Treatment with Brivudine in Immunocompromised Pediatric Patients with Herpes Zoster.

INTRODUCTION: Herpes zoster (HZ) is caused by endogenous reactivation of latent varicella-zoster virus (VZV) that persists in sensory ganglia after primary infection. The incidence and severity of HZ increase during immunosuppression. Especially, immunocompromised patients are at high risk of developing a cutaneous rash and suffering from delayed healing of lesions. Bromovinyl deoxyuridine (brivudine), one of the most potent oral inhibitors of VZV replication, is widely used in the therapy of HZ in adult patients, particularly in Europe. In this study, we investigated the efficacy of brivudine in immunocompromised children to provide an outpatient treatment option. METHODS: In this retrospective study, we included 64 immunocompromised pediatric patients with a median age of 14 years. Forty-seven patients received immunosuppressive therapy as part of hematopoietic stem cell transplantation and 17 patients as part of chemotherapy. Primary diagnosis was made clinically by examining the nature and the localization of the skin lesions. Laboratory confirmation was conducted based on the detection of VZV DNA in vesicle fluid and blood samples. Brivudine was administered orally at a single dose of 2 mg/kg per day. We monitored the patients' response for the full time of treatment and observed the time of full crusting of lesions, loss of crusts, and any adverse effects that occurred. RESULTS: Patients received medication for 7-21 days (median: 14 days). All children responded promptly to antiviral treatment and recovered completely from their HZ infections without complications. Crusting of lesions was reached after 3-14 days (median: 6 days). Full healing of skin lesions was ascertained within 7-21 days (median: 12 days). Overall, brivudine therapy was well tolerated. No clinical side effects during or after the treatment were observed. High compliance was achieved due to the once-daily dosing regimen. All patients were treated in an outpatient manner. CONCLUSION: Oral brivudine was a very effective and well-tolerated therapy in immunocompromised children with HZ infection. The oral administration offers the potential for outpatient treatment of HZ in these patients.

Burden of Herpes Zoster in Adult Patients with Underlying Conditions: Analysis of German Claims Data, 2007-2018.

INTRODUCTION: Several chronic underlying conditions (UCs) are known to be risk factors for developing herpes zoster (HZ) and to increase the severity of HZ and its risk of recurrence. The aim of this study was to investigate the incidence and recurrence of HZ in adult patients with one or multiple UCs. METHODS: A retrospective cohort study based on claims data representing 13% of the statutory health insurance population from 2007 to 2018 in Germany was performed. Patients aged ≥ 18 years were included when at least one of the following UCs was diagnosed: asthma, chronic heart failure, chronic obstructive pulmonary disease (COPD), coronary heart disease (CHD), depression, diabetes mellitus type 1 or 2, and rheumatoid arthritis (RA). Exact matching was used to account for differences in the distribution of age and sex between the case and matched control cohorts. Multi-morbidity was considered in sensitivity analyses by analyzing patients with only one UC. RESULTS: Patients with asthma, CHD, COPD, depression, and RA had, on average, a 30% increased risk of developing acute HZ compared to patients without any UC. RA was found to have the highest odds ratio among these conditions, varying from 1.37 to 1.57 for all age groups. Patients with depression also showed a high risk of developing HZ. Analysis of recurrence indicated that patients with at least one UC in the age groups 18-49 years and 50-59 years had the highest risk for a recurrent HZ. After experiencing a first recurrence, patients, regardless of age group, had a two- to threefold higher risk for a second recurrence. CONCLUSION: This study of representative claims data shows a higher HZ incidence and recurrence frequency in patients with UCs. These results provide relevant information for national health care guidelines and disease management programs.

Shingles is caused by the reactivation of the chickenpox virus and is characterized by a painful skin rash with blisters, commonly occurring on the trunk. Underlying conditions (UCs) are conditions that persist for a long time, require ongoing medical attention, and are rarely completely cured (chronic conditions). UCs can increase the severity, the risk, and the frequency of shingles. Here, data from a large German health care insurance provider was used to investigate whether patients with one or more UCs have a higher risk for getting shingles compared to healthy people. In particular, patients with asthma, chronic heart failure, chronic obstructive pulmonary disease, coronary heart disease, depression, diabetes, and rheumatoid arthritis were investigated. The study shows that patients with asthma, coronary heart disease, chronic obstructive pulmonary disease, depression, and rheumatoid arthritis have, on average, a 30% higher risk of developing shingles, regardless of their age. The risk of developing shingles two or more times is also higher for patients with at least one UC, with those aged 18­59 experiencing an even greater risk. It was found that patients with an UC are more exposed to develop shingles and that younger patients have a higher risk of a recurrent episode. The findings provide important information for the development or adaption of national health care guidelines and shingles vaccination recommendations.

Varicella vaccination in Italy and Germany - different routes to success: a systematic review.

INTRODUCTION: Italy (in pilot regions) and Germany (nationwide) were the first European countries to introduce universal varicella vaccination (UVV) programs. AREAS COVERED: A systematic review was performed to assess varicella epidemiology before UVV programs and the impact of 1-dose and 2-dose UVV programs in Italy and Germany. EXPERT OPINION: Italy implemented 1- or 2-dose UVV programs successively in eight pilot regions between 2003 and 2011 and nationwide in 2017. Germany implemented 1- and 2-dose UVV programs in 2004 and 2009, respectively. While Italy had two nationwide surveillance systems in place for varicella in the pre-vaccination era, in Germany, a mandatory notification system for varicella was only introduced in the New Federal States 2 years before the 1-dose UVV implementation. Substantial reductions in moderate/severe varicella and varicella-related hospitalization incidence occurred during the 1-dose era. Further reductions were reported in Italy and Germany after the recommendation of a second dose in a long or short schedule, respectively. Different benefit-risk evaluations of a tetravalent varicella-containing vaccine (MMRV) used as a first dose led to different recommendations (MMRV versus MMR+V) in these countries. Vaccination strategies in both countries tailored to country-specific needs and goals led to a reduction in varicella-related health care hospitalization costs.

[S2k guideline for the diagnosis and therapy of zoster and post-zoster neuralgia]. / S2k-Leitlinie zur Diagnostik und Therapie des Zoster und der Postzosterneuralgie.

This guideline is aimed at registrars and consultants in dermatology, ophthalmology, ENT, pediatrics, neurology, virology as well as infectiology, anaesthesia and generell medicine as well as policymakers and payers and purchasers of care. It was developed by dermatologists, virologists, ophthalmologists, ENT physicians, neurologists, pediatrician and anesthetists using a formal consensus process (S2k).The guideline provides an overview of clinical and molecular diagnostics as well as antigen detection, antibody culture and viral culture. Diagnostic special situations and complicated courses of the disease are also considered. The antiviral therapy of zoster and postzoster neuralgia is presented in general and for special situations. Detailed information on the treatment of pain is mentioned and presented in an overview. Likewise, the local therapeutic measures are discussed.

S2k guidelines for the diagnosis and treatment of herpes zoster and postherpetic neuralgia.

The present guidelines are aimed at residents and board-certified specialists in the fields of dermatology, ophthalmology, ENT, pediatrics, neurology, virology, infectious diseases, anesthesiology, general medicine and any other medical specialties involved in the management of patients with herpes zoster. They are also intended as a guide for policymakers and health insurance funds. The guidelines were developed by dermatologists, virologists, ophthalmologists, ENT physicians, neurologists, pediatricians and anesthesiologists/pain specialists using a formal consensus process (S2k). Readers are provided with an overview of the clinical and molecular diagnostic workup, including antigen detection, antibody tests and viral culture. Special diagnostic situations and complicated disease courses are discussed. The authors address general and special aspects of antiviral therapy for herpes zoster and postherpetic neuralgia. Furthermore, the guidelines provide detailed information on pain management including a schematic overview, and they conclude with a discussion of topical treatment options.

The impact of childhood varicella vaccination on the incidence of herpes zoster in the general population: modelling the effect of exogenous and endogenous varicella-zoster virus immunity boosting.

BACKGROUND: A controversy exists about the potential effect of childhood varicella vaccination on Herpes Zoster (HZ) incidence. Mathematical models projected temporary HZ incidence increase after vaccine introduction that was not confirmed by real-world evidence. These models assume that absence of contacts with infected children would prevent exogenous boosting of Varicella-Zoster-Virus (VZV) immunity and they do not include an endogenous VZV immunity-boosting mechanism following asymptomatic VZV reactivation. This study aims to explore the effect of various assumptions on exogenous and endogenous VZV immunity-boosting on HZ incidence in the general population after introduction of routine childhood varicella vaccination. METHODS: An age-structured dynamic transmission model was adapted and fitted to the seroprevalence of varicella in France in absence of vaccination using the empirical contact matrix. A two-dose childhood varicella vaccination schedule was introduced at 12 and 18 months. Vaccine efficacy was assumed at 65%/95% (dose 1/dose 2), and coverage at 90%/80% (dose 1/dose 2). Exogenous boosting intensity was based on assumptions regarding HZ-immunity duration, age-dependent boosting effect, and HZ reactivation rates fitted to observed HZ incidence. Endogenous boosting was the same as pre-vaccination exogenous boosting but constant over time, whilst exogenous boosting depended on the force of infection. Five scenarios were tested with different weightings of exogenous (Exo) - endogenous (Endo) boosting: 100%Exo-0%Endo, 75%Exo-25%Endo, 50%Exo-50%Endo, 25%Exo-75%Endo, 0%Exo-100%Endo. RESULTS: HZ incidence before varicella vaccination, all ages combined, was estimated at 3.96 per 1000 person-years; it decreased by 64% by year 80 post vaccine introduction, for all boosting assumptions. The 100%Exo-0%Endo boosting scenario, predicted an increase in HZ incidence for the first 21 years post vaccine introduction with a maximum increase of 3.7% (4.1/1000) at year 9. However, with 0%Exo-100%Endo boosting scenario an immediate HZ decline was projected. The maximum HZ incidence increases at 10, 3, and 2 years post vaccination were 1.8% (75%Exo-25%Endo), 0.8% (50%Exo-50%Endo) and 0.2% (25%Exo-75%Endo), respectively. CONCLUSIONS: Assuming modest levels of endogenous boosting, the increase in HZ incidence following childhood varicella vaccination was smaller and lasted for a shorter period compared with 100%Exo-0%Endo boosting assumption. Endogenous boosting mechanism could partly explain the divergence between previous HZ-incidence projections and real-world evidence.

Macaca arctoides gammaherpesvirus 1 (strain herpesvirus Macaca arctoides): virus sequence, phylogeny and characterisation of virus-transformed macaque and rabbit cell lines.

Herpesvirus Macaca arctoides (HVMA) has the propensity to transform macaque lymphocytes to lymphoblastoid cells (MAL-1). Inoculation of rabbits with cell-free virus-containing supernatant resulted in the development of malignant lymphomas and allowed isolation of immortalised HVMA-transformed rabbit lymphocytes (HTRL). In this study, the HVMA genome sequence (approx. 167 kbp), its organisation, and novel aspects of virus latency are presented. Ninety-one open reading frames were identified, of which 86 were non-repetitive. HVMA was identified as a Lymphocryptovirus closely related to Epstein-Barr virus, suggesting the designation as 'Macaca arctoides gammaherpesvirus 1' (MarcGHV-1). In situ lysis gel and Southern blot hybridisation experiments revealed that the MAL-1 cell line contains episomal and linear DNA, whereas episomal DNA is predominantly present in HTRL. Integration of viral DNA into macaque and rabbit host cell genomes was demonstrated by fluorescence in situ hybridisation on chromosomal preparations. Analysis of next-generation sequencing data confirmed this finding. Approximately 400 read pairs represent the overlap between macaque and MarcGHV-1 DNA. Both, MAL-1 cells and HTRL show characteristics of a polyclonal tumour with B- and T-lymphocyte markers. Based on analysis of viral gene expression and immunohistochemistry, the persistence of MarcGHV-1 in MAL-1 cells resemble the latency type III, whereas the expression pattern observed in HTRL was more comparable with latency type II. There was no evidence of the presence of STLV-1 proviral DNA in MAL-1 and HTRL. Due to the similarity to EBV-mediated cell transformation, MarcGHV-1 expands the available in vitro models by simian and rabbit cell lines.

Herpes zoster in the context of varicella vaccination - An equation with several variables.

BACKGROUND: Varicella and herpes zoster (HZ), diseases both caused by the varicella zoster virus (VZV), are vaccine-preventable. However, the hypothesis that childhood varicella vaccination may increase the incidence of HZ hinders varicella universal routine vaccination (URV) implementation in many countries. METHODS: This non-systematic and narrative review of the literature considers the burden of varicella and HZ, and the effectiveness of the respective vaccines. We present the factors involved in the interplay between varicella vaccination and HZ incidence, including the roles of exogenous and endogenous boosting. We review HZ incidence model predictions, and compare these with real-world evidence, which has accumulated since varicella URV was introduced. CONCLUSION: Although more research and longer surveillance are needed, available real-world evidence has not confirmed the model-predicted increase in HZ incidence, associated with childhood varicella URV. Although there is a rising incidence of HZ globally, this trend appears to be predominantly the result of an aging population. Vaccination against varicella in childhood provides significant benefits with respect to the medical, societal and economic burdens of the disease. Therefore, a theoretical concern of an increased burden of HZ with varicella vaccination programs should not prevent children from being protected against the disease.

Varicella vaccination - the global experience.

INTRODUCTION: Varicella, although a frequently benign childhood disease, nevertheless represents a considerable health burden. WHO recommends including varicella vaccines in universal routine vaccination programs, and maintaining coverage >80%. Many countries have successfully introduced varicella vaccination and have benefited from lower disease burden, but many others have not adopted the vaccine. Reasons include cost commitment for a 'mild childhood disease' or concerns that vaccination will shift varicella to older age groups or increase herpes zoster incidence. Areas covered: This literature review summarizes the effectiveness and epidemiological impact of varicella immunization programs. Expert commentary: Varicella vaccines are immunogenic with acceptable safety profiles. One and two dose schedules are highly effective against varicella and large reductions in disease incidence, particularly moderate-severe disease, have been widely reported. There is currently no evidence to suggest that the introduction of varicella vaccination results in a shift of varicella disease burden to older age groups. Although epidemiological studies have shown an increased incidence of herpes zoster since the vaccines were launched, there are many other contributing factors, and indeed, this secular trend was evident before their introduction. In conclusion, varicella vaccination easily fits into existing immunization programs and significantly reduces the often underestimated burden of varicella.

Issues in pediatric vaccine-preventable diseases in low- to middle-income countries.

The highest burden of pediatric vaccine-preventable disease is found in developing nations where resource constraints pose the greatest challenge, impacting disease diagnosis and surveillance as well as the implementation of large scale vaccination programmes. In November 2012, a Working Group Meeting convened in Casablanca to describe and discuss the status with respect to 8 vaccine-preventable diseases (pertussis, pneumococcal disease, measles-mumps-rubella-varicella (MMRV), rotavirus and meningococcal meningitis) to identify and consider ways of overcoming obstacles to pediatric vaccine implementation. Experts from Europe, Russia, the Commonwealth of Independent States, the Middle East, Africa and South East Asia participated in the meeting. A range of region-specific needs and barriers to uptake were discussed. The aim of this article is to provide a summary of the ongoing status with respect to pediatric vaccine preventable disease in the countries represented, and the experts' opinions and recommendations with respect to pediatric vaccine implementation.

Burden of influenza in Germany: a retrospective claims database analysis for the influenza season 2012/2013.

OBJECTIVE: Seasonal influenza occurs in annual epidemics. The virus can cause severe illness and concomitant diseases with the highest risk for children, the elderly, and individuals with disease dispositions. The study objective is to assess the influenza burden in Germany. METHODS: This retrospective claims data analysis used the Health Risk Institute research database containing anonymized data of 4 million individuals. The study period comprised the influenza season 2012/2013 in which patients with documented influenza were identified. Disease frequency rates were calculated for a population with disease dispositions and a population not at high risk. Disease burden was assessed based on health-services utilization during the influenza season. Vaccine rates were calculated by identifying vaccinations. RESULTS: We observed 65,826 patients with influenza, resulting in 1,160,646 documented influenza cases after extrapolation. Overall, otitis media and pneumonia was higher in the influenza-infected population compared to the non-influenza-infected population and especially high in children. Hospitalization cost amounted to €87,202,485 with a mean stay of 7 days, and total outpatient costs were €14,947,976. Vaccination rates were <4 % for children and 37 % for patients aged >60. CONCLUSIONS: Seasonal influenza can cause severe outcomes with hospitalizations and excess costs. Especially influenza-infected children are affected by concomitant diseases with higher disease burden. Furthermore, documented vaccination rates are quite low.

Pyrazolopyrimidines: Potent Inhibitors Targeting the Capsid of Rhino- and Enteroviruses.

There are currently no drugs available for the treatment of enterovirus (EV)-induced acute and chronic diseases such as the common cold, meningitis, encephalitis, pneumonia, and myocarditis with or without consecutive dilated cardiomyopathy. Here, we report the discovery and characterization of pyrazolopyrimidines, a well-tolerated and potent class of novel EV inhibitors. The compounds inhibit the replication of a broad spectrum of EV in vitro with IC50 values between 0.04 and 0.64 µM for viruses resistant to pleconaril, a known capsid-binding inhibitor, without affecting cytochrome P450 enzyme activity. Using virological and genetics methods, the viral capsid was identified as the target of the most promising, orally bioavailable compound 3-(4-trifluoromethylphenyl)amino-6-phenylpyrazolo[3,4-d]pyrimidine-4-amine (OBR-5-340). Its prophylactic as well as therapeutic application was proved for coxsackievirus B3-induced chronic myocarditis in mice. The favorable pharmacokinetic, toxicological, and pharmacodynamics profile in mice renders OBR-5-340 a highly promising drug candidate, and the regulatory nonclinical program is ongoing.

Public health impact and cost-effectiveness of intranasal live attenuated influenza vaccination of children in Germany.

In 2011, intranasally administered live attenuated influenza vaccine (LAIV) was approved in the EU for prophylaxis of seasonal influenza in 2-17-year-old children. Our objective was to estimate the potential epidemiological impact and cost-effectiveness of an LAIV-based extension of the influenza vaccination programme to healthy children in Germany. An age-structured dynamic model of influenza transmission was developed and combined with a decision-tree to evaluate different vaccination strategies in the German health care system. Model inputs were based on published literature or were derived by expert consulting using the Delphi technique. Unit costs were drawn from German sources. Under base-case assumptions, annual routine vaccination of children aged 2-17 years with LAIV assuming an uptake of 50% would prevent, across all ages, 16 million cases of symptomatic influenza, over 600,000 cases of acute otitis media, nearly 130,000 cases of community-acquired pneumonia, nearly 1.7 million prescriptions of antibiotics and over 165,000 hospitalisations over 10 years. The discounted incremental cost-effectiveness ratio was 1,228 per quality-adjusted life year gained from a broad third-party payer perspective (including reimbursed direct costs and specific transfer payments), when compared with the current strategy of vaccinating primarily risk groups with the conventional trivalent inactivated vaccine. Inclusion of patient co-payments and indirect costs in terms of productivity losses resulted in discounted 10-year cost savings of 3.4 billion. In conclusion, adopting universal influenza immunisation of healthy children and adolescents would lead to a substantial reduction in influenza-associated disease at a reasonable cost to the German statutory health insurance system. On the basis of the epidemiological and health economic simulation results, a recommendation of introducing annual routine influenza vaccination of children 2-17 years of age might be taken into consideration.

Hemagglutinin 222D/G polymorphism facilitates fast intra-host evolution of pandemic (H1N1) 2009 influenza A viruses.

The amino acid substitution of aspartic acid to glycine in hemagglutinin (HA) in position 222 (HA-D222G) as well as HA-222D/G polymorphism of pandemic (H1N1) 2009 influenza viruses (A(H1N1)pdm09) were frequently reported in severe influenza in humans and mice. Their impact on viral pathogenicity and the course of influenza has been discussed controversially and the underlying mechanism remained unclarified. In the present study, BALB/c mice, infected with the once mouse lung- and cell-passaged A(H1N1)pdm09 isolate A/Jena/5258/09 (mpJena/5258), developed severe pneumonia. From day 2 to 3 or 4 post infection (p.i.) symptoms (body weight loss and clinical score) continuously worsened. After a short disease stagnation or even recovery phase in most mice, severity of disease further increased on days 6 and 7 p.i. Thereafter, surviving mice recovered. A 45 times higher virus titer maximum in the lung than in the trachea on day 2 p.i. and significantly higher tracheal virus titers compared to lung on day 6 p.i. indicated changes in the organ tropism during infection. Sequence analysis revealed an HA-222D/G polymorphism. HA-D222 and HA-G222 variants co-circulated in lung and trachea. Whereas, HA-D222 variant predominated in the lung, HA-G222 became the major variant in the trachea after day 4 p.i. This was accompanied by lower neutralizing antibody titers and broader receptor recognition including terminal sialic acid α-2,3-linked galactose, which is abundant on mouse trachea epithelial cells. Plaque-purified HA-G222-mpJena/5258 virus induced severe influenza with maximum symptom on day 6 p.i. These results demonstrated for the first time that HA-222D/G quasispecies of A(H1N1)pdm09 caused severe biphasic influenza because of fast viral intra-host evolution, which enabled partial antibody escape and minor changes in receptor binding.

Seroprevalence of hepatitis E virus (HEV) in humans living in high pig density areas of Germany.

An increase in acute autochthonous hepatitis E virus (HEV) infections has been recorded in Germany. These are suspected to be zoonotically transmitted from wild boar, deer and domestic pig. The latter may represent a major reservoir for HEV. In this study, 537 sera from humans living in Westphalia and Lower Saxony, representing areas of high pig density in Germany, were tested for the presence of HEV-specific antibodies. Among them were 302 individuals with occupational, direct contact to pigs and 235 individuals without direct contact to pigs. Two commercial tests and one in-house assay were applied for the detection of HEV-specific immunoglobulin G (IgG) antibodies. Sera were also tested in an assay that detects all classes of HEV-specific antibodies. Depending on the test used, the seroprevalence ranged from 4.1 to 27.9 %. Exposition to pigs was found to be associated with a significantly higher seroprevalence in subjects with contact to pigs (13.2-32.8 %) compared with that in non-exposed humans (7.7-21.7 %). In particular, individuals younger than 40 years with occupational exposure exhibited a markedly higher HEV seroprevalence compared with non-exposed individuals of that age group. In general, HEV seroprevalence increased with age resulting in a similar prevalence level in the age group of ≥ 50 years for exposed and non-exposed individuals. Analysis of all sera by a commercial anti-HEV IgM ELISA revealed 35 positive and 25 borderline samples. However, only one positive serum could be confirmed by an IgM line assay. Selected samples from IgM and/or IgG as well as total HEV antibody-positive individuals were also tested for the presence of HEV RNA. In one of the 78 samples, the only IgM ELISA positive and IgM line assay confirmed sample, RNA of HEV genotype 3 was detected. This sequence has high similarity to HEV sequences obtained from wild boars and domestic pigs from Germany and The Netherlands. This study demonstrates that in addition to the consumption of raw or undercooked meat, direct contact to pigs has to be considered as an additional risk factor for HEV infection.