High prevalence of gastrointestinal manifestations among Cytomegalovirus end-organ disease in the combination antiretroviral era.

BACKGROUND: Cytomegalovirus (CMV) end-organ disease (EOD) continues to pose a significant risk to patients with advanced HIV disease despite decreased incidence with combination anti-retroviral therapy (ART) and lower mortality with effective anti-CMV therapy. Subclinical CMV shedding may also contribute to ongoing inflammation and non-infectious comorbidities. METHODS: We examined the occurrence of CMV EOD and CMV shedding in a cohort of patients participating in a prospective observational study of severely immunosuppressed (CD4 ≤100 cells/µl), ART-naïve, HIV-1 infected adult participants. RESULTS: We studied 206 participants, of whom 193 (93.7%) were CMV IgG positive. Twenty-five participants (12.1%) developed confirmed CMV EOD. At baseline, 47 (22.8%) had CMV viremia detectable by PCR in the absence of clinical disease (CMV viremia). The remaining 134 (65%) had neither CMV EOD nor CMV viremia detected at baseline. Five participants with CMV EOD (2.4% of total cohort, 20% of CMV EOD) met AIDS Clinical Trials Group criteria for CMV immune reconstitution inflammatory syndrome (IRIS). Only one-third of CMV EOD patients had retinitis, while two-thirds presented with histologically confirmed gastrointestinal illness. CMV viremia was associated with higher percentages of activated CD8+ T cells even after HIV suppression. CONCLUSION: The manifestations of CMV EOD in advanced HIV disease before and after initiation of ART may be more diverse than previously described, with high incidence of gastrointestinal illness. Recognition and treatment of unusual clinical presentations of CMV infection remains important in reducing morbidity and mortality from HIV co-infections.

The incidence of malignancy in clinically benign cystic lesions of the lateral neck: our experience and proposed diagnostic algorithm.

AIM: Solitary cystic masses of the lateral neck in an adult patient can pose a diagnostic dilemma. Malignancy must be ruled out since metastases arising from H&N cancers may mimic the presentation of benign cystic masses. Only a small number of studies have investigated the diagnostic management and malignancy rate of clinically benign solitary cervical cystic lesions. There are no established guidelines for the diagnostic evaluation. METHODS: Retrospective review of the clinical, cytological, radiological, and pathological records of all adult patients (> 18 years) operated on for second branchial cleft cysts (BrCC) between 1/2008-2010/2016. Patients with apparent primary H&N malignancy, history of H&N cancer or irradiation, preoperative fine needle aspiration (FNA) of highly suggestive or confirmed malignancy, missing pertinent data, or age less than 18 years were excluded from analysis. RESULTS: 28 patients were diagnosed as having BrCC. The diagnosis was based on clinical findings, FNA cytology, and typical sonographic features. The histologic analysis determined an overall rate of malignancy of 10.7% (3/28): two patients had metastatic papillary thyroid carcinoma, and one patient had metastatic tonsillar squamous cell carcinoma. Purely cystic features on pre-operative ultrasound was the only significant predictor for true BrCC on final histology (p = .02). CONCLUSIONS: Occult malignancy is not rare among adult patients presenting with a solitary cystic mass of the lateral neck. A diagnostic algorithm is proposed. Further studies are needed to establish the appropriate workup and management of an adult patient presenting with a solitary cystic mass of the lateral neck.

Inflammatory monocytes expressing tissue factor drive SIV and HIV coagulopathy.

In HIV infection, persistent inflammation despite effective antiretroviral therapy is linked to increased risk of noninfectious chronic complications such as cardiovascular and thromboembolic disease. A better understanding of inflammatory and coagulation pathways in HIV infection is needed to optimize clinical care. Markers of monocyte activation and coagulation independently predict morbidity and mortality associated with non-AIDS events. We identified a specific subset of monocytes that express tissue factor (TF), persist after virological suppression, and trigger the coagulation cascade by activating factor X. This subset of monocytes expressing TF had a distinct gene signature with up-regulated innate immune markers and evidence of robust production of multiple proinflammatory cytokines, including interleukin-1ß (IL-1ß), tumor necrosis factor-α (TNF-α), and IL-6, ex vivo and in vitro upon lipopolysaccharide stimulation. We validated our findings in a nonhuman primate model, showing that TF-expressing inflammatory monocytes were associated with simian immunodeficiency virus (SIV)-related coagulopathy in the progressive [pigtail macaques (PTMs)] but not in the nonpathogenic (African green monkeys) SIV infection model. Last, Ixolaris, an anticoagulant that inhibits the TF pathway, was tested and potently blocked functional TF activity in vitro in HIV and SIV infection without affecting monocyte responses to Toll-like receptor stimulation. Strikingly, in vivo treatment of SIV-infected PTMs with Ixolaris was associated with significant decreases in D-dimer and immune activation. These data suggest that TF-expressing monocytes are at the epicenter of inflammation and coagulation in chronic HIV and SIV infection and may represent a potential therapeutic target.

Tissue factor expression by myeloid cells contributes to protective immune response against Mycobacterium tuberculosis infection.

Tissue factor (TF) is a transmembrane glycoprotein that plays an essential role in hemostasis by activating coagulation. TF is also expressed by monocytes/macrophages as part of the innate immune response to infections. In the current study, we determined the role of TF expressed by myeloid cells during Mycobacterium tuberculosis (M. tb) infection by using mice lacking the TF gene in myeloid cells (TF(Δ) ) and human monocyte derived macrophages (MDMs). We found that during M. tb infection, a deficiency of TF in myeloid cells was associated with reduced inducible nitric oxide synthase (iNOS) expression, enhanced arginase 1 (Arg1) expression, enhanced IL-10 production and reduced apoptosis in infected macrophages, which augmented M. tb growth. Our results demonstrate that a deficiency of TF in myeloid cells promotes M2-like phenotype in M .tb infected macrophages. A deficiency in TF expression by myeloid cells was also associated with reduced fibrin deposition and increased matrix metalloproteases (MMP)-2 and MMP-9 mediated inflammation in M. tb infected lungs. Our studies demonstrate that TF expressed by myeloid cells has newly recognized abilities to polarize macrophages and to regulate M. tb growth.

Validation of the Hebrew Version of the Eating Assessment Tool-10 (H-EAT-10).

BACKGROUND AND OBJECTIVES: Dysphagia is a common disability with different etiologies. In order to measure dysphagia symptom severity and effects on quality of life, the Eating Assessment Tool (EAT-10) was developed and validated in the English language. We aimed to develop a Hebrew version of the EAT-10 and to evaluate its internal consistency, test-retest reliability, and validity in Hebrew-speaking adults with dysphagia. SUBJECTS AND METHODS: The Hebrew EAT-10 (H-EAT-10) questionnaire was completed by 132 patients: 56 patients with dysphagia and 76 controls. Internal consistency analysis was calculated using Cronbach α, and test-retest reliability was calculated using intraclass correlation coefficient in order to assess clinical validity. RESULTS: Internal consistency and test-retest reliability were found to be high in the H-EAT-10 (Cronbach α = 0.955 and intraclass correla tion = 0.98). In addition, H-EAT-10 scores in the dysphagia group were found to be significantly higher than those in the control group (p < 0.001). CONCLUSION: This study demonstrated that H-EAT-10 is a reliable and valid tool that may be implemented for clinical practice and research on dysphagia in a Hebrew-speaking population.

Mycobacterial antigen driven activation of CD14++CD16- monocytes is a predictor of tuberculosis-associated immune reconstitution inflammatory syndrome.

Paradoxical tuberculosis-associated immune reconstitution inflammatory syndrome (TB-IRIS) is an aberrant inflammatory response occurring in a subset of TB-HIV co-infected patients initiating anti-retroviral therapy (ART). Here, we examined monocyte activation by prospectively quantitating pro-inflammatory plasma markers and monocyte subsets in TB-HIV co-infected patients from a South Indian cohort at baseline and following ART initiation at the time of IRIS, or at equivalent time points in non-IRIS controls. Pro-inflammatory biomarkers of innate and myeloid cell activation were increased in plasma of IRIS patients pre-ART and at the time of IRIS; this association was confirmed in a second cohort in South Africa. Increased expression of these markers correlated with elevated antigen load as measured by higher sputum culture grade and shorter duration of anti-TB therapy. Phenotypic analysis revealed the frequency of CD14(++)CD16(-) monocytes was an independent predictor of TB-IRIS, and was closely associated with plasma levels of CRP, TNF, IL-6 and tissue factor during IRIS. In addition, production of inflammatory cytokines by monocytes was higher in IRIS patients compared to controls pre-ART. These data point to a major role of mycobacterial antigen load and myeloid cell hyperactivation in the pathogenesis of TB-IRIS, and implicate monocytes and monocyte-derived cytokines as potential targets for TB-IRIS prevention or treatment.