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Frontiers in Immunology 2024Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is responsible for the respiratory distress condition known as COVID-19. This disease broadly affects... (Review)
Review
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is responsible for the respiratory distress condition known as COVID-19. This disease broadly affects several physiological systems, including the gastrointestinal, renal, and central nervous (CNS) systems, significantly influencing the patient's overall quality of life. Additionally, numerous risk factors have been suggested, including gender, body weight, age, metabolic status, renal health, preexisting cardiomyopathies, and inflammatory conditions. Despite advances in understanding the genome and pathophysiological ramifications of COVID-19, its precise origins remain elusive. SARS-CoV-2 interacts with a receptor-binding domain within angiotensin-converting enzyme 2 (ACE2). This receptor is expressed in various organs of different species, including humans, with different abundance. Although COVID-19 has multiorgan manifestations, the main pathologies occur in the lung, including pulmonary fibrosis, respiratory failure, pulmonary embolism, and secondary bacterial pneumonia. In the post-COVID-19 period, different sequelae may occur, which may have various causes, including the direct action of the virus, alteration of the immune response, and metabolic alterations during infection, among others. Recognizing the serious adverse health effects associated with COVID-19, it becomes imperative to comprehensively elucidate and discuss the existing evidence surrounding this viral infection, including those related to the pathophysiological effects of the disease and the subsequent consequences. This review aims to contribute to a comprehensive understanding of the impact of COVID-19 and its long-term effects on human health.
Topics: Humans; COVID-19; SARS-CoV-2; Angiotensin-Converting Enzyme 2; Pandemics
PubMed: 38911850
DOI: 10.3389/fimmu.2024.1363572 -
Cureus May 2024Destructive thyroiditis and secondary adrenal insufficiency are major endocrinological immune-related adverse events of immune checkpoint inhibitors (ICIs). However, the...
Destructive thyroiditis and secondary adrenal insufficiency are major endocrinological immune-related adverse events of immune checkpoint inhibitors (ICIs). However, the timing at which each event occurs most frequently after drug administration varies, and cases where multiple events occur simultaneously are rare. We encountered a patient who concurrently suffered from thyrotoxicosis and adrenal insufficiency. An 80-year-old woman with a history of type 2 diabetes mellitus (DM) was diagnosed with stage IVA squamous cell carcinoma of the lungs. Treatment with a combination of nivolumab and ipilimumab was initiated. Although she tested positive for thyroglobulin antibody and transient subclinical hyperthyroidism was observed after two courses, treatment with ICIs was continued. Four months later, treatment was discontinued due to drug-induced lung disease. One month after the last administration, the patient became unconscious and was admitted to another hospital, diagnosed with diabetic ketoacidosis, urinary tract infection, and sepsis. After acute-phase treatment, she was transferred to our hospital due to persistent fever and tachycardia. Thyrotoxicosis and adrenal insufficiency were observed, with high levels of free thyroxine, low thyroid-stimulating hormone (TSH), and cortisol levels. Treatment with extracellular fluids, potassium iodide, beta-blockers, and hydrocortisone was initiated, and the patient's condition improved. No other pituitary hormone deficiencies were observed. She was diagnosed with painless thyroiditis and secondary adrenal insufficiency based on the positive thyroglobulin antibody, negative TSH receptor antibody, decreased Doppler flow in thyroid ultrasonography, low adrenocorticotrophic hormone (ACTH), and low response of ACTH and cortisol to corticotropin-releasing hormone loading test. MRI revealed no abnormalities. We report a case of thyrotoxicosis and secondary adrenal insufficiency five months after the first administration of nivolumab and ipilimumab. Careful follow-up and early detection of endocrine disorders are critical in patients treated with a combination of ICIs.
PubMed: 38910605
DOI: 10.7759/cureus.60850 -
BMC Infectious Diseases Jun 2024Respiratory infections have long been recognized as a primary cause of acute exacerbation of chronic obstructive pulmonary disease (AE-COPD). Additionally, the emergence...
BACKGROUND
Respiratory infections have long been recognized as a primary cause of acute exacerbation of chronic obstructive pulmonary disease (AE-COPD). Additionally, the emergence of antimicrobial resistance has led to an urgent and critical situation in developing countries, including Vietnam. This study aimed to investigate the distribution and antimicrobial resistance of bacteria in patients with AE-COPD using both conventional culture and multiplex real-time PCR. Additionally, associations between clinical characteristics and indicators of pneumonia in these patients were examined.
METHODS
This cross-sectional prospective study included 92 AE-COPD patients with pneumonia and 46 without pneumonia. Sputum specimens were cultured and examined for bacterial identification, and antimicrobial susceptibility was determined for each isolate. Multiplex real-time PCR was also performed to detect ten bacteria and seven viruses.
RESULTS
The detection rates of pathogens in AE-COPD patients with pneumonia were 92.39%, compared to 86.96% in those without pneumonia. A total of 26 pathogenic species were identified, showing no significant difference in distribution between the two groups. The predominant bacteria included Klebsiella pneumoniae, Haemophilus influenzae, Moraxella catarrhalis, and Streptococcus pneumoniae, followed by Acinetobacter baumannii and Streptococcus mitis. There was a slight difference in antibiotic resistance between bacteria isolated from two groups. The frequency of H. influenzae was notably greater in AE-COPD patients who experienced respiratory failure (21.92%) than in those who did not (9.23%). S. pneumoniae was more common in patients with stage I (44.44%) or IV (36.36%) COPD than in patients with stage II (17.39%) or III (9.72%) disease. ROC curve analysis revealed that C-reactive protein (CRP) levels could distinguish patients with AE-COPD with and without pneumonia (AUC = 0.78).
CONCLUSION
Gram-negative bacteria still play a key role in the etiology of AE-COPD patients, regardless of the presence of pneumonia. This study provides updated evidence for the epidemiology of AE-COPD pathogens and the appropriate selection of antimicrobial agents in Vietnam.
Topics: Humans; Pulmonary Disease, Chronic Obstructive; Cross-Sectional Studies; Vietnam; Prospective Studies; Male; Female; Aged; Middle Aged; Anti-Bacterial Agents; Drug Resistance, Bacterial; Bacteria; Pneumonia, Bacterial; Microbial Sensitivity Tests; Sputum; Aged, 80 and over; Pneumonia
PubMed: 38910264
DOI: 10.1186/s12879-024-09515-6 -
Journal of Nanobiotechnology Jun 2024Patients who suffer from sepsis typically experience acute lung injury (ALI). Extracellular vesicles (EVs) contain miRNAs, which are potentially involved in ALI....
Patients who suffer from sepsis typically experience acute lung injury (ALI). Extracellular vesicles (EVs) contain miRNAs, which are potentially involved in ALI. However, strategies to screen more effective EV-miRNAs as therapeutic targets are yet to be elucidated. In this study, functional EV-miRNAs were identified based on multiomics analysis of single-cell RNA sequencing of targeted organs and serum EV (sEV) miRNA profiles in patients with sepsis. The proportions of neutrophils and macrophages were increased significantly in the lungs of mice receiving sEVs from patients with sepsis compared with healthy controls. Macrophages released more EVs than neutrophils. MiR-125a-5p delivery by sEVs to lung macrophages inhibited Tnfaip3, while miR-221-3p delivery to lung neutrophils inhibited Fos. Macrophage membrane nanoparticles (MM NPs) loaded with an miR-125a-5p inhibitor or miR-221-3p mimic attenuated the response to lipopolysaccharide (LPS)-induced ALI. Transcriptome profiling revealed that EVs derived from LPS-stimulated bone marrow-derived macrophages (BMDMs) induced oxidative stress in neutrophils. Blocking toll-like receptor, CXCR2, or TNFα signaling in neutrophils attenuated the oxidative stress induced by LPS-stimulated BMDM-EVs. This study presents a novel method to screen functional EV-miRNAs and highlights the pivotal role of macrophage-derived EVs in ALI. MM NPs, as delivery systems of key sEV-miRNA mimics or inhibitors, alleviated cellular responses observed in sepsis-induced ALI. This strategy can be used to reduce septic organ damage, particularly lung damage, by targeting EVs.
Topics: Animals; Acute Lung Injury; Sepsis; Extracellular Vesicles; MicroRNAs; Mice; Nanoparticles; Macrophages; Mice, Inbred C57BL; Humans; Male; Lipopolysaccharides; Neutrophils; Oxidative Stress; Lung; Biomimetic Materials; Multiomics
PubMed: 38910259
DOI: 10.1186/s12951-024-02597-z -
Vaccine Jun 2024In New Zealand, approximately half reported pertussis cases are adult. Studies indicate underestimated pertussis burden in this population and probable reservoir for...
Pertussis epidemiology in adults: Retrospective analysis of pertussis incidence and association with comorbidities among adult populations in Aotearoa New Zealand, using national administrative datasets.
BACKGROUND
In New Zealand, approximately half reported pertussis cases are adult. Studies indicate underestimated pertussis burden in this population and probable reservoir for childhood pertussis. Pertussis is linked to chronic obstructive pulmonary disease (COPD) development and increased risk with pre-existing COPD. While acellular pertussis vaccines are available for adults, data on pertussis disease burden in adults and association with COPD remain limited.
AIM
To estimate pertussis incidence in New Zealand adult health service user (HSU) population aged ≥ 18 between 2008-2019 and inform adult pertussis vaccination strategies by assessing disease burden and risk factors in different adult populations.
METHODS
Retrospective observational cohort study using an HSU cohort, formed by linking administrative health data using unique National Health Index identifier. For primary analysis, annual incidence rates were calculated using pertussis hospitalisations and notifications. In secondary analysis, Cox proportional hazards survival analyses explored association between pertussis in adults and chronic comorbidities.
RESULTS
The cohort had 2,907,258 participants in 2008 and grew to 3,513,327 by 2019, with 11,139 pertussis cases reported. Highest annual incidence rate of 84.77 per 100,000 PYRS in 2012, notably affecting females, those aged 30-49 years, and European or Māori ethnicity. Adjusting for sociodemographic variables found no significant risk of prior pertussis notification leading to comorbidity diagnosis (Adjusted-HR: 0.972). However, individuals with prior comorbidity diagnosis had 16 % greater risk of receiving pertussis notification or diagnosis (Adjusted-HR: 1.162).
CONCLUSIONS
Study found significant pertussis burden among the HSU adult cohort and highlighted higher risk of pertussis for those with recent comorbidity diagnoses. Vaccination for pertussis should be recommended for individuals with comorbidities to reduce infection risk and disease severity. GPs must have capability to test for pertussis, given it is notifiable disease with implications for individuals, their families, and broader population. High-quality disease surveillance is crucial for informing policy decisions.
PubMed: 38910093
DOI: 10.1016/j.vaccine.2024.06.016 -
Journal of Global Antimicrobial... Jun 2024The World Health Organization named Stenotrophomonas maltophilia a critical multi-drug resistant threat, necessitating rapid diagnostic strategies. Traditional culturing...
OBJECTIVES
The World Health Organization named Stenotrophomonas maltophilia a critical multi-drug resistant threat, necessitating rapid diagnostic strategies. Traditional culturing methods require up to 96 hours, including 72 hours for bacterial growth, identification with matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) through protein profile analysis, and 24 hours for antibiotic susceptibility testing. In this study, we aimed at developing an artificial intelligence-clinical decision support system (AI-CDSS) by integrating MALDI-TOF MS and machine learning to quickly identify levofloxacin and trimethoprim/sulfamethoxazole resistance in S. maltophilia, optimizing treatment decisions.
METHODS
We selected 8,662 S. maltophilia from 165,299 MALDI-TOF MS-analyzed bacterial specimens, collected from a major medical center and four secondary hospitals. We exported mass-to-charge values and intensity spectral profiles from MALDI-TOF MS .mzML files to predict antibiotic susceptibility testing results, obtained with the VITEK-2 system using machine learning algorithms. We optimized the models with GridSearchCV and 5-fold cross-validation.
RESULTS
We identified distinct spectral differences between resistant and susceptible S. maltophilia strains, demonstrating crucial resistance features. The machine learning models, including random forest, light-gradient boosting machine, and XGBoost, exhibited high accuracy. We established an AI-CDSS to offer healthcare professionals swift, data-driven advice on antibiotic use.
CONCLUSIONS
MALDI-TOF MS and machine learning integration into an AI-CDSS significantly improved rapid S. maltophilia resistance detection. This system reduced the identification time of resistant strains from 24 hours to minutes after MALDI-TOF MS identification, providing timely and data-driven guidance. Combining MALDI-TOF MS with machine learning could enhance clinical decision-making and improve S. maltophilia infection treatment outcomes.
PubMed: 38909685
DOI: 10.1016/j.jgar.2024.06.004 -
The Lancet. Microbe Jun 2024Microbiota alterations are common in patients hospitalised for severe infections, and preclinical models have shown that anaerobic butyrate-producing gut bacteria...
Association between butyrate-producing gut bacteria and the risk of infectious disease hospitalisation: results from two observational, population-based microbiome studies.
BACKGROUND
Microbiota alterations are common in patients hospitalised for severe infections, and preclinical models have shown that anaerobic butyrate-producing gut bacteria protect against systemic infections. However, the relationship between microbiota disruptions and increased susceptibility to severe infections in humans remains unclear. We investigated the relationship between gut microbiota and the risk of future infection-related hospitalisation in two large population-based cohorts.
METHODS
In this observational microbiome study, gut microbiota were characterised using 16S rRNA gene sequencing in independent population-based cohorts from the Netherlands (HELIUS study; derivation cohort) and Finland (FINRISK 2002 study; validation cohort). HELIUS was conducted in Amsterdam, Netherlands, and included adults (aged 18-70 years at inclusion) who were randomly sampled from the municipality register of Amsterdam. FINRISK 2002 was conducted in six regions in Finland and is a population survey that included a random sample of adults (aged 25-74 years). In both cohorts, participants completed questionnaires, underwent a physical examination, and provided a faecal sample at inclusion (Jan 3, 2013, to Nov 27, 2015, for HELIUS participants and Jan 21 to April 19, 2002, for FINRISK participants. For inclusion in our study, a faecal sample needed to be provided and successfully sequenced, and national registry data needed to be available. Primary predictor variables were microbiota composition, diversity, and relative abundance of butyrate-producing bacteria. Our primary outcome was hospitalisation or mortality due to any infectious disease during 5-7-year follow-up after faecal sample collection, based on national registry data. We examined associations between microbiota and infection risk using microbial ecology and Cox proportional hazards.
FINDINGS
We profiled gut microbiota from 10 699 participants (4248 [39·7%] from the derivation cohort and 6451 [60·3%] from the validation cohort). 602 (5·6%) participants (152 [3·6%] from the derivation cohort; 450 [7·0%] from the validation cohort) were hospitalised or died due to infections during follow-up. Gut microbiota composition of these participants differed from those without hospitalisation for infections (derivation p=0·041; validation p=0·0002). Specifically, higher relative abundance of butyrate-producing bacteria was associated with a reduced risk of hospitalisation for infections (derivation cohort cause-specific hazard ratio 0·75 [95% CI 0·60-0·94] per 10% increase in butyrate producers, p=0·013; validation cohort 0·86 [0·77-0·96] per 10% increase, p=0·0077). These associations remained unchanged following adjustment for demographics, lifestyle, antibiotic exposure, and comorbidities.
INTERPRETATION
Gut microbiota composition, specifically colonisation with butyrate-producing bacteria, was associated with protection against hospitalisation for infectious diseases in the general population across two independent European cohorts. Further studies should investigate whether modulation of the microbiome can reduce the risk of severe infections.
FUNDING
Amsterdam UMC, Porticus, National Institutes of Health, Netherlands Organisation for Health Research and Development (ZonMw), and Leducq Foundation.
PubMed: 38909617
DOI: 10.1016/S2666-5247(24)00079-X -
STAR Protocols Jun 2024Tissue-resident macrophages (TRMs) constitute the first line of defense against infection in all organs and perform organ-specific functions during tissue homeostasis....
Tissue-resident macrophages (TRMs) constitute the first line of defense against infection in all organs and perform organ-specific functions during tissue homeostasis. Here, we present a protocol for long-term monocultures of murine macrophages from different adult organs, including the brain, liver, peritoneal cavity, and lung. We describe steps for tissue preparation and the use of a combination of organotypic conditions to maintain a TRM-like identity in vitro, resulting in an ideal screening platform for a wide range of assays and readouts. For complete details on the use and execution of this protocol, please refer to Aktories et al..
PubMed: 38909360
DOI: 10.1016/j.xpro.2024.103145 -
Immunity & Ageing : I & A Jun 2024Sepsis is a dysregulated host response to severe infections, and immune dysfunction plays a crucial role in its pathogenesis. Elderly patients, a special population...
Sepsis is a dysregulated host response to severe infections, and immune dysfunction plays a crucial role in its pathogenesis. Elderly patients, a special population influenced by immunosenescence, are more susceptible to sepsis and have a worse prognosis. However, the immunopathogenic mechanisms underlying sepsis in elderly patients remain unclear. Here, we performed single-cell RNA sequencing of peripheral blood samples from young and old subjects and patients with sepsis. By exploring the transcriptional profiles of immune cells, we analyzed immune cell compositions, phenotype shifts, expression heterogeneities, and intercellular communication. In elderly patients with sepsis, innate immune cells (e.g., monocytes and DCs) exhibit decreased antigen presentation, presenting an overactive inflammatory and senescent phenotype. However, the immunophenotype of T cells shifted to characterize effector, memory, and exhaustion. Moreover, we identified strong interferon-γ responses of T cells in both aging and sepsis groups and a deranged inflammaging status in elderly sepsis patients. Tregs in elderly patients with sepsis showed increased abundance and enhanced immunosuppressive effects. In addition, metabolism-associated pathways were upregulated in T cells in elderly patients with sepsis, and the lysine metabolism pathway was enriched in Tregs. Cell-cell interaction analysis showed that the expression profile of ligand-receptor pairs was probably associated with aggravated immune dysfunction in elderly patients with sepsis. A novel HLA-KIR interaction was observed between Tregs and CD8 + T cells. These findings illustrate the immunological hallmarks of sepsis in elderly patients, and highlight that immunosuppressive and metabolic regulatory pathways may undergo important alterations in elderly patients with sepsis.
PubMed: 38909272
DOI: 10.1186/s12979-024-00446-z -
Respiratory Research Jun 2024Pulmonary fibrosis (PF) represents the pathologic end stage of several interstitial lung diseases (ILDs) associated with high morbidity and mortality rates. However,...
BACKGROUND
Pulmonary fibrosis (PF) represents the pathologic end stage of several interstitial lung diseases (ILDs) associated with high morbidity and mortality rates. However, current treatments can only delay disease progression rather than provide a cure. The role of inflammation in PF progression is well-established, but new insights into immune regulation are fundamental for developing more efficient therapies. c-MET signaling has been implicated in the migratory capacity and effector functions of immune cells. Nevertheless, the role of this signaling pathway in the context of PF-associated lung diseases remains unexplored.
METHODS
To determine the influence of c-MET in immune cells in the progression of pulmonary fibrosis, we used a conditional deletion of c-Met in immune cells. To induce pulmonary fibrosis mice were administered with bleomycin (BLM) intratracheally. Over the course of 21 days, mice were assessed for weight change, and after euthanasia at different timepoints, bronchoalveolar lavage fluid cells and lung tissue were assessed for inflammation and fibrosis. Furthermore, c-MET expression was assessed in cryobiopsy sections, bronchoalveolar lavage fluid cells samples and single cell RNA-sequencing dataset from human patients with distinct interstitial lung diseases.
RESULTS
c-MET expression was induced in lung immune cells, specifically in T cells, interstitial macrophages, and neutrophils, during the inflammatory phase of BLM-induced PF mouse model. Deletion of c-Met in immune cells correlated with earlier weight recovery and improved survival of BLM-treated mice. Moreover, the deletion of c-Met in immune cells was associated with early recruitment of the immune cell populations, normally found to express c-MET, leading to a subsequent attenuation of the cytotoxic and proinflammatory environment. Consequently, the less extensive inflammatory response, possibly coupled with tissue repair, culminated in less exacerbated fibrotic lesions. Furthermore, c-MET expression was up-regulated in lung T cells from patients with fibrosing ILD, suggesting a potential involvement of c-MET in the development of fibrosing disease.
CONCLUSIONS
These results highlight the critical contribution of c-MET signaling in immune cells to their enhanced uncontrolled recruitment and activation toward a proinflammatory and profibrotic phenotype, leading to the exacerbation of lung injury and consequent development of fibrosis.
Topics: Animals; Pulmonary Fibrosis; Mice; Proto-Oncogene Proteins c-met; Pneumonia; Mice, Inbred C57BL; Humans; Bleomycin; Mice, Knockout; Male; Female; Lung; Disease Models, Animal
PubMed: 38909206
DOI: 10.1186/s12931-024-02884-1