Enterovirus

Etiology

Structurally, all enteroviruses are small, at 15-30 nm viruses within the Picornaviridae family. The capsids are icosahedral and contain positive-sense single-stranded RNA (+ssRNA) of approximately 7400 nucleotides in length. There is no lipid envelope, and the genome, instead of having an AUG-containing cap, has an internal ribosomal entry site (IRES), which allows for mRNA translation.

Rhinovirus species within the Enterovirus genus infect both the upper and lower respiratory tracts and rarely cause disseminated disease. Most Picornaviridae viruses show the most efficient growth at 36 degrees celsius. However, rhinoviruses (and other respiratory-type enteroviruses) demonstrate efficiency at 33 degrees celsius, which likely contributes to their tropism as upper respiratory pathogens. Investigations into this have demonstrated that while viral replication persists with little change at the higher temperatures, host cell response is altered by temperature and creates an environment less conducive to rhinoviruses at higher temperatures.

Non-rhinovirus species of enteroviruses are suspected to be the most common viral pathogen infecting the central nervous system. They initially infect the alimentary tract. Unlike rhinoviruses and other picornaviruses, they are acid-stable, able to survive at pHs below 3. This acid-stability allows them to pass through the stomach's acidic environment to the cells lining the small intestine, where pathology begins.

Diseases caused by enteroviruses include poliomyelitis, Bornholm disease (epidemic myalgia), myopericarditis, hemorrhagic conjunctivitis, nonspecific febrile illnesses, pneumonia, aseptic meningitis, herpangina, enteroviral vesicular stomatitis (hand, foot, and mouth disease), encephalitis, acute flaccid paralysis, the common cold, pharyngitis, otitis media, sinusitis, pancreatitis, and asymptomatic subclinical infections.

Serotypes most commonly identified with various diseases include:

• Poliomyelitis: PV-1-3
• Myopericarditis: CV-A, CV-B
• Hemorrhagic conjunctivitis: EV-D70
• Pneumonia: EV-68, rhinoviruses
• Herpangina: CV-A, EV-A71
• Hand, foot, and mouth disease: CV-A16, EV-A71
• Acute flaccid paralysis and other polio-like illnesses: EV-D68, EV-A71, echovirus 11
• Upper respiratory tract infections: EV-D68, rhinoviruses
• Acute exacerbations of chronic airway diseases (chronic obstructive pulmonary disease, cystic fibrosis, asthma): rhinoviruses
• Aseptic meningitis: CV-A9, CV-B, echoviruses, EV-A71[1][2][3][4][5]

Epidemiology

Enteroviruses are ubiquitous, causing disease worldwide and year-round. The majority result in primarily pediatric disease, with risk factors, prevalence, and clinical presentation varying extensively according to each serotype.

Non-rhinovirus Enterovirus Species

Non-rhinovirus enteroviruses have varying patterns of occurrences based on serotype, with peak disease prevalence in the summer. In warmer climates, circulation is seen year-round, frequently with mixed enteroviral infections. Males are infected more frequently than females, at a rate of 1.5 to 2.5 to 1, and are more likely to have severe disease.

Transmission occurs host-to-host. While there is evidence of zoonotic transmission (both human-to-animal and animal-to-human), virus passage is largely human-to-human, via the fecal-oral or fecal-hand-oral route. Enteroviruses were reclassified to remove naming specific to host species after being isolated in non-human hosts.

Evidence of a polio-like disease dates back to 2 millennium BCE. Polio itself occurred sporadically and was poorly-defined until the improvement of hygienic living conditions allowed for the development of a virgin pool susceptible to serious illness, resulting in epidemics beginning in the 1800s, first in Europe and then in North America.

Worsening epidemics led to intense scrutiny and identification of the three serotypes of poliovirus (categorized within Enterovirus C (EV-C) today) and then, in 1954, the development of the poliovirus vaccine. Polioviruses continue to be the only viruses within the Enterovirus genus for which a vaccine is available and effective. The western hemisphere was free of paralytic poliomyelitis in 1991; however, it is still found in regions of Asia and Africa.

Coxsackieviruses and echoviruses remain major causes of aseptic meningitis globally, in both epidemic and endemic forms, based on the local environment.

Recent outbreaks of the non-rhinovirus enteroviral disease include a large outbreak of Enterovirus D68 (EV-D68), which occurred in 2014. Over 1100 cases were confirmed, mostly causing respiratory symptoms ranging from cold-like symptoms to severe asthma exacerbations. This outbreak was also linked to an outbreak of acute flaccid paralysis, a disease characterized by lesions of the spinal cord gray matter, similar to poliomyelitis. The onset of this flaccid paralysis is acute, often asymmetric, and occurs following a respiratory prodrome in patients with a median age of 5 years. Both the initial decompensation and recovery from EV-D68 were more rapid than from the 2009 H1N1 influenza A. EV-D68 is considered unique in that it has many similarities to rhinoviruses.  Transmission occurs through aerosolization via large and small droplets.

Rhinovirus Species

Rhinoviruses result in billions of dollars of direct and indirect costs annually in the United States alone. They were discovered in the 1950s and today cause more than half of upper respiratory infections. Children constitute the major reservoir, experiencing 8 to 12 infections per year, compared with adults at 2 to 3 per year. Infections peak dually in the spring and fall, except for Rhinovirus C viruses, which peak in the winter. In contrast to non-rhinovirus enteroviruses, humans are the only known host.

Transmission of rhinoviruses occurs via direct inoculation of nasal mucosa or eye conjunctiva. In the latter situation, the virus is transported via the lacrimal duct to the nasal cavity, then to the nasopharynx. They can survive indoors up to days, at ambient temperature, and may live for hours on undisturbed skin. Like the respiratory enteroviruses, they may be transmitted through aerosolization. Nose blowing is associated with an increased incidence of rhinosinusitis; studies show this is related to intracavity pressure levels during nose blowing.

Healthcare-associated outbreaks, such as those in neonatal intensive care units (NICUs), pediatric intensive care units (PICUs), and long-term care facilities, have been described for enteroviruses.

Surveillance of enteroviruses tends to be passive, primarily as a result of the vast number of discrete serotypes that infect humans, but also as a result of the often mild disease caused by them. New models have been created utilizing already-present surveillance systems. These, in conjunction with more accurate PCR testing, have allowed the development of models that forecast disease patterns several years out with some accuracy, which may play an essential roll in vaccine development.

Vaccine development is limited by the limited cross-reactivity between the expansive numbers of enteroviruses, precluding the development of polyvalent vaccines. Further difficulties arise from uncertain waxing and waning of vaccine-derived immunity, as seen in the poliovirus vaccine.[2][3][4][6][7][8]

Pathophysiology

Enteroviruses trigger uptake into the various host cells by interaction with receptor molecules. Key receptors are intracellular adhesion molecule-1 (ICAM-1), low-density lipoprotein receptor (LDL-R), and non-protein factors such as heparan sulfate or sialic acid. Incubation times for enteroviral infections generally range from 12 hours to 5 days. Rarely, experimental volunteers reported non-serious symptoms several hours after artificial inoculation.

Non-rhinovirus Enteroviruses

Enteroviruses replicate in the mucosa of the oropharynx and intestines. Therefore, excretion of the virus can be detected in oral secretions as well as by rectal swabs, with excretion in stool lasting months after infection symptoms resolve. Lymphatic tissues such as Peyer's patches and tonsils are also targets. From there, spread to the lymph nodes and bloodstream is possible. This viremia contributes to disseminated disease, including myocarditis and pancreatitis, and, rarely, to an extension to the central nervous system (CNS). More often, this disseminated disease instead causes a second, stronger viremia, more likely to result in clinical illness and CNS involvement.

Non-rhinovirus enteroviruses can invade the central nervous system via the primary infection sites. Several models for this spread have been proposed, including the direct crossing of the blood-brain barrier, as mentioned above. Additionally, the neuromuscular junction may participate in this spread via a retrograde transport model. This is supported by the fact that muscular injury is associated with poliovirus neuroinfection. A “Trojan horse” entry model involving virus-infected leukocytes has also been proposed, among others.

Enteroviruses cause damage within the central nervous system by inducing apoptosis and autophagy. The immune response may also contribute to the disease state. Mechanisms of the pathophysiology are not fully understood. Once present in the central nervous system, a persistent infection may result.

Poliovirus, the most comprehensively studied enterovirus with neurological involvement, presents mostly in children under five years old, and in multiple forms. In the abortive form, a mild illness lasts approximately one week, resolves, and terminates with a full recovery. The nonparalytic form causes serous meningitis with meningeal symptoms but without lasting paralysis. The most dangerous, paralytic, form, affects 1% of patients, with paralysis occurring within hours, due to damage caused to the spinal cord anterior horn. Paralysis is irreversible in a minority of patients, but this form is associated with a 10% mortality. 90% to 95% of poliovirus infections are asymptomatic/subclinical.

Rhinoviruses

Rhinoviruses primarily infect airway epithelium and spare the subepithelial layer. Uptake occurs via endocytosis or pinocytosis, depending on the host cell and virus type. Once the virion is inside the cell, a conformational change occurs, triggered by either the low endosomal pH or receptor binding. This change exposes hydrophobic domains and results in a pore-mediated release into the cytoplasm of the genome. From there, host cell ribosomes participate in polyprotein synthesis. 

Rhinoviruses do not result in direct cell destruction. They compromise epithelial barriers by stimulating reactive oxygen species (ROS) during replication and causing dissociation of zona occludens-1 from the tight junction complex. Infection also triggers the release of cytokines that activate granulocytes, dendritic cells, and monocytes. IgG and IgA response does not occur until after the virus has already cleared, taking about 1 to 2 weeks, but is essential in preventing re-inoculation. Levels remain detectable for approximately a year but have little to no cross-serotype reactivity. At higher levels, viral load predicts disease severity.

Rhinovirus infections in infants induce cell damage within the respiratory tract and alter the immune response. They are an independent risk factor for the development of recurrent wheezing and the development of asthma. Rhinoviruses are the most common respiratory viruses causing acute exacerbations of COPD, necessitating hospital stays. They also cause about two-thirds of viral upper respiratory tract infections (URTI)-associated asthma exacerbations.

Enteroviral diseases were more likely to be severe in immunocompromised patients, including patients with diabetes, human immunodeficiency virus (HIV), neoplasm, or post-transplant status.[1][2][9][10]

History and Physical

Symptoms of enteroviral disease are specific to the course of the specific disease.

Rhinoviruses cause fever, cough, sneezing, rhinorrhea, otalgia, pharyngitis, nasal congestion, and sinus pressure. They can also cause wheezing and dyspnea.

Non-rhinovirus enteroviruses may cause fever, malaise, gastrointestinal upset, rash, lymphadenopathy, weakness, altered mental status, cough, sneezing, sore throat, and chest pain.

The diagnosis of enteroviral disease is often clinical and depends on understanding disease course, symptom severity, and risk factors. A careful history should elucidate the onset of symptoms, type and severity of symptoms, vaccination status, and possible disease exposures.

Comorbidities such as premature birth, bronchopulmonary dysplasia (BPD), underlying chronic lung disease, immunocompromised status, concomitant hematological disease, and diabetes can assist in stratifying risk and making treatment decisions. All may predispose the patient to more serious, though not necessarily more frequent, infections.

Physical exam should be directed by history and may include findings of upper or lower respiratory disease, meningeal signs, impaired muscle strength or deep tendon reflexes, hypoxia, or altered mental status.

Evaluation

Imaging and lab work may aid in the diagnosis of some enteroviruses. Respiratory disease may present with an abnormal chest x-ray or computed tomography (CT) scan. Magnetic resonance imaging (MRI) of the head or spinal cord may be indicated in cases of altered mental status or paralysis. Nasal, oropharyngeal, and rectal swabs may be sent for viral polymerase chain reaction (PCR), and lumbar puncture may be indicated based on clinical suspicion for CNS involvement.

An electrocardiogram should be performed on patients with chest pain or suspicion for myopericarditis. Clinical discernment must guide the collection of other serological studies, including kidney and liver function, complete blood count, and cardiac biomarkers.

Asymptomatic viral presence in test samples has been documented in varying frequencies. Based on the clinical concern, providers should attempt to rule out other forms of infection/co-infection by bacteria, fungi, and other viruses.

Treatment / Management

Treatment of enteroviral infections is largely supportive and symptomatic, as the diseases are self-limiting. Over the counter medications such as nonsteroidal anti-inflammatory drugs (NSAIDs), acetaminophen, and cough syrup, and nasal decongestants may address mild symptoms.  Wheezing, bronchospasm, and associated asthma exacerbations should also be treated according to standard treatment protocols. Severe respiratory symptoms may require supplemental oxygen and positive pressure ventilation. Patients with paralytic or other CNS disease require close monitoring.

There are no antivirals approved by the FDA for use against enteroviruses. Several antiviral medications have made it to clinical trial stages, but have failed to receive FDA approval for reasons including drug interactions and drug resistance and safety concerns. The antiviral pleconaril has been utilized clinically in rare cases. While it also failed to gain approval, it did demonstrate some clinical efficacy and has been extensively studied, becoming a base for future antiviral development.

Fluoxetine is the only FDA-approved drug demonstrating significant activity against the 2014 EV-D68, in a mechanism independent of SSRI activity. The activity was demonstrated in vitro and requires further clinical investigation.

Intravenous immunoglobulin therapy, utilizing neutralizing (IgG) immunoglobulins, is being investigated for prophylaxis and treatment.

Folk remedies of echinacea preparations and vitamin C may modestly reduce symptom duration or severity of rhinovirus infections; studies on this are mixed. Zinc supplementation within twenty-four hours of cold symptom onset may reduce both duration and severity of symptoms in a Cochrane review. First-generation, but not non-sedating antihistamines, reduce rhinorrhea and sneezing but do not help other symptoms.

Co-infections with bacterial or fungal pathogens should be treated with pathogen-specific antimicrobial therapy, whenever possible, and pre-existing conditions such as diabetes should be strictly controlled.

The development of vaccines against enteroviruses is hindered by the large number of distinct viruses, limited cross-reactivity, and difficulty predicting epidemiological patterns specific to serotypes. To date, only the poliovirus has an effective vaccine. Maintenance of adequate titers requires repeated boosters.

Differential Diagnosis

Differentials are necessarily broad due to the wide range of disease processes caused by enteroviruses and must be narrowed down by disease presentation.

Differential for rhinovirus infection

• Influenza
• Adenovirus infection
• Streptococcal pharyngitis
• Haemophilus influenzae
• Bacterial sinusitis
• Allergic rhinitis
• Pertussis
• Bronchitis
• COPD exacerbation
• Asthma exacerbation
• Pneumonia 

Differential for non-rhinovirus enteroviral infection

• CNS tumor
• Guillain-Barre syndrome
• Bacterial meningitis
• Autoimmune disease
• Gastroenteritis
• Toxic ingestion

Prognosis

The majority of illnesses caused by enteroviruses are mild and self-limited. The severity of the reported disease is associated with specific strains and with comorbidities and risk factors. Symptoms usually resolve within 7-14 days, with a full recovery. Persistent encephalitis, paralytic poliomyelitis, and severe respiratory illness causing respiratory failure portend the gravest prognoses.

Complications

Complications of enteroviral infections include the development of secondary infections, progression to persistent or chronic disease, irreversible paralysis, destruction of lung tissue, and exacerbation of underlying diseases. Acute exacerbations of COPD and asthma are among the most common complications of rhinoviral infections.

As there are no approved treatments for enteroviruses, mitigating risk factors and preventing co-infections is vital to reducing the risk of complications.