The spectrum of biochemical alterations associated with organ dysfunction and inflammatory status and their association with disease outcomes in severe COVID-19: A longitudinal cohort and time-series design study

Abstract

Background: In patients with severe COVID-19, no data are available on the longitudinal evolution of biochemical abnormalities and their ability to predict disease outcomes.

Methods: Using a retrospective, longitudinal cohort study design on consecutive patients with severe COVID-19, we used an extensive biochemical dataset of serial data and time-series design to estimate the occurrence of organ dysfunction and the severity of the inflammatory reaction and their association with acute respiratory failure (ARF) and death.

Findings: On the 162 studied patients, 1151 biochemical explorations were carried out for up to 59 biochemical markers, totaling 15,260 biochemical values. The spectrum of biochemical abnormalities and their kinetics were consistent with a multi-organ involvement, including lung, kidney, heart, liver, muscle, and pancreas, along with a severe inflammatory syndrome. The proportion of patients who developed an acute kidney injury (AKI) stage 3, increased significantly during follow-up (0·9%, day 0; 21·4%, day 14; P<0·001). On the 20 more representative biochemical markers (>250 iterations), only CRP >90 mg/L (odds ratio [OR] 6·87, 95% CI, 2·36-20·01) and urea nitrogen >0·36 g/L (OR 3·91, 95% CI, 1·15-13·29) were independently associated with the risk of ARF. Urea nitrogen >0·42 g/L was the only marker associated with the risk of COVID-19 related death.

Interpretation: Our results point out the lack of the association between the inflammatory markers and the risk of death but rather highlight a significant association between renal dysfunction and the risk of COVID-19 related acute respiratory failure and death.

Fig. 1

Kinetics over time of the most frequently observed biochemical abnormalities during the follow-up of patients with severe COVID-19 (part 1): A: urea nitrogen (g/L); B: creatinine (mg/L); C: osmolality, calculated (mOsmol/kg); D: phosphorus (mg/L); E: calcium (mg/L); F: albumin (g/L); G: triglycerides (g/L); and H: C-reactive protein (mg/L). The dashed lines correspond to the upper (U) and lower (L) limits of the reference range. The red line indicates the evolution trend of the biomarker during follow-up according to the isotonic regression method.

Fig. 2

Kinetics over time of the most frequently observed biochemical abnormalities during the follow-up of patients with severe COVID-19 (part 2): A: hemoglobin (g/dL); B: partial pressure of oxygen (PO₂) (mmHg); C: high-sensitivity cardiac troponin I (hs-c Troponin I) (pg/mL); D: hs-c Troponin I (view limited to hs-c Troponin I <400 pg/mL); E: N-Terminal pro-Brain Natriuretic Peptide (NT-proBNP) (pg/mL); F: NT-proBNP (view limited to NT-proBNP <1000 pg/mL); G: CK (view limited to CK < 2000 U/L); H: lactate dehydrogenase (LDH) (U/L). The dashed lines correspond to the upper (U) and lower (L) limits of the reference range. The red line indicates the evolution trend of the biomarker during follow-up according to the isotonic regression method.

Fig. 3

Kinetics over time of the most frequently observed biochemical abnormalities during the follow-up of patients with severe COVID-19 (part 3): A: aspartate aminotransferases (ASAT) (U/L); B: ASAT (U/L) (view limited to ASAT <400 U/L); C: alanine aminotransferases (ALAT) (U/L); D: ALAT (U/L) (view limited to ALAT <400 U/L); E: bilirubin, total (mg/L); F: bilirubin, conjugated (mg/L); G: alkaline phosphatase (UI/L); H: γ-glutamyltransferase (U/L). The red line indicates the evolution trend of the biomarker during follow-up according to the isotonic regression method.

Fig. 4

Biochemical abnormalities associated with the occurrence of acute respiratory failure (ARF) among patients with severe COVID-19. A set of 20 biochemical markers with at least 250 iterations was systematically screened for the association with the occurrence of ARF using ROC analysis. All markers with a statistically significant ROC-defined threshold were assessed using time series analysis to calculate the percentage of time below or above the defined threshold. The calculated summary effects are reported as percentages of the total time of observation with the 95% CI, as noted in the Forest plot.

Fig. 5

Biochemical abnormalities associated with the occurrence of in-hospital mortality among patients with severe COVID-19. A set of 20 biochemical markers with at least 250 iterations was systematically screened for the association with the occurrence of in-hospital mortality using ROC analysis. All markers with a statistically significant ROC-defined threshold were assessed using time series analysis to calculate the percentage of time below or above the defined threshold. The calculated summary effects are reported as percentages of the total time of observation with the 95% CI, as noted in the Forest plot.

Fig. 6

Overview of the evolution of the main biochemical abnormalities and potential predictors acute respiratory failure (ARF) or in-hospital mortality among patients with severe COVID-19. Predictors of ARF in bivariate analyses are highlighted in blue font. Predictors of COVID-19 related mortality in bivariate analyses are highlighted in red font. Independent predictors of ARF in the multivariable multilevel analysis are underlined. ALP: alkaline phosphatase; ASAT: aspartate aminotransferases; ALAT: alanine aminotransferases; CK: creatine kinase; CRP: C-reactive protein; GGT: γ-glutamyltransferase; hs-c Troponin l: high-sensitivity cardiac troponin I; IL-6: interleukin 6; LDH: lactate dehydrogenase; NT-pro-BNP: N-Terminal pro-Brain Natriuretic Peptide; PCT: procalcitonin; (icons made by flaticon, flaticon.com; CC-BY-3.0).