Unfolded Von Willebrand Factor Binds Protein S and Reduces Anticoagulant Activity.

Protein S (PS), the critical plasma cofactor for the anticoagulants tissue factor (TF) pathway inhibitor (TFPI) and activated protein C (APC), circulates in two functionally distinct pools: free (anticoagulant) or bound to complement component 4b-binding protein (C4BP) (anti-inflammatory). Acquired free PS deficiency is detected in several viral infections, but its cause is unclear. Here, we identified a shear-dependent interaction between PS and von Willebrand Factor (VWF) by mass spectrometry. Consistently, plasma PS and VWF comigrated in both native and agarose gel electrophoresis. The PS/VWF interaction was blocked by TFPI but not APC, suggesting an interaction with the C-terminal sex hormone binding globulin (SHBG) region of PS. Microfluidic systems, mimicking arterial laminar flow or disrupted turbulent flow, demonstrated that PS stably binds VWF as VWF unfolds under turbulent flow. PS/VWF complexes also localized to platelet thrombi under laminar arterial flow. In thrombin generation-based assays, shearing plasma decreased PS activity, an effect not seen in the absence of VWF. Finally, free PS deficiency in COVID-19 patients, measured using an antibody that binds near the C4BP binding site in SHBG, correlated with changes in VWF, but not C4BP, and with thrombin generation. Our data suggest that PS binds to a shear-exposed site on VWF, thus sequestering free PS and decreasing its anticoagulant activity, which would account for the increased thrombin generation potential. As many viral infections present with free PS deficiency, elevated circulating VWF, and increased vascular shear, we propose that the PS/VWF interaction reported here is a likely contributor to virus-associated thrombotic risk.

Beyond a team: The comprehensive interdisciplinary endocarditis program in the United States.

Although multidisciplinary teams have been shown to decrease in-hospital mortality for patient with infectious endocarditis, most studies have focused on the inpatient role of these teams, and are primarily based at European tertiary care centers. There is limited literature available on the optimal longitudinal care of this patient population. Here we outline our experience developing an interdisciplinary endocarditis program at the University of Kentucky, which cares for patients from their index hospitalization into the outpatient setting, while also coordinating transfers from regional hospitals and offering education to regional providers.

Perspectives on the Use of Outpatient Parenteral Antibiotic Therapy for People who Inject Drugs: Results From an Online Survey of Infectious Diseases Clinicians.

Injection-related infections require prolonged antibiotic therapy. Outpatient parenteral antimicrobial therapy (OPAT) has been shown to be feasible for people who inject drugs (PWID) in some settings. We report a national survey on practice patterns and attitudes of infectious diseases clinicians in the United States regarding use of OPAT for PWID.

An Atypical Presentation of Acute Syphilitic Posterior Placoid Chorioretinitis With Concurrent Psoriasis Vulgaris Flare in an African American Male Infected With HIV.

The diagnosis of secondary syphilis can be challenging due to its various clinical and histopathological presentations. A late or incorrect diagnosis can result in disease progression with consequent morbidity or mortality. Due to the importance of a correct diagnosis and specific treatment, it is of the utmost importance for healthcare providers to consider the various manifestations of syphilis. We describe an atypical presentation of secondary syphilis in an African American man infected with HIV and chronic psoriasis, who presented with two months of diffuse maculopapular rash and new visual changes, found to have acute syphilitic placoid chorioretinitis (ASPCC) and a psoriasis vulgaris flare.

Design and protocol of the Buprenorphine plus Outpatient Parenteral Antimicrobial Therapy (B-OPAT) study: a randomized clinical trial of integrated outpatient treatment of opioid use disorder and severe, injection-related infections.

Introduction: A marked increase in hospitalizations for severe, injection-related infections (SIRI) has been associated with the opioid epidemic. Outpatient parenteral antibiotic therapy (OPAT) is typically not offered to persons with opioid use disorder (OUD) and SIRI, though increasing evidence suggests it may be feasible and safe. This study evaluates the efficacy and cost-effectiveness of an integrated care model combining Buprenorphine treatment of OUD with OPAT for SIRI (B-OPAT) compared with treatment as usual on key OUD, infectious disease, and health economic outcomes. B-OPAT expands and incorporates key elements of established clinical models, including inpatient initiation of buprenorphine for OUD, inpatient infectious disease consultation for SIRI, office-based treatment of OUD, and OPAT, and includes more frequent clinical outpatient visits than standard OPAT. A qualitative evaluation is included to contextualize effectiveness outcomes and identify barriers and facilitators to intervention adoption and implementation. Methods: B-OPAT is a single-site, randomized, parallel-group, superiority trial recruiting 90 adult inpatients hospitalized with OUD and SIRI who require at least 2 weeks of intravenous (IV) antibiotic therapy. After screening, eligible participants are randomized 1:1 to either discharge once medically stable to an integrated outpatient treatment care model combining Buprenorphine and OPAT (B-OPAT) or to Treatment As Usual (TAU). The primary outcome measure is the proportion of urine samples negative for illicit opioids in the 12 weeks after discharge from the hospital. Key secondary OUD outcomes include self-reported number of days of illicit opioid abstinence and 12-week retention in buprenorphine treatment. The infection outcomes are completion of recommended IV antibiotic therapy, peripherally inserted central catheter (PICC) complications, and readmission related to primary SIRI. Conclusions: The B-OPAT study will help address the important question of whether it is clinically effective and cost-effective to discharge persons with OUD and SIRI to an integrated outpatient care model combining OUD treatment with OPAT relative to TAU (Clinicaltrials.gov Identifier: NCT04677114).

Factors Associated With Systemic Immune Activation Indices in a Global Primary Cardiovascular Disease Prevention Cohort of People With Human Immunodeficiency Virus on Antiretroviral Therapy.

BACKGROUND: Among antiretroviral therapy (ART)-treated people with human immunodeficiency virus (PWH), persistent systemic immune activation contributes to atherogenesis atherosclerotic, cardiovascular disease (CVD) events, and mortality. Factors associated with key immune activation indices have not previously been characterized among a global primary CVD prevention cohort of PWH. METHODS: Leveraging baseline Randomized Trial to Prevent Vascular Events in HIV (REPRIEVE) data, we evaluated factors associated with soluble CD14 (sCD14) and oxidized low-density lipoprotein (oxLDL). RESULTS: The primary analysis cohort included 4907 participants from 5 global-burden-of-disease regions (38% female, 48% Black, median age 50 years). In fully adjusted models for sCD14, female sex and White race (among those in high-income regions) were associated with higher sCD14 levels, while higher body mass index (BMI) and current use of nucleoside reverse transcriptase inhibitor + integrase strand transfer inhibitor ART were associated with lower sCD14 levels. In fully adjusted models for oxLDL, male sex, residence in high-income regions, White race (among those in high-income regions), and higher BMI were associated with higher oxLDL levels. In a subanalysis cohort of 1396 women with HIV, increased reproductive age was associated with higher sCD14 levels but not with higher oxLDL levels. CONCLUSIONS: Factors associated with sCD14 and oxLDL, 2 key indices of immune-mediated CVD risk, differ. Future studies will elucidate ways in which medications (eg, statins) and behavioral modifications influence sCD14 and oxLDL and the extent to which dampening of these markers mediates CVD-protective effects. CLINICAL TRIALS REGISTRATION: NCT0234429.

Long-term high-dose immunoglobulin successfully treats Long COVID patients with pulmonary, neurologic, and cardiologic symptoms.

Introduction: Long COVID is the overarching name for a wide variety of disorders that may follow the diagnosis of acute SARS-COVID-19 infection and persist for weeks to many months. Nearly every organ system may be affected. Methods: We report nine patients suffering with Long COVID for 101 to 547 days. All exhibited significant perturbations of their immune systems, but only one was known to be immunodeficient prior to the studies directed at evaluating them for possible treatment. Neurological and cardiac symptoms were most common. Based on this data and other evidence suggesting autoimmune reactivity, we planned to treat them for 3 months with long-term high-dose immunoglobulin therapy. If there was evidence of benefit at 3 months, the regimen was continued. Results: The patients' ages ranged from 34 to 79 years-with five male and four female patients, respectively. All nine patients exhibited significant immune perturbations prior to treatment. One patient declined this treatment, and insurance support was not approved for two others. The other six have been treated, and all have had a significant to remarkable clinical benefit. Conclusion: Long-term high-dose immunoglobulin therapy is an effective therapeutic option for treating patients with Long COVID.

Risk factors for loss to follow-up of persons who inject drugs enrolled at syringe services programs in Kentucky.

BACKGROUND: Syringe services programs (SSP) are an effective strategy to reduce blood-borne infections of human immunodeficiency virus (HIV) and hepatitis C virus (HCV) in persons who inject drugs (PWID). The objectives of this study were to determine the frequency and risk factors for loss to follow-up (LTFU) in PWID enrolled at SSPs in Kentucky. METHODS: A retrospective cohort study was conducted which included data of PWID enrolled at 32 SSP. Demographics, use of drugs, HIV testing, HCV testing, and medical services were analyzed. A generalized linear model (GLM), family binomial was used to determine risk factors for LTFU. RESULTS: The analysis included 5742 PWID. LTFU by year of enrollment was 287/770 (37.3%) in 2017, 796/1874 (42.5%) in 2018, and 1479/3,098 (47.7%) in 2019. LTFU was significantly associated with distance to SSP from home of more than five miles (RR 1.25; 95%CI 1.09-1.43; p = 0.002) and SSPs housed in rural counties (RR 1.22; 95%CI 1.06-1.40; p = 0.004), adjusted by age, sex, and race. The use of buprenorphine was associated with less risk of LTFU (RR 0.79, p = 0.034). CONCLUSION: The distance to an SSP from home and SSPs in rural counties were identified as risk factors for LTFU. Initiatives that bring health services closer to PWID homes and offer opioid use disorder treatment may improve repeated participation in SSPs.

Federal and State Action Needed to End the Infectious Complications of Illicit Drug Use in the United States: IDSA and HIVMA's Advocacy Agenda.

In response to the opioid crisis, IDSA and HIVMA established a working group to drive an evidence- and human rights-based response to illicit drug use and associated infectious diseases. Infectious diseases and HIV physicians have an opportunity to intervene, addressing both conditions. IDSA and HIVMA have developed a policy agenda highlighting evidence-based practices that need further dissemination. This paper reviews (1) programs most relevant to infectious diseases in the 2018 SUPPORT Act; (2) opportunities offered by the "End the HIV Epidemic" initiative; and (3) policy changes necessary to affect the trajectory of the opioid epidemic and associated infections. Issues addressed include leveraging harm reduction tools and improving integrated prevention and treatment services for the infectious diseases and substance use disorder care continuum. By strengthening collaborations between infectious diseases and addiction specialists, including increasing training in substance use disorder treatment among infectious diseases and addiction specialists, we can decrease morbidity and mortality associated with these overlapping epidemics.

Outpatient Antimicrobial Treatment for People Who Inject Drugs.

This article reviews the changing epidemiology of infections associated with injection drug use, perceived barriers to care, features of successful programs for outpatient antimicrobial treatment, models of shared decision making at the time of discharge, and linkage to preventative care after antimicrobial completion. In the search for patient-centered care associated with a rising substance use epidemic, one must continue to strive for novel collaborative approaches to ensure that each person is treated in the best way possible to successfully complete antimicrobial therapy, and then linked to a path of lifelong health care.

Impact of the Affordable Care Act on Referral to Care for People Living with HIV in Appalachia.

Introduction: The Affordable Care Act (ACA) enacted on March 23, 2010 significantly impacted access to healthcare for people living with HIV (PLWH). Expansion of care was accomplished in three areas: eliminating exclusions for pre-existing conditions, elimination of lifetime caps on healthcare expenditures, and expansion of Medicaid eligibility. Purpose: This study evaluated the impact of state implementation of the ACA Medicaid expansion on referral to HIV care at a Ryan White federally funded clinic in Kentucky (University of Kentucky Bluegrass Care Clinic [UK BCC]). Methods: Retrospective chart review of all newly enrolled patients at the UK BCC between March 2010 and June 2017. Data included patient demographics and referral source, and were divided into two groups to compare enrollments before and after Kentucky implemented the ACA Medicaid expansion. Data were collected from 2018-2019 and analyzed in 2020. Results: Following Medicaid expansion there were statistically significant changes in the patterns of referral to federally funded HIV care. These included a significant decrease in the proportion of referrals from state and local health departments, and an increase in both proportion of referrals from outpatient clinics and transfers from different HIV care providers. Implications: These results have implications for engaging more PLWH into HIV care, particularly in states where patients have increased access to screening and assessment of risk at primary care encounters through implementation of the ACA Medicaid expansion.

Outpatient Parenteral Antimicrobial Therapy Plus Buprenorphine for Opioid Use Disorder and Severe Injection-related Infections.

In a pilot randomized trial in persons with opioid use disorder hospitalized with injection-related infections, an innovative care model combining outpatient parenteral antimicrobial therapy with buprenorphine treatment had similar clinical and drug use outcomes to usual care (inpatient intravenous antibiotic completion) and shortened hospital length of stay by 23.5 days. CLINICAL TRIALS REGISTRATION: NCT03048643.

Integrated outpatient treatment of opioid use disorder and injection-related infections: A description of a new care model.

Persons with opioid use disorder (OUD) hospitalized with severe, injection-related infections (SIRI) are frequently hospitalized for the duration of IV antibiotic treatment due to concerns regarding their eligibility for outpatient parenteral antimicrobial therapy (OPAT), which is the standard of care for prolonged IV antibiotic courses for patients without drug use. As part of a pilot study, a novel, integrated care model was developed where patients with OUD and SIRI receive addiction consultation and buprenorphine induction while hospitalized, followed by ongoing management in an outpatient clinic that combines office-based opioid treatment with buprenorphine pharmacotherapy and counseling services with OPAT. Through three illustrative case vignettes the outpatient model is described along with challenges, lessons learned and future directions.

Incidence and Cost of Acute Kidney Injury in Hospitalized Patients with Infective Endocarditis.

Acute kidney injury (AKI) is a frequent complication of hospitalized patients with infective endocarditis (IE). Further, AKI in the setting of IE is associated with high morbidity and mortality. We aimed to examine the incidence, clinical parameters, and hospital costs associated with AKI in hospitalized patients with IE in an endemic area with an increasing prevalence of opioid use. This retrospective cohort study included 269 patients admitted to a major referral center in Kentucky with a primary diagnosis of IE from January 2013 to December 2015. Of these, 178 (66.2%) patients had AKI by Kidney Disease Improving Global Outcomes (KDIGO) serum creatinine criteria: 74 (41.6%) had AKI stage 1 and 104 (58.4%) had AKI stage ≥2. In multivariable analysis, higher comorbidity scores and the need for diuretics were independently associated with AKI, while the involvement of the tricuspid valve and the need for vasopressor/inotrope support were independently associated with severe AKI (stage ≥2). The median total direct cost of hospitalization was progressively higher according to each stage of AKI ($17,069 for no AKI; $37,111 for AKI stage 1; and $61,357 for AKI stage ≥2; p < 0.001). In conclusion, two-thirds of patients admitted to the hospital due to IE had incident AKI. The occurrence of AKI significantly increased healthcare costs. The higher level of comorbidity, the affection of the tricuspid valve, and the need for diuretics and/or vasoactive drugs were associated with severe AKI in this susceptible population.

Alcohol Use and Multimorbidity Among Individuals Living with HIV.

Alcohol is prevalent among people living with HIV and can lead to multiple comorbid conditions (multimorbidity). The purpose of this study was to examine the relationship between alcohol use history and multimorbidity among people living with HIV. A retrospective cohort study design was conducted at an urban, academic infectious disease clinic in Kentucky. Individuals seeking care between 2010 and 2014 were included. Modified Poisson regression was used to examine the relationship between alcohol use history (never, current, and former use) and multimorbidity (≥ 2 conditions). A total of 949 individuals were included in the study, with 5.1 and 17.6% reporting former and current alcohol use, respectively. Sixty-five percent had ≥ 1 condition and 82.6% of those had ≥ 2 conditions diagnosed. The risk of multimorbidity was 1.70 (95% CI 1.35-2.14) times higher for a current user compared to a never user. Reductions in alcohol use may lead to lower rates of multimorbidity.

A Qualitative Approach to Increasing HIV Prevention in Primary Care Settings for Older Adults: Perspectives From Primary Care Providers.

The purpose of this research was to explore primary care providers' willingness and ability to increase HIV prevention efforts among older adults and to gain recommendations for improving HIV prevention in primary care settings. Data were collected through 24 semistructured interviews with primary care providers. The results of the study reveal that the majority of providers find it necessary to increase HIV prevention efforts in primary care settings and are willing to do so; however, they cannot do so without assistance. Providers suggested strategies to increase HIV prevention in primary care, for instance, expanding the use of electronic reminders to include HIV prevention and increasing collaboration among providers of different specialties. As a result of the interviews, additional recommendations for increasing HIV prevention have been identified. These findings will aid in improving the quality of care provided to individuals older than 50 in primary care settings.

Persistence of Macrocytosis after Discontinuation of Zidovudine in HIV-Infected Patients.

The duration of macrocytosis after stopping zidovudine (ZDV) is unknown. Among 104 HIV-infected patients treated with ZDV for more than 1 year, 84 patients had macrocytosis at ZDV discontinuation. The median mean corpuscular volume (MCV) was 114.6 fL (range 100-128 fL). Patients were divided into 2 groups: those who did (resolved macrocytosis, n = 36) and did not (persistent macrocytosis, n = 48) normalize MCV at 3 to 6 months after ZDV discontinuation. Alcohol use ( P = .02), smoking ( P = .03), and lower (but within normal range) folic acid levels ( P = .05) were related to the persistence of macrocytosis. A persistence of macrocytosis was observed in 57% at 3 to 6 months, 38% at 1 year and 37% at 2 years after ZDV therapy had stopped. Duration of ZDV therapy did not have an effect on the persistence of macrocytosis ( P = .73). The median time for the MCV to normalize after stopping ZDV was 12.5 months.

Retention in Continuous Care and Sustained Viral Suppression.

OBJECTIVES: To examine the relationship between retention in continuous care and sustained viral suppression. METHODS: The authors retrospectively followed 653 persons who were virally suppressed and seeking care at an infectious disease clinic in Kentucky for an average of 6 years to determine the rates of retention in medical care (≥2 visits separated by ≥3 months within a 12-month period) and sustained viral suppression (<400 copies/mL). A generalized linear mixed model was used to determine an association between retention and suppression over time. RESULTS: Approximately 61% of the study population were retained in continuous care and 75% had sustained viral suppression for all patient-years. Persons retained in care were 3 times the odds of sustaining viral suppression over time ( P < .001). CONCLUSION: Retention is essential to achieving and maintaining viral suppression. Strategies should be set in place that emphasize increasing the rates of retention, which in turn may increase the rates of suppression.

Differences in Rhodococcus equi Infections Based on Immune Status and Antibiotic Susceptibility of Clinical Isolates in a Case Series of 12 Patients and Cases in the Literature.

Rhodococcus equi is an unusual zoonotic pathogen that can cause life-threatening diseases in susceptible hosts. Twelve patients with R. equi infection in Kentucky were compared to 137 cases reported in the literature. Although lungs were the primary sites of infection in immunocompromised patients, extrapulmonary involvement only was more common in immunocompetent patients (P < 0.0001). Mortality in R. equi-infected HIV patients was lower in the HAART era (8%) than in pre-HAART era (56%) (P < 0.0001), suggesting that HAART improves prognosis in these patients. Most (85-100%) of clinical isolates were susceptible to vancomycin, clarithromycin, rifampin, aminoglycosides, ciprofloxacin, and imipenem. Interestingly, there was a marked difference in susceptibility of the isolates to cotrimoxazole between Europe (35/76) and the US (15/15) (P < 0.0001). Empiric treatment of R. equi infection should include a combination of two antibiotics, preferably selected from vancomycin, imipenem, clarithromycin/azithromycin, ciprofloxacin, rifampin, or cotrimoxazole. Local antibiograms should be checked prior to using cotrimoxazole due to developing resistance.