A blunted GPR183/oxysterol axis during dysglycemia results in delayed recruitment of macrophages to the lung during M. tuberculosis infection

We previously reported that the oxidised cholesterol-sensing receptor GPR183 is significantly downregulated in blood from tuberculosis (TB) patients with diabetes compared to TB patients without co-morbidities and that lower GPR183 expression in blood is associated with more severe pulmonary TB on chest-x-ray consistent with observations in dysglycemic mice. To further elucidate the role of this receptor and its endogenous high affinity agonist 7α,25-dihydroxycholesterol (7α,25-OHC) in the lung, we studied high fat diet (HFD)-induced 28 dysglycemic mice infected with M.tuberculosis. We found that the 7α,25-OHC-producing enzymes cholesterol 25-hydroxylase (CH25H) and cytochrome P450 family 7 subfamily member B1 (CYP7B1) were highly upregulated upon M.tuberculosis infection in the lungs of normoglycemic mice, and this was associated with increased expression of GPR183 indicative of effective recruitment of GPR183-expressing immune cells to the site of infection. We demonstrated that CYP7B1 was predominantly expressed by macrophages in the centre of TB granulomas. Expression of CYP7B1 was significantly blunted in lungs from HFD-fed dysglycemic animals and this coincided with 36 delayed recruitment of macrophages to the lung during early infection and more severe lung pathology. GPR183 deficient mice similarly had reduced macrophage recruitment during early infection demonstrating a requirement of the GPR183/oxysterol axis for macrophage infiltration into the lung in TB. Together our data demonstrate that oxidised cholesterols and GPR183 play an important role in positioning macrophages to the site of M. tuberculosis infection and that this is impaired by HFD-induced dysglycemia, adding a mechanistic explanation to the poorer TB outcomes in patients with diabetes.

Passage of SARS-CoV-2 in cells expressing human and mouse ACE2 selects for mouse-adapted and ACE2-independent viruses

Human ACE2 (hACE2) is required for cell attachment and entry of SARS-CoV-2. Mouse ACE2 (mACE2) does not support infection of early SARS-CoV-2 isolates. Herein we describe a new system for generating mouse-adapted SARS-CoV-2 in vitro by serial passaging virus in co-cultures of cell lines expressing hACE2 and mACE2. Mouse-adapted viruses emerged with a series of spike protein amino acid changes, all of which have been reported in human isolates. Mouse-adapted viruses replicated to high titers in C57BL/6J mouse lungs and nasal turbinates, and caused severe lung histopathology. Remarkably, one mouse-adapted virus was able to replicate efficiently in ACE2-negative cell lines, a characteristic not described for any SARS-CoV-2 variants. ACE2-independent entry by SARS-CoV-2 represents a new biology for SARS-CoV-2 with potential widespread implications for disease and intervention development.

REACTIVATION OF HEPATITIS B IN PATIENTS RECOVERING FROM COVID-19

Пандемия новой короновирусной инфекции, вызванной вирусом SARS-CoV-2, явилась вызовом системе здравоохранения во всем мире. На данный момент мы обладаем большей информацией об этом заболевании, проявляющемся в основном симптомами респираторной инфекции, от легких проявлении ОРВИ до тяжелого поражения легких. Также коронавирусная инфекция проявляется симптомами поражения ЖКТ чаще всего в виде рвоты, диареи и боли в животе. Кроме того, за год наблюдении, начиная с самого начала пандемии в Китае, описаны нарушения функции печени различного генеза у пациентов с коронавирусной инфекцией. Среди возможных причин называются прямое цитопатическое действие вируса, способного связываться с AПФ2β рецепторам гепато-билиарной системы, иммуноопосредованное повреждение гепатоцитов, в том числе при «цитокиновом шторме» и гепатотоксичности препаратов, применяемых при коронавирусной инфекции. Кроме этих механизмов повреждения печени есть еще реактивация хронических персистирующих инфекции. В частности, речь идет о реактивации хронического гепатита В. Статей, описывающих такие случаи, значительно меньше, чем тех, которые практически детально описывают различные изменения ферментов печени у пациентов, наблюдавшихся с коронавирусной инфекцией. Кроме бремени инфекции в манифестный период, есть не менее тяжелые последствия у реконвалесцентов или у тех, кто перенес заболевание в легкой форме, о чем мы и должны помнить, чтобы принимать необходимые меры в ближайшем и отдаленном периоде выздоровления после COVID-19. В данной статье мы приводим собственные наблюдения реактивации хронического гепатита В у 4 пациентов, перенесших COVID-19 в манифестной форме. The pandemic of the new coronavirus infection caused by the SARS-CoV-2 virus is a challenge to the health system around the world. At the moment, we have more information about this disease, which is manifested mainly by symptoms of a respiratory infection, from mild manifestations of ARVI to severe lung damage. Also, coronavirus infection often manifests itself as symptoms of a gastrointestinal disease, in the form of vomiting, diarrhea and abdominal pain. In addition, over a year of observation, starting from the very beginning of the pandemic in China, liver dysfunctions of various origins have been described in patients with coronavirus infection. Possible reasons include the direct cytopathic effect of the virus capable of binding to ACE2β receptors of the hepato-biliary system, immune-mediated damage to hepatocytes, including during a "cytokine storm" and hepatotoxicity of drugs used in coronavirus infection. In addition to these mechanisms of liver damage, there is also a reactivation of chronic persistent infections. In particular, we are talking about the reactivation of chronic hepatitis B. In addition to the burden of infection in the manifest period, there are no less severe consequences for convalescents or those who have suffered a mild illness, which we must remember in order to take the necessary measures in the near and distant period of recovery after COVID -19. In this article, we present our own observations of the reactivation of chronic hepatitis in 4 patients who underwent manifest COVID-19.

The Release of Indium Ion Derived from Epithelial Cells and Macrophages Solubilization Contribute to Pneumotoxicity Induced by Indium Oxide Nanoparticles

Occupational exposure to indium oxide and indium containing particles has been associated with the development of severe lung diseases called “indium lung.” According to the survey of occupational hygiene, indium oxide nanoparticles have been identified in the workplaces and the lungs of workers. To date, the potential mechanism of the pneumotoxicity has been poorly understood and no effective therapies are available against “indium lung.” Our present study reported that the exposure of indium oxide nanoparticles damaged lung epithelial cells and alveolar macrophages and induced pulmonary alveolar proteinosis and inflammation in rats. In the 8-week post-exposure period, the indium oxide nanoparticles still mostly accumulated in the lungs and then persistently release indium ions in two months after exposure. In vitro, the epithelial cells show the greater potential for release of indium ions from indium oxide nanoparticles compared with the macrophages. EDTA-2Na, a metal chelating agent expected to remove the indium ions, was found to significantly reduced the cytotoxicity of indium oxide nanoparticles. Herein, the pneumotoxicity may be attributed to the slow and incremental release of indium ions from indium oxide nanoparticles primary dissolved by epithelial cells and macrophages, at least partially. The study may provide some insights to the pathogenicity mechanisms of “indium lung” and some clues against the health hazards of occupational inhaled indium oxide nanoparticles at the workplaces.

Major Neutrophil-Derived Soluble Mediators Associate With Baseline Lung Pathology and Post-Treatment Recovery in Tuberculosis Patients

BackgroundThe inflammatory response to Mycobacterium tuberculosis results in variable degrees of lung pathology during active TB (ATB) with central involvement of neutrophils. Little is known about neutrophil-derived mediators and their role in disease severity at baseline and recovery upon TB treatment initiation.Methods107 adults with confirmed pulmonary TB were categorised based on lung pathology at baseline and following successful therapy using chest X-ray scores (Ralph scores) and GeneXpert bacterial load (Ct values). Plasma, sputum, and antigen-stimulated levels of MMP1, MMP3, MMP8, MMP9, MPO, S100A8/9, IL8, IL10, IL12/23(p40), GM-CSF, IFNγ, and TNF were analysed using multiplex cytokine arrays.ResultsAt baseline, neutrophil counts correlated with plasma levels of MMP8 (rho = 0.45, p = 2.80E−06), S100A8 (rho = 0.52, p = 3.00E−08) and GM-CSF (rho = 0.43, p = 7.90E−06). Levels of MMP8 (p = 3.00E−03), MMP1 (p = 1.40E−02), S100A8 (p = 1.80E−02) and IL12/23(p40) (p = 1.00E−02) were associated with severe lung damage, while sputum MPO levels were directly linked to lung damage (p = 1.80E−03), Mtb load (p = 2.10E−02) and lung recovery (p = 2.40E−02). Six months of TB therapy significantly decreased levels of major neutrophil-derived pro-inflammatory mediators: MMP1 (p = 4.90E−12 and p = 2.20E−07), MMP8 (p = 3.40E−14 and p = 1.30E−05) and MMP9 (p = 1.60E−04 and p = 1.50E−03) in plasma and sputum, respectively. Interestingly, following H37Rv whole cell lysate stimulation, S100A8 (p = 2.80E−02), MMP9 (p = 3.60E−02) and MPO (p = 9.10E−03) levels at month 6 were significantly higher compared to baseline. Sputum MMP1 (p = 1.50E−03), MMP3 (p = 7.58E−04), MMP9 (p = 2.60E−02) and TNF (p = 3.80E−02) levels were lower at month 6 compared to baseline in patients with good lung recovery.ConclusionIn this study, patients with severe lung pathology at baseline and persistent lung damage after treatment were associated with higher plasma and sputum levels of major pro-inflammatory neutrophil-derived mediators. Interestingly, low sputum MPO levels were associated with severe lung damage, higher Mtb burden and low recovery. Our data suggest that therapeutic agents which target these mediators should be considered for future studies on biomarkers and host-directed therapeutic approaches against TB-related lung pathology and/or lung recovery.

Aging Immune System and Its Correlation With Liability to Severe Lung Complications

Aging is considered to be a decline in physical and physiological events that extensively affect the body's immunity, and is linked with deterioration in both innate and adaptive immune responses. The immune system exhibits profound age-associated variations, known as immunosenescence, comprising a significantly low production of B and T lymphocytes in bone marrow and thymus, a decreased function of mature lymphocytes in secondary lymphoid tissues, a decrease in the synthesis of fresh naïve T cells, and reduced activation of T cells. Elderly individuals face a greater risk for many diseases particularly respiratory diseases due to their poor response to immune challenges as vigorously as the young. The current review explored the aging immune system, highlight the mortality rates of severe lung complications, such as pneumonia, COVID-19, asthma, COPD, lung cancer, IPF, and acute lung injury, and their correlation with aging immunity. This study can be helpful in better understanding the pathophysiology of aging, immune responses, and developing new approaches to improve the average age of the elderly population.

Indications of Persistent Glycocalyx Damage in Convalescent COVID-19 Patients: A Prospective Multicenter Study and Hypothesis

The COVID-19 pandemic is caused by the SARS CoV-2 virus and can lead to severe lung damage and hyperinflammation. In the context of COVID-19 infection, inflammation-induced degradation of the glycocalyx layer in endothelial cells has been demonstrated. Syndecan-1 (SDC-1) is an established parameter for measuring glycocalyx injury. This prospective, multicenter, observational, cross-sectional study analyzed SDC-1 levels in 24 convalescent patients that had been infected with SARS-CoV-2 with mild disease course without need of hospitalization. We included 13 age-matched healthy individuals and 10 age-matched hospitalized COVID-19 patients with acute mild disease course as controls. In convalescent COVID-19 patients, significantly elevated SDC-1 levels were detected after a median of 88 days after symptom onset compared to healthy controls, whereas no difference was found when compared to SDC-1 levels of hospitalized patients undergoing acute disease. This study is the first to demonstrate signs of endothelial damage in non-pre-diseased, convalescent COVID-19 patients after mild disease progression without hospitalization. The data are consistent with studies showing evidence of persistent endothelial damage after severe or critical disease progression. Further work to investigate endothelial damage in convalescent COVID-19 patients should follow.

ECMO For Pediatric Cardiac Arrest Caused by Bronchial Rupture and Severe Lung Injury: a Case Report About a Life-threatening Rescue at an Adult ECMO Center

BackgroundBronchial rupture in children is a rare but dangerous complication after chest trauma that has been associated with increased mortality. Veno-venous (V-V) extracorporeal membrane oxygenation (ECMO) is reported as one of the treatments for this life-threatening complication.Case presentationA 4-year-old boy who suffered from bronchial rupture and traumatic wet lung complicated by cardiac arrest after chest trauma was admitted to an adult ECMO center. He had two cardiac arrests-one before and one during the operation. The total duration of cardiac arrest was 30 minutes. V-V ECMO was initiated because of severe hypoxia and carbon dioxide retention during the operation. ECMO was performed for 6 days, and mechanical ventilation lasted 11 days. On the 31st day after the operation, he recovered completely and discharged without neurological deficit.ConclusionV-V ECMO can be considered for support in children with severe acute respiratory failure after bronchial rupture. In an emergency, V-V ECMO can be carried out effectively in a qualified and experienced adult ECMO center. But the application of ECMO in children is different from that in adults and requires more refined management.

DEMOKRASI DI ERA PANDEMI

Democracy is a system of government in which the laws, policies, leadership, and great efforts of a country or other government are directly or indirectly decided by the people. Coronavirus or severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a virus that attacks the respiratory system. The disease due to this viral infection is called Covid-19. Corona virus can cause mild disruption of the respiratory system, severe lung infections, to death. Democracy was limited during the pandemic, fueling the assumption that many governments were trying to concentrate power. Covid-19 makes new habits and raises awareness in many ways. But it is the characteristics of government and the ability to govern that have more impact on maintaining a widespread democratic and political existence than the existence of the pandemic itself.

The need for continuous quality assessment for providing optimal comprehensive care for patients with alpha-1 antitrypsin deficiency

Background: Alpha-1-antitrypsin deficiency (AATD) is an orphan disease that mainly affecting the liver and the lung. This creates difficulties to ensure that comprehensive care is administered to both organ systems. Past assessments of care delivered to patients with AATD demonstrated that improvements are needed. For that reason, we reassessed a population of patients with AATD in a large health care system to see if past findings affected present care. Methods: We performed electronic health record (EHR) reviews on all patients with documented AATD and confirmed the diagnosis by evidence of genotyping. We then selected the patients with the ZZ genotype to review comprehensive care. We further compared the findings in patients treated by different specialists (allergy immunology, gastroenterology, and pulmonary). The data were captured and assessed by using a secure web application for building and managing online surveys and data bases. REDCap. Results: We found a total of 329 patients with diagnostic codes for AATD, of these, 203 patients had a confirmed abnormal genotype. Confirmed genotypes were MZ (n = 69), ZZ (n = 48), MS (n = 22), SZ (n = 22). Further focus was applied to the care of the ZZ population secondary to a predisposition to potential severe lung and liver disease. The findings suggest that care can be improved no matter which specialist cares for the patient. Conclusion: Our study demonstrated that all three subspecialty groups had room for improvement in providing care to patients with AATD. Our study further demonstrated the need for recurrent quality-assurance programs that may be aided by care suggestions built into the EHR.