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Background: During follow-up, patients severely affected by coronavirus disease 2019 (COVID-19) requiring invasive mechanical ventilation (IMV), show symptoms of Post-Intensive Care Syndrome (PICS) such as cognitive impairment, psychological disability, and neuromuscular deconditioning. In COVID-19 pandemic, it is a priority to develop multidisciplinary post-acute care services to address the long-term multisystemic impact of COVID-19., Research Question: Which are the most relevant multisystemic sequelae in severe post-COVID-19 patients?, Study Design and Methods: Observational chart review study that included adult patients discharged from a referral hospital for respiratory diseases in Mexico after recovering from severe COVID-19 disease from December 23, 2020, to April 24, 2021. Data were collected from 280 of 612 potentially eligible patients to evaluate persistent symptoms and compare sequelae in patients who required intubation, using a standardized questionnaire of symptoms, in addition to findings reported during the face-to-face health assessment. Univariable and multivariate analyses were performed for the association among the requirement of IMV and the long-term persistence of symptoms., Results: 280 patients were included. The median age was 55 (range, 19 to 86) years, and 152 (54.3%) were men. The mean length of hospital stay was 19 (SD, 14.1) days. During hospitalization 168 (60%) participants received IMV. A large proportion of these patients reported fatigue (38.7%), paresthesia (35.1%), dyspnea (32.7%) and headache (28%); meanwhile only 3 (1.8%) of them were asymptomatic. Patients who required intubation were more likely to have neuropsychiatric (67.3% vs 55.4%; OR, 1.79 [95% CI, 1.08 to 2.97]) and musculoskeletal involvement (38.7% vs. 25.9%; OR, 1.92 [95% CI, 1.12 to 3.27]), adjusted for age,sex and hospitalization time., Interpretation: The proportion of patients requiring intubation was 60%, reporting persistent symptoms in 98% of them. Neuropsychiatric and musculoskeletal symptoms were the most predominant symptoms in these patients, with a significant difference. Post-COVID-19 syndrome is a frequent problem in patients who required IVM. Physicians in ICU and in care of COVID-19 patients should be aware of this syndrome in order to avoid more complications., Competing Interests: The authors have declared that no competing interests exist.

Background and Objective: Idiopathic Pulmonary Fibrosis (IPF) is a progressive disease of unknown etiology. The diagnosis is based on the identification of a pattern of usual interstitial pneumonia either by high resolution computed tomography and/or histology. However, a similar pattern can be observed in other fibrotic lung disorders, and precise diagnosis remains challenging. Studies on biomarkers contributing to the differential diagnosis are scanty, and still in an exploratory phase. Our aim was to evaluate matrix metalloproteinase (MMP)-28, which has been implicated in abnormal wound healing, as a biomarker for distinguishing IPF from fibrotic non-IPF patients., Methods: The cell localization of MMP28 in lungs was examined by immunohistochemistry and its serum concentration was measured by ELISA in two different populations. The derivation cohort included 82 IPF and 69 fibrotic non-IPF patients. The validation cohort involved 42 IPF and 41 fibrotic non-IPF patients., Results: MMP28 was detected mainly in IPF lungs and localized in epithelial cells. In both cohorts, serum concentrations of MMP28 were significantly higher in IPF versus non-IPF (mostly with lung fibrosis associated to autoimmune diseases and chronic hypersensitivity pneumonitis) and healthy controls (ANOVA, p<0.0001). The AUC of the derivation cohort was 0.718 (95%CI, 0.635-0.800). With a cutoff point of 4.5 ng/mL, OR was 5.32 (95%CI, 2.55-11.46), and sensitivity and specificity of 70.9% and 69% respectively. The AUC of the validation cohort was 0.690 (95%CI, 0.581-0.798), OR 4.57 (95%CI, 1.76-12.04), and sensitivity and specificity of 69.6% and 66.7%. Interestingly, we found that IPF patients with definite UIP pattern on HRCT showed higher serum concentrations of MMP28 than non-IPF patients with the same pattern (7.8±4.4 versus 4.9±4.4; p = 0.04). By contrast, no differences were observed when IPF with possible UIP-pattern were compared (4.7±3.2 versus 3.9±3.0; p = 0.43)., Conclusion: These findings indicate that MMP28 might be a useful biomarker to improve the diagnostic certainty of IPF., Competing Interests: The authors have declared that no competing interests exist.

Idiopathic pulmonary fibrosis (IPF) is a chronic and progressive lung disease characterized by epithelial cell activation, expansion of the fibroblast population and excessive extracellular matrix accumulation. The mechanisms are incompletely understood but evidence indicates that the deregulation of several proteases contributes to its pathogenesis. Transmembrane protease serine 4 (TMPRSS4) is a novel type II transmembrane serine protease that may promote migration and facilitate epithelial to mesenchymal transition (EMT), two critical processes in the pathogenesis of IPF. Thus, we hypothesized that over-expression of TMPRSS4 in the lung could promote the initiation and/or progression of IPF. In this study we first evaluated the expression and localization of TMPRSS4 in IPF lungs by real time PCR, western blot and immunohistochemistry. Then we examined the lung fibrotic response in wild-type and TMPRSS4 deficient mice using the bleomycin-induced lung injury model. We found that this protease is upregulated in IPF lungs, where was primarily expressed by epithelial and mast cells. Paralleling the findings in vivo, TMPRSS4 was expressed by alveolar and bronchial epithelial cells in vitro and unexpectedly, provoked an increase of E-cadherin. No expression was observed in normal human or IPF lung fibroblasts. The lung fibrotic response evaluated at 28 days after bleomycin injury was markedly attenuated in the haplodeficient and deficient TMPRSS4 mice. By morphology, a significant reduction of the fibrotic index was observed in KO and heterozygous mice which was confirmed by measurement of collagen content (hydroxyproline: WT: 164±21.1 μg/lung versus TMPRSS4 haploinsufficient: 110.2±14.3 μg/lung and TMPRSS4 deficient mice: 114.1±24.2 μg/lung (p<0.01). As in IPF, TMPRSS4 was also expressed in epithelial and mast cells. These findings indicate that TMPRSS4 is upregulated in IPF lungs and that may have a profibrotic role.

Idiopathic pulmonary fibrosis (IPF) is a devastating disease of unknown etiology. The pathogenic mechanisms are unclear, but evidence indicates that aberrantly activated alveolar epithelial cells secrete a variety of mediators which induce the migration, proliferation and activation of fibroblasts and finally the excessive accumulation of extracellular matrix with the consequent destruction of the lung parenchyma. CC16 (approved symbol SCGB1A1), a putative anti-inflammatory protein produced by "club" cells in the distal airways, has not been evaluated in IPF lungs. In this study, we determined the serum and bronchoalveolar lavage (BAL) levels as well as the lung cell localization of this protein. Also, we explored the usefulness of serum levels of CC16 for the differential diagnosis of IPF (n = 85), compared with non-IPF interstitial lung diseases [chronic hypersensitivity pneumonitis (cHP; n = 85) and connective tissue diseases (CTD-ILD; n = 85)]. CC16 was significantly increased in serum and BAL fluids of IPF patients and was found not only in club cells but also in alveolar epithelial cells. When compared with non-IPF patients and controls, serum levels were significantly increased (p<0.0001). Sensitivity and specificity for CC16 (cut-off 41ng/mL) were 24% and 90%, positive predictive value 56% and negative predictive value 69%. These findings demonstrate that CC16 is upregulated in IPF patients suggesting that may participate in its pathogenesis. Although higher than the serum levels of non-IPF patients it shows modest sensitivity to be useful as a potential biomarker for the differential diagnosis., Competing Interests: The authors have declared that no competing interests exist.

Background: Idiopathic pulmonary fibrosis (IPF), a devastating lung disorder of unknown aetiology, and chronic hypersensitivity pneumonitis (HP), a disease provoked by an immunopathologic reaction to inhaled antigens, are two common interstitial lung diseases with uncertain pathogenic mechanisms. Previously, we have shown in other upper and lower airway diseases that immunoglobulin free light chains (FLCs) are increased and may be involved in initiating a local inflammation. In this study we explored if such a mechanism may also apply to HP and IPF., Methods: In this study we examined the presence of FLC in serum and BAL fluid from 21 IPF and 22 HP patients and controls. IgG, IgE and tryptase concentrations were measured in BAL fluid only. The presence of FLCs, plasma cells, B cells and mast cells in lung tissue of 3 HP and 3 IPF patients and 1 control was analyzed using immunohistochemistry., Results: FLC concentrations in serum and BAL fluid were increased in IPF and HP patients as compared to control subjects. IgG concentrations were only increased in HP patients, whereas IgE concentrations were comparable to controls in both patient groups. FLC-positive cells, B cells, plasma cells, and large numbers of activated mast cells were all detected in the lungs of HP and IPF patients, not in control lung., Conclusion: These results show that FLC concentrations are increased in serum and BAL fluid of IPF and HP patients and that FLCs are present within affected lung tissue. This suggests that FLCs may be involved in mediating pathology in both diseases.