ABSTRACT
Background: After 4 months we have shown, that DLCO is lower in severe COVID-19 patients compared to nonsevere (Guler SA, et al. Eur Respir J. 2021 Apr 29;57(4):2003690). Contributing factors are unclear. Calprotectin is an inflammatory marker released by activated neutrophils and is increased in acute severe COVID-19. Aim(s): We hypothesized that circulating calprotectin correlates with persistent lung functional impairment after COVID-19. Method(s): Calprotectin serum levels were measured in 124 patients (50% male) 4 months after COVID-19 (NCT04581135). Calprotectin was correlated with clinical parameters (Spearman's correlation). Multivariate linear regression (MLR) was performed to evaluate the independent association of calprotectin in different models. Result(s): Post-ICU patients (72% male) compared to non-ICU were significantly older (age 59.4 +/- 13.6 vs 49.2 +/- 13.1 years) and more obese (BMI 28.7 +/- 4.5 vs 25.2 +/- 6.0 kg/m2) (p=0.001, each) compared to non-ICU. DLCO was lower in post-ICU patients (75.96 +/- 19.05 %-predicted) compared to non-ICU (p<0.01). Calprotectin was significantly higher in post-ICU patients (2.74 +/- 1.15 mug/ml) compared to non-ICU (1.81 +/- 0.94 mug/ml, p<0.001). In unadjusted analysis, calprotectin correlated with DLCO (r=-0.350, p<0.001) and FVC (r=-0.417, p<0.001). In MLR adjusted for age, sex and BMI, calprotectin correlates with DLCO (R2=0.276, p<0.001). Calprotectin significantly predicted DLCO (beta=-6.463, p=0.001). Conclusion(s): Serum calprotectin is higher in post-ICU patients compared with non-ICU 4 months after COVID-19. The relationship between calprotectin levels and DLCO suggests a potential role for calprotectin in persisting lung functional impairment.
ABSTRACT
BACKGROUND: The infectious coronavirus disease 2019 (COVID-19) pandemic is an ongoing global healthcare challenge. Up to one-third of hospitalised patients develop severe pulmonary complications and acute respiratory distress syndrome. Pulmonary outcomes following COVID-19 are unknown. METHODS: The Swiss COVID-19 lung study is a multicentre prospective cohort investigating pulmonary sequelae of COVID-19. We report on initial follow-up 4 months after mild/moderate or severe/critical COVID-19 according to the World Health Organization severity classification. RESULTS: 113 COVID-19 survivors were included (mild/moderate n=47, severe/critical n=66). We confirmed several comorbidities as risk factors for severe/critical disease. Severe/critical disease was associated with impaired pulmonary function, i.e. diffusing capacity of the lung for carbon monoxide (D <sub>LCO</sub>) % predicted, reduced 6-min walk distance (6MWD) and exercise-induced oxygen desaturation. After adjustment for potential confounding by age, sex and body mass index (BMI), patients after severe/critical COVID-19 had a D <sub>LCO</sub> 20.9% pred (95% CI 12.4-29.4% pred, p=0.01) lower at follow-up. D <sub>LCO</sub> % pred was the strongest independent factor associated with previous severe/critical disease when age, sex, BMI, 6MWD and minimal peripheral oxygen saturation at exercise were included in the multivariable model (adjusted odds ratio per 10% predicted 0.59, 95% CI 0. 37-0.87;p=0.01). Mosaic hypoattenuation on chest computed tomography at follow-up was significantly associated with previous severe/critical COVID-19 including adjustment for age and sex (adjusted OR 11.7, 95% CI 1.7-239;p=0.03). CONCLUSIONS: 4 months after severe acute respiratory syndrome coronavirus 2 infection, severe/critical COVID-19 was associated with significant functional and radiological abnormalities, potentially due to small-airway and lung parenchymal disease. A systematic follow-up for survivors needs to be evaluated to optimise care for patients recovering from COVID-19.
ABSTRACT
COVID-19 is an infectious disease caused by the newly discovered coronavirus named SARS-CoV-2. The virus enters the body through the airways by exploiting the angiotensin-converting enzyme 2 (ACE2) and serine proteinase TMPRSS2. Thus, especially lung epithelial cells are attacked by the virus. In the distal lung, the virus infection leads to life-threatening alveolar damage and cytokine storm. Many excellent clinical studies described the pathology of COVID-19 progression in patients. However, impactful in vitro studies are still missing due to the exceptional difficulty to model the alveolar setting in vitro. Here, we introduce two advanced models based on organoids and lung-on-chip (LOC) technology. The models derived from primary alveolar epithelial cells were characterized by fluorescence imaging and gene expression. Barrier function and cell polarity were assessed by confocal microscopy of tight junction and transporter proteins. We showed that the LOC model and the newly developed organoids preserve alveolar type II specific markers (SP-C and HTII-280). In both models we could detect relevant amounts of ACE2 and TMPRSS2 mRNA as compared to whole lung extracts. As a next step we will optimize the infection titer for both systems to further analyze transcriptomic changes upon SARS-CoV-2 infection. The here presented advanced in vitro models, recapitulating the distal lung, serve as complementary SARS-CoV-2 lung infection models. The LOC model will allow to simulate alveolar breakdown and cytokine storm whereas the organoid models will facilitate high-content drug screening.