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Routes of transmission during a nosocomial influenza A(H3N2) outbreak among geriatric patients and healthcare workers ´net c, d, C. Regis c, d, D. Eibach a, b, *, J.-S. Casalegno a, M. Bouscambert a, T. Be B. Comte e, B.-A. Kim e, P. Vanhems c, d, B. Lina a a

Virology Department, Centre de Biologie et Pathologie Est, Hospices Civils de Lyon, Lyon, France European Public Health Microbiology Training Programme (EUPHEM), European Centre for Disease Prevention and Control, Stockholm, Sweden c Infection Control and Epidemiology Unit, Edouard Herriot Hospital, Hospices Civils de Lyon, Lyon, France d Epidemiology and Public Health Group, CNRS UMR 5558, University of Lyon 1, Lyon, France e PAM de ge´riatrie, Edouard Herriot Hospital, Hospices Civils de Lyon, Lyon, France b

A R T I C L E

I N F O

Article history: Received 9 July 2013 Accepted 20 November 2013 Available online 8 January 2014 Keywords: Healthcare worker Influenza Nosocomial infection Outbreak

S U M M A R Y

Background: Influenza presents a life-threatening infection for hospitalized geriatric patients, who might be nosocomially infected via healthcare workers (HCWs), other patients or visitors. In the 2011/2012 influenza season an influenza A(H3N2) outbreak occurred in the geriatric department at the Ho ˆpital Edouard Herriot, Lyon. Aim: To clarify the transmission chain for this influenza A(H3N2) outbreak by sequence analysis and to identify preventive measures. Methods: Laboratory testing of patients with influenza-like illness in the acute care geriatric department revealed 22 cases of influenza between 19th February and 15th March 2012. Incidences for patients and HCWs were calculated and possible epidemiological links were analysed using a questionnaire. Neuraminidase and haemagglutinin genes of culture-positive samples and community influenza samples were sequenced and clustered to detect patients with identical viral strains. Findings: Sixteen patients and six HCWs were affected, resulting in an attack rate of 24% and 11% respectively. Six nosocomial infections were recorded. The sequence analysis confirmed three independent influenza clusters on three different sections of the geriatric ward. For at least two clusters, an HCW source was determined. Conclusion: Epidemiological and microbiological results confirm influenza transmission from HCWs to patients. A higher vaccination rate, isolation measures and better hand hygiene are recommended in order to prevent outbreaks in future influenza seasons. ª 2014 The Healthcare Infection Society. Published by Elsevier Ltd. All rights reserved.

Introduction * Corresponding author. Address: Centre de Biologie et Pathologie Est, Hospices Civils de Lyon, 59 Boulevard Pinel, 69677 BRON Cedex, France. Tel.: þ33 472 12 96 16. E-mail address: [email protected] (D. Eibach).

Nosocomial influenza outbreaks have been described in acute and long-term hospital facilities.1,2 Hospital outbreaks are usually reported during the annual peak of community influenza activity, when infected patients, healthcare workers

0195-6701/$ e see front matter ª 2014 The Healthcare Infection Society. Published by Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.jhin.2013.11.009

D. Eibach et al. / Journal of Hospital Infection 86 (2014) 188e193 (HCWs) or visitors serve as a source of infection.3,4 Patients, visitors, as well as healthcare personnel are part of the transmission chain, facilitated by generally low vaccination coverage or vaccine failure.5e7 Hospital departments treating elderly patients with multiple underlying diseases are particularly affected by influenza outbreaks and excess mortality.2,8,9 Transmission of influenza occurs through aerosols, droplets or direct contact (e.g. hands, surfaces), and has been reported to affect widely separated departments, across different hospital floors.9e11 Previous outbreak reports show that a precise epidemiological description of contacts combined with genotyping and molecular phylogenetic analysis provides insight into routes of transmission.9,11e13 This combination may lead to improved control of nosocomial influenza infections and outbreaks. The Ho ˆpital Edouard Herriot in Lyon experienced an outbreak of influenza A(H3N2) during the 2011/2012 influenza season affecting three different wards of the acute care geriatric department. The aim of this study was to analyse routes of transmission during the influenza outbreak among geriatric patients and HCWs with the help of molecular-based subtyping methods in order to implement adequate control measures during future influenza seasons.

Methods Influenza diagnostics and study setting As part of the virological diagnostic testing, as detailed elsewhere, all patients and HCWs of the acute care geriatric medical ward (64 beds) of Ho ˆpital Edouard Herriot in Lyon were screened for influenza-like illness (ILI) occurrence during the peak of the influenza season 2011/2012, from 20th January to 6th April 2012.1 During this study period, research nurses contacted the geriatric units on a daily basis to search for HCWs and patients with ILI, defined as rectal or axillary temperature 37.8 C, in the absence of antipyretics, with cough or sore throat.14 Nasopharyngeal swabs were taken in case of ILI and real-time polymerase chain reaction (PCR; Respiratory MultiWell system R-gene, Argene, France) was performed to detect influenza A/B virus, respiratory syncytical virus, human metapneumovirus and rhinovirus. The acute care geriatric ward comprised three sections (A, B, C). Section A (25 single rooms, two double rooms) is a longstay unit, B (eight single rooms, four double rooms) receives post-surgical patients and planned admissions, and C (15 single rooms, two double rooms) admits emergency and unscheduled cases via the outpatient department. Sections A and B are located adjacently on the first floor and section C is located on the second floor of the ward. The three sections exchange neither patients nor staff. Staff members from outside of the geriatric unit, who might only pass the ward sporadically, were not included in the study. Visitors to admitted patients were also not included.

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symptoms, underlying diseases, and influenza vaccination status. The questionnaire was completed by a study nurse, who interviewed the study participant and assessed the patient chart. Information on HCWs’ absenteeism from work and isolation periods for patients was obtained from the hygiene department and the hospital administration. Questionnaire data were only accessible by the study investigators and were analysed completely anonymously. From this, a synoptic chart, divided into ward sections A, B and C, was drawn to indicate potential infection clusters. Those potential clusters were then compared with the results of the phylogenetic analysis to confirm the most likely routes of transmission from within the hospital. An infection was classified as nosocomial when symptoms were reported at least 72 h after admission to the hospital.4 The attack rate for HCWs was calculated as the number of HCWs with positive influenza samples divided by the total number of staff working in the geriatric department (N ¼ 57). For patients, the attack rate was calculated as the number of influenza-positive patients divided by the total number of patients admitted to the three different ward sections during the study period (N ¼ 66). An epidemiological link was postulated, when the contagious period (1 day prior to 3 days after disease onset) of one influenza-positive patient/ HCW overlapped with the susceptible period (1e4 days prior to disease onset) of another influenza-positive patient/HCW and both persons were located in the same section/geographical area.4,15 The susceptible period corresponds to the incubation period in this study.

Influenza subtyping and phylogenetic analysis Culture-based analysis was attempted for all PCR-confirmed influenza A(H3N2) samples. Culture-positive viral isolates were subjected to amplification of overlapping fragments of the neuraminidase (NA) and haemagglutinin (HA) genes by reverse transcription (RT)ePCR according to the standard operating procedure of the World Health Organization (WHO) Collaborating Centre, Medical Research Council (MRC) National Institute for Medical Research, London. Amplicons were sent for purification and sequencing to GenoScreen (Lille, France). Sequences were assembled using Sequencher 5.0 Software (Gene Codes, Ann Arbor, MI, USA) and subsequently the concatenated HA (nt 13e1688) and NA (nt 25e1322) sequences were aligned using the ClustalW program running within the BioEdit software package, version 7.0.9.0. Eleven communityacquired influenza A(H3N2) HA/NA sequences, collected during the 2011/2012 influenza season by the Southern French National Reference Laboratory for influenza, were included in the alignment as controls. With the concatenated nucleotide alignment, a maximum-likelihood tree using the Kimura twoparameter model in MEGA 5 was inferred.16 The reliability of all phylogenetic groupings was determined through a bootstrap resampling analysis (1000 replicates).

Results Epidemiological analysis Clinical information Informed consent was obtained from all participating patients and HCWs. A standardized case-based reporting form collected clinical and epidemiological data from all PCRconfirmed influenza cases including onset of illness, clinical

A total of 66 patients and 57 HCWs were screened for influenza during the study period. From 19th February to 15th March 2012, 22 cases of influenza A(H3N2) were detected,

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affecting 16 patients and six HCWs (Table I), resulting in a cumulative incidence of 11% for HCWs and 24% for patients. The mean time from admission to onset of influenza symptoms was 23.2 days (SD: 24.1). Six patients had acquired the infection nosocomially at least 72 h after admission to the geriatric ward. Of those nosocomial cases, the cumulative incidence was 9%. The mean age for influenza patients was 88.3 years (SD: 5.2) and for HCWs 30.2 years (SD: 10.4). Whereas all infected HCWs were female, patients with influenza consisted of 11 females and five males. Patients with influenza reported as having one or more underlying health conditions were as follows: (i) cardiac (12 patients), (ii) neurological (eight patients), (iii) endocrinological (six patients), (iv) pulmonary (five patients), (v) renal (three patients), (vi) gastrointestinal (two patients), (vii) rheumatological (one patient), and (viii) oncological diseases (one patient). No patient with immunosuppression was recorded. Six patients were isolated in single rooms as a result of their influenza infection and one HCW was on sick leave for two days. Eight influenza patients (67%) but only two HCWs (33%) were vaccinated with the seasonal 2011/2012 influenza vaccine (Table I). None of the patients or HCWs received antiviral treatment. All but one of the patients recovered from the infection, resulting in a case fatality rate of 6.3%. Of all the 22 samples, influenza A(H3N2) was cultured from 11 samples, belonging to four HCWs and seven patients. Those 11 cases occurred between 19th February and 15th March 2012.

Epidemiological and molecular characterization A synoptic chart was used to study potential routes of transmission among the 22 influenza A(H3N2) study

participants (Figure 1). The analysis revealed potential infection clusters in each of the three ward sections (Table I). The first cluster in section A involved one HCW and two patients. In section B the second cluster consisted of one patient and one HCW. In section C, eight patients and three HCWs were epidemiologically linked. However, five out of those eight patients acquired the infection outside of the hospital and therefore might have introduced different virus strains into the hospital at different time-points. This epidemiological analysis disregarded asymptomatic patients or visitors who might be other sources of infection. The HA and NA genes of all 11 culture-positive influenza A(H3N2) strains were sequenced. Combined with 11 community samples from the same influenza season, the phylogenetic analysis of concatenated HA and NA sequences revealed two clades (named A and B; Figure 2). Study samples from ward sections A, B and C were all in clade A. However, strains from each section formed genetically distinct sister groups with strong bootstrap support, confirming three separate outbreak clusters, as opposed to one single hospital outbreak. Clade B contained only community strains. The seasonal 2011/2012 vaccine strain A/Perth/16/2009 was quite distinct from clades A and B. All epidemiologically linked cases from section A had identical HA and NA sequences (referred to as sequence A; Figures 1 and 2). Similarly the two epidemiologically linked cases from section B grouped together in the phylogenetic tree (bootstrap value: 98) with identical sequences (referred to as sequence B; Figures 1 and 2). The patient with no epidemiological link from section B differed in four positions (A52T, A229G, G688T, A864G) of the NA gene and in six positions (C48T, A206G, A208C, A835G, T975C, T1638C) of the HA gene. In both

Table I Characteristics of patients and healthcare workers with influenza A(H3N2) Case no. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22

Section

Patient/HCW

Age (years), sex

Date of onset

Vaccine status

Transmission

Epidemiological link

Nucleotide sequence analysis

A A A A B B B B C C C C C C C C C C C C C C

HCW Patient Patient HCW Patient HCW Patient Patient Patient Patient HCW Patient HCW Patient Patient Patient Patient Patient Patient HCW Patient Patient

23, F 101, F 92, F 25, F 88, F 28, F 88, F 89, F 85, F 95, F 51, F 85, M 26, F 87, M 79, F 85, F 86, M 89, F 87, F 28, F 83, M 93, M

19 Feb 20 Feb 20 Feb 29 Feb 22 Feb 1 Mar 4 Mar 5 Mar 22 Feb 25 Feb 26 Feb 26 Feb 27 Feb 2 Mar 2 Mar 2 Mar 3 Mar 3 Mar 6 Mar 7 Mar 11 Mar 15 Mar

No No Yes No No No Yes Yes No No Yes No Yes Yes No Yes Yes Yes No No Yes Yes

NA Nosocomial Nosocomial NA Community NA Nosocomial NA Community nosocomial NA Community NA Nosocomial Community Community Community Nosocomial Community NA Community Community

Yes Yes Yes No No Yes Yes No Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes No Yes No No

Sequence A Sequence A Sequence A Not sequenced Not sequenced Sequence B Sequence B Different sequence Not sequenced Not sequenced Not sequenced Not sequenced Sequence C Sequence C Not sequenced Not sequenced Not sequenced Not sequenced Not sequenced Sequence C Different sequence Different sequence

HCW, healthcare worker; NA, not applicable.

D. Eibach et al. / Journal of Hospital Infection 86 (2014) 188e193 Number of cases

3 2 1

epidemiological link + identical sequence

February March 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 1 2 1

HCW

191

3

4

5

6

7

8

9 10 11 12 13 14 15 16 17 18 19 20

S

2 Patient S

A

3 Patient S 4

HCW

5 Patient

B

6

HCW

S

7 Patient S 8 Patient S

9 Patient 10 Patient 11

HCW

12 Patient 13

HCW

S

14 Patient S

C

15 Patient 16 Patient 17 Patient 18 Patient 19 Patient 20

HCW

S

21 Patient S 22 Patient S

Figure 1. Epidemic analysis of influenza A(H3N2) cases. The bar chart (top) shows the number of influenza cases by date of onset. In the lower panel, black bars show the period of hospitalization and red bars indicate periods when the patient was isolated. Bold black arrows represent the day of onset of symptoms and narrow black arrows in the left column indicate when cases show the identical sequence and are linked epidemiologically. ‘S’ indicates that the strain was sequenced. Red script indicates a nosocomial influenza case.

sections, A and B, it is therefore most likely that HCWs (samples 1 and 6) were the primary cases. The outbreak duration was between 2 and 4 days for sections A and B respectively. For section C, five strains were sequenced. Three of those showed an epidemiological link and clustered together in the phylogenetic tree (bootstrap: 98), differing only in the T1301C position of the NA gene (referred to as sequence C; Figures 1 and 2). The other two influenza A(H3N2) strains from section C had no epidemiological link and clustered together with other community strains. Here, HCW 13 (sample 13) might have been the primary case, having the same strains as patient 14 (sample 14) and HCW 20 (sample 20). However, HCW 13 had an epidemiological link to patient 9 (sample 9), patient 10 (sample 10) and to HCW 11 (sample 11), for which we have no sequence available and we can therefore draw no conclusions concerning the exact transmission chain. This minimum duration for the outbreak in section C was 10 days. Only routine preventive measures with droplet precautions and patient isolation in single rooms, wherever feasible, were employed during the outbreak. All influenza patients in sections A and B, but only one patient in section C, were isolated (Figure 1). HCWs as well as patients were educated in

improving handwashing and disinfection procedures. In addition, attempts were made to reduce visitor numbers to the influenza-affected wards.

Discussion The analysis of all influenza cases during the peak 2011/ 2012 season and molecular characterization of strains confirms three distinct outbreaks on the three different sections of the geriatric department of the Ho ˆpital Edouard Herriot. Only the combined epidemiological and molecular approach was able to distinguish multiple outbreaks, rather than one large outbreak across the department. It has been shown that influenza strains causing hospital outbreaks are similar to those circulating in the community during the respective season.13 The maximum likelihood tree shows that all outbreak strains cluster close to the control community strains and therefore it can be assumed that strains from the hospital do not evolve from one common ancestor, but most likely originate from several strains circulating within the community. This present study highlights the probability that HCWs introduced the virus into the hospital and acted as primary

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Sample 1 61 Sample 3 A Sequence 88 Sample 2 A/Lyon/CHU/7 674/12 80 Sample 8 42 Sample 6 41 97 Sample 7 B Sequence 80 A/Nice/953/12 44 A/StEtienne/801/12 99 A/Lyon/CHU/7 573/12 98 Sample 21 A/Lyon/CHU/6638/12 A/StEtienne/1081/12 96 99 84 A/Lyon/CHU/932/12 Sample 22 91 A/Lyon/685/12 Sample 13 100 98 Sample 14 C Sequence 75 Sample 20 A/Mars eill e/618/12 A/Lyon/223/12 100 A/Lyon/CHU/7 798/12 100 A/Perth/16/2009 Ref.

Clade A

Clade B

0.002 Figure 2. Phylogenetic tree analysis of concatenated haemagglutinin and neuraminidase influenza A(H3N2) sequences. The tree includes the 11 study strains, 11 community strains and one reference strain (Ref.).

cases in at least two out of the three geriatric sections. The transmission of influenza from hospital staff to patients is very common and has been described for other nosocomial influenza outbreaks.11 Despite local, national and international recommendations to annually vaccinate all healthcare personnel against influenza, the vaccination rates for HCWs have been poor in our hospital setting.15 A WHO position paper shows clear evidence for a protective effect of vaccinating HCWs against influenza infection and against non-specific outcomes such as ILI among the elderly in long-term care facilities.15,17 The phylogenetic analysis underlines the previously reported vaccine mismatch during the 2011/2012 influenza season.18 With a relatively high vaccination rate of 67% among the patients, this mismatch might have contributed to the outbreak. On the other hand, vaccine effectiveness among elderly patients is known to be reduced.15 Another explanation would be a lower vaccine effectiveness in the late influenza season due to virus changes or waning immunity, which has been shown for the 2011/2012 season.19 Apart from vaccination, a higher number of HCWs taking sick leave might have prevented or at least shortened the outbreaks. At 24%, the cumulative incidence is comparable to other nosocomial influenza outbreaks, where cumulative incidences of 3e50% on epidemic wards and 0.7e20% throughout the hospitals are described; however, recently a cumulative incidence of 90% from a psycho-geriatric facility has been reported.4,20 For HCWs, cumulative incidences of 11e59% have been reported.4 The case fatality rate in our study does not reach the median mortality of 16% which has been calculated in a meta-analysis for influenza hospital outbreaks.4 This observation might be based on the fact that no immunocompromised patients (i.e. patients undergoing immunosuppressive therapy, patients with haematological malignancies, or asplenic patients) and no intensive care units were affected in this study.

Interestingly, the outbreak duration varied according to the hospital ward section. Whereas the outbreak on sections A and B lasted for 2e3 days, the outbreak on ward section C stretched over at least 10 days. This might be explained by the different preventive measures that were effected. The isolation of all influenza patients in sections A and B might have shortened the outbreak. By contrast, only one patient was isolated in section C. Nevertheless, the 10-day outbreak is just above the median outbreak time of 7 days (range: 2e69) when 12 nosocomial influenza outbreaks were reviewed.4 The fact that no patients were transferred and no staff rotated between the different department sections or wards might have helped to prevent further spread throughout the department, as described for other nosocomial outbreaks.11,13 The study suffers from the limitation that not all influenza samples could be cultured and subsequently sequenced. This mainly affected samples with a low viral load and high cycle threshold (CT) value which therefore arguably might not be so highly contagious. The real extent of this outbreak might have been underestimated, as patients or HCWs, who were asymptomatically or mildly infected, were not included in the study. Further, visitors or hospital workers, just occasionally passing through the geriatric department, were not monitored for influenza. It cannot be excluded that identical influenza strains would have been found sporadically in other parts of the hospital; however, no additional influenza outbreaks were reported during the 2011/2012 season in the hospital. In order to study epidemiological links, this study defines precise contagious periods in accordance with the WHO 2012 position paper. This duration may function only as a rough estimate, as it is heavily influenced by the presence of symptoms, generating infectious aerosols (e.g. cough), by the immune status, and by age.4,15 Similarly, the definition for nosocomial

D. Eibach et al. / Journal of Hospital Infection 86 (2014) 188e193 influenza cases (onset of symptoms >72 h after admission) might underestimate nosocomial cases, as the incubation period may occasionally be as short as one day. The present study investigates a nosocomial influenza outbreak using epidemiological and molecular approaches. Sequence-based typing is performed in advanced clinical laboratories and could be combined with the rapid identification of antiviral resistance markers to be cost-effective. With decreasing costs and increasing sequence capacities, which provide real-time sequence data, this approach might help to identify outbreaks and to implement control measures in a timely manner. However, besides the added value of these new real-time technologies, influenza infection control still mainly relies on basic containment preventive measures and vaccination of HCWs, which is not optimal in our study setting. For more details on the effect of short- and long-duration contacts and the exact interactions between patients and HCWs, outbreak studies endorsed by RFID (radio-frequency identification) devices would be of added value.21,22 In conclusion, the combined epidemiological and phylogenetic analysis reveals three independent nosocomial influenza outbreak clusters in the geriatric department of the Ho ˆpital Edouard Herriot in Lyon. NA and HA genotyping has been a useful tool for outbreak analysis in the hospital setting. Isolation measures and preventing the exchange of patients or staff between the hospital sections might have contributed to shortening the outbreaks. When sick, HCWs should be encouraged to stay away from work. Higher vaccination rates among the hospital staff are desirable, in order to prevent influenza outbreaks a priori.

Acknowledgements The authors would like to thank M. Valette, V. Escuret and the technical staff of the Influenza National Reference Centre of Southern France. We wish to acknowledge A. Jasir and S. Ethelberg for their contribution to critical review of the manuscript. Conflict of interest statement B.L. declares having received an unrestricted grant from Roche and GlaxoSmithKline. He also conducted a clinical trial for Roche and one research programme funded by Sanofi Pasteur. Funding sources This project was partially supported by a grant of the ‘Programme de Recherche, A(H1N1)’ co-ordinated by the ‘Institut de Microbiologie et Maladies Infectieuses’ and INSERM. D.E. is supported by a grant from the Euopean Centre for Disease Control and Prevention.

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Routes of transmission during a nosocomial influenza A(H3N2) outbreak among geriatric patients and healthcare workers.

Influenza presents a life-threatening infection for hospitalized geriatric patients, who might be nosocomially infected via healthcare workers (HCWs),...
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