CRP is an acute-phase protein secreted by hepatocytes in the presence of pro-inflammatory cytokines (27). Under steady-state, the blood concentration of this acute-phase protein is less than 10 mg/L. In the presence of an infection, levels increase within 6-8 hours, peak at around 24-48 hours post-infection, and then rapidly return to normal levels within 4-9 hours (28). The relatively low levels of CRP during viral infections compared to bacterial infections may be described by the inhibitory role of IFN-α (29).

COVID-19 patients with a higher serum level of CRP at admission (3-5 days post-SARS-CoV-2 infection when symptoms appear), which continues for 2-3 weeks, have an additional risk for poor prognosis. Whereas a decrease in serum level of this protein on the third week, following a gentle increase during the first and second weeks post-symptom onset, correlates with good disease outcomes (30). Higher CRP levels at admission have been reported in COVID-19 patients with more severe symptoms (24, 31). Also, a positive correlation between serum levels of it at admission and chest CT progression has been detected in recent studies (24, 32–34). Han et al. have indicated the optimal cut-off point of CRP at admission is 3.38 mg/L, which may be applicable to predict COVID-19 outcomes (33).

Since patients with trauma are referred to trauma centers approximately 1-4 hours after injury, CRP levels at admission have not correlated with poor outcomes post-trauma (35, 36). It typically increases within 6-12 hours, reaching a peak after 24-72 hours (37). This increase is on days 1 to 3 after admission, which continues for the following days, and is associated with poor outcomes (38). Whereas a decrease in this protein after a temporary increase at the time of admission is correlated with good prognosis (38). Previous studies have shown a correlation of CRP serum levels within 24 to 72 hour period post-trauma with severe infectious complications (37, 39). Therefore, a cut-off point ≥154.4 mg/L of during 24-48 hours post-trauma, could help predict post-trauma infection complications (39).

PCT is a 16-amino acid peptide that is normally produced by thyroid parafollicular cells and is released by mucosal neuroendocrine cells in response to pro-inflammatory cytokines. The normal serum level of it in healthy individuals is less than 0.05 ng/mL. In inflammatory conditions it begins to increase within 4 to 12 hours, reaching up to a 1000-fold increase within 12 to 24 hours, with a decrease after 24 hours. Secondary elevation of PCT might be observed after 72 hours, depending on the severity of inflammation (40, 41). The short half-life of procalcitonin (24-30 hours) in peripheral blood makes it an ideal candidate to predict the prognosis of inflammatory disease outcomes like bacterial infections (42).

Several studies have clarified that in viral infections, such as SARS-CoV-2, the mean serum level of PCT is <0.5 μg/L (43–45). However, 15-25% of COVID-19 patients with poor outcomes have a mean serum PCT level ≥0.5 μg/L at admission (7, 46, 47). A positive correlation has been reported between serum levels of this protein at admission and severity of COVID-19 (48). The serum levels >0.5 µg/L at admission might be considered as an optimal cut-off value for the assessment of adverse outcomes (49, 50). Kinetically, serum PCT levels >0.5 µg/L at admission that continue until days 9-11 are associated with secondary elevation of it and a 5-fold increased risk of critical bacterial co-infection for COVID-19 patients. It appears that the relationship between elevated PCT sera and poor prognosis in COVID-19 is due to common bacterial co-infections (7, 46, 47).

Increased serum levels of PCT have also been reported as a poor prognostic indicator in trauma patients in at least two-time points (51, 52). The significance of the first elevation of this protein within 4 to 48 hours of trauma, is related to the magnitude of tissue injury and is a poor prognostic indicator for early complications such as SIRS, CARS, and persistent inflammation, immunosuppression, and catabolism syndrome (PICS). There is no significant increase during the period of 4 to 48 hours after mild trauma (52, 53). The second elevation of serum PCT levels within 3 to 7 days post-injury can be attributed to opportunistic bacterial infections and sepsis due to a compromised immune system and early CARS and PICS in severe trauma. Infection-induced SIRS, CARS, and PICS have stronger correlations with poor prognostic outcomes of trauma compared to trauma-induced types (38, 54, 55). These results have been observed in both survivor and non-survivors cases following traumatic injuries, respectively (56).

Ferritin is a 480-kD iron storage protein in hepatocytes and reticuloendothelial cells, which has a very low level in blood circulation. Ferritin plays an important role in cellular antioxidant defense mechanisms by sequestering free cytosolic iron rapidly (57). Increased ferritin serum level is an indicator of many inflammatory conditions, including acute infections and injuries (58). It is also the hallmark of macrophage activation syndrome, adult-onset Still’s disease, and septic shock (59, 60). Possible mechanisms increasing this protein in serum, include 1) A consequence of cell lysis, which ferritin releases from intracellular storages; 2) A reflection of inflammatory response intensity, where ferritin is produced under the effect of inflammatory cytokines such as IL-6, IL-8 and TNF-α (57, 61); and 3) A protective response in oxidative stress to sequestrate free iron (62).

One study evaluating ferritin serum levels on admission showed an increase of this protein in patients with non-severe COVID-19, within a normal range (63), however, another study identified an abnormal elevation of serum ferritin among patients with critical-to-severe COVID-19 (57). Elevation of serum ferritin level starts on the first day after infection (57) and could be considered as an indicator of poor COVID-19 prognosis. Two independent studies reported that serum levels of ferritin and IL-6 are increased in patients with severe COVID-19 and decreased in recovered cases (45, 64). These studies suggest that macrophage activation along with increased serum levels of inflammatory cytokines such as IL-6 might be contributing to an increasing ferritin serum level in COVID-19 patients. Ferritin, in turn, might promote oxidative stress, the secretion of IL-1β and IL-10, as well as, macrophage activity (57).

Similar to COVID-19, serum ferritin level at admission may be a predictor of trauma outcomes. Some studies have reported that serum levels of this storage protein depend on trauma severity, as assessed by the injury severity score (ISS) (65, 66). High serum levels of ferritin at admission are associated with poor prognosis in patients with trauma (66). Sharkey et al. showed that a serum level >270 ng/ml of ferritin for women and a level >680 ng/ml for men at admission are associated with the development of progressive complications in trauma patients (66). Meanwhile, results from another study indicated a positive correlation between serum ferritin levels during days 1 to 2 post-trauma with poor prognosis in ICU (65–68).

SSA is a multifunctional protein involved in metabolic and immunological responses and is produced as an acute-phase protein during inflammation (69). Under inflammatory conditions, SAA is changed in kinetic patterns similar to PCT. In normal level, it binds to high-density lipoproteins (HDL) to recycle cholesterol in the cell membranes and repair damaged tissue, whereas high concentrations of SAA promote gene expression of inflammatory cytokines, immune cell recruitment, low-density lipoproteins (LDL) oxidation, reactive oxygen species (ROS) generation, and the survival time of neutrophils (70, 71). Moreover, SAA is a precursor of amyloid A protein (AA), an insoluble and fibrillar protein, which causes secondary amyloidosis and increases the risk of organ failure and early death (72). Overall, high rates of SAA stimulate the inflammatory process in inflammatory conditions and might be a poor prognostic sign for inflammatory diseases.

Studies have identified significantly higher concentrations of SAA at the time of admission in patients with severe COVID-19, compared with healthy controls (30, 73, 74). A study by Fu et al. revealed that serum levels>157.9 mg/L of this protein at admission can be an appropriate cut-off point to predict the severity of COVID−19 (73). Thus, the level of the SAA at admission is associated with the incidence of poor outcomes in COVID-19 patients (30, 73, 74).

Serum levels of Amyloid A (AA) during 6 to 24 hours post-trauma have been suggested as a prognostic indicator to predict poor outcomes in patients (75, 76). Another study showed a positive association between severity of injuries and increased AA concentrations in blood circulation after trauma (77). Most data about the association between SAA levels and severity of injuries are related to traumatic brain injury (TBI) patients (78, 79). Additionally, Carabias et al. have shown that both patients with moderate-to-severe and mild TBI have higher SAA levels compared to healthy controls (75).

Overall, the dynamic changes in serum levels of inflammatory mediators are shown to have an association with prognosis in patients with COVID-19 and trauma ( Figure 1 ).

Type I (especially IFN‐α and IFN‐β) and type II (IFN-γ) IFNs are major members of a big family of cytokines, which are important in protecting against pathogens and tumor cells (93). Type I IFNs, as cytokines of the innate immunity, are produced by virus-infected cells and myeloid dendritic cells. They are at the forefront of defense against viral infections via inducing interferon-stimulated genes (ISGs) (94). Whereas, type II IFN is a critical cytokine for both innate and adaptive immunity and plays the major role as an activator of mononuclear cells to stimulate the effector function of cytotoxic T lymphocyte (CTL) and natural killer (NK) cells (95, 96). IFN-α and IFN-β are similar in anti-viral activities, whereas IFN-β appears with greater anti-proliferative and apoptotic effects (97). IFN-β-induced transcriptions are reduced over a longer period compared with IFN-α (97), which indicates the effectiveness of IFN-β in chronic viral infections (98). Although IFNs are the key players in driving anti-viral and anti-proliferative responses, they are also involved in orchestrating the inflammatory condition (99). Kinetic irregularities of IFN-α/β and IFN-γ are associated with poor prognosis in viral and inflammatory diseases (99).

Increased levels of IFN-α 8 to 10 days after the onset of COVID-19 symptoms, and a decrease after day 10, are related to good prognosis. Whereas an opposite pattern appears with a lack of infection control and advanced symptoms (82). IFN-β (both -β1a and -β1b) could facilitate early phase virus clearance (the first 14 days) and improve the survival rate by increasing endothelial barrier activity and anti-inflammatory mediators. It is also likely that IFN-β leads to adverse complications in the late phases (the second 14 days) by promoting inflammation (83–85). Type I IFNs predict positive results in the improvement of SARS-CoV-induced complications in the early phases (100), whereas a high level of IFN-γ at admission that persists in the following days can lead to poor outcomes in COVID-19 patients (87). Only one study has shown IFN-γ serum levels significantly decreased in patients with severe COVID-19 in comparison to cases with moderate symptoms, which is likely due to a decrease in IFN-γ producing lymphocytes (100). Other studies have shown higher serum levels of IFN-γ in patients with severe symptoms (7, 101). Moreover, an increase in serum concentration of this cytokine at days 4 to 6 after the onset of disease symptoms, which decreases over the next few days, is associated with good prognosis (88). It appears a high expression of IFN-γ at admission, which continues for 3 to 4 weeks, could cause negative consequences due to over-activity in the immune system, inducing ACE2 expression (the binding site for SARS-CoV-2) and promoting virus replication (87). Anti-IFN-I autoantibodies have recently been detected in COVID-19 and are associated with poor prognosis of the disease. Bastard et al. have shown at least one type of anti-IFN-I autoantibodies were detectable in 13.7% of patients with life-threatening COVID-19 pneumonia, of which 10.2% of patients had autoantibody against IFN-α (3.6%), IFN-ω (1.3%), or both (5.3%), at the onset of critical disease (102, 103). Anti-IFN-I autoantibodies were higher in males compared to females. Whereas they were found in none of the patients with asymptomatic or mild COVID-19 and were only detectable in 0.3% of healthy individuals aged 20 to 65 years (102). Remarkably, the production of anti-IFN-I autoantibodies is related to the late phase of COVID-19 (104). In the first two weeks post-infection, it is unlikely that the immune tolerance to IFN-I is lost and high titers of autoantibodies are produced (102). This suggests congenital errors of type I IFN production and function. IFN-β therapy may be effective in COVID-19 patients who have anti-IFN-I autoantibodies because auto-IFN-β antibodies are rarely produced.

IFN-α/β and IFN-γ can be prognostic indicators in trauma patients, as they change during the 7 days post- trauma. Levels elevate sharply after severe trauma in two steps; early elevations of IFN-α/β and IFN-γ can be seen 24-72 hours after severe trauma and are correlated to early complications, whereas secondary elevations of IFN-α/β and IFN-γ after 7 days can be an index for opportunistic bacterial infections and sepsis, which are associated with late complications of severe trauma (86). High concentrations of IFN-α/β, IFN-γ, and other pro-inflammatory cytokines in severe trauma, are not only associated with systemic inflammation and tissue destruction in the early phase (the first 14 days), but are also correlated with high levels of anti-inflammatory immune responses in the late phase (the second 14 days). This causes immune deficiency and increases the probability of opportunistic infections (105, 106).

IL-1α and -1β are central cytokines of innate immunity, which are produced by hematopoietic, endothelial, and epithelial cells (107). IL-1α increases immune cells migration (108), local and systemic production of inflammatory mediators (109), and lymphocytes proliferation and activation (109). Whereas IL-1β is considered as an effective cytokine on severe complications of inflammatory diseases (25, 110). Even though IL-1β requires processing by inflammasomes for activity, IL-1α can be active in its full-length form without previous processing (25, 111).

Among COVID-19 patients, one study showed no association between IL-1α/β serum levels and disease severity (112). In contrast, other studies have revealed higher levels of IL-1α/β at admission in severe and non-survivor patients compared to mild and survivor cases (7, 101). Serum levels of IL-1β in patients with severe symptoms are approximately 2–100 times above normal levels (113). These conflicting findings may be due to a highly dynamic expression of inflammatory mediator genes in COVID-19 patients. It is likely that different sampling times during the disease course could be a reason for the observed discrepancies among studies. A case-series study in patients with critical-to-severe COVID-19 has shown that most inflammatory genes reach their highest expression levels after the lowest respiratory system function (days 5 post-disease onset) (90). This is in contrast to the role of the CS hypothesis in the pathogenesis of COVID-19. The only expression of IL-1α, IL-1β, IL1 receptor and their signaling pathway molecules had been induced before the lowest respiratory system function (up to 3-5 days after the onset of COVID-19 symptoms) in patients with poor outcomes (90). This shows that the expression of IL-1α, IL-1β, and its signaling pathway molecules increase within 3-5 days post disease onset and might be positively associated with poor prognosis of COVID-19. SARS-CoV-2 induces releasing of IL-1 in macrophages and histamine in mast cells through stimulating toll-like receptor (TLR)2, TLR3, or TLR4 in the early phase of COVID-19 (25, 114). IL-1 affects mast cells and induces the production of IL-6, whereas histamine is involved in the expression of IL-8 and IL-6 in endothelial cells. Besides, histamine in combination with IL-6 stimulates excessive releasing of IL-1, IL-6, and IL-8 from macrophages, which appears as a CS (25, 115). IL-1 also elevates the production of nitric oxide, histamine, metalloproteinases, proteolytic enzymes, and cyclooxygenase (COX)-2 eicosanoid products, such as prostaglandins and thromboxane A2 (TxA2) in mast cells (116), which together with pro-inflammatory cytokines cause septic shock, metabolic dysfunction, thrombi formation, and different tissue damage that can lead to death (25, 116).

DNA microarray analyses of pathological specimens demonstrate that the expression of IL-1α is increased very early after blunt chest trauma (117), but another study has shown a decrease in levels of IL-1α in the plasma of trauma patients at admission (118). These conflicting findings may be due to the rapid fluctuation of IL-1α expression in the early hours after trauma. A very early increase of IL-1α along with elevated levels of IL-1β within 12 to 48 hours post-trauma, is associated with poor prognosis (117). Similar results have been observed in adult acute respiratory distress syndrome (ARDS) and heart and brain ischemia (119–121). Over-expression of IL-1α/β in alveolar macrophages during ARDS (119) and over-production of IL-1α (but no IL-β) in platelets during heart and brain ischemia stimulates the migration of inflammatory cells through inducing the expression of chemokines and adhesion molecules on endothelial cells. These processes could be one of the major mechanisms of type I interferons-mediated organ injuries (120, 121).

IL-6 is an acute-phase protein that plays both pro and anti-inflammatory roles in the immunopathology of inflammatory diseases (122, 123). The pro-inflammatory roles of IL-6 run through promoting acute-phase proteins (124), other pro-inflammatory cytokines (125), monocyte/macrophage chemoattractants, and T and B cells proliferation and differentiation (126, 127). Meanwhile, the anti-inflammatory mechanisms of IL-6 are through induction of the anti-inflammatory cytokines and controlling the level of pro-inflammatory cytokines (91, 128, 129).

Several studies have shown that over-production or over-function of IL-6 can be associated with poor prognosis in SARS-CoV-2 infections (45, 130, 131). Hence, serum levels of IL-6 are higher (100–10000 pg/mL) in COVID-19 patients compared to healthy controls. Moreover, COVID-19 patients with more severe symptoms have higher concentrations of IL-6 at admission (30, 132–136). Two independent studies have demonstrated that admission IL-6 serum levels are more likely to be an effective predictor of poor outcomes such as ARDS (optimal cutoff: 80 pg/mL) and death (optimal cutoff: 86 pg/mL) compared to other indicators (134, 137). However, IL-6 levels along with other laboratory indicators, like CRP, prothrombin time (PT), and D-dimer, provide a more accurate assessment of complications in COVID-19 patients (134). Consequently, the combination of a high serum level of IL-6, a high level of D-dimer, and a low level of PT, is associated with DIC-dependent deaths, meanwhile the combination of a high serum level of IL-6, D-dimer, and PT is associated with ARDS-dependent deaths (100, 138). It has been demonstrated that increased levels of IL-6 from 6 hours until ≥18 days post-COVID-19 symptom onset, is associated with poor prognosis (30, 132), whereas its gradual increase within 3-5 days, and its return to normal levels after 15-17 days, is linked to good prognosis (132).

IL-6 may predict post-traumatic complications with high accuracy (122). In homeostatic conditions, serum levels of IL-6 are less than 5 pg/mL. In inflammatory conditions such as trauma, the concentration rapidly rises within hours, reaching the highest levels after 6 to 12 hours (139). Several studies have shown that serum IL-6 concentrations increase in two time periods post-trauma. IL-6 levels in the first 24 hours after trauma are correlated with trauma severity (first hit), whereas its levels during the 48-72 hour period following trauma can be attributed to secondary effects such as infections, surgery, transfusions, and pre-traumatic conditions (91, 140–143).

During the acute phase of inflammation, TNF-α is produced primarily by monocytes/macrophages, but it can also be released by other cells (144). TNF-α plays an essential role in inflammation by inducing other pro-inflammatory cytokines such as IL-1 and IL-6, production of acute-phase proteins, and expression of adhesion molecules (144). The attachment of leukocytes to the endothelium of lymphoid organs and inflammatory sites occurs as a result of the expression of adhesion molecules, which influences the frequency of immune cells in blood circulation and promotes MOF (145). Furthermore, previous research has shown that the serum TNF-α level rises approximately 12 hours after a viral infection and remains elevated for 72 hours (146).

TNF-α levels in the serum of COVID-19 patients increase at the time of admission (3-5 days after infection), which continue until day 3 after admission. Although increased serum TNF-α levels during the first three days after the onset of disease symptoms are associated with disease severity, there are no significant differences in serum TNF-α levels among COVID-19 patients with mild, severe, and critical symptoms. The kinetics of TNF-α after day 3 is different depending on disease progression in patients (132, 147). As a result, higher and lower levels of TNF-α after day 3 are associated with poor and good COVID-19 outcomes, respectively (26, 148).

A positive correlation between serum levels of TNF-α and trauma severity has been indicated in injured patients (149). In non-severe trauma, low amounts of TNF-α are produced, which stimulate tissue repair by inducing fibroblast growth (149, 150). In contrast, excessive increase levels of TNF-α after severe trauma lead to aggravation of inflammatory and MOF (151). High levels of TNF-α and its receptors have been reported in mild trauma 2-4 hours after trauma, peaking at 24-48 hours, and gradually returning to the normal levels after about 5 days (149, 152, 153). However, high serum levels of TNF-α from 2-4 hours until 3 days post-trauma followed by a secondary elevation after day 7, may be associated with poor prognosis of trauma (152, 153).

In addition to pro-inflammatory responses, which are one side of the coin in inducing poor outcomes in inflammatory diseases, anti-inflammatory responses followed by these pro-inflammatory responses may also be present. In non-severe inflammatory conditions, there is good balance between these two sides, and inducing low levels of inflammation may promote the repairing process and manage tissue injuries (154). Over-activation of the immune system in severe inflammatory situations can cause an imbalanced immune response and may lead to early complications and MOF in patients. Furthermore, the release of large quantities of anti-inflammatory mediators to control inflammation, causes IS that might induce opportunistic infections and inflammation-dependent late complications (26, 155).

There is reported to be a higher level of IL-10 in COVID-19 patients compared to healthy controls, which is correlated with IL-6 concentrations and disease severity. In this regard, serum IL-10 levels are higher in COVID-19 patients with critical, severe, and moderate symptoms (132). The results have shown serum levels of IL-10 may be a prognostic factor for disease complications (132). Of course, dynamic changes in serum IL-10 levels may predict different outcomes in COVID-19 patients (26). During the first three days after the onset of symptoms, there are no significant differences in serum levels of IL-10 between non-survivor and survivors groups of COVID-19 patients. The significant differences start during days 4 to 7 post-symptom onset and continue until days 8 to 13. An increase of serum IL-10 levels within 4 to 19 days after initial symptoms of disease, and a decrease in the days following, is associated with poor outcomes, whereas an opposite pattern is observed in patients with good outcomes (26). Thus, serum level of IL-10 4 to 13 days following COVID-19 might be considered as another prognostic indicator.

A significant increase in serum IL-10 levels can be seen within 24 hours post-trauma (156). An early but slow increase of serum IL-10 is related to the low production of pro-inflammatory mediators after non-severe trauma and can be a regulating and repairing factor in the early phase of inflammation. Although IL-10 has the ability to modulate inflammatory responses, it has been linked to poor prognosis in severe injuries (156). Very high levels of IL-10 within 2-24 hours after trauma are linked to high levels of pro-inflammatory cytokines, which is caused by the intensity of the injury (first hit) and leads to immunodeficiency (91, 129, 139). This phenomenon increases susceptibility to opportunistic infections and sepsis (second hits), resulting in a higher secondary pro-inflammatory response and IL-10 rise after 72 hours (91, 157). Secondary elevation of IL-10 can be a poor prognosis of common bacterial infection, sepsis, and MOF in trauma patients (91).

IL-4 is produced mainly by activated type 2 helper T (Th2) cells and regulates cell apoptosis and proliferation, Th1 responses, Th2 differentiation, isotype switching to immunoglobulin E (IgE), and skewing of macrophages toward type 2 macrophages (M2MQ) (158). Respiratory infections have been shown to increase serum levels of IL-4 as an anti-inflammatory cytokine (159).

Serum levels of IL-4 are observed to be much higher among COVID-19 patients compared to healthy controls (132). In particular, higher levels of IL-4 have been reported in COVID-19 patients with more severe respiratory symptoms (7, 46). Despite this observation, a multivariable comparison has shown no significant differences between patient groups with mild, severe, and critical symptoms (132). The kinetics of IL-4 are different in COVID-19 patients with different illness severity. A decrease in serum IL-4 levels during the first week after disease onset and a gentle increase during the second week is associated with good prognosis of COVID-19 (92). Whereas, the contrary trend is associated with poor COVID-19 outcomes (92).

Serum levels of IL-4 are significantly higher in trauma patients compared to healthy controls and positively correlated with trauma severity (160). However, previous studies have reported controversial results from IL-4 levels in patients with and without post-traumatic complications (161, 162). A study on trauma patients with high serum levels of IL-6 showed that the expression of IL-4 in trauma patients with post-traumatic complications is lower than in cases without complications (163). Conflicting findings may be due to different sampling times during the disease. It seems that the correlation between IL-4 and IL-6 in the incidence of post-traumatic disorder is similar to the correlation between IL-10 and IL-6 (91, 129). Accordingly, the synchronic increase and decrease of both IL-6 and IL-4 may be related to the control of inflammatory responses in early and late phases after trauma, respectively (160). Whereas an imbalance between IL-6 or IL-4 may lead to early or late complications (160). There is limited data on the kinetics of post-traumatic IL-4; if accurately determined, it may lead to a prognostic factor for predicting post-traumatic events.

Lymphocytes including T, B, and NK cells play a pivotal role in the humoral and cellular immune response against viral infections (197). Previously, changes in the peripheral blood lymphocyte subsets have been observed in several respiratory infections caused by RNA viruses (198, 199). A reduction of the lymphocyte count, especially total T, CD4+ T, CD8+ T and NK cells along with neutrophilia and thrombocytopenia are typical phenomena following SARS-CoV-2 infection (45, 200, 201). In mild COVID-19 the decreased lymphocyte count is within the normal range, whereas it appears as lymphopenia in severe COVID-19 (165, 202, 203). In patients with severe COVID-19, lymphopenia appears within 2 days after initial symptoms and returns to normal ranges after day 18, whereas it persists for a longer time in non-survivor patients (204). Several studies have reported a state of lymphopenia in CD4+ T, CD8+ T, B and NK cells in COVID-19 patients (205, 206), however others have shown higher reductions of CD8+ T than that CD4+ T cells (207, 208). Therefore, counting the number of lymphocytes within 21 days after symptoms onset could be a prognostic indicator for future complications of COVID-19. The trend of changes in lymphocyte count in trauma patients differs from that in patients with COVID-19 ( Figure 3 ).

It has been shown that lymphocyte counts decrease immediately after trauma in patients compared to the control group (167, 209), although significant decreases in the number of lymphocytes between MOF and non-MOF groups appear after day 2 (169). Accordingly, lymphopenia is detectable during days 2 to 7 after trauma in the MOF group. Whereas in non-MOF patients, lymphocytes decrease to the lowest counts of the normal ranges on the second day after trauma, and then gradually increase (169). The persistence of lymphopenia following trauma is correlated with severity and is associated with poorer prognosis.