- The different immune states in COVID-19 are summarized.
- The possible pathophysiological mechanisms of different immune states are analyzed.
- A theoretical basis for the selection of immunotherapy strategies based on different immune states is provided.
At the end of 2019, Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-Cov-2) was found to be responsible for a cluster of patients with unknown pneumonia named subsequently as coronavirus disease 2019 (COVID-19) (1). On March 11, 2020, COVID-19 was declared a worldwide pandemic and soon swept over 235 countries, areas, and territories with more than 41 million confirmed cases up to October 22, 2020 (2, 3).
Similar to the severe acute respiratory syndrome (SARS) coronavirus (SARS-CoV) and the Middle East respiratory syndrome (MERS) coronavirus (4–6), SARS-CoV-2 is a highly pathogenic β-coronavirus virus in humans, with strong infectivity among individuals (1, 7, 8). SARS-CoV-2 and SARS-CoV have been shown to share the same binding receptor on host cells, which has been identified as angiotensin-converting enzyme-2 (ACE2) (9). Subsequent studies have revealed that SARS-CoV-2 cell entry depends on combination of the viral spike (S) protein with the ACE2 receptor on host cells, achieved with the assistance of the cellular serine protease transmembrane serine protease 2 (9–11). The exact further mechanisms by which SARS-CoV-2 invades host cells and causes a pathological state are still under investigation.
Patients with COVID-19 are characterized by fever and respiratory system manifestations including cough, dyspnea, and typical chest radiographs with pulmonary ground-glass opacification (12–14). Severe patients often experience respiratory failure, coagulation dysfunction, shock, and multiple organ dysfunction (15–17). In addition, a decrease in lymphocytes has been observed in the laboratory, suggesting an immunosuppression state (14–16, 18). On the other hand, the elevated level of inflammatory cytokines observed among patients with COVID-19 indicates a hyperinflammation state (16, 18). These studies demonstrate a paradoxical immunity status that complicates treatment of COVID-19 and causes a delay in recovery. Additionally, the relevant immunopathological mechanisms have yet not been completely determined, and effective immunological treatments for COVID-19 are still being explored. As a result, discussing the specific immunity status of COVID-19 patients and exploring proper treatments under various immune states is of great significance.
Critically ill patients with COVID-19 first go through a rapid period of inflammation in response to infection, followed by a period of coexistence of hyperinflammation and immunosuppression that eventually leads to multiple organ failures and even death. In this review, all available information about immune states of COVID-19 in severe patients and the underlying pathophysiological mechanisms will be presented and discussed. Moreover, we also look at the association between immune states and the development of disease as well as the impact on the selection of immunotherapy strategies.
IMMUNE STATES OF PATIENTS WITH COVID-19
A status of immunosuppression
Lymphocyte decrease and depletion
In the course of virus infection, both the innate and adaptive immune systems cooperatively take part in the antiviral response (19). As a vital part of the adaptive immune system, lymphocytes play an important role in clearance of the invading virus and provide effective protection of human health under the virus threat. Studies have shown that lymphopenia is a common feature in patients with COVID-19, with significant decreases in CD4+ T cells, CD8+ T cells, and B cells (14, 16, 18, 20, 21). Total T cell, CD8+ T cell, or CD4+ T cell counts have been found to be negatively correlated with patient survival (20). A similar conclusion was confirmed in another recent study demonstrating a positive correlation between lower counts of T lymphocyte subsets and in-hospital death from COVID-19 (22). An analysis of lymphocyte subgroups in hospitalized patients with COVID-19 indicated that SARS-CoV-2 primarily affects T lymphocytes, including helper T cells (CD3+ CD4+ cells), cytotoxic suppressor T cells (CD3+ CD8+ cells), and regulatory T cells (18). In severe cases, helper T cells and regulatory T cells have a more distinct decrease, along with an increase in the naive-to-memory T cell ratio (18). Differentiation of naive T cells into effector and memory T cells is regarded as the foundation of T cell-regulated immunity, and the balance between naive T cells and memory T cells has a profound impact on effective induction of the adaptive immune response (23, 24). Furthermore, CD4+ T cell counts have shown the most significant decrease in patients with severe disease compared with patients with mild symptoms (18). Another study demonstrated that a significant decrease in CD8+ T cells occurred in critically ill patients (25). Generally, both CD4+ T cells and CD8+ T cells are significantly reduced in severe cases, and larger studies are still needed to clarify which type of T cell SARS-CoV-2 mainly acts on. Moreover, interferon-&gamma (IFN-γ) secreted by CD4+ T cells, CD8+ T cells, and Natural Killer cells (NK cells) was expressed at lower levels in severe patients, suggesting a state of immunosuppression in patients with severe COVID-19 (26).
To investigate T cell dysfunction in the course of COVID-19, studies have also examined the exhaustion marker programmed death 1 (PD-1), an immune inhibitor responsible for delivering inhibitory signals after ligation with PD-1 ligands on activated T cells (27). The results demonstrated noticeably higher PD-1 expression on CD8+ and CD4+ T cells in COVID-19 cases, especially in critically ill cases, compared with healthy controls, indicating the presence of T cell dysfunction and exhaustion in COVID-19 (20).
A status of hyperinflammation
Neutrophils, a type of polymorphonuclear leukocyte, are typically the first to be recruited and to engage in the acute inflammation caused by invading pathogens (28, 29). Apart from lymphopenia, studies have also shown an increase in neutrophils in patients with COVID-19 (18, 25). Neutrophil infiltration was observed in autopsy samples from patients with COVID-19 (30–32). Furthermore, neutrophilia has been confirmed to be associated with poor outcomes of patients with COVID-19 (12). The neutrophil-to-lymphocyte ratio (NLR) index is an inflammation biomarker of infection and has been verified to be of great significance in bacterial pneumonia and sepsis (33, 34). Relatively, the NLR is also suggested to be an independent risk factor for severe patients and the most powerful prognostic factor for COVID-19, with the ability to predict COVID-19 severity and outcome (25, 35–37). A previous study demonstrated that neutrophils play a key role in the release of inflammatory mediators and the regulation of cytokines in patients with influenza, suggesting that a significant increase in neutrophil number is closely related to the occurrence of cytokine storms (38). Correspondingly, an elevation in neutrophils and white blood cells is thought to enhance cytokine release and promote cytokine storms in patients with COVID-19 (12).
To protect the body from an invading virus, immune cells are recruited and release cytokines that activate more immune cells through positive feedback loops, thereby inducing the release of more pro-inflammatory cytokines (39, 40). Remarkably cytokine production has been observed in response to SARS-CoV-2 infection, including IL-1β, IL-1RA, IL-2, IL-6, IL-8, monocyte chemotactic protein-1 (MCP-1), granulocyte-colony stimulating factor, and TNF-α (16, 18). Particularly, plasma concentrations of IL-2, IL-6, IL-8, and TNF-α have been found to be significantly elevated in patients with severe disease in comparison with patients with mild or moderate disease (18, 20). Cytokine levels are found positively correlated with disease severity and are supposed to be useful predictors for COVID-19 severity (16, 21, 41). A recent study also reported that an increased serum IL-6 level is closely correlated with a larger area of pulmonary infiltration in computed tomography scan images (42). In addition, during SARS-CoV-2 infection, severe cases are usually characterized by the inevitable development of a cytokine storm into acute respiratory distress syndrome (ARDS) (16, 43), and respiratory failure due to ARDS is considered the leading cause of death from COVID-19 (44). Innate immunity is known to be on the front line of defense against virus invasion and to restrain viral replication, but sometimes, it may turn out to be more harmful than helpful.
Endothelial dysfunction and altered coagulation
ACE2 receptor is reported to be widely expressed on endothelial cells of multiple organs throughout the body (45). Viral inclusion structures found in endothelial cells and accumulation of inflammatory cells around endothelium of deceased patients with COVID-19 revealed that SARS-CoV-2 could directly infect endothelial cells and promote the occurrence of endotheliitis (46). One typical characteristic of COVID-19 is the strong activation of coagulation system, manifested by a significant increase in D-dimer and the development of disseminated intravascular coagulation (DIC) (47, 48). This altered coagulation biology is thought to be associated with endothelial dysfunction. In response to infection, inflammatory cytokines facilitate blood clotting by damaging the endothelial cell-mediated anticoagulative pathways including protein C system and tissue factor pathway inhibitor (49). IL-1β and TNF accelerate the initiation of coagulation by promoting the expression of P-selectin, von Willebrand factor, and fibrinogen by endothelial cells (50). In addition, it has been reported in SARS infection that autoantibodies against endothelial cells could mediate complement-dependent cytotoxicity (51). This development also occurs in COVID-19 and conduces to endothelial dysfunction and abnormal activation of coagulation (52). Studies proved that disruption of endothelial barrier integrity and strongly activated coagulation contribute a lot to the development and aggravation of ARDS in COVID-19 (46, 53).
MECHANISM OF IMMUNE DISORDERS
Mechanisms of immunosuppression
Up to now, the cause and underlying mechanisms of lymphopenia are still under study. It might result from a direct viral attack of SARS-CoV-2 or be a consequence of redistribution by chemokines and apoptosis. Through quantitative transcriptome analysis of bronchoalveolar lavage fluid and peripheral blood mononuclear cells from patients with COVID-19, one study has shown that genes associated with apoptosis are significantly increased, including Cathepsin L, Cathepsin B, DNA damage inducible transcript 4, RRAS, Cathepsin D, Baculoviral IAP repeat containing 5, tumor protein P53 inducible protein 3, and so on (54). In addition, as an important part of the P53 signaling pathway and the apoptosis process, the P53 gene has been found to be overexpressed in COVID-19 patients (54). These results indicate that the occurrence of lymphopenia might be caused by apoptosis. Although ACE2 is absent in lymphocytes, evidence from a recent study demonstrated that SARS-CoV-2 could contaminate T cells through combination of S protein with an unknown receptor on T cells, suggesting that the apoptosis of T cells may be due to direct attack by SAR-CoV-2 (9, 54–56) (Fig. 1). Moreover, TNF-α has been shown to be able to promote T cell apoptosis (57, 58), and elevated Il-2 levels in local environments with high antigen level can mediate T cell apoptosis by promoting Fas signaling (59–61) (Fig. 1). Therefore, increased cytokine levels might mediate T cell apoptosis in COVID-19, which may also explain the negative correlation between cytokine levels and lymphocyte counts discovered in other studies (20, 25, 62, 63). Furthermore, as demonstrated in previous studies on SARS-CoV, an increase in cytokines such as IL-6 and IL-8 tends to weaken the ability of T cells to activate dendritic cells, resulting in an inability of the immune system to accomplish an effective adaptive immune response (64).
In addition, studies showed that emergency myelopoiesis might also be involved in the mechanisms of lymphopenia and immunosuppression in COVID-19. The emergency myelopoiesis is characterized by release of plenty of immature and dysfunctional myeloid cells which are termed myeloid-derived suppressor cells (MDSC) (65, 66). The onset of emergency myelopoiesis is thought to be primarily caused by prolonged and persistent inflammatory stimuli including granulocyte-macrophage colony stimulating factor, S100A8, S100A9, IL-1β, IL-4, IL-6, TNF-α, etc (67, 68). Generally, MDSCs are detected and discussed in cancer and recently in some infectious diseases, found to be associated with the immunosuppression of T cells through inhibition of T cell proliferation and promotion of lymphocytic apoptosis (69–75). These immunosuppressive activities of MDSC are reported to be carried out by the close cell–cell contact with T cells as well as increased expression of Arginase 1 and inducible nitric oxide synthase (76–80). Similarly, emergency myelopoiesis has also been observed in COVID-19 presented as an increase in immature neutrophils expressing PD-L1, indicating a potential immunosuppressive effect of MDSC on lymphocytes (81–87). It is important to note that this pathological process occurs only in severe patients with COVID-19; therefore, the long duration of inflammatory stimuli in severe patients contributes a lot to the occurrence of emergency myelopoiesis, leading to a state of immunosuppression.
Mechanisms of hyperinflammation
A significant increase in neutrophils was observed at illness onset in severe COVID-19 patients compared with those with mild illness, which indicates an early activated innate immune response to SARS-CoV-2 and explains the increased cytokine levels in the early phase of disease (25).
However, neutrophil counts are back to normal within a few days, whereas cytokines are continuously elevated throughout the disease (25). There could be several reasons for the continuous inflammatory response in the late stage of the disease. Studies have shown that in severe cases of COVID-19, CD4+ T cells differentiate into pathogenic type 1 T helper cells, which can generate cytokines, such as granulocyte-macrophage colony stimulating factor, followed by activated CD14+CD16+ monocytes that highly express IL-6 and promote systemic inflammation (88). Another study confirmed a higher percentage of CD14+ monocytes accompanied by amplified expression of proinflammatory cytokines such as IL-1β in patients in the early stage of COVID-19 recovery (89). The overactivated inflammatory responses conducted by pathogenic T helper cells and CD14+ monocytes could result in immune impairment with pathological lung injury and high mortality (88). Consistent with this, postmortem studies have confirmed that the exudative cells in the alveolar cavity mainly comprised monocytes and macrophages (31). On the other hand, previous studies have shown that the presence of T cells can inhibit inflammatory cytokine overexpression by blocking activation of antigen-presenting cells, such as NK cells, and therefore, a lack of normal functional T cells could lead to an overreaction of the innate immune system in response to viral stimulation, which would present as a cytokine storm (62, 63). As stated previously, T cell apoptosis might be the predominant contributor to lymphopenia in COVID-19. However, lymphocyte apoptosis could also release cytokines in bulk. Different from cytokines involved in the innate immune response to virus infection, apoptosis-associated cytokines are always characterized as IL-1β and IL-18, which can enhance the inflammatory response through mediation of immune cell maturation and pro-inflammatory signaling, such as the NF-κB signaling pathway (90–93). Furthermore, increases in White blood cells and neutrophils are observed in some cases at the end stage of COVID-19 infection, which might indicate a secondary infection caused by microbes and contribute to aggravated systemic inflammation and mortality (12, 25). Clinical trials have reported that secondary infection can occur in 5% to 27% of patients with COVID-19, 50% to 100% of whom died (47, 94, 95). Most secondary infections are caused by fungi or bacteria and are characterized by a significant increase in White blood cells, which is not very common in COVID-19, whereas either bacterial or viral infection can lead to cytokine storms (96, 97).
Some scientists have considered the cytokine storms observed in COVID-19 patients as macrophage activation syndrome (MAS) or secondary hemophagocytic lymphohistocytosis (sHLH) (44). sHLH is primarily triggered by viral infection and is an underrecognized hyperinflammation syndrome characterized by explosive inflammatory responses and multiple organ failure (98). Common features shared by COVID-19 and sHLH include fever, hyperferritinemia, excessive inflammation, and primary pulmonary involvement (14, 98–100). Markedly elevated C-reactive protein and cytokines like IL-6, TNF are reported in COVID-19, which resembles MAS (101, 102). As a result, studies have speculated whether the inflammatory responses in COVID-19 are actually caused by overactivation of macrophages mediated by antibody-dependent enhancement (ADE), especially in the lungs (103). When antibodies produced by immune cells cannot fully neutralize the virus, virus–antibody complexes can bind to Fc receptors or other receptors on host cells and assist virus invasion, which is called antibody-dependent enhancement (104). Binding of the complex to macrophages can promote pro-inflammatory polarization of macrophages, contributing to the production and release of cytokines and resulting in tissue damage (103). ADE-mediated hyperinflammation through skewing of macrophages has been confirmed in SARS, indicating that ADE might play the same role in COVID-19 (105).
In short, the bulk production of cytokines and neutrophilia in the early phase of COVID-19 is thought to be associated with an activated innate immune response directly due to viral infection, while a continuous hyperinflammation status in the late stage of disease might be caused by several possible mechanisms, including pathogenic activation of immune cells, suppression of adaptive immune response, T cell apoptosis, secondary infection, and the occurrence of ADE. (Fig. 1) To further understand the underlying mechanisms of hyperinflammation in COVID-19, more investigations are required.
DEVELOPMENT AND SEVERITY OF COVID-19
The increase in neutrophil and cytokine levels might reflect the intensity of the inflammatory response, whereas the reduction in lymphocytes might reflect the disruption of the immune system caused by viral infection (25).
As stated above, neutrophil levels increase early in the course of COVID-19, accompanied by increased cytokine levels (25). A previous study showed that a change in serum IL-6 levels is an antecedent to falling CD4+ and CD8+ T cell counts and can be considered an early biomarker of COVID-19, indicating that robust cytokine production precedes the occurrence of lymphocyte apoptosis (42). In addition, the expression of the exhaustion marker PD-1 and of T cell Ig- and mucin-domain-containing molecule-3 (TIM-3) was found to be extremely low in the prodromal stage of COVID-19 and to increase progressively in the overtly systemic and ICU-hospitalized stages, suggesting a developing immunosuppression status in patients with COVID-19 (20).
Consequently, in the early phase of COVID-19, the innate immune system is rapidly activated and produces large amounts of cytokines, followed by the release of MDSC. Subsequently, inhibition of T cell proliferation and massive apoptosis of lymphocytes occur, leading to an immunosuppression state in the late stage of disease. As a result of the several underlying mechanisms stated above, the innate immune system remains overactivated, with uncontrolled production and release of cytokines, causing extraordinary inflammatory damage and resulting in multiple organ failure (Fig. 2).
Given the immune disorders presented in sepsis patients, the immunopathological characteristics between sepsis and COVID-19 can be compared. Effective immune responses to both infection types are activated in the early stages of disease, manifested as elevated pro-inflammatory cytokine levels (106). Resembling COVID-19, hyperinflammation and immunosuppression are thought to coexist in the late stage of sepsis (107). Endothelial dysfunction and excessively activated coagulation as a result of inflammation are observed in sepsis and culminate in the occurrence of DIC (49). In addition, lymphocyte depletion and MDSCs release are both detected in sepsis, contributing to immune suppression (107, 108). Therefore, sepsis and severe COVID-19 share similar immunologic features. What's more, the clinical manifestations of COVID-19 coincide with the diagnosis of sepsis, which is defined as life-threatening organ dysfunction caused by a dysregulated host response to infection according to the Sepsis-3 International Consensus (109, 110). Thus we could also refer to COVID-19 as viral sepsis.
The disease severity of COVID-19 predominantly depends on viral load and host immunity, which is closely associated with age, gender and pre-existing comorbidities. Studies have found a positive correlation between detectable serum SARS-CoV-2 RNA (RNAaemia) and high levels of IL-6, which portends a poor prognosis (111). In addition, the SARS-CoV-2 viral load detected in the respiratory tract of patients is closely correlated with cytokine levels and NTR, effectively predicting the severity of disease (112, 113). Some studies have found that males account for more of the severe cases than females (12, 16, 114, 115). The reduced susceptibility of women to viral infection can be attributed to sex hormones, which play an important role in body defenses conducted by the innate and adaptive immune systems (116, 117). In addition, ACE2 expression and distribution have been found to be more widespread in male patients, which might also explain the difference in susceptibility between sexes (118). Elderly patients and patients with preexisting disease are more likely to develop severe cases and suffer from a significantly higher mortality (12, 16, 113). Male sex, advanced age, and accompanying hypertension have been found to be correlated with prolonged viral RNA shedding. Moreover, T cell levels are lower in elderly patients with COVID-19 in an age-dependent manner, suggesting increased susceptibility and a weaker adaptive immune response to SARS-CoV-2 in the elderly (20, 119).
On the whole, in the course of COVID-19, patients with a weak immune response or infected with higher viral loads may be unable to efficiently remove the virus and are more likely to progress to aggravated lymphopenia and sustained inflammation. (Fig. 2)
Convalescent plasma (CP), recognized as a passive immunotherapeutic strategy, contains plenty of antibodies, ant-inflammatory cytokines, and other beneficial molecules. CP therapy is thought to ameliorate infectious disease through virus neutralization and regulation of the inflammatory response (120). Recognized risks of CP therapy include inadvertent infection and possible reactions to plasma components (121). ADE is regarded as a potential risk of CP therapy since some antibodies could facilitate virus entry and enhance viral infection through secondary combination with Fc fragment of immunoglobulin G receptors on immune cells (122–124). Data have shown that CP administration can reduce the mortality of SARS and influenza compared with placebo or no therapy (125, 126). Improved clinical outcomes after CP therapy have also been recently observed in patients with COVID-19, along with increased lymphocyte counts and reduced viral load (127, 128). Despite the small sample sizes, these positive results suggest the potential therapeutic effect and safety of CP therapy in treatment of COVID-19. Further multicentral studies with more patients are still required to determine the specific role of CP therapy in COVID-19.
Intravenous immunoglobulin (IVIg)
Intravenous immunoglobulin is a blood product consisting of polyclonal immunoglobulin G derived from the plasma of healthy donors. IVIg can provide passive immune protection against many pathogens and is mainly used for severe infections, especially patients with primary or secondary immunosuppression (129, 130). A previous study confirmed that IVIg can effectively neutralize pathogens and improve host defense during infection (131). Recent studies evaluated the efficacy of intravenous immunoglobulin and showed that the administration of IVIg in the treatment of critically ill patients with COVID-19 can significantly reduce the mortality and time of hospitalization, returning temperatures back to normal and alleviating breathing difficulties (132, 133). Although IVIg treatment is expensive, it is a recommended therapeutic option for early serum conversion.
Corticosteroids are widely used to treat severe community-acquired pneumonia and sepsis due to the immunosuppressive effects of corticosteroids on dysfunctional systemic inflammation (134, 135). However, the effects of corticosteroids in SARS-CoV-2 infection remain controversial. Studies on SARS and MERS indicated that systemic corticosteroid therapy could account for delayed viral clearance and an increase in plasma viral load (136, 137). Studies on COVID-19 showed similar findings (119). Moreover, corticosteroid treatment tends to aggravate lung injury and showed no survival advantage even with the increased mortality of COVID-19 (138–140). On the other hand, some studies revealed that steroids may play a beneficial role in severe COVID-19. A small clinical trial has reported decreased risk of admission to ICU or requirement of noninvasive ventilation or death in severe patients treated with methylprednisolone (141). Afterward, results from a large-scale randomized controlled trial demonstrate that administration of dexamethasone is associated with lower 28-day mortality among severe patients with COVID-19 (142). Similar results were observed by a meta-analysis conducted by the World Health Organization whereas a recent randomized trial showed no significant difference between severe patients treated with low-dose hydrocortisone and placebo (143, 144). Consequently, further researches are still needed to clarify the effects of steroids.
As significant increases in cytokines have been observed in COVID-19, cytokine antagonists may play a positive role in the treatment of the disease. Tocilizumab, an IL-6 inhibitor, has been found to improve clinical outcomes and reduce mortality in severe and critically ill patients with COVID-19, with no adverse reactions observed (145). Similar results were shown in an another study, indicating that tocilizumab could be a safe option for patients with severe COVID-19 (146). Subsequently, tocilizumab was included in the guidelines for COVID-19 treatments in China and Italy (147, 148). In the Chinese guidelines, treatment with tocilizumab can be attempted for severe patients with extensive and bilateral lung disease and increased IL-6 levels (147). In the Italian guidelines, tocilizumab is only allowed at the end of the initial phase for severe patients with a high viral load, rapid deterioration of respiratory exchange, and high levels of Il-6 or D-dimer/C-reactive protein/ferritin/fibrinogen (148). However, a recent study showed no significant differences in ICU admission or mortality rate between the tocilizumab group and SOC (a combination of hydroxychloroquine, azithromycin and a prophylactic dose of low-weight heparin) group (149). Therefore, more data are still needed to evaluate the therapeutic effects of tocilizumab in COVID-19 and to further identify the optimal dose and timing of tocilizumab treatment.
Anakinra, a well-known IL-1 receptor antagonist, has been demonstrated to improve the survival of septic patients with MAS while showing no obvious adverse events (150). Similarly, in recent studies of COVID-19, rapidly resolved systemic inflammation and highly improved respiratory functions have been observed in patients treated with anakinra, especially in patients with sHLH, suggesting the safety and possible therapeutic effect of anakinra (151, 152). However, additional randomized controlled clinical trials are indispensable to verify the treatment effect and determine adverse reactions.
Baricitinib, a selective JAK inhibitor, is now widely approved for inflammatory and autoimmune diseases as a result of its effects on restraining systemic inflammatory responses and alleviating cytokine storms by hindering the Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway, which is associated with several cytokine signals (153, 154). In addition, by inhibiting viral entry and impairing viral endocytosis, baricitinib has been found to have potential antiviral bioactivity (155, 156). Therefore, baricitinib might be a therapeutic option for COVID-19. Results from a recent study showed that patients treated with baricitinib achieved significant improvements in clinical parameters and reduced ICU admissions, with no adverse events (157). More clinical trials of baricitinib are in progress with the aim of clarifying its therapeutic effects.
Mesenchymal stem cells (MSCs)
MSCs are hemopoietic cells derived from certain tissues, such as bone marrow, adipose tissue, the lungs, and placenta. MSCs act as immunoregulators by moderating immune responses through direct interactions with a series of immune cells, including lymphocytes, natural killer cells, dendritic cells, macrophages, and neutrophils (158). MSCs contribute to restricting immune cell activity and elevating expression of anti-inflammatory factors (159). MSCs have been approved for the treatment of autoimmune disease and ARDS and have been shown to effectively control inflammation (160, 161). Therefore, MSCs may also be a good therapeutic option for treatments of COVID-19. A recent pilot study of MSC transplantation indicated that MSC treatments can significantly improve the clinical outcomes of patients with COVID-19 (162). Considering that high anti-inflammatory factor expression has been detected in MSCs, remarkably decreased levels of pro-inflammatory cytokines and increases in lymphocytes have been observed in patients after treatment with MSCs (162). All these results suggest that MSCs might have powerful therapeutic effects in COVID-19. Furthermore, the absence of ACE2 and transmembrane serine protease 2 on MSCs confirmed through RNA-seq analysis assures the safety and effectiveness of MSC therapy for SARS-CoV-2 infection (162).
SELECTION OF IMMUNOTHERAPY STRATEGIES
With the number of patients rapidly increasing, unprecedented pressure is placed on the healthcare system. Because there is currently no vaccine or specifically effective drug against SARS-CoV-2, timely and efficient therapeutic strategies to avoid the deterioration of disease condition have become a top priority.
Based on the theoretical assumptions and assessments presented above, we recommend early use of immunoenhancement therapy, such as CP and IVIg treatments, with COVID-19 patients at illness onset, with the purpose of assisting the immune system in timely removal of the virus and mediating immune responses. Observational studies on other infectious diseases have identified the early therapeutic effects of CP, whereas CP therapy administered in mid-stage or late-stage infection showed no benefits (163, 164) (Fig. 3).
Conversely, due to possible effects of immunosuppressive therapy on the host virus clearance, premature use of cytokine inhibitors and JAK inhibitors is considered inadvisable, with the possibility of aggravating immune system impairment and increasing the risk of infections that lead to deterioration of disease condition. Thus, the time for immunosuppressive therapy should be at the end of the early stage, when the viral load has possibly decreased and patients are in a state of excessive inflammation. Accordingly, SARS-CoV-2 persists in patients for at least 10 days after illness onset, indicating that the optimal time for immunosuppressive treatment might be approximately 7 days after appearance of the initial symptoms (165, 166). The use of immunosuppressive therapy at this time point can help intervene early in the inflammatory responses and prevent lethal, irreversible, immune-mediated injuries, and the development of ARDS or multiple organ failure (Fig. 3).
Because MSCs have the potential to elevate lymphocytes while suppressing inflammation and IVIg may be able to reduce inflammatory responses, MSCs and IVIg can also be used in the later stage of COVID-19, when immunosuppression and hyperinflammation coexist (162, 167) (Fig. 3). As for the use of steroids, the optimal dose and duration of treatment still remain controversial because two recent randomized controlled trials come to opposite results (141, 144). More trials are needed to estimate the effect of steroids.
Recommended immunotherapy strategies are shown in Figure 3. Our recommendations are provided in general, and the status of each individual should be assessed carefully before administering immunotherapy.
In severe patients with COVID-19, innate immune responses are rapidly initiated on the front line of resistance to viral infection, manifested by increase and recruitment of neutrophils, massive production of inflammatory cytokines, endothelial injury, and aberrant coagulation. Attributed to the persistent viral attack and sustained excessive inflammation, the adaptive immune responses are impaired presented as lymphocyte apoptosis and dysfunction. In the struggle against SARS-CoV-2, the immune system fails to reach homeostasis and comes to a state in which hyperinflammation and immunosuppression coexist. As for the selection of immunotherapy, early use of immunoenhancement therapy including CP, IVIg treatments are thought to be beneficial whereas immunosuppressive therapy like cytokine inhibitors is supposed to be applied during the window phase of viral load reduction.
The authors acknowledge all participants involved in this work.
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