Complex immune response to infection has been highlighted, more than ever, during the COVID-19 pandemic. This review explores the immunomodulatory treatment of moderate-to-severe forms of this viral sepsis in the context of specific immunopathogenesis. Our objective is to analyze in detail the existing strategies for the use of immunomodulators in COVID-19. Immunomodulating therapy is very challenging; there are still underpowered or, in other ways, insufficient studies with inconclusive or conflicting results regarding a rationale for adding a second immunomodulatory drug to dexamethasone. Bearing in mind that a “cytokine storm” is not present in the majority of COVID-19 patients, it is to be expected that the path to the adequate choice of a second immunomodulatory drug is paved with uncertainty. Anakinra, a recombinant human IL-1 receptor antagonist, is a good choice in this setting. Yet, the latest update of the COVID-19 Treatment Guidelines Panel (31 May 2022) claims that there is insufficient evidence to recommend either for or against the use of anakinra for the treatment of COVID-19. EMA’s human medicines committee recommended extending the indication of anakinra to include treatment of COVID-19 in adult patients only recently (17 December 2021). It is obvious that this is still a work in progress, with few ongoing clinical trials. With over 6 million deaths from COVID-19, this is the right time to speed up this process. Our conclusion is that, during the course of COVID-19, the immune response is changing from the early phase to the late phase in individual patients, so immunomodulating therapy should be guided by individual responses at different time points.

Immune cells and mediators play a crucial role in the critical care setting but are understudied. This review explores the concept of sepsis and/or injury-induced immunosuppression and immuno-inflammatory response in COVID-19 and reiterates the need for more accurate functional immunomonitoring of monocyte and neutrophil function in these critically ill patients. in addition, the feasibility of circulating and cell-surface immune biomarkers as predictors of infection and/or outcome in critically ill patients is explored. It is clear that, for critically ill, one size does not fit all and that immune phenotyping of critically ill patients may allow the development of a more personalized approach with tailored immunotherapy for the specific patient. In addition, at this point in time, caution is advised regarding the quality of evidence of some COVID-19 studies in the literature.

Intravascular volume replacement fluid therapy plays a pivotal role in the treatment of patients in circulatory shock. The interaction between various lines of therapy and immune response in critically ill septic patients remains a significant clinical challenge with no simple solution. Plasma expanders, crystalloids (such as physiological saline, balanced Ringer’s lactate, and Plasma-Lyte solution), and human albumin solution–the only acceptable colloid for critically ill patients–should be considered as necessary potent drugs with significant adverse effects. Sepsis is a very heterogeneous syndrome, with various magnitudes and persistence of inflammatory responses. Bearing in mind that the natural course of sepsis is highly complex, with phases of hyperinflammation and immuno-suppression often occurring simultaneously in different locations, it is almost impossible to avoid the adverse effects of crystalloids, which are first-line intravascular volume-replacement solutions. Large-volume replacement therapy or rapid intravenous fluid infusion may induce shedding or partial denudation of the endothelial glycocalyx, thereby propagating tissue injury, leukocyte and platelet adhesion and activation. A compromised glycocalyx leads to detrimental capillary leak syndrome in sepsis. In clinical practice, serum albumin levels may indicate the timing and need to administer intravenous human albumin solution during fluid resuscitation when substantial volumes of crystalloids are required. This is an example of a “glycoprotective” fluid approach, with lower volumes and slower crystalloid infusion rates. The complex interaction among fluid therapy, the endothelium, the glycocalyx, and immune mediators is pathophysiologically relevant and very important for clinicians in therapeutic approaches.