Small airways morphological alterations associated with functional impairment in lymphangioleiomyomatosis.

BACKGROUND: Lymphangioleiomyomatosis (LAM) is a rare neoplastic and cystic pulmonary disease characterized by abnormal proliferation of the so-called LAM cells. Despite the functional obstructive pattern observed in most patients, few studies investigated the morphological changes in the small airways, most of them in patients with severe and advanced LAM undergoing lung transplantation. Understanding the morphological changes in the airways that may occur early in the disease can help us understand the pathophysiology of disease progression and understand the rationale for possible therapeutic approaches, such as the use of bronchodilators. Our study aimed to characterize the morphological alterations of the small airways in patients with LAM with different severities compared to controls, and their association with variables at the pulmonary function test and with LAM Histological Score (LHS). METHODS: Thirty-nine women with LAM who had undergone open lung biopsy or lung transplantation, and nine controls were evaluated. The histological severity of the disease was assessed as LHS, based on the percentage of tissue involvement by cysts and infiltration by LAM cells. The following morphometric parameters were obtained: airway thickness, airway closure index, collagen and airway smooth muscle content, airway epithelial TGF-ß expression, and infiltration of LAM cells and inflammatory cells within the small airway walls. RESULTS: The age of patients with LAM was 39 ± 8 years, with FEV1 and DLCO of 62 ± 30% predicted and 62 ± 32% predicted, respectively. Patients with LAM had increased small airway closure index, collagen and smooth muscle content, and epithelial TGF-beta expression compared with controls. Patients with LAM with the more severe LHS and with greater functional severity (FEV1 ≤ 30%) presented higher thicknesses of the airways. Bronchiolar inflammation was mild; infiltration of the small airway walls by LAM cells was rare. LHS was associated with an obstructive pattern, air trapping, and reduced DLCO, whereas small airway wall thickness was associated with FEV1, FVC, and collagen content. CONCLUSION: LAM is associated with small airway remodelling and partial airway closure, with structural alterations observed at different airway compartments. Functional impairment in LAM is associated with airway remodelling and, most importantly, with histological severity (LHS).

Brazilian guidelines for the treatment of outpatients with suspected or confirmed COVID-19. A joint guideline of the Brazilian Association of Emergency Medicine (ABRAMEDE), Brazilian Medical Association (AMB), Brazilian Society of Angiology and Vascular Surgery (SBACV), Brazilian Society of Geriatrics and Gerontology (SBGG), Brazilian Society of Infectious Diseases (SBI), Brazilian Society of Family and Community Medicine (SBFMC), and Brazilian Thoracic Society (SBPT).

BACKGROUND: Several therapies have been used or proposed for the treatment of COVID-19, although their effectiveness and safety have not been properly evaluated. The purpose of this document is to provide recommendations to support decisions about the drug treatment of outpatients with COVID-19 in Brazil. METHODS: A panel consisting of experts from different clinical fields, representatives of the Brazilian Ministry of Health, and methodologists (37 members in total) was responsible for preparing these guidelines. A rapid guideline development method was used, based on the adoption and/or adaptation of recommendations from existing international guidelines combined with additional structured searches for primary studies and new recommendations whenever necessary (GRADE-ADOLOPMENT). The rating of quality of evidence and the drafting of recommendations followed the GRADE method. RESULTS: Ten technologies were evaluated, and 10 recommendations were prepared. Recommendations were made against the use of anticoagulants, azithromycin, budesonide, colchicine, corticosteroids, hydroxychloroquine/chloroquine alone or combined with azithromycin, ivermectin, nitazoxanide, and convalescent plasma. It was not possible to make a recommendation regarding the use of monoclonal antibodies in outpatients, as their benefit is uncertain and their cost is high, with limitations of availability and implementation. CONCLUSION: To date, few therapies have demonstrated effectiveness in the treatment of outpatients with COVID-19. Recommendations are restricted to what should not be used, in order to provide the best treatment according to the principles of evidence-based medicine and to promote resource savings by aboiding ineffective treatments.

Brazilian guidelines for the treatment of outpatients with suspected or confirmed COVID-19. A joint guideline of the Brazilian Association of Emergency Medicine (ABRAMEDE), Brazilian Medical Association (AMB), Brazilian Society of Angiology and Vascular Surgery (SBACV), Brazilian Society of Geriatrics and Gerontology (SBGG), Brazilian Society of Infectious Diseases (SBI), Brazilian Society of Family and Community Medicine (SBFMC), and Brazilian Thoracic Society (SBPT)

ABSTRACT Background Several therapies have been used or proposed for the treatment of COVID-19, although their effectiveness and safety have not been properly evaluated. The purpose of this document is to provide recommendations to support decisions about the drug treatment of outpatients with COVID-19 in Brazil. Methods A panel consisting of experts from different clinical fields, representatives of the Brazilian Ministry of Health, and methodologists (37 members in total) was responsible for preparing these guidelines. A rapid guideline development method was used, based on the adoption and/or adaptation of recommendations from existing international guidelines combined with additional structured searches for primary studies and new recommendations whenever necessary (GRADE-ADOLOPMENT). The rating of quality of evidence and the drafting of recommendations followed the GRADE method. Results Ten technologies were evaluated, and 10 recommendations were prepared. Recommendations were made against the use of anticoagulants, azithromycin, budesonide, colchicine, corticosteroids, hydroxychloroquine/chloroquine alone or combined with azithromycin, ivermectin, nitazoxanide, and convalescent plasma. It was not possible to make a recommendation regarding the use of monoclonal antibodies in outpatients, as their benefit is uncertain and their cost is high, with limitations of availability and implementation. Conclusion To date, few therapies have demonstrated effectiveness in the treatment of outpatients with COVID-19. Recommendations are restricted to what should not be used, in order to provide the best treatment according to the principles of evidence-based medicine and to promote resource savings by aboiding ineffective treatments.

Tracking the time course of pathological patterns of lung injury in severe COVID-19.

BACKGROUND: Pulmonary involvement in COVID-19 is characterized pathologically by diffuse alveolar damage (DAD) and thrombosis, leading to the clinical picture of Acute Respiratory Distress Syndrome. The direct action of SARS-CoV-2 in lung cells and the dysregulated immuno-coagulative pathways activated in ARDS influence pulmonary involvement in severe COVID, that might be modulated by disease duration and individual factors. In this study we assessed the proportions of different lung pathology patterns in severe COVID-19 patients along the disease evolution and individual characteristics. METHODS: We analysed lung tissue from 41 COVID-19 patients that died in the period March-June 2020 and were submitted to a minimally invasive autopsy. Eight pulmonary regions were sampled. Pulmonary pathologists analysed the H&E stained slides, performing semiquantitative scores on the following parameters: exudative, intermediate or advanced DAD, bronchopneumonia, alveolar haemorrhage, infarct (%), arteriolar (number) or capillary thrombosis (yes/no). Histopathological data were correlated with demographic-clinical variables and periods of symptoms-hospital stay. RESULTS: Patient´s age varied from 22 to 88 years (18f/23 m), with hospital admission varying from 0 to 40 days. All patients had different proportions of DAD in their biopsies. Ninety percent of the patients presented pulmonary microthrombosis. The proportion of exudative DAD was higher in the period 0-8 days of hospital admission till death, whereas advanced DAD was higher after 17 days of hospital admission. In the group of patients that died within eight days of hospital admission, elderly patients had less proportion of the exudative pattern and increased proportions of the intermediate patterns. Obese patients had lower proportion of advanced DAD pattern in their biopsies, and lower than patients with overweight. Clustering analysis showed that patterns of vascular lesions (microthrombosis, infarction) clustered together, but not the other patterns. The vascular pattern was not influenced by demographic or clinical parameters, including time of disease progression. CONCLUSION: Patients with severe COVID-19 present different proportions of DAD patterns over time, with advanced DAD being more prevalent after 17 days, which seems to be influenced by age and weight. Vascular involvement is present in a large proportion of patients, occurs early in disease progression, and does not change over time.

Expression of acute-phase cytokines, surfactant proteins, and epithelial apoptosis in small airways of human acute respiratory distress syndrome.

PURPOSE: Recent studies suggest a role for distal airway injury in acute respiratory distress syndrome (ARDS). The epithelium lining the small airways secretes a large number of molecules such as surfactant components and inflammatory mediators. There is little information on how these small airway secretory functions are altered in ARDS. MATERIALS AND METHODS: We studied the lungs of 31 patients with ARDS (Pao(2)/fraction of inspired oxygen ≤200, 45 ± 14 years, 16 men) and 11 controls (52 ± 16 years, 7 men) submitted to autopsy and quantified the expression of interleukin (IL) 6, IL-8, surfactant proteins (SP) A and SP-B in the epithelium of small airways using immunohistochemistry and image analysis. In addition, an index of airway epithelial apoptosis was determined by the terminal deoxynucleotidyl transferase-mediated deoxyuridine-triphosphatase nick-end labeling assay, caspase 3, and Fas/Fas ligand expression. The density of inflammatory cells expressing IL-6 and IL-8 within the small airway walls was also quantified. RESULTS: Acute respiratory distress syndrome airways showed an increase in the epithelial expression of IL-8 (P = .006) and an increased density of inflammatory cells expressing IL-6 (P = .004) and IL-8 (P < .001) compared with controls. There were no differences in SP-A and SP-B epithelium expression or in epithelial apoptosis index between ARDS and controls. CONCLUSION: Distal airways are involved in ARDS lung inflammation and show a high expression of proinflammatory interleukins in both airway epithelial and inflammatory cells. Apoptosis may not be a major mechanism of airway epithelial cell death in ARDS.

Biopsy-proven pulmonary determinants of heart disease.

Heart disease (HD) can stress the alveolar blood-gas barrier, resulting in parenchymal inflammation and remodeling. Patients with HD may therefore display any of the symptoms commonly attributed to primary pulmonary disease, although tissue documentation of corresponding changes through surgical lung biopsy (SLB) is rarely done. Intent on exploring the basis of HD-related alveolar-capillary barrier dysfunction, a retrospective analysis of SLB histopathology was conducted in patients with clinically diagnosed HD, diffuse pulmonary infiltrates, and no evidence of primary pulmonary disease. Patients eligible for the study had a clinical diagnosis of heart disease, acute or chronic, and presented with diffuse infiltrates on chest X-ray. All qualified subjects (N = 23) who underwent diagnostic SLB between January 1982 and December 2005 were subsequently examined. Specific biopsy parameters investigated included demonstrable edema, siderophage influx, hemorrhage, venous and lymphatic ectasia, vascular sclerosis, capillary congestion, and fibroblast proliferation. Based on observed alveolar-capillary barrier (ACB) alterations, three main morphologic groups emerged: one group (6 patients) with alveolar edema; a second group (11 patients) characterized by pulmonary congestion; and a final group (6 patients) showing microscopic foci of acute ACB lung injury. Alveolar-capillary stress due to acute high-pressure or volume overload often manifests as diffuse pulmonary infiltrates with variable but generally predictable histopathology. In patients with biopsy-proven alveolar edema, pulmonary congestion, or acute microscopic lung injury, the clinician must be alert for the possibility of primary heart disease, particularly if the patient is elderly or when a history of myocardial, valvular, or coronary vascular disease exists.

Abnormal expression of telomerase/apoptosis limits type II alveolar epithelial cell replication in the early remodeling of usual interstitial pneumonia/idiopathic pulmonary fibrosis.

Idiopathic pulmonary fibrosis is a distinctive, usually fatal, type of chronic fibrosing interstitial pneumonia of unknown cause that increases in prevalence with advanced age, characterized by failure of alveolar re-epithelization and progressive scar formation. Recently, limitation of the replicative capacity of tissues determined by telomerase/apoptosis balance has been implicated in pathogenesis of age-related diseases. In this study, we validated the importance of the expression of type 2 alveolar epithelial cells telomerase protein and studied the relationships between telomerase and apoptosis in early remodeling of usual interstitial pneumonia. We determined type 2 alveolar epithelial cells density, telomerase expression, and apoptosis in surgical lung biopsies from 24 patients with usual interstitial pneumonia, and in normal lung tissues from 18 subjects. We used immunohistochemistry, deoxynucleotidyl transferase method of end labeling, electron microscopy, and histomorphometry to evaluate the amount of type 2 alveolar epithelial cells staining for surfactant-A, telomerase, and in situ detection of apoptotic cells. Unaffected areas of usual interstitial pneumonia and normal lung tissue had similar densities of type 2 alveolar epithelial cells, but a significant minor subpopulation of type 2 alveolar epithelial cells was telomerase positive and a large population was telomerase negative. A significant inverse association was found between low type 2 alveolar epithelial cell telomerase expression and high apoptosis in unaffected areas of usual interstitial pneumonia. Although type 2 alveolar epithelial cell telomerase expression was higher than apoptosis in NLT group, no significant association was found between them. Electron microscopy confirmed epithelial apoptosis, alveolar collapse, and initial fibroplasia. We conclude that abnormal type 2 alveolar epithelial cells telomerase/apoptosis balance may reduce alveolar epithelial regenerative capacity, thus contributing to the early remodeling response in usual interstitial pneumonia.

Functional implications of BAL in the presence of restrictive or obstructive lung disease.

Most of the complications associated to bronchoscopy are related to changes of the respiratory function during or after its performance. Prevention of complications should be achieved by understanding the effects of bronchoscopic procedures and their relation to the pulmonary function deterioration. Previous studies regarding the functional impairment caused by bronchoalveolar lavage (BAL) were mostly limited by the presence of interferent factors such as sedative drugs. Furthermore, it is not clear whether or not patients with different ventilatory disturbances present the same functional response to bronchoscopy and BAL. The aim of this study was to determine the additional effects of BAL over the respiratory function deterioration related to bronchoscopy in patients with different respiratory function profiles (normal, restrictive and obstructive). Forty patients submitted to bronchoscopy without premedication were divided into four groups: group I-normal pulmonary function submitted to basic bronchoscopy; group II-bronchoscopy in combination with BAL, subdivided according to pulmonary function: group IIa (normal function), group IIb (restrictive ventilatory disturbances) and group IIc (obstructive ventilatory disturbances). Spirometry was made before and after the bronchoscopic procedure. Baseline hemoglobin saturation was compared to the lowest level during the procedure. Functional worsening caused by the procedure was observed with a decrease in forced vital capacity (FVC), forced expiratory volume in the first second (FEV(1)) and Hemoglobin saturation in all groups. Comparison between groups showed no significant difference regarding the changes in FVC (P=0.8324), FEV(1) (P=0.6952) and hemoglobin saturation (P=0.5044). We conclude that standardized BAL, like the one used in our study, does not result in an increased risk for ventilatory impairment compared to bronchoscopy itself, independently of the presence of previous respiratory disease.

Structural features of epithelial remodeling in usual interstitial pneumonia histologic pattern.

Epithelial remodeling probably contributes to parenchymal deterioration in usual interstitial pneumonia/idiopathic pulmonary fibrosis (UIP/IPF), but understanding its mechanisms is still a challenge. The aim of our study was to examine apoptosis and the epithelial changes in the histologic pattern of UIP. After immunohistochemical staining we quantified the content of type I cells, type II cells, surfactant-A protein, bcl-2, and Fas-ligand (Fas-L) in control and alveolar collapse, fibroblastic foci, and honeycomb in UIP areas of 23 open lung biopsies. A significant association was found between epithelial changes and parenchymal deterioration (p < 0.05). Type I epithelial cell density was similar between control (1.7 +/- 0.7%) and UIP alveolar collapse areas (1.8 +/- 0.6%) but decreased progressively in fibroblastic foci zones (0.8 +/- 0.4%) and honeycomb changes (0.4 +/- 0.3%). Type II cell density increased from control (25.6 +/- 8.3%) to areas of alveolar collapse (34.5 +/- 11.4%), then decreased toward fibroblastic foci (15.4 +/- 6.0%) and honeycomb change areas (23.1 +/- 8.6%). The surfactant-A protein increased from control (6.7 +/- 3.2%) to areas of alveolar collapse (31.1 +/- 9.5%) and decreased toward fibroblastic foci (14.5 +/- 4.9%) and honeycomb change areas (21.1 +/- 8.9%). Fas-L positive epithelial cell density presented a progressive decline from control (48.5 +/- 9.5%), alveolar collapse (37.9 +/- 12.4%), fibroblastic foci (27.4 +/- 6.8%), and honeycomb change areas (21.9 +/- 6.5%). A similar decline in density was found for bcl-2 positive epithelial cells from control (20.4 +/- 2.7%), alveolar collapse (18.9 +/- 5.1%), and fibroblastic foci areas (13.8 +/-2.9%), then increased honeycomb change areas (16.3 +/- 2.8%). We conclude that loss of the nuclear (bcl-2) and membrane (Fas-L) regulation of normal cell population density and suppression of cell death by apoptosis in UIP may be a determinant of the abnormal epithelial/parenchymal remodeling in UIP.

Pulmonary and mediastinal "sarcoidosis" following surgical resection of cancer.

Previous reports indicate that enlarged hilar and mediastinal lymph nodes caused by sarcoid-like reactions may develop after curative resection of cancer, and their presence does not necessarily denote neoplastic recurrence. Reports further suggest that coexisting pulmonary infiltrates in this setting may be related to sarcoidosis. In this study, we describe two patients who had resected lung and gastric cancer and who later developed pulmonary interstitial infiltrate, concurrent with progressive mediastinal lymphadenopathy initially thought to be caused by intrathoracic dissemination of their cancer. These changes were shown by open lung biopsy to be a benign, granulomatous reaction interpreted as sarcoidosis. Thus, it is important to recognize this clinical pattern when pulmonary infiltrates develop after complete treatment of cancer in an otherwise relapse-free patient and to encourage lung or lymph node biopsy in these particular settings in order to confirm a sarcoid-like reaction, thereby avoiding unnecessary chemotherapy for presumed tumor recurrence.

Centrilobular fibrosis: a novel histological pattern of idiopathic interstitial pneumonia.

The classification of idiopathic interstitial pneumonias (IIP) is still under debate. In this context, we observed in some of our patients with a clinical and radiological diagnosis of IIP a different histological picture with an aggressive centrilobular scarring centered in the bronchiolar epithelia, but involving the surrounding parenchyma, which underwent extensive remodeling. We hypothesized that this pattern is a form of IIP that could be separated out histologically from the previously described patterns, in particular from usual interstitial pneumonia (UIP) and non-specific interstitial pneumonia (NSIP). Forty-nine patients with clinical and radiological diagnosis of IIP and open-lung biopsies were retrospectively selected from 1982 to 1998. The biopsies were reviewed according to the following criteria: derangement of lobular architecture, temporal homogeneity and subpleural or bronchocentric distribution of the lesions, fibroblast foci, bronchial epithelium necrosis and regeneration, exposure of the basal membrane, squamous metaplasia, basophilic intraluminal contents, and foreign bodies within the remodeling airspaces. Three groups were found: UIP (24 patients), NSIP (13), and a third that we named centrilobular fibrosis (CLF) (12). All histological parameters were significantly different among the three groups (p < 0.001). CLF is a specific, homogeneous, and recognizable histological pattern of IIP, and can be isolated from UIP and NSIP.