Prospective Validation of a Rapid Host Gene Expression Test to Discriminate Bacterial From Viral Respiratory Infection

Ko, Emily R; Henao, Ricardo; Frankey, Katherine; Petzold, Elizabeth; Isner, Pamela D; Jaehne, Anja Kathrin; Allen, Nakia; Gardner-Gray, Jayna; Hurst, Gina; Pflaum-Carlson, Jacqueline; Jayaprakash, Namita; Rivers, Emanuel P.; Wang, Henry E.; Ugalde, Irma; Amanullah, Siraj; Mercurio, Laura; Chun, Thomas H.; May, Larissa; Hickey, Robert W.; Lazarus, Jacob E.; Gunaratne, Shauna; Pallin, Daniel J.; Jambaulikar, Guruprasad; Huckins, David S.; Ampofo, Krow; Jhaveri, Ravi; Jiang, Yunyun; Komarow, Lauren; Evans, Scott; Ginsburg, Geoffrey S.; Tillekeratne, L. Gayani; McClain, Micah T.; Burke, Thomas W.; Woods, Christopher W.; Tsalik, Ephraim L.

doi:10.1001/jamanetworkopen.2022.7299

Cited by 15 publications

(11 citation statements)

References 56 publications

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“…However, technical advances have enabled highly multiplexed quantitative, real-time PCR systems that operate in a sample-in, answer-out format with results available in < 1-hour. 32,33,59 As simpler host gene expression tests continue to be developed, cost-of-goods and simplicity will be key parameters for their implementation in LMIC settings. 60 Host response-based biomarker panels have also extended to proteomics and metabolomics, 61-63 which may be less expensive and amenable to eld deployable diagnostics.…”

Section: Discussionmentioning

confidence: 99%

“…[54][55][56][57][58][59][60][61][62][63][64][65][66] vs. 37 years [IQR 26-51], p = 0.51). Those with bacterial infections were more likely to be male(p = 0.001), although this was not site or pathogen speci c. USA participants had more severe illness (intensive care [n = 25], mechanical ventilation [n = 13] and mortality [n = 11]) than those in Sri Lanka (intensive care [n = 1], mechanical ventilation [n = 1] and mortality [n = 1]).…”

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confidence: 99%

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Host-response Transcriptional Biomarkers Accurately Discriminate Bacterial and Viral Infections of Global Relevance

Reller

Tillekeratne

et al. 2023

Preprint

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Limited diagnostics challenge management of acute febrile illness and sepsis (AFI/sepsis) globally. We generated transcriptomes for a 294-participant (USA, Sri Lanka) discovery cohort with AFI/sepsis. We used lasso to derive gene expression classifiers followed by cross-validation and generated: 1) a single model to distinguish bacterial vs. viral (Global Fever-Bacterial/Viral [GF-B/V]) and 2) a two-model system to discriminate bacterial and viral in the context of noninfection (Global Fever-Bacterial/Viral/Non-infectious [GF-B/V/N]). We then translated to a multiplex RT-PCR assay and independent validation involved 101 participants (USA, Sri Lanka, Australia, Cambodia, Tanzania). The sensitivity of the GF-B/V model in the discovery cohort was 84.2% and specificity 94.7%. Validation in an independent cohort showed the GF-B/V model had sensitivity of 78.8% and specificity of 84.3%. Similarly, the discovery cohort performance characteristics for bacterial infection for the GF-B/V/N model were was 87.7% sensitivity and 84.2% specificity, respectively. For viral infection, the sensitivity was 83.7% and specificity 81.5%. In independent validation, the sensitivity and specificity were 82.7% and 80.4%, respectively, for bacterial infection and 76.5% and 80.8%, respectively, for viral infection. Performance did not vary with age, demographics, or site. Host transcriptional response diagnostics distinguish bacterial and viral illness across global sites with different endemic pathogens.

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

Host-response Transcriptional Biomarkers Accurately Discriminate Bacterial and Viral Infections of Global Relevance

Reller

Tillekeratne

et al. 2023

Preprint

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“…Using a host gene expression-based assay that quantified the expression of 45 host messenger RNAs in patients with pneumonia, Ko et al . 12 found the test had a sensitivity of 89.8% (95% CI, 77.8%–96.2%), a specificity of 82.1% (95% CI, 77.4%–86.6%) and a negative predictive value (NPV) of 97.9% (95% CI, 95.3%–99.1%) for bacterial infection. It also had an NPV of 98.9% (95% CI, 96.1%–100%) for bacterial infection when a viral aetiology was strongly suspected.…”

Section: Rapid Diagnostic Testingmentioning

confidence: 98%

“… 17 , 18 A recent study found that PCT had a sensitivity for bacterial pneumonia of only 28.6% (95% CI, 16.2%–40.9%), while the specificity was 87.0% (95% CI, 82.7%–90.7%). 12 The American Thoracic Society and IDSA CAP guidelines recommend that empirical antibiotic therapy should be initiated in adults with clinically suspected and radiographically confirmed CAP, regardless of the initial serum PCT level. 19 The COVID-19 pandemic, which has resulted in a large increase in unnecessary antibiotic use, has led to a re-examination of PCT.…”

Section: Rapid Diagnostic Testingmentioning

confidence: 99%

Antibiotic stewardship in the era of precision medicine

Watkins

2022

JAC-Antimicrobial Resistance

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Antimicrobial resistance (AMR) continues to spread at an alarming rate worldwide. Novel approaches are needed to mitigate its deleterious impact on antibiotic efficacy. Antibiotic stewardship aims to promote the appropriate use of antibiotics through evidence-based interventions. One paradigm is precision medicine, a medical model in which decisions, practices, interventions, and therapies are adapted to the individual patient based on their predicted response or risk of disease. Precision medicine approaches hold promise as a way to improve outcomes for patients with myriad illnesses, including infections such as bacteraemia and pneumonia. This review describes the latest advances in precision medicine as they pertain to antibiotic stewardship, with an emphasis on hospital-based antibiotic stewardship programmes. The impact of the COVID-19 pandemic on AMR and antibiotic stewardship, gaps in the scientific evidence, and areas for further research are also discussed.

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“…Transcriptomic signatures have specifically been studied as a means to discriminate bacterial infection (including specific pathogens, e.g., tuberculosis), non‐bacterial infection, non‐infectious processes, and guide antimicrobial interventions and have been studied in immunocompromised hosts as a way to optimize care in a challenging population 87–100 (Table 3). For example, a recent prospective study specifically examined test characteristics of an 81‐signature host‐response assay in immunocompromised versus immunocompetent subjects in discriminating bacterial, viral, and non‐infectious conditions.…”

Section: Transcriptomic Signaturesmentioning

confidence: 99%

Pathogen‐agnostic immune biomarkers that predict infection after solid organ transplantation

Imlay

Seibert

Hanson

2023

Transplant Infectious Dis

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Solid organ transplant recipients (SOTRs) remain at high risk for infection throughout their post‐transplant course. Dosing of immunosuppressive medications, strategies that prevent infection, and choice of empiric antimicrobial treatment could be optimized by a better understanding of an individual patient's risk for infectious complications. Diagnostic tests that qualitatively or quantitatively measure the function of the immune system and/or its response to infection may be useful for individualized management decisions. Numerous studies have identified an association between infectious outcomes after solid organ transplantation (SOT) and the results of a variety of non‐pathogen‐specific or “pathogen‐agnostic” immune monitoring tests. These biomarkers include humoral immune markers, functional or quantitative assessments of cellular immunity, transcriptomic‐based diagnostics, and replication of viruses within the human virome, which have been used to predict or diagnose a variety of different infectious diseases complicating SOT. In this narrative review, we discuss several host‐derived immune biomarkers that show promise for either predicting or diagnosing infection among SOTRs. However, additional studies are needed to determine the optimal use of immune response testing. Whether immune biomarkers contribute added benefits to current standard clinical care has not yet been determined. Testing must be validated across a range of clinical scenarios, including surveillance to predict infection risk and diagnosis of active infection at various time points post transplant.

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Prospective Validation of a Rapid Host Gene Expression Test to Discriminate Bacterial From Viral Respiratory Infection

Cited by 15 publications

References 56 publications

Host-response Transcriptional Biomarkers Accurately Discriminate Bacterial and Viral Infections of Global Relevance

Host-response Transcriptional Biomarkers Accurately Discriminate Bacterial and Viral Infections of Global Relevance

Antibiotic stewardship in the era of precision medicine

Pathogen‐agnostic immune biomarkers that predict infection after solid organ transplantation

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