Ole Wichmann

Atypical Chikungunya virus infections: clinical manifestations, mortality and risk factors for severe disease during the 2005-2006 outbreak on Réunion.

In April 2005, an outbreak of Chikungunya fever occurred on the island of Réunion in the Indian Ocean. During winter 2005, six patients developed meningoencephalitis and acute hepatitis due to Chikungunya virus. Our objectives were to determine the incidence and mortality of atypical Chikungunya viral infections and to identify risk factors for severe disease. A hospital-based surveillance system was established to collect data on atypical Chikungunya cases. Case reports, medical records and laboratory results were reviewed and analysed. We defined an atypical case as one in which a patient with laboratory-confirmed Chikungunya virus infection developed symptoms other than fever and arthralgia. We defined a severe atypical case as one which required maintenance of at least one vital function. We recorded 610 atypical cases of Chikungunya fever: 222 were severe cases, 65 affected patients died. Five hundred and forty-six cases had underlying medical conditions (of which 226 suffered from cardiovascular, 147 from neurological and 150 from respiratory disorders). Clinical features that had never been associated with Chikungunya fever were recorded, such as bullous dermatosis, pneumonia, and diabetes mellitus. Hypertension, and underlying respiratory or cardiological conditions were independent risk factors for disease severity. The overall mortality rate was 10.6% and it increased with age. This is the first time that severe cases and deaths due to Chikungunya fever have been documented. The information presented in this article may assist clinicians in identifying the disease, selecting the treatment strategy, and anticipating the course of illness.

Phylogenetic and case-control study on hepatitis E virus infection in Germany.

BACKGROUND Hepatitis E is a classic water-borne disease in developing countries. In Germany, hepatitis E virus (HEV) infections are notifiable. The number of non-travel-associated infections has increased in recent years, but the route of transmission in most is unknown. Our objective was to determine risk factors for autochthonous HEV infections in Germany. METHODS Cases of HEV met clinical definitions and were confirmed by laboratory analysis (defined as detection of HEV by polymerase chain reaction [PCR] or immunoglobulin M by serologic testing). PCR products from blood or stool samples were genotyped for phylogenetic analysis. A case-control study included case subjects with autochthonous HEV infection and matched control subjects who were randomly recruited from a population-based telephone list. RESULTS From May 2006 through August 2007, 76 of 96 persons for whom HEV infection had been reported to the routine surveillance system were interviewed. Sixty-six persons had disease that fulfilled the inclusion criteria: 45 (68%) had autochthonous infection, and 21 (32%) had travel-associated disease. Genotypes 3 or 4 were present in 15 of 15 persons with autochthonous infection, and genotype 1 was present in 8 of 9 persons with travel-associated infection. In conditional logistic regression involving 45 case subjects and 135 control subjects, consumption of offal (41% vs. 19%; odds ratio [OR], 2.7; 95% confidence interval [CI], 1.2-6.2) and wild-boar meat (20% vs. 7%; OR, 4.3; 95% CI, 1.2-15.9) were independently associated with autochthonous HEV infection. CONCLUSION Hepatitis E is endemic in Germany and likely exists as a food-borne zoonosis. Implicated meat products should be investigated to provide recommendations for preventive measures.

Neurological complications of dengue virus infection

Dengue is the second most common mosquito-borne disease affecting human beings. In 2009, WHO endorsed new guidelines that, for the first time, consider neurological manifestations in the clinical case classification for severe dengue. Dengue can manifest with a wide range of neurological features, which have been noted--depending on the clinical setting--in 0·5-21% of patients with dengue admitted to hospital. Furthermore, dengue was identified in 4-47% of admissions with encephalitis-like illness in endemic areas. Neurological complications can be categorised into dengue encephalopathy (eg, caused by hepatic failure or metabolic disorders), encephalitis (caused by direct virus invasion), neuromuscular complications (eg, Guillain-Barré syndrome or transient muscle dysfunctions), and neuro-ophthalmic involvement. However, overlap of these categories is possible. In endemic countries and after travel to these regions, dengue should be considered in patients presenting with fever and acute neurological manifestations.

Transmission routes and risk factors for autochthonous hepatitis E virus infection in Europe: a systematic review

Increasing numbers of non-travel-associated hepatitis E virus (HEV) infections have been reported in Europe in recent years. Our objective was to review the evidence on risk factors and transmission routes of autochthonous HEV infection and hepatitis E in Europe in order to develop recommendations for future research, prevention and control. A systematic literature review was performed to identify all primary reports and studies published during 1998-2008 on hepatitis E in humans and animals in Europe by searching Pubmed, reference lists of major articles and international conference proceedings. Each of the 106 included studies was categorized into one of three evidence levels (EL) based on study design and diagnostic methodology. The evidence was generally weak (73 were assigned to EL1, two to both EL1 and EL2, and 30 to EL2), further compounded by the use of poorly validated serological assays in some studies. Only one case-control study was assigned to EL3. Persons with autochthonous hepatitis E infection were on average older than the general population and predominantly male. There was no evidence for one main transmission route of HEV infection or risk factor for hepatitis E. However, zoonotic transmission seemed likely and person-to-person transmission too inefficient to cause clinical disease. Multiple routes of transmission probably exist and should be further investigated through analytical studies and reliable diagnostic kits. Based on current evidence that points to zoonotic transmission from pigs, thorough cooking of all porcine products, prevention of cross-contamination in the kitchen and improved education for occupationally exposed people (e.g. pig farmers, veterinarians and sewage workers) may help prevent HEV infection. Although evidence for parenteral transmission is limited, it is recommended that a risk assessment is undertaken.

Severe Dengue Virus Infection in Travelers: Risk Factors and Laboratory Indicators

BACKGROUND Dengue fever is the most common arboviral disease in travelers. In countries where dengue virus is endemic, sequential (secondary) infections with different dengue virus serotypes are associated with disease severity. Data on severity and secondary infection rates in a population of travelers are lacking. METHODS Intensified surveillance of dengue fever in travelers was performed within the European Network on Surveillance of Imported Infectious Diseases. Data were collected at 14 European clinical referral centers between 2003 and 2005. RESULTS A total of 219 dengue virus infections imported from various regions of endemicity were reported. Serological analysis revealed a secondary immune response in 17%. Spontaneous bleeding was observed in 17 (8%) patients and was associated with increased serum alanine and aspartate aminotransferase levels and lower median platelet counts. Two (0.9%) patients fulfilled the World Health Organization (WHO) case definition for dengue hemorrhagic fever. However, 23 (11%) travelers had severe clinical manifestations (internal hemorrhage, plasma leakage, shock, or marked thrombocytopenia). A secondary immune response was significantly associated with both spontaneous bleeding and other severe clinical manifestations. CONCLUSIONS In travelers, severe dengue virus infections are not uncommon but may be missed if the WHO classification is strictly applied. High liver enzyme levels and low platelet counts could serve as indicators of disease severity.

Health Economics of Dengue: A Systematic Literature Review and Expert Panel's Assessment

Dengue vaccines are currently in development and policymakers need appropriate economic studies to determine their potential financial and public health impact. We searched five databases (PubMed, EMBASE, LILAC, EconLit, and WHOLIS) to identify health economics studies of dengue. Forty-three manuscripts were identified that provided primary data: 32 report economic burden of dengue and nine are comparative economic analyses assessing various interventions. The remaining two were a willingness-to-pay study and a policymaker survey. An expert panel reviewed the existing dengue economic literature and recommended future research to fill information gaps. Although dengue is an important vector-borne disease, the economic literature is relatively sparse and results have often been conflicting because of use of inconsistent assumptions. Health economic research specific to dengue is urgently needed to ensure informed decision making on the various options for controlling and preventing this disease.

Pandemic influenza A(H1N1) 2009 breakthrough infections and estimates of vaccine effectiveness in Germany 2009-2010.

During the 2009 influenza pandemic, a monovalent AS03-adjuvanted vaccine was almost exclusively used in Germany for immunisation against the 2009 pandemic influenza A(H1N1) virus. One-dose vaccination was recommended for all age groups. We applied the screening method for the rapid assessment of vaccine effectiveness (VE) based on reported data of vaccinated and unvaccinated pandemic influenza cases and vaccination coverage estimates. Preliminary results demonstrate excellent VE in persons aged 14-59 years (96.8%; 95% confidence interval (CI): 95.2-97.9) and moderately high VE in those 60 years or older (83.3%; 95% CI: 71.0-90.5).

Communicable Diseases Prioritized for Surveillance and Epidemiological Research: Results of a Standardized Prioritization Procedure in Germany, 2011

Introduction To establish strategic priorities for the German national public health institute (RKI) and guide the institutes mid-term strategic decisions, we prioritized infectious pathogens in accordance with their importance for national surveillance and epidemiological research. Methods We used the Delphi process with internal (RKI) and external experts and a metric-consensus approach to score pathogens according to ten three-tiered criteria. Additional experts were invited to weight each criterion, leading to the calculation of a median weight by which each score was multiplied. We ranked the pathogens according to the total weighted score and divided them into four priority groups. Results 127 pathogens were scored. Eighty-six experts participated in the weighting; “Case fatality rate” was rated as the most important criterion. Twenty-six pathogens were ranked in the highest priority group; among those were pathogens with internationally recognised importance (e.g., Human Immunodeficiency Virus, Mycobacterium tuberculosis, Influenza virus, Hepatitis C virus, Neisseria meningitides), pathogens frequently causing large outbreaks (e.g., Campylobacter spp.), and nosocomial pathogens associated with antimicrobial resistance. Other pathogens in the highest priority group included Helicobacter pylori, Respiratory Syncytial Virus, Varicella zoster virus and Hantavirus. Discussion While several pathogens from the highest priority group already have a high profile in national and international health policy documents, high scores for other pathogens (e.g., Helicobacter pylori, Respiratory syncytial virus or Hantavirus) indicate a possible under-recognised importance within the current German public health framework. A process to strengthen respective surveillance systems and research has been started. The prioritization methodology has worked well; its modular structure makes it potentially useful for other settings.

Further efforts needed to achieve measles elimination in Germany: results of an outbreak investigation

OBJECTIVE To determine morbidity and costs related to a large measles outbreak in Germany and to identify ways to improve the countrys national measles elimination strategy. METHODS We investigated a large outbreak of measles in the federal state of North Rhine-Westphalia (NRW) that occurred in 2006 after 2 years of low measles incidence (< 1 case per 100,000). WHOs clinical case definition was used, and surveillance data from 2006 and 2001 were compared. All cases notified in Duisburg, the most severely affected city, were contacted and interviewed or sent a questionnaire. Health-care provider costs were calculated using information on complications, hospitalization and physician consultations. FINDINGS In NRW, 1749 cases were notified over a 48-week period. Compared with 2001, the distribution of cases shifted to older age groups (especially the 10-14 year group). Most cases (n = 614) occurred in Duisburg. Of these, 81% were interviewed; 15% were hospitalized and two died. Of the 464 for whom information was available, 80% were reported as unvaccinated. Common reasons for non-vaccination were parents either forgetting (36%) or rejecting (28%) vaccination. The average cost per measles case was estimated at 373 euros. CONCLUSION An accumulation of non-immune individuals led to this outbreak. The shift in age distribution has implications for the effectiveness of measles control and the elimination strategy in place. Immediate nationwide school-based catch-up vaccination campaigns targeting older age groups are needed to close critical immunity gaps. Otherwise, the elimination of measles in Germany and thus in Europe by 2010 will not be feasible.

Dengue incidence in urban and rural Cambodia: results from population-based active fever surveillance, 2006-2008.

Background Dengue vaccines are now in late-stage development, and evaluation and robust estimates of dengue disease burden are needed to facilitate further development and introduction. In Cambodia, the national dengue case-definition only allows reporting of children less than 16 years of age, and little is known about dengue burden in rural areas and among older persons. To estimate the true burden of dengue in the largest province of Cambodia, Kampong Cham, we conducted community-based active dengue fever surveillance among the 0-to-19–year age group in rural villages and urban areas during 2006–2008. Methods and Findings Active surveillance for febrile illness was conducted in 32 villages and 10 urban areas by mothers trained to use digital thermometers combined with weekly home visits to identify persons with fever. An investigation team visited families with febrile persons to obtain informed consent for participation in the follow-up study, which included collection of personal data and blood specimens. Dengue-related febrile illness was defined using molecular and serological testing of paired acute and convalescent blood samples. Over the three years of surveillance, 6,121 fever episodes were identified with 736 laboratory-confirmed dengue virus (DENV) infections for incidences of 13.4–57.8/1,000 person-seasons. Average incidence was highest among children less than 7 years of age (41.1/1,000 person-seasons) and lowest among the 16-to-19–year age group (11.3/1,000 person-seasons). The distribution of dengue was highly focal, with incidence rates in villages and urban areas ranging from 1.5–211.5/1,000 person-seasons (median 36.5). During a DENV-3 outbreak in 2007, rural areas were affected more than urban areas (incidence 71 vs. 17/1,000 person-seasons, p<0.001). Conclusion The large-scale active surveillance study for dengue fever in Cambodia found a higher disease incidence than reported to the national surveillance system, particularly in preschool children and that disease incidence was high in both rural and urban areas. It also confirmed the previously observed focal nature of dengue virus transmission.