Enterovirus meningitis

1. INFECTIOUS DISEASE
CPC

2.  2-year-old boy Diagnosed case of Langerhans cell
histiocytosis of the frontal, sphenoid bone, Floor of
sella, and clivus
 involvement of right cervical nodes
 Scattered lesion in L1, L5 vertebral bodies and
bilateral iliac bones
Initial excision of frontal bone done OSH in june 2022
Later he was started on chemotherapy in SKM June 2022

3. 23/10/22
He was in his usual state of health when he started having
o Fever
o Headache
o Irritability
Fever was gradual in onset, recorded up to 38 in hospital, with
no diurnal variation, intermittent, and relieved with paracetamol
Headache was not localized,
Followed by excessive cry and drowsiness
24/10/22
Given IV fluids and antibiotics OSH
Became Afebrile

4. 25/10/22
Scheduled for Chemotherapy in SKM
Was afebrile and chemotherapy was given
Febrile again
Headache worsened
Irritability worsened

5. Systemic inquiry:
Neurological There was no history of fits/seizures, loss of vision,
balance or consciousness.
GI there was no history of abdominal pain, vomiting, diarrhea, or
constipation
Resp there was no history of flu, facial tenderness, sore throat, cough or
chest pain
CVS there was no shortness of breath, swelling in the body or blueish
discoloration of extremities
Musculoskeletal there was no history of swelling of joints, body aches,
or any other bony abnormality apart from frontal bone excision done in
June 2022

6. Examination:
Irritable crying child with the following vitals:
BP– 111/74
Pulse--138
Temperature--38
Respiratory rate—24
Spo2 –99% at room air
Oral cavity– fine
There was no sinus tenderness
Right cervical lymph node palpable(disease related)
No other accessible nodes palpated,
No rash on body
Peripheries pink and well perfused
No peripheral edema

7. Systemic exam:
Neurological
E4 M6 V5
Pupils equal and reactive to light
Rest of cranial nerves could not be assessed
Moving all limbs--- was able to stand without support
Bilateral planters were down going
There was no positive signs of meningeal irritation
sensory system was not assessed

8. Chest– normal vesicular breathing with no added sound
air entry equal
The abdomen was soft and nontender no viscera palpable
CVS tachycardiac with no added sound/ murmur

9. Considering History and physical examination, meningitis was
suspected
He was started on empirical cover for meningitis – ceftriaxone
was given and lumber puncture was planned

10. Labs:
CBC: 10.84 with 49% neutrophils
Hb:11.2
Platelet 651
Serum sodium 140
Serum postaasium 4.5
Serum calcium 9.46
Serum magnesium 2.2
Creatinine 0.18
Total bilirubin 0.19
Blood culture twice-- negative

11. MRI brain:
Stable disease involving Sphenoid bone, floor of sella . Clivus
Dural thickening in middle cranial fossa causing mass effect on superior sagittal and
straight sinus
Vessels and cavernous sinus normal
Brain parenchyma normal
No focal lesion
The spinal cord also unremarkable

12. Lumber puncture:
Protein 15.7
Glucose 65(random was 94)
WBC 4
RBC nil
India ink stain – negative
Fungal culture: initial negative
AFB stain– negative
AFB culture: initial negative
PCR film array – Enterovirus detected

13. Management:
After final report of Filmarray, ID team was consulted.
Ceftriaxone was stopped
Patient was put on neuro observation
No treatmen was given for Enterovirusus and conservative approach was
taken
Patient became afebrile after 2 days and was discharged frothe m hospital
on 27/10/22

15. A very large group of RNA viruses
Size--Small viruses 28-32nm
Humans are the only natural host
There are more than 47 genre in PicoRNAviridie family

16. Symmetry = icosahedral
Capsid : VP1 to VP4
Non enveloped
RNA single-stranded positive strand
Replication in cytoplasm

17. Classification of enterovirus :
The nomenclature of this class is ever-changing
Prior to the use of Molecular methods, Enteroviruses were
assigned to 5 subgroups
In 2012, the international committee on Taxonomy reclassified
viruses based on molecular classification
More than 100 serotypes have been discovered until now

18. Hepatovirus
Enteroviruses
Rhinovirus
Par-echovirus
Polio virus with 3 serotypes 1-3
Coxsackievirus group A : 23 serotypes 1-22 and
24
Coxsackievirus group B: 6 serotypes
Echovirus :29 serotypes
Enterovirus: serotype 68-116

21. Seasonal variation: Although occur throughout the year, it more
common in the summer and fall season in temperate areas
Gender variation: for unknown reasons, it is more common in
males
Age variation: more seen in infants than adults
Incubation period: varies and difficult to measure, usually 3 to 5
days
Viral shedding: varies respiratory 1-3 weeks and fecal 3-8 weeks
usually

22. Some common infections caused by Enteroviruses
• Hand , foot and mouth disease
Caused by Enterovirus A71, CV A6
• Herpangina
caused by group A CV
• Maculopapular eruptions
Caused by Echoviurs
• Petechiae and purpura
Caused by echovirus and CVA9
• Urticaria like syndrome
Exanthems

23. Meningitis most common CNS manifestation
infants: >90% of cases of viral meningitis are caused by Enterovirus,
especially group B, which includes group B coxsackieviruses and most
echoviruses
older children and adults: >50% of meningitis is caused by Enterovirus
in some immunocompromised populations chronic meningitis is also
reported
Encephalitis in up to 5% of cases are caused by Enterovirus, clinically
indistinguishable from other causes. coxsackievirus types A9, B2, and B5 and
echovirus types 6 and 9 are the serotypes reported most often
Acute paralysis and brainstem encephalitis syndrome of acute motor neuron
weakness has been reported by many enteroviruses especially poliovirus types
1, 2, and 3, enterovirus D68, and enterovirus A71
CNS infections

24. Ocular infection- acute hemorrhagic conjuctivitis
Myopericarditis  group B coxsackieviruses are the most
frequently implicated viral cause of myocarditis
Respiratory diseases from upper RTI to lower RTI
Pleurodynia acute enteroviral illness characterized by fever and
paroxysmal spasms of the chest and abdominal muscles

25. Diagnosis
1)RT-PCR ----- recovered from fluids
of the body--- most widely used test
2) Viral isolation by cell culture
3) Serology

26. TREATMENT
Most enterovirus and parechovirus infections are self-limited and do not require
specific therapy.
Potential life-threatening exceptions include
• fulminant neonatal infection,
• severe myocarditis,
• chronic infection in B cell-immunodeficient patients,
• disseminated infections in patients with hematologic malignancies

27. TREATMENT
Antiviral options:
None is FDA approved
Some are available as IND(investigational New Drugs)
Capsid inhibitors are among INDs
1)Popcapvir
an orally administered drug under development to treat chronic enterovirus
infections.
Pocapavir is available only for poliovirus infections in B cell-deficient patients.

28. 2) Pleconaril
• An Orally administered capsid inhibitor (Not yet available for IV administration)
• Introduced in 1997
• Not approved by FDA yet.
• Has been tested clinically against a spectrum of Enterovirus and Rhinovirus
infections, including serious enterovirus infections.
• Side effects include headache, nausea, menstrual irregularities, mid –cycle bleeding

29. combined two studies enrolling 206 patients with PCR-proven enterococcal meningitis.

30. • Double blind, RCT
• 61 neonates with suspected enterovirus disease
(hepatitis, coagulopathy, and/or myocarditis)
• Randomly assigned to seven days of pleconaril or
placebo(43 in treatment group, 18 in placebo)
• Intention to treat analysis
Results:
1. More rapid viral clearance (s (median 4.0 versus 7.0
days)
2. Lower overall mortality the in treatment group (23
vs 44%)
Limitations:
1. early termination related to slow enrolment
2. Allowed concomitant use of IVIG

31. IVIG
Limited experience
• Infection in B cell-immunodeficient patients :
Limited success
Chronic meinigitis  received IVIG intraventrically (6/12) improved clinically but relapse was
seen later. All these patients were agammaglobunimic
(McKinney Jr, Katz et al. 1987)
Some studies even prefer Pleconaril over IVIGs in such patients(Rotbart, Webster et al. 2001)
• Neonatal infection:
Data is mixed again

32. • Retrospective study
• 67 neonates with culture-confirmed severe enteroviral infection,
• Included patients with early birth, hepatitis, meningitis and myocarditis.
• hepatitis defined as with coagulopathy and thrombocytopenia.
• myocarditis as presence of tachyarrhythmia, decreased cardiac output (left ventricle ejection fraction 30/uL), elevation of
CK/TROP
• meningitis as presence of pleocytosis or or enterovirus in cerebrospinal fluid (CSF).
• Premature birth was defined as a gestation age of < 37 weeks
• IVIG administered within 3 days of illness onset was classified as early IVIG therapy.

33. • 41 received IVIG
• And mortality was significantly reduced in IVIG group
• However, the study doesnot provide robust evidence of use of IVIG in neonates

34. A case series of 5 patients from Agha Khan university included patients from age 18-35.
All patients were managed conservatively and there was no residual neurological sequelae
(Lubna, Ayisha et al. 2021)

36. • To prevent spread, hand hygiene is most important
• Standard precaution is used
• For diapered and incontinent children= contact precaution
is used
• In outbreaks,(for example D 68 respiratory cases in 2014
USA) standard , contact and droplet precaution is
recommended in health care settings

37. Three inactivated enterovirus A71 vaccines have been tested in China for use in
pediatric patients since Dec2015
Multivalent vaccines are under development.

38. • randomized, double-blinded, placebo-controlled, phase 3 trial
• five hospitals in Taiwan and two in Vietnam.
• Of 3061, 3049 were vaccinated: 1521 in the intervention group and 1528 in the placebo group.
• Children aged 2-71 months were stratified by country and age.
• randomly assigned (1:1) to receive two doses of EV71vac or placebo via intramuscular injection 56 days apart.
• The primary endpoint was the clinical efficacy of the total vaccinated cohort against EV71-associated diseases
during the follow-up period,
• safety analysis included all participants who received at least one dose of EV71vac
• The vaccine efficacy of EV71vac was 96·8% (95% CI 85·5-100) against EV71 associated diseases (p<0·0001).
• The percentage of participants who reported solicited adverse events were similar in both groups: 865 (56·9%)
in the EV71vac group and 852 (55·8%) in the placebo group