OVERVIEW
Enteroviruses include polioviruses, coxsackieviruses, and echoviruses, as well as the new enterovirus types 68-71 that have been newly discovered in recent years. The relationship between coxsackieviruses, echoviruses, and new enteroviruses and human diseases is described here. These viruses cause widespread or epidemic illnesses throughout the world, affecting all systems of the body, and have become increasingly important, especially in childhood. Clinical manifestations are complex and varied, and although most are mild, they can be life-threatening. It can cause aseptic meningitis, poliomyelitis, myocarditis, epidemic chest pain, rash, herpes pharyngitis, respiratory tract infections, infantile diarrhea, and epidemic acute conjunctivitis.
Epidemiology
Patients and carriers of the virus are the source of infection. The virus is mainly excreted in the feces for 1 to 18 weeks, but can also be excreted from the pharynx for a short period of time, lasting about 3 weeks. The virus can be isolated from cerebrospinal fluid, blood, pleural fluid, rash blister plasma, bone marrow, saliva and urine of patients. Transmission is mainly through the intestinal tract, but can also occur via the respiratory tract or from contaminated hands, food, clothing, and utensils.
Coxsackieviruses and echoviruses are extremely widespread, with more epidemics occurring in summer and fall. Epidemics have been reported mainly in adults, although pediatrics are more likely to be infected than adults. These viruses are highly contagious and easily spread in families and collective institutions, and secondary infections can be as high as 40% to 70%, but hidden infections are far more common than overt infections, with a ratio of up to 130:1. The disease can be seen year-round, with a high prevalence in summer and fall. The epidemic is characterized by a change in the type of virus in the same region every year. Because of the high prevalence of fecal carriage of viruses in healthy individuals, especially in children (5%-50%), seroimmunological evidence, in addition to fecal isolation of viruses, should be required for the diagnosis of enteroviral infections.
Etiology
Thirty-one types of echovirus have been identified (types 1 to 34, of which types 10, 28, and 34 have been categorized as other viruses), which are infectious only in humans and are not pathogenic in suckling mice. Monkey kidney or human kidney cells are sensitive to echovirus and are commonly used to isolate the virus. Since 1986, new enterovirus types 68-71 have been discovered with immunologic specificities different from those of known coxsackieviruses and echoviruses. There is generally no cross-immunity between enterovirus types. Only a few types have antigenic crossover.
Symptoms
Clinical manifestations are complex and variable. The same type of virus may cause different clinical syndromes, while different types of virus may cause similar clinical manifestations.
1. Aseptic meningitis, encephalitis and paralytic disease
(1) Aseptic meningitis A7A9 and B2-5 are the most common types of Coxsackievirus. Echovirus types 4, 6, 9, 30 and enterovirus 71 often cause outbreaks of aseptic meningitis, while Echovirus types 2, 3 and 5 often cause disseminated cases. About 90% are caused by Coxsackie B and Echovirus. Aseptic meningitis outbreaks are widely dispersed and highly contagious, mostly occurring in summer and fall, with the majority of cases occurring in children under 14 years of age, and adults may also develop the disease during epidemics.
The clinical manifestations of enterovirus aseptic meningitis do not differ much from those caused by other viruses, and most of the small infants do not have neurological symptoms, while older children have fever, headache, vomiting, abdominal pain, sore throat, photophobia and other symptoms, often accompanied by a rash. Sometimes a bimodal fever may be present. Echococcal meningitis type 9 may have a rash, mostly maculopapular, sometimes with bruises. About 1/3 of patients present with signs of meningeal irritation 1 to 2 days after onset of illness. The general course of the disease is 5 to 10 days, most of them do not have paralysis, sometimes temporary muscle weakness can be seen, but the recovery of physical strength is slower, adult patients sometimes meningeal irritation signs can last for several weeks, or even months.
(2) Paralyzing diseases Coxsackie A7, 9, 10, B1 ~ 5, EK 4, 6, 9, 11, 14, 30 can be caused. However, enterovirus 71 is the main non-polio virus that can cause epidemic paralysis. The symptoms are usually mild and recovery is quick, rarely leaving sequelae, but severe cases causing medullary paralysis can be encountered in pandemics. There are reports of Coxsackie A2, 5, 6, 9 and EK 6, 22 causing multiple radiculitis.
(3) Encephalitis Coxsackie virus has been isolated from cases of summer encephalitis, and it has even been suggested that 15% of summer encephalitis is caused by Coxsackie virus. Coxsackie A2, 5, 7, 9 and B2, 3, 4 can cause encephalitis, EK 4, 6, 9, 11, 30 can also cause, especially EK 9 is common. The clinical manifestations of encephalitis caused by enteroviruses are similar to those of B encephalitis, which may include fever, confusion, convulsions, coma, imbalance, etc., and may be accompanied by electroencephalogram (EEG) abnormalities. Coxsackie group B virus can cause generalized encephalitis in neonates and infants, often accompanied by myocarditis and hepatitis, with multi-hazardous condition, acute onset, frequent convulsions, easy to develop respiratory failure, and severe cases can be fatal.
2. Heart disease
Mainly caused by Coxsackie B2, 3, 4 viruses, 1/3 to 1/2 heart disease caused by it, A4, 16 and EK 6, 8, 9, 22, 30 types of viruses can also be triggered. It has been suggested that when Coxsackie group B virus infection is prevalent, 33% of patients have cardiac lesions. It occurs mostly in newborns and young infants, occasionally in older children, and in recent years there have been a number of adult cases, with adolescents and young people being the most common, mostly disseminated, and with more males than females. Generally, it often starts with transient fever and cold symptoms for 7 to 10 days, followed by cardiac manifestations. There is weakness, chest pain, tachypnea and shortness of breath. Cardiac clinical manifestations can be categorized into the following types.
(1) Acute heart failure Most common in newborns, but can also occur in adults. The onset of disease is sudden, with bouts of cough, pallor, cyanosis and dyspnea, and heart failure also occurs rapidly. Heart sounds are muffled, heart rate increases, liver enlarges dramatically, accompanied by pulmonary edema, and ECG shows low voltage, tachycardia, T-wave inversion and ST-segment hypoplasia. Acute pericarditis may occur with myocarditis or alone. Serum cardiac enzymes are often elevated in acute myocarditis.
(2) Arrhythmia Clinical manifestations include premature beats, tachycardia or various types of conduction block. Electrocardiography helps to confirm the diagnosis. In mild cases, the recovery is fast, but it may last for months or even recur for years. This type is the most common.
(3) Sudden death often occurs at night, and autopsy confirms myocardial ischemic infarction or extensive myocardial necrosis, and enterovirus antigen can be found in cardiomyocytes.
(4) Chronic cardiomyopathy In recent years, countries have reported many subacute or chronic cardiac lesions caused by coxsackie group B virus, involving the cardiac conduction system, endocardium, heart valves, or pericardium, resulting in elastofibrillar hyperplasia, chronic cardiomyopathy, and stenotic pericarditis. Infections in the fetal period can lead to congenital heart disease, such as congenital calcific allodynia. About 1/3 of patients, especially newborns and infants, may have neurologic symptoms such as vomiting, convulsions, and unresponsiveness. The cerebrospinal fluid may have mononucleosis or may be completely normal. It can be called cerebro-cardiomyopathy.
3. Epidemic Myalgia or Epidemic Chest Pain
Most of them are caused by coxsackievirus group B types 1-6, but group A types 1, 4, 6, 9, 10 and echovirus types 1, 2, 6, 9 can also be caused. Localized outbreaks often occur. It is most common in older children and young adults. The incubation period is 2 to 5 days, which can be prolonged to 2 weeks, and the main manifestations are fever (up to 39°～40°C) and paroxysmal myalgia, which can involve all the muscles of the body, with the abdomen being the most common, especially the diaphragm being the most susceptible to involvement. The severity of myalgia varies, and in severe cases, it may even cause shock. In children, myalgia is less severe and intensifies with muscle activity. There are no abnormal findings on chest X-ray. Myalgia mostly disappears on its own after 4 to 6 days (12 hours to 3 weeks).
4. Herpes pharyngitis
It is mainly caused by coxsackie group A viruses, of which types A2, 4, 6, 9 (1-10), 16, 22 are common, and group B viruses of types 1-5 can also cause the disease, while echovirus causes fewer cases. The disease is spread all over the world, is distributed or epidemic, highly contagious. The incubation period is about 4 days on average, manifested as fever, sore throat (pain prominent when swallowing), pharyngeal congestion, pharynx with scattered gray-white herpes, 1 to 2mm in diameter, surrounded by a red halo, herpes ulceration to form yellow ulcers.
5. Rash disease
In the process of enterovirus infections often appear rash, coxsackievirus group A in 2, 4, 9, 16 types and group B in 1, 3, 5 types and rash is quite close relationship, echovirus 4, 9, 16 types of infections occur especially rash. Rash is common in infants and children, but less common in adults. The incubation period is mostly 3 to 6 days, with fever and upper respiratory symptoms such as mild cough and sore throat at the onset of the disease, followed by a rash. The rash is polymorphic, including macular rash, maculopapular rash, rubella-like rash, herpes or measles-like rash. There are also rashes that appear when the fever subsides, mostly caused by echovirus 16, which is easily mistaken for acute rash in young children. Coxsackie A9 often causes petechiae. In addition to rash, sometimes accompanied by generalized or cervical and retrooccipital lymph node swelling.
6. Respiratory tract infection
Enteroviruses often cause upper respiratory tract infections, such as Coxsackie virus A21, 24 and B2-5 types have caused light respiratory tract infections in the epidemic, A21 is mostly prevalent in the barracks, the pharyngeal swab positive rate is high. Echovirus types 4, 7, 11, 20, 25, 30 and other types can cause certain influenza-like illness or pharyngitis, Coxsackie B1, 4 can cause bronchitis, Coxsackie A9, 16 and B4, 5, as well as Echovirus types 9, 19 can cause lower respiratory infections such as infantile pneumonia and capillary bronchiolitis, which can be characterized by persistent dyspnea, cyanosis, hypoxia, etc., and even death due to asphyxia. Enterovirus 68 has been shown to be the cause of pneumonia and bronchiolitis.
7. Hand, foot and mouth disease
HFMD is mainly caused by coxsackievirus A5, 9, 10, 16 and B2, 5, especially A16, enterovirus 71 can also cause. There are reports that the causative virus has been isolated from the rash. The disease is highly contagious, commonly occurring in the whole family and can cause localized outbreaks, with an incubation period of 2 to 5 days. Initial symptoms include low-grade fever, runny nose, anorexia, sore mouth, vomiting and diarrhea. Small herpes appear in the oral mucosa, often distributed in the tongue, buccal mucosa, hard palate, can also be seen in the gums, tonsils and pharynx, soon herpes ulceration into an ulcer. In stomatitis at the same time can appear skin maculopapular rash, to hands and feet, located in the dorsum of the hands, between the fingers, occasionally in the trunk, thighs, buttocks, upper arms and other places. Papules quickly turned into small herpes, smaller than the chickenpox rash, and slightly hard, from a few to dozens, self-absorbed within 2 to 3 days, without leaving scabs. Prognosis is generally good, mostly self-healing, but can recur, sometimes accompanied by aseptic meningitis, myocarditis and so on.
8. Infantile diarrhea
Echovirus and infant diarrhea is very close, from the child feces are often isolated to 6, 7, 11, 14, 18 types of viruses, 18 types of viruses have caused diarrhea epidemics in the delivery room. Clinical symptoms are similar to those of general infantile diarrhea and are mostly mild. Because of the high culture-positive rate of enteroviruses in the feces of healthy children, other epidemiologic and serologic evidence is needed to confirm the diagnosis of the causative agent of diarrhea.
9. Acute epidemic hemorrhagic conjunctivitis
The incubation period is about 1 day. The main clinical manifestation is acute conjunctivitis. Suddenly the eyelids are red and swollen, the conjunctiva is congested and tearing, and there may be thick secretion and subconjunctival hemorrhage, but sclera and iris are rarely involved. The parotid gland may be enlarged, and systemic symptoms are minimal, mostly resolving spontaneously within 1 to 2 weeks.
10. Neonatal coxsackievirus and echovirus infection
Enteroviral infections in the neonatal period have similar clinical manifestations as those in older infants and young children, but there are also many cases of severe systemic infections, most commonly caused by Coxsackie B2-5 and Echovirus 11, and in a few cases by Coxsackie A3, 9 and 16. Most of these viruses are transmitted from the mother, but they can also be acquired from hospital staff. Intrauterine infections have an early onset, whereas most of the perinatal infections have a slightly later onset. The onset of the disease usually starts from 3 to 7 days after birth. Early general symptoms are mild and nonspecific, such as restlessness, hypomania, temporary dyspnea, fever may or may not be present, and sometimes there may be a 1 to 7 day interval of symptomatic improvement between prodromal symptoms and severe symptoms. Systemic severe symptoms are mainly characterized by acute myocarditis or extensive hepatitis, myocarditis, often caused by group B coxsackievirus, often accompanied by encephalitis. Neonates may suddenly develop dyspnea, increased heart rate often exceeding 200 beats per minute, heart enlargement, systolic murmur and electrocardiographic changes, and finally die of heart failure and shock, often accompanied by systemic damage to multiple organs such as the brain, liver, pancreas, adrenal glands have lesions, the case fatality rate is generally less than 50%, survivors of myocardial function can be recovered in a short period of time, and a small number of delayed for a few weeks.
Severe neonatal hepatitis is mostly caused by echovirus 11 and has also been reported to be caused by echovirus types 4, 6, 7, 9, 12, 14, 19, 21, and 31. Initial symptoms include refusal to eat and lethargy, deepening jaundice, progression and hemorrhagic tendency within 1 to 2 days, skin bruising, acidosis, worsening of hemorrhagic symptoms, hepatic and renal failure, and convulsions. Liver function is abnormal, aminotransferase rises, platelet decreases, prolonged prothrombin time, etc. White blood cell count and classification are normal.
11. Chronic meningoencephalitis occurring in immunocompromised patients
In congenital or secondary B-lymphocyte deficiency, mostly X-associated gammaglobulin deficiency children suffering from enteroviral infections can cause chronic, persistent central nervous system lesions. Most of them are caused by echoviruses, and there are some isolated reports caused by Coxsackie A4, 11, 15, or group B types 2 and 3. They may start with no neurological symptoms or only headache, mild neck stiffness, drowsiness, and motor weakness. Later, there is limb tremor, fundus edema, convulsions, unsteady gait, and ataxia. These symptoms and signs may be mild or severe, and fluctuate during the course of the disease. Cerebrospinal fluid lymphocytosis, protein is higher than the general aseptic meningitis, the virus can be repeatedly detected from the cerebrospinal fluid for several months to several years, but the positive rate in the feces is low, the brain, lungs, liver, spleen, kidneys, myocardium, skeletal muscle and bone marrow can also be detected virus sometimes. Therefore, it is believed that this disease is caused by the virus directly invading the tissues and organs.
12. Other
Enterovirus can also invade the parotid gland, liver, pancreas, testes and other organs, causing corresponding clinical manifestations. In recent years, it is also believed that enterovirus infection is related to rheumatism, nephritis, hemolytic uremic syndrome, diabetes mellitus and so on.
Examination
1. Blood test
The white blood cell count in peripheral blood is mostly normal, but it can be increased in some enterovirus infections, and the neutrophils can also be increased.
2. Virus isolation
Generally, pharyngeal swabs and feces are taken for virus isolation and determination, and viruses can also be isolated from cerebrospinal fluid, pleural fluid, pericardial fluid, blood, herpes plasma, and tissues obtained by biopsy or autopsy. Specimens should be sent for testing as soon as they are obtained. It can be inoculated into monkey kidney, human embryonic kidney, human amniotic membrane, human diploid or Hela cells, and KB passaged cells for tissue culture and observation of cell lesions. Simultaneous isolation with multiple tissue culture cells can increase the positive rate. Positive specimens are then type-identified by a neutralization test with type-specific immune sera. For suspected Coxsackie A virus infection, the specimen should be inoculated into suckling mice via subcutaneous, intraperitoneal or intracerebral routes for virus isolation, because the positive rate of tissue culture is not high. Coxsackie B virus can also cause disease in suckling rats.
3. Serum immunology test
Serum is taken in duplicate to determine the level of type-specific antibodies. Generally, neutralization test, complement binding test, enzyme-linked immunosorbent assay (ELISA, enzyme labeling method), radioimmunoassay and other methods can be used to determine the level of antibodies, among which the neutralization test is the most reliable, and the neutralization antibody disappears the slowest, and the type-specificity is also strong. If the antibody level rises ≥4 times in the recovery period compared with the early period, it is of great diagnostic significance.
4. Immunofluorescence rapid diagnosis method
The identification of antigen by fluorescence staining of immune antibody can achieve the purpose of rapid diagnosis. However, at present, except for poliovirus infection, not many enterovirus infections, because of the need to prepare a variety of type-specific immune sera, the procedures are cumbersome. Recently, the immunodiagnostic method has been improved by the use of VP3-ZC antigen, which is common to many serotypes, and a monoclonal antibody that cross-reacts with the VP1 capsid protein of many serotypes, but it is still at the research stage.
5. Nucleic acid hybridization
Due to the existence of homology between the genomes of different serotypes of enteroviruses, especially the 5′ end of the non-coding region of part of the region is highly conserved, so it can be used for nucleic acid hybridization, so that in recent years, the identification of enteroviruses has made a new leap forward. In recent years, PCR has been used to amplify single genes or short DNA sequences and then hybridize them with probes, and this method has been applied in the clinic. In an epidemic of enterovirus central nervous system infections, detection of enterovirus RNA from cerebrospinal fluid has a high positive rate and results can be obtained within 24 hours, which is much faster than the average viral culture that takes 6 to 8 days. Clinical specimens amplified by PCR and hybridized with non-isotopically labeled enterovirus probes yield results in a few hours, greatly assisting in confirming the clinical diagnosis.
Diagnosis
Clinical manifestations of enterovirus infection are complex and varied, and since there are many fecal carriers of the virus in the healthy population, the diagnosis must be made with great care, and the diagnosis can only be confirmed if the following points are met.
1. It is diagnostic value to isolate the virus from the patient’s body fluids (pleural fluid, pericardial fluid, cerebrospinal fluid, blood, herpetic fluid, etc.) or biopsy (or autopsy) tissues, but isolation of the virus from the pharyngeal swabs or feces alone cannot confirm the diagnosis.
2. If the antibody potency in the blood increases fourfold or more than fourfold during the recovery period (3-4 weeks after the onset of the disease) compared with that in the early stage of the disease, then there is a possibility of recent infection. Neutralizing antibodies are the most reliable.
3. Clinical syndromes such as epidemic myalgia, herpetic pharyngitis, acute infantile myocarditis, aseptic meningitis, and acute epidemic conjunctivitis are present. Repeated isolation of the same type of virus from pharyngeal swabs or feces, and detection of the same virus from people with the same disease in the periphery, with a much higher isolation rate of the virus than that of controls who have not been in contact with the patient, are diagnostic references.
Treatment
So far there is no specific treatment, mainly for general treatment and symptomatic treatment. In the acute stage, bed rest should be provided, and those with vomiting and diarrhea should pay attention to the water-electrolyte balance, and those with convulsions and severe myalgia should be given appropriate sedatives and painkillers. When acute myocarditis with heart failure occurs, early application of rapid mauve diaphragm chemotherapy, oxygen supply, diuresis and other active rescue should be applied.
Animal experiments have found that adrenocorticotropic hormone can inhibit the synthesis of interferon in the early stage, thus promoting the reproduction of the virus, so in the early stage of the disease generally do not advocate the application of the disease, but for certain serious conditions such as acute myocarditis with cardiac failure, shock or severe arrhythmia, the clinic is still the use of adrenocorticotropic hormone, and no adverse effects have been found. Hydrocortisone or prednisone is generally used in adults.
Prognosis
The vast majority of enteroviral infections are mild and generally result in uneventful recovery. Neonates with systemic infections affecting vital organs such as the heart, brain, and liver are in critical condition and have a poor prognosis. Paralysis rarely occurs in acute central nervous system infections, and those with mild paralysis recover quickly, rarely leaving sequelae. Individual viruses that invade the medulla oblongata and cerebral bridges in pandemics can also be life-threatening. Acute myocarditis mostly recovered, but sudden death can also occur, individual patients with prolonged or repeated episodes of the disease, can lead to chronic cardiomyopathy.
Prevention
Emphasis on environmental hygiene and personal hygiene, and strengthening physical exercise all help to prevent the epidemic of this disease. Infants and young children who come into contact with patients can be injected with gammaglobulin or placental globulin to prevent infection. Widespread administration of live attenuated polio vaccine has also been used to control epidemics of aseptic meningitis caused by other enteroviruses by producing an intestinal interference effect. This is a non-specific prophylactic measure that warrants further study. Since there are many types of coxsackieviruses, echoviruses and other enteroviruses, it is difficult to prepare type-specific vaccines, and they cannot be used universally at present.