There were a total of 527 EV71 cases. Of these 527 EV71 cases, 509 cases were diagnosed bybased on positive EV71 isolation plus positive serologic test;
and the other 18 cases were diagnosed bybased on positive EV71 IgM and positive EV71 neutralization antibody.
Clinical syndromes associated withof EV71 are shown inon Table 2. The number of1998-–1999 pre-stage-based managed EV71 cases came to 196; the number of 2000 – 2002 stage-based managed EV71 cases came to 331., and 331 EV71 cases after stage-based management, 2000-2002. The distribution of clinicalassociated syndromes among the patients who did not receive stage-based management was similar to that of those who didwas similar before and after stage-based management (p = 0.29). Overall, 69% (365/527) had no
complications, 20% (108/527) had CNS complications and 10% (54/527) had CNS involvement plus cardiopulmonary failure. The incidence of CNS
involvement plus cardiopulmonary failure was 9.1% (18/196) in those who did not receivebefore stage-based management and 11% (36/331) in those who didafter stage management (p = 0.64).
Clinical Ooutcomes of EV71 CNS Iinvolvement
Forty-sevenThere were 47 EV71 who did not receive stage-based management and 61 who did hadcases of CNS involvement. Its manifestations included
without stage-based management and 61 EV71 cases of CNS involvement with stage-based management. Manifestations of CNS involvement included limb weakness, limb hypesthesia, myoclonic jerk or seizure attacks/, or conscious disturbance.
Their clinical outcomes of two groups were not were not significantly
differentwith or without stage-based management as (Table 3) shows. Most (79%, 85/108) of those withthe CNS involvement cases recovered; 18% (20/108)
sufferedhad sequelae of polio-like syndrome of limb weakness or cranial nerve palsy. Three cases, who did not receive without stage-based management, died during the convalescence: two, who were left in a: two of vegetative state,us died of pneumonia 2 and 4 months after onset of the disease onset; one, who suffered subsequent, and one with sequelae of dysphagia and limb weakness, died of suffocation at home 3 months after onset of disease. onset.
Further analysis reveals that Aage, sex and stage management were not found to affect did not affect the occurrence of sequelae in CNS cases, though those with sequelae were more likely to be found to have but only CSF WBC. CNS cases with sequelae had higher CSF WBC than those without than CNS cases without sequelae(299±305/uL vs. 141±122/uL, p=0.05).
Clinical Outcomes of Enterovir us 71-related Car diopulmonar y Failure
24
All the patients withof EV71-related cardiopulmonary failure had fever and 95%
(51/54) had either HFMD or herpangina. All of the cardiopulmonary failure patients had been found to have hadThey also had preceding prior CNS involvement, includingsuch limb weakness, limb hypesthesia, myoclonic jerk or seizure attacks, /upward gaze, /and nystagmus. From sSeveral hours to 2 days after CNS involvement, these patients suddenlyy d developed sudden appearances of tachypnea, tachycardia (range 135-250 beats per minute), cyanosis and coma.
After intubation, All the chest X-ray films of these children after intubation showeddemonstrated alveolar density withand no cardiomegaly, EKG did not show arrthymia, and cardiac echography showed normal or mildly decreased ejection fractions. From the endotracheal tube cameAfter intubation, children had a white frothy secretion and then a, then pink frothy fluid, which andsometimes containedalso had fresh blood. from endotracheal tube.
Eighteen EV71 cases of CNS involvement plus cardiopulmonary failure occurred in 1998. and did not receive stage-based management. Most (83%, 15/18) of these patients, who did not receive stage-based management, m died soon after cardiopulmonary resuscitation. Three; only survived the
cardiopulmonary failure during the acute stages of the EV71- related illness.
However, One of three survivors one of these three died of ventilator
disconnectionduring sleep 6 months after onset of the disease and anotherafter disease onset; the other one died of multi-resistant Acinetobacter baumanii pneumonia 4 years after onset.disease onset. The only one who has survived survivor still has tracheostomy, dysphagia with occasionally aspiration pneumonia, left facial palsy and right hemiparesis.
Thirty-six EV71 cases with CNS plus cardiopulmonary failure received stage-based management in the in 2000-–2002 time period. Twelve (33%) died at the acute stage despite of stage management. Five (14%) cases recovered completely, and the other 19 (53%) had sequelae. Of the 19 survivors with sequelae, 2two died fromof unknown sudden cardiac arrest at a chronic respiratory care center orand at home respectively, and 1one died of pneumothorax at a chronic respiratory care center.
Factor s Aassociated with Ffatality in Eenterovir us 71-related Ccar diopulmonar y Ffailure
To analyze factors associated with fatality in EV71-related cardiopulmonary failure during the acute stage, we compared the data of those who survived EV71-related cardiopulmonary failure and those who did not.the data between alive and fatal cases of EV71-related cardiopulmonary failure. As Table 5 shows, patients over 2 years old and those with CSF WBC over 100/uL were at higher risk of dying of cardiopulmonary failure, though who received stage
25
management had less of a risk than those who did not. cases with age over 2 years, and CSF WBC over 100 /uL had higher risk of fatality but receiving stage management decreased the risk of fatality. Although the younger children tend to developed cardiopulmonary failure more often than the older oneschildren, it is much more difficult to rescuinge older children was much more difficult. with EV71-related cardiopulmonary failure. After Mmultivariate analysis found , receiving stage management to be the mostis the most significant factor affecting fatality (OR 0.1, 95% CI 0.024-0.414, p=0.0015).
26
Discussion
Our The stage-based management program we developed was found to significantly decreased the case-fatality rate (33%) in patients withof
EV71-related cases with cardiopulmonary failure when we compared the fatality rates of those who underwentin comparison with historical conventional
management (83%). The decrease may be causes of decreasing mortality may be due to earlier admission of high-risk groups, usage of IVIG, and more advanced intensive care they received. Up to now, there is no standard therapy for
EV71-related cardiopulmonary failure and we think that setup of the standard therapy for EV71 infection is necessary.
TheFirst of all, pathogenesis of the disease is very important in determining for appropriate management.
During the onset of disease, (Stage I), there is viremia occursstatus. For common acute viral infections such as chickenpox, herpes simplex or influenza viral infections, it is suggested that antiviral therapy is usually supposed to be used as soon as possible to stop further spread, as, and only early usage of anthe antiviral agent cancould have impact on disease outcome (9-11). However, since noHowever, up to now, there is no effective anti-EV71 drug has been made available, our only management choice is in the market. Therefore, only
supportive therapy withis given and close observation of the symptoms and signs of advanced disease. is necessary.
CNS involvement, the main clinical feature of During Stage 2II, CNS involvement,the main clinical feature may be caused by viral invasion of the CNS combined with the resulting immune response therein the CNS. The manifestations may be myoclonic jerk, limb weakness, cranial nerve palsy, seizure and conscious disturbance (5, 12). Increased intracranial pressure should be prevented and treated, so we recommend fluid restrictioned and osmotic diuretics. IVIG is given in all cases beyond Sstage 2 because of theII. IVIG may have two effects: one is the resulting antiviral activity, which mayto prevent further spread of the virus, and because of the resultingthe other is
immunomodulation. However, IVIG did not, however, affect the incidence of sequelae nor prevent progress to cardiopulmonary failure. Because The patients with CNS involvement that received cases with stage-based management, (including those receiving IVIG treatment, almost the same) had similar
incidence of sequelae as those do did notthan CNS cases without IVIG treatment.
Both groups had almost the same proportion of and the proportion of
cardiopulmonary failures.cases were almost the same with (in 2000-2002) or without stage management (in 1998-1999). Some cases with CNS involvement did developed cardiopulmonary failure during the administration of IVIG administration.
27
Higher CSF WBC was found in CNS cases with sequelae were found to have higher CSF WBC, possibly indicating that the more severe the CNS involvement, the higher the incidence of sequelae.. Higher CSF WBC may indicate more
severe involvement of the CNS, so the incidence of sequelae on such a condition was higher.
The pathogenesis of EV71-related pulmonary edema (Stage 3III) is still controversial. Some haveWe had hypothesized that EV71 involvement of the brainstem startsmade autonomic nervous system dysregulation (ANS dysregulation), tachycardia, rapid change of the vascular tone and resistance, left ventricular
dysfunction, and then neurogenic pulmonary edema [6, 13, 14]. A study byIn another report by Wu JM et al. found, they found that the mechanism of EV71-related
pulmonary edema not to beis not directly caused by viral myocarditis but possibly related toand may be related to increased pulmonary vascular permeability caused by brainstem lesions and/or systemic inflammatory response [15]. In our studies, patients with cardiopulmonary failure were found to have significantly elevated levels of seral proinflammatory cytokines, white blood cell counts, and glucose levels and the best predictor for this complicated condition was found to be the level of serum IL-6 (16,17). CNS proinflammatory cytokines significantly elevated on the first two days of CNS involvement regardless of whether there wasno matter cardiopulmonary failure occurred or not (17).At thisIn this stage, when there is mounting of the immune response is mounted, viral clearance can be accompanied by severe inflammatory damage of the system and CNS.
Putting all the clinical evidences together, we think that the combination of CNS, particularly the (especial brainstem,) and systemic inflammatory response may trigger EV71-related cardiopulmonary collapse (17). Therefore, usage of IVIG,
immunomodulator, to decrease both CNS and systemic inflammatory response, appropriate inotropic agents and fluid therapy are all important in treatment.
This study showsed that immune modulators such as intravenous immunoglobulin (IVIG) plus advanced cardiopulmonary failure could could
saverescue EV71 patients from fulminant cardiopulmonary failure; , however, most of the survivors suffered from sequelae related to brainstem or spinal cord dysfunction, including dysphagia, hypoventilation, facial palsy, and also polio-like syndrome. The sequelae are most related to the degrees and the location of neuron damage, and rarely related to hypoperfusion. Since their sequelae may sometimes cause life-threatening events, chronic care is also very important during the convalescence stage.
In conclusion, to date no standardized therapy for EV71-related cardiopulmonary failure has been recommended. We think that at least a preliminary one should be established. We suggest that management guidelines for EV71 infection include CNS management, cardiopulmonary support and care for convalescence based on different clinical stages; the
28
guidelines, though not perfect, are quite comprehensive, and the mortality rate of EV71-related cardiopulmonary collapse did decrease after 1999.
The possible reasons of decrease in mortality rate may be due to earlier hospitalization of the high-risk cases and thus earlier administration of intravenous immunoglobulin and appropriate cardiopulmonary support.
29
Acknowledgement
This study was supported by grants from the Chang Gung Memorial Hospital (CMRP1089) and National Science Council (NSC90-2314-B182A-028 and NSC91-3112-B182A-001).
30
References
1. Sindarov LM, Chumakov MP, Voroshilova MK, et al. Epidemiological, clinical, and pathomorphological characteristics of epidemic poliomyelitis-like disease caused by enterovirus 71. J Hyg Epidemiol Microbiol Immunol 1979; 23:284-95.
2. Nagy G, Takatsy S, Kukan E, Mihaly I, Domok I. Virological diagnosis of enterovirus type 71 infections: experiences gained during an epidemic of acute CNS disease in Hungary in 1978. Arch Virol 1982; 71: 217-27.
3. World Health Organization. Outbreak of hand, foot, and mouth disease in Sarawak:
Cluster of deaths among infants and young children. Wkly Epidemiol Rec 1997;
72:211-2.
4. Ho M, Chen ER, Hsu KH, et al. The enterovirus type 71 epidemic of Taiwan, 1998.
N Engl J Med 1999; 341:929-35.
5. Chang LY, Lin TY, Hsu KH, et al. Clinical features and risk factors of pulmonary oedema after enterovirus 71-related hand, foot and mouth disease. Lancet 1999;
354:1682-6.
6. Lin TY, Chang LY, Hsia SH, et al. The 1998 enterovirus 71 outbreak in Taiwan:
pathogenesis and management. Clin Infect Dis 2002; 34:S52-7.
7. Hsia SH, Wu CT, Chang LY. The critical care of children infected by enterovirus type 71. Taiwan Crit Care Med 2002; 4:190-6.
8. Chao KC, Chan EC, Chang LY, et al. Development and evaluation of immunoassay to detect IgM to enterovirus 71. J Med Virol 2002; 68:574-80.
9. Balfour HH Jr, Edelman CK, Anderson RS, et al. Controlled trial of acyclovir for chickenpox evaluating time of initiation and duration of therapy and viral resistance.
Pediatr Infect Dis J 2001; 20:919-26.
10. Simmons A. Clinical manifestations and treatment considerations of herpes simplex virus infection. J Infect Dis 2002; 186 Suppl 1:S71-7.
11. Uyeki TM. Influenza diagnosis and treatment in children: a review of studies on clinically useful tests and antiviral treatment for influenza. Pediatr Infect Dis J 2003; 22:164-77.
12. Huang CC, Liu CC, Chang YC, Chen CY, Wang ST, Yeh TF. Neurologic complications in children with enterovirus 71 infection. N Engl J Med 1999;
341:936-42.
13. Chang LY, Lin TY, Huang YC. Fulminant neurogenic pulmonary oedema with hand, foot and mouth disease. Lancet 1998; 352:367-68.
14. Hsueh C, Jung SM, Shih SR, et al. Acute encephalomyelitis during an outbreak of enterovirus type 71 infection in Taiwan. Report of an autopsy case with
pathologic, immunofluorescence, and molecular studies. Mod Pathol 2000;
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13:1200-5.
15. Wu JM, Wang JN, Tsai YC, et al. Cardiopulmonary manifestations of fulminant enterovirus 71 infection. Pediatrics 2002; 109:e26.
16. Lin TY, Chang LY, Huang YC, Hsu KH, Chiu CH, Yang KD. Different proinflammatory reactions in fatal and nonfatal enterovirus 71 infections:
implications for early recognition and therapy. Acta Paediatrica 2002; 91:632-5.
17. Lin TY, Hsia SH, Huang YC, Wu CT, Chang LY. Proinflammatory cytokine reactions of cerebrospinal fluid in enterovirus 71 central nervous system infections.
Clin Infect Dis 2003; 36:269-74.
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Table 1. Clinical Sstaging and Mmanagement
Stages Clinical Manifestations Management
1 HFMD/herpangina Symptomatic treatment only
2 CNS involvement Fluid restriction, osmotic diuretics for increased intracranial pressure (IICP), and furosemide for fluid overloaded (CVP>8 cmH2O), intravenous immunoglobulin (IVIG) for encephalitis and/or polio-like syndrome and close monitoring of heart rate, blood pressure, oxygenation, coma scale and blood glucose
3 Cardiopulmonary failure 3A Hypertension/pulmonary
Edema
Phosphodiesterase inhibitor, milrinone, to increase cardiac output, early intubation with positive pressure mechanical ventilation with increased positive end expiratory pressure for pulmonary edema, and high frequency oscillatory ventilator if pulmonary edema/ hemorrhage persists or severe hypoxemia develops
3B Hypotension Adding inotropic agents such as dopamine and epinephrine
4 Convalescence Rehabilitation for limb weakness, dysphagia, apnea/ or central hypoventilation, and sufficient chest care to avoid recurrent pneumonia
NOTE. HFMD, hand, foot, and mouth disease; CVP, central venous pressure; CNS, central nervous system.
33
Table 2. Clinical Syndromes of Enterovirus 71 before and after Stage-based Management
Year Before, 1998-1999
(N=196)
After, 2000-2002 (N=331)
Total (N=527)
Uncomplicated cases 131 (67%) 234 (71%) 365 (69%)
HFMD 102 209 311 Herpangina 18 14 32 Febrile illness 7 10 17
AGE 1 1
Viral exanthema 3 1 4
CNS cases 47 (24%) 61 (18%) 108 (20%)
Meningitis 12 21 33 Encephalitis 18 20 38 Polio-like syndrome 8 15 23 Encephalomyelitis 9 5 14 CNS involvement plus
cardiopulmonary failure
18 (9.1%) 36 (11%) 54 (10%)
ΝΟΤΕ. χ2=2.46, P=0.29. HFMD, hand, foot, and mouth disease; AGE, acute gastroenteritis; CNS, central nervous system.
34
Table 3. Clinical Outcomes of Enterovir us 71 CNS Involvement Without Car diopulmonar y Failure Before and After Stage-based Management
Year Before, 1998-1999
(N=47)
After, 2000-2002 (N=61)
Recovery 35 (74%) 50 (82%)
Sequelae 9 (19%) 11 (18%)
Limb weakness or cranial nerve palsy
8 11
Seizure 1
Fatality at convalescence 3 (6%)* 0
NOTE.χ2=4.1, P=0.13 *One with sequelae of dysphagia and limb weakness died of suffocation at home
3 month after EV71 encephalomyelitis. Two with sequelae of vegetative status died of pneumonia 2 and 4 months respectively after EV71 encephalitis.
35
Table 4. Clinical Outcomes of Enterovirus 71-related Cardiopulmonary Failure-Before and After Sstage-based Management
Year Before
(N=18)
After (N=36)
Recovery 0 5 (14%)
Sequelae 1 (6%) 16 (43%)
Limb weakness or cranial nerve Palsy
2
Dysphagia 1
Hypoventilation + dysphagia 1
Dysphagia + limb weakness 1 Combined (Hypoventilation +
Dysphagia + limb weakness)
12
Fatality 17 (94%) 15 (42%)
Death at acute stage 15 (83%) 12 (33%)
Death at convalescence 2* (11%) 3**(8%)
NOTE. P<0.001, χ2=13.3; + denotes plus. *One died of ventilator
disconnection-related hypoxia 6 months after disease onset, and the other died of
36
pneumonia 4 years after disease onset. ** One died of unknown sudden cardiac arrest at chronic care center, one died of unknown cause at home and one died of pneumothorax.
37
Table 5. Factor s associated with fatality in enterovir us 71-related car diopulmonar y failure
Factors Survival
(N=27)
Fatal (N=27)
Unadjusted OR (95% CI)
p
Age>=2 7% (2/27) 44% (12/27) 10 (1.96-50.94) 0.0056
Sex (Male/female) 20/7 16/11 1.964 (0.62-6.22) 0.25
Receiving stage management 89% (24/27) 44% (12/27) 0.1 (0.024-0.414) 0.0015 CSF WBC>=100 7% (2/27) 41% (11/27) 8.59 (1.68-43.95) 0.0098
NOTE. OR, odds ratio; CSF, cerebrospinal fluid; WBC, white blood cell count.
38
Manuscr ipt submitted
Tr ansmission and Clinical Features of EV71 Infections Tr ansmission of EV71 in Household Contacts and Clinical Features of Infected Children and Adults Luan-Yin Chang, MD, PhD, Kou-Chien Tsao, BS, Shao-Hsuan Hsia, MD, Shin-Ru Shih, PhD, Chuang-Guei Huang, MS, Tsui-Yen Fang, RN, Yhu-Chering Huang, MD, PhD, Tzou-Yien Lin, MD
Division of Pediatric Infectious Diseases, Department of Pediatrics, Chang Gung Children’s Hospital, Chang Gung University (DRs Chang, Huang and Lin, RN Fang),
†Division of Pediatric Critical Care and Emergency Medicine (DR Hsia); *Clinical Virology Laboratory, Chang Gung Memorial Hospital (BS Tsao and MS Huang); and
‡School of Medical Technology, Chang Gung University (DR Shih).
Cor responding Author and Repr ints: Tzou-Yien Lin, MD,
Division of Pediatric Infectious Diseases, Department of Pediatrics, Chang Gung Children’s Hospital, Chang Gung University, 5, Fu-Hsing Street, Kweishan, Taoyuan 333, Taiwan
Tel: 886-3-3281200 ext 8002; Fax: 886-3-3288957;
E-mail: [email protected] or [email protected]
Key wor ds: enterovirus 71;, hand, foot, and mouth disease;, herpangina; household transmission;, family, household, asymptomatic, complication, risk factors
Short title: Household Transmission of Enterovirus 71 Wor d count: 2524
39
Abstract
Context Although eEnterovirus 71 may has cause largecaused epidemics associated with lots ofsignificant morbidity and mortality, its fatality but transmission pattern hasis not been thoroughly investigatedwell-investigated.
Objective TTo study evaluate eEnterovirus 71 transmission within households and outcome of eEnterovirus 71 infection the in children and adults., we did a prospective family cohort study.
Design, Setting, and Subjects From February 2001 to August 2002, wWe performed a prospective family cohort study to enrolled investigate patients and family members of patients who presented with signs and symptoms suggestive of eEnterovirus 71. Household members underwent c173 possible EV71 patients at Chang Gung Children’s Hospital and their 611 family members from February 2001 to August 2002. They received clinical evaluations, virologic studies and questionnaire-based interviews. investigation. If any family member s had positive EV71 isolation, their data wer e analyzed. r e between acute and convalescent ser a.
Main Outcome Measur es Enterovirus 71 infection was confirmed by isolating eEnterovirus 71, detecting eEnterovirus 71 IgM or demonstrating a four-fold change in neutralizing antibody titers. Clinical syndromes at presentation included asymptomatic, uncomplicated and complicated illness such as central nervous system involvement or cardiopulmonary failure. Unfavorable outcome was defined as death or sequelae.
Results A total ofWe studied 433 family members in from 94 families with positive eEnterovirus 71 isolation. were further analyzed. In addition to the 94 index patients, 52% (176/339) of household contacts of all the family members were infected. In addition to 94 index patients:, 84% (68/81) of their siblings, and 84% (21/25) of their cousins, were infected whereas 41% (72/175) of their parents, 28% (10/36) of their grandparents and 26% (5/19) of their uncles/aunts were infectedgot EV71 infection.
Of Of the 183 infected children, 6% (11/183) were asymptomatic,, 73% (133/183) suffered nowere uncomplicatedions and 21% (39/183) had complications; cases, and were complicated cases among whom 10 cases were fataldied and 13 had sequelae.
40
asymptomatic adults and high household transmission rate, which make controlling transmission of enterovirus 71 infections difficult.
Household EV71 transmission was very high, and both infected children and adults could be the source of familial or extra-familial transmission. EV71-infected children tend to have severe disease than adults.
41
INTRODUCTION
Outbreaks of enterovirus 71 (Enterovirus 71 (EV71)) has caused outbreaks in some parts of the world,have been documented since it was originally recognized in California in l969.1 Forty-four fatalities have been reported in Bulgaria (1975), 47 in Hungary (1978) and 30 in Malaysia (1997)Before 1998, three large outbreaks occurred in Bulgaria with 44 deaths in 1975, Hungary with 47 deaths in1978, and
Outbreaks of enterovirus 71 (Enterovirus 71 (EV71)) has caused outbreaks in some parts of the world,have been documented since it was originally recognized in California in l969.1 Forty-four fatalities have been reported in Bulgaria (1975), 47 in Hungary (1978) and 30 in Malaysia (1997)Before 1998, three large outbreaks occurred in Bulgaria with 44 deaths in 1975, Hungary with 47 deaths in1978, and