COVID-19: Blood Chemistry Biomarkers- Down the Research Rabbit Hole

Down the Research Rabbit Hole

Dicken Weatherby, N.D. and Beth Ellen DiLuglio, MS, RDN, LDN

In this post, a part of our COVID-19 series, we discuss several meta-analyses that confirm biomarker patterns for severe COVID-19.

The ODX COVID-19 Series

1. COVID-19: The pandemic that has become endemic
2. COVID-19: Overlapping risk factors and chronic disease
3. Nutritional status COVID-19: A covert factor in disease susceptibility
4. COVID-19: Blood chemistry biomarker patterns - Clues and patterns lurking just under the surface
5. COVID-19: Blood chemistry biomarker patterns - Down the research rabbit hole
6. COVID-19: Blood Biomarkers - Neutrophils
7. COVID-19: Blood Biomarkers - Albumin
8. COVID-19: BloodBiomarkers - Cytokines
9. COVID-19: Blood Biomarkers - Interleukin-6
10. COVID-19: Blood Biomarkers - Interleukin-10
11. COVID-19: Blood Biomarkers - Vitamin C
12. COVID-19: Blood Biomarkers - Vitamin D
13. COVID-19: Blood Biomarkers - Zinc
14. Biomarker characteristics and blood type - help sharpen the COVID-19 clinical picture
15. COVID-19: Initial indications and conventional interventions
16. COVID-19: Long-term risk reduction - Naturopathic, functional medicine, and nutrition-based approaches to prevention
17. A healthy diet is primary prevention for COVID-19
18. You should have a gut feeling about COVID-19
19. Beyond dietary food patterns…plant-based compounds may mitigate COVID-19 risk
20. Targeted nutrition support in the battle against COVID-19
21. Targeted nutrition support in COVID-19: Armed with vitamin C
22. Targeted nutrition support in COVID-19: In sync with zinc
23. Targeted nutrition support in COVID-19: Micronutrients and phytonutrients are important players
24. Optimal Takeaways for improving immunity and reducing susceptibility to COVID-19
25. Optimal - The Podcast: Episode 8 -Blood Biomarkers and Risk Factors for COVID-19 and its Comorbidities

Meta-analysis of data for 4663 COVID-19 patients indicated that elevated LDH and elevated CRP (the most prevalent finding), and decreased lymphocytes were associated significantly with the severity of COVID-19. Elevations in erythrocyte sedimentation rate (ESR) and IL-6, and decreased levels of albumin and eosinophils were also associated with severe disease.[i]

A 20-study meta-analysis confirmed that those with more severe disease displayed higher WBCs, ALT, AST, total bilirubin, CRP, procalcitonin, LDH, creatine kinase, and D-dimer and lower albumin values than less severe COVID-19. [ii]

Meta-analysis of 10 studies indicated that trends in blood chemistry marker patterns associated with COVID-19 include: [iii]

• Increased ALT, AST, total bilirubin, creatine kinase, LDH, and BUN and creatinine may be elevated or decreased
• Decreased albumin
  • Changes in albumin may also be important to monitor the progression or improvement of COVID-19

A 40-study meta-analysis of 5872 COVID-19 patients revealed that severe disease was associated with significantly: [iv]

• Lower: platelet count, lymphocyte count
• Higher: CRP, LDH, WBC, procalcitonin, D-dimer, ALT, AST, creatinine, and the average age
• Researchers note that the higher levels of LDH, ALT, AST, and creatinine in the more severe or fatal groups likely represent more severe heart, liver, and kidney damage.

Meta-analysis of 2401 patients found that of those who died of COVID-19:[v]

• 6% were male
• 6% had hypertension
• 5% had chronic cardiovascular disease
• 2% had diabetes
• 6% had chronic cerebrovascular disease
• Acute respiratory distress and shock were the most common complication
• Decreased platelets and increased CRP and LDH were associated with mortality

Biomarker Result Changes as Marker of Disease Progression

Meta-analysis of 13 studies, comprising 3027 cases of SARS-CoV-2 infection, revealed laboratory characteristics of disease progression: [vi]

Data are shown as median (IQR). P values were calculated by Kruskal-Wallis rank-sum test. The levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), γ-glutamyl transpeptidase (GGT), AST/ALT, total bilirubin (TBil), direct bilirubin (DBil), and indirect Bilirubin (IBiL) on admission and after admission were compared among non-critically ill, critically ill, and death groups. If the values of biomarkers were below the lower reference limit, half of the lower reference value was used.

Source: Huang, Wei et al. “Decreased serum albumin level indicates poor prognosis of COVID-19 patients: hepatic injury analysis from 2,623 hospitalized cases.” Science China. Life sciences vol. 63,11 (2020): 1678-1687. doi:10.1007/s11427-020-1733-4. This article is made available via the PMC Open Access Subset for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgment of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.

In the retrospective study of 413 COVID-19 patients (346 severe, 67 critical), significant differences in biomarker values were observed. When comparing the two groups, critically ill patients had significantly higher total WBCs, neutrophils, D-dimer, pro-calcitonin, CRP, IL-6, IL-10, urea nitrogen, and albumin/globulin ratio. Critically ill patients also had significantly lower lymphocytes, platelets, albumin, and prealbumin.[viii]

A study of 105 PCR-positive versus 102 PCR-negative for SARS-CoV-2 was conducted to compare routine blood test results. COVID positive individuals had:[ix]

• Significantly lower total WBC counts (6.47 vs 9.79 × 109/L) (though some studies found elevated WBC comparing moderate to severe COVID-19).
  • Neutrophils were most abundant of the WBCs present, lymphocytes were suppressed
• Significantly higher CRP (87.1 vs 63.1 mg/L)
• Significantly elevated vitamin B6-dependent AST and ALT (56.2 vs 38.1 U/L and 47.9 vs 33.1 U/L)
• Significantly elevated LDH 388 vs 275.4 U/L
  • Elevated LDH can be a marker of lung damage
• Researchers conclude that “Empirical thresholds for AST and LDH allowed the identification of 70% of either COVID-19-positive or COVID-19-negative patients on the basis of routine blood test results.”

Routine blood tests may help early identification and assessment of COVID-19 patients.

The following patterns were observed in emergency room patients, 105 of whom were COVID-19 positive versus 102 of whom were COVID-19 negative: [x]

• WBC Significantly higher
• Neutrophils Significantly lower
• Lymphocytes Significantly lower
• Monocytes Significantly low
• Eosinophils Significantly lower
• Basophils Significantly lower
• Platelets No significant difference
• CRP Significantly higher
• AST Significantly higher
• ALT Significantly higher
• Alk phos No significant difference
• GGT No significant difference
• LDH Significantly higher

A retrospective study of 227 pneumonia patients and 97 hospitalized COVID-19 patients found that 71.7% of those with COVID-19 had decreased eosinophils, a finding significant when compared to non-COVID-19 pneumonia patients. The association was strengthened when the neutrophil/lymphocyte ratio (NLR) was considered, with an NLR cutoff value for COVID-19 of 2.425. [xi]

Low levels of eosinophils on admission were associated with a greater incidence of fatigue, fever, shortness of breath, chest CT lesions, extended hospital stay, and disease course. An increase to normal levels of eosinophils occurred before PCR tests for COVID-19 converted to negative.

In a small study of 28 adults with mild and 15 patients with severe COVID-19, those with severe disease had significantly higher IL-6, glucose, fibrinogen, CRP, D-dimer, and thrombin time. The cutoff for IL-6 was 24.3 ug/L.[xii] Notably, six out of seven patients with diabetes had severe versus mild COVID-19.

In a study of 9 ICU versus 58 non-ICU COVID-19 patients, those in the ICU had significantly lower lymphocytes and monocytes, and significantly higher neutrophils and peak LDH levels than non-ICU patients.[xiii]

In COVID-19 patients with ocular complications such as conjunctivitis and increased secretions, levels of WBCs, neutrophils, CRP, LDH, and procalcitonin were higher than in COVID-19 patients without ocular involvement. Researchers suggest that the virus may be transmitted via the eyes.[xiv]

In patients who recover from COVID-19, specific antibodies to SARS-CoV-2 are present, while CD4+ and CD8+ T cells, B cells, natural killer cells, and exhaustion markers on cytotoxic lymphocytes normalize.[xv]

Awareness of the biomarker patterns associated with COVID-19 will help clinicians assess, monitor, and mitigate the immune and metabolic abnormalities associated with this insidious disease.

Next Up - COVID-19: Blood Biomarkers - Neutrophils

Research

[i] Zhang, Zu-Li et al. “Laboratory findings of COVID-19: a systematic review and meta-analysis.” Scandinavian journal of clinical and laboratory investigation vol. 80,6 (2020): 441-447. doi:10.1080/00365513.2020.1768`587

[ii] Xu, Lizhen et al. “Risk factors for 2019 novel coronavirus disease (COVID-19) patients progressing to critical illness: a systematic review and meta-analysis.” Aging vol. 12,12 (2020): 12410-12421. doi:10.18632/aging.103383

[iii] Deng, Xiaoling et al. “Blood biochemical characteristics of patients with coronavirus disease 2019 (COVID-19): a systemic review and meta-analysis.” Clinical chemistry and laboratory medicine vol. 58,8 (2020): 1172-1181. doi:10.1515/cclm-2020-0338

[iv] Ou, Mingchun et al. “Risk factors of severe cases with COVID-19: a meta-analysis.” Epidemiology and infection vol. 148 e175. 12 Aug. 2020, doi:10.1017/S095026882000179X

[v] Qiu, Peishan et al. “Clinical characteristics, laboratory outcome characteristics, comorbidities, and complications of related COVID-19 deceased: a systematic review and meta-analysis.” Aging clinical and experimental research vol. 32,9 (2020): 1869-1878. doi:10.1007/s40520-020-01664-3

[vi] Zheng, Zhaohai et al. “Risk factors of critical & mortal COVID-19 cases: A systematic literature review and meta-analysis.” The Journal of infection vol. 81,2 (2020): e16-e25. doi:10.1016/j.jinf.2020.04.021

[vii] Huang, Wei et al. “Decreased serum albumin level indicates poor prognosis of COVID-19 patients: hepatic injury analysis from 2,623 hospitalized cases.” Science China. Life sciences vol. 63,11 (2020): 1678-1687. doi:10.1007/s11427-020-1733-4 

[viii] Zhao, Xiaobo et al. “Evaluation of Nutrition Risk and Its Association With Mortality Risk in Severely and Critically Ill COVID-19 Patients.” JPEN. Journal of parenteral and enteral nutrition, 10.1002/jpen.1953. 1 Jul. 2020, doi:10.1002/jpen.1953

[ix] Ferrari, Davide et al. “Routine blood tests as a potential diagnostic tool for COVID-19.” Clinical chemistry and laboratory medicine vol. 58,7 (2020): 1095-1099. doi:10.1515/cclm-2020-0398).

[x] Ferrari, Davide et al. “Routine blood tests as a potential diagnostic tool for COVID-19.” Clinical chemistry and laboratory medicine vol. 58,7 (2020): 1095-1099. doi:10.1515/cclm-2020-0398).

[xi] Xie, Guogang et al. “The role of peripheral blood eosinophil counts in COVID-19 patients.” Allergy, 10.1111/all.14465. 20 Jun. 2020, doi:10.1111/all.14465

[xii] Gao, Yong et al. “Diagnostic utility of clinical laboratory data determinations for patients with the severe COVID-19.” Journal of medical virology vol. 92,7 (2020): 791-796. doi:10.1002/jmv.25770

[xiii] Fan, Bingwen Eugene, et al. "Hematologic parameters in patients with COVID‐19 infection." American journal of hematology 95.6 (2020): E131-E134.

[xiv] Wu, Ping et al. “Characteristics of Ocular Findings of Patients With Coronavirus Disease 2019 (COVID-19) in Hubei Province, China.” JAMA ophthalmology vol. 138,5 (2020): 575-578. doi:10.1001/jamaophthalmol.2020.1291

[xv] Cao, Xuetao. “COVID-19: immunopathology and its implications for therapy.” Nature reviews. Immunology vol. 20,5 (2020): 269-270. doi:10.1038/s41577-020-0308-3