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Frontiers in Immunology 2023With the extensive use of immunosuppressants, immunosuppression-associated pneumonitis including (PCP) has received increasing attention. Though aberrant adaptive...
INTRODUCTION
With the extensive use of immunosuppressants, immunosuppression-associated pneumonitis including (PCP) has received increasing attention. Though aberrant adaptive immunity has been considered as a key reason for opportunistic infections, the characteristics of innate immunity in these immunocompromised hosts remain unclear.
METHODS
In this study, wild type C57BL/6 mice or dexamethasone-treated mice were injected with or without . Bronchoalveolar lavage fluids (BALFs) were harvested for the multiplex cytokine and metabolomics analysis. The single-cell RNA sequencing (scRNA-seq) of indicated lung tissues or BALFs was performed to decipher the macrophages heterogeneity. Mice lung tissues were further analyzed via quantitative polymerase chain reaction (qPCR) or immunohistochemical staining.
RESULTS
We found that the secretion of both pro-inflammatory cytokines and metabolites in the -infected mice are impaired by glucocorticoids. By scRNA-seq, we identified seven subpopulations of macrophages in mice lung tissues. Among them, a group of Mmp12 macrophages is enriched in the immunocompetent mice with infection. Pseudotime trajectory showed that these Mmp12 macrophages are differentiated from Ly6c classical monocytes, and highly express pro-inflammatory cytokines elevated in BALFs of -infected mice. , we confirmed that dexamethasone impairs the expression of , , and , as well as the fungal killing capacity of alveolar macrophage (AM)-like cells. Moreover, in patients with PCP, we found a group of macrophages resembled the aforementioned Mmp12 macrophages, and these macrophages are inhibited in the patient receiving glucocorticoid treatment. Additionally, dexamethasone simultaneously impaired the functional integrity of resident AMs and downregulated the level of lysophosphatidylcholine, leading to the suppressed antifungal capacities.
CONCLUSION
We reported a group of Mmp12 macrophages conferring protection during infection, which can be dampened by glucocorticoids. This study provides multiple resources for understanding the heterogeneity and metabolic changes of innate immunity in immunocompromised hosts, and also suggests that the loss of Mmp12 macrophages population contributes to the pathogenesis of immunosuppression-associated pneumonitis.
Topics: Mice; Animals; Macrophages, Alveolar; Pneumonia, Pneumocystis; Transcriptome; Glucocorticoids; Matrix Metalloproteinase 12; Multiomics; Mice, Inbred C57BL; Pneumocystis; Cytokines; Immunocompromised Host; Dexamethasone
PubMed: 37359523
DOI: 10.3389/fimmu.2023.1179094 -
Journal of Veterinary Internal Medicine 2023Sibling female and male Chihuahuas were evaluated for a 9-month history of tachypnea that failed to respond to fenbendazole, doxycycline, amoxicillin-clavulanate, and...
Sibling female and male Chihuahuas were evaluated for a 9-month history of tachypnea that failed to respond to fenbendazole, doxycycline, amoxicillin-clavulanate, and prednisone. Physical examination identified tachypnea, hyperpnea, and harsh bronchovesicular lung sounds. Fundic examination disclosed diffuse chorioretinitis, manifested as multifocal chorioretinal granulomas in the female dog and occasional chorioretinal scars in the male dog. Thoracic radiographs indicated moderate to severe interstitial to broncho-interstitial infiltrates in both dogs. Serum and urine antigen and antibody testing in the female dog failed to identify infectious agents, but cytologic assessment of hepatic lymph node, liver, and splenic aspirates identified Pneumocystis trophozoites. Infection was confirmed in both dogs by 28S rRNA PCR sequencing from multiple tissue samples. The female dog responded well to trimethoprim-sulfamethoxazole, but the male dog was euthanized because of liver failure, presumably related to antimicrobial treatment.
Topics: Male; Female; Dogs; Animals; Humans; Pneumonia, Pneumocystis; Siblings; Prednisone; Anti-Infective Agents; Tachypnea; Dog Diseases
PubMed: 37134072
DOI: 10.1111/jvim.16729 -
BioRxiv : the Preprint Server For... Feb 2024pneumonia (PjP) poses a serious risk to individuals with compromised immune systems, such as individuals with HIV/AIDS or undergoing immunosuppressive therapies for...
pneumonia (PjP) poses a serious risk to individuals with compromised immune systems, such as individuals with HIV/AIDS or undergoing immunosuppressive therapies for cancer or solid organ transplants. Severe PjP triggers excessive lung inflammation, resulting in lung function decline and consequential alveolar damage, potentially culminating in acute respiratory distress syndrome. Non-HIV patients face a 30-60%mortality rate, emphasizing the need for a deeper understanding of inflammatory responses in PjP. Prior research emphasized macrophages in infections, neglecting neutrophils' role in tissue damage. Consequently, the overemphasis on macrophages led to an incomplete understanding of the role of neutrophils and inflammatory responses. In the current investigation, our RNAseq studies on a murine surrogate model of PjP revealed heightened activation of the NLRP3 inflammasome and NETosis cell death pathways in their lungs. Immunofluorescence staining confirmed Neutrophil Extracellular Trap (NET) presence in the lungs of the -infected mice, validating our findings. Moreover, isolated neutrophils exhibited NETosis when directly stimulated with . While isolated NETs did not compromise viability, our data highlight the potential role of neutrophils in promoting inflammation during pneumonia through NLRP3 inflammasome assembly and NETosis. These pathways, essential for inflammation and pathogen elimination, bear the risk of uncontrolled activation leading to excessive tissue damage and persistent inflammation. This pioneering study is the first to identify the formation of NETs and inflammasomes during infection, paving the way for comprehensive investigations into treatments aimed at mitigating lung damage and augmenting survival rates for individuals with PjP.
PubMed: 38405901
DOI: 10.1101/2024.02.16.580773 -
Revista Espanola de Quimioterapia :... Oct 2019Due to the rise in the number and types of immunosuppressed patients, invasive fungal infections (IFI) are an increasing and major cause of morbidity and mortality in... (Review)
Review
Due to the rise in the number and types of immunosuppressed patients, invasive fungal infections (IFI) are an increasing and major cause of morbidity and mortality in immunocompromised adults and children. There is a broad group of pediatric patients at risk for IFI in whom primary and/or secondary antifungal prophylaxis (AFP) should be considered despite scant evidence. Pediatric groups at risk for IFI includes extremely premature infants in some settings, while in high-risk children with cancer receiving chemotherapy or undergoing haematopoietic stem cell transplantation (HCT), AFP against yeast and moulds is usually recommended. For solid organ transplanted, children, prophylaxis depends on the type of transplant and associated risk factors. In children with primary or acquired immunodeficiency such as HIV or long-term immunosuppressive treatment, AFP depends on the type of immunodeficiency and the degree of immunosuppression. Chronic granulomatous disease is associated with a particular high-risk of IFI and anti-mould prophylaxis is always indicated. In contrast, AFP is not generally recommended in children with long stay in intensive care units. The choice of AFP is limited by the approval of antifungal agents in different age groups and by their pharmacokinetics characteristics. This document aims to review current available information on AFP in children and to provide a comprehensive proposal for each type of patient.
Topics: Antifungal Agents; Candidiasis; Child; Drug Monitoring; HIV Infections; Hematopoietic Stem Cell Transplantation; Humans; Immunocompromised Host; Immunologic Deficiency Syndromes; Immunosuppression Therapy; Infant, Extremely Premature; Infant, Newborn; Intensive Care Units, Pediatric; Invasive Fungal Infections; Neoplasms; Pneumonia, Pneumocystis; Primary Prevention; Risk Factors; Secondary Prevention; Transplant Recipients
PubMed: 31507152
DOI: No ID Found -
Frontiers in Cellular and Infection... 2020pneumonia (PCP) is an AIDS-defining illness. In patients with HIV, the benefit of PCP prophylaxis is well-defined when the CD4 T-cell count decreases below 200...
pneumonia (PCP) is an AIDS-defining illness. In patients with HIV, the benefit of PCP prophylaxis is well-defined when the CD4 T-cell count decreases below 200 cells/μL. In other immunocompromised patients, the value of PCP prophylaxis is not always as well-established. This study aimed to describe the epidemiology of PCP in recent years and assess how many patients with PCP did or did not receive prophylaxis in the month preceding the infection. A multicenter retrospective study was performed in 3 tertiary care hospital. A list of patients that underwent broncho-alveolar lavage sampling and (PJ) PCR testing was retrieved from the microbiology laboratories. An in-house PJ quantitative PCR (qPCR) was used in each center. A cycle threshold (Ct) value of ≤ 28.5-30 was considered a probable PCP. For patients with a positive PJ qPCR but above this threshold, a predefined case definition of possible PCP was defined as a qPCR Ct value ≤ 34-35 and both of the following criteria: 1. Clinical and radiological features compatible with PCP and 2. The patient died or received PCP therapy and survived. Patient files from those with a qPCR Ct value ≤ 35 were reviewed to determine whether the patient fulfilled the case definition and if PCP prophylaxis had been used in the weeks preceding the PCP. Disease-specific guidelines, as well as hospital-wide guidelines, were used to evaluate if prophylaxis could be considered indicated. From 2012 to 2018, 482 BAL samples were tested. Two hundred and four had a qPCR Ct value ≤ 35 and were further evaluated: 90 fulfilled the definition of probable and 63 of possible PCP while the remaining 51 were considered colonized. Seventy-four percentages of the patients with PCP were HIV-negative. Only 11 (7%) of the 153 patients had received prophylaxis, despite that in 133 (87%) cases prophylaxis was indicated according to guidelines. In regions where HIV testing and treatment is available without restrictions, PCP is mainly diagnosed in non-HIV immunocompromised patients. More than four out of five patients with PCP had not received prophylaxis. Strategies to improve awareness of antimicrobial prophylaxis guidelines in immunocompromised patients are urgently needed.
Topics: Humans; Immunocompromised Host; Pneumocystis carinii; Pneumonia, Pneumocystis; Real-Time Polymerase Chain Reaction; Retrospective Studies
PubMed: 32500040
DOI: 10.3389/fcimb.2020.00224 -
BMC Infectious Diseases Jul 2023Pneumocystis jirovecii pneumonia (PJP) can be a life-threatening opportunistic infection. We aimed to evaluate the diagnostic accuracy of metagenomic next-generation... (Review)
Review
OBJECTIVE
Pneumocystis jirovecii pneumonia (PJP) can be a life-threatening opportunistic infection. We aimed to evaluate the diagnostic accuracy of metagenomic next-generation sequencing (mNGS) for PJP.
METHODS
A comprehensive electronic literature search of Web of Knowledge, PubMed, Cochrane Library, CNKI and Wanfang data was performed. Bivariate analysis was conducted to calculate the pooled sensitivity, specificity, diagnostic odds ratio (DOR), the area under the summary receiver operator characteristic (SROC) curve and the Q-point value (Q*).
RESULTS
The literature search resulted in 9 studies with a total of 1343 patients, including 418 cases diagnosed with PJP and 925 controls. The pooled sensitivity of mNGS for diagnosis of PJP was 0.974 [95% confidence interval (CI), 0.953-0.987]. The pooled specificity was 0.943 (95% CI, 0.926-0.957), the DOR was 431.58 (95% CI, 186.77-997.27), the area under the SROC curve was 0.987, and the Q* was 0.951. The I test indicated no heterogeneity between studies. The Deek funnel test suggested no potential publication bias. Subgroup analyses showed that the area under the SROC curve of mNGS for diagnosis of PJP in immunocompromised and non-HIV patients was 0.9852 and 0.979, respectively.
CONCLUSIONS
Current evidence indicates that mNGS exhibits excellent accuracy for the diagnosis of PJP. The mNGS is a promising tool for assessment of PJP in both immunocompromised and non-HIV patients.
Topics: Humans; Correlation of Data; High-Throughput Nucleotide Sequencing; Immunocompromised Host; Knowledge; Pneumonia, Pneumocystis
PubMed: 37430211
DOI: 10.1186/s12879-023-08440-4 -
Frontiers in Cellular and Infection... 2020pneumonia (PCP) remains the most frequent AIDS-defining illness in developed countries. This infection also occurs in non-AIDS immunosuppressed patients, e.g., those... (Review)
Review
pneumonia (PCP) remains the most frequent AIDS-defining illness in developed countries. This infection also occurs in non-AIDS immunosuppressed patients, e.g., those who have undergone an organ transplantation. Moreover, mild infections related to low pulmonary fungal burden, frequently designated as pulmonary colonization, occurs in patients with chronic pulmonary diseases, e.g., cystic fibrosis (CF). Indeed, this autosomal recessive disorder alters mucociliary clearance leading to bacterial and fungal colonization of the airways. This mini-review compiles and discusses available information on and CF. It highlights significant differences in the prevalence of pulmonary colonization in European and Brazilian CF patients. It also describes the microbiota associated with in CF patients colonized by . Furthermore, we have described genomic diversity in colonized CF patients. In addition of pulmonary colonization, it appears that PCP can occur in CF patients specifically after lung transplantation, thus requiring preventive strategies. In other respects, primary infection is a worldwide phenomenon occurring in non-immunosuppressed infants within their first months. The primary infection is mostly asymptomatic but it can also present as a benign self-limiting infection. It probably occurs in the same manner in CF infants. Nonetheless, two cases of severe primary infection mimicking PCP in CF infants have been reported, the genetic disease appearing in these circumstances as a risk factor of PCP while the host-pathogen interaction in older children and adults with pulmonary colonization remains to be clarified.
Topics: Adult; Brazil; Child; Cystic Fibrosis; Humans; Infant; Lung; Pneumocystis carinii; Pneumonia, Pneumocystis
PubMed: 33117730
DOI: 10.3389/fcimb.2020.571253 -
MBio Jun 2022The French National Reference Center for Invasive Mycoses and Antifungals leads an active and sustained nationwide surveillance program on probable and proven invasive...
The French National Reference Center for Invasive Mycoses and Antifungals leads an active and sustained nationwide surveillance program on probable and proven invasive fungal diseases (IFDs) to determine their epidemiology in France. Between 2012 and 2018, a total of 10,886 IFDs were recorded. The incidence increased slightly over time (2.16 to 2.36/10,000 hospitalization days, = 0.0562) in relation with an increase of fungemia incidence (1.03 to 1.19/10,000, = 0.0023), while that of other IFDs remained stable. The proportion of ≥65-year-old patients increased from 38.4% to 45.3% ( < 0.0001). Yeast fungemia ( = 5,444) was due mainly to Candida albicans (55.6%) with stable proportions of species over time. Echinocandins became the main drug prescribed (46.7% to 61.8%), but global mortality rate remained unchanged (36.3% at 1 month). Pneumocystis jirovecii pneumonia ( = 2,106) was diagnosed mostly in HIV-negative patients (80.7%) with a significantly higher mortality than in HIV-positive patients (21.9% versus 5.4% at 1 month, < 0.0001). Invasive aspergillosis ( = 1,661) and mucormycosis ( = 314) were diagnosed mostly in hematology (>60% of the cases) with a global mortality rate of 42.5% and 59.3%, respectively, at 3 months and significant changes in diagnosis procedure over time. More concurrent infections were also diagnosed over time (from 5.4% to 9.4% for mold IFDs, = 0.0115). In conclusion, we observed an aging of patients with IFD with a significant increase in incidence only for yeast fungemia, a trend toward more concurrent infections, which raises diagnostic and therapeutic issues. Overall, global survival associated with IFDs has not improved despite updated guidelines and new diagnostic tools. The epidemiology of invasive fungal diseases (IFDs) is hard to delineate given the difficulties in ascertaining the diagnosis that is often based on the confrontation of clinical and microbiological criteria. The present report underlines the interest of active surveillance involving mycologists and clinicians to describe the global incidence and that of the main IFDs. Globally, although the incidence of Pneumocystis pneumonia, invasive aspergillosis, and mucormycosis remained stable over the study period (2012 to 2018), that of yeast fungemia increased slightly. We also show here that IFDs seem to affect older people more frequently. The most worrisome observation is the lack of improvement in the global survival rate associated with IFDs despite the increasing use of more sensitive diagnostic tools, the availability of new antifungal drugs very active in clinical trials, and a still low/marginal rate of acquired resistance in France. Therefore, other tracks of improvement should be investigated actively.
Topics: Aged; Antifungal Agents; Aspergillosis; Fungemia; Humans; Invasive Fungal Infections; Mucormycosis; Pneumonia, Pneumocystis; Watchful Waiting
PubMed: 35499498
DOI: 10.1128/mbio.00920-22 -
The Journal of Infectious Diseases Jul 2019Glucan is the major cell wall component of Pneumocystis cysts. In the current study, we have characterized Pneumocystis Bgl2 (EC 3.2.1.58), an enzyme with...
Glucan is the major cell wall component of Pneumocystis cysts. In the current study, we have characterized Pneumocystis Bgl2 (EC 3.2.1.58), an enzyme with glucanosyltransferase and β-1,3 endoglucanase activity in other fungi. Pneumocystis murina, Pneumocystis carinii, and Pneumocystis jirovecii bgl2 complementary DNA sequences encode proteins of 437, 447, and 408 amino acids, respectively. Recombinant P. murina Bgl2 expressed in COS-1 cells demonstrated β-glucanase activity, as shown by degradation of the cell wall of Pneumocystis cysts. It also cleaved reduced laminaripentaose and transferred oligosaccharides, resulting in polymers of 6 and 7 glucan residues, demonstrating glucanosyltransferase activity. Surprisingly, confocal immunofluorescence analysis of P. murina-infected mouse lung sections using an antibody against recombinant Bgl2 showed that the native protein is localized primarily to the trophic form of Pneumocystis in both untreated mice and mice treated with caspofungin, an antifungal drug that inhibits β-1,3-glucan synthase. Thus, like other fungi, Bgl2 of Pneumocystis has both endoglucanase and glucanosyltransferase activities. Given that it is expressed primarily in trophic forms, further studies are needed to better understand its role in the biology of Pneumocystis.
Topics: Amino Acid Sequence; Animals; Antifungal Agents; CD40 Ligand; COS Cells; Caspofungin; Cell Wall; Chlorocebus aethiops; Glucan Endo-1,3-beta-D-Glucosidase; Glucans; Lung; Mice; Mice, Inbred C57BL; Mice, Knockout; Pneumocystis; Pneumonia, Pneumocystis; Recombinant Proteins; Sequence Alignment
PubMed: 31100118
DOI: 10.1093/infdis/jiz172 -
Folia Parasitologica Jul 2021Pulmonary pathology is common in HIV-infected individuals, but the possible role of the parasitic protist Toxoplasma gondii (Nicolle et Manceaux, 1908) is not completely...
Pulmonary pathology is common in HIV-infected individuals, but the possible role of the parasitic protist Toxoplasma gondii (Nicolle et Manceaux, 1908) is not completely known. The present account reports result of a retrospective cohort study. Medical cards of 907 HIV-positive people, which included 120 deceased patients, were analysed. During a three-year follow-up, the pulmonary pathology was diagnosed in 306 patients (33.7 ± 1.6%): pneumocystis pneumonia in 124 (13.7 ± 1.1%), primary pulmonary tuberculosis in 113 (12.5 ± 1.1%), bacterial pneumonia in 58 (6.4 ± 0.8%) toxoplasmosis pneumonia in two (0.2 ± 0.2%), and others. All patients were divided into two cohorts: 531 individuals seropositive for T. gondii and 376 seronegative ones. It has been found out that general lung pathology is more common in patients with seropositivity to T. gondii than in seronegative ones (43.3 ± 2.2% vs. 20.1 ± 2.0%, p < 0.001). The diagnosis of pneumocystis pneumonia was made ten times more often in the cohort of seropositive patients than in the cohort of seronegative ones (21.9 ± 1.8% vs. 2.1 ± 0.7%, respectively, p < 0.001) and in deceased patients of these cohorts it was 5.5 times more (45.1 ± 5.9% vs. 8.2 ± 3.9, respectively, p < 0.001). In patients with fatal outcome and seropositivity to T. gondii, the incidences of pneumocystis pneumonia increased by 23.2% (p < 0.001) and bacterial pneumonia by 12.4% (p < 0.05), whereas in seronegative individuals only pulmonary tuberculosis increased by 13.1% (p < 0.05) сompared with corresponding whole cohorts. Pearson's contingency coefficient showed the mean strength association between infection with T. gondii and incidence of pneumocystis pneumonia both in whole cohort (C = 0.272) and in patients with fatal outcomes (C = 0.368). In сonclusion, significantly increasing rate of pneumocystis pneumonia in patients with HIV/AIDS and T. gondii infection can be caused by certain synergism between T. gondii and Pneumocystis jirovecii and in some cases overdiagnosis pneumocystis pneumonia due to undiagnosed toxoplasmosis pneumonia.
Topics: Adult; Female; HIV Infections; Humans; Male; Middle Aged; Pneumonia, Pneumocystis; Retrospective Studies; Toxoplasma; Toxoplasmosis; Young Adult
PubMed: 34279242
DOI: 10.14411/fp.2021.018