Multiplexed Gastrointestinal PCR Panels for the Evaluation of Diarrhea in Hematopoietic Stem Cell Transplantation Recipients.

Multiplexed gastrointestinal PCR panels (MGPPs) are frequently used to aid the diagnosis and management of diarrhea in hematopoietic stem cell transplantation (HCT) recipients. Many issues related to the optimal use of MGPPs in HCT patients remain to be clarified. We aimed to better define MGPP diagnostic and therapeutic stewardship in HCT recipients, including indications for and benefits of testing, optimal timing of tests, and interpretation of results. We retrieved 463 consecutive MGPPs ordered on 651 consecutive first HCT (312 allogeneic, 339 autologous) performed at our institution between June 2015 and June 2023. One hundred and sixteen of the 463 MGPPs (25%) identified at least 1 diarrheagenic pathogen, and 12 (3%) identified more than 1 diarrheagenic pathogen. A positive result was more likely if the test was ordered within 48 hours of a hospital admission (41%; 32 of 78) or as an outpatient (41%; 46 of 111) compared with evaluation of hospital-onset diarrhea (14%; 38 of 274). Among the positive results, the most frequent pathogens identified included Clostridioides difficile (64%), diarrheagenic Escherichia coli (20%), norovirus (9%), and adenovirus 40/41 (5%). Thirty-eight percent of the positive C. difficile MGPP determinations were associated with a positive test for toxin. In our allogeneic HCT cohort, 3% of MGPPs for hospital-onset diarrhea yielded an organism other than C. difficile. Fifty-six percent of positive and 14% of all submitted tests resulted in a change in treatment. For organisms other than C. difficile, only 1% of all tests and 5% of positive tests resulted in initiation of therapy. For patients at risk for acute graft-versus-host disease (aGVHD), a positive or negative MGPP result was not predictive of a new diagnosis of aGVHD in proximity to diarrhea onset. These results suggest that MGPP testing is most useful when performed at hospital admission or on an outpatient basis. Because MGPPs are sensitive and do not distinguish between colonization and causes of diarrhea, caution is needed when interpreting results, especially for toxin-negative C. difficile and diarrheagenic gram-negative organisms.

Longitudinal associations of plasma amino acid levels with recovery from malarial coma.

Background: Disordered amino acid metabolism is observed in cerebral malaria (CM). We sought to determine whether abnormal amino acid concentrations were associated with level of consciousness in children recovering from coma. We quantified 21 amino acids and coma scores longitudinally and analyzed data for associations. Methods: In a prospective observational study, we enrolled 42 children with CM. We measured amino acid levels at entry and at frequent intervals thereafter and assessed consciousness by Blantyre Coma Scores (BCS). Thirty-six healthy children served as controls for in-country normal amino acid ranges. We employed logistic regression using a generalized linear mixed-effects model to assess associations between out-of-range amino acid levels and BCS. Results: At entry 16/21 amino acid levels were out-of-range. Longitudinal analysis revealed 10/21 out-of-range amino acids were significantly associated with BCS. Elevated phenylalanine levels showed the highest association with low BCS. This finding held when out-of-normal-range data were analyzed at each sampling time. Discussion: We provide longitudinal data for associations between abnormal amino acid levels and recovery from CM. Of 10 amino acids significantly associated with BCS, we propose that elevated phenylalanine may be a surrogate for impaired clearance of ether lipid mediators of inflammation contributing to CM pathogenesis.

Validation of SeptiCyte RAPID to Discriminate Sepsis from Non-Infectious Systemic Inflammation.

(1) Background: SeptiCyte RAPID is a molecular test for discriminating sepsis from non-infectious systemic inflammation, and for estimating sepsis probabilities. The objective of this study was the clinical validation of SeptiCyte RAPID, based on testing retrospectively banked and prospectively collected patient samples. (2) Methods: The cartridge-based SeptiCyte RAPID test accepts a PAXgene blood RNA sample and provides sample-to-answer processing in ~1 h. The test output (SeptiScore, range 0-15) falls into four interpretation bands, with higher scores indicating higher probabilities of sepsis. Retrospective (N = 356) and prospective (N = 63) samples were tested from adult patients in ICU who either had the systemic inflammatory response syndrome (SIRS), or were suspected of having/diagnosed with sepsis. Patients were clinically evaluated by a panel of three expert physicians blinded to the SeptiCyte test results. Results were interpreted under either the Sepsis-2 or Sepsis-3 framework. (3) Results: Under the Sepsis-2 framework, SeptiCyte RAPID performance for the combined retrospective and prospective cohorts had Areas Under the ROC Curve (AUCs) ranging from 0.82 to 0.85, a negative predictive value of 0.91 (sensitivity 0.94) for SeptiScore Band 1 (score range 0.1-5.0; lowest risk of sepsis), and a positive predictive value of 0.81 (specificity 0.90) for SeptiScore Band 4 (score range 7.4-15; highest risk of sepsis). Performance estimates for the prospective cohort ranged from AUC 0.86-0.95. For physician-adjudicated sepsis cases that were blood culture (+) or blood, urine culture (+)(+), 43/48 (90%) of SeptiCyte scores fell in Bands 3 or 4. In multivariable analysis with up to 14 additional clinical variables, SeptiScore was the most important variable for sepsis diagnosis. A comparable performance was obtained for the majority of patients reanalyzed under the Sepsis-3 definition, although a subgroup of 16 patients was identified that was called septic under Sepsis-2 but not under Sepsis-3. (4) Conclusions: This study validates SeptiCyte RAPID for estimating sepsis probability, under both the Sepsis-2 and Sepsis-3 frameworks, for hospitalized patients on their first day of ICU admission.