Clinical characteristics of respiratory tract infection caused by Klebsiella pneumoniae in immunocompromised patients: a retrospective cohort study.

Purpose: With advancements in medical technology and the growth of an aging society, the number of immunocompromised patients has increased progressively. Klebsiella pneumoniae (K. pneumoniae) is one of the most common opportunistic pathogens, causing a severe disease burden. We aimed to further clarify the differences in respiratory tract K. pneumoniae infections between immunocompromised and immunocompetent populations. Methods: We retrospectively compared cases of respiratory tract K. pneumoniae infection in immunocompromised and immunocompetent patients admitted to Ruijin Hospital in Shanghai between January 2019 and August 2020 to clarify the differences between the two groups. Results: We enrolled 400 immunocompromised patients and 386 immunocompetent patients. Compared to the immunocompetent group, immunocompromised patients were more likely to develop bacteremia and shock and to require mechanical ventilation support during hospitalization. Immunocompromised patients also had a greater probability of polymicrobial infection and a higher rate of antibacterial resistance to carbapenem, which resulted in a higher intensive care unit admission rate, 30-day case fatality rate (CFR), and 6-month CFR. Multivariate analysis indicated that immunocompromised patients with respiratory diseases (odds ratio [OR], 2.189; 95% confidence interval [CI], 1.103-4.344; P = 0.025) and cardiovascular diseases (OR, 2.008; 95% CI, 1.055-3.822; P = 0.034), using mechanical ventilation (OR, 3.982; 95% CI, 2.053-7.722; P = 0.000), or infected with multidrug-resistant K. pneumoniae (OR, 3.870; 95%, 1.577-9.498; P = 0.003) were more likely to have a higher 30-day CFR. Conclusion: The disease burden of K. pneumoniae infection in immunocompromised patients is high. Immunocompromised patients who presented with respiratory diseases and cardiovascular diseases, used mechanical ventilation, or were infected with multidrug-resistant K. pneumoniae experienced a higher 30-day mortality rate.

Diffusing capacity in chronic obstructive pulmonary disease assessment: A meta-analysis.

To achieve a multidimensional evaluation of chronic obstructive pulmonary disease (COPD) patients, the spirometry measures are supplemented by assessment of symptoms, risk of exacerbations, and CT imaging. However, the measurement of diffusing capacity of the lung for carbon monoxide (DLCO) is not included in most common used models of COPD assessment. Here, we conducted a meta-analysis to evaluate the role of DLCO in COPD assessment.The studies were identified by searching the terms "diffusing capacity" OR "diffusing capacity for carbon monoxide" or "DLCO" AND "COPD" AND "assessment" in Pubmed, Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, Scopus, and Web of Science databases. The mean difference of DLCO % predict was assessed in COPD patient with different severity (according to GOLD stage and GOLD group), between COPD patients with or without with frequent exacerbation, between survivors and non-survivors, between emphysema dominant and non-emphysema dominant COPD patients, and between COPD patients with or without pulmonary hypertension.43 studies were included in the meta-analysis. DLCO % predicted was significantly lower in COPD patients with more severe airflow limitation (stage II/IV), more symptoms (group B/D), and high exacerbation risk (group C/D). Lower DLCO % predicted was also found in exacerbation patients and non-survivors. Low DLCO % predicted was related to emphysema dominant phenotype, and COPD patients with PH.The current meta-analysis suggested that DLCO % predicted might be an important measurement for COPD patients in terms of severity, exacerbation risk, mortality, emphysema domination, and presence of pulmonary hypertension. As diffusion capacity reflects pulmonary ventilation and perfusion at the same time, the predictive value of DLCO or DLCO combined with other criteria worth further exploration.

Insights into gut microbiome and its functional pathways in asthma patients through high-throughput sequencing.

Aim: To describe gut microbiome and functional genes of asthma. Patients & methods: Fecal microbiome in controls, asthma patients with and without inhaled corticosteroid (ICS) treatment was determined. Results: Patients with ICS had lower abundance of Alloprevotella, unclassified_f_Lachnospiraceae and Lachnospiraceae_NC2004_group, higher abundance of Sutterella and Sphingomonas than patients without ICS. In all the asthma patients, there are microbial differences in aging distribution, different gender and different asthmatic phenotypes. Asthma patients without ICS treatment had more microbial genes related to geraniol degradation, ethylbenzene degradation and bladder cancer than controls; 15 pathways showed significant difference between asthma patients with and without ICS treatment. Conclusion: We found gut dysbiosis in asthma and different functional pathways associated with both asthma and ICS.

Fungal and bacterial microbiome dysbiosis and imbalance of trans-kingdom network in asthma.

BACKGROUND: Fungal and bacterial microbiota play an important role in development of asthma. We aim to characterize airway microbiome (mycobiome, bacteriome) and functional genes in asthmatics and controls. METHODS: Sputum microbiome of controls, untreated asthma patients and inhaled corticosteroid (ICS) receiving patients was detected using high throughput sequencing. Metagenomic sequencing was used to examine the functional genes of microbiome. RESULTS: 1. Mycobiome: α diversity was lower in untreated asthma group than that in controls. Mycobiome compositions differed among the three groups. Compared with controls, untreated asthma group has higher abundance of Wallemia, Mortierella and Fusarium. Compared with untreated asthma patients, ICS receiving patients has higher abundance of Fusarium and Mortierella, lower frequency of Wallemia, Alternaria and Aspergillus. 2. Bacteriome: α diversity was lower in untreated asthma group than that in controls. There are some overlaps of bacteriome compositions between controls and untreated asthma patients which were distinct from ICS receiving patients. Untreated asthma group has higher Streptococcus than controls. 3. Potential fungal and bacterial biomarkers of asthma: Trametes, Aspergillus, Streptococcus, Gemella, Neisseria, etc. 4. Correlation network: There are dense and homogenous correlations in controls but a dramatically unbalanced network in untreated asthma and ICS receiving patients, which suggested the existence of disease-specific inter-kingdom and intra-kingdom alterations. 5. Metagenomic analysis: functional pathways were associated with the status of asthma, microbiome and functional genes showed different correlations in different environment. CONCLUSION: We showed mycobiome and bacteriome dysbiosis in asthma featured by alterations in biodiversity, community composition, inter-kingdom and intra-kingdom network. We also observed several functional genes associated with asthma.

Oscillatory positive expiratory pressure treatment in lower respiratory tract infection.

Oscillatory positive expiratory pressure (OPEP) devices have been utilized as an adjunct therapy to conventional chest physiotherapy (CPT) to promote the clearance of respiratory secretions in individuals with impaired ability to cough, particularly in chronic diseases. However, few studies have focused on the effectiveness of OPEP in lower respiratory tract infection. In the present study, all patients with lower respiratory tract infections hospitalized in the Department of Pulmonary and Critical Care Medicine, Ruijin Hospital (Shanghai, China) between February 2016 and July 2017 were analyzed. Daily sputum quantity and purulence were recorded on the first 7 days of physiotherapy. Oxygenation index, partial pressure carbon dioxide, white blood cell count, neutrophil percentage, C reactive protein (CRP) and procalcitonin (PCT) levels before and after CPT were compared between patients who received OPEP and patients who received mechanical percussion (MP). Sputum was collected prior to and following CPT. A total of 17 patients received OPEP, while 10 received MP. The OPEP group exhibited improved postural drainage compared with the MP group after 7 days of physiotherapy. After 7 days of CPT, patients who received OPEP also exhibited a significantly improved oxygenation index, while the oxygenation index in the MP group did not improve. The improvement of partial pressure carbon dioxide was not significantly different between groups. The OPEP group also exhibited a greater decrease in white blood cell count, neutrophil percentage and CRP levels, compared with the MP group. However, the decrease in PCT level was similar in the OPEP and MP groups. Sputum culture results revealed that the rate of negative conversion was very low in both groups. There was no difference between the two groups in terms of hospitalization outcomes. In conclusion, OPEP exhibited a greater effectiveness in draining sputum, improving oxygenation and reducing inflammatory status in patients with lower respiratory tract infections compared with MP; however, it did not promote the elimination of microbes.

Intratracheal administration of adipose derived mesenchymal stem cells alleviates chronic asthma in a mouse model.

BACKGROUND: Adipose-derived mesenchymal stem cell (ASCs) exerts immunomodulatory roles in asthma. However, the underlying mechanism remains unclear. The present study aimed to explore the effects and mechanisms of ASCs on chronic asthma using an ovalbumin (OVA)-sensitized asthmatic mouse model. METHODS: Murine ASCs (mASCs) were isolated from male Balb/c mice and identified by the expression of surface markers using flow cytometry. The OVA-sensitized asthmatic mouse model was established and then animals were treated with the mASCs through intratracheal delivery. The therapy effects were assessed by measuring airway responsiveness, performing immuohistochemical analysis, and examining bronchoalveolar lavage fluid (BALF). Additionally, the expression of inflammatory cytokines and lgE was detected by CHIP and ELISA, respectively. The mRNA levels of serum indices were detected using qRT-PCR. RESULTS: The mASCs grew by adherence with fibroblast-like morphology, and showed the positive expression of CD90, CD44, and CD29 as well as the negative expression of CD45 and CD34, indicating that the mASCs were successfully isolated. Administering mASCs to asthmatic model animals through intratracheal delivery reduced airway responsiveness, the number of lymphocytes (P < 0.01) and the expression of lgE (P < 0.01), IL-1ß (P < 0.05), IL-4 (P < 0.001), and IL-17F (P < 0.001), as well as increased the serum levels of IL-10 and Foxp3, and the percentage of CD4 + CD25 + Foxp3+ Tregs in the spleen, and reduced the expression of IL-17 (P < 0.05) and RORγ. CONCLUSIONS: Intratracheal administration of mASCs alleviated airway inflammation, improved airway remodeling, and relieved airway hyperresponsiveness in an OVA-sensitized asthma model, which might be associated with the restoration of Th1/Th2 cell balance by mASCs.

Dephosphorylated Polymerase I and Transcript Release Factor Prevents Allergic Asthma Exacerbations by Limiting IL-33 Release.

BACKGROUND: Asthma is a chronic inflammatory disease characterized by airway inflammation and airway hyperresponsiveness (AHR). IL-33 is considered as one of the most critical molecules in asthma pathogenesis. IL-33 is stored in nucleus and passively released during necrosis. But little is known about whether living cells can release IL-33 and how this process is regulated. OBJECTIVE: We sought to investigate the role of polymerase I and transcript release factor (PTRF) in IL-33 release and asthma pathogenesis. METHODS: Ovalbumin (OVA)-induced asthma model in PTRF+/- mice were employed to dissect the role of PTRF in vivo. Then, further in vitro experiments were carried out to unwind the potential mechanism involved. RESULTS: In OVA asthma model with challenge phase, PTRF+/- mice showed a greater airway hyper-reaction, with an intense airway inflammation and more eosinophils in bronchoalveolar lavage fluid (BALF). Consistently, more acute type 2 immune response in lung and a higher IL-33 level in BALF were found in PTRF+/- mice. In OVA asthma model without challenge phase, airway inflammation and local type 2 immune responses were comparable between control mice and PTRF+/- mice. Knockdown of PTRF in 16HBE led to a significantly increased level of IL-33 in cell culture supernatants in response to LPS or HDM. Immunoprecipitation assay clarified Y158 as the major phosphorylation site of PTRF, which was also critical for the interaction of IL-33 and PTRF. Overexpression of dephosphorylated mutant Y158F of PTRF sequestered IL-33 in nucleus together with PTRF and limited IL-33 extracellular secretion. CONCLUSION: Partial loss of PTRF led to a greater AHR and potent type 2 immune responses during challenge phase of asthma model, without influencing the sensitization phase. PTRF phosphorylation status determined subcellular location of PTRF and, therefore, regulated IL-33 release.

The Imbalance of FOXP3/GATA3 in Regulatory T Cells from the Peripheral Blood of Asthmatic Patients.

BACKGROUND: Treg cells play an important role in the pathogenic progress of asthma. OBJECTIVE: To address the alterations of Treg cells in asthma. METHODS: Proliferation-and function-associated markers of Treg cells along with the percentage of Treg cells producing some cytokine from asthmatics and healthy subjects were analyzed by flow cytometry. Besides, the expressions of USP21 and PIM2 in Treg cells were measured by cell immunochemistry after Treg cells were sorted. RESULTS: Treg cells from asthmatic patients showed lower proliferation activity and were more likely to be apoptotic. These cells expressed lower levels of GITR, CTLA-4, Nrp-1, and IL-10 compared to those from the healthy control. Th2-like Treg cells increased in asthmatic patients, while the percentage of IFN-r+ Treg cells was similar between two groups. Moreover, the percentage of IL-4+ Treg cells is related to the asthma control. Treg cells from asthmatic patients expressed more FOXP3 as well as GATA3; the expression level of GATA3 negatively correlated with FEV1%pred. Increased expressions of USP21 and PIM2 in Treg cells from asthmatic patients were found. CONCLUSION: Treg cells decreased in asthmatic patients, with an impaired immunosupression function and a Th2-like phenotype, which may be due to overexpression of GATA3 and FOXP3, regulated by USP21 and PIM2, respectively.

Role of PIM2 in allergic asthma.

T cell­associated inflammation, particularly type 2 inflammation, has an important role in asthma pathogenesis, which is suppressed by regulatory T cells (Tregs). Proviral integration site for Moloney murine leukemia virus 2 (PIM2), a member off the serine/threonine kinase family, promotes the growth and survival of T cells and influences the function of Treg cells. However, whether PIM2 affects asthma pathogenesis remains unclear. Peripheral blood mononuclear cells and Treg cells from asthmatic and healthy subjects were obtained, and the expression level of PIM2 was measured by reverse transcription­quantitative polymerase chain reaction and immunocytochemistry. In addition, BALB/c female mice sensitized and challenged by ovalbumin were used as an asthma model, and PIM2 inhibitor was injected during the challenge period to observe the effect of PIM2 on asthma. The asthma symptoms were recorded, and airway hyper­responsiveness (AHR), expression levels of cytokines in the serum or bronchoalveolar lavage fluid (BALF), and the number of BALF leukocytes were evaluated. In addition, hematoxylin and eosin staining and immunohistochemistry of lung tissues was performed. The results demonstrated that PIM2 was overexpressed in patients with asthma in natural Treg cells. Inhibition of PIM2 attenuated asthma symptoms, and improved AHR and airway inflammation compared with asthmatic mice without inhibition of PIM2. In addition, expression levels of interleukin (IL)­10 and forkhead box protein 3 (FOXP3) in BALF were increased following PIM2 inhibition (IL­10, 470.3±21.78 vs. 533.7±25.55 pg/ml, P<0.05; FOXP3, 259±4.68 vs. 279.3±3.68 pg/ml; asthma and PIM2 inhibition groups, respectively; P<0.05). In conclusion, PIM2 may exhibit an important role in asthma pathogenesis and exacerbate AHR, airway inflammation and asthma symptoms. These effects of PIM2 may be dependent on Treg cells and the secretion of IL­10 by Tregs. The results of the present study suggest that PIM2 may be a potential target molecule for asthma treatment.

Clinical characteristics of patients with chronic obstructive pulmonary disease with comorbid bronchiectasis: a systemic review and meta-analysis.

BACKGROUND: In the 2014 Global initiative for chronic Obstructive Lung Disease guidelines, bronchiectasis was for the first time defined as a comorbidity of chronic obstructive pulmonary disease (COPD), and this change has been retained in the 2015 update, which emphasizes the influence of bronchiectasis in the natural history of COPD. The present meta-analysis was aimed at summarizing the impact of bronchiectasis on patients with COPD. METHODS: Databases including Embase, PubMed, and the Cochrane Central Register of Controlled Trials were searched comprehensively to identify all relevant human clinical studies published until August 2014. Bronchiectasis was confirmed either by computed tomography or high-resolution computed tomography. One or more clinicopathological or demographical characteristics, including age, sex, smoking history, daily sputum production, exacerbations, inflammatory biomarkers, lung function, and colonization by potentially pathogenic microorganisms (PPMs), were compared between COPD patients with and without bronchiectasis. RESULTS: Six observational studies with 881 patients were included in the meta-analysis. The mean prevalence of bronchiectasis in patients with COPD was 54.3%, ranging from 25.6% to 69%. Coexistence of bronchiectasis and COPD occurred more often in male patients with longer smoking history. Patients with COPD and comorbid bronchiectasis had greater daily sputum production, more frequent exacerbation, poorer lung function, higher level of inflammatory biomarkers, more chronic colonization by PPMs, and higher rate of Pseudomonas aeruginosa isolation. CONCLUSION: In spite of the heterogeneity between included studies and detectable publication bias, this meta-analysis demonstrated the impact of bronchiectasis in patients with COPD in all directions, indicating that coexistence of bronchiectasis should be considered a pathological phenotype of COPD, which may have a predictive value.