key: cord-0430862-x9tw1m3u
authors: Padhi, A.; Shaw, D.; Khatoon, S.; Ranjan, S.; Bhargava, A.; Negi, S. S.
title: A hospital-based study to assess various biomarkers for prognostic prediction of clinical outcome in COVID-19 disease.
date: 2022-05-27
journal: nan
DOI: 10.1101/2022.05.25.22275583
sha: 83af0562b8fb7f82765b9114a2d7d844c88c3174
doc_id: 430862
cord_uid: x9tw1m3u

Abstract: COVID-19 pandemic has inflicted a painful unforgettable number of deaths throughout the world. Hematological inflammatory and organ-specific biomarkers are universally practiced in helping clinical decisions in various infectious diseases. Accordingly, their role in predicting progression and severity, and fatal outcome of COVID-19 was investigated to take initial appropriate treatment measures to reduce associated mortality. Methods: The retrospective analysis of a total of 126 COVID-19 cases representing mild, moderate, severe, and succumbed cases were assessed for the pattern of hematological, inflammatory, and organ-specific biomarkers. Results: A total of 126 proven cases of SARS-CoV-2 infection were retrospectively analyzed for the association of various biomarkers with the COVID-19 disease progression. The CBC analysis showed that the median TLC was high for the severe group of both males (12.49 x 103/mcl) and females (14.23 x103/mcl). Similarly, the neutrophil count was also found high in the severe group, whereas the monocytes count showed low median values in severe cases, but both these parameters had no significant difference among the males and the females. The platelet count showed a significant difference (p=0.018) among the non-severe and severe groups between males and females. Among inflammatory markers, D-dimer, CRP, LDH, and APTT showed a higher median value in severe cases among both the males and females while ESR value was higher in non-severe cases and ferritin showed similar values in both severe and non-severe cases. The liver and kidney function parameters were also analyzed and a significant P-value was found for ALP (p=0.004), ALT (p=0.032), and AST (p=0.009) in the non-severe vs. severe category of COVID-19 patients. Discussion: High TLC, neutrophilia, lymphopenia, thrombocytopenia, and eosinopenia are the potential risk factor for the progression of COVID-19 disease for severe and fatal outcomes. Inflammatory markers of D-dimer, CRP, LDH, APTT, and ferritin above normal range also carries the potential risk of severe and fatal outcome in COVID-19 disease. Higher ALT, AST, and serum creatinine may also carry a poor prognosis.

In December 2019, the first case of COVID-19 clinically presented with atypical pneumonia was reported from China (Wuhan) (1) . Uncertainly throughout the world, the alarming rise in COVID- 19 h a s been encountered. On 11 th March 2020, World Health Organization (WHO) declared COVID-19 is a global pandemic that devastated humanity worldwide and inflicted an unprecedented dramatic loss of millions of lives (2) . As of 20 th May 2022, globally, the cumulative confirmed cases were 521,920,560, including 6,274,323 deaths (3).

These figures were 43,131,822 for confirmed cases in India, including 524,323 deaths. (3) COVID-19 pandemic has continuously shown its catastrophic effect as morbidity and mortality are still being reported from various affected countries, including India.

Based on the COVID-19 treatment guideline, the disease was clinically categorized from asymptomatic to mild/moderate, and severe presentation poses a challenge to understand its progression in the patients and better preparedness to prevent worsening of COVID-19 infection succumbed cases (4) . Various literature suggests that host cellular factors and virus components were involved in the pathogenesis of the COVID-19 disease, leading to the upthe surge of the various biological parameters indicating the level of tissue damage or infection (1, 5, 6) .

Thus, understanding the different diagnostic biomarkers might predict COVID-19 disease severity which may play a crucial role in the effective and appropriate therapeutic management of the infected cases before their progression reach a severe and subsequent fatal stage (7, 8) Various hematological, biochemical, inflammatory, and immunological biomarkers have been studied and reported from across the globe for a better understanding of COVID-19 pathogenesis to identify, stratify, and predict their prognostic efficacy in guiding the better medical management (9) . Since these laboratory biomarkers are cost-effective, they may have the potential . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted May 27, 2022. ; https://doi.org/10.1101/2022.05.25.22275583 doi: medRxiv preprint preferred modality existing before us to provide the early indication of deciding and devising the treatment management strategies to prevent the possible further progression of mild/moderate into severe and fatal stage of highly unpredictable COVID-19 disease (9, 10) .

Several published literature has shown an elevated level of white cell count (WBC), creatinine, liver function test (LFT), kidney function test (KFT) markers, C-reactive protein (CRP), D-dimer, erythrocyte sedimentation rate (ESR), ferritin, interleukin-6 (IL-6), neutrophils whereas the decreased level of lymphocytes and thrombocytes were associated with severe and fatal cases of COVID-19 (11) (12) (13) (14) (15) . However, the various factors like geographical variation and associated immune response emergence of multiple mutants of SARS-CoV-2 restrict these studies' findings from being generalized for the prognostic indication (16) (17) (18) . Moreover, there is no 

Retrospectively, a total of 126 proven cases [positive for the presence of SARS-CoV-2 virus in their clinical specimen of nasopharyngeal and oropharyngeal swabs by real-time polymerase chain reaction (RT-PCR)] of COVID-19 patients who were admitted to AIIMS Raipur between March to June 2021 during the second wave of the COVID-19 pandemic in India were included in the present study. According to the criteria and advisory issued by the Ministry of Health & Family Welfare, the patients were categorized into two groups such as non-severe (mild and moderate) and severe (critical and death) (19) (20) (21) . Severe patients were admitted to the Intensive care unit (ICU) with oxygen support, and non-severe patients were kept in the isolation ward with regular observation and medication.

All the patient's laboratory findings include complete blood count (CBC), inflammatory markers [D-Dimer, ESR, CRP, lactate dehydrogenase (LDH), ferritin, and activated partial thromboplastin time (aPTT)], liver function test (LFT), and kidney function test (KFT) were collected. Hematological tests were performed using the Mindray BC-6800 system through the electrical impedance method. D-dimer was detected using Enzyme-Linked Immunosorbent Assay (ELISA). CRP value was obtained using the electrochemicalilumisence method on Cobas 702

Autoanalyzer.

Outcome analyses for different biomarkers were performed in the COVID-19 mild, moderate, critical, and death categories associated with females and males. Further, with the total number of enrolled cases (n=126), the combined category [non-severe (mild+ moderate) and severe (critical+ death)] analysis was performed.

The present study was approved by the Institutional Ethical Committee (IEC), All India Institute of Medical Science (AIIMS), Raipur on IEC number AIIMSRPR/IEC/2021/705.

. CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) Descriptive analysis, including normality tests, was carried out for all variables using Jamovi (version 1.6.23.0). Shapiro-Wilk test was performed to analyze the Gaussian distribution of the dataset. Median was used to depict as the data did not normally distribute. To evaluate the a significant difference between the groups Mann-Whitney-U test (not normal distributed) and the Student t-tests (normal distributed) were used. Box plots were constructed using GraphPad Prism (Version 7) for each biological parameter.

Among the total enrolled proven COVID-19 patients (n=126) cases, 46 cases were female and 80 were male. Among the total cases (n=126), fifty patients (thirty-four males and sixteen females) unfortunately death to COVID-19 infection during their treatment. From the remaining cases (n=76), twenty patients were categorized in the mild category, including female (n=10) and male (n=10), twenty-one cases belonged to the moderate category, including female (n=7) and male (n=14), and thirty-five patients belong to the critical category including female (n=13) and male (n=22). In the combined category, forty-one patients [mild (n=20) and moderate (n=21)] were designated as a non-severe group, whereas the remaining eighty-five patients [critical and death] belong to the severe.

Hemoglobin (Hb): The median value was low, i.e., 10.80 g/dl in non-severe females, and was a little high, i.e., 11.30 g/dl in severe COVID-19 females, whereas approximately similar in nonsevere and severe COVID-19 males, i.e., 13.7 and 13.1 g/dl, respectively. A statistically significant value was found between the female and males in the non-severe (p= 0.003) and severe (p<0.001) cases, whereas no significant difference was observed in the case of non-severe vs. severe (p= . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)

The copyright holder for this preprint this version posted May 27, 2022. ; https://doi.org/10.1101/2022.05.25.22275583 doi: medRxiv preprint 0.523) COVID-19 cases ( Figure 1 , Table 1 ). The range of variation in Hb was high in dead (8.3-16 g/dl) compared to moderate (10.3-16.5 g/dl) and mild (9.1-15.5 g/dl) and low in critical (11.9-16.5 g/dl) COVID male patients. The range of variation in Hb was less in a female with mild (8.1-11.6 g/dl) symptoms compared to moderate (6.5-16.2 g/dl), critical (7.7-15.5 g/dl), and dead (7.1-15.2 g/dl) COVID-19 patients.

The median TLC value was low for the non-severe group of both females and males, i.e., 10 x 10 3 /µl and 12.37 x 10 3 /µl, respectively. Similarly, the median TLC value was high for the severe group of both females and males, i.e.,12.49 x 10 3 /µl and 14.23 x 10 3 /µl. However, no significant differences were observed between males and females in the nonsevere (p= 0.701) and severe (p= 0.141) cases, whereas a significant P-value was found in the case of non-severe vs. severe (p= 0.022) patients ( Figure 1 , Table 1 ). The range of variation in TLC was more in dead (3.1-32 x 10 3 /µl) COVID-19 female patients compared to critical (4.56-23.7 x 10 3 /µl), mild (5-16 x 10 3 /µl), and moderate (11.5-20.8 x 10 3 /µl) cases. The range of variation in TLC was less in mild (4.52-15.6 x 10 3 /µl) and critical (5.11-18.2 x 10 3 /µl) COVID-19 patients and a higher difference was observed in dead (3.24-40.7 x 10 3 /µl) and moderate (4.4-30.2 134 x 10 3 /µl).

The median neutrophils were found to be low in non-severe males (77.51 %) and females (84%) compared to severe COVID-19 males (91.31%) and females (90%). No significant differences were observed between males and females in the non-severe (p= 0.451) and severe (p= 0.169) cases, whereas a significant P-value was found in the case of non-severe vs. severe (p<0.001) patients ( Figure 1 , Table 1 ). The range of variation in Neutrophils was found to be less in moderate (77-94.2%) and dead patients (78-96.3%) and high in critical (48.3-95.5%) and mild . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)

The copyright holder for this preprint this version posted May 27, 2022. ; https://doi.org/10.1101/2022.05.25.22275583 doi: medRxiv preprint (56-87%) COVID positive females. In the case of male COVID patients, the range of variation was more in moderate (52.5-96.2%) and critical (53.3-96.4%) patients.

The median lymphocyte was higher in non-severe females and males, i.e., 12.5% and 13.85 %, respectively, while a low median was observed in the case of severe COVID-19 females and males, i.e., 6.9% and 3.3% respectively. The P-value between females and males for non-severe (p=0.771) and severe (p=0.114) cases were non-significant, whereas significant (p<0.001) was observed between non-severe vs. severe. (Figure 1 , Table 1 ). In females, the range of variation in lymphocytes was noticed less in moderate (3.3-10.7%) patients compared to mild 

The median monocyte was found to be high in non-severe females, i.e., 7.8%, and was low in non-severe males, i.e., 5.8%. The median monocyte value was the same in severe COVID-19 females and males, i.e., 3.8%. Further, no significant difference was observed in monocyte between males and females of non-severe (p=0.723) and severe (p=0.956) groups, while in nonsevere vs. severe, a significant statistical p<0.001 was observed. (Figure 1 , Table 1 ). The range of variations in critical cases of females (1.4-12.8%) and males (1.7-19.6%) were high compared to mild, moderate, and dead COVID-19 cases.

The median eosinophils were similar in non-severe (2.4%) and severe (2.1%) females. In the case of males, the median eosinophils were found to be high in severe patients (1.9%) compared to non-severe males (1.9%). A significant difference was found in the severe group between male and female patients (p=0.019) ( Figure 1 , Table 1 ). Like monocytes, the range . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted May 27, 2022. ; of variation in eosinophil count was more in the critical group of both females (0.1-4.69%) and 164 males (0.1-7.2%).

The median platelet value was high in severe males, i.e., 284 x 10 3 /µl, and was low in non-severe COVID-19 males, i.e., 203.5 x 10 3 /µl. The median platelet value was low in severe females, i.e., 221.6 x 10 3 /µl, and was high in non-severe COVID-19 females, i.e., 271 x 10 3 /µl. A a significant difference was observed in platelet count in the non-severe group between males and females (p=0.018) ( Figure 1 , Table 1 ). The platelet count difference was higher in death COVID-19 cases of both females (60-385 x 10 3 /µl) and males (21-1824 x 10 3 /µl).

The median D-dimer value was 0.8 and 0.54 µg/ ml in non-severe females and males.

The value was high in severe female and male COVID-19 patients, i.e., 1.69 and 2.81 µg/ ml, respectively. Significant P-value was found in non-severe vs. severe (p<0.001) and in severe COVID-19 patients female vs. males (p=0.002) COVID-19 patients. (Figure 2 , Table 1 ).

The median CRP value was low, i.e., 27.00 mg/l in non-severe males, and was high, i.e., 64.01 mg/l in severe COVID-19 males. Similarly, the median CRP value decreased, i.e., 59.48 mg/l in non-sever females, and was high, i.e., 74.27 mg/l in severe COVID-19 females. CRP level difference was found non-significant in all the three categories studied, i.e., non-severe female vs. male (p=0.103), severe female vs. male (p=0.435), and non-severe vs. severe (p=0.104). The range of variation was less in females (0.18-2.71 mg/l) with critical symptoms and was high in dead COVID positive males (0.73-8.8 mg/l) ( Figure 2 , Table 1 ).

The median was low in the non-severe group of females (562 u/l) and males (355 u/l), whereas a higher median was found in cases of females (601 u/l) and males . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

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(600 u/l). LDH values were found statistically significant in non-severe females vs. males (p=0.001) and non-severe vs. severe (p<0.001), while no significant difference was observed in the severe group of females and males (p=0.451). The range of variation was less in the female with critical (316-640 u/l) symptoms and was high in mild (132-1032 u/l) and dead (374-1207 u/l).

The range of variation was less in males with moderate (281-642 u/l) symptoms and was high (259-1393 u/l) in dead COVID positive males ( Figure 2 , Table 1 ).

The median ESR value was high, i.e., 74 mm/hr in non-severe males, and was low, i.e., 50 mm/hr in severe COVID-19 males. Similarly, the median ESR value was high, i.e., 67.50 mm/hr in non-severe females, and was low, i.e., 55 mm/hr in severe COVID-19 females. The P-value was found non-significant in female vs. male non-severe (p=0.589) and severe (p=0.287), whereas a significant P-value was noted in non-severe vs. severe (p=0.028) COVID-19 patients. The range of variation was low in a mild case of females (42-150 mm/hr) and males (14-105 mm/hr). However, it was high in critical (15-140 mm/hr) and dead (5-130 mm/hr) females and dead (5-140 mm/hr) in male COVID-19 patients ( Figure 2 , Table 1 ).

The median APTT value was less, i.e., 31.45 sec in non-sever females, and was high, i.e., 32.9 sec in severe COVID-19 females. The median APTT value was a little high, i.e., 32.85 sec in non-sever males, and was low, i.e., 30.85 sec in severe COVID-19 males. No significant difference was observed in all the categories, i.e. nonsevere (female vs. male; p=0.642), severe (female vs. male; p=0.498) and non-severe vs. severe (p=0.199) ( Figure 2 , Table 1 ). The range of variation was less in mild and moderate cases of COVID-19 in females and males.

Ferritin: The median ferritin value was similar to both non-severe (female-524 ng/ ml and male 819 ng/ml) and severe (female-512 ng/ ml and male 811.55 ng/ml). A significant P-value was . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted May 27, 2022. noted in non-severe (female vs. males; p<0.001) COVID-19 patients ( Figure 2 , Table 1 ). The variation range was less in females with severe symptoms and was high in mild, moderate, and dead COVID-19 positive females. The variation range was less in males with mild symptoms and was high in moderate COVID-19 positive males.

Various parameters for KFT (Urea, Creatinine, Uric acid, Sodium, Potassium, and Chlorine) were assessed. In the non-severe category (females vs. males), patients showed no significant difference in any KFT markers (Table 1 and Figure 3 ). In the severe category (females vs. males), all the KFT markers showed no significant P-value except for creatinine (P=0.021) and uric acid (P=0.004); a a significant difference was observed. In the case of non-severe vs. severe COVID-19 patients, a a significant difference was observed in the values of urea (p=0.002), uric acid (p<0.001), sodium (p<0.001), potassium (p=0.042) and chlorine (p<0.001) whereas no difference was seen in creatinine between male and female patients(p=0.4000).

The LFT was evaluated by screening all included patients with mild, moderate, severe, and dead patients' group on various parameters, namely total bilirubin direct, indirect, and alkaline phosphatase(ALP), total proteins, alanine aminotransferase (ALT), aspartate aminotransferase (AST). In the non-severe group, females vs. males showed no difference in Pvalue for all the parameters checked except total protein (p=0.018), found to be significant. All the checked parameters were found non-significant for severe group females vs. males. Significant Pvalue found for ALP (p=0.004), ALT (p=0.032) and AST (p=0.009) in non-severe vs. severe category of COVID-19 patients.

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The variable course of illness ranges from asymptomatic to severely ill with complications of acute respiratory failure makes it crucial to collect strong evidence to determine the patient's condition promptly and predict complications. Biomarkers are quantitative measurements that reflect the pathophysiology of disease and thus help clinicians recognize the severity of medical illness. They also aid in the developing of clinical care management algorithms that have the potential to improve patient outcomes. These laboratory indices will help differentiate severely ill patients and allow for the appropriate allocation of healthcare resources. These biomarkers in understanding COVID-19 may also help prevent the virus-induced acute inflammatory response complications such as acute hypoxemic respiratory failure and multiorgan dysfunction including acute cardiac, hepatic, and renal injury in affected patients (6) .

The increased total leukocyte count is an indicative marker for detecting an infectious condition in most diseases.(10)Thus, previous studies also evaluated leucocytes' role in the COVID-19 condition. (14, 15, 22) In their retrospective study, Qin et al. concluded that severe patients showed leukocytosis compared to non-severe COVID-19 patients. In our present study, we also found leukocytosis in severe cases, and the result was comparable with various other studies. (15, 22) The NLR, calculated simply by the ratio of neutrophils count/lymphocytes count, is an an inflammatory marker that can predict the probability of death in patients with various cardiovascular diseases (23, 24) . Moreover, NLR has been identified in a meta-analysis as a prognostic biomarker for patients with sepsis(25). For COVID-19 patients, NLR has been shown to be an independent risk factor for severe disease (26-28). Fifty (75.8%) patients with disease progression during hospitalization had an NLR of 2.973 (29), which may indicate . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. As platelet count is a simple, cheap, and easily available biomarker and has been independently associated with disease severity and mortality risk in intensive care unit (ICU) H5 (40) (41) (42) . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted May 27, 2022. ; https://doi.org/10.1101/2022.05.25.22275583 doi: medRxiv preprint , it has been rapidly adopted as a potential biomarker for COVID-19 patients. The number of platelets was reported to be significantly reduced in COVID-19 patients (43, 44) 49) The previous meta-analysis reported that platelets were not an appropriate marker for considering the severity of COVID-19 disease. (13, 14) Similarly to this finding, our data showed no significant variation between the non-severe and severe cases. In In contrast, low platelet count was suggested in the severe COVID-19 cases. (12) The increased inflammatory response in COVID-19 and hypoxia due to severe pneumonia eventually leads to the activation of coagulation and fibrinolysis, followed by a hypercoagulable patients than in patients with community-acquired pneumonia. (52) Our study also revealed that the D-dimer levels were high in severe COVID-19 cases of both male and female sex.

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The copyright holder for this preprint this version posted May 27, 2022. ; C-reactive protein (CRP) is a sensitive biomarker for inflammation. As an acute phase inflammatory mediator, CRP is synthesized and released by the liver into the bloodstream, contributing to the host's resistance to invading pathogens. (1) CRP elevation may also be caused by bacterial coinfection that occurs in severe COVID-19. Moreover, a robust inflammatory the response that occurs in severe disease may cause CRP levels to increase significantly. (1) Elevated CRP levels are directly correlated with inflammation and disease severity. Hence, it is a crucial biomarker in diagnosis and assessing the severity of infectious diseases H4. In the the present study, CRP levels were significantly elevated in severe COVID-19 cases of males and females. In non-severe cases, though CRP was raised, it was not that significant.

LDH is present in tissues throughout the body and is involved in the interconversion between pyruvate and lactate through a nicotinamide adenine dinucleotide (NADH)-dependent reaction. Abnormal LDH levels can result from decreased oxygenation, leading to an upregulation of the glycolytic pathway and from multiple organ injuries. The mechanism through which lactate leads to injury are via the action of metalloproteinases and enhanced macrophage-mediated angiogenesis. (53) In a study conducted on COVID-19 patients, it was found that levels of LDH early on in the course of the disease can be a good predictor of lung injury and severe COVID-19 cases. (54) High LDH has also been associated with worse outcomes in several studies. (55) (56) (57) In a pooled analysis, elevated LDH values were associated with a >16-fold increase in the odds of mortality and a sixfold increased odds of severe disease. (53) Our overall results demonstrated that the LDH levels were raised in non-severe COVID-19 cases as compared to severe COVID-19 cases that are contrary to the published literature.

The immunological biomarkers of serum ferritin are reported to be significantly increased in non-survivors vs. survivors (WMD: 4.6 pg/mL and 760.2 ng/mL, respectively) and as compared . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

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to severe vs. non-severe disease (WMD: 1.7 pg/mL and 408.3 ng/ mL, respectively) . ( 

In the present study ferritin was raised in non-severe cases of COVID-19 in both male and female whereas the rise was not that significant in severe COVID-19 cases. Similar to Izcovich et.al, we also found a significant association between non-severe and severe cases. is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

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The copyright holder for this preprint this version posted May 27, 2022. ; https://doi.org/10.1101/2022.05.25.22275583 doi: medRxiv preprint female patients (p=0.0059).

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Redefining cardiac biomarkers in predicting mortality of inpatients with COVID-19

Can routine laboratory tests discriminate SARS-CoV-2-infected pneumonia from other causes of community-acquired pneumonia?

Assessing thrombocytopenia in the intensive care unit: the past, present, and future

Association Between Platelet Levels and 28-Day Mortality in Patients With Sepsis: A Retrospective Analysis of a Large Clinical Database MIMIC-IV

Blood platelets and sepsis pathophysiology: A new therapeutic prospect in critical ill patients?

COVID-19: an up-to-date reviewfrom morphology to pathogenesis

Assessment of serum ferritin as a biomarker in COVID-19: bystander or participant? Insights by comparison with other infectious and non-infectious diseases

Serum ferritin as an independent risk factor for severity in COVID-19 patients

D-dimer levels on admission to predict in-hospital mortality in patients with Covid-19

D-dimer as a biomarker for disease severity and mortality in COVID-19 patients: a case control study

The impact of 2019 novel coronavirus on heart injury: a systematic review and meta-analysis. Progress in cardiovascular diseases

The diagnostic and prognostic role of myocardial injury biomarkers in hospitalized patients with COVID-19

D-dimer in patients infected with COVID-19 and suspected pulmonary embolism. Respiratory medicine

Inflammation and thrombosis: roles of neutrophils, platelets and endothelial cells and their interactions in thrombus formation during sepsis

Evaluation of variation in D-dimer levels among COVID-19 and bacterial pneumonia: a retrospective analysis

Lactate dehydrogenase levels predict coronavirus disease 2019 (COVID-19) severity and mortality: A pooled analysis

Lactate dehydrogenase, an independent risk factor of severe COVID-19 patients: a retrospective and observational study

Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. The lancet

Risk Factors Associated With Acute Respiratory Distress Syndrome and Death in Patients With Coronavirus Disease

Clinical and immunological features of severe and moderate coronavirus disease 2019

Biomarkers associated with COVID-19 disease progression