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Breaking the chain of transmission: Immunisation and outbreak investigation

Whelan, E.J.

Publication date 2013 Document Version Final published version

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UvA-DARE is a service provided by the library of the University of Amsterdam (https://dare.uva.nl) Download date:11 Oct 2021 B R E A K I N G

T H E

C

H BREAKING THE CHAIN OF A I N

O F

T TRANSMISSION R A N S

M immunisation and outbreak investigation I S S I O N i m m u n i s a t i o n a n d o u t b r e a k i n v e s t i g a t i o n

J a n e

W Jane Whelan h e l a n Breaking the chain of transmission Immunisation and outbreak investigation

26660 Whelan kopie.indd 1 02-11-13 16:03 © 2013 Jane Whelan, Amsterdam ISBN 978-90-6464-732-1 Cover: Mona Hatoum. Undercurrent (red), 2012. Cloth covered electric cable, light bulbs, dimmer device, dimensions variable. Reproduced with permission. Photo: Nick Malyon at The Goetz Collection exhibition, Munich. Reproduced with permission. Cover layout: Ebo Peerboms (www.ebokai.com) Thesis layout-design: Ferdinand van Nispen, Citroenvlinder-DTP.nl, Bilthoven, the Netherlands. Thesis DTP: Ubel Smid Vormgeving, Roden, the Netherlands. Printing: GVO drukkers & vormgevers BV, Ponsen &Looijen, Amsterdam, the Netherlands.

Publication of this thesis was financially supported by the Geneeskundige en Gezondheidsdienst (GGD) Amsterdam and the Academic Medical Centre (AMC), Amsterdam.

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ACADEMISCH PROEFSCHRIFT

ter verkrijging van de graad van doctor aan de Universiteit van Amsterdam op gezag van de Rector Magnificus prof. dr. D.C. van den Boom ten overstaan van een door het college voor promoties ingestelde commissie, in het openbaar te verdedigen in de Agnietenkapel op dinsdag 17 december 2013, te 12.00 uur

door Elizabeth Jane Whelan geboren te Carlow, Ierland.

26660 Whelan kopie.indd 3 02-11-13 16:03 Promotiecommissie

Promotor Prof. dr. M.W. Borgdorff

Co-promotores Dr. J.A.R. van den Hoek Dr. G.J.B. Sonder

Overige leden Prof. dr. R.A. Coutinho Dr. S.E. Geerlings Prof. C. Kelleher Prof. dr. M. Prins Prof. dr. H.L Zaaijer Prof. dr. A.H. Zwinderman

Faculteit der Geneeskunde

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010 Introduction 7

Part I Immunisation

020 Incidence of acute hepatitis B in different ethnic groups in a low- 21 endemic country, 1992−2009: Increased risk in second generation migrants Vaccine 2012;30:5651-55

030 Targeted vaccination programme successful in reducing acute 33 Hepatitis B in men having sex with men in Amsterdam, The Netherlands J Hepatol. 2013. In Press

040 Immunogenicity of a hexavalent vaccine co-administered with 55 7-valent pneumococcal conjugate vaccine. Findings from the National Immunisation Programme in The Netherlands Hum Vaccin Immunother 2012;8:743-8.

050 Declining incidence of hepatitis A in Amsterdam (The Netherlands), 67 1996-2011: Second generation migrants still an important risk group for virus importation Vaccine 2013;31:1806-11

060 Evaluation of hepatitis A vaccine in post-exposure prophylaxis, The 83 Netherlands, 2004−2012 PLoS ONE 2013; 8: e78914

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070 Mumps outbreak among vaccinated university students associated 97 with a large party, The Netherlands, 2010 Vaccine 2012;30:4676-80

080 Q fever among culling workers, The Netherlands, 2009–2010 109 Emerg Infect Dis 2011;17:1719-23

090 Visits on ‘lamb-viewing days’ at a sheep farm open to the public was a 119 risk factor for Q fever in 2009 Epidemiol Infect 2012;140:858-864

1101 National outbreak of Salmonella Typhimurium (Dutch) phage-type 131 132 in The Netherlands, October to December 2009 Euro Surveill 20 10;15:pii=19705.

1111 Risk factors for secondary transmission of Shigella infection within 141 households: implications for current prevention policy BMC Infect Dis 2012;12:347

1121 Discussion 155

Summary 171 Samenvatting 179 Acknowledgements 187 Biography 191 Portfolio & List of publications 193

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26660 Whelan kopie.indd 7 02-11-13 16:03 CHAPTER 1 Introduction

Introduction

‘1.3 grams of mercurous chloride, followed by 3 grams of pulverized cornachin.... The same doses followed for four days and nights.’1

The dose of mercury was considered sufficient to cause drooling and diarrhoea, and perhaps even to make a patient’s teeth fall out. Combined with cornachin, ‘a retch-inducing mixture of antimony and cream of tartar’,2 and ‘where necessary, some blood [to] gently purge the humors’,3 the cocktail was lauded in the 1750s as part of an elaborate preparation to prevent smallpox. At first, in a process known as variolation, a small amount of live smallpox virus from the pustule of an infected patient was scratched into a person’s skin with a needle or knife. This was followed by three weeks of daily vomiting, bleeding, purging, and fevers. Finally, if well enough to go home, the patients and their clothes were hosed down with sulphur.2

By today’s standards, it’s difficult to conceive that healthy individuals would volunteer themselves and their children for such a punishing preventive routine, with limited guarantee of its safety or effect. By 1800, Edward Jenner (who himself had been subjected to this miserable experience as a boy), had developed a safer and more reliable cow-pox derived vaccine, credited by a contemporary as ‘one of the greatest improvements that has ever been made in medicine’.4 It would be another 100 years before the association between microbial agents, infection, disease, and immunity would be elucidated and allied control measures effectively evolved: sanitation, disinfection, antibiotics and vaccination.

Despite extraordinary recent advances in cellular immunology, vaccinology, communications, epidemiology, mathematics and related fields, effective infectious disease control remains elusive. New threats are emerging or re-emerging as a combination of drivers result in dynamic changes in the distribution of disease over geographic areas and through populations.5-7 These include socio-demographic factors such as unprecedented population growth, changing human demography and behaviour; environmental and globalisation factors such as climate change, urbanisation, changes in food production, migration and international travel; and public health capacity factors including health care provision, animal health and food safety. Meanwhile microbes are constantly adapting beyond our technology.8,9

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1. The transmission chain and principles of infectious disease control 1

A contemporary model of infection is the transmission chain (figure 1).10 The chain comprises essential elements or links which, occurring in a sequential process, lead to infection. These elements include: an etiologic or causative agent (virus, bacterium, protozoan, fungus or the like), a reservoir or habitat where the agent pools and propagates (this may be human, animal or environmental), a source (contaminated foodstuff in a supermarket, infectious patient), a mode of transmission (direct contact with contaminated material, or indirect contact via a vector such as a mosquito), an entry portal into the host (respiratory tract, alimentary canal for example), and a susceptible host who because of genetic, immune, or other factors may be predisposed to infection. The elements are diverse and once the susceptible host has been exposed, progression to disease, cure or death is non-linear. Not all susceptible hosts exposed to an infectious agent will become infected, and agent properties and host outcomes differ: Some hosts will be infected but never develop symptoms, some will become ill but will recover, and some may die; Some agents will be eliminated from the host, and some will leave a life-long legacy as the host develops temporary or lifelong immunity in the form of antibodies and other immune markers, or becomes a carrier of the agent and can go on to infect other susceptible hosts, thus perpetuating the cycle. As chains of transmission occur in a population over time, the risk factors for exposure and disease progression, and rates of transition between states in the infectious process, undergo dynamic change.11 Change may occur rapidly, as in sudden unexpected disease outbreaks, or evolve slowly over time. Underpinning effective action is good surveillance, and focused epidemiological studies which inform public health action as problems evolve. Breaking the chain of transmission is complex, requiring timely intervention at some or every step in the transmission chain. Management of the within-host infectious process and disease progression lies within the medical realm, while controlling disease transmission through prevention of exposure and infection is traditionally a public health function. This is an interdisciplinary process involving human, environmental and animal health sectors, local and national government bodies and policy makers within countries and sometimes internationally.

2. Preventing exposure and infection: primary and secondary prevention

Protecting the susceptible host from exposure to an infectious agent is known as primary prevention. Primary prevention may involve elimination of the infectious agent at the environmental level, through reservoir destruction, pest control, water treatment etc. (figure), or may be targeted at the host (promoting healthy behaviour for example). Second to clean water, the single most effective primary public health intervention is vaccination. Vaccination

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26660 Whelan kopie.indd 9 02-11-13 16:03 CHAPTER 1 Introduction Figure . The transmission chain and intervention points for infection control.

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programmes may be universal (offered to whole populations), or targeted at particular high-risk 1 groups and individuals. In the event that exposure has already occurred, protecting the host from infection or disease is known as secondary prevention. Secondary prevention (so called post-exposure prophylaxis) may involve use of antimicrobials and antiviral agents or vaccination, and its purpose is to prevent infection, to attenuate disease morbidity and sometimes, to limit further spread of the infectious agent.

2.1 Primary prevention through vaccination An egalitarian system of vaccination, not only to protect individual health, but also for the common good was recognised as early as the 18th century in relation to smallpox:

‘ … if the inoculation be general, no subjects liable to infection would remain’12

The Netherlands has been a world leader in delivering public vaccination programmes, with a vaccination uptake among infants that consistently exceeds the World Health Organisation recommendations.13 Every child registered in the Netherlands is offered state-subsidised vaccination that is free at the point of access within the National Childhood Vaccination Programme (RVP) beginning at 2 months of age. Vaccines targeting infectious agents Corynebacterium diphtheriae (D), Clostridium tetani (T) and Bordetella pertussis (aP), were introduced in the RVP in 1953, polio in 1957 (oral polio vaccine, OPV, and later inactivated polio vaccine, IPV), rubella (R) in 1974, measles (M) in 1976, mumps (M) in 1987, Haemophilus influenza type B (Hib) in 1993, Neisseria meningitidis type C (Men C) in 2002, Streptococcus pneumoniae (Pneu) in 2006 and most recently hepatitis B (HepB) in August 2011. To boost programme efficiency and cost- effectiveness, to improve parental acceptance, and to relieve the burden of multiple injections for infants, multi-component vaccines against several infectious agents are now offered in a single shot.14,15 The maximum number of injections administered to infants at any one time is thus currently limited to two. Despite many advantages, as the composition of combination vaccines has become increasingly complex, their widespread use is not without controversy. Based on experiences in the Netherlands and elsewhere, concerns have been expressed that co- administration of multicomponent and mono- or multivalent vaccines may lead to a suboptimal induced immune response.16 The RVP closely monitors new vaccines as they are introduced into the national immunization programme, as we will report in this thesis in relation to the new hexavalent DTaP-Hib-IPV-HBV childhood vaccine, Infanrix hexa™.17

Universal vaccination & herd immunity The effectiveness of universal vaccination, as offered by the RVP, is increased by a form of

Figure . The transmission chain and intervention points for infection control. immunity known as herd immunity i.e. if a sufficient proportion of the population are immune to

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a disease, the probability that a susceptible individual will come into contact with an infectious individual is reduced, and the chain of transmission is interrupted.18 The herd immunity threshold is the proportion of immune individuals in a population above which a disease can no longer propagate. This threshold depends on a number of variables: the virulence of the disease, the efficacy of the vaccine, and the contact parameter for the population. The herd immunity thres hold for measles, for example, is reported to be 92-94% of the population, and for rubella is 80-85%. Since the inception of the RVP in the Netherlands, average national vaccination coverage has been consistently high, and for babies, it exceeded 95% in 2012, although among school children, MMR coverage is somewhat lower, at 93%.13 Despite high vaccination coverage, outbreaks have continued to occur. Firstly, there are pockets of susceptible children who are unvaccinated either due to conscientious or religious objection on behalf of their parents (particularly in the so-called ‘Bible-belt’ region of the Netherlands), or because they are too young to respond optimally to vaccination. This has resulted in intermittent outbreaks:13 In June 2013, more than 160 unvaccinated children, largely within the Bible-belt region of low vaccination coverage, developed measles; In 2012, there was a national pertussis epidemic with a large increase in the number of cases in unvaccinated infants aged 0-2 months of age. Secondly, even where children are vaccinated according to protocol, the vaccine may fail (primary failure), or the effectiveness of the vaccine may wane as the child get older (secondary failure) leading to a radical change in the epidemiology of the disease. During the pertussis epidemic for example, a peak in cases was seen in children 8-years and over, probably due to decreasing vaccine effectiveness from this age; also, between 2009 and 2012, a large outbreak of mumps affecting college students occurred despite the fact that a large majority were vaccinated.19 Why secondary vaccine failure occurs is poorly understood and the changing epidemiology of what were traditionally childhood diseases poses a particular challenge for effective intervention.

Criteria for including new vaccines in public programmes are stringent and are based on the ethical principles that the best possible protection should be afforded to the population as a whole, and that the benefit should be fairly distributed across population groups with protection provided on the basis of need.21 The criteria are hierarchal and each must be met before considering the next:20 The seriousness of the disease for the individual and the extent of the disease burden in the population must be weighed against the safety of the vaccine and its effectiveness in reducing the disease burden; The vaccine must be acceptable to the recipient and not cause undue discomfort or inconvenience; The vaccination must be efficient, i.e. the ratio between the cost of vaccination and the associated health benefit should compare favourably to that associated with other means of reducing the disease burden; Finally, the provision of the vaccination should be a priority, and serve an urgent public health need relative to other vaccines. These principles may best be met by offering universal vaccination to the entire

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population for some vaccines. For others, targeted vaccination, offered to at-risk population 1 subgroups is considered more appropriate. For others still, protection offered on an individual basis is thought to be optimal. The ratio between the costs, benefits and positive / negative health implications can change over time and so too can the criteria for inclusion in a public programme. Such a decision is highlighted by the example of the hepatitis B vaccine which was introduced into the childhood vaccination schedule for all children in the Netherlands in 2011.

Hepatitis B in the Netherlands: from targeted to universal vaccination Hepatitis B – ‘serum hepatitis’ as it was known before the causative virus was identified in 1970 is transmitted through body fluids, predominantly blood. People most at risk are babies of infected mothers (particularly in developing countries), intravenous drug addicts and men who have sex with men (MSM). Hepatitis B infection is associated with a spectrum of morbidity ranging from seemingly innocuous mild acute infections, to chronic infections that can lead many years later, to liver cirrhosis, cancer and fulminant hepatic failure. A safe effective vaccine came on the market in the 1986, and shortly thereafter the World Health Organisation (WHO) called for all countries to add hepatitis B vaccine to their childhood immunisation programmes. The Netherlands, and other similarly low–endemic countries in Europe, initially targeted the vaccine at high risk groups only. Antenatal screening was introduced in 1989,22 and neonates and household contacts of hepatitis B positive mothers were immediately vaccinated and/or given immunoprophylaxis in the form of immunoglobulin. In 2003, the neonatal vaccination programme was extended and hepatitis B vaccine was offered to children whose parent(s) comes from an intermediate- or high-endemic HBV country (approximately 18% of the total birth cohort). Screening and vaccination of high-incidence groups including commercial sex workers, drug users, MSM and heterosexuals with a high rate of partner change was introduced in 2002 (though the latter was discontinued in 2007). Initial evaluations of the programme targeting MSM were not encouraging23 and ultimately, the potential of the existing programmes to further reduce the incidence of HBV was considered to have peaked. Universal vaccination was deemed cost-effective and the vaccine was finally introduced into the childhood schedule for all children in 2011. This is not the whole story. Acute and chronic HBV infections are still being notified, particularly among migrants from mid- and high-endemic countries. Evidence supporting the cost-effectiveness of systematic screening of migrants for chronic HBV infection, suggests that a single screening could reduce mortality from liver-related diseases by 10%.24 Development of a national policy on this subject is therefore considered a priority.13 Depending on feasibility and cost-effectiveness, second generation migrants who may also at higher risk of infection, could also be considered for screening and vaccination.25

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2.2 Secondary prevention: contact tracing and post-exposure prophylaxis Vaccination pre-exposure to a pathogen is not always feasible, effective or cost-effective. In the event that an individual has been exposed to a vaccine preventable disease, but where (s)he is unvaccinated, incompletely vaccinated or the duration of protection of a vaccine has expired, (s)he may be offered post-exposure vaccination under certain conditions. This is called post- exposure prophylaxis (PEP). The premise is that sufficiently early intervention post-exposure may prevent infection or attenuate disease in the exposed individual, and for some organisms (hepatitis A, for example), it may limit further spread of the pathogen thus breaking the chain of transmission and protecting public health. PEP has involved passive immunisation since the late 1940s. Passive immunisation is the direct administration of concentrated antibody preparations (typically harvested from human or animal blood), called immunoglobulin (IG). Human normal IG preparations are used for hepatitis A, measles, polio and rubella and specific IG preparations for hepatitis B, rabies and varicella zoster.26 IG confers immediate protection, is highly effective, and is often the PEP of choice in an exposed individual who is at high risk of developing severe disease or serious complications. There are some disadvantages however. Recently, healthcare professionals and the public have become concerned about the safety of human-derived blood products, particularly in connection with Creutzfeld Jakob Disease. IG may also be prohibitively expensive, availability is sometimes limited, and protection is short-lived. Depending on the agent and the nature of the exposure, active vaccination is increasingly offered as an alternative to IG. Active vaccination as for the RVP vaccines referred to above, involves stimulation of the recipient’s immune system to produce antibodies and / or cellular immune memory. Immunity is generally assumed to arise 2-4 weeks later and protection is long-lived, and in some cases may be life-long. In recent years, as new-generation vaccines that are safe and effective become more readily available, they are being used in PEP. For hepatitis A for example, evidence of the short- term effectiveness of vaccination alone is sometimes lacking. Vaccines are offered in preference to IG if the risk of transmission is low, or if the individual is considered to be at low risk of severe disease.27

3. Information for action

3.1 Surveillance and epidemiological research Effective intervention is founded on good information conveyed in a timely fashion to policy makers and programme managers. Public health surveillance has been defined as ‘the ongo- ing systematic collection, analysis, and interpretation of health-related data essential to the planning, implementation, and evaluation of public health practice, closely integrated with the timely dissemination of these data to those who need to know. The final link in the surveillance chain is the application of the data to prevention and control’.28

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In the Netherlands, mandatory surveillance of infectious diseases that threaten public health 1 has been enshrined in law since 1865.29 Latterly, in response to the revised International Health Regulations of 2005,30 three acts governing infectious disease reporting and control were repealed (the Collective Prevention in Public Health Act of 1990 ‘Wet collectieve preventie volksgezondheid’, the Infectious Disease Act of 1998 ‘de Infectieziektenwet’ and the Quarantine Act of 1960 ‘de Quarantainewet’) and replaced with a single act, ‘the Public Health Act’ in 2008.29 Building on the earlier acts, legal requirements for infectious disease notification are extended to include 42 infectious diseases, and any unexpected or unusual public health event of known or unknown origin that may constitute a public health emergency of international concern. Notifications are made to the local Public Health Service (PHS) where the executive function of the act resides. This function is operationalised on a per disease basis in the national infectious disease control guidelines, published centrally by the Centre for Infectious Disease Control at the National Institute for Public Health and the Environment (RIVM-CIb).26 In addition to responding to cases notified under the Act, surveillance data collected by the PHS is aggregated over many years and serves multiple functions: to quantify the magnitude of a health problem at a population level; to document the distribution of disease over time and identify those at risk; and to target and evaluate public health actions and the use of resource. Surveillance data can therefore be used to facilitate epidemiologic, laboratory and behavioural research, and to generate and test hypotheses through monitoring changes in the nature and distribution of disease, infectious agents or health behaviour and practice. Finally, surveillance data allows us to establish baseline rates of disease in the local population. When unexpected events such as disease outbreaks or the emergence of new infectious diseases occur, surveillance data can provide an ‘early warning signal’ to public health officials.

3.2. Outbreak investigation An outbreak occurs when more cases of an infectious disease than are expected arise in a particular population, in a specific geographical area over a specified period of time.31 Outbreaks present a particular challenge to public health authorities. They often require swift intervention with emergency control measures and place acute demands on staffing and manpower for undefined periods of time. Outbreak investigations help to inform measures to stop the outbreak, to prevent new episodes occurring, to establish a new surveillance system and to evaluate an existing system. They are also unique opportunities to study risk factors for exposure, infection, morbidity and mortality among susceptible hosts for a known organism, and can lead to the identification of, or further the understanding of, new and emerging infectious agents. Outbreaks that are fuelled by person-to-person transmission are known as propagated outbreaks, and those attributable to a common source (e.g. contaminated foodstuff) are known as point- source outbreaks if limited to a single place and time, or ongoing exposure outbreaks, if exposure

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is not limited in time or place.11 Outbreak investigations generally require a high degree of collaboration between stakeholders.

4. Infectious Disease Control in the Netherlands

4.1 Public Health Service, Amsterdam The Public Health Service of Amsterdam (GGD Amsterdam) has a catchment population of approximately 900,000 people. The city of Amsterdam has a unique profile: it is one of the most ethnically diverse cities in the world, welcoming 178 nationalities in 2013.32 More than 35% of the population are non-Western immigrants, often from countries where infectious diseases rarely seen in the Netherlands, are endemic. Amsterdam is also known internationally for its tolerance of sexual and social diversity. It is estimated that 10% of the adult male population in Amsterdam are men who have sex with men (MSM) and is widely known as the ‘Gay Capital’ of Europe.33 The city is also tolerant of prostitution (which is legal and regulated since 2000) and drug use (principally marijuana, ‘hard’ drug use is illegal), and the attendant risk of sex- and drug-related infectious disease transmission. It is also a popular destination for sex and drug tourism. In this context, PHS Amsterdam has enhanced local surveillance systems in place since the early 1980s. In addition to routine data collection, the PHS collects details of contacts of notified cases, conducts intermittent cross-sectional studies in at-risk population groups, and longitudinal cohort studies among MSM and drug users. It has a longstanding reputation for providing evidence to support and shape local and national public health policy and programme development.

4.2 RIVM Centre for Infectious Disease Control, RIVM-CIb Local and regional notifications are aggregated within the Centre for Infectious Disease Control (Centrum Infectieziektebestrijding, CIb), a division of the National Institute for Public Health and the Environment (Rijksinstituut voor Volksgezondheid en Milieu, RIVM), which was established in 2005. In addition to its role in national surveillance, RIVM-CIb offers support and advice to regional PHS during complex or unusual disease events, coordinates collaboration between relevant partners during cross-regional or international disease outbreaks (including local PHS departments, local and national government bodies and policy makers), and communicates directly with international partners (ECDC, WHO) and the public. Its primary aims are to assure the effectiveness of the National Immunisation Programme, reduce the burden of healthcare- related infections and antimicrobial resistance, sexually transmitted disease, and zoonoses, and working with the PHS and other network partners, to provide relevant sectors with advice that is based on early detection and research.34 Data is directly applied to infectious disease prevention and control through support of policy initiatives - the final link in the chain.

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5. Aims and outline of this thesis 1

The aim of this thesis is to demonstrate the application of epidemiological studies in informing primary and secondary preventive strategies for infectious disease control in the Netherlands. This is achieved through recognition of current risk groups for known agents, identification of risk factors for new agents and unexpected disease events, and the application of this knowledge to inform infectious disease control guidelines. The thesis is divided in two parts: In the first part (Chapter 2 – Chapter 6), studies examining current risk groups for vaccine preventable diseases are described; In the second part (Chapter 7 – Chapter 11) studies identifying risk factors for emerging infectious diseases and unexpected disease events are reported.

Section 1: Immunisation Here, we focus on the epidemiology of hepatitis B virus (HBV) and hepatitis A virus (HAV) infections in current population groups at risk in the Netherlands.

In Chapter 2, we hypothesize that a recent observed increase in HBV infections through heterosexual contact may be associated with the ethnic background of the case. We describe trends in the incidence of acute HBV among heterosexual adults in ethnic groups in Amsterdam identifying ethnic sub-groups at risk of acute HBV infection, and discuss the implications for future control policy.

In Chapter 3, we focus on another population group, men who sleep with men (MSM), who are at risk of HBV infection, describing trends in the incidence of acute HBV in the MSM population in Amsterdam. We evaluate the impact of the HBV vaccination programme targeting MSM that began in 1998, and make recommendations about how the vaccination programme could be most effectively targeted in the future.

In Chapter 4, as the Netherlands prepared to introduce universal vaccination of infants against HBV, we assessed whether the immune response to the HBV component in a new hexavalent combination vaccine was sufficient according to WHO standards, and whether the immunogenicity of the other vaccine components was similar to that of the standard vaccine, which did not include the HBV component. This study was conducted in children who, because of their ethnic background, were vaccinated within the RVP under the targeted hepatitis B vaccination programme before universal vaccination was introduced.

In Chapter 5, we follow up on study conducted in 2006, which reported a downward trend in the number of imported HAV cases in Turkish and Moroccan children in Amsterdam in recent

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years. HAV is predominantly an imported infection in the Netherlands, and our aim was to describe recent trends in HAV infection in ethnic groups in Amsterdam, to identify current risk groups and to recommend targeted prevention through vaccination.

In Chapter 6, we evaluate the routine use of hepatitis A vaccine as an alternative to immunoglobulin in prevention of secondary HAV infection in contacts that have been exposed to HAV. Historically post-exposure, contacts of cases were offered immunoglobulin (IG, a human derived blood product) as an immunoprophylactic but the vaccine is increasingly recommended though its routine use in post-exposure prophylaxis has never been evaluated.

Section II: Outbreak investigation In the second section, outbreaks identified through routine surveillance are investigated and analytic studies are conducted to identify risk factors for exposure, infection and morbidity among those exposed.

In Chapter 7, we investigate risk factors for mumps in a population of highly vaccinated university students and identify factors associated with mumps vaccine failure among those who were vaccinated. This study was conducted in response to a large nationwide outbreak of mumps in the Netherlands from 2009-2011, which occurred in students, most of whom had been vaccinated in childhood.

In Chapter 8, we determine risk factors for infection associated with occupational exposure to Coxiella burnetii in culling workers who were involved in the mass slaughter of sheep and goats during the Q fever outbreak of 2007-.

In Chapter 9, we examine whether visiting a particular farm was a risk factor for the development of Q fever in local residents, and we identify other risk factors for acquiring Q fever (or a C. burnetii infection) in people who visited the farm.

In Chapter 10, we test our hypothesis that consumption of raw or undercooked meat was associated with infection with S. Typhimurium ft132 during an outbreak in 2009. We also identify other risk factors for infection, and attempt a novel approach to the traditional case-control study for investigation of a food-borne outbreak.

In Chapter 11, we examine risk factors for secondary transmission of Shigella infection within households. We consider the implications for current prevention policy and make recommendations on the basis of our findings.

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In Chapter 12, the findings of the thesis are summarised, giving an overview of what was 1 already known in each area, what the research reported here adds to the evidence base, the recommendations arising from these studies, and implications for future research.

References

1. Allen A. Prescription attibuted to Dr. Adam Thomson, circa 1748. Vaccine: The controversial story of medicine’s greatest lifesaver. London: W.W. Norton & Company, Ltd., 2007. 2. Allen A. Experimenting on the neighbors with cotton mather. In: Vaccine: The controversial story of medicine’s greatest lifesaver: W.W. Norton & Company, 2007. 3. Klebs AC. Historic Evolution of Variolation. Bulletin of the Johns Hopkin Hospital 1913;1:73. 4. Hopkins DR. The Greatest Killer: Smallpox in History. Chicago: University of Chicago Press, 2002. 5. Jones KE, Patel NG, Levy MA, Storeygard A, Balk D, et al. Global trends in emerging infectious diseases. Nature 2008;451:990-3. 6. Suk JE, Semenza JC. Future infectious disease threats to Europe. Am J Public Health 2011;101:2068-79. 7. Lindgren E, Andersson Y, Suk JE, Sudre B, Semenza JC. Public health: Monitoring EU emerging infectious disease risk due to climate change. Science 2012;336:418-9. 8. European Centre for Disease Prevention and Control. The Bacterial Challenge: Time to React. ECDC: Stockholm, 2008. 9. Lepape A, Monnet DL. Experience of European intensive care physicians with infections due to antibiotic- resistant bacteria, 2009. Euro Surveill 2009;14:pii:19393. 10. Van den Kerkhof JH, Van Steenbergen J, de Boer J, Hoebe C, Koene R, et al. Infectious disease control. Den Haag: Boom Lemma Uitgevers, 2013. [in Dutch] 11. Horsburgh CR, Mahon BE. Chapter 27: Infectious Disease Epidemiology. In: Rothman J.K., Greenland S., Lash T.L., editors. Modern Epidemiology. Third Edition. Philadelphia. Lippincott Williams and Wilkins; 2008. 12. Haygarth J. Sketch of a plan to exterminate the casual smallpox from Great Britain. London, 1793. Reprinted Gale ECCO; 2010 13. van ‘t Klooster M, de Melker, H, editors.The National Immunisation Programme in the Netherlands. Developments in 2012. RIVM report 201001002/2012T. Bilthoven: National Institute of Public Health and the Environment (RIVM), 2013. 14. Dodd D. Benefits of combination vaccines: effective vaccination on a simplified schedule. Am J Manag Care 2003;9:S6-12. 15. Kalies H, Grote V, Verstraeten T, Hessel L, Schmitt HJ, et al. The use of combination vaccines has improved timeliness of vaccination in children. Pediatr Infect Dis J 2006;25:507-12. 16. Boot HJ, Schipper CM. Simultaneous vaccination with Prevenar and multicomponent vaccines for children: interference or no interference? Hum Vaccin 2009;5:15-7. 17. Whelan J, Hahné S, Berbers G, van der Klis F, Wijnands Y, et al. Immunogenicity of a hexavalent vaccine co-administered with 7-valent pneumococcal conjugate vaccine. Findings from the National Immunisation Programme in The Netherlands. Hum Vaccin Immunother 2012;8:743-8. 18. Fine PE. Herd immunity: history, theory, practice. Epidemiol Rev 1993;15:265-302. 19. Whelan J, van Binnendijk R, Greenland K, Fanoy E, Khargi M, et al. Ongoing mumps outbreak in a student population with high vaccination coverage, Netherlands, 2010. Euro Surveill 2010;15:pii=19554 20. Houweling H, Verweij M, Ruitenberg EJ. Criteria for inclusion of vaccinations in public programmes. Vaccine 2010;28:2924-31. 21. Verweij M, Dawson A. Ethical principles for collective immunisation programmes. Vaccine 2004;22:3122-6.

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22. van Steenbergen JE, Leentvaar-Kuijpers A, Baayen D, Dukers HT, van Doornum GJ, et al. Evaluation of the hepatitis B antenatal screening and neonatal immunization program in Amsterdam, 1993-1998. Vaccine 2001;20:7-11. 23. van Houdt R, Koedijk FD, Bruisten SM, Coul EL, Heijnen ML, et al. Hepatitis B vaccination targeted at behavioural risk groups in the Netherlands: does it work? Vaccine 2009;27:3530-5. 24. Veldhuijzen IK, Toy M, Hahné SJ, De Wit GA, Schalm SW, et al. Screening and early treatment of migrants for chronic hepatitis B virus infection is cost-effective. Gastroenterology 2010;138:522-30. 25. Whelan J, Sonder G, Heuker J, van den Hoek A. Incidence of acute hepatitis B in different ethnic groups in a low-endemic country, 1992-2009: increased risk in second generation migrants. Vaccine 2012;30:5651-5. 26. National Centre for the coordination of Infectious Disease Control (LCI). LCI infectious disease control Incidence of acute hepatitis B in different ethnic guidelines. Bilthoven, 2011. [in Dutch] 27. National Institute of Public Health and the Environment (RIVM). LCI directive, hepatitis A. In: LCI group in a low-endemic country, 1992-2009: infectious disease control guidelines. Bilthoven, 2011. [in Dutch] 28. Centers for Disease Control. Comprehensive Plan for Epidemiologic Surveillance. Atlanta: US Department of Health and Human Services, Public Health Service, 1986. Increased risk in second generation migrants 29. National Institute of Public Health and the Environment (RIVM). Reporting of infectious diseases in accordance with the Public Health Act 2008. Bilthoven: National Institute of Public Health and the Environment (RIVM), 2008. [in Dutch] 30. World Health Organisation. International Health Regulations 2005. Geneva, 2005. 31. European Programme for Interventional Epidemiology Training. Field Epidemiology Manual. Outbreak investigations. Stockholm, 2013. Available at: https://wiki.ecdc.europa.eu/fem/w/wiki/outbreak-investigations.aspx 32. Bureau Onderzoek & Statistiek. Amsterdam in cijfers. Amsterdam: Gemeente Amsterdam, 2013. 33. Kuyper L, Vanwesenbeeck I. High levels of same-sex experiences in the Netherlands: prevalences of same-sex experiences in historical and international perspective. J Homosex 2009;56:993-1010. 34. National Institute of Public Health and the Environment (RIVM). Strategic Policy Plan: RIVM, Centre for Infectious Disease Control (CIb) 2011-2015. Bilthoven: RIVM, 2011.

Jane Whelan Gerard Sonder José Heuker Anneke van den Hoek

Vaccine 2012;30:5651-55 20

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Incidence of acute hepatitis B in different ethnic group in a low-endemic country, 1992-2009: Increased risk in second generation migrants 2

Jane Whelan Gerard Sonder José Heuker Anneke van den Hoek

Vaccine 2012;30:5651-55

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Abstract

Background The Netherlands is a low-incidence country for acute hepatitis B (HBV) infection (1.2/100,000 in 2010), where it is typically acquired in adulthood through injecting drug use or homosexual exposure. Recently, the number of heterosexually acquired acute infections in the Netherlands has increased. Ethnicity may be a risk factor. We describe trends in the incidence of acute HBV among heterosexual adults in ethnic groups in Amsterdam from 1992 to 2009 and discuss future control of HBV in the Netherlands.

Methods We studied all cases of acute HBV acquired in heterosexuals aged ≥15 years in the Amsterdam region (1992−2009, n=238) by ethnic group. Incidence rates were estimated as the average number of cases per 100,000 per year. Using Poisson regression, we calculated univariable and multivariable incidence rate ratios (IRR) by ethnic group over calendar year, by age and gender.

Results The incidence in first generation migrants from HBV‒endemic countries (FGM) was 4.1/100,000 showing no trend over time. Since 1999, incidence in Dutch-born cases in Amsterdam has increased by 13% annually from 0.2/100,000 in 1999 to 2.1/100,000 in 2009 (annual IRR 1.13, 95% CI:1.0−1.22). From 2004 to 2009, the incidence in native Dutch/Western in Amsterdam was 1.6/100,000 (reference for IRR), in FGM was 4.3/100,000 (IRR of 2.7, 95% CI:1.8−4.2) and in Dutch-born second generation migrants (SGM) was 3.7/100,000 (IRR:2.4, 95% CI:1.2−4.7).

Conclusion Incidence of acute hepatitis B in Amsterdam in FGM and SGM is higher than in the native Dutch population. Low-endemic countries with migrant populations from HBV-endemic areas should consider offering screening and vaccination to both FGM and SGM.

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Background Five million acute hepatitis B virus (HBV) infections occur annually worldwide. In developing 2 countries, acute HBV infection is common and usually acquired perinatally or by horizontal transmission in childhood and 95% of acute infections in childhood become chronic. Each year, up to 1.2 million people die in adulthood from chronic HBV-related hepatocellular carcinoma or cirrhosis.1,2 In industrialized countries, acute HBV infection is rare and is acquired primarily through injecting drug use (IDU) or sexual exposure in adulthood, 5% of whom will develop chronic infection.1 CDC classifies the prevalence of hepatitis B surface antigen (HBsAg) in populations as high (≥8%), intermediate (2−8%) or low (<2%). The Netherlands is a low-endemic country (incidence, 1.2/100,000 in 20103) and nationally, the estimated prevalence of HBsAg is 0.2%.4 To date, hepatitis B control measures have been targeted at specific risk groups: since 1989 all pregnant women have been screened for HBsAg. If the woman is positive, the neonate is immediately given immunoglobulin and hepatitis B vaccination, and acute infection in childhood is almost entirely prevented.5 Household contacts are also screened and vaccinated if susceptible, and uptake is high.6 In 2003, the neonatal vaccination programme was extended and hepatitis B vaccine is now offered to children with at least one parent from an intermediate- or high-endemic HBV country (approximately 18% of the total birth cohort). Of the eligible birth cohort of 2008, 94.8% completed hepatitis B vaccination in 20117).

Screening and vaccination of high-incidence groups including commercial sex workers, drug users, men having sex with men (MSM) and heterosexuals with a high rate of partner change was introduced in 2002 (the latter was discontinued in 2007 as molecular epidemiology showed that the heterosexual transmission chain was of limited importance8). The potential of these programmes to further reduce the incidence of HBV is considered to be low9 so to optimise protection for the population as a whole (in addition to current targeted programmes) universal vaccination of infants was introduced in the Netherlands in August 2011.

Despite all efforts, there has been an increase in the number of acute HBV infections through heterosexual contact since 2007, particularly in men.3 Evidence is accumulating that first generation migrants (FGM) born in countries of intermediate endemicity (such as Morocco, , Suriname and Netherlands Antilles, where the population prevalence of HBsAg is ≥2%) may be over-represented in these figures10 and that among heterosexual adults, having a partner born in an intermediate or high-endemic country is a risk factor for acute infection.11 Furthermore, there is evidence that HBV exposure among FGM and second generation migrants (SGM: Dutch-born descendants of FGM) is higher relative to the native Dutch population.4,12 In Amsterdam in 2011, 35% of the population was of non-western ethnicity predominantly Turkish,

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Moroccan, Surinamese or Antillean, many of whom migrated in 1960s.13 As the population of their descendants grows, differences in transmission and incidence between FGM and SGM have not been examined. Our aim was to describe trends in the incidence of acute HBV among heterosexual adults in ethnic groups in Amsterdam from 1992 to 2009, to identify groups at risk of acute hepatitis B infection, and to discuss implications for future control of HBV in the Netherlands.

Methodology

Notification criteria for acute HBV in the Netherlands include clinical signs or symptoms of infection and detection of HBsAg or anti-HBc type M immunoglobulin (IgM) in the serum. Cases reported to the Amsterdam public health service (1992−2009) were eligible for inclusion. Birth-date, gender, country of birth, country of birth of parents (from 2004 onwards) and date of onset of illness were collected. Country of birth was classified as: the Netherlands, Suriname, Netherlands Antilles, Turkey, Morocco, Ghana, “Western (other)” and “Non-Western (other)”. To estimate risk of transmission in those groups not otherwise targeted by screening or vaccination (i.e. in heterosexuals, or source classified as “unknown” or “other”), MSM, IDU or children <15 years (who are typically infected horizontally) were excluded. In the Netherlands, everyone is registered in their resident municipality. Annual population estimates were provided by the Research and Statistics department of Amsterdam (O&S) by age, gender, country of birth (for FGM) or country of birth of parents (for SGM, who themselves were born in the Netherlands) from 1992 to 2009.

Country of birth was dichotomised according to HBV prevalence as <2% (the Netherlands or “Western, other”) or ≥2% (Suriname, Netherlands Antilles, Turkey, Morocco, Ghana, “Non- Western, other”, hereafter, FGM). We hypothesized that children would share traits with their parents other than racial characteristics alone, such as cultural traditions and practices (including preference for a sexual partner from a similar ethnic background where there is a high prevalence of HBV carriage). Henceforth, we use the term “ethnicity” to capture this shared background. As self-reported ethnicity was not available for those born in the Netherlands or in Western Europe, we attributed their ethnicity to the country of birth of their parents. From 2004, cases born in the Netherlands were reclassified by their ethnicity as “native Dutch/Western”, or SGM according to country-of-birth of their mother, or of their father if their mother was “Dutch/ Western”.

Using STATA 11.1, univariable associations between ethnic group (Dutch/Western-born, FGM, SGM) and age, gender and calendar year were compared using chi-square test for categorical

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data and Mann−Whitney U test (MWU), Kruskal−Wallis test (KW) or “nptrend” for comparison of continuous data, as appropriate. Annual population estimates were used to approximate persons-at-risk per year, and incidence rates were estimated as the annual number of new cases 2 per 100,000 persons-at-risk. Poisson regression models adjusted for person-years of follow-up were used to quantify the incidence rate ratio (IRR) with 95% confidence intervals. The principle risk factor was ethnicity and covariates were calendar time (linear), age-group (categorical) and gender (categorical). If significant at univariable level (p<0.1), covariates were included in a multivariable model. Primary interactions were tested in each model and were included if significant (p<0.05).

Results

In Amsterdam, 509 cases of acute hepatitis B were reported (1992−2009), of whom 250 met the inclusion criteria. MSM (n=209), IDU (n=28) and children under 15 (n=22) were excluded. Of those who were included, 160 were heterosexual transmissions, 29 were classified as “other” and 61 were “unknown”. Median age was 33 years (interquartile range (IQR):27−45 years) and 60% were male (n= 150).The crude overall incidence rate (1992−2009) was 2.1/100,000. Baseline characteristics by ethnic group are in Table 1.

Acute HBV by country of birth, 1992−2009 Overall, 138 cases were Dutch/Western-born, and 100 were FGM (those for whom country of birth was missing were excluded, n=11). The median age in Dutch/Western-born was 36 years (IQR:27−48) and in FGM was 32 years (range:27−40, Mann Whitney U test, z=2.3, p=0.022). The incidence was 1.6/100,000 in Dutch/Western-born, and 4.1/100,000 in FGM (crude IRR 2.6, 95% CI:2.0−3.3, p<0.001), highest in Dutch/Western-born at age 40−49 (2.4/100,000) and in FGM at 20−24 (7.3/100,000). Incidence in Dutch/Western-born men was higher than in Dutch/Western- born women (IRR 1.6:95% CI:1.1−2.2, p=0.007). The difference between male and female FGM was not significant. Estimates of crude annual incidence with the 5-year moving average for Dutch/Western-born cases and FGM in Amsterdam are in Figure 1. There was no significant trend over time between groups overall (interaction, p=0.653), however since 1999, the incidence in Dutch/Western-born cases in Amsterdam has increased by 13% annually from 0.2/100,000 in 1999 to 2.0/100,000 in 2009 (annual IRR 1.13, 95% CI:1.04-1.22, p=0.002). There was no significant trend in age or gender over time in either group.

Acute HBV by ethnicity (FGM and SGM), 2004−2009 Ethnicity (based on country of birth of parents) of SGM was available from 2004. Of all cases (n=89), 41 were native Dutch/Western, 38 were FGM and 10 were SGM. The median age of native

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(12) (41) (36) (34) (65) (23) (59) (30) (100) 2.1 Total

11,097,997 71 81 55 97 86 28 141 155 238 (14) (21) (21) (55) (34) (66) (24) (66) (100) 4.9 587,235 Western

7 4 6 6 19 16 19 10 29 Other, non (0) (0) (0) (0) (50) (50) (100) (100) (100) 4 Ghana 100,975

4 4 4 2 2 0 0 0 0

(12) (64) (24) (72) (28) (40) (40) (20) (100) 4.6 539,342 Morocco

3

5 7 6 16 18 10 10 25

(71) (41) (12) (35) (65) (24) (24) (29) (100) 4.7 Turkey 358,043 Country of birth case

7 4 5 4 6 2 11 17 12

(4) (36) (36) (68) (28) (28) (40) (60) (100) 2.9 869,073 Antilles 1

7

7 9 9 17 15 10 25 Suriname & Netherlands

(41) (12) (35) (53) (12) (35) (47) (65) (100) 1.9 Other, 908,563 Western

7 6 9 2 6 2 8 11 17

(21) (41) (57) (33) (65) (39) (44) (59) (100) 1.6 7,734,766

71 16 53 79 26 28 50 40 121 Netherlands Unknown Other Hetero >50 30−49 15−29 Male Female

Likely source of infection, n (%)

Total number of cases, n (%) Cumulative total population, N Age-group, n (%) Estimated annual incidence per 100,000 (n/N* 100,000) Gender , n (%) Cases of acute hepatitis B in heterosexuals aged >15 years notified to the public health service of Amsterdam from 1992 to 2009 inclusive, by countryby of birthto 2009 inclusive, 1992 to the public health service from notified aged >15 years of Amsterdam B in heterosexuals hepatitis of acute 1. Cases Table ( n =238).

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Dutch/Western cases was 42 (IQR:29−48), of FGM was 35 (IQR:28−41) and of SGM was 23 (IQR: 20−24, KW chi-squared 17.277, p<0.001). From 2004 to 2009, the crude incidence in native Dutch/ Western in Amsterdam was 1.6/100,000 (reference for IRR), in FGM was 4.3/100,000 (IRR of 2 2.7, 95% CI:1.8−4.2, p<0.001) and in SGM was 3.7/100,000 (IRR:2.4, 95% CI:1.2−4.7, p=0.014). Age- adjusted IRR between ethnic groups was significant for male (IRR:1.8, 95% CI:1.0−3.3, p=0.033) and female (IRR:4.0, 95% CI:1.9−8.5, p≤0.001) FGM though not SGM, using Dutch/Western as reference. Within ethnic groups (using age “>50 years” as reference), in Dutch/Western men,

the IRR peaked in those aged 25−29 (IRR>50 years:3.6, 95% CI:1.2−11.2, p=0.027) and those aged 40−49

(IRR>50 years:3.4, 95% CI:1.3−9.3, p=0.015); In FGM men, peak incidence was in those aged 30−34

(IRR>50 years: 10.7, 95% CI:1.2−91.5, p=0.031), and 35−39 (IRR>50 years:9.1, 95% CI: 1.1−77.5, p=0.044).

Figure 1. Incidence & 5-year moving average (a) incidence of acute HBV in Dutch/Western-born (b) and first generation migrants from mid-high endemic countries (FGM), aged ≥15 in Amsterdam, 1992-2009. (a) Moving Average (MA). To produce the MA and smooth the original series, a new series was generated by adding two observations before in the original series, the nth observation, 2 after, and dividing by 5. (b) SGM are included in the numerator & denominator of Dutch/Western-born cases. (c) To provide context, the total incidence of acute HBV cases (n=509, 1992-2009) in persons >15 years in Amsterdam are also presented in this figure (MSM & IDU are included, grey line).

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0.008 <0.001 p−Value

-

3.7 4.3 n/a ref. ref. Upper 95% CI Multivariable -

1.5 1.2 n/a ref. ref. Lower -

2.1 2.6 n/a ref. ref. IRR

-

0.728 0.055 0.006 0.008 0.000 p−Value -

7.1 3.8 5.4 4.4 2.3 n/a n/a ref. ref. ref. ref. Upper Univariable 95% CI -

1.3 1.3 1.6 1.0 0.6 n/a n/a ref. ref. ref. ref. Lower a -

1.1 3.1 2.3 2.6 2.2 n/a ref. ref. ref. ref. IRR n/a

2 1.3 3.1 1.5 6.1 3.5 4.5 3.8 3.2 2.8 2.0 0.0 IR

47,404 219,951 181,605 559,041 704,041 509,738 960,597 450,859 1,410,142 1,388,642 2,047,339 2,798,784 Cumulative population, N Estimated incidence

0 11 11 16 16 18 57 39 27 10 32 30 Cases, n Male Female 2nd generation migrant (SGM) 1st generation migrant (FGM) Native Dutch/Western Male Female 2nd generation migrant (SGM) 1st generation migrant (FGM) Native Dutch Gender

Ethnicity

(B) Cases 30 years of age over Total Gender

(A) Cases under 30 years of age Total

Ethnicity

Incidence and incidence rate ratio (IRR) for acute hepatitis B, univariable and multivariable models for (A) cases under 30 years of age and (B) cases 30 years and of age and (B) cases 30 years cases under 30 years (A) models for univariable and multivariable B, hepatitis acute (IRR) for ratio rate 2. Incidence and incidence Table 2009. 2004 to from over

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In SGM men, peak IRRs did not achieve significance. In women, IRR in the Dutch/Western

group peaked at ages 15−19 (IRR>50 years:15.9, 95% CI:2.7−95.1, p=0.002). Within female FGM & SGM groups, differences were not significant. The overall trend in incidence over time and between 2 groups (2004−2009) was not significant. Given the age distribution of cases and that there were zero cases in SGM>30 years, a stratified Poisson regression analysis under/over 30 years was conducted (Table 2).

Discussion

The incidence of acute hepatitis B in heterosexual migrants born in mid/high-endemic countries (FGM) was almost three times that of Dutch/Western-born cases in Amsterdam from 1992 to 2009, and it was stable over this period. If approximately 25% of FGM in the ethnic groups we studied were already anti-HBc positive (and are therefore immune) as reported in other studies,4,12 the true incidence of acute symptomatic infection among susceptible FGM is probably closer to 5.4/100,000. In Dutch/Western-born cases, the initial decrease in incidence in the 1990s marks the end of a much greater decline from the early 1980s onwards3 as the hepatitis B vaccine became widely available and sexual behaviour changed in risk groups (as also evidenced by as a decline in other sexually transmitted diseases in the Netherlands and elsewhere).14-16 Since 1999 however, the incidence of HBV in this population in Amsterdam is increasing. This increasing incidence can largely be explained by an increase in the proportion of the SGM population in Amsterdam from 7% to 15% over the study period and that SGM have a higher risk of sexual contact with a HBV infected partner: 80% of SGM Turks and Moroccans will marry someone of the same background and one in five marry someone who has migrated from their home country especially to get married.17 Among Antillean, Aruban and Surinamese FGM and SGM teenagers, there is also evidence of more high-risk sexual activity: teenage birth rate in these groups is still many times that of native Dutch teenagers and single motherhood18 and sexually transmitted infections are more frequent.19

There were study limitations: Firstly, 50 to 67% of older children and young adults with acute infection are asymptomatic.20 Such cases are probably unreported (though not differentially, we expect, between migrants and native Dutch). Secondly, we could not account for cases that were misclassified and were in fact acute exacerbations of chronic infection, particularly in FGM where the prevalence of HBsAg is high. Thirdly, we could not exclude MSM and IDUs from the denominator, but population estimates in Amsterdam21,22 would not significantly affect our estimates of incidence. Fourthly, it is likely that some cases classified as heterosexual may in fact have been MSM. This could account for some of the male excess in cases over 30 years of age. Finally, three cases were from Eastern European countries where the seroprevalence

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is >2% and the population was included in the “Western, other” group denominator. Overall, however, the incidence in this group was <2% (1.9/100,000) and this did not change our findings or recommendations.

In conclusion, the incidence of acute hepatitis B in FGM and SGM is higher than in the native Dutch population. It is projected that the total non-western population in Amsterdam will increase by 50,000 people between 2011 and 2030, of whom an estimated 60% will be new FGM. There is currently no screening programme targeted at these groups, though vaccination is now advised for immigrants from endemic countries returning to visit friends and relatives.23 New infections among adult FGM, their partners and children could be prevented. All residents in the Netherlands are required by law to register in the municipality in which they reside and to acquire health insurance. Migrants from HBV endemic areas arriving to the country could be offered screening24 and a “catch up” screening and vaccination programme for FGM already resident and SGM born prior to 2003 should be also considered.

Acknowledgements The authors would like to thank Lian Bovée and the nursing staff in the Department of Infectious Diseases, Public Health Service Amsterdam who interviewed the patients and collected the data. Also Robin van Houdt who assisted with data collection, and Martien Borgdorff for his advice and critical review of the paper.

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References

1. Alter MJ. Epidemiology of hepatitis B in Europe and worldwide. J Hepatol 2003;39:S64-9. 2. Lai CL, Ratziu V, Yuen MF, Poynard T. Viral hepatitis B. Lancet 2003;362:2089-94. 2 3. Koedijk FD, van der Sande MA, Hahné S. Reports of acute hepatitis B in 2009. Infectieziekten Bulletin 2010;21:380-84. [in Dutch] 4. Hahné S, de Melker H, Kretzschmar M, Mollema L, Van Der Klis F, et al. Prevalence of hepatitis B virus infection in the Netherlands in 1996 and 2007. Epidemiol Infect 2012;140:1469-80. 5. van Steenbergen JE, Leentvaar-Kuijpers A, Baayen D, Dukers HT, van Doornum GJ, et al. Evaluation of the hepatitis B antenatal screening and neonatal immunization program in Amsterdam, 1993-1998. Vaccine 2001;20:7-11. 6. van Steenbergen JE, Baayen D, Peerbooms PG, Coutinho RA, Van Den Hoek A. Much gained by integrating contact tracing and vaccination in the hepatitis B antenatal screening program in Amsterdam, 1992-1999. J Hepatol 2004;40:979-85. 7. van Lier E, Oomen P, Giesbers H, Drijfhout I, de Hoogh P, et al. Immunization coverage National Immunization Programme in the Netherlands. Year of report 2011;. RIVM Report no. 210021014. Bilthoven: RIVM; 2012. Available at: http://www.rivm.nl/en/Documents_and_publications/Scientific/Reports/2011/juni/ Immunization_coverage_National_Immunization_Programme_in_the_Netherlands_Year_of_report_2011 [in Dutch] 8. van Houdt R, Bruisten SM, Koedijk FD, Dukers NH, Op de Coul EL, et al. Molecular epidemiology of acute hepatitis B in the Netherlands in 2004: nationwide survey. J Med Virol 2007;79:895-901. 9. Houweling H, Wittevrongel CF, Verweij M, Ruitenberg EJ. Public vaccination programmes against hepatitis B in the Netherlands: assessing whether a targeted or a universal approach is appropriate. Vaccine 2010;28:7723-30. 10. Veldhuijzen IK, Smits LJ, van de Laar MJ. The importance of imported infections in maintaining hepatitis B in the Netherlands. Epidemiol Infect 2005;133:113-9. 11. Hahné SJ, Veldhuijzen IK, Smits LJ, Nagelkerke N, van de Laar MJ. Hepatitis B virus transmission in the Netherlands: a population-based, hierarchical case-control study in a very low-incidence country. Epidemiol Infect 2008;136:184-95. 12. Baaten GG, Sonder GJ, Dukers NH, Coutinho RA, Van den Hoek JA. Population-based study on the seroprevalence of hepatitis A, B, and C virus infection in Amsterdam, 2004. J Med Virol 2007;79:1802-10. 13. Ersanili E. Country Profile 11: Netherlands. Focus Migration; 2007. 14. van Griensven GJ, de Vroome EM, Goudsmit J, Coutinho RA. Changes in sexual behaviour and the fall in incidence of HIV infection among homosexual men. BMJ 1989;298:218-21. 15. van Rijckevorsel GG, Sonder GJ, Bovée LP, Thiesbrummel HF, Geskus RB, et al. Trends in hepatitis A, B, and shigellosis compared with gonorrhea and syphilis in men who have sex with men in Amsterdam, 1992-2006. Sex Transm Dis 2008;35:930-4. 16. Goldstein ST, Alter MJ, Williams IT, Moyer LA, Judson FN, et al. Incidence and risk factors for acute hepatitis B in the United States, 1982-1998: implications for vaccination programs. J Infect Dis 2002;185:713-9. 17. Statistics Netherlands. Four out of five Turks and Moroccans marry within their own circles. Web Magazine, 2011. 18. Statistics Netherlands. Many Antillean and Surinamese teenage mothers. Web Magazine, 2010. 19. Vriend H, Koedijk F, van der Broek I, van Veen M, Op de Coul E, et al. Sexually transmitted infections, including HIV, in the Netherlands in 2010. Bilthoven, RIVM, 2011. 20. Shapiro CN. Epidemiology of hepatitis B. Pediatr Infect Dis J 1993;12:433-7. GGD Amsterdam EDG. Amsterdam health monitor and health research 2004. Amsterdam: GGD; 2006. [in Dutch]. 22. Buster MC, van Brussel GH, van den Brink W. Estimating the number of opiate users in amsterdam by capture-recapture: the importance of case definition. Eur J Epidemiol 2001;17:935-42.

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23. Sonder GJ, van Rijckevorsel GG, van den Hoek A. Risk of hepatitis B for travelers: is vaccination for all travelers really necessary? J Travel Med 2009;16:18-22. 24. Veldhuijzen IK, Toy M, Hahné SJ, De Wit GA, Schalm SW, et al. Screening and early treatment of migrants for chronic hepatitis B virus infection is cost-effective. Gastroenterology 2010;138:522-30.

Targeted vaccination programme successful in reducing acute Hepatitis B in men having sex with men in Amsterdam, The Netherlands

Gini van Rijckevorsel Jane Whelan Mirjam Kretzschmar Evelien Siedenburg Gerard Sonder Ronald Geskus Roel Coutinho Anneke van den Hoek

J Hepatol 2013. In Press

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Targeted vaccination programme successful 3 in reducing acute Hepatitis B in men having sex with men in Amsterdam, The Netherlands 3

Gini van Rijckevorsel Jane Whelan Mirjam Kretzschmar Evelien Siedenburg Gerard Sonder Ronald Geskus Roel Coutinho Anneke van den Hoek

J Hepatol 2013. In Press

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Abstract

Background and Aims In the Netherlands, transmission of hepatitis B virus occurs mainly within behavioural high- risk groups, such as in men who have sex with men. Therefore, a vaccination programme has targeted these high-risk groups. This study evaluates the impact of the vaccination programme targeting Amsterdam’s large population of men who have sex with men from 1998 through 2011.

Methods We used Amsterdam data from the national database of the vaccination programme for high-risk groups (January 1, 1998 to December 31, 2011). Programme and vaccination coverage were estimated with population statistics. Incidence of acute hepatitis B was analyzed with notification data from the Amsterdam Public Health Service (1992–2011). Mathematical modelling accounting for vaccination data and trends in sexual risk behaviour was used to explore the impact of the programme.

Results At the end of 2011, programme coverage was estimated at 41% and vaccination coverage 30% to 38%. Most participants (67%) were recruited from the outpatient department for sexually transmitted infections and outreach locations such as saunas and gay bars. Incidence of acute hepatitis B dropped sharply after 2005. The mathematical model in which those who engage most in high-risk sex are vaccinated, best explained the decline in incidence.

Conclusions Transmission of hepatitis B virus among Amsterdam’s men who have sex with men has decreased, despite ongoing high-risk sexual behaviour. Vaccination programmes targeting men who have sex with men do not require full coverage; they may be effective when those who engage most in high-risk sex are reached.

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Introduction

Worldwide, an estimated two billion people are infected with hepatitis B virus (HBV). More than 240 million have chronic liver infections, and approximately 600,000 die each year from HBV-associated cirrhosis or hepatocellular carcinoma.1 The endemicity of HBV differs greatly by geographical region; depending on the prevalence of HBV surface antigen (HBsAg) 3 in the population, countries may be classified endemically as high (>8%), intermediate (2- 8%), or low (<2%).2 In high- and intermediate-endemic countries, HBV transmission occurs mainly perinatally or in early childhood, whereas in low-endemic areas, HBV is more often contracted later in life, either through sexual contact or use of contaminated needles. In 1982 a safe, effective vaccine became available, and many countries have since implemented a national infant immunization programme. In the Netherlands, HBV prevalence in the general population is very low (HBsAg = 0.2%; 95% confidence interval (95% CI) 0.1-0.4%).3 Since 1983, vaccination programmes have been implemented for health care workers (1983), newborns of HBsAg-positive mothers (1989), and newborns with at least one parent from a high- or intermediate-endemic country (2003).3 In addition, in 2002, as transmission occurred mainly within behavioural high-risk groups (injecting drug users, men who have sex with men (MSM), and commercial sex workers), a vaccination programme targeting behavioural high-risk groups was implemented nationally, after a pilot programme from 1998 to 2000 in several regions, including Amsterdam.4,5 Because more recent insights have shown that vaccination of the general population is cost-effective and more beneficial in the long term than those only in the high-risk groups, a nationwide infant vaccination programme was initiated in August, 2011.6 As no catch-up campaign will be instituted, the ‘high-risk group’ policy must be continued for at least another 20 to 30 years. In this study we describe trends in the incidence of acute HBV in the MSM population in Amsterdam from 1992 through 2011 and evaluate the impact of the HBV vaccination programme targeting MSM that began in 1998. The Dutch capital, with about 800,000 inhabitants, is a popular residence for MSM from all over the world, totalling at least 26,000.7 We used a mathematical model, taking into account vaccination data, demographic aspects, and changes in sexual risk behaviour, to explore potential explanations for these trends.

Methods

Population statistics Yearly age- and gender-specific population data were obtained from the Research and Statistics Department of Amsterdam. The number of MSM residing in Amsterdam was estimated as 10% of the male population aged 15-69 years as registered on December 31 of each calendar year.8,9

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The differential effect of migration in and out of the population was accounted for; however, the changing proportions of immune, vaccinated, or susceptible MSM were unknown.

Targeted vaccination programme MSM To evaluate the programme targeting MSM in Amsterdam, data were used from the national database of the vaccination programme for high-risk groups (November 1, 2002 until December 31, 2011, including follow-up data from 2012) and the pilot project (October 1, 1998 to May 1, 2000). Details of the programme are described elsewhere.4 Male residents aged 15–69 years who were registered in Amsterdam and indicated a same-sex preference were eligible for inclusion. Demographic data, date and location of inclusion (first contact), number and dates of vaccination, and results of testing for antibodies against HBV core antigen (anti-HBc) and, if applicable, consecutive HBsAg testing were used. Programme coverage was estimated as the fraction of MSM included in the program and the estimated number of MSM aged 15–69 years residing in Amsterdam. Compliance was defined as the proportion of susceptible participants completing the series of three vaccinations. The numbers of susceptible participants who received one to three doses, in combination with the known vaccine efficacy after one dose (40%), two doses (70%), and after three doses (90%) were used to calculate the number of effectively immunised MSM.10,11 Vaccination coverage was calculated by dividing this number of effectively immunised MSM by the assumed number of susceptible MSM (the number of MSM residing in Amsterdam per calendar year, minus the assumed number of MSM immune [anti-HBc positive] by previous natural infection). Since approximately 20% (range, 10-36%) are thought to be immune by previous infection,5 we used a range of 10% to 30%.

Acute hepatitis B infections In the Netherlands, all new patients with laboratory-confirmed acute HBV infection must be reported to the Public Health Service (PHS). Criteria, which were consistent during the 20-year period of analysis, include clinical signs and symptoms, combined with findings of HBsAg and/ or type M immunoglobulin antibodies to HBV (anti-HBc) in the serum. Public-health nurses collected data from all patients on the source of infection, demographic data, and information on specific risk factors, including travel prior to infection, sexual preference, and risk behaviour. From January 1992 to January 2012, 534 patients with acute HBV were reported to the PHS in Amsterdam. Patients were ranked hierarchically according to risk of transmission into one of five transmission groups: sexual transmission (with high-risk sexual behaviour specific for HBV transmission, i.e. making distinction between sub-groups having unprotected homosexual and heterosexual contact with new and/or multiple partners); injecting drug use; horizontal transmission; health care transmission; and patients in whom none of those risks were

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identified. With this classification, 220 (41%) acute HBV infections in MSM were included in the analysis, together with baseline characteristics, including age and year of birth.

Statistical analyses Analysis was conducted with Intercooled Stata 11.1 for Windows (Stata Corp., College Station, Texas, USA). HBV incidence rates were estimated as the annual number of new cases per 100,000 3 persons-at-risk. Incidence rate ratios (IRR) with 95% CI were estimated via Poisson regression, separately for calendar time, age, and birth year, respectively. When modelling the IRR, we used natural splines to obtain smoothed trends. In each model, we tested whether the null hypothesis of constant infection rates could be rejected.

Because the variables of age, period, and birth cohort were linearly related, an age-period-cohort (APC) model was used for the multivariable analysis. The incidence of acute HBV was modelled in (log) rates as a sum of (non-linear) age-, period- (date of diagnosis), and cohort- (date of birth) effects. The model was constructed with “apcfit” in Stata which uses natural splines to estimate each of the three effects that are then combined to give estimated rates. For details, see Carstensen 2007 and Rutherford 2010.12,13 As we were interested in the age effects related to birth cohort effects, the model was parameterized to constrain the period effect to have a slope of zero and to be zero on average on the log scale. After adjustment for period effects, age-specific rates were estimated for the median birth cohort (1966). The cohort effect (cohort rate ratios) was similarly estimated and reported relative to the median 1966 birth cohort.

The mathematical model The current model, which was derived from previous models by Williams et al. and Kretzschmar et al.,11,14 demonstrates the course of the HBV epidemic among MSM in Amsterdam since 1992, taking into account demographic aspects, effects of the targeted vaccination programme, and changes in sexual risk behaviour. The model population consisted of the annual number of MSM residing in Amsterdam and was stratified by age (15–64 years) and 6 sexual activity classes.15 The activity classes were distinguished by their rates of partner change and were parameterized to reflect the large heterogeneity in partner change rates in the population. We assumed proportionate mixing by age and activity level, and that transmission takes place with a per partnership transmission probability. We do not explicitly specify transmission routes, but assume that transmission is largely driven by unprotected anal intercourse (UAI) and the contribution of transmission via injecting drug use or other modes is negligible. Migration in and out of the MSM population was incorporated into the model as a constant rate stratified by age group (mean rate more than 12 years). Vaccination rates stratified by age were calculated from the numbers of vaccinations averaged during the years since 1998 per age category.

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Partner change rates were based on data from sexual behaviour surveys and calibrated so that the model reproduced the observed incidence of notified acute HBV infections averaged over the pre-vaccination years 1992–1998. Partner change rates increased by 10% in 1997, followed by an annual increase of 5% until 2004, and a stable risk behaviour from 2005 onwards.16 Trends in sexual risk behaviour were based on data on behaviour (i.e., proportion of MSM practicing unprotected anal intercourse [UAI]) among MSM in the Amsterdam Cohort Studies (1984– 2009).17 The trends show steadily increasing sexual risk behaviour from the mid-1990s after the introduction of combination antiretroviral therapy, with a plateau from 2004 coinciding with increasing sexual risk behaviour among MSM.17,18 We assumed that incidence of infection was six times the incidence of notified cases, where a factor three is due to subclinical infection and a factor two to under-diagnosis and under-reporting.19-21 The model and its parameters are explained in detail in the Supplementary Data. Three different scenarios are processed in the model. The endemic equilibrium is based on the incidence of notified acute HBV infections before the start of the vaccination programme. Scenario one describes the trend of acute HBV without a targeted vaccination programme in the context of increasing sexual risk behaviour. Scenario two describes the effect of the current programme targeting all MSM. Scenario three describes the effect of the programme targeting the 20% of the population with higher partner change rates, i.e., the proportion of the model population in the four highest levels of sexual activity.15 This choice was motivated by our observation that men participating in vaccination often reported higher risk behaviour than other MSM and that we estimated the high risk core group to be around 10% of the Amsterdam MSM population.

Results

Targeted vaccination programme MSM From 1998 to 2012, a total of 12,273 MSM in Amsterdam participated in the targeted HBV vaccination programme. Table 1 shows the programme coverage per calendar year, which increased from 2% in 1998 to 41% in 2011. The median age at inclusion was 34 years (interquartile range [IQR] 27–41 years, range 14–83 years). Most participants were born in the Netherlands (71%) or other low-endemic countries (9%). Fifty-one percent of the participants (6306) were recruited from the outpatient department for sexually transmitted infections (STI-OPD) of the PHS in Amsterdam and 22% (2719) from the department for infectious diseases of the PHS. Other recruitment sites included outreach locations (i.e. saunas and gay bars,1965 or 16%), general practitioners’ offices (6%), and penitentiaries and hospitals (4%). Almost all participants (98%) were tested for anti-HBc, and 18.3% were positive (95% CI 17.6–19.0%). The relative distribution of recruitment location did not change significantly over time. Anti-HBc seroprevalence decreased

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over time (Table 1). Results of consecutive HBsAg testing were available from 2002 onwards for 1573 anti-HBc-positive samples; 106 participants were chronic HBsAg carriers (6.7%; 95% CI 5.5–8.0%), and HBsAg seroprevalence in all participants was 1.2% (95% CI 1.0–1.4%), decreasing over time. Results of both anti-HBc and HBsAg testing were associated with the location of recruitment. Participants recruited at STI-OPD and outreach locations were significantly more often immune by previous infection (anti-HBc+: 19–21%) compared to those recruited elsewhere, 3 and 78% of the HBsAg-seropositive MSM were recruited at these locations (data not shown).

Compliance, number of effectively immunized MSM and vaccination coverage At the time of inclusion, 82% of all participants were susceptible to infection and received a first dose of the vaccine (10,021/12,273); of those, 84% received two doses, and 71% received the full series of three vaccinations. Table 2 shows compliance with the vaccination schedule, and in 2011, after taking the vaccine efficacy after 1, 2, and 3 doses into account, the number of effectively immunized MSM was estimated at 7952. Assuming that 10%–30% of the total MSM population (29,751 in 2011) was already immune by previous infection, we estimated vaccination coverage at 30%–38%, leaving 12,875–18,825 MSM still susceptible to infection at the end of 2011.

Table 1. Programme coverage of the HBV vaccination campaign targeting MSM in Amsterdam and the proportion of immune MSM, 1998-2011.

Year Population size Number of inclusions Programme % AntiHBc+ % HBsAg+ (cumulative) coverage (%) 1998 27,078 549 (549) 2% 16,8% - 1999 27,486 2,049 (2,598) 9% 20,0% - 2000 27,692 577 (3,175) 11% 21,9% - 2001 27,851 No vaccination programme 2002 27,890 291 (3,466) 12% 21,6% 2.5% 2003 27,919 1,302 (4,768) 17% 24,6% 1.5% 2004 28,067 1,091 (5,859) 21% 23,7% 0.9% 2005 28,269 1,028 (6,887) 24% 20,7% 1.2% 2006 28,286 941 (7,828) 28% 19,0% 1.7% 2007 28,313 1,103 (8,931) 32% 17,8% 1.3% 2008 28,513 920 (9,851) 35% 14,8% 1.0% 2009 28,893 688 (10,539) 36% 10,4% 0.9% 2010 29,331 948 (11,487) 39% 10,3% 1,0% 2011 29,751 732 (12,219) 41% 9,1% 0,6%

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Table 2. Compliance and number of MSM effectively immunized against HBV in Amsterdam, the Netherlands, 1998-2011.

Vaccine Number Number Compliance Number effectively immunized (%) number in entering the vaccinated HBV series programme Number who Vaccine Number Cumulative withdrew/ left efficacyc immune post number the programme after vaccination immune post

after vaccinei vaccinei vaccination

i ni (= mi-1) mi (= mi-1-wi-1) c (mi/ni) wi Ψi xi (= wi*Ψi) yi (= xi+xi-1) 1 12,273 10,021a 0.82 1,604 0.4 642 642 2 10,021b 8,417 0.84 1,347 0.7 930 1,572 3 8,417 7,089 0.71 7,089d 0.9 6,380 7,952 a. Of those who were recruited (n=12,273), 2252 were previously immune. b. Only those who received the 1st vaccine in the series were eligible for the second vaccination, ditto 2nd & 3rd vaccinations. c. Vaccine efficacy is assumed to be 40% after one dose, 70% after 2 doses and 90% after three doses.10,11 d. Those who were vaccinated a 3rd time then left the programme.

Acute hepatitis B infections From January 1992 to January 2012, 220 MSM with acute HBV infection were reported to the Amsterdam PHS. The annual number of new patients ranged from 5 to 21 (median 12). The median age at diagnosis was 34 years (IQR 29–40 years, range 19–72 years). Figure 1a shows the measured and fitted incidence and the growing MSM population over calendar time. The incidence (mean 39.5 per 100,000 MSM, range 14.0-74.8) remained stable until 2005, but then dropped sharply from 60 to 20 out of 100,000 in 2011 (p < 0.001). Age-specific incidence peaked at 35–44 years (Figure 1b), yet its distribution shifted over calendar time (Figure 2a). In the period 1992–1996 the highest incidence was in those 25–29 years old, whereas in 2007–2011 it was in those aged 40–44 years. This is reflected in the incidence rates specific to birth year (Figure 1c), which peaked in the years between 1960 and 1969, irrespective of the period of diagnosis (Figure 2b). These findings are supported by the multivariable APC-analysis (Figure 3). The left graph shows the age-specific (longitudinal) incidence for those born in 1966, which peaked at 20 and 40 years. After adjustment for age and period, the cohort effect is evident: all rate ratios in the graph are less than one, and the highest rate is the 1966 birth cohort (centre graph). The right graph shows the non-linear effects of period, independent of age or cohort effects.

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  ●     ● ● ● ● ●  ● ● ●  ●  ● ● ● ● ●  

● ●  ● ● ●      3                    



               

                          

 

Figure 1. Acute HBV in MSM in Amsterdam (1992-2011). A: Incidence (per 100,000 MSM) per calendar year. The measured incidence is represented by the line with dots, and the fitted incidence by the smooth line with its 95% confidence interval (striped area). The grey shaded area is the population denominator data of the Amsterdam MSM population. B: Age-specific rate (per 100,000 MSM). C: Year of birth-specific rate (per 100,000 person years) The measured rate is represented by dots, and the fitted rate by the smooth line with its 95% confidence interval (striped area); py, person years.

     

  

   

 



    



 

                      

 

Figure 2. Acute HBV rates. (A) Age-specific and (B) year of birth-specific rates of acute HBV per 100,000 person years in MSM in Amsterdam stratified by 4 periods of diagnosis (‘92-‘96, ‘97-‘01, ‘02-‘06, ‘07-‘11); py, person years.

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2 A B C 15

1

10 0.5 Rate ratio

Rate per 100,000 person years 5 0.25

0.125

0 25 30 35 40 45 50 55 60 65 1950 1960 1970 1980 1990 2000 2010

Age in years Calendar year

Figure. 3 Results from the multivariable APC-analysis of the acute HBV incidence per 100,000 MSM in Amsterdam, the Netherlands 1992-2011, shown as line graphs representing log rates, with its 95% confidence interval (grey shaded area). (A) Age-specific rates adjusted for period (per 100,000 person-years on left Y-axis) for the 1966 birth cohort, which peaks at age 20 and 40. (B) Cohort effect adjusted for age and period (calendar year versus rate ratio on the right Y-axis). The highest rate is in the 1966 birth cohort, i.e. all other rates ratios are <1. (C) represents the period effect (the non-linear effects of period unexplained by the other two terms), and acts like a residual effect; py, person years.

Mathematical Model Figure 4 shows the effect of vaccination and changed sexual risk behaviour on the incidence of acute HBV infection in three different scenarios. In the first scenario, (no vaccination programme), the incidence sharply increased due to increasing risk behaviour from 1997 to 2004. In the second scenario (dashed line) the effects of the vaccination campaign directed at all MSM in the population counterbalance the increase of risk behaviour to some extent, but the vaccination programme cannot reverse the increasing trend in incidence. However, if vaccination is targeted to the population with the highest risk levels (scenario three), the current coverage is sufficient to reduce the incidence to below the baseline of the pre-vaccination era.

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







 3

 



      

 Figure 4. Effect of vaccination and increased sexual risk behaviour on the incidence of acute HBV. The endemic equilibrium (black solid line) is based on the incidence of notified acute HBV 1992-1998 before the initiation of vaccination and changes in sexual risk behaviour. Scenario 1: (green line): effect of increasing sexual behaviour from 1997 to 2004 if no MSM were vaccinated. Scenario 2: (red line) the effect of the vaccination programme targeting all MSM. Scenario 3: (black line) the effect of the vaccination programme targeting high-risk MSM only py: person years.

Discussion

From 2004 to 2012, the incidence rate of HBV infection in MSM in Amsterdam decreased by 78% (from 75 to 17/100.000), indicating that transmission among MSM has decreased.22 As in the past eight years, high-risk sexual behaviour among MSM has stabilized, and the reduced transmission is a probable effect of the targeted MSM risk-group vaccination programme started in 1998.17 Earlier evaluations of the programme (up until 2006) did not find evidence that this programme had an impact, partly because of the coincident increase in risk behaviour among MSM since the mid-1990s that counterbalanced the positive effects of the programme and partly because the uptake was too low at that time.5,17,18,22,23 In 2008, a mathematical model by Xiridou et al. predicted a greater benefit if MSM engaging most in high-risk sex (i.e. having a higher rate of partners or having more UAI) could be reached.23

The mathematical model in our study demonstrates that the current decline in incidence is best explained by the scenario in which high-risk MSM (approximately 20% of the MSM population) are vaccinated. More than two thirds of our participants were MSM recruited at STI-OPD (51%) and at saunas and gay bars (16%). These participants were significantly more often immune by previous infection (anti-HBc+: 19–21%), and 78% of the HBsAg-seropositive (infectious) MSM

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were recruited at these locations. A limitation of the model is the assumption of proportionate mixing by age and activity level. However, with more preferred mixing the impact of targeted vaccination would even be stronger, because dilution of transmission via lower activity levels would be less influential. Another limitation is our lack of sexual behaviour data from the Amsterdam MSM population, which prevented us from directly estimating partner change rates from data for that population and led us to only indirectly determine these rates via a calibration process. While the model is a simplification of reality in the sense that it does not take other transmission routes except UAI into account and that it assumes perfect targeting to the high risk core group, the qualitative differences between scenarios are robust to uncertainty in parameter values. Vaccination will also reduce transmission via other transmission routes and we already took the targeted population to be broader – namely 20% of the population – rather than the 10% estimated from data. Our aim was not to predict the future course of HBV incidence, but to identify which vaccination scenario best explained the observed trends. Those trends could not be explained by assuming equally distributed vaccination, but could well be explained by assuming a targeted vaccination approach.

Furthermore, analysis of acute HBV infection in MSM showed that those born between 1960 and 1970 have been at highest risk for the disease in the past 20 years. This aging cohort has contributed heavily to transmission of HBV in the last two decades and therefore can be considered a high- risk core group. Whether this is because they have more UAI than others is unknown, but it is possible that in their social network more acute and chronic HBV infection has occurred, meaning more infectious partners have been present. The vaccination programme included almost 4000 MSM born between 1960 and 1970, and the estimated programme coverage was highest (62%) within this group (data not shown). If we assume that this core group has become immune either by infection or vaccination, we have a potential explanation for the declining HBV incidence, despite ongoing sexual high-risk sexual behaviour.

This is the first time that a targeted HBV vaccination programme has been proven to be effective. Our findings have important policy implications. Previous evaluations of this programme up until 2006 (incidence trend analysis, mathematical modelling and molecular sequence models) could prove no impact.22-24 Concern also exists about the effectiveness of such programmes when the uptake or coverage remains low,25,26 and in the past the programme aimed to include as many MSM possible. This study shows that the targeted vaccination programme in Amsterdam is effective with vaccination coverage below 40%, most likely because MSM who engaged mostly in high-risk sex, such as clients of STI clinics, were reached.

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Since 2005, as the average age of recruitment was 39 years and similar to the average age of infection, much effort was made to reach young MSM. However, this study shows that the epidemic is driven by older MSM, and young, non-immune MSM have no particular increased risk of infection. As long as a programme reaches MSM networks in which the virus circulates, it is effective. 3 In conclusion, the targeted Amsterdam HBV vaccination programme has been successful in reducing transmission among MSM, despite ongoing high-risk sexual behaviour. HBV vaccination programmes targeting MSM do not require coverage of all MSM, but can have a substantial effect on the incidence, if those who engage most in high-risk sex and those who contribute most to transmission are reached. To make a targeted vaccination programme successful, policy decisions should focus on identifying MSM networks responsible for continued HBV transmission.

Acknowledgements This study was conducted within the Sarphati Initiative: Academic Collaborative Center on Public Health of Noord-Holland and Flevoland, the Netherlands. The Sarphati Initiative is financially supported by the Netherlands Organization for Health Research and Development (ZonMw; grant number 125010001). The authors would like to thank Mark Rutherford for his comments on the statistical procedures regarding the age-period-cohort (APC) model; and Sally Hebeling for editing the final manuscript. Furthermore the authors would like to thank the nurses of the Public Health Services in Amsterdam for their data collection on HBV.

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References

1. World Health Organization. Hepatitis B. (Factsheet No 204). Geneva, Switzerland: World Health Organization; 2012. Available from http://www.who.int/mediacentre/factsheets/fs204/en/ (accessed on November 30, 2012). 2. Lavanchy D. Worldwide epidemiology of HBV infection, disease burden, and vaccine prevention. J Clin Virol 2005;34:S1-S3. 3. Hahné SJ, de Melker HE, Kretzschmar M, Mollema L, van der Klis FR, et al. Prevalence of hepatitis B virus infection in The Netherlands in 1996 and 2007. Epidemiol Infect 2011;14:1-12. 4. van Steenbergen JE. Results of an enhanced-outreach programme of hepatitis B vaccination in the Netherlands (1998-2000) among men who have sex with men, hard drug users, sex workers and heterosexual persons with multiple partners. J Hepatol 2002;37:507-13. 5. van Houdt R, Sonder GJ, Dukers NH, Bovée LP, van den Hoek A, et al. Impact of a targeted hepatitis B vaccination program in Amsterdam, The Netherlands. Vaccine 2007;25:2698-705. 6. Health Council of the Netherlands. General vaccination against hepatitis B revisited. The Hague; 2009. Report No.: 2008/03E. 7. Veugelers PJ, van Zessen G, Hendriks JC, Sandfort TG, Coutinho RA, et al. Estimation of the magnitude of the HIV epidemic among homosexual men: utilization of survey data in predictive models. Eur J Epidemiol 1993;9:436-41. 8. Van Wesenbeeck I, Bakker F, Gesell S. Sexual health in the Netherlands: Main results of a population survey among Dutch adults. Int J Sex Health 2010;22:55-71. 9. Kuyper L, Vanwesenbeeck I. High Levels of Same-sex experiences in the Netherlands: Prevalences of same- sex experiences in historical and international perspective. J Homosex 2009;56:993-1010. 10. Mast EE, Ward JW. Hepatitis B vaccines. In: Plotkin SA, Orenstein WA, Offit PA, editors. Vaccines, 5th ed. Philadelphia: Saunders Elsevier; 2008. p. 220. 11. Williams JR, Nokes DJ, Medley GF, Anderson RM. The transmission dynamics of hepatitis B in the UK: a mathematical model for evaluating costs and effectiveness of immunization programmes. Epidemiol Infect 1996;116:71-89. 12. Carstensen B. Age-period-cohort models for the Lexis diagram. Stat Med 2007;26:3018-45. 13. Rutherford MJ, Lambert PC, Thompson JR. Age-period-cohort modeling. The Stata Journal 2010;10:606-27. 14. Kretzschmar M, Mangen MJ, van de Laar MJ, de Wit A. Model based analysis of hepatitis B vaccination strategies in the Netherlands. Vaccine 2009;27:1254-60. 15. Xiridou M, van Houdt R, Hahné S, Coutinho R, van Steenbergen J, et al. Hepatitis B vaccination of men who have sex with men in the Netherlands; should we vaccinate more men, younger men, or high-risk men? Sex Transm Infect. 2013. [Epub ahead of print.] 16. Rutgers Nisso Groep. In: Sexual Health in the Netherlands S. Vanwesenbeeck I, Bakker F, editors. 2006. Delft: Eburon; 2006:17-30. Available from http://shop.rutgerswpf.nl/webwinkel/producten/onderzoek- publicatie. Accessed: November 30, 2011. [In Dutch] 17. Jansen IA, Geskus RB, Davidovich U, Jurriaans S, Coutinho RA, et al. Ongoing HIV-1 transmission among men who have sex with men in Amsterdam: a 25-year prospective cohort study. AIDS 2011;25:493-501. 18. Stolte IG, Dukers NH, Geskus RB, Coutinho RA, de Wit JB. Homosexual men change to risky sex when perceiving less threat of HIV/AIDS since availability of highly active antiretroviral therapy: a longitudinal study. AIDS 2004;18:303-9. 19. van Damme P, Tormans G, Beutels P, van Doorslaer E. Hepatitis B prevention in Europe: a preliminary economic evaluation. Vaccine 1995;13:S54-7. 20. Ramsay M, Gay N, Balogun K, Collins M. Control of hepatitis B in the United Kingdom. Vaccine 1998;16:S52-5. 21. McMahon BJ, Alward WL, Hall DB, Heyward WL, Bender TR, et al. Acute hepatitis B virus infection: relation of age to the clinical expression of disease and subsequent development of the carrier state. J Infect Dis 1985;151:599-603.

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22. van Houdt R, Koedijk FD, Bruisten SM, op den Coul EL, Heijnen ML, et al. Hepatitis B vaccination targeted at behavioural risk groups in the Netherlands: does it work? Vaccine 2009;27:3530-5. 23. Xiridou M, Wallinga J, Dukers-Muijers N, Coutinho R. Hepatitis B vaccination and changes in sexual risk behaviour among men who have sex with men in Amsterdam. Epidemiol Infect 2009;137:504-12. 24. van Houdt R, Bruisten SM, Geskus RB, Bakker M, Wolthers KC, et al. Ongoing transmission of a single hepatitis B virus strain among men having sex with men in Amsterdam. J Viral Hepat 2010;17:108-14. 25. Houweling H, Wittevrongel CF, Verweij M, Ruitenberg EJ. Public vaccination programmes against hepatitis B in The Netherlands: assessing whether a targeted or a universal approach is appropriate. 3 Vaccine 2010;28:7723-30. 26. Zuckerman J, van Hattum J, Cafferkey M, Gjorup I, Hoel T, et al. Should hepatitis B vaccination be introduced into childhood immunisation programmes in northern Europe? Lancet Infect Dis 2007;7:410-9.

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Supplementary Data This appendix is modified from the appendix published as a supplementary information file with Xiridou et al.1

A.1. Model equations The model was developed by Kretzschmar et al.2,3 to describe the transmission of acute hepatitis B (HBV) in the Netherlands, for the whole population (heterosexuals and MSM). The submodel for the MSM population is described by the following system of partial differential equations in time t and age a X X s  s  [ (t,a)  (1 u v )  (a)  (a)   (a)   (a)  d(a)]X (t, a) t a s m e c 3 m s s H H s  s  [ (t,a)  (1 u v )  (a)]X (t,a)  [  d(a)]H (t, a) t a s m e c 3 s 1 s

Ys Ys   1H s (t, a)  [ 2  d(a)]Ys (t, a) t a Z Z s  s  [1 p(a)] Y (t, a)   C (t, a)  d(a)Z (t, a)   d(a)w N t a 2 s 3 s s z s C C s  s  p(a) Y (t, a)  [  d(a)]C (t, a)   d(a)w N t a 2 s 3 s c s V V s  s  [(a)   (a)   (a)]X (t, a)  d(a)V (t, a) t a m s s s

where the subscript s = 1, ..., 6 denotes sexual activity group. X s (t, a) denotes the density

of uninfected individuals, H s (t,a) the density of individuals with latent infection,

Ys (t,a) the density of individuals with acute HBV, Cs (t,a) the density of carriers

(chronic HBV), Z s (t,a) the density of immune individuals, and Vs (t,a) the density of vaccinated individuals, of activity group s , age a , at time t . The size of activity group s is = + + + + + and the total population size is = . The N s X s H s Ys Z s Cs Vs N ∑s N s force of infection is given by a c (a) 2 c (a')[ Y (t, a')   C (t, a')]da' s r  r 1 r 2 r a1 s (t, a)  a 2 c (a')N (t, a')da' r  r r a1

where we assume proportionate mixing by age and activity class.

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Births into the population were assumed to balance the death rate such that the population size remains constant. Death or removal from the population is assumed to occur at age 65 such that the age distribution over the population is uniform. Men are assumed to become sexually active at the age of 15. The fraction of infected individuals of age a who become carriers is given by

x2 4 the function p(a) = exp(−x1a ) , with x1 = 0.645 and x2 = 0.455. Immigration rates for the Amsterdam population were estimated from population statistics. Definitions of parameters 3 and default values are described in the following and summarized in Table 1. The model equations were solved numerically using the Escalator Boxcar Train method implemented in the package EBT tool.5

A.2. Partner change rates and model calibration

The rates of formation of new partnerships, cs (a) , for men of age a and sexual activity group s were calibrated such that the incidence of acute HBV infections in endemic steady state in the model fitted the prevaccination incidence among MSM in Amsterdam for each of the eight age categories 15–19, 20–24, ..., 45–49, and 50+, as shown in Table 2. Hereby the MSM population was subdivided into six subgroups defined by the fractions w = (0.451,0.353,0.125,0.06,0.01,0 .001) – see Tables 1 and 2. This subdivision defines the sizes of the six sexual activity groups, for example, group 1 is 45.1% of the population and group 2 is 35.3% of the population). This subdivision is arbitrary, but is chosen to reflect a skewed distribution of numbers of partners and is as defined elsewhere.6,2,3

In the years before 1998, when vaccination was introduced, HBV incidence was relatively stable at approximately 12 cases of acute HBV cases among MSM per year being reported to the Public Health Service Amsterdam. Assuming that a third of the cases are clinical and that there is 50% underreporting, it implies that the reported number of acute HBV cases should be multiplied by a factor of 6, to give the actual number of new HBV cases. This means that there were around 72 new cases of HBV in MSM per year. The total number of MSM in Amsterdam was estimated to be around 28,000. Dividing the 72 new cases by this estimate of the MSM population size, results in an incidence of around 260 new infections per 100,000. We calibrated the model by adjusting the partner change rates, such that the incidence and the age distribution of incident cases from the model in steady state would match those from the data. The resulting partner change rates are shown in Table 2. The age distribution of incident infections from the model (at the steady state without vaccination) and the age distribution of the notified acute HBV cases (in the years before the introduction of vaccination 1992–1998) are shown in Figure 1.

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A.3. Vaccination rates The vaccination rate Φ(a) represents universal vaccination and is given by the following function a+∆a Φ(a) = ∫ ud(a − P)da , a where d denotes the Dirac function, u the vaccinated fraction, and P is the age of vaccination

at puberty. The rate Φ m (a) of vaccinating children of immigrants is given by a similar function (see reference 3 for details).

The rates of risk-group vaccination, z s (a) , were calculated as follows. The size of the MSM population in Amsterdam was assumed to be 28,000. At the start of the vaccination campaign, 81% of them are susceptible for HBV and, hence, eligible for vaccination. Therefore, the number of men eligible for vaccination is given by the product of the total number of MSM and the fraction found susceptible, divided by the number of years the vaccination programme is ongoing: 28000*0.81/12=2062. During the 12 years of the vaccination campaign (1998 – 2009),

8500 men received at least one dose of HBV vaccine. The annual vaccination rates z i per age category i were estimated as

where ni is the number of vaccinations of antiHBc negative persons in age category i during the course of the vaccination campaign (see Table 4). For the default scenario, it was assumed that

this vaccination rate is the same for all activity groups, meaning z i = z s (a) , for all ages in age category i = 1,..., 12 (see Table 3) and all activity groups s =1,..., 6. The effective immunization

rate is then given as the product of vaccination rate and vaccine efficacy va (Table 4).

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References

1. Xiridou M, van Houdt R, Hahné S, Coutinho R, van Steenbergen J, et al. Hepatitis B vaccination of men who have sex with men in the Netherlands: should we vaccinate more men, younger men, or high-risk men? Sex Transm Infect. 2013 [Epub ahead of print]. 2. Kretzschmar M, de Wit G, Smits L, van de Laar M. Vaccination against hepatitis B in low endemic countries, Epidemiol. Infect. 2002;128:229–44. 3. Kretzschmar M, Mangen M, van de Laar M, de Wit A. Model based analysis of hepatitis B vaccination 3 strategies in the Netherlands, Vaccine 2009;27:1254–60. 4. Edmunds W, Medley G, Nokes D, Hall A, Whittle H. The influence of age on the development of the hepatitis B carrier state, Proc. R. Soc. Lond. B 1993;253:197–201. 5. De Roos A. A gentle introduction to models of physiologically structured populations, in S. Tuljapurkar and 6. H. Caswell. (eds), ‘Structured-population models in marine, terrestrial, and freshwater systems’, Chapmam and Hall, New York, pp. 119–204,1997. 7. Williams JR, Nokes DJ, Medley GF, Anderson RM. The transmission dynamics of hepatitis B in the UK: a mathematical model for evaluating costs and effectiveness of immunization programmes, Epidemiol. Infect. 1996;116:71–89. 8. Boot H, Schouls L, Hahné S, Berbers G, van de Laar M, Kimman T. Vaccination against preumococci and hepatitis B in the Dutch National Immunization Programme, Ned. Tijdschr. Geneesk. 2007,151:172–6. [In Dutch]

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Table 1. Model parameters and baseline values.

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Table 2. Rates of formation of sexual partnerships after model calibration. Sexual activity group 1 2 3 4 5 6 Average 0.451 0.353 0.125 0.060 0.010 0.001 Proportion in class, ws Age range Partner change rates cs (a) 15-19 0.06 0.28 0.64 1.13 1.98 3.22 0.29 3 20-24 0.07 0.63 2.19 5.32 12.62 26.95 1.00 25-29 0.17 1.28 3.89 8.53 18.33 35.81 1.75 30-34 0.27 2.20 6.79 15.13 33.00 65.36 3.05 35-39 0.18 1.61 5.34 12.59 28.96 60.17 2.42 40-44 0.12 1.26 4.59 11.59 28.51 62.90 2.12 45-49 0.15 0.73 1.68 3.00 5.30 8.70 0.78 50+ 0.06 0.36 1.00 2.03 4.05 7.43 0.45

Table 3. Age-dependent annual vaccination rates among MSM in Amsterdam, 1998-2009.

Group Age Number with Distribution Annual vaccination rate, Annual vaccination rate, range first vaccination, z i z i all years* Not targeted Targeted to core 1 < 15 0 0.00 0.00000 0.00000 2 15-19 277 0.08 0.01126 0.05882 3 20-24 1,230 0.17 0.05099 0.29255 4 25-29 1,695 0.16 0.07097 0.43006 5 30-34 1,626 0.15 0.06798 0.40842 6 35-39 1,437 0.14 0.05983 0.35144 7 40-44 1,057 0.06 0.04366 0.24586 8 45-49 528 0.06 0.02157 0.11528 9 50-54 327 0.04 0.01330 0.06981 10 55-59 187 0.04 0.00759 0.03932 11 60-64 105 0.03 0.00425 0.02189 12 65-69 31 0.03 0.00125 0.00641 13 70+ 0 0.05 0.00000 0.00000 Total 8500 1.00 * Data from the HBV Vaccination Campaign 1998-2009. In the untargeted scenario, 2062 men per age class were eligible for vaccination; in the targeted scenario 404 men per age class were eligible for vaccination. It was assumed that 19% of MSM were antiHBc+ and hence not eligible for vaccination.

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Immunogenicity of a hexavalent vaccine co-administered with 7-valent pneumococcal conjugate vaccine. Findings from the National Immunisation Programme in the Netherlands

Figure 1. Age distribution of new HBV infections from the model and from data, before the introduction of vaccination. Green columns: the age distribution of reported acute HBV infections among men who have sex with men in Amsterdam in the years 1992–1998, from notification data. Blue columns: the age distribution of new infections as calculated from the model, at the steady state without vaccination; for these results, the parameters shown in Table 1 and partner change rates in Table 2 were used.

Jane Whelan Susan Hahné Guy Berbers Fiona van der Klis Yvonne Wijnands Hein Boot

Hum Vaccin Immunother 2012;8:743-8.

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Immunogenicity of a hexavalent vaccine co-administered with 7-valent pneumococcal conjugate vaccine. Findings from the National Immunisation Programme in the Netherlands 4

Jane Whelan Susan Hahné Guy Berbers Fiona van der Klis Yvonne Wijnands Hein Boot

Hum Vaccin Immunother 2012;8:743-8.

26660 Whelan kopie.indd 55 02-11-13 16:03 CHAPTER 4 IMMUNOGENICITY OF A HEXAVALENT VACCINE

Abstract

The hexavalent vaccine Infanrix hexa™ was introduced into the national childhood vaccination schedule in the Netherlands in 2006. It is offered, concomitantly with pneumococcal vaccine (Prevenar™), to children at increased risk of hepatitis B, administered in a 4-dose schedule at 2, 3, 4 and 11 months of age. We assessed the immunogenicity of the HBV component of Infanrix hexa™ co-administered with Prevenar™, and compared pertussis and Hib components in Infanrix hexa™ with the standard Infanrix-IPV+Hib vaccine. Target thresholds for immune responses were achieved for all antigens studied. Over 99% (163/164) of children vaccinated with Infanrix hexa™ achieved an adequate immune response (≥10 mIU/ml) to the HBV component and peak anti-HBs geometric mean concentration (GMC) was 2264mIU/ml (95% CI:1850-2771mIU/ml). The GMC of a pertussis component, filamentous hemagglutinin (FHA), of Infanrix-hexa was significantly lower in children vaccinated with Infanrix hexa™ and Prevenar™ than in children vaccinated with Infanrix-IPV+Hib. Universal infant HBV vaccination using Infanrix hexa™ was introduced in the Netherlands in 2011. Despite very high rates of seroconversion for the HBV component of Infanrix hexa™, its long term immunogenicity and effectiveness should be monitored after concomitant vaccination.

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Introduction

Combination vaccines are used in national immunisation programmes for children worldwide. Simultaneous administration with newer vaccines against meningococcal or pneumococcal infection is thought to be more convenient, cost-effective and efficient for health care workers, and more acceptable to parents.1,2 However, the composition of combination vaccines has become increasingly complex and concerns have been expressed that co-administration of multicomponent and mono/multivalent vaccines may lead to a suboptimal induced immune response.3 Reduced clinical efficacy was shown in the UK with the Haemophilus influenzae type 4 b (Hib) component when given in a combined, acellular pertussis containing vaccine (DTaP- Hib)4 and detailed assessment of potential antigenic interaction is advocated as new vaccines are introduced into national immunisation programmes.3,4

The hexavalent vaccine, Infanrix hexa™ (GSK), was introduced into the national childhood vaccination schedule in the Netherlands on 1 June 2006 for children born to hepatitis B infected mothers and children of whom either parent was born in middle- or high- endemic countries for hepatitis B (prevalence ≥2%). This corresponds to approximately 18% of the total birth cohort in the Netherlands. Infanrix hexa™ contains recombinant surface antigen of the hepatitis B virus (HBV) in addition to vaccine components against diphtheria (D), tetanus (T), pertussis (Pa), poliomyelitis (IPV) and Haemophilus influenzae type b (Hib).5 It is administered by a single injection given at the same time as the pneumococcal vaccine, Prevenar™ (Pfizer Pharmaceuticals), added to the schedule in 2006. This limits the number of injections to two at 2, 3, 4 and 11 months of age, respectively. For children who are not in the target group for HBV vaccination, the pentavalent Infanrix-IPV+Hib (DTPa IPV/Hib), was given in 2005−2006. An alternative vaccine, Pediacel Prevenar™, (Sanofi Pasteur, MSD) was used in 2007, while Infanrix−IPV+Hib was reintroduced from 2008 onwards and is given concomitantly with Prevenar™. Universal infant HBV vaccination using Infanrix hexa™ will be introduced in September 2011.

Hexavalent vaccines were first licensed by the European Medicines Agency (EMEA) in 2000. In September 2005, authorization of one such vaccine, Hexavac (Sanofi Pasteur, MSD), was suspended by the EMEA: this was due to concerns about long-term immunogenicity of the hepatitis B component when co-administered with meningococcal or pneumococcal vaccines, and reduced boostability post-priming with Hexavac in infants with a low initial immune response.6 The WHO target threshold of ≥ 95% of vaccine recipients achieving a peak geometric mean concentration ≥ 10 IU/l has consistently been achieved in other research.7−9 However, reductions (albeit non-significant) have been observed in the seroconversion rate8 and geometric mean concentration (GMC)8,9 of HBV antibodies following vaccination with Infanrix

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hexa™ concomitantly with pneumococcal vaccine when compared to that of Infanrix hexa™ administered alone. Reduced Hib immunogenicity has similarly been reported in combination vaccines co-administered with meningococcal and pneumococcal vaccines conjugated to the 10,11 12,13 CRM197 carrier protein. Long term immunogenicity of the HBV component and of all components (with the exception of PT)14 of Infanrix hexa™ administered alone have been shown. This is irrespective of peak GMCs post primary vaccination, because they were not determined in these studies. The effectiveness of Prevenar™ and the Hib component of Infanrix hexa™ have also been demonstrated.15,16 There is as yet however, no evidence /data regarding the long term immunogenicity or effectiveness of Infanrix hexa™ co-administered with Prevenar™.

In the context of the National Immunisation Programme (NIP) in the Netherlands, we assessed whether the immune response to HBV vaccination within the Dutch NIP was sufficient according to WHO standards. Our secondary objective was to compare the immunogenicity of the Hib and pertussis components between Infanrix hexa™ co-administered with Prevenar™ with that of the standard vaccine, Infanrix−IPV+Hib administered alone.

Materials & Methods

Study design A sample of children vaccinated at 2, 3, 4 and 11 months of age who attended healthy baby clinics in 10 municipalities and who had an indication for hepatitis B vaccination, was invited to participate in the study. Children with chronic disease or Down’s syndrome, and children of HBsAg positive mothers were excluded. This group, Group 1, were children born after 1 June 2006 and were vaccinated with Infanrix hexa™ co-administered with Prevenar™. For children in group 1, information about the ethnicity of parents and their children, gestational age, birth weight, and gender was also recorded.

To meet the second objective, a second group of children not considered at risk of HBV, Group 2, born from 1 November 2004 through 31 March 2005 and vaccinated with Infanrix−IPV+Hib, were recruited. Parents with children aged 11 months in group 1 were invited in person to participate at the healthy baby clinic and those in group 2 received an information letter at home. Both groups were asked to return to the clinic 4 to 6 weeks after booster vaccination. Written informed consent was obtained from the parents and a blood sample was taken from the child. The study protocol was approved by the Medical Ethics Review Committee (METC) of UMC Utrecht (group 1) and by the Central Committee on Research in Human Subjects (CCMO) in the Hague (group 2).

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Laboratory methods Venous samples were collected from infants 4 to 6 weeks post-vaccination after the 4th vaccine dose. Serological testing was performed at the Dutch National Institute for Public Health and the Environment (RIVM). Hib, pertussis and pneumococcal specific antibodies were measured using an ELISA with a twofold dilution series of samples. On each plate an in-house reference serum and a control serum were included. The in-house reference sera were calibrated to international reference sera17,18 as follows: Hib IgG antibody concentrations (ug/ml) with reference serum of CBER, FDA (Lot 1983);19 pertussis IgG antibody concentrations in ELISA Units/ml (EU/ml) against pertussis antigens Ptx and FHA with lot 3 and PRN with lot 4 FDA;17,18 and pneumococcal IgG 4 antibody concentrations (μg/ml) with 89S-reference serum.11,20 Hepatitis B markers included anti- HBs and HBsAg. Anti-HBs was determined using MIA (Axsym, Abbott). HBsAg was determined only in children with an anti-HBs titer of <1000 IU/ml. The proportion of respondents achieving seroprotection was estimated according to the relative frequency of vaccinees achieving antibody concentrations above the pathogen specific cut-off levels: 0.15 μg/ml for Hib-PRP,21,22 and 0.35 μg/ml for pneumococcus.11 There are no internationally accepted standards for pertussis. Field studies have shown however, that antibodies directed against virulence factors pertactin (prn), fimbriae 2/3 (Fim), and pertussis toxin (ptx) are protective.23,24 For filamentous hemagglutinin (FHA), this is more complex.25 We used the arbitrary industry standard of 25 EU/ml.

Power calculation We determined the sample size by considering only the primary objective regarding HBV immunogenicity in group 1. The WHO standard for an adequate immune response requires ≥95% of the vaccinees to achieve an anti-HBs titre ≥ 10 IU/ml. We expected 98% of vaccines to achieve this. At a precision of 2.5%, with a confidence level of 95%, 120 children were required in group 1. Based on the response of 32% in a recent cross-sectional population-based Dutch national sero-survey,26 it was estimated that a minimum of 480 children should be invited in group 1.

Statistical analysis Data were entered and analysed using Microsoft Access and STATA 11. The proportion of respondents achieving seroprotection with its confidence limits was calculated using exact methods.27 The geometric mean concentration (GMC) was calculated using the antilog of the mean of the logarithmically transformed antibody concentrations. Given the non-normal distribution of the outcome variables, categorical associations were tested using the Kruskal- Wallis (KW) test. Based on Tukey’s ladder of powers,28 the square-root transformed outcome variable was used to conduct linear regression to determine how much of the variance in anti-

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26660 Whelan kopie.indd 59 02-11-13 16:03 CHAPTER 4 IMMUNOGENICITY OF A HEXAVALENT VACCINE EU/ml: d

[95%CI] [7.0-13.9] [118.7-151.4] [367.1-485.0] [343.7-489.2] N/A

Not applicable. g Group 2 (n=92) Infanrix IPV/Hib

9,8 134,1 410,1 GMC 422,0

[95%CI] [3.3-4.2] [3.4-4.8] [3.2-4.2] [2.3-3.0] [3.0-3.8] [5.9-9.0] [4.4-6.0] [9.6-12.8] [331.1-436.8] [130.3-168.2] [274.5-332.7] [1849.7-2771.3] Geometric Mean Concentrations Group 1 (n=164) Exact confidence intervals for a proportion; c

3,7 7,3 3,7 3,4 2,7 5,2 4,0 11,1 Infanrix hexa+ Prevenar 148,1 380,3 302,2 GMC 2264,1 IU/ml: International units per milliliter; f

[95%CI] [96.7-100] [96.7-100] [96.7-100] g [93.9-99.9]

N/A ) b

Group 2 (n=92) Infanrix IPV/Hib % (n) 98.9 (88 100.0 (92) 100.0 (92) 100.0 (92)

a ] c

[95%CI [95.9-99.9] [95.9-99.9] [95.9-99.9] [96.8-99.9] [96.8-99.9] [96.8-99.9] [95.0-99.6] [95.0-99.6] [95.0-99.6] [95.0-99.6] [97.9-100.0] [97.9-100.0] % Achieving seroprotection

Group 1 (n=164) % (n) 98.2(160) 98.2 (161) 99.4 (163) 99.4 (163) 98.8 (161) 98.8 (161) 99.4 (162) 98.7 (162) 98.2 (160) 98.2 (160) 100.0 (163) 100.0 (164) Infanrix hexa+ Prevenar f d

Target >25EU/ml >25EU/ml >25EU/ml ≥0.15μg/ml all subtypes ≥10 mIU/ml concentration ≥0.35μg/ml for e Difference between the geometric mean titres is statistically significant, p<0.001; e

4 14 9v 6b PT 19f 23f 18c PRN FHA Due to insufficient samples, results for Anti-PRP were available only n= 89 samples only; b Anti-PRP Anti HBS Immunogen =163; total Vaccine Component Prevenar, N Haemophilus Influenza B

Pneumococcus serotypes Pertussis Hepatitis B a Table 1. Proportion of samples achieving seroprotection (%), and peak antibody GMC levels Infanrix hexa™+ Prevenar™ (Group 1) Infanrix−IPV+Hib 2) vaccines. ELISA unit per milliliter;

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HBs could be explained by predictor variables. To detect significant differences between the GMCs of groups 1 and 2, Student’s t-test was conducted (independent groups, two-tailed).

Results

In total, 478 children were eligible to participate in group 1 and 1181 in group 2. The proportion of respondents was 34% (n=164) and 8% (n=92) respectively. In group 1, 100% of children were born in the Netherlands, with only 26% of fathers and 23% of mothers themselves born in the Netherlands. Parents were of mixed ethnicities and the most commonly reported were: Turkish 4 (15%), Moroccan (12%), Antillian (4%) and Surinamese (3%).The mean gestational age in group 1 was 39 weeks (range 33−42 weeks) and the mean birth weight was 3275g (range:1870g−4760g); 49% (n=72/146) were male.

At the time of booster vaccination, children were a median age of 11.1 months in group 1 (range: 9.6 to 13.4) and 11.7 months in group 2 (range: 10.1 to 13.5), p<0.001. The median time between last vaccination and blood sampling was 5.3 weeks in group 1 (range: 1.6 to 19.8) and 4.0 weeks in group 2 (range: 3.3 to 9.3 weeks), p<0.001. Proportions achieving seroprotection and geometric mean concentrations (GMCs) are presented in the table.

Of children in group 1, 99.4% (163/164) achieved an adequate immune response (≥10 mIU/ml) to the HBV component of Infanrix hexa™. The geometric mean concentration was 2264 mIU/ ml (95% CI: 1850−2771 mIU/ml). Male infants had a lower anti-HBs concentration (1830 mIU/ ml, 95% CI: 1357−2469 mIU/ml) than females (2898mIU/ml, 95% CI: 2110−3980 mIU/ml, t=(-2.1), p=0.03). This difference persisted after controlling for ethnicity of parents (dichotomised as one-Dutch versus no-Dutch parent), birth weight and gestational age and explained 5% of the variance in anti-HBs (adjusted r-squared=0.05, p=0.002).

For both groups 1 and 2, no statistically significant differences in the proportions achieving seroprotection were seen between Infanrix hexa™ and Infanrix−IPV+Hib for Hib or pertussis. An adequate immune response was consistently achieved in over 98% of samples to all antigens tested. Five different children did not reach the seroprotective level in one component only, but each child responded satisfactorily to all the other components in the vaccines. In relation to Prevenar™, seven children did not achieve the seroprotective threshold of one or more components. In 2 cases, children did not respond to several subtypes (case 1 to subtypes 4, 9,18c and 23f, and case 2 to subtypes 4 6b 9v 18c and 23f); five children showed an inadequate response to one component only (subtypes 6b (n=2), 14, 18c and 23f (n=1 for each). The proportion achieving pneumococcal antibody concentrations of ≥0.35 μg/ml ranged from 98.2% (subtypes 6B, 18C and

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23F) to 100.0% (subtype 19F). The pneumococcal antibody GMCs ranged from 2.6μg/ml (subtype 18C) to 11.0μg/ml (subtype 14) (Table).

When comparing GMCs between groups 1 and 2, the titers against the pertussis FHA component of Infanrix hexa™ was significantly lower than in Infanrix−IPV+Hib (302EU/ml versus 422EU/ ml; mean difference, 120EU/ml; p=0.001) There were no other statistically significant differences between antibody GMCs of other analysed vaccine components (Figure).

Figure 1. GMC ratio of group 1 to group 2 for vaccine components Hib, PT, FHA and PRN.

Discussion

The HBV component of Infanrix hexa™ co-administered with Prevenar™ adhered to the WHO guideline for an adequate immune response (≥95%),29 achieving seropositivity in >99% of cases. We found an anti-HBs GMC of 2264mIU/ml (95% CI:1850−2771), higher in girls than in boys. The anti-HBs GMC reported here is lower than has been reported elsewhere one month post-booster dose (given at 12−15 months) after the same primary vaccination schedule and using the same standard immune assays.8,9 Anti-HBs levels 2.6 to 3.4 times higher than those observed here are also reported where Infanrix hexa™ was administered alone (5754 mIU/ml8, 6539 mIU/ml9 and 7517 mIU/ml30 respectively, though in the latter study, the vaccination schedule differed: 2, 4, 6 months with a booster at 12−19 months). Peak GMCs achieved post-vaccination are thought to be important because they are associated with the duration that concentrations remain above accepted protective thresholds. Although these studies are not directly comparable, such differ- ences might be explained by the fact that children were boosted at 11 months here rather than at 12−19 months in the studies referenced. Second, there was a slightly longer period between the last vaccination and serum collection here (5.3 weeks), versus 4 weeks in Tichmann-Schumann et al.8 Third, children in our study who received HBV vaccination (group 1) all had parents of mixed

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ethnicities whereas the reference studies8,9 included samples of the general population. Ethnic differences have been implicated in reduced serological response in other research.31 Fourth, it is possible that the maternal anti-HBs concentrations at the time of immunisation and sampling influenced infant anti-HBs, though the effect of this on the immune response to the vaccination series is uncertain. We could not study the effect of maternal antibody concentration. Finally, gender-linked differences in vaccine immune response are not uncommon:32 females have been reported to develop a more robust immune response to rubella and mumps vaccines for exam- ple.33,34 Although there are still uncertainties about the duration of long-term protection after vaccination against hepatitis B,35,36 it is clear that immunological memory with anamnestic re- 4 sponse continues to protect children for many years against acute disease despite undetectable antibodies.13,37,38 Infanrix hexa™ was introduced into the universal childhood vaccine schedule in the Netherlands in September 2011 and protection against Hepatitis B will therefore be neces- sary for decades.39

In relation to the antibody response to Prevanar when co-administered with Infanrix hexa™, seroprotecive thresholds for all seven serotypes included in the vaccine were achieved. GMCs for all components of Prevenar™ were similar to those reported in previous studies.8,9 On comparing Infanrix hexa™ (co-administered with Prevenar™) and Infanrix− IPV+Hib (administered alone), there was no difference in the proportions seroprotected for Hib and pertussis. These findings are broadly similar to those in other research.8,9,40 Co- administration of Infanrix hexa™ with Prevenar™ did not affect GMCs for Hib, PRN or PT – but the FHA component in Infanrix hexa™ was significantly lower. Though speculative, it is hypothesized that FHA could play a role in modulating the protective immune response in combination vaccine formulations.41

There were a number of study limitations. We studied a non-randomized sample of two groups of healthy infants recruited in 2006 and 2009. Different clinics participated in 2009 (group 1) and in 2006 (group 2) but regional variation in the delivery of the vaccination programme over time, including vaccine storage and administration is unlikely. National immunisation coverage in the Netherlands has consistently exceeded 94% for DTPa−IPV/Hib in the general population since 2006. In 2009, uptake of Infanrix hexa™ in the risk group was 92.9%.42 The time of the 4th vaccination and sampling of children was statistically different between the groups (persisting when outliers were excluded i.e. those beyond +/- 2* standard deviations of the mean). In absolute terms the difference was small and both vaccination and sampling were timely. Finally, the proportion of respondents from each clinic varied significantly by study group. This is probably explained by greater staff vigilance and a higher intensity of recruitment in the minority group who were administered a new vaccine. Other differences such as socioeconomic

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background were not recorded, although, given that only healthy babies were included, it is unlikely that there were systematic differences between respondents and non-respondents that would influence the immunogenicity of the vaccines.

In conclusion, more than 99% of Infanrix hexa™ recipients vaccinated at 2, 3, 4 and 11 months of age and measured one month after booster vaccination, achieved an adequate immune response to the HBV component. For all components of both vaccines, standard seroprotective thresholds were achieved. The GMC for the anti-HBs component of Infanrix hexa™ co-administered with Prevenar™ reported here was robust, though it was lower than has been reported elsewhere. When compared to Infanrix−IPV+Hib vaccine, a significant reduction in peak GMC was observed for the FHA component of Infanrix-hexa. Antibodies to other components (Hib, PRN, PT) were similar. Despite very high rates of seroconversion, there is a lack of long term immunogenicity and effectiveness data for Infanrix hexa™ simultaneously administered with Prevenar™. Long term monitoring of children by immuno- and disease surveillance is indicated.

Acknowledgements

We would like to thank the following people for their contribution to this study: Francoise van Heijningen, Surita Vesseur-Ramlagan and Nynke Jones, who assisted in recruitment of participants and data entry; Pieter van Gageldonk and Irina Tcherniaeva who prepared, analysed and reported on the laboratory samples; Ioannis Karagiannis who kindly reviewed the manuscript on behalf of EPIET.

References

1. Dodd D. Benefits of combination vaccines: effective vaccination on a simplified schedule. Am J Manag Care 2003;9:S6-12. 2. Kalies H, Grote V, Verstraeten T, Hessel L, Schmitt HJ, et al. The use of combination vaccines has improved timeliness of vaccination in children. Pediatr Infect Dis J 2006;25:507-12. 3. Boot HJ, Schipper CM. Simultaneous vaccination with Prevenar and multicomponent vaccines for children: interference or no interference? Hum Vaccin 2009;5:15-7. 4. McVernon J, Andrews N, Slack MP, Ramsay ME. Risk of vaccine failure after Haemophilus influenzae type b (Hib) combination vaccines with acellular pertussis. Lancet 2003;361:1521-3. 5. GlaxoSmithKline Biologicals S.A. Annex 1. Summary of Product characteristics: Infanrix Hexa. Last updated: 14/09/2011. Available at: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_ Product_Information/human/000296/WC500032505.pdf 6. European Medicines Agency. Scientific conclusions and grounds for the suspension of the marketing authorisation of hexavac presented by the EMEA, 2005. 7. Zepp F, Schmitt HJ, Cleerbout J, Verstraeten T, Schuerman L, et al. Review of 8 years of experience with Infanrix hexa (DTPa-HBA-IPV/Hib hexavalent vaccine). Expert Reviews Vaccines 2009;8:663-78. 8. Tichmann-Schumann I, Soemantri P, Behre U, Disselhoff J, Mahler H, et al. Immunogenicity and

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reactogenicity of four doses of diphtheria-tetanus-three-component acellular pertussis-hepatitis B-inactivated polio virus-Haemophilus influenzae type b vaccine coadministered with 7-valent pneumococcal conjugate Vaccine. Pediatr Infect Dis J 2005;24:70-7. 9. Knuf M, Habermehl P, Cimino C, Petersen G, Schmitt HJ. Immunogenicity, reactogenicity and safety of a 7-valent pneumococcal conjugate vaccine (PCV7) concurrently administered with a DTPa-HBV-IPV/Hib combination vaccine in healthy infants. Vaccine 2006;24:4727-36. 10. Kitchin NR, Southern J, Morris R, Hemme F, Thomas S, et al. Evaluation of a diphtheria-tetanus- acellular pertussis-inactivated poliovirus-Haemophilus influenzae type b vaccine given concurrently with meningococcal group C conjugate vaccine at 2, 3 and 4 months of age. Arch Dis Child 2007;92:11-6. 11. Goldblatt D, Southern J, Ashton L, Richmond P, Burbidge P, et al. Immunogenicity and boosting after a reduced number of doses of a pneumococcal conjugate vaccine in infants and toddlers. Pediatr Infect Dis J 2006;25:312-9. 12. Steiner M, Ramakrishnan G, Gartner B, Van Der Meeren O, Jacquet JM, et al. Lasting immune memory 4 against hepatitis B in children after primary immunization with 4 doses of DTPa-HBV-IPV/Hib in the first and 2nd year of life. BMC Infect Dis 2010;10:9. 13. Zanetti AR, Romano L, Giambi C, Pavan A, Carnelli V, et al. Hepatitis B immune memory in children primed with hexavalent vaccines and given monovalent booster vaccines: an open-label, randomised, controlled, multicentre study. Lancet Infect Dis 2010;10:755-61. 14. Zinke M, Disselhoff J, Gartner B, Jacquet JM. Immunological persistence in 4-6 and 7-9 year olds previously vaccinated in infancy with hexavalent DTPa-HBV-IPV/Hib. Hum Vaccin 2010;6:189-93. 15. Kalies H, Grote V, Siedler A, Grondahl B, Schmitt HJ, et al. Effectiveness of hexavalent vaccines against invasive Haemophilus influenzae type b disease: Germany’s experience after 5 years of licensure. Vaccine 2008;26:2545-52. 16. Rodenburg GD, de Greeff SC, Jansen AG, de Melker HE, Schouls LM, et al. Effects of pneumococcal conjugate vaccine 2 years after its introduction, the Netherlands. Emerg Infect Dis;16:816-23. 17. Meade BD, Deforest A, Edwards KM, Romani TA, Lynn F, et al. Description and evaluation of serologic assays used in a multicenter trial of acellular pertussis vaccines. Pediatrics 1995;96:570-5. 18. van Gageldonk PG, van Schaijk FG, van der Klis FR, Berbers GA. Development and validation of a multiplex immunoassay for the simultaneous determination of serum antibodies to Bordetella pertussis, diphtheria and tetanus. J Immunol Methods 2008;335:79-89. 19. Phipps DC, West J, Eby R, Koster M, Madore DV, et al. An ELISA employing a Haemophilus influenzae type b oligosaccharide-human serum albumin conjugate correlates with the radioantigen binding assay. J Immunol Methods 1990;135:121-8. 20. Concepcion NF, Frasch CE. Pneumococcal type 22f polysaccharide absorption improves the specificity of a pneumococcal-polysaccharide enzyme-linked immunosorbent assay. Clin Diagn Lab Immunol 2001;8:266- 72. 21. Anderson P. The protective level of serum antibodies to the capsular polysaccharide of Haemophilus influenzae type b. J Infect Dis 1984;149:1034-5. 22. Kayhty H, Peltola H, Karanko V, Makela PH. The protective level of serum antibodies to the capsular polysaccharide of Haemophilus influenzae type b. J Infect Dis 1983;147:1100. 23. Cherry JD, Gornbein J, Heininger U, Stehr K. A search for serologic correlates of immunity to Bordetella pertussis cough illnesses. Vaccine 1998;16:1901-6. 24. Storsaeter J, Hallander HO, Gustafsson L, Olin P. Levels of anti-pertussis antibodies related to protection after household exposure to Bordetella pertussis. Vaccine 1998;16:1907-16. 25. Hewlett EL, Halperin SA. Serological correlates of immunity to Bordetella pertussis. Vaccine 1998;16:1899- 900. 26. van der Klis FR, Mollema L, Berbers GA, de Melker HE, Coutinho RA. Second national serum bank for population-based seroprevalence studies in the Netherlands. Neth J Med 2009;67:301-8. 27. Clopper C, Pearson S. The use of confidence or fiducial limits illustrated in the case of the Binomial. Biometrika 1934;26:404-13.

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28. Tukey J. Exploratory Data Analysis: Addison-Wesley, 1977 29. World Health Organisation. Hepatitis B vaccines. WHO position paper. Wkly Epidemiol Rec 2009;40:405–20. 30. Tichmann I, Grunert D, Habash S, Preidel H, Schult R, et al. Persistence of antibodies in children primed with two different hexavalent diphtheria, tetanus, acellular pertussis, hepatitis B, inactivated poliovirus and Haemophilus influenzae type B vaccines and evaluation of booster vaccination. Hum Vaccin 2006;2:249-54. 31. Hsu LC, Lin SR, Hsu HM, Chao WH, Hsieh JT, et al. Ethnic differences in immune responses to hepatitis B vaccine. Am J Epidemiol 1996;143:718-24. Declining incidence of hepatitis A 32. Klein SL, Jedlicka A, Pekosz A. The Xs and Y of immune responses to viral vaccines. Lancet Infect Dis 2010;10:338-49. 33. Dominguez A, Plans P, Costa J, Torner N, Cardenosa N, et al. Seroprevalence of measles, rubella, and in Amsterdam (The Netherlands), 1996-2011: mumps antibodies in Catalonia, Spain: results of a cross-sectional study. Eur J Clin Microbiol Infect Dis 2006;25:310-7. 34. Ovsyannikova IG, Jacobson RM, Dhiman N, Vierkant RA, Pankratz VS, et al. Human leukocyte antigen and Second generation migrants still an cytokine receptor gene polymorphisms associated with heterogeneous immune responses to mumps viral vaccine. Pediatrics 2008;121:e1091-9. important risk group for virus importation 35. Hammitt LL, Hennessy TW, Fiore AE, Zanis C, Hummel KB, et al. Hepatitis B immunity in children vaccinated with recombinant hepatitis B vaccine beginning at birth: a follow-up study at 15 years. Vaccine 2007;25:6958-64. 36. Bialek SR, Bower WA, Novak R, Helgenberger L, Auerbach SB, et al. Persistence of protection against hepatitis B virus infection among adolescents vaccinated with recombinant hepatitis B vaccine beginning at birth: a 15-year follow-up study. Pediatr Infect Dis J 2008;27:881-5. 37. Zanetti AR, Mariano A, Romano L, D’Amelio R, Chironna M, et al. Long-term immunogenicity of hepatitis B vaccination and policy for booster: an Italian multicentre study. Lancet 2005;366:1379-84. 38. Alfaleh F, Alshehri S, Alansari S, Aljeffri M, Almazrou Y, et al. Long-term protection of hepatitis B vaccine 18 years after vaccination. J Infect 2008;57:404-9. 39. Health council of the Netherlands (Gezondheidsraad). General vaccination against Hepatitis B revisited; 2007 40. Scheifele DW, Halperin SA, Smith B, Ochnio J, Meloff K, et al. Assessment of the compatibility of co- administered 7-valent pneumococcal conjugate, DTaP.IPV/PRP-T Hib and hepatitis B vaccines in infants 2-7 months of age. Vaccine 2006;24:2057-64. 41. McGuirk P, Johnson PA, Ryan EJ, Mills KH. Filamentous hemagglutinin and pertussis toxin from Bordetella pertussis modulate immune responses to unrelated antigens. J Infect Dis 2000;182:1286-9. 42. van der Avoort H, Berbers G, van Binnendijk R, Boot H, Feltkamp M, et al. The National Immunisation Programme in the Netherlands. 2010. Available at: http://www.rivm.nl/bibliotheek/rapporten/210021012.pdf

Jane Whelan Gerard Sonder Anneke van den Hoek

Vaccine 2013;31:1806-11

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Declining incidence of hepatitis A in Amsterdam (The Netherlands), 1996-2011: Second generation migrants still an

important risk group for virus importation 5

Jane Whelan Gerard Sonder Anneke van den Hoek

Vaccine 2013;31:1806-11

26660 Whelan kopie.indd 67 02-11-13 16:03 CHAPTER 5 INCIDENCE OF HEPATITIS A

Abstract

Background The Netherlands is a very low endemic country for hepatitis A virus infections (HAV, notification rate of <1/100,000). Historically in Amsterdam, a large proportion of infections are imported from Turkey and Morocco in children returning from summer holiday. Annually since 1998, the public health service of Amsterdam has targeted these children for HAV vaccination before the summer. As the population of non-western immigrants and their descendants increases, we describe recent trends in HAV in ethnic groups in Amsterdam (1996–2011), identifying current risk groups and recommending targeted prevention through vaccination.

Methods We studied all cases of non-homosexually acquired HAV infection notified in the Amsterdam region (1996–2011, n=819) by ethnic group and generation (first/second generation migrants: FGM and SGM respectively). Incidence rates were estimated as the average number of cases per 100,000/ year. Using Poisson regression, we calculated incidence rate ratios (IRR) by ethnic group and generation adjusted for age and calendar year, and modeled seasonal variation using a smoothed time series.

Results Incidence of HAV in Amsterdam dropped from 24.8/100,000 population in 1996 (178 cases) to 1.0/100,000 in 2011 (8 cases). Since 2005, 56% of cases are imported, the majority (62%) in second generation migrant (SGM) children of Moroccan, or other non-western ethnic backgrounds. The adjusted IRR in SGM relative to the ethnic Dutch population was 3.7 (95% CI: 2.3–6.1) in Moroccan SGM, 4.3 (95% CI: 2.6–7.2) in SGM of other non-western backgrounds and 1.9 (95% CI: 0.8–4.1) in Turkish SGM.

Conclusion Though incidence of HAV in Amsterdam has declined substantially since 1996, it is still higher in SGM children of Moroccan & other non-western ethnic backgrounds. In line with WHO recommendations of June 2012, introduction of single dose HAV vaccination, targeted at SGM children from HAV endemic countries, could be considered within the routine childhood vaccination schedule.

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Background

Hepatitis A virus (HAV) is transmitted via the fecal-oral route and infection causes acute inflammation of the liver. In developing countries where sanitary conditions are suboptimal, the infection is highly endemic and transmission is via contaminated food, water or the hands. Most infections occur in childhood, are asymptomatic, and ≥90% of the population have immunity by age 10.1 In industrialised, predominantly Western countries which are of low endemicity, spread is typically limited to high risk groups such as travelers to HAV endemic countries, contacts of hepatitis A patients and men who have sex with men (MSM). The case fatality is highest in older age groups (2.1% in those ≥40 years old2).

The Netherlands is a very low endemic country1 with a national HAV notification rate of 5 <1/100,000 in 20093 and a population prevalence of antibodies to HAV of 39% in 2006–2007.4 Seroprevalence has increased since the mid-1990s due to a burgeoning immigrant population and vaccination campaigns targeting travelers to high-endemic countries, in place since the early 1980s.4,5 Symptomatic HAV infection is notifiable and on receipt of a notification, the Public Health Service routinely traces and vaccinates all contacts.

For many years, after the summer vacation period, a surge in HAV notifications is received in September–October.5 The majority occur in second generation migrant (SGM) children <16, who are born in the Netherlands, but who contract the infection while on summer holiday in the country of birth of their parents (predominantly Turkey or Morocco). These notifications represent a small proportion of total infections, which are largely asymptomatic in this group. Consistent with the HAV incubation period (4–6 weeks), the initial surge in notifications is followed in November–December by an increase in HAV infections among children and adults who did not travel but instead acquired their infection in the Netherlands.6 Such seasonal introduction of HAV with secondary transmission in the second half of each year has long been recognized in the Netherlands.5,7 It is supported by molecular cluster analysis which confirms frequent importation of new HAV strains into Amsterdam which are then associated with small clusters later in the year.8

Annually since 1998, the public health service of Amsterdam has attempted to reduce the importation of HAV after the holiday season by organizing large vaccination campaigns prior to the summer. These are targeted at SGM Turkish and Moroccan children and those from other North African countries. A study evaluating these programmes in 2006 reported a downward trend in the number of imported HAV cases among Turkish and to a lesser extent among Moroccan children in Amsterdam. The trend seemed to be correlated with the estimated

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vaccination coverage in these groups.9 The city of Amsterdam (population: 790,044), is ethnically diverse and an increasing proportion of residents are of non-Western origin (35% in 201210). Our aim was to describe recent trends in hepatitis A infection in ethnic groups in Amsterdam from 1996 to 2011, to identify current risk groups and to recommend targeted prevention through vaccination.

Methodology

Notification criteria for hepatitis A include clinical signs or symptoms of infection and elevated amino-transferase levels, with detectable hepatitis A-specific immunoglobulin M (IgM) antibodies in the serum (in the absence of hepatitis A vaccination in the last 12 months) or an epidemiological link to a confirmed case. Cases reported to the Amsterdam public health service with date of symptom-onset between 1 January 1996 and 31 December 2011 were included. Demographic information including birth-date, gender, recent travel history, country of birth, country of birth of parents (recorded in those whose primary risk was travel to a HAV endemic country from 1996 to 2005, and in all cases since 2005) and other risk factors (sexual contact in MSM, known household or other contact) were collected. Patients most likely source of infection was categorised as: (1) those infected in a highly HAV-endemic country during the previous 6 weeks (imported infections); (2) those infected in the Netherlands by a hepatitis A patient in their home, school or work environment (domestic infections); (3) those who were infected as a result of male homosexual activity during the previous 6 weeks; (4) those of unknown source.

Where travel was the major risk factor, countries visited were ‘highly endemic’ if ≥90% have immunity by age 10 (India, Pakistan, sub-Saharan Africa), ‘intermediate endemic’ if ≥15% have immunity by age 15 (Latin America, North Africa, Turkey & Middle East), ‘low endemic’ if ≥50% have immunity by age 30 (East/Southeast Asia, Caribbean, Eastern and Central Europe,) and very low endemic if <50% have immunity by age 30 (The Netherlands and ‘Other Western’ countries).1 Cases born in a high/intermediate endemic country that migrated to the Netherlands were classified as ‘First generation migrants’ (FGM). Children of FGM, who themselves were born in the Netherlands or another low/very low endemic country, but where one or both parents were born in an intermediate or high HAV endemic country, were classified as ‘Second generation migrants’ (SGM). If an FGM or SGM travelled to their (or their parents’) country of origin within the HAV incubation period, their visit was regarded as ‘visiting friends and relatives’ (VFR).

To estimate incidence of notified cases of hepatitis A in Amsterdam, annual population estimates were provided by the Research and Statistics department of Amsterdam (O&S), by age and gender for FGM and SGM in the major ethnic groups in Amsterdam from 1996 to 2011.

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These were classified as ‘The Netherlands and Other Western’ (including all EU 27 countries), ‘Suriname and Netherlands Antilles’, Turkey, Morocco, and ‘Other, non-Western’.

Statistical analysis Analyses were conducted using Intercooled Stata 11.1 (Stata Corp., College Station, Texas, USA). Significant differences between proportions were assessed using Pearson’s chi-squared, and the nonparametric ‘nptrend’ was used to test for time trend in median age over calendar year. Incidence rates of hepatitis A cases in Amsterdam were estimated as the annual number of new cases per 100,000 persons-at-risk in the Amsterdam population. Poisson regression models adjusted for person-years of follow-up were used to quantify the incidence rate ratio (IRR) with 95% confidence intervals. To model total incidence over calendar time, calendar year was included as a continuous covariate. Other risk factors of interest were added separately 5 as follows: age-group (categorical), most likely source of infection (categorical), and country of infection (categorical) if travel was the primary risk factor. Interaction terms between risk factors and calendar year were included and reported if significant (p<0.05). To model incidence between ethnic groups, age was added as a continuous covariate. To better observe the seasonal variation in imported and domestic cases, the data was smoothed using a uniformly weighted moving average model. A new data series was generated by adding the current observation (n), one lagged observation (n-1) and one forward observation (n+1), and dividing by three.

Results

From 1 January 1996 to 31 December 2011, 1107 cases of HAV infection were reported of which 288 (26%) were sexually acquired in MSM and were excluded from further analysis. Of the remaining 819, the median age was 10 (interquartile range, IQR:6–25 years), and 53% were male (n=438). Case demographics and source of infection are in Table 1.

The incidence of HAV infection in Amsterdam (Figure 1a) dropped by 16% annually from 178

cases in 1996 (24.8/100,000 population) to 8 cases in 2011 (1.0/100,000, IRRref. year 1996 0.84, 95% CI:0.82–0.85,p<0.001). The incidence declined in each age-group over calendar year and the decline was not constant between age-groups (interaction term overall p<0.001): in those under

15, IRR1996 was 0.78 (95% CI:0.77–0.80). in ages 16–39, IRR1996=0.86, 95% CI:0.84–0.88), in age

≥40:IRR19960.93, 95% CI:0.90–0.97).The median age increased from 8 years in 1996 (IQR: 5–21) to 17 years in 2011 (IQR:5–22, test for trend, p<0.001). Since 1996, there has been an annual decline of

12% in the number of imported cases notified (Figure 2, IRRref year: 1996 0.88, 95% CI:0.85–0.90), and

a more marked decline in domestic secondary cases acquired in the Netherlands (IRR ref year: 1996 0.78, 95% CI:0.75–0.80, interaction p<0.001). Between 1996 and 2005, 41% of notified infections

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were domestic infections acquired in the Netherlands (n=278/675). Since 2005, this proportion has dropped to 18%, and the majority of infections are imported from HAV endemic countries (56% of all infections (n=81/144) since 2005).

Table 1. Characteristics of hepatitis A cases reported in Amsterdam, the Netherlands. 1996–2011 (n=819a).

n % Gender Male 438 53

Female 381 47 Total 819 100 Age group 0–15 546 67 16–39 201 25 ≥40 72 9 Total 819 100 Country of birth Netherlands/Western Europe (very low/ low endemic) 717 88 Morocco (intermediate endemic) 26 3 Suriname / Netherlands Antilles (low endemic) 22 3 Turkey (Intermediate endemic) 7 1 Other, non Western (mixed endemicities) 31 4 Unknown 16 2 Total 819 100 Most likely source of infection Imported from HAV endemic country SGM−VFR b 204 62 FGM−VFR c 39 12 Dutch other Western tourist 65 20 Other traveler d 23 7 Subtotal 331 40 Domestic secondary infections acquired in the Netherlandse Family or household contact 132 43 School contact 102 34 Contact in environmentf 70 23 Subtotal 304 37 Unknown source 184 22 Total 819 100 a Sexually acquired infections in MSM are excluded (n=288) b SGM−VFR: Second generation migrants, returning to visit their parent’s country of birth. c FGM−VFR: First generation migrants, returning to visit their country of birth d ‘Other travelers ‘ includes those not otherwise classified i.e. those of mixed ethnic backgrounds and destinations or Dutch expatriates living in a high endemic area. e Ethnic background was not available for domestic cases prior to 2005. f This includes workplace or other immediate environment.

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(a) (b)

Figure 1. Incidence of acute hepatitis A infection in (a) the total Amsterdam population, 1996 to 2011 and (b) in Dutch born cases by ethnic background (including native Dutch, second generation Moroccan and second generation Other-Non Western cases), 2005–2011. Observed and expected incidence with 95% CI around expected 5 values (shaded area). (a) Since 1996, total incidence in Amsterdam has dropped by 16% annually from 178 cases in

1996 (incidence of 24.8/100,000 population) to 8 cases in 2011 (incidence 1.0/100,000, IRRref. year 1996 0.84, 95% CI:0.82- 0.85, p<0.001); (b) Observed and expected incidence with 95% CI in native Dutch cases (95% CI: Dark grey shaded area), SGM Moroccan (95% CI: mid-grey shaded area) and ‘SGM, Other non Western ‘ (light-grey shaded area. Data for Turkish SGM not illustrated). Adjusting for age and calendar year, relative to ethnic Dutch, the IRR was 3.7 (95% CI:2.3–6.1) in Moroccan SGM and 4.3 in SGM of other non-Western backgrounds (95% CI: 2.6–7.2); IRR of Turkish SGM was 1.9 (95% CI:0.8–4.1) data not included in figure.

Figure 2. Number of imported HAV cases, cases acquired in the Netherlands and those of unknown origin, Amsterdam 1996 to 2011, n=819. The number of imported cases notified has declined annually by 12% since 1996

(IRRref year: 1996 0.88, 95% CI:0.85–0.90). The annual decline in domestic secondary cases acquired in the Netherlands was more marked (IRR ref year: 1996 0.78, 95% CI:0.75–0.80, interaction p<0.001). Cases of unknown source also declined (IRR ref year: 1996: 0.86, 95% CI:0.83–0.88).

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Infections imported from a HAV endemic country Of imported infections (n=331), 12% were in FGM returning from their homeland, 62% were in SGM returning from their parent’s homeland and 20% were Dutch or other Western tourists or other travelers (Table 1). Thirty-nine countries were implicated as the source of infection. Countries visited that each accounted for ≥5% of infections were Morocco (n=178/331, 54%), Pakistan (n=31/331, 9%), Egypt (n=21/331, 6%), and Turkey (n=18/331, 5%). Between 1996 and 2011, only the number of infections acquired in Morocco has declined significantly: IRR 0.83, 95% CI:0.80–0.86, p<0.001 (Figure 3). The number of infections acquired in other countries has remained relatively stable over calendar year.

Figure 3. Number of cases of acute hepatitis A, by country visited within 6 weeks prior to becoming symptomatic (n=331) Between 1996 and 2011, only the number of infections acquired in Morocco has declined significantly (IRR 0.83, 95% CI:0.80–0.86, p<0.001). The number of infections acquired in Pakistan, Egypt, Turkey and other countries, has remained relatively stable over calendar year.

SGM From 1996 to 2011, 204 SGM imported the infection from their parent’s birth-country. The youngest case was 20 months old (maximum: 39 years). Between 1996 and 2004, 75% of cases were imported from Morocco (123/164). Since 2005, cases from Morocco accounted for 53% of cases (21/40), and the median age of SGM contracting the infection in Morocco increased from 6 in 1996 (IQR:5–8), to 9.5 (IQR:2–17) in 2011 (z=1.92, p=0.055). The relative proportion of cases from other non-western countries increased from 19% (31/164) in 1996–2004 to 35% (14/40) in 2005–2011 (Pearson chi2=9.5, p=0.023). Since 2005, SGM have also imported HAV from Turkey (n=5), Pakistan (n=4), Egypt (n=4), Nigeria (n=2), South Africa (n=1), Ethiopia (n=1), Afghanistan (n=1) and India (n=1). The median age in this diverse group has not changed over calendar year (median age=7 years, IQR:4–12).

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FGM Between 1996 and 2011, 39 FGM acquired HAV whilst visiting their homeland: 15 in Morocco, 6 in Pakistan, 4 in Afghanistan, 4 in South Africa, and others in India, Turkey, Egypt, Zimbabwe and Syria. Median age was 10 (IQR:6–22) and there was no statistical trend in the number of cases in FGM over calendar year nor in their age at diagnosis.

Dutch/ Western tourists Since 1996, 65 people of Dutch or other Western ethnic backgrounds contracted the infection while travelling: 19% (n=12) in Morocco, 11% (n=7) in Egypt and 6% (n=4) in Kenya and Brazil respectively. Other cases were contracted in Africa (n=8), South America (n=6). Central America (n=7) a range of mid- and high- endemic countries (n=17). Median age was 28 (IQR:12–42). This has increased over calendar year from 26 (IQR:18–28) in 1996 to 38 (IQR:25–29) in 2010 (z=1.93, 5 p=0.054). There were no cases in this group in 2011.

Infections acquired in the Netherlands Since 1996, 304 infections were domestically acquired: 43% within the family/household, 34% within the school environment, and 23% within the workplace or other institution. The median age was 9 years (IQR:6–21) and there was no significant trend with age or calendar year. The majority (86%, n=262) were born in the Netherlands, 3% in Morocco and 3% in the Dutch Antilles.

Seasonal variation in imported and domestic infections Despite a decreasing overall trend, a similar seasonal pattern to that reported previously was seen in the smoothed time series from 1996 (Figure 4): case numbers in those who had recently travelled to an intermediate/highly HAV endemic country increased annually from August to October, peaking in September. This was followed by an increase from October to January (peaking in December) in those who were infected in the Netherlands.

Incidence of HAV in Dutch-born cases by ethnic background The total, age-specific incidence, and incidence over calendar year in Dutch born cases (n=123) from 2005–2011 by ethnic background, is in Table 2 and Figure 1b respectively. The incidence decreased with increasing age and did not change significantly over calendar year. The IRR relative to the ethnic Dutch population, adjusted for age and calendar year was 1.9 (95% CI:0.8– 4.1) in Turkish SGM, 3.7 (95% CI:2.3–6.1) in Moroccan SGM and 4.3 in SGM of other non-Western backgrounds (95% CI: 2.6–7.2). Probably due to pre-existing immunity, the incidence in FGM from high-endemic countries was lower than that of the ethnic Dutch. This data is not presented.

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Jul

Jan

Jul

Jan

Jul

Jan

Jul

Jan

Jul

Jan

2006 2007 2008 2009 2010 Jul

Jan

Jul Imported infection Imported infection imported average, Moving Netherlands the in acquired Infection Netherlands the in acquired infection average, Moving

Jan

Jul

Jan

Jul

Month and year and Month Jan

Jul

Jan

Jul

Jan

Jul

Jan

Jul

Jan

Jul

Jan

Jul

Jan

Jul

1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 Jan

8 6 4 2 0

20 18 16 14 12 10 cases of number Total Figure 4. Time series analysis of date onset hepatitis A cases ( n =819) for imported and domestic infections respectively, Jan 1996– Dec 2011. Imported – ) increased annually from August to October, peaking in September. This was followed by an increase October January (peaking December) those who were infected in the Netherlands ( – ).

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Table 2. Age-specific, and total incidence in Dutch-born casesa of hepatitis A notified in the Netherlands, 2005–2011.

Cumulative total Incidence (n/N*100,000 Ethnic Background Age-group Cases (n) population (N) with 95% CI) Dutch & Other, Western 15 or under 10 412841 2.4 (1.2-4.5)

16–39 36 1322335 2.7 (1.9-3.8)

>39 20 1717502 1.2 (0.7-1.8)

Total 66 3452678 1.9 (1.5-2.4)

Turkish 15 or under 5 71349 7 (2.3-16.4)

16–39 2 50788 3.9 (0.4-14.3)

>39 0 362 0 Total 7 122499 5.7 (2.3-11.8) 5 Moroccan 15 or under 19 144400 13.2 (7.9-20.6)

16–39 8 85233 9.4 (4.1-18.5)

>39 0 245 0

Total 27 229878 11.7 (7.7-17.1)

Other, non Western 15 or under 18 112167 16 (9.5-25.3)

16–39 4 51865 7.7 (2.1-19.8)

>39 1 4171 24 (0.6-133.58)

Total 23 168203 13.7 (8.7-20.5) a There were no cases in SGM of Surinamese or Netherlands Antilles background. Data not shown.

Discussion

Between 1996 and 2011, the incidence of symptomatic HAV infection in Amsterdam has declined substantially from 24.8/100,000 to 1.0/100,000, and is now similar to the national notification rate of 0.93/100,000 reported in 2009.3 The number of both imported and domestically acquired infections has decreased. Historically, the majority of travel associated cases were acquired in children visiting their parent’s homeland in Turkey or Morocco. From 1993 to 2002, the incidence in Turkish and Moroccan children was 143 and 219 per 100,000 respectively,7 and a similar ethnic distribution was observed in other major urban centers in the Netherlands.6 The number of cases in Turkish children has declined sharply since then (this decline was observed prior to 19967), and the incidence dropped to native Dutch levels in 2011. The decline in the number of cases acquired in Morocco has also been dramatic, but has occurred more latterly. These findings are supported by the lower seasonal peak in imported cases in the summer months and in tandem, a decrease in domestically acquired infections, probably reflecting reduced transmission in schools and other locations from imported asymptomatic cases. This may in part be attributed to the effectiveness

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of the HAV vaccination programmes targeting migrant children, but is also consistent with seroprevalence surveys in Turkey11,12 and North Africa13 which confirm with some intra-country variation, a recent decline in anti-HAV seropositivity in younger people, and a shift in the endemicity of HAV in these countries from high to intermediate as socioeconomic, sanitary and water supply conditions improve.14 Though of borderline significance, there are indications that the age of infection in cases from Morocco is increasing (cases may thus experience more symptomatic infection). This has been observed in other countries undergoing similar endemic transition,15 and in fact overall, the age at infection in cases in Amsterdam is increasing.

Most gains in relation to HAV infection in the Netherlands were made in the mid-1990s and early 2000s (and earlier according to previous research7). Although the trend in Dutch-born cases of Moroccan and other non-western ethnic backgrounds is downward, we found no further significant declines in incidence between 2005 and 2011, either overall, or within ethnic groups. The age adjusted IRR in Dutch born cases of Moroccan and non-Western ethnic background is still 3 to 4 times that of ethnic Dutch. Since 2005, 62% of all travel-related cases (38% of all cases) were in children born in the Netherlands, who returned to their parents’ country of origin during the summer holidays, and the source countries have become increasingly diverse.

In PHS Amsterdam, the pre-summer HAV vaccination campaigns target only children travelling to Turkey and North African countries on holiday. Unfortunately, overall vaccine uptake and the effectiveness of the programmes are very difficult to estimate: the absolute number or proportion of migrant children who travel to their parent’s country of origin is unknown, and less than half of vaccinations are administered at the PHS (instead by the family doctor, or elsewhere). In a nationwide, population-based sample in the Netherlands in 2006–2007, 32% of children of under 15 years of Turkish or Moroccan origin (considered as a single group) were immune to HAV.4 Given the epidemiology described here, over half of cases in Dutch-born SGM travelling to high-endemic countries are not of Turkish or north-African origin and are not targeted for inclusion in these programmes. It may be timely to reconsider this ad hoc approach: In July 2012, WHO recommended that single-dose inactivated HAV vaccine could be considered in national immunization schedules where appropriate.16 This has already been adopted with success since 2005 in Argentina.17 The inactivated HAV vaccine has been shown to be highly immunogenic (up to 100% seroconversion) in healthy children,18 and in the Netherlands and elsewhere, single dose vaccination is administered as post-exposure prophylaxis after contact with a patient, and has been successfully used to control outbreaks of HAV.19-22 In 2011, 4285 babies of non-western parents were born in Amsterdam and this population is set to increase further.10 These children could be offered a single dose of HAV vaccination at the same time as the MMR vaccine which is currently given within the national immunisation programme at 14 months. A similar strategy

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targeting children of parents from countries where hepatitis B is endemic was pursued in the Netherlands from 2003 to 2011(approximately 18% of the total birth cohort), of whom 94.3% completed hepatitis B vaccination in 2011.23 The infrastructure required and experienced staff are therefore already in situ, and country endemicity of HAV is similar to that of hepatitis B. At present, the vaccine cost is typically borne by the parents, though it is sometimes reimbursed by their health insurance. Particularly among young children who usually have asymptomatic infection, the individual benefit, and therefore the parents’ incentive to vaccinate, may be limited. A recent cost effectiveness study in the Netherlands has advocated targeted prevention vaccinating travelers and other high-risk groups,24 and an earlier study indicated that HAV vaccination of children from ethnic minorities in Amsterdam might be cost-effective,25 though more up-to-date estimates are required. 5 There were some study limitations: Before 2005, country of birth of parents was not recorded in domestically acquired infections and we cannot comment on ethnic background of these cases. However, 43% were household contacts of cases and would therefore have a shared ethnic background. Secondly, we did not have any information on the number of persons travelling to HAV endemic areas, nor their time spent abroad. Therefore, we could not account for individual time-at-risk in susceptible individuals in determining incidence rates among travelers. Also, the majority of FGM are immune and cases that occurred were young, but we didn’t know for how long they lived in their homeland before migrating to the Netherlands, and therefore cannot make specific recommendations in relation to FGM at risk. Finally we could not assess the socio- economic background of cases. This could have accounted for some of the ethnic difference observed.

In conclusion, as the incidence of hepatitis A declines and the source countries become more diverse, we suggest that single-dose, routine HAV vaccination of SGM children from HAV endemic countries could be considered within the childhood vaccination schedule. This approach could achieve comprehensive vaccination coverage within this risk group, raise awareness in FGM parents regarding their own risk, and have the greatest impact on secondary transmission through the prevention of both symptomatic and asymptomatic infection.

Acknowledgements The authors would like to thank the nursing staff in the Department of Infectious Diseases, Public Health Service Amsterdam who interviewed the patients and collected the data, and Professor Martien Borgdorff who critically reviewed the paper.

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References

1. Jacobsen KH, Wiersma ST. Hepatitis A virus seroprevalence by age and world region, 1990 and 2005. Vaccine 2010;28:6653-7. 2. Hollinger F. Hepatitis A virus. Fields Virology, 3rd ed. Philadelphia: Lippincott-Raven, 1996. pp 735-82. 3. European Centre for Disease Control. Annual epidemiological report. Reporting on 2009 surveillance data and 2010 epidemic intelligence data; 2011. Available at: http://www.ecdc.europa.eu/en/publications/ Publications/1111_SUR_Annual_Epidemiological_Report_on_Communicable_Diseases_in_Europe.pdf 4. Verhoef L, Boot HJ, Koopmans M, Mollema L, Van Der Klis F, et al. Changing risk profile of hepatitis A in The Netherlands: a comparison of seroprevalence in 1995-1996 and 2006-2007. Epidemiol Infect 2011;139:1172-80. 5. Termorshuizen F, van de Laar MJ. The epidemiology of hepatitis A in the Netherlands, 1957-1998. Ned Tijdschr Geneeskd 1998;142:2364-8. [in Dutch] 6. van Gorkom J, Leentvaar-Kuijpers A, Kool JL, Coutinho RA. Annual epidemics of hepatitis A in four large cities related to holiday travel among immigrant children. Ned Tijdschr Geneeskd 1998;142:1919-23. [in Dutch] 7. Van Der Eerden LJ, Bosman A, Van Duynhoven YT. Surveillance of hepatitis A in the Netherlands 1993-2002. Ned Tijdschr Geneeskd 2004;148:1390-4. [in Dutch] 8. Tjon G, Xiridou M, Coutinho R, Bruisten S. Different transmission patterns of hepatitis A virus for two main risk groups as evidenced by molecular cluster analysis. J Med Virol 2007;79:488-94. 9. Sonder GJ, Bovée LP, Baayen TD, Coutinho RA, van den Hoek JA. Effectiveness of a hepatitis A vaccination program for migrant children in Amsterdam, The Netherlands (1992-2004). Vaccine 2006;24:4962-8. 10. Bureau Onderzoek & Statistiek. Population by country of origin, 1 January 2008-2012. Amsterdam; 2012. Available at: http://www.os.amsterdam.nl/tabel/6595/. [in Dutch] 11. Kurugol Z, Aslan A, Turkoglu E, Koturoglu G. Changing epidemiology of hepatitis A infection in Izmir, Turkey. Vaccine 2011;29:6259-61. 12. Halicioglu O, Akman SA, Tatar B, Atesli R, Kose S. Hepatitis A seroprevalence in children and adolescents aged 1-18 years among a low socioeconomic population in Izmir, Turkey. Travel Med Infect Dis 2012;10:43-7. 13. Kamal SM, Mahmoud S, Hafez T, El-Fouly R. Viral hepatitis A to E in South Mediterranean countries. Mediterr J Hematol Infect Dis 2010;2:e2010001. 14. Baaten GG, Sonder GJ, Van Der Loeff MF, Coutinho RA, Van Den Hoek A. Fecal-orally transmitted diseases among travelers are decreasing due to better hygienic standards at travel destination. J Travel Med 2010;17:322-8. 15. Shouval D, Mikhaylov M, van Herck K. Hepatitis A vaccines − Impact of universal childhood vaccination programmes. Eur Gastroenterol & Hepatol Rev 2011;7:77-83. 16. World Health Organisation Strategic Advisory Group of Experts on Immunization. Evidence based recommendations for use of hepatitis A vaccines in immunization services: background paper for SAGE discussions. Geneva: World Health Organisation; 2011. Available at: http://www.who.int/immunization/ sage/previous_november2011/en/ 17. Vacchino MN. Incidence of Hepatitis A in Argentina after vaccination. J Viral Hepat 2008;Suppl 2:47-50. 18. Schmidtke P, Habermehl P, Knuf M, Meyer CU, Sanger R, et al. Cell mediated and antibody immune response to inactivated hepatitis A vaccine. Vaccine 2005;23:5127-32. 19. Tjon GM, Gotz H, Koek AG, de Zwart O, Mertens PL, et al. An outbreak of hepatitis A among homeless drug users in , The Netherlands. J Med Virol 2005;77:360-6. 20. National Institute of Public Health and the Environment (RIVM). LCI directive, hepatitis A. LCI directives for infectious disease control in Dutch. Bilthoven, 2011. [in Dutch] 21. Victor JC, Monto AS, Surdina TY, Suleimenova SZ, Vaughan G, et al. Hepatitis A vaccine versus immune globulin for postexposure prophylaxis. N Engl J Med 2007;357:1685-94. 22. Torner N, Broner S, Martinez A, Tortajada C, Garcia de Olalla P, et al. Factors associated to duration of hepatitis A outbreaks: implications for control. PLoS One 2012;7:e31339.

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23. van Lier E, Oomen P, Giesbers H, Drijfhout I, de Hoogh P, et al. Immunization coverage National Immunization Programme in the Netherlands Year of report 2012. Bilthoven: National Institute of Public Health and the Environment (RIVM); 2012. 24. Suijkerbuijk AW, Lugner AK, van Pelt W, Wallinga J, Verhoef LP, et al. Assessing potential introduction of universal or targeted hepatitis A vaccination in the Netherlands. Vaccine 2012;30:5199-205. 25. Postma MJ, Bos JM, Beutels P, Schilthuis H, van den Hoek JA. Pharmaco-economic evaluation of targeted hepatitis A vaccination for children of ethnic minorities in Amsterdam (The Netherlands). Vaccine 2004;22:1862

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Evaluation of hepatitis A vaccine in post-exposure prophylaxis, The Netherlands, 2004-2012

Jane Whelan Gerard Sonder Lian Bovée Arjen Speksnijder Anneke van den Hoek

PLoS One 2013; 8:e78914

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Evaluation of hepatitis A vaccine in post-exposure prophylaxis, The Netherlands, 2004-2012 6

Jane Whelan Gerard Sonder Lian Bovée Arjen Speksnijder Anneke van den Hoek

PLoS One 2013; 8:e78914

26660 Whelan kopie.indd 83 02-11-13 16:03 CHAPTER 6 HEPATITIS A POST-EXPOSURE PROPHYLAXIS

Abstract

Background The secondary attack rate of hepatitis A virus (HAV) among contacts of cases is up to 50%. Historically, contacts were offered immunoglobulin (IG, a human derived blood product) as post-exposure prophylaxis (PEP). Amid safety concerns about IG, HAV vaccine is increasingly recommended instead. Public health authorities’ recommendations differ, particularly for healthy contacts ≥40 years old, where vaccine efficacy data is limited. We evaluated routine use of HAV vaccine as an alternative to immunoglobulin in PEP, in those considered at low risk of severe infection in the Netherlands.

Methods Household contacts of acute HAV cases notified in Amsterdam (2004−2012) were invited ≤14 days post-exposure, for baseline anti-HAV testing and PEP according to national guidelines: immunoglobulin if at risk of severe infection, or hepatitis A vaccine if healthy and at low risk (aged <30, or, 30−50 years and vaccinated <8 days post-exposure). Incidence of laboratory confirmed secondary infection in susceptible contacts was assessed 4−8 weeks post-exposure. In a vaccinated subgroup, relative risk (RR) of secondary infection with estimated using Poisson regression.

Results Of 547 contacts identified, 191 were susceptible to HAV. Per-protocol, 167 (87%) were vaccinated (mean:6.7 days post-exposure, standard deviation(sd)=3.3) and 24 (13%) were given immunoglobulin (mean:9.7 days post-exposure, sd=2.8). At follow-up testing, 8/112 (7%) had a laboratory confirmed infection of whom 7 were symptomatic. All secondary infections occurred in vaccinated contacts, and half were >40 years of age. In healthy contacts vaccinated per-

protocol ≤8 days post-exposure, RRref. ≤15 years of secondary infection in those >40 years was 12.0 (95% CI:1.3−106.7).

Conclusions Timely administration of HAV vaccine in PEP was feasible and the secondary attack rate was low in those <40 years. Internationally, upper age-limits for post-exposure vaccination vary. Pending larger studies, immunoglobulin should be considered PEP of choice in people >40 years of age and those vulnerable to severe disease.

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Introduction

Hepatitis A virus (HAV) causes acute inflammation of the liver and is transmitted via the fecal-oral route. The virus is endemic in developing countries where sanitary conditions are suboptimal and ≥90% of infections occur in children, are asymptomatic, and lead to lifelong immunity.1 Incidence of symptomatic infection increases with age and 80% of adults infected will complain of symptoms.2 In industrialised, low-endemic regions such as the Netherlands, population seroprevalence of antibodies is low and much of the adult population is susceptible if exposed. Spread is typically limited to travelers to HAV endemic countries, men who have sex with men (MSM) and contacts of hepatitis A patients. The secondary attack rate can be up to 50%, and though the infection is often mild and self-limiting, HAV infection can in rare cases, lead to fulminant hepatic failure.3 6

In the Netherlands, symptomatic HAV infection is notifiable and the Public Health Service (PHS) routinely traces contacts of cases, offering post-exposure prophylaxis (PEP) according to national guidelines. Since 2004, hepatitis A vaccine has been used routinely in post- exposure prophylaxis.4 Until 2004, hepatitis A immunoglobulin (IG) was the only form of PEP recommended. Evidence dating largely from the 1940s to 1960s5−8 and clinical experience since,9 supports the effectiveness of IG in PEP. Widespread use of a human blood-derived immunoprophylactic has become controversial however,10,11 and in some countries its use is no longer recommended.12 In the interim, a safe, immunogenic vaccine which provides long term protection has been developed13,14 and evidence of its efficacy and effectiveness in preventing secondary infection is accumulating.15−17 In a randomised controlled trial conducted in 2007,18 which directly compared the vaccine and immunoglobulin, the vaccine was shown to be similarly effective in preventing laboratory confirmed, symptomatic secondary HAV infection in healthy persons 2−40 years old. While national advisory bodies are increasingly recommending HA vaccine as an alternative to IG in PEP,19−21 IG remains the PEP of choice in those considered at increased risk of severe disease: people with certain underlying conditions or those who are immunosuppressed, for example.

Internationally, guidelines take account of patient characteristics when recommending the vaccine or IG, but they diverge concerning what PEP should be used in healthy people over 40 years4,12,21−24 where evidence of vaccine efficacy is lacking. In the Netherlands, based on a review of the evidence and expert consensus,25 contacts aged <30 years, or, those aged 30−50 years and vaccinated within 8 days post-exposure, are generally considered to be at low risk of severe infection and vaccination is recommended.4 Otherwise human immunoglobulin is prescribed (details in Table 1). In this study we evaluate the routine use of hepatitis A vaccine as an alternative

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to immunoglobulin in prevention of secondary HAV infection in contacts considered at low risk of severe infection.

Table 1. Risk categories of contacts for whom active vaccination or immunoglobulin is recommended in post- exposure prophylaxis, LCI Netherlands*.

* This table is a summary of advice contained in the guideline for the control of hepatitis A infection in the Netherlands.4 1. Active immunisation is not recommended for children under 1 year. 2. The interval for a family contact is the period between the date of onset of symptoms in the index and immunisation; for other contacts, it is the interval between first contact with the index case and immunisation. 3. Passive immunisation longer than 28 days post-exposure is probably no longer effective. 4. If exposure is ongoing, active immunisation can be given simultaneously. 5. This recommendation extends to class teachers and supervisors. If, during an epidemic active immunisation occurs too late or many cases are reported simultaneously, then active immunisation of parents and siblings should also be considered. 6. Active immunisation of parents and siblings should also be considered. 7. People with liver cirrhosis, hepatitis B & hepatitis C.

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Methodology

Notified cases: routine surveillance data All index cases of hepatitis A notified to the Amsterdam PHS after the revised protocol was implemented in July 2004 until end-December 2012 were included in this evaluation. Criteria for notification of hepatitis A include clinical signs or symptoms of infection and elevated amino- transferase levels, with detectable hepatitis A-specific immunoglobulin M (IgM) antibodies in the serum (in the absence of hepatitis A vaccination in the last 12 months) or an epidemiological link to a confirmed case. The first case notified in a household or care-centre was considered the index case, and the date of onset of illness was the date on which the index case first had jaundice (conjunctival or dermal icterus, pale stools or dark urine). To characterise the index cases, their most likely source of infection was categorised as: (1) those infected in a highly HAV-endemic 6 country during the previous 6 weeks (imported infections); (2) those infected in the Netherlands by a hepatitis A patient in their home, school or work environment (domestic infections); (3) those who were infected as a result of male homosexual activity during the previous 6 weeks; (4) those of unknown source.

Contacts: co-infections and secondary cases A contact of an index case was defined as any family or household member (or equivalent) who shared toilet facilities with the index case, any sexual partner of the case, or any person who took care of an HAV-infected child while the index case was infectious (7 days before through 7 after the onset of jaundice). Once identified, contacts were invited to the PHS and were asked about signs or symptoms of HAV infection. They were offered advice on hygiene precautions and PEP according to guidelines: a single dose of hepatitis A vaccination or 0.02mls of immunoglobulin per kilogram of body weight depending on their risk category (as summarised in Table 1) and the post-exposure interval (i.e. for a family contact, the number of days between the date of onset of jaundice in the index case and the date of immunisation, and for other contacts, the period between first contact with the index and immunisation). Baseline total anti-HAV antibody test- ing was conducted at the same visit. As the incubation period of HAV is typically 15 to 50 days, contacts for whom baseline tests were conducted ≥15 days post-exposure were excluded. As- ymptomatic contacts >10 years of age who tested total anti-HAV positive ≤14 days post-exposure were considered to have pre-existing immunity and were not tested further. In symptomatic contacts (and all children under 10 years of age who may have an acute asymptomatic infection) a total anti-HAV positive result ≤14 days post-exposure was followed by a anti-IgM test. If anti- IgM positive and exposed to the same likely source as the index, these contacts were considered co-infections and were not tested further. All those that were total anti-HAV negative at baseline were considered susceptible to HAV infection and were invited for follow-up serological testing

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four to eight weeks later, earlier if symptomatic. All samples that were anti-HAV IgM positive at follow-up were tested for HAV virus RNA (PCR). Secondary cases were symptomatic i.e. those who had jaundice and who tested anti-HAV IgM positive at follow-up, or asymptomatic i.e. in the absence of jaundice, those who had HAV virus RNA detected in the same follow-up sample.

Ethics statement In the Netherlands, hepatitis A is a notifiable infectious disease under the Public Health Act of 2008.26 Under article 6c of this legislation, it is the duty of the PHS to conduct contact tracing (in translation from Dutch: ‘The mayoral college and municipal council members are responsible for the implementation of general infectious disease control including source finding and contact tracing in relation to notifications referred to in articles 21, 22, 25 and 26’). This is operationalised in the national infectious disease control guidelines.4 As a matter of routine, all contacts who receive PEP are invited to return for a follow-up blood test 4−8 weeks later to ensure seroconversion. This is entirely voluntary and for this, contacts give verbal informed consent. As this study was an evaluation of routine practice, written informed consent, ethical approval or a formal waiver of the need of ethical approval was not required.

Laboratory methods Total anti-HAV and anti-HAV-IgM were performed using the combined automated quantitative HAVT test in a VIDAS system (Biomerieux, Craponne, France). This is a 2 step ELISA competition method with fluorescent detection. Amplification of HAV RNA was performed on the same follow-up sample tested positive for IgM, by a reverse transcriptase reaction and PCR according to Tjon et al.27

Statistical analysis Data are presented categorically in proportions. The mean and standard deviation, or the median and interquartile range (IQR), are used to summarize continuous data. Significant differences between proportions were assessed using a two-sided Fischer’s exact test, and between means using two-sided independent sample t-tests. In a sub-group analysis of those considered at low- risk of severe infection who were vaccinated <8 days post-exposure, the relative risk of secondary infection was estimated using Poisson regression with clustered robust standard errors to correct for correlation between individuals within households. If the Wald test p value was <0.05, the association was considered significant. Analyses were conducted with Intercooled Stata 11.1 (Stata Corp., College Station, Texas, USA).

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Results (Figure 1)

Notified cases From 1 July 2004 to 31 December 2012, 200 cases of acute HAV infection were notified, of whom 64% were male (n=129), and the median age was 29 (IQR:12−41). Signs of jaundice included conjunctival or dermal icterus (n=178/200, 89%), pale stools or dark urine (n=22/200, 11%). Overall, 48% (n=97) were imported infections, 17% (n=34) were homosexually acquired, 11% (n=23) were domestically acquired infections and 23% (n=47) were of unknown source. The majority (75%, n=170) were born in the Netherlands, a further 21 (10%) were of other western origin, 7 were from Turkey or North Africa (3%), and 23 (11%) were other non-western countries.

Contacts 6 In total, 547 contacts were identified (Figure 1) representing a median of 1 contact per case (IQR:0−4, range 0−24); 128 (23%) of contacts were excluded because blood samples were not taken, or blood was taken >14 days after symptom onset in the index. Characteristics of the remaining 419 contacts are in Table 2, of whom 205 (49%) were immune at presentation (34 had been fully vaccinated or vaccinated once, and 171 had pre-existing natural immunity). Similar to previous research,9 84% (n=144/171) of those with pre-existing natural immunity were of Turkish, north African or other non-western descent (1st or 2nd generation) and 91% (n=159/171) were over 16 years. An additional 22 contacts were considered co-primary infections and were total anti- HAV and IgM positive ≤14 days post-exposure: 11 were contacts ranging in age from 2−45 years who complained of hepatitis A related symptoms, and 11 contacts were aged between 1 and 8 years and who were asymptomatic.

Secondary cases Overall, 192 contacts were susceptible at the time of presentation (Figure 1), of whom 167 (87%) were given hepatitis A vaccination within a median of 6 days (IQR:4−10) post-exposure, 24 (13%) got immunoglobulin within 10 days (IQR:4−14) and one refused PEP. Of 112 susceptible contacts who returned for follow-up testing, 18 (16%) were IgM HAV antibody positive, all of whom had received hepatitis A vaccine, and 8 of whom were considered secondary infections: 7 were symptomatic (5 made contact with the PHS complaining of yellowing of the eyes or skin, dark urine or pale stools among other symptoms; 2 contacts (aged 8 and 25) complained retrospectively of non-specific symptoms such as nausea, fatigue, loss of appetite when they returned for follow-up testing) and Hepatitis A virus RNA was confirmed by PCR in 6/7 of these cases (the PCR-negative case was a 25 year-old, diagnosed 17 days post-exposure by his general practitioner with conjunctival icterus, fever >38 celcius, and complaining of dark urine and

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pale stools. PCR testing was conducted 57 days post-exposure). In one additional IgM positive contact (a child aged 1 year who was asymptomatic throughout) HAV viral RNA was confirmed in the sample, bringing the total to 8 secondary cases (Figure 2). Of the remaining IgM positive but PCR negative cases (n=10), all were asymptomatic. All secondary cases were close family or household contacts (sexual partners, n=2, first degree relatives, n=6) and occurred in different family or household clusters.

Index patients n=200 (1)

Related contacts n=547

Baseline immunity unknown Contacts excluded n=128 (2)

Immune: Pre-existing Co-primary previously natural Susceptible infections vaccinated immunity contacts n=22 (5) n=34 (3) n=171 (4) n=192 (6) Refused PEP n=1 Hepatitis A Symptomatic Asymptomatic Immunoglobulin vaccine n=11 n=11 n=24 (7) n=167 (8)

Follow-up blood Follow-up blood sample sample n=11 n=101

Secondary infection Secondary infection n=0 n=8 (9)

Symptomatic Asymptomatic n=7 n=1

Figure 1. Algorithm of contacts identified, included, treatments assigned and outcomes 1. Cases notified with clinical signs or symptoms of infection and elevated amino-transferase levels, with detectable hepatitis A-specific immunoglobulin M (IgM) antibodies in the serum (in the absence of hepatitis A vaccination in the last 12 months) or an epidemiological link to a confirmed case. 2. Baseline serological status was unknown for 128: 63 were not tested, 65 were tested >15 days post exposure. 3. Vaccinated twice (or once if within one year of exposure) with inactivated hepatitis A vaccine. 4. Asymptomatic and total anti-HAV positive within 14 days of exposure. If ≤10 years, also IgM negative. 5. All IgM positive ≤14 days post-exposure 6. Total anti-HAV negative and without symptoms. 7. Immunoglobulin given as PEP according to guidelines. See Table 1. 8. Hepatitis A vaccine given as PEP according to guidelines. See Table 1. 9. Total anti-HAV negative at baseline and anti-IgM positive with jaundice (+/- HAV RNA on PCR) at follow-up, or in the absence of jaundice, anti-IgM positive and HAV RNA detected by PCR in the same follow-up sample.

None were hospitalised. All had been vaccinated, including one 57 year old who was given hepatitis A vaccine in place of immunoglobulin 6 days post-exposure, for reasons that are unclear. Excluding this contact, 7.0% of those vaccinated per-protocol became secondary cases

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(n=7/100; 6/100 were symptomatic infections): 3% of those ≤15 years (2/58), 6% (2/32) aged 16−40 years, and 30% (3/10) >40 years. All three contacts over 40 developed clinically significant disease including jaundice. Among those followed-up who received immunoglobulin (n=11) the median age was 39 years (range 26−55). There were no secondary cases in this group.

Table 2. Characteristics of contacts whose baseline immune status was known (n=419).

Gender, n (%) Female 218 (52) Male 201 (48) Age (in years) Mean (sd) 27.9 (19.1) Interquartile range 10−42 6 Visit to HAV endemic country during incubation period, n (%) Yes 234 (56) No 178 (42) Unknown 7 (2) Type of contact, n (%) Sexual Partnera 41 (10) 1st degree relative or equivalent household contact 294 (70) 2nd degree relativeb 58 (14) Otherc 26 (6) Duration, exposure to immunisation (days) Mean (sd) 6.7 (3.3) Interquartile range Range 4−10 Hepatitis A status at baseline, n (%) Previous natural immunity 171 (41) Vaccinated previously 34 (8) Co-infections 22 (5) Susceptible 192 (46) a. Of whom 7 were homosexual partnerships. b. Index was known to the contact and shared toilet facilities with or took care of the index, but was not a relative. c. Contacts were excluded if baseline blood was tested >14 days post-exposure.

Risk factors associated with secondary infection In a subgroup analysis of 72 healthy contacts aged <50 years who were vaccinated within 8 days post-exposure (Table 3), age was associated with an increased risk of secondary infection: compared to those aged ≤15 years the RR of secondary infection in those >40 years was 12.0 (95% CI:1.3−106.7). No association between gender, household size, ethnic background or the interval between exposure and vaccination, and secondary infection was shown in this group.

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Figure 2. Timeline of exposure, vaccination, symptom onset and confirmation in secondary hepatitis A cases ◊ One dose hepatitis A vaccine administered. Total anti-HAV negative and asymptomatic. • Jaundice (conjunctival icterus +/- dark urine, pale stools) � Non-specific symptoms: nausea, fatigue, loss of appetite, malaise � Date of confirmed infection: IgM positive & PCR positive. i Case was aged 57 and was not immunised according to protocol. ii This case was PCR negative, but IgM positive and symptoms and signs confirmed by general practitioner. iii Child aged 1 year who was asymptomatic throughout, but HAV RNA confirmed on PCR.

Table 3. Factors associated with secondary infection in contacts <50 years vaccinated within 8 days post exposure according to protocol (n=72).

Vaccinated per- Symptomatic secondary Univariablec protocol <8 days infection and/or PCR b post-exposure positivea RR (95%CI) p value N n % Total 72 5 6,9 Age group <=15 40 1 2,5 1,0 16-40 22 1 4,5 1.8 (0.1-28.9) 41+ 10 3 30,0 12.0 (1.3-106.7) 0.035 Gender Female 36 4 11,1 Male 36 1 2,8 0.3 (0.0-2.2) 0.21 Household sized 2 persons 9 1 11,1 1,0 3-5 persons 29 3 10,3 0.9 (0.1-8.3) 6 or more persons 34 1 2,9 0.3 (0.0-4.1) 0.5304 Ethnic background Non-Western 38 2 5,3 1,0 Dutch/western 34 3 8,8 1.7 (0.3-10.2) 0.574 Interval between exposure 4.5 (1.7) 3.4 (2.6) 0.7e (0.4-1.3) 0.223 & vaccination, mean days (standard deviation) a. Of the 5 secondary infections included in this analysis, one was a child aged 1 who was asymptomatic, but PCR positive; b. Wald test; c. All analyses are adjusted for clustering within households using clustered robust standard errors; d. 72 contacts were clustered in 44 households; e. The RR is the daily incremental risk.

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Exclusions and non-responders Of those who were excluded (n=128), 63 did not have serological testing at baseline. The major- ity received PEP (n=44), all according to protocol and a mean of 5.5 days post-exposure (range 2−20 days). They were significantly younger than those who did have baseline serological testing (p=0.002) The remainder refused both serology and PEP (n=19). An additional 65 were excluded because PEP was administered and/or baseline blood taken ≥15 days post-exposure (median: 31.5 days, range 15−62): 33 (51%) had no history of symptoms and were immune at the time of testing, 24 (37%) were negative at first and follow-up testing, 8 were considered recent infections, testing total anti-HAV and anti-IgM positive at a median of 20 days post exposure (range 15−62 days). Of those who were susceptible and received PEP, but did not return for follow-up testing (n=80/191), there were no significant differences in age, gender or ethnic background nor in the exposure interval pre-PEP compared with those who did return. Of those excluded, no symptomatic cases 6 were later reported to the PHS.

Discussion

We evaluated the routine use of hepatitis A vaccine as an alternative to immunoglobulin in the prevention of secondary hepatitis A infection in contacts considered at low risk of severe infection over an 8-year period (2004−2012). In the Netherlands, all healthy contacts aged 1−30 years, and those aged 30−50 who are within 8 days of exposure to the index case, are given hepatitis A vaccine in preference to immunoglobulin. Of contacts vaccinated according to protocol, 6.0% seroconverted, developing a symptomatic laboratory confirmed, secondary infection. In the randomised controlled trial by Victor et al,18 4.4% of vaccinated contacts developed a symptomatic secondary infection. The trial included only contacts aged 2−40 years, and when the same age- group in our evaluation is compared, the proportion was similar (3.6%). Direct evidence of the efficacy of the vaccine in PEP in those over 40 is not available, so in the Netherlands, this recommendation was made based on a combination of epidemiological data, hospitalisation and case-fatality rates in the Netherlands, and vaccine immunogenicity data (seropositivity of 77% in persons aged 40−62 years post-vaccination in one study28). In our evaluation, 30% of contacts over 40 years vaccinated per-protocol developed symptomatic infection, and half of the 8 secondary infections were over 40 years, all of whom had been vaccinated. In a subgroup analysis of all healthy contacts vaccinated within 8 days of exposure, the risk of secondary infection in those over 40 years was 12 times that of contacts aged ≤15 years (95% CI:1.3−106.7). Internationally, guidelines vary regarding the upper age limit at which vaccination is offered in preference to immunoglobulin, 21−24 and in some countries, vaccination is the only form of PEP offered.12 Though in absolute terms, the number of secondary infections in this study is low, our findings suggest that a more conservative upper age limit for contact vaccination may be appropriate.

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This real-world evaluation illustrates the complexities of post-exposure prophylaxis in a low- endemic country29 where there are high levels of pre-existing immunity in some minority groups together with susceptible older adults at risk of severe infection. In the Netherlands, the incidence of acute hepatitis A infection has declined dramatically in recent years.30 Although outcomes of this evaluation and that of 2004 are not directly comparable, the same definitions and timeframes were used throughout and the general picture in recent years is one of smaller households (median of 1 versus 3 family/ household contacts per index case), less pre-existing natural immunity among contacts (41% versus 54%), and a lower proportion of co-infections (11% versus 28%) among susceptible contacts. This picture, together with the overall decline in incidence, probably reflects reduced household exposure and transmission through improved household hygiene and reduced virus importation from countries where endemicity of HAV is decreasing as socioeconomic, sanitary and water supply conditions improve (Turkey and Morocco in particular).

The proportion of IgM positive seroconversions was also reduced, 16%, versus 34% in the previous evaluation. In the latter (where only immunoglobulin was offered), only one-fifth of those who became anti-IgM positive were symptomatic, despite the 34% IgM-positive seroconversion rate. This was attributed to the attenuation of symptomatic infection by immunoglobulin. As vaccination can induce a transient IgM seropositivity,31 we considered only those who were jaundiced and/or had detectable HAV RNA as true secondary infections. Our rate of secondary infection may therefore be an underestimate (though we think it unlikely that viral RNA would no longer be detectable given the short follow-up time). Irrespective, this would imply a relatively greater proportion of symptomatic infections among those who became IgM positive in our vaccinated population. Whether this reflects a real difference, a vaccine effect or a hygiene effect is uncertain. Ultimately, the rate of symptomatic, laboratory confirmed secondary HAV infection among susceptible contacts was similar in both evaluations: 5.3% (6/112 from 2004−2012) versus 6.4% (12/186 from 1996−2000).

There were a number of study limitations. Firstly, as in the previous evaluation, those who did not undergo baseline serological testing (and were thus excluded) were younger than those who participated. As children are more likely to be susceptible than adults, the proportion with pre- existing immunity may therefore be overestimated. Secondly, contacts ≥10 years old who were asymptomatic and total anti-HAV positive at baseline were assumed to be immune and were not screened for IgM antibody. This could have resulted in the misclassification of contacts who in fact were asymptomatically co-infected, though the majority of older children and young adults develop symptoms. Thirdly, symptomatic contacts may have been more inclined to return for follow-up testing, leading to an overestimate of the secondary infection rate, but in any case,

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the proportion of seroconversions was small. Finally, we did not find any association between gender, ethnic background or household size and secondary infection, but as the absolute number of secondary infections in this study was small, the study may have been underpowered. It is possible that factors other than age (level of education for example) contributed to secondary HAV infection in those over 40 years who were vaccinated within 8 days of exposure.

In conclusion, timely administration (≤14 days post-exposure) of HAV vaccine in routine post- exposure prophylaxis was feasible and the incidence of laboratory confirmed, symptomatic secondary infection in contacts of hepatitis A cases younger than 40 years was low. Although larger studies are required, it may be prudent to limit routine use of vaccination in those over 40 years of age, irrespective of the duration post-exposure. Retaining the use of immunoglobulin as PEP of choice in older people and those at risk of severe illness seems appropriate. 6

Acknowledgements The authors would like to thank the nursing staff in the Department of Infectious Diseases, Public Health Service Amsterdam who interviewed the patients and collected the data, and Prof. Martien Borgdorff for his critical review of the manuscript.

References

1. Jacobsen KH, Wiersma ST. Hepatitis A virus seroprevalence by age and world region, 1990 and 2005. Vaccine 2010;28:6653-7. 2. Gingrich GA, Hadler SC, Elder HA, Ash KO. Serologic investigation of an outbreak of hepatitis A in a rural day-care center. Am J Public Health 1983;73:1190-3. 3. Koff RS. Hepatitis A. Lancet 1998;351:1643-9. 4. National Center for the coordination of Infectious Disease Control (LCI). Guideline: Hepatitis A. Bilthoven: LCI; 2011. [in Dutch] 5. Stokes J, Neefe J. The prevention and attenuation of infectious hepatitis by gamma globulin: preliminary note. JAMA 1945;127:144-45. 6. Brooks BF, Hsia DY, Gellis SS. Family outbreaks of infectious hepatitis; prophylactic use of gamma globulin. N Engl J Med 1953;249:58-61. 7. Ashley A. Gamma globulin; effect on secondary attack rates in infectious hepatitis. N Engl J Med 1954;250:412-7. 8. Mosley JW, Reisler DM, Brachott D, Roth D, Weiser J. Comparison of two lots of immune serum globulin for prophylaxis of infectious hepatitis. Am J Epidemiol 1968;87:539-50. 9. Sonder GJ, van Steenbergen JE, Bovée LP, Peerbooms PG, Coutinho RA, et al. Hepatitis A virus immunity and seroconversion among contacts of acute hepatitis A patients in Amsterdam, 1996-2000: an evaluation of current prevention policy. Am J Public Health 2004;94:1620-6. 10. Taliani G, Gaeta GB. Hepatitis A: post-exposure prophylaxis. Vaccine 2003;21:2234-7. 11. Health Council of the Netherlands. Variant Creutzfeldt-Jakob disease and blood transfusion 2001 (Publication no. 2001). [in Dutch] 12. De Schrijver K, Flipse W, Laisnez V, Mak R, Steebnergen JE van, et al. Hepatitis A. Guidelines for infectious disease control, Flanders. Edition 2011, 2011. [in Dutch]

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13. Van Herck K, Jacquet JM, Van Damme P. Antibody persistence and immune memory in healthy adults following vaccination with a two-dose inactivated hepatitis A vaccine: long-term follow-up at 15 years. J Med Virol 2011;83:1885-91. 14. Shouval D, Ashur Y, Adler R, Lewis JA, Miller W, et al. Safety, tolerability, and immunogenicity of an inactivated hepatitis A vaccine: effects of single and booster injections, and comparison to administration of immune globulin. J Hepatol 1993;18 Suppl 2:S32-7. 15. Werzberger A, Mensch B, Kuter B, Brown L, Lewis J, et al. A controlled trial of a formalin-inactivated hepatitis A vaccine in healthy children. N Engl J Med 1992;327:453-7. Mumps outbreak among vaccinated 16. Sagliocca L, Amoroso P, Stroffolini T, Adamo B, Tosti ME, et al. Efficacy of hepatitis A vaccine in prevention of secondary hepatitis A infection: a randomised trial. Lancet 1999;353:1136-9. 17. Tjon GM, Gotz H, Koek AG, de Zwart O, Mertens PL, et al. An outbreak of hepatitis A among homeless drug university students associated users in Rotterdam, The Netherlands. J Med Virol 2005;77:360-6. 18. Victor JC, Monto AS, Surdina TY, Suleimenova SZ, Vaughan G, et al. Hepatitis A vaccine versus immune globulin for postexposure prophylaxis. N Engl J Med 2007;357:1685-94. with a large party, The Netherlands, 2010 19. Crowcroft NS, Walsh B, Davison KL, Gungabissoon U. Guidelines for the control of hepatitis A virus infection. Commun Dis Public Health 2001;4:213-27. 20. National Advisory Committee on Immunization (NACI). Supplementary statement on hepatitis A vaccine (ACS-4). An Advisory Committee Statement (ACS). Can Commun Dis Rep 2000;26:12-8. 21. Centers for Disease Control and Prevention. Update: Prevention of hepatitis A after exposure to hepatitis A virus and in international travelers. Updated recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Morb Mortal Wkly Rep 2007;56:1080-4. 22. National Advisory Committee on Immunization and the Public Health Agency of Canada. Hepatitis A vaccine: Post exposure immunization. Canadian Immunization Guide, Evergreen Edition. Part 4: Active Vaccines 2012. Available at: http://www.phac-aspc.gc.ca/publicat/cig-gci/p04-hepa-eng.php Accessed: 20 September 2013. 23. Thomas L, and the Hepatitis A Guidelines Group. Guidance for the prevention and control of hepatitis A infection. Health Protection Agency, 2009 24. Queensland Health. Hepatitis A: Queensland Health Guidelines for Public Health Units. 2013. Available at: http://www.health.qld.gov.au/cdcg/index/hepa.asp Accessed: 23 September 2013. 25. National Advisory Committee for Infectious Disease Control (LOI) (2002) Advice of the LOI workgroup: safety of gammaglobulin and the post-exposure policy for hepatitis A control in The Netherlands. [in Dutch] 26. Government of The Netherlands. Public Health Act of 2008 (2008). Available: https://zoek. officielebekendmakingen.nl/ stb-2008-460.html#d764e2107. Accessed 27 September 2013. 27. Tjon GM, Coutinho RA, van den Hoek A, Esman S, Wijkmans CJ, et al. High and persistent excretion of Katie Greenland hepatitis A virus in immunocompetent patients. J Med Virol 2006;78:1398-405. Jane Whelan 28. Briem H, Safary A. Immunogenicity and safety in adults of hepatitis A virus vaccine administered as a single dose with a booster 6 months later. J Med Virol 1994;44:443-5. Ewout Fanoy 29. Lee PI. Hepatitis A vaccine versus immune globulin for postexposure prophylaxis. Marjon Borgert N Engl J Med 2008;358:531-2; author reply 32. 30. Whelan J, Sonder G, van den Hoek A. Declining incidence of hepatitis A in Amsterdam (The Netherlands), Koen Hulshof 1996-2011: second generation migrants still an important risk group for virus importation. Kioe-Bing Yap Vaccine 2013;31:1806-11. Corien Swaan 31. Shouval D, Ashur Y, Adler R, Lewis JA, Armstrong ME, et al. Single and booster dose responses to an inactivated hepatitis A virus vaccine: comparison with immune serum globulin prophylaxis. Tjibbe Donker Vaccine 1993;11:S9-1 Rob van Binnendijk Hester de Melker Susan Hahné

Vaccine 2012;30:4676-80

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Mumps outbreak among vaccinated university students associated with a large party, The Netherlands, 2010 7

Katie Greenland Jane Whelan Ewout Fanoy Marjon Borgert Koen Hulshof Kioe-Bing Yap Corien Swaan Tjibbe Donker Rob van Binnendijk Hester de Melker Susan Hahné

Vaccine 2012;30:4676-80

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Abstract

We investigated a mumps outbreak within a highly vaccinated university student population in the Netherlands by conducting a retrospective cohort study among members of university societies in Delft, Leiden and Utrecht. We used an online questionnaire asking for demographic information, potential behavioural risk factors for mumps and the occurrence of mumps. Vaccine status from the national vaccination register was used. Overall, 989 students participated (20% response rate). Registered vaccination status was available for 776 individuals, of whom 760 (98%) had been vaccinated at least once and 729 (94%) at least twice. The mumps attack rate (AR) was 13.2% (95% CI:11.1–15.5%). Attending a large student party, being unvaccinated and living with more than 15 housemates were independently associated with mumps (RR 42 [95% CI:10.1– 172.4]; 3.1 [95% CI:1.7–5.6] and 1.8 [95% CI:1.1–3.1], respectively). The adjusted VE estimate for two doses of MMR was 68% (95% CI:41–82%). We did not identify additional risk factors for mumps among party attendees. The most likely cause of this outbreak was intense social mixing during the party and the dense communal living environment of the students. High coverage of MMR vaccination in childhood did not prevent an outbreak of mumps in this student population.

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Introduction

The Netherlands introduced mumps vaccination into the National Immunisation Programme in 1987 using the measles, mumps and rubella vaccine (MMR). The MMR vaccine used contains the Jeryl-Lynn mumps virus strain and is administered in a two-dose schedule at 14 months and nine years of age. Nationally, the MMR vaccination coverage at 10 years of age for the second MMR dose has been consistently above 90% since the programme’s inception.1 Nevertheless, in recent years the Netherlands has experienced localised outbreaks of mumps: in 2004 (genotype G5) among students at an international university of hospitality management (105 cases reported, of whom 62 of 64 (97%) with known vaccination status were vaccinated with a least one MMR dose);2 and between 2007 and 2009 in the so-called Bible Belt (genotype D4),3 an area traditionally associated with low vaccine uptake and outbreaks of vaccine-preventable diseases.4–6 Whereas the occurrence of mumps in communities religiously opposed to vaccination can be anticipated, mumps in highly vaccinated adult populations is concerning and warrants investigation, particularly as the rate of certain complications of mumps increases with age.7 7 Mumps became a notifiable disease in the Netherlands in December 2008. From 1 December 2009 to 20 April 2010, 172 mumps cases were notified to municipal health authorities across the country, a marked increase from the 65 cases notified in the eleven preceding months in 2009. Seventy-nine cases were notified to Municipal Health Service (MHS) Zuid-Holland West (including the city of Delft), 44 were notified in the Leiden region (MHS Hollands-Midden), 11 were notified to MHS Utrecht and 38 were notified in other regions across the country. The majority of cases (70%; n=114/164 cases with known vaccination status) had received at least one dose of MMR. Overall, 65% of cases (n=112) were students, of whom 27 (24%) reported having attended at least one evening of a large four-day party in Leiden (23–26 February, week 8). This party was organised and hosted by students in nine rooms spread across several floors of a members-only student association building. It was attended by 1175 Leiden students and 1850 students from other cities. The majority of cases reported to MHS Hollands−Midden occurred in week 11, one incubation period after the party, further implicating the event as a source of transmission, described in earlier communication about this outbreak.8

Outbreaks of mumps in educational settings such as schools and colleges have been previously reported.9–12 Explanations for this include the close contact environment that facilitates transmission and possibly a particular susceptibility for mumps in adolescents who were vaccinated in childhood.12,13 The 2009–2010 mumps outbreak in a highly vaccinated student population provided an opportunity to assess risk factors for mumps in this population and to investigate factors associated with mumps vaccine failure among vaccinated party attendees.

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Methods

We conducted a retrospective cohort study among students from the three university cities most affected by the outbreak: Delft, Utrecht and Leiden. Within these cities the study was restricted to student associations invited to the party in Leiden to permit investigation of party-related risk factors. Student associations in the Netherlands are similar to North American fraternities and sororities in that membership is applied for and approved after an initiation period. Members have close social ties: they typically live together and social events are frequently organised and attended by members only. Each of the eight student associations of this type in the Netherlands hosts a three- or four-day party once a year which is open to members of the other associations. In May 2010, all 4988 members of the four selected student associations in Delft (n=356 women; n=1044 men), Leiden (n=1400; sex break- down of members not provided but estimated by society to be an approximately equal sex ratio) and Utrecht (two societies: n=1288 women; n=900 men) were invited to the study by email. Invitation and reminder emails (sent one week later) were circulated via the society’s mailing list and contained a link to the online questionnaire (Questback, Oslo, Norway).

To investigate risk factors associated with mumps among these student associations the questionnaire asked about demographic characteristics including current living arrangements, MMR vaccination history, and history of mumps infection. Informed consent was sought to verify MMR vaccination status using the national vaccination register. A case was defined as a student with self- reported mumps (swelling of one or both cheeks with symptoms lasting at least two days) since 1st September 2009. To investigate risk factors associated with vaccine failure among vaccinated party attendees, additional information was requested from party attendees; specifically, the day(s) of party attendance, locations visited at the party (from a list of nine rooms or areas within the student association including several bars, themed rooms with DJs and two smoking rooms), contact with shared items including food, drinks and cigarettes, and close personal contact (kissing) during the party or at an after party.

Questionnaire responses were downloaded from the password- protected website and imported to STATA 10 for analysis.14 Individuals with a history of mumps prior to September 2009 (n=13) or whose MMR vaccination status could not be determined from the vaccine register (n=30) were excluded from the analysis. Associations between risk factors and self-reported mumps were first explored in univariable analysis. Variables with a p-value <0.25 (from the univariable analysis), as well as age and sex, were entered into the multivariable regression model. When we found evidence of collinearity among explanatory variables we selected the variable which gave the best model fit (based on the Bayesian Information Criterion, BIC) into the final model.

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We estimated vaccine effectiveness (VE) as 1 minus the relative risk (RR) (VE =1- RR), using the adjusted RR for mumps in vaccinated compared to unvaccinated participants.

Persons who were not susceptible to mumps at the time of the party (mumps with date of onset prior to the minimum incubation time of 12 days after the first day of the party (23rd February)) were excluded from the analysis of party-related risk factors associated with mumps failure. Cases arising after the maximum incubation time (25 days after the last day of the party (26th February)) were included as non-cases so risk factors associated with the party could be investigated.

Results

Study population Overall, 989 individuals responded to the questionnaire (response rate =20%; 10% among male students, 31% among female students) and reported studying in Delft (n=212), Utrecht (n=517) or 7 Leiden (n=195). For 65 respondents, the city of study was not available. Respondents were aged between 17 and 28 years (median age 21 years) and were predominantly female (75%; n=738). The median age of the invited population of society members in these cities was also 21 years, 47% were female. MMR vaccination status was verified for 91% (776/853) of consenting survey respondents: 94% (n=729) had received two doses of MMR vaccine, 4% (n=31) were vaccinated with one dose of MMR and 2% (n=16) had never been vaccinated with MMR (Table).

Overall, 946 of the 989 survey respondents answered questions about mumps disease, of whom 125 reported having had mumps (attack rate:13.2%, 95% CI:11.1–15.5%). Half the cases (54%) reported visiting their GP, of whom seven were diagnosed with complications, specifically meningitis (1; 0.8% of cases), pancreatitis (2; 1.6%), orchitis (3; 8% of male cases) and deafness (4; 3.2%). One additional individual was admitted to hospital for one night due to the severity of symptoms but had no complications. Date of symptom onset ranged from 25th December 2009 to 1st June 2010 (n=110) (Figure. 1). The number of cases peaked in mid-March (week 11), about one incubation period15 after the party.

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Figure. 1. Epidemic curve showing the number of mumps cases by week of symptom onset and city of study, December 2009–June 2010, the Netherlands (n=110).

Risk factors associated with mumps The attack rate among men was higher than among women (17% vs. 12%, p=0.06). Age-specific attack rates, did not significantly differ (p=0.12) and there was no difference in the mean number of years since last vaccination between cases (12.2 years) and non-cases (12.5 years), p=0.54. The attack rate was higher among respondents from Leiden (25%) than among those from Delft (12%) and Utrecht (9%) (p=0.05) and was also higher among party-attendees than non-attendees (23% vs. 10% respectively; Table). The attack rate increased with the number of household contacts, with individuals living with fifteen or more housemates (large society houses of up to 40 students, not dorms) twice as likely to have had mumps than those living with fewer than five other people (p-trend =0.001; Table). Among cases, attending the party and studying in Leiden were closely correlated: 93% of cases in Leiden attended the party, compared with 29% in Delft and 14% in Utrecht. After adjusting for age and sex and observing that party attendance gave a better model fit than city of study, not being vaccinated, having more than 15 housemates and attending the party were independently associated with developing mumps (Table). When restricting the cases to those who were susceptible at the time of the party (n=35), and including cases that arose more than one incubation time after the party as non-cases, the relative risk of acquiring mumps associated with party attendance was 42 (95% CI:10.1–172.4; p < 0.0001).

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Vaccine effectiveness In total, 92 of 101 (91%) mumps cases with known vaccination history had been twice-vaccinated with MMR. Among individuals with known vaccination history and known mumps disease status (n=751), the attack rate was 44% (7/16) among unvaccinated individuals, and 7% (2/29) and 13% (92/706) among once and twice- vaccinated individuals respectively. The adjusted VE estimate for two doses of MMR was 68% (95% CI:40.6–82.2%).

Table 1. Characteristics and risk factors for mumps among the entire study population (n=946).

7

* n=125, all mumps cases since September 2009 (excluding 3 cases with past infections). † confirmed with vaccination records. 776 records were verified out of 853 consenting participants. Not all individuals with confirmed vaccination status provided information on whether or not they had had mumps, hence denominators vary. Of 735 individuals vaccinated at least once, 729 were vaccinated twice. The 29 once- vaccinated individuals are excluded from the analysis.

Factors associated with vaccine failure among vaccinated party-attendees Analysis was restricted to vaccinated party-attendees with known mumps disease status (n=206). The attack rate among party-attendees was similar among men (14.2%) and women (11.6%) (p=0.54) and across all age groups (p=0.66). Two thirds (67%) of students who attended the party were from Leiden (the host city), 21% from Utrecht and 12% from Delft. The majority of

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Delft and Utrecht students (84% and 98%, respectively) bought a one-day ticket, typically attend- ing on the third day. Conversely, Leiden students more frequently bought four-day tickets: 87% of students from Leiden attended on at least three evenings. The attack rate was higher among students who attended the party on the third day (14.1%) than those who did not attend on this day (4.6%) but this difference was not statistically significant (RR:3.1; 95% CI:0.8–12.4, p=0.08). We found no association between any of the specific behaviours at the party or other potential risk factors studied and the occurrence of mumps.

Discussion

We report a large mumps outbreak with a self-reported attack rate of 13% among a university student population of whom 94% was fully vaccinated. Our findings suggest that, together with reduced vaccine effectiveness at student age, the most likely cause of this outbreak is a combination of intense social mixing during a student party in Leiden and the dense communal living environment of the students. The shape of the epidemic curve is consistent with a point- source exposure at the party: one third of reported cases arose about one incubation period after the party, and party attendance was found to be an independent risk factor for mumps. Among students who attended the party, no specific risk factor was identified. It seems plausible that the circumstances of this party – taking place over four days and attended by students from multiple cities at a time when mumps was known to be circulating – provided an environment that promoted transmission. Considering that the number of cases in the period after the peak following the party quickly declined may suggest that sustained mumps transmission in this population is unlikely. However, increased transmission at other social events or in the winter season could prove this assumption too optimistic.

Living with a large number of housemates increased the risk of mumps. This is consistent with results found elsewhere.16 In addition to the number of housemates, dormitory residence has also been associated with an increased risk of mumps among students.2,17 However, student dormitories do not exist in the Netherlands.

In addition to the above-discussed risk factors for exposure to the mumps virus, risk factors for vaccine failure should also be considered when studying an outbreak of a vaccine preventable disease in a highly vaccinated population.17–19 Precise estimation of vaccine effectiveness in this setting is not feasible due to the low numbers of unvaccinated cases as reflected in the wide confidence interval around the VE estimated in our study. However, even with the large confidence interval, our estimated VE supports the growing body of evidence that two doses of MMR do not confer long-term protection against mumps.12,13,18 Potential reasons for vaccine

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failure include primary vaccine failure, waning immunity over time (secondary vaccine failure) and the possibility that the vaccine strain (genotype A) affords lower than optimal protection against heterologous genotypes such as the G genotypes which caused this outbreak and outbreaks in other countries.13,18,20–24 Unfortunately we could not assess the effect of either of these factors in this outbreak, as it was a single genotype outbreak affecting a group of individuals within a narrow age-range and a long time has elapsed since vaccination. The key limitation we faced in this study was the relatively low response rate, although in a large, multi- centre study of web-based surveys in student populations in the USA, the response rate was similar (20%).25 The low response rate may not necessarily have introduced bias into our study.26 While we had no specific information on non-respondents, student association members invited to participate were a socio-demographically homogenous group. It is unknown how in this context, non-respondents’ behaviour might differ and what impact, if any, this would have on the risk of disease. Non-responders were more frequently male (53% of invitees were male compared with 25% of respondents), again not atypical in survey research.25 It is also possible that those who attended the party and people with mumps were more likely to have responded to 7 the survey. This may have caused an overestimation of the attack rate and the risk of acquisition of mumps among respondents. As nearly all cases in Leiden attended the party we were unable to disentangle the effect of living in Leiden from that of attending the party. We believe selective participation of students with other risk factors is unlikely, suggesting all other measures of association are not biased by non-response. The slight delay between the party and the study could have affected recall of party-related risk factors but it is unlikely that recall would have been associated with mumps disease status.

National recommendations to control the mumps outbreak among university students in the Netherlands have included the advice to ensure students have received two doses of MMR. The importance of this is underlined by the observation that vaccinated individuals with mumps are less likely to develop complications than unvaccinated individuals with mumps.27,28 Even though individuals with asymptomatic mumps virus infection are still infectious, the potential for transmission may be reduced by recommending students suffering from mumps not to attend large indoor social gatherings. Cancellation of a party or large social event when mumps is known to be circulating in a population is also likely to be a useful control measure. Other options for control include delaying the age of the second MMR dose in the routine vaccination schedule or adding a third MMR.16,21,23,29 The former is unlikely to be favourable, given that it would lead to an increase in measles, mumps and rubella susceptibility among children. A national outbreak control team convened in the Netherlands in January 2011, during which the addition of a third MMR dose to the vaccination schedule was discussed. It was advised that, given the cost, logistics and expected low vaccine uptake among students, and the low morbidity

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related to mumps, this intervention could not be justified based on the current available evidence and the uncertain effectiveness of a third dose. Studies that can shed more light on the reasons for waning immunity are needed so that appropriate solutions can be developed and policy recommendations can be made.

Acknowledgements We are very grateful to the President and other board members of the student associations in Delft, Utrecht and Leiden who piloted the questionnaire and sent the questionnaire to the society mailing list. We also wish to thank all members of the student associations in Delft, Leiden and Utrecht who completed the survey. We would also like to thank Hein Boot and Marianne van der Sande for reviewing the manuscript.

References

1. van Lier EA, Oomen PJ, Giesbers H, Drijfhout IH, de Hoogh PAAM, et al. National Immunisation Programme in the Netherlands. Annual Report 2011. Bilthoven: National Institute for Public Health and the Environment (RIVM). 2011. Available from: http://www.rivm.nl/bibliotheek/rapporten/210021014.html; [in Dutch] 2. Brockhoff HJ, Mollema L, Sonder GJ, Postema CA, van Binnendijk RS, et al. Mumps outbreak in a highly vaccinated student population, the Netherlands, 2004. Vaccine 2010;28:2932–6. 3. Karagiannis I, van Lier A, van Binnendijk R, Ruijs H, Fanoy E, et al. Mumps in a community with low vaccination coverage in the Netherlands. Euro Surveill 2008;13:pii:18901. 4. Oostvogel PM, van Wijngaarden JK, van der Avoort HG, Mulders MN, Conyn-van Spaendonck MA, et al. Poliomyelitis outbreak in an unvaccinated community in the Netherlands: 1992–93. Lancet 1994;344:665–70. 5. Hahné S, Macey J, van Binnendijk R, Kohl R, Dolman S, et al. Rubella outbreak in the Netherlands, 2004- 2005: high burden of congenital infection and spread to Canada. The Pediatr Infect Dis J 2009;28:795–800. 6. Rümke HC, Visser HK. Childhood vaccinations anno 2004. I. Effectiveness and acceptance of the Dutch National Vaccination Programme. Ned Tijdschr Geneeskd 2004;148:356–63. 7. Fine P, Mulholland K. Community immunity. In: Plotkin SA, Orenstein WA, Offit PA, editors. Vaccines. 5th ed. Philadelphia, PA: Elsevier Inc.; 2008. p.1573–92, chap. 71. 8. Whelan J, van Binnendijk R, Greenland K, Fanoy E, Khargi M, et al. Ongoing mumps outbreak in a student population with high vaccination coverage, Netherlands, 2010. Euro Surveill 2010;15(17):pii:19554. 9. Wharton M, Cochi SL, Hutcheson RH, Bistowish JM, Schaffner W. A large outbreak of mumps in the postvaccine era. J Infect Dis 1988;158(6):1253–60. 10. Kancherla VS, Hanson IC. Mumps resurgence in the United States. J Allergy Clin Immunol 2006;118:938–41. 11. Huang AS, Cortese MM, Curns AT, Bitsko RH, Jordan HT, et al. Risk factors for mumps at a university with a large mumps outbreak. 2009;124:419–26. 12. Whyte D, O’Dea F, McDonnell C, O’Connell NH, Callinan S, et al. Mumps epidemiology in the mid-west of Ireland 2004–2008: increasing disease burden in the university/college setting. Euro Surveill 2009;14:pii=19182. 13. Dayan GH, Quinlisk MP, Parker AA, Barskey AE, Harris ML, et al. Recent resurgence of mumps in the United States. N Engl J Med 2008;358:1580–9. 14. StataCorp. Statistical Software: Release 10. College Station: Stata Corporation; 2008. 15. Sartwell PE. The incubation period and the dynamics of infectious disease. Am J Epidemiol 1966;83:204–6.

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16. Centers for Disease Control and Prevention. Update: mumps outbreak – New York and New Jersey, June 2009–January 2010. MMWR Morb Mortal Wkly Rep. 2010;59:125–9. 17. Cortese MM, Jordan HT, Curns AT, Quinlan PA, Ens KA, et al. Mumps vaccine performance among university students during a mumps outbreak. Clin Infect Dis 2008;46:1172–80. 18. Dayan GH, Rubin S. Mumps outbreaks in vaccinated populations: are available mumps vaccines effective enough to prevent outbreaks? Clin Infect Dis 2008;47:1458–67. 19. Marin M, Quinlisk P, Shimabukuro T, Sawhney C, Brown C, et al. Mumps vaccination coverage and vaccine effectiveness in a large outbreak among college students – Iowa, 2006. Vaccine 2008;26:3601–7. 20. Bernard H, Schwarz NG, Melnic A, Bucov V, Caterinciuc N, et al. Mumps outbreak ongoing since October 2007 in the Republic of Moldova. Euro Surveill 2008;13:pii:8079. 21. Quinlisk MP. Mumps control today. J Infect Dis 2010;202:655–6. 22. Watson-Creed G, Saunders A, Scott J, Lowe L, Pettipas J, et al. Two successive outbreaks of mumps in Nova Scotia among vaccinated adolescents and young adults. CMAJ 2006;175:483–8. 23. Dominguez A, Torner N, Castilla J, Batalla J, Godoy P, et al. Mumps vaccine effectiveness in highly immunized populations. Vaccine 2010;28:3567–70. 24. Rubin SA, Qi L, Audet SA, Sullivan B, Carbone KM, et al. Antibody induced by immunization with the Jeryl Lynn mumps vaccine strain effectively neutralizes a heterologous wild-type mumps virus associated with a large outbreak. J Infect Dis 2008;198:508–15. 25. Sax LJ, Gilmartin SK, Bryant AN. Assessing response rates and nonresponse bias in web and paper surveys. Res High Educ 2003;44:409–32. 26. Krosnick JA. Survey research. Annu Rev Psychol 1999;50:537–67. 7 27. Yung CF, Andrews N, Bukasa A, Brown KE, Ramsay M. Mumps Complications and Effects of Mumps Vaccination: England and Wales, 2002–2006. Emerg Infect Dis 2011;17:661–7. 28. Hahné S, Whelan J, van Binnendijk R, Swaan C, Fanoy E, et al. Mumps vaccine effectiveness against orchitis. Emerg Infect Dis 2012;18:191–3. 29. Vandermeulen C, Leroux-Roels G, Hoppenbrouwers K. Mumps outbreaks in highly vaccinated populations: what makes good even better? Hum Vaccin 2009;5:494–6.

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Q fever among culling workers, The Netherlands, 2009–2010

Jane Whelan Barbara Schimmer Peter Schneeberger Jamie Meekelenkamp Arnold IJff Wim van der Hoek Mirna Robert-Du Ry van Beest Holle

Emerg Infect Dis 2011;17:1719-23.

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Q fever among culling workers, The Netherlands, 2009–2010 8

Jane Whelan Barbara Schimmer Peter Schneeberger Jamie Meekelenkamp Arnold IJff Wim van der Hoek Mirna Robert-Du Ry van Beest Holle

Emerg Infect Dis 2011;17:1719-23.

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Abstract

In 2009, dairy goat farms in the Netherlands were implicated in >2,300 cases of Q fever; in response, 51,820 small ruminants were culled. Among 517 culling workers, despite use of personal protective equipment, 17.5% seroconverted for antibodies to Coxiella burnetii. Vaccination of culling workers could be considered.

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Introduction

Q fever is caused by the bacterium Coxiella burnetii. Since , annual outbreaks originating from dairy goat and sheep farms have occurred. In 2009, a total of 2,354 cases in humans were reported, 20% of patients were hospitalized, and at least 6 died.1 Among acute cases, ≈2% become chronic and fatality rates for untreated chronic patients are high.2 To stop spread, culling was conducted from December 19, 2009, through June 22, 2010, on 87 infected commercial dairy goat farms and 2 dairy sheep farms (Figure 1). A total of 50,355 pregnant goats and sheep and 1,465 bucks were culled.3 Animal pregnancies were confirmed by abdominal ultrasound; pregnant animals were sedated and euthanized and their corpses were transported to a destruction facility. Culling workers were provided with personal protective equipment (PPE) and advised to read occupational health and hygiene regulations.4 To determine seropositivity of workers before culling, incidence of symptomatic and asymptomatic C. burnetii infection during culling, and risk factors associated with occupational exposure, we conducted a prospective cohort study. 8

Figure 1. Residential location of 246 culling workers who were seronegative in December 2009 and their serostatus in June 2010 with location of 89 farms declared to be infected (by PCR-positive bulk-milk monitoring) in 2009 and 2010, the Netherlands. Ig, immunoglobulin. Seroconversion detected by ELISA was confirmed by immunofluorescence assay for 40 persons (38 [95%] at titers >128 and 2 [5%] at titers of 32).

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Methods

Participants were 517 workers who culled goats and sheep during December 2009-June 2010. Serum samples were required from workers before employment in December 2009 (pre-cull)4 and voluntary post-cull samples were requested in June 2010. In June workers were asked to complete a questionnaire about symptoms, occupational exposure, adoption of hygiene measures and PPE use (filtering facepiece masks, gloves, overalls, hairnets), demographics, medical history, and other animal contact. Written informed consent was obtained. Information about farms (animal numbers and abortions), and workers (hours worked per person, job description) was available from occupational records.

Serum was tested for immunoglobulin (Ig) G and IgM antibodies against C. burnetii phase II by using ELISA (Virion/Serion, Würzburg, Germany). According to manufacturer instructions, IgG phase II seropositivity was defined as negative for titers ≤30 IU/mL and positive for titers >30 IU/ mL. IgM phase II was qualitatively positive or negative. A worker was considered seronegative if a phase II sample was IgM and IgG negative and seropositive if IgM and/or IgG positive. Positive results were confirmed by immunofluorescence assay (Focus Diagnostics, Cypress, CA, USA) titres ≥32. Symptomatic infection was defined as fever or rigors, and ≥1 of the following after December 1, 2009: malaise, headache, cough, nausea, diarrhoea, shortness of breath, pleuritic chest pain or myalgia. Intensity of occupational exposure was summarised as follows: hours worked, weighted mean farm-size (animal number), whether animal abortions were reported, and whether work was performed on average inside or outside the stable (proxy for direct/ indirect animal contact). Months worked were dichotomized as cold (December 2009-March 2010)5 and warm (April-June 2010).6 Use of PPE was classified as compliant or non-compliant.

To calculate distance of workers’ residence to the nearest infected farm, we used ArcGIS software (www.esri.com/software/arcgis/index.html). We used Stata version 11 (StataCorp LP, College Station, TX, USA) to examine univariable associations (Pearson χ2 or Fisher exact test). Variables with probability p<0.2 and known risk factors for Q fever were selected for binomial regression analyses. Interactions between significant variables in the multivariable model were investigated. Missing values were excluded.

Results

Of 517 respondents, 453 gave pre-cull blood samples, 246 of these gave post-cull samples and 351 completed the questionnaire. Age, gender and residential distance from the nearest infected farm were available from occupational health records. Participant median age was 47 years

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(range 19-67) and 97% were male. Before culling, 14 (3.1%) were IgM II and IgG II positive, 8 (1.8%) were IgM II positive only, 36 (8%) were IgG II positive only, and 395 (87%) were IgG II and IgM II negative; i.e., any seropositivity was found for 13.0%. Pre-cull blood samples indicated more seropositivity among workers who lived within 5 km of an infected farm and had regular work contact with sheep and goats (excluding culling). Prior culling experience was more common among seronegative than seropositive workers (Table 1). Among those who were IgG seropositive before culling, none became IgM seropositive after culling.

Among the 395 workers who were seronegative before culling, 246 (62%) provided a follow-up blood sample in June 2010, and 199 (80.8%) of these completed the questionnaire. Those who participated in June were more likely to be male (p=0.015) and 40-60 years of age (p<0.001). Seroconversion among 246 seronegative respondents occurred as follows: 23 (9.4%) became IgG and IgM seropositive, 7 (2.9%) became IgM positive only, 13 (5.3%) became IgG positive only, and 203 (82.5%) remained seronegative; i.e., any seroconversion was found for 17.5%. Questionnaire respondents who seroconverted had more symptoms after December 1, 2009, (9 [31%] of 29) than nonseroconverters (17 [11%] of 150; relative risk 2.7, 95% confidence interval 1.4-5.5, p=0.005). Symptomatic seroconverters reported fever and/or rigors and malaise (n=7), headache (n=6), cough (n=6) or myalgia (n=4). Mean duration of illness was 7.6 (range 1-14) days. 8

The univariable model indicated significance for total hours worked, farm size, and working inside the stable (p<0.05; Table 2). The multivariable model indicated significance for working >100 hours on the farm and working inside the stable (Table 2; Figure 2). Interaction effects were not significant.

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Table 1. Baseline characteristics of workers before culling small ruminants, the Netherlands, December 2009*.

Characteristic Total no. workers No. (%) workers

Seronegative, n=395 Seropositive, n=58 p value† Sex‡ M 342 303 (89) 39 (11) F§ 11 10 (91) 1 (9) 0.812 Age group, y‡ <40 114 95 (83) 19 (17) 40‒49 157 137 (87) 20 (13) 50‒59 154 139 (90) 15 (10) ≥60 26 22 (85) 4 (15) 0.398 Distance of residence from nearest infected farm, km‡ ≤5 116 95 (82) 21 (18) >5 317 282 (89) 35 (11) 0.052 Level of education¶ Low 48 43 (90) 5 (10) Medium 132 117 (89) 15 (11) High 53 45 (85) 8 (15) 0.725 Medical history¶ # No 159 140 (88) 19 (12) Yes 57 47 (83) 10 (18) 0.288 Current smoker¶ No 189 162 (86) 27 (14) Yes 53 48 (91) 5 (9) 0.357 Previous culling experience¶ No 116 94 (81) 22 (19) Yes 135 124 (92) 11 (8) 0.011 Regular occupational contact with sheep or goats¶ No 202 182 (90) 20 (10) Yes 34 24 (71) 10 (29) 0.002 * Missing values exlcuded from the analysis. † Pearson χ2 ‡ Maximum, 453 respondents. Data available from occupational records. § No female respondents were pregnant. ¶ Maximum, 251 respondents. Data available from questionnaire responses only. # History of cardiorespiratory disease, liver disorders, diabetes, cancer, immunosuppression, allergies, skin conditions.

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Table 2. Variables associated with Q fever seroconversion among 246 workers who were seronegative before culling small ruminants, the Netherlands, 2009* Variable No. (%) workers Univariable analysis Multivariable analysis† Total Sero− RR (95%CI) p RR (95%CI) p conversion value‡ value Total 246 (100) 43 (17) Sex F 6 (2) 2 (33) ref. M 240 (98) 41 (17) 0.51 (0.16−1.64) 0.301 Age, y ≤45 years 96 (39) 14 (15) ref. ref. >45 years 150 (61) 29 (19) 1.33 (0.74−2.38) 0.339 2.0 (0.93−4.16) 0.07 Level of education Low 39 (21) 5 (13) ref. Medium 103 (55) 18 (17) 1.36 (0.54−3.42) High 44 (24) 8 (18) 1.42 (0.51−3.98) 0.765 Minimum distance of residence from nearest infected farm, km >5km 174 (73) 32 (18) ref. <=5km 63 (27) 9 (14) 0.78 (0.39−1.53) 0.46 Medical History§ No 128 (75) 23 (18) ref. Yes 42 (25) 5 (12) 0.66 (0.27−1.63) 0.358 Current or past smoker No 84 (44) 16 (19) ref. Yes 108 (56) 16 (15) 0.78 (0.41−1.46) 0.435 Total hours worked inside farm perimieter¶ 0−20 81 (33) 5 (6) ref. ref. 8 21−100 82 (34) 18 (22) 3.56 (1.39−9.12) 5.53 (0.71−42.77) 0.102 >100 80 (33) 20 (25) 4.05 (1.60−10.26) 0.003 7.75 (1.02−58.99) 0.048 Mean farm size ≥1500 animals # No 167 (68) 22 (13) ref. ref. Yes 79 (32) 21 (27) 2.02 (1.18−3.44) 0.01 1.75 (0.93−3.30) 0.081 Worked mostly inside stable No 110 (45) 11 (10) ref. ref. Yes 133 (55) 31 (23) 2.33 (1.23−4.42) 0.006 2.58 (1.04−6.37) 0.04 Animal abortions on farm No 208 (85) 33 (16) ref. ref. Yes 38 (15) 10 (26) 1.66 (0.89−3.07) 0.119 0.93 (0.45−1.91) 0.844 Any Previous culling experience No 85 (43) 15 (18) ref. Yes 114 (57) 17 (15) 0.84 (0.45−1.59) 0.603 Adherence to hygiene and preventive Measures** Fully compliant 91 (50) 13 (14) ref. ref. Non−compliant 91 (50) 17 (19) 1.31 (0.68−2.53) 0.424 0.94 (0.51−1.72) 0.829 Months spent culling 2009 Dec−2010 Mar only (mean temperature 3.2 °C) 105 (54) 18 (17) ref. 2010 Apr−Jun only mean temperature 13.9°C) 2 (1) 1 (50) 2.92 (0.69−12.41) 2009 Dec − 2010 Jun 87 (45) 21 (24) 1.41 (0.80−2.47) 0.288 * Total for each category may not be n=246 due to missing data. RR, risk ratio; CI, confidence interval. †All data available for n=180 in multivariable analysis ‡ Pearson χ2. § History of cardiorespiratory disease, liver disorders, di- abetes, cancer, immunosuppression, allergies, skin conditions. ¶ Data only available for n=194, those who worked inside the farm perimeter. # Weighted mean number of animals on farms worked by participants. ** Includes wearing mask, gloves, overalls, hairnet, showering after exposure.

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Figure 2. Predicted probabilities of seroconversion among small ruminant culling workers by total hours worked, weighted mean farm size, and location on farm while working during December 2009-June 2010, the Netherlands. Seroconversion probabilities calculated by multivariable model adjusted for age group, occurrence of animal abortions on the farms worked, and compliance with wearing personal protective equipment.

Discussion

Seroconversion for C. burnetii among 17.5% of culling workers who were seronegative before culling provides evidence of high-risk work. Before culling, seroprevalence was 13%, similar to that among blood donors in a high-incidence area in the Netherlands in 2009 (H.L Zaaijer, pers. comm.) and in similar high-risk occupational groups.7 Laboratory testing by ELISA is an accepted method in an acute setting8 and positive results (including positive IgM only) were confirmed by immunofluorescence assay. Nonparticipants were in the youngest and oldest age-groups; their effect on the proportion of seroconversion is uncertain. Eighteen workers (excluded for not providing a follow-up blood sample) completed the questionnaire in June. Symptom incidence for these 18 workers was the same as that of included participants. Symptomatic infection (31% of seroconverters) was probably underestimated. A diagnosis of Q fever was self-reported (unconfirmed) to the occupational health service by eight workers who did not participate in the study. During December-July 2010, the national infectious disease surveillance system reported eleven culling-related cases of acute Q fever; two of these patients were hospitalized. A strong association was shown between risk for seroconversion and total hours worked on the farms and working inside the stable. In other settings internationally, a risk gradient has also been shown for close direct and indirect animal contact over time.9,10 In our study half of participants had experience with previous animal epidemics (avian influenza, foot-and-mouth disease, classical swine fever) and using PPE. Their compliance with PPE was reportedly high; however, a key

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problem was not wearing PPE while taking work breaks but remaining on the farm. Given the high risk for infection despite extensive personal protective measures during culling, additional preventive measures are needed. The Health Council of the Netherlands issued guidelines for persons in risk groups who would benefit from vaccination against Q fever.11 Culling workers were not included in these guidelines. The efficacy of human Q fever vaccine has been shown to be high for young and healthy persons in similar occupational groups.12-14 Vaccination of culling workers could be considered if further animal culling is advised.

Acknowledgements

We thank Ben Bom for providing the map and distance calculations; Daan Notermans, Marianne van der Sande, Ioannis Karagiannis, Biagio Pedalino for their scientific input; the culling workers and their affiliated organisations for their participation; and the Food and Consumer Product Safety Authority for facilitating this study.

References

1. van der Hoek W, Dijkstra F, Schimmer B, Schneeberger PM, Vellema P, et al. Q fever in the Netherlands: an 8 update on the epidemiology and control measures. Euro Surveill 2010;15(12):pii=19520. 2. European Centre for Disease Prevention and Control. Risk assessment on Q fever. Stockholm, ECDC; 2010. 3. Roest HI, Tilburg JJ, van der Hoek W, Vellema P, van Zijderveld FG, et al. The Q fever epidemic in The Netherlands: history, onset, response and reflection. Epidemiol Infect 2011;139:1-12. 4. Food and Consumer Product Safety Authority, Ministry of Agriculture Nature and Food Quality. Occupational health and hygiene Instructions for the management of Q fever, 2009. Available at: http://www.vwa.nl/txmpub/files/?p_file_id = 46449. Accessed: October 26, 2010. [in Dutch] 5. Royal Netherlands Meterological Institute. Annual Report. 2009. Available at: http://www.knmi.nl/bibliotheek/jaarverslag/annualreport2009.pdf. Accessed: November 12, 2010. 6. Royal Netherlands Meterological Institute. Climate data and advice: Monthly overview of the weather in the Netherlands, 2010. Available at: http://www.knmi.nl/klimatologie/mow/. Accessed: January 6, 2010. [in Dutch] 7. Anderson AD, Baker TR, Littrell AC, Mott RL, Niebuhr DW, et al. Seroepidemiologic survey for Coxiella burnetii among hospitalized US troops deployed to Iraq. Zoonoses Public Health 2011;58:276-83. 8. Boden K, Wagner-Wiening C, Seidel T, Baier M, Bischof W, et al. Diagnosis of acute Q fever with emphasis on enzyme-linked immunosorbent assay and nested polymerase chain reaction regarding the time of serum collection. Diagn Microbiol Infect Dis;68:110-6. 9. Porten K, Rissland J, Tigges A, Broll S, Hopp W, et al. A super-spreading ewe infects hundreds with Q fever at a farmers’ market in Germany. BMC Infectious Diseases 2006;6:147. 10. Casolin A. Q fever in New South Wales Department of Agriculture workers. J Occup Environ Med 1999;41:273-78. 11. Health Council of the Netherlands. Human vaccination against Q fever. Publication no. 2010/08E. The Hague: The Council; 2010. Available at: http://www.gezondheidsraad.nl/sites/default/files/201008E.pdf. Accessed: January 6, 2010.

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12. Gilroy N, Formica N, Beers M, Egan A, Conaty S, et al. Abattoir-associated Q fever: a Q fever outbreak during a Q fever vaccination program. Aust N Z J Public Health 2001;25:362-7. 13. Shapiro R, Siskind V, Schofield F, Stallman N, Worswick D, et al. A randomized, controlled, double-blind, cross-over, clinical trial of Q fever vaccine in selected Queensland abattoirs. Epidemiol Infect 1990;104:267-73. 14. Ackland J, Worswick D, Marmion B. Vaccine prophylaxis of Q fever. A follow-up study of the efficacy of Q-Vax (CSL) 1985-1990. Med J Aust 1994;160:704-08 Visits on ‘lamb-viewing days’ at a sheep farm open to the public was a risk factor for Q fever in 2009

Jane Whelan Barbara Schimmer Arnout de Bruin Mirna Robert – Du Ry van Beest Holle Wim van der Hoek Ronald ter Schegget

Epidemiol Infect 2012;140:858-864

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Jane Whelan Barbara Schimmer Arnout de Bruin Mirna Robert – Du Ry van Beest Holle Wim van der Hoek Ronald ter Schegget

Epidemiol Infect 2012;140:858-864

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Abstract

Between February and May 2009, 347 laboratory confirmed cases of acute Q fever were reported in a southern municipal health service region in The Netherlands. Commercial dairy-goat farms were implicated and control measures were initially targeted there. A preliminary investigation also implicated a non-dairy sheep farm, open to the public on ‘lamb-viewing days’. This study tested the association between visiting the non-dairy sheep farm and developing Q fever in residents of the region between February and May 2009. A case-control study of 146 cases and 431 address-matched controls was conducted. Multivariable logistic regression analysis confirmed the association between visits to the sheep farm and Q fever disease (matched OR 43, 95% confidence interval: 9−200). Other risk factors were being a smoker, having a past medical history and being aged >40 years. Vaccination of sheep and goats on farms open to the public should help to reduce the number of future human cases.

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Introduction

Q fever is a zoonosis caused by the bacterium Coxiella burnetii. The bacterium is found in the milk, urine, faeces and wool of infected animals (particularly sheep, goats and cattle) but birth products are known to be highly contagious.1-3 It is hypothesized that human infection occurs through inhalation of contaminated aerosols.4 Since 2007, over 3000 cases have been reported in the Netherlands (2354 cases in 2009 alone), peaking annually in spring‒early summer. Commercial dairy-goat farms and some dairy-sheep farms have been implicated in spread of disease. Control measures in 2008 and 2009 have centred on these farms, as the risk associated with non-milk-producing farms was thought to be low.5 Limited data is available in relation to what other agricultural sectors might have contributed to the spread of disease.

In 2009, the municipal health service in the southeast region of Brabant province (MHS Brabant-Southeast) received over 400 notifications of Q fever of which 379 were laboratory confirmed cases (Figure 1). The majority of these cases were probably explained by residence near an infected dairy-goat farm located north east of Helmond city.6 Following a trawling questionnaire conducted with 343 confirmed cases, a second cluster, possibly associated with a non-dairy sheep-farm, was identified in the region. Forty-six cases spontaneously indicated in an open-text question that they had visited the sheep farm (farm X) during the lambing season in February/March 2009. In the trawling questionnaires, other veterinary sources were listed, such as a visit to a pet goat farm and a zoo, but these locations were common for only two and 9 three cases, respectively.

Farm X has been open to the public during the lambing season since 2004. In 2009, it was open each Saturday from February 1 until March 31and there were an estimated 12000 visitors to the farm, most of whom lived locally within 25km of the farm. More than 1200 lambs were born that season (the majority in January and February), and visitors could occasionally witness the birth of a lamb and were encouraged to watch the lambs play. Only three abortions were reported on the farm during this season, which is less than might be expected in a typical season, unaffected by Q fever.

The aim of this study was to test whether there was an association between visiting farm X and developing Q fever among residents in Brabant South-East in February-May 2009. A secondary objective was to identify risk factors for acquiring Q fever (or a C. burnetii infection) among people who visited the farm.

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70 Did not visit farm X 60 Cases eligible for inclusion † Visited farm X 50

40

30

No.of cases Farm X open to 20 public*

10

0 1 3 5 7 9 11 13 15 17 19 21 23 25 27 29 32 34 37 42 51

Week of onset 2009

Figure 1. Q fever cases by week of onset of symptoms and visits to farm X, Brabant-Southeast, The Netherlands, 2009. *Farm X was open on weekends only from February 1 (week 5) to March 31 (week 14). †246 cases had a date on onset of illness between 1 February 2009 and 15 May 2009 and were eligible for inclusion in the study.

Methods

Epidemiological investigation Southeast Brabant is predominantly an agricultural region in the south of the Netherlands bordering Belgium. A case-control study was conducted in the region in June 2010. All adults aged 18 years and over who were normally resident in Brabant South-east between 1 February and the 31 March 2009 were eligible for inclusion (n=732731). The exposure of interest was a visit to farm X between 1 February (end of week 5) and the 31 March (beginning week 14) in 2009 (the period when the farm was open to the public). Given a minimum incubation period of 3 days and a maximum incubation period of approximately 6 weeks,4,7 cases were defined as adult inhabitants of the region who were notified with Q fever and for whom illness onset was between 1 February (end of week 5) and 15 May (end of week 20), 2009 (Figure 1). In the Netherlands, criteria for notification of acute illness are presence of at least fever, pneumonia, or hepatitis plus laboratory confirmation of C. burnetii infection with (a) PCR, or (b) detection of a four-fold rise in serum antibody titres to C. burnetii or a single high titre or a high titre in two samples without a fourfold increase or (c) detection of IgM to phase II antigen. Controls were householders randomly selected based on having an address in the same six-digit post code area (living on the same street) as each case.

Data was collected by means of a postal questionnaire addressed individually to named cases, and to ‘the householder’ at the control address. Questions related to demography (age, gender, occupation), exposure (number of visits to farm X and two additional agricultural sites Y and Z offering viewing/petting of sheep or goats, and which were open to the public in the area),

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month of visit, duration of direct contact with animals, (time spent on the premises, presence at birth of lambs on the farm), outcome (symptoms, hospitalisations for Q fever-like symptoms), behavioural factors (travel history, smoking) and medical history.

Sample size calculation and data analysis Of all notified adult cases in the region in 2009, 248 reported onset of illness between the start of week 5 and the end of week 20, and 42 of these had visited the farm between the 1st week of February and the last week of March (Figure 1). The exposure among the cases was therefore 17% (42/248). For the detection of a minimum odds ratio (OR) of 3, two controls per case were required at a precision (alpha) of 5% (two-sided 95% confidence interval) to achieve power of 80%. Assuming 50% of cases responded, the minimum number of case respondents required was therefore 134 and of controls was 268. Eight controls per case were invited to participate, with the aim of achieving a 25% response rate from controls.

Data was entered using Access and analyzed using Stata v.10.1 (StataCorp., USA). Baseline characteristics of cases and controls were compared using the χ2 test. Univariable and multivariable analyses of the distribution of exposures among cases and controls were examined using matched odds ratios (conditional logistic regression) with 95% exact confidence intervals. Risk factors which were statistically significantly associated with being a case at the 0.25 univariable level were selected for a conditional backward stepwise multivariable model. Significance level was set to 0.05 for the latter model. 9

Environmental investigation Vaginal swabs were collected from 20 sheep on farm X on 19 May 2009, and were tested by multiplex quantitative real-time polymerase chain reaction (qPCR) at the laboratory in the National Institute of Public Health and the Environment in the Netherlands. Eight environmental aerosol samples were also obtained on 20 May 2009 in the vicinity of the farm, at a distance of 500 and 1000 metres in all four wind directions (North, East, South and West). A summary description of laboratory methods is given here, but these will be discussed in detail more appropriately elsewhere (A. De Bruin et al., unpublished data). The qPCR detects two C. burnetii targets (com1 & IS1111), and one Bacillus thuringiensis internal control target (cry1b). B. thuringiensis spores were added to samples to control both DNA extraction and PCR amplification. Performance of the qPCR was guided by the MIQE guidelines8 and showed high levels of efficiency for each target, high specificity and a low limit of detection for C. burnetii. A novel multiplex real time PCR assay for C. burnetii was then carried out on a Lightcycler 480 Instrument (Roche Diagnostics Nederland B.V, Almere, The Netherlands). Three μl of C. burnetii

Nine Mile RSA phase I DNA template were included as positive control, or 3 μl H2O as negative

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control. Analysis was performed on the instruments software: Lightcycler 480 Software release 1.5.0. SP3. Cq values were calculated using the second derivative method. Samples were scored as positive when at least one of the C. burnetii targets (com1, or IS1111) showed a positive signal. Samples were scored as negative when (a) no C. burnetii targets showed positive signals, and (b) a positive result for the internal control.

Results

Epidemiological investigation Sixty-five percent (162/248) of cases responded, as did 35% (686/1985) of controls. As the sample size requirements had been fulfilled, no reminder letter was issued. Cases were individually matched on address and the matched analysis was carried out on 146 cases matched to between

1 and 6 controls per case (1:Mk matching; total matched sample, n=579). Cases were of a similar age distribution to controls (mean age of cases was 54.9 years, range 18-89; mean age of controls was 54.8, range 22-79). Fifty-seven percent of cases (n=85) and 47% (n=202) of controls were male (Table 1). Of the cases, 62% (n=86) reported having pneumonia, 2 reported having hepatitis and 3 reported endocarditis; 38% of cases reported a variety of other symptoms including exhaustion, headache, high fever and cough. Overall, 35 cases were hospitalized (25%). Mean duration of illness among the cases was 21 days (median 10 days, range 0-365). No cases were pregnant at the time.

Based on trawling questionnaire data received from the first 32 cases (where precise date of farm visit and date of onset of illness were recorded), and assuming a point-source exposure, the average incubation time, defined as the time between day of illness onset and day of visit farm X, was 20.7 days (range 9-43 days).

At univariable level, 21% of cases (n=31) reported visiting farm X compared with 1% (n=6) of controls resulting in an OR of exposure between cases and controls of 24 (95% CI 8.4-69.2). When adjusted for other risk factors based on univariable findings (age group, gender, recreational visits to other agricultural sites or events, visits to other sheep/goat farms otherwise unspecified, medical history, smoking status and having a family member who had Q fever in 2009) the multivariate adjusted OR for a visit to farm X was 43.3 (95% CI 9.4-200.1). Other significant independent risk factors (Table 1) included being a current smoker (OR 2.2, 95% CI 1.3–2.8), and being aged >40 years (40–59 years: OR 5.4, 95% CI 1.9-15.3; ≥60 years: OR 3.8, 95% CI 1.3-10.6).

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26660 Whelan kopie.indd 124 02-11-13 16:03 VISITS TO A NON-DIARY SHEEP FARM ASSOCIATED WITH Q-FEVER 0.126 0.006 0.084 0.000 0.012 0.001 P (0.6–36.1) (1.3–3.8) (0.9–2.8) (9.4–200.1) (1.3–10.6) (1.9–15.3) Ref. 95% CI 4.8 2.2 1.6 43.3 3.8 5.4 Ref. OR Multivariate matched OR 0.003 0.002 — 0.054 — — 0.473 0.671 0.620 0.186 0.520 0.076 — 0.773 0.000 0.013 0.594 0.094 P (2.2–48.7) (1.3–3.0) — (1.0–2.3) — — (0.4–8.1) (0.6–1.4) (0.1–4.9) (0.7–6.2) (0.5–3.4) (0.9–3.7) — (0.4–3.5) (8.4–69.2) (1.1–2.9) (0.6–2.3) (0.9–3.2) Ref. 95% CI 10.3 2.0 — 1.5 — — 1.8 0.9 0.6 2.1 1.4 1.9 — 1.2 24.2 1.8 1.2 1.7 Ref. OR Univariable matched† OR 0.5 20.0 0.3 47.3 0.2 0.2 1.7 40.9 1.4 2.1 3.6 5.6 0.0 3.3 1.4 47.4 41.3 42.3 16.4 n/N% 2 85 1.0 193 1 1 7 176 6 9 15 23 0 14 6 202 174 178 69 n Controls 9 6.1 35.6 0.0 60.0 0.0 2.0 2.1 39.2 0.7 4.2 5.7 12.1 0.7 3.5 21.1 57.4 37.7 50.7 11.6 n/N%* 9 52 0 80 0 3 3 58 1 6 8 17 1 5 31 85 55 74 17 Cases n Occurrence of disease in households Another person in the household with Q fever 2009 Current smoker History of Q fever prior to February 2009 General Health History of medical problems Goats at home Sheep at home Farm animals at the home–place Pets at home Other contact with animals Work in industry related to agriculture Visited other sheep or goat farm, not otherwise named Other public event with animals Other agricultural site for recreational visit (unspecified) Visited Site Z Visited Site Y Visits to agricultural sites and events Visited Farm X Gender (male) ≥60 years 40 to 59 years Demographics Age group <40 years OR, odds ratio; CI, confidence interval * N is the total number of respondents to question. Where there missing data, this may not 146 for cases and 486 controls. † 1:Mk matching: cases matched to between 1 and 6 controls. Table 1. Matched univariable and multivariable odds ratios of factors associated with the Q fever outbreak in Southeast Brabant region, The Netherlands, February–May, Table 2009.

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Sub-group analysis: Risk of Q fever among those who visited farm X Thirty-seven respondents reported visiting farm X during the specified time period. No significant association was found between different behaviours on the farm (Table 2) among cases and controls.

Table 2. Distribution of exposures on the farm among cases and controls who visited the farm between 1 February and 31 March 2009 Cases Controls Univariable matched OR n n/N*% n n/N% OR 95% CI p Held or cuddled a lamb during visit 23 85 3 60 3.8 [0.2-44.6] 0.185 Witnessed the birth of a lamb during visit 3 12 0 0 [---] [---] [---] OR, odds ratio; CI, confidence interval * N is the total number of respondents to the question. Missing data is not included.

Environmental investigation Seventeen out of 20 vaginal swabs taken from sheep on the farm were positive for C. burnetii multicopy target IS1111 only, indicating a relatively low level of C. burnetii DNA present in these samples. One sample was found positive for both C. burnetii targets (com1 & IS1111). Seven out of the total of eight aerosol samples taken 500m and 1000m from farm X were positive for C. burnetii target IS1111 in 2009; the only negative aerosol sample was located at 500 m north of the farm.

Discussion

This study confirms the association between a visit to ‘lamb viewing days’ on sheep farm X between 1 February and 31 March 2009, and Q fever in cases. Other risk factors included increasing age, smoking and positive medical history (consistent with findings elsewhere9). The reported mean incubation period of 21 days is also consistent with findings from other research.3 Increased risk associated with handling or petting sheep and lambs, or witnessing the birth of a lamb was not demonstrated here (possibly related to the small number of cases and controls who reported such behaviours).

This study had a number of limitations. A cohort study among farm visitors could not be carried out as no visitor list was available, therefore no attack rate or risk ratio could be calculated. The outbreak occurred in early 2009 and given the time lapse between the outbreak and this study and the degree of media coverage of outbreaks nationwide, there is potential recall bias. A farm visit is a distinct event however, and as the farm of interest was open for only a limited period it is likely that visitors would recall attending – in fact less than 1% reported not remembering whether they visited – although some could not remember the precise date.

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This cluster occurred in the context of a much larger outbreak in the region. Farm X is situated in a region with other infected farms in proximity,6,10 and given the potential role of the wind and other forms of indirect spread of C. burnetii,3,11,12 it would in any case prove difficult to establish a causal link to farm X. In the absence of trawling questionnaires pointing to the farm as a possible source, it is likely that this cluster would have remained unrecognised, and other unidentified sources may also be implicated in this outbreak. In this study, we matched controls to cases by street address in an attempt to control for some of these unknown factors. We tested the association with visits to other farm sites Y and Z, and public agricultural events in the area, but none was found. Q fever cases associated with flocks of non-dairy sheep and newborn lambs have been reported previously13 and in one study, hundreds of infections were attributed to a single ewe at a farmer’s market.3 Given these findings, the positive vaginal swabs from sheep on the farm, and the fact that DNA was isolated from three aerosol sampling locations proximal to the farm, it is plausible that among those who had visited farm X between 1 February and 31 March 2009, 95% of the cases that occurred were attributable to the visit (the attributable fraction among the exposed).

It is estimated that up to 60% of Q fever cases are asymptomatic, and therefore there were potentially cases among the control group. No serological testing of controls was conducted in this study; however, recent analysis of blood donor samples in the region confirms a prevalence of anti-IgG antibodies of 12% in 2009.14 If this prevalence were applied to our data, the impact on the OR reported here is uncertain. If cases and controls were correctly classified, the reported 9 OR may be an overestimate of the association. If, however, a greater proportion of farm visitors than expected were reclassified as cases, the OR of association would not necessarily be reduced. In either case, a visit to farm X would still be a strong independent risk factor for Q fever.

In the Brabant region there are 35 petting farms and 14 zoos open to the public and in 2008, there were 1.6 million recreational visits to farms and farmland in the area. ‘Lamb-viewing days’ during lambing season were particularly popular.15 ‘Agri-tourism’ is therefore an important recreational and revenue-generating activity in the region. In January 2010, the Ministry of Health issued a hygiene protocol to all farms with a public function including petting farms and those offering ‘lamb viewing days’.16 Control measures implemented throughout the country included isolation of pregnant sheep and goats (away from public areas), mandatory animal vaccination, and cessation of ‘lamb viewing days’ until vaccination was complete. As a result, farm X was closed to the public in February-March 2010, pending vaccination of the herd which has since been completed. The farm reopened to the public in spring 2011. As a result of the vaccination campaign in sheep and goats nationally, it is expected that the number of human cases will fall in the coming years,17 but farm visitors should continue to be vigilant. Vulnerable groups such

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as pregnant women, people with cardio-vascular anomalies, and those with reduced immunity, should be aware of their elevated risk with regard to Q fever. For all farm visitors, hygiene and preventive measures should continue to be practiced as recommended.18

Acknowledgements

Many thanks to Jan van den Beer for his contribution to this study. We would also particularly like to thank the farmer at farm X who readily provided information about the farm and the public function of the farm; thanks are also due to all respondents who participated in the study. Finally, thanks to EPIET coordinator Ioannis Karagiannis for his comments and suggestions in relation to the manuscript.

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References

1. Abinanti FR, Lennette EH, Winn JF, Welsh HH. Q fever studies. XVIII. Presence of Coxiella burnetii in the birth fluids of naturally infected sheep. American Journal of Hygiene 1953;58:385-8. 2. Aitken ID, Bogel K, Cracea E, Edlinger E, Houwers D, et al. Q fever in Europe: current aspects of aetiology, epidemiology, human infection, diagnosis and therapy. Infection 1987;15:323-7. 3. Porten K, Rissland J, Tigges A, Broll S, Hopp W, et al. A super-spreading ewe infects hundreds with Q fever at a farmers’ market in Germany. BMC Infectious Diseases 2006;6:147. 4. Maurin M, Raoult D. Q fever. Clin Microbiol Rev 1999;12:518–53. 5. Q fever Evaluation Commission. Q fever policy in the Netherlands 2005-2010. (http://www.rijksoverheid.nl/documenten-en-publicaties/rapporten/2010/11/22/van-verwerping-tot- verheffing.html). Accessed 5 December 2010. [in Dutch] 6. Schimmer B, Ter Schegget R, Wegdam M, Zuchner L, de Bruin A, et al. The use of a geographic information system to identify a dairy goat farm as the most likely source of an urban Q fever outbreak. BMC Infectious Diseases 2010;10:69. 7. Heymann D (ed). Control of Communicable diseases manual. Nineteenth ed. Washington, DC: American Public Health Association, 2008. 8. Bustin SA, Benes V, Garson JA, Hellemans J, Huggett J, et al. The MIQE guidelines: minimum information for publication of quantitative real-time PCR experiments. Clin Chem 2009;55:611-22. 9. Karagiannis I, Schimmer B, Van Lier A, Timen A, Schneeberger P, et al. Investigation of a Q fever outbreak in a rural area of The Netherlands. Epidemiol Infect 2009;137:1283-94. 10. Food and Consumer Product Safety Authority, Ministry of Agriculture Nature and Food Quality. Q Fever: Map with overview of infected dairy-goat and dairy-sheep farms, 2010. (http://www.vwa.nl/onderwerpen/dierziekten/dossier/q-koorts/kaart-met-overzicht-van-besmette- bedrijven). Accessed 3 December 2010. 11. Hawker JI, Ayres JG, Blair I, Evans MR, Smith DL, et al. A large outbreak of Q fever in the West Midlands: windborne spread into a metropolitan area? Commun Dis Public Health 1998;1:180-7. 12. Lyytikainen O, Ziese T, Schwartlander B, Matzdorff P, Kuhnhen C, et al. An outbreak of sheep-associated Q 9 fever in a rural community in Germany. Eur J Epidemiol 1998;14:193-9. 13. Koene RP, Schimmer B, Rensen H, Biesheuvel M, de Bruin A, et al. A Q fever outbreak in a psychiatric care institution in The Netherlands. Epidemiol Infect 2011;139:13-8. 14. Hogema BM, Slot E, Molier M, Schneeberger PM, Hermans MH, et al. Coxiella burnetii infection among blood donors during the 2009 Q fever outbreak in The Netherlands. Transfusion 2011;52:144-50. 15. Province of North-Brabant. Brabant in figures. Leisure Industry Trend Report. 2010 (http://www.vrijetijdshuis.nl/wp-content/uploads/2010/05/totaal-trendrapport2.pdf). Accessed 10 December 2010. [in Dutch] 16. Ministry of Agriculture Nature and Food Quality. Hygiene protocol for goat and sheep farms with a public function, 2010. (http://www.rijksoverheid.nl/documenten-en-publicaties/rapporten/2010/01/27/hygieneprotocol-voor- geiten-en-schapenbedrijven-met-een-publieke-functie.html). Accessed 3 December 2010. [in Dutch] 17. van der Hoek W, Dijkstra F, Schimmer B, Schneeberger PM, Vellema P, et al. Q fever in the Netherlands: an update on the epidemiology and control measures.Euro Surveill 2010;15:pii=19520. 18. Netherlands Foundation for Petting Zoos (SKBN). Hygiene Code, 2010. (http://www.kinderboerderijen.nl/kinderboerderijen/hygiene-op-de-kinderboerderij/print). Accessed 3 December 2010. [in Dutch]

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National outbreak of Salmonella Typhimurium (Dutch) phage-type 132 in the Netherlands,

October to December 2009

Jane Whelan Harold Noel Ingrid Friesema Agnetha Hofhuis Carolien de Jager Max Heck Annet Heuvelink Wilfred van Pelt

Euro Surveill 2010;15:pii=19705.

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October to December 2009 10

Jane Whelan Harold Noel Ingrid Friesema Agnetha Hofhuis Carolien de Jager Max Heck Annet Heuvelink Wilfred van Pelt

Euro Surveill 2010;15:pii=19705.

26660 Whelan kopie.indd 131 02-11-13 16:03 CHAPTER 10

Abstract

Between October and December 2009, 23 cases of Salmonella Typhimurium (Dutch) phage type 132, each with an identical multiple-locus variable-number tandem-repeat analysis (MLVA) profile (02-20-08-11-212), were reported from across the Netherlands. A case-control study was conducted using the food-consumption component of responses to a routine population-based survey as a control group. The mean age of cases was 17 years (median: 10 years, range: 1–68). Sixteen cases were aged 16 years or under. Raw or undercooked beef products were identified as the probable source of infection. Consumers, in particular parents of young children, should be reminded of the potential danger of eating raw or undercooked meat.

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Introduction

Salmonella enterica subsp. enterica serotype Typhimurium (S. Typhimurium) has historically been an important cause of human gastrointestinal disease in the Netherlands.1,2 The Dutch laboratory surveillance network for gastroenteric pathogens was established in 1987, in which 15 of the 16 regional public health laboratories participate. It serves general practices and district and university hospitals and has been estimated to cover approximately 62% of the Dutch population.3 Salmonella isolates from human, animal, food and environmental samples are sent to the National Salmonella Centre in the Dutch National Institute of Public Health and the Environment (Rijksinstituut voor Volksgezondheid en Milieu, RIVM), where they are sero- and phage typed and are reported on a weekly basis.

On 9 November 2009, the centre reported six clinical isolates (confirmed between 4 and 9 November 2009) of an unusual phage type, S. Typhimurium (Dutch) phage type 132 (ft132) to the Epidemiology and Surveillance Unit at RIVM. This phage type had been first identified in chickens in the Netherlands in the early 1980s.2 Until November 2009, there had been no further reports of this strain in either animals or humans in the country. On 16 November 2009, a further five clinical isolates of the same phage type were reported, prompting immediate investigation. Cases were traced through routine surveillance and were invited to respond to an open-ended, hypothesis-generating questionnaire. When asked what they believed the source of their infection to be, four cases implicated ‘ready-to-eat’ minced or ground raw beef in the form of steak tartare (also known as filet américain); three cases implicated rare or undercooked beef as the source. These findings led to our hypothesis that consumption of raw or rare contaminated 10 beef products was associated with infection with S. Typhimurium ft132. RIVM reported the outbreak to the Food and Consumer Product Safety Authority (Voedsel en Waren Autoriteit, VWA) on 1 December 2009. The aim of the study presented here was to test the association between consumption of raw or undercooked meat and infection with S. Typhimurium ft132 and to identify other potential risk factors.

Methods

To test the hypothesis that consumption of raw or rare contaminated beef products was associated with infection with S. Typhimurium ft132, a retrospective case-control study was conducted.

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Case definition As S. Typhimurium ft132 had not been reported in humans before, a case was defined as any individual who had laboratory-confirmed S. Typhimurium ft132 infection in the Netherlands – a time period was not specified.

Selection of controls: the quarterly control survey Controls were drawn from a random selection of people from the Dutch general population. In the Netherlands, all individuals are registered with a unique number in the municipality in which they reside. Since 2008, RIVM has received annually a computer-generated random selection of approximately 500 people from each of the 38 municipalities in the country (a total of approximately 20,000 individuals per year). From this pool, each quarter RIVM selects (using the random number generation function of Microsoft Excel) a simple random subsample of 300 to 500 people to take part in a survey of risk factors for food-borne and other infections. A questionnaire is sent by post to the selected people; if the sampled individual is under 16 years, a parent or guardian is asked to complete the questionnaire on the child’s behalf. The survey (known as a control-survey) was designed for use as a control group for enhanced surveillance and outbreak investigation of food-borne and some respiratory diseases.4 The questionnaire includes 36 questions related to demography, medical history, and gastrointestinal illness and other symptoms and behaviours in the previous 30 days: history of travel, eating in restaurants, visiting farms and other contact with domestic and farm animals. Questions also relate to the nature and type of food consumed in the week before receipt of the questionnaire (meat, fish, dairy products, fruit and vegetables). The response rate is typically over 30%.

As a faecal sample was taken from the first case of S. Typhimurium ft132 infection on 27 October 2009, and as the incubation period is between six and 72 hours, controls were defined as those who responded to the questionnaire (as part of the control-survey) between 20 October and 30 December 2009.

Interview of cases Cases were invited to complete a questionnaire, by telephone or by post. Compared with the questionnaire used for controls, the questionnaire for cases was more detailed with regard to the type and brand of each food consumed and the name and address of each shopping location visited. However, questions used in this study to compare cases and controls were the same.

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Statistical analysis Data were analysed using STATA 10.1. Odds ratios adjusted for age group and sex with 95% confidence intervals were generated using multiple logistic regression. The mean time between date of onset of illness and laboratory-confirmed diagnosis was also calculated.

Laboratory diagnosis Faecal samples were examined by medical microbiologists and isolates were sero- and phage typed at the National Salmonella Centre. Multiple-locus variable-number tandem-repeat analysis (MLVA) followed the method described by Lindsted et al.5 using the new nomenclature described by Larsson et al.6 The Food and Consumer Product Safety Authority conducted a trace- back investigation based on reported place of purchase and/or consumption of the suspected foods. When possible, leftovers of the suspected foods were collected at cases’ domicile and tested for presence of S. Typhimurium ft132.

Results

Descriptive analysis of cases A total of 23 cases of S .Typhimurium ft132 infection with an identical MLVA profile (02-20-08- 11-212)6 were confirmed by laboratory diagnosis between 4 November and 30 December 2009. Of these, 10 were male. The mean age of the cases was 17 years (median: 10 years; range: 1–68), 16 cases were children aged 16 years or under, five were aged 17–49 years and two were 50 years or older. 10 A total of 14 cases responded to the questionnaire. These cases were widely dispersed, coming from 13 different municipal health service districts across the Netherlands (Figure 1). The respondent cases became ill between 21 October and 16 November 2009 (Figure 2A). The mean time between onset of illness and laboratory-confirmed diagnosis was 10.6 days (range: 5–16) (Figure 2B). Symptoms of these 14 cases included diarrhoea (n=13), abdominal pain (n=12), fever (n=10), vomiting (n=9), nausea (n=8) and blood in stools (n=7).

The mean duration of illness of respondents (n=14) was 13.9 days (range: 5–15). Eight patients were hospitalised: seven had been discharged at the time of interview and one case with a serious underlying medical condition died. Four cases reported that household members were also symptomatic (n=5). In the week before the onset of symptoms, eight respondents had had contact with domestic animals, two had visited a foreign country and one had been to a large public event.

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Figure 1. Geographical distribution of Salmonella Typhimurium ft132 respondent cases (n=14) and controls (n=121a) by postal code, the Netherlands, October - December 2009. a Postcodes not provided by three controls. Source National Institute for Public Health and the Environment (RIVM).

A Date of onset of symptoms

5

4 Respondents (n=14)

3

2

1

0

19 26 2 9 16 23 30 7 14 21 28 31 October November December 2009

B Date of laboratory confirmed diagnosis 5 4 Respondents (n=14) 3 Non-respondents (n=9) 2 1 0 19 26 2 9 16 23 30 7 14 21 28 31 October November December 2009

Figure 2. Cases of Salmonella Typhimurium ft132 by (A) date of symptom onset of questionnaire respondents (n=14) and by (B) date of laboratory-confirmed diagnosis for all cases (n=23), the Netherlands, October 2009 - December 2009.

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Case–control study In October to December 2009, 342 people were invited to complete the questionnaire for the national quarterly control-survey. Of those, 38% (n=130) responded, of whom 124 met the control definition. Respondent cases and controls were similar in terms of sex: 50% (n=7) of cases and 38% (n=47) of controls were male, p=0.379. Controls were older than cases; 90% (n=112) of controls and 7% (n=1) of cases were aged over 16 years, but there was no difference in the proportion of children (40%) and adults (47%) who reported consuming raw or undercooked meat. Therefore, age was not considered to be a confounding factor in the relationship between the consumption of raw or undercooked meat and being a case.

When differences in exposure to the most commonly reported foods between cases and controls were examined, nine cases (64%) and 54 controls (44%) reported consuming beef that was eaten raw or rare. This included steak tartare, ossenworst (a raw beef sausage prepared with herbs) and rare fillet of beef. The association between each type of food and being a case was tested with adjustment for age group and sex (Table). The odds ratio (OR) of being a case after eating either ‘ready-to-eat’ raw beef (steak tartare or ossenworst) or fillet of beef eaten rare was 15.38 (95% confidence interval (CI): 1.8 to 131.2, p=0.012). When the analysis was repeated using the ready-to- eat raw beef products only, the odds ratio was 28.8 (95% CI: 1.7 to 490.1, p=0.02). Of respondents, 28% of cases (n=4) and 5% of controls (n=6) reported shopping at a particular supermarket chain (OR: 7.87, 95% CI: 1.36 to 39.11, p=0.001), but it was not possible to say where particular products had been purchased and no common restaurant or other public eatery was reported.

Table 1. Most commonly consumed foods reported by cases (n=14) and controls (n=124), the Netherlands, October - December 2009. 10 Type of food consumed Cases (N=14) Controls (N=124) Adjusted ORa 95% CI P value n % n % Beef eaten raw or rareb 9 64 54 44 15.38 1.80-131.16 0.012 Chicken or turkey 8 57 77 62 0.1 0.01-1.09 0.059 Fish or Shellfish 7 50 67 54 0.74 0.17-3.37 0.704 Sausage meat 6 43 59 48 0.64 0.13-3.03 0.575 Minced pork 5 36 60 48 0.38 0.07-1.99 0.252 Snack sausages 3 21 19 15 1.55 0.22-10.68 0.658 Mixed port and beef mince 3 21 23 19 0.16 0.02-1.26 0.082 Salad 3 21 74 60 0.19 0.03-1.06 0.059 Ham 3 21 49 40 0.61 0.10-3.64 0.594

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Trace-back investigation After RIVM reported the outbreak on 1 December 2009 to the Food and Consumer Product Safety Authority, the latter conducted a trace-back investigation, testing suspected beef product samples (minced beef) submitted by two cases. No evidence of S. Typhimurium was found in either sample. Given the short shelf life of ready-to-eat raw meat products, samples from the supermarket chain were not available for analysis by the time of the investigation. No common meat supplier was identified among all the different supermarket chains where cases reported to have purchased meat products in the week before the onset of symptoms.

European investigation On 23 November 2009, an appeal was made (via the European Centre for Disease Prevention and Control) to European Union Member States for information regarding recent identification of S. Typhimurium with the same MLVA pattern (02-20-08-11-212). No country in Europe reported cases infected with S. Typhimurium with the same MLVA pattern, either before or at the time of this outbreak.

Discussion

An unusual and identifying feature of this outbreak was the unique Salmonella strain involved, and the fact that the MLVA patterns of all the isolates were identical. Although the outbreak was small and the trace-back investigation inconclusive, the epidemiological investigation pointed to ready-to-eat raw or undercooked beef products as the probable vehicle of infection.

Our investigation was limited by a number of factors: small sample size, lack of available material for sampling given the short shelf life of ready-to-eat raw meat products, and a 10-day interval between onset of illness and laboratory-confirmed diagnosis, resulting in potential recall bias among the cases.

From a methodological perspective, use of a routinely surveyed population as a control group, for which known risk factors for food-borne disease have been assessed, proved effective and timely. After a food-borne outbreak, controls are often questioned about their food intake weeks to months earlier. In this study, controls returned questionnaires throughout the outbreak period and as they reported their food consumption in the week before receiving the questionnaire, their responses were potentially more reliable and less susceptible to recall bias than those of controls used in other similar retrospective studies. The surge in manpower required to conduct a case–control study after an outbreak (finding and interviewing controls and creating a database) is also reduced. For these reasons, we recommend this approach. The

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control-survey should be reviewed as necessary to take account of newly recognised or seasonal links to food and behaviours that might place individuals at risk of food-borne infection.

In this outbreak, 70% of those affected were children, Age-specific rates of Salmonella infection and rates of hospitalisation are typically highest among children (although Salmonella spp. can cause disease in persons of any age).7 In the control group, only 10% of respondents were children. Given that control responses had already been received at the time of the investigation, matching by age was not possible a priori. Age matching would have led to a better ratio of cases to controls across age strata in adults thus allowing a better examination of the effect of age. Age was not considered a confounding factor in this study, however, as similar proportions of adults and children consumed raw or undercooked meat. To achieve a better representation of groups known to be vulnerable to Salmonella and other infections, oversampling of young children and elderly people would be of benefit when conducting the quarterly control-survey.

Studies have shown considerable stability of individual food habits over time.8,9 The optimal frequency for a routine control-survey that is appropriate for use as control group for food- borne infectious disease outbreaks will depend in part on seasonal variation of food intake and in part on the frequency and nature of food-borne outbreaks in the country in question. Taking into account resource requirements, a control-survey every three months is considered optimal in the Netherlands.

This is the fourth food-borne outbreak in recent years linked to consumption of steak tartare and other raw beef products in the Netherlands.10-12 In 2006 to 2008, despite intensive monitoring 10 and control programmes, Salmonella was still found in-store in raw meats (such as steak tartare and ossenworst) intended for direct consumption.13 Consumer awareness of the potential hazard of eating raw meat is central to good control. In particular, parents should be reminded that children are vulnerable to Salmonella infection and should not eat products containing raw or undercooked meat.

Acknowledgements

We would like to thank patients and laboratory personnel for their assistance in this study. We would also like to thank Cindy Deuning and Maarten Mulder in RIVM for the mapping of cases and controls (Figure 1) and EPIET, in particular EPIET co-ordinator Biagio Pedalino.

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References

1. Doorduyn Y, Hofhuis A, de Jager C, van der Zwaluw W, Notermans D, et al. Salmonella Typhimurium outbreaks in the Netherlands in 2008. Euro Surveill. 2008;13: pii=19026. 2. van Duijkeren E, Wannet WJ, Houwers DJ, van Pelt W. Serotype and phage type distribution of Salmonella strains isolated from humans, cattle, pigs, and chickens in the Netherlands from 1984 to 2001. J Clin Microbiol. 2002;40:3980-5. Risk factors for secondary transmission of 3. van Pelt W, de Wit MA, Wannet WJ, Ligtvoet EJ, Widdowson MA, et al. Laboratory surveillance of bacterial gastroenteric pathogens in The Netherlands, 1991-2001. Epidemiol Infect. 2003;130:431-41. 4. Friesema I, Doorduyn Y, de Jager C, van der Zwaluw W, Notermans D, et al. Enhanced surveillance of Shigella infection within households: Listeria monocytogenes in the Netherlands, 2008. Infectieziekten Bulletin. 2010;2:57-62. [in Dutch]. 5. Lindstedt BA, Torpdahl M, Nielsen EM, Vardund T, Aas L, et al. Harmonization of the multiple-locus variable-number tandem repeat analysis method between Denmark and Norway for typing Salmonella implications for current prevention policy Typhimurium isolates and closer examination of the VNTR loci. J Appl Microbiol. 2007;102:728-35. 6. Larsson JT, Torpdahl M, Petersen RF, Sorensen G, Lindstedt BA, et al. Development of a new nomenclature for Salmonella typhimurium multilocus variable number of tandem repeats analysis (MLVA). Euro Surveill. 2009;14:pii=19174. Available from: http://www.eurosurveillance.org/ViewArticle.aspx?ArticleId=19174 7. Heymann DL, editor. Control of communicable diseases manual. 19th ed. Washington: American Public Health Association; 2008. 8. Borland SE, Robinson SM, Crozier SR, Inskip HM, SWS Study Group. Stability of dietary patterns in young women over a 2-year period. Eur J Clin Nutr. 2008;62:119-26. 9. Goldbohm RA, van ‘t Veer P, van den Brandt PA, van ‘t Hof MA, Brants HA, et al. Reproducibility of a food frequency questionnaire and stability of dietary habits determined from five annually repeated measurements. Eur J Clin Nutr. 1995;49:420-9. 10. Greenland K, de Jager C, Heuvelink A, van der Zwaluw K, Heck M, et al. Nationwide outbreak of STEC O157 infection in the Netherlands, December 2008-January 2009: continuous risk of consuming raw beef products. Euro Surveill. 2009;14:pii=19129. 11. Doorduyn Y, de Jager C, van der Zwaluw W, Friesema I, Heuvelink A, et al. Shiga toxin-producing Escherichia coli (STEC) O157 outbreak, The Netherlands, September-October 2005. Euro Surveill. 2006;11(7):pii=636. 12. Kivi M, Hofhuis A, Notermans DW, Wannet WJ, Heck ME, et al. A beef-associated outbreak of Salmonella Typhimurium DT104 in The Netherlands with implications for national and international policy. Epidemiol Infect. 2007;135:890-9. 13. van Pelt W, Braks M, Schimmer B, Stenvers O, Langelaar M. State of zoonoses 2007-2008 Bilthoven: National Institute for Public Health and the Environment Milieu (RIVM); 2009. Report No. 330131001/2009. [in Dutch]

Lian Bovée Jane Whelan Gerard Sonder Alje P. van Dam Anneke van den Hoek

BMC Infect Dis 2012;12:347

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Lian Bovée Jane Whelan Gerard Sonder Alje P. van Dam Anneke van den Hoek

BMC Infect Dis 2012;12:347

26660 Whelan kopie.indd 141 02-11-13 16:03 CHAPTER 11

Abstract

Background Internationally, guidelines to prevent secondary transmission of Shigella infection vary widely. Cases, their contacts with diarrhoea, and those in certain occupational groups are frequently excluded from work, school, or daycare. In the Netherlands, all contacts attending pre-school (age 0−3) and junior classes in primary school (age 4−5), irrespective of symptoms, are also excluded pending microbiological clearance. We identified risk factors for secondary Shigella infection (SSI) within households and evaluated infection control policy in this regard.

Methods This retrospective cohort study of households where a laboratory confirmed Shigella case was reported in Amsterdam (2002−2009) included all households at high risk for SSI (i.e. any household member under 16 years). Cases were classified as primary, co-primary or SSIs. Using univariable and multivariable binomial regression with clustered robust standard errors to account for household clustering, we examined case and contact factors (Shigella serotype, ethnicity, age, sex, household size, symptoms) associated with SSI in contacts within households.

Results SSI occurred in 25/337 contacts (7.4%): 20% were asymptomatic, 68% were female, and median age was 14 years (IQR: 4−38). In a multivariable model adjusted for case and household factors, only diarrhoea in contacts was associated with SSI (IRR: 8.0, 95% CI:2.7−23.8). In a second

model, factors predictive of SSI in contacts were the age of case (0−3 years [IRRcase≥6 years:2.5, 95%

CI:1.1−5.5] and 4−5 years [IRRcase≥6 years: 2.2, 95% CI:1.1−4.3]) and household size >6 persons (IRR2−4

persons:3.4, 95% CI:1.2−9.5).

Conclusions To identify symptomatic and asymptomatic SSI, faecal screening should be targeted at all household contacts of preschool cases (0−3 years) and those attending junior class in primary school (4−5 years) and any household contact with diarrhoea. If screening was limited to these groups, only one asymptomatic adult carrier would have been missed, and potential exclusion of 70 asymptomatic contacts <6 years old from school or daycare could have been avoided.

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Background

Shigellosis (bacillary dysentery) is an acute intestinal infection caused by the toxin-producing gram-negative bacterium Shigella. The route of infection is faecal-oral, via the hands or through ingestion of contaminated food or water. The incubation period is typically 1−3 days. Clinical symptoms include fever, watery diarrhoea, abdominal cramps and bloody, slimy stools.1 Disease is most severe and the case-fatality rate highest in children, the elderly and those who are immunocompromised. Case-fatality rate depends on the serotype, and is up to 20% of patients hospitalised with S. dysenteriae which occurs predominantly in less industrialised countries. In industrialised countries, S. sonnei and S. flexneri account for the majority of cases, and in the Netherlands about 75% of infections are imported, most frequently in the summer months.2 Nationally, 300−600 cases of bacillary dysentery are reported each year, yielding an approximate annual incidence of 3.2/100,000 population.2 Secondary attack rates in households can be high3 and infections are associated with significant morbidity and socioeconomic cost as infected individuals may be excluded from school or work pending microbiological clearance.

Guidelines for contact tracing and the control of shigellosis differ across jurisdictions. In Australia, contacts are screened routinely only in outbreak situations.4 They are excluded from attending work or childcare, whether symptomatic or not, if they are in risk groups such as food handlers, carers or children attending childcare, until two successive stool samples collected a minimum of 24 hours apart are negative. In the USA, it is recommended that only symptomatic attendees and staff members in childcare centres where Shigella infection has been identified should have a faecal specimen cultured.5 Children and staff can generally return to the child care facility ≥24 hours after they are symptom free. In some US states, exclusion is continued until results of two stool cultures are negative for Shigella species. In the UK, contacts in risk groups are screened routinely, but microbiological clearance (two negative faecal specimens taken at 11 intervals ≥48 hours) is required for cases of S. dysenteriae, S. flexneri or S. boydii, but not for cases of S. sonnei.6

In the Netherlands, shigellosis is notifiable by law.7 When a case is identified, it is the responsibility of the Public Health Service (PHS) to trace contacts in order to prevent secondary infection. Until 2001, it was national policy to screen all household contacts of a Shigella case. This policy was amended based on the results of a retrospective study of shigellosis cases and their contacts reported from 1991−1998 in Amsterdam, which concluded that the highest risk of secondary transmission and hospitalisation was among children under 16 years.8 It was recommended that contact tracing should specifically be targeted at households where children reside (hereafter, “high risk households”). In 2001, national guidelines were adjusted accordingly.9 Since then,

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contact tracing is limited to faecal sampling of all household contacts if the primary case is younger than 16 years or one or more contacts in the family are younger than 16 years. If the primary case is older than 16 years and there are no younger contacts in the family, selective faecal sampling of family contacts that are care-workers or food-handlers, and those that have symptoms consistent with a Shigella infection is conducted. Under current guidelines, cases who attend childcare centres (0−3 years), or those in junior classes in primary school (4−6 years) are excluded until two consecutive faecal samples, taken at least 3 days apart and 48 hours after completion of antibiotic therapy, are confirmed negative. Furthermore, it is recommended that children of the same age who are contacts of a shigellosis case, should also be excluded from school (irrespective of symptoms) until one faecal sample is confirmed negative for Shigella.9 The aim of this study was to determine the proportion of secondary transmissions in “high risk” households and the characteristics of primary cases and their contacts that are associated with secondary transmission, thereby to evaluate the appropriateness of current exclusion policies in relation to young children.

Methods

Routine Surveillance Data A confirmed case of Shigella infection was defined as any person from whom a Shigella species was isolated from a faecal sample, reported to the PHS of Amsterdam from 2002 to 2009. In addition, case data routinely collected included age, gender, occupation, country of birth, dates of departure and return on any recent foreign trips, date of onset of illness and information about hospitalisation.

Household contact study This was a retrospective cohort study including all occupants of “high risk” households in which a primary case of Shigella infection was reported to the PHS of Amsterdam from 2002 to 2009. A primary case was the first person in a high risk household to present with laboratory confirmed Shigella infection in a faecal sample. A high risk household was any household with more than one inhabitant including at least one child <16 years, where a primary case (of any age) stayed for at least one overnight, using shared toilet facilities, from the onset of symptoms to the date of notification to the PHS. Outcomes of interest were (a) any laboratory confirmed secondary infection and (b) asymptomatic laboratory confirmed secondary infection. Contacts were asked to report any symptoms experienced (diarrhoea, fever), and on what day they began relative to the primary case. For comparative purposes and to be consistent with previous research,8 secondary infection was defined as laboratory confirmed Shigella infection in a household contact developed >1 day after the primary case. If a symptomatic contact’s first day of illness

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was ≤1 day after the primary case then this contact was considered a co-primary infection and was excluded from the study. Primary cases and their contacts were also excluded if their most likely source was “Men who have sex with men” (MSM) or if the source was a common exposure to the same suspected food-source. In accordance with current guidelines, contacts were also asked to provide a faecal sample for culture by the PHS Regional Laboratory of Amsterdam, in addition to provision of general demographic information. As this research was conducted in the context of routine surveillance, no ethical approval was required.

Laboratory Methods For diagnosis of shigellosis, faecal specimens were suspended in saline and plated onto Hecto- en enteric agar. Green colonies, suspected for Shigella, were tested for fermentation of glucose and lactose using a TSI-slant and tested for urease production. Urease-negative, glucose- fermenting, lactose-nonfermenting strains were subsequently determined to the species level using API-20E tests (Biomerieux, Craponne, France) and agglutinated with polyvalent antisera against S.sonnei, S.flexneri, S.boydii and S.dysenteriae.

Statistical analysis Data were analysed using Stata 11 (StataCorp LP, College Station, TX, USA). The proportion of secondary infections was the number of laboratory confirmed infected contacts divided by the total number of household contacts tested. We hypothesized that both individual characteristics of the contact (age, sex, whether symptomatic or not, hospitalized or not) as well as contextual factors in the household (household size, characteristics of the case in the household - age and sex, Shigella serotype, ethnicity, whether hospitalized or not) could be associated with secondary transmission. Age was classified in three age-groups based on school attendance: those aged 0−3 years attending pre-school, those in junior classes in primary school aged 4−5 years, and those aged ≥6 years attending senior classes in primary school. Duration from date of onset of illness 11 to date of notification was used as a proxy measure of duration of transmission risk (i.e. prior to receipt of hygiene advice from a health professional). Univariable associations between the outcome, and individual and contextual characteristics within the household, were first tested using the Chi-squared test or Fischer’s exact test. As contacts and cases were clustered within households and there were a large number of clusters relative to the total sample of contacts, we used ordinary univariable and multivariable binomial regression models to obtain risk ratios with 95% confidence intervals. These were corrected for correlation between individuals within households using clustered robust standard errors based on the Huber-White sandwich estimator.10,11 If the univariable association was significant at p<0.1, variables were included in the multivariable analysis. Missing values were excluded. Finally, to compare with previous

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research, the annual incidence of shigellosis was estimated as the number of positive shigellosis cases per year per 100,000 residents of Amsterdam.

Results

Routine Surveillance Data From 2002 to 2009, 420 primary cases of shigellosis were reported through routine surveillance. The median age was 33 years (interquartile range: 26−42) and 57% (n=241) were male. Eighteen percent of cases (n=76) were MSM and 5 cases acquired their infection from a common suspected food-source. Of non-MSM cases born in the Netherlands, 82% (n=155/329) acquired their infection abroad. Of non-Dutch cases who had recently travelled abroad (n=90), 50% (n=45) contracted the infection while visiting their country of origin. The most common countries where infection was acquired were Morocco (n=52), Egypt (n=38), India (n=31), Ghana (n=14), Indonesia (n=10). Overall, 31% (n=130) of infections were reported in August and September. All primary cases had diarrhoea and 15% (n=63) were admitted to hospital. There were no deaths among cases.

Household study: Characteristics of cases, contacts and households MSM and those who were exposed to a common food source were excluded from the household study. Of the remaining 339 primary cases, 213 resided in non high-risk households and 24 had contacts that were selectively screened because they were symptomatic or were working as food-handlers or care-givers (Figure 1). Notably, no secondary transmissions occurred in these households. Ultimately 368 contacts related to 102 primary cases in 102 high risk households were identified. All were offered screening, 23 did not participate (Figure 1) and 8 were considered co- primary infections and were excluded from the household study. The median household size was 4 persons (Interquartile Range, IQR: 3−5): 61 households contained 2−4 people, 24 households 5−6 people, and 17 households, >6 people. A greater proportion of cases (35%) compared to contacts (23%) were under 6 years old cases (Pearson chi-squared, p=0.03). The gender distribution was similar. Baseline characteristics of cases and household contacts are presented in Table 1.

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Confirmed Shigella Cases, 2002-2009 N=420

MSM (excluded) n=76

Exposure to common food source (excluded) n=5

Primary cases n=339

Primary cases in Non high-risk households (excluded) n=213

Primary cases in “Other” households, where only selective testing of contacts conducted (excluded) n=24

Primary cases in “High risk” households n=102

Contacts in “high risk” households n=368 Household Considered co-primary contact No sample tested infection (excluded) n=23 (excluded) study n=8

Contact seropositve Contact seronegative for Shigella for shigella n=25 n=312

Symptomatic Assymptomatic n=20 n=5

Figure 1. Flowchart of study population 11

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Table 1. Baseline characteristics of primary Shigella cases (n=102) and related contacts (n=337) in high risk households, Amsterdam, the Netherlands 2002-2009.

Characteristics Index patients Household contacts p value (n=102) (n=337) n (%) n (%) Age group 0-3 20 (20) 48 (14) 4-5 15 (15) 29 (9) >6 67 (66) 260 (77) 0.030 Gender Female 53 (52) 171 (51) Male 49 (48) 166 (49) 0.802 Country of birth Netherlands 30 (29) 91 (27) Western, other 3 (3) 6 (2) Non-western 70 (68) 236 (71) Diarrhoea Yes 102 (100) 87 (26) No 0 (0) 228 (68) Unknown 0 (0) 22 (7) Shigella isolated Yes 102 (100) 27 (7) No 0 (0) 312 (86) Shigella serotype S. sonnei 57 (56) 15 (4) S. flexneri 36 (35) 8 (2) S. boyddi 6 (6) 2 (1) S. dysenteriae 3 (3) 0 (0) Seronegative 0 (0) 312 (93) Months reported Dec-Jan 9 (9) 46 (14) Feb-Mar 6 (6) 15 (4) Apr-May 9 (9) 25 (7) Jun-Jul 8 (8) 20 (6) Aug-Sep 51 (50) 168 (50) Oct-Nov 19 (19) 63 (19) Hospitalised No 22 (22) 1 (0) Yes 80 (78) 336 (100)

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Household study: Risk factors for secondary transmission Shigella was isolated from 25 of the remaining 337 contacts (7.4%) of whom 68% (n=17) were female, and the median age was 14 years (IQR: 4−38). The attack rate ranged from 6% in contacts aged 0−3 years, to 17% in 4−5 year old contacts (Table 2). Ethnic backgrounds of those who acquired secondary infection were Moroccan (n=12, 48%), Dutch (n=5, 20%), Surinamese (n=2, 8%) Turkish (n=2, 8%) Croatian (n=2, 8%) or “other” (n=2, 8%). One 8-month old contact was admitted to hospital and there were no deaths. Over half of secondary infections (56%, n=14) were associated with primary cases who were under 6 years old. The nature of the positive contact’s relationship to the primary case was as follows: sibling (n=7, median age 4, IQR: 2−12), mother (n=7), father (n=3), offspring (n=2), or other family contact (n=6, median age 5.5, IQR: 4−14). Statistically there was no association between secondary infection and the nature of the contact’s relationship to the primary case, and we did not find any difference in age between siblings who were secondary versus non-secondary cases (mean age: 8.1 and 10.6 years respectively, p=0.502). Thirteen primary cases were associated with one positive household contact and 6 primary cases were associated with 2 positive household contacts. No factor was identified that was associated with >1 secondary transmission. Overall, the mean annual incidence of Shigella infection in Amsterdam from 2002−2009 was 7.7/100,000 persons.

At the univariable level (Table 2), secondary transmission was more likely to occur if the household contact was aged 4−5 years or if they had diarrhoea, or in turn if the primary case was aged 4−5 years old, or in large households (>6 persons). In the multivariable model, the only significant correlation observed, was between secondary infection and the presence of diarrhoea in the household contact. We re-ran the multivariable model without diarrhoea as a variable (data not shown in Table 2). Independent predictors of secondary infection in contacts

were then if the case was aged 0−3 years (Incidence Rate Ratio, IRRcase≥6 years: 2.5, 95% CI:1.1−5.5) or 4−5 years (IRR : 2.2, 95% CI: 1.1−4.3) and households with more than 6 persons (IRR case≥6 years 2−4 11 persons: 3.4, 95% CI:1.2−9.5). Contact characteristics were not significant in this model. Overall, 5/25 secondary infections were asymptomatic (20%). These were persons aged 5 and 8 years old, and three were aged >30 years. When contacts who were symptomatic and positive for Shigella were excluded (n=20), we did not find any association between the age of the contact (≥6years old (ref.) versus <6 years) and the risk of asymptomatic infection (IRR: 0.9, 95% CI:0.2−5.0).

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Table 2. Univariable and multivariable risk factors for secondary Shigella transmission to 337 contacts within 102 households*, Amsterdam, the Netherlands 2002-2009. Exposure Total no. of Any Univariable Multivariable household secondary contacts transmission N n (%) RR 95% CI p value RR 95% CI p value Contact characteristics (n=337 contacts) Total 337 25 (7.4) n/a n/a n/a n/a n/a n/a Age-group ≥ 6 years 260 17 (6.5) ref. ref. ref. ref. ref. ref. 0-3 48 3 (6.3) 1.0 (0.3−3.3) 0.943 1.0 (0.3−3.2) 0.979 4-5 29 5 (17.2) 2.6 (1.0−6.8) 0.046 1.3 (0.6−3.0) 0.527 Gender Female 171 17 (9.9) ref. ref. ref. Male 166 8 (4.8) 0.5 (0.2−1.2) 0.109 Country of birth Netherlands / Other 97 7 (7.2) ref. ref. ref. Western Other 236 18 (7.6) 1.1 (0.5−2.3) 0.890 Diarrhoea No 228 5 (2.2) ref. ref. ref. ref. ref. ref. Yes 87 20 (23) 10.5 (3.7−29.9) <0.001 8.0 (2.7−23.8) <0.001 Hospitalised No 336 24 (7.1) ref. ref. ref. Yes 1 1 (100) - − − Household factors (n=102 households) Household size 2-4 persons 128 5 (3.9) ref. ref. ref. ref. ref. ref. (in 61 households) 5-6 persons 96 5 (5.2) 1.3 (0.4−4.8) 0.658 1.4 (0.4−4.6) 0.570 (in 24 households) >6 persons 113 15 (13.3) 3.4 (1.3−8.7) 0.011 3.1 (0.9−10.1) 0.064 (in 17 households) Age of primary case in household ≥ 6 years 218 11 (5.1) ref. ref. ref. ref. ref. ref. 0-3 58 6 (10.3) 2.1 (0.8−5.5) 0.152 2.6 (1−7.1) 0.061 4-5 61 8 (13.1) 2.6 (1.2−5.7) 0.018 1.9 (0.8−4.5) 0.163 Gender of primary case in household Female 174 9 (5.2) ref. ref. ref. Male 163 16 (9.8) 1.9 (0.9−4.1) 0.103 Primary case in household hospitalised No 264 21 (8) ref. ref. ref. Yes 73 4 (5.5) 1,0 (0.9−1.2) 0.405

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Time from date of onset to notification of primary case ≤1 week 95 9 (9.5) ref. ref. ref. 1-3 weeks 146 8 (5.5) 0.6 (0.2−1.5) 0.262 >3 weeks 96 8 (8.3) 0.9 (0.4-2.0) 0.761

* The unit of analysis is the individual contact (n=337) and cluster characteristics are at the household level: household size, age and gender of the primary case in the household, whether they were hospitalised and time from date of onset to notification of primary case, as above.

Discussion

The proportion of secondary transmissions of laboratory confirmed Shigella infection in high risk household contacts of primary cases reported in Amsterdam from 2002 to 2009 was 7.4%. Though not directly comparable to our study, similar intra-familial or household secondary transmission rates of Shigella have been reported in studies conducted in outbreak settings in- ternationally.12,13 This rate is also similar to that of 8% reported by Vermaak et al.8 in Amsterdam from 1992−1998. In our study, only households with contacts considered to be at high risk of sec- ondary infection were included. As this represented a smaller denominator population than in Vermaak et al.,8 we had expected to find a relative increase in the rate of secondary infection. One explanation is that we underestimated the secondary attack rate and that (unscreened) positive asymptomatic cases in non-high risk households were missed. We consider this unlikely as in Vermaak et al.8 this accounted for only 3 extra cases over 8 years. An alternative explanation is that hygiene standards in households in the Netherlands and abroad have improved over time, reducing the potential for secondary spread. The majority of Shigella infections are imported, but recent national research has shown that between 1995 and 2006 there was a significant re- duction in the incidence of Shigella infection among travelers from the Netherlands which was related to improved hygiene standards in the countries visited.14 Despite a doubling in the an- nual number of travelers to (sub)tropical countries from about 1 million in 1999 to 2 million in 15 11 2007, the incidence of shigellosis in Amsterdam has remained relatively static at 8/100,000 in 19988, and 7.7/100,000 annually from 2002−2009.

Where outbreaks of shigellosis have occurred in nurseries and schools, they have generally been attributable to children with diarrhoea who visited the institution or those who returned to school before being culture-confirmed negative.12,16 Outbreaks have been brought under control by excluding young shigellosis cases from school or daycare where supervision of a child’s hygiene may be inconsistent, pending microbiological clearance.17,18 In our first multivariable model, the only factor independently associated with Shigella positivity in a household contact was diarrhoea, irrespective of the age of the case or of the contact. The current policy, that all contacts with diarrhoea should be investigated for the presence of the bacterium Shigella, is therefore supported.

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In the second multivariable model which examined predictors of secondary infection in contacts, preschool cases aged 0−3, those in junior classes in primary school aged 4−5 years, and those in large households were more likely to transmit (both symptomatic and asymptomatic) infection. Typically, young children who use the toilet independently but have limited understanding of good hand- and toilet-hygiene may be particularly susceptible to transmitting secondary infection. We did not find any increased risk among siblings of cases, or their mothers compared to other household contacts however, unlike similar research examining household transmission of E.Coli 0157.19 Based on our findings, screening of all contacts of cases who are under 6 years is also recommended. In fact, had faecal screening been limited to household contacts of cases who were under 6 years old and contacts with diarrhoea as we suggest, 96% of secondary cases would have been detected and only one asymptomatic adult carrier would have been missed. Additional faecal sampling of 164 contacts would not have been required.

The policy in the Netherlands of excluding all contacts under 6 years old pending a single negative faecal culture sample is generally not supported by our findings. In the multivariable models, the age of the contact was not independently associated with secondary Shigella infection and we found no association between young age of contact (<6 years old) and a risk of asymptomatic infection. In our study over the 8 year period, 70 asymptomatic children under 6 years old were potentially excluded from school or daycare pending microbiological clearance. This yielded only one asymptomatic infection. Although a formal cost-benefit analysis would be necessary to systematically compare costs, given considerable practical difficulties and low added value, the policy of excluding young children who are asymptomatic contacts of a case with shigellosis should be revisited.

There were a number of study limitations: firstly, we were unable to examine the risk of asymptomatic secondary transmission in low risk households, however among those at highest risk in these households who were screened (i.e. those who were symptomatic, or were care- workers or food-handlers), no secondary transmissions occurred. Secondly, we defined a secondary infection in a household contact as one that developed >1 day after the primary case. Had we used a more conservative definition (e.g. ≥3 days, based on the median incubation period), one additional case would have been reclassified, representing a secondary attack proportion of 7.2%. The associations at both univariable and multivariable level would not change however. Thirdly, there was a delay between date of onset of illness and date of notification of >3 weeks in 28% of cases. Recall bias is therefore likely, and cases and contacts may have reported estimated rather than precise dates of onset of illness. Ultimately, delay in reporting was not associated with secondary transmission of infection. Fourthly, culture was used for diagnosis of shigellosis, though it is recommended that the sample is submitted within 24 hours, false negatives may

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have occurred. The use of more sensitive molecular methods20 might have revealed more cases of secondary transmission. Finally, given the low proportion of secondary transmissions, it is possible some differences may have been undetected due to insufficient power.

In conclusion, guidelines relating to screening and exclusion of contacts in order to prevent secondary transmission of Shigella infection vary widely internationally. Prevention of secondary transmission through education and promotion of hand washing and strict hygiene practices in affected households remain the mainstay of Shigella control.5,6,21 To identify symptomatic and asymptomatic SSI, all household contacts of young Shigella cases (<6 years old) and contacts with diarrhoea should be screened. Exclusion of cases and contacts with diarrhoea from work, school and daycare remains important to prevent spread, but our findings do not support exclusion of asymptomatic child contacts under 6 years.

Acknowledgements

This research project was supported by a grant provided by the regional programme budget of the National Centre for Infectious Disease control in the Netherlands. We would also like to thank the nurses of the department of infectious diseases in Amsterdam who collected and recorded the data of cases and their contacts, and M. Siebbeles (MD) who reviewed the case charts.

References

1. American Public Health Association. Control of Communicable Diseases Manual. 19th ed. Washington, DC: American Public Health Association, 2008. 2. van Pelt W, de Wit MA, Wannet WJ, Ligtvoet EJ, Widdowson MA, et al. Laboratory surveillance of bacterial 11 gastroenteric pathogens in the Netherlands, 1991–2001. Epidemiol Infect. 2003;130:431–41. 3. Dupont H. Shigella species. In: Mandell G, Benett J, Dolin R, editors. Mandell, Douglas and Benett’s Principles and Practice of Infectious Diseases. 6th ed. Philadelphia: Churchill Livingstone, 2005:2655-61. 4. Queensland Government. Shigella infection (Shigellosis): Queensland Health Guidelines for Public Health Units: Queensland Government, 2010. 5. American Academy of Pediatrics. Shigella infections In: Pickering L, Baker C, Long S, McMillan J, editors. Red Book: 2009 report of the Committee on Infectious Diseases 28th ed. Elk Grove Village, IL: American Academy of Pediatrics 2009:593-96. 6. PHLS Advisory Committee on Gastrointestinal Infections. Preventing person-to-person spread following gastrointestinal infections: guidelines for public health physicians and environmental health officers. Commun Dis Public Health. 2004;7:362-84. 7. National Institute of Public Health and the Environment (RIVM). Reporting of infectious diseases in accordance with the Public Health Act. Bilthoven: National Institute of Public Health and the Environment (RIVM), 2008. [in Dutch]

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8. Vermaak M, Langendam M, van den Hoek J, Peerbooms PG, Coutinho R. Shigellosis in Amsterdam, 1991- 1998: prevention and results of contact tracing. Ned Tijdschr Geneeskd 2000;144:1688-90. [in Dutch] 9. National Center for the coordination of Infectious Disease Control (LCI). LCI Directive: Shigellosis. Bilthoven: National Institute of Public Health and the Environment (RIVM), 2011. 10. Rogers, W. H. Regression standard errors in clustered samples. Stata Technical Bulletin 1993;13: 19–23. Reprinted in Stata Technical Bulletin Reprints 1994;3:88–94. 11. Williams, R. L. A note on robust variance estimation for cluster-correlated data. Biometrics 2000;56:645–646. 12. De Schrijver K, Bertrand S, Gutierrez Garitano I, Van den Branden D, Van Schaeren J. Outbreak of Shigella sonnei infections in the Orthodox Jewish community of Antwerp, Belgium, April to August 2008. Euro Surveill 2011;16:pii=19838. 13. Khan AI, Talukder KA, Huq S, Mondal D, Malek MA, Dutta DK, et al. Detection of intra-familial transmission Discussion of Shigella infection using conventional serotyping and pulsed-field gel electrophoresis. Epidemiol Infect 2006;134:605-11. 14. Baaten GG, Sonder GJ, Van Der Loeff MF, Coutinho RA, Van Den Hoek A. Faecal-orally transmitted diseases among travelers are decreasing due to better hygienic standards at travel destination. J Travel Med 2010;17:322-8. 15. Dutch Tourist Board and NIPO Research. Continuous Holiday Survey Leidschendam: Dutch Tourist Board and NIPO research, 1999-2007. [in Dutch] 16. Jonsson J, Alvarez-Castillo Mdel C, Sanz JC, Ramiro R, Ballester E, Fernanez M, et al. Late detection of a shigellosis outbreak in a school in Madrid. Euro Surveill 2005;10:268-70. 17. Mohle-Boetani JC, Stapleton M, Finger R, Bean NH, Poundstone J, Blake PA, et al. Communitywide shigellosis: control of an outbreak and risk factors in child day-care centers. Am J Public Health 1995;85:812-6. 18. Arvelo W, Hinkle C, Nguyen T, et al. Transmission risk factors and treatment of pediatric shigellosis during a large day-care center-associated outbreak of multidrug resistant Shigella sonnei. Implications for the management of shigellosis outbreaks among children. Pediatr Infect Dis J 2009;28:976-980 19. Werber D, Mason B, Evans M, Salmon R. Preventing household transmission of Shiga Toxin-producing Escherichia coli O157 infection: Promptly separating siblings might be the key. CID 2008:46:1189-96. 20. de Boer RF, Ott A, Kesztyus B, Kooistra-Smid AM. Improved detection of five major gastrointestinal pathogens by use of a molecular screening approach. J Clin Microbiol 2010;48:4140-6. 21. Centers for Disease Control (CDC). Community outbreaks of shigellosis - United States. MMWR Morb Mortal Wkly Rep 1990;39:509-13, 519.

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26660 Whelan kopie.indd 155 02-11-13 16:03 CHAPTER 12

Discussion

This thesis brings together studies in primary and secondary infectious disease prevention, using analytic epidemiology to identify risk groups and risk factors for disease in the slowly evolving context of public vaccination programmes, and in sudden-onset outbreaks. The research in this thesis develops the evidence base for, and practically supports, infectious disease control at regional and national level in the Netherlands.

Section 1. Immunisation

In the first section, we examined the epidemiology of vaccine preventable diseases, hepatitis B and hepatitis A, to define current risk groups. We make recommendations for targeted vaccination and improved disease prevention. Historically, the incidence of both diseases is higher in Amsterdam than the national average. Amsterdam is one of the most ethnically diverse cities in the world and more than 35% of the population are non-Western immigrants (compared to 8.5% nationally). It is projected that the total non-western population in Amsterdam will increase by 50,000 people between 2011 and 2030, of whom an estimated 60% will be new first generation migrants.1 In addition, it is estimated that 10% of the adult male population in Amsterdam are MSM2 (7–8% nationally) and the city is also known internationally for its sexual and social diversity, tolerance of prostitution and some drug use. Recognising the increased risk of related infectious disease transmission, PHS Amsterdam regularly conducts local research and has enhanced surveillance systems in place since the early 1980s, collecting detailed data on contacts of notified cases in addition to routine requirements. As such it has helped to shape and inform local and national public health policy and programme development.

Incidence of hepatitis B in ethnic groups (Chapter 2) What was already known on this topic Studies conducted nationally3 and in Amsterdam4 suggest that the prevalence of HBV in first and second generation migrants from countries where HBV is endemic (FGM and SGM, respectively) including Morocco, Turkey and Suriname, is higher than in the Dutch population. In recent years, as evidence of the cost-effectiveness of screening FGM at risk of chronic HBV infection has accumulated,5-7 the development of a national policy on migrant screening is now seen as a priority.8 In addition, vaccination programmes targeting children born to hepatitis B infected mothers (since 1989) and children of whom either parent was born in a middle- or high-endemic country for hepatitis B (since 2003) have been shown to be effective in preventing both acute and chronic infections.9,10 In 2012, vaccination coverage in both groups was 96.1% and 94.3% respectively,11 and vaccination of the latter cohort of children has largely eliminated

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infection in this group.10 In the Netherlands in 2011, 1732 cases of hepatitis B virus (HBV) infection were notified, of which 89% were chronic infections and 9% were acute infections.8 In terms of acute infection, this represents the lowest incidence since records began, and most of this decline is attributed to a drop in the number of notifications among MSM. The majority of acute infections were of unknown origin (25%) or were heterosexually transmitted (32%) and there are indications that adult migrants may be overrepresented in these figures.12

What this study adds The incidence of acute HBV infection in FGM in Amsterdam was 4.1/100,000 showing little fluctuation over calendar year from 1992 to 2009. Since 1999 the incidence in Dutch-born cases in Amsterdam has increased by 13% annually from 0.2/100,000 in 1999 to 2.1/100,000 in 2009. Although data regarding ethnic background of Dutch-born cases was only available from 2004, there are indications that some of this increase in incidence could be accounted for by SGM, as it also mirrors a doubling of the SGM population over the study period. The proportion of cases where the route of transmission was unknown in our study (23%) was similar to that reported nationally. Overall, between 2004 and 2009, the incidence was 4.3/100,000 in FGM, 3.7/100,000 in Dutch-born SGM, and 1.6/100,000 in native Dutch. This study confirms that new, potentially preventable infections are occurring in adult FGM and SGM who are resident in Amsterdam.

Recommendations arising from this study Our findings support the proposal that migrants from HBV endemic countries should be offered screening for HBV infection, but also highlights the risk of new infections among FGM already resident and SGM born prior to 2003. Further research will be required to determine if a screening and catch-up vaccination programme would be acceptable, feasible and cost-effective, and to better understand the routes of transmission among migrants where it is recorded as ‘unknown’.

Incidence of hepatitis B in MSM: Targeted vaccination proves successful (Chapter 3) What is already known on this topic 12 Between 1997 and 2002, the incidence of acute hepatitis B in Amsterdam was estimated at 2.2– 3.7/100,000 population compared to 1.4–1.8/100,000 nationally.13 Given this elevated risk in the Amsterdam population, screening and vaccination of behavioural risk groups including MSM, commercial sex workers and drug users was commenced (initially on a pilot basis) in 199814 and rolled out nationally in 2002. The effectiveness of these programmes has been evaluated continuously since 2002.15,16,17 Despite observed falls in the number of notifications of acute HBV in MSM in recent years, marked fluctuations in numbers reported over time, limited programme reach (an estimated 6–12% vaccination coverage in the risk group15,17) combined

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with a lack of demonstrable programme effect until 2006,17 led to concerns about the ability of these programmes to eliminate HBV disease in these groups. On this premise, supported by dynamic transmission models tailored to the Dutch context,18 universal vaccination of infants was introduced in 2011. As no “catch-up” campaign for young teenagers would be offered (due to a perceived lack of support for adolescent vaccination19), it was proposed that the targeted programmes already in situ would continue as necessary for 20 to 30 years to come.

What this study adds This study showed that the incidence of HBV infection in MSM in Amsterdam decreased by 78% between 2004 and 2012. Despite ongoing high-risk sexual behaviour and vaccination coverage below the 40% target, the Amsterdam HBV programme appears to have been successful in reducing HBV transmission among Amsterdam MSM. A mathematical model in this study demonstrated that the decline in incidence is best explained by the scenario in which high-risk MSM are vaccinated. The study also showed that MSM born between 1960 and 1970 have been at highest risk in the past 20 years.

Recommendations arising from this study HBV vaccination programmes targeting MSM do not require full coverage in order to be effective. Incidence can be substantially reduced if those who engage most in high-risk sex, and those who contribute most to transmission are reached. Policy decisions should therefore focus on identified MSM networks responsible for continued HBV transmission.

Immunogenicity of the hepatitis B component of hexavalent vaccine (Chapter 4) What is already known on this topic Children in the Netherlands have been vaccinated against infectious diseases under the National Immunisation Programme (NIP) since 1957. As vaccines against an increasing number of infectious agents have been introduced into the schedule, combination vaccines containing multiple components in a single injection are being administered simultaneously with newer vaccines against meningococcus C (since 2001) or pneumococcus (since 2006). This is thought to be easier for the vaccine recipient, more acceptable to parents and more convenient, cost- effective and efficient for health care workers.20,21 However, co-administration of multi- component vaccines with other mono- or multi-valent vaccines has lead to concerns about a suboptimal induced immune response.22 Reduced clinical efficacy was shown in the UK when the Hemophilus influenzae type b (Hib) component was given in a combined, acellular pertussis containing vaccine (DTaP-Hib).23 More latterly in 2005, authorization of a hexavalent vaccine, Hexavac™ (Sanofi Pasteur, MSD), was suspended by the European Medicines Agency (EMEA)

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due to concerns about long-term immunogenicity of the hepatitis B component when co- administered with meningococcal or pneumococcal vaccines.24

What this study adds Since June 2006, the hexavalent vaccine, Infanrix hexa™ (DTaP–IPV–Hib–HBV) has been offered concomitantly with pneumococcal vaccine (Prevenar™), to children at increased risk of hepatitis B infection. We assessed the immunogenicity of the HBV component of Infanrix hexa™ co- administered with Prevenar™, and also compared pertussis and Hib components in Infanrix hexa™ with the standard Infanrix–IPV + Hib vaccine offered to all children. Target thresholds for immune responses were achieved for all antigens studied and over 99% of children vaccinated with Infanrix hexa™ achieved an adequate immune response (≥10 mIU/ml) to the HBV component. The geometric mean concentration of the HBV component in Infanrix hexa™ when co-administered with pneumococcal vaccine was somewhat lower than expected when compared to other studies conducted internationally where Infanrix hexa was administered alone, though this is unlikely to be of any clinical significance.

Recommendations arising from this study The findings of this study are generally encouraging. Protection against hepatitis B will be required for decades in people vaccinated in infancy and long-term immunogenicity of this vaccine administered in combination with Prevenar™ should continue to be monitored. Long term monitoring will continue to be a priority as more components are added to vaccines and as more vaccinations are added to the childhood schedule.

Incidence of hepatitis A in migrants (Chapter 5) What is already known on this topic For decades, Amsterdam and other major urban centres in the Netherlands have seen a surge in hepatitis A virus (HAV) notifications in early Autumn each year.25 The majority occur in SGM children who contracted the infection while on summer holiday in the country of birth of their parents (predominantly Turkey or Morocco). The initial surge in notifications was followed 12 one incubation period later, in November–December, by an increase in HAV infections among children and adults who did not travel, but instead acquired their infection in the Netherlands.26 In response, the PHS has organized annually since 1998, large vaccination campaigns prior to the summer targeted at SGM children of Turkish and Moroccan backgrounds and those of other North African countries. Nationally, in 2012, the number of HAV infections was the lowest recorded since this disease became notifiable in 1999.27 In Amsterdam, whether or not the ethnic make-up of cases had been influenced by the vaccination campaigns was unknown, although there were earlier indications that they were indeed effective in reducing infections.28

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A formal evaluation of vaccine uptake and the effectiveness of the vaccination campaigns was not possible as the absolute number of migrant children who travel to their parent’s country of origin is unknown, and less than half of vaccinations are administered at the PHS (instead by the family doctor, or elsewhere).

What this study adds This research confirmed a dramatic decrease in the incidence of acute HAV infections since 1996 in Amsterdam. In more recent years, since 2005, 56% of cases were imported. The incidence in Moroccan SGM was 4 times higher than in ethnic Dutch children. In Turkish children, the incidence was similar to that of the ethnic Dutch. Although it is likely the programme has had some effect, a second important finding was that the ethnic background of cases was more mixed than previously with cases coming from many different non-Western backgrounds. Targeting the vaccine appropriately in the vaccination campaigns as currently organised is therefore difficult.

Recommendations arising from this study Although the number of infections occurring annually has decreased substantially, infections are still occurring and the majority are imported (since this research was conducted, 11/14 cases notified in Amsterdam in 2012 were imported). In July 2012, WHO recommended that single-dose inactivated HAV vaccine could be considered in national immunization schedules where appropriate.29 To achieve better and more consistent coverage than the current ad-hoc programmes (pending cost-effectiveness), children who are of non-western background could be offered a single dose of HAV vaccine at the same time as the MMR vaccine, which is currently given within the national immunisation programme at 14 months of age. The cost-effectiveness, acceptability, and feasibility of this approach would require further investigation.

Evaluation of hepatitis A vaccine in post-exposure prophylaxis (Chapter 6) What is already known on this topic When a patient presents with acute hepatitis A infection, persons who have had contact with them are offered post-exposure prophylaxis (PEP) in an attempt to prevent or attenuate secondary infection and limit tertiary spread.30 Historically, contacts of cases were offered immunoglobulin (IG, a human derived blood product) within the incubation period (15–50 days). Amid safety concerns about IG, public health authorities in many European countries and Canada have been recommending the vaccine to some extent for almost a decade, though guidelines differ, particularly in relation to upper age-limits for post-exposure vaccination.31-34 Evidence of vaccine effectiveness used routinely in PEP is also limited.

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What this study adds Our study was the first formal evaluation of hepatitis A vaccine in routine post-exposure prophylaxis to our knowledge. Of contacts identified between 2004 and 2012, hepatitis A vaccine was offered according to protocol, to contacts who were healthy and at low risk of severe disease (aged <30, or, 30–50 years and vaccinated <8 days post-exposure, overall 89% of contacts). Immunoglobulin was offered to the remaining 13%, who were considered at risk of severe infection because of advanced age or an underlying health disorder. At follow-up testing 4–8 weeks later, 7% had developed a laboratory confirmed infection. All secondary infections occurred in vaccinated contacts and half were >40 years of age.

Recommendations arising from this study Timely administration of HAV vaccine in PEP was feasible and the secondary attack rate was low in those <40 years. Pending larger studies, immunoglobulin should be considered the PEP of choice in people >40 years of age and those vulnerable to severe disease, irrespective of the number of days post-exposure that the vaccine is administered.

Section 2: Outbreak Investigation

In this section, we report investigations of outbreaks that were identified through routine surveillance. Specifically, these investigations were conducted to study risk factors for exposure, infection and morbidity among susceptible hosts for a known organism, to inform current and future prevention and control measures. Outbreak investigations present many challenges. If there is an ongoing exposure, finding the source is urgent and there is considerable time pressure, e.g. during food-borne outbreaks (Chapter 10). Delays lead to limited human or environmental samples for testing and difficulty confirming the source. In practice, studies may have limited statistical power and recall bias can impede objectivity, particularly during outbreaks with a high media profile (Chapter 8 and Chapter 9). Outbreaks teach us to expect the unexpected – even where populations are highly vaccinated against the agent in question (Chapter 7). In some outbreak situations, risk factors for infection are well described and the 12 added value in conducting an outbreak investigation lies in testing new research methodologies (Chapter 10), or evaluating current preventive strategies with a view to improving efficiency and maximising staff and resource capacities (Chapter 11).

Risk factors for Mumps among vaccinated university students (Chapter 7) What is already known on this topic Mumps outbreaks among highly vaccinated populations have occurred in the Netherlands35 and internationally.36,37 From 2009 to 2012, a mumps outbreak affected more than 1500 people in the

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Netherlands, the majority of whom were fully vaccinated (72% had at least two doses of MMR).38 The outbreak was first identified among university students in the cities of Leiden, Utrecht and Delft,39 and the G5 genotype was identical to the mumps virus isolated from outbreaks in the UK and USA between 2005 and 2009. Sero-epidemiological results from the PIENTER 2 study (2006/7) showed waning immunity after both the first and second MMR and a susceptible group in the low vaccine coverage areas.40

What this study adds We conducted a retrospective cohort study among almost 1000 students from the three university cities most affected by the initial outbreak in 2009–2010: Delft, Utrecht and Leiden. The mumps attack rate (AR) was 13.2% (95% CI:11.1–15.5%) among respondents. Attendance at a large student party, being unvaccinated and living in student residences with more than 15 housemates were independently associated with clinical mumps infection. The adjusted vaccine effectiveness (VE) estimate for two doses of MMR was 68% (95% CI:41–82%). We concluded that despite high MMR vaccination coverage, the most likely cause of this outbreak was intense social mixing during the party and the dense communal living environment of the students.

Recommendations arising from this study On the basis of this outbreak, young adults were advised to ensure they had received two doses of MMR vaccination (particularly to reduce the risk of complications if infected). They were also advised to consider postponing parties or large social gatherings when mumps was known to be circulating. Consideration was also given to offering a third MMR dose to the vaccination schedule. Given low mumps-related morbidity, low expected vaccine uptake and cost and logistical concerns, it was considered that a third dose could not be justified based on current available evidence.

Risk factors for Q fever exposure and infection (Chapter 8 and Chapter 9) What is already known on this topic From 2007 to 2009 an arguably unprecedented outbreak of Q fever caused by the bacterium Coxiella burnetii occurred in the Netherlands, resulting in the notification of more than 4000 patients.41 Q fever outbreaks have been described in other populations, often where sheep and goats have been implicated in human infection,42 but never on such a scale. There were many unknowns in this outbreak related to the pathogen, the transmission dynamics and risk factors for human disease.

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What these studies add In Chapter 8, we examined risk factors for infection during occupational exposure to Q fever. Workers involved in culling more than 50,000 sheep and goats were recruited into a prospective cohort study to examine Coxiella burnetii seroconversion and related morbidity while culling. Despite the fact that workers were given a presentation, advised to read the occupational health and hygiene regulations, and were provided with personal protective equipment (PPE) including FFP3 masks (‘Face Filtering Pieces’ thought to filter at least 99% of airborne particles), 17.5% seroconverted for antibodies to Coxiella burnetii. Working in close proximity to the animals inside the stable and prolonged contact (>100 hours per week) were risk factors for seroconversion. Anecdotally, culling workers reported removing PPE during coffee breaks and lunch breaks which may have contributed to the high proportion of seroconversions recorded. In Chapter 9, we examined recreational exposure as a risk factor for Q fever. Preliminary investigations into an outbreak of 350 people implicated a public ‘lamb-viewing day’ on a non-dairy sheep farm. In a matched case-control study, the association was confirmed, and other risk factors identified were being a smoker, having a past medical history and being aged >40 years.

Recommendations arising from these studies In the context of inevitable exposure during animal culling, workers should be carefully instructed on PPE compliance in designated risk areas. Vaccination of culling workers could be considered in this context. Where exposure to infected animals could be avoided (i.e. visiting infected farms) the advice was to do so, and the farm involved in this investigation was closed to the public pending vaccination of the herd (the farm reopened in the spring of 2011).

Risk factors for infectious gastrointestinal disease (Chapter 10 and Chapter 11) What is already known on this topic Outbreaks of infectious gastrointestinal disease are common and risk factors are often well recognised, but each outbreak affords us new insights. In 2011, Salmonella spp. was estimated to cause around 37,000 cases of gastroenteritis. This cost in the region of 22–23 million euro in the Netherlands, 12 million of which was estimated to be related to foodborne infections.43 Raw 12 or rare contaminated meat products have been implicated in previous outbreaks.44-46 Despite advice about the potential danger of eating raw or undercooked meat, such outbreaks continue to occur. Shigella, an organism that is closely related to Salmonella, is also spread through the faecal-oral route. In the Netherlands, 75% of infections are imported. Nationally, 300–600 cases of bacillary dysentery attributed to Shigella are reported each year, yielding an approximate annual incidence of 3.2/100,000 population.47 Secondary infections are common and related socioeconomic costs can be high.

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What these studies add During some outbreaks, the added value in conducting an outbreak investigation lies in testing new research methodologies, or evaluating current practice with a view to improving efficiency and maximising staff and resource capacities. In 2009, an outbreak of a previously unreported Salmonella Typhimurium (Dutch) phage type 132 affected 23 people in the Netherlands. It was attributed to contaminated raw or undercooked beef products. A novel approach to the traditional case–control study was attempted using the food consumption component of responses to a routine quarterly population-based survey as a control group. In Chapter 11, also to ensure efficient use of staff and resources, we examined the incidence of secondary Shigella infection (SSI) in households. SSI occurred in 7.4% of household contacts. This was lower than expected, probably due to improved hygiene standards in households in the Netherlands and abroad. Diarrhoea in a contact was an indicator of SSI, and independently, being a contact of a case where the case was aged less than 6 years, was a predictor of SSI.

Recommendations arising from these studies Use of the food consumption component of a routine quarterly population-based survey was timely and could be employed in other food-borne outbreaks. This approach reduced the surge in manpower required to conduct a case–control study after an outbreak, and proved effective and timely as controls returned questionnaires throughout the outbreak period reflecting food intake in the previous week. The control-survey should be reviewed as necessary to take account of newly recognised or seasonal links to food and behaviours that might place individuals at risk of food-borne infection. Children and elderly could be oversampled to achieve a better representation of groups known to be vulnerable to Salmonella and other infections. During outbreaks, contact tracing and screening also increase manpower requirements and cost. For contacts of Shigella cases, faecal screening should be targeted at all household contacts of preschool cases (0–3 years) and cases attending junior class in primary school (4–5 years) and any household contact with diarrhoea. We did not find evidence to support the exclusion of all asymptomatic contacts <6 years old (irrespective of the age of the case) from school or day-care pending microbiological clearance, as is currently recommended.48

Conclusion and future research

Nationally, and regionally in the Amsterdam Public Health Service, the Netherlands has a longstanding reputation for high-quality infectious disease surveillance, epidemiological research and public health programme evaluation. Descriptive and analytic epidemiological studies as described in this thesis help to interrupt chains of infectious disease transmission by identifying risk groups and risk factors for exposure as they change and evolve over time.

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They practically inform primary and secondary preventive strategies for infectious disease control, which prevent disease at an individual level and are responsive to changes in disease epidemiology in the population over time.

The Netherlands will become increasingly ethnically diverse in the coming years, and minority ethnic groups are over-represented in infectious disease surveillance figures. Emerging infectious diseases, hepatitis C for example, rarely prevalent in the Netherlands previously, are likely to become more common as the population migrating from disease-endemic countries grows. Internationally, there is no consensus on the definition of ethnicity. It is variously defined by the country of birth of the individual, their nationality, self-declared racial/ethnic background, race, country of birth of the individual and his/her parents, or any combination of these. In the Netherlands, country of birth of both the individual and his or her parents are recorded. This allows for differences between first generation migrants and their Dutch-born descendants to be examined and is a particular strength of Dutch infectious disease surveillance. Also, as everyone in the Netherlands must register in the municipality in which they reside, population incidence rates can then be estimated by ethnic group and generation at the regional and national level. This facilitates future estimates of multi-generational differences in disease, targeted intervention through screening and/ or vaccination, and evaluation of policy changes at a population level. For diseases that are of low endemicity in the Netherlands (such as hepatitis B and A), 10 year epidemiological evaluations are probably sufficient.

In MSM in Amsterdam, an early evaluation of the targeted hepatitis B vaccination programme was not encouraging due to low uptake and limited observed programme impact. Fourteen years after its introduction however, we demonstrated a decreasing incidence attributable to the programme, and showed that low coverage (<40%) did not impede its success. This has important policy implications. Rather than targeting all MSM, we recommend that future vaccination efforts should be concentrated among those to engage most in high-risk sexual contact. For hepatitis A disease, we showed that acute infections are at the lowest level ever recorded in Amsterdam, and that among cases occurring, the ethnic background is more 12 diverse than previously. The current annual vaccination campaign targeting migrant children of Turkish and North African origin in Amsterdam may not be reaching those most at risk and should be reconsidered. Use of enhanced surveillance data, as collected by PHS Amsterdam, has helped to highlight evolving health inequalities in minority groups that might otherwise go unrecognised. It also allows evaluation, not just of individual cases, but of risk for contacts and secondary transmission. This in turn has direct implications for disease control guidelines as demonstrated with hepatitis A PEP and shigellosis contact screening. These examples show how preventive programmes must be adaptable. Where changes in vaccination guidelines are

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proposed, ethical issues, acceptability, feasibility and cost-effectiveness of new programmes must be investigated. Criteria and strategies for reduction or discontinuation of vaccination programmes, where relevant, also need to be established.

Surveillance data has its limitations: cases who are asymptomatic or with mild disease may not seek health care and cases may be underreported or misclassified. For conditions that are still culturally sensitive or stigmatised, risk behaviour may go unreported: in 23% of acute HBV cases notified in Amsterdam, no route of transmission was identified. Molecular epidemiology and typing combined with surveillance data will contribute to a better understanding of transmission routes. Also, where the population denominator is uncertain (e.g. in behavioural risk groups such as MSM), molecular methods and behavioural surveillance help to evaluate programme effectiveness.

New and unexpected infectious disease events continue to occur, most recently, an outbreak of Q fever in the Netherlands, and the novel coronavirus (MERS) and SARS internationally. Even where successful vaccination programmes with high vaccination coverage have been implemented, diseases are re-emerging. This is illustrated here by the mumps outbreak in highly vaccinated students and probable waning mumps immunity as the first generation to be vaccinated reach adulthood. Waning protection post-vaccination has been observed in relation to other pathogens, and adaptation of the pathogen to vaccination is also occurring (pertussis, for example). Where such outbreaks occur, research to better understand transmission dynamics, the role of cellular immunity and viral evolution will be required. Intermittent sero- epidemiological studies (such as PIENTER in the Netherlands) help to identify waning immunity when it occurs and are required as population susceptibility changes post-vaccination. They help us to anticipate outbreaks (the current measles epidemic in an under-vaccinated group in the Netherlands, for example49), and support planning and placement of a research infrastructure prior to or early in an outbreak, as the timing of outbreaks are unpredictable. In combination with case surveillance, sero-epidemiological studies will continue to be a priority as more components are added to vaccines and as more vaccinations are added to the childhood schedule. Finally, in some outbreak situations, risk factors for infection are well described, and the added value of conducting an outbreak investigation may lie in testing new research methodologies, evaluating current practice and applying the findings to improve day-to-day infectious disease prevention and control. The final link in the chain.

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“I often say that when you can measure what you are speaking about, and express it in

numbers, you know something about it; but when you cannot express it in numbers, your

knowledge is of a meagre and unsatisfactory kind; it may be the beginning of knowledge,

but you have scarcely, in your thoughts, advanced to the stage of science….”

William Thompson, Lord Kelvin.

Lecture on “Electrical Units of Measurement”, Popular Lectures, 1883.

12

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References

1. Bureau Onderzoek & Statistiek. Amsterdam in cijfers. Amsterdam: Gemeente Amsterdam, 2013. [in Dutch] 2. Kuyper L, Vanwesenbeeck I. High levels of same-sex experiences in the Netherlands: prevalences of same- sex experiences in historical and international perspective. J Homosex 2009;56:993-1010. 3. Hahné S, de Melker H, Kretzschmar M, Mollema L, Van Der Klis F, et al. Prevalence of hepatitis B virus infection in the Netherlands in 1996 and 2007. Epidemiol Infect 2012;140:1469-80. 4. Baaten GG, Sonder GJ, Dukers NH, Coutinho RA, Van den Hoek JA. Population-based study on the seroprevalence of hepatitis A, B, and C virus infection in Amsterdam, 2004. J Med Virol 2007;79:1802-10. 5. Veldhuijzen IK, Wolter R, Rijckborst V, Mostert M, Voeten HA, et al. Identification and treatment of chronic hepatitis B in Chinese migrants: results of a project offering on-site testing in Rotterdam, the Netherlands. J Hepatol 2012;57:1171-6. 6. Richter C, Beest GT, Sancak I, Aydinly R, Bulbul K, et al. Hepatitis B prevalence in the Turkish population of Arnhem: implications for national screening policy? Epidemiol Infect 2012;140:724-30. 7. Veldhuijzen IK, Toy M, Hahné SJ, De Wit GA, Schalm SW, et al. Screening and early treatment of migrants for chronic hepatitis B virus infection is cost-effective. Gastroenterology 2010;138:522-30. 8. Hahné S, Koedijk FDH, Kemmeren JM, Rots NY, Boot HJ. Hepatitis B. In: van ‘t Klooster T.M., de Melker H.E., editors. The National Immunisation Programme in the Netherlands. Developments in 2012. Report no. 201001002/2012. Bilthoven: RIVM, 2012. 9. Health Council of the Netherlands. Universal vaccination against hepatitis B. Report nr. 2001/03 The Hague: Health Council of The Netherlands, 2001. [in Dutch] 10. Health Council of The Netherlands. Vaccination of children against hepatitis B. Report nr. 2003/14. The Hague: Health Council of The Netherlands, 2003. [in Dutch] 11. van Lier EA, Mollema L. Vaccination Coverage. In: Van ‘t Klooster M, de Melker HE, Editors. The National Immunisation Programme in The Netherlands. Developments in 2012. Report no. 201001002/2012T. Bilthoven: RIVM, 2012. 12. Veldhuijzen IK, Smits LJ, van de Laar MJ. The importance of imported infections in maintaining hepatitis B in the Netherlands. Epidemiol Infect 2005;133:113-9. 13. Rijlaarsdam J, Smits L, van de Laar M. Notifcation of hepatitis B in the Netherlands in the period 1976-1998. Infectieziekten Bulletin (Infectious Disease Bulletin) 1999;10:185-86 [in Dutch] 14. van Steenbergen JE. Results of an enhanced-outreach programme of hepatitis B vaccination in the Netherlands (1998-2000) among men who have sex with men, hard drug users, sex workers and heterosexual persons with multiple partners. J Hepatol 2002;37:507-13. 15. van Houdt R, Koedijk FD, Bruisten SM, Coul EL, Heijnen ML, et al. Hepatitis B vaccination targeted at behavioural risk groups in the Netherlands: does it work? Vaccine 2009;27:3530-5. 16. Koedijk FDH, Op de Coul E, Cremer J, Hahné S, Coutinho R, et al. Incidence and molecular epidmiology of hepatitis B virus, the Netherlands, 2004-2007. Report nr. 2010011001/2008. Bilthoven:RIVM, 2008. [in Dutch] 17. van Houdt R, Sonder GJ, Dukers NH, Bovée LP, van den Hoek A, et al. Impact of a targeted hepatitis B vaccination program in Amsterdam, the Netherlands. Vaccine 2007;25:2698-705. 18. Kretzschmar M, Mangen MJ, van de Laar M, de Wit A. Model based analysis of hepatitis B vaccination strategies in the Netherlands. Vaccine 2009;27:1254-60. 19. Klink A. Universal vaccination against hepatitis B in the National Immunisation Programme (Letter of the Minister of Health to the Second Chamber of Parliament). The Hague: Ministry of Health, Social Welfare and Sports (VWS), 2010. 20. Dodd D. Benefits of combination vaccines: effective vaccination on a simplified schedule. Am J Manag Care 2003;9:S6-12. 21. Kalies H, Grote V, Verstraeten T, Hessel L, Schmitt HJ, et al. The use of combination vaccines has improved timeliness of vaccination in children. Pediatr Infect Dis J 2006;25:507-12. 22. Boot HJ, Schipper CM. Simultaneous vaccination with Prevenar and multicomponent vaccines for children: interference or no interference? Hum Vaccin 2009;5:15-7.

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23. McVernon J, Andrews N, Slack MP, Ramsay ME. Risk of vaccine failure after Haemophilus influenzae type b (Hib) combination vaccines with acellular pertussis. Lancet 2003;361:1521-3. 24. European Medicines Agency. Scientific conclusions and grounds for the suspension of the marketing authorisation of hexavac presented by the EMEA, 2005. 25. Termorshuizen F, van de Laar MJ. The epidemiology of hepatitis A in the Netherlands, 1957-1998. Ned Tijdschr Geneeskd 1998;142:2364-8. [in Dutch] 26. van Gorkom J, Leentvaar-Kuijpers A, Kool JL, Coutinho RA. Annual epidemics of hepatitis A in four large cities related to holiday travel among immigrant children. Ned Tijdschr Geneeskd 1998;142(34):1919-23. [in Dutch] 27. Friesema IHM, Verhoef LPB, Luytjes W, Kemmeren JM, Suijkerbuijk AWM. Hepatitis A. In: Van ‘t Klooster M., de Melker H., editors. The National Immunisation Programme in the Netherlands. Developments in 2012. RIVM report 201001002/2012T. Bilthoven: RIVM, 2012. 28. Sonder GJ, Bovée LP, Baayen TD, Coutinho RA, van den Hoek JA. Effectiveness of a hepatitis A vaccination program for migrant children in Amsterdam, the Netherlands (1992-2004). Vaccine 2006;24:4962-8. 29. World Health Organisation Strategic Advisory Group of Experts on Immunization. Evidence based recommendations for use of hepatitis A vaccines in immunization services: background paper for SAGE discussions. Geneva: World Health Organisation, 2011. 30. National Center for the coordination of Infectious Disease Control (LCI). Guideline: Hepatitis A. Bilthoven: RIVM, 2011. 31. Crowcroft NS, Walsh B, Davison KL, Gungabissoon U. Guidelines for the control of hepatitis A virus infection. Commun Dis Public Health 2001;4:213-27. 32. Centers for Disease Control and Prevention. Update: Prevention of hepatitis A after exposure to hepatitis A virus and in international travelers. Updated recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Morb Mortal Wkly Rep 2007;56:1080-4. 33. National Advisory Committee on Immunization and the Public Health Agency of Canada. Hepatitis A vaccine: Post exposure immunization Canadian Immunization Guide, Evergreen Edition. Part 4: Active Vaccines 2012. 34. De Schrijver K, Flipse W, Laisnez V, Mak R, Steebnergen JE van, et al. Hepatitis A. Guidelines for infectious disease control, Flanders. Edition 2011, 2011. 35. Brockhoff HJ, Mollema L, Sonder GJ, Postema CA, van Binnendijk RS, et al. Mumps outbreak in a highly vaccinated student population, the Netherlands, 2004. Vaccine 2010;28:2932-6. 36. Dayan GH, Quinlisk MP, Parker AA, Barskey AE, Harris ML, et al. Recent resurgence of mumps in the United States. N Engl J Med 2008;358:1580-9. 37. Kay D, Roche M, Atkinson J, Lamden K, Vivancos R. Mumps outbreaks in four universities in the North West of England: prevention, detection and response. Vaccine 2011;29:3883-7. 38. Hahné SJM, Rots NY, Kemmeren J, van Binnendijk RS. Mumps. In: Van ‘t Klooster M., de Melker H., editors. The National Immunisation Programme in the Netherlands. Developments in 2012. Report no. 201001002/2012. Bilthoven: RIVM, 2012. 39. Whelan J, van Binnendijk R, Greenland K, Fanoy E, Khargi M, et al. Ongoing mumps outbreak in a student population with high vaccination coverage, Netherlands, 2010. Euro Surveill 2010;15: pii=19554. 12 40. Smits G, Mollema L, Hahné S, de Melker H, Tcherniaeva I, et al. Seroprevalence of mumps in the Netherlands: dynamics over a decade with high vaccination coverage and recent outbreaks. PLoS One 2013;8:e58234. 41. van der Hoek W. The 2007-2010 Q fever epidemic in the Netherlands: risk factors and risk groups [PhD thesis]. Utrecht: Utrecht University, 2012. 42. EFSA Panel on Animal Health and Welfare. Scientific opinion on Q fever. EFSA Journal 2010;8:1595. 43. Mangen MJJ, Bouwknegt M, Friesema IHM, Kortbeek LM, van Pelt W, et al. Disease burden and cost-of- illness of food-related pathogens in the Netherlands, 2011. Report no. 330331007/2013. Bilthoven:RIVM, 2013.

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44. Greenland K, de Jager C, Heuvelink A, van der Zwaluw K, Heck M, et al. Nationwide outbreak of STEC O157 infection in the Netherlands, December 2008-January 2009: continuous risk of consuming raw beef products. Euro Surveill 2009;14:pii=19129. 45. Doorduyn Y, de Jager C, van der Zwaluw W, Friesema I, Heuvelink A, et al. Shiga toxin-producing Escherichia coli (STEC) O157 outbreak, The Netherlands, September-October 2005. Euro Surveill 2006;11:pii=636. 46. Kivi M, Hofhuis A, Notermans DW, Wannet WJ, Heck ME, et al. A beef-associated outbreak of Salmonella Typhimurium DT104 in the Netherlands with implications for national and international policy. Epidemiol Infect 2007;135:890-9. Summary 47. van Pelt W, de Wit MA, Wannet WJ, Ligtvoet EJ, Widdowson MA, Laboratory surveillance of bacterial gastroenteric pathogens in the Netherlands, 1991-2001. Epidemiol Infect 2003;130:431-41. 48. National Center for the coordination of Infectious Disease Control (LCI). LCI Directive: Shigellosis. Bilthoven: RIVM, 2011. 49. Mollema L, Smits GP, Berbers GA, Van der Klis FR, Van Binnendijk RS, et al. High risk of a large measles outbreak despite 30 years of measles vaccination in the Netherlands. Epidemiol Infect. 2013. [Epub ahead of print]

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The transmission of infections through populations is a complex and dynamic process. The chain of transmission can be thought of as the process and events that lead from exposure to a pathogen, to transmission to others in the community. As chains of transmission occur through a population over time, the risk factors for exposure and disease progression also undergo dynamic change. Depending on the pathogen, change may occur rapidly resulting in sudden- onset disease outbreaks or it may evolve more slowly over time. Population susceptibility and disease prevalence may be altered, for example, due to vaccination programmes and changing population dynamics over many years. To control disease effectively and influence the epidemiology of disease in a population, timely surveillance and focused epidemiological studies are required, which inform public health action as problems evolve. This is the responsibility regionally of the Amsterdam Public Health Service, and nationally of the Centre for Infectious Disease Control at the National Institute for Public Health and the Environment (RIVM) in the Netherlands. Control measures may be primary (i.e. before exposure to a pathogen has occurred, such as targeted and mass population vaccination programmes), or secondary (i.e. post-exposure prophylaxis (PEP), or other specific interventions in response to unusual or unexpected events and outbreak investigations).

The aim of this thesis is to demonstrate the application of epidemiological studies to inform primary and secondary preventive strategies for infectious disease control. This is achieved through recognition of current risk groups for known pathogens, identification of risk factors for emerging pathogens and unexpected disease events, and the application of this knowledge to inform infectious disease control guidelines. The thesis is divided in two parts: In the first part (Chapter 2 – Chapter 6), studies examining current risk groups for vaccine preventable diseases are described; In the second part (Chapter 7 – Chapter 11) studies identifying risk factors for emerging diseases and unexpected disease events are reported.

Chapter 1 provides a general introduction, describing elements of the transmission chain and the principles of primary and secondary prevention in infectious disease control. The rationale behind primary preventive programmes, such as universal and targeted vaccination, is explained, and an overview of current programmes in the Netherlands is given. Secondary prevention is discussed in relation to contact tracing and post-exposure prophylaxis. The concepts of disease surveillance and outbreak investigation are introduced and an overview of the contents of each chapter is provided.

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Part I: Immunisation

In Chapter 2, we describe trends in the incidence of acute Hepatitis B virus (HBV) infection among heterosexual adults in ethnic groups, from 1992 to 2009 in Amsterdam. Routinely collected surveillance data was used to estimate the incidence of HBV in the largest ethnic groups in Amsterdam, classified as Dutch, Surinamese, Turkish, Moroccan, Ghanaian, other Western or non-Western. We found that the incidence among first generation migrants (FGM) was on average three times higher, and among their children (second generation migrants; SGM, themselves born in the Netherlands), two times higher than in the native Dutch population. The incidence in Dutch-born cases has increased by 13% annually since 1992. This may in part be explained by a doubling of the population of Dutch-born SGM whose parents originate from mid and high-endemic HBV countries. The non-Western population in Amsterdam is set to increase by approximately 50,000 people between 2011 and 2030, and 60% will be FGM. We recommend that consideration should be given to offering HBV screening and vaccination to prevent new infections in FGM and SGM born prior to 2003 (who are not currently targeted in any vaccination programme).

In Chapter 3, we focus on another population group who are at risk of HBV infection, men who sleep with men (MSM), describing trends in the incidence of acute HBV in MSM in Amsterdam. We evaluated the effectiveness of the HBV screening and vaccination programme targeted at high-risk behavioural groups using mathematical modelling. The models accounted for vaccination data and trends in sexual risk behaviour among MSM. It is estimated that 10% of the Amsterdam population are MSM. Since the late 1990s, an active HBV screening and vaccination programme has been offered to MSM. Between 1998 and 2012, over 12,000 participated in the programme in Amsterdam. By the end of 2011, we estimated that 41% of MSM had come in contact with the programme, mainly via the Sexually Transmitted Infection outpatient clinic (STI-OPD) of the Public Health Service of Amsterdam and other recruitment sites such as saunas and gay bars. Eighty-two percent of programme participants were susceptible to HBV infection at the outset, of whom 71% went on to complete the 3-vaccination series. Since 2004, the incidence of acute HBV in MSM has dropped by 78%. According to model predictions, HBV vaccination programmes targeting MSM do not require full coverage in order to be effective, and the incidence can be substantially reduced if those who engage most in high-risk sex (estimated at 20% of the MSM population) and who contribute most to transmission are reached. Policy decisions should therefore focus on identified MSM networks responsible for continued HBV transmission.

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26660 Whelan kopie.indd 173 02-11-13 16:03 Within the National Childhood Vaccination programme (RVP), children born to a parent from a country that is mid- or high-endemic for HBV have been offered HBV vaccination since 2003. In recent years, the HBV component has been integrated in a ‘hexavalent’ vaccine i.e. one that contains components against 6 infectious diseases in a single shot: diphtheria, tetanus, pertussis, polio, Haemophilus influenzae type b (Hib) and hepatitis B. Other children were offered a similar shot, but without the HBV component. Following an evaluation of HBV vaccination by the Health Council of the Netherlands, a decision was made to move to universal vaccination of all infants born in the Netherlands. This was implemented in 2011. Worldwide, combination vaccines are becoming increasingly complex as more components are added. In the Netherlands and elsewhere, concern had been expressed that combination vaccines containing multiple components may lead to a suboptimal immune response in the child.

In Chapter 4, we assessed whether the immune response to the hepatitis B component in the hexavalent vaccine was sufficient according to WHO standards, and whether the immune response to the other vaccine components was similar to that of the standard vaccine offered to all other children. Target thresholds for immune responses were achieved for all antigens studied. Over 99% of children vaccinated with the hexavalent vaccine achieved an adequate immune response to the HBV component (≥10 mIU/ml), although the peak level achieved (known as the geometric mean concentration; GMC) was somewhat lower than might have been expected.

In Chapter 5, the focus was again on health of minority ethnic groups in Amsterdam. Here, we examined trends within ethnic groups, in the number of cases of acute hepatitis A virus (HAV) infection notified in Amsterdam between 1996 and 2011. Every year there is a surge in HAV notifications after the summer holiday period, typically affecting SGM children of Turkish or Moroccan background who have returned from holiday after visiting their parents’ homeland, where HAV is endemic. Four to six weeks later (one incubation period of HAV), this is followed by a secondary wave of infections in children and adults in the Netherlands who have not travelled. Since 1998, PHS Amsterdam has run annual pre-summer hepatitis A vaccination campaigns targeted at children of Turkish and North African background planning to visit their parent’s country of origin. In a study conducted in 2006, there were suggestions that this programme was effective in reducing infections. In accordance with this study, we found that acute HAV notifications in 2011 were at the lowest level recorded to date in Amsterdam. The incidence in children of Moroccan and other non-Western backgrounds returning form holiday is still higher than in the native Dutch population however. As long as HAV is endemic in the countries visited, we suggest that it is necessary to continue with the vaccination campaigns as currently offered. An alternative would be to offer hepatitis A vaccine within the national immunisation schedule

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at the same time as the MMR vaccine (at 14 months of age), to children known to be at risk of HAV infection.

When a case of acute HAV is notified, it is the duty of the PHS to identify contacts and offer post-exposure prophylaxis (PEP) in the form of immunisation to prevent or attenuate secondary infection and to prevent further spread of the virus. Two agents are currently offered: human immunoglobulin (IG), which is derived from human blood products and provides very effective, but short-lived protection; and hepatitis A vaccine, a newer agent which is known to be safe and to stimulate long lasting immunity, but evidence of its effectiveness in PEP is limited. The vaccine is increasingly being offered in preference to IG because of safety concerns about the latter.

In Chapter 6, we evaluated the routine use of hepatitis A vaccine as an alternative to IG in the prevention of secondary HAV infection in contacts that have been exposed to HAV. According to guidelines, 87% of contacts were offered the vaccine, and 13% IG. Overall, 7% developed a secondary laboratory-confirmed infection: all occurred in those who had received the vaccine and half were over 40 years of age. Among those vaccinated according to protocol, the risk of a secondary HAV infection was 12 times higher in those ≥40 years, compared to those ≤15 years. We concluded the vaccine was effective in younger people, where the secondary attack rate was low and consistent with international norms. We recommend that, pending larger studies, IG should remain the PEP of choice in contacts over 40 years of age, and in those otherwise vulnerable to severe disease.

Part II: Outbreak Investigation

The Netherlands is a world leader in delivering public vaccination programmes, with a vaccination uptake among infants that consistently exceeds World Health Organisation recommendations. Despite this, from 2009 to 2012, a mumps outbreak affected more than 1500 people in the Netherlands. The majority were students who were fully vaccinated.

In Chapter 7, we investigated risk factors for mumps in this population of highly vaccinated students (72% had at least two doses of MMR) and identified factors associated with mumps vaccine failure. The mumps attack rate (AR) was 13.2% (95% CI 11.1–15.5%) among study respondents. Being unvaccinated, attending a large student party, and living in student residences with more than 15 housemates were independently associated with clinical mumps infection. The adjusted vaccine effectiveness (VE) estimate for two doses of MMR was 68% (95% CI: 41–82%). We concluded that, despite high MMR vaccination coverage, the most likely cause

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26660 Whelan kopie.indd 175 02-11-13 16:03 of this outbreak was intense social mixing during the party and the dense communal living environment of the students. On the basis of this outbreak, young adults were advised to ensure that they were fully vaccinated, and to consider postponing parties or large social gatherings when mumps was known to be circulating. Consideration was also given to offering a third MMR dose to the vaccination schedule, but it was considered that a third dose could not be justified based on current evidence.

Under the international health regulations of 2005, any unexpected or unusual public health event (of known or unknown origin), which may constitute a public health emergency of international concern is notifiable. In 2007, two patients with severe pneumonia who had not responded to antibiotic treatment were reported to the local Brabant Public Health Service by a medical microbiologist. An unusually high number of cases of pneumonia and severe flu-like symptoms were simultaneously notified in the province of Noord-Brabant. Testing implicated a hitherto relatively rare human pathogen in the Netherlands, Coxiella burnetii, the causative bacterium of Q fever. The outbreak that ensued between 2007 and 2010 was of an unprecedented scale, ultimately resulting in more than 4000 notified patients. Q fever outbreaks in humans, often implicating sheep and goats as the source, have been described in other regions. Despite this, there were many unknown factors in this outbreak related to the pathogen, the transmission dynamics and risk factors for human disease. In Chapter 8 and Chapter 9 we examined risk factors associated with occupational and recreational exposure to Coxiella burnetii.

In Chapter 8, over 500 workers who were involved in culling more than 50,000 sheep and goats during the epidemic took part in the study. Among those who showed no signs of exposure to Coxiella burnetii prior to the culling, 17.5% later seroconverted for antibodies to Coxiella burnetii. To avoid infection, workers had been provided with personal protective equipment (PPE) including gloves, overalls and FFP3 masks (“Face Filtering Pieces” thought to filter at least 99% of airborne particles). Despite this, prolonged time working in close proximity to the animals was a risk factor for infection. Anecdotally, culling workers removed some of their PPE during coffee breaks and lunch breaks. This may have contributed to the high proportion of seroconversions recorded, though we couldn’t directly test this. We recommended that, should similar culling be required again, vaccination of workers could be considered, and long-term follow-up of infected workers will be required.

In Chapter 9, we examined whether visiting a particular farm was a risk factor for the development of Q fever in local residents. Of the cases affected in this outbreak, 62% (162/248) took part in a case-control study and 433 address-matched controls were recruited in the area. As there were other farms in the area that were infected with Coxiella burnetii, we couldn’t

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prove a causal association between visiting the farm and developing Q fever, but we found that the adjusted odds ratio for having visited the farm in question was 43.3 in cases compared to controls. Other risk factors for infection were being a smoker, having a history of other medical problems and being aged >40 years. The farm was closed to the public in the spring of 2010. After all animals were vaccinated, the farm reopened to the public in spring, 2011.

In some outbreak situations, risk factors for infection are well described and the added value in conducting an outbreak investigation may lie in testing new research methodologies, or evaluating current practice with a view to improving efficiency and maximising staff and resource capacities.

In Chapter 10, we describe a Salmonella Typhimurium outbreak that occurred in 2011 and was linked to consumption of raw or undercooked beef. An unusual aspect of this outbreak was that it was caused by a unique strain of S. Typhimurium (Dutch) phage type 132. We also used this opportunity to test a novel approach to a case–control study. Traditionally, such studies are time consuming, requiring a surge in manpower to source and interview controls during or after an outbreak. Controls are often questioned about their food intake weeks to months earlier leading to recall bias. We used responses from a routine food consumption survey, which is conducted quarterly. This proved effective and timely, as controls returned questionnaires throughout the outbreak period reflecting food intake in the previous week. We recommend that this approach could be used in future food-borne outbreaks, incorporating questions related to newly recognised or seasonal links to food and behaviours as appropriate, which might place individuals at risk of food-borne infection. Children and elderly could be oversampled to achieve a better representation of groups known to be vulnerable to Salmonella and other infections.

In Chapter 11, we examined risk factors for secondary transmission of Shigella infection within households. Under current guidelines, household contacts who are attending pre-school or junior classes in primary school (aged ≤6 years) are excluded from school, irrespective of whether or not they have symptoms, pending microbiological clearance. In our study, we found a secondary infection rate of 7.4% in household contacts. We determined that cases aged 6 years or under were most likely to transmit secondary infections; however, the risk for the contact did not depend on the age of the contact, but on whether or not they were symptomatic. We did not find evidence to support the exclusion of asymptomatic contacts <6 years old from school or day- care while awaiting microbiological clearance, as is currently recommended.

Finally, in Chapter 12, the findings of this thesis are synthesized into a brief overview of what was already known in each area, what the research reported here adds to the evidence base,

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26660 Whelan kopie.indd 177 02-11-13 16:03 and what recommendations arise from the research. This is followed by a brief discussion of the contribution of epidemiological research to infectious disease control and suggestions for further areas of research in the coming years. The studies in this thesis were carried out with the Amsterdam Public Health Service (PHS), and the National Institute of Public Health and the Environment (RIVM) in the Netherlands. Samenvatting

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De transmissie van infecties binnen populaties is een complex en dynamisch proces. De transmissieketen kan gezien worden als het proces en de gebeurtenissen die leiden van blootstelling aan een pathogeen tot infectie en overdracht op anderen binnen de gemeenschap. Omdat transmissieketens gedurende een bepaalde tijd plaatsvinden in een populatie, kan een verandering optreden in de risicofactoren voor blootstelling en in het verloop van de ziekte. De verandering kan snel plaatsvinden, zoals bij voedsel uitbraken, of geleidelijk optreden, bijvoorbeeld bij ziekten met een lange incubatietijd, zoals hepatitis B. De prevalentie en vatbaarheid voor infecties kan veranderen door vaccinatieprogramma’s, of veranderingen in de samenstelling van de populatie door geboorte of migratie. Om infectieziekten zo effectief mogelijk te bestrijden, zijn surveillance en gerichte epidemiologische studies van belang om inzicht te verkrijgen in genoemde dynamiek. Regionaal is dit de verantwoordelijkheid van de Geneeskundige Gezondheidsdienst (GGD), en landelijk van het Centrum Infectieziektebestrijding (CIb) van het Rijksinstituut voor Volksgezondheid en Milieu (RIVM). Preventiemaatregelen kunnen primair zijn (dat wil zeggen voordat er blootstelling aan het pathogeen heeft plaatsgevonden, zoals gerichte en massavaccinatieprogramma’s) of secundair (dat wil zeggen vroegopsporing, post- expositie profylaxe (PEP) of andere specifieke interventies naar aanleiding van ongewone of onverwachte gebeurtenissen of uitbraakonderzoek).

De doelstelling van dit proefschrift is door middel van epidemiologische studies inzicht te krijgen in de dynamiek van een aantal infectieziekten. Primaire en secundaire preventieve strategieën in de bestrijding van infectieziekten worden geëvalueerd om zo te komen tot beter onderbouwde strategieën in de bestrijding van infectieziekten. Dit wordt bereikt door (veranderingen in) risicogroepen en risicofactoren voor reeds bekende en nog onbekende infectieziekte problemen te identificeren en deze kennis waar mogelijk toe te passen in preventieprogramma’s en richtlijnen voor infectieziektebestrijding. Het proefschrift bestaat uit twee delen: in het eerste deel (hoofdstuk 2 tot en met hoofdstuk 6) worden de studies beschreven waarin risicogroepen voor reeds bekende, door vaccinatie te voorkomen, infectieziekten worden onderzocht. In het tweede deel (hoofdstuk 7 tot en met hoofdstuk 11) wordt verslag gedaan van de studies naar risicofactoren voor nieuwe infectieziekte problemen en uitbraken.

Hoofdstuk 1 geeft een algemeen overzicht van dit proefschrift waarin de elementen van de transmissieketen beschreven worden, evenals de principes van primaire en secundaire preventie in infectieziektebestrijding. Het idee achter primaire preventieprogramma’s, zoals universele vaccinatieprogramma’s en vaccinatieprogramma’s gericht op risicogroepen, wordt toegelicht en er wordt een overzicht gegeven van de huidige vaccinatieprogramma’s in Nederland. Ook

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wordt secundaire preventie met betrekking tot contactonderzoek en postexpositie profylaxe besproken. Het concept van ‘surveillance’ en onderzoek naar uitbraken wordt geïntroduceerd en er wordt een overzicht gegeven van de inhoud van elk hoofdstuk.

Deel 1: Immunisatie

In hoofdstuk 2 beschrijven we de trends in de incidentie van acute hepatitis B virus infectie (HBV) onder heteroseksuele volwassen in etnische groepen in Amsterdam in de periode 1992 tot 2009. Routinematig verzamelde surveillance data zijn gebruikt om een schatting te maken van de incidentie van HBV in de grootste etnische groepen in Nederland, te weten Nederlanders, Turken, Marokkanen, Ghanezen, ‘overig westers’ en ‘overig niet-westers’. We vonden dat de incidentie onder eerste generatie migranten gemiddeld drie keer hoger was dan in de van oorsprong Nederlandse populatie, en in hun kinderen (de tweede generatie migranten die zelf in Nederland geboren zijn) twee keer hoger. De incidentie bij diegenen die in Nederland zijn geboren is sinds 1992 jaarlijks met 13% toegenomen. Dit kan deels verklaard worden door een verdubbeling van de populatie van de in Nederland geboren tweede generatie migranten, van wie de ouders oorspronkelijk uit hoog- en midden-endemische HBV landen afkomstig zijn. Aangenomen wordt dat de niet-westerse populatie in Amsterdam met ongeveer 50.000 mensen per jaar zal groeien tussen 2011 en 2030 en dat hiervan 60% eerste generatie migranten zal zijn. Wij raden aan dat het aanbieden van screening op HBV en HBV vaccinatie moet worden overwogen om nieuwe infecties te voorkomen in eerste generatie migranten en tweede generatie migranten die geboren zijn vóór 2003 (toen er nog geen vaccinatieprogramma’s waren voor deze groepen).

In hoofdstuk 3 ligt de focus op een andere risicogroep voor hepatitis B infectie en beschrijven we trends in incidentie van acute HBV in Amsterdam bij mannen die seks hebben met mannen (MSM). We evalueerden de effectiviteit van screening op HBV en vaccinatieprogramma’s speciaal gericht op hoogrisico groepen door gebruik te maken van mathematische modellen. De modellen hielden rekening met vaccinatiegegevens en seksueel risicogedrag onder MSM. Geschat wordt dat 10% van de Amsterdamse mannelijke bevolking MSM is. Sinds eind jaren negentig wordt HBV screening en vaccinatie actief aangeboden aan MSM. Tussen 1998 en 2012 hebben meer dan 12.000 mannen in Amsterdam hieraan deelgenomen. Aan het eind van 2011 werd geschat dat 41% van de MSM in contact was geweest met het programma, vooral via de soa-poli van de GGD Amsterdam en het actief opzoeken van de doelgroep op locatie zoals in sauna’s en homobars. 82% van de deelnemers aan de screening en het vaccinatieprogramma kwam in aanmerking voor vaccinatie en 71% van hen voltooide de complete serie van drie hepatitis B vaccinaties. Sinds 2004 is de incidentie van acute hepatitis B afgenomen met 78%.

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26660 Whelan kopie.indd 181 02-11-13 16:03 Volgens rekenkundige voorspellingen is het voor de effectiviteit van het programma niet nodig dat de volledige populatie MSM gevaccineerd wordt; de incidentie kan al wezenlijk gereduceerd worden als diegenen bereikt worden die deelnemen aan seksuele activiteiten met het hoogste risico (een geschatte 20% van de MSM) en daarmee het meest bijdragen aan verspreiding.

Vanaf 2003 werd alleen aan kinderen met een vader of moeder geboren in een midden- of hoog-endemisch land voor HBV een hepatitis B vaccinatie aangeboden. Evaluatie door de gezondheidsraad van de bestaande hepatitis B vaccinatieprogramma’s voor risicogroepen leidde tot het advies toe te werken naar universele hepatitis B vaccinatie in Nederland. Daartoe werd in 2011 hepatitis B vaccinatie voor alle kinderen opgenomen in het Rijksvaccinatieprogramma (RVP). Het hiervoor gebruikte vaccin, dat bekend staat als ‘hexavalent vaccin’, bevat componenten tegen zes infectieziekten: difterie, tetanus, kinkhoest, polio, haemophilus influenzae b (Hib) en HBV. Vóór 2011 kregen kinderen buiten de risicogroepen dezelfde vaccinatie maar zonder de hepatitiscomponent in het vaccin. Wereldwijd worden vaccins steeds complexer door de toevoeging van meer componenten. Zowel in Nederland als daarbuiten werden zorgen geuit dat het toedienen van zulke combinatievaccins zou kunnen leiden tot een verminderde immuunrespons in het kind.

In hoofdstuk 4 hebben we onderzocht of de immuunrespons op de hepatitis B component in het hexavalente vaccin voldeed aan de standaarden van de Wereldgezondheidsorganisatie (WHO), en of de immuunrespons op de overige componenten in het vaccin vergelijkbaar was met die van het standaardvaccin dat aan alle andere kinderen werd gegeven. De drempelwaarde voor de immuunresponses op alle bestudeerde componenten werd bereikt. Meer dan 99% van de kinderen bereikte een adequate immuunrespons voor de hepatitis B component, echter wel met een iets lager piek niveau dan verwacht.

In hoofdstuk 5 ligt de focus wederom bij de etnische minderheidsgroepen in Amsterdam. We bestudeerden trends binnen etnische groepen in het aantal gemelde gevallen van acute hepatitis A infectie in Amsterdam in de periode 1996 tot 2011. Elk jaar is er een golfbeweging zichtbaar in het aantal hepatitis A gevallen na de zomervakantie. Dit is vooral het geval bij tweede generatie migranten kinderen met een Turkse of Marokkaanse achtergrond na terugkomst van familiebezoek in het land van oorsprong van hun ouders (waar het hepatitis A virus endemisch is). Vier tot zes weken later (de incubatietijd van het hepatitis A virus (HAV)) wordt deze gevolgd door een tweede golf van infecties in Nederland bij kinderen en volwassen die niet gereisd hebben. De GGD Amsterdam organiseert vanaf 1998 vlak voor de zomervakantie een jaarlijkse hepatitis A vaccinatiecampagne voor kinderen met een Turkse of Noord-Afrikaanse achtergrond die van plan zijn naar het land van herkomst van hun ouders te reizen. Een studie uit 2006 liet zien dat

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dit programma effectief leek te zijn in het reduceren van infecties. We vonden dat het aantal meldingen van acute hepatitis A infecties bij de GGD Amsterdam geleidelijk daalde. In 2011 was het aantal meldingen het laagst. De incidentie bij kinderen van Marokkaanse of andere niet- westerse afkomst bleek echter nog wel hoger dan in de van oorsprong Nederlandse populatie. Zo lang hepatitis A nog endemisch is in de bezochte landen, vinden wij dat het noodzakelijk is door te gaan met de huidige vaccinatiecampagnes. Een andere mogelijkheid zou kunnen zijn de hepatitis A vaccinatie aan te bieden binnen het RVP, gelijktijdig met de BMR vaccinatie (op de leeftijd van 14 maanden) aan kinderen die een verhoogd risico lopen op hepatitis A infectie.

Zodra er een hepatitis A geval gemeld wordt is het de taak van de GGD om de contacten op te sporen en postexpositie profylaxe (PEP) aan te bieden om een secundaire infectie te voorkomen, en verdere verspreiding van het virus tegen te gaan. Twee soorten profylaxe kunnen aangeboden worden: humaan immuunglobuline (IG) dat wordt verkregen uit menselijke bloedproducten en een effectieve maar kortdurende bescherming biedt, en hepatitis A vaccin dat veilig is en een langdurige bescherming geeft, maar waarvan weinig bewijs voor de effectiviteit is wanneer het gebruikt wordt als PEP. De voorkeur wordt in toenemende mate gegeven aan hepatitis A vaccin boven IG, omdat er zorgen zijn over de veiligheid van IG.

In hoofdstuk 6 evalueerden we het routinematig gebruik van hepatitis A vaccin als een alternatief voor IG met betrekking tot de preventie van secundaire hepatitis A infectie bij contacten van mensen met een hepatitis A infectie. Volgens de richtlijnen kreeg 87% van de contacten het vaccin en 15% IG. In totaal werd bij 7% door middel van laboratoriumonderzoek een secundaire hepatitis A infectie vastgesteld, allemaal bij mensen die het vaccin hadden gekregen en van wie meer dan de helft ouder was dan 40. Onder de mensen die gevaccineerd waren volgens protocol was het risico op een secundaire HAV infectie 12 keer groter bij degenen van 40 jaar en ouder vergeleken met diegenen van 15 jaar of jonger. We concluderen dat het vaccin effectief is bij jongere mensen en dat er sprake is van een lage secundaire ‘attack rate’ die in overeenstemming is met internationale normen. Wij adviseren dat, in afwachting van grotere studies, voor mensen ouder dan 40 en voor degene met een verhoogd risico op een ernstig beloop van de ziekte, IG de eerste keus voor PEP zou moeten blijven.

Deel II: Uitbraak Onderzoek

Nederland loopt wereldwijd voorop als het gaat om vaccinatieprogramma’s, waarbij sprake is van een vaccinatiegraad onder kinderen die vaak hoger is dan de WHO aanbeveelt. Desondanks was er een uitbraak van bof gaande in de periode 2009 tot 2012 met meer dan 1500 gevallen. De meerderheid betrof studenten die volledig gevaccineerd waren (72% had tenminste twee BMR vaccinaties gehad).

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26660 Whelan kopie.indd 183 02-11-13 16:03 In hoofdstuk 7 onderzochten we risicofactoren voor de bof in deze goed gevaccineerde studentenpopulatie en vonden we factoren die geassocieerd waren met het falen van het vaccin. De ‘attack rate’ (AR) van de bof was 13.2% (95% CI 11.1-15.5%). Ongevaccineerd zijn, deelname aan grote studentenfeesten en wonen in studentenhuizen met meer dan 15 huisgenoten waren onafhankelijk geassocieerd met klinische bofinfectie. De geschatte vaccin effectiviteit (VE) voor twee BMR doses was 68% (95% CI 41-82%). We concludeerden dat ondanks de hoge vaccinatiegraad van het BMR vaccin de meest waarschijnlijke oorzaak van de uitbraak de intensieve sociale interactie op de studentenfeesten was en het dicht op elkaar leven in een gemeenschappelijk leefomgeving. Op basis van deze uitbraak werd jonge volwassenen geadviseerd hun vaccinatiestatus na te gaan en om te overwegen feesten en grote sociale bijeenkomsten uit te stellen zo lang de bof virus circuleerde. Er is ook overwogen om een derde BMR dosis toe te voegen aan het vaccinatieschema, maar hier werd van afgezien omdat er onvoldoende bewijs was een derde dosis te rechtvaardigen.

Sinds de Internationale Gezondheidsregeling van de WHO van 2005 is geïmplementeerd is elke onverwachte of ongewone gebeurtenis in de publieke gezondheidszorg (van bekende of onbekende oorsprong), waarbij sprake kan zijn van een noodsituatie voor de internationale publieke gezondheid, meldingsplichtig. In 2007 werden door een medisch microbioloog twee patiënten met een ernstige pneumonie, welke niet op antibiotica had gereageerd, gemeld aan de lokale GGD in Brabant. Tegelijkertijd werd een ongewoon hoog aantal patiënten met pneumonieën en ernstige griepachtige klachten gerapporteerd in Noord-Brabant. Uit testen bleek dat het hier ging om een tot dan toe in Nederland in mensen zeldzame pathogeen, te weten Coxiella burnetii, de oorzaak van Q-koorts. De uitbraak die volgde tussen 2007 en 2010 was van een ongekende omvang en resulteerde uiteindelijk in meer dan 4000 gemelde gevallen. Q-koorts uitbraken in mensen, waarbij vaak schapen en geiten betrokken waren als bron, zijn eerder beschreven in andere regio’s. Toch waren er veel zaken onbekend in deze uitbraak met betrekking tot pathogeen, dynamiek van de transmissie en risicofactoren voor ziekte bij mensen. In hoofdstuk 8 en 9 onderzochten we risicofactoren die geassocieerd waren met beroepsmatige en recreatieve blootstelling aan Coxiella burnetii.

In hoofdstuk 8 beschrijven we de studie waarin meer dan 500 mensen deelnamen, die betrokken waren bij het ruimen van meer dan 50.000 schapen en geiten tijdens de epidemie. Onder diegenen die geen klachten of symptomen van blootstelling aan Coxiella burnetii hadden vóór de ruiming had 17.5% later antistoffen tegen Coxiella burnetii. Om te voorkomen dat de arbeiders besmet raakten kregen ze persoonlijke beschermende maatregelen (PPE) in de vorm van handschoenen, overalls en maskers (FFP3 maskers, ‘face filtering pieces’, waarvan aangenomen wordt dat ze tenminste 99% van de deeltjes in lucht tegenhouden). Ondanks deze maatregelen

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was het langdurig werken in nabijheid van de dieren een risicofactor voor infectie. Een enkele keer hadden de arbeiders tijdens de koffie- en lunchpauze hun PPE (deels) verwijderd. Dit kan bijgedragen hebben aan het hoge aantal seroconversies, hoewel we dit niet konden testen. We adviseerden dat, indien er in de toekomst een vergelijkbare situatie van ruimen van dieren noodzakelijk zou zijn, vaccinatie van de ruimingswerkers overwogen moet worden en dat een follow-up op de langere termijn nodig is.

In hoofdstuk 9 onderzochten we of een bezoek aan een specifieke boerderij een risicofactor was voor de ontwikkeling van Q-koorts in de lokale bevolking. Van de in deze uitbraak gemelde gevallen (‘cases’) nam 62% (162/248) deel in de case controle studie en vonden we 433 gematchte controles uit dezelfde omgeving. Aangezien er andere boerderijen in de omgeving waren die besmet waren met Coxiella burnetii konden we een oorzakelijk verband tussen het bezoeken van een boerderij en het ontwikkelen van Q-koorts niet bewijzen, maar we vonden wel dat de gecorrigeerde odds ratio (OR) voor een bezoek aan de boerderij in kwestie 43.3 was bij de groep ‘cases’ ten opzichte van de controlegroep. Andere risicofactoren voor infectie waren roken, overige medische problemen en leeftijd ouder dan 40. De boerderij was gesloten voor publiek gedurende de lente van 2010 en werd nadat alle dieren gevaccineerd waren voor publiek heropend in de lente van 2011. In bepaalde uitbraaksituaties zijn de risicofactoren goed beschreven en de toegevoegde waarde van het uitvoeren van een uitbraakonderzoek ligt in dat geval in het testen van nieuwe onderzoeksmethodologieën of het evalueren van de huidige praktijk met het doel de efficiëntie te verbeteren en het inzetten van de medewerkers en onderzoekscapaciteiten te optimaliseren.

In hoofdstuk 10 beschrijven we een uitbraak van Salmonella Typhimurium die plaatsvond in 2011 en die gelinkt was aan het eten van rauw of onvoldoende gebakken biefstuk. Een opvallend aspect van deze uitbraak was dat deze veroorzaakt werd door een unieke stam van S. Typhimurium (Dutch) phage type 132. We hebben ook van deze gelegenheid gebruik gemaakt om een nieuwe benadering voor een case-control studie te testen. Van oudsher zijn deze case-control studies tijdrovend en vereisen ze veel mankracht voor het zoeken en interviewen van controles tijdens en na een uitbraak. Omdat vinden van een controlegroep tijd vergt, moet deze controlegroep vaak worden gevraagd naar hun voedselinname van weken of maanden daarvoor, wat tot ‘recall bias’ kan leiden. Wij hebben daarom de antwoorden gebruikt van een routinematig uitgevoerde steekproef naar voedselconsumptie, welke vier keer per jaar wordt gehouden. Deze methode bleek effectief en tijdsbesparend te zijn omdat van de controlegroep de vragenlijsten afgenomen tijdens de periode van de uitbraak gebruikt werden die de voedselinname van een week voor het begin van de uitbraak bevatte. We concludeerden dat deze benadering in toekomstige voedselgerelateerde uitbraken gebruikt kan worden, omdat de vragenlijsten veel uitgebreider

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26660 Whelan kopie.indd 185 02-11-13 16:03 zijn zodat naast het voordeel van het verminderen van ‘recall bias’ ook onderzoek kan worden gedaan naar onverwachte bronnen en naar een eventuele seizoensgebonden relatie met eten en gedrag waardoor bepaalde mensen een hoger risico kunnen lopen op voedselgerelateerde infecties. Kinderen en ouderen zouden preferentieel kunnen worden geïncludeerd om een betere weergave te krijgen van de groepen waarvan bekend is dat ze kwetsbaar zijn voor Salmonella en andere infecties. Acknowledgements In hoofdstuk 11 onderzochten we de risicofactoren voor secundaire transmissie van Shigella infectie binnen huishoudens. Volgens de huidige richtlijnen mogen contacten die naar de peuter- of kleuterschool gaan (jonger dan 6 jaar) niet naar school, ongeacht of zij al dan niet symptomen hebben, in afwachting van de microbiologische uitslag. In onze studie vonden we een secundair infectie percentage (infection rate) van 7.4% bij contacten in een huishouden met een Shigella patiënt. Wij stelden vast dat het vooral kinderen van 6 jaar of jonger met Shigella waren die secundaire infecties overbrachten, maar dat het risico voor contacten niet afhing van de leeftijd van het contact maar van het al dan niet hebben van symptomen. Wij vonden daarom geen bewijs om de huidige richtlijn, waarin asymptomatische contacten jonger dan 6 jaar niet naar school of kinderdagverblijf mogen gaan zolang de uitslag van de microbiologische test nog niet bekend is, te ondersteunen.

Ten slotte worden in hoofdstuk 12 de bevindingen uit dit proefschrift samengevoegd tot een kort overzicht van wat al bekend was op elk gebied, wat het onderzoek heeft bijgedragen aan ‘evidence based Public Health medicine’ en welke aanbevelingen zijn voortgekomen uit het onderzoek. Daarna volgt een korte discussie over de bijdrage van epidemiologisch onderzoek in infectieziektebestrijding en worden er suggesties voor verder onderzoek gedaan. De studies in dit proefschrift werden uitgevoerd binnen de GGD Amsterdam en het Rijksinstituut voor Volksgezondheid en Milieu (RIVM).

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It’s been a privilege for me to live and work for the last 4 years in the Netherlands, and to enjoy the level of support, positivity and creativity among my colleagues that I have. When I first arrived, the challenge of working in a new health care system on new subject matter in a different language all seemed a bit insurmountable. However, with the enthusiasm and encouragement of colleagues (now friends), I’ve learned that step-by-step, everything is possible…well almost!! Thanks particularly to the following people:

To my co-promoters, Anneke and Gerard: From the first day when they interviewed me (and though I wasn’t entirely sure what I was signing up for at the time!), they have been endlessly supportive. They are both passionate guardians of public health in Amsterdam, always questioning and full of ideas. Again and again, research within the department has helped to inform local and national infection control policy and led to tangible changes in practice. It is a credit to their perseverance and commitment, and it has been a real pleasure and inspiration to work with them.

To my promoter, Martien, who from the outset supported my Ph.D. candidacy. He responded to draft manuscripts so quickly and always with razor sharp insight. I thank him for always being so approachable and ready to offer advice.

No research is possible without cooperation and teamwork and I would like to thank all my co- authors and the many individuals who were willing to share their time and expertise. Within the GGD, I would like to thank my fellow doctors, Gini, Floor, Femke and Sanne, from whom I am learning all the time. Not just about medicine, but about life, love, good coffee….and Dutch grammar!! Particular thanks to Floor, whose help with translation was invaluable. To Dorothé and all the nurses and doctors assistants in infectious disease control and the travel clinic, and the staff of LCR: for their collegiality, their patience with my unique Dutch/English blend, and of course their longstanding commitment to research. To my co-author Lian, whose experience, openness and guidance were very much appreciated. Thanks also to Maarten Schim van der Loeff and Ronald Geskus who were always willing to assist with statistical advice when I needed it (it helped maintain my sanity).

My story in the Netherlands begins of course in RIVM, where there are so many people, without whom, the last 4 years would not have been possible. To Marianne van der Sande who gave me the opportunity to come to RIVM in the first place, thus opening up to me the world of infectious disease epidemiology; To Wim van der Hoek, Hester de Melker and Wilfred van Pelt who

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welcomed me into their teams, encouraged me to get involved and were always willing to offer advice. Also to Hein Boot, with whom it was a special privilege to have worked.

To my fellow EPIETers/ EUPHEMers at RIVM: Harold Noel (the STATA king!), Marc Rondy, Katie Greenland, Sabine Dittrich, Barbara Schimmer, Georgia Ladbury, Giovanna Jaramillo Gutierrez, and my EPIET supervisers, Mirna Robert - Du Ry van Beest Holle and Maaike van Veen: It is a tangled web we weave! I know our paths will always cross and there’ll always be time for rosé in the sun somewhere! To my office mates and colleagues– Ewout, Remko, Rolf and particularly Sabine de Greeff, who made it all great fun. When in doubt, there’s always chocolate! Finally, to Roel Coutinho, without whom, I don’t think I would have made my way eventually to the GGD.

To my paranymphs: Susan Hahné has been both a friend and mentor since the very start. Her thoughtful integrity and willingness to be a support to the EPIET fellows both personally and professionally is inspiring. From dodgy taxis in Kazakhstan to running around Rome (literally), it’s been a great fun and a real adventure. I hope we’ll share many more. And Sanne Belderok, with whom I shared so many laughs at the GGD, often over “the y axis of life”, which leads too often from order to chaos. Remember: deviation is standard and quite acceptable!!

To all those at home who enabled me from the very outset to pursue this career path: my colleagues in Public Health in Ireland who, through the Specialist Registrar Training Programme, gave me every opportunity to explore public health at local, regional, national and international level during my training, and supported (and continue to support) the EPIET programme. I hope that I can give back some of the time, commitment and energy that you invested in me and in my training.

Finally, to my family and friends who have shaped who I am. To my parents, Noreen and Tim, who always gave me the freedom and support to choose my own path; and my husband, Richard, who shared wholeheartedly in this adventure.

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Elizabeth Jane Whelan was born on 28 February 1976, in Carlow, Ireland. She completed her secondary school education at St. Leo’s College, Carlow in 1994 and went on to study Medicine in University College Dublin, graduating in 2000. After her intern year (City Hospital, Belfast), she travelled to New Zealand where she worked for a year as a Resident Medical Officer (Canterbury District Health Board, Christchurch). A love of travel and a long overland trip home fuelled an Portfolio and Peer Reviewed Publications interest in the differences between people at a population level and a passionate belief in the importance of poverty, context and the broader determinants of health in the prevention and control of disease.

On returning home, she undertook a Master degree in Public Health (2003–2004, University College Dublin) and subsequently completed a 4-year higher specialist training in Public Health Medicine, joining the register of medical specialists in Ireland in 2009. During her training, she was awarded the Jacqueline Horgan Bronze Medal in Epidemiology (Royal Academy of Medicine in Ireland, 2008) for her work on the health status of older people in the South East of Ireland.

To further her interest in epidemiology and international health, she joined the European Programme for Interventional Epidemiology Training (EPIET) in 2009 and was a fellow at the National Institute for Public Health and the Environment (RIVM) in the Netherlands until 2011. Since completing the fellowship, she works with the Amsterdam Public Health Service in travel medicine and infectious disease control. She enrolled as an external PhD candidate with the University of Amsterdam, completing her thesis in October 2013.

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26660 Whelan kopie.indd 193 02-11-13 16:03 AMC Graduate School for Medical Science – PhD Portfolio

Name PhD Student: E.J.Whelan PhD period: 2009-2013 Name PhD supervisor: Prof. dr. M.W. Borgdorff

Relevant Training

In conjunction with the European Programme for Interventional Epidemiology Training: Computer Tools for Outbreak Investigations, December 2009 Multivariable Analysis, February 2010 Sampling, June 2010 Time Series Analysis, March 2011

Presentations

� 15 th International Congress on Infectious Diseases, Bangkok, Thailand, 2012. (Poster presentation). Incidence of acute hepatitis B in different ethnic groups in a low-endemic country, 1992-2009: increased risk in second generation migrants.

� 15 th International Congress on Infectious Diseases, Bangkok, Thailand, 2012. (Poster presentation). Characteristics of cases and contacts associated with secondary transmission of Shigella infection. Implications for current prevention policy.

� ESCAIDE, Stockholm, 2011. (Poster presentation). Immunogenicity of a hexavalent childhood vaccine & 7-valent pneumococcal conjugate vaccine.

� ESCAIDE, Lisbon, Portugal. 2010. (Oral presentation). Q fever in culling workers before and after animal culling in the Netherlands, 2010.

� ESCAIDE, Lisbon, Portugal. 2010. (Oral presentation). Burden of disease and risk factors for mumps in an outbreak affecting students in the Netherlands, December 2009 - June 2010.

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Peer Reviewed publications

Hepatitis B � Whelan J, Sonder G, Bovée L, van den Hoek A. Incidence of acute hepatitis B in different ethnic groups in a low-endemic country, 1992–2009: increased risk in second generation migrants. Vaccine 2012; 30: 5651–55. � van Rijckevorsel G, Whelan J, Sonder G, van den Hoek A. Targeted vaccination programme successful in reducing acute Hepatitis B in men having sex with men in Amsterdam, The Netherlands. J Hepatol 2013. [in press] � Whelan J, Hahné S, Berbers G, van der Klis, F, Netten Y, Boot H. Immunogenicity of a hexavalent vaccine co-administered with 7-valent pneumococcal conjugate vaccine. Findings from the National Immunisation Programme in the Netherlands. Hum Vaccin Immunother 2012;8:743–8. � Boot HJ, Berbers GA, Whelan J, Hahné SJM. Combination vaccines: the sky is the limit? [in Dutch] Infectieziektebulletin 2012;23: 268–70.

Hepatitis A � Whelan J, Sonder G, Bovée L, van den Hoek A. Evaluation of hepatitis A vaccine in post– exposure prophylaxis, the Netherlands, 2004–2012. PLoS One 2013;8:e78914 � Whelan J, Sonder G, van den Hoek A. Declining incidence of hepatitis A in Amsterdam, 1996– 2011: second generation migrants still an important risk group for virus importation. Vaccine 2013;31:1806–11.

Mumps � Whelan J, van Binnendijk R, Greenland K, Fanoy E, Khargi M, Yap K, Boot H, Veltman N, Swaan C, van der Bij A, de Melker H, Hahné S. Ongoing mumps outbreak in a student population with high vaccination coverage, Netherlands, 2010. Euro Surveill 2010;15:pii=19554. � Greenland K , Whelan J, Fanoy E, Borgert M, Hulshof K, Yap KB, Swaan C, Donker T, Melker H, Hahné S. Mumps outbreak among vaccinated university students associated with a large party, The Netherlands: December 2009–June 2010. Vaccine 2012;30:4676–80.

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26660 Whelan kopie.indd 195 02-11-13 16:03 � Hahné S, Whelan J, van Binnendijk R, Swaan C, Fanoy E, Boot H, et al. Mumps vaccine effectiveness against orchitis. Emerg Infect Dis 2012;18:191–3

Q Fever � Whelan J, Schimmer B, Schneeberger P, Meekelenkamp J, IJff A, van der Hoek W, et al. Q fever among culling workers, the Netherlands, 2009–2010. Emerg Infect Dis 2011;17:1719–23. � Whelan J, Schimmer B, de Bruin A, Robert – Du Ry van Beest Holle M, van der Hoek W, ter Schegget R. Visits on “lamb–viewing days” at a sheep farm open to the public was a risk factor for Q–fever in 2009. Epidemiol Infect 2011;140:858-64.

Pandemic Influenza A(H1N1) � Whelan J, Greenland K, Rondy M, Roberts M, Hoek W van der. Case registry systems for pandemic influenza A(H1N1) in Europe: are there lessons for the future? Euro Surveill 2012;17:pii=20167.

Infectious gastrointestinal disease � Bovée L, Whelan J, Sonder G, van den Hoek A. Seroconversion among contacts of Shigella patients in Amsterdam 1999–2009. BMC Infectious Diseases. 2012, 12:347 � Whelan J, Noel H, Friesema I, Hofhuis A, de Jager CM, Heck M, Heuvelink A, van Pelt W. National outbreak of Salmonella Typhimurium (Dutch) phage–type 132 in the Netherlands, October to December 2009. Euro Surveill 2010;15:pii=19705.

Health Status and behaviour � Whelan J, Belderok S, van den Hoek A, Sonder G. Unprotected casual sex equally common with local and western partners among long-term Dutch travelers to (sub)tropical countries. Sex trans dis 2013:40;797-800 � Kelleher C, Whelan J, Daly L, Fitzpatrick P. Socio–demographic, environmental, lifestyle and psychosocial factors predict self rated health in Irish Travellers, a minority nomadic population. Health & Place 2012;18:330–8. � Whelan J. Being old in Ireland: a fit state? Ir Med J 2009;102:220–3.

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