Five-year follow-up of 96 weeks peginterferon plus tenofovir disoproxil fumarate in hepatitis D.

BACKGROUND & AIMS: Until recently, pegylated interferon-alfa-2a (PEG-IFNa) therapy was the only treatment option for patients infected with hepatitis D virus (HDV). Treatment with PEG-IFNa with or without tenofovir disoproxil fumarate (TDF) for 96 weeks resulted in HDV RNA suppression in 44% of patients at the end of therapy but did not prevent short-term relapses within 24 weeks. The virological and clinical long-term effects after prolonged PEG-IFNa-based treatment of hepatitis D are unknown. METHODS: In the HIDIT-II study patients (including 40% with liver cirrhosis) received 180 µg PEG-IFNa weekly plus 300 mg TDF once daily (n = 59) or 180 µg PEG-IFNa weekly plus placebo (n = 61) for 96 weeks. Patients were followed until week 356 (5 years after end of therapy). RESULTS: Until the end of follow-up, 16 (13%) patients developed liver-related complications (PEG-IFNa + TDF, n = 5 vs PEG-IFNa + placebo, n = 11; p = .179). Achieving HDV suppression at week 96 was associated with decreased long-term risk for the development of hepatocellular carcinoma (p = .04) and hepatic decompensation (p = .009). Including complications irrespective of PEG-IFNa retreatment status, the number of patients developing serious complications was similar with (3/18) and without retreatment with PEG-IFNa (16/102, p > .999) but was associated with a higher chance of HDV-RNA suppression (p = .024, odds ratio 3.9 [1.3-12]). CONCLUSIONS: Liver-related clinical events were infrequent and occurred less frequently in patients with virological responses to PEG-IFNa treatment. PEG-IFNa treatment should be recommended to HDV-infected patients until alternative therapies become available. Retreatment with PEG-IFNa should be considered for patients with inadequate response to the first course of treatment. CLINICAL TRIAL REGISTRATION: NCT00932971.

Rapid and Sensitive SERS-Based Lateral Flow Test for SARS-CoV2-Specific IgM/IgG Antibodies.

As an immune response to COVID-19 infection, patients develop SARS-CoV-2-specific IgM/IgG antibodies. Here, we compare the performance of a conventional lateral flow assay (LFA) with a surface-enhanced Raman scattering (SERS)-based LFA test for the detection of SARS-CoV-2-specific IgM/IgG in sera of COVID-19 patients. Sensitive detection of IgM might enable early serological diagnosis of acute infections. Rapid detection in serum using a custom-built SERS reader is at least an order of magnitude more sensitive than the conventional LFAs with naked-eye detection. For absolute quantification and the determination of the limit of detection (LOD), a set of reference measurements using purified (total) IgM in buffer was performed. In this purified system, the sensitivity of SERS detection is even 7 orders of magnitude higher: the LOD for SERS was ca. 100 fg/mL compared to ca. 1 µg/mL for the naked-eye detection. This outlines the high potential of SERS-based LFAs in point-of-care testing once the interference of serum components with the gold conjugates and the nitrocellulose membrane is minimized.

A transient early HBV-DNA increase during PEG-IFNα therapy of hepatitis D indicates loss of infected cells and is associated with HDV-RNA and HBsAg reduction.

HBV-DNA levels are low or even undetectable in the majority HDV-infected patients. The impact of PEG-IFNα on HBV-DNA kinetics in HDV-infected patients has not been studied in detail. We analysed data of a prospective treatment trial where 120 HDV-RNA-positive patients were randomized to receive PEG-IFNα-2a plus tenofovir-disoproxil-fumarate (PEG-IFNα/TDF, n = 59) or placebo (PEG-IFNα/PBO; n = 61) for 96 weeks. At week 96, HBV-DNA was still quantifiable in 71% of PEG-IFNα/PBO-treated patients but also in 76% of PEG-IFNα/TDF-treated patients, despite low HBV-DNA baseline values. Surprisingly, a transient HBV-DNA increase between weeks 12 and 36 was observed in 12 in PEG-IFNα/TDF-treated and 12 PEG-IFNα/PBO-treated patients. This increase was positively associated with HBsAg loss [(P = 0.049, odds ratio (OR) 5.1] and HDV-RNA suppression (P = 0.007, OR 4.1) at week 96. Biochemical markers of cell death (M30 and ALT) were higher during the HBV-DNA peak but no distinct systemic immune pattern could be observed by screening 91 soluble inflammatory markers. In conclusion, an early increase in HBV-DNA during PEG-IFNα-2a therapy occurred in more than 20% of patients, even in TDF-treated patients. This transient HBV-DNA rise may indicate PEG-IFNα-induced cell death and lead to long-term HDV-RNA suppression and HBsAg loss.

Common respiratory viral infections: Bilateral versus unilateral bronchoalveolar lavage versus endotracheal aspiration.

Data about the diagnostic efficiency of bilateral bronchoalveolar lavage (BAL) samples and endotracheal aspirates (EA) testing for common viral respiratory infections are scarce. We analyzed data from 167 cases, where bilateral BAL samples were tested, and from 101 cases, where BAL samples and EA were tested. Multiplex polymerase chain reaction (PCR) was performed with the fast track diagnostics viral respiratory panel, producing data on the adenovirus, coronavirus, enterovirus, human metapneumovirus, bocavirus, influenza virus, parainfluenza virus, rhinovirus, and respiratory syncytial virus status of patients with respiratory disease symptoms. In the bilateral BAL cohort, 46 (27.5%) cases were positive for at least one of the viruses mentioned above in both samples. Discrepant results (virus not detected on one side) were seen in six (3.6%) cases. In the BAL versus EA cohort, 12 (11.9%) cases were positive in both materials, discrepant results (only one material being positive) were observed in 11 (10.9%) cases, with seven (63.6%) BAL samples, and four (36.4%) EA being positive. Bilateral sampling does not significantly improve the diagnostic efficiency of BAL for the detection of common respiratory viral pathogens via PCR. The diagnostic quality of EA and BAL samples for the detection of common viral respiratory pathogens is comparable.

Over 90% of clinical swabs used for SARS-CoV-2 diagnostics contain sufficient nucleic acid concentrations.

During the coronavirus disease 2019 pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), reliable diagnostics are absolutely indispensable. Molecular SARS-CoV-2 diagnostics based on nucleic acids (NA) derived from oro- or nasopharyngeal swabs constitute the current gold standard. Given the importance of test results, it is crucial to assess the quality of the underlying swab samples and NA extraction procedures. We determined NA concentrations in clinical samples used for SARS-CoV-2 testing applying an NA-specific dye. In comparison to cut-offs defined by SARS-CoV-2-positive samples, internal positive controls, and references from a federal laboratory, 90.85% (923 of 1016) of swabs contained NA concentrations enabling SARS-CoV-2 recognition. Swabs collected by local health authorities and the central emergency department either had significantly higher NA concentrations or were less likely to exhibit insufficient quality, arguing in favor of sampling centers with routined personnel. Interestingly, samples taken from females had significantly higher NA concentrations than those from males. Among eight longitudinal patient sample sets with intermitting negative quantitative reverse transcription polymerase chain reaction results, two showed reduced NA concentrations in negative specimens. The herein described fluorescence-based NA quantification approach is immediately applicable to evaluate swab qualities, optimize sampling strategies, identify patient-specific differences, and explain some peculiar test results including intermittent negative samples with low NA concentrations.

Hepatitis B Virus Particles Activate Toll-Like Receptor 2 Signaling Initially Upon Infection of Primary Human Hepatocytes.

BACKGROUND AND AIMS: To date, conflicting data exist as to whether hepatitis B virus (HBV) has the ability to induce innate immune responses. Here, we investigated cellular changes after the first contact between HBV and primary human hepatocytes (PHH) in vitro and in vivo. APPROACH AND RESULTS: The exposure of PHH to HBV particles resulted in nuclear translocation of NFκB, followed by the expression and secretion of inflammatory cytokines (IL [interleukin] 1B, IL6, and TNF [tumor necrosis factor]). Ultraviolet irradiation of viral particles suppressed HBV infectivity but not the induction of cytokines in PHH, suggesting that the inoculum contains the immune-inducing agent. Purified HBV particles on the whole, which were prepared from HBV DNA-positive and protein-rich fractions after heparin column separation, still had immune-inducing capacity in PHH. The HBV-induced gene expression profile was similar to that induced by toll-like receptor 2 (TLR2) ligand Pam3Cys, but different from those induced by the viral sensors TLR3 or TLR7-9. Treatment of PHH with both HBV particles and Pam3Cys led to phosphorylation of ERK (extracellular signal-regulated kinase), JNK, and p38 mitogen-activated protein kinases as well as NFκB (nuclear factor kappa B). Finally, HBV-induced gene expression could be neutralized by TLR2-specific antibodies. Of note, pretreatment with an HBV entry inhibitor attenuated the TLR2-mediated response to HBV, suggesting a receptor binding-related mechanism. In liver-humanized uPA/severe combined immunodeficient (SCID)/beige mice challenged with HBV in vivo, immune induction could only marginally be seen. CONCLUSIONS: PHHs are able to sense HBV particles through TLR2, leading to an activation of anti-HBV immune responses in vitro. These findings challenge the previously described stealth properties of HBV.

The impact of hepatitis B surface antigen on natural killer cells in patients with chronic hepatitis B virus infection.

BACKGROUND & AIMS: During chronic hepatitis B virus (HBV) infection, suppressed functionality of natural killer (NK) cells might contribute to HBV persistence but the underlying mechanisms remain elusive. A peculiar feature of HBV is the secretion of large amount of hepatitis B surface antigen (HBsAg). However, the effect of HBsAg quantities on NK cells is unclear. The aim was to determine the effects of HBsAg quantities on NK cell functionality in patients with chronic hepatitis B (CHB). METHODS: Eighty CHB patients were included and categorized into four groups based on their HBsAg levels. As a control, 30 healthy donors were enrolled. NK cell frequency, phenotype and function were assessed using flow cytometry and correlated with HBsAg levels and liver enzymes. RESULTS: Compared to the healthy controls, a reshaping of NK cell pool towards more CD56bright NK cells was observed during CHB infection. Importantly, NK cells in patients with low HBsAg levels (<100 IU/mL) displayed an activated phenotype with increased expression of activation makers CD38, granzyme B and proliferation marker Ki-67 while presenting with defective functional responses (MIP-1ß, CD107a) at the same time. Furthermore, NK cell activation was negatively correlated with patient HBsAg levels while NK function correlated with patient age. CONCLUSIONS: The differential regulation of NK cell phenotype and function suggests that activation of NK cells in patients with low serum HBsAg levels may contribute to HBV clearance.

Residual low HDV viraemia is associated HDV RNA relapse after PEG-IFNa-based antiviral treatment of hepatitis delta: Results from the HIDIT-II study.

The role of low levels of HDV-RNA during and after interferon therapy of hepatitis D is unknown. We re-analysed HDV RNA in 372 samples collected in the HIDIT-2 trial (Wedemeyer et al, Lancet Infectious Diseases 2019) with the Robogene assay (RA; Jena Analytics). Data were compared with the previously reported in-house assay (IA). We detected HDV-RNA in one-third of samples previously classified as undetectable using the highly sensitive RA. Low HDV viraemia detectable at week 48 or week 96 was associated with a high risk for post-treatment relapse, defined as HDV RNA positivity in both assays at week 120. HDV RNA relapses occurred in 10/15 (67%) patients with detectable low HDV RNA at week 48 and in 10/13 (77%) patients with low viraemia samples at week 96. In contrast, the post-treatment relapse rate was lower in patients with undetectable HDV RNA in both assays during treatment.

Mild versus Severe Liver Injury in SARS-CoV-2 Infection.

BACKGROUND: Abnormal liver function has been reported in patients with COVID-19 infection. The aim of our study was to report on the prevalence of liver injury in our cohort, to evaluate the association of mild versus severe liver injury with mortality in COVID-19 patients and to scrutinize the temporal pattern of viral detection and liver injury. METHODS: We present data from a German cohort of 147 SARS-CoV-2 infected patients. The patients were divided into 3 groups according to their liver status during treatment. The first group included patients without elevated alanine aminotransferase or bilirubin, the third group patients meeting the biochemical criteria of acute liver failure (ALF), and the second group all other patients. RESULTS: Liver injury was detected in 75 (50.7%) and 93 (63%) patients by admission and during treatment, respectively. ALF was associated with the male sex, younger age, and higher BMI. Mortality was associated with the presence of ALF (OR = 9.423, 95% CI: 2.410-36.858) in contrast to milder liver injury (OR 1.101, 95% CI: 0.435-2.791). In 30% of patients with mild liver injury and in 50% of ALF patients, peak liver injury was observed at a time point when the virus was no longer detectable in the respiratory tract. CONCLUSION: Mild liver injury was not associated with worse outcome in our cohort, and the pattern of liver injury did not fit well to the theory of SARS-CoV-2 directly causing liver impairment. Instead, severe liver injury in our cohort was associated multiple-organ failure and acute vascular events.

Clinical Outcome and Viral Genome Variability of Hepatitis B Virus-Induced Acute Liver Failure.

Acute hepatitis B virus (HBV) infection remains a frequent cause of acute liver failure (ALF) worldwide. ALF occurs in 0.1%-0.5% of infected patients. The aim of this study was to scrutinize the outcome of patients with HBV-induced ALF and mutational patterns of HBV variants, which might contribute to ALF. From 2005 to 2016, 42 patients were treated for HBV-induced ALF in the University Hospital Essen, Germany. Clinical and virological data from these patients were collected. As a control, 38 patients with acute hepatitis B (AHB) without liver failure were included. The HBV genome was sequenced by next-generation sequencing (NGS). Mutations that were found by NGS were analyzed in vitro. Of 42 patients, 8 had ALF without spontaneous recovery (NSR): Seven patients underwent liver transplantation (LT) and one patient died before LT. Of 42 patients, 34 (81%) had spontaneous recovery (SR) and cleared the infection, achieving either anti-HBs seroconversion or hepatitis B surface antigen (HBsAg) loss. HBV genotype (GT)-D was the most frequent GT in patients with ALF. Mutations in HBV core, preS2, and small hepatitis B surface antigen (SHB) were more frequent in patients with ALF-NSR compared with those with ALF-SR or AHB. Amino acid deletions (del; 16-22 and 20-22) in preS2 and SHB mutation L49R were exclusively detected in patients with ALF-NSR. In vitro analyses reveal that these mutations did not influence HBsAg secretion or infectivity. Conclusion: HBV GT-D and increased variability in HBV core, preS2 region, and SHB are associated with a worse clinical outcome of acute HBV infection.

SEC14L2, a lipid-binding protein, regulates HCV replication in culture with inter- and intra-genotype variations.

BACKGROUND & AIMS: The lipid-binding protein, SEC14L2, is crucial for the efficient viral replication of clinical hepatitis C virus (HCV) isolates in cell culture. Given the role of SEC14L2 in HCV replication, we aimed to study a large number of HCV positive sera carrying genotypes 1-4, to identify viral factors associated with efficient replication in culture. Additionally, we investigated whether 13 single nucleotide polymorphisms (SNPs) of SEC14L2 have an impact on RNA replication of naturally occurring HCV isolates. METHODS: We generated Huh-7.5 cell lines overexpressing SEC14L2 or 13 coding SNPs and tested 73 different HCV positive sera for in vitro replication. Furthermore, we genotyped a cohort of 262 patients with chronic HCV for the common SNP (rs757660) and investigated its effect on the clinical phenotype. RESULTS: HCV isolates from genotype 1, 2, 3 and 4 replicate in Huh-7.5 cells overexpressing SEC14L2. Interestingly, only subgenomic replicons from genotypes 1 and 3 showed enhanced replication whereas genotypes 2 and 4 remained unaffected. Furthermore, replication was independent of viral load. Importantly, all tested SNPs supported HCV RNA replication in vitro, while 1 SNP was associated with decreased SEC1L2 expression and viral RNA. All SNPs exhibited comparable cellular cholesterol and vitamin E abundance in naïve Huh-7.5 cells. CONCLUSIONS: This large screen of natural HCV isolates of 4 genotypes underscores the relevance of SEC14L2 as an in vitro HCV host factor. Additionally, SEC14L2 variants appear to recapitulate the wild-type enhancement of HCV replication. Variant rs191341134 showed a decreased effect due to lowered stability, whereas variant rs757660, a high prevalence mutant, showed a similar phenotype to the wild-type. LAY SUMMARY: Until the year 2015, consistent replication of patient-derived isolates of hepatitis C virus (HCV) in an in vitro model remained a limitation in HCV research. In 2015 a group of authors identified a protein named SEC14L2 that enabled the replication of HCV isolates in cell culture. We performed a large screen encompassing 73 isolates of 4 different HCV genotypes. Additionally, we replaced the natural SEC14L2 with 13 different mutants to test if the protein variation significantly altered its HCV replication enhancing functions. We showed that different genotypes of HCV react differently to the presence of this protein and the variants of the protein mimic the behavior of the wild-type.

Clinical patterns associated with the concurrent detection of anti-HBs and HBV DNA.

Simultaneous detection of anti-HBs and HBV DNA is a rare serological combination and has been described in acute and chronic HBV infection. To scrutinize viral and clinical patterns associated with concurrent detection of anti-HBs and HBV DNA. Simultaneous detection of anti-HBs and HBV DNA was observed in 64/1444 (4.4%) patients treated for HBV infection at the University Hospital of Essen from 2006 to 2016 (8 with acute, 20 with reactivated, and 36 chronic HBV infection). Clinical data and laboratory parameters were analyzed. Regions of the small hepatitis B surface antigen (SHB) and the reverse transcriptase (RT) were sequenced using next generation sequencing (NGS). Among the 64 patients with detectable HBV DNA and anti-HBs, 17 were HBsAg negative (HBsAg[-]), and two had acute liver failure. Patients with acute HBV infection had fewer genotype specific amino acid substitutions in the SHB region than patients with reactivated HBV infection (4 [4.5] vs 9 [16.25], P = 0.043). However, we could observe a significantly higher number of mutations in the a-determinant region when comparing chronically infected patients to patients with acute infection (0 [1] vs 1 [1], P = 0.044). The ratio of nonsynonymous to synonymous mutations (Ka/Ks) was on average >1 for the SHB region and <1 for the RT region. The Ka/Ks ratio (>1) in the SHB region indicates that anti-HBs might have exerted selection pressure on the HBsAg. In three cases the diagnosis of acute HBV infection would have been at least delayed by only focusing on HBsAg testing.

Corticosteroid Therapy Improves the Outcome of Autoimmune Hepatitis-Induced Acute Liver Failure.

BACKGROUND/AIMS: Autoimmune hepatitis (AIH) is a relatively rare cause of liver dysfunction and may lead in some cases to acute liver failure (ALF). The aim of our study was to evaluate the clinical course and outcome of patients with AIH-induced ALF. METHODS: We retrospectively enrolled 32 patients with AIH-induced ALF and 93 age- and sex-matched patients with chronic AIH (cAIH) who were enrolled at the University Clinic Essen from 1988 to 2014. All ALF patients were treated with corticosteroids after diagnosis. RESULTS: Overweight, higher γ-globulin levels, the absence of anti-smooth muscle antibodies and human leukocyte antigen (HLA) B8 and the presence of anti-mitochondrial antibodies and HLA DR7 were risk factors for an ALF vs chronic hepatitis manifestation of AIH. Liver histology was significantly more often typical for AIH in an ALF setting than in cAIH. The spontaneous survival rate was 91% and 97% in ALF and cAIH patients, respectively, at 6 months after diagnosis and only 1 patient in the ALF group developed sepsis under therapy. CONCLUSION: Liver biopsy in an AIH-mediated ALF setting was both safe and effective in diagnosing AIH. Corticosteroid therapy was not associated with high mortality or sepsis. Our findings suggest that corticosteroid treatment of AIH-mediated ALF may improve the outcome.

Low transferrin and high ferritin concentrations are associated with worse outcome in acute liver failure.

BACKGROUND & AIMS: Serum ferritin and transferrin have been identified as prognostic markers in patients with chronic diseases. In this study, we investigated if these parameters can predict outcome in patients with acute liver failure. METHODS: A total of 102 consecutive patients with acute liver failure were retrospectively analysed. The patients were grouped by outcome: spontaneous recovery vs liver transplantation and/or death or survival vs death. Routine laboratory parameters, transferrin and ferritin concentrations in serum, and anthropomorphic data collected on admission were analysed. RESULTS: Non-spontaneously recovering patients had higher ferritin (12 252±25 791 vs 4434.4±9027.2 µg/L; P<.05) and lower transferrin levels (140.4±66.7 vs 206.9±65.8 mg/dL; P<.05) than spontaneously recovering patients. Similarly non-survivors exhibited higher serum ferritin and lower transferrin than non-transplanted survivors. Patients with severe hepatic inflammation (A3) had higher ferritin levels compared to patients with mild-moderate inflammation (A1-2) (5280±5094 vs 2361±2737 µg/L; P=.025). ROC analysis of single parameters was performed in non-transplanted patients, resulting in an area under the curve, sensitivity and specificity of 0.812%, 83.3%, and 77.1% for age, 0.871%, 84.1% and 75% for transferrin and 0.802%, 91.7% and 62.9% for ferritin. A model incorporating age, MELD and transferrin had the best predictive value with an area under the curve of 0.947, a sensitivity of 100% and corresponding specificity of 77.8%. CONCLUSIONS: High ferritin and low transferrin levels are associated with worse outcome in patients with acute liver failure. A model incorporating age, MELD score and transferrin outperformed MELD score for 90-day overall survival of non-transplanted patients.

Metabolic and androgen profile in underweight women with polycystic ovary syndrome.

INTRODUCTION: Polycystic ovary syndrome (PCOS) is a disorder associated with insulin resistance and obesity. Aim of our study is to clarify the prevalence of underweight in PCOS patients and whether metabolic and androgen profiles of PCOS differ depending on normal or low body weight. METHODS: Out of 1269 consecutive patients with PCOS recruited from the Department of Endocrinology and Metabolism at the University of Duisburg-Essen, 19 patients (1.5%) were underweight and were compared to 375 lean PCOS subjects (29.6%). Clinical and endocrine parameters were evaluated. Insulin resistance was assessed by 3-h oral glucose tolerance test (OGTT). RESULTS: Prevalence of type 2 diabetes and free androgen index did not differ between the two groups. Total cholesterol and low density lipoprotein levels were significantly lower in the group of underweight patients. While no significant difference was found for the Homeostasis model assessment (HOMA) index at fasting state, the HOMA-M120, calculated 2 h after glucose intake in OGTT, was significantly higher in underweight patients. Underweight patients also showed significantly higher postprandial insulin secretion after glucose intake in OGTT. Six underweight PCOS patients received metformin treatment for oligomenorrhea. An improvement of the menstrual cycle was observed in three cases, while two patients were lost to follow up and one discontinued therapy due to side effects. CONCLUSIONS: The prevalence of underweight in patients with PCOS is very low. Underweight in PCOS is associated with higher postprandial insulin levels. Several of our underweight patients were able to achieve regular menstrual cycle under metformin therapy.

Seasonal Patterns of Common Respiratory Viral Infections in Immunocompetent and Immunosuppressed Patients.

INTRODUCTION: Several respiratory viruses have been shown to have seasonal patterns. The aim of our study was to evaluate and compare these patterns in immunocompetent and immunosuppressed patients for five different respiratory viruses. METHODS: We performed a retrospective analysis of results for 13,591 respiratory tract samples for human metapneumovirus (HMPV), influenza virus, parainfluenza virus (PIV) and respiratory syncytial virus (RSV) in immunocompetent and immunosuppressed patients. A seasonal pattern was aligned to the data of immunocompetent patients through a logistic regression model of positive and negative test results. RESULTS: A narrow seasonal pattern (January to March) was documented for HMPV. Most RSV infections were detected in the winter and early spring months, from December to March, but occasional cases of RSV could be found throughout the year. The peak season for PIV-3 was during the summer months, and that for PIV-4 was mostly in autumn. A narrow seasonal pattern emerged for influenza virus as most infections were detected in the winter, in January and February. The seasonal patterns of HMPV, RSV, PIV, and influenza virus were similar for both immunocompetent and immunocompromised patients. CONCLUSIONS: We found no difference in the seasonality of HMPV, RSV, PIV, and influenza virus infections between immunosuppressed and immunocompetent hosts.

Burden of HPV-Related Hospitalization in Germany from 2000 to 2021.

HPV has been linked to the development of precancerous and cancerous lesions. The aim of this study was to evaluate the burden of HPV-related hospitalization in Germany from 2000 to 2021 and the potential impact of the COVID-19 pandemic on it. METHODS: We performed a retrospective query using data from the German Statistical Office from 2000 to 2021, including hospital admission, inpatient mortality and hospital stay length data on cervical cancer/dysplasia, female genitourinary tract, anal, penile, head and neck cancers. RESULTS: The HPV-attributable hospitalization rate per 100,000 inhabitants in Germany has decreased over time, from 89 cases in 2000 to 60 in 2021, with an average annual percent change (AAPC) of -1.93 (CI -2.08--1.79, p < 0.05). The same trend was observed for the average hospital stay, which declined from 9 to 7 days, with an AAPC of -1.33 (CI -1.52--1.21, p < 0.05). An undulating but overall slightly declining pattern was observed for the inpatient mortality (AAPC -0.92, CI -1.21--0.64, p < 0.05). We observed a reduction in the hospitalization rates for invasive and non-invasive cervical cancer, which was observed in almost all age groups and in all German federal states. CONCLUSION: Our study provides a comprehensive analysis of the trends in HPV-related hospitalizations over the past two decades. The decline in hospitalization rates for cervical cancer and dysplasia suggests the potential efficacy of the HPV vaccination and screening programs.

A simple algorithm based on initial Ct values predicts the duration to SARS-CoV-2 negativity and allows more efficient test-to-release and return-to-work schedules.

Especially during global pandemics but also in the context of epidemic waves, the capacity for diagnostic quantitative reverse transcription-polymerase chain reactions (qRT-PCRs) rapidly becomes a limiting factor. The aim of the study was to optimize retesting regimens for test-to-release from isolation and return-to-work applications. For this purpose, we investigated the association between Ct values at the first diagnosis of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and the period until test negativity was reached, or at least until the Ct value exceeded 30, which is considered to indicate the transition to a non-infectious state. We included results from the testing of respiratory material samples for the detection of SARS-CoV-2 RNA, tested from March 1, 2020 to January 31, 2022. Lower initial Ct values were associated with longer periods of SARS-CoV-2 RNA positivity. Starting with Ct values of <20, 20 to 24.99, 25 to 29.99, 30 to 34.99, and ≥35, it took median intervals of 20 (interval: 14-25), 16 (interval: 10-21), 12 (interval: 7-16), 7 (interval: 5-14), and 5 (interval: 2-7) days, respectively, until the person tested negative. Accordingly, a Ct threshold of 30 was surpassed after 13 (interval: 8-19), 9 (interval: 6-14), 7 (interval: 6-11), 6 (interval: 4-10), and 3 (interval: 1-6) days, respectively, in individuals with aforementioned start Ct values. Furthermore, the time to negativity was longer for adults versus children, wild-type SARS-CoV-2 variant versus other variants of concern, and in patients who were treated in the intensive care units. Based on these data, we propose an adjusted retesting strategy according to the initial Ct value in order to optimize available PCR resources.

Durability of Immune Response after Application of a Third Dose of SARS-CoV-2 Vaccination in Liver Transplant Recipients.

Immunogenicity after SARS-CoV-2 vaccination is known to be impaired in liver transplant (LT) recipients, but the results after the application of a third dose show significant improvement in seroconversion rates. In the general population, the antibody response wanes over the course of time after two doses of the vaccination, but seems to be more robust after the application of three doses. Still, the durability of the antibody response in LT recipients who receive a third dose of SARS-CoV-2 vaccination has not been analyzed yet. We therefore assessed antibody responses in a total of 300 LT recipients and observed antibody titers for six months each after patients had received the second and the third doses of the vaccination, explicitly excluding all patients who had suffered from SARS-CoV-2 infection. The initial antibody response was compared to a control group of 122 healthcare workers. After the application of two doses of the vaccination, 74% of LT recipients (158 out of 213) developed antibodies against SARS-CoV-2; this result depended significantly on whether the patients were taking the medication mycophenolate mofetil, and on the age of the patients. Antibody titers declined significantly within six months from 407 BAU/mL (IQR: 0-1865) to 105 BAU/mL (IQR: 0-145) (p ≤ 0.001), but increased after the application of the third vaccine dose in 92% of patients (105 out of 114), showing an antibody response (p ≤ 0.001). After a further six-month period, despite showing a decline from 2055 BAU/mL (IQR: 500 to >2080) to 1805 BAU/mL (IQR: 517 to >2080), the waning of antibody titers was not significant (p = 0.706), and antibody durability appeared to be more robust than that after the second dose. In conclusion, our study confirms the high efficacy of the application of a third dose of SARS-CoV-2 vaccination in LT recipients, and a reasonably sustained humoral response with superior durability in comparison to antibody kinetics after the application of the second dose of the vaccination.