Enterovirus Infection

What is Enterovirus Infection?

Enterovirus infection is a group of acute infectious diseases caused by intestinal viruses (enteroviruses) characterized by fever and polymorphism of clinical symptoms caused by damage to the central nervous system, cardiovascular system, gastrointestinal tract, muscular system, lungs, liver, kidneys and other organs.

In recent years, there has been a clear trend towards the intensification of enterovirus infection in the world, as evidenced by the epidemiological upsurges and outbreaks constantly recorded in different countries. The geography of enterovirus infections is extremely wide and covers all countries of the world, including the post-Soviet space. Thus, in the scientific literature outbreaks of enterovirus (aseptic) meningitis in France (2002, 559 cases, ECHO viruses 13, 20, 6) are described, in Japan (2000, several hundred people became ill, there were deaths, enterovirus 71- type), USA (2001, more than 100 cases, ECHO 13 virus), Spain (2000, 135 cases, ECHO 13 virus), Germany (2001, 70 people fell ill, Coxsack B5 virus), Turkey. The largest of the described outbreaks were observed in Taiwan (1998, 2000, about 3 thousand people fell ill, ECHO 13, 30 viruses, type 71 enterovirus prevailed) and in Singapore (2000, 1 thousand cases, 4 deaths, the outbreak is caused by an enterovirus type 71), Tunisia (2003, 86 people, represented by ECHO viruses 6, 13). In the post-Soviet space, the largest outbreaks in recent years have been observed in Russia, in the Primorsky Territory (Khabarovsk, 1997, Koksaki B3, 4, 5 viruses, ECHO 6, 17, enterovirus of the 70th type prevailed) and in Kalmykia (2002 , 507 cases, ECHO virus 30), as well as in Ukraine (1998, 294 people got sick, Coxsack B4 virus).

One of the main features of these infections is a healthy virus carrier, which is constantly responsible for the occurrence of sporadic forms and mass diseases, which, like the incidence, is observed not only among young and older children, but also among adults. It is established that the duration of stay of enteroviruses in the intestine does not exceed 5 months.

However, two factors seem to be of primary importance in maintaining the circulation of enteroviruses among the population – the presence of susceptible contingents and the significant duration of virus carriage. The latter feature allows the virus after infection of non-immune individuals, creating a highly immune layer, to wait for new susceptible contingents.

Causes of Enterovirus Infection?

The modern classification of enteroviruses was developed in 2000 on the basis of accumulated data on the genetic structure and phylogenetic relationships of various representatives of the genus Enterovirus. This genus includes the family Picornoviridae, which, in turn, includes 5 types of non-polio enterovirus, namely Enterovirus A, B, C, D, E. Poliovirus according to this classification are a separate species in the genus Enterovirus. The structure of type A includes Coxsackie A2–8, 10, 12, 14, 16 viruses and enterovirus 71.

Enterovirus B is the most numerous and includes all Coxsack B viruses and ECHO, except for ECHO 1, as well as Koksaki A9 virus and enterovirus 69, 73, 77, 78 types. The Enterovirus C type combines the remaining representatives of the Coxsackie A viruses, including types 1, 11, 13, 15, 17–22, 24. Enterovirus D and E species are relatively few and include 2 (Enterovirus 68 and 70) and 1 (A2 plaque virus) representatives, respectively. In addition, the genus includes a significant number of unclassifiable enteroviruses. Thus, the genus Enterovirus includes more than 100 dangerous for humans viruses. They are widespread and highly resistant to the effects of physicochemical factors.

Pathogenesis during enterovirus infection

Enterovirus infections are a group of anthroponoses. The existence of entroviruses in nature is due to the presence of two main reservoirs – a person in whom multiplication and accumulation of the virus takes place, and an external environment (water, soil, foodstuffs), in which they are able to survive due to high resistance. The risk of outbreaks significantly increases with the “injection” into the human population of massive enterovirus contamination, which can often be realized through water and food transmission.

Describes the vertical route of transmission of enterovirus infections. The high risk of congenital enterovirus infection, as a rule, is determined not by the acute enterovirus disease that the mother had during the pregnancy, but by the persistent form of the enterovirus infection in the woman. Associated with congenital enterovirus infection syndrome of sudden infant death.

The source of infection is a sick person or a virus carrier. The transmission mechanism is airborne or fecal-oral. More often, children and young people are ill. Characteristic summer-autumn season. Immunity after suffering the disease is quite long (up to several years).

The entrance gate of the infection is the mucous membranes of the upper respiratory tract or the digestive tract, where the virus multiplies, accumulates and causes a local inflammatory reaction, which is manifested by symptoms of herpes sore throat, acute respiratory infections, pharyngitis or intestinal dysfunction. As a result of subsequent viremia, viruses are hematogenously spread throughout the body and are deposited in various organs and tissues.

The tropism of enteroviruses to the nervous tissue, muscles, epithelial cells causes a variety of clinical forms of infection. With the penetration of the virus in the CNS, it is possible to defeat it with the development of aseptic meningitis, meningoencephalitis or paralytic poliomyelitis-like forms.

ECHO viruses usually do not disseminate from the sites of primary penetration, only sometimes they are hematogenously transferred to other organs.

Symptoms of Enterovirus Infection

The wide pantopropicity of enteroviruses underlies a wide variety of clinical forms of infection caused by them, affecting almost all organs and tissues of the human body: nervous, cardiovascular systems, gastrointestinal, respiratory tract, and also kidneys, eyes, skin muscles, oral mucosa, liver, endocrine organs. The particular danger of enterovirus infections is in immunodeficient individuals.

Most cases of enterovirus infections are asymptomatic. Most of the clinically significant manifestations are cold-like diseases, and enteroviruses are considered the second most common causative agent of acute respiratory viral infections.

It is conditionally possible to distinguish two groups of diseases caused by enteroviruses:
Potentially heavy:

• serous meningitis;
• encephalitis;
• acute paralysis;
• neonatal septic-like diseases;
• myo- (peri-) carditis;
• hepatitis;
• chronic infections of immunocompromised persons.

Less dangerous:

• three-day fever with or without a rash;
• herpangina;
• pleurodynia;
• vesicular pharyngitis;
• conjunctivitis;
• uveitis;
• gastroenteritis.

1. Herpangina sore throat. On the first day of the disease, red papules appear, which are located on the moderately hyperemic mucous membrane of the palatine arches, uvula, soft and hard palate, quickly turning into vesicles of 1-2 mm in size, ranging from 3-5 to 15-18, not merging with each other. After 1-2 days, the bubbles open with the formation of erosion or completely dissolve by the 3-6th day of the disease. Pain when swallowing is absent or insignificant, salivation sometimes occurs. The increase in the cervical and submandibular lymph nodes is small, but their palpation is painful.
2. Epidemic myalgia (Bornholm disease, “fucking dance”, pleurodynia). It is characterized by acute pains with localization in the muscles of the anterior abdominal wall of the abdomen, lower chest, back, limbs. The pains are paroxysmal in nature, lasting from 30–40 seconds to 15–20 minutes, recur for several days, they can be recurrent, but with less intensity and duration.
3. Meningeal syndrome persists from 2-3 days to 7-10 days; recovery of cerebrospinal fluid occurs on the 2nd – 3rd week. Possible residual effects in the form of asthenic and hypertensive syndromes.Other neurological symptoms in meningitis of enteroviral etiology may include disorders of consciousness, increased tendon reflexes, absence of abdominal reflexes, nystagmus, clonus of the feet, short-term oculomotor disorders.
4. Paralytic forms of enterovirus infection are distinguished by polymorphism: spinal, bulbospinal, pontine, polyradiculoneurous forms can develop. The spinal form is most common, which is characterized by the development of acute flaccid paralysis of one or both legs, more rarely, of hands with severe muscle pain syndrome. For these forms of light, does not leave persistent paresis and paralysis.
5. Enterovirus fever (minor illness, 3 day fever). This is the most common form of enterovirus infection, but difficult to diagnose in sporadic morbidity. It is characterized by short-term fever without pronounced symptoms of local lesions. It occurs with moderate general infectious symptoms, the state of health is poorly disturbed, there is no toxicosis, the temperature lasts for 2-4 days. It can be clinically diagnosed when there is an outbreak in the team, when other forms of enterovirus infection are found.
6. Enterovirus rash (“Boston fever”). Characterized by the appearance from the 1st – 2 days of the disease on the face, torso, limbs rashes pink, spotted or spotted-papular nature, sometimes there may be hemorrhagic elements. The rash lasts 1-2 days, at least – longer and disappears without a trace.
7. Intestinal (gastroenteric) form. It occurs with watery diarrhea up to 5–10 times a day, abdominal pain, flatulence, and infrequent vomiting. Symptoms of intoxication are mild. In children under 2 years of age, intestinal syndrome is often combined with catarrhal symptoms of the nasopharynx. The duration of the disease in young children within 1–2 weeks, in older children, 1–3 days.
8. Respiratory (catarrhal) form is manifested by mild catarrhal phenomena in the form of nasal congestion, rhinitis, and dry rare cough. On examination revealed hyperemia of the mucous membrane of the oropharynx, soft palate and posterior pharyngeal wall. Mild dyspepsia may occur. Recovery occurs within 1–1.5 weeks.
9. Myocarditis, encephalomyocarditis of the newborn, hepatitis, kidney and eye damage (uveitis) – these forms of enterovirus infection in children are rare. Their clinical diagnosis is possible only in the presence of manifest forms of enterovirus infection or epidemic outbreaks of the disease. More often they are diagnosed during virologic and serologic studies.

The high tropism of the enterovirus to the nervous system is characterized by a variety of clinical forms of the most common lesions of the nervous system: serous meningitis, encephalitis, polyradiculoneuritis, neuritis of the facial nerve.

The leading place among childhood neuroinfections is still occupied by meningitis, which accounts for 70–80% of the total number of infectious lesions of the central nervous system. Every year there is an increase in the incidence of enteroviral meningitis in the summer-autumn period. Children of preschool and school age are ill mainly. Clinically aseptic serous meningitis caused by different types of polioviruses, ECNO viruses, Coxsackie A and B viruses is almost impossible to distinguish. Changes in cerebrospinal fluid are also indistinguishable. To date, the most common clinical form of enteroviral meningitis is well described.

According to the WHO, enteroviral infections of the heart are regularly registered in the world pathology. Depending on the causative agent, enteroviral infections of the heart have a quite definite share in the structure of the general infectious morbidity, which is about 4% of the total number of registered viral diseases. The largest number of enteroviral infections of the heart is due to Coxsackie B viruses, the second place among the causative agents of enteroviral infections of the heart (according to the specific weight in infectious diseases) is occupied by Coxsacke A viruses, followed by ECHO viruses and polioviruses.

The following clinical forms of virus-induced heart disease are distinguished: myo-, peri-, endocarditis, cardiomyopathy, congenital and acquired heart defects.

Clinical manifestations of enterovirus infections of the heart depend on the degree of myocardial involvement in the pathological process and can be accompanied by the almost complete absence of myocardial functional disorders and by severe cardiac damage, accompanied by dilatation of all chambers of the heart with a significant violation of systolic function. Enteroviruses have a high tropism for heart tissues, in which alternative-destructive processes develop first, due to the direct cytopathic effect of the virus, and subsequently virus-induced inflammation occurs with the formation of myo-, endo- and epicarditis, diffuse cardiosclerosis, leading to the development of dilated cardiomyopathy.

Of interest are the reports of vascular lesions in Coxsackie infections detected in patients with entroviral myocarditis.

Enterovirus 70 in recent years has caused numerous outbreaks of acute epidemic hemorrhagic conjunctivitis, prone to spread. In some patients, paralysis and paresis of varying severity and localization developed over a period of time from the onset of the disease. There are uveitis caused by ECHO 11, 19.

Enterovirus infections are most dangerous for immunosuppressive individuals: patients with malignant blood diseases, newborns, bone marrow transplants, HIV-infected patients.

Infection caused by the Coxsackie A9 virus is associated with the development of autoimmune diseases. The role of enteroviruses in the development of type 1 diabetes has been proven.

The literature discusses the role of enteroviral infections, in particular, Coxsackie viral, in the etiology of spontaneous miscarriages.

The defeat of the genital area is manifested by the clinic of parenchymal orchitis and epididymitis, caused most often by Coxsackie B1-5, ECHO 6, 9, 11 viruses. Enteroviruses as the cause of infectious orchitis take the second place after the virus of mumps. The peculiarity of this disease lies in the fact that at the first stage the clinic of another symptom complex, characteristic of enterovirus infection (herpangina, meningitis, etc.), develops, and after 2-3 weeks there are signs of orchitis and epididymitis. The disease occurs in children of pubertal age and is relatively benign, but may result in the development of azo-spermia.

Diagnosis of Enterovirus Infection

Diagnosis of enterovirus infection includes 4 main methods:

1. serological;
2. immunohistochemical;
3. molecular biological;
4. cultural.

Serological methods are aimed at identifying markers of enterovirus infections in the serum of patients. Early markers of infection include IgM and IgA. When detecting serological markers of enteroviral infections, the IgM titer is the most representative, which indicates a recent infection. Therefore, virus-specific IgM are convenient markers of a “fresh” antigenic stimulus, while IgG can be stored and circulated in the blood of a person who has been ill for several years or even the rest of their lives. Immunofluorescence and enzyme immunoassay are used to indicate IgM. In patients with acute symptoms of the disease, EV-specific IgM is determined 1–7 days after the onset of infection. After 6 months, IgM usually disappears.

Among the oldest, but relevant serological methods is the identification of virus-neutralizing antiviral antibodies in the neutralization reaction, a 4-fold or more increase in titer is considered diagnostically significant.

Virological methods of research are aimed at isolating enteroviruses from sensitive materials from clinical material (blood, feces, cerebrospinal fluid) of enteroviruses.

The main purpose of immunohistochemical methods is the detection of enteroviral antigens in situ. Immunofluorescence and immunoperoxidase assays are among the most accessible methods for immunohistochemistry.

Molecular biological research methods are aimed at identifying the genetic material of enteroviruses.

For the diagnosis of enteroviral infections, a polymerase chain reaction is used with a reverse transcription stage, which has several advantages over the above methods: high specificity, sensitivity and speed of execution.

Treatment of Enterovirus Infection

Interferons are used to prevent viral infections. This group of compounds belonging to low molecular weight glycoproteins, including those with anti-picornovirus activity, is produced by the cells of the body when exposed to viruses. An increased level of endogenous interferon in the cerebrospinal fluid has been shown in children with acute epidemic enteroviral meningitis, which plays a large role in the release of infection. Interferons are formed at the very beginning of a viral infection. They increase the resistance of cells to the defeat of their viruses. Interferons are characterized by a wide antiviral spectrum (they do not possess specificity of action against individual viruses). Resistance to interferon in viruses does not occur.

Currently, alpha-interferon drugs (alpha-2a, alpha-2b), both natural and recombinant, are mainly used as antiviral agents. Interferons are used topically and parenterally.

The second group of drugs used to treat enterovirus infections is immunoglobulins. Their clinical efficacy was shown in patients with enterovirus infection against the background of an immunodeficient state (congenital or acquired), as well as in neonatal practice in newborns with enteroviral infections who did not have antibodies to enterovirus infections (with neonatal sepsis in congenital enterovirus infection). The most effective was the intravenous administration of the drug, which is widely used in the treatment of immunodeficient patients with acute and chronic meningoencephalitis caused by enteroviruses. However, the experience of using immunoglobulins in this situation is not well understood. There is evidence of the successful cure of meningoencephalitis with intraventricular gamma globulin.

The third group – capsidin-inhibiting drugs. The most effective of this group is pleconaril. This is the most widely used etiotropic agent that has passed clinical trials. Pleconaril has demonstrated a broad spectrum of antiviral activity against both rhinovirus and enterovirus infections, and is distinguished by high bioavailability (70%) upon enteral administration.

This drug can be used and used in newborns with enteroviral meningitis at a dose of 5 mg / kg enterally 3 times a day for 7 days. There is a high level of pleconaril in the central nervous system and epithelium of the nasopharynx. When using pleconaril in different age groups, no side effects were noted. This drug is widely used for the treatment of meningitis, encephalitis, respiratory infections caused by enteroviruses. When pleconaril was used in the treatment of meningitis in children, a reduction in meningeal symptoms by 2 days was reliably observed.

Prevention of Enterovirus Infection

Specific prevention. Not developed.

Non-specific prophylaxis. In the focus of infection, contact children can bury leukocyte interferon in 5 caps. in the nasal passages 3-4 times a day for 7 days. Immunoglobulin has a protective effect in a dose of 0.2 ml / kg, in / m.
Airing and disinfection of premises, compliance with the rules for the removal and disinfection of sewage, providing the population with epidemiologically safe products.