Diagnostic limitations and challenges in current clinical guidelines and potential application of metagenomic sequencing to manage pulmonary invasive fungal infections in patients with haematological malignancies.

BACKGROUND: Pulmonary invasive fungal infections (pIFI) disproportionately affect patients with haematological malignancies (HM). Establishing a rapid and accurate diagnosis of pIFI is challenging. Multiple guidelines recommend diagnostic testing of invasive fungal infections but lack consensus and may contribute to inconsistent diagnostic approaches. OBJECTIVE: To identify key diagnostic challenges and review metagenomic sequencing data. SOURCES: PubMed, professional consortium, and scientific society websites search to identify relevant, published, evidence-based clinical guidelines within the past 5 years. PubMed searchs for papers describing clinically relevant novel diagnostic technologies. CONTENT: Current guidelines for patients with HM and suspected pIFI recommend chest computed tomography imaging and specimen testing with microscopic examination (including calcofluor white stain, histopathology, cytopathology, etc.), Aspergillus galactomannan, ß-D-glucan, PCR, and culture, each with certain limitations. Emerging real-world data support the adjunctive use of metagenomic sequencing-based tests for the timely diagnosis of pIFI. IMPLICATIONS: High-quality evidence from robust clinical trials is needed to determine whether guidelines should be updated to include novel diagnostic technologies. Trials should ask whether the combination of powerful novel diagnostics, such as pathogen-agnostic metagenomic sequencing technologies in conjunction with conventional testing can optimize the diagnostic yield for all potential pIFI pathogens that impact the health of patients with HM.

Plasma Microbial Cell-Free DNA Sequencing for Pathogen Detection and Quantification in Children With Musculoskeletal Infections.

BACKGROUND: Nearly half of all pediatric musculoskeletal infections (MSKIs) are culture negative. Plasma microbial cell-free DNA (mcfDNA) sequencing is noninvasive and not prone to the barriers of culture. We evaluated the performance of plasma mcfDNA sequencing in identifying a pathogen, and examined the duration of pathogen detection in children with MSKIs. METHODS: We conducted a prospective study of children, aged 6 months to 18 years, hospitalized from July 2019 to May 2022 with MSKIs, in whom we obtained serial plasma mcfDNA sequencing samples and compared the results with cultures. RESULTS: A pathogen was recovered by culture in 23 of 34 (68%) participants, and by initial mcfDNA sequencing in 25 of 31 (81%) participants. Multiple pathogens were detected in the majority (56%) of positive initial samples. Complete concordance with culture (all organisms accounted for by both methods) was 32%, partial concordance (at least one of the same organism(s) identified by both methods) was 36%, and discordance was 32%. mcfDNA sequencing was more likely to show concordance (complete or partial) if obtained prior to a surgical procedure (82%), compared with after (20%), (RR 4.12 [95% CI 1.25, 22.93], p = .02). There was no difference in concordance based on timing of antibiotics (presample antibiotics 60% vs no antibiotics 75%, RR 0.8 [95% CI 0.40, 1.46], p = .65]). mcfDNA sequencing was positive in 67% of culture-negative infections and detected a pathogen for a longer interval than blood culture (median 2 days [IQR 1, 6 days] vs 1 day [1, 1 day], p < .01). CONCLUSIONS: Plasma mcfDNA sequencing may be useful in culture-negative pediatric MSKIs if the sample is obtained prior to surgery. However, results must be interpreted in the appropriate clinical context as multiple pathogens are frequently detected supporting the need for diagnostic stewardship.

A Systematic Literature Review to Identify Diagnostic Gaps in Managing Immunocompromised Patients With Cancer and Suspected Infection.

Patients with cancer are increasingly vulnerable to infections, which may be more severe than in the general population. Improvements in rapid and timely diagnosis to optimize management are needed. We conducted a systematic literature review to determine the unmet need in diagnosing acute infections in immunocompromised patients with cancer and identified 50 eligible studies from 5188 records between 1 January 2012 and 23 June 2022. There was considerable heterogeneity in study designs and parameters, laboratory methods and definitions, and assessed outcomes, with limited evaluation of diagnostic impact on clinical outcomes. Culture remains the primary diagnostic strategy. Fewer studies employing molecular technologies exist, but emerging literature suggests that pathogen-agnostic molecular tests may add to the diagnostic armamentarium. Well-designed clinical studies using standardized methodologies are needed to better evaluate performance characteristics and clinical and economic impacts of emerging diagnostic techniques to improve patient outcomes.

Gaps in diagnosing suspected infection in immunocompromised children with cancer: A systematic review.

While the survival of children with cancer has improved over time, infection remains a major morbidity and mortality risk. We conducted a systematic literature review to determine the unmet needs in diagnosing infection in immunocompromised children with cancer. The comprehensive search strategy followed the guidelines established by the Cochrane Handbook for Systematic Reviews of Interventions and the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) 2020 statement, and spanned multiple bibliographic databases and other public sources from January 1, 2012 to June 23, 2022. From 5188 records, 34 unique pediatric-focused studies met inclusion criteria. This review highlights the lack of published data on infectious disease testing in pediatric oncology patients, and the need for well-designed clinical impact and cost-effectiveness studies of both existing and novel diagnostic platforms. Such studies are necessary to optimize diagnostic and antimicrobial stewardship, leading to improvement in patient outcomes.

Plasma Microbial Cell-Free DNA Sequencing from over 15,000 Patients Identified a Broad Spectrum of Pathogens.

Microbial cell-free DNA (mcfDNA) sequencing is an emerging infectious disease diagnostic tool which enables unbiased pathogen detection and quantification from plasma. The Karius Test, a commercial mcfDNA sequencing assay developed by and available since 2017 from Karius, Inc. (Redwood City, CA), detects and quantifies mcfDNA as molecules/µL in plasma. The commercial sample data and results for all tests conducted from April 2018 through mid-September 2021 were evaluated for laboratory quality metrics, reported pathogens, and data from test requisition forms. A total of 18,690 reports were generated from 15,165 patients in a hospital setting among 39 states and the District of Columbia. The median time from sample receipt to reported result was 26 h (interquartile range [IQR] 25 to 28), and 96% of samples had valid test results. Almost two-thirds (65%) of patients were adults, and 29% at the time of diagnostic testing had ICD-10 codes representing a diverse array of clinical scenarios. There were 10,752 (58%) reports that yielded at least one taxon for a total of 22,792 detections spanning 701 unique microbial taxa. The 50 most common taxa detected included 36 bacteria, 9 viruses, and 5 fungi. Opportunistic fungi (374 Aspergillus spp., 258 Pneumocystis jirovecii, 196 Mucorales, and 33 dematiaceous fungi) comprised 861 (4%) of all detections. Additional diagnostically challenging pathogens (247 zoonotic and vector-borne pathogens, 144 Mycobacterium spp., 80 Legionella spp., 78 systemic dimorphic fungi, 69 Nocardia spp., and 57 protozoan parasites) comprised 675 (3%) of all detections. This is the largest reported cohort of patients tested using plasma mcfDNA sequencing and represents the first report of a clinical grade metagenomic test performed at scale. Data reveal new insights into the breadth and complexity of potential pathogens identified.

Underdiagnosis of primary hyperparathyroidism in patients with osteoarthritis undergoing arthroplasty.

BACKGROUND: Primary hyperparathyroidism (HPT) is commonly underdiagnosed and undertreated. Joint pain is a nonspecific symptom associated with osteoarthritis or primary HPT. We hypothesize that patients treated for osteoarthritis are underdiagnosed with primary HPT. METHODS: Adult patients diagnosed with hip/knee osteoarthritis at the Medical College of Wisconsin from January 2000 to October 2020 were queried. Patients with a calcium level drawn within 1 year of diagnosis of osteoarthritis were included. Patients who had undergone prior parathyroidectomy were excluded. Patients were stratified by serum calcium level, HPT diagnosis, and PTH level. Arthroplasty rates were compared between groups. RESULTS: Of 54,788 patients, 9,967 patients (18.2%) had a high serum calcium level, of whom 1,089 (10.9%) had a diagnosis of HPT. Only 76 (7.0%) patients with HPT underwent parathyroidectomy, 208 (19.1%) underwent knee/hip arthroplasty, and 14 (1.3%) underwent both. Arthroplasty was performed in 1,793 patients without evaluation and/or definitive treatment for HPT. There were higher rates of arthroplasty performed in patients with a high serum calcium level compared with those without (21.2% vs 17.4%, P < .001). CONCLUSION: Patients with high serum calcium levels were more likely to undergo arthroplasty than those with normocalcemia. Hypercalcemia in the setting of hip or knee osteoarthritis should prompt a full evaluation for primary HPT.

Bleeding After LVAD Implant: If Things Do Not Add Up, Take a Look!

A 63-year-old male underwent re-exploration after HVAD implantation due to persistent postoperative bleeding. We present an unusual cause of postoperative bleeding after LVAD implantation for which early re-exploration and consideration of unusual etiologies is appropriate.