• B‐cell‐targeted therapy
• consensus recommendations
• immunoglobulin replacement therapy
• immunosuppression
• infection
• secondary hypogammaglobulinemia
• systemic autoimmune rheumatic diseases

• Humans
• Agammaglobulinemia/diagnosis
• Agammaglobulinemia/immunology
• Agammaglobulinemia/therapy
• Agammaglobulinemia/chemically induced
• Agammaglobulinemia/blood
• Rheumatic Diseases/immunology
• Rheumatic Diseases/drug therapy
• Rheumatic Diseases/diagnosis
• Rheumatic Diseases/complications
• Taiwan
• Consensus
• Autoimmune Diseases/immunology
• Autoimmune Diseases/drug therapy
• Autoimmune Diseases/diagnosis
• Autoimmune Diseases/complications
• Evidence-Based Medicine/standards
• Rheumatology/standards
• Predictive Value of Tests
• Immunosuppressive Agents/adverse effects
• Risk Factors
• Immunoglobulins, Intravenous/therapeutic use
• Immunocompromised Host
• Delphi Technique
• Biomarkers/blood
• Treatment Outcome

• Critical illness
• Hypogammaglobulinemia
• Intravenous immunoglobulins
• Personalized medicine
• Pneumonia

• Humans
• Female
• Male
• Community-Acquired Infections/blood
• Critical Illness
• Middle Aged
• Aged
• Disease Progression
• Cohort Studies
• Pneumonia/physiopathology
• Longitudinal Studies
• Immunoglobulin M/blood
• Immunoglobulin M/analysis
• Immunoglobulins/blood
• Immunoglobulins/analysis
• Immunoglobulins/therapeutic use
• Immunoglobulin G/blood
• Organ Dysfunction Scores

• Humans
• Sepsis/genetics
• Mendelian Randomization Analysis
• Herpesvirus 1, Human/immunology
• Risk Factors
• Cytomegalovirus Infections/genetics
• Cytomegalovirus/genetics
• Herpes Simplex/genetics
• Genome-Wide Association Study
• Male
• Genetic Predisposition to Disease
• Severity of Illness Index
• Female

• bacterial infection
• coagulation
• human polyvalent immunoglobulins
• neutrophils
• sCAP
• sepsis
• tissue damage

• Biomarkers
• Community-acquired pneumonia
• Immunoglobulin therapy
• Immunomodulation
• Inflammation
• Outcome

• Humans
• Prospective Studies
• Pneumonia
• C-Reactive Protein/analysis
• Procalcitonin
• Inflammation
• Immunoglobulin M
• Immunoglobulin A
• Immunoglobulin G
• Biomarkers

• immunotherapy
• sepsis
• septic shock

• antibody-secreting cells
• biomarker
• prognosis
• sepsis
• septic shock

• Biomarkers
• Endotype
• Organ dysfunction
• Phenotype
• Precision medicine
• Sepsis
• Septic shock

• intensive care unit
• intravenous immunoglobulin therapy
• low immunoglobulin G level
• outcome
• retrospective study
• sepsis

The role of intravenous immunoglobulins (IVIG) during sepsis is controversial, as different trials on IVIG have observed inconsistent survival benefits. We aimed to elucidate the possible association and clinical significance between circulating levels of immunoglobulins.

In a subset of 956 patients with severe sepsis and septic shock of the multicentre, open-label RCT ALBIOS, venous blood samples were serially collected 1, 2, and 7 days after enrolment (or at ICU discharge, whichever came first). IgA, IgG and IgM concentrations were assayed in all patients on day 1 and in a subgroup of 150 patients on days 2 and 7. Ig concentrations were measured employing a turbidimetric assay, OSR61171 system.

IgA on day 1 had a significant predictive value for both 28-day and 90-day mortality (28-day mortality, HR: 1.50 (95% CI 1.18–1.92); 90-day mortality, HR: 1.54 (95% CI 1.25–1.91)). IgG, but not IgM, on day 1 showed similar results for 28-day (HR 1.83 (95% CI 1.33–2.51) and 90-day mortality HR: 1.66 (95% CI 1.23–2.25)). In addition, lower levels of IgG but not of IgA and IgM, at day 1 were associated with significantly higher risk of secondary infections (533 [406–772] vs 600 [452–842] mg/dL, median [Q1–Q3], p = 0.007).

In the largest cohort study of patients with severe sepsis or septic shock, we found that high levels of IgA and IgG on the first day of diagnosis were associated with a decreased 90-day survival. No association was found between IgM levels and survival. As such, the assessment of endogenous immunoglobulins could be a useful tool to identify septic patients at high risk of mortality.

Trial registration #NCT00707122, Clinicaltrial.gov, registered 30 June 2008

The online version contains supplementary material available at 10.1186/s13613-021-00952-z.

• IgA
• IgG
• IgM Immunoglobulins
• Mortality
• Sepsis
• Septic shock

Immunoglobulin IgM is important for controlling viral and bacterial infections, and low immunoglobulin levels have been found in sepsis. There is a clear need to stratify sepsis patients according to the presence of an invading organism, compared to no organism identified, and SIRS patients, where organ dysfunction is a result of a non-infective process. The aim of this pilot study in a small cohort of patients with sepsis was to evaluate the association between IgM plasma levels and survival in 47 patients with sepsis and 11 patients diagnosed with organ failure without the identification of a pathogen (SIRS). Patients were admitted to the intensive care unit (ICU) at The Royal Glamorgan Hospital, Llantrisant, UK between 2010 and 2014. We found that low IgM levels were associated with sepsis, but not SIRS. IgM levels did not differ significantly for culture-positive (CP) compared with culture-negative (CN, no organism found) sepsis samples. Kaplan–Meier analysis was used to compare survival curves according to IgM levels, with no significant difference. We observed significantly higher survival in the CP samples when comparing with CN. Cut-off value for IgM (266 μg/mL) for diagnosis of sepsis patients was determined using receiver operator characteristic (ROC) curves with 70% sensitivity, 69% specificity and 92% negative predictive values (NPV), respectively. The corresponding area under the curve (AUC) for the discrimination of sepsis patients was AUC = 0.73, and in a subgroup analysis of CP was AUC = 0.77 and for CN was AUC = 0.79. We confirm IgM as a good diagnostic marker of sepsis. These findings indicate a difference in the pathology between culture-positive versus negative sepsis, SIRS and survival. This indicates that IgM is likely relevant to pathology, because of its role in the early immune response against pathogens, the potentially protective role of natural IgM antibodies, and supports its application in immunoglobulin therapy.

• SIRS
• culture-negative
• immunoglobulins
• sepsis

Introduction: Adjunctive therapy with polyclonal intravenous immunoglobins (IVIg) is currently used for preventing or managing infections and sepsis, especially in immunocompromised patients. The pathobiology of COVID-19 and the mechanisms of action of Ig led to the consideration of this adjunctive therapy, including in patients with respiratory failure due to the SARS-CoV-2 infection. This manuscript reports the rationale, the available data and the results of a structured consensus on intravenous Ig therapy in patients with severe COVID-19. Methods: A panel of multidisciplinary experts defined the clinical phenotypes of COVID-19 patients with severe respiratory failure and, after literature review, voted for the agreement on the rationale and the potential role of IVIg therapy for each phenotype. Due to the scarce evidence available, a modified RAND/UCLA appropriateness method was used. Results: Three different phenotypes of COVID-19 patients with severe respiratory failure were identified: patients with an abrupt and dysregulated hyperinflammatory response (early phase), patients with suspected immune paralysis (late phase) and patients with sepsis due to a hospital-acquired superinfection (sepsis by bacterial superinfection). The rationale for intravenous Ig therapy in the early phase was considered uncertain whereas the panelists considered its use in the late phase and patients with sepsis/septic shock by bacterial superinfection appropriate. Conclusion: As with other immunotherapies, IVIg adjunctive therapy may have a potential role in the management of COVID-19 patients. The ongoing trials will clarify the appropriate target population and the true effectiveness.

• COVID-19
• intravenous immunoglobulin therapy
• respiratory failure

Sepsis is a life-threatening condition and a global disease burden. Today, the heterogeneous syndrome is defined as severe organ dysfunction caused by a dysregulated host response to infection, with renewed emphasis on immune pathophysiology. Despite all efforts of experimental and clinical research during the last three decades, the ability to positively influence course and outcome of the syndrome remains limited. Evidence-based therapy still consists of basic causal and supportive measures, while adjuvant interventions such as blood purification or targeted immunotherapy largely remain without proof of effectiveness so far. With this review, we aim to provide an overview of sepsis immune pathophysiology, to update the choice of therapeutic approaches targeting different immunological mechanisms in the course of sepsis and septic shock, and to call for a paradigm shift from the pathogen to the host response as a potentially more promising angle.

• immune pathology
• inflammation
• sepsis
• sepsis therapy
• septic shock

Objective: To assess the variations of the blood levels of immunoglobulins (Ig) in septic shock patients treated with an Ig preparation enriched in IgM and IgA (eIg).

Design: The blood levels of Ig in survivors (S) and non-survivors (NS) of a group of septic shock patients were measured before the initial administration (D0) and 1 (D1), 4 (D4), and 7 (D7) days thereafter. The SAPS II score, the capillary permeability, the primary site of infection, the antibiotic appropriateness, and the outcome at 28 days were also assessed.

Results: In the interval D0–D7, the IgM increased significantly only in the S while remained stable in NS; the IgA significantly increased in both groups; the IgG did not vary significantly in both groups. At D4, the capillary permeability significantly decreased in S but not in NS.

Conclusions: The kinetics of the different classes of Ig after eIg were different between S and NS. This could be related either to (a) different capillary permeability in the two groups or to (b) higher Ig consumption in NS. Further studies to confirm the benefits of eIg in the treatment of sepsis syndrome and to define the specific target population and the correct eIg dose are warranted.

• IgM
• immunoglobulins (G&M) IgG
• infections
• plasma concentration
• septic shock

Septic shock still has a high mortality rate which has not hinted at decreasing in recent years. Unfortunately, randomized trials failed mainly because the septic patient was considered as a homogeneous entity. All this creates a sort of therapeutic impotence in everyday clinical practice in treating patients with septic shock. The need to customize therapy on each patient with sepsis has now become an established necessity. In this scenario, adjuvant therapies can help if interpreted as modulators of the immune system. Indeed, the host's immune response differs from patient to patient based on the virulence of the pathogen, comorbidity, infection site, and prolonged hospitalization. In this review, we summarize the rationale for using immunoglobulins as an adjunctive treatment. Furthermore, we would like to suggest a possible protocol to personalize treatment in the different clinical scenarios of the host's response to serious infectious events.

• adjunctive treatment
• immunoglobulins
• protocol
• sepsis
• septic shock

• immunology
• infectious diseases
• intensive & critical care

• COVID-19
• Humans
• Immunization, Passive
• Immunoglobulin M
• Prospective Studies
• SARS-CoV-2
• Shock, Septic/drug therapy
• Treatment Outcome

• extracorporeal treatment
• immunoglobulin deficiency
• plasma exchange
• septic shock

Sepsis is a life-threatening organ dysfunction caused by a dysregulated host response to infection. Despite treatment being in line with current guidelines, mortality remains high in those with septic shock. Intravenous immunoglobulins represent a promising therapy to modulate both the pro- and anti-inflammatory processes and can contribute to the elimination of pathogens. In this context, there is evidence of the benefits of immunoglobulin M (IgM)- and immunoglobulin A (IgA)-enriched immunoglobulin therapy for sepsis. This manuscript aims to summarize current relevant data to provide expert opinions on best practice for the use of an IgM- and IgA-enriched immunoglobulin (Pentaglobin) in adult patients with sepsis.

Sepsis patients with hyperinflammation and patients with immunosuppression may benefit most from treatment with IgM- and IgA-enriched immunoglobulin (Pentaglobin). Patients with hyperinflammation present with phenotypes that manifest throughout the body, whilst the clinical characteristics of immunosuppression are less clear. Potential biomarkers for hyperinflammation include elevated procalcitonin, interleukin-6, endotoxin activity and C-reactive protein, although thresholds for these are not well-defined. Convenient biomarkers for identifying patients in a stage of immune-paralysis are still matter of debate, though human leukocyte antigen–antigen D related expression on monocytes, lymphocyte count and viral reactivation have been proposed. The timing of treatment is potentially more critical for treatment efficacy in patients with hyperinflammation compared with patients who are in an immunosuppressed stage. Due to the lack of evidence, definitive dosage recommendations for either population cannot be made, though we suggest that patients with hyperinflammation should receive an initial bolus at a rate of up to 0.6 mL (30 mg)/kg/h for 6 h followed by a continuous maintenance rate of 0.2 mL (10 mg)/kg/hour for ≥ 72 h (total dose ≥ 0.9 g/kg). For immunosuppressed patients, dosage is more conservative (0.2 mL [10 mg]/kg/h) for ≥ 72 h, without an initial bolus (total dose ≥ 0.72 g/kg).

Two distinct populations that may benefit most from Pentaglobin therapy are described in this review. However, further clinical evidence is required to strengthen support for the recommendations given here regarding timing, duration and dosage of treatment.

• Hyperinflammation
• IgM- and IgA-enriched immunoglobulin
• Immunoglobulin
• Immunosuppression
• Pentaglobin
• Sepsis

• Immunoglobulin G
• Mortality
• Outcome
• Sepsis

Septic shock (SS) and cardiogenic shock (CS) are two types of circulatory shock with a different etiology. Several studies have described the molecular alterations in SS patients, whereas the molecular factors involved in CS have been poorly investigated. We aimed to assess in the whole blood of CS and SS patients, using septic patients without shock (SC) as controls, transcriptomic modifications that occur over 1 week after ICU admission and are common to the two types of shock.

We performed whole blood RNA sequencing in 21 SS, 11 CS, and 5 SC. In shock patients, blood samples were collected within 16 h from ICU admission (T1), 48 h after ICU admission (T2), and at day 7 or before discharge (T3). In controls, blood samples were available at T1 and T2. Gene expression changes over time have been studied in CS, SS, and SC separately with a paired analysis. Genes with p value < 0.01 (Benjamini-Hochberg multiple test correction) were defined differentially expressed (DEGs). We used gene set enrichment analysis (GSEA) to identify the biological processes and transcriptional regulators significantly enriched in both types of shock.

In both CS and SS patients, GO terms of inflammatory response and pattern recognition receptors (PRRs) were downregulated following ICU admission, whereas gene sets of DNA replication were upregulated. At the gene level, we observed that alarmins, interleukin receptors, PRRs, inflammasome, and DNA replication genes significantly changed their expression in CS and SS, but not in SC. Analysis of transcription factor targets showed in both CS and SS patients, an enrichment of CCAAT-enhancer-binding protein beta (CEBPB) targets in genes downregulated over time and an enrichment of E2F targets in genes with an increasing expression trend.

This pilot study supports, within the limits of a small sample size, the role of alarmins, PRRs, DNA replication, and immunoglobulins in the pathophysiology of circulatory shock, either in the presence of infection or not. We hypothesize that these genes could be potential targets of therapeutic interventions in CS and SS.

ClinicalTrials.gov, NCT02141607. Registered 19 May 2014.

• Cardiogenic shock
• Circulatory shock
• Critical illness
• Immunoglobulin
• PRR
• RNA-Seq
• Septic shock

• IgM
• Immunoglobulins
• Intensive care unit
• Multiple drug resistance
• Septic shock
• Severe sepsis

• ARDS
• ECMO
• Inflammation
• Intravenous immunoglobulin

• Evidence-based medicine
• Guidelines
• Medical Information Network Distribution Service (Minds)
• Sepsis
• Septic shock
• Systematic review

Immunoglobulins have been used widely in medicine for a variety of diseases including infectious diseases. While the main clinical applications of immunoglobulin therapy concern their use as replacement for patients with primary immunodeficiencies, or as treatment for autoimmune and inflammatory disorders, their role in infectious disease is limited largely to viral and toxin neutralization and replacement therapy in patients with immunoglobulin deficiencies. Many aspects of the therapeutic regimen of immunoglobulins even in the established indications remain open. Recently, due to the worldwide surge of immunosuppression caused by AIDS, organ transplantation, cancer, and autoimmune therapies, as well as the emergence of multidrug-resistant bacteria, there has been renewed interest in the use of antibody preparation to prevent infections in high-risk groups.

Knowing the limitations of the current anti-infective armamentarium, approaches that target the host through manipulations to augment the host immune response provide a helpful aid to conventional treatment options. A substantial body of evidence has demonstrated that strategies aiming to support or stimulate immune response could be feasible approaches that would benefit immunocompromised patients. In the present chapter, we present contemporary indications of immunoglobulin administration for therapy and prophylaxis of infections in the immunocompromised population.

• Medical Information Network Distribution Service (Minds)
• Sepsis
• evidence‐based medicine
• guidelines
• septic shock
• systematic review

• cervical necrotizing fasciitis
• descending necrotizing mediastinitis
• immunoglobulin
• ludwig angina

• Agammaglobulinemia/complications
• Anti-Bacterial Agents/therapeutic use
• Debridement
• Dental Implants/adverse effects
• Fasciitis, Necrotizing/etiology
• Fasciitis, Necrotizing/therapy
• Humans
• Immunoglobulin G
• Ludwig's Angina/complications
• Ludwig's Angina/etiology
• Mediastinitis/etiology
• Mediastinitis/therapy
• Middle Aged
• Neck
• Risk Factors

• Immunoglobulins
• Interleukin 10
• Pneumonia
• Sepsis
• Tumor necrosis factor

• Bacteremia
• Pathogenesis
• Sepsis
• Septic shock
• Treatment

• Community-acquired pneumonia
• Corticosteroid
• Immunoglobulin

• Cytokines
• bacterial toxins
• clinical trials
• genetic susceptibility to sepsis
• immunoglobulins (IGs)
• sepsis, outcome
• septic shock
• single nucleotide polymorphisms (SNPs)
• therapeutic monoclonal antibodies to infectious diseases