Definition, Etiology, PathogenesisTop
1. Etiologic agent: RNA viruses belonging to the Picornaviridae family, Enterovirus genus. Two subgroups are distinguished: Coxsackie A (23 serotypes) and Coxsackie B (6 serotypes). For hand-foot-and-mouth disease (HFMD), the most common Coxsackie serotype is A16.
2. Pathomechanism: The virus enters the host’s body through the respiratory tract and infects lymphatic tissue within 24 hours. Initially it replicates in the tonsils and lymphatic system of the gastrointestinal (GI) tract. Low-level viremia occurs after ~3 days, and then the infection spreads to other organs. Coxsackie serotypes differ in their tissue tropism and may infect various organs, eg, the meninges and brain, skeletal muscles, myocardium, skin, pancreas, and liver. In the second stage of infection, replication occurs in the affected organs. The virus has a direct cytopathic effect resulting in the presence of inflammatory infiltrates and perivascular necrosis in the tissue. The viral load is high and clinical manifestations of infection occur (typically between day 3 and 7 of infection). After ~7 days neutralizing antibodies are produced and the viremia decreases.
3. Reservoir and transmission: Primary transmission is fecal-oral, through contact with infected secretions (oral, respiratory, conjunctival) or contaminated fomites.
4. Incubation and contagious period: The incubation period is 3 to 6 days, except for acute hemorrhagic conjunctivitis, where the incubation period is from 1 to 3 days. Coxsackie viruses are most contagious during the first week of symptoms. The virus can persist in the respiratory system for up to 3 weeks and may be shed with feces for 2 months, but it becomes less contagious over this time period. Coxsackie viruses are resistant to external environmental factors (at 4 degrees of Celsius they can remain contagious for several weeks).
Clinical Features and Natural HistoryTop
The course of infection depends on the Coxsackie virus serotype. In some cases (eg, infection with serotypes A16, B3, B4), ~90% of infections are asymptomatic. Most commonly infections are self-limited, including HFMD, herpangina, and pleurodynia. Severe manifestations are rare and include meningitis, encephalitis, and myocarditis.
1. Fever, sometimes with manifestations of respiratory tract infection: A typical course has 2 phases: after 1 to 2 days of fever, the patient feels well for another 2 to 3 days, and then fever recurs and persists for 2 to 4 days.
2. Rash (multiple forms): Macular, maculopapular, or vesicular; rubella-like, measles-like, petechial, or resembling allergic lesions. Rash may accompany changes in other organs.
3. HFMD: It most frequently affects children aged <10 years. It has an acute onset with fever and malaise. After 1 to 2 days vesicles with erythematous rims appear on the dorsal and palmar hand surfaces, on feet, and in the mouth. Ulceration may be seen, particularly in the oral mucosa. If no bacterial superinfection develops, lesions heal spontaneously after ~7 days without scarring.
4. Conjunctivitis, uncommonly hemorrhagic conjunctivitis.
5. Herpangina: As the name indicates, the disease manifests with herpes-like vesicles on the tonsils. It usually occurs in summer, most often in children aged 2 to 10 years. Herpangina starts with high-grade fever, sore throat, and vomiting. Vesicles have several millimeters in diameter and are surrounded by erythematous rims. They appear on the tonsils, palate, and palatine arches. Unlike in HFMD and herpes simplex virus (HSV) infection, lesions do not form in the mouth or on the tongue. Single or multiple vesicles may be observed. Mild erythema of the pharyngeal and oral mucosa may develop. Pharyngeal lesions may be accompanied by sialadenitis. The disease subsides spontaneously after 3 to 6 days.
6. Epidemic pleurodynia (epidemic myositis, Bornholm disease, devil’s grip): An acute condition that manifests with severe paroxysmal pain in the chest and epigastrium, accompanied by elevated body temperature; during an attack the patient is pale and sweats. The name of the disease may be misleading, as the condition actually does not affect the pleura (or peritoneum), and the pain originates in the muscles. Pleural rub is sporadically found on auscultation. The affected muscles of the chest and abdomen are tense and tender on palpation; signs and symptoms may sometimes raise a suspicion of “acute abdomen.” The manifestations usually persist for 4 to 6 days; in adults they may last longer and be more severe than in children.
7. Myocarditis and pericarditis: see Pericarditis.
8. Central nervous system (CNS) inflammation:
1) Aseptic meningitis: Coxsackie virus infection is the underlying cause in the majority of cases. Epidemics usually occur in September and October. The course of the disease is typical as in viral meningitis, sometimes accompanied by rash, gastroenteritis, or pharyngitis. Signs and symptoms usually resolve within ~7 days in children but may persist longer in adults.
2) Encephalitis may occur independently or in conjunction with meningitis. The majority of patients (except for neonates) reach full recovery; permanent neurologic complications and death occur rarely.
9. Other manifestations: GI infection, hepatitis, acute pancreatitis, epididymo-orchitis, urinary tract infection, conjunctivitis; Coxsackie viruses are thought to contribute to the pathogenesis of type 1 diabetes.
Identification of the etiologic agent:
1) Serologic tests: Specific IgM antibodies appear in blood 1 to 3 days after symptom onset and are detectable for 2 to 3 months. IgG antibodies can be detected within 7 to 10 days of infection and circulate in the host’s body for lifetime.
2) Culture and molecular studies: Material: stool, cerebrospinal fluid, and pharyngeal smears. These investigations are helpful in establishing epidemic outbreaks. In clinical practice molecular studies have been increasingly used (reverse transcriptase–polymerase chain reaction [RT-PCR]). In myocarditis the diagnosis can be confirmed based on PCR testing of an endomyocardial biopsy specimen.
In the case of herpangina and HFMD, the diagnosis is made based on clinical features, and in other forms of infection, based on results of serologic and molecular studies.
1) Rash: Scarlet fever, rubella, measles, allergic rash.
2) HFMD: Varicella, herpes.
3) Herpangina: Viral or bacterial pharyngotonsillitis, oral herpes simplex infection (involving the mouth and gums), aphthae.
4) Pleurodynia: Pneumonia, pleuritis, herpes zoster, myocardial infarction, pulmonary infarction, acute abdomen.
6) CNS inflammation (see Central Nervous System (CNS) Infections).
Depending on presentation, antipyretic, analgesic (in pleurodynia), and anti-inflammatory agents are used. Treatment of myocarditis: see Myocarditis.
1) Bacterial superinfection in diseases accompanied by vesicular rash.
2) Dilated cardiomyopathy in diseases accompanied by myocarditis (in ~10% of such patients).
3) Chronic meningitis and encephalitis in patients with impaired humoral immune response (particularly with agammaglobulinemia).
The prognosis is good in the majority of cases, except for neonates, who may have long-term neurologic sequela.
Immunoprophylaxis: None available.
1. Patient isolation: Hand hygiene; contact and droplet precautions should be taken in patients with involvement of the respiratory system, skin, and mucosa.
2. Personal protective measures: Strict hygiene: hand washing and avoidance of bathing in small, natural water reservoirs (ponds).