Interferon alpha is the only treatment option for hepatitis delta virus (HDV). Trials investigating the efficacy of pegylated interferon alpha (PEG‐IFNa) showed HDV RNA negativity rates of 25‐30% 24 ...weeks after therapy. However, the clinical and virological long‐term outcome of HDV‐infected patients treated with PEG‐IFNa is unknown. We performed a retrospective‐prospective follow‐up of 77 patients treated for 48 weeks with either PEG‐alfa‐2a and adefovir (ADV) or either drug alone in the Hep‐Net‐International‐Delta‐Hepatitis‐Intervention‐Study 1 (HIDIT‐1) trial. Long‐term follow‐up data were available for 58 out of 77 patients (75%) with a median time of follow‐up of 4.5 (0.5‐5.5) years and a median 3 visits per patient. Patients treated with ADV alone received retreatment with PEG‐IFNa (48% versus 19%; P = 0.02) more often. Hepatitis B virus surface antigen (HBsAg) became negative in six PEG‐IFNa‐treated patients until the end of long‐term follow‐up (10%). Sixteen patients tested HDV RNA‐negative 6 months after PEG‐IFNa treatment who were entered in the long‐term follow‐up study. Out of these, nine individuals tested HDV RNA‐positive at least once during further long‐term follow‐up, with seven patients being HDV RNA‐positive at the most recent visit. Clinical endpoints (liver‐related death, liver transplantation, hepatic decompensation, hepatocellular carcinoma) were observed in three PEG‐IFNa‐treated (8%) and three ADV‐treated (14%) patients during posttreatment long‐term follow‐up with an overall annual event rate of 2.5% (4.9% in cirrhosis). Sequencing confirmed the reappearance of pretreatment virus strains in all cases. Conclusion: Late HDV RNA relapses may occur after PEG‐IFNa therapy of hepatitis delta and thus the term sustained virological response should be avoided in HDV infection. The annual posttreatment rate of clinical events in hepatitis delta patients eligible for PEG‐IFNa therapy is about 2.5% and 4.9% in patients with cirrhosis. (Hepatology 2014;60:87‐97)
Background & Aims The quantifiable level of HBsAg has been suggested as a predictor of treatment response in chronic hepatitis B. However, there is limited information on HBsAg levels considering the ...dynamic natural course of HBV-infection. This study aimed to determine HBsAg levels in the different phases of HBV-infection in European HBsAg-positive patients. Methods 226 HBV-monoinfected patients, not undergoing antiviral therapy, were analyzed in a cross-sectional study. Patients were categorized according to the phase of HBV-infection: HBeAg(+) immune tolerance phase (IT, n = 30), immune clearance phase (IC, n = 48), HBeAg(−) low-replicative phase (LR, n = 68), HBeAg(−) hepatitis (ENH, n = 68), and acute hepatitis B ( n = 12). HBsAg was quantified and correlated with HBV-DNA, HBV-genotypes and clinical parameters. In addition, 30 LR-patients were followed longitudinally. Results HBsAg levels were higher in IT-patients and IC-patients compared to LR-patients and ENH-patients (4.96/4.37/3.09/3.87-log10 IU/ml, p < 0.001). HBsAg showed a strong correlation with HBV-DNA during acute hepatitis B ( R = 0.79, p < 0.01). Correlation of HBsAg and HBV-DNA was weak or missing when analyzing different phases of persistent HBV-infection separately. However, associations between HBsAg and HBV-DNA were observed in patients infected with HBV-genotype D but not with HBV-genotype A. LR-patients with HBV-reactivation during follow-up (increase of HBV-DNA >2000 IU/ml) showed >3-fold higher baseline HBsAg levels with a NPV of 95% for an HBsAg cut-off of 3500 IU/ml. Conclusions HBsAg levels show significant differences during the natural course of HBV-infection and between HBV-genotypes. These findings may have important implications for understanding the natural history of HBV-infection and for using quantitative HBsAg as a diagnostic tool, i.e. as a marker for predicting HBV-reactivation.
Occult hepatitis B virus infection (OBI) characterized by the absence of detectable HBsAg remains a potential threat in blood safety. We investigated the actual prevalence, viral factors and genotype ...of OBI infections in Nigerian blood donors.
Serum collected from two blood banks were reconfirmed as HBsAg seronegative by ELISA. Forty HBsAg positive samples were employed as controls. HBV-DNA was amplified from all donors and viral loads were determined using quantitative real-time PCR. Antibodies to the HBV core, surface and HBe antigen (anti-HBc,anti-HBs,HBeAg) were measured. The PreS/S and PreC/C regions of the HBV genome were sequenced.
Of the 429 blood donors, 72(17%) were confirmed as OBI by DNA detection in different reference labs and excluded the concern of possible contamination. Of the 72 OBI samples, 48(67%) were positive for anti-HBc, 25(35%) positive for anti-HBs, and 2(3%) positive for HBeAg. Of the 72 OBI samples, 31(43%) were seropositive for either anti-HBc, anti-HBs or HBeAg, 21 (30%) positive for both anti-HBc and anti-HBs,one positive for both anti-HBc and HBeAg. None of the OBI samples were positive for all three serological markers. The viral load was <50copies/ml in the OBI samples and genotype E was predominant. The L217R polymorphism in the reverse transcriptase domain of the HBV polymerase gene was observed significantly higher in OBI compared with HBsAg positive individuals (P<0.0001).
High incidence of OBI is relevant in high endemic areas worldwide and is a general burden in blood safety. This study signifies the high prevalence of OBI and proposes blood donor samples in Nigeria should be pre-tested for OBI by nucleic acid testing (NAT) and/or anti-HBc prior to transfusion to minimize the HBV infection risk.
The hepatitis E virus (HEV) is one of the most common causes of hepatitis worldwide. HEV is also widespread in many developed countries, where the number of infections is steadily increasing. In ...those countries, the virus is transmitted mainly through consumption of undercooked or raw food or through contact with animals. Especially, pigs serve as a main reservoir of HEV. Here, we investigated the prevalence of HEV RNA in pork livers and pork meat products to assess the actual risk of HEV infection through food consumption in Germany. A total of 131 pork products were collected from grocery stores and butcher shops between October 2019 and February 2020 and screened for HEV RNA using nested PCR and subsequent sequencing. Overall, 10% of the samples were positive for HEV, including pork livers (5%), spreadable liver sausages (13%) and liver pâté samples (15%). Sequence analyses indicated that the large majority of HEV strains belonged to subtype HEV‐3c, representing the most frequent subtype in Germany. One sample belonged to subtype HEV‐3f. Further sequence analysis revealed large sequence variation between the samples; however, most of the mutations identified were synonymous. Although infectivity of the virus was not tested, the results suggest a considerable risk of HEV infection through food consumption. Therefore, preventive measures should be taken according to a One Health approach.
Human norovirus is a major cause of viral gastroenteritis in all age groups. The virus is constantly and rapidly changing, allowing mutations and recombination events to create great diversity of ...circulating viruses. With the start of the COVID-19 pandemic in 2020, a wide range of public health measures were introduced worldwide to control human-to-human transmission of SARS-CoV-2. In Germany, control measures such as distance rules, contact restrictions, personal protection equipment as well as intensive hand hygiene were introduced. To better understand the effect of the measures to control the COVID-19 pandemic on incidence and the molecular epidemiological dynamics of norovirus outbreaks in Germany, we analyzed national notification data between July 2017 and December 2022 and characterized norovirus sequences circulating between January 2018 and December 2022. Compared to a reference period before the pandemic, the incidence of notified norovirus gastroenteritis decreased by 89.7% to 9.6 per 100,000 during the 2020/2021 norovirus season, corresponding to an incidence rate ratio (IRR) of 0.10. Samples from 539 outbreaks were genotyped in two regions of the viral genome from pre-pandemic (January 2018 to February 2020) and samples from 208 outbreaks during pandemic time period (March 2020 to December 2022). As expected, norovirus outbreaks were mainly found in child care facilities and nursing homes. In total, 36 genotypes were detected in the study period. A high proportion of recombinant strains (86%) was found in patients, the proportion of detected recombinant viruses did not vary between the pre-pandemic and pandemic phase. The proportion of the predominant recombinant strain GII.4 SydneyP16 was unchanged before pandemic and during pandemic at 37.5%. The diversity of most common genotypes in nursing homes and child care facilities showed a different proportion of genotypes causing outbreaks. In nursing homes as well as in child care facilities GII.4 SydneyP16 was predominant during the whole study period. Compared to the nursing homes, a greater variety of genotypes at the expense of GII.4 SydneyP16 was detected in child care facilities. Furthermore, the overall proportion of recombinant strain GII.3P12 increased during the pandemic, due to outbreaks in child care facilities. The COVID-19 pandemic had a high impact on the occurrence of sporadic cases and norovirus outbreaks in Germany, leading to a near suppression of the typical norovirus winter season following the start of the pandemic. The number of norovirus-associated outbreak samples sent to the Consultant Laboratory dropped by 63% during the pandemic. We could not identify a clear influence on circulating norovirus genotypes. The dominance of GII.4 Sydney recombinant strains was independent from the pandemic. Further studies are needed to follow up on the diversity of less predominant genotypes to see if the pandemic could have acted as a bottleneck to the spread of previously minoritized genotypes like GII.3P12.
Avian hepatitis E virus (aHEV) is associated with hepatitis-splenomegaly syndrome, big liver and spleen disease and hepatic rupture haemorrhage syndrome. However, the knowledge about aHEV in ...commercial layer chickens in Nigeria is scarce. In this study, 460 serum samples obtained from 36 apparently healthy commercial layer chicken flocks in three states (Ogun, Osun and Oyo States) of southwestern Nigeria were analysed by enzyme linked immunosorbent assay for the presence of anti-aHEV immunoglobulin Y (IgY) antibodies. In total, the overall seroprevalence of anti-aHEV antibodies was 14.6%. The serological analysis revealed that 75% of the flocks examined were positive for anti-aHEV IgY antibodies from chickens of various ages in all three states. The percentage of the seropositive chickens in the three states varied from flock to flock ranging from 60% to 88.8% and seropositive chickens were detected at any age (24-52 weeks of age) without significant differences between the age groups. This is the first report assessing the presence of aHEV antibodies in chickens from Nigeria. The detection of anti-aHEV antibodies in commercial layer chickens in this study emphasizes the importance of serosurveillance in disease monitoring due to the economic threat posed by aHEV as a result of decreased egg production and increased mortality in affected commercial layer chicken farms. However, further studies are essential to reveal the clinical implications and to assess the real burden of aHEV in Nigeria.
The diagnosis of acute and chronic myocarditis remains a challenge for clinicians. Characterization of this disease has been hampered by its diverse etiologies and heterogeneous clinical ...presentations. Most cases of myocarditis are caused by infectious agents. Despite successful research in the last few years, the pathophysiology of viral myocarditis and its sequelae leading to severe heart failure with a poor prognosis is not fully understood and represents a significant public health issue globally. Most likely, at a certain point, besides viral persistence, several etiological types merge into a common pathogenic autoimmune process leading to chronic inflammation and tissue remodeling, ultimately resulting in the clinical phenotype of dilated cardiomyopathy. Understanding the underlying molecular mechanisms is necessary to assess the prognosis of patients and is fundamental to appropriate specific and personalized therapeutic strategies. To reach this clinical prerequisite, there is the need for advanced diagnostic tools, including an endomyocardial biopsy and guidelines to optimize the management of this disease. The severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) has currently led to the worst pandemic in a century and has awakened a special sensitivity throughout the world to viral infections. This work aims to summarize the pathophysiology of viral myocarditis, advanced diagnostic methods and the current state of treatment options.
Enteroviruses and adenoviruses have been considered the most common causes of viral myocarditis, but parvovirus B19 (PVB19) and human herpesvirus 6 (HHV6) are increasingly found in endomyocardial ...biopsy samples.
Consequently, our aim was to evaluate the prevalence and clinical presentation of cardiac PVB19 and/or HHV6 infection in a cohort of myocarditis patients and to follow its clinical course. In addition, we sought to demonstrate patterns of myocardial damage and to determine predictors for chronic heart failure. Our study design consisted of a cardiovascular magnetic resonance protocol as well as endomyocardial biopsies in the myocardial region affected as indicated by cardiovascular magnetic resonance. One hundred twenty-eight patients were enrolled by clinical criteria. In the group of myocarditis patients (n=87), PVB19 (n=49), HHV6 (n=16), and combined PVB19/HHV6 infections (n=15) were detected most frequently. The remaining patients were diagnosed with healing myocarditis (n=15) or did not have myocarditis (n=26). Patients with PVB19 presented in a manner similar to that of myocardial infarction; most had typical subepicardial late gadolinium enhancement in the lateral wall and recovered within months. Conversely, patients with HHV6 and especially with HHV6/PVB19 myocarditis presented with new onset of heart failure, had septal late gadolinium enhancement, and frequently progressed toward chronic heart failure.
Our data indicate that PVB19 and HHV6 are the most important causes for viral myocarditis in Germany and that the clinical presentation is related to the type of virus. Furthermore, clinical presentation, type of virus, and pattern of myocardial damage are related to the clinical course.
Human group A rotaviruses (RVA) are important enteric pathogens, as they are a leading cause of acute gastroenteritis (AGE) in children worldwide. Since 2013, the German Standing Committee on ...vaccination recommended the routine rotavirus vaccination for infants in Germany. While vaccination has significantly decreased RVA cases and worldwide mortality, in some cases, infants can develop acute gastroenteritis as an adverse reaction after immunization with an attenuated live vaccine. Pediatricians, as well as clinicians and diagnostic laboratories, contacted the Consultant Laboratory for Rotaviruses and inquired whether cases of RVA-positive AGE after vaccination were associated with vaccine or with wild-type RVA strains. A testing algorithm based on distinguishing PCRs and confirmative sequencing was designed, tested, and applied. Diagnostic samples from 68 vaccinated children and six cases where horizontal transmission was suspected were investigated in this study. Using a combination of real-time PCR, fragment-length analysis of amplicons from multiplex PCRs and confirmative sequencing, vaccine-like virus was detected in 46 samples and wild-type RVA was detected in 6 samples. Three mixed infections of vaccine and wild-type RVA were detectable, no RVA genome was found in 19 samples. High viral loads (>1.0 × 107 copies/g stool) were measured in most RVA-positive samples. Furthermore, information on co-infections with other AGE pathogens in the vaccinated study population was of interest. A commercial multiplex PCR and in-house PCRs revealed three co-infections of vaccinated infants with bacteria (two samples with Clostridioides difficile and one sample with enteropathogenic E. coli) and six co-infections with norovirus in a subset of the samples. Human astrovirus was detected in one sample, with suspected horizontal transmission. The cases of suspected horizontal transmission of vaccine RVA strains could not be confirmed, as they either involved wild-type RVA or were RVA negative. This study shows that RVA-positive AGE after vaccination is not necessarily associated with the vaccine strain and provides a reliable workflow to distinguish RVA vaccine strains from wild-type strains.
Rodents are common reservoirs for numerous zoonotic pathogens, but knowledge about diversity of pathogens in rodents is still limited. Here, we investigated the occurrence and genetic diversity of ...enteric viruses in 51 Norway rats collected in three different countries in Europe. RNA of at least one virus was detected in the intestine of 49 of 51 animals. Astrovirus RNA was detected in 46 animals, mostly of rat astroviruses. Human astrovirus (HAstV-8) RNA was detected in one, rotavirus group A (RVA) RNA was identified in eleven animals. One RVA RNA could be typed as rat G3 type. Rat hepatitis E virus (HEV) RNA was detected in five animals. Two entire genome sequences of ratHEV were determined. Human norovirus RNA was detected in four animals with the genotypes GI.P4-GI.4, GII.P33-GII.1, and GII.P21. In one animal, a replication competent coxsackievirus A20 strain was detected. Additionally, RNA of an enterovirus species A strain was detected in the same animal, albeit in a different tissue. The results show a high detection rate and diversity of enteric viruses in Norway rats in Europe and indicate their significance as vectors for zoonotic transmission of enteric viruses. The detailed role of Norway rats and transmission pathways of enteric viruses needs to be investigated in further studies.
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