More than 90% of coxsackieviruses infections are asymptomatic or cause nonspecific febrile illnesses. In neonates, they are the most common cause of febrile illnesses during the summer and fall months. As measured yearround, thirteen percent of newborns with fever in the first month of life were noted to have an enteroviral infection. In addition to nonspecific febrile illnesses, various well-described syndromes also have been associated with coxsackievirus infections.
Aseptic meningitis
Patients with aseptic meningitis may have rapid or gradual onset of fever and chills, nausea and vomiting, malaise, headaches, neck pain, light sensitivity, and upper respiratory symptoms. Infants younger than 3 months have been noted to have the highest incidence of clinically recognized aseptic meningitis, partly because lumbar punctures often are performed for the evaluation of fever in this age group. These infants often present with only a febrile illness characterized by irritability and anorexia. Meningismus occurs in approximately 50% of infants with enteroviral meningitis.
Coxsackievirus B infection is more likely than coxsackievirus A to be associated with meningitis. [12]
Seizures, lethargy, and movement disorders can occur early in the course of disease and have been reported in 5-10% of patients with enteroviral meningitis. No long-term neurologic deficits appear to exist in infants with aseptic meningitis caused by coxsackievirus. Adults may experience a more prolonged period of fever and headache compared with infants and children.
Encephalitis
Encephalitis is an unusual manifestation of CNS infection, although it sometimes is observed in association with aseptic meningitis. Enteroviruses account for approximately 5% of all cases of encephalitis. Coxsackievirus types A9, B2, and B5 have been linked with encephalitis.
Other neurologic syndromes
Rarely, coxsackieviruses have been implicated in other sporadic neurologic syndromes such asacute flaccid myelitis(AFM)that closely mimics poliovirus infection.In particular, Enterovirus D68 (EV-D68) is of prime interest as a causative agent of AFM. Initially described in the context of AFM in 2005, EV-D68 was associated with a sizable AFM outbreak in the United States in 2014, with additional outbreaks described in 2016 and 2018. [5] Enterovirus A71 and coxsackievirus A16 also have been described in cases of AFM. [5] Additionally, cases of Guillain-Barré syndrome have been described with coxsackievirus serotypes A2, A5, and A9.
Myopericarditis
Myopericarditis can occur at any age, but the condition occurs more often in adolescents and young adults. Enteroviruses account for half of all cases of acute viral myopericarditis.
Manifestations of myopericarditis range from an asymptomatic presentation to heart failure and death. Between the two extremes, most patients report dyspnea, chest pain, fever, and malaise.
Symptoms may be preceded by an upper respiratory infection within the preceding 7 to 14 days.
Presenting signs include pericardial friction rub, gallop rhythm, and cardiomegaly and/or pericardial effusion on chest radiography.
ECG abnormalities range from ST-segment elevations to heart block. Echocardiography can show diminished ejection fraction and/or left ventricular wall-motion abnormalities. Myocardial enzyme levels in the serum frequently are elevated.
The male-to-female ratio of myopericardtis is 2:1. The overall mortality rate is low, and the prognosis generally is better in children than adults. Complications include pericardial effusion, arrhythmia, heart block, valvular dysfunction, and dilated cardiomyopathy.
Diabetes
Although principally correlative, data suggests that autoimmune insulin-dependent diabetes is associated with group B coxsackievirus infections.Viral infection alone is not thought to be sufficient to cause autoimmune insulin-dependent diabetes. [3] However, multiple factors, including viral load and type of infection along with host genetics and the pancreatic environment are thought to play significant roles in disease development. [3, 13] Epidemiologic data note that clustering of new onset diabetes mellitus occurs 1 to 3 months following infection. Similarly, animal models have described infection of pancreatic islet cells by coxsackieviruses with multiple proposed mechanisms of action. Persistent rather than acute coxsackievirus B infection of the islet cells has been demonstrated, which can lead to beta-cell destruction via interferon and T-cell-mediated autoimmune pathways. [14] Thymic dysfunction also has been implicated by means of coxsackievirus-B-induced thymic atrophy, apoptosis, and lymphocyte maturation impairment, leading to autoreactive T-cell production. [15]
Exanthems and enanthems
Two of the most distinctive rash syndromes caused by coxsackieviruses are hand, foot, and mouth disease (HFMD) and herpangina.
HFMD often affects children and easily spreads to close contacts. Patients present with a sore throat and painful lesions in the mouth. Vesicles that coalesce, form bullae, and then ulcerate, occur on the buccal mucosa and tongue. Seventy-five percent of patients have simultaneous peripheral cutaneous lesions. HFMD also can present more atypically, including as eczema coxsackium, with erosions or bullous lesions. [16, 17] Biopsy reveals intracytoplasmic viral particles. Coxsackieviruses A16, A6, and A10 are among the most common types implicated in HFMD. Numerous cases of a more severe HFMD caused by coxsackievirus A6 were reported between 2004 and 2011 in several Asian and European countries. Additionally, between 2011 and 2012 in the United States, among cases of severe HFMD that were reported, 74% had a positive PCR test for coxsackievirus A6; about 25% of reported cases occured in adults.
Herpangina is a vesicular enanthem of the posterior oropharynx. Patients often present with fever, sore throat, occasional throat exudate, odynophagia, and dysphagia. Dysphagia is observed more often in young children than in adolescents and adults. Prompt recovery is typical, with almost all patients recovering completely. Group A coxsackieviruses are the most common viruses isolated from herpangina patients.
Epidemic pleurodynia
Epidemic pleurodynia is a muscular disease in which viral invasion of muscle tissue causing inflammation is suspected; however, direct histologic evidence is lacking. Epidemic pleurodynia usually is associated with outbreaks of group B coxsackievirus infection.
Patients present with fever and sharp, paroxysmal, spasmodic pain in the chest and upper abdomen.
Acute hemorrhagic conjunctivitis
Pain and edema of the eyelids and subconjunctival hemorrhage are present.
Patients may report photophobia, foreign body sensation, fever, malaise, and headache. Symptoms usually resolve spontaneously within 1 week.
Rare complications include keratitis and motor paralysis.
This condition is highly contagious and has resulted in epidemics and pandemics. [18]
Sepsis
Coxsackieviruses have been identified in young pediatric patients with sepsis. Five coxsackievirus A serotypes (2, 4, 6, 10, 16) and one coxsackievirus B serotype (9) have been implicated. Coxsackievirus B9 also has been identified in neonatal sepsis. [19]
