Daily Respiratory Research Analysis
Analyzed 196 papers and selected 3 impactful papers.
Summary
Analyzed 196 papers and selected 3 impactful articles.
Selected Articles
1. Targeted next-generation sequencing implementation in Eswatini identifies rifampicin and bedaquiline resistance undetected by routine diagnostic testing.
Targeted next-generation sequencing revealed widespread rifampicin diagnostic escape due to rpoB I491F and high rates of Rv0678-mediated bedaquiline resistance in Eswatini. Routine tests under-classified resistance; tNGS informed treatment changes in 53% of patients with an 88% treatment success rate among those with outcome data, supporting regimen revision and expanded sequencing-based surveillance.
Impact: This study exposes a critical diagnostic blind spot for rifampicin and bedaquiline resistance and demonstrates real-world clinical impact of tNGS on treatment selection.
Clinical Implications: Programs in high-burden settings should incorporate tNGS to detect rpoB I491F and Rv0678 mutations, adapt DST algorithms, and reconsider BPaLM regimens where bedaquiline resistance is prevalent. Results argue for updating global drug resistance classifications and routine surveillance.
Key Findings
- tNGS detected rifampicin resistance in 159 strains; 101/159 (64%) carried rpoB I491F.
- Rv0678 mutations indicating bedaquiline resistance were found in 87 strains; 55% of all RR strains and 85% of rpoB I491F strains were genotypically BDQ-resistant.
- Routine diagnostics (Xpert Ultra, LPA, MGIT pDST) substantially under-classified resistance.
- tNGS-informed regimen changes occurred in 53% (31/59) of patients with detailed data; treatment success was 88% (52/59).
Methodological Strengths
- Real-world national implementation of tNGS with mutation-level resolution
- Linkage of genotypic resistance to clinical management changes and outcomes
Limitations
- Observational design with potential selection bias toward complex cases
- Detailed clinical outcomes available for a subset (n=59); limited phenotypic confirmation for all detected mutations
Future Directions: Scale tNGS in high-burden regions, integrate with rapid triage algorithms, and conduct prospective studies to evaluate regimen adaptations (e.g., alternatives to BPaLM) in settings with high BDQ resistance.
In Eswatini, multidrug-resistant (MDR) Mycobacterium tuberculosis (Mtb) strains harbouring the rifampicin-resistance (RR) rpoB I491F mutation are missed by routine diagnostics, including GeneXpert MTB/RIF Ultra (Xpert Ultra), line probe assays (LPA), and mycobacterium growth indicator tube (MGIT) phenotypic drug susceptibility testing (pDST). To address this diagnostic gap, Eswatini introduced targeted next-generation sequencing (tNGS) in 2019. We analysed 234 patient samples enrolled from June 2021 to December 2024 with isoniazid and/or rifampicin resistance detected by routine diagnostics, or suspected treatment failure, and obtained detailed clinical and outcome data from 59 patients. tNGS detected RR in 159 strains, of which 101 (64%) carried the rpoB I491F mutation.
2. Oral Wash PCR Improves the Diagnosis of Pneumocystis Pneumonia in Immunocompromised Patients Without HIV: A Prospective Multicenter Study.
In a prospective multicenter cohort of 369 HIV-negative immunocompromised patients, oropharyngeal wash PCR showed high positivity in definite PCP and minimal positivity in non-PCP, with markedly higher fungal loads in PCP than colonization. A 7 copies/mL threshold achieved a PPV of 90% (sensitivity 73.5%), and combining positive BDG with OW PCR further increased PPV to 92%.
Impact: Provides a scalable, noninvasive diagnostic alternative to BAL with quantitative thresholds to guide decision-making in fragile, HIV-negative immunocompromised patients.
Clinical Implications: OW PCR can be integrated into diagnostic algorithms for suspected PCP when BAL is unsafe or unavailable; adopting a load threshold (e.g., ≥7 copies/mL) and combining with serum BDG can improve rule-in accuracy and triage urgent therapy.
Key Findings
- OW PCR positivity: 81.6% in definite PCP, 30.9% in colonization, and 0% in non-PCP.
- Mean OW fungal loads were 4251±15501 copies/mL in PCP vs 3±8.5 copies/mL in colonized patients (p<0.0001).
- A 7 copies/mL OW threshold yielded PPV 90% with 73.5% sensitivity; BDG+/OW+ combined PPV was 92%.
Methodological Strengths
- Prospective multicenter design with multidisciplinary adjudication of PCP vs colonization vs non-PCP.
- Quantitative fungal load analysis and ROC-derived actionable threshold; evaluation of combinatorial testing with BDG.
Limitations
- Agreement between OW PCR and BDG was poor, indicating differing diagnostic information.
- Potential spectrum and colonization-related false positives; external validation of thresholds is needed.
Future Directions: Prospective impact and cost-effectiveness studies comparing OW-first vs BAL-first strategies, external validation of copy-number thresholds, and integration into risk-based diagnostic pathways.
BACKGROUND: Pneumocystis pneumonia (PCP) is increasingly common in HIV-negative immunocompromised patients, who generally have low fungal burdens. Bronchoalveolar lavage (BAL) may be poorly tolerated in fragile patients, and oropharyngeal wash (OW) could be an interesting alternative, but its effectiveness remains underexplored in these patients. METHODS: A prospective multicenter cohort study was conducted to assess PCR on OW in HIV-negative patients undergoing BAL to document respiratory symptoms. Beta-1-3-D-glucan (BDG) was also measured on blood samples. Patients were classified by a multidisciplinary committee as having definite PCP, colonization, possible PCP or without Pneumocystis. Positive predictive value (PPV), negative predictive value (NPV) and ROC analysis were determined for each test. Agreement between BAL PCR, OW PCR and BDG was assessed. RESULTS: Statistical analyses were performed on 369 patients: 76 with PCP, 55 colonized, 214 without Pneumocystis, and 24 possible PCP. PCR in OW was positive in 81.6%, 30.9%, 0%, and 45.8% of patients with PCP, colonization, no PCP, and possible PCP, respectively. Mean fungal loads in OW were 4251±15501 and 3±8.5 copies/mL in PCP and colonized patients, respectively (p<0.0001). PPV and NPV of OW PCR were 78.5% and 73.1%, respectively. ROC analysis identified a threshold of 7 copies/mL for OW to achieve a PPV of 90%, with a sensitivity of 73.5%. Agreement between OW PCR and BDG was poor (κ<0.4), but the combination of BDG+/OW PCR+ yielded a PPV of 92%. CONCLUSIONS: PCR on OW is a useful non-invasive tool for diagnosing PCP in HIV-negative patients.
3. Identification of Pulmonary Arterial Hypertension Patients with Venous or Capillary Involvement.
A literature-derived, clinically practical PVOD/PCH likelihood score using DLCO, exertional desaturation, PaO2, sex, smoking, and CT features achieved an AUC of 0.97 across three transplant-eligible cohorts. The tool maintained accuracy with missing data and could prevent harmful PAH therapy titrations while expediting transplant referral.
Impact: Early discrimination of PVOD/PCH within incident PAH addresses a high-mortality phenotype prone to treatment-related complications, enabling safer therapy and timely transplant evaluation.
Clinical Implications: In suspected incident PAH, applying the PVOD/PCH score before initiating vasodilator titrations may reduce risk of pulmonary edema, prioritize transplant workup, and guide tailored monitoring (e.g., oxygenation, CT reassessment).
Key Findings
- Top discriminative variables: DLCO, 6-minute walk desaturation, PaO2, sex, smoking history, CT septal line thickening, and lymphadenopathy.
- Validated across three international transplant-eligible cohorts, the score achieved ROC AUC 0.97 (95% CI 0.93–1.00).
- Model retained high accuracy despite missing data, supporting real-world applicability.
Methodological Strengths
- Pathology-confirmed cases with multi-country external validation across transplant-eligible cohorts.
- Integration of physiologic, exercise, and imaging biomarkers; robust ROC performance including simulations and missing-data tolerance.
Limitations
- Small absolute numbers inherent to a rare disease; potential selection bias toward transplant-eligible patients.
- Derivation based on literature pooling rather than large prospective registry; prospective implementation studies are lacking.
Future Directions: Prospective, pre-treatment implementation in incident PAH pathways, assessment of impact on adverse events and transplant timing, and calibration across diverse care settings.
RATIONALE: While therapeutic advances have improved survival in Group 1 Pulmonary Arterial Hypertension (PAH), patients with Group 1.5 "PAH with features of venous/capillary involvement" (formerly Pulmonary Veno-Occlusive Disease or Pulmonary Capillary Hemangiomatosis, now collectively termed PVOD/PCH) remain underrecognized, develop serious complications from usual PAH therapy titrations, and suffer high mortality awaiting necessary lung transplant. Identifying PVOD/PCH early before therapy initiation could aid management and expedite transplant referral. OBJECTIVE: We aimed to develop a likelihood score distinguishing PVOD/PCH from other forms of PAH using clinical variables. METHODS: Due to low PVOD/PCH prevalence and no dedicated registries, we leveraged published case control/series studies to assess the ability of several clinical variables to discriminate PVOD/PCH from PAH. From pooled literature-derived data, we performed Sensitivity/Specificity and simulation-based Receiver Operator Characteristic (ROC) analyses to estimate variable performance. Top-performing variables formed a PVOD/PCH Likelihood score, which had its accuracy tested for distinguishing histopathology-confirmed PVOD/PCH cases (n = 37) from PAH controls (n = 60) in three cohorts of transplant-eligible patients from the United States, Spain, and the Netherlands. MEASUREMENTS AND MAIN RESULTS: DLCO, six-minute walk desaturation, PaO2, sex, smoking history, CT septal line thickening, and CT lymphadenopathy had the highest sensitivity and specificity performance and were incorporated into the PVOD score. Across test cohorts, the score achieved a ROC area under the curve of 0.97 (95% CI 0.93-1.00) for discriminating PVOD/PCH and it retained accuracy when data were missing. CONCLUSIONS: This score could facilitate early PVOD/PCH identification in incident PAH, potentially helping expedite transplant referral and informing therapy initiation/titration decisions.