Table 1 Studies reporting on immunoglobulin levels and kinetics in patients with sepsis

Taccone et al. [14]

Evaluate the time course of gamma-globulin concentrations in patients with septic shock, to define the frequency of low immunoglobulin concentrations, and to investigate the relationship of immunoglobulin concentrations to disease severity and outcome

Prospective observational study

21 patients (aged ≥ 18 years old) with community-acquired septic shock

76% of patients (16/21) had hypo-gammaglobulinemia (single or combined immunoglobulin deficiency) at admission: 7 patients had isolated low IgG concentrations, 4 patients had isolated low IgM concentrations, and 3 patients had low IgG and IgM concentrations

Two patients had low concentrations of IgG, IgM, and IgA and died

with refractory shock within 2 days

Patients with low IgG concentration on Day 1 had persistent low levels throughout the ICU stay. Almost all patients with normal IgG levels maintained normal concentrations throughout their stay (1 patient had a transient decrease in IgG on Day 3)

Patients with low IgG concentrations were indistinguishable at baseline from patients with normal IgG concentrations but had fewer vasopressor-free days (P = 0.02) and more frequently developed acute lung injury/acute respiratory distress syndrome (P = 0.02)

There was no significant difference in outcomes in patients with normal or low IgM levels

All deaths occurred in patients with low IgG concentrations (P = 0.01)

Myrianthefs et al. [15]

Investigate the time course of IgG and IgM concentrations in patients who developed septic shock during their ICU stay

Observational cohort study

38 patients who developed septic shock during their ICU stay

45% of patients (17/38) had hypo-gammaglobulinemia (single or combined immunoglobulin deficiency) on admission: 7 patients had isolated low IgG levels, 5 patients had isolated low IgM concentrations, and 5 patients had low IgG and IgM levels

Low levels of IgG were resolved within 10 days in the 5 patients who survived in the group with low IgG

IgM concentrations improved over time in patients with and without low IgG levels

There were no significant differences regarding length of ICU or hospital stay, oxygenation index (PaO₂/FIO₂), duration of vasopressor use, or duration of mechanical ventilation in those with low or normal IgG levels

No comparative analyses were provided for patients with low or normal IgM levels

Andaluz-Ojeda et al. [16]

Evaluate the quantitative changes in the status of immunocompetence in severe sepsis over time and its potential influence on clinical outcome

Prospective observational cohort study

50 patients (aged ≥ 18 years old) with severe sepsis or septic shock

Survivors exhibited a progressive increase in IgG, IgA, and IgM levels from Day 1 to Day 10

Compared to survivors, septic patients who did not survive had significantly lower levels of IgG in the first 24 h following admission to the ICU

There was no significant difference in IgA or IgM levels between survivors and non-survivors

Venet et al. [17]

Measure the endogenous levels of circulating IgG, IgA, and IgM in a cohort of septic shock patients

Prospective observational cohort study

62 consecutive patients (aged ≥ 18 years old) with septic shock

At Days 1–2, 61%, 40%, and 9% of patients had IgG, IgM, and IgA concentrations below the lowest limit of age-matched reference values, respectively

Circulating IgG and IgM concentrations increased over time, by Days 5–7, 61% of patients had IgG and IgM levels within the range of normal values

Changes in immunoglobulin levels did not appear to be associated with increased mortality, morbidity, or severity after septic shock

Reduced immunoglobulin level was correlated with reduced protein concentrations at Days 1–4 suggesting an apparent hypogammaglobulinemia is present during this time period in septic shock patients

Tamayo et al. [18]

Investigate the relationship between endogenously produced immunoglobulins and the clinical outcome in septic shock

Retrospective study

42 patients with septic shock and 36 patients with systemic inflammatory response syndrome

Both patients with systemic inflammatory response syndrome and septic shock showed subnormal levels of total IgG, IgG2, and IgM

Patients with septic shock who died showed the lowest levels of total IgG and IgG1

Univariate Cox regression analysis showed that levels of IgG1, IgG2, IgG3, IgM, IgA, and total IgG were inversely associated to the probability of death at 28 days

Multivariate analysis showed that IgG1, total IgG, IgM, and IgA behaved as independent protective factors against mortality (HR, P): 0.23, 0.026; 0.16, 0.028; 0.11, 0.042; 0.05, 0.010, respectively

Giamarellos-Bourboulis et al. [19]

Investigate the kinetics of IgM during the different stages of sepsis

Prospective observational multicenter cohort study

332 critically ill patients were enrolled

Serum IgM was decreased in septic shock compared to patients with systemic inflammatory response syndrome and patients with severe sepsis

Paired comparisons at distinct time points of the sepsis course showed that IgM was decreased only when patients deteriorated from severe sepsis to septic shock

Serial measurements in patients who progressed from severe sepsis to septic shock, beginning from the early start of vasopressors, showed that the distribution of IgM over time was significantly greater for survivors than for non-survivors

Průcha et al. [20]

Assess the frequency of hypogammaglobulinemia in patients with systemic inflammatory response syndrome, severe sepsis, and septic shock

Retrospective study 708 patients with systemic inflammatory response syndrome, severe sepsis, and septic shock

IgG, IgA, and IgM hypogammaglobulinemia was demonstrated in 25%, 3%, and 12% of patients with severe sepsis, and 24%, 2%, and 13% of septic shock patients, respectively

Mortality in patients with severe sepsis or septic shock and IgG hypogammaglobulinemia was significantly higher than in those with normal IgG levels

Mortality in patients with septic shock and IgM hypogammaglobulinemia was significantly higher than in those with normal IgM levels. In patients with severe sepsis, no significant difference in mortality was observed

Bermejo-Martín et al. [21]

Evaluate the association between immunoglobulin levels in plasma and survival in patients with severe sepsis

Prospective observational multicenter cohort study

172 patients (aged > 18 years old) admitted to the ICU with severe sepsis/septic shock

At time of diagnosis, 27.9%, 39.2%, and 19.2% of patients had immunoglobulin concentrations below the normal reference values for IgG1, IgM, and IgA, respectively

Kaplan–Meier analysis showed that levels below normal reference values for IgG1, IgM, and IgA were associated with shorter survival times

Multivariate regression analysis showed that low levels of IgG1 were a risk factor for mortality (OR: 2.50, 95% CI 1.04–6.03; P = 0.042)

The combined presence of IgG1, IgM, and IgA levels below the normal threshold had a synergistic impact on mortality risk (OR: 5.27, 95% CI 1.41–19.69; P = 0.013). A similar effect was observed for combined low levels of IgG1 and IgA:,and IgG1 and IgM

Shankar-Hari et al. [22]

Evaluate the additional mortality risk associated with subnormal IgG concentrations in adults with sepsis managed in an ICU setting

Systematic review of 8 studies

438 adult patients with sepsis

IgG concentrations increased over time in most studies

Subnormal IgG levels on the day of sepsis diagnosis did not increase the risk of death in adult patients with severe sepsis and/or septic shock by both fixed effect and random effect meta-analysis (M-H pooled OR: 1.32 [95% CI 0.93–1.87] and D + L pooled OR: 1.48 [95% CI 0.78–2.81], respectively)

Tian et al. [23]

Study the relationship between circulating B cells and plasma IgM levels and sepsis survival rate

Systematic review and meta-analysis of 11 studies

829 patients (aged > 18 years old) with sepsis and/or septic shock

Plasma IgM level was significantly decreased in septic patients (SMD = − 2.35, 95% CI − 2.94, − 1.76; P < 0.00001, I² = 0%) compared with healthy controls

Plasma IgM level was significantly lower in sepsis survivors versus sepsis non-survivors (SMD = − 0.31, 95% CI − 0.53, − 0.09; P = 0.005, I² = 50%)

The reduction of circulating B cells and IgM plasma levels is negatively correlated with sepsis survival