Pandemic Covid-19 infection is an occurrence of a newly virus that discovered spreads quickly over the world, causing systemic or local pneumonia consequences, and was dubbed the virus in China. In 02/ 2020, This illness has been classified as Covid-19 by the WHO [2]. On 11/03/2020, the world health organization declared a SARS-CoV-2 contagion [3]. Severe Acute Respiratory Syndrome Corona virus two disease was previously known as Corona virus disease of 2019 by world health organization. The term was coined to prevent criminalizing the virus's origins in terms of community, region, or animal link [4,5]. To prevent the spread of COVID-19, the Centers for Disease Control and Prevention (CDC) published a guideline on 3 April 2020 advising the population, including those who were lacking signs, in public settings where maintaining social-distancing interventions is challenging, to think about wearing face coverings [6]. Based on daily data released by the Iraqi Ministry of Health, Al Najaf city was the location of the initial COVID-19 case. in March 2020, After that, the virus quickly spread across the nation, resulting in over fifty thousand cases and over seven thousand fatalities. Infection with SARS-CoV-2 appears to have a wide clinical spectrum, from asymptomatic infection to mild upper respiratory tract illness to severe viral pneumonia with respiratory failure and even death, with many patients hospitalized with pneumonia. [7].

According to past immunological investigations, severe patients had much higher levels of circulating inflammatory cytokines, especially interleukin-6 (IL-6). [8-12]. Additionally, postmortem examinations showed that pulmonary, cardiac, and gastrointestinal tissues from COVID-19 patients had higher levels of inflammatory markers that were connected to necrosis and interstitial macrophage infiltration. [13]. T-Cells are essential for eradication viral infection; however, when SARS- CoV 2 invades the host body, it disrupts the immunological response [14-16]. In addition, SARS-CoV 2 infection increases the quantity of neutrophils and monocytes in patients with severe COVID-19, and lympopenia is a common clinical laboratory test abnormality in these individuals [17-19]. Elevated blood levels ofC-reactive protein (CRP), IL-6, D-dimer, ferritin, lactate dehydrogenase (LDH), myoglobin, and fibrinogen indicate that processes are probably mediated by an inflammatory cytokine storm as a result of an uncontrolled and dysfunctional immune response. [20,21]. Furthermore, researchers have recently focused on CBC resulting characteristics in addition to their associations to specific disorders. The neutrophil-to-lymphocyte ratio (NLR) is one of these CBC measures. NLR is a marker of inflammation that has been examined in a variety of medical disorders due to its ease of use and low cost [22]. Infection with COVID-19 is linked to a higher inflammatory load. Indeed, the ratio of neutrophils to lymphocytes has been linked to a variety of inflammatory disorders, including irritable bowel syndrome [23], Thyroid problems, type 2 diabetes, diabetic nephropathy [24-26]. Angiotensin Converting Enzyme 2 (ACE2), is the principal receptor by which the SARS-CoV-2 virus binds to and enters host cells. This enzyme is highly produced and broadly distributed in pancreatic cells, and it plays a key role in reducing insulin secretion and developing insulin resistance, implying that the virus induces inflammatory-mediated islet damage [27-29]. Severe renal injury is a dominant problem in SARS-CoV-2 patients that is compound and related to complex concentrated care unit admission and mortality [30,31]. Additionally, some biotic characteristics of the host have been suggested as significant indicators of COVID-19 vulnerability. Recently, among these determinants, ABO blood groups have been found to be important risk factors for the development of infection. [32-40].

The current review, discusses the findings of some studies conducted in Iraq on the relationship of Covid-19 infections with some blood biomarkers including, hematological, biochemical and immunological parameters, and compare them with other studies conducted in different countries. 

Hematological Parameters

White Blood Cells: The most prevalent type of circulating white blood cells are neutrophils, which play a critical role in the immune system. Innate immunity uses them as the initial line of protection against bacterial and fungal infection. These cells play a crucial protective role by phagocytosing the bacteria and creating neutrophil extracellular traps (NETs). But nothing is known about its role in viral infections. It was observed that neutrophils are not necessary for viral clearance from pulmonary cells and host survival in SARS-CoV-infected mice. [41]. A COVID-19-affected inanimate subject, however, displayed a substantial neutrophil infiltration in pulmonary capillaries with extravasation into the alveolar space. As a result, the presence of tracheal neutrophilic mucositis and acute capillaritis indicates the degree of airway inflammation. [41]. The immune system is significantly impacted by SARS-COV-2. It has an effect on the adaptive immune system by inhibiting antibody formation and the T-cell response. As a result, inflammation develops [42]. Additionally, it has an effect on lymphocyte count, resulting in lymphopenia [43]. In a study performed in Kufa, Najaf, Iraq [44], demonstrated a correlation between the occurrence of lymphopenia (37.7%) and neutrophilia (26.9%) in corona patients' blood. These results are probably a result of the fact that when viruses infect people, they typically generate lymphocytosis in lymphocytes, which are effector cells that fight viruses. [45]. SARS-CoV, MERS-CoV, and SARS-CoV-2 are all coronaviruses that produce a reduction in infected patients' lymphocytes [46,47]. The direct lymphocyte attack by the virus or immune-mediated programmed lymphocyte death may be the mechanism causing this. [48-50]. Other mechanisms, such as the likelihood that COVID-19 cell receptors and SARS-CoV receptors are angiotensin-converting enzyme 2 receptors (ACE2 receptors), can support this conclusion. [51]. COVID-19's direct action on lymphocytes could result in their lysis. Furthermore, COVID-19 infection causes the creation of a cytokine storm, which includes TNF-alpha, interferon-gamma, interleukin-7, interleukin-2, interleukin-6, and interleukin-2. This cytokine storm can cause lymphocyte death as well as lymphoid organ atrophy [52]. These findings matched those of previous studies, such as [48, 53, 54]. Furthermore, in the same study [44], the COVID-19 patients' red blood cell count was found to be low when versus the typical reference value. The COVID-19 infection that affected the patients' bone marrow and caused hematopoiesis suppression may have contributed to this outcome. Autopsy results of four affected patients were reported in a research by Andrey Prilutskiy et al [55]. They discovered that three of the pulmonary lymph nodes hemophagocytosis may be the source of the anemia because one of the patients had histologic evidence of the condition, the other had hemophagocytosis just in the spleen and neither patient had hemophagocytosis in the liver or bone marrow. As a result, in COVID-19 pneumonia, the lymphocytes ratio may be a stronger predictor of infection severity than the WBC count. The use of a generic classification of WBC is one of the study's weaknesses. In another study [56], done in Amara city. Iraq showed that, Increased neutrophils and lymphopenia were effective predictors of disease progression. In another study [57], performed in Erbil city, revealed that, a clinically necessary increase in WBC count among patients who passed away, and a reasonable rise in WBC count among patients with severe illness found. As a result, a substantial rise in WBCs in patients with advanced illness could indicate clinical deterioration and an increased chance of bad result. He et al. [58] Researchers examined the effects of SARS coronavirus infection on peripheral blood cells and subsets and discovered a correlation between an increase in WBCs and an increase in neutrophils, whereas lymphocytes, monocytes, and eosinophils all had diminishing trends. In a different investigation in Najaf, Iraq [59], showed that, both leukocytes and lymphocytes have decreased. These finding may be due to that the patients were diabetic. The above findings were agreed with a studies [60,62,67], performed in Saudi Arabia, and Iran, and China but disagreed with another studies [61, 63, ], done in Saudi Arabia, and Turkey were they found normal WBCs count. Several studies [64-66], have examined the neutrophil-to-lymphocyte ratio (NLR) as a biomarker for COVID-19 severity and discovered that it has a significant ability to predict the severity of the illness. these differences in the results may be due to the kinetic of WBCs responses in community, differences in the types of patients in regards to age and sex, technical issues, and sample size.

ABO, Rh, Blood Groups

Zhao et al [68], were the first to document how the ABO blood type system affected COVID-19 susceptibility in instances of the virus that had been diagnosed at three hospitals in China. In a setting where blood categories A and O make up 31 percent and 34 percent of the population, respectively, patients with blood group A had a higher rate of COVID-19 infection than patients with blood group O. Individuals with blood group A made up 37% of all COVID-19 instances that were validated, compared to only 26% of patients with blood group O. These findings suggest that whereas blood group A increases a person's susceptibility to COVID-19 infection, blood group O may protect against infection. A case-control study by Wu et al. that included 187 confirmed COVID-19 cases and discovered that 37% of COVID-19 patients had blood type A whereas only 22% had blood group O further demonstrated the plausibility of an ABO blood group relationship. [69]. In another case-control study with 265 COVID-19 patients, Li et al. found that patients with blood group A accounted for 39% of cases, whereas those with blood group O accounted for 26% of instances. [70]. A research [71], done in Baghdad, Iraq, also found that blood group A is linked to an increased risk of COVID-19 infection. 

In keeping with the findings from China, and Iraq, According to studies from Turkey, Lebanon, Iraq, and Denmark, blood group A patients had the highest percentage of COVID-19 positive cases when compared to the other blood types, and the O type had the lowest prevalence of infected individuals [72-75]. Barnkob et al. also discovered that, despite the fact that 42 percent of Danish people have blood types O and A, group O had a 38 percent infection rate and group A had a 44 percent infection rate, indicating that group O is less susceptible to SARS-CoV-2 infection [76]. Studies in the United States and Spain found a low incidence of the O blood group among COVID-19 cases [77-79]. Additionally, those with blood group A were discovered to be more susceptible to the infection in a recent meta-analysis of the ABO blood type's sensitivity to the COVID-19 infection [80]. 

Numerous studies examined the connection between COVID-19 severity and mortality and ABO blood groups. Reports on the connection between blood group and severe COVID-19 scores are currently in dispute. In fact, it was discovered that blood type A had the highest proportion of COVID-19 individuals with severe symptoms. [81,82], the least severe effects were observed in those with blood group O [83]. Similar reports indicated that COVID-19 cases with blood group A were more severe in Lebanon [84]. 

The results of these experiments suggest that one of the variables affecting COVID-19 susceptibility, severity, and mortality is the ABO blood group. According to the findings in this review, blood group O may lessen a person's vulnerability to SARS-CoV-2 infection and the severity of their sickness. On the other hand, those with blood type A have been demonstrated to be more vulnerable to SARS-CoV-2 infection and its disastrous effects. The outcomes of the research discussed here could have been impacted by a number of confounding factors. Confounding variables include the number of patients included, the kind of controls used for comparison, and the relative ABO frequencies in the population under investigation, as well as variations in the ABO blood group frequencies between populations from various geographic regions could be a major source of bias. As a result, more research is needed to properly understand the ABO association and the actual mechanism/s.

Biochemical Parameters

D-dimer and Ferritin Levels: A plasma fibrinolytic enzyme produces D-dimer, a cross-linked fibrin metabolite [85]. Secondary fibrinolysis is indicated by the raised D-dimer concentration. D-dimer has been used to identify pulmonary embolism, pulmonary vein thrombosis (DVT) in the lower extremities, disseminated intravascular coagulation (DIC), surgical trauma, and malignant tumors [86].             

Procalcitonin, C-reactive protein (ESR), and serum amyloid A are among inflammatory indicators, have been seen in COVID-19 patients in research. However, ferritin has gotten little attention. High ferritin levels have been linked to additional consequences of viral illnesses such as dengue fever [87]. Sepsis is observed in all corona virus-infected patients, in addition to acute respiratory distress syndrome (ARDS) [88]. 

Study [89], done in Anbar city, Iraq, on the association of D-dimer, and serum Ferritin with Covid-19, showed that in both sex and age, the D-dimer level increased significantly (p0.001). In comparison to the healthy group, ferritin levels increased significantly. In another study [90], conducted in Najaf city, Iraq, revealed that A greater prevalence of severity sickness and liver injury in patients with increased levels of serum ferritin and D-dimer is associated with a higher incidence of severity illness and rate of mortality in COVID-19 patients with abnormal liver function tests. These findings agreed with Tang et al [91], Higher fibrin-relevant (d-dimer and fibrin degradation product) levels have been linked in studies to non-survivors of COVID-19 patients when compared to survivors of severe SARS-CoV-2 infection with elevated d-dimer or sepsis-induced disseminated intravascular coagulation. Low molecular heparin use has also been linked to non-survivors. Increased d-dimer levels can predict COVID-19 death cases and severe cases in hospital admissions. A comparable study, although lacked mortality data, discovered that the D-dimer can distinguish between patients with and without substantial COVID-19 forms [92]. However, ferritin is not a diagnostic marker for hemophagocytic lymphohistiocytosis. Several investigations have found that ferritin levels are much higher in hospitalized individuals. As a result of a number of inflammatory conditions, including cancer, iron excess, liver or kidney disease, and other inflammatory disorders, the acute protein ferritin rises [93]. In 5700 people hospitalized for COVID-19 in the United States, ferritin levels were found to be pathologically high. Whatever underlying illnesses are present, hyperferritinemia is accompanied with anemiaThere is probably a ticking time bomb of inflammation there. When ferritin levels begin to grow. Inflammatory processes cause elevated amounts of ferritin reports state that in COVID-19 patients. In the worst instances, serum ferritin levels were significantly higher [94]. 

Berger et al. found that aberrant D-dimer levels were frequently found upon admission to COVID-19 and were associated with a higher risk of critical illness, thrombotic events, acute renal injury, and death [95]. The D-dimer is accountable for clotting stimulation and lysis of fibrin and is formed from the synthesis and lysis of cross-linked fibrin. Non-survivors were shown to have much greater D-dimer levels than survivors, and COVID-19 has been associated to hemostatic problems [96]. In the initial phases of COVID-19 disease, research has shown an increase in D-dimer and fibrinogen levels. A three- to four-fold increase in d-dimer levels is associated with poor predictions. COVID-19 can also be brought on by conditions that increase D-dimer levels in the blood, including diabetes, cancer, stroke, and pregnancy. Measurements of the d-dimer and coagulation parameters can be helpful in the command COVID-19 control and management as well as in the early stages of the disease [97]. The hypercoagulability of COVID-19 patients was discovered, and DIC criteria were met in 71 percent of individuals who died from the virus. This indicates that, in this instance, 71% of COVID-19 patients met the DIC requirement while just 29% did not. In addition, patients with severe COVID-19 were found to have pulmonary embolism in 30% of cases and venous thromboembolism in 25% of cases. Higher blood levels of D-dimer were seen in COVID-19 individuals who had an ischemic stroke [98]. 

In individuals with COVID-19, early ferritin levels analysis could be used to determine the severity of the condition. D-dimer can be used as a biomarker by tracking D-dimer levels and examining mortality and severity in COVID-19 patients. It is necessary to incorporate the serum ferritin and d-dimer tests. upcoming studies to predict the severity of those who have been diagnosed A virus that makes people sick is COVID-19.

Blood Urea and Serum Creatinine

Male patients were more sensitive to advanced renal function impairment than female patients, according to the findings of a study [99], done in Karbala city, Iraq Karbala. This supports earlier observations that revealed male gender was linked to a more severe form of COVID-19 infection and a poorer prognosis [100]. A different study also found that patients with COVID-19 who were admitted to the hospital had a disproportionately high SCr among them. Recent articles found that COVID-19 patients frequently have acute kidney injury (AKI), and that this condition may increase the risk of death for those patients [101]. Furthermore, roughly 15% of COVID-19 patients had elevated levels of SCr and blood urea nitrogen, according to research [102]. Although the actual process causing COVID-19 infection to affect the kidneys is unknown, several theories have been offered. Angiotensin-converting enzyme receptor 2 (ACE2), which is necessary for SARSCoV-2 binding, is expressed more frequently in the kidney and renal tubular cells, indicating that one of them is direct tubular injury brought on by the virus itself [103]. This was confirmed by Cheng Y, et al [104], who discovered that SARS-CoV-2 patients had higher levels of serum Creatinine and blood urea. This was also supported by a study conducted in Iran by Boroujeni et al [104], It discovered that a lot of people with SARS-CoV-2 pneumonia had renal disease signs, like elevated blood urea and serum creatinine, which might be explained by the various pathophysiologies that occur in SARS-CoV-2 pneumonia. These findings suggest that COVID-19 might enter the peripheral bloodstream, find its way to kidney tissues as a result of elevated ACE2 expression in kidney cells, and subsequently destroy the nearby kidney cells [106]. Patients with chronic renal disease may be more vulnerable to Covid-19 pneumonia because of a proinflammatory state accompanied by a deficiency in innate and adaptive immune cell activity [107]. As a result, you're more likely to get an upper respiratory infection or pneumonia [108].

It is obvious that there is an association between the severity of the disease and kidney problems.

Blood Sugar

Due to the diminished ability of antibodies to defend against protein antigens, diabetes mellitus increases the risk of getting a variety of infections, notably respiratory infections, with an increased risk of hospitalization [109]. Infection rates rise in lockstep with HbA1c levels and are statistically linked to poor glycemic management, which leads to higher infection-related hospitalization rates [110]. Diabetes mellitus is likely to be linked to COVID-19 progression as well [111]. Angiotensin Converting Enzyme 2 is the principal mechanism by which the SARS-CoV-2 virus enters host cells (ACE2). This enzyme is highly produced and broadly distributed in pancreatic cells, and it plays a key role in reducing insulin secretion and raising insulin resistance, implying that the virus causes inflammatory-mediated islet damage [112-114]. However, because of the lower cytosolic pH in diabetes individuals, as well as other comorbidities, SARS-CoV-2 enters host cells more easily via ACE2 due to the large viral load; the consequent COVID-19 infection is thus more likely to be severe [115]. In a study [116], performed in Al- Najaf city- Iraq, revealed that infected diabetic patients with uncontrolled glycemia are predisposed to COVID-19 infection, and the severity of the disease is linked to the degree of hyperglycemia. This was also agreed with another study [117], done in Baghdad, Iraq. Where they revealed that COVID-19 could be a risk factor for diabetes, or the condition could be linked to a higher risk of diabetes. According to research from China and Italy, people with diabetes who were infected with Covid-19 had higher hospital admission rates [118]. As part of the pathophysiology of diabetes, especially in those with uncontrolled glycemia, the innate immune system and humoral immunity are compromised against any infection, including SARS-Cov-2 ineffectiveness [119]. Additionally, diabetes results in an elevated cytokine response, which causes an inflammatory condition. Interleukin-6 and C-reactive protein levels in people with diabetes who are infected with Covid-19 are noticeably greater than those in non-diabetic individuals [120]. A cytokine storm is produced when SARS-Cov-2 enters the host cell through ACE2 and triggers an inflammatory response, the recruitment of T-helper cells, and the creation of interferon gamma [121]. People with diabetes are more susceptible to a cytokine storm and potential organ damage if infected with Covid-19 because of the cellular mechanisms Covid-19 triggers and the pathophysiology of diabetes.

Immunological Parameters

Reactive Protein: The complement system is activated by high-sensitivity C-reactive protein, which boosts phagocytosis and clears pathogens from the body [122]. Blood CRP levels may function as a general inflammatory indicator and naturally contribute to the immune response [123]. Its presence has been found to be connected to pneumonia and bronchitis [124]. A high sensitivity-CRP level in the blood can be used to make a quick diagnosis of pneumonia [125]. In response to the activation of IL-6, it is released from hepatocytes. It might be used as a cytokine storm warning sign. Thus, in severe COVID-19 individuals, elevated levels of high sensitivity-CRP may be linked to enhanced inflammatory cytokine production. This was corroborated by a study [126], IL-6 and high sensitivity-CRP have a strong positive relationship, according to research carried out in Basrah, Iraq, using the Pearson correlation coefficient. This finding was in agreement with earlier findings [127]. The mean IL-6 level in the severe group was more than three times higher than that in the other two groups, although there was no discernible difference between the moderate and healthy groups. This finding matched what other research had discovered [128], IL-6 appears to perform a unique role in COVID-19 development and is linked to infection severity. In addition to its role in pneumonia, its concentration was shown to be higher in patients with pulmonary impairment, indicating that it plays a role in the pathogenesis of COVID-19-induced lung injury [128]. These results also were agreed with a study [129], conducted in Turkey. C-reactive protein appears to be one of the key factors for assessing the severity of COVID-19 pneumonia, according to previous research.

IL-6

The severity of a disease may also be related to cytokine storms. Increased serum expression of interleukin (IL)-2R and IL-6 appears to be a predictor of the severity and prognosis of COVID-19 patients. A biopsy sample from a COVID-19 patient revealed interstitial mononuclear inflammatory infiltration in both lungs, according to pathological investigation. Furthermore, a peripheral cytometric assessment of blood flow demonstrated that T cell over activation partially compensated for the patient's severe immunological damage. These results suggest that the cytokine storm in Covid-19 may have a part in the pathogenesis [130].

Based on a study [131], done in Amara city. Iraq, showed that the intensity of COVID-19 symptoms is highly linked to IL-6. Zhu et al.,2020 [132], detected that IL-6 was found to be high in COVID-19 patients, and its level was found to be substantially linked with the severity of symptoms. Similarly, Huang et al.,2020 [133], also revealed that in patients with SARS CoV-2 infection, IL-6 levels are elevated, and their high levels are linked to the amount of viral RNA in the blood as well as illness development. IL-6, in combination with transforming growth factor-beta, is thought to trigger the production of Th17 cells from naive CD4 cells, which are essential for the mucosal body's defense against viruses and other pathogens. Additionally, IL-6, IL-7, and IL-15 work together synergistically to boost CD8 T cell differentiation and cytolytic activity, which is important in the body's response to viral infections [134]. COVID-19 caused significant increases in IL-6. These changes were found to be associated with disease severity and progression, implying that such clinical markers could be used to identify serious disorders.

• Covid-19 patients suffer from lymphopenia and neutrophilia and they were mostly with blood group A

• There is an association between the severity of Covid-19 disease and serum levels of D-dimer and serum ferritin

• There is relationship between the intensity of the disease and kidney problems

• C-reactive protein levels increased with the severity of the disease

• IL-6 levels linked with the severity of Covid-19

Recommendations

• Doing more research on other parameters such as TNF-a

• Doing intensive studies on the relationship of SARS-CoV-2 infections and LDH levels

• Making comparison between studies conducted on the same parameters in Kurdistan region and rest of Iraq

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