The Limit of Detection Matters: The Case for Benchmarking Severe Acute Respiratory Syndrome Coronavirus 2 Testing.

BACKGROUND: Resolving the coronavirus disease 2019 (COVID-19) pandemic requires diagnostic testing to determine which individuals are infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The current gold standard is to perform reverse-transcription polymerase chain reaction (PCR) on nasopharyngeal samples. Best-in-class assays demonstrate a limit of detection (LoD) of approximately 100 copies of viral RNA per milliliter of transport media. However, LoDs of currently approved assays vary over 10,000-fold. Assays with higher LoDs will miss infected patients. However, the relative clinical sensitivity of these assays remains unknown. METHODS: Here we model the clinical sensitivities of assays based on their LoD. Cycle threshold (Ct) values were obtained from 4700 first-time positive patients using the Abbott RealTime SARS-CoV-2 Emergency Use Authorization test. We derived viral loads from Ct based on PCR principles and empiric analysis. A sliding scale relationship for predicting clinical sensitivity was developed from analysis of viral load distribution relative to assay LoD. RESULTS: Ct values were reliably repeatable over short time testing windows, providing support for use as a tool to estimate viral load. Viral load was found to be relatively evenly distributed across log10 bins of incremental viral load. Based on these data, each 10-fold increase in LoD is expected to lower assay sensitivity by approximately 13%. CONCLUSIONS: The assay LoD meaningfully impacts clinical performance of SARS-CoV-2 tests. The highest LoDs on the market will miss a majority of infected patients. Assays should therefore be benchmarked against a universal standard to allow cross-comparison of SARS-CoV-2 detection methods.

Infection prevention measures in acute care settings based on severe acute respiratory syndrome coronavirus 2 transmission patterns and risk: a review.

PURPOSE OF REVIEW: During the coronavirus disease 2019 pandemic, when facing extraordinary infection prevention challenges, acute care settings have balanced routine patient safety needs while minimizing severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) transmission risk to patients and healthcare personnel (HCP). Mitigation strategies in acute care settings are based on a combination of basic science, environmental, and epidemiologic evidence. Here, we review the literature on SARS-CoV-2 transmission, how it has shaped infection prevention interventions in acute care settings, and the results of such measures to reduce transmission. RECENT FINDINGS: HCP adherence to transmission-based precautions in acute care settings, such as the use of personal protective equipment (PPE), is essential to mitigating SARS-CoV-2 spread. Although the SARS-CoV-2 virus has been isolated in nonrespiratory body sites, such exposure has not been shown to definitively cause transmission in humans. Epidemiologic evidence has demonstrated that implementation and adherence to infection prevention strategies reduces acute setting transmission. SUMMARY: Given SARS-CoV-2 infection occurs primarily through respiratory transmission, preventing HCP acquisition requires fidelity to consistent PPE usage. Infection prevention strategies and implementation of transmission-based precautions have reduced spread and outbreaks. Epidemiologic studies of acute care outbreaks often include reports of PPE nonadherence and community exposure contributing to SARS-CoV-2 transmission within this setting.

Clinical and radiological septic joint analysis of spontaneous sternoclavicular joint infections: achieving the best outcomes-a systems engineering approach.

OBJECTIVES: Spontaneous sternoclavicular joint infection (SSCJI) is a rare and poorly understood disease process. This study aims to identify factors guiding effective management strategies for SSCJI by using data mining. METHODS: An Institutional Review Board-approved retrospective review of patients from 2 large hospitals (2010-2022) was conducted. SSCJI is defined as a joint infection without direct trauma or radiation, direct instrumentation or contiguous spread. An interdisciplinary team consisting of thoracic surgeons, radiologists, infectious disease specialists, orthopaedic surgeons, hospital information experts and systems engineers selected relevant variables. Small set data mining algorithms, utilizing systems engineering, were employed to assess the impact of variables on patient outcomes. RESULTS: A total of 73 variables were chosen and 54 analysed against 11 different outcomes. Forty-seven patients [mean age 51 (22-82); 77% male] met criteria. Among them, 34 underwent early joint surgical resection (<14 days), 5 patients received delayed surgical intervention (>14 days) and 8 had antibiotic-only management. The antibiotic-only group had comparable outcomes. Indicators of poor outcomes were soft tissue fluid >4.5 cm, previous SSCJI, moderate/significant bony fragments, HgbA1c >13.9% and moderate/significant bony sclerosis. CONCLUSIONS: This study suggests that targeted antibiotic-only therapy should be considered initially for SSCJI cases while concurrently managing comorbidities. Patients displaying indicators of poor outcomes or no symptomatic improvement after antibiotic-only therapy should be considered for surgical joint resection.

Multidisciplinary Teams for the Management of Infective Endocarditis: A Systematic Review and Meta-analysis.

Background: The management of infective endocarditis (IE) is complex owing to a high burden of morbidity and mortality. Recent guidelines recommend dedicated multidisciplinary teams (MDTs) for the management of IE. The aim of this systematic review and meta-analysis was to evaluate and summarize the effect of MDT management on patient outcomes. Methods: A systematic review was performed and, where feasible, results were meta-analyzed; otherwise, results were summarized narratively. Data extraction and quality assessment were performed in duplicate. Restricted maximum likelihood random effects models were used to calculate unadjusted risk ratios and 95% CIs. Results: Screening of 2343 studies based on title and abstract yielded 60 full-text reviews; 18 studies were summarized narratively, of which 15 were included in a meta-analysis of short-term mortality. Meta-analysis resulted in a risk ratio of 0.61 (95% CI, .47-.78; I2 = 62%) for mortality in favor of a dedicated MDT as compared with usual care. Length of stay was variable, with 55% (10/18) of studies reporting an increased length of stay. Most studies (16/18, 88.9%) reported a decreased time to surgery and an increased rate of surgery (13/18, 73%). No studies reported on patient-reported outcomes. Conclusions: This is the first systematic review and meta-analysis to assess the impact of MDT management on IE. The sum of evidence demonstrated a significant association between MDTs and improved short-term mortality. Further research is needed to evaluate benefits of virtual MDT care, cost-effectiveness, and the impact on patient-reported outcomes and long-term mortality.

Assessing changes to N95 respirator filtration efficiency, qualitative and quantitative fit, and seal check with repeated vaporized hydrogen peroxide (VHP) decontamination.

N95 respirators were reprocessed using vaporized hydrogen peroxide to supplement limited supplies during the COVID-19 pandemic. In this study, we found no statistically significant differences in qualitative and quantitative fit or filtration efficiency with reprocessing. Filtration efficiency remained above 95% even at 25 cycles of reprocessing without statistically significant change from cycle 20-25 compared to cycle 0 (P = .10, P = .05, respectively). Vaporous hydrogen peroxide is an effective option to augment N95 respirator supplies.

Antimicrobial ethicists: Making ethics explicit in antimicrobial stewardship.

Antimicrobial prescribing and the associated discipline of antimicrobial stewardship have inherent ethical and moral dimensions. We contend that the explicit, formal application of ethical principles and frameworks can strengthen and further justify the value of antimicrobial stewardship programs and their work. To illustrate the value of this process, we highlight 3 ethical scenarios that antimicrobial stewardship programs regularly encounter at the prescriber, institutional, and societal levels, and we analyze these scenarios using the Beauchamp and Childress biomedical ethics framework.

Intravenous cephalosporin versus non-cephalosporin-based prophylaxis to prevent surgical site infections in colorectal surgery patients: A systematic review and meta-analysis.

BACKGROUND: Surgical site infection (SSI) is common in colorectal surgery patients and associated with morbidity and mortality. Guidelines recommend preoperative intravenous antimicrobial prophylaxis with aerobic and anaerobic coverage to reduce SSI risk. Cephalosporin based prophylaxis (CBP) regimens are recommended as first-line prophylaxis, and non-cephalosporin based are recommended as alternative prophylaxis (AP). We evaluate the efficacy of CBP versus AP in preventing surgical site infections in colorectal surgery patients. METHODS: A systematic review and meta-analysis was conducted of studies published between 2005 and 2020 in MEDLINE and Web of Science. Studies were excluded if intravenous antimicrobial prophylaxis was not administered, or if oral and intravenous prophylaxis were routinely co-administered. Heterogeneity was reported using the Q-statistic and I2-statistic. Publication bias was evaluated using a funnel plot and Egger test for small study effects. Statistical significance was defined as a two-sided p < 0.05. RESULTS: 11 studies met inclusion criteria. AP was not associated with increased SSI risk at 30 days compared to CBP (OR 1.01, 95% CI 0.91, 1.13; OR < 1 favors AP). There was no effect size variability in subgroup analysis comparing higher-to lower-quality studies (I2 = 99%, P = 0.17). Subgroup analysis by publication year approached a significant difference in effect size between studies published prior to 2014 and later than 2014 (I2 = 99%, P = 0.06). CONCLUSIONS: Meta-analysis of 11 studies of SSI risk in adult colorectal surgery patients suggest that SSI risk is similar for patients receiving CBP or AP, subgroup analysis of studies published since 2014 suggest increased SSI risk with AP compared to CBP.

Diminishing returns, increasing risks: Impact of antibiotic duration of therapy on respiratory bacterial isolates in hospitalized patients during the coronavirus disease 2019 (COVID-19) pandemic.

In 829 hospital encounters for patients with COVID-19, 73.2% included orders for antibiotics; however, only 1.8% had respiratory cultures during the first 3 hospital days isolating bacteria. Case-control analysis of 30 patients and 96 controls found that each antibiotic day increased the risk of isolating multidrug-resistant gram-negative bacteria (MDR-GNB) in respiratory cultures by 6.5%.

Case Report: Refractory Cryptosporidiosis after CAR T-Cell Therapy for Lymphoma.

Cryptosporidial diarrhea is uncommon in immunocompetent individuals, more often seen in severely immunocompromised patients. Severe refractory cases have been described in patients with HIV/AIDS before the advent of modern antiretroviral therapy due to an inability to mount an adequate cellular immune response. We describe an 85-year-old patient post-chimeric antigen receptor T-cell therapy relapsed lymphoma who developed refractory Cryptosporidium spp. diarrhea in the setting of persistent CD4+ cytopenia. Despite receiving multiple antiparasitic agents, including failure of a prolonged course of nitazoxanide, the patient experienced persistent symptoms for 9 months with repeatedly positivity stool Cryptosporidium spp. direct fluorescent antibody (DFA) test. We highlight this case of refractory Cryptosporidium spp. and the importance of recognizing the pathogen in a non-HIV-infected immunosuppressed host.

Risk of QT Interval Prolongation Associated With Use of Hydroxychloroquine With or Without Concomitant Azithromycin Among Hospitalized Patients Testing Positive for Coronavirus Disease 2019 (COVID-19).

IMPORTANCE: Administration of hydroxychloroquine with or without azithromycin for the treatment of coronavirus disease 2019 (COVID-19)-associated pneumonia carries increased risk of corrected QT (QTc) prolongation and cardiac arrhythmias. OBJECTIVE: To characterize the risk and degree of QT prolongation in patients with COVID-19 in association with their use of hydroxychloroquine with or without concomitant azithromycin. DESIGN, SETTING, AND PARTICIPANTS: This was a cohort study performed at an academic tertiary care center in Boston, Massachusetts, of patients hospitalized with at least 1 positive COVID-19 nasopharyngeal polymerase chain reaction test result and clinical findings consistent with pneumonia who received at least 1 day of hydroxychloroquine from March 1, 2020, through April 7, 2020. MAIN OUTCOMES AND MEASURES: Change in QT interval after receiving hydroxychloroquine with or without azithromycin; occurrence of other potential adverse drug events. RESULTS: Among 90 patients given hydroxychloroquine, 53 received concomitant azithromycin; 44 (48.9%) were female, and the mean (SD) body mass index was 31.5 (6.6). Hypertension (in 48 patients [53.3%]) and diabetes mellitus (in 26 patients [28.9%]) were the most common comorbid conditions. The overall median (interquartile range) baseline QTc was 455 (430-474) milliseconds (hydroxychloroquine, 473 [454-487] milliseconds vs hydroxychloroquine and azithromycin, 442 [427-461] milliseconds; P < .001). Those receiving concomitant azithromycin had a greater median (interquartile range) change in QT interval (23 [10-40] milliseconds) compared with those receiving hydroxychloroquine alone (5.5 [-15.5 to 34.25] milliseconds; P = .03). Seven patients (19%) who received hydroxychloroquine monotherapy developed prolonged QTc of 500 milliseconds or more, and 3 patients (8%) had a change in QTc of 60 milliseconds or more. Of those who received concomitant azithromycin, 11 of 53 (21%) had prolonged QTc of 500 milliseconds or more and 7 of 53 (13 %) had a change in QTc of 60 milliseconds or more. The likelihood of prolonged QTc was greater in those who received concomitant loop diuretics (adjusted odds ratio, 3.38 [95% CI, 1.03-11.08]) or had a baseline QTc of 450 milliseconds or more (adjusted odds ratio, 7.11 [95% CI, 1.75-28.87]). Ten patients had hydroxychloroquine discontinued early because of potential adverse drug events, including intractable nausea, hypoglycemia, and 1 case of torsades de pointes. CONCLUSIONS AND RELEVANCE: In this cohort study, patients who received hydroxychloroquine for the treatment of pneumonia associated with COVID-19 were at high risk of QTc prolongation, and concurrent treatment with azithromycin was associated with greater changes in QTc. Clinicians should carefully weigh risks and benefits if considering hydroxychloroquine and azithromycin, with close monitoring of QTc and concomitant medication usage.

SARS-CoV2 Testing: The Limit of Detection Matters.

Resolving the COVID-19 pandemic requires diagnostic testing to determine which individuals are infected and which are not. The current gold standard is to perform RT-PCR on nasopharyngeal samples. Best-in-class assays demonstrate a limit of detection (LoD) of ~100 copies of viral RNA per milliliter of transport media. However, LoDs of currently approved assays vary over 10,000-fold. Assays with higher LoDs will miss more infected patients, resulting in more false negatives. However, the false-negative rate for a given LoD remains unknown. Here we address this question using over 27,500 test results for patients from across our healthcare network tested using the Abbott RealTime SARS-CoV-2 EUA. These results suggest that each 10-fold increase in LoD is expected to increase the false negative rate by 13%, missing an additional one in eight infected patients. The highest LoDs on the market will miss a majority of infected patients, with false negative rates as high as 70%. These results suggest that choice of assay has meaningful clinical and epidemiological consequences. The limit of detection matters.

Case report: herpes simplex encephalitis in cancer patients.

The manifestation of herpes simplex encephalitis in patients can often be interpreted as a possible brain tumor. In order to make a definite diagnosis, subsequent invasive testing is frequently required. In addition to other routine diagnostic measures, particular symptoms, especially those indicating that a patient is immunocompromised, should be considered as possible evidence indicating presence of this central nervous system (CNS) viral infection.