Application of Contrast-Enhanced Ultrasound to Detect Hepatic Hydrothorax in Patients with Liver Cirrhosis.

PURPOSE: Hepatic hydrothorax (HH) is defined as transudate in the pleural cavity in patients with decompensated liver cirrhosis (DC) without concomitant cardiopulmonary or pleural disease. It is associated with high short-term mortality. HH can evolve via translocation through diaphragmatic gaps. The aim of this study was to evaluate the feasibility and safety of injecting ultrasound contrast medium into the peritoneal cavity to detect HH. MATERIALS AND METHODS: This study included patients with concomitant ascites and pleural effusion who were admitted to our hospital between March 2009 and February 2019. A peritoneal catheter was inserted and ultrasound contrast medium was injected into the peritoneal cavity. In parallel, the peritoneal and pleural cavities were monitored for up to 10 minutes. RESULTS: Overall, 43 patients were included. The median age was 60 years and the majority of patients were male (n = 32, 74 %). Most patients presented with right-sided pleural effusion (n = 32, 74 %), 3 (7 %) patients with left-sided and 8 (19 %) patients had bilateral pleural effusion. In 12 (28 %) patients ascites puncture was not safe due to low volume ascites. Thus, the procedure could be performed in 31 (72 %) patients. No adverse events occurred. In 16 of 31 (52 %) patients we could visualize a trans-diaphragmic flow of microbubbles. The median time until transition was 120 seconds. CONCLUSION: Our clinical real-world experience supports the safety and feasibility of intraperitoneal ultrasound contrast medium application to detect HH in patients with DC, as a non-radioactive real-time visualization of HH. Our study comprises the largest cohort and longest experience using this method to date.

Influence of tenofovir exposure in utero on primary dentition.

Tenofovir disoxoproxil fumarate (TDF) is recommended for antiretroviral treatment for pregnant women living with HIV. As a comparative method to study bone density, we investigated the influence of in utero tenofovir exposure on the prevalence and distribution of developmental defects of enamel (DDE) in the primary dentition, as the mineralization process in teeth is higher and more complex and thus more vulnerable. HIV-exposed children with in utero exposition to tenofovir were included in this prospective observational single-center study. Dental status and enamel defects were assessed by an experienced dentist following a standardized protocol. Further information was collected using a standardized questionnaire, available in German and English. The prevalence of developmental defects in children with intrauterine tenofovir exposure was compared with literature data from a recent study of 377 healthy children in Germany and literature data from a study of 1221 healthy African children. Thirty-one children (mean age 2.1 ± 0.3 years; 41.9% female) were included. Median tenofovir exposure in utero was 28 weeks (mean ± 10.52 SD). Prevalence of developmental defects in the primary dentition in tenofovir-exposed children was similar compared to data of unexposed children (16.1% vs. 5.3%, p = 0.051 (compared to German cohort); 16.1% vs. 33.3%, p = 0.068 (compared to African cohort)).Conclusion: HIV-uninfected infants with in utero exposure to TDF showed no significant differences in the prevalence of DDE in comparison to cross-sectional data of HIV- and TDF-unexposed children; thus, the in utero exposure to TDF did not negatively influence the prevalence or distribution of DDE. What is Known: • There are no data available on the prevalence of developmental defects of enamel (DDE) in the primary dentition in intrauterine HIV- and tenofovir-exposed children. • Conclusions can be drawn from intrauterine milk tooth development to bone development and mineralization. What is New: • Prevalence of developmental defects in the primary dentition in tenofovir-exposed children was similar compared to data of unexposed children. • Preterm birth and hospitalization did not show a significant association on the prevalence of developmental defects in the primary dentition.

New Lineage of Lassa Virus, Togo, 2016.

We describe a strain of Lassa virus representing a putative new lineage that was isolated from a cluster of human infections with an epidemiologic link to Togo. This finding extends the known range of Lassa virus to Togo.

Favipiravir and Ribavirin Treatment of Epidemiologically Linked Cases of Lassa Fever.

Two patients with Lassa fever are described who are the first human cases treated with a combination of ribavirin and favipiravir. Both patients survived but developed transaminitis and had prolonged detectable virus RNA in blood and semen, suggesting that the possibility of sexual transmission of Lassa virus should be considered.

Severe Ebola virus disease with vascular leakage and multiorgan failure: treatment of a patient in intensive care.

BACKGROUND: In the current epidemic of Ebola virus disease in western Africa, many aid workers have become infected. Some of these aid workers have been transferred to specialised hospitals in Europe and the USA for intensified treatment, providing the potential for unique insight into the clinical course of Ebola virus disease under optimised supportive measures in isolation units. METHODS: A 38-year-old male doctor who had contracted an Ebola virus infection in Sierra Leone was airlifted to University Hospital Frankfurt, Germany, on day 5 after disease onset. Within 72 h of admission to the hospital's high-level isolation unit, the patient developed signs of severe multiorgan failure, including lungs, kidneys, and gastrointestinal tract. In addition to clinical parameters, the diagnostic work-up included radiography, ultrasound, pulse contour cardiac output technology, and microbiological and clinical chemistry analyses. Respiratory failure with pulmonary oedema and biophysical evidence of vascular leak syndrome needed mechanical ventilation. The patient received a 3 day treatment course with FX06 (MChE-F4Pharma, Vienna, Austria), a fibrin-derived peptide under clinical development for vascular leak syndrome. After FX06 administration and concurrent detection of Ebola-virus-specific antibodies and a fall in viral load, vascular leak syndrome and respiratory parameters substantially improved. We gave broad-spectrum empiric antimicrobial therapy and the patient needed intermittent renal replacement therapy. The patient fully recovered. FINDINGS: This case report shows the feasibility of delivery of successful intensive care therapy to patients with Ebola virus disease under biosafety level 4 conditions. INTERPRETATION: The effective treatment of vascular leakage and multiorgan failure by combination of ventilatory support, antibiotic treatment, and renal replacement therapy can sustain a patient with severe Ebola virus disease until virological remission. FX06 could potentially be a valuable agent in contribution to supportive therapy. FUNDING: University Hospital of Frankfurt.

Biliary strictures and recurrence after liver transplantation for primary sclerosing cholangitis: A retrospective multicenter analysis.

Liver transplantation (LT) is the only definitive treatment for patients with end-stage liver disease due to primary sclerosing cholangitis (PSC), but a high rate of biliary strictures (BSs) and of recurrent primary sclerosing cholangitis (recPSC) has been reported. In this multicenter study, we analyzed a large patient cohort with a long follow-up in order to evaluate the incidence of BS and recPSC, to assess the impact on survival after LT, and to identify risk factors. We collected clinical, surgical, and laboratory data and records on inflammatory bowel disease (IBD), immunosuppression, recipient and graft outcome, and biliary complications (based on cholangiography and histology) of all patients who underwent LT for PSC in 10 German transplant centers between January 1990 and December 2006; 335 patients (68.4% men; mean age, 38.9 years; 73.5% with IBD) underwent transplantation 8.8 years after PSC diagnosis with follow-up for 98.8 months. The 1-, 5-, and 10-year recipient and graft survival was 90.7%, 84.8%, 79.4% and 79.1%, 69.0%, 62.4%, respectively. BS was diagnosed in 36.1% after a mean time of 3.9 years, and recPSC was diagnosed in 20.3% after 4.6 years. Both entities had a significant impact on longterm graft and recipient survival. Independent risk factors for BS were donor age, ulcerative colitis, chronic ductopenic rejection, bilirubin, and international normalized ratio (INR) at LT. Independent risk factors for recPSC were donor age, IBD, and INR at LT. These variables were able to categorize patients into risk groups for BS and recPSC. In conclusion, BS and recPSC affect longterm graft and patient survival after LT for PSC. Donor age, IBD, and INR at LT are independent risk factors for BS and recPSC and allow for risk estimation depending on the recipient-donor constellation.

HIV-1 replication in central nervous system increases over time on only protease inhibitor therapy.

There are concerns about central nervous system (CNS)-replication of HIV-1 in patients on boosted protease inhibitors. Purpose of this study was to compare HIV-1 viral loads (VLs) from patients treated with only boosted dual protease inhibitor (bdPI), versus combination antiretroviral therapy (cART group), containing two nucleoside analogue reverse transcriptase inhibitors (NRTI) and a third partner. All patients from a large German HIV-treatment cohort with available medication, clinical and demographic data, including results from simultaneous HIV-1 viral load (VL) assessments in cerebrospinal fluid (CSF) and blood plasma, were retrospectively evaluated as controlled cross-sectional study. CSF had been obtained from patients with variable neurological symptoms during 2005-2014. Statistical analysis comprised nonparametric tests, regression and correlation techniques accounting for undetectable quantifications. Statistical analysis comprised nonparametric tests, regression and correlation techniques accounting for undetectable quantifications. Overall, 155 patients were evaluable (bdPI: 24; cART: 131). At time of CSF-collection, both groups were comparable in age, gender, CD4-cell counts, or primary HIV-transmission risks, though bdPI patients were clinically more advanced. The proportion of patients with undetectable HIV-1 (<50 copies/ml) in CSF was lower for bdPI group (25 vs 49.6 %; p = 0.026), but similar in plasma (46 vs 41 %). Median CSF-VL was higher in bdPI group (600 vs 50 copies/ml; p = 0.027) and similar in plasma. Mean VL CSF/plasma ratio was 342.91 for bdPI- and 54.48 for cART patients (p < 0.001). Pearson's regression analysis revealed a trend for an elevated VL-ratio over time within bdPI group. HIV-1 replication was higher and more frequently detectable in CSF from bdPI patients, indicating a worse CNS penetration effectiveness of used boosted PI. Within bdPI group, measured CNS-viral replication was increasing over time, suggesting an over time impaired HIV-1 suppression in CSF.

Vaccine-derived yellow fever in an immunocompromised patient on anti-CD20-antibody therapy and its treatment with sofosbuvir.

Yellow fever (YF) is a potentially lethal viral hemorrhagic fever that can be prevented with the 17D live attenuated YF vaccine. However, this vaccination can cause severe adverse reactions including vaccine-associated YF. Here, we describe the case of a 32-year-old female who was permanently immunosuppressed with an anti-CD20 antibody due to multiple sclerosis. Following YF vaccination, the patient developed a variety of symptoms such as febrile temperatures, muscle and joint pain, headaches, and dysuria. A vaccine-associated YF with viremia was diagnosed. To avoid a potentially severe course of the disease, sofosbuvir was used as antiviral treatment followed by the resolution of symptoms and serological response. As travelers with chronic diseases and immunosuppression will increasingly engage in long distance travel, this case demonstrates the importance of assessing patient history prior to the administration of live vaccines and points towards a possible therapeutic approach in those suffering from vaccine-associated YF.

Long-term cardiac pathology in individuals with mild initial COVID-19 illness.

Cardiac symptoms are increasingly recognized as late complications of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in previously well individuals with mild initial illness, but the underlying pathophysiology leading to long-term cardiac symptoms remains unclear. In this study, we conducted serial cardiac assessments in a selected population of individuals with Coronavirus Disease 2019 (COVID-19) with no previous cardiac disease or notable comorbidities by measuring blood biomarkers of heart injury or dysfunction and by performing magnetic resonance imaging. Baseline measurements from 346 individuals with COVID-19 (52% females) were obtained at a median of 109 days (interquartile range (IQR), 77-177 days) after infection, when 73% of participants reported cardiac symptoms, such as exertional dyspnea (62%), palpitations (28%), atypical chest pain (27%) and syncope (3%). Symptomatic individuals had higher heart rates and higher imaging values or contrast agent accumulation, denoting inflammatory cardiac involvement, compared to asymptomatic individuals. Structural heart disease or high levels of biomarkers of cardiac injury or dysfunction were rare in symptomatic individuals. At follow-up (329 days (IQR, 274-383 days) after infection), 57% of participants had persistent cardiac symptoms. Diffuse myocardial edema was more pronounced in participants who remained symptomatic at follow-up as compared to those who improved. Female gender and diffuse myocardial involvement on baseline imaging independently predicted the presence of cardiac symptoms at follow-up. Ongoing inflammatory cardiac involvement may, at least in part, explain the lingering cardiac symptoms in previously well individuals with mild initial COVID-19 illness.

How to use virological tools for the optimal management of chronic hepatitis C.

Approximately 180 million individuals are chronically infected with hepatitis C, which is strongly associated with the development of cirrhosis, end-stage liver disease and hepatocellular carcinoma. Several virological tools (anti-HCV antibody assays, measurement of HCV-RNA, HCV-genotyping) are useful in management of hepatitis C infected patients. The primary goal of antiviral therapy in chronic hepatitis C is a sustained virological response (SVR). The HCV genotype should be determined in every patient considered for antiviral therapy because the currently recommended treatment duration and ribavirin doses differ among HCV genotypes. Exact subtyping might gain increased importance for future therapies with direct-acting antiviral agents (DAA) because of differences of antiviral activities and barriers to resistance among HCV subtypes. Monitoring HCV RNA by a highly sensitive assay (LOD ≤ 15 IU/ml) is the basis for management of response guided therapy of chronic hepatitis C with pegylated IFN plus ribavirin. Rules for early discontinuation of antiviral therapy in non-responders and determination of optimal treatment durations in virologic responders have been developed for application of individualized treatment strategies.

Risk factors for IRIS in HIV-associated Pneumocystis-pneumonia following ART initiation.

BACKGROUND: HIV-infected patients with Pneumocystis-pneumonia (PCP) may develop paradoxical immune reconstitution inflammatory syndrome (IRIS), when combination antiretroviral therapy (cART) is started early during the course of PCP-treatment (PCPT). The aim of this study was to identify risk factors and predictors for PCP-IRIS and to improve individualized patient care. METHODS: An ICD-10 code hospital database query identified all Frankfurt HIV Cohort patients being diagnosed with PCP from January 2010 - June 2016. Patient charts were evaluated retrospectively for demographic, clinical and therapeutic (cART/PCPT) characteristics and incidence of paradoxical IRIS according to French's case definitions. RESULTS: IRIS occurred in 12/97 patients that started cART while on PCPT (12.4%). They had a higher rate of re-hospitalization (41.7vs. 4.7%; odds ratio (OR) 14.46; p = 0.009), intensive care treatment (66.7vs. 30.6%; OR = 4.54; p = 0.018), and longer median hospitalization (48 days vs. 23; p < 0.001). A high HIV-RNA level (> 6Log10/ml) before cART initiation was associated with IRIS development (41.6vs. 15.0%; OR 4.05; p = 0.042). Serum immunoglobulin G-levels (IgG) [mg/dl] were lower (894.0 vs. 1446.5; p = 0.023). CONCLUSION: Higher hospitalization rate and morbidity parameters underscore the clinical importance of PCP-related paradoxical IRIS. A baseline viral load of > 6Log10/ml and serum IgG may help to assess individual risks for PCP-IRIS.

Myocardial Fibrosis and Inflammation by CMR Predict Cardiovascular Outcome in People Living With HIV.

OBJECTIVES: The goal of this study was to examine prognostic relationships between cardiac imaging measures and cardiovascular outcome in people living with human immunodeficiency virus (HIV) (PLWH) on highly active antiretroviral therapy (HAART). BACKGROUND: PLWH have a higher prevalence of cardiovascular disease and heart failure (HF) compared with the noninfected population. The pathophysiological drivers of myocardial dysfunction and worse cardiovascular outcome in HIV remain poorly understood. METHODS: This prospective observational longitudinal study included consecutive PLWH on long-term HAART undergoing cardiac magnetic resonance (CMR) examination for assessment of myocardial volumes and function, T1 and T2 mapping, perfusion, and scar. Time-to-event analysis was performed from the index CMR examination to the first single event per patient. The primary endpoint was an adjudicated adverse cardiovascular event (cardiovascular mortality, nonfatal acute coronary syndrome, an appropriate device discharge, or a documented HF hospitalization). RESULTS: A total of 156 participants (62% male; age [median, interquartile range]: 50 years [42 to 57 years]) were included. During a median follow-up of 13 months (9 to 19 months), 24 events were observed (4 HF deaths, 1 sudden cardiac death, 2 nonfatal acute myocardial infarction, 1 appropriate device discharge, and 16 HF hospitalizations). Patients with events had higher native T1 (median [interquartile range]: 1,149 ms [1,115 to 1,163 ms] vs. 1,110 ms [1,075 to 1,138 ms]); native T2 (40 ms [38 to 41 ms] vs. 37 ms [36 to 39 ms]); left ventricular (LV) mass index (65 g/m2 [49 to 77 g/m2] vs. 57 g/m2 [49 to 64 g/m2]), and N-terminal pro-B-type natriuretic peptide (109 pg/l [25 to 337 pg/l] vs. 48 pg/l [23 to 82 pg/l]) (all p < 0.05). In multivariable analyses, native T1 was independently predictive of adverse events (chi-square test, 15.9; p < 0.001; native T1 [10 ms] hazard ratio [95% confidence interval]: 1.20 [1.08 to 1.33]; p = 0.001), followed by a model that also included LV mass (chi-square test, 17.1; p < 0.001). Traditional cardiovascular risk scores were not predictive of the adverse events. CONCLUSIONS: Our findings reveal important prognostic associations of diffuse myocardial fibrosis and LV remodeling in PLWH. These results may support development of personalized approaches to screening and early intervention to reduce the burden of HF in PLWH (International T1 Multicenter Outcome Study; NCT03749343).

HLA-B57.01 shields people living with HIV for significantly better periodontal health.

BACKGROUND: To assess the association between HLA-B57.01 (Human leukocyte antigen) and clinical parameters of chronic periodontitis in people living with HIV (PLWHIV). METHODS: All patients were recruited from the HIVCENTER at the University Hospital Frankfurt during April 2014 and July 2015. Periodontal examination included Periodontal Screening Index (PSI), Gingivalindex (GI), Bleeding on Probing Index (BOP), Periodontal Probing Depth (PD), Clinical Attachment Level (CAL) and DMF-T Score (decayed, missing, filled teeth). Associations among periodontitis, HLA-system and additional risk factors in PLWHIV were evaluated in multivariate analyses. RESULTS: One hundred PLWHIV were enrolled. Forty-five patients were naive, meaning that these patients never took antiretroviral (ARV) drugs before, 55 patients treated with combined antiretroviral therapy (cART). Nineteen patients presented a positive HLA-B 57.01 status. PLWHIV who were carriers of HLA-B 57.01 had significantly lower PSI-scores (Grade 3 or higher; 0/19 [0%] versus 16/41 [39%] versus 17/40 [42%]; p = < 0.001), GI-scores (Grade 2 or higher; 0/19 [0%] versus 19/41 [46%] versus 28/40 [70%]; p = < 0.001) and BOP-Scores (2/19 [1%] versus 38/41 [92%] versus 40/40 [100%]; p = < 0.001) in comparison to naive PLWHIV and PLWHIV receiving cART, who were both not carriers of HLA-B 57.01. A lower value of PSI-, GI- and BOP-Score is associated with improved periodontal health. The adjusted odds ratio (OR) of periodontitis was decreased in patients who were carriers of HLA-B 57.01 by measurement of PSI-Score (OR = 0.006, 95% confidence interval (CI) = 0.001 to 0.026), GI-Score (OR = 0.018, 95% confidence interval (CI) = 0.003 to 0.104) and BOP-Score (OR = 0.003, 95% confidence interval (CI) = < 0.001 to 0.011). CONCLUSIONS: HLA-B 57.01 is an independent resistance indicator for generalized periodontitis in PLWHIV with respect to established cofactors.

Protease inhibitors for the treatment of hepatitis C virus infection.

The hepatitis C virus (HCV) has affected an estimate of 80 million individuals worldwide and is a strain of public health. Around 25-30% of patients in Europe and the US infected with HIV are coinfected with HCV. Despite treatment modalities containing a NS3/4A protease inhibitor in combination with pegylated interferon and ribavirin prior to 2013 improved SVR rates, the amount of severe side effects was high. Nowadays, oral direct-acting antivirals (DAAs) combination therapy offers excellent treatment efficacy, safety and tolerability. This review focuses on current literature and clinical evidence and their impact regarding NS3/4A protease inhibitors. In addition, pitfalls in treatment from HIV- and HBV-coinfected patients will also be discussed. In the era of DAA treatment, the third-generation pan-genotypic NS3/4A protease inhibitors (mainly grazoprevir, glecaprevir and voxilaprevir) show a high antiviral activity and genetic resistance barrier with cure rates of over 95% when combined with an NS5A inhibitor, irrespectively of baseline resistance associated variants (RASs) being present. These new key components of DAA combination therapy are impressive options to eradicate HCV in the so called difficult-to-treat population (e.g. compensated cirrhosis, end-stage renal disease and patients who failed previous DAA treatment).

Criteria Used in Clinical Practice to Guide Immunosuppressive Treatment in Patients with Primary Sclerosing Cholangitis.

BACKGROUND & AIMS: Current guidelines recommend immunosuppressive treatment (IT) in patients with primary sclerosing cholangitis (PSC) and elevated aminotransferase levels more than five times the upper limit of normal and elevated serum IgG-levels above twice the upper limit of normal. Since there is no evidence to support this recommendation, we aimed to assess the criteria that guided clinicians in clinical practice to initiate IT in patients with previously diagnosed PSC. METHODS: This is a retrospective analysis of 196 PSC patients from seven German hepatology centers, of whom 36 patients had received IT solely for their liver disease during the course of PSC. Analyses were carried out using methods for competing risks. RESULTS: A simplified autoimmune hepatitis (AIH) score >5 (HR of 36, p<0.0001) and a modified histological activity index (mHAI) greater than 3/18 points (HR 3.6, p = 0.0274) were associated with the initiation of IT during the course of PSC. Of note, PSC patients who subsequently received IT differed already at the time of PSC diagnosis from those patients, who did not receive IT during follow-up: they presented with increased levels of IgG (p = 0.004) and more frequently had clinical signs of cirrhosis (p = 0.0002). CONCLUSIONS: This is the first study which investigates the parameters associated with IT in patients with PSC in clinical practice. A simplified AIH score >5 and a mHAI score >3, suggesting concomitant features of AIH, influenced the decision to introduce IT during the course of PSC. In German clinical practice, the cutoffs used to guide IT may be lower than recommended by current guidelines.