An Outbreak of Infection with Bacillus Anthracis in Injecting Drug Users in Scotland 2 Preliminary Case Report of Fatal Anthrax in an Injecting Drug User in North-rhine- Epidemiological Analysis of Mosquito-borne Pogosta Disease in Finland, 2009 6 Surveillance and Outbreak Reports an Outbreak of Inf

An investigation is currently underway to explore and control an outbreak of Bacillus anthracis among drug users (mainly injecting) in Scotland. Contaminated heroin or a contaminated cutting agent mixed with the heroin is considered to be the most likely source and vehicle of infection. Heroin users have been advised of the risk. The risk to the general public is regarded as very low. was informed of two hospitalised injecting drug users (IDUs) with blood cultures positive for Bacillus sp. Further testing identified that these cultures were provisionally positive for anthrax on 16 December 2009. One of the patients had died earlier that day. The other patient was stable and responding to a cocktail of antibiotics. In the following weeks further suspected cases were reported and investigated in Glasgow, Lanarkshire, Tayside, Forth Valley, Fife and other Scottish NHS Board areas. As of 14 January 2010, there were a total of 14 confirmed cases of anthrax infection in Scotland of whom seven have died: seven confirmed cases in the NHS GGC area, four fatal; three cases in Lanarkshire NHS area, one of whom remains in hospital; two fatal cases in Tayside one fatal case in the Forth Valley NHS area, and one surviving case in Fife. All cases reported a history of taking heroin by intramuscular, intravenous or subcutaneous injection and/or by other routes including smoking or snorting. Case definitions were established to classify cases as 'confirmed', 'probable' or 'possible' [1]. Only laboratory confirmed cases are being reported publicly. The 14 confirmed cases are 10 men and four women* aged between 27 and 55 years for the men and between 39 and 43 years for the women. The mean age of the cases is 38 years for both men and women. The mean age of the fatal cases is slightly higher at 42 years. and died on 8 January following a rapid deterioration. Over the five weeks of the outbreak to date, the peak incidence of admissions was in week 3 (six new confirmed cases, week beginning 28 December 2009), dropping to one new confirmed case in week 4 (beginning 4 January 2010). The peak of the outbreak may therefore have already occurred, but it is too early yet to state this with confidence. There are estimated to be around 55,000 (illegal) drug users in Scotland (not all of whom use heroin) giving a very approximate incidence of 2.5 cases per 10,000 …


Introduction
On 10 December 2009 the National Health Service Greater Glasgow and Clyde (NHS GGC) was informed of two hospitalised injecting drug users (IDUs) with blood cultures positive for Bacillus sp.Further testing identified that these cultures were provisionally positive for anthrax on 16 December 2009.One of the patients had died earlier that day.The other patient was stable and responding to a cocktail of antibiotics.
In the following weeks further suspected cases were reported and investigated in Glasgow, Lanarkshire, Tayside, Forth Valley, Fife and other Scottish NHS Board areas.As of 14 January 2010, there were a total of 14 confirmed cases of anthrax infection in Scotland of whom seven have died: seven confirmed cases in the NHS GGC area, four fatal; three cases in Lanarkshire NHS area, one of whom remains in hospital; two fatal cases in Tayside one fatal case in the Forth Valley NHS area, and one surviving case in Fife.All cases reported a history of taking heroin by intramuscular, intravenous or subcutaneous injection and/or by other routes including smoking or snorting.

Epidemiological information
Case definitions were established to classify cases as 'confirmed', 'probable' or 'possible' [1].Only laboratory-confirmed cases are being reported publicly.The 14 confirmed cases are 10 men and four women* aged between 27 and 55 years for the men and between 39 and 43 years for the women.The mean age of the cases is 38 years for both men and women.The mean age of the fatal cases is slightly higher at 42 years.
The first confirmed case in Glasgow was admitted to hospital on 7 December 2009; the latest confimed case was admitted to hospital in Dundee on 6 January 2010 and died on 8 January following a rapid deterioration.Over the five weeks of the outbreak to date, the peak incidence of admissions was in week 3 (six new confirmed cases, week beginning 28 December 2009), dropping to one new confirmed case in week 4 (beginning 4 January 2010).The peak of the outbreak may therefore have already occurred, but it is too early yet to state this with confidence.
There are estimated to be around 55,000 (illegal) drug users in Scotland (not all of whom use heroin) giving a very approximate incidence of 2.5 cases per 10,000 drug users.This is set in the context of approximately 34% of IDUs reporting an injection site wound in any year.
Generally, the cases have presented with inflammation or abscesses related to sites of heroin injection.Symptoms began between one and two days or longer after injection of heroin and admission to hospital generally followed within four days.Localised lesions developed into necrotising fasciitis in a number of cases, some of whom died.The fatal cases in Glasgow (three men and one woman) died between three and seven days after admission.Cellulitis with very marked oedema has been noted in limbs with infection sites in a number of these cases.In a few cases the presentation has been of patients in advance stages of systemic sepsis some of whom died within hours.At least two cases presented with symptoms thought of at initial assessment as suggestive of a sub-arachnoid haemorrhage or haemorrhagic meningitis.Others presented with relatively localised lesions which have not progressed.The range of presentations is therefore wide and inconsistent.
Diagnosis has been confirmed by isolation of Bacillus anthracis in early blood cultures in some patients, supported by PCR testing of blood or excised tissues at the Health Protection Agency (HPA) Special Pathogens Reference Unit (SPRU) at Porton Down.In others, no blood cultures were obtained before antibiotic therapy was started and no organism was cultured, but PCR evidence was obtained.In at least one case confirmation was on the basis of finding only significant anti-toxin antibodies on sera following treatment with antibiotics.This raises the possibility that other milder cases may have not been identified who may have antibody evidence of exposure to the organism.Where practical (in the context of the case population), possible cases who have not been confirmed by isolation or PCR will be followed up to obtain convalescent sera, to identify late sero-converters.
Management has consisted of treatment with relevant intravenous antibiotics, with the close involvement of local microbiologists, and surgical debridement where appropriate.
Four cases have been treated with anthrax immunoglobulin (AIG) supplied courtesy of the United States Centres for Disease Control and Prevention (US CDC), under the supervision of CDC staff who were temporarily on site to assist the investigation and have provided advice and guidance in relation to recent US experience with clinical anthrax infection.AIG was provided under the CDC investigational new drug protocol.
Information on injecting drug use, social circumstances and other possible risk factors for developing anthrax has been obtained from these cases wherever possible.A difficulty in this investigation is obtaining reliable accurate histories of recent drug use, given the nature of the situation and the seriousness of illness in some cases.Some cases died before complete histories could be obtained.Information collected to date has indicated that the majority (but not all) had a recent history of injecting heroin, which they had obtained primarily within the Greater Glasgow and Clyde area or neighbouring Lanarkshire.For more recent cases residing outside the Glasgow/Lanarkshire area, the source of their heroin is under investigation.There does not appear to be another common factor for possible anthrax exposure other than the acquisition and taking of heroin by one or more methods.Dissolving agents (mainly citric acid) were purchased at separate locations and are not considered to be implicated as possible vehicles of transmission or contamination.

Response to the outbreak
Initially the outbreak was managed via an Outbreak Control Team (OCT) based in NHS GGC with support from local microbiologists, Strathclyde Police, Health Protection Scotland, and the HPA SPRU (who have acted as the reference laboratory for the confirmation of all cases to date).
The OCT formulated three working hypotheses.Firstly, that there was anthrax in the heroin which may have entered the supply chain at any point from its original source to the final point of acquisition.Secondly, that either the dissolving agent or cutting agent were contaminated with anthrax.Thirdly, that there was an as yet undiscovered link between the cases.
Information was released via the press advising the drug injecting community of the additional risk associated with taking heroin and that they should seek urgent medical advice if they developed an infection.Subsequently specific information leaflets and posters have been developed in collaboration with the Scottish Drugs Forum.
Evidence suggests that subcutaneous and intramuscular routes have been associated with the majority of infections and confirmed cases to date.However, some cases reported multiple routes of administration in sequence.Hence, in contrast to the previous outbreak of Clostridium novyi infection (which also affected IDUs in Scotland in 2000) [2,3], it has not been possible to offer advice on harm-minimising methods of taking heroin.Due to the potential risk of inhalational anthrax from smoking (or snorting) heroin, and the potential risk from injecting anthrax spores intravenously, from ingesting or from any other parenteral route of administration, addiction services and pharmacies were alerted to the fact that no 'safe' route of administration of heroin could be advocated.The key harm reduction advice message remains that focused on avoiding the use of heroin if possible and seeking alternatives via drug treatment services, highlighting awareness of the dangers and early symptom identification.General practitioners, hospital departments, and microbiology departments were also alerted.Information has been cascaded across all NHS Boards in Scotland and to specialist community addiction services.

Progress of investigation
Given the confirmation of cases outside the Glasgow conurbation, the outbreak investigation has now been upgraded to a national OCT, coordinated by Health Protection Scotland.Representatives of agencies working with drug users have also been co-opted to the national OCT including the Scottish Drugs Forum and Scottish Drug Deaths Forum.The most likely cause of the outbreak is considered to be exposure by injection (or other routes) to heroin either directly contaminated at the source or contaminated as a result of mixing with other substances contaminated with anthrax at some point in the supply chain.The distribution of cases suggests either that small batches of contaminated heroin may still be circulating in Scotland or that there is a continuing source of contamination in material used to cut (dilute down) the heroin before supply to end users.Further investigations are proceeding to try to trace the supply network and validate the existing hypothesis.
Risk assessments have been undertaken regarding the potential risks to others including health service staff.Police and others involved in searching premises and in handling the cases' belongings.To date there has been no evidence to suggest a risk to the general public or any other parties who have had access to clothing, belongings or the living quarters of cases.No special protective measures are therefore being advised at present and there are no plans to decontaminate any such personal items or premises, on the basis that the risk to date has been confined to an association with personal intake of heroin, not other casual exposures.

Discussion
Although rare, outbreaks or cases of illness among IDUs have been documented in recent years.In 2000, an outbreak among IDUs, involving 60 cases and 20 deaths, occurred in Scotland.The most frequently isolated pathogen among the cases was C. novyi and transmission was believed to have occurred via a contaminated batch of heroin [2,3].Similarly in 2000, a case of 'injectional' anthrax was identified in a heroininjecting drug user in Norway.A contaminated batch of heroin was believed to be the source of the infection [4].
Between December 2003 and April 2004, reports of C. hystoliticum from 12 cases of infection in IDUs were identified in England and Scotland.Again, it was believed that the source of the infection was a contaminated batch of heroin distributed across the UK [5].
Setting an appropriate diagnostic threshold for this outbreak is a challenge in that approximately 34% of IDUs per year report signs of an infected injection site.Hence wound infections in this population are not unusual.However, none of the cases have presented with a classical cutaneous anthrax pattern.It is perhaps surprising given the source and nature of heroin preparation and anecdotal reports that heroin is transported in animal skins, that more cases of infections in heroin users has not been identified before now.
The Robert Koch Institute, in collaboration with the Friedrich Loeffler Institute in Jena, the Federal Research Institute for Animal Health, and the respective local and regional health authorities in the Aachen district, North-Rhine-Westphalia, Germany, are currently investigating a fatal case of anthrax in a 42 year-old male injecting drug user.
The individual was hospitalised on 6 December 2009, complaining of a swelling of his leg following drug injection into the popliteal fossa -reportedly attempting to inject into a vein.He probably injected heroin, however, details are unknown.Following treatment with meropenem and surgical debridement of a subsequent necrotising fasciitis, the patient died with multiorgan failure on 13 December 2009.Anthrax had not been suspected clinically.
Spore-forming bacteria from a wound swab specimen were identified, and on 18 December, the diagnosis of anthrax was confirmed by PCR.The last case of human anthrax in Germany had been reported in 1994, at that time affecting a 66 year-old man [1].
At this point in time, it is not clear whether there is a link between this case and the anthrax outbreak among injecting drug users in Scotland.As far as we know, the deceased had no travel history to Scotland.However, it can be assumed that other drug users in the same area in Germany, or perhaps elsewhere in the country, have been exposed.In case the hypothesis of a potential link to the Scottish cases proves true, it might well be that also other countries have been supplied with contaminated injectable drugs.
We launched an epidemiological investigation and exchanged information with the colleagues in the United Kingdom and, in particular, Scotland to coordinate the approach.So far, the following measures have been taken: • We have distributed information to public health colleagues, medical care facilities and low-threshold facilities in Germany to raise awareness of the event.
• We are collecting information on the case and his contacts, and on the substances consumed.• We attempt further case finding.
• We aim at a microbiological comparison of isolates to establish a potential epidemiological link with the Scottish cases.
The success of the epidemiological investigation will rely on public health authorities' efforts, alertness amongst clinicians and medical microbiologists, but also on the degree to which drug users themselves can be reached.Therefore, it is of utmost importance to utilise existing communication channels to inform those who might be at risk.

Introduction
Sindbis virus (SINV) is a mosquito-borne alphavirus (of the family Togaviridae), present in Eurasia, Africa and Oceania [1,2].Antibodies to SINV are detected in humans in various geographical areas but clinical infections caused by SINV are reported mostly from Finland where SINV is associated with fever, rash and arthritis, known as Pogosta disease [3].The treatment is symptomatic.Clinically similar diseases are found in Sweden (Ockelbo disease) and in Russia (Karelian fever) [4,5].The majority of clinical cases occur in Finland during August and September when the primary vectors, the ornitophilic late summer mosquito species Culex and Culiseta, are abundant.The incidence of Pogosta disease has been highest in the eastern parts of Finland in recent decades.[3,6].
Remarkably, outbreaks of Pogosta disease have thus far emerged every seven years since the first outbreak was noted in 1974, and the cause for this phenomenon is yet to be discovered.Tetraonid birds such as grouse, might contribute to this pattern [3].Grouse have previously shown population cycles with population "crashes" coinciding with SINV outbreaks [7].Antibodies to SINV have been detected in grouse and migratory birds [3,6] The  and by hospital district of treatment.Finland has a population of 5.3 million and is divided into 20 hospital districts.Laboratory diagnosis is based on enzyme immunoassays (EIA) and/or in some cases a haemagglutination inhibition test (HI) (5).

Results
From June through October 2009, a total of 105 laboratory confirmed cases were reported to the NIDR and the incidence of SINV infection was two cases per 100,000 inhabitants per year (Figure 1).Most of the cases occurred in September (n=60) followed by August (n=33).Sixty percent (n=63) of the cases were females.The highest incidence (4.6/100,000/year) was among persons aged 50-59 years.Only two of the cases were aged under 18 years.The incidence was highest in north Karelia, followed by east Savo, central Ostrobothnia and central Finland together with southern Ostrobothnia (Figure 2).The incidence rates in 2009 were considerably lower than those in 2002.
The number of cases was highest in central Finland (n=15).The majority of the cases (n=10) in central Finland occurred in July-August whereas only one case was reported from north Karelia during this time period (Figure 3).On the contrary, 13 cases were reported from north Karelia and five from central Finland during the months of September-October.In 2002, cases peaked in September in both of the hospital districts.

Discussion
A major Pogosta disease outbreak has occurred every seven years in Finland since 1974, with hundreds or even thousands of patients.Following this pattern, another outbreak was expected for 2009.However, the number of cases was substantially lower than in previous epidemics in 1995 and 2002 when 1301 and 597 cases were reported respectively [6].The factors behind the puzzling cycles in the epidemiology of Pogosta disease are unclear but recently attention has focused on tetraonid birds.In the epidemic years of 1974 and 1981, grouse population crashed in north Karelia [4].Further, detection of SINV antibodies in one quarter of grouse examinated in the year following the 2002 epidemic, indicated vast exposure of grouse to SINV, and suggested that the virus may have an endemic cycle in tetraonid birds [6].The density of grouse was above average in 2007 but the population crashed in 2008.The recovery of grouse population can be rapid and was anticipated to occur in 2009.However, the density of their population continued to decline to an all time low (since the measurements from 1980s) [8].Hence, it is plausible that grouse play a significant role in the human epidemiology of SINV.It is possible that the continuing decline in the grouse population in 2009 diminished the role of grouse as amplifying hosts and that therefore, a milder outbreak than expected was observed.
Similar to previous findings, the incidence of SINV was highest in the hospital district of north Karelia.The difference in incidence of this hyperendemic region with other hospital districts was not, however, as prominent as previously.In 2009 many of the hospital districts with high incidence were located in central and northwestern parts of Finland.These observations may point towards a geographical shift in the incidence of SINV virus infection.The relatively low incidence in north Karelia compared to the epidemic in 2002 may also reflect the increased human seroprevalence towards SINV which indicates immunity.The district of Kainuu had no cases, which was surprising since previous studies showed high seroprevalence in that area [6].This could be attributable to significant underdiagnosis or acquired immunity, which may result from high number of cases during the 1970s and 1980s.
Most cases in central Finland occurred in August whereas in north Karelia the number of cases peaked in September.This could reflect the variations in mosquito activity and population size due to differences in weather conditions in these areas.The month of May was drier than normally in Joensuu (the largest city in north Karelia) but the rainfall in June-July was considerably higher than on average [9].We analysed and reported on a weekly basis clinical and epidemiological characteristics of patients hospitalised in the Netherlands for the 2009 pandemic influenza A(H1N1) using information from the national mandatory notification system.The notification criteria changed on 15 August 2009 from all possible, probable and confirmed cases to only laboratoryconfirmed pandemic influenza hospitalisations and deaths.In the period of comprehensive case-based surveillance (until 15 August), 2% (35/1,622) of the patients with pandemic influenza were hospitalised.From 5 June to 31 December 2009, a total of 2,181 patients were hospitalised.Of these, 10% (219/2,181) were admitted to an intensive care unit (ICU) and 53 died.Among non-ICU hospitalised patients, 56% (961/1,722) had an underlying medical condition compared with 70% (147/211) of the patients in ICU and 46 of the 51 fatal cases for whom this information was reported.Most common complications were dehydration among non-ICU hospitalised patients and acute respiratory distress syndrome among patients in ICU and patients who died.Children under the age of five years had the highest age-specific hospitalisation rate (62.7/100,000), but relatively few were admitted to an ICU (1.7/100,000).Characteristics and admission rates of hospitalised patients were comparable with reports from other countries and previous influenza seasons.The national notification system was well suited to

Introduction
On 30 April 2009, the first case of human infection with the 2009 pandemic influenza A(H1N1) was reported in the Netherlands, and on 5 June 2009 the first patient was hospitalised [1].From 15 August 2009, only patients with a laboratory-confirmed pandemic influenza infection who were hospitalised and/or died because of the severity of their illness were notifiable.This was in line with international consensus that registration of all cases of pandemic influenza A(H1N1) is not efficient anymore when there is widespread community transmission and that surveillance efforts should focus on severe disease to enable mitigating the impact of the pandemic [2][3].The World Health Organization (WHO) suggested surveillance of severe acute respiratory illness (SARI) in a number of sentinel hospitals, with a case definition of sudden onset of fever (>38°C) and cough or sore throat in the absence of other diagnoses, shortness of breath or breathing difficulty, and requiring hospital admission [4].As it was not a realistic option to establish and validate such a novel surveillance system in the Netherlands in a very short time, it was decided to modify the nationwide mandatory notification system and limit this system to hospital admissions and/or deaths due to laboratoryconfirmed pandemic influenza virus infection.Reports from the southern hemisphere give important information on the impact of the first wave of the pandemic.However, such data cannot be transferred directly to Europe because of the differences in population composition, health systems, notification systems, climate and the prevalence of other infectious diseases that can all affect the spread and impact of an epidemic.
In this report, we analyse the clinical and epidemiological characteristics of the first patients hospitalised and deceased in the Netherlands with a confirmed 2009 pandemic influenza A(H1N1) virus infection and we discuss the mandatory notification system for all hospital admissions.

Notification system
From 30 April to 14 August 2009 all possible, probable and confirmed cases of 2009 pandemic influenza A(H1N1) were notifiable.On 15 August, the notification criteria changed, and from that date only cases who were admitted to hospital or died because of the severity of a laboratory-confirmed pandemic influenza virus infection had to be notified.Within a few days a new questionnaire was developed, which had to be as short as possible in order not to overburden the municipal health services and physicians.In the Netherlands, the attending medical doctor and the head of the involved microbiology laboratory both have to report the name and clinical characteristics of the hospitalised patient to the municipal health service.Notifications are entered by the municipal health services into a national anonymous and password-protected web-based database, including information on underlying medical conditions (co-morbidity), vaccination status, treatments, complications such as pneumonia, and admission to an intensive care unit (ICU).

Laboratory confirmation
In the Netherlands, initially the National Influenza Centre (NIC, consisting of the National Institute for Public Health and the Environment (RIVM), Bilthoven and the Erasmus Medical Centre, Rotterdam) and later the 11 laboratories of the Outbreak Assistance Laboratories Network tested nose and throat samples for pandemic influenza A(H1N1) virus [5].When the pandemic was evolving, additional peripheral and hospital laboratories also performed diagnosis of pandemic influenza using molecular diagnostic tests made available by the NIC in conjunction with an external quality assurance programme.The Centre for Infectious Disease Control at RIVM acted as central confirmation laboratory.
For diagnostics, real-time RT-PCR assays for general detection of influenza virus type A and specific detection of pandemic influenza A(H1N1) virus were used with a confirmation by sequencing [5].

Dissemination
Weekly reports summarising new and cumulative numbers of hospitalisations by age and by underlying conditions were prepared for discussion by the multidisciplinary response team of RIVM.In these reports, notification data were linked to data from the sentinel surveillance of influenza-like illness (ILI), c For 240 hospitalised patients, for 13 of the patients admitted to an ICU and for seven of the patients who died, information on pneumonia was not available.d For 20 of the patients admitted to an ICU and for four of the patients who died it was unknown whether they had received mechanical ventilation.

Data analysis
We calculated descriptive statistics for all study variables.For categorical variables percentages were reported and for continuous variables the median (with range).Only laboratory-confirmed cases were included in the analysis.We categorised patients according to age groups.All descriptive statistics were calculated for non-ICU hospitalised patients, patients admitted to an ICU and deceased patients.All statistical analyses were conducted using SAS version 9.1 (SAS Institute).

Clinical characteristics
From 5 June to 14 August 2009, the period before the notification criteria changed, 2.2% (35/1,622) of the notified patients with a confirmed pandemic influenza infection were admitted to a hospital [1].From 5 June to 31 December 2009, a total of 2,181 patients were hospitalised for severe laboratory-confirmed infection with pandemic influenza.Of these, 10.0% (219/2,181) were admitted to an ICU.In the same period, a total of 53 patients died due to laboratory-confirmed infection with pandemic influenza, five of whom died without hospital admission.

Epidemiological characteristics
The median age of non-ICU hospitalised patients was 17 years (range 0-89 years).For patients admitted to an ICU the median age was 42 years (range 0-82 years), and for patients who died the median age was 52 years (range 0-85 years) (Table 1).Incidence of non-ICU hospitalisations peaked in the group of 0-4 year-olds and thereafter declined with age.Incidence of ICU admissions and deaths, however, showed a second peak in the group of 55-64 year-olds (Table 2).The highest incidence for ICU admission overall was observed in patients aged between 55 and 64 years (2.06 per 100,000 population), whereas the highest incidence for non-ICU hospitalisation was among children under the age of five years (62.7 per 100,000 population).
Of incidence of non-ICU hospitalisations and ICU admissions for pandemic influenza by week decreased.There was only limited geographical variation in the incidence of hospital admissions (ICU and non-ICU) due to pandemic influenza by municipal health service region in the Netherlands (Figure 4).

Underlying medical conditions
An underlying medical condition was reported for 961 (55.8%) of the 1,722 non-ICU hospitalised patients for whom this information was available (Table 3).Of these, 6.2% (60/961) were pregnant, most of them in the third trimester.Nine of the pregnant patients also had another underlying medical condition.The most common conditions were chronic pulmonary diseases (48.6%; 467/961), especially asthma and chronic obstructive pulmonary disease (COPD).Of the patients admitted to an ICU, 69.7% (147/211) had an underlying medical condition.5.4% (8/147) of these patients were pregnant, mainly in the third trimester.The most common medical condition for ICU-admitted patients were chronic pulmonary diseases (43.5%; 64/147), especially asthma and COPD.Underlying medical conditions were present in 46 of the 51 patients who died and for whom this information was available.

Complications
For 15.7% (309/1,962) of the non-ICU hospitalised patients it was unknown whether they had complications.Specific complications were reported for 365 (21.1% of the remaining 1,653) patients, with dehydration as the most common complication (Table 4).For 14.2% (31/219) of ICU-admitted patients information on complications was not available.Among the remaining 188, 123 (65.4%) had a complication, mostly acute respiratory distress syndrome (ARDS) (36.6%; 45/123).Among the 53 patients who died, 30 had a complication reported and for nine no information was available.

Discussion and conclusion
The data reported in this paper are based entirely on the routine national infectious disease notification system.This system made it possible to provide weekly updates of relevant pandemic monitoring information on severe pandemic influenza for dissemination to professionals, decision makers, the media, and the public.Changes in the web-based notification system were communicated by the Centre for Infectious Disease Control and implemented rapidly by municipal health services, physicians and heads of medical microbiology laboratories.Nevertheless, a nation-wide mandatory notification system puts restrictions on the amount of information that can be requested from hospital and public health physicians.Therefore, it was not possible to provide information on the reason for hospital admission, other than that it was for laboratory-confirmed pandemic influenza.Also, follow-up of patients by the municipal health service, for example to obtain information on date of discharge from the hospital, was not considered feasible.
The highest age-specific rates of hospital admission were seen in the age group of 0-25 year-olds.In absolute numbers and in incidence, most admissions occurred in the age group of the 0-4 year-olds, but only 3% (16/581) of them were admitted to an ICU.Of the admitted patients older than 45 years, 18% (105/580) were admitted to an ICU.Infants might have been admitted to hospital for observation even in the absence of signs of respiratory distress or other complications, or for supervised oseltamivir therapy, although personal communications from a number of paediatricians suggested that the majority of small children admitted with laboratory-confirmed pandemic influenza were admitted because of serious illness.
The observed hospitalisation, ICU and mortality rates are compatible with data reported from other countries [6][7][8][9][10].Hospitalisation rates from countries in the southern hemisphere ranged (by country) from 2.0 to 31.8 per 100,000 population, and mortality rates ranged from 0 to 3.6 per 100,000 population [8].In the Netherlands, hospitalisation rates due to pandemic influenza by age group ranged from 2.8 to 62.7 (overall 13.1) per 100,000 population and mortality rates ranged from 0.05 to 0.61 (overall 0.32) per 100,000 population.High rates of hospitalisation in the age group of 0-4 year-olds were also reported for Queensland and New South Wales (Australia), Ireland and other European countries [6][7][10][11].While in seasonal influenza epidemics, the highest incidence of severe morbidity and deaths is expected in the oldest age groups, we observed the declining incidence in ICU admissions and deaths in patients older than 65 years following a peak in the age group of 55-64 year-olds, which could be compatible with a reported protection of those exposed to influenza A(H1N1) before 1957.
The majority of severe cases were people with preexisting underlying medical conditions: 55.8% (961/1,722) of the hospitalised patients, 69.7% (147/211) of the cases admitted to ICU, and 46 of the 51 deceased patients.Asthma was the most common underlying condition, followed by other chronic lung disease and cardiovascular disease.This is in line with reports from other countries [6][7]11].However, a The total number of complications is more than the total number of patients with complications because one patient can have more than one complication compared with other countries, obesity was reported for very few hospitalised patients and was not a risk factor in the Netherlands.However, no systematic data was collected on length and weight of the hospitalised patients not reported to be obese, which may have resulted in underreporting as obesity is likely to have been a subjective assessment of the attending physician.
A further limitation of this study is the fact that the Dutch notification system does not provide specific data on SARI.The reported cases include patients admitted for severe influenza illness with other complications than respiratory distress.Therefore, the Dutch SARI cases that are reported to the WHO and the European Centre for Disease Prevention and Control (ECDC) are laboratory-confirmed pandemic influenza cases, in contrast to some other countries that report all clinical SARI cases.Also, we could not determine why no complications were reported for 65 of 188 patients who were admitted to an ICU.It is possible that the attending physicians did not consider ARDS as a specific complication or that patients with respiratory distress did not fulfil all the diagnostic criteria for ARDS.
Comparison of the severity of the current epidemic with previous influenza seasons can not be based on direct analyses of hospital-based surveillance data, as there are no reliable historical records of hospital admissions and deaths related to laboratory-confirmed influenza, but will need to rely on the ongoing ILI sentinel surveillance among general practitioners (GPs).We recently related this GP ILI surveillance to retrospective respiratory hospitalisation rates over the years 1999 to 2005 [12][13][14].So far, the admission rates in 2009 seem similar to the estimates over the period 1999-2005, although the admission rates for children and adults seem among the highest rates compared with the 1999-2005 influenza seasons, whereas the admission rates for the elderly (≥65 years of age) seem among the moderate or lowest rates compared with 1999-2005.Analyses as in [13] on trends in ILI GP consultations by age or in [14] on hospitalisations and mortality for respiratory diseases versus ILI GP consultations including 2009, could allow comparing the severity of the current epidemic with previous influenza seasons.A surveillance system with real-time availability of SARI cases would have made such analyses possible during the ongoing epidemic, but only if data on SARI cases (or similar clinical diagnosis) had also been available for earlier seasons, which is not the case in the Netherlands.
In conclusion, the national notification system was well suited and could rapidly be adapted to changing information requirements, although a national notification system puts restrictions on the amount of information that can be requested.While we could not confirm an association with obesity, other reported characteristics of hospitalised patients with confirmed pandemic influenza in the Netherlands were in line with those reported by other countries, including countries in the southern hemisphere.This report is based on the 2009 phase of the pandemic in the Netherlands.Numbers, distribution by age group and characteristics could still change when the pandemic develops further, thus continued surveillance and vigilance is essential.

Introduction
On 1 May 2009, the first two cases of 2009 pandemic influenza A(H1N1) were identified in France [1].At this time, hospitalisation of all cases was required, irrespective of their clinical presentation.After the virus had spread more widely and community transmission had increased, systematic hospitalisation was discontinued on 1 July.At the same time, a national hospital-based surveillance system of hospitalised 2009 pandemic influenza cases was set-up by the National Institute for Public Health Surveillance (Institut de veille sanitaire, InVS).The surveillance of hospitalised pandemic influenza cases was restricted to patients with severe disease on 2 November when there had been a sharp rise in the total number of cases requiring hospital admission.
In this paper we describe the characteristics and outcome of severe cases of pandemic influenza hospitalised in metropolitan France between 1 July and 15 November, 2009 and identify risk factors for severe outcome and death, respectively.

Methods
In France, a nationwide hospital-based surveillance system was implemented on 1 July 2009.Clinicians were requested to report to InVS all hospitalised cases of pandemic influenza through a standardised notification form available on the InVS website.Patients to be notified included (i) those with a positive RT-PCR performed on a nasal swab, (ii) patients with a severe clinical influenza, likely to be caused by 2009 pandemic influenza virus according to the clinician, even in the absence of laboratory confirmation, and (iii) patients with an epidemiological link with a confirmed case of pandemic influenza.Two levels of severity of disease were defined: non-severe (hospitalised in medical wards for at least 24 hours) and severe (admitted to ICU or death while hospitalised).
Follow-up data for cases were collected weekly by telephone contact between InVS staff (epidemiologists or physicians) and physicians in charge of the patient until discharge or death.At discharge, clinicians were invited to return a second notification form also available on the InVS website.The forms received were cross-checked with individual positive PCR results coming from the network of all laboratories performing the RT-PCR for the 2009 pandemic influenza virus.
Descriptive statistics included frequency analysis (percentages) for categorical variables and median and interquartile ranges (IQR) for continuous variables.The differences in characteristics according to outcomes were tested using chi-squared test for categorical variables and Mann-Whitney rank sum test for continuous variables.A p-value under 0.05 was considered statistically significant.Two types of comparison were made.First, the clinical characteristics of patients with severe disease were compared with those of patients admitted to medical wards until 2 November 2009.Second, clinical characteristics of surviving severe cases discharged before 15 November, were compared with those of fatal cases.Odds ratios (OR), including 95% confidence intervals (CI), were calculated through multivariate logistic regression analysis.We included in the analysis the presence or absence of each of the following underlying medical conditions/ potential risk factors: chronic respiratory disease, pregnancy, diabetes, obesity (body mass index ≥30 Kg/m 2 ), immuno-supression and chronic cardiac disease as categorical variables.The analysis was performed with Stata V9.

Results
From 1 July to 15 November and 2 November 2009 respectively, 244 severe cases of 2009 pandemic influenza and 514 cases hospitalised in medical wards were reported to InVS.The number of hospitalisations increased sharply from week 41 (Figure 1).Almost all cases (98%) were laboratory confirmed as 2009 pandemic influenza A(H1N1), the 2% non-laboratory confirmed cases were patients with clinical influenza and/ or patients with an epidemiological link with a confirmed case.

Clinical characteristics
Among the 244 severe cases, 48 (20%) were children under 15 years of age, the male/female ratio was 1. Underlying conditions were present in 188 (80%) patients.This proportion was 67% among children.
Chronic respiratory diseases were the most common underlying condition, both in adults and children.Of the 117 women, 18 were either pregnant, mainly in the second (n=5) and third trimester, or had recently delivered (i.e.within a week) (n=11).Among these 18 women, 61% had an underlying medical condition.
Compared with non-severe hospitalised paediatric cases, the risk of severe disease was significantly higher for children with an underlying condition (ageadjusted OR: 3.3); the excess risk associated with younger age (<1 year) however, did not reach statistical significance (Table 2).
In the multivariate analysis, increasing age and obesity were significantly associated with severe disease when compared with non-severe hospitalised adult cases (adjusted OR 2.

Interval from symptom to admission and treatment
The interval from onset of symptoms to admission was available for 216 severe cases and 427 non-severe cases.The median interval was 2.0 days (range 0-31)  for severe cases and significantly longer than for cases without severity criteria: 1.2 days (range 0-13) (p<0.001).Data about antiviral therapy were available for 153 severe and 306 non-severe cases; 93% of severe cases had received antiviral therapy (oseltamivir) versus 81% of non-severe cases.Information for the interval from onset of symptoms to antiviral treatment initiation was available for 322 patients (207 non-severe and 115 severe).This interval was ≤2 days for 153 (74%) non-severe cases and for 45 (39%) cases patients (p<0.001).Similar results were obtained when the analysis was restricted to cases with underlying disease: 100 (72%) of the non-severe cases and 38 (41%) of severe cases had received early antiviral therapy (p<0.001).

Outcome
Of the 244 severe cases, 147 (60%) required ventilator support, 60 (25%) had an acute respiratory distress syndrome (ARDS) and 21 (9%) required extracorporeal membrane oxygenation (ECMO).At the time of analysis, 143 patients had been discharged from the ICU, and 37 (15%) had died.The median length of stay in the ICU was five days (IQR 3-8).The median age of patients who died was 42 years (range 8 months-71 years) and the median time from hospital admission to death was four days (range 0-74).Among the five children who died, three were one year old or under, one was six and one was 14 years old and all of them had at least one underlying condition.Among the 32 adults who died, 30 (94%) had at least one underlying condition (Table 1).A pregnant woman with underlying condition died.
Chronic cardiac disease and immunosuppression were associated with fatal outcome but this was not the case for chronic respiratory diseases.Obesity had an OR point estimate of 2.6 but was not statistically significant (Table 3).

Discussion
This series of hospitalised patients with 2009 pandemic influenza confirms that the 2009 pandemic virus can induce severe illness among children and adults, even for those with no underlying medical conditions.The epidemic started almost two months before the usual influenza season in France.No co-circulation of other influenza viruses was identified through the enhanced virological surveillance during the period of data collection.
In our series, the highest ICU admission rate was found in infants and the lowest in the elderly.Being 65 years old or more seems, to be a risk factor for severe disease when hospitalised, but not for death, after adjustment for the presence of co-morbidities.Our results are coherent with other reports on 2009 pandemic influenza.In Australia and New Zealand, the rate of admission to ICU was low in the elderly but the risk of death increased with age [2].In the analysis of Mexican data, confirmed cases aged 70 years or more, had the lowest mortality rate but the highest death to hospital admission ratio [3].We did not identify an association for cases between death and being more than 65 years old.This could be explained by the fact that our analysis was adjusted to the presence of co-morbidity.It may also be due to the limited sample size of our series.
The underlying conditions leading to more severe illness we found are those reported in the literature.Chronic respiratory illness is the most prevalent in our case series, as described also by Jain et al. [4], but it is not associated with a higher risk of more severe disease or death among hospitalised cases.In contrast, obesity is clearly a risk factor for severe disease and probably for death as was reported in the literature [2,4,5].Obesity is a risk factor for severe viral pneumonia [6] while severity connected to chronic respiratory disease is related to the exacerbation of the disease, and is usually responsive to bronchodilatator treatment [7].Pregnancy, especially at the end of the gestation, is overrepresented among the patients hospitalised and accounts for 7% of admissions to ICU whereas pregnancy (estimated from the number of live birth in 2008 and the number of abortions in France) represents around 1% of the general population.Our finding confirms that pregnancy should be considered as a risk factor for complications from 2009 pandemic influenza [8].A similar conclusion stands for infants, also accounting for 7% of admissions to ICU.
The interval from the onset of symptoms to admission was longer for severe cases than for non-severe cases.Furthermore, antiviral treatment was initiated less than 48 hours after the onset of symptoms for 74% of non-severe hospitalised cases and 39% for severe cases.As already suggested by data from the United States, it is possible that delayed initiation of antiviral therapy may have contributed to increased severity of illness [4,9].Communication to patients and physicians should be strengthened on the need for rapid initiation of treatment, whenever indicated.
Of the 244 patients with severe disease, 60% required ventilator support, 25% had an acute respiratory distress syndrome (ARDS) and 9% required extracorporeal membrane oxygenation (ECMO).Theses results are also consistent with previously published reports [2,4].
Our study has several limitations.Although our surveillance was implemented in the context of public health emergency some cases may have not been reported to InVS.However, several factors are in favour of only few cases having been missed.Firstly, only a few additional cases were identified after cross-checking with data from laboratories.Secondly, cases considered by clinicians as likely to be due to 2009 pandemic influenza, even in the absence of laboratory confirmation, were included in the definition of cases to be notified.Thirdly, regular phone calls with physicians of ICU wards were made by InVS staff in order to complete missing information on received forms and ask for cases not notified.Last but not least, the hospital surveillance is strongly supported by various ICU medical practitioners' societies.
To assess risk factors for severe clinical presentation we used 2009 pandemic influenza cases admitted to medical wards as a control group.This choice of controls may have lead to an underestimation of odds ratios because for some specific population groups potentially more prone to complications such as pregnant women and children, individuals may have been hospitalised as a precautionary measure even in the absence of severe disease.This could explain our finding of a higher proportion of non-severely ill pregnant women hospitalised in medical wards compared to those admitted to ICU.
Our study confirms the role of the underlying conditions as risk factors for severe disease and strengthens the need for a rapid start of antiviral therapy, especially for patients with underlying conditions.Furthermore, it confirms the French national strategy which recommends priority vaccination of pregnant women, close contacts of infants and patients of any age with co-morbidities known to increase the risk of severe influenza.
Our analysis will be renewed when a larger series of cases will be available: as of 2 December, 511 severe cases have been identified with 74 deaths and the epidemic does not seem to have reached its peak yet.

Figure 2 Figure 3
Figure 2 Number and incidence rates of laboratory confirmed Sindbis virus cases, by health care districts, Finland 2009 (n=105) and 2002 (n=597)

Figure 4 3
Figure 4 Incidence of hospital admissions (ICU and non-ICU) due to 2009 pandemic influenza A(H1N1) by municipal health service region, the Netherlands, 5 June-31 December 2009 (n=2,181)

nl) 1 , C C Wielders 1,2 , T Donker 1 , L Isken 1 , A Meijer 1 , C C van den Wijngaard1, M A van der Sande 1 , W van der Hoek 1
Perhaps the dry May in Joensuu contributed to fewer cases in July-August but the high rainfalls in June and July created better environmental conditions for mosquito development and thus, more human cases of SINV occurred in September-October.Weather conditions are also likely to influence human outdoor activities, and thereby exposure to SINV. 1. Centre for Infectious Disease Control, National Institute for Public Health and the Environment (RIVM), Bilthoven, The Netherlands 2. Pallas health research and consultancy B.V., Rotterdam, the Netherlands Citation style for this article: van 't Klooster TM, Wielders CC, Donker T, Isken L, Meijer A, van den Wijngaard CC, van der Sande MA, van der Hoek W. Surveillance of Hospitalisations for 2009 Pandemic Influenza A(H1N1) in the Netherlands, 5 June -31 December 2009.Euro Surveill.2010;15(2):pii=19461. Available online: http:// www.eurosurveillance.org/ViewArticle.aspx?ArticleId=19461 This article has been published on 14 January 2010 In summary, a limited outbreak of SINV in humans took place in Finland in late summer and autumn of 2009 but the expected seven-year cycle did not recur.The data suggest a geographical shift in disease incidence.It is likely that fluctuations in grouse populations play a major role in the occurrence of SINV epidemics.To further elucidate the role of tetraonid birds and other factors, such as weather and climate variations, more epidemiological studies and proper mathematical modeling of SINV epidemics is needed.T M van 't Klooster (tessa.van.t.klooster@rivm.

Table 1
Characteristics of patients hospitalised for 2009 pandemic influenza A(H1N1), the Netherlands, 5 June-31 December 2009 (n=2,186) a For 20 hospitalised patients sex was unknown.b For 18 hospitalised patients the age group was unknown.

Table 2
Cumulative incidence for hospitalisation, admission to an ICU and deaths due to 2009 pandemic influenza A(H1N1) per 100,000 population by age group, the Netherlands, 5 June-31 December 2009 (n=2,186)

ICU) (per 100,000) Incidence of ICU admission (per 100,000) Incidence of death (per 100,000)
Hospital admissions (ICU and non-ICU) due to laboratory confirmed 2009 pandemic influenza A(H1N1) by week of hospitalisation, the Netherlands, 5 June-31 December 2009 (n=2,034 with a reported admission date) ICU: intensive care unit.Figure 1

Table 4
Specific complications of hospitalised patients (non-ICU), patients admitted to an ICU and deaths due to 2009 pandemic influenza, the Netherlands, 5 June-31 December 2009 (n=473 with specific complications reported) ARDS: acute respiratory distress syndrome; COPD: chronic obstructive pulmonary disease; ICU: intensive care unit.
1 (Table 1).The age-specific incidence of admission to ICU was highest among infants (children under one year of age, 2.03 cases per 100,000 of the age group and lowest among those 65 years of age or older (0.18 cases/100,000 of the age group).

Table 2
Factors associated with severe disease in hospitalised 2009 pandemic influenza A(H1N1) cases (multivariate analysis), France, 1 July-15 November 2009 (n=758) AOR: Adjusted odds ratio for age and underlying condition; CI: Confidence interval.a Admitted for at least 24h in a medical ward.b Risk factors were available for 463 cases.Multiple entries per patient possible.

Table 3
Risk factors for death, among hospitalised severe adult cases of 2009 pandemic influenza A(H1N1) (multivariate analysis), France, 1 July-15 November 2009 (n=140) ICU: intensive care unit; OR aj: adjusted odds ratio; CI: confidence interval.a Multiple entries per patient possible.