Alveolar cells under mechanical stressed niche: critical contributors to pulmonary fibrosis.

Pulmonary fibrosis arises from the repeated epithelial mild injuries and insufficient repair lead to over activation of fibroblasts and excessive deposition of extracellular matrix, which result in a mechanical stretched niche. However, increasing mechanical stress likely exists before the establishment of fibrosis since early micro injuries increase local vascular permeability and prompt cytoskeletal remodeling which alter cellular mechanical forces. It is noteworthy that COVID-19 patients with severe hypoxemia will receive mechanical ventilation as supportive treatment and subsequent pathology studies indicate lung fibrosis pattern. At advanced stages, mechanical stress originates mainly from the stiff matrix since boundaries between stiff and compliant parts of the tissue could generate mechanical stress. Therefore, mechanical stress has a significant role in the whole development process of pulmonary fibrosis. The alveoli are covered by abundant capillaries and function as the main gas exchange unit. Constantly subject to variety of damages, the alveolar epithelium injuries were recently recognized to play a vital role in the onset and development of idiopathic pulmonary fibrosis. In this review, we summarize the literature regarding the effects of mechanical stress on the fundamental cells constituting the alveoli in the process of pulmonary fibrosis, particularly on epithelial cells, capillary endothelial cells, fibroblasts, mast cells, macrophages and stem cells. Finally, we briefly review this issue from a more comprehensive perspective: the metabolic and epigenetic regulation.

NK cells: A double edge sword against SARS-CoV-2.

Natural killer (NK) cells are pivotal effectors of the innate immunity protecting an individual from microbes. They are the first line of defense against invading viruses, given their substantial ability to directly target infected cells without the need for specific antigen presentation. By establishing cellular networks with a variety of cell types such as dendritic cells, NK cells can also amplify and modulate antiviral adaptive immune responses. In this review, we will examine the role of NK cells in SARS-COV2 infections causing the ongoing COVID19 pandemic, keeping in mind the controversial role of NK cells specifically in viral respiratory infections and in inflammatory-driven lung damage. We discuss lessons learnt from previous coronavirus outbreaks in humans (caused by SARS-CoV-1 and MERS-COV).

ILC2 Lung-Homing in Cystic Fibrosis Patients: Functional Involvement of CCR6 and Impact on Respiratory Failure.

Cystic fibrosis patients suffer from a progressive, often fatal lung disease, which is based on a complex interplay between chronic infections, locally accumulating immune cells and pulmonary tissue remodeling. Although group-2 innate lymphoid cells (ILC2s) act as crucial initiators of lung inflammation, our understanding of their involvement in the pathogenesis of cystic fibrosis remains incomplete. Here we report a marked decrease of circulating CCR6+ ILC2s in the blood of cystic fibrosis patients, which significantly correlated with high disease severity and advanced pulmonary failure, strongly implicating increased ILC2 homing from the peripheral blood to the chronically inflamed lung tissue in cystic fibrosis patients. On a functional level, the CCR6 ligand CCL20 was identified as potent promoter of lung-directed ILC2 migration upon inflammatory conditions in vitro and in vivo using a new humanized mouse model with light-sheet fluorescence microscopic visualization of lung-accumulated human ILC2s. In the lung, blood-derived human ILC2s were able to augment local eosinophil and neutrophil accumulation and induced a marked upregulation of pulmonary type-VI collagen expression. Studies in primary human lung fibroblasts additionally revealed ILC2-derived IL-4 and IL-13 as important mediators of this type-VI collagen-inducing effect. Taken together, the here acquired results suggest that pathologically increased CCL20 levels in cystic fibrosis airways induce CCR6-mediated lung homing of circulating human ILC2s. Subsequent ILC2 activation then triggers local production of type-VI collagen and might thereby drive extracellular matrix remodeling potentially influencing pulmonary tissue destruction in cystic fibrosis patients. Thus, modulating the lung homing capacity of circulating ILC2s and their local effector functions opens new therapeutic avenues for cystic fibrosis treatment.

Complex Immune Dysregulation in COVID-19 Patients with Severe Respiratory Failure.

Proper management of COVID-19 mandates better understanding of disease pathogenesis. The sudden clinical deterioration 7-8 days after initial symptom onset suggests that severe respiratory failure (SRF) in COVID-19 is driven by a unique pattern of immune dysfunction. We studied immune responses of 54 COVID-19 patients, 28 of whom had SRF. All patients with SRF displayed either macrophage activation syndrome (MAS) or very low human leukocyte antigen D related (HLA-DR) expression accompanied by profound depletion of CD4 lymphocytes, CD19 lymphocytes, and natural killer (NK) cells. Tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) production by circulating monocytes was sustained, a pattern distinct from bacterial sepsis or influenza. SARS-CoV-2 patient plasma inhibited HLA-DR expression, and this was partially restored by the IL-6 blocker Tocilizumab; off-label Tocilizumab treatment of patients was accompanied by increase in circulating lymphocytes. Thus, the unique pattern of immune dysregulation in severe COVID-19 is characterized by IL-6-mediated low HLA-DR expression and lymphopenia, associated with sustained cytokine production and hyper-inflammation.

Acute Respiratory Failure Associated With Vaping.

The use of e-cigarettes to deliver aerosolized nicotine has gained popularity in recent years. Numerous reports have cited the development of acute pulmonary disease linked to vaping nicotine as well as marijuana-based products. As cultural attitudes evolve and policies shift toward the legalization of marijuana, its use has become more prevalent. Given the increased prevalence of marijuana consumption and e-cigarette usage, better insight into its potential to cause lung toxicity is warranted. The clinical, radiographic, and histopathologic characteristics of lung injury associated with vaping, particularly with marijuana-based products, have yet to be well described in the literature. We present eight patients, most of whom were admitted recently to our institution with acute respiratory failure following vaping. The majority of patients were young, with a median age of 31.5 years (range, 24-62 years) and with no known underlying lung disease. This case series highlights common clinical findings as well as the varied radiographic and histopathologic features of acute respiratory failure associated with vaping predominantly marijuana-based products. As more cases of vaping-associated pulmonary injury unfold, data will be available to further characterize this emerging disease entity. Improved understanding of disease pathogenesis and its clinical course will help clinicians determine optimal management and follow-up strategies for this patient population.

Diagnostic utility of transbronchial lung cryobiopsy: Two cases of anti-aminoacyl-tRNA synthetase syndrome with respiratory failure.

Transbronchial lung cryobiopsy (TBLC) is a useful and safe method for the diagnosis of interstitial lung disease (ILD). Herein, we describe the cases of two patients who developed ILD from anti-aminoacyl-tRNA synthetase syndrome with respiratory failure. TBLC was performed instead of surgical lung biopsy. There were no complications, and sufficient specimens were harvested to make the precise histopathological diagnosis. TBLC should be considered as a critical approach for the histopathological diagnosis of ILD in patients who cannot undergo surgical lung biopsy because of respiratory failure.

Acute respiratory failure in immunocompromised adults.

Acute respiratory failure occurs in up to half of patients with haematological malignancies and 15% of those with solid tumours or solid organ transplantation. Mortality remains high. Factors associated with mortality include a need for invasive mechanical ventilation, organ dysfunction, older age, frailty or poor performance status, delayed intensive care unit admission, and acute respiratory failure due to an invasive fungal infection or unknown cause. In addition to appropriate antibacterial therapy, initial clinical management aims to restore oxygenation and predict the most probable cause based on variables related to the underlying disease, acute respiratory failure characteristics, and radiographic findings. The cause of acute respiratory failure must then be confirmed using the most efficient, least invasive, and safest diagnostic tests. In patients with acute respiratory failure of undetermined cause, a standardised diagnostic investigation should be done immediately at admission before deciding whether to perform more invasive diagnostic procedures or to start empirical treatments. Collaborative and multidisciplinary clinical and research networks are crucial to improve our understanding of disease pathogenesis and causation and to develop less invasive diagnostic strategies and more targeted treatment options.

High-flow nasal oxygen vs. standard oxygen therapy in immunocompromised patients with acute respiratory failure: study protocol for a randomized controlled trial.

BACKGROUND: Acute respiratory failure (ARF) is the leading reason for intensive care unit (ICU) admission in immunocompromised patients. High-flow nasal oxygen (HFNO) therapy is an alternative to standard oxygen. By providing warmed and humidified gas, HFNO allows the delivery of higher flow rates via nasal cannula devices, with FiO2 values of nearly 100%. Benefits include alleviation of dyspnea and discomfort, decreased respiratory distress and decreased mortality in unselected patients with acute hypoxemic respiratory failure. However, in preliminary reports, HFNO benefits are controversial in immunocompromised patients in whom it has never been properly evaluated. METHODS/DESIGN: This is a multicenter, open-label, randomized controlled superiority trial in 30 intensive care units, part of the Groupe de Recherche Respiratoire en Réanimation Onco-Hématologique (GRRR-OH). Inclusion criteria will be: (1) adults, (2) known immunosuppression, (3) ARF, (4) oxygen therapy ≥ 6 L/min, (5) written informed consent from patient or proxy. Exclusion criteria will be: (1) imminent death (moribund patient), (2) no informed consent, (3) hypercapnia (PaCO2 ≥ 50 mmHg), (4) isolated cardiogenic pulmonary edema, (5) pregnancy or breastfeeding, (6) anatomical factors precluding insertion of a nasal cannula, (7) no coverage by the French statutory healthcare insurance system, and (8) post-surgical setting from day 1 to day 6 (patients with ARF occurring after day 6 of surgery can be included). The primary outcome measure is day-28 mortality. Secondary outcomes are intubation rate, comfort, dyspnea, respiratory rate, oxygenation, ICU length of stay, and ICU-acquired infections. Based on an expected 30% mortality rate in the standard oxygen group, and 20% in the HFNO group, error rate set at 5%, and a statistical power at 90%, 389 patients are required in each treatment group (778 patients overall). Recruitment period is estimated at 30 months, with 28 days of additional follow-up for the last included patient. DISCUSSION: The HIGH study will be the largest multicenter, randomized controlled trial seeking to demonstrate that survival benefits from HFNO reported in unselected patients also apply to a large immunocompromised population. TRIAL REGISTRATION: ClinicalTrials.gov, ID: NCT02739451 . Registered on 15 April 2016.

MOG-antibody demyelinating diseases: a case of post-partum severe rhombencephalitis and transverse myelitis.

INTRODUCTION: Myelin oligodendrocyte glycoprotein antibodies (MOG-IgG) associated disorders present with a spectrum of clinical pictures including brainstem involvement. CASE REPORT: A patient with the sudden onset of a post-partum severe rhombencephalitis causing respiratory failure (12 years after a mild transverse myelitis). Despite the aggressive clinical course, she had an impressive recovery after plasmapheresis, and no further relapses on immunosuppression. CONCLUSION: MOG-IgG disorders could relapse several years after onset and involve brainstem. Good prognosis is possible after treatment.

Immune function monitoring in lung transplantation using adenosine triphosphate production: time trends and relationship to postoperative infection.

PURPOSE: The ImmuKnow (IK) assay is a comprehensive immune function test that involves measuring adenosine triphosphate produced by the cluster of differentiation 4+ T lymphocytes in peripheral blood. The aim of this study was to analyze the time trends of IK values and assess the relationship between IK values and infections in lung transplants. METHODS: We prospectively collected 178 blood samples from 22 deceased-donor lung transplant (DDLT) recipients and 17 living-donor lobar lung transplant (LDLLT) recipients. A surveillance IK assay was performed postoperatively, then after 1 week and 1, 3, 6, and 12 months. RESULTS: Time trends of IK values in stable recipients peaked 1 week after DDLT (477 ± 247 ATP ng/ml), and 1 month after LDLLT (433 ± 134 ng/ml), followed by a gradual decline over 1 year. The mean IK values in infections were significantly lower than those in the stable state (119 vs 312 ATP ng/ml, p = 0.0002). CONCLUSIONS: IK values increased sharply after lung transplantation and then decreased gradually over time in the first year, suggesting a natural history of immune function. IK values were also significantly reduced during infections. These results may provide new insights into the utility of immune monitoring after lung transplantation.

Can N-terminal pro B-type natriuretic peptide, neutrophil-to-lymphocyte ratio, C-reactive protein help to predict short and long term mortality?

BACKGROUND: There is limited data about ICU, short and long-term mortality prediction of severe CAP with neutrophil-to-lymphocyte ratio (NLR): N-terminal proB- type natriuretic peptide (NT-proBNP): C-reactive protein (CRP). AIM: Besides the known severity indexes of ICU, can NLR, NT-proBNP, CRP predict ICU, short and long term mortality? METHODS: A retrospective cohort study was carried out in a level III ICU of a tertiary training hospital for chest diseases and thoracic surgery. RESULTS: Over the study period, a total of 143 patients were enrolled in the study. The APACHE II scoring showed a significantly higher predicting performance for ICU mortality (p = 0.002). The performance for predicting short term mortality NLR (p = 0.039) and long term mortality NTproBNP (p = 0.002) had a significantly higher performance. The survival analysis revealed that mortality was significantly higher in patients with CURB65 score ≥ 4 (p = 0.047). CONCLUSION: NLR, NTproBNP > 2000pg/mL can be used to predict pneumonia severity in ICU alike CURB65 and PSI. Higher NLR, APACHE II and atrial fibrillation can cause an important mortality factor in long term. Consequently, clinicians should take an attention for good cardiac evaluation and cardiac follow-up of patients with CAP (Tab. 4, Fig. 3, Ref. 36).

Comparison of 1,3-ß-d-glucan with galactomannan in serum and bronchoalveolar fluid for the detection of Aspergillus species in immunosuppressed mechanical ventilated critically ill patients.

PURPOSE: Invasive pulmonary aspergillosis (IPA) is an important cause of morbidity/mortality in immunocompromised critically ill patients. New diagnostic strategies for early detection of IPA include the noninvasive biomarkers 1,3-ß-d-glucan (BDG), serum, and bronchoalveolar (BAL) fluid galactomannan (GM). The aim of this study was to compare these markers for early detection of IPA in immunosuppressed critically ill patients. METHODS: Between December 2014 and December 2015, 49 immunosuppressed patients with respiratory failure were treated at our intensive care unit (ICU). We compared the BDG Fungitell assay with GM Platelia assay in serum and BAL for early detection of IPA. All tests were performed initially after admission at the ICU. RESULTS: In our study with 49 patients, 13 (26%) had probable IPA. These patients had a higher Acute Physiology And Chronic Health Evaluation II score (28 vs 23, P<.001), Sequential Organ Failure Assessment score (16 vs 14, P<.001), more neutropenia (77% vs 30%, P<.001), worse Horowitz Index (99 vs 73 P<.020), a longer ICU stay (26 vs 17 days, P<.044), and a higher mortality rate (77% vs 58%, P<.001) as compared with patients without probable IPA. The used biomarker BDG presented in patients with probable IPA showed significantly higher levels as compared with patients without probable IPA (375 [103-1000 pg/mL; P<.001] vs 64 [30-105 pg/mL; P < .001]). Comparison of BDG with GM showed that positive serum GM could be detected in only 4 (30%), whereas positive BAL GM could be detected in 12 (92%; mean optical density index, 3.7) of 13 probable IPA cases. These results can be expressed as an overall sensitivity of 88% and a specificity of 82% for probable IPA using the BDG Fungitell assay, a sensitivity of 35% and a specificity of 70% using the serum GM Platelia assay, and a sensitivity of 70% and a specificity of 94% using the BAL GM Platelia assay. The negative predictive values of the used tests were 94% for the BDG Fungitell assay, 94% for the serum GM Platelia assay, and 90% for the BAL GM Platelia assay. CONCLUSION: 1,3-ß-d-Glucan may be a useful marker for patients under surveillance at risk for IPA. In critically ill patients with immunosuppression, early diagnosis of IPA may be improved by BDG as compared with serum GM. However, diagnostic performance and accuracy increase when BDG is run in parallel with GM from BAL; moreover, the association of the 2 parameters has also the advantage of detecting early and reliable IPA.

The Cause of Acute Respiratory Failure Predicts the Outcome of Noninvasive Ventilation in Immunocompromised Children.

BACKGROUND: Noninvasive ventilation (NIV) may be superior to conventional therapy in immunocompromised children with respiratory failure. METHODS: Mortality, success rate, prognostic factors and side effects of NIV for acute respiratory failure (ARF) were investigated retrospectively in 41 in children with primary immunodeficiency, after stem cell transplantation or chemotherapy for oncologic disease. RESULTS: In 11/41 (27%) children invasive ventilation was avoided and patients were discharged from ICU. In children with NIV failure ICU-mortality was 19/30 (63%). 8/11 (72%) children with NIV success had recurrence of ARF after 27 days. Only 4/11 (36%) children with first episode NIV success and 8/30 (27%) with NIV failure survived to hospital discharge. Lower FiO2, SpO2/FiO2 and blood culture positive bacterial sepsis were predictive for NIV success, while fungal sepsis or culture negative ARF were predictive for NIV failure. We observed catecholamine treatment in 14/41 (34%), pneumothorax in 2/41 (5%), mediastinal emphysema in 3/41 (7%), a life threatening nasopharyngeal hemorrhage and need for resuscitation during intubation in 5/41 (12%) NIV-episodes. CONCLUSIONS: The prognosis of ARF in immunocompromised children remains guarded independent of initial success or failure of NIV due to a high rate of recurrent ARF. Reversible causes like bacterial sepsis had a higher NIV response rate. Relevant side effects of NIV were observed.

Candida pneumonia in a term infant after prolonged use of inhaled corticosteroids for bronchopulmonary dysplasia (BPD).

Candida spp. frequently cause invasive fungal disease in neonates, and many organs or apparatus can be involved through bloodstream dissemination. Though Candida spp. can heavily colonize the upper and lower respiratory tract, an end-organ localization to the lung is not frequent and acquisition via descending/respiratory route is a questioned entity. Here we report the case of a young infant affected by bronchopulmonary dysplasia (BPD) and treated with inhaled steroids who developed Candida pneumonia likely acquired through descending route.

Phase I/II trial of adeno-associated virus-mediated alpha-glucosidase gene therapy to the diaphragm for chronic respiratory failure in Pompe disease: initial safety and ventilatory outcomes.

Pompe disease is an inherited neuromuscular disease caused by deficiency of lysosomal acid alpha-glucosidase (GAA) leading to glycogen accumulation in muscle and motoneurons. Cardiopulmonary failure in infancy leads to early mortality, and GAA enzyme replacement therapy (ERT) results in improved survival, reduction of cardiac hypertrophy, and developmental gains. However, many children have progressive ventilatory insufficiency and need additional support. Preclinical work shows that gene transfer restores phrenic neural activity and corrects ventilatory deficits. Here we present 180-day safety and ventilatory outcomes for five ventilator-dependent children in a phase I/II clinical trial of AAV-mediated GAA gene therapy (rAAV1-hGAA) following intradiaphragmatic delivery. We assessed whether rAAV1-hGAA results in acceptable safety outcomes and detectable functional changes, using general safety measures, immunological studies, and pulmonary functional testing. All subjects required chronic, full-time mechanical ventilation because of respiratory failure that was unresponsive to both ERT and preoperative muscle-conditioning exercises. After receiving a dose of either 1×10(12) vg (n=3) or 5×10(12) vg (n=2) of rAAV1-hGAA, the subjects' unassisted tidal volume was significantly larger (median [interquartile range] 28.8% increase [15.2-35.2], p<0.05). Further, most patients tolerated appreciably longer periods of unassisted breathing (425% increase [103-851], p=0.08). Gene transfer did not improve maximal inspiratory pressure. Expected levels of circulating antibodies and no T-cell-mediated immune responses to the vector (capsids) were observed. One subject demonstrated a slight increase in anti-GAA antibody that was not considered clinically significant. These results indicate that rAAV1-hGAA was safe and may lead to modest improvements in volitional ventilatory performance measures. Evaluation of the next five patients will determine whether earlier intervention can further enhance the functional benefit.

Molecular detection of respiratory viruses in immunocopromised ICU patients: incidence and meaning.

PURPOSE: Prospective single-center study to assess the sensitivity and clinical relevance of molecular testing for respiratory viruses in critically ill immunocompromised patients with acute respiratory failure (ARF). METHODS: 100 consecutive critically ill immunocompromised patients with ARF in 2007-2009. Among them, 65 had hematologic malignancies (including 14 hematopoietic stem cell transplant recipients), 22 had iatrogenic immunosuppression, and 13 had solid malignancies. A multiplex molecular assay (MMA) was added to the usual battery of tests performed to look for causes of ARF. RESULTS: Nasopharyngeal aspirates and/or bronchoalveolar lavage fluid were tested for respiratory viruses using both the MMA and immunofluorescence. A virus was detected in 47 (47%) patients using the MMA and 8 (8%) patients using immunofluorescence (P = 0.006). MMA-positive and MMA-negative patients had similar clinical and radiographic presentations and were not significantly different for the use of ventilatory support (58% vs. 76%, P = 0.09), occurrence of shock (43% vs. 53%, P = 0.41), use of renal replacement therapy (26% vs. 23%, P = 0.92), SAPS II (35 [26-44] vs. 38 [27-50], P = 0.36), time spent in the ICU (6 vs. 7 days, P = 0.35), or ICU mortality (17% vs. 28%, P = 0.27). Using MMA, a virus was found in 6 of the 12 patients with no diagnosis at the end of the etiologic investigations. CONCLUSIONS: In critically ill immunocompromised patients, an MMA was far more sensitive than immunofluorescence for respiratory virus detection. Patients with RVs detected in the respiratory tract had the same clinical characteristics and outcomes as other patients.