ENTEROVIRUS 71 EPIDEMIC, CHILDREN: CLINICAL SIGNS *************************************************A ProMED-mail post<http://www.healthnet.org/programs/promed.html> [see also:Enterovirus 71 epidemic, children - Taiwan (08) 980619014532] Date: Fri, 19 Jun 1998 19:27:17 -0700

From: Dr. Tan Poh Tin tpt@fhs.unimas.my

Clinical presentation of 27 deaths in Sarawak 14 April - 22 June 1997

In response to the urgent questions now posted by concerned pediatricians,
I apologise for not posting this information earlier as there were some
troubling ethical and moral issues I had to sort out first.

I was appointed by the Minister of Health, Malaysia 13th June 1997 to an
independent panel of three members, to review the epidemic in Sarawak (as a
community pediatrician with public health training and someone not directly
involved with the management of the cases.)   With the assistance of the
pediatricians,  case notes of   27 of the initial deaths, and 326
admissions during the period 14th April  - 22nd June 97 were
retrospectively reviewed. 

This posting is a summary of the salient findings in one of the two reports
which were submitted to the Minister  22nd July 1997.  It does not include
epidemiological, therapeutic or pathological data, and is solely based on
documented case charts and laboratory reports available at the time.

(for statistics & details of clinical findings see attachment)

The Ministry of Health Malaysia is in the final stages of the country
report , which I am sure will provide a more complete picture, in due course.

In view of the clinical urgency and need for vigilance in other countries,
I hope by  presenting the clinical  findings in Sarawak now,   I may be
able to help  pediatricians elsewhere   have some idea as to  the range of
clinical problems the children in our deaths and admissions had.   Whether
the Taiwan outbreak is due to the same infection or not remains to be
confirmed.  

During the  outbreak of sudden unexplained pediatric deaths in Sarawak in
1997
(April to July)  ,  the questions the clinicians wanted answered urgently
were:
What should we look for?
What constitutes a case?
What  should we investigate for when we do have a suspect case?


Over a period of nine days in mid April 1997,  the pediatricians in Sibu
(in the central region of the state of Sarawak)  had three unexplained
pediatric deaths  (17mo, 9mo and 6 month infants ).

All three were admitted after a short febrile illness,  in compensated
shock, with tachycardia (180 -200/min)  and tachypnea (one gasping) , lung
crepitation (liver size normal) ,  poor perfusion. All  died within 24 hrs
of admission.
One had fits, another had Right upper limb weakness, two had vomiting and
changes in mental status (irritability, drowsiness).  
There was no record of skin rash. Lumbar puncture was not done.
Echocardiography revealed poorly contracting dilated Left ventricle. 
In the child with fits, LDH was 512IU/l,  CK was not done. 
CPK for the second case (AFP) was 1500, 148 IU/l in the third.
CXR showed normal  heart size with pulmonary edema.

Pediatricians in  the state were alerted.  From the fourth case onwards,
specimens were sent for viral studies with the Institute of Health and
Community Medicine, Universiti Malaysia Sarawak,   which coincidentally
was running a Japanese B encephalitis surveillance study. 

During the outbreak, the criteria for hospital admission were all cases of :
suspected myocarditis  (*  see below) , 
acute flaccid paralysis,
aseptic meningitis, 
shallow mouth ulcers,
rash on hands and feet in a child less than 3 years old
and looking ill ( poor oral intake, high fever, vomiting, fits , altered
consciousness, tachypnoea,)
heart rate more than 160/min)

* The Acute Viral Myocarditis clinical diagnostic guideline used were:
(National Heart Institute, Kuala Lumpur  21  June 1997 )  

symptoms
unexplained tiredness
cough, dyspnoea
in association with a febrile illness

clinical signs
tachypnoea, usually mild
inappropriate and persistent tachycardia
neonate 180 -200/min
infant <6months < 180
6mo - 1yr <160
1 - 4 yrs <130
basal crepitation of lungs
gallop rhythm
CXR may show cardiomegaly of varying degrees with features of pulmonary
edema
Echocardiography
Left ventricular function (LV ejection fraction < 60%) with chamber
dilatation (reference range given)  often regional in nature

Summary of clinical presentations of the 27 deaths  14th April - 22nd June
1997

There were 17 males and 10 females, mean age  19 months ( 5-53 months )
with a  mode 22months. 
The mean survival time from  admission to death  (excluding the two brought
in died)  was 11hr 41min  (35 min - 29Hrs).  9 cases died within  6-10hrs

The majority of cases were admitted critically ill, with tachycardia and
compensated shock.  Most died within 24 hours of admission despite
respiratory and inotropic support.

In the presence of a clinical Hand Foot and Mouth epidemic in the state,
only 16 had documentation to suggest the presence of hand, foot or mouth
lesions
Painful ulcers on the palate and tongue are striking features.

All except one had a fever history.
GIT symptoms were seen in more than half,
with vomiting more common than diarrhoea. 
Respiratory symptoms were present in less than a third.
Half had neurological symptoms of seizures and definite limb paresis in
addition to less specific complaints of drowsiness, irritability or headache.
Sinus tachycardia is universal. 
Cardiomegaly was not a feature, but signs of left heart failure were found
(lung crepitation, pulmonary oedema and poor periferal perfusion despite
normal BP). This was confirmed by echocardiography in some cases. 
Liver enlargement was present in five.
BP is maintained to the terminal event..
Cardiac enzymes were definitely raised. 
The renal and liver function were not abnormal. 
Leukocytosis and thrombocytosis were marked.
CSF normal in two and six  had  pleocytosis with normal protein and glucose
The children were not malnuorished nor anemic.
There were no documentation in  their Under Seven records to suggest
immunodeficiency, or coexisting cardiac or neurological abnormalities.


Conclusions (made by the study group at that time)

The condition is probably communicable,  as shown by the two cousins dying
within a week of each other, and siblings of fatalities admitted.  The
outbreak coincided with the extensive travelling during the school holidays
as well as the Gawai festivities.

This agent(s)  causes a febrile exanthema  with central nervous system and
cardiac dysfunction , without significant renal or hepatic involvement.
Despite the low CSF cell counts, the definite fits and mono/limb paresis
are striking features. 
The intractable heart failure seem to be more left ventricular as the liver
was noted to be enlarged in only 5 cases. The raised CPK, AST, and LDH in
the absence of significant liver, renal, muscular (7 children had fits
only two of these had CK results - 115, 259)  or hematologic pathology is
consistent with injury to the myocardium and/or brain. 

The marked thrombocytosis may have contributed to the tissue anoxia and
metabolic acidosis. 

Virology results
(Institute of Health and Community Medicine, Unimas only)
(I do not have access to the results from other labs)

Of the 27 fatal cases,  no specimens were available for 6
(this included the first three cases which alerted the pediatricians)
21 had samples for viral culture & PCR - 
4   No growth
17 Viral isolated - Adenovirus (fastidious  - untypable with current probes) 
  2  with EV71  (serum, throat swab, rectal swab)
1 with enterovirus (typing in progress)  (serum)
1 with Echo 25  (serum)
PCR was  weakly positive for EV in 2 others (brain & heart)

None of the fatal cases had enteroviruses as a single infection
The adenovirus was cultured from the heart, brain, csf, throat swabs  and
serum (also adrenal and lung in one autopsy case)
Enterovirus was isolated from the serum,  throat and rectum,  not from
brain, csf, or heart.


Questions

Is this strain of Adenovirus the sole agent responsible for the cardiac and
neurological findings, and causing death?

What is the significance of the dual infections with enteroviruses?

This outbreak occurred in the midst of a widespread clinical Hand foot and
mouth outbreak - is this of clinical relevance and in some way contributory
to death?

In all cases presenting with  shock should echocardiogram be routine to
exclude LV dysfunction, BEFORE fluid resuscitation as this precipitated the
pulmonary edema in some of our cases??.

Or is the pulmonary edema (frothy red aspirate) a result of  infection of
the lungs by this particular strain of adenovirus?


I pray we find the answers soon.

tpt


Interesting References (among others on EV and Adeno) that you may want to
read:

"It is of note that all of the samples that amplified enterovirus RNA were
histologically correlated with inflammation, whereas most of the PCR
positive adenovirus heart samples showed  no evidence of inflammation. This
could possibly occur if the enterovirus elicit a stronger inflammatory
response as compared to the adenoviruses" [1,2]

On other presentations of myocarditis -  "a syndrome mimicking acute
myocardial incarction , but with normal coronary arteries , may also oocur"
[5,6]

1. Viral Heart Muscle Disease in Children
Neil E Bowles, Jeffrey A Towbin ,  Department of Pediatrics and Human and
Molecular Genetics,  Houston,  Texas, USA
<Viral  Myocarditis - Enteroviral Research Laboratory> on internet

2. Martin AB, WebberS, Fricker FJ, Jaffe, Demmler G, Kearney D, Zhang YH,
Bodurtha J, Gelb, Ni J, Bricker T, Towbin JA.  Acute Myocarditis: Rapid
diagnosis by PCR in children.    Circulation.  1994;90:330-339

3. Einar G Torfason, et al . PCR for detection of Adenoviral Central
Nervous System infections  (poster presentation Bologna, Italy, Sept 1997)

4. Shimizu C etal  Molecular identification of viruses in sudden infant
death associated with myocarditis and pericarditis.  Pediatr Infect Dis J ,
1995 Jul, 14:7,  548-8

5. Costanzo-Nordin MR etal  Myocarditis confirmed by biopsy presenting as
acute myocardial infarction  Br Heart J 1985:53:25-9

6. Dec WG etal  Viral Myocarditis mimicking acute Myocardial infarction J
Am Coll Cardiol 1992;20:85-9

--Dr. Tan Poh TinMalaysiae-mail: tpt@fhs.unimas.my

[We are extremely grateful to Dr. Tan Poh Tin of Malaysia for sharing this potentially life-saving information. We sincerely hope it will assist inthe investigation of the current outbreak in Taiwan - Mod.JW]............................jw/es


 

27 Initial deaths due to suspected viral myocarditis/infection 14th April – 22June 1997, Sarawak

Presenting symptoms and signs

Fever - history of fever in a ll except one, mean duration of 2.8 days (range 1-6 days).

Records of temperature on admission available in 15 patients (32.8 – 42.4 C) .

Subnormal in two (32.8, 35.0 C) , normal in one. The rest were febrile.

Skin Rash

14 had recorded history of rash, but 16 had skin lesions on examination

The skin lesions varied from petechiae to erythema to maculapapular or vesicular lesions.

Where specified, the number of lesions were more often "few" than multiple.

Ulcers in the mouth

12 patients had complaints of ulcers in the mouth, 10 of whom had ulcers on examination which were painful and caused the child to drool and have difficulty feeding.

Not all children with skin involvement had oral lesions, but all (except one) with oral lesions had skin lesions.

URTI – only three had documented symptoms of running nose or sore throat. .

7 had history of cough

Cardiorespiratory

16 had one or more CVS symptoms ,

Of the 23 recorded heart rate on admission, the mean was 172 (range 100 – 245). Only 3 had normal pulse rate (100 –108) The rest were all more than 140/min

Capillary refill – noted in 18 cases – 4 were less than 2sec, the rest were prolonged

This did not include those who were noted to be cold and clammy but whose refill time was not noted.

The respiratory rate (on admission) 14 records mean 52/min (30 – 64 mode 60)

BP – only 14 recorded on admission (A&E notes/admission) All within normal for age.

 CNS symptoms

13 had one or more neurological complaint , 2 had headache, 6 were said to be drowsy,

7 had fits.

6 had definite weakness ( 3 monoparesis upper limb, 1 generalised weakness and 2 toddlers were unable to walk or stand.)

Bleeding tendency

Only one had coffee grounds in the nasogastric aspirate, another had bloody sputum. There was no bruising or prolonged bleeding.

Investigations on admission (based on available records as of 22.7.97)

Haemoglobin : 19 records, mean 12.8g/dl (range 10 - 17.4). Hb of 16.2 and 17.4 were noted for 2 cases.

Total White Count 16 records mean of 23,269 (range 7,700 - 40, 000). Only one was 7,700. 15 were more than 14,000. 10 had leucocytosis more than 60 %. (range 10 - 80%, ) Eosinophil count was 2%, and 5% for one patient each, and 0% for the others.

Monocyte count varied from 1 - 8% in 8 patients, 0% in the others

One had a 1% basophil count.

Platelet count - 16 records Mean 452,687 (range 20,000 - 844,000). Thrombocytopenia (20,000) was found in 1, and more than 199,000 in 15 .

Blood urea 18 cases Mean of 43.7 ( 15 - 92 mg/dl). 9 had urea less than 40mg/dl

Serum sodium : 20 results Mean 135.6 (range 125 - 144). 18 normal, 2 less than 130.

Serum Potassium : 20 results Mean 4.9 (3.1 - 9.9) mode 4.3, 2 were below 3.5, 6 (3.5- 4.5) 4 were above 5.5 mmol/l .

Serum Bilirubin was done for 9 patients (range 0.2 - 1.4mg/dl mean 0.46)

AST 11 results mean 100.8 IU/l (55 - 228). All were above the normal range (>50 IU/L )

ALT 10 results - all normal mean 21.8 (range 10 - 48) IU/L

ALP 8 results mean 164. 9 IU/L (range 107 - 213).

Serum protein 8 results mean 6.9 (range 5.0 - 7.6) - within normal

Serum Albumin 8 results mean 4.2 (3.2 - 4.7) - all normal.

Other enzymes

Creatine Kinase –

14 results mean 504 (range 52 - 1593) - only 1 was normal for age (<80 IU/l).

Case 2 , 6 & 27 had levels of 1500 , 1593; and 1218 respectively (none of these had history of seizures. But 2 & 27 had upper limb weaknesses RUL, LUL respectively..)

Case 22 and 25 had 2 serial CKs ( which showed a rise from 52 to 149, and 154 to 251 respectively).

CKMB 1 was done for only one case (case 27 ). 130.0

LDH 7 results mean 782 (400 - 1312), all had levels above the normal range for age (40 - 150 IU/l), the lowest level being 400.

Trop T was done for 5 cases, positive in 2 and negative in 3

Blood culture was available for 6 patients - all were sterile.

CSF

8 results - 2 were normal with 1 and 4 cells respectively,

the rest (6) had cell counts ranging from 12 to 256.

The mean cell count was 71 (1-256) with lymphocytosis (60 % - all).

CSF protein ranged from 8 - 55 mg/dl mean of 33.9 mg/dl.

The CSFglucose level (range 34 - 206) mean of 82.4mg/dl.

Gram stain for negative for 2, not done for 3.

3 bacteriological cultures were reported negative

Arterial Blood gases

The first recorded ABG following or on admission were available for 16 cases

pH mean 7.32 (7.03-7.5) 5 had pH < 7.30 with base excesses of -13 to -21. and low bicarbonate. (These pH were corrected prior to death) .

4 had pH > 7.45 with normal BE but low PaCO2 and HCO.

The mean anion gap was 18.7 (range 9.3 - 37.3) .

Pre arrest ABG results available for 13 patients - pH with mean 7.35 (6.68 - 7.57) only one case was severely acidotic, all the rest were more than 7.30. Alkalosis (>7.45) was seen in 4.

Oxygenation improved with assisted ventilation. High pressures were not needed.

Hypocarbia was seen in most cases, on admission and predeath.

Chest Xray - Pulmonary edema was reported in the chest xrays of 7 patients. "Borderline cardiomegaly" was reported in only one case. All others had normal CT ratios and lung fields.

ECG strips were available for 12 cases - all showed sinus tachycardia, with Ventricular tachycardia as the terminal event in 3.

Echo cardiography was done for 19 cases (mostly by attending pediatricians, some confirmed by cardiologists), all were reported as "poorly contracting dilated Left Ventricle).

Findings as per report by Tpt etal 22 July 1997