Clues and Patterns Lurking Just Under the Surface
Dicken Weatherby, N.D. and Beth Ellen DiLuglio, MS, RDN, LDN
Observation and research have revealed some significant COVID-19 biomarker patterns, including those that help differentiate between severe and moderate disease.
The ODX COVID-19 Series
- COVID-19: The pandemic that has become endemic
- COVID-19: Overlapping risk factors and chronic disease
- Nutritional status and COVID-19: A covert factor in disease susceptibility
- COVID-19: Blood chemistry biomarker patterns - Clues and patterns lurking just under the surface
- COVID-19: Blood chemistry biomarker patterns - Down the research rabbit hole
- COVID-19: Blood Biomarkers - Neutrophils
- COVID-19: Blood Biomarkers - Albumin
- COVID-19: BloodBiomarkers - Cytokines
- COVID-19: Blood Biomarkers - Interleukin-6
- COVID-19: Blood Biomarkers - Interleukin-10
- COVID-19: Blood Biomarkers - Vitamin C
- COVID-19: Blood Biomarkers - Vitamin D
- COVID-19: Blood Biomarkers - Zinc
- Biomarker characteristics and blood type - help sharpen the COVID-19 clinical picture
- COVID-19: Initial indications and conventional interventions
- COVID-19: Long-term risk reduction - Naturopathic, functional medicine, and nutrition-based approaches to prevention
- A healthy diet is primary prevention for COVID-19
- You should have a gut feeling about COVID-19
- Beyond dietary food patterns…plant-based compounds may mitigate COVID-19 risk
- Targeted nutrition support in the battle against COVID-19
- Targeted nutrition support in COVID-19: Armed with vitamin C
- Targeted nutrition support in COVID-19: In sync with zinc
- Targeted nutrition support in COVID-19: Micronutrients and phytonutrients are important players
- Optimal Takeaways for improving immunity and reducing susceptibility to COVID-19
- Optimal - The Podcast: Episode 8 -Blood Biomarkers and Risk Factors for COVID-19 and its Comorbidities
Literature review reveals that COVID-19 patients with severe disease had significantly lower levels of lymphocytes, natural killer cells, B cells, and CD4+ and CD8+ T cells compared to those with mild or moderate disease. Increases in basophils and neutrophils reflected increased severity as well.[i]
A significant correlation was found between mortality and[ii]
- Increased WBC, neutrophil count, AST, ALT, creatinine, LDH, procalcitonin, CRP
- Decreased albumin and lymphocyte count
Advanced COVID-19 pattern
|
|
Elevated |
Decreased |
|
AST and ALT Blood urea nitrogen (may be elevated or decreased) C-reactive protein Creatine kinase Creatinine (may be elevated or decreased) Cytokines IL-6, IL-8, IL-10, IL-2R, IL-1β, and TNF-α D-dimer Erythrocyte sedimentation rate (ESR) Ferritin Fibrinogen Glucose LDH Neutrophils NLR Neutrophil to lymphocyte ratio Procalcitonin RDW-CV Thrombin time Total bilirubin |
Albumin Basophils Eosinophils Lymphocytes Monocytes Prealbumin Selenium Super oxide dismutase (SOD) Total protein Total white blood cells Vitamin C Vitamin D Zinc
|
Specific biomarker range clues for COVID-19
Biomarker |
Relevant ranges |
Background |
|
Albumin |
Below 3.5 mg/dL Associated with severe COVID-19 [xxii] [xxiii] [xxiv] [xxv] 2.9 mg/dL Predicted ICU admission and 1.8 mg/dL or lower Predicted mortality from COVID-19[xxvi] |
Visceral carrier protein, decreases with inflammation, critical illness, prognostic indicator for progression to pneumonia.[xxvii] |
|
LDH |
388 u/L (6.48 ukat/L) Associated with positive PCR test for COVID-19[xxviii] 731 U/L (12.2 ukat/L) and above predicted mortality from COVID-19[xxix] |
Lactate dehydrogenase enzyme is found in many tissues, an increase in serum levels is associated with tissue and organ damage, including lung damage. |
|
NLR |
2.425 cutoff for COVID-19 [xxx] 3.0 Associated with clinical improvement[xxxi] 3.27 Predicted severe disease and 5.72 predicted mortality[xxxii] |
Neutrophil/lymphocyte ratio (NLR) is a marker of inflammation. Elevated levels are associated with critical illness and more severe COVID-19. |
|
Vitamin C |
0.19 mg/dL (11 umol/L) Deficient and 0.41 mg/dL (23 umol/L) insufficient[xxxiii] 1.3-4 mg/dL (73.8-227 umol/L) can be achieved with dietary intake[xxxiv] |
Vitamin C is an important antioxidant that also exerts anti-inflammatory, anti-viral, and immune-modulating effects. [xxxv] It protects epithelium, stimulates lymphocyte proliferation, reduces proinflammatory cytokines, and can reduce the risk of ARDS. Critically ill may need 20-30 times more vitamin C.[xxxvi] |
|
Vitamin D 25(OH)D |
10 ng/mL (25 nmol/L) Severe deficiency 11.1 ng/mL (27.7 nmol/L) more likely to test positive for COVID-19[xxxvii] 20 ng/mL (50 nmol/L) Insufficiency[xxxviii] 30 ng/mL (75 nmol/L) Reduced severity of COVID-19[xxxix] 40-60 ng/mL (100-150 nmol/L) Reduced risk of respiratory infection, COVID-19.[xl] 50-70 ng/mL (125-175 nmol/L) Robust serum Vitamin D for disease prevention[xli] |
Vitamin D is converted to an active hormone with anti-inflammatory, antifibrotic, antioxidant, and immune-modulating functions. [xlii] COVID-19 patients with serum 25(OH)D below 20 ng/mL (50 nmol/L) were more likely to be critically ill versus COVID-19 patients with serum levels above 20 ng/mL who were more likely to be asymptomatic. [xliii] |
|
Selenium |
Below 100 ug/L (1.27 umol/L) Indication for supplementation[xliv] |
Selenium is a trace mineral required for innate immunity, normal T cell function, antibody production, and antioxidant, anti-inflammatory, and antimicrobial actions. [xlv]
|
|
Zinc |
Below 60 ug/dL (9.2 umol/L) Deficient[xlvi] and loss of sense of smell[xlvii] Below 70 ug/dL (10.7 umol/L) Increased risk of pneumonia in elderly[xlviii] 80-120 ug/dL (12.24-18.4 umol/L) Hospital reference range[xlix] |
Zinc is a trace mineral required for antioxidant systems, immunity, activation of T-lymphocytes, and inhibition of viral replication. [l] Both zinc deficiency and excess can compromise immunity.[li] |
Next Up - COVID-19: Blood Chemistry Biomarker patterns - Down the Research Rabbit Hole
Research
[i] Gallo Marin, Benjamin et al. “Predictors of COVID-19 severity: A literature review.” Reviews in medical virology, e2146. 30 Jul. 2020, doi:10.1002/rmv.2146
[ii] Li, Jie et al. “Epidemiology of COVID-19: A systematic review and meta-analysis of clinical characteristics, risk factors, and outcomes.” Journal of medical virology, 10.1002/jmv.26424. 13 Aug. 2020, doi:10.1002/jmv.26424
[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] Gallo Marin, Benjamin et al. “Predictors of COVID-19 severity: A literature review.” Reviews in medical virology, e2146. 30 Jul. 2020, doi:10.1002/rmv.2146
[v] Li, Jie et al. “Epidemiology of COVID-19: A systematic review and meta-analysis of clinical characteristics, risk factors, and outcomes.” Journal of medical virology, 10.1002/jmv.26424. 13 Aug. 2020, doi:10.1002/jmv.26424
[vi] 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
[vii] 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
[viii] Fan, Bingwen Eugene, et al. "Hematologic parameters in patients with COVID‐19 infection." American journal of hematology 95.6 (2020): E131-E134.
[ix] 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
[x] 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
[xi] 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).
[xii] 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
[xiii] 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
[xiv] 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
[xv] Li, Jie et al. “Epidemiology of COVID-19: A systematic review and meta-analysis of clinical characteristics, risk factors, and outcomes.” Journal of medical virology, 10.1002/jmv.26424. 13 Aug. 2020, doi:10.1002/jmv.26424
[xvi] Gallo Marin, Benjamin et al. “Predictors of COVID-19 severity: A literature review.” Reviews in medical virology, e2146. 30 Jul. 2020, doi:10.1002/rmv.2146
[xvii] Richardson, David P, and Julie A Lovegrove. “Nutritional status of micronutrients as a possible and modifiable risk factor for COVID-19: a UK perspective.” The British journal of nutrition, 1-7. 20 Aug. 2020, doi:10.1017/S000711452000330X
[xviii] 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
[xix] 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
[xx] Zhao, Guolian et al. “A comparative study of the laboratory features of COVID-19 and other viral pneumonias in the recovery stage.” Journal of clinical laboratory analysis vol. 34,10 (2020): e23483. doi:10.1002/jcla.23483
[xxi] Chen, Zaishu et al. “Laboratory markers associated with COVID-19 progression in patients with or without comorbidity: A retrospective study.” Journal of clinical laboratory analysis vol. 35,1 (2021): e23644. doi:10.1002/jcla.23644
[xxii] 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
[xxiii] Aziz, Muhammad et al. “The association of low serum albumin level with severe COVID-19: a systematic review and meta-analysis.” Critical care (London, England) vol. 24,1 255. 26 May. 2020, doi:10.1186/s13054-020-02995-3 [R] Open Access This article is licensed under a Creative Commons Attribution 4.0 International License.
[xxiv] Huang, Jiaofeng et al. “Hypoalbuminemia predicts the outcome of COVID-19 independent of age and co-morbidity.” Journal of medical virology, 10.1002/jmv.26003. 14 May. 2020, doi:10.1002/jmv.26003
[xxv] Li, Juyi et al. “Plasma albumin levels predict risk for nonsurvivors in critically ill patients with COVID-19.” Biomarkers in medicine vol. 14,10 (2020): 827-837. doi:10.2217/bmm-2020-0254 This work is licensed under the Creative Commons Attribution 4.0 License
[xxvi] Aloisio, Elena et al. “A comprehensive appraisal of laboratory biochemistry tests as major predictors of COVID-19 severity.” Archives of pathology & laboratory medicine, 10.5858/arpa.2020-0389-SA. 10 Jul. 2020, doi:10.5858/arpa.2020-0389-SA
[xxvii] Caccialanza, Riccardo et al. “Early nutritional supplementation in non-critically ill patients hospitalized for the 2019 novel coronavirus disease (COVID-19): Rationale and feasibility of a shared pragmatic protocol.” Nutrition (Burbank, Los Angeles County, Calif.) vol. 74 (2020): 110835. doi:10.1016/j.nut.2020.110835
[xxviii] 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).
[xxix] Aloisio, Elena et al. “A comprehensive appraisal of laboratory biochemistry tests as major predictors of COVID-19 severity.” Archives of pathology & laboratory medicine, 10.5858/arpa.2020-0389-SA. 10 Jul. 2020, doi:10.5858/arpa.2020-0389-SA
[xxx] 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
[xxxi] Ciccullo, Arturo et al. “Neutrophil-to-lymphocyte ratio and clinical outcome in COVID-19: a report from the Italian front line.” International journal of antimicrobial agents vol. 56,2 (2020): 106017. doi:10.1016/j.ijantimicag.2020.106017
[xxxii] Ok, Fesih 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, 10.1002/jmv.26300. 14 Jul. 2020, doi:10.1002/jmv.26300
[xxxiii] Carr, Anitra C, and Sam Rowe. “The Emerging Role of Vitamin C in the Prevention and Treatment of COVID-19.” Nutrients vol. 12,11 3286. 27 Oct. 2020, doi:10.3390/nu12113286 [R] This article is an open-access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license.
[xxxiv] Klimant, E et al. “Intravenous vitamin C in the supportive care of cancer patients: a review and rational approach.” Current oncology (Toronto, Ont.) vol. 25,2 (2018): 139-148. doi:10.3747/co.25.3790
[xxxv] Richardson, David P, and Julie A Lovegrove. “Nutritional status of micronutrients as a possible and modifiable risk factor for COVID-19: a UK perspective.” The British journal of nutrition, 1-7. 20 Aug. 2020, doi:10.1017/S000711452000330X
[xxxvi] Abobaker, Anis et al. “Overview of the possible role of vitamin C in management of COVID-19.” Pharmacological reports : PR vol. 72,6 (2020): 1517-1528. doi:10.1007/s43440-020-00176-1
[xxxvii] Benskin, Linda L. “A Basic Review of the Preliminary Evidence That COVID-19 Risk and Severity Is Increased in Vitamin D Deficiency.” Frontiers in public health vol. 8 513. 10 Sep. 2020, doi:10.3389/fpubh.2020.00513
[xxxviii] Im, Jae Hyoung et al. “Nutritional status of patients with COVID-19.” International journal of infectious diseases : IJID : official publication of the International Society for Infectious Diseases vol. 100 (2020): 390-393. doi:10.1016/j.ijid.2020.08.018
[xxxix] Maghbooli, Zhila et al. “Vitamin D sufficiency, a serum 25-hydroxyvitamin D at least 30 ng/mL reduced risk for adverse clinical outcomes in patients with COVID-19 infection.” PloS one vol. 15,9 e0239799. 25 Sep. 2020, doi:10.1371/journal.pone.0239799
[xl] Benskin, Linda L. “A Basic Review of the Preliminary Evidence That COVID-19 Risk and Severity Is Increased in Vitamin D Deficiency.” Frontiers in public health vol. 8 513. 10 Sep. 2020, doi:10.3389/fpubh.2020.00513
[xli] Zotarelli Filho, Idiberto José, et al. “Major Meta-Analysis, Randomized Clinical Studies, and International Consensus on Serum Levels and Importance of Supplementing Vitamin D:State of the Art.” MedNEXT Journal of Medical and Health Sciences, 2021, pp. 54–66., doi:10.34256/mdnt2129.
[xlii] Maghbooli, Zhila et al. “Vitamin D sufficiency, a serum 25-hydroxyvitamin D at least 30 ng/mL reduced risk for adverse clinical outcomes in patients with COVID-19 infection.” PloS one vol. 15,9 e0239799. 25 Sep. 2020, doi:10.1371/journal.pone.0239799
[xliii] Jain, Anshul et al. “Analysis of vitamin D level among asymptomatic and critically ill COVID-19 patients and its correlation with inflammatory markers.” Scientific reports vol. 10,1 20191. 19 Nov. 2020, doi:10.1038/s41598-020-77093-z
[xliv] Alexander, Jan et al. “Early Nutritional Interventions with Zinc, Selenium and Vitamin D for Raising Anti-Viral Resistance Against Progressive COVID-19.” Nutrients vol. 12,8 2358. 7 Aug. 2020, doi:10.3390/nu12082358
[xlv] Fernández-Quintela, Alfredo et al. “Key Aspects in Nutritional Management of COVID-19 Patients.” Journal of clinical medicine vol. 9,8 2589. 10 Aug. 2020, doi:10.3390/jcm9082589
[xlvi] Mayor-Ibarguren, Ander et al. “A Hypothesis for the Possible Role of Zinc in the Immunological Pathways Related to COVID-19 Infection.” Frontiers in immunology vol. 11 1736. 10 Jul. 2020, doi:10.3389/fimmu.2020.01736
[xlvii] Abdelmaksoud, Aida A et al. “Olfactory Disturbances as Presenting Manifestation Among Egyptian Patients with COVID-19: Possible Role of Zinc.” Biological trace element research, 1–8. 7 Jan. 2021, doi:10.1007/s12011-020-02546-5
[xlviii] Alexander, Jan et al. “Early Nutritional Interventions with Zinc, Selenium and Vitamin D for Raising Anti-Viral Resistance Against Progressive COVID-19.” Nutrients vol. 12,8 2358. 7 Aug. 2020, doi:10.3390/nu12082358
[xlix] Jothimani, Dinesh et al. “COVID-19: Poor outcomes in patients with zinc deficiency.” International journal of infectious diseases : IJID : official publication of the International Society for Infectious Diseases vol. 100 (2020): 343-349. doi:10.1016/j.ijid.2020.09.014
[l] Mayor-Ibarguren, Ander et al. “A Hypothesis for the Possible Role of Zinc in the Immunological Pathways Related to COVID-19 Infection.” Frontiers in immunology vol. 11 1736. 10 Jul. 2020, doi:10.3389/fimmu.2020.01736
[li] Mossink, J P. “Zinc as nutritional intervention and prevention measure for COVID-19 disease.” BMJ nutrition, prevention & health vol. 3,1 111-117. 17 Jun. 2020, doi:10.1136/bmjnph-2020-000095