Randomized Trial of a Vaccine Regimen to Prevent Chronic HCV Infection.

BACKGROUND: A safe and effective vaccine to prevent chronic hepatitis C virus (HCV) infection is a critical component of efforts to eliminate the disease. METHODS: In this phase 1-2 randomized, double-blind, placebo-controlled trial, we evaluated a recombinant chimpanzee adenovirus 3 vector priming vaccination followed by a recombinant modified vaccinia Ankara boost; both vaccines encode HCV nonstructural proteins. Adults who were considered to be at risk for HCV infection on the basis of a history of recent injection drug use were randomly assigned (in a 1:1 ratio) to receive vaccine or placebo on days 0 and 56. Vaccine-related serious adverse events, severe local or systemic adverse events, and laboratory adverse events were the primary safety end points. The primary efficacy end point was chronic HCV infection, defined as persistent viremia for 6 months. RESULTS: A total of 548 participants underwent randomization, with 274 assigned to each group. There was no significant difference in the incidence of chronic HCV infection between the groups. In the per-protocol population, chronic HCV infection developed in 14 participants in each group (hazard ratio [vaccine vs. placebo], 1.53; 95% confidence interval [CI], 0.66 to 3.55; vaccine efficacy, -53%; 95% CI, -255 to 34). In the modified intention-to-treat population, chronic HCV infection developed in 19 participants in the vaccine group and 17 in placebo group (hazard ratio, 1.66; 95% CI, 0.79 to 3.50; vaccine efficacy, -66%; 95% CI, -250 to 21). The geometric mean peak HCV RNA level after infection differed between the vaccine group and the placebo group (152.51×103 IU per milliliter and 1804.93×103 IU per milliliter, respectively). T-cell responses to HCV were detected in 78% of the participants in the vaccine group. The percentages of participants with serious adverse events were similar in the two groups. CONCLUSIONS: In this trial, the HCV vaccine regimen did not cause serious adverse events, produced HCV-specific T-cell responses, and lowered the peak HCV RNA level, but it did not prevent chronic HCV infection. (Funded by the National Institute of Allergy and Infectious Diseases; ClinicalTrials.gov number, NCT01436357.).

Sharing the cure: Building primary care and public health infrastructure to improve the hepatitis C care continuum in Maryland.

In 2014, trained healthcare provider capacity was insufficient to deliver care to an estimated 70 000 persons in Maryland with chronic hepatitis C virus (HCV) infection. The goal of Maryland Community Based Programs to Test and Cure Hepatitis C, a public health implementation project, was to improve HCV treatment access by expanding the workforce. Sharing the Cure (STC) was a package of services deployed 10/1/14-9/30/18 that included enhanced information technology and public health infrastructure, primary care provider training and practice transformation. Nine primary care sites enrolled. HCV clinical outcomes were documented among individuals who presented for care at sites and met criteria for HCV testing including risk factor or birth cohort (born between 1945 and 1965) based testing. Fifty-three providers completed the STC training. STC providers identified 3237 HCV antibody-positive patients of which 2624 (81%) were RNA+. Of those HCV RNA+, 1739 (66%) were staged, 932 (36%) were prescribed treatment, 838 (32%) started treatment, 721 (27%) completed treatment and 543 (21%) achieved cure. Among 1739 patients staged, 693 (40%) patients had a liver fibrosis assessment score < F2, rendering them ineligible for treatment under Maryland Medicaid guidelines. HCV RNA testing among HCV antibody-positive people increased from 40% (baseline) to 95% among STC providers. Of 554 patients with virologic data reported, 543 (98%) achieved cure. Primary care practices can effectively serve as HCV treatment centers to expand treatment access. However, criteria by insurance providers in Maryland were a major barrier to treatment.

Clinical coaching: Evolving the apprenticeship model for modern housestaff.

Feedback is one of the core components of teaching in the clinical setting. Traditionally, this activity has emphasized observations made by senior physicians and delivered to medical trainees. However, the optimal approach to feedback remains uncertain, and the literature abounds with trainee-perceived inadequacies in feedback content, quality, and impact. Moreover, given the multiplicity of demands on trainees and their physician mentors, we propose that medical trainees themselves-specifically, medical residents-are poised to serve as unique adjunct effectors of feedback. We propose a model of "clinical coaching" for residents as teachers, with emphasis on the active roles of both the feedback "giver" and "recipient". We define "clinical coaching" as "a helping longitudinal relationship between coach and apprentice that provides continuing feedback on and assistance with improving performance." Here, "coach" is the more experienced trainee (e.g. supervising resident), and "apprentice" is the less experienced trainee (e.g. intern or medical student). By working to better recognize and prepare residents for this vital role, we propose to encourage efforts to optimize the structure, execution, and impact of feedback in the contemporary climate of medical education.

Infections during peginterferon/ribavirin therapy are associated with the magnitude of decline in absolute lymphocyte count: results of the IDEAL study.

BACKGROUND: Myelosuppression due to pegylated interferon (peg-IFN) is common during treatment for hepatitis C virus. The relationship between infection risk and decreases in leukocyte lines, however, is not well established. The objective of this analysis was to determine the incidence of and risk factors for infections during peg-IFN/ribavirin (RBV) therapy. METHODS: A total of 3070 treatment-naive, chronic hepatitis C genotype 1-infected patients were treated for up to 48 weeks with peg-IFN alfa-2b 1.5 µg/kg/week or 1 µg/kg/week, or peg-IFN alfa-2a 180 µg/week plus RBV. On-treatment leukocyte counts were obtained every 2-6 weeks. Dose reduction was required for a neutrophil count <0.75 × 10(9) cells/L, and treatment discontinuation was required for a neutrophil count <0.5 × 10(9) cells/L. Granulocyte colony-stimulating factor was prohibited. Data on infections were captured at each study visit and categorized according to MedDRA version 13.0. RESULTS: A total of 581 (19%) patients experienced moderate, severe, or life-threatening infections as assessed by the investigator; 648 (21%) patients had at least 1 neutrophil count <0.75 × 10(9) cells/L, but only 242 (8%) sustained an infection and had a neutrophil count <0.75 × 10(9) cells/L at any time while on treatment. Twelve patients had severe or life-threatening infection and grade 3/4 neutropenia, but only 4 had temporally related infections. In a multivariate logistic regression model, nadir lymphocyte count, history of depression, and female sex, but not nadir neutrophil count, were associated with moderate, severe, or life-threatening infection. CONCLUSIONS: Nadir lymphocyte count, not nadir neutrophil count, was independently associated with moderate, severe, or life-threatening infections in the IDEAL study. Clinicians should be aware of their patients' absolute lymphocyte counts during peg-IFN/RBV therapy; peg-IFN dose reductions may be a consideration in patients with significant lymphocytopenia (<0.5 × 10(9) cells/L).

The first US domestic report of disseminated Mycobacterium avium complex and anti-interferon-γ autoantibodies.

INTRODUCTION: Anti-interferon-γ (IFNγ) autoantibodies have been associated with disseminated mycobacterial infections, mostly in patients from Southeast Asia. PURPOSE: We studied an American-born, Caucasian female with M. avium complex infection of the subglottic mucosa and brain for underlying etiologies of infection. METHODS: Plasma was screened for anticytokine autoantibodies using a Luminex-based approach. The ability of patient plasma to block IFNγ-induced STAT1 phosphorylation in normal blood cells was evaluated by flow cytometry with intracellular staining. Plasma inhibition of IFNγ production and IFNγ-induced cytokines in normal and patient blood cells washed of autologous plasma was also evaluated. RESULTS: Patient plasma contained high-titer IgG anti-IFNγ autoantibodies, primarily of the IgG1 subclass. Patient but not control plasma prevented IFNγ-induced STAT1 phosphorylation and expression of the IFNγ-inducible cytokines tumor necrosis factor (TNF) α and interleukin (IL)-12 in normal blood cells. Patient blood cells washed free of autologous plasma demonstrated normal IFNγ production and response. CONCLUSIONS: Disseminated nontuberculous mycobacterial infections should always prompt immune evaluation. This first case of disseminated nontuberculous mycobacterial infection and anti-IFNγ autoantibodies in an American-born Caucasian suggests that anti-cytokine autoantibodies are not racially or regionally restricted.

Constrictive pleuropericarditis: a dominant clinical manifestation in Whipple's disease.

BACKGROUND: Whipple's disease is a rare, multisystemic, chronic infectious disease which classically presents as a wasting illness characterized by polyarthralgia, diarrhea, fever, and lymphadenopathy. Pleuropericardial involvement is a common pathologic finding in patients with Whipple's disease, but rarely causes clinical symptoms. We report the first case of severe fibrosing pleuropericarditis necessitating pleural decortication in a patient with Whipple's disease. CASE PRESENTATION: Our patient, an elderly gentleman, had a chronic inflammatory illness dominated by constrictive pericarditis and later severe fibrosing pleuritis associated with a mildly elevated serum IgG4 level. A pericardial biopsy showed dense fibrosis without IgG4 plasmacytic infiltration. The patient received immunosuppressive therapy for possible IgG4-related disease. His poor response to this therapy prompted a re-examination of the diagnosis, including a request for the pericardial biopsy tissue to be stained for Tropheryma whipplei. CONCLUSIONS: Despite a high prevalence of pleuropericardial involvement in Whipple's disease, constrictive pleuropericarditis is rare, particularly as the dominant disease manifestation. The diagnosis of Whipple's disease is often delayed in such atypical presentations since the etiologic agent, Tropheryma whipplei, is not routinely sought in histopathology specimens of pleura or pericardium. A diagnosis of Whipple's disease should be considered in middle-aged or elderly men with polyarthralgia and constrictive pericarditis, even in the absence of gastrointestinal symptoms. Although Tropheryma whipplei PCR has limited sensitivity and specificity, especially in the analysis of peripheral blood samples, it may have diagnostic value in inflammatory disorders of uncertain etiology, including cases of polyserositis. The optimal approach to managing constrictive pericarditis in patients with Whipple's disease is uncertain, but limited clinical experience suggests that a combination of pericardiectomy and antibiotic therapy is of benefit.

Teaching Everyone Everywhere All at Once: Leveraging Social Media to Implement a Multisite Fungal Diagnostics Curriculum.

Background: Environmental fungi are threats to personal and public health. Fungal in vitro diagnostics help diagnose invasive fungal infections (IFIs), but clinicians remain underinformed about their use and interpretation. Given the increasing use of social media to share infectious diseases-related content, we designed and implemented a multisite Twitter-based curriculum focused on IFIs and related diagnostics. Methods: Questions were posted through a dedicated Twitter account twice weekly over 8 weeks. We surveyed clinicians at 3 US academic centers before and after completion of the curriculum and interviewed a subset of participants. We undertook quantitative and qualitative evaluations and reviewed Twitter analytics. Results: We surveyed 450 participants. One hundred twenty-one participants (27%) completed the knowledge assessment precurriculum, 68 (15%) postcurriculum, and 53 (12%) pre- and postcurriculum. We found a significant increase (72% vs 80%, P = .005) in the percentage of correct answers in the pre- versus postcurriculum knowledge assessments. Perceived benefits included a well-executed curriculum that facilitated engagement with appropriately detailed tweetorials from a dedicated Twitter account. Perceived barriers included lack of awareness of tweetorial posts and timing, competing priorities, and the coronavirus disease 2019 pandemic. The Twitter account accrued 1400 followers from 65 countries during the 8-week period. Tweets with multiple-choice questions had a median of 14 904 impressions (interquartile range [IQR], 12 818-16 963), 798 engagements (IQR, 626-1041), and an engagement rate of 6.1% (IQR, 4.2%-6.6%). Conclusions: Educators can leverage social media to share content with a large audience and improve knowledge while being mindful of the barriers associated with implementing a curriculum on social media.

Racial differences in hepatitis C treatment eligibility.

UNLABELLED: Black Americans are disproportionally infected with hepatitis C virus (HCV) and are less likely than whites to respond to treatment with peginterferon (PEG-IFN) plus ribavirin (RBV). The impact of race on HCV treatment eligibility is unknown. We therefore performed a retrospective analysis of a phase 3B multicenter clinical trial conducted at 118 United States community and academic medical centers to evaluate the rates of and reasons for HCV treatment ineligibility according to self-reported race. In all, 4,469 patients were screened, of whom 1,038 (23.2%) were treatment ineligible. Although blacks represented 19% of treated patients, they were more likely not to be treated due to ineligibility and/or failure to complete required evaluations (40.2%) than were nonblack patients (28.5%; P < 0.001). After the exclusion of persons not treated due to undetectable HCV RNA or nongenotype 1 infection, blacks were 65% less likely than nonblacks to be eligible for treatment (28.1% > 17.0%; relative risk, 1.65; 95% confidence interval, 1.46-1.87; P < 0.001). Blacks were more likely to be ineligible due to neutropenia (14% versus 3%, P < 0.001), anemia (7% versus 4%, P = 0.02), elevated glucose (8% versus 3%, P < 0.001), and elevated creatinine (5% versus 1%, P < 0.001). CONCLUSION: Largely due to a higher prevalence of neutropenia and uncontrolled medical conditions, blacks were significantly less likely to be eligible for HCV treatment. Increased access to treatment may be facilitated by less conservative neutrophil requirements and more effective care for chronic diseases, namely, diabetes and renal insufficiency.

Bullying Borrelia: when the culture of science is under attack.

Although Lyme disease responds to short courses of antibiotics, tick-borne Borrelia burgdorferi has been advanced by some as a frequent explanation for medically unexplained symptoms such as continual fatigue, musculoskeletal pains, and subjective neurocognitive dysfunction. Often called "chronic Lyme disease" by adherents of this philosophy, it is loosely defined, and practitioners liberally prescribe nostrums, including prolonged antimicrobial therapies, in a belief that this eradicates suspected infection. Perhaps due to the lack of supportive data, proponents of this theory have developed their own meetings, literature, activist groups, and substantial internet activities to advance their views. Forces motivating this movement are explored, as are tactics used to advance non-scientific ideas that have included legal action and garnering legislative endorsement. While neither logical nor evidence-based, "chronic Lyme disease" harnesses corrosive energies that taint modern medicine and society.

Mistaken Identity: Many Diagnoses are Frequently Misattributed to Lyme Disease.

BACKGROUND: Prior studies have demonstrated that Lyme disease is frequently over-diagnosed. However, few studies describe which conditions are misdiagnosed as Lyme disease. METHODS: This retrospective observational cohort study evaluated patients who lacked evidence for Borrelia burgdorferi infection referred for Lyme disease to a Mid-Atlantic academic center from 2000-2013. The primary outcome is clinically described diagnoses contributing to symptoms. Secondary outcomes included symptom duration and determination whether diagnoses were new or attributed to existing medical conditions. RESULTS: Of 1261 referred patients, 1061 (84%) had no findings of active Lyme disease, with 690 (65%) receiving other diagnoses; resulting in 405 (59%) having newly diagnosed medical conditions, 134 (19%) attributed to pre-existing medical issues, and 151 (22%) with both new and pre-existing conditions. Among the 690 patients, the median symptom duration was 796 days, and a total of 139 discrete diagnoses were made. Infectious disease diagnoses comprised only 3.2%. Leading diagnoses were anxiety/depression 222 (21%), fibromyalgia 120 (11%), chronic fatigue syndrome 77 (7%), migraine disorder 74 (7%), osteoarthritis 62 (6%), and sleep disorder/apnea 48 (5%). Examples of less frequent but non-syndromic diseases newly diagnosed included multiple sclerosis (n = 11), malignancy (n = 8), Parkinson's disease (n = 8), sarcoidosis (n = 4), or amyotrophic lateral sclerosis (n = 4). CONCLUSIONS: Most patients with long-term symptoms have either new or pre-existing disorders accounting for their symptoms other than Lyme disease, suggesting overdiagnosis in this population. Patients referred for consideration of Lyme disease for chronic symptoms deserve careful assessment for diagnoses other than Borrelia burgdorferi infection.

Tocilizumab for the Treatment of COVID-19 Among Hospitalized Patients: A Matched Retrospective Cohort Analysis.

BACKGROUND: There is currently no single treatment that mitigates all harms caused by severe acute respiratory syndrome coronavirus 2 infection. Tocilizumab, an interleukin-6 antagonist, may have a role as an adjunctive immune-modulating therapy. METHODS: This was an observational retrospective study of hospitalized adult patients with confirmed coronavirus disease 2019 (COVID-19). The intervention group comprised patients who received tocilizumab; the comparator arm was drawn from patients who did not receive tocilizumab. The primary outcome was all-cause mortality censored at 28 days; secondary outcomes were all-cause mortality at discharge, time to clinical improvement, and rates of secondary infections. Marginal structural Cox models via inverse probability treatment weights were applied to estimate the effect of tocilizumab. A time-dependent propensity score-matching method was used to generate a 1:1 match for tocilizumab recipients; infectious diseases experts then manually reviewed these matched charts to identify secondary infections. RESULTS: This analysis included 90 tocilizumab recipients and 1669 controls. Under the marginal structural Cox model, tocilizumab was associated with a 62% reduced hazard of death (adjusted hazard ratio [aHR], 0.38; 95% CI, 0.21 to 0.70) and no change in time to clinical improvement (aHR, 1.13; 95% CI, 0.68 to 1.87). The 1:1 matched data set also showed a lower mortality rate (27.8% vs 34.4%) and reduced hazards of death (aHR, 0.47; 95% CI, 0.25 to 0.88). Elevated inflammatory markers were associated with reduced hazards of death among tocilizumab recipients compared with controls. Secondary infection rates were similar between the 2 groups. CONCLUSIONS: Tocilizumab may provide benefit in a subgroup of patients hospitalized with COVID-19 who have elevated biomarkers of hyperinflammation, without increasing the risk of secondary infection.

Virtual Recruitment Is Here to Stay: A Survey of ID Fellowship Program Directors and Matched Applicants Regarding Their 2020 Virtual Recruitment Experiences.

BACKGROUND: Graduate Medical Education training programs transitioned to all-virtual recruitment in 2020. Limited data have been published regarding the consequences of this transition. We aimed to understand (1) infectious diseases (ID) fellowship programs' recruitment efforts and the effect of virtual recruitment on application and interview numbers and (2) the number of programs to which matched applicants applied and interviewed and applicants' perspectives on virtual recruitment. METHODS: In 2020-2021, we surveyed all US ID fellowship program directors (PDs) and matched applicants. Descriptive data analysis was performed on quantitative survey items. Free-text responses were analyzed through a quantitative content analysis approach. RESULTS: The PD response rate was 68/158 (43%); the applicant response rate was at least 23% (85/365). PDs reported a 27% increase in mean number of applications received and a 45% increase in mean number of applicants interviewed compared with the previous year. Applicants especially valued the online program structure information, PD program overview videos, didactic and curriculum content, and fellow testimonials and profiles. Most applicants preferred interviews lasting no more than 40 minutes and interview days lasting no more than 5 hours. Nearly all (60/64, 94%) PDs adequately learned about candidates; most (48/64, 75%) felt unable to showcase their program as well as when in-person. Most PDs (54/64, 84%) and applicants (56/73, 77%) want an option for virtual recruitment. CONCLUSIONS: Virtual recruitment enabled programs to accommodate more applicants and highlighted applicants' preferences for programs' augmented online presences and time-limited interview days. Most programs and applicants want an option for virtual interviews.

Impact of Coronavirus Disease 2019 on Infectious Diseases Fellows in the United States: Perspectives From the First National Infectious Diseases Fellows Call.

The coronavirus disease 2019 (COVID-19) pandemic has affected many providers, but its impact on Infectious Diseases (ID) fellows in the United States is largely undescribed. In this study, we discuss key issues that emerged from the first national ID Fellows Call with respect to the ID fellow's role during the COVID-19 pandemic, teaching/learning, and research.

Education of Infectious Diseases Fellows During the COVID-19 Pandemic Crisis: Challenges and Opportunities.

One of the many challenges that has befallen the Infectious Diseases and Graduate Medical Education communities during the coronavirus disease 2019 (COVID-19) pandemic is the maintenance of continued effective education and training of the future leaders of our field. With the remarkable speed and innovation that has characterized the responses to this pandemic, educators everywhere have adapted existing robust and safe learning environments to meet the needs of our learners. This paper will review distinct aspects of education and training of the Infectious Diseases fellows we believe the COVID-19 pandemic has impacted most, including mentoring, didactics, and wellness. We anticipate that several strategies developed in this context and described herein will help to inform training and best practices during the pandemic and beyond.

The Struggling Infectious Diseases Fellow: Remediation Challenges and Opportunities.

Remediation of struggling learners is a challenge faced by all educators. In recognition of this reality, and in light of contemporary challenges facing infectious diseases (ID) fellowship program directors, the Infectious Diseases Society of America Training Program Directors' Committee focused the 2018 National Fellowship Program Directors' Meeting at IDWeek on "Remediation of the Struggling Fellow." Small group discussions addressed 7 core topics, including feedback and evaluations, performance management and remediation, knowledge deficits, fellow well-being, efficiency and time management, teaching skills, and career development. This manuscript synthesizes those discussions around a competency-based framework to provide program directors and other educators with a roadmap for addressing common contemporary remediation challenges.

Misdiagnosis of Lyme Disease With Unnecessary Antimicrobial Treatment Characterizes Patients Referred to an Academic Infectious Diseases Clinic.

BACKGROUND: Although Lyme disease is the most common vector-borne infection in the United States, diagnostic accuracy within community settings is not well characterized. METHODS: A retrospective observational cohort study of patients referred to an academic center with a presumed diagnosis or concern for Lyme disease between 2000 and 2013 was performed to analyze diagnoses and treatments. Characteristics of those with Lyme disease and those misdiagnosed as having Lyme disease were compared. RESULTS: Of 1261 patients, 911 (72.2%) did not have Lyme disease, 184 (14.6%) had active or recent Lyme disease, 150 (11.9%) had a remote history of Lyme disease, and 16 (1.3%) were identified as having possible Lyme disease. Patients without current Lyme disease were more likely to be female (odds ratio [OR], 1.56; 95% confidence interval [CI], 1.08-2.45), to have had symptoms for >3 months (OR, 8.78; 95% CI, 5.87-13.1), to have higher symptom counts (OR per additional symptom, 1.08; 95% CI, 1.02-1.13), to have had more Lyme-related laboratory testing (OR per additional laboratory test, 1.17; 95% CI, 1.03-1.32), and to have been diagnosed with what were regarded as coinfections (OR, 3.13; 95% CI, 1.14-8.57). Of the 911 patients without Lyme disease, 764 (83.9%) had received antimicrobials to treat Lyme disease or their coinfections. The percentage of patients established to have Lyme disease was lower than in earlier studies of referred populations. CONCLUSIONS: Among patients referred to an academic Infectious Diseases practice for Lyme disease, incorrect diagnoses and unnecessary antibiotic treatment were common, both for Lyme disease and for coinfections.