# IFNγ in human sepsis: a scoping review

Daniel Thomas-Rüddel, Evangelos Giamarellos-Bourboulis, Caroline Neumann, Josef Briegel, Antoine Roquilly, Djillali Annane, Reinhard Wetzker, Michael Bauer

► To cite this version:

Daniel Thomas-Rüddel, Evangelos Giamarellos-Bourboulis, Caroline Neumann, Josef Briegel, Antoine Roquilly, et al.. IFNγ in human sepsis: a scoping review. Annals of Intensive Care, 2025, 15 (1), pp.112. 10.1186/s13613-025-01534-z. inserm-05308595

HAL Id: inserm-05308595

https://inserm.hal.science/inserm-05308595v1

Submitted on 10 Oct 2025

HAL is a multi-disciplinary open access
archive for the deposit and dissemination of sci-
entific research documents, whether they are pub-
lished or not. The documents may come from
teaching and research institutions in France or
abroad, or from public or private research centers.

L'archive ouverte pluridisciplinaire HAL, est
destinée au dépôt et à la diffusion de documents
scientifiques de niveau recherche, publiés ou non,
émanant des établissements d'enseignement et de
recherche français ou étrangers, des laboratoires
publics ou privés.

<figure><img src="image_1.png" /></figure>

Distributed under a Creative Commons Attribution 4.0 International License
REVIEW

Open Access

<figure><img src="image_2.png" /></figure>

Check for
updates

# IFNy in human sepsis: a scoping review

Daniel Thomas-Rüddel¹, Evangelos Giamarellos-Bourboulis², Caroline Neumann¹, Josef Briegel³, Antoine Roquilly⁴, Djillali Annane⁵, Reinhard Wetzker¹, Michael Bauer¹* for the iRECORDS study group

**Abstract**

**Background** The cytokine IFNy is released primarily by lymphocytes to initiate and orchestrate immune responses in a broad range of target cells. Whereas immune cells release inflammatory mediators and initiate antimicrobial responses when stimulated by IFNy, parenchymal cells frequently display increased immunogenicity and incidental cell death. In addition to these well-characterized effects of IFNy, recent studies disclose a key role of the cytokine in sepsis and organ dysfunction.

**Main** This review summarizes current knowledge on the IFNy response to infection and attempts to relate the IFNy response to endophenotypes of sepsis in the human host. Both, excessive pro-inflammatory responses with high IFNy and downstream mediators, such as chemokines (CXCL9), as well as immunosuppression with low IFNy levels are associated with unfavorable outcomes in sepsis. Pilot studies suggested beneficial effects of recombinant IFNy in counteracting immunosuppression associated with low IFNy levels. On the other hand, IFNy may induce macrophages to release chemokines CXCL9, 10, and 11 to attract B and T lymphocytes to the sites of infection. Downstream induction of CXCL9 (but not of CXCL10 and 11) occurring in a subset of patients with high IFNy levels has been shown to correlate with the hyper-inflammatory phenotype of sepsis. Both, high- and low-expressing IFNy phenotypes of sepsis, might be related to nucleotide polymorphisms of the human IFNy gene.

**Conclusion** Association of IFNy activity states with sepsis outcome renders this key regulatory protein of immunity a top candidate for theranostic interventions in a “personalized medicine approach” to infection and sepsis, especially when combined with additional biomarkers, such as CXCL9, reflecting or even mediating maladaptive downstream actions.

**Keywords** Sepsis, IFNy, Hyperinflammation, Immunosuppression, Immunosuppressive therapy, Immunostimulatory therapy

Collaborator author informations are listed in Acknowledgement section.

*Correspondence:

Michael Bauer
Michael.Bauer@med.uni-jena.de

Full list of author information is available at the end of the article

<figure><img src="image_3.png" /></figure>
## Graphical Abstract

<figure><img src="image_4.png" /></figure>

## Background

Together with the emergence of first vertebrates 500 million years ago, the crude innate immune responses of lower eukaryotes to pathogens have been complemented by “adaptive” immune reactions exhibiting high specificity and memory traits [1]. Proper functioning of the advanced vertebrate immune system required efficient coordination of the humoral and cellular elements of innate and adaptive immunity. The cytokine interferon gamma (IFNγ) plays a key role in the underlying regulatory network [2].

Experimental studies in vitro and in vivo identified lymphocytes, the main cellular entity of adaptive immunity, as the main source of IFNγ [2]. IFNγ was found to be released by T-cells and B-cells after stimulation by pathogens which are presented by professional antigen-presenting cells and by pro-inflammatory cytokines released by myeloid cells [3]. In addition, innate lymphoid NK cells after “missing self-recognition” have been found to release IFNγ [4]. IFNγ released by activated lymphocytes has been originally identified as a key mediator of monocyte and macrophage functions [5]. Basically, all major functions of these innate immune cells can be affected by the cytokine. This includes production of bactericidal oxygen radicals, migration, phagocytosis of pathogenic microorganisms and release of additional humoral immune mediators, such as cytokines and chemokines (Fig. 1) [6, 7]. Parenchymal cell functions affected by IFNγ include proliferation, apoptosis and secretion [5, 6]. Innate immune cells, such as macrophages, as well as

parenchymal cells express specific IFNγ receptors. Corresponding downstream signaling proteins include the Janus tyrosine kinases JAK1 and JAK2 and so-called signal transducers and activators of transcription (STATs) [8].

One of the key responses initially induced by IFNγ in macrophages is the release of the chemokines CXCL9, CXCL10 and CXCL11, which attract additional T-lymphocytes and other immune cells from the bloodstream to the focus of infection (Fig. 1) [7]. These chemokines and a series of cytokines, represented here by the prototypical IL-12, are secreted by macrophages, cause further stimulation of IFNγ producing lymphocytes leading to a cooperative self-accelerating immune response circuit between lymphocytes and macrophages as the key representatives of adaptive and innate immunity [9, 10].

Considering the predominant role of IFNγ as a stimulator of innate immune cells, significant pathological effects of dysregulated IFNγ levels seem plausible. Indeed, IFNγ deficiency has been shown to induce a pronounced increase of susceptibility to infection. A prominent example for hereditary disease with impaired IFNγ activity is Mendelian susceptibility to mycobacterial disease (MSMD) but other entities characterized by low production or decreased activity of IFNγ or its receptors and downstream signaling mediators like STATs are also described [2, 9]. Significant progress in the treatment of these immunodeficiency-related diseases has been achieved with the application of recombinant IFNγ protein [2, 11], supporting its role as a candidate
<figure><img src="image_5.png" /><figcaption>**Fig. 1** IFNγ and downstream cytokines and chemokines implicated in innate and adaptive immune responses to infection. IFNγ and several downstream cytokines and chemokines act as main players of the cooperative immune response to infection. After initial contact of tissue macrophages and resident T cells, lymphocytes release IFNγ, which boosts innate resistance responses of macrophages. These responses include secretion of the cytokine IL-12 and of chemokines, which are aimed to attract and to further stimulate lymphocytes. In a self-accelerating circuit the overall immune response further increases (ideally) until complete elimination of invading pathogens</figcaption></figure>

immunostimulatory drug for a personalized approach in the critically ill [12].

In contrast to increased susceptibility to infection induced by suboptimal activity of IFNγ, patients with IFNγ overproduction exhibit typical hyperinflammatory disorders, such as lupus erythematodes and hemophagocytic lymphohistiocytosis (HLH), including macrophage activation syndrome [13], the latter reflecting a rare but well defined endotype of sepsis. Interferon therapy can, similar to its role in autoimmune disease, cause a range of off-target effects related to its (intended) immune-stimulatory action, such as flu-like symptoms and fatigue, cognitive and mood changes, and altered organ function e.g. in the gastrointestinal tract. Of note, these effects can augment an ongoing inflammatory process in the septic host [14] as will be discussed in detail below.

Notably, current understanding of sepsis can involve either IFNγ suppression or hyperactivity [11, 15–17]. In this scoping review, we explore the correlation of IFNγ levels to sepsis endotypes and put these into perspective of the knowledge on chronic states of altered IFNγ signaling. The review also presents recent insights validating IFNγ-induced immune responses as a target for therapeutic intervention.

## Method

The significance of IFNγ in sepsis has been explored systematically by a PUBMED search for "("Sepsis"[Mesh]) AND "Interferon-gamma"[Mesh]" on 8th of August 2024.

All search results were screened in three steps for eligibility, titles only first, then abstracts and in a final step full texts after retrieval. All steps were performed by a single researcher (DTR). We included papers that reported on human patients and either the effects of IFNγ therapy in sepsis, a prognostic role of IFNγ in sepsis, an identification of sepsis subtypes by IFNγ levels or the role of IFNγ in the risk for developing sepsis or the use of IFNγ for sepsis prevention. We did not include studies that assessed IFNγ production in vitro. The initial screening resulted in 1100 potentially relevant records found in PubMed and were screened for inclusion in this review as detailed Fig. 2.

## Results and discussion

Current concepts suggest that sepsis immune phenotypes can be characterized by predominant hyper-inflammation or immunosuppression [18, 19]. We searched for connections of these phenotypes with the key immune effector molecule IFNγ in sepsis patients. The related references include assessment of IFNγ levels in phenotypically characterized sepsis patients, investigations of the correlation of polymorphisms in the IFNγ gene with sepsis phenotypes and attempts to treat failing immune responses and immunosuppression by therapeutic application of recombinant IFNγ [summarized in Table 1].

Our literature search suggests a clear assignment of high IFNγ levels to sepsis patients exhibiting the hyper-inflammatory phenotype, whereas a low or diminished IFNγ response is associated with the immunosuppressive endophenotype. Basic characteristics of both patient phenotypes will be now introduced in more detail.

### IFNγ deficiency in immunosuppression

The significance of the IFNγ response for the development of septic immunosuppression was originally shown in studies investigating IFNγ release of whole blood or isolated leukocytes from sepsis patients to agents stimulating T-cells. These studies revealed significant decrease of IFNγ production in nonsurvivors in comparison to healthy donors or surviving patients [16–20].

An exemplary comparative analysis of Barrios et al. [16] showed in addition to downregulation of IFNγ a decreased expression the MHC class II cell surface receptor HLA-DR on monocytes, i.e. a validated readout for immunosuppression in the critically ill, in nonsurviving patients indicating extensive loss of innate immune responses in the nonsurviving patients. Septic patients with low IFNγ expression were older and had lower absolute leukocyte counts and higher level of the immunosuppressive mediators PD-L1 and IL-10. Feasibly, these findings pave the way for novel treatment options of immunosuppressed sepsis patients using the clinically
<figure><img src="image_6.png" /><figcaption>**Fig. 2** PRISMA flow diagram of selection of sources of evidence</figcaption></figure>

established “checkpoint” PD-L1 inhibitors or IL-10 antibodies for restoring T-cell functions presumably inducing restauration of the IFNγ response.

## Increased IFNγ in septic hyperinflammation

Increased IFNγ levels in blood were reported for bacteremia treated outside the ICU and for severe sepsis [21, 22]. High IFNγ levels were also observed in survivors of septic shock [23] or sepsis in general [21], while others reported no significant differences [24]. One study reported an association of high initial IFNγ levels with secondary Candida infections in the survival phase of bacterial sepsis [25]. The IFNγ/IL-10 ratio was suggested as a potential marker for a favorable response to hydrocortisone treatment [26, 27].

A recent clinical study reports a pro-inflammatory endotype of sepsis associated with high blood levels of IFNγ and increased mortality [28]. The endotype of IFNγ-driven sepsis (IDS) was defined as blood IFNγ levels above 3 pg/mL (associated with a low risk for immunoparalysis) and simultaneously increased CXCL9 levels (2200 pg/mL), a chemokine selectively induced by IFNγ in macrophages. While IDS has been identified as an independent risk factor for death in sepsis patients,

decreases of IFNγ and CXCL9 blood levels within the first 72 h were associated with better outcome.

Together these studies reveal a frequent increase of IFNγ blood level in patients exhibiting the hyperinflammatory phenotype of sepsis. Another recent report claims a crucial role of the balance between transcriptional programs for regular “resistance” responses and pathological “systemic inflammation” in sepsis etiology [29]. IFNγ and the downstream chemokines CXCL10 and CXCL11 were identified as key biomarkers for the “resistance” pattern. Sepsis was characterized by a low resistance vs. high systemic inflammatory response, marked by low expression of IFNγ and the related chemokines [29]. Interestingly, the chemokines CXCL10 and CXCL11 seem to play the predominant role as mediators of appropriate antimicrobial resistance responses, in contrast to CXCL9.

The given studies suggest a predominant role of the chemokines CXCL9, CXCL10 and CXCL11 as “executors” of IFNγ functions, while the mechanistic background underlying their differential functionality remains unclear. All three chemokines are released by macrophages, dendritic cells or parenchymatous tissue following stimulation with IFNγ [10]. While CXCL9 expression requires IFNγ, CXCL10 and CXCL11 production are also stimulated by other type I and type II
<table><caption>**Table 1** Summary of selected clinical studies describing observational as well as interventional studies, which involve IFNy as a diagnostic or therapeutic target and with respect to underlying clinical phenotype</caption><thead><tr><th>Short description and citation</th><th>Patient population</th><th>Patient numbers</th><th>Study design</th><th>Summary of outcomes</th><th>Susceptibility to infection</th><th>Immune pathology</th></tr></thead><tbody><tr><td>IFNy as a diagnostic marker<br>Restauration of monocyte function in septic patients [11]</td><td>Patients with sepsis (II)</td><td>9</td><td>Pilot trial: treatment of septic patients with HLA-DR<sup>+</sup> &lt;30% of monocytic cells with 100 µg IFNy per day (s.c.)<br>Endpoint: positivity of &gt;50% mono-cytes HLA-DR<sup>+</sup> for 3 consecutive days</td><td>Improvement of lipopolysaccharide TNFα response in 8 of 9 patients; Recovery in 7 patients from sepsis with significant improvement of organ dysfunction score</td><td>X</td><td></td></tr><tr><td>Risk stratification of immunosuppressed endotypes with adverse outcome [16]</td><td>Patients with sepsis (III)</td><td>107</td><td>Prospective, observational multicentre trial in comparison to 68 non-septic ICU controls and 46 healthy controls<br>Longitudinal design (days 1, 4 and 7)<br>Endpoints: long term mortality rate (180 days)</td><td>Discrimination of later non-survivors by determination of cellular IFNy release analysed ex-vivo by whole-blood immunosorbent assay</td><td>X</td><td></td></tr><tr><td>Endotype classification of IFNy-driven sepsis (IDS) [28]</td><td>Patients with sepsis (III)</td><td>5503</td><td>Discovery set: 3670 patients<br>Validation set: 1833 patients<br>Endpoints: frequency of IDS as independent sepsis endotype associated with 28-day mortality (primary)<br>Association of over-time changes of IDS endotype with 28-day outcome (secondary)</td><td>Differentiation IDS from macrophage activation-like syndrome<br>Identification of IDS as an independent risk factor for death in presence of other endotypes, severity and organ dysfunction</td><td>X</td><td></td></tr><tr><td>Decreased PBMC-expression of IFNγ and TNFα is associated with unfavourable outcome [21]</td><td>Patients with sepsis/septic shock (II)</td><td>62</td><td>Monocentric observational trial (day 1, day 7)<br>Disease controls: Bloodstream infection with gram<sup>-</sup> bacteria w/o organ failure, healthy controls<br>Endpoints: development/persistance of septic shock; mortality rate</td><td>Expression profile of IFNγ (decrease) is associated with sepsis/sepsis shock; Low expression of IFNγ and TNFα is associated with shock, severity and unfavourable outcome at day 7; no correlation with circulating protein levels</td><td>X</td><td></td></tr><tr><td>Increased levels of IFNγ indicates risk for secondary Candida infection [25]</td><td>Patients with sepsis (III)</td><td>31</td><td>Monocentric observational study<br>19 patients with sepsis<br>12 patients with sepsis/secondary Candida infection<br>Endpoints: IFNγ</td><td>Exogeneous IFNγ suppressed macrophage phagocytosis of zymosan, blockade improved survival of secondary candidemia following endotoxemia</td><td>X</td><td></td></tr></tbody></table>
<table><caption>**Table 1 (continued)**</caption><thead><tr><th>Short description and citation</th><th>Patient population</th><th>Patient numbers</th><th>Study design</th><th>Summary of outcomes</th><th>Susceptibility to infection</th><th>Immune pathology</th></tr></thead><tbody><tr><td>IFNγ ratio to IL10 for risk stratification of septic shock patients for hydrocortisone treatment [26]</td><td>Patients with septic shock (III)</td><td>467</td><td>Multicentric interventional trial (CORTICUS)<br/>Hellenic sepsis: study group (HSSG)<br/>83 patients for explorative analysis (CORTICUS)<br/>329 patients for validation (HSSG etc.)<br/>Endpoints: survival rate</td><td>IFNγ/IL10 ratio identified as a molecular marker supporting the decisions for administration of hydrocortisone in patients with septic shock</td><td>X</td><td></td></tr><tr><td>Molecular fingerprinting of resistance towards pathogens and systemic inflammation [29]</td><td>Patients with septic shock (III)</td><td>125</td><td>Monocentric observational study (FUSE)<br/>Comparison of datasets obtained in eight other trials<br/>Endpoints: 28d-survival rate</td><td>Clinical phenotype is reflected in protein and gene expression profile allowing sub-classification with respect to impaired balance between resistance and systemic inflammation prediction short-term survival rate</td><td>X</td><td></td></tr><tr><td>Functional comparison of four IFNγ-polymorphisms and its association with pneumonia-induced sepsis [60]</td><td>Patients with pneumonia induced sepsis</td><td>196</td><td>Observational trial<br/>213 age- and sex-matched control subjects<br/>Endpoints: severity</td><td>Association with progression and outcome: +874T as well as -1616T genotype were found protective against development of severe sepsis</td><td>X</td><td></td></tr><tr><td>Genetic variants in a master regulator of IFNγ expression (STAT4) in non-thyphoidal Salmonella (NTS) bacteremia [61]</td><td>Patients with NTS bacteremia</td><td>180</td><td>Genome wide association study (2677 controls)</td><td>Context-specific expression quantitative trait locus for STAT4 expression is described as an NTS risk genotype resulting in decreased IFNγ expression either in natural killer cells as well as in circulation during bacteremia</td><td>X</td><td></td></tr><tr><td>IFNγ as a therapeutic target</td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Reversal of immunoparalysis following endotoxemia [36]</td><td>Administration of either rhIFNγ or rhGM-CSF</td><td>18</td><td>Double-blind placebo-controlled randomized study<br/>Endpoints: normalization of biochemical parameters</td><td>IFNγ-treatment attenuated ex vivo impaired TNFα release as a marker of immunoparalysis as well as normalized HLA-DR expression</td><td>X</td><td></td></tr><tr><td>Adjuvant immune-stimulation in immunoparalysed septic patient with IFNγ [37]</td><td>Patient (58 yrs) with prolonged disseminated Staph. aureus sepsis</td><td>1</td><td>Case-report<br/>Endpoints: clinical recovery</td><td>Immuno-monitoring and gene expression profiling (antigen presentation, T-Helper cell function etc.) resolution of immune dysfunction</td><td>X</td><td></td></tr><tr><td>Adjunctive immunotherapy in immunosuppressed patients [39]</td><td>Septic patients (II) with immunosuppression</td><td>20</td><td>Multicentric interventional trial<br/>Endpoints: normalization of HLA-DR expression</td><td>Adjunctive immunotherapy with IFNγ improved immune host defence in sepsis induced immune suppression</td><td>X</td><td></td></tr></tbody></table>
<table><caption>**Table 1 (continued)**</caption><thead><tr><th>Short description and citation</th><th>Patient population</th><th>Patient numbers</th><th>Study design</th><th>Summary of outcomes</th><th>Susceptibility to infection</th><th>Immune pathology</th></tr></thead><tbody><tr><td>Immuno activation targeted immunotherapy in patients with sepsis [40]</td><td>Septic Patients (III) with either macropathogen activation-like syndrome (MALS), immune paralysis or mixed phenotype</td><td>240</td><td>Double blind, double-dummy randomized trial<br>Endpoints: 28-day survival rate</td><td>Identification of three independent immune classification strata (MALS, paralysis or mixed), which are proposed as stratification for personalized adjuvant immunotherapy</td><td>X</td><td></td></tr><tr><td>Administration of IFNγ for prevention of severe infection [41]</td><td>Patients with chronic granulomatous disease</td><td>128</td><td>Double-blind placebo contr.trial (IFNγ 50 µg/m², 3x/s for 1y)<br>Endpoints: Time to infection (i.e. hospitalization due to infection/administration of parenteral antibiotics)</td><td>Increase in time to infection and decrease of absolute numbers of infections in IFNγ treated group</td><td>X</td><td></td></tr><tr><td>Prevention of hospital acquired pneumonia in ventilated patients by IFNγ [14]</td><td>Patients with organ failure (≥1) undergoing invasive ventilation</td><td>109</td><td>Multicentre, placebo-controlled randomized trial<br>Endpoint: hospital acquired pneumonia (HAP)/all cause 28d-mortality (composite)</td><td>Early treatment with IFNγ resulted in an adjusted hazard ratio for HAP or death of 1.76<br>Discontinuation due to safety concerns</td><td>X</td><td></td></tr></tbody></table>

Enrolled patients and inclusion according to sepsis-II or -III definitions and readout for outcome are indicated

Underline is used to mark the "endpoints" studied but can be omitted
interferons [10, 28] indicating its candidate role to spe-
cifically mediate downstream actions of IFNγ. Induced
by IFNγ in macrophages all three chemokines attract B
and T lymphocytes to the sites of inflammation but only
CXCL9 expression has been shown to correlate with
severity of hyper-inflammatory states including the IDS
endotype of sepsis [28]. Jointly these findings disclose
CXCL9 as specific marker of sepsis pathology and pre-
sumably other hyper-inflammatory syndromes [10, 28].

Collectively these studies characterize IFNγ as a key
mediator of infection-induced inflammatory responses in
infectious diseases including sepsis.

The inducible expression of IFNγ displays high inter-
individual variance, which is frequently caused by genetic
polymorphisms. In the human IFNγ gene a single nucle-
otide T to A polymorphism in position 874 of the first
intron appears of particular significance for expression
control. This polymorphism is followed by a variable CA
microsatellite sequence, which has been shown to affect
IFNγ expression level via a putative NF-κB binding site of
the gene [30]. The regulatory effects of the polymorphic
CA repeat on IFNγ expression are tightly connected to
the 874 T/A polymorphism. In fact, 874 TT, AA and AT
genotypes are associated with high, low and intermediate
production of IFNγ in vitro and in vivo [30, 31]. Major-
ity of related studies indicate an increased susceptibil-
ity of the high IFNγ expressing TT genotype connected
to allele 2 with 12 CA repeats to hyper-inflammatory
syndromes and autoimmune diseases [32]. In contrast
the low IFNγ expressing AA genotype occurs more fre-
quently in patients suffering from immunosuppression
and increased susceptibility to infections, particularly
tuberculosis [31].

Despite these initial reports, the diagnostic poten-
tial of these polymorphisms in sepsis has not yet been
exploited. These regulatory elements are especially prom-
ising for correlative analysis of sepsis endotypes and pre-
dictive enrichment for immune modulation among sepsis
patients.

IFNγ as a target for treatment of sepsis

Analysis of IFNγ status in patients suffering from auto-
immune diseases or infections unveils association of
inflammatory responses with high IFNγ levels whereas
low IFNγ goes parallel with a decline of antimicrobial
defense. Consequently, treatment approaches have been
developed for diseases induced by deviant levels of IFNγ
(Fig. 3). Exemplarily, patients with inborn low level of
IFNγ activity like MSMD have been successfully treated
by compensatory therapy with recombinant IFNγ [33].
Initial findings also indicate improved immune host
defense in patients exhibiting sepsis-induced immuno-
suppression by adjunctive immunotherapy with IFNγ [11,

[34]. As IFNγ reflects a double-edged sword and increas-
ing evidence supports a “compartmentalization” of (mal)
adaptive immune responses, particularly in the lungs,
alternative routes to administer IFNγ, such as inhalation,
might be promising to prevent off-target effects [35].

IFNγ enhanced HLA-DR expression and reversed immunoparalysis in an experimental LPS model [36], in two case reports [37, 38] and in uncontrolled case series [11, 39, 40] (the largest with 18 cases). A very small trial (NCT01649921, 2 vs 2, initially planned larger) and a multicenter trial (ImmunoSep; NCT04990232) are currently unpublished.

IFNγ was effective for infection prevention in granu-
lomatous disease [41], showed some signal for infection
prevention in critically ill injured patients [42, 43] and
failed to prevent hospital-acquired pneumonia (HAP)
with a signal for harm in a recent trial [14].

The latter study by Roquilly administered IFNγ-1b
without further stratification in critically ill patients with
one or more organ failures under mechanical ventilation
in a randomized placebo-controlled design to prevent
HAP. It seems feasible that the recently described endo-
type of IFNγ/CXCL9 driven sepsis [28] could have con-
tributed to harm from rhIFNγ-1b treatment. Consistent
with harm in an endophenotypic subgroup, the authors
reported in a nested exploratory study association of
HAP with IFNγ-1b induced decrease in C-C motif
chemokine ligand 17 (CCL17) [14]. Autoimmune dis-
eases induced by high IFNγ levels, such as systemic lupus
erythematosus have been effectively covered with IFNγ
antibodies albeit with substantial variability [44] and
support potential harm-mediating effects of IFNγ in the
immunopathology of hyper-inflammatory sepsis. Appli-
cation of IFNγ antibodies in hyper-inflammatory sepsis
has not been investigated yet. Compensatory application
of IFNγ recombinant protein or antibodies to modulate
IFNγ activity in sepsis using HLA-DR expression to iden-
tify an immunosuppressive endotype has been studied in
the ImmunoSep trial (inclusion completed, results pend-
ing) and could be included in a theranostic approach
(Fig. 3).

Pharmako-kinetic behaviour of IFNγ is an impor-
tant treatment variable [45]. A rapid decline of serum
concentration in a monoexponentially manner after
intravenous administration is reflected by a short half
time of only 30 min [46, 47]. Intramuscular and subcu-
taneous administration as well results in protracted but
fairly good absorption rate ranging between 30 to 70%,
resulting in peak concentration occurring after several
hours followed by measurable concentrations in a time
frame of 24 h [48]. Renal elimination is held responsible
for the major route of inactivation and elimination: fol-
lowing glomerular filtration and tubular reabsorption,
<figure><img src="image_7.png" /><figcaption>**Fig. 3** Prospects of modulation of IFNγ and its downstream signaling cascades in adjunctive therapy of sepsis. Topology of the IFNγ—chemokine signaling circuit between lymphocytes and macrophages and related treatment options for immunosuppression (blue) and hyperinflammatory (red) phenotypes of sepsis. Studies reporting use of recombinant IFNγ are two case reports [37, 38] and in uncontrolled case series [11, 39, 40]. Results of a multicenter trial (ImmunoSep; NCT04990232) are currently unpublished. All other drugs have been only testet in animal experiments or preclinical settings</figcaption></figure>

interferons undergo proteolytic degradation by lysosomal enzymes, thus negligible amounts of intact and active proteins are detectable in urine [49]. Interestingly, plasma concentration of IFNγ (also of other cytokines) are only modestly influenced in septic patients undergoing continuous veno-venous haemodialysis using a 45 kDa cut-off filtration system demonstrating a small to no adsorptive capacity despite a decline in plasma cytokine concentrations [50].

In addition, hepatic deglycosylation is described as a clearance mechanism. A number of technologies have been developed to prolong the short in vivo half-life of protein drugs such as IFNγ, a few systems have been designed or intended to use for IFNγ such as controlled release formulations by minipellets or conjugation of with polyethylene glycol (i.e. PEGylation) to protect the interferon from proteolytic degradation and to reduce its renal clearance and antigenicity [45, 51–53].

In addition to the available treatment options, i.e. recombinant IFNγ application in the “immunoparalytic” endotype and treatment of the hyperinflammatory phenotype with IFNγ antibodies, signaling events downstream of IFNγ could alternatively be targeted to restore this key pathway. As illustrated in Fig. 3, JAK tyrosine kinase inhibitors, such as ruxolitinib, baricitinib and momelotinib, are potentially able to interrupt IFNγ

receptor signaling and suppress the pro-inflammatory endotype of sepsis [54, 55]. Baricitinib has been successfully tested in severe COVID-19 patients [56]. Similar suppressive effects could be expected by drugs inhibiting the chemokine receptor CXCR3 including NBI 74330, AMG 487, SCH 546738 and ACT-777991 [57–59]. However, none of these inhibitors have been approved or tested for sepsis in clinical trials to date. Novel clinical studies in a theranostic design might thus pave the way for these attractive treatment options in human sepsis. Implications of IFNγ related sepsis endotypes in the clinical context and remaining questions are summarized in Boxes 1 and 2.

## Conclusions and future directions

The present literature overview reveals a central role of IFNγ in sepsis pathology and is supported by association of nucleotide polymorphisms in the IFNγ gene with endotypes of sepsis. Regarding clinical evaluation of manipulation of this signaling pathway is currently focused on recombinant IFNγ to treat sepsis-induced immunosuppression. There are promising results indicating that treatment with the recombinant protein improves host defense in the immunosuppressive phenotype of sepsis, but due to the dose-dependent ambivalent physiological and pathophysiological effects of IFNγ much work is still necessary in particular to establish which subgroups might be harmed. In contrast to the discussed efforts to restore adaptive and innate immunity in immunosuppressed sepsis patients, evidence for the benefit of IFNγ antibody therapy for the hyper-inflammatory phenotype is still missing. Due to the key importance of highly contrasting phenotypes and the dynamics of patient responses in sepsis pathogenesis, reliable diagnostics are essential prerequisites for assessing IFNγ-targeted treatment approaches in sepsis patients. In addition to established markers like HLA-DR, IFNγ-related biomarkers, such as CXCL9 or polymorphisms in the IFNγ gene, might be of potential theranostic value.

### BOX 1 Implications for clinical practice

- Monitoring of plasma-IFNγ in sepsis patients (in particular when part of a panel of immune effector molecules, such as HLA-DR on monocytes and chemokines) might identify endotypes amenable to immunomodulatory therapy

- Subgroups of immunosuppressed patients with sepsis might benefit from recombinant IFNγ

- Therapy with IFNγ antibodies represents a concept to treat hyperinflammatory patients expressing high IFNγ level and an “interferon-driven sepsis” endotype that has currently not been explored

- “Theranostic” clinical trials that take the ambivalent role of IFNγ into consideration are warranted
## BOX 1 Implications for clinical practice

- Both treatment options with recombinant IFNγ for immunosuppressed patients and IFNγ antibodies for hyperinflammatory patients need careful dose management and monitoring of clinical effects

## BOX 2 Open questions

- Do circulating and tissue-resident immune cells respond the same to IFNγ?

- How does IFNγ mediate hyper-inflammatory and immunosuppressive phenotypes in the pathogenesis of sepsis?

- How do IFNγ polymorphisms correlate to these phenotypes?

- How does IFNγ signaling contribute to the hyper-inflammatory phenotype and what are the treatment options?

- Are IFNγ signaling pathways, such as JAK 2 or STAT1, effective targets for therapy of hyper-inflammation and immunosuppression in sepsis?

- How does IFNγ (differentially) cooperate with other inflammatory mediators, such as the chemokines CXCL9, CXCL10 and CXCL11 and cytokines, such as IFNβ or IL-12 in the course of sepsis?

### Abbreviations

CCL Chemokine ligand with C-C motif

CXCL Ligand belonging to the chemokine family with a C-X-C motif

CXCR Chemokine receptor respond to cytokines of the CXC chemokine family

HAP Hospital acquired pneumonia

HLA-DR Human leukocyte antigen system

HLH Hemophagocytic lymphohistiocytosis

ICU Intensive care unit

IDS IFNγ-driven sepsis

IFNγ/β Interferon-gamma/beta

IL Interleukin

ISS Injury severity score

JAK1, JAK2 Janus tyrosine kinases JAK1 and JAK2

LPS Lipopolysaccharide

MALS Macrophage activation-like syndrome

MSMD Mendelian susceptibility to mycobacterial disease

NCT National clinical trial

NF-κB Nuclear factor kappaB

NK cells Natural killer cells

NTS Non-thyphoidal salmonella

PBMC Peripheral blood mononuclear cells

rh Recombinant human

STATs Signal transducers and activators of transcription

TNF-α Tumor necrosis factor alpha

UTR Untranslated region

### Acknowledgements

The authors thank Dr. Margit Leitner and Dr. Ralf A. Claus for support with generation of the figures and tables.

The work has been conducted in the context of an EU-funded project to elucidate biomarker signatures of endotypes amenable to immunomodulatory therapy, in particular corticosteroids and the authors thank the iRECORDS collaborators:

EGYPT: Sara Aly Abdelghany, Maha Aly Khalaf Aly, Mohamed Gamal Elansary, Shereen Mustafa Elengeehy, Heba Mostafa Elwi, Yasser Sadek Nassar, Rania Yehia Hash (all Faculty of Medicine, Cairo University).

FRANCE: Rania Bouneb (Assistance Publique—Hôpitaux de Paris), Zaineb Chelly-Dagdia (Université de Versailles Saint-Quentin-en-Yvelines), Katy Diallo (Assistance Publique—Hôpitaux de Paris), Jérome Fleuriet (Université Paris-Saclay), Henri-Jean Garchon (Université de Versailles Saint-Quentin-en-Yvelines), Stanislas Grassin Delyle (Université de Versailles Saint-Quentin-en-Yvelines/ Hôpital Foch), Rahma Hellali (Université de Versailles Saint-Quentin-en-Yvelines), Nicholas Heming (Assistance Publique—Hôpitaux de Paris, Nicolas Hunzinger (Université de Versailles Saint-Quentin-en-Yvelines),

Elodie Lamy (Université de Versailles Saint-Quentin-en-Yvelines), Jihene Mahmoud (Assistance Publique—Hôpitaux de Paris), Virginie Maxime (Assistance Publique—Hôpitaux de Paris), Pierre Moine (Assistance Publique—Hôpitaux de Paris), Camille Roquencourt (Hôpital Foch), Marie Alice Vovy (Assistance Publique—Hôpitaux de Paris), Karine Zeitouni (Université de Versailles Saint-Quentin-en-Yvelines).

GERMANY: Manuela Adling-Ehrhardt (Institute of Laboratory Medicine/LMU University Hospital/LMU Munich), Frank Bloos (Jena University Hospital), Sandra Frank (LMU University Hospital/LMU Munich), Katharina Habler (Institute of Laboratory Medicine/LMU University Hospital/LMU Munich), Ludwig Hinske (Institute of Digital Medicine/LMU University Hospital/LMU Munich), Rainer König (Jena University Hospital), Dorothea Lange (LMU University Hospital/LMU Munich), Margit Leitner (Jena University Hospital), Marcus Oswald (Jena University Hospital), Christina Scharf-Janssen (LMU University Hospital/LMU Munich), ichael Vogeser (Institute of Laboratory Medicine/LMU University Hospital/LMU Munich).

SPAIN: Carlos Flores (Research Unit, Hospital Universitario Nuestra Señora de Candelaria, Instituto de Investigación Sanitaria de Canarias (IISC), Santa Cruz de Tenerife, Spain / Genomics Division, Instituto Tecnológico y de Energías Renovables (ITER), Santa Cruz de Tenerife, Spain / CIBER de Enfermedades Respiratorias (CIBERES), Instituto de Salud Carlos III, Madrid, Spain / Facultad de Ciencias de la Salud, Universidad Fernando Pessoa Canarias, Las Palmas de Gran Canaria, Spain), Jesús Villar (Research Unit at Hospital Universitario Dr. Negrín, Fundación Canaria Instituto de Investigación Sanitaria de Canarias, Las Palmas, Spain / Faculty of Health Sciences, Universidad del Atlántico Medio (UNAM), Las Palmas, Spain / CIBER de Enfermedades Respiratorias, Instituto de Salud Carlos III, Spain / Li Ka Shing Knowledge Institute at St Michael's Hospital, Toronto, Canada).

### Author contributions

All authors have contributed to the conceptualization, writing and revising of this review. All authors read and approved the final manuscript.

### Funding

Open Access funding enabled and organized by Projekt DEAL. MB is supported by the Deutsche Forschungsgemeinschaft (German Research Foundation) under Germany's Excellence Strategy (EXC 2051). This work was supported by the Federal Ministry of Education and Research (Grant No. 01KU2209) within the ERA PerMed consortium iRECORDS (International— Rapid rRecognition of CORticosteroiDs sensitivity or resistance in Sepsis).

### Declarations

### Ethics approval and consent to participate

Not applicable.

### Consent for publication

Not applicable.

### Availability of data and materials

Data sharing is not applicable to this article as no datasets were generated or analysed during the current study.

### Competing interests

The authors declare that they have no competing interests.

### Author details

¹Department of Anesthesiology and Intensive Care Medicine, Jena University Hospital, Am Klinikum 1, 07747 Jena, Germany. ²⁴th Department of Internal Medicine, Medical School, National and Kapodistrian University of Athens, Athens, Greece. ³Department of Anesthesiology, University Hospital, LMU Munich, Munich, Germany. ⁴Center for Research in Transplantation and Translational Immunology, UMR 1064; and Anesthesie Reanimation, Nantes Université, CHU Nantes, INSERM, CIC 1413, Nantes, France. ⁵Department of Intensive Care, Raymond Poincaré Hospital, APHP, University Versailles Saint-Quentin-University Paris Saclay, INSERM, Garches, France.

Received: 8 May 2025 Accepted: 24 July 2025

Published online: 05 August 2025
## References

1. Cooper MD, Alder MN. The evolution of adaptive immune systems. Cell. 2006;124:815-22.

2. Casanova JL, MacMicking JD, Nathan CF. Interferon-gamma and infectious diseases: lessons and prospects. Science. 2024;384:ead1206.

3. Roquilly A, McWilliam HEG, Jacqueline C, Tian Z, Cinotti R, Rimbert M, Wakim L, Caminschi I, Lahoud MH, Belz GT, Kallies A, Mintern JD, Asehnoune K, Villadangos JA. Local modulation of antigen-presenting cell development after resolution of pneumonia induces long-term susceptibility to secondary infections. Immunity. 2017;47(135-147):e135.

4. Roquilly A, David G, Cinotti R, Vourc'h M, Morin H, Rozec B, Retiere C, Asehnoune K. Role of IL-12 in overcoming the low responsiveness of NK cells to missing self after traumatic brain injury. Clin Immunol. 2017;177:87-94.

5. Schroder K, Hertzog PJ, Ravasi T, Hume DA. Interferon-gamma: an overview of signals, mechanisms and functions. J Leukoc Biol. 2004;75:163-89.

6. Kak G, Raza M, Tiwari BK. Interferon-gamma (IFN-gamma): exploring its implications in infectious diseases. Biomol Concepts. 2018;9:64-79.

7. Cautivo KM, Matatia PR, Lizama CO, Mroz NM, Dahlgren MW, Yu X, Sbierski-Kind J, Taruselli MT, Brooks JF, Wade-Vallance A, Caryotakis SE, Chang AA, Liang HE, Zikherman J, Locksley RM, Molofsky AB. Interferon gamma constrains type 2 lymphocyte niche boundaries during mixed inflammation. Immunity. 2022;55(254-271):e257.

8. Ding H, Wang G, Yu Z, Sun H, Wang L. Role of interferon-gamma (IFN-gamma) and IFN-gamma receptor 1/2 (IFNgammaR1/2) in regulation of immunity, infection, and cancer development: IFN-gamma-dependent or independent pathway. Biomed Pharmacother. 2022;155:113683.

9. Rubinstein A, Kudryavtsev I, Arsentieva N, Korobova ZR, Isakov D, Totolian AA. CXCR3-expressing T cells in infections and autoimmunity. Front Biosci. 2024;29:301.

10. Metzemaekers M, Vanheule V, Janssens R, Struyf S, Proost P. Overview of the mechanisms that may contribute to the non-redundant activities of interferon-inducible CXC chemokine receptor 3 ligands. Front Immunol. 2017;8:1970.

11. Docke WD, Randow F, Syrbe U, Krausch D, Asadullah K, Reinke P, Volk HD, Kox W. Monocyte deactivation in septic patients: restoration by IFN-gamma treatment. Nat Med. 1997;3:678-81.

12. Monneret G, Payen D. Immunostimulation in critically ill patients: do not forget to consider the timing, stratification, and monitoring. Ann Intensive Care. 2024;14:75.

13. De Benedetti F, Prencipe G, Bracaglia C, Marasco E, Grom AA. Targeting interferon-gamma in hyperinflammation: opportunities and challenges. Nat Rev Rheumatol. 2021;17:678-91.

14. Roquilly A, Francois B, Huet O, Launey Y, Lasocki S, Weiss E, Petrier M, Hourmant Y, Bouras M, Lakhal K, Le Bel C, Flattres Duchaussoy D, Fernandez-Barat L, Ceccato A, Flet L, Jobert A, Poschmann J, Sebille V, Feuillet F, Koulenti D, Torres A, Altanrea study g, the Societe Francaise d'Anesthesia Reanimation Research A. Interferon gamma-1b for the prevention of hospital-acquired pneumonia in critically ill patients: a phase 2, placebo-controlled randomized clinical trial. Intensive Care Med. 2023;49:530-44.

15. Green DS, Young HA, Valencia JC. Current prospects of type II interferon gamma signaling and autoimmunity. J Biol Chem. 2017;292:13925-33.

16. Barrios EL, Mazer MB, McGonagill PW, Bergmann CB, Goodman MD, Gould RW, Rao M, Polcz VE, Davis RJ, Del Toro DE, Dirain ML, Dram A, Hale LO, Heidarian M, Kim CY, Kucaba TA, Lanz JP, McCray AE, Meszaros S, Miles S, Nelson CR, Rocha IL, Silva EE, Ungaro RF, Walton AH, Xu J, Zeuner-Spataro L, Drewry AM, Liang M, Bible LE, Loftus TJ, Turnbull IR, Efron PA, Remy KE, Brakenridge SC, Badovinac VP, Griffith TS, Moldawer LL, Hotchkiss RS, Caldwell CC. Adverse outcomes and an immunosuppressed endotype in septic patients with reduced IFN-gamma ELISpot. JCI Insight. 2024;9.

17. Loftus TJ, Ungaro R, Dirain M, Efron PA, Mazer MB, Remy KE, Hotchkiss RS, Zhong L, Bacher R, Starostik P, Moldawer LL, Brakenridge SC. Overlapping but disparate inflammatory and immunosuppressive responses to SARS-CoV-2 and bacterial sepsis: an immunological time course analysis. Front Immunol. 2021;12:792448.

18. Mazer MB, Caldwell CC, Hanson J, Mannion D, Turnbull IR, Drewry A, Osborne D, Walton A, Blood T, Moldawer LL, Brakenridge S, Remy KE, Hotchkiss RS. A whole blood enzyme-linked immunospot assay for functional immune endotyping of septic patients. J Immunol. 2021;206:23-36.

19. Haem Rahimi M, Daniel S, Venet F, Bidar F, Cour M, Ducrot S, Argaud L, Lukaszewicz AC, Berthier F, Monneret G. Fully automated interferon-γ release assay to monitor antigen-independent T cell functionality: a proof of concept study in septic shock. Cytokine. 2023;169:156263.

20. Bonavia AS, Samuelsen A, Liang M, Hanson J, McKeone D, Chroneos ZC, Halstead ES. Comparison of whole blood cytokine immunoassays for rapid, functional immune phenotyping in critically ill patients with sepsis. Intensive Care Med Exp. 2023;11:70.

21. O'Dwyer MJ, Mankan AK, Stordeur P, O'Connell B, Duggan E, White M, Kelleher DP, McManus R, Ryan T. The occurrence of severe sepsis and septic shock are related to distinct patterns of cytokine gene expression. Shock. 2006;26:544-50.

22. Li J, Li M, Su L, Wang H, Xiao K, Deng J, Jia Y, Han G, Xie L. Alterations of T helper lymphocyte subpopulations in sepsis, severe sepsis, and septic shock: a prospective observational study. Inflammation. 2015;38:995-1002.

23. Pinsky MR, Vincent JL, Deviere J, Alegre M, Kahn RJ, Dupont E. Serum cytokine levels in human septic shock. Relation to multiple-system organ failure and mortality. Chest. 1993;103:565-75.

24. de Pablo R, Monserrat J, Reyes E, Diaz-Martin D, Rodriguez Zapata M, Carballo F, de la Hera A, Prieto A, Alvarez-Mon M. Mortality in patients with septic shock correlates with anti-inflammatory but not proinflammatory immunomodulatory molecules. J Intensive Care Med. 2011;26:125-32.

25. Kim EY, Ner-Gaon H, Varon J, Cullen AM, Guo J, Choi J, Barragan-Bradford D, Higuera A, Pinilla-Vera M, Short SA, Arciniegas-Rubio A, Tamura T, Leaf DE, Baron RM, Shay T, Brenner MB. Post-sepsis immunosuppression depends on NKT cell regulation of mTOR/IFN-gamma in NK cells. J Clin Invest. 2020;130:3238-52.

26. Konig R, Kolte A, Ahlers O, Oswald M, Krauss V, Roell D, Sommerfeld O, Dimopoulos G, Tsangaris I, Antoniadou E, Jaishankar N, Bogatsch H, Loffler M, Rodel M, Garcia-Moreno M, Tuchscherr L, Sprung CL, Singer M, Brunkhorst F, Oppert M, Gerlach H, Claus RA, Coldewey SM, Briegel J, Giamarellos-Bourboulis EJ, Keh D, Bauer M. Use of IFNgamma/IL10 ratio for stratification of hydrocortisone therapy in patients with septic shock. Front Immunol. 2021;12:607217.

27. Roquilly A, Broquet A, Jacqueline C, Masson D, Segain JP, Braudeau C, Vourc'h M, Caillon J, Altare F, Josien R, Retiere C, Villadangos J, Asehnoune K. Hydrocortisone prevents immunosuppression by interleukin-10+ natural killer cells after trauma-hemorrhage. Crit Care Med. 2014;42:e752-761.

28. Giamarellos-Bourboulis EJ, Antonelli M, Bloos F, Kotsamidi I, Psarrakis C, Dakou K, Thomas-Ruddel D, Montini L, Briegel J, Damoraki G, Koufargyris P, Anisoglou S, Antoniadou E, Vlachogianni G, Tsiantas C, Masullo M, Ioakeimidou A, Kondili E, Ntaganou M, Gkeka E, Papaioannou V, Polyzogopoulou E, Reininger AJ, De Pascale G, Kiehntopf M, Mouloudi E, Bauer M. Interferon-gamma driven elevation of CXCL9: a new sepsis endotype independently associated with mortality. EBioMedicine. 2024;109:105414.

29. Brandes-Leibovitz R, Riza A, Yankovitz G, Pirvu A, Dorobantu S, Dragos A, Streata I, Ricano-Ponce I, de Nooijer A, Dumitrescu F, Antonakos N, Antoniadou E, Dimopoulos G, Koutsodimitropoulos I, Kontopoulou T, Markopoulou D, Aimoniotou E, Komnos A, Dalekos GN, Ioana M, Giamarellos-Bourboulis EJ, Gat-Viks I, Netea MG. Sepsis pathogenesis and outcome are shaped by the balance between the transcriptional states of systemic inflammation and antimicrobial response. Cell Rep Med. 2024;5:101829.

30. Pravica V, Perrey C, Stevens A, Lee JH, Hutchinson IV. A single nucleotide polymorphism in the first intron of the human IFN-gamma gene: absolute correlation with a polymorphic CA microsatellite marker of high IFN-gamma production. Hum Immunol. 2000;61:863-6.

31. Vallinoto AC, Graca ES, Araujo MS, Azevedo VN, Cayres-Vallinoto I, Machado LF, Ishak MO, Ishak R. IFNG +874T/A polymorphism and cytokine plasma levels are associated with susceptibility to *Mycobacterium tuberculosis* infection and clinical manifestation of tuberculosis. Hum Immunol. 2010;71:692-6.

32. Sarangi S, Nahak SK, Padhi S, Pradhan B, Nayak N, Pati A, Panda AK. Interferon-gamma (IFN-gamma) intronic variant (rs2430561) is a risk factor for systemic lupus erythematosus: observation from a meta-analysis. Lupus. 2023;32:284-94.

33. Rosain J, Kiykim A, Michev A, Kendir-Demirkol Y, Rinchai D, Peel JN, Li H, Ocak S, Ozdemir PG, Le Voyer T, Philippot Q, Khan T, Neehus AL, Migaud M, Soudee C, Boisson-Dupuis S, Marr N, Borghesi A, Casanova JL, Bustamante J. Recombinant IFN-gamma1b treatment in a patient with inherited IFN-gamma deficiency. J Clin Immunol. 2024;44:62.
34. Peters van Ton AM, Kox M, Abdo WF, Pickkers P. Precision immunotherapy for sepsis. Front Immunol. 2018;9:1926.

35. Smaldone GC. Repurposing of gamma interferon via inhalation delivery. Adv Drug Deliv Rev. 2018;133:87-92.

36. Leentjens J, Kox M, Koch RM, Preijers F, Joosten LA, van der Hoeven JG, Netea MG, Pickkers P. Reversal of immunoparalysis in humans in vivo: a double-blind, placebo-controlled, randomized pilot study. Am J Respir Crit Care Med. 2012;186:838-45.

37. Bonig H, Korholz D, Lex C, Wolfel S, Gobel U. Monocyte deactivation and its reversal in a patient with chemotherapy-induced leukopenia and severe systemic infection. Med Pediatr Oncol. 2000;34:39-42.

38. Nalos M, Santner-Nanan B, Parnell G, Tang B, McLean AS, Nanan R. Immune effects of interferon gamma in persistent staphylococcal sepsis. Am J Respir Crit Care Med. 2012;185:110-2.

39. Payen D, Faivre V, Miatello J, Leentjens J, Brumpt C, Tissieres P, Dupuis C, Pickkers P, Lukaszewicz AC. Multicentric experience with interferon gamma therapy in sepsis induced immunosuppression. A case series. BMC Infect Dis. 2019;19:931.

40. Leventogiannis K, Kyriazopoulou E, Antonakos N, Kotsaki A, Tsangaris I, Markopoulou D, Grondman I, Rovina N, Theodorou V, Antoniadou E, Koutsodimitropoulos I, Dalekos G, Vlachogianni G, Akinosoglou K, Koulouras V, Komnos A, Kontopoulou T, Prekates A, Koutsoukou A, van der Meer JWM, Dimopoulos G, Kyprianou M, Netea MG, Giamarellos-Bourboulis EJ. Toward personalized immunotherapy in sepsis: the PROVIDE randomized clinical trial. Cell Rep Med. 2022;3:100817.

41. International Chronic Granulomatous Disease Cooperative Study G. A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease. N Engl J Med. 1991;324:509-16.

42. Polk HC Jr, Cheadle WG, Livingston DH, Rodriguez JL, Starko KM, Izu AE, Jaffe HS, Sonnenfeld G. A randomized prospective clinical trial to determine the efficacy of interferon-gamma in severely injured patients. Am J Surg. 1992;163:191-6.

43. Dries DJ, Jurkovich GJ, Maier RV, Clemmer TP, Struve SN, Weigelt JA, Stanford GG, Herr DL, Champion HR, Lewis FR, et al. Effect of interferon gamma on infection-related death in patients with severe injuries. A randomized, double-blind, placebo-controlled trial. Arch Surg. 1994;129:1031-1041; discussion 1042.

44. Pollard KM, Cauvi DM, Toomey CB, Morris KV, Kono DH. Interferon-gamma and systemic autoimmunity. Discov Med. 2013;16:123-31.

45. Hamidi M, Zarrin A, Foroozesh M. Novel delivery systems for interferons. Crit Rev Biotechnol. 2007;27:111-27.

46. Gutterman JU, Rosenblum MG, Rios A, Fritsche HA, Quesada JR. Pharmacokinetic study of partially pure gamma-interferon in cancer patients. Cancer Res. 1984;44:4164-71.

47. Kurzrock R, Rosenblum MG, Sherwin SA, Rios A, Talpaz M, Quesada JR, Gutterman JU. Pharmacokinetics, single-dose tolerance, and biological activity of recombinant gamma-interferon in cancer patients. Cancer Res. 1985;45:2866-72.

48. Wills RJ. Clinical pharmacokinetics of interferons. Clin Pharmacokinet. 1990;19:390-9.

49. Bocci V, Pacini A, Pessina GP, Paulesu L, Muscettola M, Lunghetti G. Cata-
bolic sites of human interferon-gamma. J Gen Virol. 1985;66(Pt 4):887-91.

50. Lumlergul N, Hall A, Camporota L, Crichton S, Ostermann M. Clearance of inflammatory cytokines in patients with septic acute kidney injury during renal replacement therapy using the EMiC2 filter (Clic-AKI study). Crit Care. 2021;25:39.

51. Ghosh D, Ghosh D, Parida P. Physiological proteins in therapeutics: a current review on interferons. Mini Rev Med Chem. 2016;16:947-52.

52. Harris JM, Chess RB. Effect of pegylation on pharmaceuticals. Nat Rev Drug Discov. 2003;2:214-21.

53. Foster GR. Review article: pegylated interferons: chemical and clinical differences. Aliment Pharmacol Ther. 2004;20:825-30.

54. Qi F, Liu F, Gao L. Janus kinase inhibitors in the treatment of vitiligo: a review. Front Immunol. 2021;12:790125.

55. McLornan DP, Pope JE, Gotlib J, Harrison CN. Current and future status of JAK inhibitors. Lancet. 2021;398:803-16.

56. Selvaraj V, Finn A, Lal A, Khan MS, Dapaah-Afriyie K, Carino GP. Baricitinib in hospitalised patients with COVID-19: a meta-analysis of randomised controlled trials. EClinicalMedicine. 2022;49:101489.

57. Pawlik K, Mika J. Targeting members of the chemokine family as a novel approach to treating neuropathic pain. Molecules. 2023. https://doi.org/10.3390/molecules28155766.

58. Jenh CH, Cox MA, Cui L, Reich EP, Sullivan L, Chen SC, Kinsley D, Qian S, Kim SH, Rosenblum S, Kozlowski J, Fine JS, Zavodny PJ, Lundell D. A selective and potent CXCR3 antagonist SCH 546738 attenuates the development of autoimmune diseases and delays graft rejection. BMC Immunol. 2012;13:2.

59. Christen U, Pouzol L, Tunis M, Sassi A, Tondello C, Bayer M, Hintermann E, Strasser DS, Schuldes S, Mentzel U, Martinic MM. Combination treatment of a novel CXCR3 antagonist ACT-777991 with an anti-CD3 antibody synergistically increases persistent remission in experimental models of type 1 diabetes. Clin Exp Immunol. 2023;214:131-43.

60. Wang D, Zhong X, Huang D, Chen R, Bai G, Li Q, Yu B, Fan Y, Sun X. Func-
tional polymorphisms of interferon-gamma affect pneumonia-induced
sepsis. PLoS ONE. 2014;9:e87049.

61. Gilchrist JJ, Rautanen A, Fairfax BP, Mills TC, Naranbhai V, Trochet H, Pirinen M, Muthumbi E, Mwarumba S, Njuguna P, Mturi N, Msefula CL, Gondwe EN, MacLennan JM, Chapman SJ, Molyneux ME, Knight JC, Spencer CCA, Williams TN, MacLennan CA, Scott JAG, Hill AVS. Risk of nontyphoidal *Salmonella* bacteraemia in African children is modified by STAT4. Nat Commun. 2018;9:1014.

**Publisher's Note**

Springer Nature remains neutral with regard to jurisdictional claims in pub-
lished maps and institutional affiliations.