Norovirus infection in primary immune deficiency

Abstract

Norovirus is acknowledged to be a leading cause of acute gastroenteritis worldwide, and its importance as a cause of chronic infection in immune deficient hosts is increasingly recognised. Current evidence suggests that a coordinated response of innate immune mechanisms, CD8+ cytotoxicity and a humoral response, with CD4+ orchestration, is necessary for norovirus clearance. We explain how primary immune deficiency impairs these host defences and predisposes to chronic infection, associated with protracted diarrhoea, weight loss, and requirement for parenteral nutrition. The mucosal villous atrophy frequently seen in norovirus infection appears to be immune mediated, suggesting that some functional immune response is required in order for chronic norovirus infection to become symptomatic in primary immune deficiency. We provide a comprehensive summary of published cases of norovirus infection in patients with primary immune deficiency. Spontaneous viral clearance has been described; however, the majority of reported cases have had prolonged and severe illness. Treatment strategies are discussed in detail. Approaches that have been tried in patients with primary immune deficiency include exclusion diets, enteral and intravenous immunoglobulins, breast milk, immunosuppressants, ribavirin, and nitazoxanide. To date, only ribavirin has been used with apparent success to achieve clearance of chronic norovirus in primary immune deficiency, and randomised controlled trials are needed to evaluate a number of promising therapies that are discussed.

Viral infection in primary antibody deficiency syndromes

“…Prolonged shedding times of norovirus have been reported by several studies in both symptomatic and apparently asymptomatic individuals with CVID. Shedding times have been reported by others as long as 1200 days with serial positive faecal samples and gastrointestinal biopsies, while we have recently described a patient infected with the US95/96 strain of norovirus (which circulated until 2002) who was still excreting virus in 2017 .…”

“…Another potential treatment under evaluation is nitazoxanide, currently being formally evaluated in post‐stem cell transplant patients in the United States . While the use of oral IVIg and colostral breast milk has been quite successful in solid organ transplant recipients, this approach has not been proven effective in patients with primary immunodeficiency …”

“…It remains to be seen therefore if norovirus is the sole pathogen, or one of many, driving intraepithelial lymphocyte accumulation and villous atrophy—or indeed whether the mechanism is independent of pathogens in some individuals. We have previously reviewed norovirus infection in primary immunodeficiency in more detail …”

Humoral immunodeficiencies: conferred risk of infections and benefits of immunoglobulin replacement therapy

“…More recently, infection with norovirus has been reported as an important enteric infection in patients with CVID, and it has also been associated with chronic infection that causes malabsorption and severe enteropathy. [21][22][23] Some patients may benefit from antiviral therapy to clear norovirus infection. 22 Patients are also predisposed to GI infections with Campylobacter jejuni, Salmonella species, and cytomegalovirus (CMV).…”

“…Enterovirus infections can progress to meningoencephalitis and fatal disseminated disease. 21,34,35 Fortunately, these complications have decreased since Ig replacement therapy has become routine. 27…”