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Infectious Disease Clinics of North... Sep 2023Pneumocystis infection manifests predominantly as an interstitial pneumonia in immunocompromised patients. Diagnostic testing in the appropriate clinical context can be... (Review)
Review
Pneumocystis infection manifests predominantly as an interstitial pneumonia in immunocompromised patients. Diagnostic testing in the appropriate clinical context can be highly sensitive and specific and involves radiographic imaging, fungal biomarkers, nucleic acid amplification, histopathology, and lung fluid or tissue sampling. Trimethoprim-sulfamethoxazole remains the first-choice agent for treatment and prophylaxis. Investigation continues to promote a deeper understanding of the pathogen's ecology, epidemiology, host susceptibility, and optimal treatment and prevention strategies in solid organ transplant recipients.
Topics: Humans; Pneumonia, Pneumocystis; Pneumocystis carinii; Organ Transplantation; Trimethoprim, Sulfamethoxazole Drug Combination; Immunocompromised Host
PubMed: 37142510
DOI: 10.1016/j.idc.2023.03.005 -
Journal of Molecular Medicine (Berlin,... Oct 2023The transcription factor GATA2 is involved in human diseases ranging from hematopoietic disorders, to cancer, to infectious diseases. GATA2 is one of six GATA-family... (Review)
Review
The transcription factor GATA2 is involved in human diseases ranging from hematopoietic disorders, to cancer, to infectious diseases. GATA2 is one of six GATA-family transcription factors that act as pioneering transcription factors which facilitate the opening of heterochromatin and the subsequent binding of other transcription factors to induce gene expression from previously inaccessible regions of the genome. Although GATA2 is essential for hematopoiesis and lymphangiogenesis, it is also expressed in other tissues such as the lung, prostate gland, gastrointestinal tract, central nervous system, placenta, fetal liver, and fetal heart. Gene or transcriptional abnormalities of GATA2 causes or predisposes patients to several diseases including the hematological cancers acute myeloid leukemia and acute lymphoblastic leukemia, the primary immunodeficiency MonoMAC syndrome, and to cancers of the lung, prostate, uterus, kidney, breast, gastric tract, and ovaries. Recent data has also linked GATA2 expression and mutations to responses to infectious diseases including SARS-CoV-2 and Pneumocystis carinii pneumonia, and to inflammatory disorders such as atherosclerosis. In this article we review the role of GATA2 in the etiology and progression of these various diseases.
PubMed: 37624387
DOI: 10.1007/s00109-023-02359-8 -
Infection and Drug Resistance 2023Metagenomic next-generation sequencing (mNGS) is a promising tool for improving antimicrobial therapy and infection control decision-making in complex infections....
BACKGROUND
Metagenomic next-generation sequencing (mNGS) is a promising tool for improving antimicrobial therapy and infection control decision-making in complex infections. Secondary infection surveillance using mNGS in COVID-19 patients has rarely been reported.
METHODS
Respiratory pathogen and antibiotic resistance prediction were evaluated by BALF mNGS for 192 hospitalized COVID-19 patients between December 2022 and February 2023.
RESULTS
Secondary infection was confirmed in 83.3% (160/192) of the COVID-19 patients, with bacterial infections (45%, 72/160) predominating, followed by mixed bacterial and fungal infections (20%, 32/160), and fungal infections (17.5%, 28/160). The incidence of bacterial or viral secondary infection was significantly higher in patients who were admitted to the ICU, received mechanical ventilation, or developed severe pneumonia (all p<0.05). (n=30, 8.4%) was the most prevalent pathogen associated with secondary infection followed by (n=29, 8.1%), (n=29, 8.1%), (n=27, 7.6%), (n=23, 6.4%), (n=20, 5.6%) and (n=14, 3.9%). The overall concordance between the resistance genes detected by mNGS and the reported phenotypic resistance in 69 samples containing five clinically important pathogens (ie, and ) that caused secondary infection was 85.5% (59/69).
CONCLUSION
mNGS can detect pathogens causing secondary infection and predict antimicrobial resistance for COVID19 patients. This is crucial for initiating targeted treatment and rapidly detect unsuspected spread of multidrug-resistant pathogens.
PubMed: 37795203
DOI: 10.2147/IDR.S424061 -
Diagnostics (Basel, Switzerland) Apr 2024A 54-year-old woman presented to an outpatient clinic with a recurrence of triple-negative breast cancer and multiple bone metastases. The patient had a large mass...
A 54-year-old woman presented to an outpatient clinic with a recurrence of triple-negative breast cancer and multiple bone metastases. The patient had a large mass lesion of 10 cm on the sternum. She received the immune checkpoint inhibitors pembrolizumab and taxane. Initially, the patient responded excellently to treatment, but stopped pembrolizumab for grade IV skin toxicity with multiple ulcerative wounds over the bilateral leg and trunk. The lesions abated following administration of antibiotics and oral prednisolone for two months. After that, she was referred to the radiation oncology department for further treatment. She received radiotherapy for the sternum mass but stopped radiation at 42Gy/21 fractions for severe dyspnea and fever. Blood sampling found leukocytosis with neutrophil predominance. Chest radiography showed bilateral lung infiltration. Pulmonary CT scan yielded bilateral lung patchy consolidation compatible with radiation isodose-line. Bronchial lavage showed positive Pneumocystis jiroveci PCR. Dyspnea improved after titrating methylprednisolone within two days. The patient recovered well with TMP-SMX and glucocorticoids after the initiation of therapy.
PubMed: 38667495
DOI: 10.3390/diagnostics14080850 -
Medical Mycology Sep 2023Pneumocystis jirovecii is a transmissible fungus responsible for severe pneumonia (Pneumocystis pneumonia [PCP]) in immunocompromised patients. Missense mutations due to... (Review)
Review
Pneumocystis jirovecii is a transmissible fungus responsible for severe pneumonia (Pneumocystis pneumonia [PCP]) in immunocompromised patients. Missense mutations due to atovaquone selective pressure have been identified on cytochrome b (CYB) gene of P. jirovecii. It was recently shown that atovaquone prophylaxis can lead to the selection of specific P. jirovecii CYB mutants potentially resistant to atovaquone among organ transplant recipients. In this context, our objectives were to provide data on P. jirovecii CYB mutants and the putative selective pressure exerted by atovaquone on P. jirovecii organisms in France. A total of 123 patients (124 P. jirovecii specimens) from four metropolitan hospitals and two overseas hospitals were retrospectively enrolled. Fourteen patients had prior exposure to atovaquone, whereas 109 patients did not at the time of P. jirovecii detection. A 638 base-pair fragment of the CYB gene of P. jirovecii was amplified and sequenced. A total of 10 single nucleotide polymorphisms (SNPs) were identified. Both missense mutations C431T (Ala144Val) and C823T (Leu275Phe), located at the Qo active site of the enzyme, were significantly associated with prior atovaquone exposure, these mutations being conversely incidental in the absence of prior atovaquone exposure (P < 0.001). Considering that the aforementioned hospitals may be representative of the national territory, these findings suggest that the overall presence of P. jirovecii CYB mutants remains low in France.
Topics: Animals; Pneumocystis carinii; Atovaquone; Cytochromes b; Retrospective Studies; Mutation
PubMed: 37656874
DOI: 10.1093/mmy/myad095 -
Clinical Microbiology and Infection :... Jul 2024Pneumocystis jirovecii pneumonia (PCP) is a common opportunistic infection among people living with HIV (PWH), particularly among new and untreated cases. Several... (Meta-Analysis)
Meta-Analysis Comparative Study Review
Comparative efficacy and safety of Pneumocystis jirovecii pneumonia prophylaxis regimens for people living with HIV: a systematic review and network meta-analysis of randomized controlled trials.
BACKGROUND
Pneumocystis jirovecii pneumonia (PCP) is a common opportunistic infection among people living with HIV (PWH), particularly among new and untreated cases. Several regimens are available for the prophylaxis of PCP, including trimethoprim-sulfamethoxazole (TMP-SMX), dapsone-based regimens (DBRs), aerosolized pentamidine (AP), and atovaquone.
OBJECTIVES
To compare the efficacy and safety of PCP prophylaxis regimens in PWH by network meta-analysis.
METHODS
DATA SOURCES: Embase, MEDLINE, and CENTRAL from inception to June 21, 2023.
STUDY ELIGIBILITY CRITERIA
Comparative randomized controlled trials (RCTs).
PARTICIPANTS
PWH.
INTERVENTIONS
Regimens for PCP prophylaxis either compared head-to-head or versus no treatment/placebo.
ASSESSMENT OF RISK OF BIAS
Cochrane risk-of-bias tool for RCTs 2.
METHODS OF DATA SYNTHESIS
Title or abstract and full-text screening and data extraction were performed in duplicate by two independent reviewers. Data on PCP incidence, all-cause mortality, and discontinuation due to toxicity were pooled and ranked by network meta-analysis. Subgroup analyses of primary versus secondary prophylaxis, by year, and by dosage were performed.
RESULTS
A total of 26 RCTs, comprising 55 treatment arms involving 7516 PWH were included. For the prevention of PCP, TMP-SMX was ranked the most favourable agent and was superior to DBRs (risk ratio [RR] = 0.54; 95% CI, 0.36-0.83) and AP (RR = 0.53; 95% CI, 0.36-0.77). TMP-SMX was also the only agent with a mortality benefit compared with no treatment/placebo (RR = 0.79; 95% CI, 0.64-0.98). However, TMP-SMX was also ranked as the most toxic agent with a greater risk of discontinuation than DBRs (RR = 1.25; 95% CI, 1.01-1.54) and AP (7.20; 95% CI, 5.37-9.66). No significant differences in PCP prevention or mortality were detected among the other regimens. The findings remained consistent within subgroups.
CONCLUSIONS
TMP-SMX is the most effective agent for PCP prophylaxis in PWH and the only agent to confer a mortality benefit; consequently, it should continue to be recommended as the first-line agent. Further studies are necessary to determine the optimal dosing of TMP-SMX to maximize efficacy and minimize toxicity.
Topics: Humans; Pneumonia, Pneumocystis; Randomized Controlled Trials as Topic; Network Meta-Analysis; Trimethoprim, Sulfamethoxazole Drug Combination; Pneumocystis carinii; HIV Infections; AIDS-Related Opportunistic Infections; Dapsone; Pentamidine; Atovaquone; Antifungal Agents; Treatment Outcome
PubMed: 38583518
DOI: 10.1016/j.cmi.2024.03.037 -
Current Opinion in Infectious Diseases Apr 2024This review highlights the epidemiology of Pneumocystis jirovecii pneumonia in solid organ transplant recipients, advancements in the diagnostic landscape, and updates... (Review)
Review
PURPOSE OF REVIEW
This review highlights the epidemiology of Pneumocystis jirovecii pneumonia in solid organ transplant recipients, advancements in the diagnostic landscape, and updates in treatment and prevention.
RECENT FINDINGS
The increasing use of immune-depleting agents in the context of solid organ transplantation has given rise to P. jirovecii pneumonia in this population. The use of prophylaxis has dramatically reduced risk of infection; however, late-onset infections occur after cessation of prophylaxis and in the setting of lymphopenia, advancing patient age, acute allograft rejection, and cytomegalovirus infection. Diagnosis requires respiratory specimens, with PCR detection of Pneumocystis replacing traditional staining methods. Quantitative PCR may be a useful adjunct to differentiate between infection and colonization. Metagenomic next-generation sequencing is gaining attention as a noninvasive diagnostic tool. Trimethoprim-sulfamethoxazole remains the drug of choice for treatment and prevention of Pneumocystis pneumonia. Novel antifungal agents are under investigation.
SUMMARY
P. jirovecii is a fungal opportunistic pathogen that remains a cause of significant morbidity and mortality in solid organ transplant recipients. Early detection and timely treatment remain the pillars of management.
Topics: Humans; Pneumocystis carinii; Pneumonia, Pneumocystis; Trimethoprim, Sulfamethoxazole Drug Combination; Organ Transplantation; Transplantation, Homologous; Transplant Recipients
PubMed: 38230604
DOI: 10.1097/QCO.0000000000001002 -
Chest Jun 2024Pneumocystis jirovecii pneumonia (PcP) remains associated with high rates of mortality, and the impact of immunocompromising underlying disease on the clinical... (Observational Study)
Observational Study
BACKGROUND
Pneumocystis jirovecii pneumonia (PcP) remains associated with high rates of mortality, and the impact of immunocompromising underlying disease on the clinical presentation, severity, and mortality of PcP has not been adequately evaluated.
RESEARCH QUESTION
Does the underlying disease and immunosuppression causing PcP impact the outcome and clinical presentation of the disease?
STUDY DESIGN AND METHODS
In this multicenter retrospective observational study, conducted from January 2011 to December 2021, all consecutive patients admitted with a proven or probable diagnosis of PcP according to the European Organisation for Research and Treatment of Cancer consensus definitions were included to assess the epidemiology and impact of underlying immunosuppressive diseases on overall and 90-day mortality.
RESULTS
Overall, 481 patients were included in the study; 180 (37.4%) were defined as proven PcP and 301 (62.6%) were defined as probable PcP. Patients with immune-mediated inflammatory diseases (IMIDs) or solid tumors had a statistically poorer prognosis than other patients with PcP at day 90. In multivariate analysis, among the HIV-negative population, solid tumor underlying disease (OR, 5.47; 95% CI, 2.16-14.1; P < .001), IMIDs (OR, 2.19; 95% CI, 1.05-4.60; P = .037), long-term corticosteroid exposure (OR, 2.07; 95% CI, 1.03-4.31; P = .045), cysts in sputum/BAL smears (OR, 1.92; 95% CI, 1.02-3.62; P = .043), and SOFA score at admission (OR, 1.58; 95% CI, 1.39-1.82; P < .001) were independently associated with 90-day mortality. Prior corticotherapy was the only immunosuppressant associated with 90-day mortality (OR, 1.67; 95% CI, 1.03-2.71; P = .035), especially for a prednisone daily dose ≥ 10 mg (OR, 1.80; 95% CI, 1.14-2.85; P = .010).
INTERPRETATION
Among patients who were HIV-negative, long-term corticosteroid prior to PcP diagnosis was independently associated with increased 90-day mortality, specifically in patients with IMIDs. These results highlight both the needs for PcP prophylaxis in patients with IMIDs and to early consider PcP curative treatment in severe pneumonia among patients with IMIDs.
Topics: Humans; Pneumonia, Pneumocystis; Male; Female; Retrospective Studies; Middle Aged; Prognosis; Aged; Pneumocystis carinii; Immunocompromised Host; Risk Factors
PubMed: 38215935
DOI: 10.1016/j.chest.2024.01.015 -
Antimicrobial Agents and Chemotherapy Mar 2024cyst life forms contain abundant β-glucan carbohydrates, synthesized using β-1,3 and β-1,6 glucan synthase enzymes and the donor uridine diphosphate (UDP)-glucose....
cyst life forms contain abundant β-glucan carbohydrates, synthesized using β-1,3 and β-1,6 glucan synthase enzymes and the donor uridine diphosphate (UDP)-glucose. In yeast, phosphoglucomutase (PGM) plays a crucial role in carbohydrate metabolism by interconverting glucose 1-phosphate and glucose 6-phosphate, a vital step in UDP pools for β-glucan cell wall formation. This pathway has not yet been defined in . Herein, we surveyed the and genomes, which predicted a homolog of the major PGM enzyme. Furthermore, we show that PjPgm2p and PmPgm2p function similarly to the yeast counterpart. When both homologs are heterologously expressed in cells, both genes can restore growth and sedimentation rates to wild-type levels. Additionally, we demonstrate that yeast cell lysates expressing the two transcripts individually can restore PGM activities significantly altered in the yeast strain. The addition of lithium, a competitive inhibitor of yeast PGM activity, significantly reduces PGM activity. Next, we tested the effects of lithium on viability and found the compound displays significant anti- activity. Finally, we demonstrate that a para-aryl derivative (ISFP10) with known inhibitory activity against the PGM protein and exhibiting 50-fold selectivity over the human PGM enzyme homolog can also significantly reduce Pmpgm2 activity . Collectively, our data genetically and functionally validate phosphoglucomutases in both and and suggest the potential of this protein as a selective therapeutic target for individuals with pneumonia.
Topics: Humans; Pneumocystis carinii; Pneumonia, Pneumocystis; Phosphoglucomutase; Saccharomyces cerevisiae; Lithium; Pneumocystis; beta-Glucans; Phosphates; Glucose; Uridine Diphosphate
PubMed: 38259086
DOI: 10.1128/aac.00756-23 -
Cureus Oct 2023Infections caused by ()and ( pneumonia (PJP)) require weight-based dosing for co-trimoxazole. The aim of this study is to assess the appropriateness of co-trimoxazole...
BACKGROUND
Infections caused by ()and ( pneumonia (PJP)) require weight-based dosing for co-trimoxazole. The aim of this study is to assess the appropriateness of co-trimoxazole dosing in adult inpatients for the treatment of these infections.
METHODOLOGY
This is a single-center, cross-sectional study that included adult inpatients treated with co-trimoxazole for a weight-based dose indication ( and PJP). The primary outcome was the appropriateness of co-trimoxazole dosing for these infections.
RESULTS
Forty-three patients were included in the study. Of the 43 patients, 29 (67.4%) were using co-trimoxazole for PJP treatment, and 14 (32.6%) were using it for treatment. The co-trimoxazole dose was appropriate in 22 (51.2%) patients, 21 (72.4%) in the PJP treatment group, and one (7.1%) in the treatment group. Underdosing was observed in 21 (48.8%) patients, of whom eight (27.6%) were in the PJP treatment group and 13 (92.9%) were in the treatment group.
CONCLUSIONS
This study found a relatively high rate of underdosing of co-trimoxazole based on weight in hospitalized adults with PJP and infections.
PubMed: 38022178
DOI: 10.7759/cureus.47400