Autopsy examination of lungs from seven patients who died from Covid-19 showed intussusceptive angiogenesis in greater profusion than was found in lungs from patients who died from influenza or in ...uninfected lungs that were rejected for transplantation.
Anosmia, the loss of smell, is a common and often the sole symptom of COVID-19. The onset of the sequence of pathobiological events leading to olfactory dysfunction remains obscure. Here, we have ...developed a postmortem bedside surgical procedure to harvest endoscopically samples of respiratory and olfactory mucosae and whole olfactory bulbs. Our cohort of 85 cases included COVID-19 patients who died a few days after infection with SARS-CoV-2, enabling us to catch the virus while it was still replicating. We found that sustentacular cells are the major target cell type in the olfactory mucosa. We failed to find evidence for infection of olfactory sensory neurons, and the parenchyma of the olfactory bulb is spared as well. Thus, SARS-CoV-2 does not appear to be a neurotropic virus. We postulate that transient insufficient support from sustentacular cells triggers transient olfactory dysfunction in COVID-19. Olfactory sensory neurons would become affected without getting infected.
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•A postmortem bedside surgical procedure was developed for COVID-19 and control patients•Ciliated cells are the main target cell type for SARS-CoV-2 in the respiratory mucosa•Sustentacular cells (non-neuronal) are the main target cell type in the olfactory mucosa•No evidence for infection of olfactory sensory neurons or olfactory bulb parenchyma
Postmortem samples of respiratory and olfactory mucosa and whole olfactory bulbs are harvested immediately after the death of COVID-19 patients revealing ciliated cells and sustentacular cells but not olfactory sensory neurons as the main target cell types for SARS-CoV-2 infection and replication.
Long-term survival after lung transplantation (LTx) is hampered by development of chronic lung allograft dysfunction (CLAD).
is an established risk factor for CLAD. Therefore, we investigated the ...effect of
eradication on CLAD-free and graft survival.Patients who underwent first LTx between July, 1991, and February, 2016, and were free from CLAD, were retrospectively classified according to
presence in respiratory samples between September, 2011, and September, 2016.
-positive patients were subsequently stratified according to success of
eradication following targeted antibiotic treatment. CLAD-free and graft survival were compared between
-positive and
-negative patients; and between patients with or without successful
eradication. In addition, pulmonary function was assessed during the first year following
isolation in both groups.CLAD-free survival of
-negative patients (n=443) was longer compared with
-positive patients (n=95) (p=0.045). Graft survival of
-negative patients (n=443, 82%) was better compared with
-positive patients (n=95, 18%) (p<0.0001). Similarly,
-eradicated patients demonstrated longer CLAD-free and graft survival compared with patients with persistent
Pulmonary function was higher in successfully
-eradicated patients compared with unsuccessfully eradicated patients (p=0.035).
eradication after LTx improves CLAD-free and graft survival and maintains pulmonary function. Therefore, early
detection and eradication should be pursued.
Exercise-induced bronchoconstriction (EIB) is a transient airway narrowing, occurring during or shortly after intensive exercise. It is highly prevalent in non-asthmatic outdoor endurance athletes ...suggesting an important contribution of air pollution in the development of EIB. Therefore, more research is necessary to investigate the combination of exercise and pollutants on the airways.
Balbc/ByJ mice were intranasally challenged 5 days a week for 3 weeks with saline or 0.2 mg/ml diesel exhaust particles (DEP), prior to a daily incremental running session or non-exercise session. Once a week, the early ventilatory response was measured and lung function was determined at day 24. Airway inflammation and cytokine levels were evaluated in bronchoalveolar lavage fluid. Furthermore, innate lymphoid cells, dendritic cells and tight junction mRNA expression were determined in lung tissue.
Submaximal exercise resulted in acute alterations of the breathing pattern and significantly improved FEV
at day 24. DEP exposure induced neutrophilic airway inflammation, accompanied with increased percentages of CD11b
DC in lung tissue and pro-inflammatory cytokines, such as IL-13, MCP-1, GM-CSF and KC. Occludin and claudin-1(Cldn-1) expression were respectively increased and decreased by DEP exposure. Whereas, exercise increased Cldn-3 and Cldn-18 expression. Combining exercise and DEP exposure resulted in significantly increased SP-D levels in the airways.
DEP exposure induced typical airway neutrophilia, DC recruitment and pro-inflammatory cytokine production. Whereas, intensive exercise induced changes of the breathing pattern. The combination of both triggers resulted in a dysregulation of tight junction expression, suggesting that intensive exercise in polluted environments can induce important changes in the airway physiology and integrity.
Background
Connective tissue growth factor (CTGF) is an important mediator in several fibrotic diseases, including lung fibrosis. We investigated CTGF-expression in chronic lung allograft dysfunction ...(CLAD) and pulmonary graft-versus-host disease (GVHD).
Materials and Methods
CTGF expression was assessed by quantitative real-time polymerase chain reaction (qPCR) and immunohistochemistry in end-stage CLAD explant lung tissue (bronchiolitis obliterans syndrome (BOS), n=20; restrictive allograft syndrome (RAS), n=20), pulmonary GHVD (n=9). Unused donor lungs served as control group (n=20). Next, 60 matched lung transplant recipients (BOS, n=20; RAS, n=20; stable lung transplant recipients, n=20) were included for analysis of CTGF protein levels in plasma and broncho-alveolar lavage (BAL) fluid at 3 months post-transplant, 1 year post-transplant, at CLAD diagnosis or 2 years post-transplant in stable patients.
Results
qPCR revealed an overall significant difference in the relative content of CTGF mRNA in BOS, RAS and pulmonary GVHD vs. controls (p=0.014). Immunohistochemistry showed a significant higher percentage and intensity of CTGF-positive respiratory epithelial cells in BOS, RAS and pulmonary GVHD patients vs. controls (p<0.0001). BAL CTGF protein levels were significantly higher at 3 months post-transplant in future RAS vs. stable or BOS (p=0.028). At CLAD diagnosis, BAL protein content was significantly increased in RAS patients vs. stable (p=0.0007) and BOS patients (p=0.042). CTGF plasma values were similar in BOS, RAS, and stable patients (p=0.74).
Conclusions
Lung CTGF-expression is increased in end-stage CLAD and pulmonary GVHD; and higher CTGF-levels are present in BAL of RAS patients at CLAD diagnosis. Our results suggest a potential role for CTGF in CLAD, especially RAS, and pulmonary GVHD.
Systemic juvenile idiopathic arthritis (sJIA) is an immune disorder characterized by fever, skin rash, arthritis and splenomegaly. Recently, increasing number of sJIA patients were reported having ...lung disease. Here, we explored lung abnormalities in a mouse model for sJIA relying on injection of IFN-γ deficient (IFN-γ KO) mice with complete Freund's adjuvant (CFA). Monitoring of lung changes during development of sJIA using microcomputer tomography revealed a moderate enlargement of lungs, a decrease in aerated and increase in non-aerated lung density. When lung function and airway reactivity to methacholine was assessed, gender differences were seen. While male mice showed an increased tissue hysteresivity, female animals were characterized by an increased airway hyperactivity, mirroring ongoing inflammation. Histologically, lungs of sJIA-like mice showed subpleural and parenchymal cellular infiltrates and formation of small granulomas. Flow cytometric analysis identified immature and mature neutrophils, and activated macrophages as major cell infiltrates. Lung inflammation in sJIA-like mice was accompanied by augmented expression of IL-1β and IL-6, two target cytokines in the treatment of sJIA. The increased expression of granulocyte colony stimulating factor, a potent inducer of granulopoiesis, in lungs of mice was striking considering the observed neutrophilia in patients. We conclude that development of sJIA in a mouse model is associated with lung inflammation which is distinct to the lung manifestations seen in sJIA patients. Our observations however underscore the importance of monitoring lung disease during systemic inflammation and the model provides a tool to explore the underlying mechanism of lung pathology in an autoinflammatory disease context.
Chronic rejection is a major complication post-transplantation. Within lung transplantation, chronic rejection was considered as airway centred. Chronic Lung Allograft Dysfunction (CLAD), defined to ...cover all late chronic complications, makes it more difficult to understand chronic rejection from an immunological perspective. This study investigated the true nature, timing and location of chronic rejection as a whole, within mouse lung transplantation.
40 mice underwent an orthotopic left lung transplantation, were sacrificed at day 70 and evaluated by histology and in vivo µCT. For timing and location of rejection, extra grafts were sacrificed at day 7, 35, 56 and investigated by ex vivo µCT or single cell RNA (scRNA) profiling.
Chronic rejection originated as innate inflammation around small arteries evolving toward adaptive organization with subsequent end-arterial fibrosis and obliterans. Subsequently, venous and pleural infiltration appeared, followed by airway related bronchiolar folding and rarely bronchiolitis obliterans was observed. Ex vivo µCT and scRNA profiling validated the time, location and sequence of events with endothelial destruction and activation as primary onset.
Against the current belief, chronic rejection in lung transplantation may start as an arterial response, followed by responses in venules, pleura, and, only in the late stage, bronchioles, as may be seen in some but not all patients with CLAD.
Pulmonary alveolar proteinosis (PAP) is a rare, diffuse lung disorder characterized by surfactant accumulation in the small airways due to defective clearance by alveolar macrophages, resulting in ...impaired gas exchange. Whole lung lavage is the current standard of care treatment for PAP. Lung transplantation is an accepted treatment option when whole lung lavage or other experimental treatment options are ineffective, or in case of extensive pulmonary fibrosis secondary to PAP. A disadvantage of lung transplantation is recurrence of PAP in the transplanted lungs, especially in hereditary PAP. The hereditary form of PAP is an ultra-rare condition caused by genetic mutations in genes encoding for the granulocyte macrophage-colony stimulating factor (GM-CSF) receptor, and intrinsically affects bone marrow derived-monocytes, which differentiate into macrophages in the lung. Consequently, these macrophages typically display disrupted GM-CSF receptor-signaling, causing defective surfactant clearance. Bone marrow/hematopoietic stem cell transplantation may potentially reverse the lung disease in hereditary PAP. In patients with hereditary PAP undergoing lung transplantation, post-lung transplant recurrence of PAP may theoretically be averted by subsequent hematopoietic stem cell transplantation, which results in a graft-versus-
disease (PAP)
effect, and thus could improve long-term outcome. We describe the successful long-term post-transplant outcome of a unique case of end-stage respiratory failure due to hereditary PAP-induced pulmonary fibrosis, successfully treated by bilateral lung transplantation and subsequent allogeneic hematopoietic stem cell transplantation. Our report supports treatment with serial lung and hematopoietic stem cell transplantation to improve quality of life and prolong survival, without PAP recurrence, in selected patients with end-stage hereditary PAP.
Background
VEXAS ‘Vacuoles, E1 Enzyme, X‐linked, Autoinflammatory, Somatic syndrome’ is a rare autoinflammatory syndrome, first described in October 2020 by Beck et al. It is caused by somatic ...mutations in the UBA1 gene, coding for the E1 enzyme, responsible for ubiquitination. It manifests in adulthood, mainly in men, with constitutional symptoms, haematological abnormalities and often skin lesions with neutrophilic dermatoses most frequently reported. Since skin lesions are a frequent and early manifestation, recognising these may prove very useful for diagnosis.
Objectives
To focus on the dermatological manifestations of VEXAS and their histopathological correlate.
Methods
We retrospectively collected data and revised skin biopsies of VEXAS patients diagnosed in our tertiary care centre, and compared those with the literature.
Results
We identified nine men between 62 and 84 years old. The most frequently encountered UBA1 mutation was p.Met41Thr. Skin manifestations occurred in all patients; mostly as erythematous to purpuric papules/plaques, often with annular pattern. Histopathological, early VEXAS lesions showed a gradient in infiltrate with neutrophils being concentrated in the superficial interstitium and lymphocytes situated deeper around the blood vessels. Later in the disease course, the pattern became more variable and less specific with more nuclear debris, histiocytes, neutrophils and ulceration. Haematological and constitutional manifestations were present in all patients, followed by musculoskeletal (88.8%), eye (77.7%) and cardiovascular manifestations (66.6%). Polychondritis was present in 6/9 (66.6%) patients, as were respiratory symptoms, though only 33.3% had proven lung disease. The mortality rate was 22% 10 months after diagnosis.
Conclusions
This is the first cohort which describes in detail VEXAS skin manifestations with revision of all available skin biopsies, which led to the conclusion that early histopathological abnormalities in VEXAS syndrome may be easy to recognise, while the histopathological image becomes less specific over time and mimics other diseases as VEXAS progresses.
Myeloid-derived suppressor cells (MDSC) are a heterogeneous group of immune cells from the myeloid lineage. MDSCs expand in pathological situations, such as chronic infection, cancer, autoimmunity, ...and allograft rejection. As chronic lung allograft dysfunction (CLAD) limits long-term survival after lung transplantation (LTx), MDSCs may play a role in its pathophysiology. We assessed phenotype and frequency of MDSCs in peripheral blood from lung transplant recipients and its relationship to post-transplant complications and immunosuppression. Granulocytic (G)-MDSC were identified and quantified by flow cytometry of blood from 4 control subjects and 20 lung transplant patients (stable
= 6, infection
= 5; CLAD
= 9). G-MDSC functionality was assessed
by their capability to block CD4 and CD8 T cell proliferation. More G-MDSC could be assessed using EDTA tubes compared to heparin tubes (
= 0.004). G-MDSC were increased in stable lung transplant recipients vs. non-transplant controls (52.1% vs. 9.4%;
= 0.0095). The infection or CLAD groups had lower G-MDSCs vs. stable recipients (28.2%
= 0.041 and 33.0%;
= 0.088, respectively), but were not different among CLAD phenotypes. G-MDSC tended to correlate with cyclosporine A and tacrolimus levels (
= 0.18;
= 0.17). CD4 and CD8 cells proliferation decreased by 50 and 80% if co-cultured with MDSCs (1:6 and 1:2 MDSC:T-cell ratio, respectively). In conclusion, circulating MDSCs are measurable, functional and have a G-MDSC phenotype in lung transplant patients. Their frequency is increased in stable patients, decreased during post-transplant complications, and related to level of immunosuppression. This study may pave the way for further investigations of MDSC in the context of lung transplantation.
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