The SARS Coronavirus 2 (SARS-CoV-2) originated in China and spread to most countries worldwide in 2019. Generally, more than 200 million confirmed cases and more than 4 million deaths have been reported. SARS-CoV-2 is more infectious than SARS-CoV (1–3). The new Coronavirus is classified into critical and non-critical cases based on symptoms. Description of critical patients require mechanical ventilation and intensive care unit (ICU) admission, and Non-critical patients don’t require mechanical ventilation and ICU admission (3, 4). Accordingly, comparing critical and non-critical groups can describe the difference between the presence and absence of co-infection. After three years of the first appearance of COVID-19, researchers examined essential factors for evaluating COVID-19 disease.

As a first step, the blood cell count was evaluated. Some papers suggest that the number of white blood cells (WBCs), lymphocytes, and platelets may vary as a result of COVID-19, including critical, mild, moderate, and severe cases (5, 6). The difference between these cells may show the infection and inflammation in critical and non-critical groups (7, 8). Another factor associated with COVID-19 may be enzymes and proteins. Alanine aminotransferase (ALT), Aspartate aminotransferase (AST), and C reactive protein (CRP) levels were inconsistent between critical and non-critical groups. The level of these markers can determine the prognosis of the two groups (9, 10).

Underlying diseases such as high blood pressure, diabetes, cardiovascular disease, and dyslipidemia can play a crucial role in the clinical course of COVID-19 patients. Critical and non-critical patients exhibit varying levels of comorbidities; these have a different impact on morbidity (11). Moreover, there is evidence to suggest that the mortality rate can be affected by comorbidities (12, 13).

Co-infection is an essential factor in morbidity and mortality. Globally, the prevalence of bacterial co-infection in COVID-19 patients is unknown and different micro-organisms lead to co-infection (14). Most of the organisms differ in their distribution in different organs, such as the respiratory, blood, and urinary tracts (15). As a result, the reaction of critical and non-critical groups to co-infections will be considerably variable. Bacterial co-infection plays a vital role in the clinical course of the COVID-19 disease, which can be treated with various antibiotics.

The mortality rate of COVID-19 disease can be affected by factors such as blood cell count, blood markers, comorbidities, and co-infections (4). Therefore, the mortality rate can differ between critical and non-critical groups. In this study, blood markers, comorbidities, co-infections, and their relationship to mortality rates were compared between critical and non-critical patients.

The COVID-19 pandemic has reached a global scale, and medical systems in many countries are experiencing severe problems as a result (32, 33). The COVID-19 pandemic in 2019 has caused significant hospitalizations and deaths. According to the clinical course on COVID-19, we can classify patients with COVID-19 into critical and non-critical groups (4). The results showed that there are several differences between critical and non-critical groups. In this study, we examined the blood cell count, blood markers, and the comorbidities difference between critical and non-critical groups.

Due to the correlation between the immune system function and the clinical course of COVID-19, we compared the blood cell count between groups (34). The production of cytokines is crucial for the growth and specialization of immune cells. In COVID-19 pneumonia patients, certain inflammatory cytokines like IL-6 and IL-10 were found to be elevated in critical cases (35). However, IL-2 levels were increased in non-critical patients but decreased in critical ones. When present in low concentrations, IL-2 can prevent CD4+ T and CD8+ T-cell activation by maintaining T regulatory cell activity and survival (36). As a result, this could lead to a significant drop in CD8+ T-cells and lymphocytes in COVID-19 critical patients (37). Furthermore, critical patients had significantly lower T-cell, B-cell, and NK cell counts compared to controls (38). A gradual decrease in peripheral blood lymphocytes is a common early indicator of adult patients with non-critical and critical illnesses (39). IL-6 can stimulate T cell differentiation, and its increased levels are associated with producing acute-phase proteins like CRP and inflammatory cytokines. It is also possible that increased WBC in critical patients with low lymphocytes may be caused by an increase in PMNs, which can be indicated by an increase in CRP levels.

This study analysis indicated the higher platelet count in non-critical patients. Platelets and other related indicators play a crucial role in inflammation and prothrombotic responses during numerous viral infections (19). Apart from their traditional function in hemostasis and thrombosis, platelets also contribute significantly to the immune and inflammatory processes. Research suggests that platelets express surface receptors that enable them to bind and allow entry to various viruses. Furthermore, the rise in platelets and neutrophils could be due to anti-apoptotic cytokines and stimulation by specific pro-inflammatory cytokines (40). In addition to the immune system, enzymes and inflammation markers play an essential role in the course of COVID-19 disease (9). As a result of this study, ALT, AST, and CRP levels are significantly higher in the critical group than in the non-critical group. During acute inflammatory responses to COVID-19, there is usually a rapid and significant increase in serum CRP levels. Elevated CRP fluctuation during hospitalization has been identified as the primary cause of ICU admission with a poor prognosis (41). Analysis revealed that critical patients have higher CRP levels, indicating a more significant inflammatory response than non-critical patients (13). Although CRP is a sensitive indicator of disease activity and an independent risk factor for various diseases, studies have shown that CRP fluctuation is a better indicator of inflammation severity for guiding treatment in sepsis, systemic inflammatory response syndrome (SIRS), and community-acquired pneumonia (9, 42).

An elevated CRP level in critical patients may hint to SIRS and multi organ damage. An elevated level of ALT and AST in critically ill patients may indicate liver damage and a change in bacterial co-infection in COVID-19 disease, both of which are associated with mortality (10). Lipopolysaccharides (LPS) are always considered a major contributor to liver damage (43). In critical patients with elevated liver enzymes that are indicative of acute liver damage, LPS may be one of the contributing factors. Our analysis of critical patients reveals a high prevalence of bacterial co-infection and LPS is predominantly present in bacterial cell walls. LPS is generally released from bacterial walls during bacterial proliferation or destruction (44). Therefore, it is possible that the overused broad-spectrum antibiotics in COVID-19 patients may suddenly destroy gram-negative bacteria and induce liver damage with a large amount of LPS toxin (45). Bactericide antibiotics may cause bacteria to release LPS, so bacteriostatic are recommended instead. The bacteriostatic inhibits the proliferation of bacteria, but does not kill them, therefore the level of LPS remains low until the body can recover from COVID-19. Once COVID-19 has been eliminated, bactericide antibiotics can be used. ALT, AST, and CRP levels are associated with ICU admission risk based on the results of this study and according to the definition of critical patients.

In univariable analysis, hypertension, diabetes, cardiovascular disease, and cancer were associated with critical illnesses (24). In this study, a statistical meta-analysis revealed that comorbidities, such as hypertension and diabetes, are more prevalent in critical groups than in non-critical groups. However, some previous studies state that comorbidities are common in non-critical groups, contrary to recent studies and our meta-analysis (46). A common element of COVID-19 patients with hypertension and diabetes is the use of angiotensin-converting enzyme inhibitors (ACEI). A membrane receptor known as ACE2 is responsible for binding SARS-CoV-2 to cells and promoting its entry into the respiratory tract. The downregulation of ACE2 by SARS-Cov-2 spike protein binding reduces the protective effects of ACE2 during acute inflammation (47). ACE inhibitors may induce the ACE2 expression, the cellular receptor for SARS-Cov-2, and can aggravate the disease course (48). It has been identified that SARS-CoV-2 is able to invade cells via this previously established cell receptor which is facilitating the invasion of SARS-CoV-2 cells (49). The higher incidence of diabetes in critically ill patients can be attributed to three well-defined mechanisms (50): 1) The direct entry of viruses through various receptors in β-cells can directly cause β-cell dysfunction and apoptosis or trigger β-cell autoimmunity. Alternatively, viruses can enter pancreatic cells that express viral receptors, leading to structural and functional changes, local inflammation, and the creation of a pro-diabetic environment. This can disrupt the integrity of nearby non-infected β-cells in a paracrine manner, potentially leading to loss or dysfunction of these cells (51). 2) Targeting putative viral receptor-expressing cells in metabolic organs like the liver and adipose tissue can induce insulin resistance and result in the loss of disease tolerance mechanisms (52). 3) Induction of systemic inflammation and accumulation of prediabetic metabolites can lead to metabolic derangement and maladaptive functions (53).

Critical patients with COVID-19 pneumonia exhibit a state of immune deficiency and hypo immunity. These factors can further worsen the situation by causing severe infection and leading to fatal outcomes (54). The prevalence of bacterial co-infection in COVID-19 patients can also be another difference between critical and non-critical patients. Our meta-analysis showed bacterial co-infection is more common in critical than non-critical patients. Bronchoalveolar lavage (BAL) and sputum are usually collected in the first week of ICU admission. The majority of COVID-19 patients with bacterial co-infection previously received antibiotics. Overall, our results revealed that the frequency of bacterial co-infection is higher in critical patients following ICU admission than in non-critical patients.

Therefore, the risk of inflammation, organ damage, and previous disease is significantly higher in the critical group. According to the comparison of co-infection rates, critical patients are more likely to have co-infections than non-critical patients. Also, the critical group had a higher death rate than the non-critical group (Graphical abstract).

In conclusion, our findings suggested that critical patients have a suppressed immune system and that inflammation, organ damage, and co-infections are significantly higher. Due to these factors, critical groups have a worsened course of the disease and a high mortality rate, so these patients require rapid diagnosis and careful management. Additionally, bactericide antibiotics may cause liver failure in critical patients due to the risk of liver damage. Therefore, we suggest that this relationship be fully evaluated in future studies.

The original contributions presented in the study are included in the article/ Supplementary Material . Further inquiries can be directed to the corresponding author.

MH-C: Project administration, Resources, Supervision, Writing – review & editing. HE-S: Investigation, Methodology, Software, Validation, Writing – review & editing. AB: Conceptualization, Methodology, Writing – original draft.