May 26, 2020

Elevated levels of IL-6, CRP highly predictive for invasive ventilation

A study published in the Journal of Allergy and Clinical Immunology looking at laboratory parameters to help predict impending respiratory failure in COVID-19 found that high levels of interleukin-6 (Il-6) over the course of disease, followed by C-reactive protein (CRP), were the best predictors of respiratory failure. "This suggests the possibility of using IL-6 or CRP levels to guide escalation of treatment in patients with COVID-19-related hyperinflammatory syndrome," wrote Tobias Herold, University Hospital, LMU Munich, Munich, Germany, and colleagues.

Patients with COVID-19 hospitalised from February 29, 2020, to April 9, 2020, were analyzed for baseline clinical and laboratory findings at admission and during the disease. Data from 89 evaluable patients were available for the purpose of analysis comprising an initial evaluation cohort (n=40) followed by a temporally separated validation cohort (n=49). Use of compassionate medication was low in the study cohort before mechanical ventilation, with 5 patients receiving lopinavir/ritonavir and 8 patients receiving hydroxychloroquine.

In the initial cohort, recruited from February 29, 2020, to March 27, 2020, 13 patients (32.5%) deteriorated during hospitalization and required mechanical ventilation. The time from hospital admission to intubation varied from less than 2 hours to 9 days (median 2 days).

Heart rate, markers of inflammation, lactate dehydrogenase (LDH) and creatinine at admission were significantly associated with respiratory failure. Maximal IL-6 levels before intubation showed the strongest association with the need for mechanical ventilation followed by maximal CRP. The calculated optimal cutoff for maximal IL-6 was 80 pg/mL, after which the median time to mechanical ventilation was 1.5 days (range 0–4 days). The optimal cutoff for maximal CRP was 97 mg/L, with the median time to mechanical ventilation of 0 days after reaching the cutoff (range 0–4 days).

The validation cohort prospectively recruited patients from March 27, 2020, to April 9, 2020, of which 19 (39%) required mechanical ventilation. As in the initial evaluation cohort, creatinine, LDH, and several markers of inflammation were significantly elevated in those requiring intubation, with maximal IL-6 being again the best predictor of future respiratory failure. CRP values at initial assessment were also significantly associated with respiratory failure.

To validate findings from the initial cohort, researchers analyzed the number of patients correctly classified regarding their need of mechanical respiratory support by the determined cutoffs of IL-6 and CRP at presentation and in the course of disease. At presentation, IL-6 >35 pg/mL as well as CRP >32.5 mg/L showed high sensitivity to detect patients at risk for respiratory failure (84% and 95%) with moderate specificity (63% for both parameters). Meanwhile, in total, the calculated cutoffs for maximal IL-6 and CRP both correctly classified 80% of patients regarding their risk of respiratory failure, while values at assessment show poorer predictor properties owing to the moderate specificity (correct classification of 71% for IL-6 and 76% for CRP).

The authors concluded that "IL-6 and CRP are useful markers that predict impending respiratory failure with high accuracy and can help physicians correctly allocate patients who might benefit from early treatment escalation, for example using anti-cytokine strategies." They added "to our knowledge, our study is the first to demonstrate a prospective prediction of the end point 'mechanical ventilation,' which is of high clinical relevance not only for patient treatment, but also for resource planning…in the current situation with overwhelmed intensive care units and overcrowded emergency rooms."

Still, the authors noted that it remains "unclear whether elevated inflammatory markers merely represent an epiphenomenon or a causal pathogenic element of severe COVID-19." They also pointed out that even though IL-6 and CRP levels are significantly higher in patients who need ventilation, they are "relatively low" compared to levels observed in patients with septic shock.

SOURCE: Journal of Allergy and Clinical Immunology