Keywords

Introduction

In April 2022, the number of death due to COVID-19 is almost 6 million (despite it is predicted that it may be even 13–16 million excess deaths due to COVID-19) and fatality rate is 2%. Fatality rate of COVID-19 continues to change as the pandemic progress [1]. The disease course of COVID-19 varies greatly from asymptomatic infection to severe condition resulting in death [2]. The prognosis of most patients is good but approximately 20% of all COVID-19 patients develop severe or life-threatening complications [3]. The average time from SARS-CoV-2 exposure to symptom onset is 5 days [4,5,6]. According to data from China, an estimated 10–15% of mild cases progress to severe, and 15–20% of severe cases go on to become critical [3].

Identification of prognostic factors is important for reducing morbidity and mortality caused by the disease [2]. Due to limited antiviral treatment options for COVID-19, the severity of disease is closely related to the prognosis [7]. There is a significant difference between severe and non-severe patients with COVID-19 in terms of demographic features, clinical symptoms, comorbidities, laboratory parameters, complications, and outcomes [8,9,10]. The most important factors influencing the prognosis of patients with COVID-19 are discussed below and summarized in Fig. 5.1.

Fig. 5.1
The demographic features, comorbidities, clinical symptoms, laboratory markers, and complications of S A R S- C O V 2.

Risk factors associated with the prognosis in COVID-19 patients. CVD cardiovascular disease, COPD chronic obstructive pulmonary disease, CKD chronic kidney disease, ARDS acute respiratory distress syndrome, AKI acute kidney injury, ACI acute cardiac injury, NLR neutrophil-to-lymphocyte ratio, PLR platelet-to-lymphocyte ratio, CRP C-reactive protein, PCT procalcitonin, LDH lactate dehydrogenase, AST Aminotransferase, ALT alanine aminotransferase, IL-6 Interleukin 6

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Demographic Features

Age and Sex

COVID-19 causes infection in all age groups, although severe disease is more common in older adults [9]. Older age (>65) is closely associated with the worse prognosis of COVID-19 [7, 11]. The median age of hospitalized patients varies between 49 and 70 years and from 66 to 77 for fatal cases [12,13,14,15,16,17,18]. COVID-19 associated hospitalization by age is shown in Fig. 5.2.

Fig. 5.2
The pie chart represents the percentage of hospitalization by age during COVID-19. The maximum number of patients was in the age group of 0-4 years.

COVID-19 associated hospitalization by age, preliminary data as of 02 APR 2022 (COVID-NET). (Based on the data from [64])

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It was found that older age is significantly associated with the disease severity and endpoints including death, admission to intensive care unit (ICU), acute respiratory distress syndrome (ARDS), invasive ventilation, and cardiac abnormality [7, 19]. Increased age in patients with COVID-19 is the strongest predictor of death [20]. Elderly patients were more than twice as likely to have severe or critical illness when compared with middle-aged patients [21].

Moreover, it was indicated that ARDS, multiple organ failure, and death are more often in older subjects with pre-existing diseases including diabetes, hypertension, and cardiovascular disease. Reason for poor prognosis for elderly patients is probably associated with a higher frequency of comorbidities or/and age-related immune dysfunction resulting from low-grade chronic inflammation [8].

At advanced age, there is an increased risk of death for both sexes, but at all ages above 30 years males have a significantly higher risk of death than females [22]. The Global Health 50/50 research initiative, which presents an overview of sex-disaggregated data from countries worldwide, indicated that despite similar numbers of COVID-19 cases in men and women there is an increased case fatality rate in men [23]. Some studies indicated that up to 90% of severe cases were men [24].

Large-scale meta-analysis of more than 3 million global cases showed that male patients have almost three times the odds of requiring intensive care unit admission and higher odds of death compared to females [25]. ICU mortality in female COVID-19 patients was lower than in male patients (27% vs. 39% respectively), independent of age, disease severity, smoking, obesity, comorbidities, anti-infection/inflammatory therapy, and country [26]. Males had higher risk of reaching severe disease and adverse prognostic endpoints including death, ARDS, admission to ICU, invasive ventilation, and cardiac abnormality [19].

The cause of worse prognosis and death in males compared to females is probably associated with the protection of the X chromosome and sex hormones, which play an essential role in innate and acquired immunity [27, 28]. The greater predisposition of men to become infected with COVID-19 may result from differences in the levels of cell receptors (angiotensin converting enzyme) and molecules that assist the entry of SARS-CoV-2 through the fusion of the virus with the cell membrane (transmembrane serine protease 2) [29].

Ethnicity

Ethnic and race differences among COVID-19 patients’ hospitalizations and mortality have been widely reported. African-Caribbean (Black), Latin, and South Asian origin experience grater hospitalization and mortality from COVID-19 than white individuals [30, 31]. Single-site studies revealed that Black people were 1.7 to 2. times more likely to be hospitalized due to COVID-19 than White or other racial and ethnic minority groups [32, 33].

Meta-analysis of 45 articles indicated that race may be associated with COVID-19 outcomes because of the increased occurrence of comorbidities in racial and ethnic minority groups but did not confirmed ethnicity as an independent poor prognostic factor for COVID-19 [34]. However, this study did not analyze the role of socioeconomic determinants, which disproportionately affect racial and ethnic minority populations [35].

Ethnicities other than White were associated with higher COVID-19-related mortality in type 1 and type 2 diabetes [36]. It was found that comorbidities and socioeconomic status only partly contributed to greater admission risk of COVID-19 in Black and mixed ethnicity [37]. Asian patients had a higher risk of experiencing greater COVID-19 cardiorespiratory disease severity than non-Hispanic White patients [38]. Retrospective cohort study of more than one million of individuals, representing diverse racial and ethnic minority groups indicated that an increase incidence of severe COVID-19 among Black/African American and Hispanic individuals is due to higher infection rates, not increased susceptibility to the severe course of disease [39]. The authors concluded that the differences associated with COVID-19 among patients of different races are most likely due to social, not biological, factors [39].

Clinical Symptoms

COVID-19 infection is now recognized as a multisystem disease, causing a wide range of clinical manifestations [40]. Approximately 80% of all SARS-CoV-2 infected patients are asymptomatic or develop symptoms characteristic of mild or moderate pneumonia [41]. Approximately 15% of COVID-19 patients develop severe condition with viral pneumonia with the need of hospitalization. Only about 5% of cases develop critical illness, presenting acute respiratory distress syndrome, all types of shock or multiple organ failure, and require mechanical ventilation or admission to ICU; approximately 2% of cases are fatal [3, 42].

The most common clinical symptoms are fever, cough, dyspnea, fatigue, malaise, and sputum production [8, 43, 44]. Meta-analysis of 45 studies with 4203 patients indicated that the most common clinical symptoms are fever, cough, and dyspnea (80.5%, 58.3%, and 23.8%, respectively) [45]. Early recognition of severe infection may allow early medical intervention and improve outcomes in patients with COVID-19 [7].

Another meta-analysis of 20 studies and in 3326 patients with COVID-19 indicated that some initial symptoms including abdominal pain, dyspnea, hemoptysis, anorexia, diarrhea, fatigue, expectoration, fever, and cough occurred more frequently in severe COVID-19 patients than in mild COVID-19 patients [46]. Recent study indicated that clinical symptoms associated with critical illness were dyspnea, hypoxia, and hemoptysis [47]. Meta-analysis of 26 studies involving 7274 COVID-19 patients indicated that non-survivors in compering to survivors were more likely to present with dyspnea (66% vs. 34%), hemoptysis (4% vs. 3%), chest tightness (46% vs. 30%), expectoration (42% vs. 32%), and fatigue (50% vs. 44%). Moreover, dyspnea, hemoptysis, expectoration, chest tightness, fatigue, and sputum production were found to be significant risk factors of mortality [10, 48].

Patients with dyspnea were six times more likely to have an ICU admission and were more likely to die compared to those without dyspnea [43] what might relate to the fact that dyspnea is more common in COVID-19 patients with ≥2 comorbidities than in those with one comorbidity [49]. Dyspnea and hypoxemia may be developed in severe ill patients within 1 week after onset of the disease and may quickly progress to acute respiratory distress syndrome or end-organ failure [14].

Hypoxemia is an independent prognostic factor for the severe course of COVID-19 [50] and is associated with in-hospital mortality [51]. The study of Huang et al. indicated that 32% of COVID-19 patients showed varying degrees of hypoxemia [12]. The most serious manifestation is worsening arterial hypoxemia, eventually leading to acute respiratory distress syndrome promptly needing mechanical ventilation [3, 49]. Patients with fever had a higher risk of the worse course of COVID-19, mechanical ventilation, and mortality than those without fever [52,53,54]. Fever greater than 38.5 °C on admission was positively correlated with the severity and mortality of COVID-19 [55].

It was reported that the duration of fever was associated with the prognosis. The time from admission to a normal temperature was 7 days for patients with severe disease and 2 days for patients with mild disease [56]. Although respiratory manifestations are the most common, studies have reported that gastrointestinal symptoms including diarrhea, nausea/vomiting, and abdominal pain, are also frequent in patients with COVID-19, with a prevalence of up to 30% [57, 58]. It was indicated that gastrointestinal symptoms were strongly associated with severe COVID-19 disease and might be associated with the prognosis with COVID-19 [59,60,61]. Meta-analysis of 35 studies, including 6686 patients found that gastrointestinal symptoms were a significant risk factor for disease severity [61]. However, last meta-analysis including 53 studies and 55,245 COVID-19 patients found that gastrointestinal symptoms were not associated with higher mortality so the prognostic value of these symptoms in COVID-19 requires further investigation [62]. The prognostic value of gastrointestinal symptoms in COVID-19 might not be as significant as other factors such as age, concomitant diseases, and respiratory manifestations.

Comorbidities and the Course of COVID-19

The presence of comorbidities influences the prognosis and prolongs the recovery time. Individuals with underlying chronic disease have greater risk for severe course of COVID-19 and death [63]. Underlying comorbidities in COVID-19 patients were shown in Fig. 5.3 [64]. The most prevalent affecting the course of the COVID-19 disease and prognosis are hypertension, cardiovascular disease (CVD), diabetes mellitus, and respiratory diseases [8,9,10, 45, 65]. Recent systemic review including ten studies and 3912 participants indicated hypertension as the most common disease linked with the severe COVID-19 (59.3%), followed by obesity (48.7%), chronic lung disease (19.8%), metabolic disease (43.6%), and CVD (35.6%) [66]. Study by Hatmi et al. suggested that among comorbidities in COVID-19 patients the most powerful prognostic factors for mortality rate were pre-existing CVD, diabetes mellitus, respiratory disease, and hypertension. Whereas the most important prognostic factors for severity of COVID-19 were CVD and hypertension [3, 65, 67].

Fig. 5.3
The bar graph plot percentage versus medical condition. Hypertension has the maximum value and gastrointestinal, and liver disease has the minimum value.

Underlying comorbidities in COVID-19 patients (COVID-NET). Hospitalization data (March 2020–July 2021). (Based on the data from [64])

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COVID-19 itself also may induced cardiovascular complications such as myocardial injury, myocarditis, arrhythmias, acute coronary syndrome, and venous thromboembolism [66,67,68,69,70,71]. It was indicated that even small amounts of myocardial injury were associated with an increased risk of patient mortality [68]. Meta-analysis of 17 studies with a total of 5815 patients revealed that the most common cardiovascular complications in COVID-19 patients were heart failure, myocardial injury, cardiac arrhythmia, and acute coronary syndrome [69].

Evaluation of the early development of persistent myocardial injury is a useful prognostic tool in patients with severe COVID-19 [72]. Cardiovascular risk factors such as hypertension, diabetes mellitus, and obesity were associated with ICU admission and poor prognosis [66]. Interestingly that lipid disorders are not associated with the severe course of the disease, in opposite in patients in acute phase reduced cholesterol level is observed.

Hypertension

Hypertension is thought to be an independent risk factor for severe COVID-19 and a strong predictor of poor prognosis including ARDS, ICU admission and mortality [73, 74]. Hypertension is found to be the most common comorbidity in COVID-19 patient. Individual studies have shown that the prevalence of hypertension in fatal cases is from 39% to 65% [16,17,18, 75]. A systematic review indicated that COVID-19 patients with hypertension were two times more likely to require ICU admission and 1.7 times more likely to have more severe disease [74]. In a retrospective study of 803 COVID-19 patients with hypertension, high mean systolic blood pressure, and high variability of systolic / diastolic blood pressure during hospitalization were independently associated with mortality, ICU admission, and heart failure [76]. The prognosis for patients with hypertension is markedly worse when SARS-Cov-2 infection was complicated by myocardial injury and in the presence of CVD [77].

Diabetes Mellitus

Diabetes as a common underlying disease in COVID-19 patients is associated with worse prognosis [12, 78,79,80,81,82,83,84,85,86,87,88]. Diabetes in hospitalized patients with COVID-19 was reported in 3–25% of non-critical [80, 81] and in 15–31% of critical cases [7, 80, 81]. COVID-19 patients with diabetes mellitus have high risk of severe disease, ARDS, shock, multi-organ failure, death, and ICU admissions [80,81,82,83]. Recent meta-analysis with 344,431 COVID-19 patients indicated that the proportion of patients with diabetes was dramatically higher in the severe or non-survival group then in controls. Patients with diabetes had a 3.55-fold higher risk of progression of COVID-19 and 3.83-fold higher risk of mortality compared with those without diabetes [10]. Newly diagnosed diabetes was associated with higher mortality than known diabetes in hospitalized COVID-19 patients [84, 85]. Well-controlled diabetes correlated with a reduced risk of detrimental complications and all-cause mortality in subjects with COVID-19 and pre-existing diabetes [88].

Obesity

Obesity may also be a prognostic factor for severity of COVID-19 and fatal outcomes [89,90,91]. A meta-analysis of 208 studies and total of more than three million participants from over 32 countries revealed that overweight increased the risk of COVID-19-related hospitalizations but not death while obesity and extreme obesity increase the risk of both hospitalizations and death [92]. In the recent meta-analysis of ten observational studies with 10,233 COVID-19 patients the prevalence of obesity in persons with poor outcomes was 34% [93]. Patients with body mass index (BMI) >35 kg/m2 need seven times more often the use of mechanical ventilation compared [94]. Moreover, BMI >40 kg/m2 was found as an independent risk factor associated with mortality, more prominent in patients younger than 50 years [95].

Chronic Obstructive Pulmonary Disease (COPD)

Nationwide population study with 4610 patients indicated that COPD patients had higher risk of ICU care and mechanical ventilation than patients without COPD and the risk for all-cause mortality was approximately two times higher in patients with COPD than in those without [96]. The prevalence of COPD among COVID-19 patients ranges from 0 to 10% worldwide, but most reports are from China [49, 97, 98]. In Europe, the prevalence of COPD is 5.6–11% [99,100,101,102]. Progression to severe course of COVID-19 in COPD patients has ranged from 20 to 50% [49, 103, 104]. Mortality with COVID-19 and COPD is also lower compering to other major comorbidities (CVD, diabetes); whereas risk severity seems to be comparable (3–4 folds) [105, 106].

Chronic Kidney Disease

Chronic kidney disease (CKD) is one of the factors that significantly impact COVID-19 patients’ prognosis, and influence on the disease severity [106, 107]. Prevalence of CKD in patients with COVID-19 ranged from 0.4 to 49% [108]. Data on mortality in patients with COVID-19 and CKD are limited and varying from 16% to 53% [109, 110]. Recent review indicated that patients with CKD are more likely to have worse outcomes from COVID-19 compared to individuals without CKD [108]. More advanced CKD relates to higher risk of COVID-19 severity, hospitalization, and mortality [108].

Cancer

The prevalence of cancer among COVID-19 patients range from 0.29% to 2.6% [106, 111,112,113] and, mortality is estimated from 5% to 8.3% [106, 111] and research results regarding the prognostic significance of cancers in COVID 19 patients are inconclusive. Some studies have found comparable mortality rates between patients with cancer and those without cancer after adjusting for age and comorbidities [114, 115]. Recent large electronic health record based on US study reported higher rates of death among patients with COVID-19 and cancer compared to those without (14.9% vs. 5.26%) [112]. Studies regarding influence of cancer treatment for outcomes in COVID-19 patients are inconsistent [111, 116,117,118].

Recently published large cohort study indicated that patients with recent cancer treatment and COVID-19 had a significantly higher risk of adverse outcomes, and subjects with no recent chemotherapy and chemoimmunotherapy had similar risk of mortality and ICU stay and a lower risk of mechanical ventilation and hospitalization compared with COVID-19 patients without cancer [119]. It was also found that patients with metastatic solid tumors and hematologic malignant neoplasms had worse outcomes compared with patients with nonmetastatic solid tumors [119].

Special Conditions and Populations of Patients and the COVID-19 Course

Smoking

Smoking history is a high-risk factor for severe course and mortality among patients hospitalized for COVID-19 [65, 120]. Recent meta-analysis of 47 studies with a total of 32,849 hospitalized COVID-19 patients indicated that current smokers have an increased risk of admitting to hospital with severe COVID-19 and are approximately twice as likely to develop severe or critical COVID-19 as former or never-smokers [121]. Authors suspected that smokers are exposed to higher SARS-CoV-2 loads due to elevated expression of angiotensin converting enzyme 2 (ACE2), which may provide a mechanistic explanation for the higher risk of severe disease and mortality in smoking patients with COVID-19 [121, 122].

Mendelian randomization analyses of 281,105 White British subjects showed that genetically predicted propensity to initiate smoking was associated with 45% higher risks of SARS-CoV-2 infection (OR 1.45, 95% CI: 1.10 to 1.91) and 60% higher risk of hospitalization (OR 1.60, 95% CI: 1.13 to 2.27). Genetically predicted increase in number of cigarettes smoked per day was associated with higher risks of infection, hospitalization, and death [120].

Pregnancy

Physiological changes in the immune and respiratory systems during pregnancy may make pregnant women more susceptible to COVID-19 infection. Especially the first trimester of pregnancy may be the period most susceptible to SARS-CoV-2 infection due to early ACE2 expression associated with placental immaturity [123, 124]. Pregnant women with SARS-CoV-2 infection are at increased risk of ICU admission, mechanical ventilation, and death compared with both pregnant women without COVID-19 and nonpregnant individuals with COVID-19 [125,126,127,128]. Retrospective cohort study with 14,104 patients indicated that a composite outcome of maternal death or serious morbidity associated with hypertension in pregnancy, postpartum hemorrhage, or infection other than SARS-CoV-2 occurred significantly more common in women with COVID-19 compared with individuals without COVID-19 [129].

Children

Children can be infected as easily as adults but are more often asymptomatic and have milder course of disease due to their immature immune systems [130]. A small percentage (<7%) of children admitted to the hospital for COVID-19 develop severe disease requiring mechanical ventilation [131]. The risks factors for the infection of SARS-CoV-2 and the severity of disease are children age and comorbidities [131]. Young infants and older adolescents had higher risk of developing severe disease [131, 132]. Additionally, older children may develop multisystem inflammatory syndrome (MIS-C) with severe disease [133]. This multisystem inflammatory syndrome in children is uncommon (2 in 100,000 persons aged <21 years) [134].

Selected Laboratory Parameters Values and the COVID-19 Course

Leukocyte Counts

Elevated leukocyte count (≥9.5 × 109/L) is associated with course of COVID-19 disease [14, 49]. Leukocytosis was observed in 28.1% to 68.1% of patients, depending on the severity of the disease and comorbidities [135,136,137,138]. Patients with severe and fatal COVID-19 had significantly increased leukocyte count compared to non-severe disease and survivors [49, 139, 140]. Leukocyte counts were found to be a prognostic marker in diagnosis of progression to serious or severe disease in COVID-19 patients [141]. A meta-analysis of 45 studies identified that elevated leukocyte predicted ICU admission and mortality [45]. Another meta-analysis on 21 studies including 3377 patients indicated that patients with severe disease had a mild increased in leukocyte level (WMD: 0.41 × 109/L), while patients who died had higher level of this parameter (WMD: 4.15 × 109/L) [139]. Meat-analysis of 13 studies with 3027 participants indicated that white blood cells (WBC) < 4 × 10 9/L predicted better clinical status in COVID-19 patients [9]. Myari et al. assessed that WBC belong to one of the most efficient indicators of critical disease [142]. Current evidence suggests that although leukocyte counts can be used as a predictor factor for severe COVID-19 condition, however, other factors should be also taken into account [143].

Lymphocyte Counts

Decreased level of lymphocytes is one of the typical characteristics of SARS-CoV-2 infection, which is associated with poor outcomes [144]. Lymphopenia was observed in up to 96.1% of severe COVID-19 patients, and its degrees correlate with the intensity of proinflammatory cytokine storm, disease severity, and outcome [7, 145,146,147]. A meta-analysis of 28 studies involving 6449 COVID-19 patients demonstrated that lymphopenia (<1500 lymphocytes/μL) had nearly threefold higher risk of poor outcomes compared with better outcomes [148]. Study on peripheral lymphocyte subset alteration in COVID-19 indicated that severe ill patients had lower total lymphocytes CD4+ T cells, CD8+ T cells, and B cells in compering to patients with mild illness. CD8+ T cells were found to be a potential predictor of COVID-19 severity [149].

Decrease of T-lymphocyte subsets was associated with in-hospital death and severe course of COVID-19. Lower counts of T lymphocyte subsets; lymphocyte (<500/μL), CD3 +T-cell (<200/μL), CD4+ T-cell (<100/μL), CD8+ T-cell (<100/μL), and B-cell (<50/μL) were linked to higher risk of in-hospital death. The alarming values that can predict in-hospital death of lymphocyte, CD3+ T-cell, CD4+ T-cell, CD8+ T-cell, and B-cell were 559/μL, 235/μL, 104/μL, 85/μL, and 82/μL, respectively [150].

Neutrophil Counts

Neutrophil count was found to be a prognostic marker in diagnosis of progression to severe and critical disease in COVID-19 patients [141, 142]. Meta-analysis of 34 studies and 344,431 participants revealed that increased neutrophil count is significantly higher in the severe group than in the non-severe [10]. Neutrophilia was found to be associated with both ARDS development and progression to death [54]. A meta-analysis of 6320 patients found that neutrophil counts identified severe patients with 100% sensitivity and 81% specificity at a cut-off value of >3.74 × 109/L [141]. It was found that neutrophil-to-lymphocyte ratio (NLR) is one of the powerful prognostic factors of an early identification of severe COVID-19 [152]. Increase in NLR is commonly observed in COVID-19 patients and is associated with poor clinical outcomes [146, 153].

A scoping review of 529 studies involving 165,020 patients from 28 different countries investigating the correlation between initial laboratory values with mortality and disease severity in COVID-19 indicated that among many reported laboratory values, NLR was the most frequent statistically significant laboratory parameter in predicting disease severity [154].

Study of Liu et al. reported that NLR could be an independent predictor of mortality and the risk of in-hospital mortality was higher by 8% for each unit increase in NLR. This risk was independent of other risk factors of death such as older age, comorbidities, and high level of D-dimer [140, 152]. The cut-off value of NLR (7.4) allowed predicting mortality with high accuracy [155]. Another study revealed that high NLR (≥10) and D-dimer (≥2.0 μg/mL), especially when combined, are strong predictors of death risk for patients with severe COVID-19 [156]. NLR is not only important to stratify the severity of the disease, but also to predict mortality in severe cases [156].

Platelet Counts

Low platelet counts were commonly observed in SARS-CoV-2 infections, it can be detected in almost half of the COVID-19 patients and in almost 95% of those critically ill [10, 157]. Thrombocytopenia usually occurs more than 10 days after the onset of symptoms [150]. The meta-analysis of Zong et al. revealed the association between thrombocytopenia and three-fold enhanced risk of a composite outcome of ICU admission, progression to ARDS, and mortality [158]. Several other studies confirmed that low platelets counts may be predictive markers of the severity of COVID-19 [159, 160]. It was found that platelet count is an independent risk factor of mortality among COVID-19 patients, where a 50 × 109/L increase is associated with 40% decreased mortality [148, 161]. Some authors suggested the value of 150 × 109/L as a cut-off level for platelet count to predict poor prognosis [151]. Among the most common hematologic parameters with evidenced prognostic value in diagnosis of progression to serious or severe disease in COVID-19 patients belongs also platelet-to-lymphocyte ratio (PLR) [162, 163]. Systematic review reported that an elevated PLR is associated with severe illness in COVID-19 patients compering to those with mild disease however cut-off levels for this parameter differ significantly in studies [162, 164,165,166]. Recent systemic review and meta-analysis revealed that elevated level of PLR on admission in COVID-19 patients is associated with higher morbidity and mortality but further studies regarding the cut-off value of PLR are needed [167].

C-Reactive Protein (CRP)

C-reactive protein after lymphopenia is the most frequently described prognostic biomarker in COVID-19 [148, 168,169,170]. Meta-analysis of 20 studies including 4843 COVID-19 patients, indicated that elevated CRP (>10 mg/L) is associated with nearly fourfold higher risk of poor outcomes [148]. Another study found that median concentration of CRP was nearly ten-fold higher in critically ill patients compering to mildly ill patients [171]. A study of 1834 COVID-19 patients from Italy and the United Kingdom showed that CRP levels ≥40.0 mg/L were associated with 31.9% mortality, whereas mortality in patients with CRP levels <40.0 mg/L was 15% [172]. High levels of CRP are prognostic markers of disease progression and a risk factor for mortality of severe COVID-19 patients and are indicators of a developing cytokine storm [168,169,170,171,172,173,174,175].

Procalcitonin (PCT)

Procalcitonin is a promising prognostic biomarker of COVID-19 progression [176]. Patients with increased procalcitonin levels are at high risk of progression to critical illness [9]. Increased PCT values are associated with a nearly five-fold higher risk of severe COVID-19 and may have been a marker of bacterial coinfection, thereby resulting in complications of COVID-19 and hence a higher rate of ICU admission in these patients [171, 177]. Single study of Hu et al. indicated that serial PCT measurements may be helpful in predicting the prognosis [178]. The cut-off value of 0.16 ng/mL for PCT predicted mortality with high accuracy [155].

Lactate Dehydrogenase (LDH)

Meta-analysis of 18 studies with 5394 patients showed that elevated LDH values are associated with approximately fivefold more risk of poor outcomes in COVID 19 patients [148]. Similarly study of Henry et al. indicated that elevated LDH levels were associated with six-fold increase odds of severe disease and a 16-fold increase in odds of mortality in COVID-19 patients [139]. A meta-analysis of 45 studies identified that elevated LDH predicted mortality and was the only laboratory parameter which predicted both ARDS and ICU admission [45]. Another meta-analysis of 10,399 patients from 21 studies indicated that the association between LDH elevation and poor prognosis was not affected by age, gender, hypertension, or diabetes [179]. The value of 280 U/L is suggested as a cut-off level for LDH to predict poor prognosis [151]. Moreover, LDH levels >400 U/L on admission to the hospital were independently associated with the severity of the disease, so measuring the LDH value at the beginning of the infection may be a biomarker of severe and critical course of COVID-19 [180].

Interleukin 6 (IL-6)

Interleukin 6 may be increased in COVID-19 patients, and it was indicated as an important marker of disease severity and predictor of mortality [181], and its expression time is longer than other cytokines (TNF and IL-1) [182]. Increased IL-6 was recorded in 87% of severe cases [50]. When identifying patients at high risk for severe COVID-19, a cut-off value for IL-6 greater than 55 pg/mL was indicated. Critically ill patients have significantly higher IL-6 levels compared with moderate and severe patients. IL-6 > 80 pg/mL predicts respiratory failure and need for mechanical ventilation [175] and value of ≥100 pg/mL was associated with mortality in COVID-19 [183, 184]. The concentration of IL-6 > 24 pg/mL at initial assessment predicted the development of hypoxemia requiring hospitalization [185]. The currently accepted theory is that overexpression of IL-6 has a crucial role in the induction and propagation of cytokine storm leading to lung injury and ARDS [186,187,188,189].

D-Dimer

D-dimer levels are associated with COVID-19 severity and in-hospital mortality [190]. Elevated D-dimer levels are common in patients with COVID-19, suggest extensive thrombin generation and fibrinolysis and are revealed almost three-fold higher risk of poor outcomes [148, 191, 192]. Meta-analysis of six studies indicated that COVID-19 patients with elevated D-dimers have worse clinical outcomes including all-cause mortality, ICU admission, and acute respiratory distress syndrome [193]. D-dimer level that could predict worse prognosis in COIVD-19 patients varies in literatures between >1 mg/L and >2.14 mg/L [7, 194]. It was proposed that a level of >2.0 mg/L on admission could predict death [194, 195]. COVID-19 patients with high D-dimer levels have longer hospitalizations in ICU and lengths of hospital stay [7]. Monitoring the dynamic changes of D-dimer is a useful marker in predicting the prognosis of COVID-19 patients, and peak D-dimer levels were strongly associated with mortality [196].

Ferritin

Elevated levels of serum ferritin were associated with the development of severe outcomes and mortality in COVID-19. Serum ferritin was proposed as one of the markers for potential progression to critical illness [139]. A single study of 141 patients with COVID-19 indicated that elevated ferritin (>500 μg/L) was observed in all severe patients on admission, and the mild patients had a normal mean serum ferritin level; moreover, severe patients and patients who needed admission to the ICU had higher ferritin levels than the mild patients (2.6 times and 5.8 times, respectively) [197]. It was showed that each 0.1 mg/L increase of ferritin was associated with 3% shortened ICU survival time [198]. Serum ferritin levels were reported to be significantly increased in non-survivors vs. survivors (WMD: 760.2 ng/mL) and as compared to severe vs. non-severe disease (WMD: 408.3 ng/mL) and were suggested as a parameter to be used for monitoring prognosis in COVID-19 patients over the course of hospitalization [193]. Non-survivors showed ferritin levels on admission around 1400 ng/mL, which is between 3 and 4 times higher than that observed in survivors [199]. Meta-analyses revealed that high ferritin levels were associated with severe COVID-19 mortality and development of ARDS as well as with thrombotic complications [200, 201].

Albumin

Albumin levels were found to be a predictive biomarker for outcomes in COVID-19 patients [202,203,204]. Decreased levels of albumin are among the most common abnormal laboratory findings in COVID-19 patients [151]. Low serum albumin concentrations in critical illness have been associated with poor outcomes. Hypoalbuminemia (<3.5 g/dL) is present in 74% of patients with severe COVID-19 [205]. It was found that hypoalbuminemia was an independent predictor for mortality in COVID-19 patients [206, 207]. Similarly, a multicenter retrospective cohort study of 1555 COVID-19 patients indicated that low serum albumin levels on admission were associated with a higher risk of all-cause mortality within 30 days of hospitalization. Albumin levels below 2.5 g/dL were associated with an almost 60% higher <30 days in-hospital all-cause mortality [208]. Patients with higher albumin levels on admission had a 72% decreased risk of developing venous thromboembolism for every 1 g/dL increase of albumin. Moreover, higher albumin levels on admission were associated with a lower risk of developing ARDS, admission to the ICU and fewer total adverse events [209].

Aspartate Aminotransferase (AST) and Alanine Aminotransferase (ALT)

Meta-analysis of 18 studies with 6,383 patients reported that elevated AST (>40 IU/L) values are associated with nearly threefold higher risk of poor outcomes in COVID-19 patients [148]. Similarly, elevated ALT (>40 IU/L) were associated with twofold increased likelihood of poor outcomes [148]. Patients with abnormal liver enzyme tests at the time of admission had a higher rate of transfer to the ICU (20% vs. 8%), need for mechanical ventilation (14% vs. 6%), acute kidney injury (22% vs. 13%), and mortality (21% vs. 11%) compared to patients with normal results [210]. In contrary, Huang et al. did not find any difference in AST and ALT values between severe and no severe cases [12]. Similarly, studies of Aloiso et al. did not confirm prognostic values of ALT in COVID-19 patients [202, 211]. Thus, the role of liver enzymes as prognostic biomarkers is debatable and probably have minimal clinical significance [212].

Cardiac Troponin

Troponin is one of the biomarkers of cardiac injury. In the study of Shi et al. elevation of cardiac troponin I (cTnI) > 28 pg/mL was an independent risk factor for COVID-19 severity and mortality [213]. Elevated troponin levels were rare in COVID-19 patients with a mild course (1–20%), common in severe patients (46–100%), and frequent in the critically ill and fatal outcomes [213,214,215]. Patients with underlying CVD and increased troponin levels had the higher mortality almost 70% compared to patients with only one of these two risk factors [82].

Elevated levels of cTnI remain an independent predictor of death compering to other elevated acute phase proteins and inflammatory markers in patients with CVD [68]. In the study of Peiró et al. cardiac troponin I was a significantly better predictor for 30-day all-cause death compared to other inflammatory biomarkers such as CRP, D-dimer, and lactate dehydrogenase, and the level as low as 21 ng/L was able to provide excellent prediction capacity [216].

Complications

Complications (early, not associated with the long COVID) are another risk factors associated with death among critically ill patients. Common complication in COVID-19 patients include acute respiratory distress syndrome, acute kidney injury (AKI), acute cardiac injury (ACI), thrombosis, gastrointestinal complications, neurologic complications, sepsis, shock, multi-organ failure, and secondary infections [47, 217, 218]. Experiencing adverse complications has a high risk of COVID-19 mortality. Study of Yang et al. indicated that 67%, 29%, 29%, and 23% of hospitalized COVID-19 patients, experienced adverse complications such as ARDS, AKI, liver dysfunction, and ACI, respectively. Of patients developing ARDS, AKI, ACI, and liver dysfunction adverse complications, 74%, 80%, 75%, and 60% of them died, respectively [15].

Meta-analysis of 12 studies with a total of 3064 COVID-19 patients indicated that the most common complications were acute respiratory distress syndrome (30.93%) followed by acute liver injury (22.8%), shock (10.9%), acute kidney injury (7%), and acute cardiac injury (6.4%). Older populations were a high-risk group of developing adverse complications. It was revealed that as the mean age increased by 1 year, the ARDS, AKI, ACI, and shock increased by a factor of 2.9 [219]. Development of ARDS and progression from ARDS to death is associated with risk factors such as older age, neutrophilia, organ, and coagulation dysfunction [220]. Cardiovascular complications in COVID-19 patients may include myocardial injury, heart failure, arrhythmias, acute coronary syndrome, and venous thromboembolism [66, 221, 222]. Meta-analysis of 3044 confirmed COVID-19 cases from 12 studies indicated that the most common cardiovascular complications were myocardial injury (21.2%) and arrhythmia (15.3%), then heart failure (14.4%) and acute coronary syndrome (1.0%). Myocardial injury and heart failure were more frequent in non-survivors, regardless of a history of CVD [221]. Cardiac complications, which are becoming more prevalent with the progress in the study of COVID-19, influence the development and prognosis of disease.

Reinfection

It was thought that individuals who recovered from COVID-19 generate a robust immune response and develop protective immunity; however, since August 2020, numerous cases with reinfection have been documented [223,224,225]. Positive COVID-19 antibodies after infection can provide protection against reinfection in most studied patients [226]. Cases of reinfection in patients are relatively rare [227], however, in the time of omicron there were many new cases of reinfection.

A systematic review indicated 17 cases of individuals infected with different genetic strains of SARS-CoV-2 confirmed by PCR. The results indicated that reinfection with different strains is possible, and the second episode of the infection might be more severe in nearly 20% of patients and result in serious complications in elderly and immunocompromised [86]. At present it is unclear how long serum antibodies and virus-specific T cells persist after infection, how common reinfection with SARS-CoV-2 can be and whether it occur in individuals with detectable immune memory [228, 229].

Conclusions and Take-Home Message

Prognosis in COVID-19 patients is closely related to the severity of disease. Between patients with severe and none-severe course of the disease significant difference exists in terms of demographic features, clinical symptoms, comorbidities, laboratory parameters, and complications. Laboratory biomarkers are fast and easy to obtain and preferred modality to monitor and predict prognosis of disease. Continuous controlling of laboratory parameters is essential to identify those patients who may progress to severe status and allow timely preventative efforts and optimization of high-risk patients. Knowledge on COVID-19 prognostic factors is constantly changing (however, hypertension, obesity, diabetes, COPD, seems to be the ones that occur the most often in the available analyses); new biomarkers are analyzing which could be useful in COVID-19 prognosis [230,231,232,233,234,235,236]. Available data also suggest that the optimalization of the underlaying conditions and risk factors may significantly decrease the risk of severe COVID-19 course [230,231,232,233,234,235,236]. The creation of a machine learning system to fully analyze the profile of a patient with COVID 19, both in terms of demography, comorbidities, previous infections, and the concentration of laboratory biomarkers, may be an option for early detection of patients at risk of severe COVID-19 requiring hospitalization.