We present a precision-engineered lung-on-chip platform that replicates the biomechanical and structural features of the human alveolar microenvironment for respiratory disease modeling and therapeutic evaluation. At the core of the device is a thin, suspended hydrogel membrane composed of biologically relevant collagen and elastin, engineered to mimic the dimensions and mechanical fragility of the native alveolar basement membrane. This membrane supports a geometrically defined array of alveolar units, each capable of undergoing finely controlled, physiologically relevant deflections under cyclic mechanical actuation-emulating the subtle deformations that occur during human breathing. To address the challenges posed by the membrane's mechanical fragility and the requirement for accurately controlled micron-scale deflections, the platform is fabricated using precision injection molding. This manufacturing strategy ensures structural integrity and reproducibility, creating a rigid support structure around the suspended hydrogel membrane. The design is integrated into a SBS microwell plate format, facilitating robust fluidic interfacing, consistent cyclic actuation, and medium-throughput operation. Human alveolar epithelial cells and lung fibroblasts are co-cultured on a membrane and subjected to cyclic biomechanical stress that mimics respiratory movements. We demonstrate that cyclic stretching significantly amplifies fibrotic signaling in the presence of transforming growth factor-beta 1 (TGF-β1), evidenced by increased expression of extracellular matrix (ECM) components such as collagen I, collagen III, and fibronectin. Treatment with the anti-fibrotic drug nintedanib reduced expression of ECM proteins and plasminogen activator inhibitor-1 (PAI-1), validating the system's utility for pharmacological testing. This alveolar array-based lung-on-chip system bridges a critical gap between conventionalin vitromodels and the physiological complexity of human lung tissue, offering a robust platform for mechanistic studies and preclinical evaluation in pulmonary fibrosis and related disorders.

Respiratory viruses pose a constant threat to public health as highlighted by the pandemic outbreak of COVID-19. The most severe manifestation of COVID-19 is observed in the distal lung, where SARS-CoV-2 infection can result in massive inflammation and barrier breakdown. To date, few therapies are approved for clinical use in COVID-19 patients partially due to the lack of highly translational pre-clinical models of the alveoli. Human-derived microphysiological systems pose a promising new class of in vitro models to study viral infection in a relevant context. Therefore, we aimed to develop a Lung-on-Chip (LOC) model for studying SARS-CoV-2 infection at the alveolar barrier. Using an immortalized alveolar epithelial cell line, AXiAEC, and human lung microvascular endothelial cells (hLMVEC) we established a SARS-CoV-2 infection model on a LOC system. The LOC models the alveolar epithelial/endothelial barrier under physiological breathing motion. Our results demonstrated that AXiAEC maturation at the air-liquid interface (ALI) is essential for SARS-CoV-2 infection. SARS-CoV-2 infected the breathing LOC model and induced breakdown of the air-blood barrier. Finally, we evaluated the application of the LOC SARS-CoV-2 infection model for efficacy testing and demonstrated the antiviral effect of remdesivir. Drug treatment not only inhibited viral replication but also protected the alveolar barrier from damage and partially reverted SARS-CoV-2-mediated transcriptional dysregulation in AXiAEC. This novel LOC infection model recapitulates aspects of COVID-19. Our results highlight the importance of physiological cues such as ALI and stretch to accurately model host-pathogen interactions in the distal lung. Application of LOC models in pre-clinical drug testing may facilitate candidate compound selection at an early stage, allowing the allocation of resources to a few promising candidate compounds raising the potential to accelerate drug development and reduce costs and animal testing. ### Competing Interest Statement MK, LdM, NR, LF, JS and NH are current or former employees of AlveoliX AG (Switzerland). TG is a member of the AlveoliX AG Board and scientific advisor. TG and NH are shareholder of AlveoliX AG. All other authors declare no conflict of interest. Innosuisse – Swiss Innovation Agency, https://ror.org/05a2bhn71, 53709.1 IP-LS Bern Center for Precision Medicine (BCPM) Lungenliga Bern

Masked autoencoders (MAEs) have emerged as a powerful approach for pre-training on unlabelled data, capable of learning robust and informative feature representations. This is particularly advantageous in diffused lung disease research, where annotated imaging datasets are scarce. To leverage this, we train an MAE on a curated collection of over 5,000 chest computed tomography (CT) scans, combining in-house data with publicly available scans from related conditions that exhibit similar radiological patterns, such as COVID-19 and bacterial pneumonia. The pretrained MAE is then fine-tuned on a downstream classification task for diffused lung disease diagnosis. Our findings demonstrate that MAEs can effectively extract clinically meaningful features and improve diagnostic performance, even in the absence of large-scale labelled datasets. The code and the models are available here: https://github.com/eedack01/lung_masked_autoencoder.

BACKGROUND:Patients with pulmonary hypertension (PH) experience reduced physical capacity, which affects daily life functionality. Frailty signifies increased vulnerability due to diminished physiological reserves and is common in the elderly and those with chronic diseases, but has not been investigated in PH. This study aimed to create a frailty index for PH, to assess the prevalence of frailty, to determine frailty severity and progression over time and to establish a potential association between frailty and mortality in patients with PH. METHODS:This retrospective cohort study included patients with right heart catheter confirmed PH. Frailty was assessed using a cumulative frailty index (FI). Logistic regression, Cox proportional hazard models and causal mediation analyses were used to determine the relationship between frailty and time from FI assessment to death or censoring. RESULTS:After dropping 22 items with item-score correlation <0.7, a 30-item-FI was developed, demonstrating high internal consistency. At baseline 117/189 (62 %) patients were frail (FI > 0.12) and this proportion increased to 71 % at follow-up. Frail patients were older, had lower 6-min walk distance (6MWD), higher NT-proBNP, and lower pulmonary vascular resistance (PVR). Risk of death was significantly higher in patients with frailty after adjustment for age, sex, PVR, and PH treatment (HR 6.4, 95 % CI 2.14-19.1, p = 0.001); only a small proportion of this effect was mediated by 6MWD. CONCLUSIONS:Frailty is common in PH and an independent risk factor for mortality beyond confounding/effect modification. Future research should explore underlying mechanisms and the utility of integrating frailty assessment in routine PH patient care.

ABSTRACT Iron deficiency (ID) is prevalent in pulmonary hypertension(PH), but there is no consensus on ID definition and its possible correlation to prognostic markers. Hence, in this study, PH‐patients were recruited at the University Hospital Zurich from May 2019 to April 2021. Clinical and hemodynamic characteristics were recorded at inclusion and venous blood samples were taken. ID was defined as: (i) ferritin‐ID: ferritin< 100 µg/L or 100–299 µg/L plus a transferrin saturation (TSAT) < 20%; (ii) TSAT‐ID: a TSAT < 20% (males)/< 15% (females) and (iii) TFRI‐ID: a transferrin receptor index (TFRI) > 3.2/ > 2.0 depending on CRP < / > 5 mg/L. 94 patients (52% female, mean age 62.9 ± 14.6 years) with pulmonary arterial hypertension(48%), PH associated with lung disease (20%) or chronic thromboembolic PH (32%) were included. Sixty‐seven percent fulfilled criteria for ferritin‐ID, 35% for TSAT‐ID, and 13% for TFRI‐ID. Mean pulmonary arterial pressure (mPAP) was elevated in TFRI‐ID patients compared to non‐ID (50 ± 12.2 mmHg vs. 35.9 ± 11.7 mmHg); however, after correction for age, sex, PH‐type, and anticoagulation, the difference was nonsignificant ( p = 0.085). NT‐proBNP was significantly higher in TFRI‐ID‐positive (1237 ± 1166 pg/mL vs. 334 ± 417 pg/mL, p = 0.004). No significant differences were found for ferritin‐ID and TSAT‐ID ( p > 0.05). Six‐minute walk distance (6MWD) was reduced for both TSAT‐ID (402 ± 133 m vs. 469 ± 152 m, p = 0.006) and TFRI‐ID (370 ± 112 m vs. 459 ± 151 m, p = 0.052), but not for ferritin‐ID ( p > 0.05). In conclusion, TFRI‐ID is seemingly associated with clinical markers of right heart parameters and disease severity. This could not be seen with the currently recommended ferritin‐ID‐definition or TSAT‐ID. More data is needed to assess the use of the TFRI‐ID instead of the ferritin‐ID‐definition as a method to identify PH‐patients at risk and as a threshold for iron substitution.

Abstract Rationale Knowledge about the clinical importance of patient-reported outcome measures (PROMs) in severe asthma is limited. Objectives To assess whether and to what extent asthma exacerbations affect changes in PROMS over time and asthma-specific PROMs can predict exacerbations in adult patients with severe asthma in usual care. Methods Data of 421 patients with severe asthma (62% female; mean age 51.9 ± 13.4 years; mean FEV1 67.5 ± 21.3%pred) from the U-BIOPRED cohort were analyzed. The included PROMs were: Asthma Control Questionnaire (ACQ5); Asthma Quality of Life Questionnaire (AQLQ); Hospital Anxiety and Depression scale (HADS); Epworth Sleepiness Scale (ESS); Medication Adherence Report Scale (MARS); Sino-Nasal Outcomes Test (SNOT20). Participants were assessed at baseline and after 12–18 months of usual care. Results PROMs showed very weak to weak correlations with clinical characteristics such as age, body mass index, FEV1, FeNO and eosinophilic cell count. Patients presenting no exacerbations during follow-up showed a statistically significant improvement in all PROMs (except for MARS), whereas individuals experiencing > 2 exacerbations showed a deterioration. Baseline ACQ5 was a predictor of exacerbations with an AUC of 0.590 (95%CI 0.514–0.666). Conclusions The association of PROMs with clinical measures was poor in severe asthmatics. Moreover, PROMs were prone to changes in usual care, with exacerbations playing a key role. PROMs need to be systematically evaluated in severe asthma to improve clinical care based on specific patient’s needs.

Induced pluripotent stem cells (iPSCs) have emerged as promising in vitro tools, providing a robust system for disease modelling and facilitating drug screening. Human iPSCs have been successfully differentiated into lung cells and three-dimensional lung spheroids or organoids. The lung is a multicellular complex organ that develops under the symphonic influence of the microenvironment. Here, we hypothesize that the generation of lung organoids in a controlled microenvironment (cmO) (oxygen and pressure) yields multicellular organoids with architectural complexity resembling the lung alveoli. iPSCs were differentiated into mature lung organoids following a stepwise protocol in an oxygen and pressure-controlled microenvironment. The organoids developed in the controlled microenvironment displayed complex alveolar architecture and stained for SFTPC, PDPN, and KRT5, indicating the presence of alveolar epithelial type II and type I cells, as well as basal cells. Moreover, gene and protein expression levels were also increased in the cmO. Furthermore, pathway analysis of proteomics revealed upregulation of lung development-specific pathways in the cmO compared to those growing in normal culture conditions. In summary, by using a controlled microenvironment, we established a complex multicellular lung organoid derived from iPSCs as a novel cellular model to study lung alveolar biology in both lung health and disease.

Idiopathic pulmonary fibrosis (IPF) represents a terminal, age-related disease characterized by a complex pathophysiology. Recent studies have reported the presence of basal cells in IPF lungs, yet their specific role and impact on other cell types within the fibrotic lung remains unclear. Lung resident mesenchymal stem cells (MSCs) are a crucial resident stem cell population essential for maintaining lung homeostasis; MSCs exhaustion, a hallmark of aging, has been implicated in IPF through poorly understood mechanisms. In this study, we investigated the effects of hepatocyte growth factor (HGF), an anti-fibrotic factor, on MSCs quiescence using a bleomycin-induced lung injury model. RNA-sequencing analysis of basal cells isolated from IPF lungs identified upregulation of matrix metalloproteinase 24 (MMP24) in IPF (2.45±0.53) compared to non-IPF basal cells (1.12±0.2) (p˂0.05). Moreover, in vivo experiments indicated increased MMP24 levels in bleomycin injured lung homogenates compared to healthy lungs (6.89±0.78 vs 3.52±0.65 ng/mL) p<0.01, and decreased frequencies of activated lung MSCs in bleomycin-injured lungs compared to healthy lungs (21.8±6.2% vs 51.0±9.3%) p<0.01. Consistently, in vivo overexpression of MMP24 resulted in enhanced quiescence of lung MSCs and increased fibrosis. Conversely, in vivo HGF gene transfer increased frequencies of activated lung MSCs (27.5±3.2%, p<0.05) and reduced MMP24 levels in lung homogenates (4.39±0.38 ng/mL, p<0.001). Mechanistically, HGF reduced MMP24 expression through the YAP-1 pathway. Collectively, our findings uncover MMP24 as a pro-fibrotic mediator in IPF patients and in bleomycin injured lung and identify HGF-YAP1-MMP24 as a novel therapeutic axis in lung fibrosis.

Currently, 8.7 million people live in Switzerland—a number that has more than doubled in the past 100 years. In the same time, the population has become significantly older, and today, one-fifth is beyond retirement age (65 y in Switzerland). With an average life expectancy of 82 years in men and 86 years in women, Switzerland has one of the highest life expectancies worldwide.1 Annually, 43,000 people are diagnosed with having cancer in Switzerland. The estimated age-standardized lung cancer incidence in Switzerland is lower than that in surrounding countries (Fig. 1).

Rationale Patients with severe asthma are dependent upon treatment with high doses of inhaled corticosteroids (ICS) and often also oral corticosteroids (OCS). The extent of endogenous androgenic anabolic steroid (EAAS) suppression in asthma has not previously been described in detail. The objective of the present study was to measure urinary concentrations of EAAS in relation to exogenous corticosteroid exposure. Methods Urine collected at baseline in the U-BIOPRED (Unbiased Biomarkers for the Prediction of Respiratory Disease outcomes) study of severe adult asthmatics (SA, n=408) was analysed by quantitative mass spectrometry. Data were compared to that of mild-to-moderate asthmatics (MMA, n=70) and healthy subjects (HC, n=98) from the same study. Measurements and main results The concentrations of urinary endogenous steroid metabolites were substantially lower in SA than in MMA or HC. These differences were more pronounced in SA patients with detectable urinary OCS metabolites. Their dehydroepiandrosterone sulfate (DHEA-S) concentrations were <5% of those in HC, and cortisol concentrations were below the detection limit in 75% of females and 82% of males. The concentrations of EAAS in OCS-positive patients, as well as patients on high-dose ICS only, were more suppressed in females than males (p<0.05). Low levels of DHEA were associated with features of more severe disease and were more prevalent in females (p<0.05). The association between low EAAS and corticosteroid treatment was replicated in 289 of the SA patients at follow-up after 12–18 months. Conclusion The pronounced suppression of endogenous anabolic androgens in females might contribute to sex differences regarding the prevalence of severe asthma.

Background Systemic sclerosis (SSc) is a heterogeneous disease with frequently associated interstitial lung disease (SSc-ILD). We aimed to determine the prognostic potential of phenotyping patients with SSc and SSc-ILD by inflammation and to describe disease trajectories stratified by inflammation and immunosuppressive treatment.Methods Patients from the European Scleroderma Trials and Research (EUSTAR) group cohort were allocated to persistent inflammatory, intermediate and non-inflammatory phenotypes if C-reactive protein (CRP) levels were >= 5 mg/L at >= 80%, at 20-80% and at <20% of visits, respectively. Cox regression models were used to analyse mortality risk and mixed effect models to describe trajectories of FVC and diffusing capacity for carbon monoxide (DLCO) %-predicted stratified by inflammation and immunosuppressive treatment.Results 2971 patients with SSc and 1171 patients with SSc-ILD had at least three CRP measurements available. Patients with SSc-ILD with a persistent inflammatory phenotype had a 6.7 times higher risk of mortality within 5 years compared with those with a persistent non-inflammatory phenotype (95% CI 3 to 15). In the inflammatory phenotype, FVC %-predicted was declining without (-1.11 (95% CI -2.14 to -0.08)/year), but stable with immunosuppressive treatment (-0.00 (95% CI -0.92 to 0.92)/year). In the non-inflammatory phenotype, patients with and without immunosuppressive treatment had a significant decline in FVC %-predicted, which was more pronounced in those with immunosuppressive treatment (-1.26 (95% CI -1.87 to -0.64) and -0.84 (95% CI -1.35 to -0.33)/year, respectively).Conclusions Phenotyping by persistent inflammation provides valuable prognostic information, independent of demographics, disease duration, cutaneous subtype, treatment and SSc-ILD severity. The findings from this study support early immunosuppressive treatment in patients with SSc-ILD with persistent inflammation.

The endothelium of blood vessels is a vital organ that reacts differently to subtle changes in stiffness and mechanical forces exerted on its environment (extracellular matrix (ECM)). Upon alteration of these biomechanical cues, endothelial cells initiate signaling pathways that govern vascular remodeling. The emerging organs-on-chip technologies allow the mimicking of complex microvasculature networks, identifying the combined or singular effects of these biomechanical or biochemical stimuli. Here, we present a microvasculature-on-chip model to investigate the singular effect of ECM stiffness and mechanical cyclic stretch on vascular development. Following two different approaches for vascular growth, the effect of ECM stiffness on sprouting angiogenesis and the effect of cyclic stretch on endothelial vasculogenesis are studied. Our results indicate that ECM hydrogel stiffness controls the size of the patterned vasculature and the density of sprouting angiogenesis. RNA sequencing shows that the cellular response to stretching is characterized by the upregulation of certain genes such as ANGPTL4+5, PDE1A, and PLEC.

Idiopathic pulmonary fibrosis (IPF), hypersensitivity pneumonitis (HP) and systemic sclerosis (SSc) are among the most common entities that cause pulmonary fibrosis. Alveolar collapse with subsequent collapse induration of lung tissue is thought to contribute to the fibrotic transformation. The purpose of this study was to examine lung tissue in computed tomography (CT) of non-diseased appearance during expiration for signs of increased density suggesting collapsibility in fibrosing lung diseases. We further analyzed the diaphragmatic movements during the respiratory cycle to determine relationships between density differences and the apex–diaphragm diameter. Significant differences in attenuation changes between inspiration and expiration of unaffected lung parenchyma were detected between IPF and controls and between HP and controls for all lung lobes (p < 0.001). Only minor differences were found between SSc and controls. There was no clinically relevant difference between patients with IPF and those with HP. The measured absolute apex–diaphragm diameter in inspiration and expiration demonstrated a statistically significant difference between patients with IPF versus normal controls. However, the diaphragmatic excursions were not different between these groups. Compared to controls, CT lung density increases significantly more during expiration in the fibrotic lungs of IPF and HP patients. The observed increase in density might indicate the collapse of alveoli during expiration and may represent a common pathophysiologic feature of fibrosing lung diseases. The density changes and lung extensions do not have the same ratios across different diseases and controls.

(1) Introduction: Chronic obstructive pulmonary disease (COPD) and its associated morbidity and mortality are a global burden on both affected patients and healthcare systems. The Global Initiative for Chronic Obstructive Lung Disease (GOLD) issues guidelines with the aim of improving COPD management. Previous studies reported significant variability in adherence to these recommendations. The objective of this study was to evaluate Swiss primary practitioners’ adherence to the GOLD guidelines for the pharmacological treatment of stable COPD. (2) Methods: We studied patients who were included in the Swiss COPD cohort study, an ongoing prospective study in a primary care setting, between 2015 and 2022. The key inclusion criteria are age ≥ 40 years, FEV1/FVC ratio < 70%, and a smoking history of at least 20 pack-years. Adherence to the GOLD guidelines was assessed per visit and over time. (3) Results: The data of 225 COPD patients (mean age 67 ± 9 years, 64% male) and their respective 1163 visits were analyzed. In 65% of visits (726/1121), treatment was prescribed according to the GOLD guidelines. Non-adherence was most common in GOLD groups A and B (64% and 33%) and mainly consisted of over-treatment (two long-acting bronchodilators in group A (98/195, 50%) and ICS in groups A (21/195, 11%) and B (198/808, 25%)). In group D, the prescriptions conformed with the guidelines in 99% of cases (109/108). Guideline adherence was associated with high symptom load (COPD Assessment Test) (OR 1.04, p = 0.002), high number of exacerbations (OR = 2.07, p < 0.001), asthma overlap (OR 3.36, p = 0.049), and diabetes mellitus (OR 2.82, p = 0.045). (4) Conclusion: These results confirm a conflict between the GOLD recommendations and primary practice, mainly concerning over-treatment in GOLD groups A and B. Patients with high symptom load, high exacerbation risk, asthma overlap, and diabetes mellitus are more likely to be treated in conformity with the guidelines. Further research is needed to uncover the reasons for the discrepancies and to design strategies for improvement.

Background: Patients with chronic obstructive pulmonary disease (COPD) often suffer from acute exacerbations. Our objective was to describe recurrent exacerbations in a GP-based Swiss COPD cohort and develop a statistical model for predicting exacerbation. Methods: COPD cohort demographic and medical data were recorded for 24 months, by means of a questionnaire—based COPD cohort. The data were split into training (75%) and validation (25%) datasets. A negative binomial regression model was developed using the training dataset to predict the exacerbation rate within 1 year. An exacerbation prediction model was developed, and its overall performance was validated. A nomogram was created to facilitate the clinical use of the model. Results: Of the 229 COPD patients analyzed, 77% of the patients did not experience exacerbation during the follow-up. The best subset in the training dataset revealed that lower forced expiratory volume, high scores on the MRC dyspnea scale, exacerbation history, and being on a combination therapy of LABA + ICS (long-acting beta-agonists + Inhaled Corticosteroids) or LAMA + LABA (Long-acting muscarinic receptor antagonists + long-acting beta-agonists) at baseline were associated with a higher rate of exacerbation. When validated, the area-under-curve (AUC) value was 0.75 for one or more exacerbations. The calibration was accurate (0.34 predicted exacerbations vs 0.28 observed exacerbations). Conclusion: Nomograms built from these models can assist clinicians in the decision-making process of COPD care.

Since the publication of the first lung-on-a-chip in 2010, research has made tremendous progress in mimicking the cellular environment of healthy and diseased alveoli. As the first lung-on-a-chip products have recently reached the market, innovative solutions to even better mimic the alveolar barrier are paving the way for the next generation lung-on-chips. The original polymeric membranes made of PDMS are being replaced by hydrogel membranes made of proteins from the lung extracellular matrix, whose chemical and physical properties exceed those of the original membranes. Other aspects of the alveolar environment are replicated, such as the size of the alveoli, their three-dimensional structure, and their arrangement. By tuning the properties of this environment, the phenotype of alveolar cells can be tuned, and the functions of the air-blood barrier can be reproduced, allowing complex biological processes to be mimicked. Lung-on-a-chip technologies also provide the possibility of obtaining biological information that was not possible with conventional in vitro systems. Pulmonary edema leaking through a damaged alveolar barrier and barrier stiffening due to excessive accumulation of extracellular matrix proteins can now be reproduced. Provided that the challenges of this young technology are overcome, there is no doubt that many application areas will benefit greatly.

BACKGROUND:Lung function impairment persists in some patients for months after acute coronavirus disease 2019 (COVID-19). Long-term lung function, radiological features, and their association remain to be clarified.OBJECTIVES:We aimed to prospectively investigate lung function and radiological abnormalities over 12 months after severe and non-severe COVID-19.METHODS:584 patients were included in the Swiss COVID-19 lung study. We assessed lung function at 3, 6, and 12 months after acute COVID-19 and compared chest computed tomography (CT) imaging to lung functional abnormalities.RESULTS:At 12 months, diffusion capacity for carbon monoxide (DLCOcorr) was lower after severe COVID-19 compared to non-severe COVID-19 (74.9% vs. 85.2% predicted, p < 0.001). Similarly, minimal oxygen saturation on 6-min walk test and total lung capacity were lower after severe COVID-19 (89.6% vs. 92.2%, p = 0.004, respectively, 88.2% vs. 95.1% predicted, p = 0.011). The difference for forced vital capacity (91.6% vs. 96.3% predicted, p = 0.082) was not statistically significant. Between 3 and 12 months, lung function improved in both groups and differences in DLCO between non-severe and severe COVID-19 patients decreased. In patients with chest CT scans at 12 months, we observed a correlation between radiological abnormalities and reduced lung function. While the overall extent of radiological abnormalities diminished over time, the frequency of mosaic attenuation and curvilinear patterns increased.CONCLUSIONS:In this prospective cohort study, patients who had severe COVID-19 had diminished lung function over the first year compared to those after non-severe COVID-19, albeit with a greater extent of recovery in the severe disease group.

Background Calprotectin is an inflammatory marker mainly released by activated neutrophils that is increased in acute severe COVID-19. After initial recovery, some patients have persistent respiratory impairment with reduced diffusion capacity of the lungs for carbon monoxide (DLCO) months after infection. Underlying causes of this persistent impairment are unclear. We aimed to investigate the correlation between circulating calprotectin, persistent lung functional impairment and intensive care unit (ICU) stay after COVID-19 in two university hospital centres in Switzerland. Methods Calprotectin levels were measured in serum from 124 patients (50% male) from the Bern cohort (post-ICU and non-ICU patients) and 68 (76% male) from the Lausanne cohort (only post-ICU patients) four months after COVID-19. Calprotectin was correlated with clinical parameters. Multivariate linear regression (MLR) was performed to evaluate the independent association of calprotectin in different models. Results Overall, we found that post-ICU patients, compared to non-ICU, were significantly older (age 59.4 ± 13.6 (Bern), 60.5 ± 12.0 (Lausanne) vs. 48.8 ± 13.4 years) and more obese (BMI 28.6 ± 4.5 and 29.1 ± 5.3 vs. 25.2 ± 6.0 kg/m2, respectively). 48% of patients from Lausanne and 44% of the post-ICU Bern cohort had arterial hypertension as a pre-existing comorbidity vs. only 10% in non-ICU patients. Four months after COVID-19 infection, DLCO was lower in post-ICU patients (75.96 ± 19.05% predicted Bern, 71.11 ± 18.50% Lausanne) compared to non-ICU (97.79 ± 21.70% predicted, p < 0.01). The post-ICU cohort in Lausanne had similar calprotectin levels when compared to the cohort in Bern (Bern 2.74 ± 1.15 µg/ml, Lausanne 2.49 ± 1.13 µg/ml vs. non-ICU 1.86 ± 1.02 µg/ml; p-value < 0.01). Calprotectin correlated negatively with DLCO (r= -0.290, p < 0.001) and the forced vital capacity (FVC) (r= -0.311, p < 0.001). Conclusions Serum calprotectin is elevated in post-ICU patients in two independent cohorts and higher compared to non-ICU patients four months after COVID-19. In addition, there is a negative correlation between calprotectin levels and DLCO or FVC. The relationship between inflammation and lung functional impairment needs further investigations. Trial registration NCT04581135.