Immunomodulation in Infectious Diseases; A review of current applications and future directions

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ACHAIKI IATRIKI | 2023; 42(4):201–214

Review

Georgios Schinas1*, Eleni Polyzou1,2*, Stamatia Tsoupra1,2, Christina Petropoulou1,2, Karolina Akinosoglou1,2

1School of Medicine, University of Patras, Rio, Greece
2Department of Internal Medicine, University of Patras, Rio, Greece

*Equal authorship

Received: 07 May 2023; Accepted: 24 Jul 2023

Corresponding author: Karolina Akinosoglou, Internist-Infectiologist, Associate Professor, Medical School University of Patras, Depts of Internal Medicine and Infectious Diseases University General Hospital of Patras, 26504, Greece, E-mail: akin@upatras.gr

Key words: Immunomodulation, infectious diseases, immunomodulatory strategies, sepsis, Covid-19

 

Abstract

Infectious diseases are a major global health issue, particularly at a time when resistance to antibiotics is increasing. Viewing infections as a consequence of immune system dysfunction, immunomodulation offers an alternative approach that shifts the focus to the host. Among the immunomodulation strategies, vaccines and adjuvants aim to shape the patient’s immunity to prevent the severity of the infection, whereas immunomodulating peptides, based on derivatives from the immune system, exert both immunoregulatory and antibacterial activity. Hematopoietic growth factors regulate the production of blood cells, while cytokines specifically modulate the immune response against a particular pathogen, exhibiting both enhancing and anti-inflammatory properties. Monoclonal antibodies exert a dual action, as in addition to targeting a specific antigen, they prevent excessive anti-inflammatory activity. At the molecular level, factors acting through TLR receptors regulate the immune response against microbial pathogens, whereas immune checkpoint inhibitors remove the inhibition of the immune system, allowing for a targeted response. CAR-T cells are another approach, where specially engineered T cells target pathogens with greater precision. The present review seeks to highlight immunomodulation as a potential adjunctive therapy for infectious diseases and emphasizes the need for further personalization of antimicrobial treatment strategies. In line with this, we also discuss documented cases of infections, such as COVID-19, malaria, and sepsis, where immunomodulation strategies have been effectively utilized.

INTRODUCTION

Infectious diseases constantly threaten global health, with emerging pathogens often posing challenges to humanity. For many years, traditional approaches to fighting these diseases have mainly focused on the use of antimicrobial agents to either kill or directly inhibit pathogen growth. However, increasing antibiotic resistance, in conjunction with the limitations faced in the development of new antibiotics, has shifted the focus of attention to the direction of immune modulatory therapies, since in one sense infectious diseases, can be considered as immunological disorders. Immunomodulatory-based treatments focus on the hosts’ reaction rather than on the pathogen itself. Either natural or synthetic and further divided into three categories, i.e., immunoadjuvants, immunosuppressants, and immunostimulants, immunomodulators assert their action either by mitigating the immune response and, thereby, limiting the auto-inflammatory damage or by enhancing its defensive capabilities through adaptive immune system stimulation [1].

The introduction of corticosteroids in the treatment protocols of sepsis dates back to the mid-twentieth century [2]. The potential of immune-based therapies as sustainable, long-term solutions to the global burden of infectious diseases has been evident ever since. However, limitations in terms of technology and pharmacology may have stalled investment and attention in the field. The COVID-19 pandemic renewed interest in terms of therapy for immune modulation, owing to the widespread research on the discovery and use of novel immunoregulatory therapies to tackle disease severity and prevent adverse outcomes in Sars-CoV-2-related pneumonia [3]. Breakthrough use of immunomodulatory agents such as Tocilizumab – a monoclonal antibody that targets and binds to the interleukin-6 (IL-6) receptor- and Baricitinib -Janus kinase (JAK) inhibitor- for COVID-19 has ascertained their clinical value and significance.

The concept of immune modulation in the treatment of infections has been widely explored. However, a “one size fits all” approach is, by definition, flawed when taking into account the variability of pathogens and the particularities of the hosts’ reactions. Multiple pathogens, including bacteria, viruses, and fungi, have been proven to cause immune system checkpoint inhibition through numerous mechanisms, thereby leading to an exaggerated or diminished immune response from the host’s side [4,5]. For instance, cytomegalovirus (CMV), directly encode proteins that are homologs of immune checkpoint ligands which inhibit T-cell activation, helping the virus to evade the immune response [6]. Similarly, hepatitis B and C viruses induce the expression of PD-L1 [7], a checkpoint ligand, on the surface of infected cells, which, when binding to PD-1 on T cells, suppresses their activation and thus allows the virus to proliferate unchecked.

Moreover, immune adaptations, ranging from total immune paralysis to markedly severe systemic inflammation, are commonly encountered in cases of infection. It becomes evident that many parameters need to be addressed when it comes to personalized clinical decision-making and individualization of clinical care in infection. Living and practicing in the modern world of personalized medicine brings a whole new meaning to the matter.

This review aims to further emphasize the potential of immune modulation in the treatment of infections and the need for individualized approaches in the modern world of personalized medicine by examining some of the key strategies and immune-based therapies being developed to combat infectious diseases.

IMMUNOMODULATORY STRATEGIES IN INFECTIOUS DISEASES

Vaccines

Vaccines play a crucial role in modulating the immune system by providing a safe and controlled exposure to antigens, allowing the immune system to generate a robust, specific, and long-lasting response. Through this exposure, vaccines stimulate the production of memory B and T cells, providing long-term protection against subsequent infections [8,9]. Evidence has shown that, vaccination affects some innate immunity cells apart from adaptive immunity. Vaccines indirectly enhance the innate immune response by regulating an epigenetic reprogramming of innate immune cells such as monocytes, macrophages, and NK cells. This process, also known as ‘Trained Immunity,’ acts in favor of reducing the possibility of reinfection in a non-lymphocyte-inducing manner [10]. Vaccines can also help reduce symptoms’ severity and duration by boosting the immune response. This can be particularly beneficial in individuals with weakened immune systems or those at a higher risk of severe disease. Vaccines are, therefore, not only an effective preventive measure against infectious diseases but also an essential tool for immunomodulation. Attempts to combat the susceptibility and severity of SARS-CoV2, as well as, respiratory infections in the elderly by administering the BCG vaccine are examples of novel approaches to vaccines that provide an immunomodulatory platform against infections [11,12].

Historically, adjuvants are substances utilized to enhance the strength of an adaptive response elicited by a vaccine, as measured by metrics such as antibody titer or protective efficacy. Hence, a secondary function of adjuvants, as equally important, has lately emerged: the ability to steer the nature of the adaptive response towards the most optimal forms of immunity tailored to each pathogen. Presently, adjuvants utilized in human vaccines are designed to bolster primarily humoral immunity. However, in various stages of clinical or preclinical testing, many new adjuvants are aimed at amplifying specific T-cell responses and fostering the multifarious immune reactions necessary to counteract complex diseases such as HIV or malaria [13].

Immunomodulatory peptides

Immunomodulatory peptides, such as, thymosin alpha 1, and vasoactive intestinal peptide (VIP) [14], are compounds being explored as a potential treatment for preventing and treating infections. These compounds are based on natural peptides produced by the innate immune system and are typically enriched with cationic and hydrophobic amino acids. They have diverse mechanisms of action, including the direct killing of bacterial pathogens and modulation of the host’s immune system. For example, the peptide thymosin alpha 1 has been shown to enhance immune responses, particularly T-cell responses, and has been proposed as an adjuvant to various infections and cancers [15]. Other peptides, referred to as host defense peptides (HDPs), such as the antimicrobial peptide LL-37 [16], have been developed for their bilateral immunomodulatory properties and protective activity against bacterial pathogens, such as suppressing proinflammatory chemokines in reaction to bacterial lipopolysaccharides and lipoteichoic acids or enhancing the production of chemokines, angiogenesis promotion, and wound healing [17]. These are under consideration for preventing infections in immunosuppressed patients undergoing cancer chemotherapy. Synthetic peptides, such as cyclic di-GMP [18], are also being used as components of vaccine adjuvants to stimulate adaptive immunity and antibody production. Bacteriocins, a diverse class of bacterially produced antimicrobial peptides, such as nisin [19] and pediocin [20], are also being explored for their potential to prevent and treat bacterial infections as well as for their immunomodulatory properties [21]. Inducing the expression of endogenous peptides, such as interleukins, is another approach under investigation and may be a cheaper alternative to the administration of synthetic peptides. Overall, immunomodulatory peptides show promise as a potential immunomodulatory treatment. However, further research and clinical trials are needed to fully understand their mechanisms of action and efficacy in preventing and treating infections.

Cytokines and hematopoietic growth factors

Cytokines and hematopoietic growth factors serve as chemical messengers to regulate blood cell production and immune responses. Their versatility and low concentration efficacy make them highly effective as immunomodulatory treatments. For instance, the growth factors G-CSF and GM-CSF have been utilized for several years to prevent infections in patients suffering from neutropenia [22,23]. These growth factors stimulate the production of neutrophils and other leukocytes in patients with congenital abnormalities in neutrophil production and immunosuppressed patients undergoing cancer chemotherapy or bone marrow transplantation [24]. The administration of these growth factors consistently reduces the incidence of infections and the duration of hospitalization in these patient groups.

Interleukins (ILs) and tumor necrosis factors (TNFs) are among the most well-studied cytokines and have been the subject of numerous clinical trials. These signaling molecules are pivotal in directing immune responses towards a particular pathogen and regulating the magnitude and duration of these responses. For example, Interferons (IFNs) have been used as therapeutic agents for decades in treating viral infections and certain cancers. Type-I interferons are major mediators of antiviral immune response and are utilized in patients with chronic hepatitis B and C viral infections.[25] Interferon-alpha (IFN-α) has been approved for the treatment of hepatitis B and C, as well as for certain types of leukemia. At the same time, Interferon-beta (IFN-β) has been used to treat multiple sclerosis [26]. TNF-α blocking agents such as etanercept and infliximab have been approved for the treatment of rheumatoid arthritis, Crohn’s disease, and other chronic inflammatory conditions [27].

Similarly, several cytokines that can stimulate T-cell functions and immunity against intracellular pathogens are being investigated in patients with tuberculosis, with promising results of IFN-γ administration observed so far. IL-7, which instructs standard B and T lymphocyte development, has shown promise in stimulating T cell expansion and improving T cell function in HIV-infected patients [28]. Further clinical trials for IL-7 and other cytokines with the potential to stimulate T-cell functions are ongoing.

Monoclonal Antibodies

Monoclonal and polyclonal antibodies (Abs) have been utilized as a form of immunomodulatory therapy in various medical fields, particularly in the treatment of inflammatory diseases and cancer. Monoclonal abs (mabs) can bind directly to pathogenic antigens, neutralizing the pathogen and blocking its ability to cause harm. Additionally, mabs can target immune mediators, such as cytokines and chemokines, that regulate the host response to infection. By targeting these mediators, they can modulate the intensity of the immune response and prevent excessive auto-inflammatory damage, which can cause harm to the host. This dual mode of action makes mabs highly versatile immunomodulators that can be used to treat various infectious diseases, including viral infections, bacterial infections, and toxin-mediated diseases [29].

In the field of infectious diseases, immunoglobulin replacement therapy, which involves administering polyvalent IgG, is used in patients with agammaglobulinemia and other congenital disorders of B cell function and constitutes the most effective therapeutic strategy for avoiding recurrent infections in these patients [30]. Due to the recognized risks of systemic inflammation, their use to stimulate immune response has yet to be attempted in an active infection. Currently, the application of mabs for the prevention and treatment of infectious diseases includes the neutralizing antibody against the F protein of respiratory syncytial virus (RSV), known as Palivizumab, which is approved for the prevention of respiratory disease in infants and immunocompromised adults [31],  the fully humanized mab that targets the toxin B of Clostridium , Bezlotοxumab, acknowledged for its use against C. difficile recurrence [32] and the SARS-CoV2 spike-targeting monoclonal antibody, tixagevimab /cilgavimab, that was recently developed to combat the pandemic and has shown promising results, especially in immunocompromised populations.

The numerous successful applications of mabs in other medical fields highlight their potential as an up-and-coming class of agents for the modulation of immune responses.

TLR targeting

Immunomodulatory agents acting through TLRs are attracting interest for use in immunotherapy and are being exploited as adjuvants to trigger humoral and cell-mediated immune responses. The discovery of TLRs, NOD-like receptors, and RIG-like receptors has revolutionized the field of molecular mechanisms mediating pathogen recognition by the innate immune system, leading to the identification of many new drug targets. TLRs that interrelate with microbial molecules are crucial in activating innate immunity and shaping adaptive immunity [33]. TLR agonists are being explored for the stimulation of immune responses in chronic viral infections. Most clinical trials involving TLRs ligands evaluate them primarily as adjuvants, with double the number of trials investigating TLRs ligands as adjuvants compared to those considering them as drugs. The Food and Drug Administration has approved TLR ligands, such as MPLA and imiquimod, to be used as adjuvants in various vaccine formulations and as drugs to cure viral diseases [34]. The advances in our understanding of the innate immune system hold promise for creating more effective vaccine adjuvants, with new formulations targeting different innate immune system receptors currently in development [35].

Immune checkpoint inhibitors

Another promising approach to immunomodulation is immune checkpoint inhibitors, designed to block the inhibitory signals that regulate the immune response and prevent excessive activation of immune cells. In a variety of chronic infectious diseases such as malaria, HIV, HCV and HBV infection, where upregulation of immune checkpoint receptors such as CTLA-4 and PD-1 has been described, drug administration has not yet been most potent. Blockade of these pathways may thus serve as an additional approach in tackling drug efficacy issues or eliminating viral reservoirs. Table 1 summarizes the available clinical trial data on the efficacy and safety of such compounds in the management of chronic viral infections. Moreover, in the case of infections where highly effective vaccines have not yet been discovered, immune checkpoint inhibitors may help prevent the blockade of the immune system and thus ensure an efficient immune response against infectious pathogens [36].

CYTOTOXIC T LYMPHOCYTE-ASSOCIATED ANTIGEN 4 (CTLA-4)-TARGETED AGENTS

CTLA-4, the first recognized immune checkpoint inhibitor, is important in regulating T-cell priming during antigen presentation [37]. It further transmits an inhibitory signal that results in the downregulation of the immune response [38]. Mabs that bind with high affinity to CTLA-4 and conclusively inhibit its action have been widely used to treat melanoma and do not seem to correlate with susceptibility to infections if used as the only immunotherapy [39].

PROGRAMMED DEATH (PD)-1 AND PD-1 LIGAND 1 (PD-L1)-TARGETED AGENTS.

PD-1 is considered an inhibitory immune factor of T-cells in the peripheral tissues, expressed in various immune system cells. Through binding to its ligand PD-L1, which is also found in the microenvironment of tumors, PD-1 suppresses the CD8 T cells’ activity [38].  The use of agents targeting PD-1 and PD-L1 does not increase susceptibility to infections on its own [40]; however, their immune-related adverse event potential may necessitate immunosuppressive therapy, resulting in opportunistic infections. In addition, there have been reports of latent TB reactivating with their use [41].

CAR T CELLS

Chimeric Antigen Receptor (CAR) T cells are created by modifying a patient’s own T cells in vitro so that they express a CAR on their surface. CARs are artificial receptors that consist of a targeting component connected to a spacer, which is then attached to a transmembrane domain and an intracellular signaling domain [42]. The production of CAR T cells is a strategy of creating more specialized and effective T cells to successfully eradicate targets such as neoplastic cells, specifically hematologic malignancies. They may also conduct an important role in some cases of infections, especially when adaptive and innate immune cells lack in frequency, thus in efficacy to be used in immunotherapy. Such cases include viral diseases like HIV, HBV, HCV, and fungal infections. Through their chimeric antigen receptor, these redirected T cells can avoid the escape mechanisms of bacteria, viruses, and fungi and effectively attach to their target since they do not require MHC presentation and HLA restriction [43]. Although targeting specific pathogens can provide greater precision and reduce the risk of affecting non-target organisms, avoiding off-target effects, pathogen escape mechanisms, and reservoirs remain significant challenges.

Τhe most proposed application of CAR T cells therapy in the field of infectious diseases is HIV-infection. CAR T cells can recognize and eliminate HIV-infected cells independently of the major histocompatibility complex (MHC) [44, 45] and can generate functional memory T cells for rapid response to reinfection [46]. Two main approaches for designing anti-HIV CAR constructs are based on CD4 receptors [47] or broadly neutralizing antibodies [bNAbs) [48]. While CD4 receptor-based CARs have shown limitations [49], bNAb-based CARs hold potential due to their ability to target HIV envelope glycoprotein and deactivate various HIV strains [50]. Furthermore, the HIV-specific CD8+ cytotoxic T lymphocyte (CTL) response plays a crucial role in host immunity against HIV infection [51]. Therefore, designing CD8+ T cells with a CAR that can recognize HIV antigens may be an important aspect of future therapies.

Early clinical trials have shown the potential of CD4-CAR T cell therapy in extending T cell survival and reducing HIV burden [47,52]. Ongoing and recently completed clinical trials are evaluating the safety and efficacy of CAR T cell therapy in HIV-positive patients under cART treatment, using different CAR designs such as bNAb-based CARs [53] and CD4-CARs (Clinical Trial NCT03617198) modified for HIV resistance.

However, several limitations have been identified, such as challenges in achieving sufficient expansion [47,54], susceptibility of CAR T cells to HIV infection [55], off-target effects [56,57] and toxicity mainly referring to severe cytokine release syndrome and neurologic toxicity [58,59].

NK CELLS

Natural killer (NK) cells are important mediators of the body’s innate immune system and are primarily involved in defending against viral infections. The release of interferon-gamma (IFN-γ) and tumor necrosis factor-alpha (TNF-α) by activated NK cells not only facilitates the killing of target cells but also triggers an inflammatory response, highlighting their immunomodulatory capabilities [60]. Nonetheless, the development of immunomodulatory treatments targeting NK cells implicates various other mechanisms including the direct cytotoxic activity against target cells, the ability to mediate cell killing through antibody-dependent processes and the interaction with dendritic cells [61]. Moreover, another significant mechanism involving NK cells is the memory response. Some subsets of NK cells, often termed ‘memory NK cells’, are capable of generating a robust and enhanced response to antigens they have previously encountered. This aspect of NK cell functionality allows for a more rapid and potent immune response upon re-exposure to the same antigen, thereby playing a crucial role in immunological memory, traditionally thought to be exclusive to adaptive immunity.

Two crucial elements must align for NK cells to identify and neutralize target cells: the absence of inhibitory signals and the presence of activating signals. This intricate process involves a variety of receptors, each capable of recognizing distinct molecular markers on target cells. These receptors relay either activating or inhibitory signals, thus determining the course of NK cell response. When activated, NK cells undertake several defensive strategies such as releasing cytotoxic granules, expressing death-inducing ligands, and secreting Th1-type cytokines or chemokines [61]. Specific activating receptors like NKp30, NKp44, and NKp46 have been identified and linked to viral infections such as influenza virus [62, 63] and human cytomegalovirus [64], while the interaction between activating killer Ig-like receptors (KIR) and human leukocyte antigen (HLA) molecules is associated with the progression or control of viral infections, including HIV.

In fact, considerable evidence exists to investigate the potential use of ΝΚ cells in HIV-infection. Boosting the activity of NK cells, which have shown a protective role during HIV-1 infection, could help eliminate viral reservoirs and prevent infection. In particular, NK cells exhibit natural cytotoxicity and antibody-dependent cellular cytotoxicity (ADCC), which can control cell-associated virus and block cell-to-cell transmission [65]. Preclinical studies have evaluated the administration of molecules like IL-15 to promote NK cell activation and proliferation [66]. The administration of IL-15 is considered as part of the “kick and kill” strategy, aiming to induce viral replication in latently infected cells while boosting NK cell activity to eliminate them in combination with antiretroviral therapy [67]. However, further evaluation is required to determine if this induced NK cell phenotype can be effective in controlling HIV infection [65].

Overall, the extensive and multifaceted mechanisms deployed by NK cells, along with their involvement in antigen-targeting specificity and immune memory, illustrate their profound potential in orchestrating immune responses. This potential notably distinguishes NK cells from other forms of immunomodulatory therapy, such as T-cell targeting agents. Given their distinct attributes, NK cells have become a primary focus in immunological research, underscoring their immense potential in advancing therapeutic immunomodulatory strategies.

Building on this understanding of the unique and powerful capabilities of NK cells, we propose a research protocol that seeks to further explore their immunomodulatory capabilities. This protocol, titled “Development of Memory-Like NK Cells for Vaccine Strategies Based on Cellular Immunity,” is inspired by a previous clinical trial that evaluated the efficacy of memory-like NK cells against leukemia cell lines [68] and demonstrated the enhanced responses of memory-like NK cells against myeloid leukemia.

Our proposal aims to extend this understanding by investigating the potential of these cells in the development of new vaccine strategies based on cellular rather than adaptive immunity. Specifically, this protocol will involve the in-vitro development of memory-like NK cells, followed by an evaluation of their cytotoxic response and IFN-γ production. The ultimate goal is to assess whether this response may provide sufficient coverage during early infection, possibly employing animal models in future studies in order to determine safety and efficacy. It is our hope that this study will contribute to the growing body of knowledge on NK cells and their potential applications in immunotherapy, and ultimately lead to the development of more effective vaccine strategies.

Table 2 delineates a proposed research protocol for the investigation of memory-like natural killer (NK) cells in the development of new vaccine strategies and outlines the steps from the initial objective of developing memory-like NK cells in vitro through the evaluation of their cytotoxic response and IFN-γ production, to the assessment of their potential in new vaccine strategies. Furthermore, the table also acknowledges potential limitations and analyses the expected outcomes of the proposed research

EXPLORING APPLICATIONS OF IMMUNOMODULATORY STRATEGIES IN INFECTIOUS DISEASES

Many cases of infectious diseases have been studied to understand the immune-modulatory mechanisms, which are activated during infection, in an effort to update the existing strategies and treatments with the latest scientific knowledge in the field of immune activation. We hereby present an example of 3 cases, that of malaria (parasitic disease), sepsis (mostly attributed to bacteria) and COVID-19 (viral infection) that immunomodulatory regimens have found room for implementation. Of note, this is more of a proof-of-concept rather than an exhaustive list, thus not all relevant applications are included e.g tuberculosis.

A. Malaria

Malaria is a potentially life-threatening parasitic disease caused by infection with Plasmodium protozoa, that still afflicts the global health community due to its high morbidity and mortality. Many studies have been conducted to uncover an appropriate treatment, based on host-mediated immunopathology to reduce the severe manifestations and the mortality rates of the disease. In this setting, the complexity of the life cycle of Plasmodium is a predominant cause of difficulty in developing protective strategies such as an efficient malaria vaccine. In severe malaria, an intense proliferation of immune cells (i.e., macrophages, neutrophils, and effector T cells) and increased production of proinflammatory cytokines, such as TNF, IFN-g, IL-6, and IL-1b [69], has been described. Experimental malaria models demonstrate the innate, cellular, and humoral immune responses that IFN-γ and TH1 cells orchestrated during the Plasmodium blood stages. Patients with acute-phase infection were found to express PD1 on CD4+ and CD8+ T-cells, and CTLA4, OX40, glucocorticoid-induced TNFR-related protein (GITR), and CD69 on CD4+ cells, suggesting a role for regulatory T (Treg) cells in suppressing immunity to malaria and also highlighting the feasible contribution of  immune checkpoint blockade to more prolonged vaccine efficacy, prevention of reinfection, fewer complications, better immune response and survival rates [36].

Other cytokines, such as TGF-β and IL-10,  have been identified as important anti–inflammatory immunomodulators, that help to limit inflammation and pathology during the course of disease [70]. The anti-inflammatory effects, including inhibition of proinflammatory cytokine expression of corticosteroids (dexamethasone) and the use of intravenous immunoglobulin, were the first immunomodulation strategies that had an impact on cerebral Malaria. Despite the promising reports from anti-TNF models [71], the trials with monoclonal antibody B-C7, pentoxifylline, and thalidomide in cerebral malaria have controversial clinical outcomes [72]. Recent reviews highlighted some promising new therapies, including arginine and inhaled NO to increase NO concentrations, and peroxisome proliferator-activated receptor (PPARγ) agonists, such as rosiglitazone, which can modify CD36 transcription and TLR2-dependent innate inflammatory immune responses and suppression of genes involved in proinflammatory cytokine secretion, as potential agents to adjunctive immunomodulatory strategies in the management of severe malaria [72]. In conclusion, the complexity of the undergoing pathways of the immune response to Plasmodium spp leaves the field open for further research into the immunomodulatory therapies in Malaria.

Β. COVID-19

The COVID-19 pandemic provided an excellent opportunity to test efficacy of immunomodulation in the acute treatment of infectious diseases. Given SARS-CoV2 unique pattern of immune dysregulation [73], immunomodulation has proven crucial in controlling and preventing the severity of COVID-19 disease. In critically ill patients with COVID-19 pneumonia, a cytokine storm or cytokine release syndrome (CRS) is accountable for multiple organ failure and disease progression [74,75]. Anakinra, tocilizumab, baricitinib, and anti-SARS-CoV-2 mAb (tixagevimab-cilgavimab) represent the most widely used (currently) and approved for the management of severe COVID-19 disease, immunomodulatory factors.

Anakinra, an Interleukin-1 (IL-1) receptor antagonist, constitutes an important therapeutic tool in COVID-19 management, as confirmed by the SAVE-MORE double-blinded randomized clinical trial [76,77]. SARS-COV-2 enters the epithelial cells through the ACE receptor and consequently releases cytokines such as IL-1β, leading to hyperinflammation, cytokine storm, and tissue damage [78].

Tocilizumab is a recombinant humanized monoclonal IgG1 antibody against the interleukin-6 (IL-6) receptor. The central role of  IL-6 in the progress of inflammation and, thus, in cytokine storm, hyperinflammation, and acute respiratory distress (ARDS) in patients with severe COVID-19 pneumonia is confirmed by various studies. Tocilizumab seems to reduce mortality in hospitalized adults with severe or critical COVID-19  that meet the WHO severity criteria [79], and its use in combination with corticosteroids is indicated for these patients [80].

Baricitinib is an orally administered JAK inhibitor, that interrupts the multiple cytokine pathways implicated in COVID-19 immunopathology. It also acts via reported antiviral activity by blocking viral cell entry and suppressing type I interferon-driven angiotensin-converting-enzyme-2 upregulation [81]. Combined with remdesivir, it shortens the time to recovery in COVID-19 hospitalized patients and reduces mortality when added to corticosteroids [82,83]. Clinical data on baricitinib›s use in COVID-19 are lacking, and evidence of its anti-inflammatory effects mainly derives from rheumatoid arthritis clinical trial programs [30].

Several anti-SARS-CoV-2 mAb products directed against the SARS-CoV-2 spike protein have been evaluated to treat COVID-19, with tixagevimab-cilgavimab, a monoclonal antibody combination, being the one currently still in use. Its use for pre-exposure prophylaxis was, until recently, the only option for individuals (including pregnant people) with moderate to severe immunosuppression or for those who cannot receive a recommended series of COVID-19 vaccine because of a severe adverse reaction to the vaccines or their components [84].

C. Sepsis

Sepsis, a potentially fatal complication caused by an abnormal response to an infection, is a wide-ranging and complicated condition. Patients on the one side of the septic spectrum experience hyperinflammation as a result of the overproduction of proinflammatory cytokines [85], predominantly interleukin-1β, which can potentially cause pancytopenia, liver failure, and disseminated intravascular coagulation [86]. On the other extreme of the spectrum, we find patients that may become “immunoparalyzed”, meaning that their immune system may not be capable of mounting a sufficient response, hence; constituting them vulnerable to secondary infections and resulting in increased hospitalization and fatality rates. This manifestation of sepsis is defined by reduced expression of human leukocyte antigen-DR on circulating monocytes coupled with lymphopenia [87,88]. However, a rise in T regulatory cells and a decrease in B cell markers has also been described in some patients [89]. Pilot trials have shown that immunoparalysis can be restored by administering recombinant human interferon-γ [90].

The timing of intervention in immunotherapies is vital for determining their efficacy; therefore, individualized diagnosis and pattern recognition analysis are required to determine the optimum approach. Identification of the clinical phenotype is essential for directing the administration of immunomodulatory therapies for such complex disorders. Immunomodulatory medications will likely become more effective for treating infections in general, leading to improved outcomes and survival rates, as the value of clinical phenotypic recognition becomes more widely acknowledged [91].

CONCLUSION

Immunomodulation can present an effective complement to traditional antimicrobial treatments for infectious illnesses. Immunomodulators can either minimize auto-inflammatory damage or boost the host’s defenses by targeting the immune response. A personalized treatment approach along with a clinically-driven insight into the timing of intervention are essential for optimizing outcomes. In the modern age of personalized medicine, recognizing the unique characteristics of each individual’s immune response may allow for tailored immunomodulatory therapies, enabling more effective control and/or treatment of infectious diseases. Future research should focus on developing these customized solutions and improving our understanding of the complex interplay between infections, hosts, and immune responses, which will ultimately result in more effective treatment plans for our patients.

Conflict of interest: None to declare

Declaration of funding sources: None to declare

Author contributions: GS, EP, ST, CP collected and analyzed data, GS EP, ST, CP, KA wrote manuscript, KA critically corrected the manuscript, KA finally approved the article

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