MICROBIOLOGY

  • Member of Picornaviridae, (+) single strand RNA virus.
    • Formerly classified as belonging to four groups (echoviruses, Coxsackie A, Coxsackie B and polioviruses), but now non-polio enteroviruses separated into Coxsackie A, Coxsackie B, echovirus and others (newly discovered enteroviruses named by consecutive number: e.g., EV70).
    • Ubiquitous virus, totaling 62 non-polio enterovirus types: Group A Coxsackieviruses (1-22, 24), Group B Coxsackieviruses (1-6), Echoviruses (1-9, 11-21, 24-27, 29-33) and Enteroviruses (68-71).
  • Believed to be second most common cause of human viral infection after rhinoviruses.

CLINICAL

  • Enteroviruses spread mostly by fecal-oral route, but also found in respiratory secretions.
  • Peak acquisition typically in late summer and early fall.
    • Often spread in schools, daycare centers, and/or by contact with infected infants/toddlers during diaper changes.
      • Summer/Fall 2014: widespread outbreak, mostly in Midwest, school-aged children of severe respiratory infection with enterovirus d68 [EV-D68] strain, with fatal cases reported. More up to date information from CDC, 1035 cases reported in 47 states and D.C. (as 2014).
        • Typical sx: difficulty breathing, wheezing, hypoxemia; only a minority with fever.
        • Many afflicted have existing history of asthma.
        • Full spectrum of EV-D68 infection not yet understood, unclear if linked to acute flaccid paralysis investigated Aug 2014-July 2015 (in late 2015, only sporadic cases seen but vigilance for cases of acute flaccid myelitis emphasized by CDC).
    • Enterovirus 71: notable for epidemics of severe neurological disease, mostly children. Reports of increased cases seen in China, SE Asia since 2008.
    • Incubation period typically 3-5 days, but for CNS may be up to 12d after acquisition of infection.
  • Causes spectrum of human illness:
  • Dx: isolation of virus by culture or PCR (preferred) from normally sterile fluid/tissue diagnostic.
    • PCR superior to culture (in CSF PCR >80% yield vs. 30% for culture methods).
      • CSF findings may include PMN predominance early in infection that then changes to mononuclear cell pleocytosis.
      • EV-D68: first contact local/state health department.
        • CDC has testing available for faster, real-time RT-PCR.
        • Testing information from CDC. Submit nasopharyngeal or orpharyngeal swabs (preferred).
    • Note viral isolation from stool, especially in children given frequency of infection, is not sufficient to offer a definitive (but can be a supportive) diagnosis. Stool carriage of enterovirus may go on for over 8 wks from initial infection.
    • Serology available, but acute and convalescent specimens needed to secure diagnosis. Rarely helpful for acute diagnosis.

SITES OF INFECTION

  • Most infections (estimated 90%) are asymptomatic or only cause mild illness.
  • General viremia
  • Gastrointestinal: gastroenteritis, asymptomatic viral shedding.
  • Mucocutaneous: many manifestations.
    • Non-specific maculopapular rashes are most common [Figure 1], but petechial and purpuric rashes can also be seen.
    • Hand, foot and mouth disease (HFMD): lesions on hands/feet [Figure 2] and oral vesicles on tongue or buccal mucosa [Figure 3] is typically due to Coxsackie A virus.
    • Herpangina (tonsillar and posterior pharyngeal vesicles with associated severe sore throat) also typically due to Coxsackie A.
  • Nervous system: most common cause of aseptic meningitis (with enteroviruses accounting for perhaps 50% of cases in adults); also acute flaccid paralysis (polio, non-polio enteroviruses especially EV 71), meningoencephalitis, encephalitis.
    • EV71: capable of causing severe neurologic disease with epidemics especially in China, SE Asia, Taiwan, though found elsewhere. Virus can also cause asymptomatic infection, gastroenteritis, HFMD.
  • Cardiac: pericarditis, myocarditis.
  • Ocular: acute hemorrhagic conjunctivitis.
  • Respiratory: upper respiratory tract infections ("head colds," acute viral bronchitis), pleurodynia (epidemic pleurodynia sometimes called Bornholm’s disease, usually coxsackie B)
  • Neonatal infection: may be disseminated and fulminant, resulting in death.

TREATMENT

General recommendations

  • Most infections are self-limiting, with only supportive care needed.
  • Exceptions: severely immunodeficient patients (e.g., x-linked agammaglobulinemia), severe acute myocarditis, some cases of meningitis.

Meningoencephalitis

  • Treatment usually reserved for patients with severe immunodeficiency or persisting infection.
  • IVIG: data is mixed with reports of both successes and failures.
    • Most try it for severe cases, typical dose is 1-2 gm/kg IV infused over 24h.
  • Pleconaril, an experimental antiviral drug, appeared to have some benefit, but is no longer available.

Myocarditis

  • Severe cases in neonatal infants, children and adults have been treated with IVIG, with two trials showing some benefit (e.g., improved LV function[22][18]).
  • IVIG: typical dose is 2 gm/kg IV infused over 24h.

Prevention

  • EV71 vaccine: large trial completed in >10,000 patients demonstrating ~90% vaccine efficacy[8].
  • EV-D68: follow standard contact and respiratory droplet precautions.

FOLLOW UP

  • Most infections are without sequelae.
  • Severe infections can occasionally result in paralysis or other neurologic sequelae or, for cardiac cases, dilated cardiomyopathy.
  • Immunity is specific to a given serotype.

OTHER INFORMATION

  • Enteroviruses may play role in autoimmunity, provoking Type I, juvenile-onset diabetes mellitus.
  • EV-D68 resources for parents from CDC.

References

  1. Wang Z et al: Pulmonary and central nervous system pathology in fatal cases of hand foot and mouth disease caused by enterovirus A71 infection. Pathology 48:267, 2016  [PMID:27020504]

    Comment: Autopsy study of 15 cases of confirmed E-A71 infection. Most cases had death ascribed to neurogenic pulmonary edema. Brainstem involvement seen in most (11/15) with inflammation and clastmodendrosis but no viral antigen present. Lungs and hearts lacked evidence of any viral induced inflammation or pathology. For 11 of the 15 cases, reduction in lung aquaporin-4 staining possibly may play a role in the development of fatal pulmonary oedema.

  2. Abedi GR et al: Enterovirus and Human Parechovirus Surveillance - United States, 2009-2013. MMWR Morb Mortal Wkly Rep 64:940, 2015  [PMID:26334674]

    Comment: As of August 2015, 16 HPeV and 118 EV (4 EV species infect humans: A, B, C, and D) identified through surveillance in an effort to follow trends in these virus which usually cause mild infection (URI, herpangina, HFM disease) but can cause acute flaccid paralysis, myocarditis, meningoencephalitis.
    Most commonly reported types of EV and HPeV were coxsackievirus (CV) A6 and HPeV3 with results promoted likely by increased testing in response to outbreaks in 2011 & 2012.

  3. Farrell JJ et al: Enterovirus D68-associated acute respiratory distress syndrome in adult, United States, 2014. Emerg Infect Dis 21:914, 2015  [PMID:25897542]

    Comment: 26 yr old in Midwest with infection proven by RT-PCR. Authors suggest younger adults and obesity may be contributing to more severe infection.

  4. Buttery VW et al: Atypical Presentations of Hand, Foot, and Mouth Disease Caused by Coxsackievirus A6--Minnesota, 2014. MMWR Morb Mortal Wkly Rep 64:, 2015  [PMID:26225481]

    Comment: Rash in child (2 yrs) and pregnant mother was suspected to be varicella. Enterovirus instead detected by RT-PCR, Coxsackie A6.

  5. Midgley CM et al: Severe respiratory illness associated with enterovirus d68 - missouri and illinois, 2014. MMWR Morb Mortal Wkly Rep 63:798, 2014  [PMID:25211545]

    Comment: Outbreak of previously known but not widely circulated strain of enterovirus (first noted in 1962), noted due to emergence of NAAT-multiplex PCR of respiratory secretions. THis appears to cause os severe respiratory illness in children with fatalities. Only 79 EV-D68 reports during 2009–2013, current numbers unclear but thought to be vastly higher. Strain has been reported in Asia, Europe in older MMWR report, and associated with CNS dysfunction.

  6. Ayscue P et al: Acute flaccid paralysis with anterior myelitis - california, june 2012-june 2014. MMWR Morb Mortal Wkly Rep 63:903, 2014  [PMID:25299608]

    Comment: Cases of a polio-like paralysis are described. No clear etiology was identified to explain these reported cases, although EV-D68 was recovered from upper respiratory tract specimens of two patients. EV infection, including poliovirus infection, should be considered in the differential diagnosis in cases of AFP with anterior myelitis and testing performed per CDC guidelines.

  7. Fang Y et al: Risk factors of severe hand, foot and mouth disease: a meta-analysis. Scand J Infect Dis 46:515, 2014  [PMID:24832848]

    Comment: Analysis done given increase in severe HFM disease ascribed to enterovirus 71 mostly. Risks for severity include: fever ≥ 3 days, T ≥ 37.5°C, lethargy, hyperglycemia, vomiting, increased neutrophil count, EV71 infection, and young age.

  8. Zhu FC et al: Efficacy, safety, and immunology of an inactivated alum-adjuvant enterovirus 71 vaccine in children in China: a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial. Lancet 381:2024, 2013  [PMID:23726161]

    Comment: Since E71 has caused epidemics of severe neurological infection especially in children now for many years in SE Asia and Taiwan especially, there has been interest in a protective vaccine. This large trial showed about 90% vaccine efficacy with only a small percent of serious ADRs not significantly different than placebo

  9. Chi CY et al: Milrinone therapy for enterovirus 71-induced pulmonary edema and/or neurogenic shock in children: a randomized controlled trial. Crit Care Med 41:1754, 2013  [PMID:23685637]

    Comment: Small study of severe E71 infections in Vietnam in patients all receiving dopamine or dobutamine and intravenous immunoglobulin, with the milrinone arm with lower mortality and less time spent on ventilator. Milrinone is a phosphodiesterase 3 inhibitor that was developed to treat heart failure patients.

  10. Nigrovic LE: Aseptic meningitis. Handb Clin Neurol 112:1153, 2013  [PMID:23622323]

    Comment: Frequent problem in Emergency departments and hospital wards; PCR enterovirus diagnostics help avoid unnecessary antibiotics and/or hospital admission if done on a timely basis. Despite the advances and the frequency of enteroviral infections, the main issue is to rule-out bacterial infections due to their life-threatening nature. Supportive care remains the norm for enteroviral meningitis (up to 85-95% of acute, aseptic menignitis in some series) as it is usually a benign childhood infection.

  11. Yeung WC, Rawlinson WD, Craig ME: Enterovirus infection and type 1 diabetes mellitus: systematic review and meta-analysis of observational molecular studies. BMJ 342:, 2011  [PMID:21292721]

    Comment: Review of a growing body of evidence regarding the link of enteroviral infection and the development of insulin dependent diabetes mellitus. Authors suggest an overall odds ratio of 3.7, 95% CI 2.1-6.8)

  12. Cheng MF et al: Clinical application of reverse-transcription polymerase chain reaction and intravenous immunoglobulin for enterovirus encephalitis. Jpn J Infect Dis 61:18, 2008  [PMID:18219129]

    Comment: Study suggests that use of RT-PCR to hasten enterovirus diagnosis, with institution of IVIG if positive, may shorten duration of illness. It should be noted that number in study was 75, but no RT-PCR positive patient receiving IVIG had any sequelae, whereas one patient randomized to viral cx isolation had seizures.

  13. Fowlkes AL et al: Enterovirus-associated encephalitis in the California encephalitis project, 1998-2005. J Infect Dis 198:1685, 2008  [PMID:18959496]

    Comment: Seminal case series found that 4.6% of 1571 patients with encephalitis had enterovirus infection (45 confirmed cases, 28 possible). Only four cases were fatal, with 2 due to EV71. Most cases correlated with the prevalent circulating enteroviruses for that year.
    Rating: Important

  14. King RL et al: Routine cerebrospinal fluid enterovirus polymerase chain reaction testing reduces hospitalization and antibiotic use for infants 90 days of age or younger. Pediatrics 120:489, 2007  [PMID:17766520]

    Comment: One of many studies finding that use of enteroviral PCR on CSF leads to reductions in length of stay (by 1.54d) and use of antibiotics (by approximately one-third).

  15. Chang LY et al: Neurodevelopment and cognition in children after enterovirus 71 infection. N Engl J Med 356:1226, 2007  [PMID:17377160]

    Comment: Study examined neurological sequelae of EV71 infection. A total of 142 children were studied for an average of ~ 3yrs. 56% of pts with a poliomyelitis-like syndrome and 20% with encephalomyelitis experienced limb weakness and atrophy. For pts with cardiopulmonary failure and CNS involvement, about two-thirds had limb weakness and atrophy, while 61% needed tube feeding and 57% underwent ventilator support. Most strikingly, delayed neurodevelopment was found in only 1/20 patients (5%) with severe CNS involvement alone but in 21/28 pts (75%) with co-existent cardiopulmonary failure (P<0.001).

  16. Nasri D et al: Basic rationale, current methods and future directions for molecular typing of human enterovirus. Expert Rev Mol Diagn 7:419, 2007  [PMID:17620049]

    Comment: Authors note molecular diagnostics that have improved detection, mainly targeting the capsid (structural) proteins of enteroviruses (VP1, VP2 or VP4).

  17. Desmond RA et al: Enteroviral meningitis: natural history and outcome of pleconaril therapy. Antimicrob Agents Chemother 50:2409, 2006  [PMID:16801419]

    Comment: The drug failed (for other reasons), but use of pleconaril early in the course of enteroviral meningitis appeared to shorten illness, although impact was more modest in the severely ill group.

  18. Robinson J et al: Intravenous immunoglobulin for presumed viral myocarditis in children and adults. Cochrane Database Syst Rev  [PMID:15674945]

    Comment: Cochrane study states that evidence from only one RCT trial of 62 patients is insufficient to recommend IVIG for presumed viral myocarditis in adults.
    Rating: Important

  19. Lin TY et al: Enterovirus 71 outbreaks, Taiwan: occurrence and recognition. Emerg Infect Dis 9:291, 2003  [PMID:12643822]

    Comment: Several epidemics of EV71 in Taiwan have caused hand, foot and mouth disease in children, but some were afflicted with great severity, including cases of neurological and cardiopulmonary illness resulting in death.
    Rating: Important

  20. Huang CC et al: Neurologic complications in children with enterovirus 71 infection. N Engl J Med 341:936, 1999  [PMID:10498488]

    Comment: Main serious complication in this EV 71 outbreak was rhomboencephalitis among children (mean age 2.5 y) with two-thirds first presenting with hand-foot-mouth disease. Mortality rate was 14%.

  21. Ho M et al: An epidemic of enterovirus 71 infection in Taiwan. Taiwan Enterovirus Epidemic Working Group. N Engl J Med 341:929, 1999  [PMID:10498487]

    Comment: EV71 epidemic that may have afflicted >1 million individuals. Most cases initiated as HFM or herpangina in children <5 yrs of age. Of the 129,106 cases described in this report, 78 died, of whom 83% had pulmonary edema or hemorrhage.

  22. Drucker NA et al: Gamma-globulin treatment of acute myocarditis in the pediatric population. Circulation 89:252, 1994  [PMID:8281654]

    Comment: Open label trial using high-dose IVIG (2 gm/kg) vs. historical controls suggested benefit, as 21 patients receiving IVIG had improved LV function at 3 to 6 months.

  23. Misbah SA et al: Chronic enteroviral meningoencephalitis in agammaglobulinemia: case report and literature review. J Clin Immunol 12:266, 1992  [PMID:1512300]

    Comment: Data are mixed on whether IVIG is helpful, with multiple reports of successes but also failures.

  24. Ramers C et al: Impact of a diagnostic cerebrospinal fluid enterovirus polymerase chain reaction test on patient management. JAMA 283:2680, 2000 May 24-31  [PMID:10819951]

    Comment: Employment of enterovirus PCR resulted in faster hospital discharge, fewer tests, and less antibiotic use.

Media

Enteroviral Rash

Pt with non-specific febrile syndrome that defervesced once maculopapular rash developed.

Enteroviral enanthem

Lesions may be seen on palate or buccal mucosa.

Hand, foot, and mouth enteroviral infection

maculopapular lesions on palms and soles characteristic

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Last updated: May 29, 2016

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