REVIEW

CURRENT
OPINION Intravenous immunoglobulin for adjunctive
treatment of severe infections in ICUs
Cécile Aubron a,b, Florian Berteau a, and Rosemary L. Sparrow c
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Purpose of review
This review focuses on the emerging literature regarding the use of intravenous immunoglobulins (IVIg) in
critically ill patients with severe infections. The aim is to provide an accessible summary of the most recent
evidence of IVIg use in sepsis and septic shock and to help clinicians to understand why there is still
equipoise regarding the potential benefit of this adjunctive therapy in this setting.
Recent findings
Observational studies with propensity score matching analyses and investigating the effect of IVIg in severe
infections including necrotizing soft tissue infection have been recently published. These studies suffer
important flaws precluding robust conclusion to be drawn. Some recent randomized controlled trials raised
interesting findings supportive of personalized medicine but are likely to be underpowered or confounded.
Summary
Insufficient evidence is available to support IVIg use in sepsis and septic shock, apart from the specific case
of streptococcal toxic shock syndrome. Current literature suggests that IVIg efficacy in sepsis or septic shock
could depend on the IVIg preparation (IgM-enriched or minimal IgM), time of administration (<24 h), dose,
and the inflammatory/immunomodulation profile of the patients. Investigator-initiated research,
incorporating these parameters, is warranted to determine whether IVIg benefits critically ill patients with
severe infection.
Keywords
intravenous immunoglobulins, sepsis, septic shock, severe bacterial infection

INTRODUCTION donated human plasma. They contain antibodies

Sepsis is a leading cause for admission to the ICU [1].
Both sepsis and septic shock are associated with
increased risk of death, with septic shock having
a high mortality of more than 50% [2,3]. With a
relatively frequent incidence, an associated high cost
and long-term disability in survivors, sepsis and
septic shock are major public health issues [1,3,4].
Early recognition and resuscitation, including
prompt infection control, treatment with empiric
broad-spectrum antibiotics and maintenance of
hemodynamic stability, are cornerstones of the
early-phase management of sepsis and septic shock
&&
[5 ]. However, these measures and therapeutics do
not counteract the inflammatory imbalance and
immunological dysregulation and the subsequent
prolonged immunosuppression that are characteris-
tic of sepsis and septic shock [6]. Immunoadjuvant
therapy to bolster the impaired host immune system
because of sepsis or septic shock has been identified
as the next major advance in the treatment of sepsis
[7]. Intravenous polyclonal immunoglobulins (IVIg)
are immunoglobins produced from large pools of
with a large array of unspecified reactivities repre-
sentative of those found in normal human adult
plasma. IVIg have a direct activity against pathogens
and a complex immunomodulatory effect. They
have been investigated to be an adjunctive therapy
in severe infections since the 1980s, with high
heterogeneity in studies’ results [8].
The purpose of this review is to provide an
accessible summary of the most recent findings of
a
Departement de Médecine Intensive Réanimation, Centre Hospitalier
Régional et Universitaire de Brest, site La Cavale Blanche, Université de
Bretagne Occidentale, Brest, France, bDepartment of Epidemiology and
Preventive Medicine, Australian and New Zealand Intensive Care
Research Centre (ANZIC-RC) and cDepartment of Epidemiology and
Preventive Medicine, Monash University, Melbourne, Australia
Correspondence to Cécile Aubron, MD, Ph.D., Centre Hospitalier
Régional et Universitaire de Brest, site La Cavale Blanche, Bvd Tanguy
Prigent, 29609 Brest Cedex, France. Tel: +61 2 98 34 71 81;
fax: +61 2 98 34 79 65;
e-mail: cecile.aubron@chu-brest.fr, cecile.aubron@monash.edu
Curr Opin Crit Care 2019, 25:417–422
DOI:10.1097/MCC.0000000000000639

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Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Severe infections
KEY POINTS
 Significant inflammatory and immunologic
dysregulation supports the benefit for IVIg use in sepsis
and septic shock.
 Efficacy of IVIg in patients with sepsis and septic shock
remains unknown.
 Recent literature suggests that future clinical trials
should investigate early and prolonged administration
of IgM-enriched IVIg to patients with high inflammatory
response to severe infection.
 Personalized medicine might help to resolve the
equipoise around IVIg efficacy in severe infection.
IVIg use in sepsis and septic shock and to help
clinicians to understand why there is still equipoise
regarding the use of IVIg in these conditions.
PHYSIOPATHOLOGY SUPPORTING
INTRAVENOUS IMMUNOGLOBULINS USE
IN SEVERE INFECTIONS
In sepsis and septic shock, the plasma concentration
of all classes of immunoglobulins is decreased. Rea-
sons for this decrease in endogenous immunoglob-
ulin are incompletely understood and are certainly
multifactorial, including higher immunoglobulin
consumption, extravascular leak or sequestration
of immunoglobulin, decreased immunoglobulin
production, and preexisting immunosuppression
&&
[9 ]. Depressed levels of immunoglobulin at onset
and during the course of sepsis/septic shock have
been associated with poorer patient prognosis, sug-
gesting that endogenous immunoglobulin replace-
& &
ment might improve outcomes [10 ,11 ]. The
hypothetical premise for the use of IVIg in severe
infections is based on the two main functions of
immunoglobulin: antimicrobial activity and immu-
nomodulatory activity (Table 1).
Antimicrobial activity involves several
mechanisms including antibody-recognition of
Table 1. Main mechanisms underlying the microbial effects and the immunomodulation effect of polyclonal intravenous
immunoglobulin
Antimicrobial effects
Neutralize pathogens and toxins
Activate complement, leading to phagocytosis, bacterial lysis,
and attraction of leucocytes
Opsonization
Antibody-dependent cellular cytotoxicity
INFg, interferon gamma; TNFa, tumor necrosis factor alpha. Adapted from [12,13,15–20,43].
418 www.co-criticalcare.com
Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.
pathogen-specific receptors and opsonization of
the pathogen via the antibody-binding domains
[12,13]. Apart from the antimicrobial activities of
immunoglobulin, an immunomodulatory effect
can be obtained with nonphysiologically high doses
&
of immunoglobulin [14 ]. The immune mechanisms
responsible for the clinical efficacy of IVIg therapies
remain unclear. In in-vitro studies, IVIg has a
concentration-dependent inhibitory effect on T
lymphocyte [15] and monocytic proliferation
after antigenic stimulation [16]. Also, IVIg can alter
cytokine secretion [17,18] and accelerate opsoniza-
tion by several mechanisms [19,20].
CLINICAL STUDIES AND CONTROVERSIAL
FINDINGS OF THE LAST DECADES
Effects of IVIg preparations in sepsis and septic shock
have been investigated in clinical studies over the last
decades with inconsistent findings reported on
patient outcomes. Most of the randomized con-
trolled trials (RCTs) of IVIg in sepsis suffered poten-
tially important limitations, including absence of
blinding, small sample size with lack of power, and
no concealed randomization [21,22–24,25]. Results
from the largest available phase III RCT investigating
the role of IVIg G (Polyglobin, Bayer Biological Prod-
ucts, Leverkusen, Germany) in 653 patients with
sepsis or septic shock did not report any effect of IVIg
G (600 mg/kg on day one and 300 mg/kg on day 2) on
28-day mortality or morbidity [26]. Metaanalyses,
including RCTs, have reported a benefit of IVIg on
mortality; however, sensitivity analyses excluding
highly biased studies did not find this positive effect
[25,27]. Therefore, the International Guidelines for
Management of Sepsis and Septic shock suggest
against the use of IVIg in patients with sepsis or septic
shock on the basis of the low quality of evidence [5 ].
&&
Despite this recommendation and findings, IVIg
appears to be widely used in some countries
&
highlighting the equipoise [28,29 ]. Some reasons
for these controversial findings and practices have
been suggested, including differences in IVIg prepa-
rations, IVIg regimen (dose and treatment duration),
Immunomodulation effects (high dose) (putative mechanisms)
Downregulate immune responses
Downregulate production of inflammatory cytokines (interleukin-1,
interleukin-2, TNFa, INFg)
Accelerate clearance of antibodies
–
Volume 25  Number 5  October 2019
 Intravenous immunoglobulin for adjunctive treatment Aubron et al.
heterogeneity in patients, and diseases [25]. In the
sections below, we review these parameters that
might impact on the observed effect of IVIg.
PARAMETERS THAT MIGHT IMPACT ON
THE OBSERVED EFFECT OF
INTRAVENOUS IMMUNOGLOBULINS
Infections characteristics and pathogens
Efficacy of IVIg in adjunctive therapy of severe
infections might depend on infection characteris-
tics and type of pathogens as immune-response and
pathogen-virulence mechanisms might be differ-
ently accessible to immunoglobulin activities. Nec-
rotizing soft tissue infection (NSTI) with and
without streptococcal toxic shock syndrome (STSS)
is one of the main infectious conditions where the
effect of IVIg has been investigated.
The only available double-blind, placebo-con-
trolled trial conducted in a homogeneous popula-
tion of patients with STSS investigating IVIg
potential benefit was inconclusive for the primary
outcome because the study was underpowered
because of being prematurely terminated for slow
patient recruitment [21]. In this trial, there was a
3.6-fold higher mortality in the placebo group and
patients who received IVIg had a significant
decrease in the sepsis-related organ failure assess-
ment score at day two and 3. It is unlikely that
another RCT with sufficient power will be con-
ducted and achieved in this population. In 2018,
a metaanalysis reported an association between IVIg
administration and decreased mortality (33.7% con-
trol group versus 15.7% intervention group) (rela-
tive risk, 0.46; 95% confidence interval (CI), 0.26–
0.83; P ¼ 0.01) in patients with clindamycin-treated
STSS; there was a strong homogeneity between four
&&
of the five included studies [30 ]. The last recom-
mendations of World Society Emergency Surgery
and Surgical Infection Society Europe in 2018 con-
sider IVIg as an adjunctive therapy for source control
in necrotizing soft tissues infections by Streptococcus
group A (recommendation 2B) [31].
&
In a recent study, Kadri et al. [32 ] performed a
propensity score-matched subset analysis from a mul-
ticenter retrospective cohort of 4127 patients with
NSTI-related septic shock. The 161 propensity-
matched patients treated with IVIg had similar out-
comes (mortality or length of stay) as the 161 patients
who did not receive IVIg, suggesting no benefit of
&
IVIg in this condition [32 ]. A Danish randomized,
double-blinded, placebo-controlled trial
(INSTINCT), published in 2017 by Madsen et al.
&&
[30 ], randomized 100 patients with NTSI to receive
either polyclonal IVIg G (Privigen, CSL Behring, Bern,
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Switzerland) 25 g/day during 3 days or 0.9% saline
&
[29 ]. There were no differences in physical health at
day 180, mortality or any adverse effect. However,
40% of patients in the placebo group had received
IVIg prior to randomization compared with 16% in
the intervention group, leading to a high risk of bias
&
[29 ]. A Cochrane database systematic review from
Hua et al. [33] exploring the impact of various inter-
ventions for NSTI in adults found only the
&
‘INSTINCT’ trial from Madsen et al. [29 ] to have
reported on IVIg intervention and therefore came
to the same conclusion as the trial investigators.
Although there is a large body of literature on
IVIg in patients with sepsis and shock septic from
various etiologies, recent or ongoing studies attempt
to have a more homogeneous population, supported
by the fact that some IVIg might be more beneficial in
some pathologies. In a double-blind, multicenter,
randomized controlled phase II trial (CIGMA study),
&&
Welte et al. [34 ] randomized 160 patients with
severe community-acquired pneumonia requiring
invasive mechanical ventilation to receive either
IgM-enriched IVIg (Trimodulin; Biotest AG, Dreieich,
Germany) or albumin for 5 days. There was no signif-
icant difference in the primary outcome (number of
ventilation free days) between groups nor in second-
ary outcomes including 28-day mortality. However,
the difference in 28-day mortality (relative reduction
of 20%) between groups was in favor of the interven-
&& &
tion [34 ]. Giamarellos-Bourboulis et al. [10 ] in a
retrospective study analyzed the outcomes of 200
patients with ICU-acquired sepsis because of multi-
drug-resistant (MDR) gram-negative bacteria. In this
study, treatment with IgM-enriched IVIg (Pentaglo-
bin, Biotest, Dreieich, Germany) was an independent
factor related with favorable outcome [odd ratio
(OR) 0.34, 95% CI 0.17–0.67, P ¼ 0.002] suggesting
&
a benefit of IVIg in this condition [10 ]. Peritonitis
morbimortality remains high despite adequate man-
agement and often leads to an important inflamma-
tory response that might be accessible to the
potential IVIg effects. Based on these elements, the
ongoing PEPPER (Personalised Medicine With
IgGAM Compared With Standard of Care for Treat-
ment of Peritonitis After Infectious Source Control)
randomized open controlled phase II trial (Clinical-
Trials.gov NCT03334006) will randomize 200
patients with peritonitis to receive either standard
of care (SOC) or SOC and IVIg (Pentaglobin; Biotest,
&
Dreieich, Germany) [35 ] in patients with peritonitis.
Characteristics of intravenous
immunoglobulins preparation
Different IVIg preparations have been investigated
in the last decades. Regarding the most recent
www.co-criticalcare.com 419
Severe infections

Table 2. Intravenous immunoglobulin preparations available and used in severe infections in critically ill patients in the most
recent published randomized controlled trials
Indications where
Commercial Composition Composition Composition immunoglobulins
name Company, country % IgG % IgM % IgA were tested

Trimodulin Biotest, AG Dreieich, Germany 56% 23%, 21% Severe CAP [34 ]
&&

Pentaglobulin Biotest, AG Dreieich, Germany 76% 12%, 12% Sepsis, septic shock,
peritonitis [24,35 ]
&

Privigen CSL Behring, Bern, Switzerland >98% IgG Nonsignificant Nonsignificant NSTI [29 ]
&

Polyglobin N Bayer Biological Products, >97% Nonsignificant NS Sepsis [26]

(Flebogamma) Leverkusen, Germany
Endobulin (Kiovig) Baxter, Deerfield, IL (USA) >98% Nonsignificant Nonsignificant STSS [21]

CAP, community-acquired pneumonia, NSTI, necrotizing soft tissue infection; STSS, streptococcal toxic shock syndrome.

literature, three main types of IVIg can be distin-
guished based on the percentage of immunoglobu-
lin G (IgG), immunoglobulin M (IgM), and
immunoglobulin A. Characteristics of these prepa-
rations are summarized in Table 2. No studies have
compared IVIg preparations to one another; how-
ever, clinicians must be aware of differences in
composition as that might impact on the therapeu-
tic effect. The use of IgM-enriched IVIg in patients
with severe infections is supported by the physiopa-
thology, and the association between plasma and
kinetic IgM levels during the sepsis course and
& &
patient outcomes [10 ,11 ]. Two recent metaanaly-
ses summarized the evidence around IgM-enriched
&& &&
IVIg [36,37 ]. Cui et al. [37 ] reported decreased
mortality (relative risk 0.60; 95% CI, 0.52–0.69) in
patients with sepsis or septic shock who received
IgM-enriched IVIg. However, both reviews
highlighted the heterogeneity among studies and
&&
the need for further research [36,37 ].
Intravenous immunoglobulins regimen
No RCTs have compared IVIg regimens (that is dose
and/or treatment duration) to one another. Com-
parison between studies is difficult as immunoglob-
ulin doses are given either in absolute values or on
the basis of body weight; furthermore, the time
schedule of dose delivery and total dose varies
between studies.
Based on a prolonged decrease in endogenous
&
immunoglobulin in sepsis [11 ] and a previous study
that reported a beneficial effect of IVIg given for
5 days [24], most of the recent and ongoing trials
&&
now propose a 5-day treatment regimen [34 ,35 ].
High-dose IVIg preparations are required to ini-
tiate immunomodulatory activity, whereas lower
dose IVIg preparations may be sufficient to bolster
antimicrobial responses in patients [20]. A recent
propensity score matched subanalysis of a large
retrospective multicenter observational study of
3195 patients with sepsis and septic shock, com-
pared outcomes of 653 patients who received low-
dose IVIg (0.3 g/day for 3 days) to 653 patients who
did not receive IVIg [28]. With no association
between low-dose IVIg and mortality, the authors
concluded that low-dose IVIg did not impact on
prognosis [28]. Nakamura et al. [38] compared the
outcomes of 57 patients with sepsis receiving 15 g of
IVIg on the first day of management to patients who
received the same total dose of IVIg but spread across
3 days (i.e., 5 g/day for 3 days). Length of stay was
shorter and coagulopathy improved earlier for
patients who received the total dose of IVIg on
the first day. Although suggesting an impact of IVIg
dose, the retrospective design and the small sample
size did not allow robust conclusion to be made [38].
Finally, in a recent metaanalysis, including 16 stud-
ies where the daily dose used of enriched IgM IVIg
&&
varied from 0.15 to 0.35 g/kg/day, Cui et al. [37 ] did
not find any association between daily dose or total
dose and effect on mortality IVIg.
Timing of administration
There is a body of evidence suggesting that admin-
istration of IVIg must be early to have a beneficial
effect on patients with sepsis and septic shock.
However, there is no high-quality study investigat-
ing delay of administration.
Two retrospective single-center studies from the
same investigators reported an independent
decreased risk of death when IVIg was administered
&
earlier to patients with septic shock [39,40 ]. In the
&
most recent, Berlot et al. reported an independent
association between the delay in enriched-IgM IVIg
administration from admission to ICU and ICU
mortality in 335 patients with septic shock (for each
24-h increase, adjusted OR, 1.15; 95% CI, 1.05–1.27;
P ¼ 0.0005) [40 ]. Keeping with these findings, in the
&

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 Intravenous immunoglobulin for adjunctive treatment Aubron et al.
CIGMA trial, IVIg was required to have been admin-
istered in the first 12 h following mechanical venti-
lation initiation and in the INSTINCT study, IVIg
was required to be administered immediately upon
ICU admission or in the operating room when
& &&
appropriate before ICU admission [29 ,34 ].
Patient immune-response profile
Based on pathophysiological data, immunosup-
pressed patients, and/or patients with an important
inflammatory imbalance and/or a low level of
endogenous immunoglobulin would be likely to
better respond to IVIg than those without these
disorders. The results of the recently published
&&
CIGMA RCT [34 ], of IgM-enriched IVIg in severe
community-acquired pneumonia strongly support
this hypothesis. Although for the whole study pop-
ulation of 160 patients, there was no difference in
patient outcomes, between study groups, posthoc
analyses performed in patient groups with either
high C-reactive protein (CRP) level (70 mg/l),
low IgM (0.8 g/l), high procalcitonin (2 ng/ml)
or combined high CRP and low IgM reported a
significant beneficial effect of the IgM-enriched IVIg
on the number of ventilator-free days, and an abso-
lute reduction of 28-day mortality of 16.6–24.8% in
these three patient subgroups in favor of IgM-
&&
enriched IVIg therapy [34 ]. This supports the view
that patients with heightened inflammatory signals
&&
may benefit the most from IVIg therapy [34 ]. The
ongoing PEPPER randomized open controlled trial
(ClinicalTrials.gov NCT03334006) that enrolled
patients with peritonitis to receive either SOC and
IVIg or SOC alone is moving toward personalized
medicine. In this study, eligible patients need to
have a proinflammatory interleukin-6 level equal
to or above 1000 pg/ml, which is the level that has
&
been correlated to sepsis severity [35 ]. Although
such personalized medicine seems promising, its
widespread implementation is unlikely to occur in
the near future.
SAFETY, COST, AND CONFLICT OF
INTEREST
Although IVIg might be largely used in other indi-
cations in critically ill patients [41], the balance
between IVIg benefits and adverse effects must be
considered. Critically ill patients with severe infec-
tion are at higher risk to develop IVIg-associated
adverse effects including renal failure or cholestasis,
compared with noncritically ill patients. The recent
phase II CIGMA trial conducted in a critically ill
patient with severe community-acquired pneumo-
nia reported a two-fold increase in acute renal failure
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in patients receiving IgM-enriched IVIg than in
patients receiving placebo (21 versus 10.1%) and a
3.5-fold increase in cholestasis in the intervention
&&
group (9.9 versus 2.5%) [34 ]. Recently, severe fluid
overload was reported in a patient with septic shock
secondary to a necrotizing mediastinitis treated
with high volume of IgM-enriched IVIg questioning
the safety of such practices [42].
Apart from patient-centered outcomes, health-
cost analysis should be performed as IVIg prepara-
tions are expensive and a limited resource.
Cost-benefit in terms of patient safety and quality
of life outcomes need to be carefully considered.
Finally, the largest IVIg RCT conducted to date
was sponsored by a private company [26], and two of
the three most recent randomized trials were sup-
ported by an IVIg manufacturing company, whereas
all of the authors disclosed conflict of interest with
& && &
an IVIg company [29 ,34 ,35 ]. This raises some
concerns about the influence of financial interests.
There is a need for investigator-initiated random-
ized trials of IVIg independent of companies with
direct financial interests.
CONCLUSION
Apart from the specific cases of STSS where the
literature strongly supports the use of IVIg therapy,
administration of IVIg to patients with severe infec-
tion should not be SOC. Nevertheless, the most
recent literature, including findings from RCTs
and metaanalyses, has provided new insights
toward potentially efficacious strategies for the
use of IVIg to treat severe infections in critically
ill patients. If IVIg improves outcomes in these
patients, it may be that it must be given at the very
early phase, at a high dose and for a prolonged
duration of at least five days. Treatment with
IgM-enriched IVIg preparations may be more effi-
cacious, particularly in patients with the high
inflammatory response and immunological dysre-
gulation. Whether answering these questions will
close the debate on IVIg efficacy in severe infection
and septic shock is uncertain; the state of equipoise
may remain for some time yet.
Acknowledgements
We would like to thank Bénédicte Rouvière for her
assistance with the review.
Financial support and sponsorship
None.
Conflicts of interest
There are no conflicts of interest.
www.co-criticalcare.com 421
Severe infections
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The most recent randomized controlled trial on IVIg in necrotizing soft-tissue
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&& clindamycin-treated patients with streptococcal toxic shock syndrome: a
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This metaanalysis describes the evidence around IVIg in STSS analyzing carefully
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Volume 25  Number 5  October 2019