CMAAO CORONA FACTS and MYTH CRP Update

Dr K Aggarwal, President CMAAO : With input from Dr Monica Vasudev

India

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New Delhi, November 07, 2020 :

COVID-19 is associated with a hypercoagulable state

1. Associated with acute inflammatory changes
2.  Lab findings are distinct from acute DIC except for those with very severe disease.
3.  Fibrinogen and D-dimer are increased in COVID 19
4.  Only modest prolongation of the prothrombin time (PT) and activated partial thromboplastin time (aPTT)
5.  Mild thrombocytosis or thrombocytopenia.
6.  The presence of a lupus anticoagulant (LA) is common in individuals with a prolonged aPTT.
7.  The risk for venous thromboembolism 25 to 43 percent in ICU patients, often despite prophylactic-dose anticoagulation.
8.  Pulmonary microvascular thrombosis is also increased.
9.  The risk for arterial thrombotic events such as stroke, myocardial infarction, and limb ischemia also appears to be increased.
10. All inpatients should receive thromboprophylaxis unless contraindicated.
11. Individuals who have not had a VTE are not routinely given thromboprophylaxis after discharge from the hospital. A period of thromboprophylaxis following discharge may be appropriate in selected individuals.
12. High IL6is liked with high DMR and high CRP

CRP

1. CRP=  the upper limit of the reference range (mg/dL) equals (age in years)/50 for men and (age in years/50) + 0.6 for women [J Rheumatol. 2000;27(10):2351,  J Rheumatol. 2005;32(6):1040. ]
2.  CRP over 10 mg/L = clinically significant inflammation while concentrations between 3 and 10 mg/L indicate what is commonly referred to as low-grade inflammation [
   Ann Intern Med. 2015;163(4):326]
3. Minor CRP elevation (concentrations between 3 and 10 mg/L) has been generally regarded as a marker of what has been called low-grade inflammation. However, this poorly defined state, sometimes referred to as mini-inflammation or subclinical inflammation, occurs in many conditions in which there are minor degrees of metabolic dysfunction, such as obesity and insulin resistance, unlike inflammation as it has traditionally been understood
4. Markedly elevated levels of CRP are strongly associated with infection. Infections, most often bacterial, were found in approximately 80 percent of patients with values in excess of 10 mg/dL (100 mg/L) and in 88 to 94 percent of patients with values over 50 mg/dL (500 mg/L) [Eur J Intern Med. 2006;17(6):430, Pathol Biol (Paris). 2011 Dec;59(6):319-20. Epub 2010 May 18. ]
5. Levels of CRP may also be elevated in patients with viral infections, although usually not to the degree seen in patients with bacterial infection [Clin Infect Dis. 2004;39(2):206. Epub 2004 Jul 2. ]
6. C-reactive protein (CRP) over 40 mg/L had a sensitivity and specificity for bacterial pneumonia of 70 and 90 percent, respectively [Am J Med. 2004;116(8):529.]
7. CRP levels in patients with pneumococcal pneumonia (mean 178 mg/L) [Chest. 2004;125(4):1335.]
8. CRP appears to be less sensitive than procalcitonin for the detection of bacterial pneumonia [Intensive Care Med. 2006;32(3):469. Epub 2006 Feb 14].
9.  C-reactive protein levels that rapidly return to baseline are an index of resolving tissue damage as may occur with favorable patient responses to treatments. At the early stage of COVID-19, CRP levels were positively correlated with lung lesions.
10. In COVID-19 infections, CRP levels that are minimally elevated (10 – 20 μg/mL) can be diagnostic of mild viral disease.
11. COVID-19 patients with moderate elevations of CRP levels (Over 20–40 μg/mL) may harbor some level of (reversible) tissue damage associated with the natural response to combating the viral disease. If these levels are measured relatively early in disease progression, before a cytokine storm response, these levels may suggest a confounding bacterial infection or more significant tissue involvement in disease.
12. COVID-19 patients with significantly elevated CRP levels (e.g., > 100 μg/mL) more readily reflect advanced tissue damage and pathologies associated with cytokine storm, coagulation abnormalities, and multiple organ failure. Such high CRP levels would correlate with a life-threatening prognosis.[The American Journal of Tropical Medicine and Hygiene, Volume 103, Issue 2, 5 Aug 2020, p. 561 – 563]

CRP cut offs :

CRP levels can be used for early diagnosis of pneumonia [PloS one, 11 (3) (2016), p. e0150269, 10.1371/journal.pone.0150269]

11mg / L: ROC curves showed a sensitivity of 75% and specificity of 70% for the LDH cut-off value of 450 U/L and a sensitivity of 72% and specificity of 71% for the CRP cut-off value of 11 mg/dl in identifying CoVID-19 with moderate-severe ARDS. [ Clinica Chimica Acta, Volume 509, October 2020, Pages 135-138]

16.60 mg/L: Moderate-severe vs mild [77.0% sensitivity, 72.0% specificity). [ Annals of Clinical Microbiology and Antimicrobials volume 19, Article number: 18 (2020)]

20.42mg/L: Area under the curve of CRP on the first visit for predicting severe COVID‐19 was 0.87 (95% CI 0.10–1.00) at 20.42 mg/L with sensitivity and specificity 83% and 91%, respectively. CRP in severe COVID‐19 patients increased significantly at the initial stage, before CT findings. Importantly, CRP, which was associated with disease development, predicted early severe COVID‐19.  [https://doi.org/10.1002/jmv.25871 Journal of medical virology]

Only CRP was significantly associated with the progression of non-severe COVID-19 patients (OR, 1.056; 95% CI, 1.025–1.089; P = .000) as determined by multivariate analysis, which suggested that for every 1-unit increase in CRP level, the risk of developing severe events increased by about 5%. )  [Open Forum Infectious Diseases, Volume 7, Issue 5, May 2020, ofaa153].

KM curve showed that patients with high levels of CRP (≥26.9 mg/L) had significantly elevated risks of developing into severe cases when compared with patients with low levels (24.5% vs 1.9%; log-rank P < .001)  [Open Forum Infectious Diseases, Volume 7, Issue 5, May 2020, ofaa153].

40-5- mg/L:      Chinese guideline: For follow up

41.4 mg/L: CRP exhibited sensitivity 90.5%, specificity 77.6%, positive predictive value 61.3%, and negative predictive value 95.4%. [ doi: https://doi.org/10.1101/2020.03.21.20040360]

Over 100 mg/L: At admission associated with increased ICU admissions and 30-day mortality [J Crit Care 2020; 56: 73 – 9]

D Dimer over 1000 ng/ml (Less than 500)

CRP over 100 mg/L (Less than 8)

LDH Over 245 units / L (Less than 110-210)

Troponin Over 2 x ULN (F 0-9 ng/L, Males 0-14 ng/L)

Ferritin over 500 mcg/L (F 10-200, M 30-300]

CPK Over 2 x uln (40-150 units/L)

Reduced absolute lymphocyte count: less than 800 /microl [18—to 7700 in over 21 years age]

References:

1. Guan WY, Ni ZY, Hu Y, et al. Clinical characteristics of coronavirus disease 2019 in China. N Engl J Med 2020.
2. Huang C, Wang Y, Li X, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet 2020; 395:497.
3. Zhou F, Yu T, Du R, et al. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. Lancet 2020; 395:1054.
4. 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.
5. Wu Z, McGoogan JM. Characteristics of and important lessons from the coronavirus disease 2019 (COVID-19) outbreak in China: Summary of a report of 72,314 cases from the Chinese Center for Disease Control and Prevention. JAMA 2020.
6. Ruan Q, Yang K, Wang W, et al. Clinical predictors of mortality due to COVID-19 based on an analysis of data of 150 patients from Wuhan, China. Intensive Care Med 2020.

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