Sepsis was defined in 1991 by the systemic inflammatory response syndrome (SIRS) criteria which consisted mostly of physiologic responses to infection or inflammation (fever, tachycardia, tachypnea, and leukocytosis). These criteria were initially proposed to identify patients with gram-negative bloodstream infection (BSI). However, most patients with BSI are not critically ill at initial presentation using objective clinical scores for acute severity of illness, such as the Pitt bacteremia score (PBS). Lack of specificity and low positive predictive value (PPV) are other pitfalls of the SIRS criteria. Moreover, the implementation of sepsis interventions based on this outdated definition failed to improve patients’ outcomes and in some settings was associated with increased use of broad-spectrum antibiotics and Clostridioides difficile (C. difficile) infection. In 2016, sepsis was redefined as a dysregulatory host response to life-threatening infections using quick sequential organ failure assessment (qSOFA) score. The presence of two of three bedside clinical variables (hypotension, respiratory distress, and altered mental status) that have consistently predicted mortality in patients with infections now constitutes sepsis. The scientific debate continues in the medical literature regarding the performance of the new criteria. Some medical professionals and quality organizations consider these changes to the sepsis definition too revolutionary and are resistant to altering existing medical practice. This narrative review presents infection as a continuum from localized to systemic infection (pre-sepsis) with the potential progression into sepsis and septic shock if appropriate antibiotic therapy and source control are delayed. The review assesses host and microbial factors that may influence the rate of progression through the sepsis cascade and proposes diagnostic considerations and management decisions at each step of the way. It emphasizes the need to utilize precision medicine concepts in selecting empirical antibiotic therapy based on patient-specific risk factors for infections due to resistant bacteria and potential benefits from appropriate therapy across the sepsis spectrum.

Sepsis is a life-threatening condition caused by dysregulated host immune response to infection, leading to persistent inflammation followed by immunosuppression. Sepsis represents a substantial global health problem owing to protracted inflammation, immune suppression, and susceptibility to nosocomial infections. Despite continuing progress in the development of antibiotics, fluid resuscitation, and other supportive care therapies, no specific immunomodulatory drugs or immunotherapeutic adjuncts for the treatment of sepsis are available to date. The advances in tertiary care facilities and patient care have improved the survival of sepsis patients in the initial hyper-inflammatory phase of sepsis. However, the majority of sepsis patients succumb later due to prolong immunosuppression. The sepsis-induced immune dysregulation and its long-term effects on mortality are under meticulous investigations that are still poorly defined. Sepsis leads to the impaired functions of the innate and adaptive immune systems. The exhaustion of T cells, reduced expression of human leukocytes antigen (HLA)-DR on monocytes, and induced uncontrolled apoptosis of immune cells have been reported as hallmark features of sepsis. Sepsis-induced immune cell apoptosis of immune cells is a primary contributing factor to the immunosuppression in sepsis. Preclinical studies have identified several new therapeutic targets for therapy in sepsis, including monoclonal antibodies (Abs) and anti-apoptotic agents to reduce T cells exhaustion, immune cells apoptosis, and restoring immune cells functions. Recent studies have centered on immune-modulatory therapy. The review article will focus solely on sepsis’ effects on innate and adaptive cells functions that contribute to immunosuppression. Finally, it is discussed how immune cells responsible for immunosuppression might be directly targeted to provide potential therapeutic benefits in treating sepsis and improving long-term survival.

Sepsis and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, and its severe form coronavirus disease 2019 (COVID-19), represent the major medical challenges of the modern era. Therapeutic options are limited, mostly symptomatic, partially relying on antibodies and corticosteroids and, in the case of SARS-CoV-2 infection, supplemented by the antiviral drug remdesivir, and more recently by molnupiravir, nirmatrelvir/ritonavir, and the Janus kinase (JAK) inhibitors tofacitinib and baricitinib. Sepsis and severe SARS-CoV-2 infection/COVID-19 share many features at the level of pathophysiology and pro-inflammatory mediators, thus enabling a common disease management strategy. New ideas in successfully targeting the prognostic severity and mortality marker pentraxin 3 (PTX3) in sepsis and severe SARS-CoV-2 infection/COVID-19; the complement (C3/C3a/C3aR and C5/C5a/C5aR axis); tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and IL-6 expression; IL-6-triggered expression of C5aR receptor in vascular endothelial cells; and release of anti-inflammatory IL-10 are still missing. Small molecules with lysosomotropic characteristics such as the approved drugs amitriptyline, desloratadine, fluvoxamine, azelastine, and ambroxol have demonstrated their clinical benefits in rodent models of sepsis or clinical trials in COVID-19; however, their exact mode of action remains to be fully elucidated. Addressing disease-relevant targets such as viral infection of host cells, shedding of toll-like receptors (TLRs), expression of pro-inflammatory mediators such as TNF-α, IL-1β, IL-6, PTX3, and the complement receptor C5aR, highlight the advantages of this multi-target approach in comparison to current standards. Rational drug repurposing of approved drugs or screening for active compounds with virtually exclusively lysosomotropic pharmacologic effects is a major opportunity to improve prophylaxis and treatment of sepsis and/or SARS-CoV-2 infection, and its severe form COVID-19.

This review pretends to shed light on the immune processes occurring in the coronavirus disease 2019 (COVID-19) from a perspective based on the antigens size, lower or larger than 70 kDa. This cutoff size point explains the host type of immune response against the antigenic proteins of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which may lead to the development of the memory B cells or, conversely, the immune suppression, apoptosis, viral escape, and sepsis. Here, based on previous experimental work and the review of related literature, the following is proposed: antigens < 70 kDa can access the germinal center through the follicular conduits, where the activated B cells can present the processed antigen to specific naive CD4⁺ T cells that, in interaction with the major histocompatibility complex class II (MHC-II), trigger the immune response T helper type 2 (Th2). Conversely, antigens > 70 kDa cannot circulate through the narrow follicular conduits network and might be captured within the subcapsular sinus by the macrophages and dendritic follicular cells. Then, these cognate antigens are presented, via complement receptors, to the B cells that acquire and present them through the MHC-II to the specific naive CD4⁺ T cells, triggering the immune response Th1. The sustained infected cells lysis can overfeed high levels of unassembled viral proteins < 70 kDa, which can lead to a strong and persistent B cell receptor (BCR) activation, enhancing the Th2 immune response, releasing interleukin-10 (IL-10) and transforming growth factor-beta (TGF-β) that may lead to the immune paralysis, apoptosis, sepsis, and death. Finally, it is suggested that the polymerization of the viral antigens < 70 kDa into an antigenic polymer > 70 kDa could shift the immune response type from Th2 to Th1, developing the memory B cells and immunoglobulin G2 (IgG2) production, and avoiding the sepsis.

Treatment of sepsis currently relies on eliminating the causal pathogen and supportive care, whereas almost no approaches to interfere with the defining event of a “dysregulated host response” are available. This review points to the striking correlation of two phenotypes of sepsis etiopathology with the concept of bipartite response patterns of higher organisms to microbial attacks. According to this concept, the phenotypes of sepsis can be interpreted as either resistance or tolerance responses to infection that got out of hand. This concept might allow focusing sepsis research and related patient studies on key conundrums of current sepsis research: how do resistance responses result in immunopathology and how can tolerance lead to systemic immunosuppression or even immunoparalysis? The heuristic vigor of these questions might inspire experimental efforts and clinical studies and ultimately advance the therapeutic armamentarium for sepsis care.