Clinical trial of raltegravir, an integrase inhibitor, in HAM/TSP.

OBJECTIVE: Human T-cell lymphotropic virus 1 (HTLV-1)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is a chronic, progressive myelopathy. A high proviral load (PVL) is one of the main risk factors for HAM/TSP. Recently, it was shown that raltegravir could inhibit cell-free and cell-to-cell transmission of HTLV-1 in vitro. Given the substantial clinical experience in human immunodeficiency virus infection and its excellent safety profile, this agent may be an attractive therapeutic option for HAM/TSP patients. METHODS: Sixteen subjects with HAM/TSP received raltegravir 400 mg orally twice daily in an initial 6-month treatment phase, followed by a 9-month post-treatment phase. HTLV-1 PVLs were assessed using droplet digital PCR from the PBMCs every 3 months, and from the CSF at baseline, month 6, and month 15. We also evaluated the ability of raltegravir to regulate abnormal immune responses in HAM/TSP patients. RESULTS: While a downward trend was observed in PBMC and/or CSF PVLs of some patients, raltegravir overall did not have any impact on the PVL in this HAM/TSP patient cohort. Clinically, all patients' neurological scores and objective measurements remained relatively stable, with some expected variability. Immunologic studies showed alterations in the immune profiles of a subset of patients including decreased CD4+ CD25+ T cells and spontaneous lymphoproliferation. INTERPRETATION: Raltegravir was generally well tolerated in this HAM/TSP patient cohort. A subset of patients exhibited a mild decrease in PVL as well as variations in their immune profiles after taking raltegravir. These findings suggest that raltegravir may be a therapeutic option in select HAM/TSP patients. CLINICAL TRIAL REGISTRATION NUMBER: NCT01867320.

Orf virus infection after Eid al-Adha.

Human orf, also called ecthyma contagiosum, is a zoonotic infection that causes self-resolving skin lesions after contact with infected livestock. We present the case of a 45-year-old Moroccan-born man who developed multiple painful erythematous, violaceous plaques on his hands after butchering a sheep to celebrate the Muslim holiday Eid al-Adha. The diagnosis of orf virus infection was established based on exposure history, histopathology, and classic skin lesions. Although orf virus infection is traditionally seen in individuals with frequent animal contact such as farmers and veterinarians, clinicians evaluating suspicious lesions in patients without occupational risk factors should consider additional cultural practices that may expose the patient to orf virus.

Clinical trial of a humanized anti-IL-2/IL-15 receptor ß chain in HAM/TSP.

OBJECTIVE: Human T cell lymphotropic virus 1 (HTLV-1)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is a chronic, progressive, neurological disease. Chronic activation of CD8+ T cells, as evidenced by increased spontaneous lymphoproliferation and HTLV-1-specific cytotoxic T cells, has been demonstrated in HAM/TSP patients. Since IL-2 and IL-15 stimulate memory CD8+ T cell activity, these cytokines have been implicated in the immunopathogenesis of HAM/TSP. In this phase I trial, we evaluated the safety, pharmacokinetics, and ability of Hu-Mikß1, a humanized monoclonal antibody directed toward the IL-2/IL-15 receptor ß-chain (IL-2/IL-15Rß: CD122), to saturate CD122 and regulate abnormal immune responses in patients with HAM/TSP by inhibition of IL-15 action. METHODS: Hu-Mikß1 was administered intravenously at doses of 0.5 mg/kg, 1.0 mg/kg, or 1.5 mg/kg in a total of nine HAM/TSP patients. Five doses of Hu-Mikß1 were administered at 3-week intervals. The clinical response was evaluated using standardized scales. Viral and immunologic outcome measures were examined including HTLV-1 proviral load, T cell phenotypic analysis and spontaneous lymphoproliferation in HAM/TSP patients. RESULTS: There was no significant toxicity associated with Hu-Mikß1 administration in HAM/TSP patients. Saturation of CD122 by Hu-Mikß1 was achieved in five out of nine HAM/TSP patients. Administration of Hu-Mikß1 was associated with inhibition of aberrant CD8+ T cell function including spontaneous lymphoproliferation and degranulation and IFN-γ expression, especially in HAM/TSP patients that achieved CD122 saturation. INTERPRETATION: The treatment with Hu-Mikß1 had a number of immunological effects on HAM/TSP patients although no clinical efficacy was observed. We also did not see any dose-related toxicity.

Immunophenotypic characterization of CSF B cells in virus-associated neuroinflammatory diseases.

Intrathecal antibody synthesis is a well-documented phenomenon in infectious neurological diseases as well as in demyelinating diseases, but little is known about the role of B cells in the central nervous systems. We examined B cell and T cell immunophenotypes in CSF of patients with HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) compared to healthy normal donors and subjects with the other chronic virus infection and/or neuroinflammatory diseases including HIV infection, multiple sclerosis (MS) and progressive multifocal leukoencephalopathy. Antibody secreting B cells (ASCs) were elevated in HAM/TSP patients, which was significantly correlated with intrathecal HTLV-1-specific antibody responses. High frequency of ASCs was also detected in patients with relapsing-remitting multiple sclerosis (RRMS). While RRMS patients showed significant correlations between ASCs and memory follicular helper CD4+ T cells, CD4+CD25+ T cells were elevated in HAM/TSP patients, which were significantly correlated with ASCs and HTLV-1 proviral load. These results highlight the importance of the B cell compartment and the associated inflammatory milieu in HAM/TSP patients where virus-specific antibody production may be required to control viral persistence and/or may be associated with disease development.

Using Droplet Digital PCR to Detect Coinfection of Human Herpesviruses 6A and 6B (HHV-6A and HHV-6B) in Clinical Samples.

Droplet digital™ polymerase chain reaction (ddPCR™) is a unique digital PCR technique that allows for absolute quantification of nucleic acid samples. This technique operates on the basis of amplification within water-oil emulsion droplets and can detect very small quantities of target molecules, yielding extremely precise data. Here, we describe in detail a ddPCR procedure for multiplexed detection of two clinically relevant herpesviruses, HHV-6A and HHV-6B.

Imaging spinal cord atrophy in progressive myelopathies: HTLV-I-associated neurological disease (HAM/TSP) and multiple sclerosis (MS).

OBJECTIVE: Previous work measures spinal cord thinning in chronic progressive myelopathies, including human T-lymphotropic virus 1 (HTLV-1)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) and multiple sclerosis (MS). Quantitative measurements of spinal cord atrophy are important in fully characterizing these and other spinal cord diseases. We aimed to investigate patterns of spinal cord atrophy and correlations with clinical markers. METHODS: Spinal cord cross-sectional area was measured in individuals (24 healthy controls [HCs], 17 asymptomatic carriers of HTLV-1 (AC), 47 HAM/TSP, 74 relapsing-remitting MS [RRMS], 17 secondary progressive MS [SPMS], and 40 primary progressive MS [PPMS]) from C1 to T10. Clinical disability scores, viral markers, and immunological parameters were obtained for patients and correlated with representative spinal cord cross-sectional area regions at the C2 to C3, C4 to C5, and T4 to T9 levels. In 2 HAM/TSP patients, spinal cord cross-sectional area was measured over 3 years. RESULTS: All spinal cord regions are thinner in HAM/TSP (56 mm2 [standard deviation, 10], 59 [10], 23 [5]) than in HC (76 [7], 83 [8], 38 [4]) and AC (71 [7], 78 [9], 36 [7]). SPMS (62 [9], 66 [9], 32 [6]) and PPMS (65 [11], 68 [10], 35 [7]) have thinner cervical cords than HC and RRMS (73 [9], 77 [10], 37 [6]). Clinical disability scores (Expanded Disability Status Scale [p = 0.009] and Instituto de Pesquisas de Cananeia [p = 0.03]) and CD8+ T-cell frequency (p = 0.04) correlate with T4 to T9 spinal cord cross-sectional area in HAM/TSP. Higher cerebrospinal fluid HTLV-1 proviral load (p = 0.01) was associated with thinner spinal cord cross-sectional area. Both HAM/TSP patients followed longitudinally showed thoracic thinning followed by cervical thinning. INTERPRETATION: Group average spinal cord cross-sectional area in HAM/TSP and progressive MS show spinal cord atrophy. We further hypothesize in HAM/TSP that is possible that neuroglial loss from a thoracic inflammatory process results in anterograde and retrograde degeneration of axons, leading to the temporal progression of thoracic to cervical atrophy described here. Ann Neurol 2017;82:719-728.

Role of HTLV-1 Tax and HBZ in the Pathogenesis of HAM/TSP.

Human T cell lymphotropic virus type 1 (HTLV-1) infection can lead to development of adult T cell leukemia/lymphoma (ATL) or HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) in a subset of infected subjects. Understanding the interaction between host and HTLV-1 and the molecular mechanisms associated with disease pathogenesis is critical for development efficient therapies. Two HTLV-1 genes, tax and HTLV-1 basic leucine zipper factor (HBZ), have been demonstrated to play important roles in HTLV-1 infectivity and the growth and survival of leukemic cells. Increased HTLV-1 Tax expression induces the expression of various cellular genes such as IL-2 and IL-15, which directly contributes to lymphocyte activation and immunopathogenesis in HAM/TSP patients. However, little is known about the molecular and cellular mechanism of HBZ in development of HAM/TSP. It has been reported that HBZ mRNA expression was detected in HAM/TSP patients higher than in asymptomatic carriers and correlated with proviral load and disease severity. Unlike HTLV-1 tax, HBZ escapes efficient anti-viral immune responses and therefore these reactivities are difficult to detect. Thus, it is important to focus on understanding the function and the role of HTLV-1 tax and HBZ in disease development of HAM/TSP and discuss the potential use of these HTLV-1 viral gene products as biomarkers and therapeutic targets for HAM/TSP.

A bitter pill to swallow: dysphagia in cervical spine injury.

BACKGROUND: Dysphagia is a common complication after cervical spine trauma with spinal cord injury. We sought to characterize the prevalence of dysphagia within a total cervical spinal injury (CSI) population, considering the implications of spinal cord injury status and age on dysphagia development. We hypothesized that while greater rates of dysphagia would be found in geriatric and spinal cord-injured subgroups, all patients presenting with CSI would be at heightened risk for swallowing dysfunction. METHODS: All trauma admissions to a level II trauma center from January 2010 to April 2014 with CSI were retrospectively reviewed. CSI was classified as any ligamentous or cervical spinous fracture with or without cord injury. Patients failing a formal swallow evaluation were considered dysphagic. The implications of dysphagia development on age and spinal cord injury status were assessed in univariate and multivariate analyses. RESULTS: A total of 481 patients met study inclusion criteria, of which 123 (26%) developed dysphagia. Within the dysphagic subpopulation, 90 patients (73%) were geriatric, and 23 (19%) sustained spinal cord injury. The dysphagic subpopulation was predominantly free from spinal cord injury (81%). Multivariate analyses found age (adjusted odds ratio: 1.06; 95% confidence interval 1.04-1.07; P < 0.001) and spinal cord injury (adjusted odds ratio: 2.69; 95% confidence interval 1.30-5.56; P = 0.008) to be significant predictors of dysphagia development. CONCLUSIONS: Despite spinal cord-injured patients being at increased risk for dysphagia, most of the dysphagic subpopulation was free from spinal cord injury. Geriatric and CSI patients with or without cord injury should be at heightened suspicion for dysphagia development.

Under fire: gun violence is not just an urban problem.

BACKGROUND: Gun violence continues to be a source of trauma patient morbidity and mortality annually in the United States. We sought to characterize gun violence in the combined suburban and rural county of Lancaster, PA, and compare it with gun violence results obtained in urban areas. MATERIALS AND METHODS: All gunshot wound (GSW) admissions from January 2000-December 2013 were queried from trauma registry. Patients sustaining ball bearing/ball bullet (BB) or pellet gun injury were excluded. Data collected included mortality, injury severity score (ISS), number of GSW per patient, and cost data. Linear trend tests assessed the change in mortality, patients with three or more GSWs, and patients with an ISS ≥15 and ISS ≥25 over the study period. Statistical significance was defined as P < 0.05. RESULTS: A total of 478 patients met our inclusion criteria. Linear trend tests revealed no significant changes in percent mortality (P = 0.973), percent of patients with three or more GSWs (P = 0.692), percent of patients with an ISS ≥15 (P = 0.545), and percent of patients with an ISS ≥25 (P = 0.343) over the 14-y study period. No significant change in cost per case was observed over the study period (P = 0.246); however, percent reimbursement significantly increased (P = 0.012). CONCLUSIONS: In the relatively affluent suburban and rural community of Lancaster, PA, there is a low-level pattern of gunshot violence and subsequent mortality that has not changed over time. This continuing pattern of gunshot violence speaks to the need for development of innovative preventative measures, as well as continuing efforts against gunshot violence by health care and law-enforcement personnel in suburban and urban centers alike.

An Innovative Approach for Decreasing Fall Trauma Admissions from Geriatric Living Facilities: Preliminary Investigation.

Geriatric living facilities have been associated with a high rate of falls. We sought to develop an innovative intervention approach targeting geriatric living facilities that would reduce geriatric fall admissions to our Level II trauma center. In 2011, a Trauma Prevention Taskforce visited 5 of 28 local geriatric living facilities to present a fall prevention protocol composed of three sections: fall education, risk factor identification, and fall prevention strategies. To determine the impact of the intervention, the trauma registry was queried for all geriatric fall admissions attributed to patients living at local geriatric living facilities. The fall admission rate (total fall admissions/total beds) of the pre-intervention period (2010-2011) was compared with that of the postintervention period (2012-2013) at the 5 intervention and 23 control facilities. A P value < 0.05 was considered statistically significant. From 2010 to 2013, there were 487 fall admissions attributed to local geriatric living facilities (intervention: 179 fall admissions; control: 308 fall admissions). The unadjusted fall rate decreased at intervention facilities from 8.9 fall admissions/bed pre-intervention to 8.1 fall admissions/bed postintervention, whereas fall admission rates increased at control sites from 5.9 to 7.7 fall admissions/bed during the same period [control/intervention odds ratio (OR), 95% confidence interval (CI) = 1.32, 1.05-1.67; period OR, 95%CI = 1.55, 1.18-2.04, P = 0.002; interaction of control/intervention group and period OR 95% CI = 0.68, 0.46-1.00, P = 0.047]. An aggressive intervention program targeting high-risk geriatric living facilities resulted in a statistically significant decrease in geriatric fall admissions to our Level II trauma center.

An alarming presentation of Creutzfeldt-Jakob disease following a self-inflicted gunshot wound to the head.

Transmissible spongiform encephalopathies (TSE), also known as prion diseases, are characterized by rapid and fatal neurological decline. They not only detrimentally affect the patient, but also present additional challenges to healthcare systems due to the infectivity of the tissues and the difficulty of inactivating the prion. The most common TSE is Creutzfeldt-Jakob disease (CJD), which can occur after familial, spontaneous or acquired transmission. TSEs received more attention after the development of variant CJD (vCJD), also known as Mad Cow Disease, in the UK during the mid-1990s. Unlike familial or spontaneous CJD, this variant was connected to consumption of cattle contaminated with the prion disease, bovine spongiform encephalopathy.This development increased interest in the etiology of CJD and other TSEs and the risk it presents as an infectious disease. The following details the case of a 59-year-old male infected with CJD presented to our level II trauma center for treatment following a self-inflicted gunshot wound to the head.