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HFMD

(Hand-Foot-Mouth
Disease)
An emerging disease
Wong Ann Cheng
MD (UKM) MRCPCH (UK)
Wednesday October 8, 2008
Sarawak on high alert for HFM disease

KUCHING: Sarawak is on high alert for hand, foot and mouth disease
following the detection of the EV71 virus, which causes a more severe
form of the disease.
Deputy Chief Minister Tan Sri Dr George Chan said the situation was under
control and steps were being taken to prevent an outbreak.“We monitor
for hand, foot and mouth disease all the time. “As soon as we detected
EV71 in the state, we went on high alert because we know this virus can
cause death,” he told a press conference at his office here yesterday.
A total of 5,686 cases have been reported in Sarawak as of Saturday,
compared with 6,286 in the same period last year.
On Sept 30, a four-year-old child in Sibu died from suspected hand, foot
and mouth disease.
SPOT DIAGNOSIS ?
HFMD
Myth

Foot and mouth disease Hand, foot and mouth diseas


Returning Coxsackie
Virus Threatens
Sarawak
The Star, March 30,
2000 Media insistence of
  using “Coxsackie
Kuala Lumpur
(Malaysia) - All
Outbreak” had misled
hospitals and clinics in the public. Virus later
Sarawak have been identified as EV71.
directed to step up
surveillance following the
Subsequent lots of
death of two children effort to correct this
from symptoms similar misconception
to the Coxsackie
outbreak three years
ago. A Coxsackie
outbreak in Sarawak in
early 1997 killed 29
children, mostly below
five years old.  
The facts
 HFMD is typically a benign and
common illness of infants and
children
 It caused by human enterovirus.
 Often in children under 10 years old.
 It also affect older children and adult
but with milder symptoms

http://www.cdc.gov/ncidod/dvrd/revb/enterovirus/hfhf.htm
Symptoms (case
definition)
 Usually begins with fever, poor appetite
and malaise, often with sore throat
 After 1-2 days after onset of fever,
sores/ulcers develop in the mouth, side of
cheek, gum and tongue
 The non-itchy skin rash/ maculopapular or
vesicular appears on palms of the hands
and soles of the feet.
 The rashes may also appear on buttocks
and on the legs and arms.
http://www.cdc.gov/ncidod/dvrd/revb/enterovirus/hfhf.htm
HAND
FOOT
MOUTH
Differentials

Herpangina

Herpetic gingivostomatitis Aphthous ulcers


Enterovirus
 Human enteroviruses comprise one
genus in the family of Picornaviridae
 Enterovirus genus that infect humans:
 Poliovirus
 Coxsackievirus A

 Coxsackievirus B

 Echovirus

 Enterovirus 68-71

 HFMD are due to coxsackie virus A16,


A5, A9, A10, B2, B5 and EV71
Coxsackie virus
 Coxsackie A16 is a frequently encountered
pathogen in cases of HFMD occurring
throughout the year
 Clinical course usually uneventful, with full
recovery
 Fatal cases of Cox A16 rare
 Literature search only revealed 3 fatal
cases since 1963. All the cases were infant
 Wright et al: 10-month-old with respiratory
infection
 Goldberg et al: 7-month-old with grunting and
tongue ulcer
 Wang et al: 15-month-old with HFMD
Enterovirus 71 (EV71)
 Responsible for sporadic outbreak
 More severe course
 Maybe complicated by meningitis,
encephalitis and neurogenic
pulmonary oedema
 In Taiwan, based on 1998 epidemic,
significant difference between Cox
A16 and EV71 are the higher fever
>39ºC and >3 days in EV71
Phylogenetic study of
EV71
 EV71 strains divided into genogroup
A, B, C
 Further subdivided to (4, 8-10)
 four genetic lineages of EV71 have
been prevalent in the Asia-Pacific
region since 1997, including two
previously undescribed genogroups
(B3 and B4).
 Genogroups of EV71 isolated during
each major outbreak are genetically
Molecular Epidemiology
Epidemiological data
 Most HFMD patients were very young
children (<4 years old) with a peak
incidence at 1 year.
 Male outnumber female 1.7 to 1
 Predominance has also been
observed in other enteroviral
infection
 Suggest possible susceptibility at
host genetic level
Emerging Infectious Diseases • Vol. 9, No. 1, January 2003
Epidemiological data
 Large outbreak maybe due to changes in the
viral factors
 Different strain of EV71 were obtained from
the each outbreak
 Genetic determinant of virulence still unclear
 Co-infection with second virus had been
suggested as possible pathogenic factor,
supported by concomitant isolation of
subgenus B adenovirus from 3 fatal cases in
Sarawak.
 Consideration of unusual medications,
treatment or dietary exposure contributed to
fatality found no conclusive evidence.
Emerging Infectious Diseases • Vol. 9, No. 1, January 2003
Global Epidemiology
 Enterovirus 71 (EV71) infection was
first reported in 1969 in California,
United States;
 subsequent outbreaks were reported
in worldwide distribution
 Mainly during summer and early
autumn months in temperate
countries while prevalent year round
in tropical climates
Recorded outbreak of EV71
2008 China 27 500 HFMD, 34 died
2006 Malaysia 14 253 HFMD, 13 died
2005 Thailand 4646 HFMD
2003 Malaysia Most self limited, few neurological death
2000 Singapore 3526 cases 83% EV71 4 died of pneumonia,
Malaysia, encephalitis
1998 Taiwan
Taiwan Also
>300outbreak
000 HFMD, 386 ICU due to
1997 Malaysia encephalitis,
2140 patients78
31died
died
1987 US 45 patients high rate of meningitis and
1987 Philadelphia paralysis
5 polio-like disease, 1 brain stem
1986 Australia encephalitis
140 cases, 61 HFMD, 34 meningitis and
1986 Hong Kong encephalitis
5 HFMD with flaccid monoplegia
1979 France 5 cases with CNS signs
1978 Hungary 1550 HFMD, 826 meningitis, 724
1978 Japan encephalitis, 45 death encephalitis
692 HFMD, meningitis,
1977 New York 29 HFMD, meningitis, encephalitis,
1975 Bulgaria monoparesis
705 cases, 149 paralysis, 44 died
Large Outbreaks of HFMD in
Asia
China
2008
27,500/34
Japan
Thailand 1978
36,301/ ?
2005
4,646/ 0
Taiwan
1998
129,106/ 78

Malaysia
1997
5,999/ 31 Malaysia
2006
14,253/ 13

Singapore
2000
> 4,000/ 7
An emerging infectious
disease

Malaria
Typhoid

Dengue Leptospirosis

Chikungunya Melioidosis

HIV JE

Tuberculosis HFMD Hepatitis


Malaysia top five notifiable
diseases in 2006
1. Tuberculosis
2. Food poisoning
3. Dengue fever
4. Hand, foot and mouth disease
5. Malaria
HFMD in Sarawak
 HFMD is endemic in Sarawak.
 Prior to 1997, no baseline data on the
epidemiology of HFMD in Sarawak as it is
not a notifiable disease.   
 Between 15 April and 30 June 1997, 31
previously healthy infants and young
children in Sarawak died after a short
febrile illness against a background of an
outbreak of HFMD in the State.
 Sibu was badly affected during this
outbreak as 11 of the death cases were
http://www.sarawak.health.gov.my/hfmd.htm
reported from Sibu followed by Sarikei with
HFMD in Sarawak
 Surveillance of HFMD was initiated by
Sarawak Health Department from 6 June
1997 till December 1997.
 However, in 1998, following a report of
increased cases of HFMD seen in private
paediatrician clinics, sentinel surveillance
of HFMD in collaboration with UNIMAS was
re-started in the State involving urban
public and private clinics in Kuching, Sibu
and Miri and 3 government hospitals in
Sarawak.
 When the enterovirus outbreak was
reported in Taiwan in May 1998, the
surveillance of outpatient and inpatient
http://www.sarawak.health.gov.my/hfmd.htm
List of HFMD Sentinel Surveillance Clinics in Sarawak ( 2008 )

No. Clinic Location

1 T.Y Wee Specialist Clinic For Children Kuching

2 Bibiana Teo's Specialist Clinic Kuching

3 KK Jalan Masjid Kuching

4 KK Kota Sentosa Kota Sentosa

5 KK Tanah Puteh Pending, Kuching

6 KK Kota Samarahan Samarahan

7 Betty Kong's Clinic Sibu

8 K.T Ting Specialist Clinic For Children Sibu

9 Sibu Polyclinic Sibu

10 Sarikei Polyclinic Sarikei

11 Dr Chen WS Child Specialist Miri


Sarawak Surveillance
programme
 EV71 outbreaks has occurred every 3
years in Sarawak – 1997, 2000, 2003,
2006( as predicted)
 The shape of HFMD epidemiological curves
are influence by social factors such as
media and people movements during
major public holidays (especially Gawai)
 Only EV71 causes large outbreak
 The genogroups of EV71 isolated during
major outbreak are genetically distinct
from each other, but all are first identified
in Sarawak and some had spread to
Peninsular Malaysia, Singapore and
Australia Podin et al; licensee BioMed Central Ltd.
Sarawak Surveilance
programme
 The transmission of EV71 in a
susceptible cohort is extremely rapid
with only 4-6 weeks between first
identification of an EV71 case in our
sentinel clinics to peaking.
 These outbreaks can drag on for
many months after they peaked,
especially if the outbreak has not
reached baseline before people start
travelling or moving about in the
state (eg State elections in 2006,
Podin et al; licensee BioMed Central Ltd.
http://www.sarawak.health.gov.my/hfmd.htm
http://www.sarawak.health.gov.my/hfmd.htm
http://www.sarawak.health.gov.my/hfmd.htm
HFMD CASES FOR SARAWAK, 2006

1345
1400 1282
1300 1234
1212
1200
1100 1017
1000
900
800
Cases

700 633
567
600
500 435 412
403 431
397
400 332 315 326 322
310
265
232 198 239 274
271
253
300 193 228 220
156 174 147
200 98105 112 859795
53 6340313322372936 26
100 4 15 14 171723
0
1

10

13

16

19

22

25

28

31

34

37

40

43

46

49

52
Epid Week

Sarawak centre for disease control (CDC)


HFM D CASES FOR SARAWAK, 2008

500

428

400 385

315 320

300
252 254
245

197 192 198


200 183 175 189
172
154
139 142
121 116
10410810598
88 95
100 78 81 79 74 87
69 75 61 54
58 51 48 47 49
30

0
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40
EPID WEEK

Sarawak centre for disease control (CDC


HFMD CASES FOR KUCHING DIVISION 2008

300
270
275
251
250

225
193
200
181

175
143
150
131
125 113
99
100 89
83
76
75
49 49 51 47
50
26 28 26 28
19 18 21 23 19 16 17
25
6 6 7 11 7
13 12 11 15 9 7 10
3 2
0
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40

EP ID WEEK

Sarawak centre for disease control (CDC)


HFMD Cases ( Death )
Year No.'s Cases No.'s Death
1997 2628 31
1998 455 0
1999 65 0
2000 3560 3
2001 667 0
2002 621 1
2003 2113 4
2004 56 0
2005 3558 0
2006 14875 13
2007 6571 0
5716 ( Till 4th October
2008 1
2008 )
2009 ? ?
Total 40885 53

Sarawak centre for disease control (CDC)


SARS
Deaths of children during an outbreak of HFMD in
Sarawak, clinical and pathological characteristics
of the disease.
 April -June 1997, 29 previously healthy
children aged <6 years (median, 1.5 years)
in Sarawak, died of rapidly progressive
cardiorespiratory failure during an outbreak
of HFMD caused primarily by EV71.
 Hospitalized after a short illness (median
duration, 2 days) that usually included fever
(in 100% of case children), oral ulcers (66%),
and extremity rashes (62%).
 Illness rapidly progressed to include seizures
(28%), flaccid limb weakness (17%), or
cardiopulmonary symptoms (of 24 children,
17 had CXR showing pulmonary edema, and
24 had ECHO showing left ventricular
dysfunction), resulting inChan
cardiopulmonary
et al, CID 2000; 31 (Septembe
Chan et al, CID 2000; 31 (September)
Chan et al, CID 2000; 31 (September)
Pathology
 CNS:
 extensive inflammation of brain stem and
spinal cord.
suggesting that a central nervous
 Lung:
system infection was responsible for the
 marked pulmonary oedema with focal
disease, with the cardiopulmonary
haemorrhage
dysfunction being neurogenic in origin.
 Heart:
 Normal myocardium
 Virus:
 EV 71 isolated from fresh brain tissue
(brainstem, C-spinal cord, cerebrum)
Hsueh C, et al. Modern Pathology 2000
 NOT from heart, lung or other organs
Postulated pathogenesis of severe EV71 infection
EV71 infection classified into
4 stages
Stage 1 Hand, foot and mouth disease

Stage 2 CNS involvement

Stage 3 Cardiopulmonary failure

Stage 4 Convalescence

Malaysian Hand-Foot-Mouth disease guideline


FLOW CHART OF HFMD & HERPANGINA MANAGEMENT
Hand,Foot & Mouth Disease
and Herpangina

Admit if have 1 or more following criteria Does not fit admission criteria

<12 months Discharge with advice (Page 8)


Vomiting or feeding poorly or dehydration
Fever>38.5C or history for fever >/48 hours
Toxic/ill looking
Inappropriate Tachycardia
Tachypnoea
Poor perfusion
Reduced level of consciousness
Seizures or history of seizures
Reduced motor activity
Increased startle during sleep or when awake
Neurological deficit (limb paralysis, cranial nerve palsy, cerebellar signs, nystagmas)
Signs of meningism (neck stiffness, Kernig’s sign)
Hyperglycaemia > 8.5 mmol/L or total white cell count > 17 500/mL (Page1-2)

Clinical Staging (Page 3)


• History taking Notification by phone & written form
• Physical examination To use standard clerking sheet for HFMD
• Investigations (Page 3)

Stage I Stage 2 Stage 3 Stage 4


Symptomatic treatment Admit acute cubicle/ HDU Admit HDU/ICU Convalescence
Ensure adequate hydration Frequent vital signs monitoring Intensive monitoring
Ensure normal hydration status Ensure normal vascular filling pressure
Empirical IV antibiotics Empirical IV antibiotics
Aggressive control of seizure Oxygen
Intubation & mechanical ventilation when Intubation & mechanical ventilation when
indicated indicated
Measures to ↓ ICP (adequate cerebral Fluid restriction
perfusion, IV Mannitol, hyperventilation) IV Frusemide
IVIG when indicated Correction of metabolic acidosis
(Page 5) Use of inotropes: Dobutamine, Dopamine,
Milrinone, Adrenaline
Use of vasodilator: Nitroglycerin
(Page 6 – 7)

Discharge when criteria fulfilled (Page 8)


Clinical sample types
 Establishing the actual cause of HFMD
cases relies on laboratory identification of
the virus
 Diagnostic techniques include isolating
virus in continuous cell lines or detecting
viral RNA by PCR.
 Virus isolation remains gold standard; it is
cheaper than PCR and more widely used
method particularly in developing countries
 Ranges of sample for virus isolation include
throat and rectal swab, serum
Ooi, et al. and
J. Clinical CSF
Microbiology,
June 2007
Ooi, et al. J. Clinical Microbiology, June 2007
Clinical sample types
 Throat swabs single most useful
specimen (49%)
 Vesicles swab (48%) in patient with
vesicles; yield greater if 2 or more
vesicles swab
 Combination of throat and vesicle
swab enable identification of virus
(67%)
 Rectal and ulcerOoi,
swab identified
et al. J. Clinical Microbiology, June 2007
additional (8%)
HFMD guidelines
Transmission
Nose
Throat
discharg
e

Saliva

Fluid from
blisters

Stools
Mode of transmission
 HFMD is moderately contagious.
 Most contagious during the first week of
the illness.
 The virus can be transmitted from person
to person via
 direct contact with nose and throat discharges,
saliva, fluid from blisters, or the stool of
infected persons.
 The virus may continue to be excreted in the
stools of infected persons up till 1 month.
HFMD is not transmitted to or from pets or
other animals.
Transmission
 Infants in diapers appears to be the
most efficient transmitter.
 The virus may be excreted in stools
for many weeks
 The virus can survive for days on
formites at room temperature
 Resistant to many disinfectants – use
chlorinated or iodinized disinfectant
Transmission rate
 To household contacts 52%
 Siblings 84%
 Cousins 83%
 Parents 41%
 Grandparents 28%
 Uncle and aunts 26%
 Intrafamilial and kindergarden
transmission major mode of transmission
(both in Taiwan and Singapore)
JAMA 2004; 291: 222-7 Pediatr 2002; 109: e88
Risks factors
 Children more susceptible due to
lack of immunity
 Parents sending sick children to
centre
 Cases not detected and isolated
 Close contact among classmates
 Asymptomatic cases
 Poor personal hygiene
 Contamination of toys, furniture and
premises
Immunity
 Infection results in immunity to
specific virus
 Second episode may occur following
infection with other enterovirus
Treatment
 No specific antiviral treatment
available for HFMD
 Mainly supportive.
 ?immunoglobulin
Health screening for
HFMD
 Early detection and prompt isolation
 Children should be monitored daily,
noting any unusual symptoms or
behaviour
 A child should not be allowed to
continue class if he/she appears
unwell
Hygiene and sanitation
 Hand washing not emphasized
enough
 One of the most important route of
transmission of infection
 Single most effective practice to
prevent spread of germs
 Practice it
 Teach it
 Monitor and enforcement of good
handwashing practices
Outbreak control
measures
 Continue health screening
 Ensure high level of personal and
environmental hygiene
 Eliminate communal activities where
all children congregate
 Public educational effort
 Closure of kindergarden and school
for 10 days to break the chain of
transmission
Poster
Pamphlets
Booklets
Message
 From Sarawak, since 1997, EV71 outbreak
had occurred every three years
 Shape of epidemiological curve influence
by social factors such as media and
people’s movement during public holidays
 Genogroups of EV71 isolated during each
major outbreak are genetically distinct
from each other
 Transmission of EV71 in susceptible cohort
extremely rapid with only 4-6 weeks
between first identification in sentinel
clinics to peaking
Message
 From Singapore, transmission occur
mainly in places where preschool children
congregate, and public health measures to
focus on these places
 From Taiwan 1998 outbreak showed that
HFMD spreads easily through contact
leading to mostly symptomatic cases in
children and mostly asymptomatic cases
in adult
 Proper surveillance system works showing
trends and the current circulating viruses
and predicting coming outbreak
Challenges
 Identify reservoir of EV71 in the
inter-epidemic periods
 Develop simple rapid diagnostic tests
that can be used to differentiate
EV71 from CA16
References
 http://www.sarawak.health.gov.my/hfmd.htm
 http://en.wikipedia.org/wiki/HFMD
 Chan, L. G., U. D. Parashar, M. S. Lye, et al. 2000. Deaths of children during an
outbreak of hand, foot and mouth disease in Sarawak, Malaysia: clinical and
pathological characteristics of the disease. Clin. Infect. Dis. 31:678-683[Medline]
 Cardosa, M. J., S. Krishnan, P. H. Tio, et al. 1999. Isolation of subgenus
B adenovirus during a fatal outbreak of enterovirus 71-associated
hand, foot and mouth disease in Sibu, Sarawak. Lancet 354:987-991
[Medline].
 Chong CY, Chan KP, Shah VA, Ng WY, Lau G, Teo TE, et al. Hand, foot and mouth
disease in Singapore: a comparison of fatal and non-fatal cases. Acta
Paediatr. Oct 2003;92(10):1163-9. [Medline].
 Ooi MH, Wong SC, Clear D, Perera D, Krishnan S, Preston T, et al. Adenovirus
type 21-associated acute flaccid paralysis during an outbreak of hand-foot-and-
mouth disease in Sarawak, Malaysia. Clin Infect Dis. Mar 1 2003;36(5):550-9. 
[Medline].
 Shekhar K, Lye MS, Norlijah O, Ong F, Looi LM, Khuzaiah R, et al. Deaths in
children during an outbreak of hand, foot and mouth disease in Peninsular
Malaysia--clinical and pathological characteristics. Med J
Malaysia. Aug 2005;60(3):297-304. [Medline].
 Tseng FC, Huang HC, Chi CY, Lin TL, Liu CC, Jian JW, et al. Epidemiological survey
of enterovirus infections occurring in Taiwan between 2000 and 2005: Analysis
of sentinel physician surveillance data. J Med Virol. Dec 2007;79(12):1850-60. 
[Medline].
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