The objectives of this session are to Describe the principles of outbreak investigation Describe a systematic approach and different steps in

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1 We shall spend this hour on the methodology of outbreak investigation, wich is probably the most fascinating and challenging tasks of a field epidemiologist. I would like to give you an overview of the method used, give some practical advice. The example I use are related to the episode of infectious origin but the same approach can be used when investigating outbreaks caused by a toxic.

2 The objectives of this session are to Describe the principles of outbreak investigation Describe a systematic approach and different steps in outbreak investigation Highlight some co-ordination and methodological issues And I will illustrate this with an example of a community epidemic due to Salmonella Typhimurium investigated by DeValk and her colleagues in Jura, France, in May-June 1997.

3 An outbreak is usually defined as to the occurrence of more cases than expected in a given area in the same population at the same time. But what exactly is «more than» and do we always know what the epexted number of cases is? We do not. It will always take judgement and skill sometimes even special investigation when you believe an outbreak is underway and there are a range of tools available to you to assist with this. An outbreak is thus relative to the usual frequency of the disease in the same area, among the same population, at the same season. A single case of a communicable disease long absent in population can therefore be an outbreak. Eg : rabies, firts invasion by a disease WNV Conversely, multiple cases of some common diseases (eg influenza) may represent only the endemic level.

4 Why should we investigate outbreaks? First of all to identify the cause, eliminate the source, interrupt transmission to stop the outbreak. But it is not rare that the outbreak has already halted when we start the investigation. Even then there are many reasons to investigate. We need to understand what exactly happened and why it happened, because only with this knowledge we can prevent future outbreaks. This lead to public health regulations and guidelines. We may want improve hour knowledge of the disease, about the relation between the agent, the host and the environment. For ex an outbreak can be a great opportunity to study modes of transmission, or a dose response effect, or the efficacy of a vaccin. It is also the occasion to discover new agents : legionellosis (77), hantavirus, pulmonary sndrome, TCS due to staph. The investigation can help us evaluate our surveillance and the outbreak detection mechanism in place. And last but not least, an outbreak is a great opportunity to teach and acquire field epidemiology experience.

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6 An investigation is by nature retrospective. It is rare to be involved very early in the course of an outbreak However, with modern communication means, real time investigation has become possible (e.g. SARS). Most of the time cases have already been detected for several days or weeks. Most of the information collected will rely on quality of documents and patients memory. The investigation is done in real life condition and is therefore subject to many biases. The purpose of a field investigation is to draw sensible evidence from imperfect data. Sometimes data have already been collected and the task of the epidemiologist is to critically appraise the available information. Delays between disease or outbreak occurrence and alert may be long. This should however not be a reason not to investigate. Even if an event is out of media sight it remains a public health problem of interest which merits to be clarified and understood

7 The investigation I shall present as an exempple is an episode of infectious disease origin. The alert has been given by the district medical officer of the Jura district. Several cases of S T had been notified by two labs in the south of the district By contacting other labs and hospitals, the DMO identified approximatively 80 cases that had occurred over 5 week period No link identified between cases (meal, day care, zoo..) High political and media profil : article drinking water, Governr worried about tourisme Local outbreak team set up : DMO, veterinarian, consumer protection officers, and now INVS and NRC. Cases continued to occur.

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9 In an investigation a whole set of different groups intervene : clinicians who diagnose the case and identify the death, the laboratory for confirmation diagnosis, in case of foodborne outbreak there is a whole of iinvestigators involved in food safety : veterinarian, fraud contrôl officers, consumer protection. In case of vector borne transmission, there are entomologists and vector control officers, in case of a disease with mainly person to person transmission, the educational component is of high importance. And there are the contact with the authorities (local and national level) and the media The epidemiologist has to find a place in this

10 By identify the RF, he contribute to identify the source and the route of transmssion

11 We can summarise the methods of investigation in 9 steps which we can group in tree phases The first phase is descriptive and start with the confirmation of the existence of the outbreak and confirmation of the diagnosis Then, it is define what, for the investigation, will be consider to be a case. This allows to identify and count the cases and collect information on them. A descriptive analysis of the data collected allows to develop hypotheses on the cause Sometimes the descriptive phase gives us sufficient information to take appropriate control measures and no analytical or special studies are undertaken. In other situation, there is a second phase, an analytical phase in which the develop hypothesis are tested. Specific studies are carried out to confirm the hypothesis or collect additional information. Throughout the investigation, communication with the authorities, the medical professionals, the concerned population and the media, is an important activity. The outbreak report which must be written at the end of the investigation is an important part of the communication. And finally the identification and implementation of control measures which is a step which, according to the different situations, can be carried out at the start, throughout and the end of the investigation REALITY : there is no strict order

12 Outbreaks are detected through various sources of information. They include formal sources such as surveillance systems monitoring occurrence of cases over time. Those are usually based either on clinical reports by hospitals, general practitioners, specialists, etc. or upon laboratory data reported by peripheral or national reference laboratories. The timeliness of detection and report is a prerequisite for an efficient investigation and response. In fact, most of the time, outbreaks are detected via rumours or direct calls from health practitioners who observed what appears to them as being an unusual event (signal). Sometimes the information may come from the public or the media. At the international level, some systems (GLOPHIN), using web scanning, automatically review media information available worldwide on a daily basis.

13 Example of an outbreak detection through routine surveillance In the Jura, the district officer has been alerted by two labs that noted an unusual number of salmonella infections Surveillance is critically important in outbreak detection because it provides early warning that an epidemic is underway a measure of endemic rate

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15 Are there more cases than expected? Assumes we know how many case usually are expected to occur This could be if we have surveillance data These data are often not available and it is necessary to coonsult several sources of information We performed Survey among hospitals, labs, physicians We have to be careful because several sources of error are possible Taking into account seasonal variation (salmonellosis in summer, winter vomiting by norovirus) Think to notification artefacts (improvement of a surveillance system, after holiday, at the end of the month) Diagnosis bias (new technique) Diagnostic error (pseudo-outbreak)

16 The following graphics illustrates the occurrence of cases of Legionellosis in France by week of report. The increase in the number of cases reported does not correspond to an increase in the incidence.

17 In fact, a national meeting was organised to motivate laboratories and physicians to report cases. Following the meeting, more cases were reported. This is a notification artefact flagged by our alert system. From approximativelly 100 case per year to 1200 / year or 2/week t 25/week

18 Whenever possible, the clinical diagnosis should be confirmed by laboratory tests, if possible by isolation and identification of the agent (infectious or toxic) which can be typed. Sometimes it is necessary to meet the clinicians or even examine some cases because of incorrect diagnosis of clinical entity. In 1980 at a jazz festival in Nottingam, around 400 people became unwell and collapse. A t the beginning, food poisoning was suggested. In fact when the symptoms were systematically described, they were not compatble with any known type of foodpoisoning. Further investigation concluded that the cause was MSI. False confirmation of specimen by labs It is important to confirm several cases but not necessarily all. It is important to continue to confirm cases throughout the outbreak not just in the beginning (first cases can be atypical).

19 This represents a pseudo outbreak due to incorrect diagnosis. This slide shows the number of appendectomies in inhabitants of the Carabean island the desirade that was investigated by an Epiet fellow AI. The investigation showed it was an outbreak of appendectomies but not of appendicits. The diagnosis could not be confirmed for any of the patients by pathology. This was a situation of an overzealeous GP and surgeons.

20 When the outbreak is confirmed, following decision could be taken : Implement immediate control measures? Or Perform further investigation in order to identify aetiological agent (bacteria, virus, parasite, toxine) -mode of transmission (food borne, air borne, vector borne, person to person ) -vehicle of transmission (food, water) - source of contamination (production site, water well, foodhandler in a restaurant ) - population at risk (region, school, day care centre, guest at meal..) - exposure causing illness (visit to zoo, contact with mud, with animal )

21 Set up a team which coordinates field investigation

22 Once confirmed, we can engaged the descriptive phase which aims to describe the cases in terms of Person Time and Place

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24 Defining a case is a fundamental step in the investigation. A case definition is a standard set of criteria for deciding if a person should be classified as suffering from the disease under investigation. It based on clinical and or biological criteria and precises criteria of time (when the cases occurred), place (where) and person (in what population). It is not a diagnosis made by a clinician. It should be simple, practical (not based lab exam that is not avilable) and objective (characteristics of diarrhea). The choice of definition carries dangers : To include non cases among the cases (too sensitive case definition : eg any person with 2 loose stools in an outbreak of salmonellosis) To exclude real cases (too specific case definition : only person with an isolate of salmonella) The choice depend on the feasability and the use of the data For case finding and for identifying the scope and spread of an outbreak : sensitive definition For an analytical study, non case classified as cases will bias the results towards zero, It is better to use a specific definition Often multiple definition in the same investigation

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26 Once case has been defined we can now move to the third step : identify and count cases

27 Cases may have occurred in a clearly identified group : health staff in an Ebola outbreak, guest at wedding in a foodborne outbreak Sometimes notification is sufficient (listeriosis and legionellosis cases in France) Sometimes we have to contact hospitals, GP actively Laboraories Schools Population survey (water borne outbreak)

28 In the salmonellosis outbreak occurred in the Jura,

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30 In this investigation we set a long questionnaire including..blabla

31 Then with these information collected we can move to the fourth step to describe cases.

32 In TIME, PLACE and PERSON

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34 The Epicure is an histogram representing cases plotted on the Y axis by date of onset of the disease. On the X axis, the time interval choice is based on the incubation period and the time period over which cases occur.

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37 This Epicurve shows a sudden increase, cases clustered in time but continuing for several week, one peak, suggesting a common source that persists over several weeks. The outbreak started in the middle of May and ended at the beginning of July.

38 Often cases occurred in a same and unique area. To identify the area we describe the geographical distribution of the cases by place of residence, of possible exposure (work, school, etc). These distribution are illustrated by mapping dot, or AR by region of exposure allowing identifying area at risk.

39 The last aspect of the descriptive epidemiological phase of an investigation is to describe cases according to their personal characteristics. Distribution of cases, or better risk of illness according to age, sex, and professional activities, are important information allowing to generate hypotheses regarding the mode of transmission of the disease. Computation of risk (also frequently called attack rate) needs to assemble numerator data (number of cases) and a denominator (population at risk of developing the disease of interest).

40 In this slide you see the number of cases, as absolute numbers by age group. As first glance you first impression is that age groups between 1year and 64 years are the most affected. However when you present data by person the best way is to present the data as rate, using therefore a denominator, which usually is the population from where cases are coming. In their investigation DeValk et al computed risk of illness by age group. The computationb of attack rates by ahe group suggest highest risks observed in children less than five years of age.

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42 Using the results of the descriptive epidemiology, the knowledge of the disease, and exploratory interviews of some of the cases the field epidemiologist will be able to generate hypotheses. Those hypotheses should help identifying and explaining the role plaid by the causal agent, the source of infection, the mode of transmission, and carriers if any.

43 Taking as an example the investigation conducted by DeValk et al, we can suggest that: the causative agent was S. Typhimurium lysotype 12 atypical. The descriptive epidemiology was in favour of a continuing common source of infection. Cases were clustered in a single area of Jura, France. The risk of illness was higher in children less than five years of age. Additional information collected among cases identified a high proportion of Muslim. The information available allowed to further target the investigation. S Typhimurium is usually found in meat (beef), salami, poultry, milk products, etc. The investigators developed hypotheses including local products and local distribution. Since the risk of illness was higher in children, products targeted at children were also investigated. Many cases were Muslim which made consumption of pork products less likely. The outbreak occurred during a season with particularly good weather conditions pointing potentially to barbecue cooked products. Finally the review of the literature revealed the occurrence of similar outbreaks due to roasted poultry products. However the above does not constitute an explanation of the outbreak. It is only a collection of information helping to generate hypotheses to be later tested using an epidemiological study.

44 Further hypotheses generation can also be carried out by interviewing the first cases regarding their food habits and consumption and looking for common exposures among cases (restaurant, markets, particular events, etc.). In Jura, a large trawling questionnaire was used and included, among others, many regional products available in the outbreak area (cheese included). Seventeen early cases were interviewed with this questionnaire.

45 The following table illustrates food habits among the first set of early cases interviewed by DeValk et al. Fromage A, Comté, and Bleu de Gex (other cheeses) were very popular among cases.

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47 Once hypotheses are generated from the results of descriptive epidemiology and the trawling questionnaire, the next step involves developing analytical studies to test those hypotheses. Two major types of studies are commonly used by epidemiologists: cohort studies which can be prospective or retrospective and case control studies. In cohort studies the risk of illness is compared between a group of people exposed (e.g. who consumed food A) and a group of people who did not consume it. The ratio of the two risks is computed. In case control studies the proportion of cases who had eaten food A is compared to the proportion of people who have eaten food A in a sample of the source population (the population giving rise to cases). This comparison group is called the control group. DeValk et al used a case control design to test the various hypotheses they had generated. The proportions of cases and controls who had eaten the various food items were compared. Odds ratio were computed for each food item. In their traditional type of case control studies, controls were selected among people who did not develop the disease during the outbreak. Each control was susceptible to illness. They were assumed to properly represent exposure in the source population which gave rise to cases.

48 The following table shows the results of the case control study. 42 cases and 42 age matched controls Were interviewed on food eaten the 3 days before onset of illness Cases were more likely to have eaten morbier 83% of cases had eaten : explained the majority of cases

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50 Special investigations can be conducted parallel with and guided by the results of epidemiological investigation. Food inspection of the production sites etc Additional studies are sometimes needed to refine the hypothesis and explain all cases. At the same time as the epidemiological study an environmental investigation can be conducted. Sometimes biological surveys (e.g. sero-surveys) conducted in the population may help precise the magnitude of the outbreak. If needed additional studies (e.g. with more cases and more controls) can be conducted to test more precise hypotheses (e.g. dose response) or to identify sub groups of the population in which the incriminated food item expresses itself more or less severely (effect modification). In such studies additional risk factors or protective factors can also be searched for.

51 In the Jura outbreak.blabla

52 The trace back investigation showed that the majority of the shops where cases had bought their Morbier were supplied by 2 wholesales, both supplied by the same cheesefactory on the same date with a same batch.

53 The next step involves comparing the results suggested by the analytical study with clinical data and biological examinations. In addition the validity of the study needs to be discussed as well as the statistical signification of the suggested results. Overall the main hypothesis should be biologically plausible. It should explain the role plaid by the causal agent, fit with the likely source, and match with the mode of transmission and the time of exposure.

54 De Valk et al suggested that using raw milk for making the incriminated cheese was fitting with the biological plausibility criteria. The cheese was popular among children and this was consistent with the higher risk of illness in children. Cheese A is a regional product whose distribution matched the distribution of cases. Finally samples of cheese A collected among cases yielded S Typhimurium in 3 samples. Samples from other cheese tested negative.

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56 Last but not least preventive and control measures need to be taken early enough in the course of the investigation. However one does not need to wait for taking those measures. General recommendations can be formulated at the beginning of the investigation. More specific measures can be suggested towards the end and be based on the results of the investigation. Control measures can address: the source (e.g. chlorination of water); the transmission (hygienic precautions); the vehicle (e.g. recall of the incriminated product); or the reduction of transmission (e.g. vaccination if applicable). In the Jura outbreak it was recommended to improve personal hygiene (hand washing, etc.) and to recall cheese A.

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58 No work is completed before paper work is done. A concise, clear and action oriented, report is rapidly needed. This report is preferably written on site. It will force the investigators to make the synthesis of the objectives, of the methods used and of the suggested results of the investigation. Any additional information is much easily collected when still on site. The report will allow a precise documentation of the event and may suit evaluation or legal purposes if any. The report will allow communicating results in a standardised format. Different formats may be needed according to the audience: the authorities, the media, the scientific community, etc. Recommendations are the key component of the report. They should be realistic and timely. Finally any good report will potentially constitute the basis for field epidemiology training material. Many outbreak investigation have led to change in public health regulation : Cooking temperature of hamburger Mandatory control of horsemeat for trichinella Regulation for Air-conditioning/cooling tower after epidemic of legionellosi

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60 Thank you for your attention

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