High-altitude pulmonary edema: the intercellular network hypothesis.

The pathophysiology of high-altitude pulmonary edema is currently attributed to exacerbated heterogeneous hypoxic pulmonary vasoconstriction. However, although other cellular mechanisms have been hypothesized, they are still poorly understood. In this review, we focused on cells of the pulmonary acinus, the distal unit for gas exchange, known to be responders to acute hypoxia, notably through many humoral or tissue factors that connect this intercellular network constituting the alveolo-capillary barrier. Hypoxia could drive alveolar edema by: 1) damaging the fluid reabsorption capacity of alveolar epithelial cells, 2) increasing the endothelial and epithelial permeability, especially by alteration of occluding junctions, 3) triggering the inflammation mainly led by alveolar macrophages, 4) increasing interstitial water accumulation by disruption of extracellular matrix architecture and tight junctions, 5) inducing pulmonary vasoconstriction through an orchestrated response of pulmonary arterial endothelial and smooth muscle cells. Hypoxia may also alter the function of fibroblasts and pericytes that contribute to the interconnection of the cells of the alveolar-capillary barrier. Due to its complex intercellular network and delicate pressure gradient equilibrium, the alveolar-capillary barrier is simultaneously affected by acute hypoxia in all its components, leading to rapid accumulation of water in the alveoli.

Estimation of Regional Pulmonary Compliance in Idiopathic Pulmonary Fibrosis Based on Personalized Lung Poromechanical Modeling.

Pulmonary function is tightly linked to the lung mechanical behavior, especially large deformation during breathing. Interstitial lung diseases, such as idiopathic pulmonary fibrosis (IPF), have an impact on the pulmonary mechanics and consequently alter lung function. However, IPF remains poorly understood, poorly diagnosed, and poorly treated. Currently, the mechanical impact of such diseases is assessed by pressure-volume curves, giving only global information. We developed a poromechanical model of the lung that can be personalized to a patient based on routine clinical data. The personalization pipeline uses clinical data, mainly computed tomography (CT) images at two time steps and involves the formulation of an inverse problem to estimate regional compliances. The estimation problem can be formulated both in terms of "effective", i.e., without considering the mixture porosity, or "rescaled," i.e., where the first-order effect of the porosity has been taken into account, compliances. Regional compliances are estimated for one control subject and three IPF patients, allowing to quantify the IPF-induced tissue stiffening. This personalized model could be used in the clinic as an objective and quantitative tool for IPF diagnosis.

Lung transplantation for sarcoidosis: outcome and prognostic factors.

STUDY QUESTION: In patients with sarcoidosis, past and ongoing immunosuppressive regimens, recurrent disease in the transplant and extrapulmonary involvement may affect outcomes of lung transplantation. We asked whether sarcoidosis lung phenotypes can be differentiated and, if so, how they relate to outcomes in patients with pulmonary sarcoidosis treated by lung transplantation. PATIENTS AND METHODS: We retrospectively reviewed data from 112 patients who met international diagnostic criteria for sarcoidosis and underwent lung or heart-lung transplantation between 2006 and 2019 at 16 European centres. RESULTS: Patient survival was the main outcome measure. At transplantation, median (interaquartile range (IQR)) age was 52 (46-59) years; 71 (64%) were male. Lung phenotypes were individualised as follows: 1) extended fibrosis only; 2) airflow obstruction; 3) severe pulmonary hypertension (sPH) and airflow obstruction; 4) sPH, airflow obstruction and fibrosis; 5) sPH and fibrosis; 6) airflow obstruction and fibrosis; 7) sPH; and 8) none of these criteria, in 17%, 16%, 17%, 14%, 11%, 9%, 5% and 11% of patients, respectively. Post-transplant survival rates after 1, 3, and 5 years were 86%, 76% and 69%, respectively. During follow-up (median (IQR) 46 (16-89) months), 31% of patients developed chronic lung allograft dysfunction. Age and extended lung fibrosis were associated with increased mortality. Pulmonary fibrosis predominating peripherally was associated with short-term complications. ANSWER TO THE STUDY QUESTION: Post-transplant survival in patients with pulmonary sarcoidosis was similar to that in patients with other indications for lung transplantation. The main factors associated with worse survival were older age and extensive pre-operative lung fibrosis.

Granulomatous lung inflammation is nanoparticle type-dependent.

BACKGROUND: Nanoparticles are increasingly suspected as a strong etiologic factor of granuloma formation. AIM OF THE STUDY: The aim of our study was to compare lung inflammatory response and histology changes following exposure of mice to two widely used nanoparticles: carbon nanotubes (MWCNT) and cadmium-based nanoparticles (QDOT705) in an attempt to better our understanding of granulomatous inflammation. MATERIALS AND METHODS: Various groups of mice were included: control mice and mice that were intranasally instilled with QDOT or MWCNT. At defined time points post-challenge, bronchoalveolar lavages (BALs) and lung tissues were collected to study inflammatory and histologic changes. RESULTS: Analyses of lung BAL fluids and tissues of nanoparticles-challenged mice in comparison to controls found: (1) increased cellularity in BALs, (2) increase of total protein concentration, LDH activity and proteolytic activity in BALs; (3) patchy granulomas, (4) macrophages, CD3 ± T, Treg and B cell infiltration in granulomatous areas; and (5) altered regulation of key inflammatory mediators and receptors. Importantly, these changes were nanoparticle type-dependent. CONCLUSION: Our work enhances understanding of nanoparticles-induced lung inflammatory and histological changes that result in granuloma formation. We provide compelling evidence that not only exposure to nanoparticles leads to granulomatous lung inflammation, but the severity of this latter is nanostructure type-dependent. Of importance, while nanotechnology has the potential to revolutionize various fields including medicine, nanoparticles form the potential for an entirely new lung health risk that it is necessary to take seriously into consideration by setting up and/or reinforcing adequate safety measures.

The Lung in Dysregulated States of Humoral Immunity.

In common variable immunodeficiency, lung manifestations are related to different mechanisms: recurrent pneumonias due to encapsulated bacteria responsible for diffuse bronchiectasis, diffuse infiltrative pneumonia with various patterns, and lymphomas, mostly B cell extranodal non-Hodgkin type. The diagnosis relies on significant serum Ig deficiency and the exclusion of any primary or secondary cause. Histopathology may be needed. Immunoglobulin (IgG) replacement is crucial to prevent infections and bronchiectasis. IgG4-related respiratory disease, often associated with extrapulmonary localizations, presents with solitary nodules or masses, diffuse interstitial lung diseases, bronchiolitis, lymphadenopathy, and pleural or pericardial involvement. Diagnosis relies on international criteria including serum IgG4 dosage and significantly increased IgG4/IgG plasma cells ratio in pathologically suggestive biopsy. Respiratory amyloidosis presents with tracheobronchial, nodular, and cystic or diffuse interstitial lung infiltration. Usually of AL (amyloid light chain) subtype, it may be localized or systemic, primary or secondary to a lymphoproliferative process. Very rare other diseases due to nonamyloid IgG deposits are described. Among the various lung manifestations of dysregulated states of humoral immunity, this article covers only those associated with the common variable immunodeficiency, IgG4-related disease, amyloidosis, and pulmonary light-chain deposition disease. Autoimmune connective-vascular tissue diseases or lymphoproliferative disorders are addressed in other chapters of this issue.

Experimental models of sarcoidosis.

PURPOSE OF REVIEW: Sarcoidosis is a disease caused by a complex combination of genetic susceptibility, immune networks and infectious and/or environmental agents. The onset and phenotypic variability of sarcoidosis remain poorly elucidated, not only due to the lack of clearly identified causes, but also because it is widely considered that no reliable model of this disease is available. In this review, we discuss the various models of granulomatous diseases in order to challenge this assertion. RECENT FINDINGS: A large number of models of granulomatous diseases are available, both cellular models used to study the natural history of granulomas and experimental animal models mostly developed in rodents. SUMMARY: Although none of the available models fully reproduces sarcoidosis, most of them generate various data supporting key concepts. Selected models with a high level of confidence among those already published may provide various pieces of the sarcoidosis jigsaw puzzle, whereas clinical data can provide other elements. A 'systems biology' approach for modelling may be a way of piecing together the various pieces of the puzzle. Finally, experimental models and a systemic approach should be considered to be tools for preclinical evaluation of the efficacy of drugs prior to testing in clinical trials.

The pathologist's view of silicosis in 1930 and in 2015. The Johannesburg Conference legacy.

The 1930 International Labour Office Conference on silicosis in Johannesburg was a turning point in the history of silicosis and in the recognition of the associated pathologic patterns. Since 1930, pneumoconioses such as silicosis have become much rarer in developed countries and can now be diagnosed at an early stage based on clinical and radiologic criteria. However, in spite of these advances, pathologists must remember to look for silica in tissues, particularly when clinical and radiologic findings are more uncertain. Furthermore, nowadays pathologists essentially observe silicotic lesions as incidental findings adjacent to lung cancers. In addition to identifying the characteristic lesions, pathologists must also try to identify their causative agent, in the case of crystalline silica firstly by using polarized light examination, followed as appropriate by more sophisticated devices. Finally, pathologists and clinicians must always keep in mind the various implications of exposure to silica compounds in a wide range of diseases.

Prognostic relevance of histological variants in nonspecific interstitial pneumonia.

AIMS: Although histological non-specific interstitial pneumonia (NSIP) is concisely defined, overlap with other patterns is described. While most frequently idiopathic, NSIP is seen in various clinical contexts such as connective tissue diseases (CTDs) and chronic hypersensitivity pneumonitis (cHP). This study was designed to determine if NSIP could be separated into subgroups based on minor histological features and to correlate these subgroups with clinical associations and survival. METHODS AND RESULTS: One hundred and thirty-six patients with biopsy-proven NSIP were included [clinical diagnosis: CTDs (23%), cHP (12%), idiopathic (65%)]. In addition to the agreed NSIP criteria, seven subgroups were identified: essential NSIP and six overlap subgroups according to superimposed minor histological features. Interobserver concordance resulted in the following consensus: essential NSIP (36%), usual interstitial pneumonia (UIP) overlap (26%), cHP overlap (10%), organizing pneumonia (OP) overlap (6%), organizing diffuse alveolar damage (DAD) overlap (10%), desquamative interstitial pneumonia overlap (7%) and lymphoid interstitial pneumonia overlap (2%). OP overlap was associated with CTDs (P = 0.04) and cHP overlap with a cHP clinical diagnosis (P = 0.02). Survival was different between subgroups (P = 0.0002). Organizing DAD overlap exhibited poorer survival at 5 years (32%), followed by UIP overlap (57%). Independent predictors of mortality were organizing DAD overlap (HR = 4.99, 95% CI = 2.15-11.58, P = 0.0002), UIP overlap (HR = 2.11, 95% CI = 1.12-3.99, P = 0.02) and a clinical diagnosis of cHP (HR = 2.17, 95% CI = 1.05-4.47, P = 0.035). CONCLUSIONS: Non-specific interstitial pneumonia subdivision into pathological subgroups is clinically relevant from a prognostic and causal perspective.

Advanced pulmonary sarcoidosis.

PURPOSE OF REVIEW: To present an update on the most recent contributions in advanced pulmonary sarcoidosis (APS). RECENT FINDINGS: Pathology is better described and the differences between fibrosing pulmonary sarcoidosis and usual interstitial pneumonia (UIP) are clarified. Serial spirometry is the most reliable tool for monitoring evolution. Survival may be predicted by an integrative algorithm based on pulmonary function and computed tomography (CT). SUMMARY: APS is characterized by significant fibrocystic pulmonary lesions at CT and pathology. There are two main patterns of APS, one with predominant central bronchovascular distortion, often associated with airflow limitation, and the other with predominant honeycombing with a different location than in UIP with severe restrictive impairment and very low diffusion capacity of the lung for carbon monoxide. APS may be burnt out but is most often still active as evidenced by several findings, including on F-fluorodeoxyglucose-PET. There is an increased mortality and morbidity with chronic respiratory insufficiency, pulmonary hypertension stemming from multiple mechanisms, chronic pulmonary aspergillosis and extra infections. Acute worsening episodes are frequent. Serial spirometry, particularly forced vital capacity, is the most reliable tool for monitoring evolution. A new elegant algorithm based on pulmonary function and CT may predict survival. Despite important stakes, there is still a lack of therapeutic recommendations. However, the use of antisarcoidosis treatment is most often required at least as a temporary trial. Finally, the effect of pulmonary hypertension treatment has recently been the object of further evaluation.

Clinical presentation of sarcoidosis and diagnostic work-up.

Sarcoidosis is a systemic disease of unknown cause characterized by the formation of immune granulomas which most often involve the lung and the lymphatic system. Sarcoidosis may encompass numerous different clinical presentations. Typical presentations often prompt a rapid diagnosis while in 25 to 50% of cases, diverse and less typical presentations may lead to delayed diagnosis. The mediastinopulmonary sphere is involved in 85 to 95% of cases, associated with extrapulmonary localizations in half of cases while extrapulmonary localizations without lung involvement may be seen in 5 to 15% of cases. Bilateral hilar lymphadenopathy is the most typical sign at chest radiography. Computed tomography (CT) is essential face for atypical manifestations of the disease to avoid confusion with differential diagnoses and, sometimes, comorbidities. CT typically evidences diffuse pulmonary perilymphatic micronodules, with a perilobular and fissural distribution and upper and posterior predominance, even when an atypical CT pattern is predominant. CT allows deciphering pulmonary lesions in cases of pulmonary fibrosis, pulmonary hypertension, and airflow limitation. Pulmonary function tests generally correlate with the overall disease process. Forced vital capacity is the simplest and most accurate parameter to reflect the impact of pulmonary sarcoidosis. Cardiopulmonary exercise testing helps in understanding the mechanism behind dyspnea of uncertain origin. Endoscopic transbronchial needle aspiration is an extra tool to support diagnosis in addition to more classical biopsy means. Bronchoalveolar lavage (BAL) may be used for individual patients while it is not really decisive for the diagnosis of sarcoidosis for most patients. Diagnosis relies on compatible clinical and radiological presentation, evidence of noncaseating granulomas and exclusion of other diseases with a similar presentation or histology. The probability of diagnosis at presentation is variable from case to case and may often be reinforced with time. Some investigations are mandatory at diagnosis to assess organ involvement and disease activity. However, there are important variations in diagnostic work-up due to diverse expressions of sarcoidosis and differences in clinical practices among physicians.

Infectious Complications of Pulmonary Sarcoidosis.

In this review, the infectious complications observed in sarcoidosis are considered from a practical point of view to help the clinician not to overlook them in a difficult context, as pulmonary sarcoidosis makes the recognition of superinfections more difficult. An increased incidence of community-acquired pneumonia and of opportunistic pneumonia has been reported, especially in immunosuppressed patients. Pulmonary destructive lesions of advanced sarcoidosis increase the incidence of chronic pulmonary aspergillosis and infection by other agents. Screening and treatment of latent tuberculosis infection are crucial to prevent severe tuberculosis. Severity in COVID-19 appears to be increased by comorbidities rather than by sarcoidosis per se. The diagnosis of infectious complications can be challenging and should be considered as a potential differential diagnosis when the exacerbation of sarcoidosis is suspected. These complications not only increase the need for hospitalizations, but also increase the risk of death. This aspect must be carefully considered when assessing the overall health burden associated with sarcoidosis. The impact of immune dysregulation on infectious risk is unclear except in exceptional cases. In the absence of evidence-based studies on immunosuppressants in the specific context of pulmonary sarcoidosis, it is recommended to apply guidelines used in areas outside sarcoidosis. Preventive measures are essential, beginning with an appropriate use of immunosuppressants and the avoidance of unjustified treatments and doses. This approach should take into account the risk of tuberculosis, especially in highly endemic countries. Additionally, parallel emphasis should be placed on vaccinations, especially against COVID-19.

Fibrotic Pulmonary Sarcoidosis.

Fibrotic pulmonary sarcoidosis (fPS) affects about 20% of patients. fPS carries a significant morbidity and mortality. However, its prognosis is highly variable, depending mainly on fibrosis extent, functional impairment severity, and the development of pulmonary hypertension. Moreover, fPS outcomes are also influenced by several other complications, including acute exacerbations, and infections. fPS natural history is unknown, in particular regarding the risk of progressive self-sustaining fibrosis. The management of fPS is challenging, including anti-inflammatory treatment if granulomatous activity persists, rehabilitation, and in highly selected patients antifibrotic treatment and lung transplantation.

U-net convolutional neural network applied to progressive fibrotic interstitial lung disease: Is progression at CT scan associated with a clinical outcome?

BACKGROUND: Computational advances in artificial intelligence have led to the recent emergence of U-Net convolutional neural networks (CNNs) applied to medical imaging. Our objectives were to assess the progression of fibrotic interstitial lung disease (ILD) using routine CT scans processed by a U-Net CNN developed by our research team, and to identify a progression threshold indicative of poor prognosis. METHODS: CT scans and clinical history of 32 patients with idiopathic fibrotic ILDs were retrospectively reviewed. Successive CT scans were processed by the U-Net CNN and ILD quantification was obtained. Correlation between ILD and FVC changes was assessed. ROC curve was used to define a threshold of ILD progression rate (PR) to predict poor prognostic (mortality or lung transplantation). The PR threshold was used to compare the cohort survival with Kaplan Mayer curves and log-rank test. RESULTS: The follow-up was 3.8 ± 1.5 years encompassing 105 CT scans, with 3.3 ± 1.1 CT scans per patient. A significant correlation between ILD and FVC changes was obtained (p = 0.004, ρ = -0.30 [95% CI: -0.16 to -0.45]). Sixteen patients (50%) experienced unfavorable outcome including 13 deaths and 3 lung transplantations. ROC curve analysis showed an aera under curve of 0.83 (p < 0.001), with an optimal cut-off PR value of 4%/year. Patients exhibiting a PR ≥ 4%/year during the first two years had a poorer prognosis (p = 0.001). CONCLUSIONS: Applying a U-Net CNN to routine CT scan allowed identifying patients with a rapid progression and unfavorable outcome.

Influence of ABCB1 polymorphisms and docetaxel pharmacokinetics on pathological response to neoadjuvant chemotherapy in breast cancer patients.

We have previously reported an association between ABCB1 C3435T polymorphism and docetaxel pharmacokinetics in breast cancer patients. We therefore investigated whether these parameters could account for variations in pathological response. Five ABCB1 polymorphisms including C3435T polymorphism were analyzed in breast cancer patients receiving neoadjuvant chemotherapy with doxorubicin and docetaxel (n = 101). Pathological response was assessed using the Sataloff classification. Pharmacokinetic analysis was performed for the first course of docetaxel (n = 84). No significant association was found between ABCB1 polymorphisms or docetaxel pharmacokinetics and pathological complete response. C3435T genotype was an independent predictive factor of good response in breast (response >50 %, i.e., Sataloff T-A and T-B): OR: 4.6 (95 % CI: 1.3-16.1), p = 0.015, for TT patients versus CT and CC patients. Area under the plasma concentration-time curve (AUC) of docetaxel was the only independent predictive factor of the total absence of response in breast (Sataloff T-D): OR: 14.3, (95 % CI: 1.7-118), p = 0.015, for AUC of docetaxel <3,500 µg h/L versus ≥3,500 µg h/L. These results suggest that C3435T polymorphism and docetaxel exposure are involved in the response to neoadjuvant chemotherapy in breast cancer patients and may be useful to optimize individualized therapy.

Chronic pulmonary fibrosis alters the functioning of the respiratory neural network.

Some patients with idiopathic pulmonary fibrosis present impaired ventilatory variables characterised by low forced vital capacity values associated with an increase in respiratory rate and a decrease in tidal volume which could be related to the increased pulmonary stiffness. The lung stiffness observed in pulmonary fibrosis may also have an effect on the functioning of the brainstem respiratory neural network, which could ultimately reinforce or accentuate ventilatory alterations. To this end, we sought to uncover the consequences of pulmonary fibrosis on ventilatory variables and how the modification of pulmonary rigidity could influence the functioning of the respiratory neuronal network. In a mouse model of pulmonary fibrosis obtained by 6 repeated intratracheal instillations of bleomycin (BLM), we first observed an increase in minute ventilation characterised by an increase in respiratory rate and tidal volume, a desaturation and a decrease in lung compliance. The changes in these ventilatory variables were correlated with the severity of the lung injury. The impact of lung fibrosis was also evaluated on the functioning of the medullary areas involved in the elaboration of the central respiratory drive. Thus, BLM-induced pulmonary fibrosis led to a change in the long-term activity of the medullary neuronal respiratory network, especially at the level of the nucleus of the solitary tract, the first central relay of the peripheral afferents, and the Pre-Bötzinger complex, the inspiratory rhythm generator. Our results showed that pulmonary fibrosis induced modifications not only of pulmonary architecture but also of central control of the respiratory neural network.