Fortunato D'Ancona

Hepatitis B immune memory in children primed with hexavalent vaccines and given monovalent booster vaccines: an open-label, randomised, controlled, multicentre study

BACKGROUNDnIn 2000, hexavac and infanrix hexa were licensed in Europe for primary immunisation of children against diphtheria, tetanus, pertussis, poliomyelitis, hepatitis B, and invasive infections caused by Haemophilus influenzae b. In 2005, hexavac was suspended because of concerns about the long-term immunogenicity of its hepatitis B component. We aimed to assess the duration of immunity and need for booster injections in children primed with these vaccines.nnnMETHODSnIn an open-label, randomised, controlled, multicentre study in six local health units and at the Bambino Gesù Paediatric Research Hospital in Italy, antibody concentrations were measured 5 years after immunisation of infants with hexavac or infanrix hexa. Children with concentrations of antibodies to hepatitis B surface antigen (anti-HBs) lower than 10 mIU/mL were randomly assigned by simple randomisation to receive a booster of HBVaxPro or engerix B monovalent hepatitis B vaccine and tested 2 weeks later. Primary endpoints were the proportion of children with anti-HBs concentrations of at least 10 mIU/mL, geometric mean concentrations (GMCs) of antibody 5 years after vaccination, and the proportion of children with anti-HBs concentrations lower than 10 mIU/mL who had anamnestic response to booster. The study is registered with Agenzia Italiana del Farmaco, code FARM67NFPN.nnnFINDINGSn1543 children were enrolled, 833 had received hexavac and 710 infanrix hexa. 831 children who received hexavac and 709 who received infanrix hexa were included in the analysis. 319 children who received hexavac (38.4%, 95% CI 35.1-41.7) had anti-HBs concentrations of at least 10 mIU/mL compared with 590 who received infanrix hexa (83.2%, 80.5-86.0; p<0.0001). GMCs before booster were 4.5 mIU/mL in the hexavac group compared with 61.3 mIU/mL in the infanrix hexa group (p<0.0001). After booster 409 (92.1%, 89.6-94.6) of 444 children primed with hexavac and 99 (94.3%, 89.8-98.7) of 105 primed with infanrix hexa had anti-HBs concentrations of at least 10 mIU/mL (p=0.4); GMCs were 448.7 mIU/mL and 484.9 mIU/mL (p=0·6). The two booster vaccine groups did not differ in number of side-effects; no serious adverse events were reported.nnnINTERPRETATIONn5 years after immunisation with hexavalent vaccines, immunological memory seems to persist in children with anti-HBs concentrations lower than 10 mIU/mL, suggesting that booster doses are not needed. Additional follow-up is needed.nnnFUNDINGnAgenzia Italiana del Farmaco.

Pneumococcal disease surveillance in Europe

Pneumococcal disease (Pnc) is responsible for invasive pneumococcal disease (IPD) - mainly meningitis and septicaemia - and is an infection of public health importance in Europe. Following the licensure of an effective conjugate vaccine (PCV) in Europe, several European countries, including France, Germany, the Netherlands, Norway, Spain and the United Kingdom, are introducing universal Pnc childhood immunisation programmes. As part of a European Union (EU) funded project on pneumococcal disease (Pnc-EURO), a questionnaire was distributed in late 2003 to each of the current 25 European Union member states as well as Norway and Switzerland to get a clearer picture of national surveillance for invasive pneumococcal disease (IPD) in Europe. All respondents were contacted in 2006 and asked to provide an update to the questionnaire. Twenty two of the 27 countries targeted completed and returned the questionnaire. Four of the 22 responding countries have no reporting requirement for IPD. Eighteen countries reported a total of 27 national surveillance systems. Case definitions employed in these systems differed. Fourteen of the 18 countries reported collection of IPD strains to a single reference lab for serotyping and in 12 countries to a single laboratory for susceptibility testing. Thirteen countries undertook laboratory quality assurance. Information on age and sex were widely collected, but only 11/27 systems collected information on pneumococcal polysaccharide vaccine status, while 5/27 systems collected information on pneumococcal conjugate vaccine status. The incidence of IPD reported in each of the 18 countries ranged from 0.4 to 20/100 000 in the general population, with a total of 23 470 IPD cases reported over a 12 month period. Surveillance for IPD in Europe is very heterogeneous. Several countries lack surveillance systems. Large differences in reported disease incidence may reflect both true differences, and also variations in patient and healthcare factors, including surveillance. If IPD surveillance in Europe can be strengthened, countries will be able to make informed decisions regarding the introduction of new pneumococcal vaccines and also to monitor and compare the impact and effectiveness of new programmes.

Botulism and Preserved Green Olives

To the Editor: In March 2004, a total of 16 suspected cases of botulism were reported to the Italian National Institute of Health by hospitals in 3 adjoining regions in central and southern Italy (Molise, Campania, and Puglia). Initial investigation showed that all patients had eaten at the same restaurant in Molise on February 22 or 24, 2004. The restaurant provided reservation lists for those dates (the restaurant was closed on February 23). It also provided a list of foods that had been served each evening. Persons on the reservation lists were contacted and asked to provide the names of others who had been at their tables to ensure that as many diners as possible were traced. Of 73 persons who had been identified as having eaten at the restaurant on either evening, 66 were successfully contacted and interviewed in person or by telephone about symptoms and food consumed at the restaurant. n nFor purposes of the investigation, a probable case-patient was defined as a person who had dined at the restaurant on February 22 or 24 and had experienced diplopia or blurred vision and at least 1 of the following symptoms: dysphagia, dry mouth, dysarthria, upper/lower extremity weakness, dyspnea, and severe constipation. Those who met the probable case definition and had laboratory-confirmed botulism were considered definite case-patients. n nWe tested for botulinum neurotoxin in serum and spores in stool samples as described (1). Serum or stool specimens from 24 patients with ≥2 symptoms were sent to the Italian National Institute of Health for testing. n nTwenty-eight persons reported ≥2 symptoms (42% attack rate); 25 (89%) were considered probable cases and 3 (11%) were considered confirmed cases. Two members of the restaurant owners family and 1 employee were among the probable case-patients. Onset of symptoms occurred 4 hours to 6.5 days after eating at the restaurant (median 36 hours). Twenty persons (71%) had been seen in emergency rooms, 15 (53%) were admitted to a hospital, and 18% were admitted to intensive care. None required ventilatory support, and no deaths occurred. n nThe main symptoms reported by 28 probable and confirmed patients included dry mouth in 25 (89%), dysphagia in 25 (89%), severe constipation in 22 (79%), and blurred vision in 27 (96%). Three weeks after onset of symptoms, 15 (68%) reporting severe constipation, 11 (41%) reporting blurred vision, 10 (40%) reporting dry mouth, and 11 (44%) reporting dysphagia still had these symptoms. Of the 24 patients for whom rectal swabs were available, 3 were culture-positive for Clostridium botulinum type B. None of 5 serum samples tested positive. n nFood-specific attack rates, relative risks (RRs), and 95% confidence intervals (CIs) were calculated. A Poisson model with robust error variance was used to estimate RR with adjustments for possible confounding and effect modification (2). Foods associated with illness with p values <0.20 were considered in the model. n nIn a univariate analysis in which all 28 patients were considered, the RR of illness was higher among diners who ate home-preserved green olives in salt water (RR 5.2, 95% CI 1.4–19.8), ate cream pastries (RR 2.5, 95% CI 1.8–3.4), and drank homemade lemon liqueur (RR 2.1, 95% CI 1.3–3.4). After multivariate analysis, only the risk associated with eating green olives remained significant (RR 5.2, 95% CI 1.4–19.8). n nNone of the food items served on February 22 or 24 was available for sampling, and none of the other 13 food samples obtained from the restaurant was positive for C. botulinum. However, the pH of a jar of olives that had been prepared at the same time as those eaten on February 22 and 24 was 6.2, far above the level of 4.6 required to prevent growth of C. botulinum. No salinity testing was performed by the local laboratory, and inadequate storage during transit made it impossible to conduct salinity and water activity tests at the national reference laboratory. n nInterviews with the restaurant proprietors indicated that the olives were prepared on site during the fall of 2003 from local olives. After soaking in salt water for ≈35 days, the olives had been decanted into jars, and salt water had been replaced with fresh water. Neither the amount of salt used in the salt water mixture nor the pH at any stage was standardized during preparation. n nBoth epidemiologic evidence and information obtained regarding preparation of the olives strongly suggest that they were the likely source of the outbreak. This outbreak highlights the previously documented risk associated with improperly prepared olives (3–5). In Italy and elsewhere in Europe, an increasing trend favors traditional foods and preparation methods over large-scale industrial products. This outbreak underlines the importance of providing training and periodic monitoring of those involved in small-scale preparation to ensure that disease risks from improperly prepared or stored foods are minimized.

Incidence of malaria and risk factors in Italian travelers to malaria endemic countries

BACKGROUNDnImported malaria has been an increasing problem in Italy in the last three decades of the 1900s, representing the main risk for travelers visiting tropical and sub-tropical countries where malaria is endemic. Even though the total number of imported cases has been declining since 2000, malaria still represents the most frequent notifiable imported disease in Italy. The present study analyzes all the malaria cases reported in Italy in 2000-2006 in order to assess the trend of incidence over the time and reviewing the risk factors for travelers visiting malaria endemic countries.nnnMETHODSnAll 2000-2006 case report forms were analyzed. The incidence of malaria in Italian travelers was calculated by continent and by countries most visited, using data provided by the Ministry of Transportation.nnnRESULTSnOut of the 5219 malaria cases reported and confirmed in the study period five were autochthonous and 5214 imported, 1518 of which occurred in Italian citizen and 3696 in foreigners. Between 2000 and 2006 imported malaria cases fell from 977 to 630 respectively, with a total reduction of about 36%. Most of the cases were contracted in Africa (93%) and Plasmodium falciparum was the etiological agent in 83% of the cases, with an annual average fatality rate of about 0.5%. The average of the crude incidence rate (CIR) among Italians was calculated by continent for both global cases (gCIR) and for P. falciparum cases (pfCIR) resulting of 1.2/1000 and 0.9 for Africa, 0.08/1000 and 0.02 for Asia, 0.03/1000 and 0.003 for Central and South America, respectively. The gCIR by continent slightly but decreased constantly over the study period.nnnDISCUSSIONnThe different factors which may influence the risk of contracting malaria for travelers visiting endemic countries and the strategy to reduce completely the number of fatal cases were considered and discussed.

Emergence of Escherichia coli ST131 sub-clone H30 producing VIM-1 and KPC-3 carbapenemases, Italy

Department of Infectious, Parasitic and Immune-mediated Diseases, Istituto Superiore di Sanita, Rome, Italy; Department of Medical Biotechnologies, University of Siena, Siena, Italy; National Centre for Epidemiology, Surveillance and Health Promotion, Istituto Superiore di Sanita, Rome, Italy; Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy; Clinical Microbiology and Virology Unit, Department of Laboratory Medicine, Careggi University Hospital, Florence, Italy

The epidemiology of invasive meningococcal disease in EU/EEA countries, 2004–2014

BACKGROUNDnInvasive meningococcal disease (IMD) is a major cause of bacterial meningitis and septicaemia although infection by some serogroups may be prevented through vaccination. We aimed to describe the epidemiology of IMD in EU/EEA countries during 2004-2014 to monitor serogroup- and age-specific trends, and compare country trends by the period of meningococcal C conjugate (MCC) vaccine introduction.nnnMETHODSnWe analysed IMD surveillance data by age, gender, serogroup, country and outcome. We estimated the percentage change in annual notification rate (NR), using linear regression analysis of the log of the annual NR. We grouped countries by the year they introduced MCC vaccination into their routine immunisation programmes.nnnRESULTSnThe overall NR was 0.9/100 000 population, and decreased 6.6% (95%CI: -8.0%;-5.1%) annually. Infants had the highest NR (16.0/100 000), and there were decreasing trends in all age groups <50years. Serogroup B (SgB) caused 74% of all cases, and the majority of cases in all age groups. There were decreasing trends in SgB and serogroup C (SgC) and an increasing trend in serogroup Y. Countries that introduced MCC vaccination before, and between 2004 and 2014, had decreasing trends in NR of SgC, but not countries without routine MCC vaccination.nnnCONCLUSIONSnOur findings support evidence that routine MCC vaccination was the driving force behind the decreasing SgC trend. Vaccinating against SgB in the first year of life could help reduce the burden of IMD due to this serogroup. Changing serogroup-specific NR trends highlight the need for high-quality surveillance data to accurately assess the changing epidemiology of IMD, the effectiveness and impact of implemented vaccines, and the need for future vaccines.

Evaluation of the SIMI system, an experimental computerised network for the surveillance of communicable diseases in Italy

In Italy, the current communicable disease notification system is organised as follows: in each region, Local Health Units (LHU) fill in and forward case report forms (CRF) to the Regional Health Authority, which send aggregated and individual notifications to several central-level institutions. In most regions, all data are recorded manually on hard-copy. Although most relevant data from CRFs are eventually entered into a computerised database at the National Institute of Statistics (ISTAT), the national database is only available 3–4 years later and no data-quality control is performed at that time. To improve the quality and timeliness of notification, in 1994, the Istituto Superiore di Sanità (the National Institute of Health) began to develop an experimental computerised surveillance network for communicable diseases (referred to as ‘SIMI’). Specifically, a software was created and distributed to the LHUs and the Regional Health Authorities; staff training was performed; and feedback and analyses of collected data was promoted. SIMI was evaluated in the 13 regions that were participating in 1997 (out of a total of 20 regions in Italy), using criteria commonly used for surveillance systems (i.e., completeness and coherence of data, case definitions, costs, timeliness, and feedback). SIMI was implemented at a limited cost and the data collected were observed to have had a high degree of completeness and internal consistency. The SIMI system has since been adopted for the routine notification of communicable diseases in nearly all regions. Similar evaluations will be necessary for assessing the performance of the various notification systems used across Europe and to include them in a European network.

Hepatitis B immunisation programmes in European Union, Norway and Iceland: where we were in 2009?

In January 2009 25 European Union (EU) Member States (MSs), Norway and Iceland, participated in a survey seeking information on national hepatitis B vaccination programmes. Details of vaccination policy, schedule, population groups targeted for vaccination, programme funding, vaccine coverage and methods of monitoring of vaccine coverage were obtained. Twenty (74%) countries reported that they have a universal hepatitis B vaccination programme, in addition to immunisation of at risk groups; seven (26%) countries recommend HBV for high risk groups only (with some inter-country variation on groups considered at high risk). Among countries without universal hepatitis B vaccination programmes, the major factor for non-introduction is low disease endemicity.

National Advisory Groups and their role in immunization policy-making processes in European countries

During the twenty-first century, the development of national immunization programmes (NIP) has matured into robust processes where evidence-based methodologies and frameworks have increasingly been adopted. A key role in the decision-making and recommending processes is played by National Immunization Technical Advisory Groups (NITAGs). In a survey performed among European Union member states, Norway and Iceland, in February 2013, 85% of the 27 responding countries reported having established a NITAG, and of these, 45% have formal frameworks in place for the systematic development of vaccination recommendations. Independent of whether a formal framework is in place, common key factors are addressed by all NITAGs and also in countries without NITAGs. The four main factors addressed by all were: disease burden in the country, severity of the disease, vaccine effectiveness or efficacy, and vaccine safety at population level. Mathematical modelling and cost-effectiveness analyses are still not common tools. Differences in the relative weighting of these key factors, differences in data or assumptions on country-specific key factors, and differences in existing vaccination systems and financing, are likely to be reasons for differences in NITAG recommendations, and eventually NIPs, across Europe. Even if harmonization of NIPs is presently not a reasonable aim, systematic reviews and the development of mathematical/economic models could be performed at supranational level, thus sharing resources and easing the present work-load of NITAGs. Nevertheless, it has been argued that harmonization would ease central purchase of vaccines, thus reducing the price and increasing access to new vaccines.

Malaria epidemiological trends in Italy

Based on the official reports received from local health laboratories, an epidemiological analysis of malaria cases reported in Italy from 1989 to 1992 is presented. A total of 1,941 cases were reported, 1,287 among Italians and 654 among foreigners. The incidence of cases was on average 500 per year with a maximum in 1990. A slight, but constant decrease of incidence of malaria cases was recorded in this period among Italian citizens (−21.5%), while the incidence among foreigners increased (+80%).Plasmodium falciparum accounted for 74.2% of total infections, followed byP. vivax (19%). The highest number of cases was imported from Africa (86.5%), followed by Asia, South America, and Oceania. 11 cases were contracted in Europe (transfusion, airport and cryptic malaria). 26 people died from malaria during the four years, with a fatality rate of 2.3% among Italians. Other epidemiological features concerning incidence in the different categories of travellers, countries of infection, clinical and therapeutic aspects of cases, are also discussed.