Circulating microbial cell-free DNA is associated with inflammatory host-responses in severe pneumonia

Yang, Haopu; Haidar, Ghady; Al-Yousif, Nameer; Zia, Hassaan; Kotok, Daniel; Ahmed, Asim A.; Blair, Lily; Dalai, Sudeb C.; Bercovici, Sivan; Ho, Ching Lin; McVerry, Bryan J.; Morris, Alison; Kitsios, Georgios D

doi:10.1136/thoraxjnl-2020-216013

Cited by 14 publications

(19 citation statements)

References 11 publications

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“…McfDNA species may reflect SI-causal pathogens (regardless of their viability in the bloodstream), but may also signify lung barrier disruption in patients with acute lung injury from COVID-19, or even gut barrier disruption in patients with circulatory shock and hypoperfusion. 14 Thus, positive mcfDNA calls should not be directly interpreted as evidence of superinfecting pathogens, but interpreted within the context of a critical illness with colonized mucosal surfaces by microbiota and impaired barrier function. The significant correlation between hcfDNA levels and RALE scores suggests that lung injury may account, at least in part, for the systemic levels of circulating hfcDNA.…”

Section: Discussionmentioning

confidence: 99%

“…14 For contextualization, we compared mcfDNA levels among subjects with COVID-19 with our previously published dataset of mechanically ventilated patients with and without pneumonia. 14 To profile the host response, we measured plasma levels of nine prognostic biomarkers (eight interleukin [IL]-6, IL-8, pentraxin-3, procalcitonin, receptor for advanced glycation end products [RAGE], angiopoietin-2 (Ang-2), suppression of tumorigenicity [ST]-2, and tumor necrosis factor receptor [TNFR]-1 with Luminex, and surfactant Protein D [SPD] with ELISA; R&D Systems, Minnesota). We measured plasma SARS-CoV-2 viral levels (vRNA) following RNA extraction and qPCR amplification with a sensitive in-house method.…”

Section: Methodsmentioning

confidence: 99%

“…We classified microbes identified by mcfDNA-Seq into recognized respiratory pathogens vs. microbes of unclear clinical importance. 14 For contextualization, we compared mcfDNA levels among subjects with COVID-19 with our previously published dataset of mechanically ventilated patients with and without pneumonia. 14…”

Section: Methodsmentioning

confidence: 99%

“…14 For contextualization, we compared mcfDNA levels among subjects with COVID-19 with our previously published dataset of mechanically ventilated patients with and without pneumonia. 14…”

Section: Methodsmentioning

confidence: 99%

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Noninvasive diagnosis of secondary infections in COVID-19 by sequencing of plasma microbial cell-free DNA

Lisius

Duttagupta²,

Ahmed³

et al. 2022

Preprint

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Background: Secondary infection (SI) diagnosis in COVID-19 is challenging, due to overlapping clinical presentations, practical limitations in obtaining samples from the lower respiratory tract (LRT), and low sensitivity of microbiologic cultures. Research Question: Can metagenomic sequencing of plasma microbial cell-free DNA (mcfDNA-Seq) help diagnose SIs complicating COVID-19? Study Design and Methods: We enrolled 42 inpatients with COVID-19 classified as microbiologically-confirmed SI (Micro-SI, n=8), clinically-diagnosed SI (Clinical-SI, n=13, i.e. empiric antimicrobials), or no clinical suspicion for SI (No-Suspected-SI, n=21) at time of enrollment. From baseline and follow-up plasma samples (days 5 and 10 post-enrollment), we quantified mcfDNA for all detected microbes by mcfDNA sequencing and measured nine host-response biomarkers. From LRT samples among intubated subjects, we quantified bacterial burden with 16S rRNA gene quantitative PCR. Results: We performed mcfDNA-Seq in 82 plasma samples. Sequencing was successful in 60/82 (73.2%) samples, which had significantly lower levels of human cfDNA than failed samples (p<0.0001). McfDNA detection was significantly higher in Micro-SI (15/16 [94%]) compared to Clinical-SI samples (8/14 [57%], p=0.03), and unexpectedly common in No-Suspected-SI samples (25/30 [83%]), similar to detection rate in Micro-SI. We detected culture-concordant mcfDNA species in 13/16 Micro-SI samples (81%) and mcfDNA levels tracked with SI outcome (resolution or persistence) under antibiotic therapy. McfDNA levels correlated significantly with LRT bacterial burden (r=0.74, p=0.02) as well as plasma biomarkers of host response (white blood cell count, IL-6, IL-8, and SPD, all p<0.05). Baseline mcfDNA levels were predictive of worse 90-day survival (hazard ratio 1.30 [1.02-1.64] for each log10 mcfDNA, p=0.03). Interpretation: High circulating levels of mcfDNA in a substantial proportion of patients with COVID-19 without clinical suspicion for SI suggest that SIs may often remain undiagnosed. McfDNA-Seq, when clinically available, can offer a non-invasive diagnostic tool for pathogen identification, with prognostic value on host inflammatory response and clinical outcomes.

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

“…14 For contextualization, we compared mcfDNA levels among subjects with COVID-19 with our previously published dataset of mechanically ventilated patients with and without pneumonia. 14…”

Section: Methodsmentioning

confidence: 99%

See 2 more Smart Citations

Noninvasive diagnosis of secondary infections in COVID-19 by sequencing of plasma microbial cell-free DNA

Lisius

Duttagupta²,

Ahmed³

et al. 2022

Preprint

Self Cite

View full text Add to dashboard Cite

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“…[19][20][21][22][23] Studies have reported that plasma mNGS has moderate sensitivity and high specificity for invasive mold infections in pulmonary patients 23 and is highly consistent with BALF mNGS in patients with severe pneumonia. 19 Yang et al 24 also found a novel link between plasma mNGS and systemic inflammation in patients with severe pneumonia. However, two other studies suggested that BALF mNGS is more sensitive than plasma mNGS in patients with pneumonia, and concordance between paired BALF and plasma was not sufficient.…”

Section: Introductionmentioning

confidence: 93%

A Paired Comparison of Plasma and Bronchoalveolar Lavage Fluid for Metagenomic Next-Generation Sequencing in Critically Ill Patients with Suspected Severe Pneumonia

Sun¹,

Liu²,

Cai³

et al. 2022

IDR

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Purpose Plasma metagenomic next-generation sequencing (mNGS) has emerged as an attractive and minimally invasive technique for pathogen detection. However, few studies have demonstrated the need for simultaneous plasma and bronchoalveolar lavage fluid (BALF) mNGS in patients with severe pneumonia. Patients and Methods This study retrospectively performed a paired comparison of BALF and plasma mNGS in critically ill patients with suspected severe pneumonia from April 2019 to December 2020. The diagnostic performance of BALF and plasma mNGS was compared using the clinical composite diagnosis as the reference standard. Results In total, 57 patients were included in this study. Patients with positive plasma mNGS had shorter hospital stay days at the time of specimen acquisition (4.5 vs 11, P = 0.028) and a higher positivity rate of BALF culture (50% vs 22.9%, P = 0.033) than patients with negative plasma mNGS. Fifty-three patients (93%) were finally diagnosed with severe pneumonia. Significant differences were observed in the sensitivity of BALF and plasma mNGS (100% vs 42%, P < 0.001), and the diagnostic accuracy was 96% and 46%, respectively. The proportion of virus in positive plasma mNGS results was higher than that in BALF mNGS (23% vs 11%, P = 0.173) without significant difference. Although plasma mNGS detected additional microorganisms in 11/53 patients, the beneficial effect was observed in only 5/53 (9%) patients. Conclusion In this study, the clinical effect of simultaneously conducting mNGS of BALF and plasma samples was found to be limited. For patients with the suspected virus infection, plasma mNGS may be a supplementary test. Further studies are needed to identify the optimal indications for plasma mNGS.

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Molecular insight into pentraxin-3: Update advances in innate immunity, inflammation, tissue remodeling, diseases, and drug role

Zhang

Wang

et al. 2022

Biomedicine & Pharmacotherapy

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Circulating microbial cell-free DNA is associated with inflammatory host-responses in severe pneumonia

Cited by 14 publications

References 11 publications

Noninvasive diagnosis of secondary infections in COVID-19 by sequencing of plasma microbial cell-free DNA

Noninvasive diagnosis of secondary infections in COVID-19 by sequencing of plasma microbial cell-free DNA

A Paired Comparison of Plasma and Bronchoalveolar Lavage Fluid for Metagenomic Next-Generation Sequencing in Critically Ill Patients with Suspected Severe Pneumonia

Molecular insight into pentraxin-3: Update advances in innate immunity, inflammation, tissue remodeling, diseases, and drug role

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