Evaluation of the diagnostic utility of metagenomic next-generation sequencing testing for pathogen identification in infected hosts: a retrospective cohort study.

Background: Metagenomic next-generation sequencing (mNGS) testing identifies thousands of potential pathogens in a single blood test, though data on its real-world diagnostic utility are lacking. Objectives: Determine the diagnostic utility of mNGS testing in practice and factors associated with high clinical utility. Design: Retrospective cohort study of mNGS tests ordered from June 2018 through May 2020 at a community teaching hospital. Methods: Tests were included if ordered for diagnostic purposes in patients with probable or high clinical suspicion of infection. Exclusions included patient expiration, hospice care, or transfer outside of the institution. Utility criteria were established a priori by the research team. Two investigators independently reviewed each test and categorized it to either high or low diagnostic utility. Reviewer discordance was referred to a third investigator. The stepwise multiple regression method was used to identify clinical factors associated with high diagnostic utility. Results: Among 96 individual tests from 82 unique patients, 80 tests met the inclusion criteria for analysis. At least one potential pathogen was identified in 58% of tests. Among 112 pathogens identified, there were 74 bacteria, 25 viruses, 12 fungi, and 1 protozoon. In all, 46 tests (57.5%) were determined to be of high diagnostic utility. Positive mNGS tests were identified in 36 (78.3%) and 11 (32.4%) of high and low diagnostic utility tests, respectively (p < 0.001). Antimicrobials were changed after receiving test results in 31 (67.4%) of high utility tests and 4 (11.8%) of low utility tests (p < 0.0001). In the multiple regression model, a positive test [odds ratio (OR) = 10.9; 95% confidence interval (CI), 3.2-44.4] and consultation with the company medical director (OR = 3.6; 95% CI, 1.1-13.7) remained significantly associated with high diagnostic utility. Conclusion: mNGS testing resulted in high clinical utility in most cases. Positive mNGS tests were associated with high diagnostic utility. Consultation with the Karius® medical director is recommended to maximize utility.

Evaluating the real world utility of using a diagnostic test that uses cell-free DNA to identify bacteria, viruses, fungi and protozoa from blood in hospitalized adult and pediatric patients Our institution has utilized a meta-genomic test that identifies bacteria, DNA-based viruses, fungi and protozoa from blood sample in hospitalized patients to support diagnostics in select clinical cases. We evaluated the utility of these tests in an adult and pediatric population. We found that 58% of the 96 tests from 82 unique patients produced a pathogen. Overall, a majority (58%) of tests were deemed to be of high utility which directly resulted in changes in antimicrobial therapy, selection of duration of therapy, direction for new diagnostics, or avoidance of further need for diagnostics. Positive tests and consultation with the medical director of the laboratory were both associated with high utility of the tests.

Clinical Utility and Cost Effectiveness of Long-Acting Lipoglycopeptides Used in Deep-Seated Infections among Patients with Social and Economic Barriers to Care.

The use of long-acting lipoglycopeptides (LaLGPs) in serious, deep-seated infections is of increasing interest. The purpose of this study is to evaluate the economic and clinical utility of LaLGPs in patients requiring protracted antibiotic courses who are not ideal candidates for oral transition or outpatient parenteral antibiotic therapy (OPAT). This is a retrospective, observational, matched cohort study of adult patients who received a LaLGP. Patients were matched 1:1 to those who received standard of care (SOC). Cost effectiveness was evaluated as total healthcare-related costs between groups. Clinical failure was a composite endpoint of mortality, recurrence, or need for extended antibiotics beyond planned course within 90 days of initial infection. There was no difference in clinical failure between the two cohorts (22% vs. 30%; p = 0.491). Six patients in the SOC cohort left against medical advice (AMA) prior to completing therapy. Among those who did not leave AMA, receipt of LaLGPs resulted in a decreased hospital length of stay by an average of 13.6 days. The average total healthcare-related cost of care was USD 295,589 in the LaLGP cohort compared to USD 326,089 in the SOC cohort (p = 0.282). Receipt of LaLGPs may be a beneficial treatment option for patients with deep-seated infections and socioeconomic factors who are not candidates for oral transition or OPAT.

Thrombophilia in 153 Patients With Premature Cardiovascular Disease ≤Age 45.

We assessed contributions of thrombophilia to premature cardiovascular disease (CVD) events (≤ age 45) in 153 patients. Test results of thrombophilia-hypofibrinolysis were obtained in 153 patients with CVD ≤ age 45, 110 healthy normal controls, and 110 patients who had venous thromboembolism (VTE) without CVD. Of the 153 patients with CVD, 121 (79%) had sustained myocardial infarction, 70 (46%) had coronary artery stenting, and 53 (35%) had coronary artery bypass grafts. The first CVD events occurred at ages >20 to 35 in 47 patients and at ages >35 to 45 in 106 patients. At study entry, median low-density lipoprotein cholesterol was 126 mg/dL, 56 (37%) smoked, 56 (37%) had hypertension, and 56 (37%) were diabetic. Cases differed from normal controls for high factor VIII (10 [22%] of 45 vs 7 of 103 [7%], P = .007), high homocysteine (32 [21%] of 151 vs 5 [5%] of 107, P = .0002), low free protein S (5 [11%] of 44 vs 2 [2%] of 96, P = .032), high anticardiolipin antibodies (ACLA) IgM (11 [9%] of 129 vs 2 [2%] of 109, P = .024), high lipoprotein (a) [Lp(a)] (46 [30%] of 151 vs 21 [19%] of 110, P = .038), and the lupus anticoagulant (4 [11%] of 37 vs 2 [2%] of 110, P = .035). There were no differences ( P > .05) between cases and VTE controls except free protein S and Lp(a). Free protein S was more often low in VTE controls (24 [28%] of 85 vs 5 [11%] of 44, P = .03) and Lp(a) was more often high in cases (46 [30%] of 151, VTE controls 12 [17%] of 71, P = .032). In 153 patients with premature CVD ≤ age 45, thrombophilia was pervasive (high factor VIII, homocysteine, ACLA IgM, low free protein S, high Lp(a), and lupus anticoagulant), evidencing thrombotic contribution to premature CVD. Moreover, thrombophilia in patients with premature CVD was comparable to VTE controls, emphasizing the pervasive nature of thrombophilia in premature CVD.

Case report: primary osteonecrosis associated with thrombophilia-hypofibrinolysis and worsened by testosterone therapy.

BACKGROUND: Familial and acquired thrombophilia are often etiologic for idiopathic hip and jaw osteonecrosis (ON), and testosterone therapy (TT) can interact with thrombophilia, worsening ON. CASE PRESENTATION: Case 1: A 62-year-old Caucasian male (previous deep venous thrombosis), on warfarin 1 year for atrial fibrillation (AF), had non-specific right hip-abdominal pain for 2 years. CT scan revealed bilateral femoral head ON without collapse. Coagulation studies revealed Factor V Leiden (FVL) heterozygosity, 4G/4G plasminogen activator inhibitor (PAI) homozygosity, high anti-cardiolipin (ACLA) IgM antibodies, and endothelial nitric oxide (NO) synthase (eNOS) T786C homozygosity (reduced conversion of L-arginine to NO, required for bone health). Apixaban 5 mg twice daily was substituted for warfarin; and L-arginine 9 g/day was started to increase NO. On Apixaban for 8 months, he became asymptomatic. Case 2: A 32-year-old hypogonadal Caucasian male had 10 years of unexplained tooth loss, progressing to primary jaw ON with cavitation 8 months after starting TT gel 50 mg/day. Coagulation studies revealed FVL heterozygosity, PAI 4G/4G homozygosity, and the lupus anticoagulant. TT was discontinued. Jaw pain was sharply reduced within 2 months. CONCLUSIONS: Idiopathic ON, often caused by thrombophilia-hypofibrinolysis, is worsened by TT, and its progression may be slowed or stopped by discontinuation of TT and, thereafter, anticoagulation. Recognition of thrombophilia-hypofibrinolysis before joint collapse facilitates anticoagulation which may stop ON, preserving joints.