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Therapeutic Advances in Infectious... 2024Chronic pulmonary aspergillosis (CPA) is a challenging respiratory infection caused by the environmental fungus . CPA has a poor prognosis, with reported 1-year... (Review)
Review
Chronic pulmonary aspergillosis (CPA) is a challenging respiratory infection caused by the environmental fungus . CPA has a poor prognosis, with reported 1-year mortality rates ranging from 7% to 32% and 5-year mortality rates ranging from 38% to 52%. A comprehensive understanding of the pathogen, pathophysiology, risk factors, diagnosis, surgery, hemoptysis treatment, pharmacological therapy, and prognosis is essential to manage CPA effectively. In particular, drug resistance and cryptic species pose significant challenges. CPA lacks tissue invasion and has specific features such as aspergilloma. The most critical risk factor for the development of CPA is pulmonary cavitation. Diagnostic approaches vary by CPA subtype, with computed tomography (CT) imaging and IgG antibodies being key. Treatment strategies include surgery, hemoptysis management, and antifungal therapy. Surgery is the curative option. However, reported postoperative mortality rates range from 0% to 5% and complications range from 11% to 63%. Simple aspergilloma generally has a low postoperative mortality rate, making surgery the first choice. Hemoptysis, observed in 50% of CPA patients, is a significant symptom and can be life-threatening. Bronchial artery embolization achieves hemostasis in 64% to 100% of cases, but 50% experience recurrent hemoptysis. The efficacy of antifungal therapy for CPA varies, with itraconazole reported to be 43-76%, voriconazole 32-80%, posaconazole 44-61%, isavuconazole 82.7%, echinocandins 42-77%, and liposomal amphotericin B 52-73%. Combinatorial treatments such as bronchoscopic triazole administration, inhalation, or direct injection of amphotericin B at the site of infection also show efficacy. A treatment duration of more than 6 months is recommended, with better efficacy reported for periods of more than 1 year. In anticipation of improvements in CPA management, ongoing advances in basic and clinical research are expected to contribute to the future of CPA management.
PubMed: 38899061
DOI: 10.1177/20499361241253751 -
Lung Jun 2024Treatment of allergic bronchopulmonary aspergillosis (ABPA) is challenging. Biological therapies have been reported as adjunctive treatments for ABPA, primarily in case... (Review)
Review
BACKGROUND
Treatment of allergic bronchopulmonary aspergillosis (ABPA) is challenging. Biological therapies have been reported as adjunctive treatments for ABPA, primarily in case series or case reports. This study aimed to analyze the efficacy of biologics for managing ABPA both qualitatively and quantitatively.
METHODS
All articles on APBA published in October 2023 were searched in PubMed, Web of Science, ClinicalTrials.gov, and Embase databases. The effects of interest were the mean changes from baseline for outcomes, including exacerbation rates, oral corticosteroids usage (OCS), and total immunoglobulin E (IgE) levels. Reported outcomes were quantitatively synthesized by usual or individual patient data (IPD) meta-analyses. PROSPERO registration number: CRD42022373396.
RESULTS
A total of 86 studies were included in the systematic review including 346 patients. Sixteen studies on omalizumab were pooled for the usual meta-analysis. Omalizumab therapy significantly reduced exacerbation rates (- 2.29 [95%CI - 3.32, - 1.26]), OCS dosage (- 10.91 mg [95%CI - 18.98, - 2.85]), and total IgE levels (- 273.07 IU/mL [95%CI - 379.30, - 166.84]), meanwhile improving FEV1% predicted (10.09% [95%CI 6.62, 13.55]). Thirty-one studies on dupilumab, mepolizumab, or benralizumab were pooled to perform an IPD meta-analysis, retrospectively. Both dupilumab and mepolizumab significantly reduced exacerbation rates, OCS, and total IgE levels. Benralizumab showed a similar trend, but it was not statistically significant. Tezepelumab showed weak evidence of its effects on ABPA. All five biologics led to milder clinical symptoms (e.g., cough, wheezing) with serious adverse effects that happened once in omalizumab treatment.
CONCLUSION
These results indicate the clinical benefit of omalizumab, dupilumab, and mepolizumab in patients with ABPA. Further randomized, controlled studies with a larger sample size and longer follow-up are needed to confirm these findings.
PubMed: 38898129
DOI: 10.1007/s00408-024-00717-y -
PLoS Pathogens Jun 2024Invasive aspergillosis causes significant morbidity and mortality in immunocompromised patients. Natural killer (NK) cells are pivotal for antifungal defense. Thus far,...
Invasive aspergillosis causes significant morbidity and mortality in immunocompromised patients. Natural killer (NK) cells are pivotal for antifungal defense. Thus far, CD56 is the only known pathogen recognition receptor on NK cells triggering potent antifungal activity against Aspergillus fumigatus. However, the underlying cellular mechanisms and the fungal ligand of CD56 have remained unknown. Using purified cell wall components, biochemical treatments, and ger mutants with altered cell wall composition, we herein found that CD56 interacts with the A. fumigatus cell wall carbohydrate galactosaminogalactan (GAG). This interaction induced NK cell activation, degranulation, and secretion of immune-enhancing chemokines and cytotoxic effectors. Supernatants from GAG-stimulated NK cells elicited antifungal activity and enhanced antifungal effector responses of polymorphonuclear cells. In conclusion, we identified A. fumigatus GAG as a ligand of CD56 on human primary NK cells, stimulating potent antifungal effector responses and activating other immune cells.
PubMed: 38889192
DOI: 10.1371/journal.ppat.1012315 -
Microbiology Spectrum Jun 2024During construction work (2017-2019), an increase in infections was noted among pediatric patients, the majority of whom were receiving amphotericin B prophylaxis....
UNLABELLED
During construction work (2017-2019), an increase in infections was noted among pediatric patients, the majority of whom were receiving amphotericin B prophylaxis. Microsatellite genotyping was used to characterize the outbreak. A total of 153 . isolates of clinical and environmental origin were included. Clinical isolates included 140 from 119 patients. Eight patients were outbreak-related patients, whereas 111 were outbreak-unrelated patients from Danish hospitals (1994-2023). We further included four control strains. Nine isolates were from subsequent air sampling in the outbreak ward (2022-2023). Typing followed Rudramurthy et al.(S. M. Rudramurthy, H. A. de Valk, A. Chakrabarti, J. Meis, and C. H. W. Klaassen, PLoS One 6:e16086, 2011, https://doi.org/10.1371/journal.pone.0016086). Minimum spanning tree (MST) and discriminant analysis of principal components (DAPC) were used for cluster analysis. DAPC analysis placed all 153 isolates in five clusters. Microsatellite marker pattern was clearly distinct for one cluster compared to the others. The same cluster was observed in an MST. This cluster included all outbreak isolates, air-sample isolates, and additional patient isolates from the outbreak hospital, previously undisclosed as outbreak related. The highest air prevalence of was found in two technical risers of the outbreak ward, which were then sealed. Follow-up air samples were negative for . Microsatellite typing defined the outbreak as nosocomial and facilitated the identification of an in-hospital source. Six months of follow-up air sampling was without . Outbreak-related/non-related isolates were easily distinguished with DAPC and MST, as the outbreak clone's distinct marker pattern was delineated in both statistical analyses. Thus, it could be a variant of , with a niche ability to thrive in the outbreak-hospital environment.
IMPORTANCE
can cause severe infections and hospital outbreaks in immunocompromised individuals. Although lack of isogeneity does not preclude an outbreak, our study underlines the value of microsatellite genotyping in the setting of potential outbreaks. Microsatellite genotyping documented an isogenic hospital outbreak with an internal source. This provided the "smoking gun" that prompted the rapid allocation of resources for thorough environmental sampling, the results of which guided immediate and relevant cleaning and source control measures. Consequently, we advise that vulnerable patients should be protected from exposure and that genotyping be included early in potential outbreak investigations. Inspection and sampling are recommended at any site where airborne spores might disperse from. This includes rarely accessed areas where air communication to the hospital ward cannot be disregarded.
PubMed: 38888358
DOI: 10.1128/spectrum.00273-24 -
Respirology (Carlton, Vic.) Jun 2024
PubMed: 38887939
DOI: 10.1111/resp.14775 -
Open Forum Infectious Diseases Jun 2024Treatments for emerging and rare invasive fungal diseases (IFDs) represent a critical unmet medical need. For IFDs that occur less frequently than invasive... (Review)
Review
Treatments for emerging and rare invasive fungal diseases (IFDs) represent a critical unmet medical need. For IFDs that occur less frequently than invasive aspergillosis, such as mucormycosis, hyalohyphomycosis, and phaeohyphomycosis, randomized controlled clinical trials are impractical and unlikely to meet urgent public health needs. Understanding regulatory approaches for approval of drugs for rare cancers and rare metabolic diseases could help meet the challenges of studying drugs for rare IFDs. A single-arm, controlled clinical trial with a high-quality external control(s), with confirmatory evidence from nonclinical studies, including pharmacokinetic/pharmacodynamic data in predictive animal models of the disease may support findings of effectiveness of new drugs and biologics. Control populations may include historical controls from published literature, patient registries, and/or contemporaneous external control groups. Continuous engagement among clinicians, industrial sponsors, and regulatory agencies to develop consensus on trial design and innovative development pathways for emergent and rare invasive fungal diseases is important.
PubMed: 38887484
DOI: 10.1093/ofid/ofae257 -
Open Forum Infectious Diseases Jun 2024Among solid organ transplant recipients taking belatacept, 15% developed invasive fungal diseases. The most common invasive fungal diseases were aspergillosis (56%) and...
An Unexpectedly High Incidence of Invasive Fungal Diseases in Solid Organ Transplant Recipients Taking Belatacept for Organ Rejection Prophylaxis: A Single-Center Retrospective Cohort Study.
Among solid organ transplant recipients taking belatacept, 15% developed invasive fungal diseases. The most common invasive fungal diseases were aspergillosis (56%) and candidiasis (22%). The infected cohort was more likely to receive basiliximab, undergo lung transplantation, or identify as White. Higher rates of aspergillosis were seen in this lung cohort than previously reported.
PubMed: 38887477
DOI: 10.1093/ofid/ofae158 -
Open Forum Infectious Diseases Jun 2024Prior reports have suggested a possible increase in the frequency of invasive fungal infections (IFIs) with use of a Bruton tyrosine kinase inhibitor (BTKi) for...
Risk of Invasive Fungal Infections in Patients With Chronic Lymphocytic Leukemia Treated With Bruton Tyrosine Kinase Inhibitors: A Case-Control Propensity Score-Matched Analysis.
BACKGROUND
Prior reports have suggested a possible increase in the frequency of invasive fungal infections (IFIs) with use of a Bruton tyrosine kinase inhibitor (BTKi) for treatment of chronic lymphoid malignancies such as chronic lymphocytic leukemia (CLL), but precise estimates are lacking. We aim to characterize the prevalence of IFIs among patients with CLL, for whom a BTKi is now the first-line recommended therapy.
METHODS
We queried TriNetX, a global research network database, to identify adult patients with CLL using the code (C91.1) and laboratory results. We performed a case-control propensity score-matched analysis to determine IFIs events by BTKi use. We adjusted for age, sex, ethnicity, and clinical risk factors associated with an increased risk of IFIs.
RESULTS
Among 5358 matched patients with CLL, we found an incidence of 4.6% of IFIs in patients on a BTKi versus 3.5% among patients not on a BTKi at 5 years. Approximately 1% of patients with CLL developed an IFI while on a BTKi within this period. Our adjusted IFI event analysis found an elevated rate of pneumonia (PJP) (0.5% vs 0.3%, = .02) and invasive candidiasis (3.5% vs 2.7%, = .012) with the use of a BTKi. The number needed to harm for patients taking a BTKi was 120 and 358 for invasive candidiasis and PJP, respectively.
CONCLUSIONS
We found an adjusted elevated rate of PJP and invasive candidiasis with BTKi use. The rates are, however, low with a high number needed to harm. Additional studies stratifying other IFIs with specific BTKis are required to identify at-risk patients and preventive, cost-effective interventions.
PubMed: 38887474
DOI: 10.1093/ofid/ofae115 -
The Clinical Respiratory Journal Jun 2024
Allergic Bronchopulmonary Aspergillosis (ABPA) With Colonized Aspergillus fumigatus Detected by Metagenomic Next-Generation Sequencing on Tissue Samples: A Distinct Subset of ABPA With a Higher Risk of Exacerbation.
Topics: Humans; Aspergillosis, Allergic Bronchopulmonary; Aspergillus fumigatus; Male; High-Throughput Nucleotide Sequencing; Female; Middle Aged; Metagenomics; Adult; Disease Progression; Aged
PubMed: 38886877
DOI: 10.1111/crj.13794 -
Mycoses Jun 2024Serum galactomannan (GM) testing is essential for diagnosing invasive aspergillosis (IA), particularly in immunocompromised individuals. The global lack of on-site GM... (Comparative Study)
Comparative Study
BACKGROUND
Serum galactomannan (GM) testing is essential for diagnosing invasive aspergillosis (IA), particularly in immunocompromised individuals. The global lack of on-site GM testing capacities necessitates cost-effective alternatives, such as .the clarus Aspergillus GM enzyme immunoassay prototype (clarus AGM prototype).
METHODS
This single-centre, cross-sectional study compared the diagnostic performance of the clarus AGM prototype (IMMY, Norman, Oklahoma) with the serological gold standard (=Platelia AGM assay; Bio-Rad, Marnes-la-Cocquette, France). IA was classified according to modified 2020 EORTC/MSG consensus and 2024 FUNDICU criteria. In total, 300 prospectively (May-Dec 2023) and retrospectively (2012-2015) collected samples were included.
RESULTS
Among 300 samples from 232 patients, 49 (16%) were classified as proven (n = 1) or probable IA (n = 48). In non-IA cases (n = 250), one patient was classified as possible IA. With the manufacturer recommended cut-off of ≥0.2, sensitivity and specificity of the clarus AGM prototype were 27% (13/49; 95% confidence interval [CI]: 15%-41%) and 99% (248/250; 95% CI: 97%-100%), respectively, while sensitivity and specificity were 78% and 79% when using the optimised Youden's cut-off of 0.0045 ODI. ROC curve analysis demonstrated an area under the curve (AUC) of 0.829 (95% CI: 0.760-0.898) for the clarus AGM prototype in distinguishing between proven/probable IA and non-IA. The AUC for the Platelia AGM was 0.951 (95% CI: 0.909-994). Spearman's correlation analysis showed a weak correlation between the two assays (0.382; p < .001).
CONCLUSIONS
The weak correlation between the clarus AGM prototype and Platelia AGM highlights the need for further investigation into the clinical performance of the clarus AGM prototype, giving the different antigen epitopes addressed.
Topics: Humans; Mannans; Galactose; Invasive Pulmonary Aspergillosis; Immunoenzyme Techniques; Cross-Sectional Studies; Male; Middle Aged; Female; Sensitivity and Specificity; Aged; Retrospective Studies; Aspergillus; Adult; Prospective Studies; Antigens, Fungal; Aged, 80 and over; Young Adult; ROC Curve
PubMed: 38886163
DOI: 10.1111/myc.13756