Twins with alveolar capillary dysplasia with misalignment of pulmonary veins: Strategies for diagnosis and management.

We present a case of dichorionic-diamniotic twin females who developed hypoxemic respiratory failure. They were ultimately diagnosed by lung biopsy with alveolar capillary dysplasia with misalignment of pulmonary veins. This case highlights a practical approach to reaching a diagnosis in infants with suspected developmental lung disease.

Diffuse Alveolar Hemorrhage Synergistically Induced by Amiodarone and Rheumatoid Arthritis.

Diffuse alveolar hemorrhage (DAH) syndrome is characterized by bleeding into the alveolar spaces of the lungs and occurs when there is an injury to the alveolar microcirculation that leads to hemorrhage from the alveolar capillaries. We report a case of an 82-year-old woman who presented with acute respiratory distress. The patient had a history of rheumatoid arthritis (RA) and was on amiodarone for atrial fibrillation therapy. Initial diagnostic workup, including bronchoscopy and imaging studies, revealed diffuse opacities and the bronchoalveolar lavage fluid consistent with DAH. The patient required aggressive management with supportive care and corticosteroids. Laboratory work showed a synergistic effect between amiodarone and RA in inducing DAH. This makes the report unique as no reports in the literature described a synergic effect of amiodarone and RA in inducing DAH. The primary objective of this report is to guide physicians and remind them to keep DAH at the top of their differential diagnosis in the setting of an RA patient taking amiodarone.

Pulmonary alveolar capillary dysplasia in infants: A rare and deadly missed diagnosis.

The pulmonary alveolocapillary dysplasia (ACD) with pulmonary vein misalignment (PVM) is a rare condition characterized by a congenital anomaly of the development of the pulmonary parenchyma. We present a case of an 8-month-old infant who died quickly from acute respiratory failure complicating an unknown ACD. We also describe its epidemiological characteristics in infants and we discuss the diagnosis's difficulties. In this case, a pulmonary arterial hypertension was decompensated by an infection. A medico-legal autopsy was performed. As for the Histological examination, it showed the features of ACD/PVM.

Gene transfer of MRCKα rescues lipopolysaccharide-induced acute lung injury by restoring alveolar capillary barrier function.

Acute Lung Injury/Acute Respiratory Distress Syndrome (ALI/ARDS) is characterized by alveolar edema accumulation with reduced alveolar fluid clearance (AFC), alveolar-capillary barrier disruption, and substantial inflammation, all leading to acute respiratory failure. Enhancing AFC has long been considered one of the primary therapeutic goals in gene therapy treatments for ARDS. We previously showed that electroporation-mediated gene delivery of the Na+, K+-ATPase ß1 subunit not only increased AFC, but also restored alveolar barrier function through upregulation of tight junction proteins, leading to treatment of LPS-induced ALI in mice. We identified MRCKα as an interaction partner of ß1 which mediates this upregulation in cultured alveolar epithelial cells. In this study, we investigate whether electroporation-mediated gene transfer of MRCKα to the lungs can attenuate LPS-induced acute lung injury in vivo. Compared to mice that received a non-expressing plasmid, those receiving the MRCKα plasmid showed attenuated LPS-increased pulmonary edema and lung leakage, restored tight junction protein expression, and improved overall outcomes. Interestingly, gene transfer of MRCKα did not alter AFC rates. Studies using both cultured microvascular endothelial cells and mice suggest that ß1 and MRCKα upregulate junctional complexes in both alveolar epithelial and capillary endothelial cells, and that one or both barriers may be positively affected by our approach. Our data support a model of treatment for ALI/ARDS in which improvement of alveolar-capillary barrier function alone may be of more benefit than improvement of alveolar fluid clearance.

Characteristics of pulmonary microvascular structure in postnatal yaks.

Yaks are typical plateau-adapted animals, however the microvascular changes and characteristics in their lungs after birth are still unclear. Pulmonary microvasculature characteristics and changes across age groups were analysed using morphological observation and molecular biology detection in yaks aged 1, 30 and 180 days old in addition to adults. Results: Our experiments demonstrated that yaks have fully developed pulmonary alveolar at birth but that interalveolar thickness increased with age. Immunofluorescence observations showed that microvessel density within the interalveolar septum in the yak gradually increased with age. In addition, transmission electron microscopy (TEM) results showed that the blood-air barrier of 1-day old and 30-days old yaks was significantly thicker than that observed at 180-days old and in adults (P < 0.05), which was caused by the thinning of the membrane of alveolar epithelial cells. Furthermore, Vegfa and Epas1 expression levels in 30-day old yaks were the highest in comparison to the other age groups (P < 0.05), whilst levels in adult yaks were the lowest (P < 0.05). The gradual increase in lung microvessel density can effectively satisfy the oxygen requirements of ageing yaks. In addition, these results suggest that the key period of yak lung development is from 30 to 180 days.

Simultaneous Measurement of Lung Diffusing Capacity and Pulmonary Hemodynamics Reveals Exertional Alveolar-Capillary Dysfunction in Heart Failure With Preserved Ejection Fraction.

Background Hemodynamic perturbations in heart failure with preserved ejection fraction (HFpEF) may alter the distribution of blood in the lungs, impair gas transfer from the alveoli into the pulmonary capillaries, and reduce lung diffusing capacity. We hypothesized that impairments in lung diffusing capacity for carbon monoxide (DLCO) in HFpEF would be associated with high mean pulmonary capillary wedge pressures during exercise. Methods and Results Rebreathe DLCO and invasive hemodynamics were measured simultaneously during exercise in patients with exertional dyspnea. Pulmonary pressure waveforms and breath-by-breath pulmonary gas exchange were recorded at rest, 20 W, and symptom-limited maximal exercise. Patients with HFpEF (n=20; 15 women, aged 65±11 years, body mass index 36±8 kg/m2) achieved a lower symptom-limited maximal workload (52±27 W versus 106±42 W) compared with controls with noncardiac dyspnea (n=10; 7 women, aged 55±10 years, body mass index 30±5 kg/m2). DLCO was lower in patients with HFpEF compared with controls at rest (DLCO 10.4±2.9 mL/min per mm Hg versus 16.4±6.9 mL/min per mm Hg, P<0.01) and symptom-limited maximal exercise (DLCO 14.6±4.7 mL/min per mm Hg versus 23.8±10.8 mL/min per mm Hg, P<0.01) because of a lower alveolar-capillary membrane conductance in HFpEF (rest 16.8±6.6 mL/min per mm Hg versus 28.4±11.8 mL/min per mm Hg, P<0.01; symptom-limited maximal exercise 25.0±6.7 mL/min per mm Hg versus 45.5±22.2 mL/min per mm Hg, P<0.01). DLCO was lower in HFpEF for a given mean pulmonary artery pressure, mean pulmonary capillary wedge pressure, pulmonary arterial compliance, and transpulmonary gradient. Conclusions Lung diffusing capacity is lower at rest and during exercise in HFpEF due to impaired gas conductance across the alveolar-capillary membrane. DLCO is impaired for a given pulmonary capillary wedge pressure and pulmonary arterial compliance. These data provide new insight into the complex relationships between hemodynamic perturbations and gas exchange abnormalities in HFpEF.

Pravastatin attenuates sepsis-induced acute lung injury through decreasing pulmonary microvascular permeability via inhibition of Cav-1/eNOS pathway.

BACKGROUND: Disruption of alveolar endothelial barrier caused by inflammation drives the progression of septic acute lung injury (ALI). Pravastatin, an inhibitor of HMG Co-A reductase, has potent anti-inflammatory effects. In the present study, we aim to explore the beneficial role of pravastatin in sepsis-induced ALI and its related mechanisms. METHODS: A septic ALI model was established by cecal ligation and puncture (CLP) in mice. The pulmonary microvascular endothelial cells (PMVECs) were challenged with lipopolysaccharide (LPS). The pathological changes in lung tissues were examined by HE staining. The pulmonary microvascular permeability was determined by lung wet-to-dry (W/D) weight ratio and Evans blue staining. The total protein concentration in bronchoalveolar lavage fluid (BALF) was detected by BCA assay. The levels of TNF-α, IL-1ß, and IL-6 were assessed by qRT-PCR and ELISA. Apoptosis was determined by flow cytometry and TUNEL. Western blotting was performed for detection of target protein levels. The expression of VE-Cadherin in lung tissues was evaluated by immunohistochemical staining. RESULTS: Pravastatin improved survival rate, attenuated lung pathological changes and reduced pulmonary microvascular permeability in septic mice. In addition, pravastatin restrained sepsis-induced inflammatory response and apoptosis in the lung tissues and PMVECs. Moreover, pravastatin up-regulated the levels of junction proteins ZO-1, JAM-C, and VE-Cadherin. Finally, pravastatin suppressed inflammation, apoptosis and enhanced the expression of junction proteins via regulating Cav-1/eNOS signaling pathway in LPS-exposed PMVECs. CONCLUSION: Pravastatin ameliorates sepsis-induced ALI through improving alveolar endothelial barrier disruption via modulating Cav-1/eNOS pathway, which may be an effective candidate for treating septic ALI.

Week to week variability of pulmonary capillary blood volume and alveolar membrane diffusing capacity in patients with heart failure.

BACKGROUND: Alveolar-capillary membrane diffusing capacity for carbon monoxide (DMCO) and pulmonary capillary volume (Vcap) can be estimated by the multi-step Roughton and Foster (RF, original method from 1957) or the single-step NO-CO double diffusion technique (developed in the 1980s). The latter method implies inherent assumptions. We sought to determine which combination of the alveolar membrane diffusing capacity for nitric oxide (DMNO) to DMCO ratio, an specific conductance of the blood for NO (θNO) and CO (θCO) gave the lowest week-to-week variability in patients with heart failure. METHODS: 44 heart failure patients underwent DMCO and Vcap measurements on three occasions over a ten-week period using both RF and double dilution NO-CO techniques. RESULTS: When using the double diffusing method and applying θNO = infinity, the smallest week-to-week coefficient of variation for DMCO was 10 %. Conversely, the RF method derived DMCO had a much greater week-to-week variability (2x higher coefficient of variation) than the DMCO derived via the NO-CO double dilution technique. The DMCO derived from the double diffusion technique most closely matched the DMCO from the RF method when θNO = infinity and DMCO = DLNO/2.42. The Vcap measured week-to-week was unreliable regardless of the method or constants used. CONCLUSIONS: In heart failure patients, the week-to-week DMCO variability was lowest when using the single-step NO-CO technique. DMCO obtained from double diffusion most closely matched the RF DMCO when DMCO/2.42 and θNO = infinity. Vcap estimation was unreliable with either method.

Capillary Changes Precede Disordered Alveolarization in a Mouse Model of Bronchopulmonary Dysplasia.

Bronchopulmonary dysplasia (BPD), the most common sequela of preterm birth, is a severe disorder of the lung that is often associated with long-lasting morbidity. A hallmark of BPD is the disruption of alveolarization, whose pathogenesis is incompletely understood. Here, we tested the vascular hypothesis that disordered vascular development precedes the decreased alveolarization associated with BPD. Neonatal mouse pups were exposed to 7, 14, or 21 days of normoxia (21% O2) or hyperoxia (85% O2) with n = 8-11 for each group. The right lungs were fixed by vascular perfusion and investigated by design-based stereology or three-dimensional reconstruction of data sets obtained by serial block-face scanning EM. The alveolar capillary network of hyperoxia-exposed mice was characterized by rarefaction, partially altered geometry, and widening of capillary segments as shown by three-dimensional reconstruction. Stereology revealed that the development of alveolar epithelium and capillary endothelium was decreased in hyperoxia-exposed mice; however, the time course of these effects was different. That the surface area of the alveolar epithelium was smaller in hyperoxia-exposed mice first became evident at Day 14. In contrast, the surface area of the endothelium was reduced in hyperoxia-exposed mouse pups at Day 7. The thickness of the air-blood barrier decreased during postnatal development in normoxic mice, whereas it increased in hyperoxic mice. The endothelium and the septal connective tissue made appreciable contributions to the thickened septa. In conclusion, the present study provides clear support for the idea that the stunted alveolarization follows the disordered microvascular development, thus supporting the vascular hypothesis of BPD.

The pentose phosphate pathway mediates hyperoxia-induced lung vascular dysgenesis and alveolar simplification in neonates.

Dysmorphic pulmonary vascular growth and abnormal endothelial cell (EC) proliferation are paradoxically observed in premature infants with bronchopulmonary dysplasia (BPD), despite vascular pruning. The pentose phosphate pathway (PPP), a metabolic pathway parallel to glycolysis, generates NADPH as a reducing equivalent and ribose 5-phosphate for nucleotide synthesis. It is unknown whether hyperoxia, a known mediator of BPD in rodent models, alters glycolysis and the PPP in lung ECs. We hypothesized that hyperoxia increases glycolysis and the PPP, resulting in abnormal EC proliferation and dysmorphic angiogenesis in neonatal mice. To test this hypothesis, lung ECs and newborn mice were exposed to hyperoxia and allowed to recover in air. Hyperoxia increased glycolysis and the PPP. Increased PPP, but not glycolysis, caused hyperoxia-induced abnormal EC proliferation. Blocking the PPP reduced hyperoxia-induced glucose-derived deoxynucleotide synthesis in cultured ECs. In neonatal mice, hyperoxia-induced abnormal EC proliferation, dysmorphic angiogenesis, and alveolar simplification were augmented by nanoparticle-mediated endothelial overexpression of phosphogluconate dehydrogenase, the second enzyme in the PPP. These effects were attenuated by inhibitors of the PPP. Neonatal hyperoxia augments the PPP, causing abnormal lung EC proliferation, dysmorphic vascular development, and alveolar simplification. These observations provide mechanisms and potential metabolic targets to prevent BPD-associated vascular dysgenesis.

Epidemiology, Risk Factors, and Outcomes of Diffuse Alveolar Hemorrhage After Hematopoietic Stem Cell Transplantation.

BACKGROUND: Diffuse alveolar hemorrhage (DAH) is an uncommon complication of hematopoietic stem cell transplantation (HCT) that carries high morbidity and mortality. Limited contemporary data are available regarding the incidence, outcomes, and risk factors for DAH. RESEARCH QUESTION: What are the incidence, outcomes, and risk factors for DAH developing after HCT? METHODS: This was a single-center retrospective cohort study of patients who underwent HCT between January 1, 2005, and December 31, 2016. The incidence and outcomes of DAH development were evaluated. A multivariate logistic regression model was used to analyze differences between survivors and nonsurvivors. RESULTS: Of 4,350 patients undergoing first-time HCT, DAH was diagnosed in 99 (2.3%). DAH was seen in 40 of 3,536 autologous HCT recipients (1.1%) and 59 of 814 allogeneic HCT recipients (7.2%). Mean age was 53 ± 13 years, and median time of DAH diagnosis was 126 days (interquartile range, 19-349 days) after HCT. In-hospital mortality and mortality 1 year after DAH diagnosis were 55.6% and 76.8%, respectively. DAH diagnosis more than 30 days after transplantation (OR, 7.06; 95% CI, 1.65-30.14), low platelet count (OR, 0.98; 95% CI, 0.96-1.0; P = .02), elevated international normalized ratio (INR; OR, 4.08; 95% CI, 0.64-25.88; P = .046) and need for invasive mechanical ventilation (OR, 8.18; 95% CI, 1.9-35.21) were associated with higher in-hospital mortality. Steroid treatment did not alter mortality (P = .80) or length of stay (P = .65). However, among those who received steroids, survival was higher in whose who received modest-dose steroids (< 250 mg methylprednisolone equivalent/d) compared with those who received high-dose steroids (≥ 250 mg methylprednisolone equivalent/d; OR, 0.21; 95% CI, 0.07-0.72). INTERPRETATION: The mortality of DAH after HCT remains high, and DAH can occur long after transplantation. Later development of DAH (>30 days after HCT), need for invasive mechanical ventilation, thrombocytopenia, and elevated INR are all associated with worse outcomes.

The architecture of alveolar capillaries in the lungs of bactrian camels (Camelus bactrianus) / Arquitectura de los capilares alveolares de pulmones de camellos bactrianos (Camelus bactrianus)

SUMMARY: The Bactrian camel, which is native to China and Mongolia, is large in size and is an even-toed ungulate species. The double humps on the Bactrian camel back differentiate it from the dromedary camel, which has a single hump. This species has adapted to unsuitable conditions (lack of food and water) in the Gobi Desert and is advanced in unique anatomical and physiological characteristics during a prolonged evolution period. Several studies have been conducted on the anatomical features of the Bactrian camel, but none have given attention to the alveolar capillaries of the Bactrian camel lung. Therefore, the current study aims to explore the architecture of the alveolar capillary in the Bactrian camel lung and further explain the mechanism of blood flow in its lung. The current study extracted and examined the architecture of the alveolar capillary in the lung of the Bactrian camel (Camelus bactrianus) and further explained the mechanism of blood flow by performing lung casting and replica scanning electron microscopy methods. The reports showed that the resources of the alveolar-capillary originated from the capillaries of the subpleural space or interlobular septulum, sometimes originating from the precapillary arterioles or directly from the terminal arterioles. The alveolar capillaries anastomosed and formed a single layer of dense, basket-like network surrounding the alveolus. The mash diameter of the alveolar-capillary network was larger than that of the capillary, and the appearance of the mash was oval and elliptical. Many of the collapsed alveolar-capillary networks were found in the alveolar microvascular architecture in the lung of the Bactrian camel. The study found that, due to many collapsed alveoli in the Bactrian camel lung, the disproportional pressure between the pulmonary alveoli induced less imbalance of blood flow in the alveolar capillary, which affected the gas exchange efficiency. Therefore, the function of the anastomosing capillary branch was likely to regulate the blood flow between the alveolar-capillary network.

RESUMEN: El camello bactriano, es originario de China y Mongolia, es de gran tamaño y es una especie de ungulado de dedos pares. Las dobles jorobas del lomo del camello bactriano lo diferencian del dromedario, que tiene una sola joroba. Esta especie se ha adaptado a condiciones inadecuadas (falta de alimento y agua) en el desierto de Gobi y ha avanzado en características anatómicas y fisiológicas únicas durante un período de evolución prolongado. Se han realizado varios estudios sobre las características anatómicas del camello bactriano, pero ninguno ha prestado atención a los capilares alveolares del pulmón de este animal. Por lo tanto, el presente estudio tuvo como objetivo principal explorar la arquitectura del capilar alveolar en el pulmón del camello bactriano y explicar el mecanismo del flujo sanguíneo. A partir de nuestro trabajo se examinó la arquitectura del capilar alveolar en el pulmón del camello bactriano (Camelus bactrianus) mediante la realización de métodos de microscopía electrónica de barrido y escaneo pulmonar. Los informes mostraron que los recursos del alvéolo-capilar se originaban en los capilares del espacio subpleural o del tabique interlobulillar y a veces se originaban en las arteriolas precapilares o directamente en las arteriolas terminales. Los capilares alveolares se anastomosaban y formaban una densa red de capa única en forma de cesta que rodeaba el alvéolo. El diámetro del macerado de la red alveolar-capilar era mayor que el del capilar y el aspecto del macerado era ovalado y elíptico. Muchas de las redes alvéolo-capilares colapsadas se encontraron en la arquitectura microvascular alveolar en el pulmón del camello bactriano. El estudio encontró que, muchos alvéolos colapsados en el pulmón del camello bactriano, la presión desproporcionada entre los alvéolos pulmonares inducía un menor desequilibrio del flujo sanguíneo en el capilar alveolar, lo que afectaba la eficiencia del intercambio de gases. Por lo tanto, la función de la rama capilar anastomosante probablemente regularía el flujo sanguíneo entre la red alveolar-capilar.

Delineation of the healthy rabbit lung by immunohistochemistry - a technical note.

Investigation and studies of pulmonary diseases and injuries require pre-clinical animal models. The rabbit lung model is widely used and allows for a diverse set of readouts. Among them, histology and immunohistochemistry are of invaluable merit because qualitative and quantitative information about tissue morphology and composition can be easily obtained. In this technical note, we performed several histological and immunohistochemical stainings in the rabbit healthy naïve lung tissue. Overnight formalin fixation with subsequent paraffin embedding was compared to cryopreservation with a subsequent 10-minute formalin fixation prior to staining. Antigen retrieval (AR) for paraffin embedded sections proved to enhance the corresponding signals compared to analogous staining without AR. Advantages and disadvantages of chromogenic versus immunofluorescence stainings were discussed. In addition, several morphological structures, such as the intrapulmonary bronchus with its mucosal folds, the pulmonary artery, the alveoli and the lymph nodes, were stained with various stainings at the same site in order to give a comprehensive picture of their composition. Besides Haematoxylin&Eosin and Elastica van Gieson staining, collagen I, collagen III, fibronectin, α-SMA, ki-67 and protease-activated receptor-2 (PAR-2) immunohistochemistry was performed. Collagen I, collagen III and fibronectin expression was positive at the outer rim of the pulmonary arteries, while the inner rim was collagen III positive. Moreover, the fibronectin staining in the intrapulmonary bronchus showed an opposite trend when compared to the collagen III staining. The alveoli exhibited PAR-2 expression, while PAR-2 was not expressed in lymph nodes of the healthy rabbit lung.

Capillary cell-type specialization in the alveolus.

In the mammalian lung, an apparently homogenous mesh of capillary vessels surrounds each alveolus, forming the vast respiratory surface across which oxygen transfers to the blood1. Here we use single-cell analysis to elucidate the cell types, development, renewal and evolution of the alveolar capillary endothelium. We show that alveolar capillaries are mosaics; similar to the epithelium that lines the alveolus, the alveolar endothelium is made up of two intermingled cell types, with complex 'Swiss-cheese'-like morphologies and distinct functions. The first cell type, which we term the 'aerocyte', is specialized for gas exchange and the trafficking of leukocytes, and is unique to the lung. The other cell type, termed gCap ('general' capillary), is specialized to regulate vasomotor tone, and functions as a stem/progenitor cell in capillary homeostasis and repair. The two cell types develop from bipotent progenitors, mature gradually and are affected differently in disease and during ageing. This cell-type specialization is conserved between mouse and human lungs but is not found in alligator or turtle lungs, suggesting it arose during the evolution of the mammalian lung. The discovery of cell type specialization in alveolar capillaries transforms our understanding of the structure, function, regulation and maintenance of the air-blood barrier and gas exchange in health, disease and evolution.

Diffuse alveolar hemorrhage secondary to plastic fume exposure: A case report.

A 31-year non-smoker man, working in plastic making industry for 12 years presented with cough and streaking hemoptysis for 2 days. Computed tomography (CT) of chest showed patchy ground glass opacities with interlobular septal thickening in bilateral lung parenchyma. Fiber optic bronchoscopy (FOB) was done. Sequential lavage was taken which showed progressively increasing hemorrhagic fluid. His diffusion capacity for carbon monoxide (DLCO) was 38.08 mL/mmHg/Mi (126%) predicted on day 2 of admission, 32.36 ml/mmHg/Mi (106%) predicted on discharge and 39.63 mL/mmHg/Mi (130%) predicted on going back to work. He was diagnosed with plastic fume exposure related pulmonary alveolar hemorrhage.

Disequilibrium between the classic renin-angiotensin system and its opposing arm in SARS-CoV-2-related lung injury.

A dysregulation of the renin-angiotensin system (RAS) has been involved in the genesis of lung injury and acute respiratory distress syndrome from different causes, including several viral infections. The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection of pneumocytes, the hallmark of the pandemic coronavirus disease 2019 (COVID-19) involving both alveolar interstitium and capillaries, is linked to angiotensin-converting enzyme 2 (ACE2) binding and its functional downregulation. ACE2 is a key enzyme for the balance between the two main arms of the RAS: the ACE/angiotensin (Ang) II/Ang II type 1 receptor axis ("classic RAS") and the ACE2/Ang(1-7)/Mas receptor (MasR) axis ("anti-RAS"). The ACE2 downregulation, as a result of SARS-coronaviruses binding, enhances the classic RAS, leading to lung damage and inflammation with leaky pulmonary blood vessels and fibrosis, when the attenuation mediated by the anti-RAS arm is reduced. ACE inhibitors (ACE-I) and Ang II type 1 receptor blockers (ARB), effective in cardiovascular diseases, were found to prevent and counteract acute lung injury in several experimental models by restoring the balance between these two opposing arms. The evidence of RAS arm disequilibrium in COVID-19 and the hypothesis of a beneficial role of RAS modulation supported by preclinical and clinical studies are the focus of the present review. Preclinical and clinical studies on drugs balancing RAS arms might be the right way to counter COVID-19.

Pulmonary post-mortem findings in a series of COVID-19 cases from northern Italy: a two-centre descriptive study.

BACKGROUND: COVID-19 is characterised by respiratory symptoms, which deteriorate into respiratory failure in a substantial proportion of cases, requiring intensive care in up to a third of patients admitted to hospital. Analysis of the pathological features in the lung tissues of patients who have died with COVID-19 could help us to understand the disease pathogenesis and clinical outcomes. METHODS: We systematically analysed lung tissue samples from 38 patients who died from COVID-19 in two hospitals in northern Italy between Feb 29 and March 24, 2020. The most representative areas identified at macroscopic examination were selected, and tissue blocks (median seven, range five to nine) were taken from each lung and fixed in 10% buffered formalin for at least 48 h. Tissues were assessed with use of haematoxylin and eosin staining, immunohistochemical staining for inflammatory infiltrate and cellular components (including staining with antibodies against CD68, CD3, CD45, CD61, TTF1, p40, and Ki-67), and electron microscopy to identify virion localisation. FINDINGS: All cases showed features of the exudative and proliferative phases of diffuse alveolar damage, which included capillary congestion (in all cases), necrosis of pneumocytes (in all cases), hyaline membranes (in 33 cases), interstitial and intra-alveolar oedema (in 37 cases), type 2 pneumocyte hyperplasia (in all cases), squamous metaplasia with atypia (in 21 cases), and platelet-fibrin thrombi (in 33 cases). The inflammatory infiltrate, observed in all cases, was largely composed of macrophages in the alveolar lumina (in 24 cases) and lymphocytes in the interstitium (in 31 cases). Electron microscopy revealed that viral particles were predominantly located in the pneumocytes. INTERPRETATION: The predominant pattern of lung lesions in patients with COVID-19 patients is diffuse alveolar damage, as described in patients infected with severe acute respiratory syndrome and Middle East respiratory syndrome coronaviruses. Hyaline membrane formation and pneumocyte atypical hyperplasia are frequent. Importantly, the presence of platelet-fibrin thrombi in small arterial vessels is consistent with coagulopathy, which appears to be common in patients with COVID-19 and should be one of the main targets of therapy. FUNDING: None.