The Association of Inflammatory Cytokines in the Pulmonary Pathophysiology of Respiratory Failure in Critically Ill Patients With Coronavirus Disease 2019

Abstract

Objectives: The majority of coronavirus disease 2019 mortality and morbidity is attributable to respiratory failure from severe acute respiratory syndrome coronavirus 2 infection. The pathogenesis underpinning coronavirus disease 2019-induced respiratory failure may be attributable to a dysregulated host immune response. Our objective was to investigate the pathophysiological relationship between proinflammatory cytokines and respiratory failure in severe coronavirus disease 2019.

Design: Multicenter prospective observational study.

Setting: ICU.

Patients: Critically ill patients with coronavirus disease 2019 and noncoronavirus disease 2019 critically ill patients with respiratory failure (ICU control group).

Interventions: Daily measurement of serum inflammatory cytokines.

Measurements and main results: Demographics, comorbidities, clinical, physiologic, and laboratory data were collected daily. Daily serum samples were drawn for measurements of interleukin-1β, interleukin-6, interleukin-10, and tumor necrosis factor-α. Pulmonary outcomes were the ratio of Pao₂/Fio₂ and static lung compliance. Twenty-six patients with coronavirus disease 2019 and 22 ICU controls were enrolled. Of the patients with coronavirus disease 2019, 58% developed acute respiratory distress syndrome, 62% required mechanical ventilation, 12% underwent extracorporeal membrane oxygenation, and 23% died. A negative correlation between interleukin-6 and Pao₂/Fio₂ (rho, -0.531; p = 0.0052) and static lung compliance (rho, -0.579; p = 0.033) was found selectively in the coronavirus disease 2019 group. Diagnosis of acute respiratory distress syndrome was associated with significantly elevated serum interleukin-6 and interleukin-1β on the day of diagnosis.

Conclusions: The inverse relationship between serum interleukin-6 and Pao₂/Fio₂ and static lung compliance is specific to severe acute respiratory syndrome coronavirus 2 infection in critically ill patients with respiratory failure. Similar observations were not found with interleukin-β or tumor necrosis factor-α.

Keywords: acute respiratory distress syndrome; coronavirus disease 2019; interleukin-6; respiratory failure; severe acute respiratory syndrome coronavirus 2.

Figure 1.

Association of oxygenation, as measured by the ratio of Pao₂/Fio₂, static lung compliance, and serum proinflammatory cytokines in coronavirus disease 2019 (COVID-19) patients and ICU controls. Levels of (A, D, G, J) interleukin (IL)–6, (B, E, H, K) IL-1β, and (C, F, I, L) tumor necrosis factor-α (TNFα) were quantified in serum samples taken upon study enrollment in (A–C) 26 COVID-19 patients, and (D–F) 22 ICU controls and plotted against their initial ratio of Pao₂/Fio₂. Within the subset of ventilated patients where static lung compliance could be calculated (on assist control or pressure control ventilators), serum cytokines were plotted against initial static lung compliance in (G–I) 14 COVID-19 patients and (J–L) 11 ICU controls. Data were analyzed using a Spearman correlation. In all graphs, circles represent males, whereas squares represent females; blue/teal represents nonventilated patients, whereas orange/red represents mechanically ventilated patients.

Figure 2.

Serum inflammatory markers in coronavirus disease 2019 patients diagnosed with or without acute respiratory distress syndrome (ARDS). Concentration of (A) interleukin (IL)–6, (B) IL-1β, and (C) tumor necrosis factor-α (TNFα) were compared between patients diagnosed without (no) ARDS (n = 13) versus those with an ARDS diagnosis (yes; n = 13). Graph represents median and interquartile range. Data were analyzed using a Mann-Whitney U test.

Figure 3.

Characterization of pulmonary pathophysiology, serum inflammation, and postmortem histopathology in an individual patient with coronavirus disease 2019 (COVID-19). This patient was intubated and ventilated on day 1 (27 d follow symptom onset), placed onto extracorporeal membrane oxygenation on day 7, and succumb to COVID-19 on day 16. A, Graph displaying daily measures of Pao₂/Fio₂ (blue, graphed on right-hand y-axis) and interleukin-6 (IL-6) (orange, graphed on left-hand y-axis) during 1 wk of ICU stay. B, Chest radiographs (L, left; R, right) of patient 7 taken on days 0, 3, 15, and 16. C, Chest CT scans taken on days 3 and 15, with two axial slices shown per day. D–F, Postmortem lung histopathology. D, Scanning low power micrograph showing large zones of atelectatic and fibrotic parenchyma with compressed and obliterated airspaces. A small organizing pulmonary arterial thrombus is identified (arrow) (hematoxylin and eosin stain; bar = 1 mm). E, Higher magnification of one of the advanced zones of fibrosis demonstrating collagenized granulation tissue plugs, with a slight arborizing pattern, filling airspaces (white and black asterisks). Movat pentachrome stain (a connective tissue stain; alveolar and vascular elastica stain black) (bar = 125 μm). F, Medium magnification demonstrating a hyaline membrane (white arrow) applied to the inner wall of an alveolus. An adjoining alveolus is lined with hyperplastic type II pneumocytes showing reactive cytological atypia (hematoxylin and eosin stain; bar = 250 μm). br = bronchioles.

Figure 4.

Cross-platform validation of serum interleukin-6 (IL-6) quantification using the Quanterix Simoa HD-1 (Billerica, MA) and Siemens ADVIA Centaur XP platforms (Munich, Germany). IL-6 was quantified in 39 serum samples on both the Quanterix and Siemens platforms. All measures were performed in duplicate. A, Scatter-plot of IL-6 quantified using Quanterix (x-axis) versus Siemens (y-axis). Data were analyzed using a Spearman correlation (Rho, 0.903; 95% CI, 0.819–0.949; p < 0.0001). B, Bland-Altman plot of average IL-6 versus % bias ([Quanterix–Siemens]/average) × 100%. The mean (sd) bias (41.8% [58.3]) is noted by a red line, and 95% limit of agreement (–72%, 156%) is noted by black horizontal lines.