The fatal trajectory of pulmonary COVID-19 is driven by lobular ischemia and fibrotic remodelling.

BACKGROUND: COVID-19 is characterized by a heterogeneous clinical presentation, ranging from mild symptoms to severe courses of disease. 9-20% of hospitalized patients with severe lung disease die from COVID-19 and a substantial number of survivors develop long-COVID. Our objective was to provide comprehensive insights into the pathophysiology of severe COVID-19 and to identify liquid biomarkers for disease severity and therapy response. METHODS: We studied a total of 85 lungs (n = 31 COVID autopsy samples; n = 7 influenza A autopsy samples; n = 18 interstitial lung disease explants; n = 24 healthy controls) using the highest resolution Synchrotron radiation-based hierarchical phase-contrast tomography, scanning electron microscopy of microvascular corrosion casts, immunohistochemistry, matrix-assisted laser desorption ionization mass spectrometry imaging, and analysis of mRNA expression and biological pathways. Plasma samples from all disease groups were used for liquid biomarker determination using ELISA. The anatomic/molecular data were analyzed as a function of patients' hospitalization time. FINDINGS: The observed patchy/mosaic appearance of COVID-19 in conventional lung imaging resulted from microvascular occlusion and secondary lobular ischemia. The length of hospitalization was associated with increased intussusceptive angiogenesis. This was associated with enhanced angiogenic, and fibrotic gene expression demonstrated by molecular profiling and metabolomic analysis. Increased plasma fibrosis markers correlated with their pulmonary tissue transcript levels and predicted disease severity. Plasma analysis confirmed distinct fibrosis biomarkers (TSP2, GDF15, IGFBP7, Pro-C3) that predicted the fatal trajectory in COVID-19. INTERPRETATION: Pulmonary severe COVID-19 is a consequence of secondary lobular microischemia and fibrotic remodelling, resulting in a distinctive form of fibrotic interstitial lung disease that contributes to long-COVID. FUNDING: This project was made possible by a number of funders. The full list can be found within the Declaration of interests / Acknowledgements section at the end of the manuscript.

SARS-CoV-2 and Placental Pathology: Malperfusion Patterns Are Dependent on Timing of Infection During Pregnancy.

The extent to which severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection at different points in the pregnancy timeline may affect maternal and fetal outcomes remains unknown. We sought to characterize the impact of SARS-CoV-2 infection proximate and remote from delivery on placental pathology. We performed a secondary analysis of placental pathology from a prospective cohort of universally tested SARS-CoV-2 positive women >20 weeks gestation at 1 institution. Subjects were categorized as having acute or nonacute SARS-CoV-2 based on infection <14 or ≥14 days from delivery admission, respectively, determined by nasopharyngeal swab, symptom history, and serologies, when available. A subset of SARS-CoV-2 negative women represented negative controls. Placental pathology was available for 90/97 (92.8%) of SARS-CoV-2 positive women, of which 26 were from women with acute SARS-CoV-2 infection and 64 were from women with nonacute SARS-CoV-2. Fetal vascular malperfusion lesions were significantly more frequent among the acute SARS-CoV-2 group compared with the nonacute SARS-CoV-2 group (53.8% vs. 18.8%; P=0.002), while frequency of maternal vascular malperfusion lesions did not differ by timing of infection (30.8% vs. 29.7%; P>0.99). When including 188 SARS-CoV-2 negative placentas, significant differences in frequency of fetal vascular malperfusion lesions remained between acute, nonacute and control cases (53.8% vs. 18.8% vs. 13.2%, respectively; P<0.001). No differences were noted in obstetric or neonatal outcomes between acutely and nonacutely infected women. Our findings indicate timing of infection in relation to delivery may alter placental pathology, with potential clinical implications for risk of thromboembolic events and impact on fetal health.

A case of rapidly progressive upper limb ischemic necrosis in a patient with COVID-19.

BACKGROUND: For more than a year, health systems all over the world have been combating the global coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The disease was first described in the city of Wuhan in China, presenting as an atypical infection of the lower respiratory tract. METHODS: COVID-19 is characterized by multisystemic involvement, and mortality is attributed mainly to the respiratory system involvement, which may lead to severe acute respiratory distress syndrome and respiratory failure. Several COVID-19-associated complications are being increasingly reported, including arterial and venous thromboembolic events that may lead to amputation of the affected limbs. So far, a large number of reports have described hypercoagulability crises leading to amputation of the lower limbs. However, a search of the National Library of Medicine (MEDLINE) revealed no cases of urgent upper limb amputation in COVID-19 patients. RESULTS: This article describes a novel case of upper limb ischemia in a COVID-19 patient, with rapid progression to hand necrosis, requiring urgent through-arm amputation of the upper limb. CONCLUSIONS: This case emphasizes the need for anticoagulant therapy in COVID-19 patients and to maintain a constant awareness of the possible thromboembolic COVID-19-related sequelae.

Intestinal Abnormalities in Patients With SARS-CoV-2 Infection: Histopathologic Changes Reflect Mechanisms of Disease.

Approximately 20% of patients with symptomatic syndrome-associated coronavirus-2 (SARS-CoV-2) infection have gastrointestinal bleeding and/or diarrhea. Most are managed without endoscopic evaluation because the risk of practitioner infection outweighs the value of biopsy analysis unless symptoms are life-threatening. As a result, much of what is known about the gastrointestinal manifestations of coronavirus disease-2019 (COVID-19) has been gleaned from surgical and autopsy cases that suffer from extensive ischemic injury and/or poor preservation. There are no detailed reports describing any other gastrointestinal effects of SARS-CoV-2 even though >3,000,000 people have died from COVID-19 worldwide. The purpose of this study is to report the intestinal findings related to SARS-CoV-2 infection by way of a small case series including one with evidence of direct viral cytopathic effect and 2 with secondary injury attributed to viral infection. Infection can be confirmed by immunohistochemical stains directed against SARS-CoV-2 spike protein, in situ hybridization for spike protein-encoding RNA, and ultrastructural visualization of viruses within the epithelium. It induces cytoplasmic blebs and tufted epithelial cells without inflammation and may not cause symptoms. In contrast, SARS-CoV-2 infection can cause gastrointestinal symptoms after the virus is no longer detected, reflecting systemic activation of cytokine and complement cascades rather than direct viral injury. Reversible mucosal ischemia features microvascular injury with hemorrhage, small vessel thrombosis, and platelet-rich thrombi. Systemic cytokine elaboration and dysbiosis likely explain epithelial cell injury that accompanies diarrheal symptoms. These observations are consistent with clinical and in vitro data and contribute to our understanding of the protean manifestations of COVID-19.

Histological findings in skeletal muscle of SARS-CoV2 infected patient.

Autopsies represent medical procedures through which the causes of patients' deaths are determined or, through tissue sampling and microscopic examination of slides in usual stains or special tests, one can offer the basis for understanding the physiopathological mechanisms that contribute to the patients' death Histological findings of tissue samples from patients who have died of COVID-19 have been mainly orientated to lung, heart, liver, kidney damage with a small percent of them following other organs, but none has, to our knowledge, studied skeletal muscle.

Axillary artery thrombosis resulting in upper limb amputation as a COVID-19 sequela.

Novel COVID-19 continues to intrigue medical professionals with its varied presentations. Though it affects the respiratory tract primarily, thrombogenesis has been the Achilles' heel. A 44-year-old man diagnosed with COVID-19 presented with upper limb pain at a local hospital and was found to have thrombosis of the right axillary artery. Despite a successful embolectomy at the local hospital, there was re-occlusion of the axillary artery and the limb became ischaemic. He was referred to our institution by which time the limb became gangrenous above the elbow and had to be amputated. Extensive sloughing of the nerves was also seen in the local area. Hypercoagulability presenting with various manifestations is common in COVID-19 and needs early anticoagulation. We present this asymptomatic patient who lost a limb to this COVID-19 sequelae.

[Cutaneous Manifestations Associated with COVID-19: A Narrative Review]. / Manifestações Cutâneas Associadas à COVID-19: Uma Revisão Narrativa.

INTRODUCTION: COVID-19 is an infectious disease caused by the new coronavirus, SARS-CoV-2, that has spread rapidly throughout the world. This has resulted in an urgent need to obtain information regarding its pathogenesis, diagnosis and clinical manifestations. More specifically, skin manifestations, seldom reported initially, have been increasingly described. MATERIAL AND METHODS: We performed a literature search in the PubMed database, regarding cutaneous manifestations associated with COVID-19. This article describes the clinical and histological findings of the main skin lesions observed in the context of SARS-CoV-2 infection. DISCUSSION: Cutaneous manifestations associated with COVID-19 have been described in multiple retrospective and prospective studies, case series and case reports. The reported incidence reached 20.4%. Although there was substantial heterogeneity in terms of clinical patterns, the main ones include: erythematous/maculopapular, urticarial, papulovesicular, and purpuric/petechial eruptions, chilblain-like lesions and livedoid/acro-ischemic lesions. In the vast majority, the underlying pathophysiologic mechanisms are not fully understood, although histopathological findings and biomolecular studies can add relevant data. CONCLUSION: The recognition of cutaneous manifestations associated with COVID-19 is of utmost importance. They may help establishing an early diagnosis, namely in oligosymptomatic patients or when confirmatory tests are impossible to perform. Moreover, chilblain-like lesions and acro-ischemia, also seem to play an important role in terms of prognosis.

Introdução: A COVID-19, doença infeciosa causada por um novo coronavírus, SARS-CoV-2, propagou-se rapidamente pelo mundo inteiro, resultando numa necessidade emergente de obtenção de conhecimentos alusivos à sua patogénese, diagnóstico e sintomatologia. Mais especificamente, um número cada vez maior de casos relativos a manifestações cutâneas, previamente desconhecidas, tem vindo a ser descrito.Material e Métodos: Foi realizada uma pesquisa de literatura, através da base de dados PubMed, referente às manifestações dermatológicas associadas à COVID-19. O presente artigo descreve os achados clínicos e histológicos das principais lesões cutâneas observadas em contexto da infeção por SARS-CoV-2.Discussão: Manifestações cutâneas associadas à COVID-19 foram descritas em múltiplos estudos retrospetivos e prospetivos, séries de casos e casos clínicos isolados. A incidência reportada atingiu os 20,4%, verificando-se uma heterogeneidade de padrões clínicos substancial. Destes destacam-se as erupções eritematosas/maculopapulares, urticariformes, papulovesiculares, purpúricas/petequiais, lesões tipo-perniose e lesões livedóides/acro-isquémicas. O conhecimento dos mecanismos fisiopatológicos subjacentes tem vindo a ser enriquecido com achados os histológicos e de biologia molecular.Conclusão: É essencial o reconhecimento das manifestações dermatológicas associadas à COVID-19, uma vez que podem permitir o diagnóstico precoce da infeção, nomeadamente em casos oligossintomáticos ou quando não é possível a realização de testes confirmatórios. Embora menos estabelecido, lesões tipo-perniose e acro-isquémicas, parecem ter também um papel importante a nível prognóstico.

Caspase1/11 signaling affects muscle regeneration and recovery following ischemia, and can be modulated by chloroquine.

BACKGROUND: We previously showed that the autophagy inhibitor chloroquine (CQ) increases inflammatory cleaved caspase-1 activity in myocytes, and that caspase-1/11 is protective in sterile liver injury. However, the role of caspase-1/11 in the recovery of muscle from ischemia caused by peripheral arterial disease is unknown. We hypothesized that caspase-1/11 mediates recovery in muscle via effects on autophagy and this is modulated by CQ. METHODS: C57Bl/6 J (WT) and caspase-1/11 double-knockout (KO) mice underwent femoral artery ligation (a model of hind-limb ischemia) with or without CQ (50 mg/kg IP every 2nd day). CQ effects on autophagosome formation, microtubule associated protein 1A/1B-light chain 3 (LC3), and caspase-1 expression was measured using electron microscopy and immunofluorescence. Laser Doppler perfusion imaging documented perfusion every 7 days. After 21 days, in situ physiologic testing in tibialis anterior muscle assessed peak force contraction, and myocyte size and fibrosis was also measured. Muscle satellite cell (MuSC) oxygen consumption rate (OCR) and extracellular acidification rate was measured. Caspase-1 and glycolytic enzyme expression was detected by Western blot. RESULTS: CQ increased autophagosomes, LC3 consolidation, total caspase-1 expression and cleaved caspase-1 in muscle. Perfusion, fibrosis, myofiber regeneration, muscle contraction, MuSC fusion, OCR, ECAR and glycolytic enzyme expression was variably affected by CQ depending on presence of caspase-1/11. CQ decreased perfusion recovery, fibrosis and myofiber size in WT but not caspase-1/11KO mice. CQ diminished peak force in whole muscle, and myocyte fusion in MuSC and these effects were exacerbated in caspase-1/11KO mice. CQ reductions in maximal respiration and ATP production were reduced in caspase-1/11KO mice. Caspase-1/11KO MuSC had significant increases in protein kinase isoforms and aldolase with decreased ECAR. CONCLUSION: Caspase-1/11 signaling affects the response to ischemia in muscle and effects are variably modulated by CQ. This may be critically important for disease treated with CQ and its derivatives, including novel viral diseases (e.g. COVID-19) that are expected to affect patients with comorbidities like cardiovascular disease.

Why is SARS-CoV-2 infection more severe in obese men? The gut lymphatics - Lung axis hypothesis.

Consistent observations report increased severity of SARS-CoV-2 infection in overweight men with cardiovascular factors. As the visceral fat possesses an intense immune activity, is involved in metabolic syndrome and is at the crossroad between the intestines, the systemic circulation and the lung, we hypothesized that it plays a major role in severe forms of SARS-CoV-2 infection. SARS-CoV2 presents the ability to infect epithelial cells of the respiratory tract as well as the intestinal tract. Several factors may increase intestinal permeability including direct enterocyte damage by SARS-CoV2, systemic inflammatory response syndrome (SIRS) and epithelial ischemia secondary to SARS-CoV2- associated endothelial dysfunction. This increase permeability further leads to translocation of microbial components such as MAMPs (microbial-associated molecular pattern), triggering an inflammatory immune response by TLR-expressing cells of the mesentery fat (mostly macrophages and adipocytes). The pro-inflammatory cytokines produced by the mesentery fat mediates systemic inflammation and aggravate acute respiratory distress syndrome (ARDS) through the mesenteric lymph drainage.