Obesity, Inflammation, and Clinical Outcomes in COVID-19: A Multicenter Prospective Cohort Study.

CONTEXT: Obesity is a risk factor for coronavirus disease 2019 (COVID-19)-related outcomes; however, the mechanism remains unclear. OBJECTIVE: The objective of this analysis was to determine whether inflammation mediates the association between obesity and COVID-19 outcomes. DESIGN: The International Study of Inflammation in Covid-19 (ISIC): A Prospective Multi-Center Observational Study Examining the Role of Biomarkers of Inflammation in Predicting Covid-19 Related Outcomes in Hospitalized Patients. SETTING: Ten hospitals in the United States and Europe. PARTICIPANTS: Adults hospitalized specifically for COVID-19 between February 1, 2020, through October 19, 2022. MAIN OUTCOME MEASURES: Inflammatory biomarkers, including soluble urokinase plasminogen activator receptor (suPAR), were measured at admission. Associations were examined between body-mass index (BMI, kg/m2) and a composite of death, need for mechanical ventilation, and renal replacement therapy, stratified by pre- and post-Omicron variants. The contribution of inflammation to the relationship between obesity and outcomes was assessed. RESULTS: Among 4644 participants (mean age 59.3, 45.6% male, 21.8% BMI≥35), those with BMI>40 (n=485) had 55% higher odds of the composite outcome (95% CI[1.21 to 1.98]) compared to non-obese individuals (BMI<30, n=2358) in multivariable analysis. In multiple mediation analysis, only suPAR remained a significant mediator between BMI and composite outcome. Associations were amplified for participants younger than 65 years and with pre-Omicron variants. CONCLUSION: Obesity is associated with worse outcomes in COVID-19, notably in younger participants and in the pre-Omicron era. Inflammation, as measured by suPAR, is a significant mediator of the association between obesity and COVID-19 outcomes.

An evaluation of secukinumab for the treatment of moderate-to-severe hidradenitis suppurativa.

INTRODUCTION: Until recently, biological therapy for hidradenitis suppurativa was limited to anti-tumor necrosis factor (TNF) blockade with adalimumab (ADA). However, not all patients respond to treatment with ADA. This highlighted the need for more therapeutic options. Interleukin (IL)-17/T-helper 17 (Th17) axis may play an important role in the pathophysiology of HS. Recently, the IL-17A inhibitor secukinumab, which targets IL-17A specifically and prevents it from interacting with the IL-17 receptor, has been FDA-approved for HS. AREAS COVERED: Secukinumab, represents a novel therapeutic strategy in HS management. An overview of structural and pharmacological characteristics is provided. Described efficacy in clinical trials and case reports and safety data from is presented. EXPERT OPINION: As response to anti-TNFas is lost over time, secukinumab has provided an alternative HS treatment option in clinical practice. Overall, secukinumab has shown good efficacy and a favorable side effect profile in HS clinical trials but may be avoided in patients with inflammatory bowel disease. Long-term and real-life data on the use of secukinumab are essential for improving decision-making in HS therapy.

Transitions of blood immune endotypes and improved outcome by anakinra in COVID-19 pneumonia: an analysis of the SAVE-MORE randomized controlled trial.

BACKGROUND: Endotype classification may guide immunomodulatory management of patients with bacterial and viral sepsis. We aimed to identify immune endotypes and transitions associated with response to anakinra (human interleukin 1 receptor antagonist) in participants in the SAVE-MORE trial. METHODS: Adult patients hospitalized with radiological findings of PCR-confirmed severe pneumonia caused by SARS-CoV-2 and plasma-soluble urokinase plasminogen activator receptor levels of ≥ 6 ng/ml in the SAVE-MORE trial (NCT04680949) were characterized at baseline and days 4 and 7 of treatment using a previously defined 33-messenger RNA classifier to assign an immunological endotype in blood. Endpoints were changes in endotypes and progression to severe respiratory failure (SRF) associated with anakinra treatment. RESULTS: At baseline, 23.2% of 393 patients were designated as inflammopathic, 41.1% as adaptive, and 35.7% as coagulopathic. Only 23.9% were designated as the same endotype at days 4 and 7 compared to baseline, while all other patients transitioned between endotypes. Anakinra-treated patients were more likely to remain in the adaptive endotype during 7-day treatment (24.4% vs. 9.9%; p < 0.001). Anakinra also protected patients with coagulopathic endotype at day 7 against SRF compared to placebo (27.8% vs. 55.9%; p = 0.013). CONCLUSION: We identify an association between endotypes defined using blood transcriptome and anakinra therapy for COVID-19 pneumonia, with anakinra-treated patients shifting toward endotypes associated with a better outcome, mainly the adaptive endotype. Trial registration ClinicalTrials.gov, NCT04680949, December 23, 2020.

HEPARIN-BINDING PROTEIN LEVELS PREDICT UNFAVORABLE OUTCOME IN COVID-19 PNEUMONIA: A POST HOC ANALYSIS OF THE SAVE TRIAL.

ABSTRACT: We aimed to evaluate heparin-binding protein (HBP) as a marker of prognosis of unfavorable outcome in COVID-19 pneumonia. This was a post hoc analysis of the SAVE clinical trial investigating anakinra treatment, guided by suPAR (soluble urokinase plasminogen activator receptor) levels ≥6 ng/mL, for the prevention of severe respiratory failure in hospitalized patients with COVID-19 pneumonia. Baseline HBP plasma levels were measured in 534 patients by fluorescence dry quantitative immunoassay using the Jet-iStar 800 analyzer. Concentrations higher than 35 ng/mL predicted 30-day mortality with a moderate specificity of 53.3% and negative predictive value 78.1%; sensitivity was low (29.0%). After multivariate Cox analysis, HBP higher than 35 ng/mL was an independent predictor of 30-day unfavorable outcome (adjusted hazard ratio, 1.77; 95% CI, 1.06-2.94; P = 0.028) and these patients were also at greater risk of death after 90 days (hazard ratio, 1.85; 95% CI, 1.25-2.74; P = 0.002). The cutoff was not predictive of development of severe respiratory failure, septic shock or acute kidney injury. Among patients with baseline HBP levels higher than 35 ng/mL, anakinra treatment was associated with decreased mortality (7.2%) versus comparators (18.1%; P < 0.001). Results confirm that HBP may be an early biomarker of poor outcome among preselected patients at risk from COVID-19 pneumonia.ClinicalTrials.gov registration NCT04357366.

qSOFA combined with suPAR for early risk detection and guidance of antibiotic treatment in the emergency department: a randomized controlled trial.

BACKGROUND: Sepsis guidelines suggest immediate start of resuscitation for patients with quick Sequential Organ Failure Assessment (qSOFA) 2 or 3. However, the interpretation of qSOFA 1 remains controversial. We investigated whether measurements of soluble urokinase plasminogen activator receptor (suPAR) may improve risk detection when qSOFA is 1. METHODS: The study had two parts. At the first part, the combination of suPAR with qSOFA was analyzed in a prospective cohort for early risk detection. At the second part, the double-blind, randomized controlled trial (RCT) SUPERIOR evaluated the efficacy of the suPAR-guided medical intervention. SUPERIOR took place between November 2018 and December 2020. Multivariate stepwise Cox regression was used for the prospective cohort, while univariate and multivariate logistic regression was used for the RCT. Consecutive admissions at the emergency department (ED) with suspected infection, qSOFA 1 and suPAR ≥ 12 ng/mL were allocated to single infusion of placebo or meropenem. The primary endpoint was early deterioration, defined as at least one-point increase of admission Sequential Organ Failure Assessment (SOFA) score the first 24 h. RESULTS: Most of the mortality risk was for patients with qSOFA 2 and 3. Taking the hazard ratio (HR) for death of patients with qSOFA = 1 and suPAR < 12 ng/mL as reference, the HR of qSOFA = 1 and suPAR ≥ 12 ng/mL for 28-day mortality was 2.98 (95% CI 2.11-3.96). The prospective RCT was prematurely ended due to pandemia-related ED re-allocations, with 91 patients enrolled: 47 in the placebo and 44 in the meropenem arm. The primary endpoint was met in 40.4% (n = 19) and 15.9% (n = 7), respectively (difference 24.5% [5.9-40.8]; odds ratio 0.14 [0.04-0.50]). One post hoc analysis showed significant median changes of SOFA score after 72 and 96 h equal to 0 and - 1, respectively. CONCLUSIONS: Combining qSOFA 1 with the biomarker suPAR improves its prognostic performance for unfavorable outcome and can help decision for earlier treatment. Trial registration EU Clinical Trials Register (EudraCT, 2018-001008-13) and Clinical-Trials.gov (NCT03717350). Registered 24 October 2018.

Intubation Decision Based on Illness Severity and Mortality in COVID-19: An International Study.

OBJECTIVES: To evaluate the impact of intubation timing, guided by severity criteria, on mortality in critically ill COVID-19 patients, amidst existing uncertainties regarding optimal intubation practices. DESIGN: Prospective, multicenter, observational study conducted from February 1, 2020, to November 1, 2022. SETTING: Ten academic institutions in the United States and Europe. PATIENTS: Adults (≥ 18 yr old) confirmed with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and hospitalized specifically for COVID-19, requiring intubation postadmission. Exclusion criteria included patients hospitalized for non-COVID-19 reasons despite a positive SARS-CoV-2 test. INTERVENTIONS: Early invasive mechanical ventilation (EIMV) was defined as intubation in patients with less severe organ dysfunction (Sequential Organ Failure Assessment [SOFA] < 7 or Pao2/Fio2 ratio > 250), whereas late invasive mechanical ventilation (LIMV) was defined as intubation in patients with SOFA greater than or equal to 7 and Pao2/Fio2 ratio less than or equal to 250. MEASUREMENTS AND MAIN RESULTS: The primary outcome was mortality within 30 days of hospital admission. Among 4464 patients, 854 (19.1%) required mechanical ventilation (mean age 60 yr, 61.7% male, 19.3% Black). Of those, 621 (72.7%) were categorized in the EIMV group and 233 (27.3%) in the LIMV group. Death within 30 days after admission occurred in 278 patients (42.2%) in the EIMV and 88 patients (46.6%) in the LIMV group (p = 0.28). An inverse probability-of-treatment weighting analysis revealed a statistically significant association with mortality, with patients in the EIMV group being 32% less likely to die either within 30 days of admission (adjusted hazard ratio [HR] 0.68; 95% CI, 0.52-0.90; p = 0.008) or within 30 days after intubation irrespective of its timing from admission (adjusted HR 0.70; 95% CI, 0.51-0.90; p = 0.006). CONCLUSIONS: In severe COVID-19 cases, an early intubation strategy, guided by specific severity criteria, is associated with a reduced risk of death. These findings underscore the importance of timely intervention based on objective severity assessments.

SuPAR, biomarkers of inflammation, and severe outcomes in patients hospitalized for COVID-19: The International Study of Inflammation in COVID-19.

Severe coronavirus disease 2019 (COVID-19) is a hyperinflammatory syndrome. The biomarkers of inflammation best suited to triage patients with COVID-19 are unknown. We conducted a prospective multicenter observational study of adult patients hospitalized specifically for COVID-19 from February 1, 2020 to October 19, 2022. Biomarkers measured included soluble urokinase plasminogen activator receptor (suPAR), C-reactive protein, interleukin-6, procalcitonin, ferritin, and D-dimer. In-hospital outcomes examined include death and the need for mechanical ventilation. Patients admitted in the United States (US, n = 1962) were used to compute area under the curves (AUCs) and identify biomarker cutoffs. The combined European cohorts (n = 1137) were used to validate the biomarker cutoffs. In the US cohort, 356 patients met the composite outcome of death (n = 197) or need for mechanical ventilation (n = 290). SuPAR was the most important predictor of the composite outcome and had the highest AUC (0.712) followed by CRP (0.642), ferritin (0.619), IL-6 (0.614), D-dimer (0.606), and lastly procalcitonin (0.596). Inclusion of other biomarkers did not improve discrimination. A suPAR cutoff of 4.0 ng/mL demonstrated a sensitivity of 95.4% (95% CI: 92.4%-98.0%) and negative predictive value (NPV) of 92.5% (95% CI: 87.5%-96.9%) for the composite outcome. Patients with suPAR < 4.0 ng/mL comprised 10.6% of the cohort and had a 0.8% probability of the composite outcome. Applying this cutoff to the validation cohort yielded a sensitivity of 93.8% (90.4%-96.7%) and NPV of 95.5% (93.1%-97.8%) for the composite outcome. Among commonly measured biomarkers, suPAR offered stronger discriminatory ability and may be useful in triaging low-risk patients with COVID-19.

Clarithromycin for early anti-inflammatory responses in community-acquired pneumonia in Greece (ACCESS): a randomised, double-blind, placebo-controlled trial.

BACKGROUND: Addition of macrolide antibiotics to ß-lactam antibiotics for the treatment of patients in hospital with community-acquired pneumonia is based on results from observational studies and meta-analyses rather than randomised clinical trials. We investigated if addition of the macrolide clarithromycin to treatment with a ß-lactam antibiotic in this population could improve early clinical response-the new regulatory endpoint for community-acquired pneumonia-and explored the possible contribution of modulation of the inflammatory host response to that outcome. METHODS: The ACCESS trial was a phase 3 prospective, double-blind, randomised controlled trial, in which adults in hospital with community-acquired pneumonia who had systemic inflammatory response syndrome, Sequential Organ Failure Assessment (SOFA) score of 2 or more, and procalcitonin 0·25 ng/mL or more were enrolled in 18 internal medicine departments of public Greek hospitals. Patients were randomly assigned (1:1) by computer-generated block randomisation to standard of care medication (including intravenous administration of a third-generation cephalosporin or intravenous administration of ß-lactam plus ß-lactamase inhibitor combination) plus either oral placebo or oral clarithromycin 500 mg twice daily for 7 days. Investigators, staff, and patients were masked to group allocation. The primary composite endpoint required that patients fulfilled both of the following conditions after 72 hours (ie, day 4 of treatment): (1) decrease in respiratory symptom severity score of 50% or more as an indicator of early clinical response and (2) decrease in SOFA score of at least 30% or favourable procalcitonin kinetics (defined as ≥80% decrease from baseline or procalcitonin <0·25 ng/mL), or both, as an indicator of early inflammatory response. Participants who were randomly assigned and received allocated treatment were included in the primary analysis population. This trial is complete and is registered with the EU Clinical Trials Register (2020-004452-15) and ClinicalTrials.gov (NCT04724044). FINDINGS: Patients were enrolled between Jan 25, 2021, and April 11, 2023, and 278 individuals were randomly allocated to receive standard of care in combination with either clarithromycin (n=139) or placebo (n=139). 134 patients in the clarithromycin group (five withdrew consent) and 133 patients in the placebo group (six withdrew consent) were included in the analysis of the primary endpoint. The primary endpoint was met in 91 (68%) patients in the clarithromycin group and 51 (38%) patients in the placebo group (difference 29·6% [95% CI 17·7-40·3]; odds ratio [OR] 3·40 [95% CI 2·06-5·63]; p<0·0001). Serious treatment-emergent adverse events (TEAEs) occurred in 58 (43%) patients in the clarithromycin group and 70 (53%) patients in the placebo group (difference 9·4% [95% CI -2·6 to 20·9]; OR 0·67 [95% CI 0·42 to 1·11]; p=0·14). None of the serious TEAEs was judged to be related to treatment assignment. INTERPRETATION: Addition of clarithromycin to standard of care enhances early clinical response and attenuates the inflammatory burden of community-acquired pneumonia. The mechanism of benefit is associated with changes in the immune response. These findings suggest the importance of adding clarithromycin to ß-lactams for treatment of patients in hospital with community-acquired pneumonia to achieve early clinical response and early decrease of the inflammatory burden. FUNDING: Hellenic Institute for the Study of Sepsis and Abbott Products Operations.

The pathophysiology of sepsis and precision-medicine-based immunotherapy.

Sepsis remains a major cause of morbidity and mortality in both low- and high-income countries. Antibiotic therapy and supportive care have significantly improved survival following sepsis in the twentieth century, but further progress has been challenging. Immunotherapy trials for sepsis, mainly aimed at suppressing the immune response, from the 1990s and 2000s, have largely failed, in part owing to unresolved patient heterogeneity in the underlying immune disbalance. The past decade has brought the promise to break this blockade through technological developments based on omics-based technologies and systems medicine that can provide a much larger data space to describe in greater detail the immune endotypes in sepsis. Patient stratification opens new avenues towards precision medicine approaches that aim to apply immunotherapies to sepsis, on the basis of precise biomarkers and molecular mechanisms defining specific immune endotypes. This approach has the potential to lead to the establishment of immunotherapy as a successful pillar in the treatment of sepsis for future generations.

Association of Vitamin D with Severity and Outcome of COVID-19: Clinical and Experimental Evidence.

INTRODUCTION: The role of vitamin in COVID-19 remains controversial. We investigated the association between endogenous vitamin D and the severity of COVID-19 as well as the mechanisms of action of vitamin D supplementation. METHODS: 25(OH)D3 in serum was associated with disease severity and outcome in 190 COVID-19 patients. In a COVID-19 animal model using intravenous injection of plasma from patients with COVID-19 acute respiratory distress syndrome into C57/BL6 mice, mice were treated with 0.25 µg human 1,25(OH)D3 or vehicle. Mice were sacrificed on day 4. Cytokines and myeloperoxidase (MPO) in tissues were measured. Changes in gene expression after vitamin D supplementation were measured. RESULTS: Vitamin D deficiency and insufficiency were associated with increased severity and unfavorable outcome after 28 days. Vitamin D levels were negatively associated with biomarkers of COVID-19 severity. Vitamin D supplementation after challenge of mice with COVID-19 plasma led to reduced levels of TNFα, IL-6, IFNγ, and MPO in the lung, as well as down-regulation of pro-inflammatory pathways. CONCLUSION: Normal levels of endogenous vitamin D are associated with reduced severity and risk of unfavorable outcome in COVID-19, possibly through attenuation of tissue-specific hyperinflammation.

Developing a Tool for Differentiation Between Bacterial and Viral Respiratory Infections Using Myxovirus Resistance Protein A and C-Reactive Protein.

INTRODUCTION: The aim was to assess the performance of a blood assay combining measurements of MxA (myxovirus resistance protein A) and CRP (C-reactive protein) to differentiate viral from bacterial respiratory infections. METHODS: In a prospective study, MxA and CRP were measured in the blood by the AFIAS panel in adults admitted with respiratory infection. Patients were split into discovery and validation cohorts. Final diagnosis was adjudicated by a panel of experts. Microbiology-confirmed cases comprised the discovery cohort, and infections adjudicated as highly probable viral or bacterial comprised the validation cohort. RESULTS: A total of 537 patients were analyzed: 136 patients were adjudicated with definitive viral infections and 131 patients with definitive bacterial infections. Using logistic regression analysis, an equation was developed to calculate the probability for bacterial infection using the absolute value of MxA and CRP. Calculated probability ≥ 0.5 and/or MxA to CRP ratio less than 2 applied as the diagnostic rule for bacterial infections. This rule provided 91.6% sensitivity and 90.4% negative predictive value for the diagnosis of bacterial infections. This diagnostic sensitivity was confirmed in the validation cohort. A MxA/CRP ratio less than 0.15 was associated with unfavorable outcome. CONCLUSION: The calculation of the probability for bacterial infection using MxA and CRP may efficiently discriminate between viral and bacterial respiratory infections.

Profiling the dysregulated immune response in sepsis: overcoming challenges to achieve the goal of precision medicine.

Sepsis is characterised by a dysregulated host immune response to infection. Despite recognition of its significance, immune status monitoring is not implemented in clinical practice due in part to the current absence of direct therapeutic implications. Technological advances in immunological profiling could enhance our understanding of immune dysregulation and facilitate integration into clinical practice. In this Review, we provide an overview of the current state of immune profiling in sepsis, including its use, current challenges, and opportunities for progress. We highlight the important role of immunological biomarkers in facilitating predictive enrichment in current and future treatment scenarios. We propose that multiple immune and non-immune-related parameters, including clinical and microbiological data, be integrated into diagnostic and predictive combitypes, with the aid of machine learning and artificial intelligence techniques. These combitypes could form the basis of workable algorithms to guide clinical decisions that make precision medicine in sepsis a reality and improve patient outcomes.

Fatty acid desaturation and lipoxygenase pathways support trained immunity.

Infections and vaccines can induce enhanced long-term responses in innate immune cells, establishing an innate immunological memory termed trained immunity. Here, we show that monocytes with a trained immunity phenotype, due to exposure to the Bacillus Calmette-Guérin (BCG) vaccine, are characterized by an increased biosynthesis of different lipid mediators (LM) derived from long-chain polyunsaturated fatty acids (PUFA). Pharmacological and genetic approaches show that long-chain PUFA synthesis and lipoxygenase-derived LM are essential for the BCG-induced trained immunity responses of human monocytes. Furthermore, products of 12-lipoxygenase activity increase in monocytes of healthy individuals after BCG vaccination. Grasping the underscoring lipid metabolic pathways contributes to our understanding of trained immunity and may help to identify therapeutic tools and targets for the modulation of innate immune responses.

Adjunctive treatment in COVID-19 and sepsis-What did we learn?

The introduction of anakinra, baricitinib and tocilizumab into the treatment armamentarium of severe coronavirus disease 2019 (COVID-19) reinforced the concept of immunotherapy for bacterial sepsis. The current review investigates how the example of COVID-19 may be extrapolated to sepsis using a three-step approach. In the first step, the clinical evidence on how the immunotherapy of COVID-19 assisted viral clearance is presented. In a second step, the indications acquired from human and animal studies on the need to employ strategies with primary effective phagocytosis in sepsis are presented. In a final step, lessons learnt from COVID-19 immunotherapy are applied for sepsis. The end result is that sepsis immunotherapy should rely on the use of biomarkers which provide information on the activation of a specific prevailing mechanism in order to enable the selection of the appropriate drug.

Immune responses of patients on maintenance hemodialysis after infection by SARS-CoV-2: a prospective observational cohort study.

BACKGROUND: Immune dysregulation in patients with acute COVID-19 under chronic hemodialysis (CHD) is fully not elucidated. The changes of mononuclear counts and mediators before and after HD and associations with final outcome were studied. METHOD: In this prospective study, hospitalized patients with moderate-to-severe COVID-19 under CHD and matched comparators under HD were analyzed for their absolute counts of lymphoid cells and circulating inflammatory mediators. Blood samples were collected before start and at the end of the first HD session; dialysate samples were also collected. RESULT: Fifty-nine patients with acute COVID-19 under CHD and 20 uninfected comparators under CHD were enrolled. Circulating concentrations of tumor necrosis factor-alpha (TNFα), interleukin (IL)-10, interferon-γ and platelet-derived growth factor-A were increased in patients. Concentrations of mediators did not differ before and after HD. Significant decreases of CD4-lymphocytes and CD19-lymphocytes were found in patients. The decrease of the expression of HLA-DR on CD14-monocytes was associated with unfavorable outcome (defined as WHO-CPS 6 or more by day 28); increased counts of CD19-lymphocytes were associated with better outcomes. CONCLUSION: Patients under CHD develop an inflammatory reaction to SARS-CoV-2 characterized by increase of inflammatory mediators, decrease of circulating T-lymphocytes and decrease of the expression of HLA-DR on CD14-monocytes.

A randomized clinical trial of bermekimab treatment for clinical improvement of systemic sclerosis.

Increased concentrations of interleukin (IL)-1α have been recently described in tissues of patients with systemic sclerosis (SSc) suggesting that IL-1α inhibition may be a target for treatment. We conducted a double-blind, placebo-controlled study to assess the safety and efficacy of the fully humanized IL-1α blocking monoclonal antibody bermekimab in SSc. To evaluate response to treatment, we developed the score of inhibition of progression of SSc which was validated using the CRISS index and the modified CRISS index. The primary endpoint was met in 80% of bermekimab-treated patients vs. 20% of placebo-treated patients (p: 0.023). Most of efficacy was found for increase of carbon monoxide lung diffusion capacity. Production of IL-1α and TNF by circulating mononuclear cells was decreased and the absolute count of CD42/Cd62-platelets was decreased. Results suggest that bermekimab is a promising treatment for SSc.

Biomarkers to guide immunomodulatory treatment: where do we stand?

INTRODUCTION: This review summarizes current progress in the development of biomarkers to guide immunotherapy in oncology, rheumatology, and critical illness. AREAS COVERED: An extensive literature search was performed about biomarkers classifying patients' immune responses to guide immunotherapy in oncology, rheumatology, and critical illness. Surface markers, such as programmed death-ligand 1 (PD-L1), genetic biomarkers, such as tumor mutation load, and circulating tumor DNA are biomarkers associated with the effectiveness of immunotherapy in oncology. Genomics, metabolomics, and proteomics play a crucial role in selecting the most suitable therapeutic options for rheumatologic patients. Phenotypes and endotypes are a promising approach to detect critically ill patients with hyper- or hypo-inflammation. Sepsis trials using biomarkers such as ferritin, lymphopenia, HLA-DR expression on monocytes and PD-L1 to guide immunotherapy have been already conducted or are currently ongoing. Immunotherapy in COVID-19 pneumonia, guided by C-reactive protein and soluble urokinase plasminogen activator receptor (suPAR) has improved patient outcomes globally. More research is needed into immunotherapy in other critical conditions. EXPERT OPINION: Targeted immunotherapy has improved outcomes in oncology and rheumatology, paving the way for precision medicine in the critically ill. Transcriptomics will play a crucial role in detecting the most suitable candidates for immunomodulation.