Astrovirus

Astroviruses, family Astroviridae, are small, nonenveloped, single-stranded RNA viruses ¹.. The family Astroviridae is currently divided into 2 genera: Mamastrovirus species that infect mammals, including humans, and Avastrovirus species infect poultry and other birds ². Human astroviruses were first identified in 1975 ³; until recently, only classic human astroviruses that belonged to the species Mamastrovirus 1 were recognized as human pathogens ⁴. Human astroviruses contribute to ≈10% of nonbacterial, sporadic gastroenteritis in children (around 90% of the population 9 years) ⁵, with the highest prevalence observed in community healthcare centers ⁶. Symptoms are generally mild, with patient hospitalization usually not required; asymptomatic carriage has been described in 2% of children ⁷.

Astrovirus infections were thought to be species-specific, yet turkey, chicken, and duck astroviruses share genetic features, indicating that cross-species transmission may be frequent ⁸. Poultry abattoir workers were three times more likely to test positive for antibodies against turkey astrovirus than people with no contact with poultry ⁹, and perhaps the most compelling evidence was the detection of astrovirus strains previously shown to be limited to human infections in non-human primates by real-time polymerase chain reaction (RT-PCR) ¹⁰. These studies and others suggest that astroviruses can cross species barriers; however, whether these transmissions result in disease remains unclear.

Despite the high prevalence of astrovirus ¹¹ and the advances made in the identification of novel genotypes, there is still little known about human astrovirus pathogenesis—especially among the different human astrovirus genotypes. Previous studies demonstrated that human astroviruss increase epithelial cell permeability by disrupting cellular tight junctional complexes ¹². Since the intestinal tract depends on tight junctions to separate the lumen from the basal lamina, the loss of integrity increases ion, solute, and water trafficking across the compartments, reducing the ability of the intestine to reabsorb water and nutrients, leading to diarrhea. Additionally, extra-gastrointestinal astrovirus-associated disease has been reported in animals and humans ¹³, which could result from the increased intestinal permeability. The definite mechanisms underlying diarrhea and systemic spread remain an area of continual research; increasing our understanding of astrovirus disease will be integral for future treatment and prevention strategies. Recently, studies in both humans and animals have helped to elucidate the molecular and cellular attributes of astrovirus disease.

Figure 1. Astroviridae family

Footnote: A brief phylogenetic tree of the Astroviridae family. Phylogenetic tree with representative Avastrovirus (red) and Mamastrovirus (black) genotypes. Using full genome sequences, the evolutionary history was inferred using the Maximum Likelihood method based on the Kimura 2-parameter model. Trees were constructed using 500 bootstrapped replicates, with values above 70 shown. Branch lengths represent the number of substitutions per site.

Abbreviations: HAstV = Human astrovirus; MLB = Melbourne; VA = Virginia.

[Source ¹⁴ ]

Human astrovirus infection

Within the years following the discovery of human astrovirus, eight distinct genotypes (human astrovirus type 1–8, also referred to as classical or canonical human clades) were identified, with infections caused by human astrovirus-1 shown to be the most prevalent worldwide ¹⁵. In the late 2000s, through pathogen discovery investigations of diarrheal outbreaks, two divergent human astrovirus genotypes were discovered: human astrovirus-MLB (Melbourne) clade containing at least three strains (MLB1, MLB2, MLB3) and the human astrovirus-VA/HMO (Virginia/Human-Mink-Ovine-like) clade containing at least five strains (VA1, VA2, VA3, VA4, VA5) ¹⁴. The human astrovirus-MLB and human astrovirus-VA/HMO viruses have been designated as non-canonical human genotypes. human astrovirus-MLB1 was initially discovered in pediatric stool samples from Australia ¹⁶, whereas human astrovirus-MLB2 and human astrovirus-MLB3 were discovered in India ¹⁷. The human astrovirus-VA1–VA3 viruses were first discovered in an outbreak of gastroenteritis in Virginia, USA ¹⁸; human astrovirus-VA4 in a cohort of Indian children with diarrhea ¹⁹; and human astrovirus-VA5 in a cohort in Gambia ²⁰. The prevalence of the non-canonical viruses varies greatly according to geographic location ²¹, and their association with clinical disease remains somewhat of a mystery in comparison to the canonical strains.

Astrovirus infections are of clinical concern in the immunocompromised population due to their increased severity of symptoms and extra-gastrointestinal involvement ²¹. Human astrovirus has also been suggested to be the causative agent in encephalitis and meningitis, which was brought to light in a case report of a 15-year old boy with X-linked agammaglobulinemia by Quan et al. ²². The patient was admitted to a psychiatric ward due to cognitive decline, became comatose, and died 71 days post admission. RNA was extracted from the patient’s biopsy and postmortem samples, and sequenced and amplified with virus-specific primers, but results were negative. As an alternative approach, next-generation sequencing was utilized to identify the presence of human astrovirus in the biopsy samples. Consequently, there have now been nine cases of astrovirus-associated encephalitis and meningitis reported in predominately immunocompromised patients, although one case was in an individual without overt immunosuppression ²³. Interestingly, in eight out of the nine cases, a non-canonical strain was detected in patient samples. Next-generation sequencing identified human astrovirus-VA1 in a nasopharyngeal specimen from a child with an acute respiratory infection in Tanzania, but it is unclear if human astrovirus-VA1 was responsible for the respiratory disease ²⁴. These studies suggest that astroviruses have systemic potential, reiterating the importance of studying astrovirus pathogenesis of both canonical and non-canonical subtypes, especially since infections caused by non-canonical viruses do not appear to be rare in immunocompromised populations. In a cohort of immunocompromised pediatric oncology patients, while human astrovirus-1 was identified in 50% of samples, human astrovirus-VA2 and human astrovirus-MLB1 were also present in 21% and 13% of samples, respectively ²⁵. However, it was noted that the PCR screening used in this study was unable to detect other members of the human astrovirus-VA and human astrovirus-MLB clades, meaning that these genotypes may be even more prevalent than reported. With improved molecular techniques for detection and diagnosis, surveillance efforts will afford a better understanding of prevalence.

There are many parallels that can be drawn between human and animal astrovirus disease, but the area remains understudied. Like humans, many of the animals infected with astrovirus exhibit diarrhea, including turkeys ²⁶, chickens ²⁷, calves ²⁸, lambs ²⁹, piglets ³⁰, and deer ³¹. However, there is a subset of animals that are asymptomatic ³². Much like the human astroviruses, the impact of the asymptomatic infection on epidemiology and transmission in animal astrovirus remains unclear. Chicken astrovirus has been associated with “white chick” condition that causes a decrease in hatch-rate and an increase in chick mortality and weakness ³³. Along with this, there is evidence of astrovirus-associated encephalitis and meningitis in mink and cows ¹³ and respiratory disease in calves ³⁴. As with the human viruses, improved molecular techniques would lead to a better understanding of prevalence and genotype-specific astrovirus disease.

Astrovirus transmission

Astrovirus is most frequently transmitted through a fecal-oral route ³⁵. Contaminated food, water, or fomites have been suspected in several breakouts. Adults usually do not develop gastroenteritis when deliberately given astrovirus in volunteer studies ³⁵. In outbreaks in military barracks and childcare settings, adults may have been exposed to high doses of virus and only then have fallen ill. Astrovirus is believed to replicate in the intestinal tissue of the jejunum and ileum. Volunteer studies with healthy adults found that the average incubation period for astrovirus infection was 3 to 4 days.

Astrovirus prevention

There is no vaccine for astrovirus. Personal hygiene and decontamination of outbreak settings are important to reducing transmission and infection. Individuals can continue to shed astrovirus in their feces several days after illness resolves, and so should continue to take precautions after recovering from overt illness.

Although the survival of classic human astrovirus in drinking water is high, disinfection treatments of 2 hours with 1 mg/ml of free chlorine is quite effective ³⁶. However, genogroup B is somewhat more resistant to chlorine disinfection than genogroup A ³⁷, suggesting that differences in environmental persistence may exist between strains. Astrovirus survival and inactivation in food matrices have not been extensively studied, probably because only a few human astrovirus food-borne outbreaks have been described ³⁸ and because efforts have been dedicated to the application of emerging technologies for the inactivation of other viral agents, such as norovirus and hepatitis A virus ³⁹. Regarding disinfection of contaminated fomites, 90% alcohol has been proved useful ⁴⁰. Unfortunately, no information on inactivation is yet available for nonclassic human astroviruss.

Astrovirus symptoms

Astrovirus infection causes gastroenteritis, which is characterized by the production of copious, watery diarrhea that lasts for 2 to 3 days, followed for complaints such as nausea, vomiting, fever, malaise, anorexia, headaches and abdominal pain for up to 4 days ⁴¹. However, many of the human astrovirus infections in healthy children and adults tend to be asymptomatic ⁴². The consequence of these asymptomatic cases on the epidemiology and transmission of astrovirus remain unclear. Further research is needed to understand the clinical disease associated with the different human astrovirus genotypes.

Astrovirus diagnosis

Due to the lack of readily available viral testing capabilities in most clinics and emergency departments, acute viral gastroenteritis is a clinical diagnosis. Therefore, patients who appear clinically well-hydrated and who lack risk factors for severe disease do not necessarily warrant further testing. Diagnostics are used to help rule out other causes of the patient’s symptoms. Complete blood counts may reveal a mild leukocytosis in a patient with viral gastroenteritis. Other serum inflammatory markers may also show mild elevation. Patients who are suffering from significant dehydration may demonstrate hemoconcentration on complete blood count testing as well as electrolyte disturbances on chemistry panels. Dehydration may also present as acute kidney injury, evidenced by changes in the blood urea nitrogen (BUN) and creatinine on chemistry panel.

Imaging studies of the abdomen most often appear normal. CT scans may reveal mild, diffuse colonic wall thickening or other inflammatory changes of the bowel. However, there are no specific findings, and CT scanning should be performed to rule out other, more severe etiologies. Stool studies may be obtained, but readily available laboratory testing assays assess only for bacterial causes and do not diagnose specific viral causes. Patients with bloody stool, high fever, severe abdominal pain, or severe dehydration warrant stool studies as these symptoms are not consistent with simple viral gastroenteritis.

Astrovirus treatment

The treatment of astrovirus gastroenteritis is based on symptomatic support ⁴³. The most important goal of treatment is to maintain hydration status and effectively counter fluid and electrolyte losses ⁴⁴. Fluid therapy is a fundamental part of treatment. Intravenous fluids may be administered to those individuals who appear dehydrated or to those unable to tolerate oral fluids. Antiemetic medications such as ondansetron or metoclopramide may be used to assist with controlling nausea and vomiting symptoms. Patients demonstrating severe dehydration or intractable vomiting may require hospital admission for continued intravenous fluids and careful monitoring of electrolyte status. Electrolyte abnormalities may be addressed on an individual level, although often these are caused by an overall fluid volume depletion which, when corrected, will also cause electrolytes to normalize. Both saline and lactated Ringer’s solutions appear to be effective for the treatment of dehydration due to viral gastroenteritis.

Debate exists over antidiarrheal medication usage. Medications such as diphenoxylate/atropine or loperamide are not recommended in patients who are 65 or older. Younger patients may benefit from antimotility medications ⁴⁵. However, some feel that if a patient can maintain a well-hydrated status, antidiarrheal treatment should not be initiated. For oral rehydration, some studies have shown that commercially available oral rehydration solutions containing electrolytes are superior to sports drinks and other forms of oral rehydration ⁴⁶. However, a recent study using children with mild dehydration demonstrated no differences between children receiving oral rehydration solutions versus ad lib oral intake ⁴⁷. No specific nutritional recommendations are universal for patients with viral gastroenteritis. A diet of banana, rice, apples, tea, and toast is often advised, but several studies have failed to show any significant outcome difference when compared to regular diets ⁴⁸.

Most patients who present to outpatient clinics or the emergency department with acute viral gastroenteritis can be discharged home safely. Adults often benefit from antiemetic medications at home although home antiemetic medication is not recommended in young children. Patients who may benefit from hospital observation or admission are those that demonstrate signs or symptoms of dehydration, intractable vomiting, severe electrolyte disturbances, significant renal failure, severe abdominal pain, or pregnancy.

Astrovirus prognosis

Astrovirus infection is generally mild and self-limiting, rarely leading to severe dehydration, hospitalization, or death. Symptoms usually resolve on their own, although individuals may continue to shed virus in their feces for days afterward. Persistent gastroenteritis occasionally occurs.

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