Biomarkers and Scoring Systems

As more patients are reported, this information is likely to change. The following is mainly based on the case reports mostly from the Chinese data that has been published so far in the literature.

Key Points

• Lymphopenia has been the most prevalent and consistent finding in both severe and non-severe COVID presentations in the cases published to date.
• Elevation in D-Dimers, CRP, LDH, and a lower serum albumin may also be seen in COVID infections, but varied based on severity.
• There is no clear evidence that tracking any specific biomarkers throughout hospitalization provides any diagnostic or clinical value, though most of the available data referenced only provides biomarker data on admission.
• RT-PCR remains the most widely used testing modality for COVID. Some Chinese institutions also employed next generation sequencing; however, this technique has limited availability in most of the world.
• There is no clear scoring system available to prognosticate COVID-19 patients. Some prior scores for community acquired pneumonia, such as CURB-65 and PSI/PORT, have been suggested for application in this population with caveats. A recent score derived for viral pneumonia in a Chinese population, the MulBSTA score, has been proposed, but has not been validated.
• Available data suggests the experience of critically ill patients in China, Italy, and United States vary in the COVID 19 pandemic.^1–3 More data will need to be analyzed before determining how best to risk stratify these patients.

Biomarkers

CBC

• Leukocytosis/Leukopenia. There is no consistent pattern of leukocytosis or leukopenia in COVID patients, either severe or non-severe in the literature at this time.
• Lymphopenia (defined as less than 1500 cells/mm³). There is a consistent pattern towards lymphopenia in patients who are COVID positive in both severe and non-severe cases. In the largest series out of China of 1099 patients across 522 hospitals in 30 providences, lymphopenia was present in 83.2% and more prominent in the subgroups identified as severe pneumonia per ATS definitions (173 patients) – 96.1% and the subgroup needing ICU care, mechanical ventilation, or progressing to death (67 patients) – 92.6%.¹ This pattern was also seen in small case reports and case series out of Singapore and Seattle.^2,4,5
• Thrombocytopenia (defined as less than 150 platelets/mm3). A recent metanalysis of 9 Chinese case series claims the presence of thrombocytopenia is associated five-fold risk of severe COVID6; however, this paper has several flaws: The Guan et al. case series attempts to centrally report from all regions of China including Hubei, the cases from Wuhan. There is a strong possibility that previously reported patients are also reflected in the larger cases series.1 In addition, multiple papers were reported from COVID patients from the same hospitals in Wuhan (JinyinTan Hospital7,8 and Zhongnan University Hospital9–11). This double reporting of patients in multiple publications is a concern that has been expressed by the Editor in Chief of JAMA.12 A clear association between thrombocytopenia and COVID severity has not been shown by the patients reported to date.

Other Biomarkers

• BMP. An elevation in BUN/Cr has been suggested; however, there is no clear signal towards abnormality in COVID patients compared to other critically ill patients based on the patients reported to date. No other clear electrolyte abnormalities have been consistently associated with COVID based on the cases published to date. 1,4,5,7–10
• LFTs (AST/ALT/TBili). An elevation in LFTs (AST/ALT/TBili) has been suggested; however there is no clear signal towards abnormality in COVID patients compared to other critically ill patients based on the patients reported to date1,4,5,7–10
• Elevated Troponin/BNP. The relationship between COVID-19 and elevation in cardiac biomarkers is unclear. However case reports do suggests a notable proportion of critically ill COVID-19 patients are found with cardiomyopathy (possibly from a viral myocarditis component or exacerbation of an underlying cardiomyopathy), and patients with underlying cardiac dysfunction have been shown to likely present with more severe presentations.1–3
• CK. An elevation in creatinine kinase has been suggested; however there is no clear signal towards abnormality in COVID patients compared to other critically ill patients based on the patients reported to date1,5,10
• Elevated D-Dimer (defined as greater than 0.5mg/L). There may be a small signal that a higher D-Dimer level may relate to a greater severity of illness in COVID positive patients in the patients reported to date. 1,7,8,10,11 In the largest series out of China of 1099 patients across 522 hospitals in 30 providences, elevated D-Dimers was present in 43.2% and more prominent in the subgroups identified as severe pneumonia per ATS definitions (173 patients) – 59.6% and the subgroup needing ICU care, mechanical ventilation, or progressing to death (67 patients) –69.4%.1 There is no clear evidence that tracking D-Dimers through admission provides any prognostic value or indication of a change in clinical condition in the patients presented to date.
• Elevated CRP (defined as greater than 10mg/L). CRP has been reported elevated in COVID positive patients, in both non-severe and severe presentations, but has been reported higher than severe presentations1,4,8,9,11 In the largest series out of China of 1099 patients across 522 hospitals in 30 providences, elevated CRP was present in 60.7% and more prominent in the subgroups identified as severe pneumonia per ATS definitions (173 patients) – 81.5% and the subgroup needing ICU care, mechanical ventilation, or progressing to death (67 patients) – 91.1%1
• Lower Serum Albumin. There is a trend in some reports towards lower serum albumin in more severe presentations of COVID-19, including ARDS, than non-severe presentations7–9
• Elevated LDH (defined as greater than 245). There is a trend towards an elevated LDH in more severe presentations of COVID-19, including ARDS, than non-severe presentations1,5,7,8,10
• Elevated Procalcitonin (Greater than 0.5ng/ml). A small Italian meta-analysis of 4 case series suggested an increased procalcitonin value was associated with a nearly 5-fold higher risk of severe SARS-CoV-2 infection (OR, 4.76; 95% CI, 2.74–8.29)13; however this conclusion is very misleading. The four studies in the meta-analysis are Guan et al., Huang et al., Zhang et al., Wang et al. In Guan et al., the largest series out of China of 1099 patients across 522 hospitals in 30 providences, an elevated procalcitonin was present in 5.5% and 13.7% in the subgroup identified as severe pneumonia per ATS definitions (173 patients). In the subgroup needing ICU care, mechanical ventilation, or progressing to death (67 patients), only 24.0% of the subgroup had an elevated procalcitonin.1 In Huang et al, the procalcitonin was elevated in 3/12 ICU COVID-19 patients (25%) versus in 0 of the non-severe patients.7 In Zhang et al., the definition of an elevated procalcitonin is lower than the other studies (0.1ng/ml compared to 0.5ng/ml) and at this lower value, the procalcitonin was above 0.1ng/ml in 50% of the severe patients and 25% of the non-severe patients with no descriptions on the amount above 0.1ng/ml. It is unclear how many patients are between 0.1 ng/ml and 0.5ng/ml.11 In Wang et al, the definition of an elevated procalcitonin is the lowest in all other studies (0.05ng/ml compared to 0.5ng/ml) and at this lower value, the procalcitonin was above 0.05ng/ml in 75% of the severe patients and 21.6% of the non-severe patients with no descriptions on the amount above 0.05ng/ml. It is unclear how many patients are between 0.05 ng/ml and 0.5ng/ml.10 Also, this calculation also has a large possibility of double reporting the same patients. The Guan et al. case series attempts to centrally report from all regions of China including Hubei, the cases from Wuhan. There is a strong possibility that previously reported patients are also reflected in the larger cases series.1 In addition, multiple papers were reported from COVID patients from the same hospitals in Wuhan (notably Zhongnan University Hospital).10,11 This double reporting of patients in multiple publications is a concern that has been expressed by the Editor in Chief of JAMA.12

COVID-19 Specific Testing

• Real Time RT (reverse transcription)-PCR has been the most common method employed to detect the new coronavirus, SARS-CoV 2. Next generation sequencing has also been utilized in certain areas of China, but given cost and logistics, most labs around the world are using RT (reverse transcriptase)-PCR- with the for N, S, ORFlab gene sequences as the common primers being identified; however, there has been some variation internationally with the primers being searched.^4,14 The most sensitive sample appears to be from bronchoalveolar lavage specimens (up to 93%)¹⁰; however given aerosolizing concerns with acquisition with BAL and sputum specimens, the nasopharyngeal swab is most frequent method employed. Case reports document a lower frequency of appearance in the stool, blood, and urine.⁴ Case reports also describe having positive nasopharyngeal PCRs for up to 2 weeks after resolution of symptoms. This is assumed to correlate with active viral shedding, but more research is needed to determine the relationship.^4,15,16 The sensitivity and specificity of the nasopharyngeal PCR is unclear as case series show intermittent negative PCRs in COVID positive patients. This may have a relationship to viral load but it is unclear.^4,14,16 The FDA has recently approved an emergency use authorization for a point-of-care RT-PCR COVID-19 diagnostic – the Cepheid Xpert Xpress SARS-CoV-2 test. Widespread availability is pending.¹⁷
• Antibody Testing. There has been discussion of antibody testing but none has been widely available for commercial use at this time.
• Viral Culture. None of this has been reported in the case reports to date as being used in the diagnosis of COVID-19.

Scoring Systems

• CDC Triage Tool – “Clara” Bot¹⁸. The CDC has launched a chatbot named “Clara” to help patients at home decide on pursuing the next steps of care. Developed in cooperation with Microsoft Azure’s Healthcare Bot service, the program uses an undisclosed algorithm with a series of pre-programmed questions about symptoms and exposures to advise patients to “go to the hospital” or “stay home and monitor symptoms.”Given the proprietary development with Microsoft, the CDC has not disclosed how the chatbot calculates a risk score.
• CURB65 and PSI/PORT. Both the CURB65¹⁹ and PSI/PORT²⁰ scores are well-established risk stratification scores determining risk of mortality in community acquired pneumonia and have been suggested as having benefit in the risk stratification of acute presentations of COVID-19. MDCalc has launched a COVID-19 Resource Center on their website (mdcalc.com), and the editors suggest PSI/PORT may be a better score to use over CURB65 as PSI/PORT places a greater weight on age and comorbidities which is in line with what is known about COVID 19. This resource center also provides information on other scores such as: SMART-COP, SCAP, LIPS, CAP-PIRO as well as the Murray Score for ECMO might be used in helping make clinical decisions for these COVID patients.²¹ The danger of using these scores is that both were created and validated prior to the arrival of COVID-19 and how COVID-19 behaves may differ from other community acquired pneumonias.
• MulBSTA Score. The MulBSTA Score, derived in China and recently released, has been suggested as possible alternative in risk stratifying COVID-19 patients.²² MuLBSTA stands for: Multifocal PNA, Lymphopenia, Bacterial Co-Infection, Smoking History, HTN, Age. The score attempts to predict risk of 90-day mortality in patients with a confirmed viral pneumonia and was retrospectively derived from a single center with 528 patients with a confirmed viral pneumonia at RuiJin Hospital in Shanghal from May 2015 to May 2019 (Prior to COVID-19 Pandemic). The patients must have been a positive RT-PCR for a viral cause (not excluding bacterial co-infection): influenza A, adenovirus, bocavirus, human rhinovirus, influenza B, parainfluenza, coronavirus, respiratory syncytial virus A, respiratory syncytial virus B, enterovirus, or human metapneumovirus (HMPV) and argued the score was a better predictor of 90-day mortality when compared to the CURB 65 score. The potential benefits when used in the COVID population is that it weighs factors more consistently associated with severity of illness in the COVID-19 pandemic, such advanced age, multifocal infiltration, smoking history, and lymphopenia. The notable disadvantage is that this score has NOT been Externally Validated and derived from a single retrospective single center, and clinical decision rules usually require more study before accepted widely into clinical use.

References

1. Guan W, Ni Z, Hu Y, et al. Clinical Characteristics of Coronavirus Disease 2019 in China. N Engl J Med. February 2020. doi:10.1056/NEJMoa2002032
2. Arentz M, Lim E, Klaff L, et al. Characteristics and Outcomes of 21 Critically Ill Patients With COVID-19 in Washington State. 2020:3.
3. Onder G, Rezza G, Brusaferro S. Case-Fatality Rate and Characteristics of Patients Dying in Relation to COVID-19 in Italy. JAMA. March 2020. doi:10.1001/jama.2020.4683
4. Young BE, Ong SWX, Kalimuddin S, et al. Epidemiologic Features and Clinical Course of Patients Infected With SARS-CoV-2 in Singapore. JAMA. March 2020. doi:10.1001/jama.2020.3204
5. Holshue ML, DeBolt C, Lindquist S, et al. First Case of 2019 Novel Coronavirus in the United States. N Engl J Med. 2020;382(10):929-936. doi:10.1056/NEJMoa2001191
6. Lippi G, Plebani M, Michael Henry B. Thrombocytopenia is associated with severe coronavirus disease 2019 (COVID-19) infections: A meta-analysis. Clin Chim Acta. March 2020. doi:10.1016/j.cca.2020.03.022
7. Huang C, Wang Y, Li X, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. The Lancet. 2020;395(10223):497-506. doi:10.1016/S0140-6736(20)30183-5
8. Wu C, Chen X, Cai Y, et al. Risk Factors Associated With Acute Respiratory Distress Syndrome and Death in Patients With Coronavirus Disease 2019 Pneumonia in Wuhan, China. JAMA Intern Med. March 2020. doi:10.1001/jamainternmed.2020.0994
9. Liu W, Tao Z-W, Lei W, et al. Analysis of factors associated with disease outcomes in hospitalized patients with 2019 novel coronavirus disease: Chin Med J (Engl). February 2020:1. doi:10.1097/CM9.0000000000000775
10. Wang D, Hu B, Hu C, et al. Clinical Characteristics of 138 Hospitalized Patients With 2019 Novel Coronavirus–Infected Pneumonia in Wuhan, China. JAMA. 2020;323(11):1061. doi:10.1001/jama.2020.1585
11. Zhang J, Dong X, Cao Y, et al. Clinical characteristics of 140 patients infected with SARS‐CoV‐2 in Wuhan, China. Allergy. February 2020. doi:10.1111/all.14238
12. Bauchner H, Golub RM, Zylke J. Editorial Concern—Possible Reporting of the Same Patients With COVID-19 in Different Reports. JAMA. March 2020. doi:10.1001/jama.2020.3980
13. Lippi G, Plebani M. Procalcitonin in patients with severe coronavirus disease 2019 (COVID-19): A meta-analysis. Clin Chim Acta. 2020;505:190-191. doi:10.1016/j.cca.2020.03.004
14. Sharfstein JM, Becker SJ, Mello MM. Diagnostic Testing for the Novel Coronavirus. JAMA. March 2020. doi:10.1001/jama.2020.3864
15. Lan L, Xu D, Ye G, et al. Positive RT-PCR Test Results in Patients Recovered From COVID-19. JAMA. February 2020. doi:10.1001/jama.2020.2783
16. Ng O-T, Marimuthu K, Chia P-Y, et al. SARS-CoV-2 Infection among Travelers Returning from Wuhan, China. N Engl J Med. March 2020. doi:10.1056/NEJMc2003100
17. Coronavirus (COVID-19) Update: FDA Issues first Emergency Use Authorization for Point of Care Diagnostic | FDA. https://www.fda.gov/news-events/press-announcements/coronavirus-covid-19-update-fda-issues-first-emergency-use-authorization-point-care-diagnostic. Accessed March 23, 2020.
18. Symptoms & Testing | CDC. https://www.cdc.gov/coronavirus/2019-ncov/symptoms-testing/index.html. Accessed March 23, 2020.
19. Lim WS. Defining community acquired pneumonia severity on presentation to hospital: an international derivation and validation study. Thorax. 2003;58(5):377-382. doi:10.1136/thorax.58.5.377
20. Fine MJ, Auble TE, Yealy DM, et al. A Prediction Rule to Identify Low-Risk Patients with Community-Acquired Pneumonia. N Engl J Med. 1997;336(4):243-250. doi:10.1056/NEJM199701233360402
21. COVID-19 Resource Center. https://www.mdcalc.com/covid-19. Accessed March 23, 2020.
22. Guo L, Wei D, Zhang X, et al. Clinical Features Predicting Mortality Risk in Patients With Viral Pneumonia: The MuLBSTA Score. Front Microbiol. 2019;10. doi:10.3389/fmicb.2019.02752