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).
  • A 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 the second most common cause of human viral infection after rhinoviruses.

CLINICAL

• Enteroviruses spread mostly by the 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 during summer and fall.
    • Outbreaks of severe respiratory infection with enterovirus d68 [EV-D68] strain, with fatal cases reported in 2014, 2016 and 2018.
      
      • Typical sx: difficulty breathing, wheezing, hypoxemia; only a minority with fever.
      • Many afflicted have an existing history of asthma.
      • Full-spectrum of EV-D68 infection not yet understood.
        • Has been associated with acute flaccid myelitis (AFM).
  • Enterovirus 71: notable for epidemics of severe neurological disease, mostly children. Reports of increased cases seen in China, SE Asia since 2008.
  • The incubation period typically 3-5 days, but for CNS may be up to 12d after the acquisition of infection.
• Causes spectrum of human illness:
  
  • Respiratory: bronchitis, common cold, severe respiratory infection.
    • Enterovirus 71: most fatal cases ascribed to neurogenic pulmonary edema[2].
  • Cutaneous: febrile illness with a rash (hand, foot and mouth disease)
  • GI: gastroenteritis
  • Ocular: acute hemorrhagic conjunctivitis
  • Neuro: aseptic meningitis, encephalitis, acute flaccid myelitis
  • Cardiac: myocarditis
  • Neonatal sepsis-like disease
• 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 oropharyngeal swabs (preferred).
  • Note viral isolation from the stool, especially in children given the frequency of infection, is insufficient to offer a definitive (but can be a supportive) diagnosis. Stool carriage of enterovirus may go on for over 8 wks from the initial infection.
  • Serology available, but acute and convalescent specimens needed to secure a 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.
  
  • Nonspecific 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 the tongue or buccal mucosa [Figure 3] are typically due to coxsackie A virus.
  • Herpangina (tonsillar and posterior pharyngeal vesicles with an 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. The virus can also cause asymptomatic infection, gastroenteritis, HFMD.
  • EV D68: associated with sporadic cases and outbreaks of acute flaccid myelitis (AFM) across the U.S. AFM criteria: sudden onset of flaccid limb weakness and laboratory/imaging criteria(MRI showing a spinal cord lesion in at least some gray matter and excluding persons with gray matter lesions in the spinal cord resulting from physician-diagnosed malignancy, vascular disease, or anatomic abnormalities) for AFM.
• 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

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 a role in autoimmunity, provoking type I, juvenile-onset diabetes mellitus.
• EV-D68 resources for parents from the CDC.

References

1. Kujawski SA, Midgley CM, Rha B, et al. Enterovirus D68-Associated Acute Respiratory Illness - New Vaccine Surveillance Network, United States, July-October, 2017 and 2018. MMWR Morb Mortal Wkly Rep. 2019;68(12):277-280.  [PMID:30921299]

   Comment: This report provides updated information on EV-D68 prevalence in children through active surveillance of pediatric children at 7 US medical centers throught the New Vaccine Surveillance Network. EV-D68 testing occurred in all patients who visited the emergency department (ED) or were hospitalized with acute respiratory illness (ARI) at all NVSN sites during July 1–October 31, 2017, and the same period in 2018. Among patients with ARI who were tested, EV-D68 was detected in two patients (0.8%) in 2017 and 358 (13.9%) in 2018. Detections in 2018 oeaked in September.
   Rating: Important
   

2. Wang Z, Nicholls JM, Liu F, et al. Pulmonary and central nervous system pathology in fatal cases of hand foot and mouth disease caused by enterovirus A71 infection. Pathology. 2016;48(3):267-74.  [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.
   

3. Abedi GR, Watson JT, Pham H, et al. Enterovirus and Human Parechovirus Surveillance - United States, 2009-2013. MMWR Morb Mortal Wkly Rep. 2015;64(34):940-3.  [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.
   

4. Buttery VW, Kenyon C, Grunewald S, et al. Atypical Presentations of Hand, Foot, and Mouth Disease Caused by Coxsackievirus A6--Minnesota, 2014. MMWR Morb Mortal Wkly Rep. 2015;64(29):805.  [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, Jackson MA, Selvarangan R, et al. Severe respiratory illness associated with enterovirus d68 - missouri and illinois, 2014. MMWR Morb Mortal Wkly Rep. 2014;63(36):798-9.  [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, Haren KV, Sheriff H, et al. Acute flaccid paralysis with anterior myelitis - california, june 2012-june 2014. MMWR Morb Mortal Wkly Rep. 2014;63(40):903-6.  [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, Wang S, Zhang L, et al. Risk factors of severe hand, foot and mouth disease: a meta-analysis. Scand J Infect Dis. 2014;46(7):515-22.  [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, Meng FY, Li JX, 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. 2013;381(9882):2024-32.  [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, Khanh TH, Thoa le PK, et al. Milrinone therapy for enterovirus 71-induced pulmonary edema and/or neurogenic shock in children: a randomized controlled trial. Crit Care Med. 2013;41(7):1754-60.  [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. Yeung WC, Rawlinson WD, Craig ME. Enterovirus infection and type 1 diabetes mellitus: systematic review and meta-analysis of observational molecular studies. BMJ. 2011;342:d35.  [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)
    

11. Cheng MF, Chen BC, Huang TS, et al. Clinical application of reverse-transcription polymerase chain reaction and intravenous immunoglobulin for enterovirus encephalitis. Jpn J Infect Dis. 2008;61(1):18-24.  [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.
    

12. Fowlkes AL, Honarmand S, Glaser C, et al. Enterovirus-associated encephalitis in the California encephalitis project, 1998-2005. J Infect Dis. 2008;198(11):1685-91.  [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
    

13. Chang LY, Huang LM, Gau SS, et al. Neurodevelopment and cognition in children after enterovirus 71 infection. N Engl J Med. 2007;356(12):1226-34.  [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).
    

14. Desmond RA, Accortt NA, Talley L, et al. Enteroviral meningitis: natural history and outcome of pleconaril therapy. Antimicrob Agents Chemother. 2006;50(7):2409-14.  [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.
    

15. Robinson J, Hartling L, Vandermeer B, et al. Intravenous immunoglobulin for presumed viral myocarditis in children and adults. Cochrane Database Syst Rev. 2005.  [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
    

16. Lin TY, Twu SJ, Ho MS, et al. Enterovirus 71 outbreaks, Taiwan: occurrence and recognition. Emerg Infect Dis. 2003;9(3):291-3.  [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
    

17. Huang CC, Liu CC, Chang YC, et al. Neurologic complications in children with enterovirus 71 infection. N Engl J Med. 1999;341(13):936-42.  [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%.
    

18. Drucker NA, Colan SD, Lewis AB, et al. Gamma-globulin treatment of acute myocarditis in the pediatric population. Circulation. 1994;89(1):252-7.  [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.
    

19. Misbah SA, Spickett GP, Ryba PC, et al. Chronic enteroviral meningoencephalitis in agammaglobulinemia: case report and literature review. J Clin Immunol. 1992;12(4):266-70.  [PMID:1512300]

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

20. Ramers C, Billman G, Hartin M, et al. Impact of a diagnostic cerebrospinal fluid enterovirus polymerase chain reaction test on patient management. JAMA. 2000;283(20):2680-5.  [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