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1.
Crit Care Med ; 49(10): 1664-1673, 2021 10 01.
Article in English | MEDLINE | ID: covidwho-1452743

ABSTRACT

OBJECTIVES: The rapid diagnosis of acute infections and sepsis remains a serious challenge. As a result of limitations in current diagnostics, guidelines recommend early antimicrobials for suspected sepsis patients to improve outcomes at a cost to antimicrobial stewardship. We aimed to develop and prospectively validate a new, 29-messenger RNA blood-based host-response classifier Inflammatix Bacterial Viral Non-Infected version 2 (IMX-BVN-2) to determine the likelihood of bacterial and viral infections. DESIGN: Prospective observational study. SETTING: Emergency Department, Campus Benjamin Franklin, Charité-Universitätsmedizin Berlin, Germany. PATIENTS: Three hundred twelve adult patients presenting to the emergency department with suspected acute infections or sepsis with at least one vital sign change. INTERVENTIONS: None (observational study only). MEASUREMENTS AND MAIN RESULTS: Gene expression levels from extracted whole blood RNA was quantified on a NanoString nCounter SPRINT (NanoString Technologies, Seattle, WA). Two predicted probability scores for the presence of bacterial and viral infection were calculated using the IMX-BVN-2 neural network classifier, which was trained on an independent development set. The IMX-BVN-2 bacterial score showed an area under the receiver operating curve for adjudicated bacterial versus ruled out bacterial infection of 0.90 (95% CI, 0.85-0.95) compared with 0.89 (95% CI, 0.84-0.94) for procalcitonin with procalcitonin being used in the adjudication. The IMX-BVN-2 viral score area under the receiver operating curve for adjudicated versus ruled out viral infection was 0.83 (95% CI, 0.77-0.89). CONCLUSIONS: IMX-BVN-2 demonstrated accuracy for detecting both viral infections and bacterial infections. This shows the potential of host-response tests as a novel and practical approach for determining the causes of infections, which could improve patient outcomes while upholding antimicrobial stewardship.


Subject(s)
Bacterial Infections/diagnosis , RNA, Messenger/analysis , Virus Diseases/diagnosis , Aged , Aged, 80 and over , Area Under Curve , Bacterial Infections/blood , Bacterial Infections/physiopathology , Berlin , Biomarkers/analysis , Biomarkers/blood , Emergency Service, Hospital/organization & administration , Emergency Service, Hospital/statistics & numerical data , Female , Humans , Male , Middle Aged , Prospective Studies , RNA, Messenger/blood , ROC Curve , Virus Diseases/blood , Virus Diseases/physiopathology
2.
Intensive Care Med Exp ; 9(1): 31, 2021 Jun 18.
Article in English | MEDLINE | ID: covidwho-1376600

ABSTRACT

BACKGROUND: Whether or not to administer antibiotics is a common and challenging clinical decision in patients with suspected infections presenting to the emergency department (ED). We prospectively validate InSep, a 29-mRNA blood-based host response test for the prediction of bacterial and viral infections. METHODS: The PROMPT trial is a prospective, non-interventional, multi-center clinical study that enrolled 397 adult patients presenting to the ED with signs of acute infection and at least one vital sign change. The infection status was adjudicated using chart review (including a syndromic molecular respiratory panel, procalcitonin and C-reactive protein) by three infectious disease physicians blinded to InSep results. InSep (version BVN-2) was performed using PAXgene Blood RNA processed and quantified on NanoString nCounter SPRINT. InSep results (likelihood of bacterial and viral infection) were compared to the adjudicated infection status. RESULTS: Subject mean age was 64 years, comorbidities were significant for diabetes (17.1%), chronic obstructive pulmonary disease (13.6%), and severe neurological disease (6.8%); 16.9% of subjects were immunocompromised. Infections were adjudicated as bacterial (14.1%), viral (11.3%) and noninfected (0.25%): 74.1% of subjects were adjudicated as indeterminate. InSep distinguished bacterial vs. viral/noninfected patients and viral vs. bacterial/noninfected patients using consensus adjudication with AUROCs of 0.94 (95% CI 0.90-0.99) and 0.90 (95% CI 0.83-0.96), respectively. AUROCs for bacterial vs. viral/noninfected patients were 0.88 (95% CI 0.79-0.96) for PCT, 0.80 (95% CI 0.72-89) for CRP and 0.78 (95% CI 0.69-0.87) for white blood cell counts (of note, the latter biomarkers were provided as part of clinical adjudication). To enable clinical actionability, InSep incorporates score cutoffs to allocate patients into interpretation bands. The Very Likely (rule in) InSep bacterial band showed a specificity of 98% compared to 94% for the corresponding PCT band (> 0.5 µg/L); the Very Unlikely (rule-out) band showed a sensitivity of 95% for InSep compared to 86% for PCT. For the detection of viral infections, InSep demonstrated a specificity of 93% for the Very Likely band (rule in) and a sensitivity of 96% for the Very Unlikely band (rule out). CONCLUSIONS: InSep demonstrated high accuracy for predicting the presence of both bacterial and viral infections in ED patients with suspected acute infections or suspected sepsis. When translated into a rapid, point-of-care test, InSep will provide ED physicians with actionable results supporting early informed treatment decisions to improve patient outcomes while upholding antimicrobial stewardship. Registration number at Clinicaltrials.gov NCT03295825.

3.
Crit Care Med ; 49(7): e720-e721, 2021 07 01.
Article in English | MEDLINE | ID: covidwho-1307567
4.
Eur J Clin Invest ; 51(12): e13626, 2021 Dec.
Article in English | MEDLINE | ID: covidwho-1273086

ABSTRACT

BACKGROUND: Fever-7 is a test evaluating host mRNA expression levels of IFI27, JUP, LAX, HK3, TNIP1, GPAA1 and CTSB in blood able to detect viral infections. This test has been validated mostly in hospital settings. Here we have evaluated Fever-7 to identify the presence of respiratory viral infections in a Community Health Center. METHODS: A prospective study was conducted in the "Servicio de Urgencias de Atención Primaria" in Salamanca, Spain. Patients with clinical signs of respiratory infection and at least one point in the National Early Warning Score were recruited. Fever-7 mRNAs were profiled on a Nanostring nCounter® SPRINT instrument from blood collected upon patient enrolment. Viral diagnosis was performed on nasopharyngeal aspirates (NPAs) using the Biofire-RP2 panel. RESULTS: A respiratory virus was detected in the NPAs of 66 of the 100 patients enrolled. Median National Early Warning Score was 7 in the group with no virus detected and 6.5 in the group with a respiratory viral infection (P > .05). The Fever-7 score yielded an overall AUC of 0.81 to predict a positive viral syndromic test. The optimal operating point for the Fever-7 score yielded a sensitivity of 82% with a specificity of 71%. Multivariate analysis showed that Fever-7 was a robust marker of viral infection independently of age, sex, major comorbidities and disease severity at presentation (OR [CI95%], 3.73 [2.14-6.51], P < .001). CONCLUSIONS: Fever-7 is a promising host immune mRNA signature for the early identification of a respiratory viral infection in the community.

6.
Crit Care Med ; 49(2): e170-e178, 2021 02 01.
Article in English | MEDLINE | ID: covidwho-930107

ABSTRACT

OBJECTIVES: Complex critical syndromes like sepsis and coronavirus disease 2019 may be composed of underling "endotypes," which may respond differently to treatment. The aim of this study was to test whether a previously defined bacterial sepsis endotypes classifier recapitulates the same clinical and immunological endotypes in coronavirus disease 2019. DESIGN: Prospective single-center observational cohort study. SETTING: Patients were enrolled in Athens, Greece, and blood was shipped to Inflammatix (Burlingame, CA) for analysis. PATIENTS: Adult patients within 24 hours of hospital admission with coronavirus disease 2019 confirmed by polymerase chain reaction and chest radiography. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We studied 97 patients with coronavirus disease 2019, of which 50 went on to severe respiratory failure (SRF) and 16 died. We applied a previously defined 33-messenger RNA classifier to assign endotype (Inflammopathic, Adaptive, or Coagulopathic) to each patient. We tested endotype status against other clinical parameters including laboratory values, severity scores, and outcomes. Patients were assigned as Inflammopathic (29%), Adaptive (44%), or Coagulopathic (27%), similar to our prior study in bacterial sepsis. Adaptive patients had lower rates of SRF and no deaths. Coagulopathic and Inflammopathic endotypes had 42% and 18% mortality rates, respectively. The Coagulopathic group showed highest d-dimers, and the Inflammopathic group showed highest C-reactive protein and interleukin-6 levels. CONCLUSIONS: Our predefined 33-messenger RNA endotypes classifier recapitulated immune phenotypes in viral sepsis (coronavirus disease 2019) despite its prior training and validation only in bacterial sepsis. Further work should focus on continued validation of the endotypes and their interaction with immunomodulatory therapy.


Subject(s)
COVID-19/diagnosis , SARS-CoV-2/isolation & purification , Sepsis/classification , Sepsis/genetics , Adult , COVID-19/complications , Female , Gene Expression Profiling , Humans , Male , Middle Aged , Respiratory Insufficiency , Severity of Illness Index
7.
Ageing Res Rev ; 62: 101091, 2020 09.
Article in English | MEDLINE | ID: covidwho-343168

ABSTRACT

Fighting the current COVID-19 pandemic, we must not forget to prepare for the next. Since elderly and frail people are at high risk, we wish to predict their vulnerability, and intervene if possible. For example, it would take little effort to take additional swabs or dried blood spots. Such minimally-invasive sampling, exemplified here during screening for potential COVID-19 infection, can yield the data to discover biomarkers to better handle this and the next respiratory disease pandemic. Longitudinal outcome data can then be combined with other epidemics and old-age health data, to discover the best biomarkers to predict (i) coping with infection & inflammation and thus hospitalization or intensive care, (ii) long-term health challenges, e.g. deterioration of lung function after intensive care, and (iii) treatment & vaccination response. Further, there are universal triggers of old-age morbidity & mortality, and the elimination of senescent cells improved health in pilot studies in idiopathic lung fibrosis & osteoarthritis patients alike. Biomarker studies are needed to test the hypothesis that resilience of the elderly during a pandemic can be improved by countering chronic inflammation and/or removing senescent cells. Our review suggests that more samples should be taken and saved systematically, following minimum standards, and data be made available, to maximize healthspan & minimize frailty, leading to savings in health care, gains in quality of life, and preparing us better for the next pandemic, all at the same time.


Subject(s)
Aging/immunology , Biomarkers , Coronavirus Infections , Inflammation/diagnosis , Mass Screening/methods , Pandemics , Pneumonia, Viral , Aged , Betacoronavirus , COVID-19 , Frailty , Humans , Quality of Life , SARS-CoV-2
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