Integrated host/microbe metagenomics enables accurate lower respiratory tract infection diagnosis in critically ill children

Mick, Eran; Tsitsiklis, Alexandra; Kamm, Jack; Kalantar, Katrina; Caldera, Saharai; Lyden, Amy; Tan, Michelle; Detweiler, Angela M.; Neff, Norma; Osborne, Christina; Williamson, Kayla; Soesanto, Victoria; Leroue, Matthew K.; Maddux, Aline B; Simões, Eric A F; Carpenter, Todd; Wagner, Brandie D.; DeRisi, Joseph L.; Ambroggio, Lilliam; Mourani, Peter M.; Langelier, Charles

doi:10.1172/jci165904

Cited by 17 publications

(24 citation statements)

References 58 publications

(80 reference statements)

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“…To address these challenges, Mick and colleagues, in a recent issue of the JCI , developed a multipronged approach that distinguished pediatric patients with LRTIs from those with alternative diagnoses (including noninfectious illness and nonpulmonary infections), while simultaneously identifying the microbiological cause of the LRTI ( 4 ). Other studies combining the host immune response with microbial metagenomic next-generation sequencing (mNGS) have focused on RSV ( 5 ), adult LRTI ( 6 ), sepsis ( 7 ), and tuberculous meningitis ( 8 ).…”

Section: A Multipronged Approachmentioning

confidence: 99%

“…Other studies combining the host immune response with microbial metagenomic next-generation sequencing (mNGS) have focused on RSV ( 5 ), adult LRTI ( 6 ), sepsis ( 7 ), and tuberculous meningitis ( 8 ). In this study, the authors leveraged a previously enrolled cohort of critically ill children aged 31 days to 18 years with acute respiratory failure requiring mechanical ventilation and from whom tracheal aspirate samples were available ( 4 ). Of 261 children with confirmed infection, 95% were intubated within two days of admission, timing that is consistent with community-acquired pneumonia.…”

Section: A Multipronged Approachmentioning

confidence: 99%

“…Comparing this pediatric host response signature to one developed in an adult cohort ( 5 ), there was no overlap in differentially expressed genes. Nevertheless, it is possible the pediatric signature would perform well in the adult cohort or vice versa, because many combinations of differentially expressed genes can substitute for one another in a given classification task ( 9 ), though this possibility was not evaluated in Mick et al ( 4 ). Ideally, a universal, age-agnostic signature could be identified for future development.…”

Section: The Host Responsementioning

confidence: 99%

“…Microbial mNGS provides a broad screen for potential pathogens that is not available by standard PCR panels or culture. To distinguish potential bacterial and fungal pathogens from commensals, Mick and colleagues applied a rules-based model that ranked high-abundance species relative to the abundance of background species ( 4 , 6 ). 70% of the samples showed concordance with culture.…”

Section: Pathogen Detectionmentioning

confidence: 99%

“…Host response also provides context when microorganisms of unclear clinical importance are identified, such as through metagenomic approaches. The study presented by Mick, Tsitsiklis, and colleagues ( 4 ) goes beyond these scenarios by revealing how analysis of the host response and metagenomics can be combined synergistically. By simultaneously viewing both sides of the coin, host and pathogen, they generated a harmonious characterization of LRTI status with exceptional accuracy.…”

Section: Seeing Both Sides Of the Coinmentioning

confidence: 99%

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Viewing both sides of the coin for infectious disease diagnosis

Strouts¹,

McAllister²,

Tsalik³

2023

Journal of Clinical Investigation

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Optimal management of lower respiratory tract infection relies on distinguishing infectious from noninfectious etiologies and identifying the microbiologic cause if applicable. This process is complicated by overlapping clinical symptoms and the colonizing lung microbiota. In a recent issue of the JCI , Mick, Tsitsiklis, and colleagues apply RNA-Seq to tracheal aspirates from critically ill children and demonstrate how integration of the host response with microbial identification results in a harmonious and accurate diagnostic classifier. Though promising, there are numerous barriers to realizing a combined host and pathogen diagnostic.

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Section: A Multipronged Approachmentioning

confidence: 99%

Section: A Multipronged Approachmentioning

confidence: 99%

Section: The Host Responsementioning

confidence: 99%

Section: Pathogen Detectionmentioning

confidence: 99%

Section: Seeing Both Sides Of the Coinmentioning

confidence: 99%

See 3 more Smart Citations

Viewing both sides of the coin for infectious disease diagnosis

Strouts¹,

McAllister²,

Tsalik³

2023

Journal of Clinical Investigation

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The antibiotic resistance reservoir of the lung microbiome expands with age in a population of critically ill patients

Chu,

Tsitsiklis,

Mick

et al. 2024

Nat Commun

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Antimicrobial resistant lower respiratory tract infections are an increasing public health threat and an important cause of global mortality. The lung microbiome can influence susceptibility of respiratory tract infections and represents an important reservoir for exchange of antimicrobial resistance genes. Studies of the gut microbiome have found an association between age and increasing antimicrobial resistance gene burden, however, corollary studies in the lung microbiome remain absent. We performed an observational study of children and adults with acute respiratory failure admitted to the intensive care unit. From tracheal aspirate RNA sequencing data, we evaluated age-related differences in detectable antimicrobial resistance gene expression in the lung microbiome. Using a multivariable logistic regression model, we find that detection of antimicrobial resistance gene expression was significantly higher in adults compared with children after adjusting for demographic and clinical characteristics. This association remained significant after additionally adjusting for lung bacterial microbiome characteristics, and when modeling age as a continuous variable. The proportion of adults expressing beta-lactam, aminoglycoside, and tetracycline antimicrobial resistance genes was higher compared to children. Together, these findings shape our understanding of the lung resistome in critically ill patients across the lifespan, which may have implications for clinical management and global public health.

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Prevalence of Bacterial Codetection and Outcomes for Infants Intubated for Respiratory Infections*

Karsies,

Shein,

Diaz

et al. 2024

Pediatric Critical Care Medicine

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Objectives: To determine the prevalence of respiratory bacterial codetection in children younger than 2 years intubated for acute lower respiratory tract infection (LRTI), primarily viral bronchiolitis, and identify the association of codetection with mechanical ventilation duration. Design: Prospective observational study evaluating the prevalence of bacterial codetection (moderate/heavy growth of pathogenic bacterial plus moderate/many polymorphonuclear neutrophils) and the impact of codetection on invasive mechanical ventilation (IMV) duration. Setting: PICUs in 12 high and low/middle-income countries. Patients: Children younger than 2 years old requiring intubation and ICU admission for LRTI and who had a lower respiratory tract culture obtained at the time of intubation between December 1, 2019, and November 30, 2020. Interventions: None. Measurements and Main Results: Of the 472 analyzed patients (median age 4.5 mo), 55% had a positive respiratory culture and 29% (n = 138) had codetection. 90% received early antibiotics starting at a median of 0.36 hours after respiratory culture. Median (interquartile range) IMV duration was 151 hours (88, 226), and there were 28 deaths (5.3%). Codetection was more common with younger age, a positive respiratory syncytial virus test, and an admission diagnosis of bronchiolitis; it was less common with an admission diagnosis of pneumonia, with admission to a low-/middle-income site, and in those receiving vasopressors. When adjusted for confounders, codetection was not associated with longer IMV duration (adjusted relative risk 0.854 [95% CI 0.684–1.065]). We could not exclude the possibility that codetection might be associated with a 30-hour shorter IMV duration compared with no codetection, although the CI includes the null value. Conclusions: Bacterial codetection was present in almost a third of children younger than 2 years requiring intubation and ICU admission for LRTI, but this was not associated with prolonged IMV. Further large studies are needed to evaluate if codetection is associated with shorter IMV duration.

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Integrated host/microbe metagenomics enables accurate lower respiratory tract infection diagnosis in critically ill children

Cited by 17 publications

References 58 publications

Viewing both sides of the coin for infectious disease diagnosis

Viewing both sides of the coin for infectious disease diagnosis

The antibiotic resistance reservoir of the lung microbiome expands with age in a population of critically ill patients

Prevalence of Bacterial Codetection and Outcomes for Infants Intubated for Respiratory Infections*

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