Non-Polio enterovirus infections

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

Enteroviruses are a genus of positive-sense single-stranded RNA viruses associated with several human and mammalian diseases. Serologic studies have distinguished 66 human enterovirus serotypes on the basis of antibody neutralization tests. Additional antigenic variants have been defined within several of the serotypes on the basis of reduced or nonreciprocal cross-neutralization between variant strains.

On the basis of their pathogenesis in humans and animals, the enteroviruses were originally classified into four groups, polioviruses, Coxsackie A viruses (CA), Coxsackie B viruses (CB), and echoviruses, but it was quickly realized that there were significant overlaps in the biological properties of viruses in the different groups. Enteroviruses isolated more recently are named with a system of consecutive numbers: EV68, EV69, EV70, and EV71, etc.^[1].

Enteroviruses can be found in respiratory secretions (e.g., saliva, sputum, or nasal mucus) and stool of an infected person. Other persons may become infected by direct contact with secretions or stool from an infected person or by contact with contaminated surfaces or objects, such as a drinking glass or telephone. Parents, teachers, and child care center workers may also become infected by contamination of the hands with stool from an infected infant or toddler during diaper changes.

Non-polio enterovirus infections are caused by enteroviruses. Enteroviruses are a genus of positive-sense single-stranded RNA viruses associated with several human and mammalian diseases. Enteroviruses are made of ribonucleic acid (RNA) and protein. This group includes the polioviruses, coxsackieviruses, echoviruses, and other enteroviruses. In addition to the three different polioviruses, there are over 60 types of non-polio enteroviruses that can cause disease in humans. Non-polio enteroviruses are very common. They are second only to the “common cold” viruses, the rhinoviruses, as the most common viral infectious agents in humans.

Non-polio enteroviruses are very common. They are second only to the “common cold” viruses, the rhinoviruses, as the most common viral infectious agents in humans. The enteroviruses cause an estimated 10-15 million or more symptomatic infections a year in the United States. However, all three types of polioviruses have been eliminated from the Western Hemisphere, as well as Western Pacific and European regions, by the widespread use of vaccines.

Parents, teachers, and child care center workers may be prone to non-polio enterovirus infections as they can become infected by contamination of the hands with stool from an infected infant or toddler during diaper changes.

Although everyone is at risk of infection, factors such as age and season can increase the chance of an individual getting infected by non-polio enteroviruses.

Most people who are infected with a non-polio enterovirus have no disease at all. Infected persons who become ill usually develop either mild upper respiratory symptoms (a “summer cold”), a flu-like illness with fever and muscle aches, or an illness with rash.

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The first documented outbreak of Acute hemorrhagic conjunctivitis due to ED-70 occurred in Ghana in 1969.EV D68, considered to be a pathogen exclusive to the respiratory tract for a long time, was first isolated in 1962 from four children in California suffering from pneumonia and bronchiolitis.CV-A24v was first isolated in 1970 in Singapore.

• The first documented outbreak of Acute hemorrhagic conjunctivitis due to ED-70 occurred in Ghana in 1969^[1]. From 1970 and 1971, till the mid-1990s, the virus spread globally to produce the first AHC pandemic^[2].
• Over the past decade, EV 71 has been implicated in many outbreaks of acute flaccid paralysis AFP in the Asia-Pacific region^[3].
• In a systematic review evaluating surveillance data, case reports and case series of AFP, EV 71, echovirus 11 and echovirus 6 were reported more through surveillance while EV 71 and EV 68 were the predominant serotypes in case reports and case series^[4].
• EV D68, considered to be a pathogen exclusive to the respiratory tract for a long time, was first isolated in 1962 from four children in California suffering from pneumonia and bronchiolitis^[5]. Only sporadic cases were reported till the late 2000s with 26 between 1970 and 2005^[6]. It caused the largest outbreak in 2014 in the USA, the first cases reported in August from Missouri and Illinois. Almost all the cases were children with a predominant history of asthma or wheezing^[7].
• CV-A24v was first isolated in 1970 in Singapore^[8] and remained restricted to South-East Asia and India until 1985, when it started causing widespread outbreaks.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Sujaya Chattopadhyay, M.D.[2]

The genus Enterovirus belongs to the Picornaviridae family. It consists of 13 species of which seven contain human pathogens of more than 250 types, excluding three poliovirus serotypes. They include coxsackievirus, echovirus, numbered enterovirus and rhinovirus.

• A6
• A10
• A16

• A71

• B types
• A9

• A21
• A24

• D68
• D70

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: {Sujaya}}

Enteroviral diseases are more likely to be severe in the immunocompromised, including patients with diabetes, HIV, neoplasms, or post-transplant status.The cellular uptake of enteorviruses is mediated by receptor molecules such as, intracellular adhesion molecule-1 (ICAM-1), low-density lipoprotein receptor (LDL-R), and non-protein factors such as heparan sulfate and sialic acid. Incubation periods range from 12 hours to 5 days, with experimental volunteers reporting symptoms several hours after aritficial inoculation.

• Replicate in the oropharyngeal mucosa and the intestines, leading to their detection in oral secretions and stool, the latter showing evidence of the pathogen months after resolution of the symptoms.
• Targets the lymphatic tissues such as the Peyer’s patches and the tonsils, paving the way for lymphatic and hematogenous dissemination
• Manifestations include myocarditis, pancreatitis and often a second, stronger viremia. This can cause serious clinical illness and facilitate direct crossing of the blood-brain barrier to affect the central nervous system.
• Alternative mechanisms include a “Trojan horse”entry model mediated by virus-infected leukocytes.
• Once present in the CNS, persistent infection is possible, likely by an immune response to the apoptosis and autophagy induced by this group of viruses.

• Exclusively affects the epithelial layer of the airways
• The mechanisms of uptake into cell include endocytosis and pinocytosis depending on the host and the virus type.
• On entry into the cell, the virion induces a conformational change by lowering the pH of the endosome or altering the receptor binding. This results in the exposure of hydrophobic domains and pore-mediated release of the viral particles into the cytoplasm of the genome, marking the beginning of viral polyprotein synthesis by the host cells.
• They do not participate in direct cell destruction, instead disrupting the epithelial barriers by stimulating Reactive oxygen species during their replication and dissociating zona occludens-1 from the tight junction complex. This triggers the release of cytokines, that activate granulocytes, monocytes and dendritic cells. IgG and IgA response takes about 1 to 2 weeks, usually after the virus has been eliminated but is crucial in preventing re-inoculation. Levels may remain high till a year after, but do not exhibit cross-reactivity among serotypes. On the contrary, viral load can indicate severity of the disease.
• In infants, rhinoviruses damage the respiratory cells and damage the immune response. They are an independent risk factor for the development of asthma and recurrent wheezing.
• In adults, they are the most common causes of acute exacerbations of COPD, necessitating hospital stays. They also contribute to abut two-thirds of viral upper respiratory tract infections-associated asthma exacerbations.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Sujaya Chattopadhyay, M.D.[2]

Non-polio enterovirus infections are caused by a genus of positive-sense single-stranded RNA viruses associated with several human and mammalian diseases. Enteroviruses are made of ribonucleic acid (RNA) and protein. This group includes the coxsackieviruses, and echoviruses. Non-polio enteroviruses are very common. They are second only to the “common cold” viruses, the rhinoviruses, as the most common viral infectious agents in humans.

• A6
• A10
• A16

• A71

• B types
• A9

• A21
• A24

• D68
• D70

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Sujaya Chattopadhyay, M.D.[2]

The differential diagnoses of non-polio enterovirus infections spans diseases affecting the respiratory, gastrointestinal and central nervous systems:

• Influenza
• Adenovirus
• Upper respiratory tract infections (pharyngitis, sinusitis)
• Allergic rhinitis
• Meningitis
• Gastroenteritis

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Sujaya Chattopadhyay, M.D.[2]

The long-term circulation dynamics are characterised by distinct epidemic and endemic patterns.Epidemics in temperate regions exhibit a characteristic seasonal variation, with peaks in summer and early autumn. This is less apparent in tropical regions. Climate, socio-economic factors and homotypic immunity likely contribute to the geographic distribution of different types. Enterovirus A sequences dominate in East and Southeast Asia while Enterovirus B is most common in Western Asia, Europe, Africa, South America, Southern Asia, and Oceania. Enteroviruses C and D are relatively rare.

The long-term circulation dynamics is characterised by distinct epidemic and endemic patterns^[2].

• New types or strains can start off with a cryptic, endemic phase before assuming epidemic proportions (e.g. EV-A71^[3], EV-D68^[4])
• Bottlenecks from epidemic epidemiological cycles can limit diversity in certain areas, leading to a self-limiting pattern^[5].
• Epidemics in temperate regions exhibit a characteristic seasonal variation, with peaks in summer and early autumn. This is less apparent in the tropical regions^[6].
• Differences in geography can also change the timing of epidemic cycles, making them longer or even variable.
• The cause for the cyclical patterns is likely multifactorial, being a combination of weather, geographic barriers, hygiene, viral evolution, herd immunity, changes in the susceptible population and host factors.
• Homotypic immunity is probably the most important factor dictating transmission dynamics^[6].
• The relative species prevalence also changes throughout the year^[7].

Climate, socio-economic factors and homotypic immunity likely contribute to the geographic distribution of different types^[8].

Sequences dominate in East (71%) and South-east Asia (73.4%), with the most common EV-A71, EV-A6, EV-A16, EV-A10 occurring in that order. Very low levels are detected in Africa, North America and Western Asia.

Most common in Western Asia(81.4%), Europe(63.1%), Africa(63%), South America(61.3%), Southern Asia(61%), Oceania (55.1%).

• A significant proportion exists in Africa(22.1%) and South America (21.2%); rarer in rest of the world
• CV-A 24 is the most commonly sequenced EV-C type, with higher proportion in South America

• Relatively rare worldwide; represent 76.7% of sequences in North America.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Sujaya Chattopadhyay, M.D.[2]

EV infections vary greatly in severity. Understanding the risk factors for severe infection may help clinicians identify infants at risk for adverse outcomes.

• Prematurity
• Early age on onset of illness (<7 days of age)

• Higher WBC count: A higher degree of inflammation and consequent hepatic/myocardial damage
• Low hemoglobin: May signal a bleeding diathesis

Mothers infected shortly before delivery may pass the virus to the newborn. Babies born to mothers who have symptoms of enteroviral illness around the time of delivery are more likely to be infected.

• Low accessibility to water and high density and intimacy among family members due to small housing space [4.3m^2(1.10 m^2 per person)]: Apparent major reasons for high infectivity, although not statistically evident
• Sharing a kitchen and/or bathroom
• Inside toilet: Higher risk of intrafamilial spread
• Lack of cleaning of kitchen, bathroom, toilets and waste disposal areas
• Improper hand hygiene

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