10.1200/JCO.2015.62.3488

129. Becker PS Griffiths EA Alwan LM Bachiashvili K Brown A Cool R Curtin P Dinner S Gojo I Hicks A Kallam A NCCN guidelines insights: hematopoietic growth factors, version 1.2020: featured updates to the NCCN guidelines J Nat Compr Cancer Netw 2020 18 1 12 22 10.6004/jnccn.2020.0002 31910384 Becker PS, Griffiths EA, Alwan LM, Bachiashvili K, Brown A, Cool R, Curtin P, Dinner S, Gojo I, Hicks A, Kallam A. NCCN guidelines insights: hematopoietic growth factors, version 1.2020: featured updates to the NCCN guidelines. J Nat Compr Cancer Netw. 2020;18(1):12–22. 10.6004/jnccn.2020.0002 31910384

130. Munshi L Dumas G Rochwerg B Shoukat F Detsky M Fergusson DA Long-term survival and functional outcomes of critically ill patients with hematologic malignancies: a Canadian multicenter prospective study Intensive Care Med 2024 50 561 572 10.1007/s00134-024-07349-z 38466402 Munshi L, Dumas G, Rochwerg B, Shoukat F, Detsky M, Fergusson DA, et al. Long-term survival and functional outcomes of critically ill patients with hematologic malignancies: a Canadian multicenter prospective study. Intensive Care Med. 2024;50:561–72. 38466402 10.1007/s00134-024-07349-z

131. García Herreros M Laguna JC Padrosa J Barreto TD Chicote M Font C Grafia I Llavata L Seguí E Tuca A Viladot M Characterisation and outcomes of patients with solid organ malignancies admitted to the intensive care unit mortality and impact on functional status and oncological treatment Diagnostics 2024 14 7 730 10.3390/diagnostics14070730 38611643 PMC11011727 García Herreros M, Laguna JC, Padrosa J, Barreto TD, Chicote M, Font C, Grafia I, Llavata L, Seguí E, Tuca A, Viladot M. Characterisation and outcomes of patients with solid organ malignancies admitted to the intensive care unit mortality and impact on functional status and oncological treatment. Diagnostics. 2024;14(7):730. 38611643 10.3390/diagnostics14070730 PMC11011727

132. Temel JS Petrillo LA Greer JA Patient-centered palliative care for patients with advanced lung cancer J Clin Oncol 2022 40 626 634 10.1200/JCO.21.01710 34985932 Temel JS, Petrillo LA, Greer JA. Patient-centered palliative care for patients with advanced lung cancer. J Clin Oncol. 2022;40:626–34. 34985932 10.1200/JCO.21.01710

133. Rocque GB Andrews C Lawhon VM Ingram SA Frazier RM Smith ML Physician perspectives on reducing curative cancer treatment intensity for populations underrepresented in clinical trials Oncologist 2022 27 1067 1073 10.1093/oncolo/oyac191 36215065 PMC9732232 Rocque GB, Andrews C, Lawhon VM, Ingram SA, Frazier RM, Smith ML, et al. Physician perspectives on reducing curative cancer treatment intensity for populations underrepresented in clinical trials. Oncologist. 2022;27:1067–73. 36215065 10.1093/oncolo/oyac191 PMC9732232

134. Hernandez González VL Alaminos MO Mir AS Borges M Aranda M Castillo A Can artificial intelligence and machine learning techniques improve the ability to detect sepsis and septic shock. A retrospective study of 218562 adult patients in a university hospital J Crit care 2024 81 154684 10.1016/j.jcrc.2024.154684 Hernandez González VL, Alaminos MO, Mir AS, Borges M, Aranda M, Castillo A, et al. Can artificial intelligence and machine learning techniques improve the ability to detect sepsis and septic shock. A retrospective study of 218562 adult patients in a university hospital. J Crit care. 2024;81:154684. 10.1016/j.jcrc.2024.154684

135. Henry KE Adams R Parent C Soleimani H Sridharan A Johnson L Factors driving provider adoption of the TREWS machine learning-based early warning system and its effects on sepsis treatment timing Nat Med 2022 28 1447 1454 10.1038/s41591-022-01895-z 35864251 Henry KE, Adams R, Parent C, Soleimani H, Sridharan A, Johnson L, et al. Factors driving provider adoption of the TREWS machine learning-based early warning system and its effects on sepsis treatment timing. Nat Med. 2022;28:1447–54. 35864251 10.1038/s41591-022-01895-z

136. van der Zee EN Benoit DD Hazenbroek M Bakker J Kompanje EJO Kusadasi N Outcome of cancer patients considered for intensive care unit admission in two university hospitals in the Netherlands: the danger of delayed ICU admissions and off-hour triage decisions Ann Intensive Care 2021 11 125 10.1186/s13613-021-00898-2 34379217 PMC8357904 van der Zee EN, Benoit DD, Hazenbroek M, Bakker J, Kompanje EJO, Kusadasi N, et al. Outcome of cancer patients considered for intensive care unit admission in two university hospitals in the Netherlands: the danger of delayed ICU admissions and off-hour triage decisions. Ann Intensive Care. 2021;11:125. 34379217 10.1186/s13613-021-00898-2 PMC8357904

137. MacPhail A Dendle C Slavin M Weinkove R Bailey M Sepsis mortality among patients with haematological malignancy admitted to intensive care 2000–2022: a binational cohort study Crit Care 2024 28 148 10.1186/s13054-024-04932-0 38711155 PMC11075186 MacPhail A, Dendle C, Slavin M, Weinkove R, Bailey M, et al. Sepsis mortality among patients with haematological malignancy admitted to intensive care 2000–2022: a binational cohort study. Crit Care. 2024;28:148. 38711155 10.1186/s13054-024-04932-0 PMC11075186

138. Babu M Lautman Z Lin X Sobota MHB Snyder MP wearable devices: implications for precision medicine and the future of health care Annu Rev Med 2024 75 401 415 10.1146/annurev-med-052422-020437 37983384 Babu M, Lautman Z, Lin X, Sobota MHB, Snyder MP. wearable devices: implications for precision medicine and the future of health care. Annu Rev Med. 2024;75:401–15. 37983384 10.1146/annurev-med-052422-020437

139. Impact of Aminoglycosides-based Antibiotics Combination and Protective Isolation on Outcomes in Critically-ill Neutropenic Patients With Sepsis: (Combination-Lock01) ClinicalTrials.gov. https://clinicaltrials.gov/study/NCT05443854 . Last accessed June 24, 2024.

140. Cuenca JA Nates JL Laserna A Heatter AJ Manjappachar N Martin P Long-term survival of patients with cancer, sepsis, and vasopressor requirements based on lactate levels Crit Care Explor 2024 6 e1070 10.1097/CCE.0000000000001070 38572448 PMC10990307 Cuenca JA, Nates JL, Laserna A, Heatter AJ, Manjappachar N, Martin P, et al. Long-term survival of patients with cancer, sepsis, and vasopressor requirements based on lactate levels. Crit Care Explor. 2024;6: e1070. 38572448 10.1097/CCE.0000000000001070 PMC10990307

141. Ko BS Jeon S Son D Choi SH Shin TG Jo YH Machine learning model development and validation for predicting outcome in stage 4 solid cancer patients with septic shock visiting the emergency department: a multi-center Prospective Cohort Study J Clin Med 2022 11 7231 36498805 10.3390/jcm11237231 PMC9737041 Ko BS, Jeon S, Son D, Choi SH, Shin TG, Jo YH, et al. Machine learning model development and validation for predicting outcome in stage 4 solid cancer patients with septic shock visiting the emergency department: a multi-center. Prospective Cohort Study J Clin Med. 2022;11:7231. 36498805 10.3390/jcm11237231 PMC9737041

142. Kim SM Kim YJ Kim YJ Kim WY Prognostic impact of neutropenia in cancer patients with septic shock: a 2009–2017 nationwide cohort study Cancers 2022 14 3601 10.3390/cancers14153601 35892860 PMC9332608 Kim SM, Kim YJ, Kim YJ, Kim WY. Prognostic impact of neutropenia in cancer patients with septic shock: a 2009–2017 nationwide cohort study. Cancers. 2022;14:3601. 35892860 10.3390/cancers14153601 PMC9332608

143. Awad WB Nazer L Long-term outcomes of cancer patients admitted to the ICU with septic shock Gulf J Oncolog 2024 1 51 53 38205573 Awad WB, Nazer L. Long-term outcomes of cancer patients admitted to the ICU with septic shock. Gulf J Oncolog. 2024;1:51–3. 38205573

144. Kim YJ Kang J Kim MJ Ryoo SM Kang GH Shin TG Development and validation of the vital class score to predict mortality in stage IV solid cancer patients with septic shock in the emergency department: a multi-center, prospective cohort study BMC Med 2020 18 390 10.1186/s12916-020-01875-5 33308206 PMC7733739 Kim YJ, Kang J, Kim MJ, Ryoo SM, Kang GH, Shin TG, et al. Development and validation of the vital class score to predict mortality in stage IV solid cancer patients with septic shock in the emergency department: a multi-center, prospective cohort study. BMC Med. 2020;18:390. 33308206 10.1186/s12916-020-01875-5 PMC7733739

145. Rasheed M Khan YH Mujtaba G Mallhi TH Saadullah M Saifullah A Assessment of clinical features and determinants of mortality among cancer patients with septic shock of pulmonary origin: a prospective analysis Postgrad Med J 2020 96 277 285 10.1136/postgradmedj-2019-136987 31685679 Rasheed M, Khan YH, Mujtaba G, Mallhi TH, Saadullah M, Saifullah A. Assessment of clinical features and determinants of mortality among cancer patients with septic shock of pulmonary origin: a prospective analysis. Postgrad Med J. 2020;96:277–85. 31685679 10.1136/postgradmedj-2019-136987

146. Mokart D Saillard C Zemmour C Bisbal M Sannini A Chow-Chine L Early prognostic factors in septic shock cancer patients: a prospective study with a proteomic approach Acta Anaesthesiol Scand 2018 62 493 503 10.1111/aas.13060 29315472 Mokart D, Saillard C, Zemmour C, Bisbal M, Sannini A, Chow-Chine L, et al. Early prognostic factors in septic shock cancer patients: a prospective study with a proteomic approach. Acta Anaesthesiol Scand. 2018;62:493–503. 29315472 10.1111/aas.13060

147. Ñamendys-Silva SA González-Herrera MO Texcocano-Becerra J Herrera-Gómez A Clinical characteristics and outcomes of critically ill cancer patients with septic shock QJM 2011 104 505 511 10.1093/qjmed/hcq260 21258055 Ñamendys-Silva SA, González-Herrera MO, Texcocano-Becerra J, Herrera-Gómez A. Clinical characteristics and outcomes of critically ill cancer patients with septic shock. QJM. 2011;104:505–11. 21258055 10.1093/qjmed/hcq260

148. Park HY Suh GY Jeon K Koh WJ Chung MP Kim H Outcome and prognostic factors of patients with acute leukemia admitted to the intensive care unit for septic shock Leuk Lymphoma 2008 49 1929 1934 10.1080/10428190802353609 18949617 Park HY, Suh GY, Jeon K, Koh WJ, Chung MP, Kim H, et al. Outcome and prognostic factors of patients with acute leukemia admitted to the intensive care unit for septic shock. Leuk Lymphoma. 2008;49:1929–34. 18949617 10.1080/10428190802353609

149. Kim YJ, Seo DW, Kang J, Huh JW, Kim KW, Kim WY. Impact of body composition status on 90-day mortality in cancer patients with septic shock: sex differences in the skeletal muscle index. J Clin Med. 2019;8:1583. 10.3390/jcm8101583 PMC6832584 31581650

150. Lee MR, Lai CL, Chan KA. Intensive care unit admission and survival in stage iv cancer patients with septic shock: a population-based cohort study. J Cancer. 2019;10(14):3179–3187. 10.7150/jca.30278 PMC6603387 31289588