MICROBIOLOGY

• Member of Picornaviridae, (+) single-stranded RNA virus.
  • Formerly classified as belonging to four groups (echoviruses, coxsackie A, coxsackie B and polioviruses), but now non-polio enteroviruses are 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 chiefly by the fecal-oral route, but are also found in respiratory secretions.
• Peak acquisition typically occurs in late summer and early fall.
  • It often spreads in schools, daycare centers, and/or through contact with infected infants and 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. Numbers have decreased since COVID-19.
      
      • Typical sx: difficulty breathing, wheezing, hypoxemia; only a minority with fever.
      • Asthma in ~30% of cases.
      • Has been associated with acute flaccid myelitis (AFM).
  • Enterovirus 71 is notable for epidemics of severe neurological disease, mostly in children. Since 2008, there have been reports of increased cases in China and Southeast Asia.
  • The incubation period is typically 3-5 days, but for the CNS, it may be up to 12 days after the acquisition of infection.
• Causes a spectrum of human illness:
  
  • Respiratory: bronchitis, common cold, severe respiratory infection.
    • Enterovirus 71: most fatal cases ascribed to neurogenic pulmonary edema[6].
  • 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 the 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 continue for over 8 weeks from the initial infection.
  • Metagenomic analysis can be considered for cases with negative workups (discuss the benefit of mNGS with microbiology based on the case)[4].

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) is 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, Southeast Asia, Taiwan, though found elsewhere. The virus can also cause asymptomatic infection, gastroenteritis, and 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.

Basis for recommendation

1. Meinhardt A, Reilly L, Kaliakatsos M, et al. Novel antivirals for severe enterovirus infection in immunocompromised hosts; A case series. J Infect. 2024;88(5):106142.  [PMID:38527653]

   Comment: Case series of 8 patients with severe EV-CNS disease (neonates, children, and adults) who received high-dose IVIG + antiviral treatment. 2/8 patients died (both neonates, one with severe immunodeficiency). Rx duration usually 14 days (longer if persistent pos EV in CSF).
   

References

2. Shah MM, Perez A, Lively JY, et al. Enterovirus D68-Associated Acute Respiratory Illness ─ New Vaccine Surveillance Network, United States, July-November 2018-2020. MMWR Morb Mortal Wkly Rep. 2021;70(47):1623-1628.  [PMID:34818320]

   Comment: MMWR reports on EV_D68 2018-2020, including the spectrum of disease and patient characteristics. Allergy was a comorbidity in ~30% of cases across years.
   Rating: Important
   

3. Piantadosi A, Mukerji SS, Ye S, et al. Enhanced Virus Detection and Metagenomic Sequencing in Patients with Meningitis and Encephalitis. mBio. 2021;12(4):e0114321.  [PMID:34465023]

   Comment: mNGS prospective analysis of 68 patients with known (n = 44) or suspected (n = 24) CNS viral infection from a single center in New England.
   Rating: Important
   

4. Anh NT, Nhu LNT, Hong NTT, et al. Viral Metagenomic Analysis of Cerebrospinal Fluid from Patients with Acute Central Nervous System Infections of Unknown Origin, Vietnam. Emerg Infect Dis. 2021;27(1):205-213.  [PMID:33350920]

   Comment: Among 204 patients from Vietnam with acute CNS infection and negative workup, metagenomic analysis identified a virus in 15% of cases, enterovirus being the most common.
   

5. Messacar K, Asturias EJ, Hixon AM, et al. Enterovirus D68 and acute flaccid myelitis-evaluating the evidence for causality. Lancet Infect Dis. 2018;18(8):e239-e247.  [PMID:29482893]

   Comment: The authors investigate the causal relationship of ED-68 and acute flaccid myelitis. Currently available evidence supports a causal role.
   Rating: Important
   

6. 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 (disintegration of the distal cell processes of astrocytes, along with a fragmentation or beading of proximal processes closer to the astrocyte cell body), but no viral antigen present. Lungs and hearts lacked evidence of any virus-induced inflammation or pathology. For 11 of the 15 cases, a reduction in lung aquaporin-4 staining may play a role in developing fatal pulmonary edema.
   

7. 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.
   

8. 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 the child (2 yrs) and the pregnant mother was suspected to have varicella. Enterovirus instead detected by RT-PCR, Coxsackie A6.
   

9. 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), indicated due to the 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 and Europe in older MMWR reports and is associated with CNS dysfunction.
   

10. Ayscue P, Van Haren K, 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.
    

11. 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 the 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.
    

12. 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, for many years in Southeast Asia and Taiwan, especially, there has been interest in a protective vaccine. This large trial showed about 90% vaccine efficacy, with only a small percentage of serious ADRs that were not significantly different from the placebo.
    

13. 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: A small study of severe E71 infections in Vietnam involved patients all receiving dopamine or dobutamine and intravenous immunoglobulin. The milrinone arm had lower mortality and less time spent on the ventilator. Milrinone is a phosphodiesterase 3 inhibitor developed to treat heart failure patients.
    

14. 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 between 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).
    

15. 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 the number in the study was 75. Still, no RT-PCR positive patient receiving IVIG had any sequelae, whereas one patient randomized to viral cx isolation had seizures.
    

16. 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: A 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
    

17. 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: A study examined the neurological sequelae of EV71 infection. A total of 142 children were studied for an average of ~ 3 years. 56% of patients with a poliomyelitis-like syndrome and 20% with encephalomyelitis experienced limb weakness and atrophy. For patients 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 patients (75%) with co-existent cardiopulmonary failure (P< 0.001).
    

18. 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). Still, use of pleconaril early in the course of enteroviral meningitis appeared to shorten illness, although the impact was more modest in the severely ill group.
    

19. 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
    

20. 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. Still, some were afflicted with great severity, including cases of neurological and cardiopulmonary illness resulting in death.
    Rating: ImportantImportant
    

21. 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: The 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%.
    

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

23. 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 and failures.
    

24. 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