Learning from scaling up ultra-rapid genomic testing for critically ill children to a national level.
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ABSTRACT:
SUBMITTER: Best S
PROVIDER: S-EPMC7843635 | biostudies-literature | 2021 Jan
REPOSITORIES: biostudies-literature
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Learning from scaling up ultra-rapid genomic testing for critically ill children to a national level.
Best Stephanie S Brown Helen H Lunke Sebastian S Patel Chirag C Pinner Jason J Barnett Christopher P CP Wilson Meredith M Sandaradura Sarah A SA McClaren Belinda B Brett Gemma R GR Braithwaite Jeffrey J Stark Zornitza Z
NPJ genomic medicine 20210128 1
In scaling up an ultra-rapid genomics program, we used implementation science principles to design and investigate influences on implementation and identify strategies required for sustainable "real-world" services. Interviews with key professionals revealed the importance of networks and relationship building, leadership, culture, and the relative advantage afforded by ultra-rapid genomics in the care of critically ill children. Although clinical geneticists focused on intervention characterist ...[more]
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Project description:PurposeRespiratory infections are the most common reason for admission to paediatric intensive care units (PICU). Most patients with lower respiratory tract infection (LRTI) receive broad-spectrum antimicrobials, despite low rates of bacterial culture confirmation. Here, we evaluated a molecular diagnostic test for LRTI to inform the better use of antimicrobials.MethodsThe Rapid Assay for Sick Children with Acute Lung infection Study was a single-centre, prospective, observational cohort study of mechanically ventilated children (> 37/40 weeks corrected gestation to 18 years) with suspected community acquired or ventilator-associated LRTI. We evaluated the use of a 52-pathogen custom TaqMan Array Card (TAC) to identify pathogens in non-bronchoscopic bronchoalveolar lavage (mini-BAL) samples. TAC results were compared to routine microbiology testing. Primary study outcomes were sensitivity and specificity of TAC, and time to result.ResultsWe enrolled 100 patients, all of whom were tested with TAC and 91 of whom had matching culture samples. TAC had a sensitivity of 89.5% (95% confidence interval (CI95) 66.9-98.7) and specificity of 97.9% (CI95 97.2-98.5) compared to routine bacterial and fungal culture. TAC took a median 25.8 h (IQR 9.1-29.8 h) from sample collection to result. Culture was significantly slower: median 110.4 h (IQR 85.2-141.6 h) for a positive result and median 69.4 h (IQR 52.8-78.6) for a negative result.ConclusionsTAC is a reliable and rapid adjunct diagnostic approach for LRTI in critically ill children, with the potential to aid early rationalisation of antimicrobial therapy.
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Project description:Diagnosing pediatric intensive care unit-acquired weakness (PICU-AW) is challenging. The Medical Research Council (MRC) score is a widely used screening method for muscle weakness in critically ill adults; however, its utility in critically ill children has not been established. Our objective was to determine the feasibility and interobserver reliability of muscle strength testing using MRC score in critically ill children. A prospective observational substudy of critically ill children aged 1 to 17 years and limited to bed rest during the first 48 hours of PICU admission was evaluated with weekly MRC exams independently performed by two clinical raters. MRC exams were attempted on all 33 participants, but could be completed in only 21 (64%), 9 of who (43%) received at least one exam while in the PICU, and in the remaining 12 (57%), MRC exams could only be completed after PICU discharge. Of the 95 attempted MRC exams, 55 (57%) could not be conducted or completed, most commonly due to patient sedation, and inability to comply due to cognitive ability, pain, or noncooperation. The inter-rater reliability for MRC sum score was excellent (intraclass correlation coefficient: 0.87). However, the inter-rater reliability was only moderate when used to determine PICU-AW (Cohen kappa: 0.48). MRC testing in the PICU was not feasible as an early screening tool for muscle weakness in the majority of critically ill children in this study. Further research is needed to find an appropriate screening tool that is both feasible and predicts clinically relevant outcomes in children, such as function and recovery following critical illness.
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Project description:WHO recommends a minimum of 80% sensitivity and 97% specificity for antigen-detection rapid diagnostic tests (Ag-RDTs), which can be used for patients with symptoms consistent with COVID-19. However, after the acute phase when viral load decreases, use of Ag-RDTs might lead to high rates of false negatives, suggesting that the tests should be replaced by a combination of molecular and serological tests. When the likelihood of having COVID-19 is low, such as for asymptomatic individuals in low prevalence settings, for travel, return to schools, workplaces, and mass gatherings, Ag-RDTs with high negative predictive values can be used with confidence to rule out infection. For those who test positive in low prevalence settings, the high false positive rate means that mitigation strategies, such as molecular testing to confirm positive results, are needed. Ag-RDTs, when used appropriately, are promising tools for scaling up testing and ensuring that patient management and public health measures can be implemented without delay.
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Project description:IntroductionEarly infant diagnosis (EID) and treatment can prevent much of the HIV-related morbidity and mortality experienced by children but is challenging to implement in sub-Saharan Africa. Point-of-care (PoC) testing would decentralize testing and increase access to rapid diagnosis. The objective of this study was to determine the cost-effectiveness of PoC testing in Southern Province, Zambia.MethodsA decision tree model was developed to compare health outcomes and costs between the standard of care (SoC) and PoC testing using GeneXpert and m-PIMA platforms. The primary health outcome was antiretroviral treatment (ART) initiation within 60 days of sample collection. Additional outcomes included ART initiation by 12 months of age and death prior to ART initiation. Costs included both capital and recurrent costs. Health outcomes and costs were combined to create incremental cost effectiveness ratios (ICERs).ResultsThe proportion of children initiating ART within 60 days increased from 27.8% with SoC to 79.8-82.8% with PoC testing depending on the algorithm and platform. The proportion of children initiating ART by 12 months of age increased from 50.9% with SoC to 84.0-86.5% with PoC testing. The proportion of HIV-infected children dying prior to ART initiation decreased from 18.1% with SoC to 3.8-4.6% with PoC testing. Total program costs were similar for the SoC and GeneXpert but higher for m-PIMA. ICERs for PoC testing were favorable, ranging from $23-1,609 for ART initiation within 60 days, $37-2,491 for ART initiation by 12 months of age, and $90-6,188 for deaths prior to ART initiation. Factors impacting the costs of PoC testing, including the lifespan of the testing instruments and integrated utilization of PoC platforms, had the biggest impact on the ICERs. Integrating utilization across programs decreased costs for the EID program, such that PoC testing was cost-saving in some situations.ConclusionPoC testing has the potential to improve linkage to care and ART initiation for HIV-infected infants and should be considered for implementation within EID programs to achieve equity in access to HIV services and reduce HIV-related pediatric morbidity and mortality.
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Project description:Background: Systemic inflammation is a whole body reaction that can have an infection-positive (i.e. sepsis) or infection-negative origin. It is important to distinguish between septic and non-septic presentations early and reliably, because this has significant therapeutic implications for critically ill patients. We hypothesized that a molecular classifier based on a small number of RNAs expressed in peripheral blood could be discovered that would: 1) determine which patients with systemic inflammation had sepsis; 2) be robust across independent patient cohorts; 3) be insensitive to disease severity; and 4) provide diagnostic utility. The overall goal of this study was to identify and validate such a molecular classifier. Methods and Findings: We conducted an observational, non-interventional study of adult patients recruited from tertiary intensive care units (ICU). Biomarker discovery was conducted with an Australian cohort (n = 105) consisting of sepsis patients and post -surgical patients with infection-negative systemic inflammation. Using this cohort, a four-gene classifier consisting of a combination of CEACAM4, LAMP1, PLA2G7 and PLAC8 RNA biomarkers was identified. This classifier, designated SeptiCyte® Lab, was externally validated using RT-qPCR and receiver operating characteristic (ROC) curve analysis in five cohorts (n = 345) from the Netherlands. Cohort 1 (n=59) consisted of unambiguous septic cases and infection-negative systemic inflammation controls; SeptiCyte® Lab gave an area under curve (AUC) of 0.96 (95% CI: 0.91-1.00). ROC analysis of a more heterogeneous group of patients (Cohorts 2-5; 249 patients after excluding 37 patients with infection likelihood possible) gave an AUC of 0.89 (95% CI: 0.85-0.93). Disease severity, as measured by Sequential Organ Failure Assessment (SOFA) score or the Acute Physiology and Chronic Health Evaluation (APACHE) IV score, was not a significant confounding variable. The diagnostic utility o f SeptiCyte® Lab was evaluated by comparison to various clinical and laboratory parameters that would be available to a clinician within 24 hours of ICU admission. SeptiCyte® Lab was significantly better at differentiating sepsis from infection-negative systemic inflammation than all tested parameters, both singly and in various logistic combinations. SeptiCyte® Lab more than halved the diagnostic error rate compared to PCT in all tested cohorts or cohort combinations. Conclusions: SeptiCyte® Lab is a rapid molecular assay that may be clinically useful in the management of ICU patients with systemic inflammation. SIRS and Sepsis ICU patients, admission samples Retrospective, mutli-site sutdy using retrospective physician adjudication as a comparator
2015-10-24 | E-GEOD-74224 | biostudies-arrayexpress
Project description:ImportanceWidespread adoption of rapid genomic testing in pediatric critical care requires robust clinical and laboratory pathways that provide equitable and consistent service across health care systems.ObjectiveTo prospectively evaluate the performance of a multicenter network for ultra-rapid genomic diagnosis in a public health care system.Design, setting, and participantsDescriptive feasibility study of critically ill pediatric patients with suspected monogenic conditions treated at 12 Australian hospitals between March 2018 and February 2019, with data collected to May 2019. A formal implementation strategy emphasizing communication and feedback, standardized processes, coordination, distributed leadership, and collective learning was used to facilitate adoption.ExposuresUltra-rapid exome sequencing.Main outcomes and measuresThe primary outcome was time from sample receipt to ultra-rapid exome sequencing report. The secondary outcomes were the molecular diagnostic yield, the change in clinical management after the ultra-rapid exome sequencing report, the time from hospital admission to the laboratory report, and the proportion of laboratory reports returned prior to death or hospital discharge.ResultsThe study population included 108 patients with a median age of 28 days (range, 0 days to 17 years); 34% were female; and 57% were from neonatal intensive care units, 33% were from pediatric intensive care units, and 9% were from other hospital wards. The mean time from sample receipt to ultra-rapid exome sequencing report was 3.3 days (95% CI, 3.2-3.5 days) and the median time was 3 days (range, 2-7 days). The mean time from hospital admission to ultra-rapid exome sequencing report was 17.5 days (95% CI, 14.6-21.1 days) and 93 reports (86%) were issued prior to death or hospital discharge. A molecular diagnosis was established in 55 patients (51%). Eleven diagnoses (20%) resulted from using the following approaches to augment standard exome sequencing analysis: mitochondrial genome sequencing analysis, exome sequencing-based copy number analysis, use of international databases to identify novel gene-disease associations, and additional phenotyping and RNA analysis. In 42 of 55 patients (76%) with a molecular diagnosis and 6 of 53 patients (11%) without a molecular diagnosis, the ultra-rapid exome sequencing result was considered as having influenced clinical management. Targeted treatments were initiated in 12 patients (11%), treatment was redirected toward palliative care in 14 patients (13%), and surveillance for specific complications was initiated in 19 patients (18%).Conclusions and relevanceThis study suggests feasibility of ultra-rapid genomic testing in critically ill pediatric patients with suspected monogenic conditions in the Australian public health care system. However, further research is needed to understand the clinical value of such testing, and the generalizability of the findings to other health care settings.
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Project description:Medical specialty usage of COVID-19 survivors after hospital discharge is poorly understood. This study investigated medical specialty usage at 1-12 and 13-24 months post-hospital discharge in critically ill and non-critically ill COVID-19 survivors. This retrospective study followed ICU (N = 89) and non-ICU (N = 205) COVID-19 survivors who returned for follow-up within the Stony Brook Health System post-hospital discharge. Follow-up data including survival, hospital readmission, ongoing symptoms, medical specialty care use, and ICU status were examined 1-12 and 13-24 months after COVID-19 discharge. "New" (not previously seen) medical specialty usage was also identified. Essentially all (98%) patients survived. Hospital readmission was 34%, but functional status scores at discharge were not associated with hospital readmission. Many patients reported ongoing [neuromuscular (50%) respiratory (39%), chronic fatigue (35%), cardiovascular (30%), gastrointestinal (28%), neurocognitive (22%), genitourinary (22%), and mood-related (13%)] symptoms at least once 1-24 months after discharge. Common specialty follow-ups included cardiology (25%), vascular medicine (17%), urology (17%), neurology (16%), and pulmonology (14%), with some associated with pre-existing comorbidities and with COVID-19. Common new specialty visits were vascular medicine (11%), pulmonology (11%), and neurology (9%). ICU patients had more symptoms and follow-ups compared to the non-ICU patients. This study reported high incidence of persistent symptoms and medical specialty care needs in hospitalized COVID-19 survivors 1-24 months post-discharge. Some specialty care needs were COVID-19 related or exacerbated by COVID-19 disease while others were associated with pre-existing medical conditions. Longer follow-up studies of COVID-19 survivor medical care needs are necessary.
| S-EPMC9887251 | biostudies-literature
Project description:This SuperSeries is composed of the SubSeries listed below.
2022-02-28 | GSE197259 | GEO
Project description:BackgroundThe past years have witnessed dramatic changes in the population admitted to the intensive care unit (ICU). Older and sicker patients are now commonly treated in this setting due to the newly available sophisticated life support. However, the short- and long-term benefit of this strategy is scarcely studied.MethodsThe Critically Ill patients' mortality by age: Long-Term follow-up (CIMbA-LT) was a multicentric, nationwide, retrospective, observational study addressing short- and long-term prognosis of patients admitted to Portuguese multipurpose ICUs, during 4 years, according to their age and disease severity. Patients were followed for two years after ICU admission. The standardized hospital mortality ratio (SMR) was calculated according to the Simplified Acute Physiology Score (SAPS) II and the follow-up risk, for patients discharged alive from the hospital, according to official demographic national data for age and gender. Survival curves were plotted according to age group.ResultsWe included 37.118 patients, including 15.8% over 80 years old. The mean SAPS II score was 42.8 ± 19.4. The ICU all-cause mortality was 16.1% and 76% of all patients survive until hospital discharge. The SAPS II score overestimated hospital mortality [SMR at hospital discharge 0.7; 95% confidence interval (CI) 0.63-0.76] but accurately predicted one-year all-cause mortality [1-year SMR 1.01; (95% CI 0.98-1.08)]. Survival curves showed a peak in mortality, during the first 30 days, followed by a much slower survival decline thereafter. Older patients had higher short- and long-term mortality and their hospital SMR was also slightly higher (0.76 vs. 0.69). Patients discharged alive from the hospital had a 1-year relative mortality risk of 6.3; [95% CI 5.8-6.7]. This increased risk was higher for younger patients [21.1; (95% CI 15.1-39.6) vs. 2.4; (95% CI 2.2-2.7) for older patients].ConclusionsCritically ill patients' mortality peaked in the first 30 days after ICU admission. Older critically ill patients had higher all-cause mortality, including a higher hospital SMR. A long-term increased relative mortality risk was noted in patients discharged alive from the hospital, but this was more noticeable in younger patients.
| S-EPMC9918627 | biostudies-literature
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