Coxsackieviruses & other Enteroviruses

Fellow’s curriculum conference

Hunter Ratliff

12/01/2025

Overview

• Classification, virology, transmission, and epidemiology
• Clinical manifestations
• Boring viral illness
• Dermatologic
• Neurologic
• Respiratory
• Cardiac / muscular
• And more
• Management
• Diagnosis
• Treatment
• Prevention

Classification & virology

• Taxonomy
• …and why it doesn’t matter
• Virology with a focus on pathogenesis
• Modes of transmission
• Epidemiology

Taxonomy & classification

Historically, there were 4 species in the Enterovirus genus

• Enterovirus A: Coxsackievirus A2, CV-A2, etc
• Enterovirus B: Coxsackievirus B1, CV-B2, etc
• Enterovirus C: Polioviruses 1-3 (but also CV-A1..?)
• Enterovirus D: EV-D68

Then they discovered more… over 100 more

• Started changing the classification scheme around
• Wanted to move polio out of the genus

The classification we care about

Now, we refer to them by serotypes

• Group A coxsackievirus (CV-A)
• Group B coxsackievirus (CV-B)
• Polioviruses (PV) - Not covered today
• Numbered enteroviruses (EV-D68, EV-D70, AV-A71)
• Echoviruses (E)
• Parechovirus is still separate genus
• Present clinically similarly to echoviruses

Enteroviruses: Virology

• Small (30 nm), non-enveloped (important for prevention)
• Single-stranded, positive sense RNA
• Bind to cellular attachment factors to allow for intracellular replication
• A variety of attachment factors are shared across serotypes
• This might be why so many different serotypes can cause similar syndromes

Enteroviruses: Pathogenesis

• Small (30 nm), non-enveloped (important for prevention)
• Single-stranded, positive sense RNA
• Bind to cellular attachment factors to allow for intracellular replication
• A variety of attachment factors are shared across serotypes
• This might be why so many different serotypes can cause similar syndromes

Viral uptake & initial replication occurs in pharynx and terminal ileum

• Has a transient viremia → hematogenous spread → target organs
• Are relatively resistant to acid → allows for fecal oral transmission

Enteroviruses: Transmission

• Predominantly spread via fecal oral transmission
• Respiratory spread has been seen for some (CV-A21, EV-D68)

Enteroviruses: Transmission

• Predominantly spread via fecal oral transmission
• Respiratory spread has been seen for some (CV-A21, EV-D68)
• Coxsackievirus A21: Severe respiratory illness, seen in military recruits
• Enterovirus D68: also can cause severe respiratory illness + acute flaccid myelitis
• EV-70 (causes acute hemorrhagic conjunctivitis) is shed in tears and can be spread via fingers
• Vertical transmission can cause spread to infant, especially if infected in the peripartum period

Enteroviruses: Epidemiology

• Seasonal trends, but commonly higher in the summer and fall
• Highest rates are in those under one year old

Figure 1C of Baker et al (2024).

Weekly cases of EV-A71 by Chinese province, ordered from north (top) to south (bottom)

Enteroviruses: Epidemiology

• Seasonal trends, but commonly higher in the summer and fall
• Highest rates are in those under one year old

Some serotypes follow multi-year cycles (with different periodicities) following a pattern

Figure 2

Simulated data for CV-A16 and polio

Enteroviruses: Epidemiology

• Seasonal trends, but commonly higher in the summer and fall
• Highest rates are in those under one year old

Some serotypes follow multi-year cycles (with different periodicities) following a pattern

Large # of kids infected → they are immune (for now) → waning immunity → reaches a critical mass of susceptible kids → sustained transmission → Large # of kids infected

​

This was seen post-COVID:

↑ masking ⇒ ↓ immunity ⇒ no more masks ⇒ ↑ older kids infected

Clinical syndromes

• Boring viral illness
• Dermatologic
• Neurologic
• Respiratory
• Cardiac / muscular
• More

Isolated fever

Exanthems & enanthems

Dermatologic manifestations

​

• Herpetiform exanthems:
• Hand-foot-mouth disease
• Herpangina
• Other exanthems:
• Rubelliform
• Roseoliform
• Petechial/purpuric

Enteroviruses: Exanthems

• Wide spectrum of presentation
• Aside from hand-foot-mouth disease (HFMD), these are generally not specific enough to make a diagnosis of an enterovirus infection on exam alone
• Substantial overlap among the exanthems
• Exanthems themselves cause little morbidity, but can be mistaken for other more worrisome infectious conditions
• Unclear if result of direct skin invasion by the virus or immune mediated

Hand-Foot-Mouth disease

• Enanthem: Vesicular stomatitis (painful oral lesions)
• Mainly buccal mucosa and tongue
• Accompanied by 1-2 days of low fevers (42%)
• Exanthem: Vesicles/papules on palms of hands & feet (occurs in 75% of patients)
• May also involve the buttocks or genitals
• May or may not be tender

DDx palm lesions:

• HFMD
• RMSF
• Syphilis
• Measles

Mandell Figure 178.1

Hand-Foot-Mouth disease

• Enanthem: Vesicular stomatitis (painful oral lesions)
• Mainly buccal mucosa and tongue
• Accompanied by 1-2 days of low fevers (42%)
• Exanthem: Vesicles/papules on palms of hands & feet (occurs in 75% of patients)
• May also involve the buttocks or genitals
• May or may not be tender

Atypical HFMD (novel CV-A6) - Basically everything is worse

• Wider distribution of lesions (more like VZV)
• Higher fever
• Lasts longer (12 days on average)
• May have fingernails fall off 1-2 months later

DDx palm lesions:

• HFMD
• RMSF
• Syphilis
• Measles

Herpangina

• Enanthem: Abrupt, painful vesicles of posterior oropharynx (soft palate, tonsils, anterior pillars)
• Sore throat & odynophagia
• Unlike HFMD, fevers are high (102 - 104 F / 39 - 40 C)
• Exanthem: No rash (generally no other symptoms)

​

Mainly reported in children (very few adults)

Comparing the herpetiform exanthems

Rash

In 75% of cases

Age

Mostly kids, but adults can get it too

Rash

None

Age

Almost only kids

Herpetic exanthems

• Coxsackie A group
• CV-A9: atypical HFMD
• EV-A71 (also causes other stuff too)

DDx: Herpetiform exanthems

And don’t forget MPox (mistaken for atypical HFMD)

Rubelliform and Morbilliform Exanthems

Enteroviruses account for about 5% of acute morbilliform exanthems (in populations with high MMR immunity)

Summer echovirus epidemics (E-9) produce a rash very similar to Rubella

• Rash begins at same time as fevers
• Spreads down from the face
• But not itchy (✘ Rubella)

Rare cases where an enanthem resembles Koplik spots

• Absence of coryza and conjunctivitis
• ✘ measles

Other Exanthems

Mandell & UTD did not say where the rash occurs

Seen with CV-A9 & echovirus 9, which also causes encephalitis

Neurologic manifestations

• Aseptic meningitis
• Encephalitis (EV–A71)
• Acute flaccid myelitis (AFM)
• EV–A71 & EV-A68

Viral/aseptic meningitis

The enterovirus genus is the leading cause of aseptic meningitis in adults & kids

• Mainly the EV-B species (coxsackievirus B & most echoviruses)
• Highest rates are in infants (perhaps because neonatal fever buys you a LP)

Clinical manifestations vary widely

• 1/3rd of adults have signs of meningeal irritation
• Often have pharyngitis / URI symptoms
• Encephalitis may develop in 5-10% of cases

Prognosis is generally good

• Kiddos can recover in days
• Adults might take longer

Diagnosis can still be challenging

• 18-30% of infants have no pleocytosis
• Glucose can be low in up to 1 in 3 cases

Can follow biphasic pattern (like polio)

1. Prodromal illness with fever and myalgias
2. Defervescence & asymptomatic for a few days
3. Abrupt fever recurrence + meningismus

​

Encephalitis

Still good prognosis unless…

​

Encephalitis

Detour: Enterovirus A71

Summarize the clinically relevant information for enterovirus A71. Please use #f3f3ed as the background color and #025558 as the color for the text

Acute Flaccid Myelitis/Paralysis

A variety of enteroviruses can cause acute flaccid paralysis/myelitis, but the key ones to know are poliovirus, enterovirus A71 (just discussed), and enterovirus A68 as their sequelae is most severe

Clinically, they all look like polio:

• Biphasic pattern
• Abrupt onset asymmetric motor deficit
• Sensory nerves spared
• May progress to other limbs in 1-3 days
• +/- cranial nerve involvement

• Prodromal illness with fever and pharyngitis
• Defervescence & asymptomatic for a few days
• Abrupt fever + meningismus + weakness

​

Acute Flaccid Myelitis/Paralysis

Diagnosis is often indirect

• CSF: Pleocytosis, but CSF PCR may be negative
• MRI: longitudinally extensive nonenhancing lesions of the gray matter of spinal cord or brainstem

Fewer than 5% have full recovery

Etiology: Acute Flaccid Myelitis/Paralysis

Poliovirus: Used to be the main cause, but much less common with the vaccine

Enterovirus A71: Outbreaks following HFMD (also meningitis/encephalitis). The EV-A71 vaccine in China has been 100% effective in preventing AFM

Enterovirus A68: This one causes respiratory disease and is not commonly isolated in the CSF. But there has been inferential links between outbreaks of EV-A68 and increased cases of AFM

Respiratory manifestations

• Mild URI
• Severe respiratory disease
• Acute hemorrhagic conjunctivitis

URIs and lower respiratory infections

URIs and lower respiratory infections

URIs and lower respiratory infections

Acute hemorrhagic conjunctivitis

Highly contagious, but generally self-limiting conjunctivitis; often from EV-D70 or CV-A24

• Unlike other EV infections, spreads from fingers or fomites directly to the eye
• Often associated with outbreaks, most commonly in poor sanitary conditions & crowding

Abrupt onset of symptoms (peaks within 24h, unlike adenovirus)

• Most often burning, ocular pain, photophobia, eyelid swelling, and watery discharge
• ~1 in 5 have constitutional symptoms
• Hallmark is subconjunctival hemorrhage

Generally resolves within a week

Other clinical manifestations

• Cardiac: Myopericarditis
• Muscular: Pleurodynia
• Diabetes..??

Myopericarditis

Common cause of acute viral myopericarditis, mainly from Coxsackie B

• Accounted for >⅓ cases (before COVID)
• Tends to happen in physically active adolescents & young adults

​

Presentation: Typically (2/3rd) have preceding URI in past 1-2 weeks

• Followed by typical pericarditis &/or CHF symptoms
• Ranges from asymptomatic to florid heart failure with complete heart block (may need ECMO)

Myopericarditis

Diagnosis: Often is circumstantial (e.g. pericarditis + biofire positive), but can be isolated from tissue

• But it depends on which test you are using (recall, over 100 types of EVs)

Treatment:

• Largely supportive (up to and including LVAD)
• Has been interest in therapy (e.g. IVIG, steroids) but inconclusive results

Prognosis: About 1/3rd have long term damage

Pleurodynia (“Devil’s Grippe”)

• Acute infection of skeletal muscle, classically from Coxsackie B
• Tends to affect older kids & adults
• Observed in infrequent outbreaks (10-20 year intervals)
• Spasmodic and paroxysmal pain (hallmark) with fever
• Often in the chest or upper part of the abdomen
• Mimics ACS, PE, acute abdomen
• Is not a whole body myositis
• Tends to be localized to a body area (but not a focal point)
• First paroxysm is most severe (4-6 days)
• May be confined to bed
• One in four will have a recurrence of pain
• Sometimes days later (in rare cases, months later)
• Half of the time, pain is at another site

Diabetes?

There are temporal & geographic associations with between enterovirus infections and onset of type 1 diabetes

One meta-analysis of 26 case-control studies found that EV infection was associated with development of

• Islet cell autoimmunity: OR 3.7 (2.1 - 6.8)
• Type 1 diabetes: OR 9.8 (5.5 - 17.4)

Exact mechanism still not clear

Figure 1 of Yeung et al (2011)

Management

• Diagnosis
• Treatment
• Prevention

Diagnosis & Treatment

Laboratory diagnosis is generally not needed (clinical dx, self-limited disease). When it is, RT-PCR is king

• Shares same 5’ nontranslated region with rhinovirus (hard to distinguish the two)

Generally, do a PCR the organ that is involved

• Conjunctivitis often has negative resp PCR
• CSF pretty good for meningitis
• Not great for encephalitis
• AFM and myopericarditis are more challenging

Symptomatic & supportive care

In life-threatening cases, there are no evidence-based therapies, but some have tried IVIG and select capsid inhibitors

Diagnosis

Treatment

Prevention

China has a few vaccines for EV-A71

• >90% protective of HFMD (from EV-A71)
• 100% for preventing neurologic complications
• Suggestive it might protect from other genotypes

Not available outside of China

Hand washing is key, especially with changing diapers

• Alcohol based sanitizers may be suboptimal

Isolation: Generally standard precautions

• Contact if incontinent (or diapers)
• During outbreaks of EV-D68 (the one that causes a bad pneumonia), contact + droplet
• Pregnant patients should avoid contact with those who have EV infections

Vaccination

Hygiene & IPC

Learning points & take aways

Who does what?

Echoviruses

Coxsackie-

viruses

Named Enteroviruses

Coxsackie

CV-A

Coxsackie

CV-B

Echoviruses

(E)

Enterovirus

EV-A71

Enterovirus

EV-A68

Herpetiform exanthems

Herpangina

HFMD

Muscle/heart

Myopericarditis

Myositis

Severe

Pneumonia

Neurologic

Aseptic meningitis

Rhomb-

encephalitis

Acute flaccid myelitis

Polioviruses

= Strongest association with that disease/condition

Will AI replace me?

Prompt: “Describe the clinical manifestations of enterovirus infections”. No additional feedback given (zero touch deployment)

Model: Nano Banana Pro (Gemini 3 Pro Image) via NotebookLM (11/24/25)

Sources: Three PDFs (chapter 178 of Mandell & two UpToDate articles)

Will AI replace me?

Aside from labeling the stomach as the lungs, the highlighted (typographic) errors are all easily edited out in Adobe Acrobat (took <15 mins)

Sources

• Chapter 178 of Mandell (Coxsackieviruses, Echoviruses, and Numbered Enteroviruses [EV-D68, EV-D70, EV-A71]), 10th edition
• UpToDate: Hand, foot, and mouth disease and herpangina (accessed 11/24/25)
• UpToDate: Enterovirus and parechovirus infections: Epidemiology and pathogenesis (accessed 11/24/25)
• UpToDate: Enterovirus and parechovirus infections: Clinical features, laboratory diagnosis, treatment, and prevention (accessed 11/24/25)

Access the NotebookLM I used here (I still confirmed all of the written text that I used in these slides with the primary material, but it’s not like the AI made many mistakes)

Slides available on hunterratliff1.com/talk/