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International Journal of Molecular... Apr 2023This multicenter retrospective study aimed to clarify the prognostic factors for mortality and changes in treatment modalities and disease activities after the onset of...
This multicenter retrospective study aimed to clarify the prognostic factors for mortality and changes in treatment modalities and disease activities after the onset of pneumonia (PCP) in patients with rheumatoid arthritis (RA). Data regarding the clinical background, treatment modalities, and disease activity indicators of RA at the onset of PCP (baseline), and 6 months and 12 months after treatment were extracted. Of the 37 patients with RA-PCP (median age, 69 years; 73% female), chemical prophylaxis was administered to 8.1%. Six patients died during PCP treatment. The serum C-reactive protein (CRP) levels and the prednisolone (PDN) dose at baseline in the PCP death group were significantly higher than those in the survivor group. Multivariate analysis using a Cox regression model showed that PDN dose at baseline was a predictor of death from PCP in patients with RA. During the 12 months from baseline, the RA disease activity significantly decreased. A high dose of corticosteroids for RA may result in a poor prognosis when PCP is complicated. In the future, preventive administration techniques must be established for patients with RA who need PCP prevention.
Topics: Humans; Female; Aged; Male; Pneumonia, Pneumocystis; Retrospective Studies; Cohort Studies; Pneumocystis carinii; Prognosis; Arthritis, Rheumatoid; Prednisolone
PubMed: 37108561
DOI: 10.3390/ijms24087399 -
Infection and Immunity Jan 2020The pulmonary immune response protects healthy individuals against pneumonia (PcP). However, the immune response also drives immunopathogenesis in patients who develop...
The pulmonary immune response protects healthy individuals against pneumonia (PcP). However, the immune response also drives immunopathogenesis in patients who develop severe PcP, and it is generally accepted that optimal treatment requires combination strategies that promote fungal killing and also provide effective immunomodulation. The anti-inflammatory drug sulfasalazine programs macrophages for enhanced phagocytosis and also suppresses PcP-related immunopathogenesis. Anti- antibody opsonizes organisms for greater phagocytosis and may also mask antigens that drive immunopathogenesis. Thus, we hypothesized that combining antibody and sulfasalazine would have the dual benefit of enhancing fungal clearance while dampening immunopathogenesis and allow the rescue of severe PcP. To model a clinically relevant treatment scenario in mice, therapeutic interventions were withheld until clear symptoms of pneumonia were evident. When administered individually, both passive antibody and sulfasalazine improved pulmonary function and enhanced clearance to similar degrees. However, combination treatment with antibody and sulfasalazine produced a more rapid improvement, with recovery of body weight, a dramatic improvement in pulmonary function, reduced lung inflammation, and the rapid clearance of the organisms. Accelerated fungal clearance in the combination treatment group was associated with a significant increase in macrophage phagocytosis of Both passive antibody and sulfasalazine resulted in the suppression of Th1 cytokines and a marked increase in lung macrophages displaying an alternatively activated phenotype, which were enhanced by combination treatment. Our data support the concept that passive antibody and sulfasalazine could be an effective and specific adjunctive therapy for PcP, with the potential to accelerate fungal clearance while attenuating PcP-associated immunopathogenesis.
Topics: Animals; Anti-Inflammatory Agents; Antibodies; Cytokines; Female; Fungi; Immunologic Factors; Immunomodulation; Immunotherapy; Inflammation; Lung; Macrophage Activation; Macrophages, Alveolar; Mice; Mice, SCID; Phagocytosis; Pneumonia, Pneumocystis; Sulfasalazine
PubMed: 31611280
DOI: 10.1128/IAI.00640-19 -
Antimicrobial Agents and Chemotherapy Oct 2019
Topics: Caspofungin; Catalytic Domain; Echinocandins; Glucosyltransferases; Humans; Mutagenesis, Site-Directed; Pneumocystis carinii; Pneumonia, Pneumocystis
PubMed: 31548210
DOI: 10.1128/AAC.01296-19 -
JCI Insight Jan 2021Pneumocystis is an important opportunistic fungus that causes pneumonia in children and immunocompromised individuals. Recent genomic data show that divergence of major...
Pneumocystis is an important opportunistic fungus that causes pneumonia in children and immunocompromised individuals. Recent genomic data show that divergence of major surface glycoproteins may confer speciation and host range selectivity. On the other hand, immune clearance between mice and humans is well correlated. Thus, we hypothesized that humanize mice may provide information about human immune responses involved in controlling Pneumocystis infection. CD34-engrafted huNOG-EXL mice controlled fungal burdens to a greater extent than nonengrafted mice. Moreover, engrafted mice generated fungal-specific IgM. Fungal control was associated with a transcriptional signature that was enriched for genes associated with nonopsonic recognition of trophs (CD209) and asci (CLEC7A). These same genes were downregulated in CD4-deficient mice as well as twins with bare lymphocyte syndrome with Pneumocystis pneumonia.
Topics: Animals; Antibodies, Fungal; Antigens, CD34; Cell Adhesion Molecules; Disease Models, Animal; Female; Gene Expression; Hematopoietic Stem Cell Transplantation; Heterografts; Host Microbial Interactions; Host Specificity; Humans; Immunoglobulin G; Immunoglobulin M; Lectins, C-Type; Lung; Mice; Mice, Transgenic; Pneumocystis; Pneumonia, Pneumocystis; Receptors, Cell Surface; Species Specificity
PubMed: 33491669
DOI: 10.1172/jci.insight.139573 -
Medical Mycology Sep 2021We conducted a pilot study of patients with cystic fibrosis (CF) to assess intra-family transmission of P. jirovecii and compare it with data on other prevalent... (Comparative Study)
Comparative Study Observational Study
UNLABELLED
We conducted a pilot study of patients with cystic fibrosis (CF) to assess intra-family transmission of P. jirovecii and compare it with data on other prevalent pathogens such as P. aeruginosa and S. pneumoniae, in which respiratory transmission has already been documented. Oral swab samples from 10 patients with CF and 15 household members were collected at baseline and 2 weeks later. P. aeruginosa and S. pneumoniae were assessed using standardized culture methods and PCR, and P. jirovecii was assessed using real and nested PCR, genotyping the positive samples by direct sequencing. P. aeruginosa cultures were positive for 7/10 (70%) of patients with CF at baseline and was identified by PCR in 8/10 (80%) of cases at baseline and 2 weeks later. S. pneumoniae cultures were negative for all patients, but the microorganism was identified by PCR in two cases. P. jirovecii was detected by real time and nested PCR in 5/10 (50%) of the patients at the two time points. In the household members, P. aeruginosa and P. jirovecii were identified in 7/15 (46.7%), and S. pneumoniae was identified in 8/15 (53,3%). The concordance of positive or negative pairs of patients with CF and their household members was 33.3% (5/15) for P. aeruginosa, 46.7% (7/15) for S. pneumonia and 93.3% (14/15) for P. jirovecii. The concordance for P. jirovecii genotypes among five pairs with available genotype was 100%. This study suggests for the first time the possible transmission of Pneumocystis in the home of patients with CF, indicating that patients and their household members are reservoirs and possible sources of infection.
LAY SUMMARY
This study suggests for the first time the possible transmission of Pneumocystis in the family environment of patients with cystic fibrosis, indicating that patients and their household members are reservoirs and possible sources of this infection.
Topics: Adolescent; Adult; Child; Cystic Fibrosis; Family Characteristics; Female; Genotype; Humans; Infectious Disease Transmission, Vertical; Male; Pilot Projects; Pneumococcal Infections; Pneumocystis carinii; Pneumonia, Pneumocystis; Polymerase Chain Reaction; Pseudomonas Infections; Pseudomonas aeruginosa; Streptococcus pneumoniae; Young Adult
PubMed: 33693837
DOI: 10.1093/mmy/myab010 -
The Journal of Experimental Medicine Dec 2021AIOLOS/IKZF3 is a member of the IKAROS family of transcription factors. IKAROS/IKZF1 mutations have been previously associated with different forms of primary...
AIOLOS/IKZF3 is a member of the IKAROS family of transcription factors. IKAROS/IKZF1 mutations have been previously associated with different forms of primary immunodeficiency. Here we describe a novel combined immunodeficiency due to an IKZF3 mutation in a family presenting with T and B cell involvement, Pneumocystis jirovecii pneumonia, and/or chronic lymphocytic leukemia. Patients carrying the AIOLOS p.N160S heterozygous variant displayed impaired humoral responses, abnormal B cell development (high percentage of CD21low B cells and negative CD23 expression), and abrogated CD40 responses. Naive T cells were increased, T cell differentiation was abnormal, and CD40L expression was dysregulated. In vitro studies demonstrated that the mutant protein failed DNA binding and pericentromeric targeting. The mutant was fully penetrant and had a dominant-negative effect over WT AIOLOS but not WT IKAROS. The human immunophenotype was recapitulated in a murine model carrying the corresponding human mutation. As demonstrated here, AIOLOS plays a key role in T and B cell development in humans, and the particular gene variant described is strongly associated with immunodeficiency and likely malignancy.
Topics: Adult; Animals; B-Lymphocytes; Child; Female; Humans; Ikaros Transcription Factor; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Mice, Inbred C57BL; Mice, Mutant Strains; Middle Aged; Mutation; Pneumonia, Pneumocystis; T-Lymphocytes; Exome Sequencing; Mice
PubMed: 34694366
DOI: 10.1084/jem.20211118 -
Clinical Infectious Diseases : An... Mar 2021Pneumocystis jirovecii pneumonia (PCP) causes substantive morbidity in immunocompromised patients. The EORTC/MSGERC convened an expert group to elaborate consensus...
BACKGROUND
Pneumocystis jirovecii pneumonia (PCP) causes substantive morbidity in immunocompromised patients. The EORTC/MSGERC convened an expert group to elaborate consensus definitions for Pneumocystis disease for the purpose of interventional clinical trials and epidemiological studies and evaluation of diagnostic tests.
METHODS
Definitions were based on the triad of host factors, clinical-radiologic features, and mycologic tests with categorization into probable and proven Pneumocystis disease, and to be applicable to immunocompromised adults and children without human immunodeficiency virus (HIV). Definitions were formulated and their criteria debated and adjusted after public consultation. The definitions were published within the 2019 update of the EORTC/MSGERC Consensus Definitions of Invasive Fungal Disease. Here we detail the scientific rationale behind the disease definitions.
RESULTS
The diagnosis of proven PCP is based on clinical and radiologic criteria plus demonstration of P. jirovecii by microscopy using conventional or immunofluorescence staining in tissue or respiratory tract specimens. Probable PCP is defined by the presence of appropriate host factors and clinical-radiologic criteria, plus amplification of P. jirovecii DNA by quantitative real-time polymerase chain reaction (PCR) in respiratory specimens and/or detection of β-d-glucan in serum provided that another invasive fungal disease and a false-positive result can be ruled out. Extrapulmonary Pneumocystis disease requires demonstration of the organism in affected tissue by microscopy and, preferably, PCR.
CONCLUSIONS
These updated definitions of Pneumocystis diseases should prove applicable in clinical, diagnostic, and epidemiologic research in a broad range of immunocompromised patients without HIV.
Topics: Adult; Child; Diagnostic Tests, Routine; HIV; HIV Infections; Humans; Pneumocystis carinii; Pneumonia, Pneumocystis; Sensitivity and Specificity
PubMed: 33709126
DOI: 10.1093/cid/ciaa1805 -
Frontiers in Immunology 2022pneumonia (PCP) is a common medical issue in immunosuppressive patients. Increasing evidence supports that B cells may play an essential role in PCP individuals. The...
BACKGROUND
pneumonia (PCP) is a common medical issue in immunosuppressive patients. Increasing evidence supports that B cells may play an essential role in PCP individuals. The present study aims to integrate lncRNA and mRNA expression profiles and further investigate the molecular function of mature B cells in PCP.
METHODS
The lung tissue of wild-type (WT) mice and B-cell-activating factor receptor-deficient (mature B-cell deficiency, BAFF-R) mice were harvested at 3 weeks after being infected with pneumocystis. After total RNAs were extracted, transcriptome profiling was performed following the Illumina HiSeq 3000 protocol. lncRNA-targeted miRNA pairs were predicted using the online databases. The Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) enrichment pathways were analyzed to functionally annotate these differentially expressed genes. Additionally, the immune-related lncRNA-miRNA-mRNA-ceRNA network was subsequently performed. The quantitative real-time PCR (RT-PCR) analysis was conducted to evaluate the lncRNA and mRNA expression profiles in WT-PCP mice and BAFF-R PCP mice.
RESULTS
Compared with the control group, 166 mRNAs were observed to be aberrantly expressed (fold change value ≥2; 0.05) in the BAFF-R PCP group, including 39 upregulated and 127 downregulated genes, while there were 69 lncRNAs differently expressed in the BAFF-R PCP group, including 15 upregulated and 54 downregulated genes. In addition, GO and KEGG pathway analyses showed that BAFF-R deficiency played an important role in the primary and adaptive immune responses in PCP. Furthermore, the lncRNA and mRNA co-expression network was established. We noted that the core network of lncRNA-TF (transcription factor) pairs could be classified into the categories including infection and immunity pathways.
CONCLUSION
In summary, in this study, we further explored the role of mature B cells in the pathogenesis and progression of PCP and the data demonstrated that BAFF-R deficiency could play a significant role in immune regulation in the PCP population.
Topics: Animals; B-Cell Activation Factor Receptor; Lung; Mice; MicroRNAs; Pneumocystis; RNA, Long Noncoding; RNA, Messenger
PubMed: 35774783
DOI: 10.3389/fimmu.2022.898660 -
Medical Mycology Oct 2019The genus Pneumocystis comprises potential pathogens that reside normally in the lungs of a wide range of mammals. Although they generally behave as transient or...
The genus Pneumocystis comprises potential pathogens that reside normally in the lungs of a wide range of mammals. Although they generally behave as transient or permanent commensals, they can occasionally cause life-threatening pneumonia (Pneumocystis pneumonia; PCP) in immunosuppressed individuals. Several decades ago, the presence of Pneumocystis morphotypes (trophic forms and cysts) was described in the lungs of normal cats and cats with experimentally induced symptomatic PCP (after immunosuppression by corticosteroids); yet to date spontaneous or drug-induced PCP has not been described in the clinical feline literature, despite immunosuppression of cats by long-standing retrovirus infections or after kidney transplantation. In this study, we describe the presence of Pneumocystis DNA in the lungs of normal cats (that died of various unrelated causes; n = 84) using polymerase chain reactions (PCRs) targeting the mitochondrial small and large subunit ribosomal RNA gene (mtSSU rRNA and mtLSU rRNA). The presence of Pneumocystis DNA was confirmed by sequencing in 24/84 (29%) cats, with evidence of two different sequence types (or lineages). Phylogenetically, lineage1 (L1; 19 cats) and lineage 2 (L2; 5 cats) formed separate clades, clustering with Pneumocystis from domestic pigs (L1) and carnivores (L2), respectively. Results of the present study support the notion that cats can be colonized or subclinically infected by Pneumocystis, without histological evidence of damage to the pulmonary parenchyma referable to pneumocystosis. Pneumocystis seems most likely an innocuous pathogen of cats' lungs, but its possible role in the exacerbation of chronic pulmonary disorders or viral/bacterial coinfections should be considered further in a clinical setting.
Topics: Animals; Cat Diseases; Cats; DNA, Fungal; Female; Lung; Male; Phylogeny; Pneumocystis; Pneumonia, Pneumocystis; RNA, Mitochondrial; RNA, Ribosomal
PubMed: 30566653
DOI: 10.1093/mmy/myy139 -
Medical Science Monitor : International... Aug 2022BACKGROUND Sepsis is a serious threat to human life, particularly in immunocompromised patients; hence, early diagnosis and targeted treatment are important. Metagenomic...
BACKGROUND Sepsis is a serious threat to human life, particularly in immunocompromised patients; hence, early diagnosis and targeted treatment are important. Metagenomic next-generation sequencing (NGS) has significant advantages over traditional diagnostic methods. This study investigated the clinical value of NGS for pathogen identification in immunocompromised patients with sepsis. MATERIAL AND METHODS From July 2020 to September 2021, 90 consecutive patients with sepsis were enrolled in this prospective study. The patients were divided into 2 groups: an immunocompromised group (n=30) and an immunocompetent group (n=60). The pathogens causing sepsis were concurrently identified using NGS and traditional diagnostic methods. The pathogen detection rates and the spectrum of pathogens identified were compared according to the method of detection and between the immunocompromised and immunocompetent groups. RESULTS Of the 90 patients, 77 (86%) were positive for 1 or more pathogens using NGS, and 50 (56%) were positive using traditional detection methods. The positivity rate of sputum and bronchoalveolar lavage fluid was higher than that of blood samples. Pneumocystis jirovecii and cytomegalovirus infections were more common in the immunocompromised group than in the immunocompetent group. CONCLUSIONS The performance of NGS in identifying pathogens for patients with sepsis is better than that of traditional detection methods, especially in immunocompromised patients. Pneumocystis jirovecii and cytomegalovirus infections are more common in immunocompromised patients.
Topics: Bronchoalveolar Lavage Fluid; Cytomegalovirus Infections; High-Throughput Nucleotide Sequencing; Humans; Immunocompromised Host; Pneumocystis carinii; Prospective Studies; Sepsis
PubMed: 35957507
DOI: 10.12659/MSM.937041