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Flow cytometry of blood samples is a very valuable clinical and research tool to monitor the immune response in human patients. Furthermore, it has been successfully applied in cats, such as for infections with feline immune deficiency virus (FIV). However, if cells are not isolated and frozen, analysis of anticoagulated blood samples requires mostly prompt processing following blood collection, making later analysis of stored full blood samples obtained in clinical studies often impossible. The SMART Tube system (SMART TUBE Inc., California, United States; SMT) allows fixation and long-term preservation of whole blood samples at -80°C. However, this system has so far only been applied to human biological samples. In the present study, a new flow cytometry SMART Tube protocol adapted for feline whole blood samples was successfully established allowing quantification of T-helper cells, cytotoxic T-cells, B-cells, monocytes, and neutrophils up to 2 years post sampling. Results obtained from frozen stabilized and fresh blood samples were compared for validation purposes and correlated to differential blood counts from a conventional hematology analyzer. Clinical applicability of the new technique was verified by using samples from a treatment study for feline infectious peritonitis (FIP). Using the new SMT protocol on retained samples, it could be demonstrated that long-term storage of these SMT tubes is also possible. In summary, the newly adapted SMT protocol proved suitable for performing flow cytometry analysis on stored feline whole blood samples, thus opening up new avenues for veterinary research on a variety of aspects of clinical interest.
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In the past, feline infectious peritonitis (FIP) caused by feline coronavirus (FCoV) was considered fatal. Today, highly efficient drugs, such as GS-441524, can lead to complete remission. The currently recommended treatment duration in the veterinary literature is 84 days. This prospective randomized controlled treatment study aimed to evaluate whether a shorter treatment duration of 42 days with oral GS-441524 obtained from a licensed pharmacy is equally effective compared to the 84-day regimen. Forty cats with FIP with effusion were prospectively included and randomized to receive 15 mg/kg of GS-441524 orally every 24h (q24h), for either 42 or 84 days. Cats were followed for 168 days after treatment initiation. With the exception of two cats that died during the treatment, 38 cats (19 in short, 19 in long treatment group) recovered with rapid improvement of clinical and laboratory parameters as well as a remarkable reduction in viral loads in blood and effusion. Orally administered GS-441524 given as a short treatment was highly effective in curing FIP without causing serious adverse effects. All cats that completed the short treatment course successfully were still in complete remission on day 168. Therefore, a shorter treatment duration of 42 days GS-441524 15 mg/kg can be considered equally effective.
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Antivirais , Coronavirus Felino , Peritonite Infecciosa Felina , Carga Viral , Animais , Gatos , Peritonite Infecciosa Felina/tratamento farmacológico , Peritonite Infecciosa Felina/virologia , Estudos Prospectivos , Coronavirus Felino/efeitos dos fármacos , Feminino , Administração Oral , Masculino , Antivirais/administração & dosagem , Antivirais/uso terapêutico , Carga Viral/efeitos dos fármacos , Resultado do Tratamento , Adenosina/análogos & derivadosRESUMO
A subset of patients with post-COVID-19 condition (PCC) fulfill the clinical criteria of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). To establish the diagnosis of ME/CFS for clinical and research purposes, comprehensive scores have to be evaluated. We developed the Munich Berlin Symptom Questionnaires (MBSQs) and supplementary scoring sheets (SSSs) to allow for a rapid evaluation of common ME/CFS case definitions. The MBSQs were applied to young patients with chronic fatigue and post-exertional malaise (PEM) who presented to the MRI Chronic Fatigue Center for Young People (MCFC). Trials were retrospectively registered (NCT05778006, NCT05638724). Using the MBSQs and SSSs, we report on ten patients aged 11 to 25 years diagnosed with ME/CFS after asymptomatic SARS-CoV-2 infection or mild to moderate COVID-19. Results from their MBSQs and from well-established patient-reported outcome measures indicated severe impairments of daily activities and health-related quality of life. Conclusions: ME/CFS can follow SARS-CoV-2 infection in patients younger than 18 years, rendering structured diagnostic approaches most relevant for pediatric PCC clinics. The MBSQs and SSSs represent novel diagnostic tools that can facilitate the diagnosis of ME/CFS in children, adolescents, and adults with PCC and other post-infection or post-vaccination syndromes. What is Known: ⢠ME/CFS is a debilitating disease with increasing prevalence due to COVID-19. For diagnosis, a differential diagnostic workup is required, including the evaluation of clinical ME/CFS criteria. ⢠ME/CFS after COVID-19 has been reported in adults but not in pediatric patients younger than 19 years. What is New: ⢠We present the novel Munich Berlin Symptom Questionnaires (MBSQs) as diagnostic tools to assess common ME/CFS case definitions in pediatric and adult patients with post-COVID-19 condition and beyond. ⢠Using the MBSQs, we diagnosed ten patients aged 11 to 25 years with ME/CFS after asymptomatic SARS-CoV-2 infection or mild to moderate COVID-19.
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COVID-19 , Síndrome de Fadiga Crônica , Adolescente , Adulto , Criança , Humanos , Adulto Jovem , COVID-19/diagnóstico , Teste para COVID-19 , Síndrome de Fadiga Crônica/diagnóstico , Síndrome de Fadiga Crônica/etiologia , Síndrome de Fadiga Crônica/epidemiologia , Qualidade de Vida , SARS-CoV-2 , Inquéritos e QuestionáriosRESUMO
OBJECTIVES: Feline infectious peritonitis (FIP), a common disease in cats caused by feline coronavirus (FCoV), is usually fatal once clinical signs appear. Successful treatment of FIP with oral GS-441524 for 84 days was demonstrated recently by this research group. The aim of this study was to evaluate the long-term outcome in these cats. METHODS: A total of 18 successfully treated cats were followed for up to 1 year after treatment initiation (9 months after completion of the antiviral treatment). Follow-up examinations were performed at 12-week intervals, including physical examination, haematology, serum biochemistry, abdominal and thoracic ultrasound, FCoV ribonucleic acid (RNA) loads in blood and faeces by reverse transciptase-quantitative PCR and anti-FCoV antibody titres by indirect immunofluorescence assay. RESULTS: Follow-up data were available from 18 cats in week 24, from 15 cats in week 36 and from 14 cats in week 48 (after the start of treatment), respectively. Laboratory parameters remained stable after the end of the treatment, with undetectable blood viral loads (in all but one cat on one occasion). Recurrence of faecal FCoV shedding was detected in five cats. In four cats, an intermediate short-term rise in anti-FCoV antibody titres was detected. In total, 12 cats showed abdominal lymphadenomegaly during the follow-up period; four of them continuously during the treatment and follow-up period. Two cats developed mild neurological signs, compatible with feline hyperaesthesia syndrome, in weeks 36 and 48, respectively; however, FCoV RNA remained undetectable in blood and faeces, and no increase in anti-FCoV antibody titres was observed in these two cats, and the signs resolved. CONCLUSIONS AND RELEVANCE: Treatment with GS-441524 proved to be effective against FIP in both the short term as well as the long term, with no confirmed relapse during the 1-year follow-up period. Whether delayed neurological signs could be a long-term adverse effect of the treatment or associated with a 'long FIP syndrome' needs to be further evaluated.
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Doenças do Gato , Coronavirus Felino , Peritonite Infecciosa Felina , Gatos , Animais , Peritonite Infecciosa Felina/diagnóstico , Seguimentos , Reação em Cadeia da Polimerase/veterinária , RNA Viral/análise , Coronavirus Felino/genética , Doenças do Gato/tratamento farmacológicoRESUMO
[This corrects the article DOI: 10.2196/41010.].
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BACKGROUND: Acute gastroenteritis (AGE) is a major medical condition for travellers worldwide, particularly travellers to low- and middle-income countries. Norovirus (NoV) is the most common cause of viral AGE in older children and adults, but data on prevalence and impact among travellers is limited. METHODS: Prospective, multi-site, observational cohort study conducted 2015-2017, among adult international travellers from the US and Europe to areas of moderate to high risk of travel-acquired AGE. Participants provided self-collected pre-travel stool samples and self-reported AGE symptoms while travelling. Post-travel stool samples were requested from symptomatic subjects and a sample of asymptomatic travellers within 14days of return. Samples were tested for NoV by RT-qPCR, genotyped if positive, and tested for other common enteric pathogens by Luminex xTAG GPP. RESULTS: Of the 1109 participants included, 437 (39.4%) developed AGE symptoms resulting in an overall AGE incidence of 24.7 per 100 person-weeks (95% CI: 22.4; 27.1). Twenty NoV-positive AGE cases (5.2% of those tested) were identified at an incidence of 1.1 per 100 person-weeks (95% CI: 0.7; 1.7). NoV-positive samples belonged mostly to genogroup GII (18, 85.7%); None of the 13 samples sequenced belonged to genotype GII.4. Clinical severity of AGE was higher for NoV-positive than for NoV-negative cases (mean modified Vesikari Score 6.8 vs 4.9) with more cases classified as severe or moderate (25% vs 6.8%). Eighty percent of NoV-positive participants (vs. 38.9% in NoV-negative) reported at least moderate impact on travel plans. CONCLUSIONS: AGE is a prevalent disease among travellers with a small proportion associated with NoV. Post-travel stool sample collection timing might have influenced the low number of NoV cases detected; however, NoV infections resulted in high clinical severity and impact on travel plans. These results may contribute to targeted vaccine development and the design of future studies on NoV epidemiology.
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BACKGROUND: Some children and adolescents suffer from late effects of a SARS-CoV-2 infection despite a frequently mild course of the disease. Nevertheless, extensive care for post-COVID-19 condition, also known as post-COVID-19 syndrome, in children and young people is not yet available. A comprehensive care network, Post-COVID Kids Bavaria (PoCo), for children and adolescents with post-COVID-19 condition has been set up as a model project in Bavaria, Germany. OBJECTIVE: The aim of this study is to evaluate the health care services provided within this network structure of care for children and adolescents with post-COVID-19 condition in a pre-post study design. METHODS: We have already recruited 117 children and adolescents aged up to 17 years with post-COVID-19 condition who were diagnosed and treated in 16 participating outpatient clinics. Health care use, treatment satisfaction, patient-reported outcomes related to health-related quality of life (the primary endpoint), fatigue, postexertional malaise, and mental health are being assessed at different time points (at baseline and after 4 weeks, 3 months, and 6 months) using routine data, interviews, and self-report questionnaires. RESULTS: The study recruitment process ran from April 2022 until December 2022. Interim analyses will be carried out. A full analysis of the data will be conducted after follow-up assessment is completed, and the results will be published. CONCLUSIONS: The results will contribute to the evaluation of therapeutic services provided for post-COVID-19 condition in children and adolescents, and avenues for optimizing care may be identified. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/41010.
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International travels with children need special planning and preparation. Besides considering general aspects, such as the age of the child, physical fitness, pre-existing illnesses, type and extent of the journey, climatic conditions at the destination and previous travel experiences, it is important to discuss relevant travel-associated risks in the context of travel consulting. This includes extensive advice concerning mosquito protection and malaria prophylaxis and counselling and implementation of travel vaccinations. Depending on the situation of the family, an individualized travel concept can be prepared, creating the foundation for a possible problem-free international travel.
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This is the first report on a clinical follow-up and postmortem examination of a cat that had been cured of feline infectious peritonitis (FIP) with ocular manifestation by successful treatment with an oral multicomponent drug containing GS-441524. The cat was 6 months old when clinical signs (recurrent fever, lethargy, lack of appetite, and fulminant anterior uveitis) appeared. FIP was diagnosed by ocular tissue immunohistochemistry after enucleation of the affected eye. The cat was a participant in a FIP treatment study, which was published recently. However, 240 days after leaving the clinic healthy, and 164 days after the end of the 84 days of treatment, the cured cat died in a road traffic accident. Upon full postmortem examination, including histopathology and immunohistochemistry, there were no residual FIP lesions observed apart from a generalized lymphadenopathy due to massive lymphoid hyperplasia. Neither feline coronavirus (FCoV) RNA nor FCoV antigen were identified by quantitative reverse transcription polymerase chain reaction (RT-qPCR) and immunohistochemistry, respectively, in any tissues or body fluids, including feces. These results prove that oral treatment with GS-441524 leads to the cure of FIP-associated changes and the elimination of FCoV from all tissues.
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Coronavirus Felino , Peritonite Infecciosa Felina , Adenosina/análogos & derivados , Animais , Antivirais/uso terapêutico , Autopsia , Gatos , Coronavirus Felino/genética , Seguimentos , Humanos , RNARESUMO
As previously demonstrated by our research group, the oral multicomponent drug Xraphconn® containing GS-441524 was effective at curing otherwise fatal feline infectious peritonitis (FIP) in 18 feline coronavirus (FCoV)-infected cats. The aims of the current study were to investigate, using samples from the same animals as in the previous study, (1) the effect of treatment on fecal viral RNA shedding; (2) the presence of spike gene mutations in different body compartments of these cats; and (3) viral RNA shedding, presence of spike gene mutations, and anti-FCoV antibody titers in samples of 12 companion cats cohabitating with the treated cats. Eleven of the eighteen treated FIP cats (61%) were shedding FCoV RNA in feces within the first three days after treatment initiation, but all of them tested negative by day 6. In one of these cats, fecal shedding reoccurred on day 83. Two cats initially negative in feces were transiently positive 1-4 weeks into the study. The remaining five cats never shed FCoV. Viral RNA loads in feces decreased with time comparable with those in blood and effusion. Specific spike gene mutations linked to systemic FCoV spread were consistently found in blood and effusion from treated FIP cats, but not in feces from treated or companion cats. A new mutation that led to a not yet described amino acid change was identified, indicating that further mutations may be involved in the development of FIP. Eight of the twelve companion cats shed FCoV in feces. All but one of the twelve companion cats had anti-FCoV antibodies. Oral treatment with GS-441524 effectively decreased viral RNA loads in feces, blood, and effusion in cats with FIP. Nonetheless, re-shedding can most likely occur if cats are re-exposed to FCoV by their companion cats.
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Coronavirus Felino , Peritonite Infecciosa Felina , Adenosina/análogos & derivados , Animais , Gatos , Coronavirus Felino/genética , Fezes , Peritonite Infecciosa Felina/tratamento farmacológico , Furanos , Mutação , RNA Viral/genéticaRESUMO
This current consensus paper for long COVID complements the existing AWMF S1 guidelines for long COVID with a detailed overview on the various clinical aspects of long COVID in children and adolescents. Members of 19 different pediatric societies of the DGKJ convent and collaborating societies together provide expert-based recommendations for the clinical management of long COVID based on the currently available but limited academic evidence for long COVID in children and adolescents. It contains screening questions for long COVID and suggestions for a structured, standardized pediatric medical history and diagnostic evaluation for patients with suspected long COVID. A time and resource-saving questionnaire, which takes the clinical complexity of long COVID into account, is offered via the DGKJ and DGPI websites as well as additional questionnaires suggested for an advanced screening of specific neurocognitive and/or psychiatric symptoms including post-exertional malaise (PEM) and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). According to the individual medical history as well as clinical signs and symptoms a step by step diagnostic procedure and a multidisciplinary therapeutic approach are recommended.
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Feline infectious peritonitis (FIP) caused by feline coronavirus (FCoV) is a common dis-ease in cats, fatal if untreated, and no effective treatment is currently legally available. The aim of this study was to evaluate efficacy and toxicity of the multi-component drug Xraphconn® in vitro and as oral treatment in cats with spontaneous FIP by examining survival rate, development of clinical and laboratory parameters, viral loads, anti-FCoV antibodies, and adverse effects. Mass spectrometry and nuclear magnetic resonance identified GS-441524 as an active component of Xraphconn®. Eighteen cats with FIP were prospectively followed up while being treated orally for 84 days. Values of key parameters on each examination day were compared to values before treatment initiation using linear mixed-effect models. Xraphconn® displayed high virucidal activity in cell culture. All cats recovered with dramatic improvement of clinical and laboratory parameters and massive reduction in viral loads within the first few days of treatment without serious adverse effects. Oral treatment with Xraphconn® containing GS-441524 was highly effective for FIP without causing serious adverse effects. This drug is an excellent option for the oral treatment of FIP and should be trialed as potential effective treatment option for other severe coronavirus-associated diseases across species.
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Adenosina/análogos & derivados , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/veterinária , Coronavirus Felino/efeitos dos fármacos , Peritonite Infecciosa Felina/tratamento farmacológico , Peritonite Infecciosa Felina/virologia , Adenosina/farmacologia , Animais , Anticorpos Antivirais , Antivirais/farmacologia , Gatos , Linhagem Celular , Infecções por Coronavirus/virologia , Coronavirus Felino/genética , Feminino , Seguimentos , Masculino , Estudos Prospectivos , RNA Viral , Taxa de Sobrevida , Carga ViralAssuntos
COVID-19 , Doenças do Gato , Síndrome de Resposta Inflamatória Sistêmica , Animais , Gatos , Criança , Humanos , Pandemias , SARS-CoV-2 , SíndromeRESUMO
BACKGROUND: Intravenous artesunate (ivA) is the standard treatment for severe malaria. Data systematically evaluating the use of ivA in pediatric patients outside malaria-endemic regions are limited. The aim of this case series was to summarize efficacy and safety of ivA for imported severe malaria in children in Germany. METHODS: Our retrospective case series included pediatric patients with imported severe malaria treated with at least 1 dose of ivA (Artesun, Guilin Pharmaceutical; Shanghai, China) at 4 German tertiary care centers. Severe malaria was defined according to World Health Organization criteria. RESULTS: Between 2010 and 2018, 14 children with a median [interquartile range (IQR)] age of 6 (1;9.5) years were included. All children were of African descent. All but 2 patients had Plasmodium falciparum malaria; 1 child had P. vivax malaria and 1 child had P. falciparum and P. vivax co-infection. Median (IQR) parasitemia at admission in patients with P. falciparum was 9.5% (3;16.5). Patients were treated with 1-10 [median (IQR) 3 (3;4)] doses ivA. All but one patient received a full course of oral antimalarial treatment. Parasite clearance was achieved within 2-4 days, with the exception of 1 patient with prolonged clearance of peripheral parasitemia. Three patients experienced posttreatment hemolysis but none needed blood transfusion. Otherwise ivA was safe and well tolerated. CONCLUSIONS: ivA was highly efficacious in this pediatric cohort. We observed episodes of mild to moderate posttreatment hemolysis in approximately one-third of patients. The legal status and usage of potentially lifesaving ivA should be evaluated in Europe.
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Antimaláricos/uso terapêutico , Artesunato/uso terapêutico , Malária Falciparum/tratamento farmacológico , Malária Vivax/tratamento farmacológico , Doença Aguda/terapia , Administração Intravenosa , Adolescente , Antimaláricos/administração & dosagem , Artesunato/administração & dosagem , Criança , Pré-Escolar , Doenças Transmissíveis Importadas/tratamento farmacológico , Doenças Transmissíveis Importadas/parasitologia , Feminino , Alemanha , Humanos , Lactente , Masculino , Parasitemia/tratamento farmacológico , Estudos Retrospectivos , Centros de Atenção TerciáriaRESUMO
BACKGROUND: Acute gastroenteritis (AGE) is the leading cause of illness among returning travelers seeking medical care. Multiple types of enteric pathogens can cause travel-acquired AGE and, while bacterial pathogens have a predominant role, the importance of viruses, such as norovirus, is increasingly recognized. There is a lack of information on travel-acquired norovirus incidence among symptomatic and asymptomatic individuals irrespective of healthcare-seeking behavior. Our aim is to estimate the incidence of travel-acquired AGE due to norovirus and to characterize the burden of disease among international travelers from the United States and Europe. METHODS: We describe a prospective cohort study implemented in five US and European sites to estimate the role of AGE due to norovirus among adult international travelers. We enrolled individuals aged 18 years and older who are traveling to regions of moderate-high risk of AGE, or via cruise ship with an international port stop, with a trip duration of 3-15 days. The study will generate a wide range of health and travel-related data for pre-, during, and up to 6-months post-travel. We will identify laboratory-confirmed travel-acquired norovirus infections among both symptomatic and asymptomatic individuals from self-collected whole stool samples tested via quantitative RT-PCR. Coinfections will be identified in a subset of travelers with AGE using a multiplex molecular-based assay. DISCUSSION: This study is unique in design and breadth of data collected. The prospective collection of health and behavioral data, as well as biologic samples from travelers irrespective of symptoms, will provide useful data to better understand the importance of norovirus AGE among international travelers. This study will provide data to estimate the incidence of norovirus infections and AGE and the risk of post-infectious sequelae in the 6-month post-travel period serving as a baseline for future norovirus AGE vaccination studies. This study will contribute valuable information to better understand the role of norovirus in travel-acquired AGE risk and the impact of these infections on a broad set of outcomes.
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Infecções por Caliciviridae/epidemiologia , Diarreia/epidemiologia , Gastroenterite/epidemiologia , Norovirus , Doença Relacionada a Viagens , Viagem/estatística & dados numéricos , Doença Aguda , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Diarreia/virologia , Disenteria/epidemiologia , Disenteria/virologia , Europa (Continente)/epidemiologia , Feminino , Humanos , Incidência , Internacionalidade , Masculino , Pessoa de Meia-Idade , Norovirus/isolamento & purificação , Fatores de Risco , Estados Unidos/epidemiologia , Adulto JovemRESUMO
BACKGROUND: This study aimed to investigate the morbidity profile and the sociodemographic characteristics of unaccompanied refugee minors (URM) arriving in the region of Bavaria, Germany, between October 2014 and February 2016. METHODS: The retrospective cross sectional study included 154 unaccompanied refugee minors between 10 and 18 years of age. The data was derived from medical data records of their routine first medical examination in two paediatric practices and one collective housing for refugees in the region of Bavaria, Germany. RESULTS: Only 12.3% of all participants had no clinical finding at arrival. Main health findings were skin diseases (31.8%) and mental disorders (25%). In this cohort the hepatitis A immunity was 92.8%, but only 34.5% showed a constellation of immunity against hepatitis B. Suspect cases for tuberculosis were found in 5.8% of the URM. There were no HIV positive individuals in the cohort. Notably, 2 females were found to have undergone genital mutilations. CONCLUSIONS: The majority of arriving URM appear to have immediate health care needs, whereas the pathologies involved are mostly common entities that are generally known to the primary health care system in Germany. Outbreaks due to hepatitis A virus are unlikely since herd immunity can be assumed, while this population would benefit from hepatitis B vaccination due to low immunity and high risk of infection in crowded housing conditions. One key finding is the absence of common algorithms and guidelines in health care provision to URM.
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Serviços de Saúde da Criança/estatística & dados numéricos , Menores de Idade/estatística & dados numéricos , Refugiados/estatística & dados numéricos , Adolescente , Criança , Estudos Transversais , Demografia , Feminino , Alemanha/epidemiologia , Humanos , Masculino , Programas de Rastreamento , Transtornos Mentais/epidemiologia , Morbidade , Estudos Retrospectivos , Tuberculose/epidemiologiaRESUMO
PURPOSE: In 2016, the number of refugees worldwide reached 65.6 million. So far, only limited data are available on the health status of refugees and asylum seekers (RAs). Especially, notifiable infectious diseases (NIDs) carry the risk of outbreaks in communal accommodations hosting RAs. METHODS: We conducted a monocentric retrolective cross-sectional study including 15,137 RAs treated in a special health care unit for RAs located in the major reception center in Munich from November 2014 to October 2016. Altogether 811 RAs with NIDs according to sections 6 and 7 of the German Infection Protection Act or with other infections relevant in the setting of a communal accommodation (RIDs) could be identified. RESULTS: The gender and age distribution was generally comparable to that of refugees in Germany. However, patients from East Africa and Nigeria were significantly overrepresented. NIDs/RIDs were dominated by cases of tuberculosis, hepatitis B, and vaccine-preventable and parasitic diseases. Significant risk factors included country of origin (COI) and age for hepatitis B, age for hepatitis C, gender and age for HIV, and COI, gender and age for tuberculosis and ectoparasitosis. Calculated prevalences of hepatitis B, hepatitis C, and HIV were mostly below those of the COI. Incidences of tuberculosis were mostly strongly elevated. CONCLUSIONS: COI, gender, and age have an impact on the occurrence of NIDs/RIDs. Early vaccinations and improved hygiene could be effective in preventing NIDs/RIDs in communal accommodations. Screening, prompt therapy, and infection protection measures are necessary to prevent the transmission of diseases.
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Doenças Transmissíveis/epidemiologia , Notificação de Doenças/estatística & dados numéricos , Refugiados/estatística & dados numéricos , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Estudos Transversais , Feminino , Alemanha/epidemiologia , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Prevalência , Estudos Retrospectivos , Fatores de Risco , Adulto JovemRESUMO
BACKGROUND: Vaccines based on mRNA coding for antigens have been shown to be safe and immunogenic in preclinical models. We aimed to report results of the first-in-human proof-of-concept clinical trial in healthy adults of a prophylactic mRNA-based vaccine encoding rabies virus glycoprotein (CV7201). METHODS: We did an open-label, uncontrolled, prospective, phase 1 clinical trial at one centre in Munich, Germany. Healthy male and female volunteers (aged 18-40 years) with no history of rabies vaccination were sequentially enrolled. They received three doses of CV7201 intradermally or intramuscularly by needle-syringe or one of three needle-free devices. Escalating doses were given to subsequent cohorts, and one cohort received a booster dose after 1 year. The primary endpoint was safety and tolerability. The secondary endpoint was to determine the lowest dose of CV7201 to elicit rabies virus neutralising titres equal to or greater than the WHO-specified protective antibody titre of 0·5 IU/mL. The study is continuing for long-term safety and immunogenicity follow-up. This trial is registered with ClinicalTrials.gov, number NCT02241135. FINDINGS: Between Oct 21, 2013, and Jan 11, 2016, we enrolled and vaccinated 101 participants with 306 doses of mRNA (80-640 µg) by needle-syringe (18 intradermally and 24 intramuscularly) or needle-free devices (46 intradermally and 13 intramuscularly). In the 7 days post vaccination, 60 (94%) of 64 intradermally vaccinated participants and 36 (97%) of 37 intramuscularly vaccinated participants reported solicited injection site reactions, and 50 (78%) of 64 intradermally vaccinated participants and 29 (78%) of 37 intramuscularly vaccinated participants reported solicited systemic adverse events, including ten grade 3 events. One unexpected, possibly related, serious adverse reaction that occurred 7 days after a 640 µg intramuscular dose resolved without sequelae. mRNA vaccination by needle-free intradermal or intramuscular device injection induced virus neutralising antibody titres of 0·5 IU/mL or more across dose levels and schedules in 32 (71%) of 45 participants given 80 µg or 160 µg CV7201 doses intradermally and six (46%) of 13 participants given 200 µg or 400 µg CV7201 doses intramuscularly. 1 year later, eight (57%) of 14 participants boosted with an 80 µg needle-free intradermal dose of CV7201 achieved titres of 0·5 IU/mL or more. Conversely, intradermal or intramuscular needle-syringe injection was ineffective, with only one participant (who received 320 µg intradermally) showing a detectable immune response. INTERPRETATION: This first-ever demonstration in human beings shows that a prophylactic mRNA-based candidate vaccine can induce boostable functional antibodies against a viral antigen when administered with a needle-free device, although not when injected by a needle-syringe. The vaccine was generally safe with a reasonable tolerability profile. FUNDING: CureVac AG.
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Imunogenicidade da Vacina , RNA Mensageiro/imunologia , Vacina Antirrábica/administração & dosagem , Raiva/prevenção & controle , Adolescente , Adulto , Anticorpos Neutralizantes/sangue , Anticorpos Antivirais/sangue , Método Duplo-Cego , Vias de Administração de Medicamentos , Esquema de Medicação , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Feminino , Alemanha , Humanos , Masculino , Estudos Prospectivos , Vacina Antirrábica/imunologia , Adulto JovemRESUMO
[This corrects the article DOI: 10.1155/2017/3472537.].