Safety and efficacy of IgM-enriched intravenous immunoglobulins as adjunctive therapy in patients with sepsis-review of literature Sanja Sakan1, Jasminka Persec1,2, Dinko Milavec1, Daniela Bandic Pavlovic3,4 1Clinical department of anesthesia and intensive medicine, University Hospital Dubrava, Zagreb, Croatia 2 School of dental medicine, University of Zagreb, Zagreb, Croatia 3Clinical department of anesthesia and intensive care, Clinical Hospital Center Zagreb, Zagreb,Croatia 4School of medicine, University of Zagreb, Zagreb, Croatia Correspondence to: Sanja Sakan, PhD, Clinical department of anesthesiology and intensive medicine, University hospital Dubrava ,Zagreb, Croatia e-mail: sanja.sakan@hotmail.com Abstract Treatment of sepsis still represents a big medical challenge and a great burden for the cost of healthcare system. Immunomodulatory therapy with IgM-enriched intravenous immunoglobulis could be a novel effective adjunctive therapy to 24-hrs surviving sepsis bundels. However there are not so many large homogenous clinical studies to justify cost-benefit of the IgM-enriched immunoglobulins use and the right timing for their application. For now the results of the present clinical studies are controversial. Keywords: IgM-enriched IVIG, pentaglobin, sepsis, septic shock

1. Safety and efficacy of IgM-
enriched intravenous
immunoglobulins as adjunctive
therapy in patients with sepsis-
review of literature
Sanja Sakan, MD,PhD
Clinical department of anesthesia
and intensive medicine, University
Hospital Dubrava, Zagreb, Croatia

2. Introduction
• Sepsis and septic shock are major reasons for death in
noncardiologic ICU
• Sepsis is defined as a life-threatening organ dysfunction
caused by disregulated host response to infection
• Septic shock is defined as a consequence of sepsis in which
profound circulatory, cellular and metabolic abnormalities
happen
• Incidence rate of sepsis increases by 9% every year
• The occurrence of sepsis peaks in the six decade of life
• Sepsis and modest degree of organ dysfunction are
associated with hospital mortality of 10%
• Septic shock increases hospital mortality for 40%
Martin et al (200). N Engl J Med; Schefold et al(2009);Blood Purif; Singer et al (2016);JAMA

3. Immunopathophysiology of sepsis
Aziz et al (2013). J Leukoc Biol

4. Immunopathophysiology of sepsis
• Vast majority of nonsurviving septic shock patients die in
the late hyporesponsive phase from the second or third
infectious kick, not from the initial infectious impact!!!!
• The reason is onset of functional immunodeficiency
mechanisms (disturbed monocytic phagocytosis, altered
cytokine profiles, inadequate antigen presentation
capacities, dysfunction and apoptosis of both T and B
lymphocytes) which result a shutdown of innate and
adaptive immunity or state of “immunoparalysis”
• Immunoparalysis is clinically quantative parameter by
measurement of diminished monocytic HLA-DR
expression
• Functional monocytic failure is associated with reduced
survival from sepsis
Schefold et al (2009).Blood Purif; Docke et al (2005). Clin Chem; Monneret et al (2006).
Intensive Care Med; Schefold et al (2008). Med Hypothese.

5. Immunomodulatory drugs
• Immunosuppresants or immunostimulants
• Mechanisms include
1. inhibiting or increasing cytokine release
2. affecting cytokine receptor expression
3. affecting response of cells to cytokines
4. perform phagocytic or cytotoxic actions of cells
5. regulate transcription or translation of protein
mediators
• Immunomodulation can be intentional, incidental or
inadvertent
Webster et al (2009). Br J Anaesth

6. Intravenous immunogobulins in
sepsis- literature review
• Use of intravenous immunoglobulins (IVIG) in sepsis is still a controversial
issue
• Bermejo et al showed that simultaneous presence of low levels of
IgG,IgA,IgM was a consistent predictor of both acute mortality (at the
ICU) and post-acute mortality (at hospital), independently of the presence
or absence of previous immunosupression in septic patients
• IgG and IgG1 were good predictors of acute mortality in
immunosupressed and non-immunosupressed septic patients
• IgG2 predictive ability of acute mortality was shown only in non-
immunosupressed patients
• Study emphasized the need for pre-evaluation of endogenous
immunoglobulins score and combined immunoglobulin endogenous levels
score over immunoglobulins individually to identify sepsis patients at risk
for poor outcomes
Martin-Loeches et al (2017). Ann Intensive Care; Bermejo et al (2014). J Intern Med

7. Intravenous immunogobulins in
sepsis- literature review
• Kreymann et al, published a metaanalysis in 2007 of all RCTs on
polyvalent IVIG for the treatment of sepsis or septic shock, and
observed a strong protective trend in favor of an IVIG
preparation containing three major immunoglobulin isotypes
• Werdan et al, in 2007 published a RT (n=653) which did not show
the effect of polyclonal IVIG therapy on the 28-day mortality rate
in patients with severe sepsis
Kreymann et al (2007). Crit Care Med; Werdan et al (2007). Crit Care Med

8. IgM-enriched intravenous immunoglobulins
(IgM-IVIG) in sepsis- literature review
• Hellenic Sepsis Study Group in 2013 conducted a multicentre
observational study which demonstrated a significant decrease
in IgM serum concentrations when sepsis progresses to septic
shock, and nonsurvivors have lower levels of IgM
Superiority of IgM-IVIG preparations are:
1. IgM polyreactivity
2. rapid complement activation for bacteria neutralisation
3. higher titre of bacteria reactive antibodies
4. recognition of broad spectrum of bacterial pathogens
5. removal of apoptotic cells
6. resolution of inflammatory response
Giamarellos –Bourboulis et al (2013). Crit Care; Trautman et al (1998). Clin Exp Immunol; Ehrenstein et al
(2010), Nat Rev Immunol; Rieben et al (1999). Blood.

9. IgM-enriched intravenous immunoglobulins
(IgM-IVIG) in sepsis- literature review
• Cavazzuti et al in 2009 (168) showed that administration of
IgM-IVIG within the 24 hrs of the onset of septic shock as a
part of 24-hrs surviving sepsis bundles for 3 consecutive days
at dosage of 250 mg/kg/day (20 mg/kg/h) reduced 30-day
mortality rate by 21.1% compared to control group (p<0.05)
• Cui et al, published a metaanalysis in 2019 which showed that
IgM-IVIG in the sepsis and septic shock patients significantly
reduced mortality risk (RR 0.60,CI 95% 0.52-069), shortened
length of mechanical ventilation, but did not significantly
shorten the length of the ICU stay
Cavazzutti et al (2009). Intensive Care Med; Cui et al (2019). Ann Intensive Care

10. IgM-enriched intravenous immunoglobulins
(IgM-IVIG) in sepsis- literature review
• Rodriguez et al, in 2005 conducted a multicenter randomized double blind study
of patients with abdominal sepsis (n=56) and observed a 25% reduction in 30-day
mortality in patients treated IgM-IVIG (7 ml/kg/day for 5 days) and appropriate
antibiotic therapy
• Berlot et al, published in 2012 a retrospective study (n=129) which revealed that
the effectiveness of IgM-IVIG depends on the time delay between the occurrence
of sepsis and administration of IgM-IVIG (odds ratio for 1 hr of delay,1.007;
p<0.01;99%CI 1.001-1.0010)
• Study showed that the risk of death increased by 3% for each day IgM-IVIG
treatment was delayed
• In 2018 Berlot et al published another study (n=305) which confirmed time
dependant benefit of IgM-IVIG in septic patients as in previous study
• The benefit was more intense in less severe patients and for abdominal sepsis
• Time effect was found to be independent from the adequacy of antibiotic therapy
Rodriguez et al (2005). Shock; Berlot et al. (2017). J Crit Care; Berlot et al(2018). Ann Intensive Care

11. IgM-enriched intravenous immunoglobulins
(IgM-IVIG) in sepsis- literature review
• Wand et al in 2016 published study (n=26) which observed a
significant reduction in endotoxin activity levels 6 and 12 hrs over
the first day of IgM-IVIG application compared to control group
(p=0.01, p=0.03)
• During 3 day follow up there was no significant difference between
the IgM-IVIG and control group, but endotoxin activity had
tendency to be lower in the IgM-IVIG group
• IgM-IVIG was administered for 3 consecutive days with a dose of 5
mg/kg/day over 12 hrs followed by a 12-hrs pause
• Tugrul et al in 2001 revealed in a small study (n=39) that patients
who received IgM-IVIG(n=21) with a dose 5 ml/kg/day for 3 days
had a significant decrease in procalcitonin levels (p=0.001)
Wand et al (2016). PloS One; Tugrul et al (2001). Ulus Travma Derg

12. Adverse effects of IgM-IVIG
1. Immediate
-anaphylactoid reactions due to presence of IgA
in IgA deficient individuals
2. Delayed
-pulmonary, renal, hematologic and neurologic
events
3. Late
- transmission of infectious agents such as
hepatitis C and prion disease
Norrby-Teglund et al (2006). J Intern Med. Alejandria et al (2013). Cochrane Database of Systematic Review

13. Cost-effectiveness of IgM-IVIG
Cost-effectiveness is calculated as incremental cost per lives
saved (LS)
Cost-effectiveness per LS
Tazobactam/piperacillin 55 686 euros/LS
Imipenem/cilastatin 55 686 euros/LS
Activated rhAPC 100 728-120 176 euros/LS
IgM-IVIG (Pentaglobin) 10 565 euros/LS
5715-28 443 euros /LS
Norrby-Teglund et al (2006). J Intern Med; Neilson et al (2005). J Crit Care (n=435)

14. Cost-effectiveness of IgM-IVIG
Sepsis therapy Cost of 1 day therapy
Meropenem Dosage 3x 1 gr= 402,57 kn
Piperacilin/tazobactam Dosage 4x4,5 gr=287,68 kn
Ertapenem Dosage 1x1 gr=344,94 kn
IgM-IVIG (Pentaglobin) Dosage for patient 70 kg (5
ml/kg/day) 350 ml=6238,28 kn

15. Conclusion
• Study limitations (patient-related factors, lack of homogenous
population, dosage, administration time)
• Pivotal is timing of IgM-IVIG administration within 24 hrs of
occurrence of sepsis
• IgM-IVIG are for now considered only as adjunctive therapy in
sepsis and septic shock
• C level of recommendation!!!
Morgenstern et al (2015). Infection

16. Sepsis bundles