Thomas Horvatits

Von Willebrand factor antigen for detection of hepatopulmonary syndrome in patients with cirrhosis.

BACKGROUND & AIMS Hepatopulmonary syndrome (HPS) occurs in 20-30% of patients with liver cirrhosis and is associated with a >2 fold increased mortality. Endothelial dysfunction seems to play a central role in its pathogenesis. von Willebrand factor antigen (vWF-Ag), an established marker of endothelial dysfunction, is significantly elevated in patients with liver cirrhosis, portal hypertension, and in experimental HPS. Aim of the present study was to evaluate the impact of vWF-Ag as a screening marker for presence of HPS in patients with stable cirrhosis. METHODS 145 patients with stable liver cirrhosis were screened for presence of HPS in this prospective cohort type cross sectional diagnostic study. vWF-Ag and SaO2 levels were assessed at time of screening for HPS. Criteria of HPS were fulfilled in 31 (21%) patients. RESULTS vWF-Ag levels were significantly higher in patients with HPS compared to patients without HPS (p<0.001). Furthermore, vWF-Ag correlated significantly with gas exchange in HPS positive patients (p<0.05). vWF-Ag is an independent predictor of HPS after correction for sex, age, model for endstage-liver disease (MELD), and hepatic venous pressure gradient (HVPG) (OR per 1% increase of vWF-Ag: 1.02, 95% CI: 1.00-1.04, p<0.05). The best cut-off was 328% at a sensitivity of 100% and specificity of 53.5%; positive predictive value: 36.9%; negative predictive value: 100%. CONCLUSIONS HPS is associated with elevated vWF-Ag levels. vWF-Ag may be a useful screening tool for early detection of HPS. Further studies investigating vWF-Ag in HPS will be needed to confirm our findings.

HEV-positive blood donations represent a relevant infection risk for immunosuppressed recipients

BACKGROUND & AIMS Routine HEV testing of blood products has recently been implemented in Great Britain and the Netherlands. The relevance of transfusion-transmitted HEV infections is still controversially discussed in Europe. METHODS All blood donations at the University Medical Center Hamburg-Eppendorf were prospectively tested for HEV RNA by pooled PCR from October 2016 to May 2017. Reactive samples were individually retested. Additionally, stored samples from previous donations of positive donors were tested to determine the duration of HEV viraemia. HEV RNA-positive donors and a control cohort were asked to answer a questionnaire. RESULTS Twenty-three out of 18,737 HEV RNA-positive donors were identified (0.12%). Only two of the positive donors (8.7%) presented with elevated aminotransferases at time of donation (alanine aminotransferase: 192 and 101 U/L). The retrospective analysis of all positive donors revealed that four asymptomatic donors had been HEV viraemic for up to three months with the longest duration of HEV viraemia exceeding four months. Despite the HEV-testing efforts, 14 HEV RNA-positive blood products were transfused into 12 immunocompromised and two immunocompetent patients. One recipient of these products developed fatal acute-on-chronic liver failure complicated by Pseudomonas septicemia. The questionnaire revealed that HEV RNA-positive donors significantly more often consumed raw pork meat (12 out of 18; 67%) than controls (89 out of 256; 35%; p = 0.01). In two donors, undercooked pork liver dishes were identified as the source of infection. HEV genotyping was possible in 7 out of 23 of HEV viraemic donors and six out of seven isolates belonged to HEV Genotype 3, Group 2. CONCLUSIONS Prolonged HEV viraemia can be detected at a relatively high rate in Northern German blood donors, leading to transfusion-transmitted HEV infections in several patients with the risk of severe and fatal complications. Eating raw pork tartare represented a relevant risk for the acquisition of HEV infection. LAY SUMMARY The relevance of transfusion-transmitted hepatitis E virus infections has been discussed controversially. Herein, we present the first report on routine hepatitis E virus screening of blood donations at a tertiary care centre in Germany. Hepatitis E viraemia was found at a relatively high rate of 0.12% among blood donors, which represents a relevant transfusion-related risk for vulnerable patient populations.

Lactate improves prediction of short‐term mortality in critically ill cirrhosis patients: a multinational study

Lactate levels and lactate clearance are known predictors of outcome in critically ill patients in the intensive care unit (ICU). The prognostic value of lactate is not well established in liver cirrhosis and acute‐on‐chronic liver failure (ACLF). The aim of this study was to assess the prognostic value of lactate levels and clearance in critically ill patients with cirrhosis. Patients with cirrhosis admitted to the ICU were studied at the University Medical Center Hamburg‐Eppendorf (n = 566, derivation cohort) and the Medical University of Vienna and the University Hospitals Leuven (n = 250, validation cohort). Arterial lactate was measured on admission and during the first 24 hours. Patients were followed for 1 year and outcome was assessed. Admission lactate was directly related to the number of organs failing and to 28‐day mortality (area under receiver operating characteristic [AUROC] 0.72; P < 0.001). This also applied to lactate follow‐up measurements after 6, 12, and 24 hours (P < 0.001 for all, AUROC > 0.70 for all). Lactate clearance had significant predictive ability for 28‐day mortality in patients with elevated serum lactate ≥5 mmol/L. Admission lactate and 12‐hour lactate clearance (in patients with admission lactate ≥5 mmol/L), respectively, were identified as significant predictors of 1‐year mortality, independent of Chronic Liver Failure Consortium acute‐on‐chronic liver failure score (CLIF‐C ACLFs). A lactate‐adjusted CLIF‐C ACLFs was developed (CLIF‐C ACLFsLact), which performed significantly better than the original CLIF‐C ACLFs in prediction of 28‐day mortality in the derivation and validation cohort. Conclusion: Lactate levels appropriately reflect severity of disease and organ failure and were independently associated with short‐term mortality in critically ill patients with liver cirrhosis. Lactate is a simple but accurate prognostic marker, and its incorporation improved performance of CLIF‐C ACLFs significantly.

Epidemiology and outcome of cardiac arrest in patients with liver cirrhosis

Sudden cardiac arrest (CA) is one of the leading causes of death in adults in many parts of the world [1]. Every year estimated 350.000 to 700.000 people in Europe are suffering CA and receive cardiopulmonary resuscitation (CPR) [2]. To date, there is no data available on CA and CPR in patients with liver cirrhosis.

Lack of evidence for human serum albumin as major source of HEV infections: Letter to the Editor

Dear Sir, We read with interest the recent article by Juhl et al., regarding transmission of the hepatitis E virus (HEV) by coagulation factor concentrates (Juhl et al., 2017). Based on seroprevalence data, the authors interpret their results as evidence that HEV is efficiently inactivated during the manufacturing process of coagulation factor concentrates. In our region, HEV genotype 3 infections can be acquired autochthonously (Hoofnagle et al., 2012). The most relevant sources of transmission are swine contact and consumption of undercooked swine meat. Individuals in contact with swine have a two-fold increased risk for anti-HEV positivity compared to healthy controls (blood donors without swine contact) (Krumbholz et al., 2012). Within the last few years, blood products have been identified as a relevant source of HEV transmission. Transmission via blood products is assumed to be less frequent compared to transmission via swine consumption. However, detailed epidemiological data are still lacking. Recently, we demonstrated, in a large cohort of almost 19·000 blood donations, that approximately 1/1000 blood donations in Germany tested positive for positive by polymerase chain reaction (PCR) (Westholter et al., 2018). Therefore, in our opinion, it is crucial to further investigate other products derived from blood donations as potential source of infection: Human serum albumin (HSA) is a product manufactured from mixed pools of plasma donations (1000 to 1660 L) of several thousands of donors (Horowitz et al., 2004). Human albumin is usually administered to patients with liver cirrhosis and refractory ascites (8 g L−1 of removed ascites) (EASL, 2010). Some of these patients develop acute-on-chronic liver failure, with potentially fatal outcomes. It still needs to be determined if HEV infection transmitted by HSA infusions can play a role in this context, perhaps as a trigger or additional hit. In 2015, in a British/French study of 343 patients with decompensated chronic liver disease demonstrated, it was found that 11 patients (3·2%) had acute hepatitis E, and 3 of these 11 died (Blasco-Perrin et al., 2015). How many of these patients received albumin, and whether this could have been their source of infection, is unknown. As HSA is a product derived from pooled human plasma, it represents a potential source of HEV transmission.

Hepatitis E seroprevalence in the Americas: A systematic review and meta-analysis

While hepatitis E virus infections are a relevant topic in Europe, knowledge about epidemiology of hepatitis E virus infections in the USA and Latin America is still limited. Aim of this study was to estimate anti‐hepatitis E virus IgG seroprevalence in the Americas and to assess whether low socioeconomic status is associated with hepatitis E virus exposure.

Course of HEV viremia and anti-HEV IgM/IgG response in asymptomatic blood donors

BACKGROUND Globally, an estimated 20 million Hepatitis E infections occur every year. The course of viremia and antibody response has been investigated in patients with symptomatic hepatitis E. However, the majority of HEV infections in industrialized countries take a subclinical course. OBJECTIVES To investigate the course of HEV viremia and epitope specific anti-HEV IgM/IgG response in asymptomatic blood donors in order to understand the immune response and viral clearance in asymptomatic blood donors with HEV infections. METHODS In this study 27 HEV viremic donors were identified by HEV-PCR during routine screening of blood donors and the course of anti-HEV IgM/IgG and HEV-RNA was retrospectively studied using RT-PCR and a commercial immunoblot (Mikrogen®) allowing classification of the antibody response according to HEV epitopes. RESULTS At time of donation, serological testing failed to identify viremic donors as 70.4% had no detectable antibody response. Anti-HEV IgM could be detected in 22.2% of viremic donors while anti-HEV IgG could be found in 7.4%. At least three donors experienced prolonged viremia beyond 100 days. Spontaneous HEV-RNA clearance within a median time span of 57 days was observed in all 27 donors. In all donors anti-HEV IgG specific for the immunogenic viral epitope O2C could be detected in close temporal association with viral clearance. CONCLUSION Serological testing is inappropriate for identifying HEV-viremic blood donors. Acute HEV infection in asymptomatic blood donors can persist for more than 100 days. HEV-RNA clearance coincided with the appearance of anti-HEV IgM/IgG confirming the importance of a B-cell mediated response in clearing acute infections. Anti-HEV IgM and IgG specific for the epitope O2C are associated with the clearance of HEV-viremia.

Extrahepatic manifestations and HEV, the genotype matters

Extrahepaticmanifestations and viral hepatitis: a topic attracting the syndrome. Notably, rate of anti-HEV IgG antibodies did not show a attention of hepatologists formore than 30 years. Hepatitis B andC virus infections have been associated with various extrahepatic diseases and in some of these phenomena a causal relationship has been proven. Within the last two decades there was growing interest and awareness for hepatitis E virus (HEV) infections worldwide [1,2]. HEV genotype (GT) 3, the predominant GT in Europe and the USA, presents as zoonosis, mainly transmitted by infectious swine meat [3]. In contrast GT 1 and 2 are mainly transmitted by contaminated drinking water in tropical developing countries. A special situation is the setting of GT 4. This is a tropical virus, but in contrast to GT 1 and 2 it ismainly transmitted by consumption of swine meat, as GT 3 [1,2]. In the last five years several assumed extrahepatic manifestations have been observed in the context of HEV infections [4]. In particular, pancreatitis has been associatedwith HEV GT 1 infections, while neurological diseases as neuralgic amyotrophy or Guillain-Barré syndrome have been observed in patients with GT 3 infections. One of the most impressive studies regarding this topic was the paper by Dalton et al. [5]. They studied theprevalence of acuteHEV infections in a large cohort of neurological patients presenting with various non-traumatic acute neurological diseases. They reported evidence of current HEV infection in 11/464 patients (2.4%): HEV viremia was shown in seven patients and anti HEV IgM positivity only in four patients. Notably, none of these patients had jaundice or other clinically signs of acute hepatitis. Themajority of these cases includedNeuralgic amyotrophy and cerebral ischemia/infarction but also patients with seizures, encephalitis and acute facial and vestibular neuropathy. This observation affirmed an association of HEV and neurological diseases in general and especially Neuralgic amyotrophy. In EBioMedicine, Wang et al. studied a similar approach from China, an area endemic for GT 4 [5]. They enrolled 1117 patients with neurological illness and 1475 healthy controls and tested them for HEV and anti-HEV. In contrast to the previous study from Europe, the rate of anti-HEV IgM antibodies did not differ significantly between groups, as authors found 6 positive cases in the neurological illness cohort (0.54%) and 10 positive cases in the healthy controls (0.68%). All detected individuals were HEV RNA positive. Patients with acute HEV infection included cases of viral encephalitis, posterior circulation ischemia, peripheral neuropathy as well as one case of Guillain-Barré

Gerinnungsparameter und Mortalität bei kritisch kranken Patienten mit Leberzirrhose – eine präliminäre Analyse

Einleitung: Veranderungen der Hamostase finden sich haufig bei Patienten mit Leberzirrhose. Der „disseminated intravascular coagulation score“ (DIC score) errechnet sich aus Routine-Gerinnungsparametern (Thrombozytenzahl, D-Dimere, Fibrinogen und Prothrombinzeit/-index) und ist ein bekannter Uberlebenspradiktor bei kritisch kranken Patienten. Aufgrund der Haufigkeit von „pathologischen“ Gerinnungsparametern bei Patienten mit Leberzirrhose ist bislang jedoch unklar, ob der DIC score eine prognostische Aussagekraft bei diesen Patienten besitzt. Ziele: Ziel dieser Studie ist die Bestimmung und die Beurteilung der Anwendbarkeit des DIC Score bei kritisch kranken Patienten mit Leberzirrhose. Methodik: Zirrhose-Patienten, die an der Intensivstation zur Aufnahme gelangten, wurden in dieser Arbeit analysiert. Detaillierte Laboruntersuchungen inklusive Gerinnungsanalysen wurden bei Aufnahme durchgefuhrt und der DIC Score berechnet. Das 28-Tage-Uberleben der Patienten wurde erhoben. Ergebnis: Hundertfunfzig Intensivstations-Aufnahmen mit Leberzirrhose wurden analysiert. Neununddreisig Prozent waren weiblich. Das mediane Alter betrug 56 (IQR 49 – 63) Jahre. Der mediane SOFA Score bei Aufnahme betrug 9 (6 – 13), der mediane MELD score 26 (IQR 18 – 36). Die 28-Tage-Mortalitat lag bei 59%. Der mediane DIC score bei Aufnahme betrug 5 (IQR 4 – 6). „Overt DIC“ (DIC Score ≥5) fand sich bei 65% der Aufnahmen. Bezogen auf die 28-Tage-Mortalitat war der DIC Score bei Nicht-Uberlebenden signifikant hoher als bei Uberlebenden (5 (IQR 4 – 7) vs. 4 (IQR 3 – 6); p < 0.01). Die AUROC fur den DIC Score hinsichtlich der Vorhersage der 28-Tage-Mortalitat war 0.68 (95% CI 0.59 – 0.77). Das Vorhandensein einer „Overt DIC“ bei Aufnahme war signifikant mit der 28-Tage-Mortalitat assoziiert (OR = 3.4 (95% CI 1.69 – 6.84), p < 0.01). Die 28-Tage-Mortalitatsrate bei Aufnahmen mit Zirrhose und „Overt DIC“ betrug 70% verglichen zu 40% bei Patienten mit einem DIC score < 5. Schlussfolgerung: Veranderungen der Hamostase finden sich in der Mehrzahl der Patienten mit Leberzirrhose auf der Intensivstation. Der DIC score ist ein Pradiktor fur das 28-Tage-Uberleben bei kritisch kranken Patienten mit Leberzirrhose.

Prediction of major bleeding in cirrhotic ICU patients using the dic score and coagulation parameters

The disseminated intravascular coagulation (DIC) score is a predictor of outcome in critically ill patients [1]. Yet, disturbances of coagulation are a common finding in patients with liver cirrhosis. Thus, the prognostic value of the DIC score and its subcomponents in patients with liver cirrhosis is unclear.