Investigation and successful control of an echovirus 11 outbreak in neonatal intensive care units

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Pediatrics and Neonatology xxx (xxxx) xxx

Available online at www.sciencedirect.com

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Original Article

Investigation and successful control of an echovirus 11 outbreak in neonatal intensive care units Sheng-Yuan Ho a,b, Cheng-Hsun Chiu c,d, Yhu-Chering Huang c,d, Chih-Jung Chen c,d, Reyin Lien b,c, Shih-Ming Chu b,c, Chung-Guei Huang e,f,g, Kuo-Chien Tsao e,g, Shin-Ru Shih e,f,g,h,i,j, Jen-Fu Hsu b,c,* a Department of Pediatrics, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan b Division of Neonatology, Department of Pediatrics, Chang Gung Memorial Hospital, Taoyuan, Taiwan c College of Medicine, Chang Gung University, Taoyuan, Taiwan d Division of Pediatric Infectious Disease, Department of Pediatrics, Chang Gung Memorial Hospital, Taoyuan, Taiwan e Research Center for Emerging Viral Infections, Chang Gung University, Taoyuan, Taiwan f Graduate Institute of Biomedical Sciences, Department of Medical Biotechnology and Laboratory Science, College of Medicine, Chang Gung University, Taoyuan, Taiwan g Department of Laboratory Medicine, Linkou Chang Gung Memorial Hospital, Taoyuan, Taiwan h Research Center for Chinese Herbal Medicine, College of Human Ecology, Chang Gung University of Science and Technology, Taoyuan, Taiwan i Research Center for Food and Cosmetic Safety, College of Human Ecology, Chang Gung University of Science and Technology, Taoyuan, Taiwan j Graduate Institute of Health Industry Technology, College of Human Ecology, Chang Gung University of Science and Technology, Taoyuan, Taiwan

Received Aug 5, 2019; received in revised form Sep 18, 2019; accepted Sep 24, 2019

Available online - - -

Key Words echovirus 11; outbreak; neonatal intensive care unit

Background: Echovirus 11 emerged as a predominant enterovirus strain and was associated with neonatal mortalities in Taiwan in 2018. We investigated an echovirus 11 outbreak in the neonatal intensive care units (NICUs) in a tertiary hospital in northern Taiwan and analyzed infection control efforts. Methods: Between May and June 2018, an outbreak of 10 infants with echovirus 11 infections occurred in the NICUs. Comprehensive surveillance, including virus isolation, real-time reverse

* Corresponding author. Division of Pediatric Neonatology, Department of Pediatrics, Chang Gung Memorial Hospital, College of Medicine, Chang Gung University No. 5, Fushing St, Guishan Dist, Taoyuan City 333, Taiwan. Fax: þ886 3 3288957. E-mail address: [email protected] (J.-F. Hsu). https://doi.org/10.1016/j.pedneo.2019.09.012 1875-9572/Copyright ª 2019, Taiwan Pediatric Association. Published by Elsevier Taiwan LLC. This is an open access article under the CC BYNC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). Please cite this article as: Ho S-Y et al., Investigation and successful control of an echovirus 11 outbreak in neonatal intensive care units, Pediatrics and Neonatology, https://doi.org/10.1016/j.pedneo.2019.09.012

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S.-Y. Ho et al transcription-polymerase chain reaction (RT-PCR), and consequential degenerate hybrid oligonucleotide primer (CODEHOP) methods, were arranged for specimens (rectal or throat swabs), which were obtained from all contacts, newly admitted cases, and suspected cases during the outbreak since June 2. Results: Ten cases were identified with echovirus 11 infection in this outbreak. Eight of these 10 confirmed cases were identified by viral isolation, and the remaining two cases were identified by RT-PCR surveillance. In addition to confirmed cases, the surveillance of 19 contacts, 47 newly admitted cases, and nine suspected cases showed negative results. All confirmed cases eventually recovered. Conclusion: RT-PCR and CODEHOP methods significantly shorten the time of laboratory diagnosis of enterovirus infection compared with conventional methods. The outbreak of echovirus 11 in the NICUs was caused by three imported cases and was successfully controlled by the implementation of isolation, rapid surveillance, reinforced disinfection, and infection control measures. Copyright ª 2019, Taiwan Pediatric Association. Published by Elsevier Taiwan LLC. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/ by-nc-nd/4.0/).

1. Introduction Enterovirus (EV) infection is one of the most frequent viral outbreaks in neonatal intensive care units (NICUs)1 and nurseries.2 However, the majority of infants who acquired nonpolio EVs were asymptomatic or had a mild infection; infants who acquired severe EV infection still had high mortality rates.3e5 Severe neonatal EV infection is difficult to differentiate from severe bacterial infection, which leads to unnecessary interventions and antibiotics exposure. The predominant types of severe neonatal EV infection included echovirus 11, coxsackieviruses B2-5, and parechovirus 3 in previous research.5 Echovirus 11, which is categorized into nonpolio enteroviruses, is one of the predominant causative agents of epidemics of EV infection in nurseries.2,4,6e11 However, the outbreaks of echovirus 11 infections have rarely been reported in the NICU.12 This article reports an outbreak of echovirus 11, which led to EV control efforts that occurred in the NICUs and intermediate care units (IMCUs) of a tertiary hospital in northern Taiwan. The identification of the outbreak on May 31 led to the quick implementation of infection control measures in the hospital. We also highlight the impact of infection control measures on healthcareassociated EV infection and the results of molecular epidemiologic surveillance.

2. Patients and methods 2.1. Study populations This was a retrospective study, including three NICUs (referred to as A, B, and C) and two IMCUs (referred to below as D and E), which could accommodate up to 47 and 54 patients, respectively, at Chang Gung Memorial Hospital in northern Taiwan between the months of May and June, 2018 (Fig. 1). Each area has six to 10 facilities that allow healthcare workers to practice hand hygiene and alcohol-

based hand rub is accessible at the point of care at each bedside. Admissions to NICUs A, B, and C were more critical cases than those in other areas, and we adjusted the patient’s admission area according to the clinical condition. This study was approved by the Chang Gung Memorial Hospital Institutional Review Board (IRB#201801167A3). A confirmed case was defined as an infant within 3 months of age in our IMCUs or NICUs who presented with symptoms with laboratory-confirmed echovirus 11. A case of healthcare-associated EV infection was defined as disease onset 3 days after admission. The definition of severe complicated EV infection, which was modified from the definition provided by the committee of the Taiwan Society of Neonatology and Taiwan Centers for Disease Control (CDC) in 2016, included confirmed cases meeting one of the following criteria: (1) myocarditis or pericarditis; (2) hepatitis with coagulopathy; (3) encephalitis; (4) pneumonia complicated with respiratory failure; and (5) sepsis and excluded other common pathogens. Hepatitis with coagulopathy was defined as a serum aspartate aminotransferase (AST) level higher than three times the upper limit of normal, thrombocytopenia (platelet count <105/mm3), and prolonged prothrombin time/activated partial thromboplastin time.13 Myocarditis was defined as ejection fraction <50% on echocardiography, arrhythmia, or an elevation in the serum level of the cardiac fraction of creatine kinase or troponin-I, which couldn’t be explained by other reasons.

2.2. The outbreak On May 31, a clinician reported a probable echovirus 11 outbreak in both the NICUs and IMCUs to the infection control department and national public health authorities, with ten patients affected. A Hospital Emergency Response Team was then organized to manage the situation, initiate the epidemiological investigation, and implement infection control measures on May 31. The epidemiological investigation led to the retrospective identification of three potential cases, which might be responsible for this outbreak

Please cite this article as: Ho S-Y et al., Investigation and successful control of an echovirus 11 outbreak in neonatal intensive care units, Pediatrics and Neonatology, https://doi.org/10.1016/j.pedneo.2019.09.012

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Echovirus 11 outbreak in NICUs

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Figure 1 There are three NICUs (referred to as follows as A, B and C) and two IMCUs (referred to below as D and E) in Chang Gung Memorial Hospital. The way of transferring, hospitalization locations and hospitalized time of the 10 confirmed cases, of which three were community transmission (C1, 2, 7) and seven were healthcare-associated transmission (N3-6, 8e10), with echovirus 11 infection are shown. (NICU, neonatal intensive care unit; IMCU, intermediate care unit).

in our NICU. Case 1 (index case 1) was an outborn neonate and presented with fever on May 15. Echovirus 11 infection of Case 1 was identified on May 21. The secondary imported index case was Case 2, a 1-day-old outborn neonate, who was admitted to the NICU in area C because of petechiae on May 19. Fever and oral ulcer were found in Case 2 on May 23, and echovirus 11 infection was identified on May 29. These two index cases were investigated for viral infection on the day of admission but were not placed in isolated rooms. The index cases were transferred extensively in our NICUs and IMCUs while transmissible. The third imported index case, Case 7, was a 1-month-old infant who presented with fever and emesis two days before admission. All index cases were born in different clinics and had no relationship in the community before admission. Cases 3e6 were cared for in close proximity to the index cases during this epidemic. Inpatient Case 9 was only exposed to Case 6 during the incubation period. We could not identify the epidemiological links of Case 6 and Case 10 because of multiple infectious cases in the later periods. Case 10 was identified by rapid screening on June 4 and presented with symptoms on June 7. Patient transfers and the dates of hospitalization are shown in Fig. 1. The epidemiologic curve indicating the dates of onset of echovirus 11 infections, and the dates of interventions are shown in Fig. 2. Therefore, no further cases have been identified or linked to this hospital setting after interventions (described below) were conducted in June.

2.3. Clinical investigation and intervention An isolation area was created in part of area D to evaluate possible and confirmed cases in the IMCUs after the on-site inspection on May 31. Bundle implementation, including hand washing (with povidone-iodine and water, and bedside disinfectant with 75% ethanol then 95% ethanol for 20e30 s), glove and isolation gown use, was reinforced to

healthcare workers and visitors. Only one visitor was allowed, and the entrance of people with EV-associated symptoms was prohibited during this epidemic. In addition, patient transfers were restricted to the same floor. The infection control practitioners conducted strict monitoring of hand hygiene and provided feedback to improve compliance with outbreak control measures. The environment was disinfected with a 1:100 dilution of sodium hypochlorite with a concentration of 500 ppm for 10 min every day. Pacifiers and baby bottles that had been used by confirmed cases were concentrated for pasteurization and were not shared with others. Quarantine measures and rapid screening tools with real-time RT-PCR surveillance (described below) were applied to 19 contacts, 47 quarantined, and nine possible cases between June 2 and June 15, 2018.

2.4. Laboratory investigations Specimens (cerebrospinal fluid [CSF], rectal or throat swabs, and similar items) were collected from cases admitted to our neonatal units and sent to our laboratory. In the laboratory confirmation process, samples are isolated and identified by viral isolation and immunofluorescence assay (IFA), real-time reverse transcription-polymerase chain reaction (RT-PCR), or consensus degenerate hybrid oligonucleotide primer (CODEHOP) detection of EV. Virus isolation and identification with an indirect IFA was performed by the methods provided in detail previously.14,15 Pan-Enterovirus RT-PCR was used for specimens from the throat and rectal swabs since June 2. Viral RNA was extracted from the clinical specimens using a Viral RNA Extraction Mini Kit (QIAgen, Germany). An RT-PCR procedure was applied, and PCR amplification was performed using Pan-Enterovirus primers as previously described.16,17 Pan-Enterovirus RT-PCR was replaced by CODEHOP methods since June 6. The EV VP1 gene was amplified by

Please cite this article as: Ho S-Y et al., Investigation and successful control of an echovirus 11 outbreak in neonatal intensive care units, Pediatrics and Neonatology, https://doi.org/10.1016/j.pedneo.2019.09.012

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S.-Y. Ho et al

Figure 2 Epidemiologic curve indicating the date of interventions, the date of onset, and the date of confirmed echovirus 11 infection from 10 patients, of which three were community transmission (C1, 2, 7) and seven were healthcare-associated transmission (N3-6, 8e10) in neonatal units in one tertiary hospital, northern Taiwan, MayeJune, 2018. (ICP, infection control practitioner; RT-PCR, reverse transcription-polymerase chain reaction).

VP1 RT-snPCR from each of these extracted RNA templates. The amplified DNA was sequenced using an ABI 3730 XL DNA Analyzer (Applied Biosystem Inc., Foster City, CA). Nucleotide sequences of the partial VP1 gene were analyzed and aligned, as described in detail previously.15,17,18

3. Results 3.1. Descriptive epidemiology The 10 confirmed patients had a mean age of onset of 21.5 days (interquartile range [IQR]: 13.8e59.3 days), mean gestational age of 35 weeks (IQR: 32e39 weeks), and mean birth weight of 2007.5 g (IQR: 1552.5e3165.0 g). Detailed demographic data are summarized in Table 1. The common manifestations included fever (80%), and tachycardia or bradycardia (70%). Elevated serum C-reactive protein concentrations (>15.8 mg/l) were noted in eight cases (80%), whereas thrombocytopenia was found in three infants (30%). Only Case 1 met the definition of neonatal EV infection with severe complications (hepatitis with coagulopathy), and immunoglobulin (1 g/kg/dose) was administered intravenously. One case developed acute myocarditis, and five cases developed meningitis. Among the ten confirmed cases, the infection source of the three

index cases was almost certainly from the community, and the remaining seven were healthcare-associated infections. All patients survived.

3.2. Laboratory investigations Eight cases with echovirus 11 infections (Cases 1e8) were subjected to viral isolation. Among Cases 1e8, four were detected from throat swabs, five were detected from rectal swabs, and five were detected from CSF samples. Another nine suspected cases received Pan-Enterovirus RT-PCR or the CODEHOP method. Only Case 9 was identified from a rectal swab using Pan-Enterovirus RT-PCR, and Case 10 was identified from a rectal swab by the CODEHOP method. The viral studies of the 10 confirmed neonates in this outbreak are shown in Table 1. Besides confirmed cases, 19 hospitalized contacts and 47 quarantined cases in NICUs and IMCUs were screened by real-time RT-PCR between May 31 and June 15, which showed negative findings.

3.3. Further interventions 3.3.1. Rapid screening and quarantine measures New patient admissions were suspended until the quarantine areas in IMCUs of areas D and E were established on

Please cite this article as: Ho S-Y et al., Investigation and successful control of an echovirus 11 outbreak in neonatal intensive care units, Pediatrics and Neonatology, https://doi.org/10.1016/j.pedneo.2019.09.012

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Echovirus 11 outbreak in NICUs Table 1

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Demographic data and laboratory results of the ten echovirus 11 infected infants.

Case Sex GA Birth Date of Date of Age at Date of Laboratory Investigation Clinical (wk) wt (g) Admission Onset Onset Laboratory Viral isolation Pan-EV PCR CODEHOP Manifestations (days) Confirmation C1

M

38

3120

May 15

May 15 7

May 21

U(þ), T(), CSF(þ)

NM

NM

C2

M

40

3300

May 19

May 19 1

May 29

T(þ), R(þ), CSF(þ)

NM

NM

N3

F

36

1876

May 3

May 23 57

May 29

T(þ), R(þ)

NM

NM

N4 N5

M F

33 27

2200 618

May 7 Mar. 18

May 24 17 May 23 66

May 31 June 1

NM NM

NM NM

N6 C7 N8 N9

M M M M

27 40 35 34

1140 3505 2075 1940

Feb. 25 May 26 May 8 May 9

May May May May

June June June June

CSF(þ) T(þ), R(þ), CSF(þ) T(þ), R(þ) R(þ) CSF(þ) R(þ)

NM NM T() T(), R(þ)

NM NM NM NM

N10

F

33

1690

May 10

June 7 26

NM

T()

T(þ)

26 24 25 25

90 38 17 16

1 1 4 5

June 5

Fever, hepatitis, coagulopathy, thrombocytopenia, tachycardia Fever, oral ulcer, petechiae, thrombocytopenia Fever, apnea, cyanosis Fever, tachycardia Fever, poor activity, tachycardia Fever, tachycardia Fever, cough Fever Feeding intolerance, apnea, cyanosis, tachycardia, thrombocytopenia Feeding intolerance, apnea, bradycardia, cyanosis, emesis

CODEHOP, consequential degenerate hybrid oligonucleotide primer; CSF, cerebrospinal fluid; EV, enterovirus; GA, gestational age; NM, not measured; RT-PCR, reverse transcription-polymerase chain reaction; T, throat; U, urine; R, rectum.

June 2. To reduce the source of community infection, extra beds were set up in general wards to receive the noncritical outborn neonates. New critical patients of admission to the NICUs of area A, B, and C were quarantined in situ. Throat and rectal swabs from all new cases were investigated with real-time RT-PCR surveillance. If the result of real-time RT-PCR was negative, the case could come out of quarantine. However, if a case had EVassociated presentations, additional virus isolation had to be tested and kept quarantined until the negative result of viral isolation was confirmed. Our team reviewed the results of rapid screening tests daily. We have known that EV can be detected from feces for up to two months,19 so two months isolation is recommended for confirmed cases who require long-term hospitalization. The comprehensive screening of new admission cases was terminated on June 15, which was the date of diagnosis of the last confirmed case plus a maximum incubation period of 10 days. The neonatal division provided up-to-date EV epidemic information from national and hospital sources weekly and established standard quarantine measures (Supplementary Figures S1 and S2) based on the experience learned from this outbreak. 3.3.2. Hospital information system settings Confirmed cases or patients who were exposed from May 15 to June 1 were all noted as EV contacts in the information system for tracking by the emergency department or outpatient department. These patients were followed up by clinicians one week later after being discharged. The

hospital sent out text messages about the newly confirmed results of cases with EV infection to healthcare workers via cellphone and the information system immediately. 3.3.3. Infection control measures for the delivery room and nursery Infection control measures were conducted at the nursery and delivery room to prevent the risk of EV vertical transmission from mothers. Care from the same visitor during the hospitalization was advised. We designed a questionnaire, including three questions, to be filled out by each mother (Table 2). If the mother answered “Yes” to one of these three questions, her neonate was quarantined in an isolation area in the nursery. Control measures and device disinfection were as same as the isolation areas in NICUs. Breastfeeding and rooming-in were prohibited. Posters were created to raise public awareness of EV infection in the delivery room and the nursery. Neonates, who became symptomatic, were transferred to the quarantined areas of the NICUs or IMCUs. During this epidemic, 52 cases were quarantined in the nursery, and there were no confirmed cases of EV infection.

4. Discussion This investigation is the first study of an echovirus 11 outbreak in NICUs in Taiwan in 2018, and the source of this outbreak could be traced back to three community cases. There are two possible causes for the outbreak in this

Please cite this article as: Ho S-Y et al., Investigation and successful control of an echovirus 11 outbreak in neonatal intensive care units, Pediatrics and Neonatology, https://doi.org/10.1016/j.pedneo.2019.09.012

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S.-Y. Ho et al Table 2

1.

2. 3.

Survey questionnaire for a parturient woman during the prevalent season of enterovirus infection. Item

Yes

No

Have you or the family members you live with had any of the following symptoms: fever, abdominal pain, cough, runny nose, chest pain, in the last two weeks? Have your other children been infected with the enterovirus in the last two weeks? Have you been exposed to patients with the enterovirus infection in the last two weeks?

,

,

,

,

,

,

Table is modified from the “Recommendations for the Prevention of Enterovirus Infection” of the Infectious Diseases Society of Taiwan and Child Health Research Center of National Health Research Institute of Taiwan.

study. First, it is challenging to differentiate presentations of neonatal EV infection from other common diseases (e.g., sepsis, respiratory distress syndrome, and transient tachypnea of newborns). Without tools for rapid surveillance, healthcare workers may ignore the possibility of EV infection. Second, some healthcare workers seemed to underestimate the attack rate of this outbreak and delayed the implementation of stricter isolation and control measures. The neonate’s ability to respond to infections is limited, so they may be susceptible to contracting EV infection and have a higher risk of EV outbreak in NICUs.20e22 In this outbreak, index cases from the community were not adequately isolated. The echovirus 11 might have subsequently spread to another seven cases because contacts were cared for by the same healthcare workers during the same shift as index cases. Therefore, reinforcing stricter isolation and setting up a quarantine area in general wards to receive non-critical outborn neonates would be an effective control measure to reduce the possible infection sources from the community during this epidemic. During the prevalent seasons of EV from April to October, healthcare workers should inquire about perinatal events, contact history, and EV-related manifestations by continuous medical education on infection control issues. EV infection is common in pregnant women, and up to 42% of pregnant women were found to be infected with EVs in a serology study.23 Neonates can acquire EV transmission in uterine, intrapartum, or postpartum through contact with feces and mucosal secretions,24 with an average incubation period of 3e10 days.25 EV is most infectious within one week after the onset of disease,26,27 and can be shed in feces for as long as 8e12 weeks.19 Neonates with disease onset between one and seven days of life may have acquired EV infection from vertical transmission with majority of intrapartum exposure.5,28,29 Therefore, the two cases of community infections, Case 1 and Case 2, with disease onset on days 1 and 7 of life were classified as vertical transmissions in this outbreak. Case 7 (index 3) developed symptoms before admission. The other seven cases were eligible for secondary infection. Contagious viral shedding was detected before the onset of symptoms as previously mentioned,26,27 so rapid surveillance was performed in all quarantined cases during this epidemic. The neonatal EV infection also could be transmitted via infected parents during rooming-in30 or via breastfeeding in some studies.31,32 Therefore, rooming-in and breastfeeding were prohibited from the quarantined neonates in the nursery during this outbreak in our hospital. Using sodium

hypochlorite as an environmental disinfectant is known to be effective.33 In addition to handwashing with soap and water, past research has confirmed that the use of gloves and 90%e95% alcohol-based hand rub offer benefits in compliance and effectiveness.34,35 The same strategy for hand and environmental disinfection was conducted in this outbreak and seemed successful. As of September 14, 2018, 35 cases with neonatal echovirus 11 infection were notified at the national level on the surveillance system provided by the Taiwan CDC, with eight severely complicated cases. Echovirus 11 infection was prevalent in the community and was the predominant enterovirus type in northern Taiwan from the seventeenth to the thirty-first week (April 22 to August 4) of 2018, and we also found a similar trend from the laboratory database in our hospital (Fig. 3). We successfully stopped this outbreak in our NICUs by following infection control measures in the twenty-third week of 2018. Echovirus 11 was the predominant serotype of severely complicated EV infection in Taiwan in 2018 through laboratory surveillance by the Taiwan CDC. As previously mentioned, echovirus 11 accounted for 14% of neonatal EV infections, of which 19% were fatal in the United States.9 Echovirus 11 outbreaks and the first case of a patient dying of echovirus 11 sepsis in Taiwan was reported in 2003.28,29 Among the last epidemics in 2003, an echovirus 11 outbreak was reported in an obstetric clinic in Taiwan, during which 13 infants were admitted to the NICU; one infant died, and one patient presented with fulminant hepatitis. The Taiwan CDC investigated the outbreak in the above obstetric clinic and found that echovirus 11 was also detected in two asymptomatic neonates.29 Therefore, comprehensive surveillance for asymptomatic cases was also conducted in this study. Previous studies confirmed that using the CODEHOP method as a tool for EV surveillance is more sensitive and saves time compared with virus isolation.17,18 Using the CODEHOP method, we can facilitate timely intervention as early as 48 h in cases with severe complications, and reduce unnecessary use of antibiotics and hospitalization. However, the cost of the CODEHOP method is higher than that of traditional methods. The use of the CODEHOP method as a comprehensive screening tool is not cost effective for asymptomatic cases because of all the negative results in this outbreak. Compared with comprehensive CODEHOP surveillance, early awareness of possible EV infection, strict quarantine and isolation, and implementation of hand hygiene may be more cost effective. Many studies have

Please cite this article as: Ho S-Y et al., Investigation and successful control of an echovirus 11 outbreak in neonatal intensive care units, Pediatrics and Neonatology, https://doi.org/10.1016/j.pedneo.2019.09.012

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Echovirus 11 outbreak in NICUs

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Figure 3 Chronological trend of weekly isolated echovirus 11 infection cases in Chang Gung Memorial Hospital and monthly isolated echovirus infection cases at the national level in Taiwan Centers for Disease Control in 2018. Data were from the laboratories of Chang Gung Memorial Hospital and Taiwan CDC. * National data from Taiwan CDC were presented as month of specimen receipt. (CDC, Centers for Disease Control).

documented that the 50 nontranslated region of the PanEnterovirus RT-PCR is more timesaving but less sensitive than the CODEHOP method for the detection of EV infection.17,36 In our study, only Case 10 received both the PanEnterovirus RT-PCR and CODEHOP methods. Echovirus 11 was detected by the CODEHOP method but revealed a negative result by Pan-Enterovirus RT-PCR in Case 10. There are several limitations to this study. First, this was a retrospective study. No further phylogenetic analysis was performed to confirm the propagation path of this outbreak. Further molecular typing of isolated strains in this outbreak should be applied to confirm the propagation path subsequently. Second, the costs associated with outbreak control have not been estimated, but may be considerable. In conclusion, RT-PCR and CODEHOP methods significantly shorten the time of laboratory diagnosis of EV infection compared with conventional methods but have higher medical expenses. Through a series of outbreak control measures, including epidemic investigation, stricter isolation, and the bundle implementation of disinfection and hand washing, we successfully stopped the spread of EV infection in this outbreak.

Declaration of Competing Interest The authors declare no conflicts of interest.

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Appendix A. Supplementary data Supplementary data to this article can be found online at https://doi.org/10.1016/j.pedneo.2019.09.012.

Please cite this article as: Ho S-Y et al., Investigation and successful control of an echovirus 11 outbreak in neonatal intensive care units, Pediatrics and Neonatology, https://doi.org/10.1016/j.pedneo.2019.09.012