A comprehensive characterization of chronic norovirus infection in immunodeficient hosts

Brown, Li-An K; Ruis, Christopher; Clark, Ian A.; Roy, Sunando; Brown, Julianne R.; Albuquerque, Adriana S.; Patel, Smita Y.; Miller, Joanne; Karim, Mohammed Yousuf; Dervisevic, Samir; Moore, Jennifer; Williams, Charlotte A.; Cudini, Juliana; Moreira, Fernando; Neild, P; Seneviratne, Suranjith L.; Workman, Sarita; Toumpanakis, Christos; Atkinson, Claire; Burns, Siobhan O.; Breuer, Judith; Lowe, David M.

doi:10.1016/j.jaci.2019.07.036

Cited by 24 publications

(25 citation statements)

References 9 publications

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“…Woodward et al (12) suggested norovirus to be causative of the coeliac-like enteropathy observed in CVID. Our study does not look at histology, but all our patients with norovirus infection had villous atrophy on thorough assessment (40). We have recently described our patients with norovirus infection in detail (40).…”

Section: Discussionmentioning

confidence: 90%

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Altered Microbiota, Impaired Quality of Life, Malabsorption, Infection, and Inflammation in CVID Patients With Diarrhoea

Schewick

Nöltner²,

Abel

et al. 2020

Front. Immunol.

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Background: Diarrhoea is the commonest gastrointestinal symptom in patients with common variable immunodeficiency (CVID). Objective: The aim of this study was to describe the prevalence and clinical presentation of chronic and recurrent diarrhoea in the Royal-Free-Hospital (RFH) London CVID cohort, including symptoms, infections, level of inflammation, and microbial diversity. Methods: A cross-sectional study of adult CVID patients (139 out of 172 diagnosed with CVID completed the screening questionnaire). Those with diarrhoea ≥6 days/month had stool and blood samples analysed and completed the short Inflammatory Bowel Disease Questionnaire (sIBDQ). BMI, spleen-size, lymphocytes and gut-microbial diversity were compared. Due to logistical and clinical restraints, not all patients could be analysed on all measures. Results: 46/139 (33.1%) patients had current significant diarrhoea. In patients with past or present diarrhoea, BMI was lower (median 23.7 vs. 26, p = 0.005), malabsorption more common (57.97 vs. 35.71%, p = 0.011). CD4+ lymphocytes were higher in patients with diarrhoea (p = 0.028; n = 138), but CD4+ naïve lymphocytes were significantly higher in non-diarrhoea patients (p = 0.009, N = 28). Nine patients had confirmed or probable current gastrointestinal infections. Calprotectin was >60 µg/g in 13/29 with significant diarrhoea including 9 without infection. SIBDQ revealed a low median score of 4.74. Microbial alpha diversity was significantly lower in CVID patients compared to healthy household controls. There was no significant difference in alpha diversity in relation to antibiotic intake during the 6 weeks prior to providing samples. Conclusion: Patients with CVID and significant diarrhoea had infections, raised calprotectin, malabsorption, a lower BMI, an impaired quality of life (comparable van Schewick et al. Longstanding Diarrhoea in CVID to active IBD), and they differed from non-diarrhoea patients in their lymphocyte phenotyping. Furthermore, microbial diversity was altered. These findings strongly imply that there may be an inflammatory nature and a systemic predisposition to diarrhoea in CVID, which necessitates further investigation.

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Section: Discussionmentioning

confidence: 90%

“…One further patient was assumed to have been norovirus positive [No. 2, infection interval estimated by calculating divergence and ancestor dates (40)], one had very rare CMV inclusions in an ileal histopathological sample 2 years earlier (No. 6).…”

Section: Cvid Patients With Diarrhoea Have An Altered Microbiomementioning

confidence: 99%

Altered Microbiota, Impaired Quality of Life, Malabsorption, Infection, and Inflammation in CVID Patients With Diarrhoea

Schewick

Nöltner²,

Abel

et al. 2020

Front. Immunol.

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“…Studies on large cohorts also revealed that Norovirus and Cytomegalovirus (CMV) were among the most common viral causes of gastrointestinal infections in CVID ( 38 , 39 , 98 ). Others reported that Norovirus can be very severe, causing malabsorption and enteropathy requiring parenteral nutrition ( 42 , 99 ). Although most patients with PADs, efficiently clear oral polio vaccine (OPV)-related virus ( 100 ), viral shedding up to 28 years after OPV was reported in one patient ( 101 ).…”

Section: Introductionmentioning

confidence: 99%

Update on Infections in Primary Antibody Deficiencies

Demirdağ

Gupta

2021

Front. Immunol.

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Bacterial respiratory tract infections are the hallmark of primary antibody deficiencies (PADs). Because they are also among the most common infections in healthy individuals, PADs are usually overlooked in these patients. Careful evaluation of the history, including frequency, chronicity, and presence of other infections, would help suspect PADs. This review will focus on infections in relatively common PADs, discussing diagnostic challenges, and some management strategies to prevent infections.

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“…8 Currently no proven treatment exists. 9 The antiviral medication favipiravir is licensed in Japan for novel or pandemic influenza and has also been used for Ebola virus disease. It has shown promise in pre-clinical and early clinical usage in chronic norovirus infection.…”

Section: A Dose-finding Clinical Trial In Norovirusmentioning

confidence: 99%

“…Chronic norovirus infection is a serious complication of immune deficiency states leading to considerable morbidity, healthcare utilization, and death 8 . Currently no proven treatment exists 9 . The antiviral medication favipiravir is licensed in Japan for novel or pandemic influenza and has also been used for Ebola virus disease.…”

Section: Introductionmentioning

confidence: 99%

Early phase dose‐finding trials in virology

Dehbi

Lowe

O’Quigley

2020

Statistics in Medicine

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Little has been published in terms of dose-finding methodology in virology. Aside from a few papers focusing on HIV, the considerable progress in dose-finding methodology of the last 25 years has focused almost entirely on oncology. While adverse reactions to cytotoxic drugs may be life threatening, for anti-viral agents we anticipate something different: side effects that provoke the cessation of treatment. This would correspond to treatment failure. On the other hand, success would not be yes/no but would correspond to a range of responses, from small, no more than say 20% reduction in viral load to the complete elimination of the virus. Less than total success matters since this may allow the patient to achieve immune-mediated clearance. The motivation for this article is an upcoming dose-finding trial in chronic norovirus infection. We propose a novel methodology whose goal is twofold: first, to identify the dose that provides the most favorable distribution of treatment outcomes, and, second, to do this in a way that maximizes the treatment benefit for the patients included in the study. K E Y W O R D S continual reassessment method, coronavirus, dose-finding, early phase trials, norovirus, virology 1 INTRODUCTION This introduction has three subsections: the first provides a broad description of our goals, the second a summary of the study motivating this current work, and, finally, a subsection making these goals more specific and anticipating the section that follows on statistical methodology. 1.1 Background and motivation Antiviral agents can fail to be of benefit to a patient in two different ways. The first is where the toxic side effects are such that the patient is unable to take the full course of treatment, thereby not being in a position to experience treatment benefit. The second type of failure is where the treatment is well tolerated but fails to achieve a meaningful clinical or virological effect, for example, a lessening of symptoms, reduction in viral load, or complete elimination of the virus (or, for some viruses, induction of viral latency). When viral load is the main focus, efficacy may be categorized into three or possibly more outcomes, ranging from a small, insignificant reduction in viral load to a large reduction or total elimination (or suppression) of the virus. Given a new candidate treatment, and some range of possible treatment levels, This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

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A comprehensive characterization of chronic norovirus infection in immunodeficient hosts

Cited by 24 publications

References 9 publications

Altered Microbiota, Impaired Quality of Life, Malabsorption, Infection, and Inflammation in CVID Patients With Diarrhoea

Altered Microbiota, Impaired Quality of Life, Malabsorption, Infection, and Inflammation in CVID Patients With Diarrhoea

Update on Infections in Primary Antibody Deficiencies

Early phase dose‐finding trials in virology

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