Hematological and Biochemical Parameters as Prognostic Markers of COVID-19 Disease Progression in Hospitalized Patients: A Study in Gabon

Berthe Amélie Iroungou^1,2*, Larson Boundenga^3,4, Edith Sylvie Manga Manguiya⁵, Aurore Pryslya Bouassa¹, Jean Raymond Nzenze², Guignali Laurette Mangouka²

¹Unité Mixte de Recherche Centre International de Recherches Médicales de Franceville – Service de Santé Militaire, Libreville, Gabon

²Service de Médecine Interne, Hôpital d’Instruction des Armées Omar Bongo Ondimba, Libreville, Gabon

³Unité de Recherches en Écologie de la Santé (URES), International Centre for Medical Research in Franceville (CIRMF), Franceville BP 769, Gabon

⁴Department of Anthropology, Durham University, South Road, Durham DH1 3LE, UK

⁵Hôpital d’Instruction des Armées d’Akanda, Libreville, Gabon

^*Corresponding Author: Berthe Amélie Iroungou, Unité Mixte de Recherche Centre International de Recherches Médicales de Franceville - Service de Santé Militaire, Libreville, Gabon

Received: 21 April 2023; Accepted: 03 May 2023; Published: 15 May 2023

1. Introduction

In December 2019, an outbreak of pneumonia cases with an unknown etiology occurred in Wuhan, Hubei Province, China. The identified pathogen was named new coronavirus 2019 (2019-nCoV) or SARS-CoV-2 [1-3]. The transmission of SARS-CoV-2 occurs primarily through respiratory droplets that are generated when an infected individual talks, coughs, or sneezes. Direct transmission occurs when these droplets come into contact with the mucous membranes of a susceptible person, while indirect transmission occurs through contact with contaminated surfaces and subsequent transfer of the virus to mucous membranes [4, 5]. These droplets can travel several meters but do not remain suspended in the air. However, the virus can remain viable on surfaces for several days [6, 7].

Although COVID-19 is primarily a respiratory disease, it can present as a systemic illness, leading to complications such as thrombosis and affecting multiple organ systems, including the neurological, digestive, cardiac, hepatic, ocular, otorhinolaryngology, and skin systems [6]. The first case of COVID-19 in Gabon, which was imported from France, was reported on March 13, 2020. From January 3, 2020 to April 1, 2022, Gabon experienced four waves of COVID-19, with cases ranging from mild to critical forms, mostly exhibiting respiratory symptoms. During this period, 47,584 cases were reported to the World Health Organization (WHO), with 303 deaths [8, 9].

Biological abnormalities in affected individuals can serve as important tools for healthcare personnel in developing countries [10, 11]. However, there is a lack of information on biological abnormalities and the role of biomarkers in patients infected with SARS-CoV-2 in Africa, particularly in Gabon. Early diagnosis is crucial in the care and survival of people with COVID-19. In Africa, the high cost of diagnostic tools limits access to diagnosis, making it necessary to set up diagnostic tools that allow for better patient monitoring preventing deaths.

Standard biomarkers such as C-reactive protein and lactate are frequently used in the diagnosis and monitoring of COVID-19 patients. It is important to identify other biomarkers indicative of the different stages of the disease to reduce the costs of certain tests and improve accessibility to diagnosis and patient follow-up. Thus, it was necessary to investigate the impact of COVID-19 on the health of the population in Gabon to provide important information that will allow for better management of COVID-19 cases, not only in Gabon but also in other African countries.

Our study aimed to evaluate the prognostic role of certain biomarkers in severely ill COVID-19 patients. We considered it important to report these abnormalities in a country where obtaining PCR tests may be difficult. This work focuses on the prognostic importance of biomarkers in determining the progression of SARS-CoV-2 infection. Rapid diagnosis is crucial for adequate treatment, and our study sought to provide insights that could aid in achieving this goal.

2. Materials and Methods

2.1 Study design

For this study, we analyzed patients who were hospitalized for COVID-19 at the Akanda Military Hospital (HIAA) in Libreville, the capital of Gabon, between March and June 2020. Our patient selection criteria included clinical symptoms, a positive PCR test following nasopharyngeal swab analysis, or images of pneumonia observed by chest CT using a Philips Brilliance CT 64-slice scanner from Amsterdam, the Netherlands. We subdivided all patients into three groups: (i) severe cases requiring treatment in the intensive care unit, (ii) mild symptomatic cases with fever, respiratory symptoms, or influenza-like syndrome, or positive cases without further clinical signs, and (iii) mostly asymptomatic cases without a positive chest CT scan and without symptoms except anosmia or ageusia.

2.2 Laboratory tests

We conducted laboratory tests on all patients to assess their liver and renal functions, lactate dehydrogenase (LDH) levels, C-Reactive Protein (CRP) concentrations, blood cell counts (BCC), and kalemia stages. Based on the results, we divided the patients into two groups according to their kalemia levels: hypokalemia (<3.5 mM) and severe hyperkalemia (>5.0 mM). Kalemia is a good indicator of health status, particularly cardiac health (PMID: 32498812). We then compared the clinical features of the two groups to explore the association between hypokalemia or hyperkalemia and clinical features.

PCR was performed in four different laboratories using the same protocol recommended by the CDC, with reagents and primers according to the Berlin protocol 14. Clinical biochemistry samples were processed on COBAS C311 or C11 analyzers (Roche Diagnostics, Basel, Switzerland), while hematologic analysis was performed on an automat XP-300 from Sysmex (Kobe, Japan). Inpatient data were obtained from electronic medical records of the hospital. All protocols were approved by the scientific committee of Gabon, based on data from the literature.

2.3 Statistical analysis

We performed all statistical analyses using the Prism 8.4.2 statistical package (GraphPad, San Diego, CA, US). Numerical variables were analyzed by their mean and standard deviation or median and interquartile range, depending on their distribution (normal or not). We compared values using either Student's t-test or Mann-Whitney U test, as appropriate. For comparison of frequencies, we used Fisher's exact test. All tests were two-sided, and the level of significance was set at p-value < 0.05.

3. Results

3.1 Laboratory findings

After analyzing our data, we observed that most biochemical variables were worse in patients with severe COVID-19 compared to those with milder forms of the disease (Table 1). Our results indicated that CRP, the hallmark of inflammation, was the most significantly affected feature in these patients. Additionally, we observed that renal and liver functions were also affected, while glycemia was normal. On the other hand, we found that even mild forms of COVID-19 showed an elevation of some parameters such as Gamma-GT, LDH, or CRP, compared to asymptomatic subjects.

LDH: Lactate Dehydrogenase; ALP: Alkaline Phosphatase; CRP: C-reactive protein; Gamma-GT: Gamma-Glutamyl Transferase; LMR: Lymphocyte-to-Monocyte Ratio; PI: Analysis of the BCC showed an increased number of neutrophils and a relative lymphopenia.

Table 1: Features of the patient according to deceased or alive status.

We observed thrombocytopenia in 38.4% of patients with severe COVID-19, compared with 19.3% in patients with mild disease and 12.3% in asymptomatic patients. Hyperkalemia was more common in severe forms (32%), while hypokalemia was more pronounced in mild symptoms (65.3%) and asymptomatic forms (64.4%) (Table 2). In patients with severe COVID-19, we observed changes in the Neutrophil-to-Lymphocyte Ratio (NLR), Lymphocyte-to-Monocyte Ratio, and Prognostic Index (based on CRP and leukocyte count), which all showed deterioration. However, platelet counts were unchanged (Table 2).

OR: Odds ratio, CI: Confidence Intervals, Asympto: asymptomatic, Sev: Severe case.

Table 2: Ionic and platelet disorders according to severity of disease.

In our laboratory screening, we also found that transaminases Aspartate aminotransferase (AST) and Alanine aminotransferase (ALT) showed high levels and strongly discriminated between severe, paucisymptomatic, and asymptomatic patients in our study, revealing liver injury (Table 3).

Additionally, we observed significant differences in certain biochemical markers such as urea, creatinine, and potassium levels between patients with severe, paucisymptomatic, and asymptomatic forms of the disease (Table 3).

Table 3: Biological feature according to the affection level.

3.2 Characterization of severe forms of COVID-19 with fatal outcome

We found that a series of biochemical parameters, hematological features, and inflammation scores were significantly worse in patients who ultimately died, including CRP levels (378±248 mg/mL vs 91±123 mg/mL, p-value=0.001), lymphopenia (6.7±6.6% vs 28.7±10.8%, p-value=3.7e-06), and Lymphocyte-to-Monocyte Ratio (LMR, 0.7±0.6 vs 2.1±0.9, p-value=2.8e-04).

3.3 COVID-19 and older age

The proportion of patients over 65 years old in our current series was very low (2.0%, n=17/832). To identify relevant biological parameters that may predict deterioration of health status, we first stratified patients with milder forms of the disease based on the median age (41 years), and used this cutoff to stratify asymptomatic subjects. We then compared biological parameters between symptomatic (n=135) and asymptomatic (n=146) patients over 41 years old to identify those parameters that tend to deteriorate in case of symptomatic disease.

Among older patients, a single variable, LDH, was significantly altered (234±88 IU/mL vs 144±50 mM, p-value=0.0040). Other variables, such as CRP (32±49 IU/mL vs 8±12 IU/mL, p-value=0.081, not shown) and Lymphocyte-to-Monocyte Ratio (LMR) (4.1±2.5 IU/mL vs 10.8±23.9, p-value=0.082, not shown), tended to worsen in case of symptoms without reaching a significant level.

4. Discussion

Our study analyzed biological parameters in severe, mild, and asymptomatic cases of COVID-19, and we found that certain parameters could serve as excellent markers of disease severity. For example, we observed that CRP was a reliable marker to predict the presence of infection in asymptomatic patients and the severity of disease in symptomatic patients, where it could reach very high values (up to 30 times the normal value). Our results are consistent with previous studies that have shown CRP to be a good marker of inflammation in patients with COVID-19 [12-14]. Furthermore, our findings revealed that other markers, such as LDH and Gamma-GT, could also be used as biomarkers to predict the severity of SARS-CoV-2 infection in Gabon (Central Africa), as has been reported in Asia (China and India), Europe (Italy and France), and America (add countries) [15-17].

LDH has been shown to play an important role in the entry of the SARS-CoV-2 virus into cells, as has been demonstrated in previous studies [18-22]. Our results also showed that LDH concentrations were higher in symptomatic patients (severe and paucisymptomatic cases) than in asymptomatic patients, suggesting that LDH could be a prognostic marker for the evolution of COVID-19, as reported by previous studies [23-25]. LDH could be an interesting criterion for better monitoring the disease progression in the elderly, who constitute the most vulnerable age group in the Gabonese population, as has been observed elsewhere [26-31]. Therefore, we believe that both CRP and LDH are good markers for monitoring the evolution of COVID-19 in all symptomatic patients, and not just in severe cases, as proposed in previous studies [12, 14].

Our results showed an increase in Gamma-GT (GGT) and transaminase (AST) concentrations, which are known to be hepatic enzymes that indicate good liver function. Thus, the elevation of these liver enzymes in patients with COVID-19 suggests abnormalities in liver function in infected individuals. Therefore, our findings suggest that patients with a significant deterioration (increase) in liver function are more likely to progress to a severe form of the disease [32, 33]. These observations are consistent with previous studies that have shown that GGT and AST are associated with increased risks of mortality and reflect disease severity [34-36]. Monitoring both markers will enable clinicians to predict the disease's evolution by taking into account the variation in their concentration in the patients' blood [37-39]. This will help them to classify patients based on their stage of severity.

We also evaluated renal functions and observed a significant difference in blood urea and creatinine levels between patients with severe forms (Table 3). This suggests that only serious cases are likely to lead to renal dysfunction (> urea level above the normal range: 2.5-7.6 mM/L), which can result in the gradual onset of acute renal failure in patients with COVID-19 [13, 40-42]. The decline in blood lymphocyte levels in infected patients is likely a consequence of the virulence of the SARS-CoV-2 pathogen on the patient's organism. During an external aggression, the infected organism develops defense mechanisms that involve blood lymphocytes contributing to the destruction of virus-infected cells, to eliminate them from the body [43, 44]. The pronounced decline in lymphocytes observed in our study may be explained by virus-induced lymphocyte dysfunction that could directly affect lymphatic organs, as previously suggested [43]. We believe that monitoring the blood lymphocyte count would also be a good marker for disease severity, as seen in our results (considerable decrease in severe cases (Table 3). This is consistent with the literature on the relationship between COVID-19 infection and lymphocytes [43, 45, 46]. In addition to lymphopenia, we observed thrombocytopenia in severe forms of COVID-19 compared to other forms (mild or asymptomatic). Thrombocytopenia might indicate a severe stage of the disease [47]. This thrombocytopenia might be the consequence of a combination of several factors, including lung injury, an increase of autoantibodies and immune complexes, cytokine storm, and direct infection of hematopoietic and bone marrow stromal cells, which could cause hematological changes due to the presence of the virus within the infected organism [48, 49].

Finally, blood electrolytes may also be useful markers for monitoring the evolution of COVID-19 in hospitals. We observed hyperkalemia in patients with severe forms, which could be explained by the fact that the kidneys are unable to eliminate potassium normally due to acute renal failure in this group of patients [50-52]. Another hypothesis is that the binding of SARS-CoV-2 to the ACE2 receptor may increase the degradation of ACE2, leading to an increase in the reabsorption of sodium, water and the reciprocal excretion of potassium [53, 54].

5. Conclusions

COVID-19 is a systemic disease with several clinical and biological manifestations, which has a significant impact on coagulation disorder also kalemia and involves an increase in inflammatory parameters such as CRP. We observe that in the lack of D-dimer, several other biochemical tests can be used as markers of severity (CRP, LDH, Gamma-GT). In the present study, we showed that LDH levels might be an important criterion to monitor older patients in early steps of the disease. Thrombocytopenia should also be a good predictive marker of severity and could easily be used in countries with low and middle income. To conclude, we think that aside from the result from PCR to confirm the diagnosis and in addition to clinical symptoms; our study suggests that, CRP, ionic disorders and LDH must be used as prognosis parameters to evaluate gravity of illness and classify COVID19 patients in sub-Saharan Africa countries.

Author Contributions

Conceptualization, BAI and LB; methodology, APB and ESM; formal analysis, LB; investigation, BAI and GLM; resources, JRN; data curation, LB; writing—original draft preparation, BAI and GLM; writing—review and editing, LB; supervision, JRN and GLM; project administration, GLM; funding acquisition, BAI. All authors have read and agreed to the published version of the manuscript.”

Funding

The authors received no financial support for the research, authorship, and publication of this article.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

The National Scientific Committee of Gabon approved this study and the administration of the military hospital. All patients received written informed consent has been obtained from the patients to publish this paper.

Data Availability Statement

Data are available on request from the authors.

Acknowledgments

We thank all patients enrolled in this study, the Hospital of Instruction of the Armies of Akanda, Libreville, and the Internal Medicine Department, Hôpital d'Instruction des Armées Omar Bongo Ondimba, Libreville, Gabon.

Conflicts of Interest

The authors declare no conflict of interest.

References

1. Lu H, Stratton CW, Tang YW. Outbreak of pneumonia of unknown etiology in Wuhan, China: The mystery and the miracle. Journal of medical virology 92 (2020): 401-402.
2. Huang C, Wang Y, Li X, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet (London, England) 395 (2020): 497-506.
3. Abduljalil JM, Abduljalil BM. Epidemiology, genome, and clinical features of the pandemic SARS-CoV-2: a recent view. New microbes and new infections 35 (2020): 100672.
4. Karia R, Gupta I, Khandait H, et al. COVID-19 and its Modes of Transmission. SN comprehensive clinical medicine 2 (2020): 1798-1801.
5. Mukhra R, Krishan K, Kanchan T. Possible modes of transmission of Novel coronavirus SARS-CoV-2: a review. Acta bio-medica : Atenei Parmensis 91 (2020): e2020036.
6. Bonny V, Maillard A, Mousseaux C, et al. [COVID-19: Pathogenesis of a multi-faceted disease]. La Revue de medecine interne 41 (2020): 375-389.
7. Adhikari SP, Meng S, Wu YJ, et al. Epidemiology, causes, clinical manifestation and diagnosis, prevention and control of coronavirus disease (COVID-19) during the early outbreak period: a scoping review. Infectious diseases of poverty 9 (2020): 29.
8. Iroungou BA, Mangouka LG, Bivigou-Mboumba B, et al. Demographic and Clinical Characteristics Associated With Severity, Clinical Outcomes, and Mortality of COVID-19 Infection in Gabon. JAMA network open 4 (2021): e2124190.
9. WHO Coronavirus (COVID-19) Dashboard [Internet]. On line (2022).
10. Dubey DB, Mishra S, Reddy HD, et al. Hematological and serum biochemistry parameters as a prognostic indicator of severally ill versus mild Covid-19 patients: A study from tertiary hospital in North India. Clinical epidemiology and global health 12 (2021): 100806.
11. Zong X, Gu Y, Yu H, et al. Thrombocytopenia Is Associated with COVID-19 Severity and Outcome: An Updated Meta-Analysis of 5637 Patients with Multiple Outcomes. Laboratory medicine 52 (2021): 10-15.
12. Akdogan D, Guzel M, Tosun D, et al. Diagnostic and early prognostic value of serum CRP and LDH levels in patients with possible COVID-19 at the first admission. Journal of infection in developing countries 15 (2021): 766-772.
13. Izcovich A, Ragusa MA, Tortosa F, et al. Prognostic factors for severity and mortality in patients infected with COVID-19: A systematic review. PloS one 15 (2020): e0241955.
14. Önder O, Zeynep E, INCEOGLU F, et al. CRP and LDH Levels Can Be Used for Support the COVID-19 Diagnose in Intensive Care Unit Patients. Medical Records 5: 170-175.
15. Cecconi M, Piovani D, Brunetta E, et al. Early predictors of clinical deterioration in a cohort of 239 patients hospitalized for Covid-19 infection in Lombardy, Italy. Journal of clinical medicine 9 (2020): 1548.
16. Monari C, Pisaturo M, Maggi P, et al. Early predictors of clinical deterioration in a cohort of outpatients with COVID-19 in southern Italy: A multicenter observational study. Journal of medical virology 94 (2022): 5336-5344.
17. Bousquet G, Falgarone G, Deutsch D, et al. ADL-dependency, D-Dimers, LDH and absence of anticoagulation are independently associated with one-month mortality in older inpatients with Covid-19. Aging 12 (2020): 11306-11313.
18. Palacios-Rápalo SN, De Jesús-González LA, Cordero-Rivera CD, et al. Cholesterol-Rich Lipid Rafts as Platforms for SARS-CoV-2 Entry. Frontiers in immunology 12 (2021): 796855.
19. Kocar E, Rezen T, Rozman D. Cholesterol, lipoproteins, and COVID-19: Basic concepts and clinical applications. Biochimica et biophysica acta. Molecular and cell biology of lipids 1866 (2021): 1866, 158849.
20. Wei C, Wan L, Yan Q, et al. HDL-scavenger receptor B type 1 facilitates SARS-CoV-2 entry. Nature metabolism 2 (2020): 1391-1400.
21. Kluck GEG, Yoo JA, Sakarya EH, et al. Good Cholesterol Gone Bad? HDL and COVID-19. International journal of molecular sciences 22 (2021).
22. Tang Y, Hu L, Liu Y, et al. Possible mechanisms of cholesterol elevation aggravating COVID-19. International journal of medical sciences 18 (2021): 3533-3543.
23. Huang Y, Guo L, Chen J, et al. Serum Lactate Dehydrogenase Level as a Prognostic Factor for COVID-19: A Retrospective Study Based on a Large Sample Size. Frontiers in medicine 8 (2021): 671667.
24. Martha JW, Wibowo A, Pranata R. Prognostic value of elevated lactate dehydrogenase in patients with COVID-19: a systematic review and meta-analysis. Postgraduate medical journal 98 (2022): 422-427.
25. Bartziokas K, Kostikas K. Lactate dehydrogenase, COVID-19 and mortality. Medicina clinica (English ed.) 156 (2021): 37.
26. Machiraju PK, Alex NM, Safinaaz, et al. Hyponatremia in Coronavirus Disease-19 Patients: A Retrospective Analysis. Canadian journal of kidney health and disease 8 (2021): 20543581211067069.
27. Li X, Xu S, Yu M, et al. Risk factors for severity and mortality in adult COVID-19 inpatients in Wuhan. The Journal of allergy and clinical immunology 146 (2020): 110-118.
28. Taha EM, Mohialdeen Taha M, Al-Obaidy SK, et al. Association between Atherogenic Index and Cholesterol to HDL Ratio in COVID-19 Patients During the Initial Phase of Infection. Archives of Razi Institute 77 (2022): 1311-1318.
29. Stasi A, Franzin R, Fiorentino M, et al. Multifaced Roles of HDL in Sepsis and SARS-CoV-2 Infection: Renal Implications. International journal of molecular sciences 22 (2021).
30. Mietus-Snyder M, Suslovic W, Delaney M, et al. Changes in HDL cholesterol, particles, and function associate with pediatric COVID-19 severity. Frontiers in cardiovascular medicine 9 (2022): 1033660.
31. Lahoz C, Salinero-Fort MA, Cárdenas J, et al. HDL-cholesterol concentration and risk of SARS-CoV-2 infection in people over 75 years of age: a cohort with half a million participants from the Community of Madrid. Clinica e investigacion en arteriosclerosis: publicacion oficial de la Sociedad Espanola de Arteriosclerosis 34 (2022): 113-119.
32. Saidi I, Aitbatahar S, Amro L. Les anomalies de la fonction hépatique au cours de l’infection par le SARS-CoV-2. Revue des Maladies Respiratoires Actualités 13 (2021): 112.
33. Wijarnpreecha K, Ungprasert P, Panjawatanan P, et al. COVID-19 and liver injury: a meta-analysis. European journal of gastroenterology and hepatology 33 (2021): 990-995.
34. Ferrari D, Motta A, Strollo M, et al. Routine blood tests as a potential diagnostic tool for COVID-19. Clinical chemistry and laboratory medicine 58 (2020) 1095-1099.
35. Chen LY, Chu HK, Bai T, et al. Liver damage at admission is an independent prognostic factor for COVID-19. Journal of digestive diseases 21 (2020): 512-518.
36. Bloom PP, Meyerowitz EA, Reinus Z, et al. Liver Biochemistries in Hospitalized Patients with COVID-19. Hepatology (Baltimore, Md.) 73 (2021): 890-900.
37. Wang Y, Liu S, Liu H, et al. SARS-CoV-2 infection of the liver directly contributes to hepatic impairment in patients with COVID-19. Journal of hepatology 73 (2020): 807-816.
38. Kasapoglu B, Yozgat A, Tanoglu A, et al. Gamma-glutamyl-transferase may predict COVID-19 outcomes in hospitalised patients. International journal of clinical practice 75 (2021): e14933.
39. Alroomi M, Rajan R, Alsaber A, et al. In-hospital mortality in SARS-CoV-2 stratified by gamma-glutamyl transferase levels. Journal of clinical laboratory analysis 36 (2022): e24291.
40. Cheng Y, Luo R, Wang K, et al. Kidney disease is associated with in-hospital death of patients with COVID-19. Kidney international 97 (2020): 829-838.
41. Cotton DM, Liu L, Vinson DR, et al. Clinical characteristics of COVID-19 patients evaluated in the emergency department: A retrospective cohort study of 801 cases. Journal of the American College of Emergency Physicians open 2 (2021): e12538.
42. Ok F, Erdogan O, Durmus E, et al. Predictive values of blood urea nitrogen/creatinine ratio and other routine blood parameters on disease severity and survival of COVID-19 patients. Journal of medical virology 93 (2021): 786-793.
43. Tan L, Wang Q, Zhang D, et al. Lymphopenia predicts disease severity of COVID-19: a descriptive and predictive study. Signal transduction and targeted therapy 5 (2020): 33.
44. Al-Saadi E, Abdulnabi MA. Hematological changes associated with COVID-19 infection. Journal of clinical laboratory analysis 36 (2022): e24064.
45. Murt A, Eskazan AE, Y?lmaz U, et al. COVID-19 presenting with immune thrombocytopenia: A case report and review of the literature. Journal of medical virology 93 (2021): 43-45.
46. Jafarzadeh A, Jafarzadeh S, Nozari P, et al. Lymphopenia an important immunological abnormality in patients with COVID-19: Possible mechanisms. Scandinavian journal of immunology 93 (2021): e12967.
47. Buisson LS. Coagulopathie associée au COVID-19: les éléments essentiels pour l’anesthésiste-réanimateur. Le praticien en anesthesie reanimation 24 (2020): 190-195.
48. Xu P, Zhou Q, Xu J. Mechanism of thrombocytopenia in COVID-19 patients. Annals of hematology 99 (2020): 1205-1208.
49. Mei H, Luo L, Hu Y. Thrombocytopenia and thrombosis in hospitalized patients with COVID-19. Journal of hematology and oncology 13 (2020): 161.
50. Kanduri SR, Ramanand A, Varghese V, et al. Refractoriness of Hyperkalemia and Hyperphosphatemia in Dialysis-Dependent AKI Associated with COVID-19. Kidney 360 3 (2022): 1317-1322.
51. Sadiq A, Khurram M, Malik J, et al. Correlation of biochemical profile at admission with severity and outcome of COVID-19. Journal of community hospital internal medicine perspectives 11 (2021): 740-746.
52. Noori M, Nejadghaderi SA, Sullman MJM, et al. How SARS-CoV-2 might affect potassium balance via impairing epithelial sodium channels? Molecular biology reports 48 (2021): 6655-6661.
53. Chen D, Li X, Song Q, et al. Assessment of Hypokalemia and Clinical Characteristics in Patients With Coronavirus Disease 2019 in Wenzhou, China. JAMA network open 3 (2020): e2011122.
54. Prasad S, Patel S, Behera AK, et al. Early Biochemical Markers in Predicting the Clinical Outcome of COVID-19 Patients Admitted in Tertiary Care Hospital. Journal of laboratory physicians 14 (2022): 295-305.