The prevalence and rate of undiagnosed celiac disease in an adult general population, the Trøndelag Health Study, Norway.

BACKGROUND & AIMS: This study aimed to determine the total prevalence of celiac disease (CeD), including undiagnosed cases, in a population-based study of adults screened for CeD. METHODS: The study utilized the fourth Trøndelag Health Study (HUNT4), conducted in 2017-2019, where 56,042 adult (aged >20 years) residents of Nord-Trøndelag County, Norway, participated. Serum samples from 54,505 participants were analysed for anti-transglutaminase 2 immunoglobulin A and G. Seropositive individuals were invited for a clinical assessment, including upper endoscopy with duodenal biopsies. Previously diagnosed and seronegative CeD cases were identified through linkage to hospital records and the Norwegian Patient Registry. RESULTS: The rate of CeD seropositivity was 2.0% (1107/54,505). Out of these, 724 individuals attended the clinical assessment. Additionally, the hospital records and registry identified individuals with a known CeD diagnosis, that were seronegative or without serology in HUNT4 or seropositive in HUNT4 but did not participate in the clinical assessment. In total, the study confirmed a new CeD diagnosis after participation in HUNT4 in 470 individuals and a known CeD diagnosis before participation in HUNT4 in 383 individuals. The total biopsy-confirmed prevalence of CeD was 1.5% (853/56,042), and the ratio of new, previously undiagnosed CeD cases (after HUNT4) to known, previously diagnosed CeD cases (before HUNT4) was 1.2:1 (470/383). CONCLUSION: The total prevalence of CeD in this population-based study of adults in Norway was high and many individuals were previously undiagnosed. Detection of CeD should be improved, as early diagnosis is crucial for effective management and prevention of complications.

HLA-DQ2 is associated with anti-drug antibody formation to infliximab in patients with immune-mediated inflammatory diseases.

BACKGROUND: Immunogenicity to tumour necrosis factor inhibitors is a significant clinical problem leading to treatment failure and adverse events. The study aimed to assess human leukocyte antigen (HLA) associations with anti-drug antibody (ADAb) formation to infliximab. METHODS: Immune-mediated inflammatory disease patients on infliximab therapy (n = 612) were included. Neutralising ADAb were assessed with a drug-sensitive assay. Next generation sequencing-based HLA typing was performed. RESULTS: Overall, 147 (24%) patients developed ADAb. Conditional analyses indicated HLA-DQB1 (p = 1.4 × 10-6 ) as a primary risk locus. Highest risk of ADAb was seen when carrying at least one of the HLA-DQ2 haplotypes; DQB1*02:01-DQA1*05:01 or DQB1*02:02-DQA1*02:01 (OR 3.18, 95% CI 2.15-4.69 and p = 5.9 × 10-9 ). Results were consistent across diseases and when adjusting for concomitant immunomodulator. Computational predictions indicated that these HLA-DQ2 haplotypes bind to peptide motifs from infliximab light chain. CONCLUSION: A genome-wide significant association between two HLA-DQ2 haplotypes and the risk of ADAb formation to infliximab was identified, suggesting that HLA-DQ2 testing may facilitate personalised treatment decisions.

Adalimumab serum levels and anti-drug antibodies: associations to treatment response and drug survival in inflammatory joint diseases.

OBJECTIVES: To explore associations between serum adalimumab level, treatment response and drug survival in order to identify therapeutic drug levels for therapeutic drug monitoring of adalimumab. Also, to assess occurrence and risk factors of anti-drug antibody (ADAb) formation. METHODS: Non-trough adalimumab and ADAb levels were measured by automated fluorescence assays in serum collected after 3 months of adalimumab treatment in patients with rheumatoid arthritis (RA), psoriatic arthritis (PsA) or axial spondyloarthritis (axSpA) included in the observational NOR-DMARD study. Treatment response was evaluated after 3 months, and drug survival during long-term follow-up. RESULTS: In 340 patients (97 RA, 69 PsA, 174 axSpA), median adalimumab level was 7.3 mg/l (IQR 4.0-10.3). 33 (10%) patients developed ADAb. Findings were comparable across diagnoses. In RA and PsA, adalimumab levels ≥6.0 mg/l were associated with treatment response (Odds Ratio [OR] 2.2 [95% CI 1.0, 4.4]) and improved drug survival (Hazard Ratio [HR] 0.49 [0.27, 0.80]). In axSpA, a therapeutic level could not be identified, but higher adalimumab levels were associated with response. Factors associated with ADAb formation were previous bDMARD use, no methotrexate comedication and use of adalimumab originator compared with GP2017. CONCLUSION: Higher adalimumab levels were associated with better response and improved drug survival for all diagnoses, with a suggested lower threshold of 6.0 mg/l for RA/PsA. This finding, the large variability in drug levels among patients receiving standard adalimumab dose, and the high proportion of patients developing ADAb, encourages further investigations into the potential role of therapeutic drug monitoring of adalimumab.

Switching from intravenous to subcutaneous vedolizumab maintenance treatment in patients with inflammatory bowel disease followed by therapeutic drug monitoring.

OBJECTIVE: Vedolizumab (VDZ) for subcutaneous (SC) administration has recently become available. We aimed to assess feasibility, safety and clinical outcome when switching from intravenous (IV) to SC VDZ maintenance treatment in a real world cohort of patients with inflammatory bowel disease (IBD) followed by therapeutic drug monitoring (TDM). METHODS: Eligible IBD patients were switched from IV to SC treatment and assessed six months prior to switch, at baseline and six, twelve and twenty-six weeks after switch. Primary outcome was proportion of patients on SC treatment after 26 weeks. Secondary outcomes included adverse events (AEs), clinical disease activity, biochemical markers, treatment interval, serum-VDZ (s-VDZ), preferred route of administration and health-related quality of life. RESULTS: In total, 108 patients were switched. After 26 weeks, 100 patients (92.6%) were still on SC treatment and median s-VDZ was 47.6 mg/L (IQR 41.3 - 54.6). The most frequent AE was injection site reaction (ISR), reported by 20 patients (18.5%). There were no clinically significant changes in disease activity, biochemical markers and quality of life. The proportion of patients preferring SC administration increased from 28.0% before switch to 59.4% after 26 weeks (p < 0.001). CONCLUSIONS: Nine out of ten patients still received SC treatment after 26 weeks. No change in disease activity occurred, and levels of serum VDZ increased. Although almost one fifth of patients experienced ISRs, a higher proportion favored SC administration at 26 weeks. This study demonstrates that SC maintenance treatment is a safe and feasible alternative to IV treatment.

Humoral immune response to SARS-CoV-2 vaccination in patients with inflammatory bowel disease on immunosuppressive medication: association to serum drug levels and disease type.

OBJECTIVES: Immune responses following SARS-CoV-2 vaccination in patients with inflammatory bowel disease (IBD) are not well characterized. The aims of this study were to explore the serological response associated with IBD, and immunosuppressive medications including serum concentrations of biologics and thiopurine metabolites. MATERIALS AND METHODS: This prospective, observational study included adult patients with ulcerative colitis (UC) and Crohn's disease (CD), and healthy controls. Antibodies to the receptor-binding domain of SARS-CoV-2 spike proteins, and serum concentrations of ongoing biologic and immunomodulatory medications were assessed prior to, and 2-5 weeks after the second vaccine dose. Serologic response was defined as anti-Spike antibodies ≥70 AU/ml. RESULTS: In 958 IBD patients (380 UC, 578 CD) and 323 healthy controls, the median (Q1; Q3) anti-Spike antibody level (AU/ml) was lower in patients (618 (192; 4370)) compared to controls (3355 (896; 7849)) (p < 0.001). The antibody levels were lower in CD (439 (174; 3304)) compared to UC (1088 (251; 5975)) (p < 0.001). No associations were demonstrated between antibody levels and serum drug concentrations for TNF inhibitor (TNFi), vedolizumab and ustekinumab. Patients receiving TNFi + thiopurines with a subtherapeutic 6-thioguanine nucleotide (6-TGN) level had higher response rate (93%) compared to patients with 6-TGN within the therapeutic range (53%) (p = 0.003). A diagnosis of UC, mRNA-1273 vaccine, and other treatments than TNFi + thiopurines were associated with humoral response. CONCLUSIONS: Patients with CD had an attenuated humoral response to SARS-COV-2 vaccination as compared to patients with UC. The lack of association between serum levels of biologics and serologic response indicates vaccination regardless of proximity to drug administration.

Stopping Hospital Infections With Environmental Services (SHINE): A Cluster-randomized Trial of Intensive Monitoring Methods for Terminal Room Cleaning on Rates of Multidrug-resistant Organisms in the Intensive Care Unit.

BACKGROUND: Multidrug-resistant organisms (MDROs) frequently contaminate hospital environments. We performed a multicenter, cluster-randomized, crossover trial of 2 methods for monitoring of terminal cleaning effectiveness. METHODS: Six intensive care units (ICUs) at 3 medical centers received both interventions sequentially, in randomized order. Ten surfaces were surveyed each in 5 rooms weekly, after terminal cleaning, with adenosine triphosphate (ATP) monitoring or an ultraviolet fluorescent marker (UV/F). Results were delivered to environmental services staff in real time with failing surfaces recleaned. We measured monthly rates of MDRO infection or colonization, including methicillin-resistant Staphylococcus aureus, Clostridioides difficile, vancomycin-resistant Enterococcus, and MDR gram-negative bacilli (MDR-GNB) during a 12-month baseline period and sequential 6-month intervention periods, separated by a 2-month washout. Primary analysis compared only the randomized intervention periods, whereas secondary analysis included the baseline. RESULTS: The ATP method was associated with a reduction in incidence rate of MDRO infection or colonization compared with the UV/F period (incidence rate ratio [IRR] 0.876; 95% confidence interval [CI], 0.807-0.951; P = .002). Including the baseline period, the ATP method was associated with reduced infection with MDROs (IRR 0.924; 95% CI, 0.855-0.998; P = .04), and MDR-GNB infection or colonization (IRR 0.856; 95% CI, 0.825-0.887; P < .001). The UV/F intervention was not associated with a statistically significant impact on these outcomes. Room turnaround time increased by a median of 1 minute with the ATP intervention and 4.5 minutes with UV/F compared with baseline. CONCLUSIONS: Intensive monitoring of ICU terminal room cleaning with an ATP modality is associated with a reduction of MDRO infection and colonization.

The persistence of anti-Spike antibodies following two SARS-CoV-2 vaccine doses in patients on immunosuppressive therapy compared to healthy controls-a prospective cohort study.

BACKGROUND: The durability of vaccine-induced humoral immunity against SARS-CoV-2 in patients with immune-mediated inflammatory diseases (IMIDs) on immunosuppressive therapy is not known. The aim of this study was to compare the persistence of anti-Spike antibodies following two-dose SARS-CoV-2 vaccination between IMID patients and healthy controls and to identify factors associated with antibody decline. METHODS: IMID patients on immunosuppressive medication enrolled in the prospective observational Nor-vaC study were included. Participants received two-dose SARS-CoV-2 vaccination. Serum collected at two time points following vaccination (first assessment within 6-48 days, second within 49-123 days) were analyzed for antibodies binding the receptor-binding domain (RBD) of the SARS-CoV-2 Spike protein. Multivariable regression models estimated percent reduction in anti-RBD over 30 days and factors associated with reduction. RESULTS: A total of 1108 patients (403 rheumatoid arthritis, 195 psoriatic arthritis, 195 spondyloarthritis, 124 ulcerative colitis, 191 Crohn's disease) and 134 controls provided blood samples within the defined intervals (median 19 days [IQR 15-24] and 97 days [87-105] after second vaccine dose). Antibody levels were lower in patients compared to controls at both time points, with median anti-RBD 2806 BAU/ml [IQR 1018-6068] in patients and 6187 BAU/ml [4105-7496] in controls (p<0.001) at first assessment, and 608 BAU/ml [IQR 58-1053] in patients and 1520 BAU/ml [979-3766] in controls (p<0.001) at second assessment. At second assessment, low anti-RBD antibody levels (defined as <200 BAU/ml) were found in 449 (41%) patients, and 6 (5%) controls (p<0.001). The change was - 83% in patients and - 66% in controls (p<0.001). Patients had a greater estimated 30 days percent reduction in anti-RBD levels compared to controls - 4.9 (95% CI - 7.4 to - 2.4), (p<0.05). Among therapies, mono- or combination treatment with tumor necrosis factor inhibitors was associated with the greatest decline. CONCLUSIONS: Within 4 months after vaccination, antibody levels declined considerably in both IMID patients and controls. Patients had lower initial antibody levels and a more pronounced decline compared to healthy controls and were therefore more likely to decline to low antibody levels. These results support that IMID patients need additional vaccine doses at an earlier stage than healthy individuals.

Risk factors for anti-drug antibody formation to infliximab: Secondary analyses of a randomised controlled trial.

BACKGROUND: Anti-drug antibodies (ADAb) frequently form early in the treatment course of infliximab and other tumour necrosis factor (TNF) inhibitors, leading to treatment failure and adverse events. OBJECTIVE: To identify risk factors for ADAb in the early phase of infliximab treatment. METHODS: Patients (n = 410) with immune-mediated inflammatory diseases who initiated infliximab treatment were included in the 38-week Norwegian Drug Monitoring Trial (NOR-DRUM) A and randomised 1:1 to therapeutic drug monitoring (TDM) or standard therapy. Serum levels of infliximab and ADAb were measured at each infusion. Possible risk factors for ADAb formation were assessed using logistic regression, adjusting for potential confounders. RESULTS: ADAb were detected in 78 (19%) patients. A diagnosis of rheumatoid arthritis (RA) (odds ratio [OR], 1.9 [95% confidence interval [CI] 1.0-3.6]) and lifetime smoking (OR, 2.0 [CI 1.1-3.6]) were baseline risk factors, while baseline use of concomitant immunosuppressors (OR, 0.4 [CI 0.2-0.8]) and a diagnosis of spondyloarthritis (SpA) (OR, 0.4 [CI 0.2-0.8]) reduced the risk of ADAb. Higher disease activity during follow-up (OR, 1.1 [CI 1.0-1.1]) and "drug holidays" of more than 11 weeks (OR, 4.1 [CI 1.2-13.8]) increased the risk of ADAb, whereas higher infliximab doses (OR, 0.1 [CI 0.0-0.3) and higher serum infliximab concentrations (OR, 0.7 [CI 0.6-0.8]) reduced the risk of immunogenicity. CONCLUSION: Several risk factors for ADAb formation during early-phase infliximab treatment were identified. This knowledge provides a basis for treatment strategies to mitigate the formation of ADAb and identify patients in whom these measures are of particular importance.

The Impact of Implementing the Virtuo Blood Culture System on the Characteristics and Management of Patients with Staphylococcus aureus Bacteremia.

Persistent Staphylococcus aureus bacteremia (SAB) has been associated with increased mortality. Enhanced microbial detection with new blood culture technology may improve detection of S. aureus in patients with SAB. We performed a 24-month retrospective study of hospitalized adults with SAB and an infectious diseases consult comparing two time periods pre- (January to December 2018) and postimplementation (January to December 2019) in which the VersaTREK and BacT/Alert Virtuo blood culture systems were used, respectively. Measurements included SAB duration, time to positivity, source of bacteremia, antimicrobial therapy, and mortality. A total of 416 episodes of SAB occurred during the study period: 176 (42%) pre- and 240 (58%) postimplementation. Patients in both periods had similar clinical characteristics; however, patients in the postimplementation period were more likely to have intermediate (3 to 6 days; 23% versus 40%; P < 0.001) and prolonged SAB duration (>7 days; 4% versus 14%; P < 0.001). Combination antistaphylococcal therapy was more frequent postimplementation (6.3% pre- versus 15.8% postimplementation; P = 0.003), and the median time to source control was shorter (4 versus 2 days; P = 0.02). Median time to positivity for the index blood culture was shorter postimplementation (17.8 h pre- versus 13.3 h postimplementation; P < 0.001). There was no difference in 90-day all-cause readmissions (51% versus 44%; P = 0.11) or mortality (32% versus 32%; P = 0.95). An increased frequency of prolonged SAB with increased use of combination antistaphylococcal therapy was noted with implementation of a new blood culture system, likely secondary to the blood culture media; however, no differences on adverse outcomes were noted.

Lack of association of post-discharge prophylactic antibiotics with decreased risk of surgical site infection following spinal fusion.

OBJECTIVES: To determine the prevalence and factors associated with post-discharge prophylactic antibiotic use after spinal fusion and whether use was associated with decreased risk of surgical site infection (SSI). METHODS: Persons aged 10-64 years undergoing spinal fusion between 1 January 2010 and 30 June 2015 were identified in the MarketScan Commercial Database. Complicated patients and those coded for infection from 30 days before to 2 days after the surgical admission were excluded. Outpatient oral antibiotics were identified within 2 days of surgical discharge. SSI was defined using ICD-9-CM diagnosis codes within 90 days of surgery. Generalized linear models were used to determine factors associated with post-discharge prophylactic antibiotic use and with SSI. RESULTS: The cohort included 156 446 fusion procedures, with post-discharge prophylactic antibiotics used in 9223 (5.9%) surgeries. SSIs occurred after 2557 (1.6%) procedures. Factors significantly associated with post-discharge prophylactic antibiotics included history of lymphoma, diabetes, 3-7 versus 1-2 vertebral levels fused, and non-infectious postoperative complications. In multivariable analysis, post-discharge prophylactic antibiotic use was not associated with SSI risk after spinal fusion (relative risk 0.98; 95% CI 0.84-1.14). CONCLUSIONS: Post-discharge prophylactic oral antibiotics after spinal fusion were used more commonly in patients with major medical comorbidities, more complex surgeries and those with postoperative complications during the surgical admission. After adjusting for surgical complexity and infection risk factors, post-discharge prophylactic antibiotic use was not associated with decreased SSI risk. These results suggest that prolonged prophylactic antibiotic use should be avoided after spine surgery, given the lack of benefit and potential for harm.

Drug Levels Associated With Optimal Discrimination Between Remission and Nonremission and Comparison of Antibody Assays During First Year of Stable Infliximab Maintenance Therapy in Inflammatory Bowel Disease.

BACKGROUND: To implement therapeutic drug monitoring-based strategies for infliximab (IFX) in inflammatory bowel disease, the authors assessed IFX levels for optimal discrimination between remission and nonremission and compared assays for anti-IFX antibodies (Abs). METHODS: The retrospective cohort comprised 163 bionaive patients with inflammatory bowel disease who received stable IFX maintenance therapy (5 mg/kg every 8 weeks [q8w]) for 1 year. The clinical and biochemical remission status was assessed at all infusions (weeks 14-22-30-38-46-54), and IFX and anti-IFX Abs were estimated using a time-resolved fluorometric assay (n = 690; 88% of infusions). Samples positive for anti-IFX Abs or IFX levels < limit of detection (n = 102) were analyzed by 2 binding assays [enzyme-linked immunosorbent assay (ELISA)] and functional reporter gene assay/drug-tolerant enzyme immunoassay. RESULTS: At all assessed time points, IFX levels were more than double in patients presenting clinical or biochemical remission. An IFX concentration of 4.5 mcg/mL was associated with clinical remission during the entire first year of therapy [sensitivity 54% (49-59), specificity 73% (67-78), AUCROC 0.65 (0.60-0.69), P < 0.0001]; these values were comparable with biochemical remission. Exploratory assessments for endoscopic remission (n = 131) were performed at the discretion of the treating physician. Anti-IFX Abs were associated with undetectable IFX and treatment failure [OR 2.9 (1.4-6.0), P < 0.01], irrespective of persistency or transiency. All performed assays detected anti-IFX Abs were picked up by all assays in ∼2/3 of samples. Binding assays demonstrated a higher sensitivity to anti-IFX Abs. CONCLUSIONS: IFX at ∼5 mcg/mL was associated with clinical and biochemical remission during the first year of maintenance therapy. During this phase of therapy, standard binding assays are appropriate for therapeutic drug monitoring.

Blood culture utilization practices among febrile and/or hypothermic inpatients.

BACKGROUND: Predictors associated with the decision of blood culture ordering among hospitalized patients with abnormal body temperature are still underexplored, particularly non-clinical factors. In this study, we evaluated the factors affecting blood culture ordering in febrile and hypothermic inpatients. METHODS: We performed a retrospective study of 15,788 adult inpatients with fever (≥ 38.3℃) or hypothermia (< 36.0℃) from January 2016 to December 2017. We evaluated the proportion of febrile and hypothermic episodes with an associated blood culture performed within 24h. Generalized Estimating Equations were used to determine independent predictors associated with blood culture ordering among febrile and hypothermic inpatients. RESULTS: We identified 21,383 abnormal body temperature episodes among 15,788 inpatients (13,093 febrile and 8,290 hypothermic episodes). Blood cultures were performed in 36.7% (7,850/ 21,383) of these episodes. Predictors for blood culture ordering among inpatients with abnormal body temperature included fever ≥ 39℃ (adjusted odd ratio [aOR] 4.17, 95% confident interval [CI] 3.91-4.46), fever (aOR 3.48, 95% CI 3.27-3.69), presence of a central venous catheter (aOR 1.36, 95% CI 1.30-1.43), systemic inflammatory response (SIRS) plus hypotension (aOR 1.33, 95% CI 1.26-1.40), SIRS (aOR 1.26, 95% CI 1.20-1.31), admission to stem cell transplant / medical oncology services (aOR 1.09, 95% CI 1.04-1.14), and detection of abnormal body temperature during night shift (aOR 1.06, 95% CI 1.03-1.09) or on the weekend (aOR 1.05, 95% CI 1.01-1.08). CONCLUSION: Blood culture ordering for hospitalized patients with fever or hypothermia is multifactorial; both clinical and non-clinical factors. These wide variations and gaps in practices suggest opportunities to improve utilization patterns.

Resting-state functional connectivity of the human hippocampus in periadolescent children: Associations with age and memory performance.

The hippocampus is necessary for declarative (relational) memory, and the ability to form hippocampal-dependent memories develops through late adolescence. This developmental trajectory of hippocampal-dependent memory could reflect maturation of intrinsic functional brain networks, but resting-state functional connectivity (rs-FC) of the human hippocampus is not well-characterized for periadolescent children. Measuring hippocampal rs-FC in periadolescence would thus fill a gap, and testing covariance of hippocampal rs-FC with age and memory could inform theories of cognitive development. Here, we studied hippocampal rs-FC in a cross-sectional sample of healthy children (N = 96; 59 F; age 9-15 years) using a seed-based approach, and linked these data with NIH Toolbox measures, the Picture-Sequence Memory Test (PSMT) and the List Sorting Working Memory Test (LSWMT). The PSMT was expected to rely more on hippocampal-dependent memory than the LSWMT. We observed hippocampal rs-FC with an extensive brain network including temporal, parietal, and frontal regions. This pattern was consistent with prior work measuring hippocampal rs-FC in younger and older samples. We also observed novel, regionally specific variation in hippocampal rs-FC with age and hippocampal-dependent memory but not working memory. Evidence consistent with these findings was observed in a second, validation dataset of similar-age healthy children drawn from the Philadelphia Neurodevelopment Cohort. Further, a cross-dataset analysis suggested generalizable properties of hippocampal rs-FC and covariance with age and memory. Our findings connect prior work by describing hippocampal rs-FC and covariance with age and memory in typically developing periadolescent children, and our observations suggest a developmental trajectory for brain networks that support hippocampal-dependent memory.

Real-World Evaluation of the Impact of Implementation of the Virtuo Blood Culture System in a Tertiary Care Hospital.

The bioMérieux BacT/Alert Virtuo blood culture system used in combination with resin-containing media may enhance the growth of microorganisms. Our objective was to assess the impact of transitioning to the Virtuo system in comparison to the VersaTREK blood culture system at a tertiary care medical center. We retrospectively reviewed all blood cultures performed at a 1,250-bed academic medical center between January and December 2018 (VersaTREK) and January and December 2019 (Virtuo). Blood culture positivity rates and contamination rates were compared before and after Virtuo implementation. Of 101,438 blood cultures performed during the study period, 48,839 (48.1%) were processed preimplementation and 52,599 (51.9%) postimplementation. The blood culture positivity rate increased from 8.1% preimplementation to 11.7% postimplementation (P < 0.001). Staphylococcus aureus was the most frequently isolated species in both time periods and had a higher recovery rate postimplementation (1.5% of all blood cultures obtained preimplementation versus 3.4% postimplementation; P < 0.001). A higher recovery rate in the postimplementation period was also noted for coagulase-negative staphylococci (1.9% preimplementation versus 2.7% postimplementation; P < 0.001), as well as modest but statistically significant changes for Escherichia coli (0.8% versus 1.0%; P < 0.001), Klebsiella pneumoniae (0.4% versus 0.5%; P = 0.005), and Candida albicans. (0.1% versus 0.2%; P = 0.038). The inpatient blood culture contamination rate was higher postimplementation (1.5% preimplementation versus 1.9% postimplementation; P < 0.001). The Virtuo blood culture system was associated with a higher observed proportion of positive blood cultures than the VersaTREK system. Future studies are needed to assess whether an increased rate of positive blood cultures is associated with changes in clinical outcomes.

Falsely markedly elevated 25-hydroxyvitamin D in patients with monoclonal gammopathies.

OBJECTIVES: Monoclonal immunoglobulins can cause interference in many laboratory analyses. During a 4 month period we observed seven patients with monoclonal disease and falsely extremely elevated 25-hydroxyvitamin D (25(OH)D) results above 160 ng/mL (>400 nmol/L) measured using an immunoassay from Abbott Diagnostics. Based on these findings, we studied the occurrence of falsely elevated 25(OH)D in samples with paraproteins and investigated possible mechanisms of the observed interference. METHODS: 25(OH)D was analyzed using the Architect i2000 platform from Abbott Diagnostics and a higher order method, liquid chromatography-mass spectrometry (LC-MS/MS), in serum samples from 50 patients with known monoclonal disease. Patients with falsely elevated 25(OH)D were included in further studies to elucidate the cause of interference. Spuriously elevated results were in addition analyzed on two alternative platforms (Siemens and Roche). RESULTS: Falsely elevated 25(OH)D levels were present in eight patients on the Abbott analyzer and one on the Siemens platform. Results from Roche were comparable with LC-MS/MS. Additional investigations excluded elevated concentrations of rheumatoid factor and heterophilic antibodies as the cause of interference in the Abbott assay. CONCLUSIONS: Laboratories should be aware of the risk of falsely elevated 25(OH)D in samples run on the Architect analyzer from patients with monoclonal disease. Highly elevated vitamin D results should be diluted and if the dilution is non-linear, rerun by a different method, preferably LC-MS/MS. In patients with spuriously elevated 25(OH)D without known monoclonal disease, the laboratory should consider requesting protein electrophoresis to exclude paraprotein interference.

Rheumatoid factor and falsely elevated results in commercial immunoassays: data from an early arthritis cohort.

The aim of the study was to  assess RF cross-reactivity to animal antibodies used in immunoassays, and to test if selected commercial immunoassays are vulnerable to interference from RF, causing false test results. Our study included samples from patients with RF-positive rheumatoid arthritis (RA) and controls (patients with RF-negative RA and psoriatic arthritis), included in an early arthritis-cohort. Reactivity to mouse IgG1, mouse IgG2a, rabbit IgG, bovine IgG, sheep/goat IgG and human IgG was analysed using in-house interference assays. RF-positive sera with strong reactivity to mouse IgG1 were analysed in three commercial immunoassays. To reveal interference, results before and after addition of blocking aggregated murine IgG1 were compared. Samples from 124 RF-positive RA patients and 66 controls were tested. We found considerably stronger reactivity toward animal antibodies, particularly mouse IgG1 (73% vs. 12%) and rabbit IgG (81% vs. 6%), in sera from RF-positive RA-patients compared to controls (p < 0.001). After selecting samples for testing in commercial assays, interference was revealed in 6/30 sera in the Architect ß-hCG assay, 7/10 sera in the 27-plex cytokine assays, and in 2/33 samples in the Elecsys Soluble Transferrin Receptor assay. Our study revealed considerable RF reactivity to animal antibodies used in immunoassays and RF was associated with falsely elevated results in immunoassays used in clinical care and research. Clinicians, laboratorians, researchers and assay manufacturers must be alert to the risk of falsely elevated test results in RF-positive RA patients.

Effect of Therapeutic Drug Monitoring vs Standard Therapy During Maintenance Infliximab Therapy on Disease Control in Patients With Immune-Mediated Inflammatory Diseases: A Randomized Clinical Trial.

Importance: Proactive therapeutic drug monitoring (TDM), consisting of individualized treatment based on scheduled assessments of serum drug levels, has been proposed as an alternative to standard therapy to optimize efficacy and safety of infliximab and other biologic drugs. However, it remains unclear whether proactive TDM improves clinical outcomes during maintenance therapy. Objective: To assess whether proactive TDM during maintenance therapy with infliximab improves treatment efficacy by preventing disease worsening compared with standard infliximab therapy without TDM. Design, Setting, and Participants: Randomized, parallel-group, open-label clinical trial including 458 adults with rheumatoid arthritis, spondyloarthritis, psoriatic arthritis, ulcerative colitis, Crohn disease, or psoriasis undergoing maintenance therapy with infliximab in 20 Norwegian hospitals. Patients were recruited from June 7, 2017, to December 12, 2019. Final follow-up took place on December 14, 2020. Interventions: Patients were randomized 1:1 to proactive TDM with dose and interval adjustments based on scheduled monitoring of serum drug levels and antidrug antibodies (TDM group; n = 228) or to standard infliximab therapy without drug and antibody level monitoring (standard therapy group; n = 230). Main Outcome and Measures: The primary outcome was sustained disease control without disease worsening, defined by disease-specific composite scores or consensus about disease worsening between patient and physician leading to a major change in treatment (switching to another biologic drug, adding an immunosuppressive drug including glucocorticoids, or increasing the infliximab dose), during the 52-week study period. Results: Among 458 randomized patients (mean age, 44.8 [SD, 14.3] years; 216 women [49.8%]), 454 received their randomly allocated intervention and were included in the full analysis set. The primary outcome of sustained disease control without disease worsening was observed in 167 patients (73.6%) in the TDM group and 127 patients (55.9%) in the standard therapy group. The estimated adjusted difference was 17.6% (95% CI, 9.0%-26.2%; P < .001) favoring TDM. Adverse events were reported in 137 patients (60%) and 142 patients (63%) in the TDM and standard therapy groups, respectively. Conclusions and Relevance: Among patients with immune-mediated inflammatory diseases undergoing maintenance therapy with infliximab, proactive TDM was more effective than treatment without TDM in sustaining disease control without disease worsening. Further research is needed to compare proactive TDM with reactive TDM, to assess the effects on long-term disease complications, and to evaluate the cost-effectiveness of this approach. Trial Registration: ClinicalTrials.gov Identifier: NCT03074656.

Effect of Therapeutic Drug Monitoring vs Standard Therapy During Infliximab Induction on Disease Remission in Patients With Chronic Immune-Mediated Inflammatory Diseases: A Randomized Clinical Trial.

Importance: Proactive therapeutic drug monitoring (TDM), defined as individualized drug dosing based on scheduled monitoring of serum drug levels, has been proposed as an alternative to standard therapy to maximize efficacy and safety of infliximab and other biological drugs. However, whether proactive TDM improves clinical outcomes when implemented at the time of drug initiation, compared with standard therapy, remains unclear. Objective: To assess whether TDM during initiation of infliximab therapy improves treatment efficacy compared with standard infliximab therapy without TDM. Design, Setting, and Participants: Randomized, parallel-group, open-label clinical trial of 411 adults with rheumatoid arthritis, spondyloarthritis, psoriatic arthritis, ulcerative colitis, Crohn disease, or psoriasis initiating infliximab therapy in 21 hospitals in Norway. Patients were recruited from March 1, 2017, to January 10, 2019. Final follow-up occurred on November 5, 2019. Interventions: Patients were randomized 1:1 to receive proactive TDM with dose and interval adjustments based on scheduled monitoring of serum drug levels and antidrug antibodies (TDM group; n = 207) or standard infliximab therapy without drug and antibody level monitoring (standard therapy group; n = 204). Main Outcomes and Measures: The primary end point was clinical remission at week 30. Results: Among 411 randomized patients (mean age, 44.7 [SD, 14.9] years; 209 women [51%]), 398 (198 in the TDM group and 200 in the standard therapy group) received their randomized intervention and were included in the full analysis set. Clinical remission at week 30 was achieved in 100 (50.5%) of 198 and 106 (53.0%) of 200 patients in the TDM and standard therapy groups, respectively (adjusted difference, 1.5%; 95% CI, -8.2% to 11.1%; P = .78). Adverse events were reported in 135 patients (68%) and 139 patients (70%) in the TDM and standard therapy groups, respectively. Conclusions and Relevance: Among patients with immune-mediated inflammatory diseases initiating treatment with infliximab, proactive therapeutic drug monitoring, compared with standard therapy, did not significantly improve clinical remission rates over 30 weeks. These findings do not support routine use of therapeutic drug monitoring during infliximab induction for improving disease remission rates. Trial Registration: ClinicalTrials.gov Identifier: NCT03074656.

A Comparison of Medication for Opioid Use Disorder Treatment Strategies for Persons Who Inject Drugs With Invasive Bacterial and Fungal Infections.

BACKGROUND: Patients with opioid use disorder (OUD) are frequently admitted for invasive infections. Medications for OUD (MOUD) may improve outcomes in hospitalized patients. METHODS: In this retrospective cohort of 220 admissions to a tertiary care center for invasive infections due to OUD, we compared 4 MOUD treatment strategies: methadone, buprenorphine, methadone taper for detoxification, and no medication to determine whether there were differences in parenteral antibiotic completion and readmission rates. RESULTS: The MOUDs were associated with increased completion of parenteral antimicrobial therapy (64.08% vs 46.15%; odds ratio [OR] = 2.08; 95% CI, 1.23-3.61). On multivariate analysis, use of MOUD maintenance with either buprenorphine (OR = 0.38; 95% CI, .17-.85) or methadone maintenance (OR = 0.43; 95% CI, .20-.94) and continuation of MOUD on discharge (OR = 0.35; 95% CI, .18-.67) was associated with lower 90-day readmissions. In contrast, use of methadone for detoxification followed by tapering of the medication without continuation on discharge was not associated with decreased readmissions (OR = 1.87; 95% CI, .62-5.10). CONCLUSIONS: Long-term MOUDs, regardless of selection, are an integral component of care in patients hospitalized with OUD-related infections. Patients with OUD should have arrangements made for MOUDs to be continued after discharge, and MOUDs should not be discontinued before discharge.

Evaluation of Partial Oral Antibiotic Treatment for Persons Who Inject Drugs and Are Hospitalized With Invasive Infections.

BACKGROUND: Persons who inject drugs (PWID) are at risk of invasive infections; however, hospitalizations to treat these infections are frequently complicated by against medical advice (AMA) discharges. This study compared outcomes among PWID who (1) completed a full course of inpatient intravenous (IV) antibiotics, (2) received a partial course of IV antibiotics but were not prescribed any antibiotics on AMA discharge, and (3) received a partial course of IV antibiotics and were prescribed oral antibiotics on AMA discharge. METHODS: A retrospective, cohort study of PWID aged ≥18 years admitted to a tertiary referral center between 01/2016 and 07/2019, who received an infectious diseases consultation for an invasive bacterial or fungal infection. RESULTS: 293 PWID were included in the study. 90-day all-cause readmission rates were highest among PWID who did not receive oral antibiotic therapy on AMA discharge (n = 46, 68.7%), compared with inpatient IV (n = 43, 31.5%) and partial oral (n = 27, 32.5%) antibiotics. In a multivariate analysis, 90-day readmission risk was higher among PWID who did not receive oral antibiotic therapy on AMA discharge (adjusted hazard ratio [aHR], 2.32; 95% confidence interval [CI], 1.41-3.82) and not different among PWID prescribed oral antibiotic therapy on AMA discharge (aHR, .99; 95% CI, .62-1.62). Surgical source control (aHR, .57; 95% CI, .37-.87) and addiction medicine consultation (aHR, .57; 95% CI, .38-.86) were both associated with reduced readmissions. CONCLUSIONS: Our single-center study suggests access to oral antibiotic therapy for PWID who cannot complete prolonged inpatient IV antibiotic courses is beneficial.