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.
Since its first identification in Scotland, over 1000 cases of unexplained pediatric hepatitis in children have been reported worldwide, including 278 cases in the UK 1 . Here we report investigation of 38 cases, 66 age-matched immunocompetent controls and 21 immunocompromised comparator subjects, using a combination of genomic, transcriptomic, proteomic and immunohistochemical methods. We detected high levels of adeno-associated virus 2 (AAV2) DNA in liver, blood, plasma or stool from 27/28 cases. We found low levels of Adenovirus (HAdV) and Human Herpesvirus 6B (HHV-6B), in 23/31 and 16/23 respectively of the cases tested. In contrast, AAV2 was infrequently detected at low titre in blood or liver from control children with HAdV, even when profoundly immunosuppressed.AAV2, HAdV and HHV-6 phylogeny excluded emergence of novel strains in cases. Histological analyses of explanted livers showed enrichment for T-cells and B-lineage cells.Proteomic comparison of liver tissue from cases and healthy controls, identified increased expression of HLA class 2, immunoglobulin variable regions and complement proteins.HAdV and AAV2 proteins were not detected in the livers. Instead, we identified AAV2 DNA complexes reflecting both HAdV and HHV-6B-mediated replication. We hypothesize that high levels of abnormal AAV2 replication products aided by HAdV and in severe cases HHV-6B, may have triggered immune-mediated hepatic disease in genetically and immunologically predisposed children.
C hildren have been disproportionately affected by public health measures in the current coronavirus disease (COVID-19) pandemic (1). In contrast to other age groups, children have shown lower rates of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-positive cases; lower risk for symptomatic, acute, COVID-19; a generally milder course of disease with the exception of some rare manifestations and the post-COVID-19 multisystem infl ammatory syndrome in children; and lower secondary attack rates (2-4). Susceptibility to infection in <10 years of age is estimated to be lower than that for teenagers. Accumulating evidence shows that, given limited infection control measures, SARS-CoV-2 might spread sustainably in secondary/high schools but to a lesser degree in primary schools and nurseries (2,5).Closure of childcare facilities and schools has been shown to negatively affect the physical and emotional well-being of children, teenagers, and parents, potentially having a long-term impact on their lives (6). Thus, various expert groups called for avoiding closing of these institutions (7,8). Against the background of presymptomatic transmission found in adults, it is critical to public health authorities to be able to rely on real-life data monitoring the number of asymptomatic yet infected children attending educational institutions (9). Some studies have reported low numbers of infected cases in primary schools or childcare facilities but were conducted during a lockdown or semi-lockdown period (5,10). The aim of our study (the Münchner Virenwächter Study) was to implement a real-time sentinel program in a representative number of 5 primary schools and 5 (6 in phase 2) nurseries/kindergartens in Munich, Germany. The StudyThis study was approved by the ethics committee of the Ludwig-Maximilians University under project no. 20-484. We intended to accomplish a timely detection of infected cases and offer an additional level of safety to participating institutions during regular operating mode. The study spanned over 2 phases (Figure 1): phase 1, June 15-July 26, 2020; and phase 2, September 7-November 1, 2020. Participating institutions were randomly selected, and written informed consent was obtained in the fi rst week of each phase. To correct for underrepresentation of younger children (<5 years of age), we included an additional nursery/ kindergarten into phase 2.We tested oropharyngeal swab specimens for SARS-CoV-2 by using real-time reverse transcription PCR (rRT-PCR); weekly samples were obtained from randomly selected children (n = 20) and staff (n = 5) in each institution. Swab specimens were taken on-site by trained medical personnel, and results were timely reported. For rRT-PCR, we processed specimens
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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