Epidemiology and transmission characteristics of early COVID-19 cases, 20 January-19 March 2020, in Bavaria, Germany.

Severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) led to a significant disease burden and disruptions in health systems. We describe the epidemiology and transmission characteristics of early coronavirus disease 2019 (COVID-19) cases in Bavaria, Germany. Cases were reverse transcription polymerase chain reaction (RT-PCR)-confirmed SARS-CoV-2 infections, reported from 20 January-19 March 2020. The incubation period was estimated using travel history and date of symptom onset. To estimate the serial interval, we identified pairs of index and secondary cases. By 19 March, 3546 cases were reported. A large proportion was exposed abroad (38%), causing further local transmission. Median incubation period of 256 cases with exposure abroad was 3.8 days (95%CI: 3.5-4.2). For 95% of infected individuals, symptom onset occurred within 10.3 days (95%CI: 9.1-11.8) after exposure. The median serial interval, using 53 pairs, was 3.5 days (95%CI: 3.0-4.2; mean: 3.9, s.d.: 2.2). Travellers returning to Germany had an important influence on the spread of SARS-CoV-2 infections in Bavaria in early 2020. Especially in times of low incidence, public health agencies should identify holiday destinations, and areas with ongoing local transmission, to monitor potential importation of SARS-CoV-2 infections. Travellers returning from areas with ongoing community transmission should be advised to quarantine to prevent re-introductions of COVID-19.

Effect of vaccination on severity and infectiousness of measles during an outbreak in the Netherlands, 2013-2014.

An outbreak of measles in the Netherlands in 2013-2014 provided an opportunity to assess the effect of MMR vaccination on severity and infectiousness of measles.Measles is notifiable in the Netherlands. We used information on vaccination, hospitalisation, complications, and most likely source(s) of infection from cases notified during the outbreak. When a case was indicated as a likely source for at least one other notified case, we defined it as infectious. We estimated the age-adjusted effect of vaccination on severity and infectiousness with logistic regression.Of 2676 notified cases, 2539 (94.9%) were unvaccinated, 121 (4.5%) were once-vaccinated and 16 (0.6%) were at least twice-vaccinated; 328 (12.3%) cases were reported to have complications and 172 (6.4%) cases were hospitalised. Measles in twice-vaccinated cases led less often to complications and/or hospitalisation than measles in unvaccinated cases (0% and 14.5%, respectively, aOR 0.1 (95% CI 0-0.89), P = 0.03). Of unvaccinated, once-vaccinated and twice-vaccinated cases, respectively, 194 (7.6%), seven (5.1%) and 0 (0%) were infectious. These differences were not statistically significant (P > 0.05).Our findings suggest a protective effect of vaccination on the occurrence of complications and/or hospitalisation as a result of measles and support the WHO recommendation of a two-dose MMR vaccination schedule.

The tip of the iceberg: incompleteness of measles reporting during a large outbreak in The Netherlands in 2013-2014.

Measles is a notifiable disease, but not everyone infected seeks care, nor is every consultation reported. We estimated the completeness of reporting during a measles outbreak in The Netherlands in 2013-2014. Children below 15 years of age in a low vaccination coverage community (n = 3422) received a questionnaire to identify measles cases. Cases found in the survey were matched with the register of notifiable diseases to estimate the completeness of reporting. Second, completeness of reporting was assessed by comparing the number of susceptible individuals prior to the outbreak with the number of reported cases in the surveyed community and on a national level.We found 307 (15%) self-identified measles cases among 2077 returned questionnaires (61%), of which 27 could be matched to a case reported to the national register; completeness of reporting was 8.8%. Based on the number of susceptible individuals and number of reported cases in the surveyed community and on national level, the completeness of reporting was estimated to be 9.1% and 8.6%, respectively. Estimating the completeness of reporting gave almost identical estimates, which lends support to the credibility and validity of both approaches. The size of the 2013-2014 outbreak approximated 31 400 measles infections.

Quantifying the impact of mass vaccination programmes on notified cases in the Netherlands.

Vaccination programmes are considered a main contributor to the decline of infectious diseases over the 20th century. In recent years, the national vaccination coverage in the Netherlands has been declining, highlighting the need for continuous monitoring and evaluation of vaccination programmes. Our aim was to quantify the impact of long-standing vaccination programmes on notified cases in the Netherlands. We collected and digitised previously unavailable monthly case notifications of diphtheria, poliomyelitis, mumps and rubella in the Netherlands over the period 1919-2015. Poisson regression models accounting for seasonality, multi-year cycles, secular trends and auto-correlation were fit to pre-vaccination periods. Cases averted were calculated as the difference between observed and expected cases based on model projections. In the first 13 years of mass vaccinations, case notifications declined rapidly with 82.4% (95% credible interval (CI): 74.9-87.6) of notified cases of diphtheria averted, 92.9% (95% CI 85.0-97.2) cases of poliomyelitis, and 79.1% (95% CI 67.1-87.4) cases of mumps. Vaccination of 11-year-old girls against rubella averted 49.9% (95% CI 9.3-73.5) of cases, while universal vaccination averted 68.1% (95% CI 19.4-87.3) of cases. These findings show that vaccination programmes have contributed substantially to the reduction of infectious diseases in the Netherlands.

Public health measures to control the spread of antimicrobial resistance in Neisseria gonorrhoeae in men who have sex with men.

Gonorrhoea is one of the most common sexually transmitted infections. The control of gonorrhoea is extremely challenging because of the repeated development of resistance to the antibiotics used for its treatment. We explored different strategies to control the spread of antimicrobial resistance and prevent increases in gonorrhoea prevalence. We used a mathematical model that describes gonorrhoea transmission among men who have sex with men and distinguishes gonorrhoea strains sensitive or resistant to three antibiotics. We investigated the impact of combination therapy, switching first-line antibiotics according to resistance thresholds, and other control efforts (reduced sexual risk behaviour, increased treatment rate). Combination therapy can delay the spread of resistance better than using the 5% resistance threshold. Increased treatment rates, expected to enhance gonorrhoea control, may reduce gonorrhoea prevalence only in the short term, but could lead to more resistance and higher prevalence in the long term. Re-treatment of resistant cases with alternative antibiotics can substantially delay the spread of resistance. In conclusion, combination therapy and re-treatment of resistant cases with alternative antibiotics could be the most effective strategies to prevent increases in gonorrhoea prevalence due to antimicrobial resistance.

Exceptionally low rotavirus incidence in the Netherlands in 2013/14 in the absence of rotavirus vaccination.

An unexpected drop in rotavirus (RV) detections was observed in the Netherlands in 2014, without RV vaccination. The estimated decrease in RV detections and gastroenteritis consultations in under five year-olds, in January-April 2014, compared to the same months in previous years, was 72% and 36%, respectively. The low birth rate, mild winter, high RV incidence in the previous year and the introduction of RV vaccination in neighbouring countries may have contributed to this decrease.

The 2009 influenza A (H1N1) pandemic. Management and vaccination strategies in The Netherlands.

Prior to 2009, The Netherlands had prepared itself extensively for a potential pandemic. Multidisciplinary guidelines had been drafted to control transmission and limit adverse outcomes for both a phase of early incidental introduction and for a phase with widespread transmission. The Ministry of Health had ensured a supply and distribution schedule for antivirals and negotiated a contract for vaccine purchases. During the pandemic, existing surveillance was expanded, the established infectious disease response structure was activated, and the previously prepared protocols for communication, diagnostics, use of antivirals, and vaccination implementation were operationalized and implemented. When the pandemic turned out to be less severe than many had anticipated, risk communication and rapid modification of guidelines and communication became a major challenge. Antivirals and pandemic vaccines were reserved for those at high risk for severe outcomes only. Overall, the impact of the pandemic was comparable to the impact of an average seasonal influenza epidemic, but with a shift in (severe) outcomes from the very young and elderly toward young adults. Established prepared protocols enabled timely coordinated responses. In preparing for the worst, sufficient attention must be given to preparing for a mild scenario as well.

Unravelling transmission trees of infectious diseases by combining genetic and epidemiological data.

Knowledge on the transmission tree of an epidemic can provide valuable insights into disease dynamics. The transmission tree can be reconstructed by analysing either detailed epidemiological data (e.g. contact tracing) or, if sufficient genetic diversity accumulates over the course of the epidemic, genetic data of the pathogen. We present a likelihood-based framework to integrate these two data types, estimating probabilities of infection by taking weighted averages over the set of possible transmission trees. We test the approach by applying it to temporal, geographical and genetic data on the 241 poultry farms infected in an epidemic of avian influenza A (H7N7) in The Netherlands in 2003. We show that the combined approach estimates the transmission tree with higher correctness and resolution than analyses based on genetic or epidemiological data alone. Furthermore, the estimated tree reveals the relative infectiousness of farms of different types and sizes.

Evaluation of three enzyme immunoassays and a loop-mediated isothermal amplification test for the laboratory diagnosis of Clostridium difficile infection.

The laboratory diagnosis of Clostridium difficile infection (CDI) consists of the detection of toxigenic Clostridium difficile, and/or its toxins A or B in stool preferably in a two-step algorithm. In a prospective study, we compared the performance of three toxin enzyme immunoassays (EIAs)-ImmunoCard Toxins A & B, Premier Toxins A & B and C. diff Quik Chek Complete, which combines a toxins test and a glutamate dehydrogenase (GDH) antigen EIA in one device -and the loop-mediated isothermal amplification assay Illumigene C. difficile. In total 986 stool samples were analyzed. Compared with toxigenic culture as the gold standard, sensitivities, specificities, PPV and NPV values of the toxin EIAs were 41.1-54.8 %, 98.9-100 %, 75.0-100 % and 95.5-96.5 % respectively, of the Illumigene assay 93.3 %, 99.7 %, 95.8 % and 99.5 %. Illumigene assays performed significantly better for non-014/020 PCR-ribotypes than for C. difficile isolates belonging to 014/020. Discrepant analysis of three culture-negative, but Illumigene-positive samples, revealed the presence of toxin genes using real-time PCRs. In addition to the GDH EIA (NPV of 99.8 %), the performance of Illumigene allows this test to be introduced as a first screening test for CDI- or as a confirmation test for GDH -positive samples, although the initial invalid Illumigene result of 4.4 % is a point of concern.

[No scientific lower threshold for compulsory vaccination]. / Geen wetenschappelijke ondergrens voor verplicht vaccineren.

The national vaccination rate in young children in the Netherlands has decreased in recent years. This has led to social and political discussions, for instance about compulsory vaccination for children in child-care. The national commission on child-care and vaccination has advised that vaccination should be made compulsory when the rate of vaccination has declined to a pre-determined lower threshold, to be determined by the government. A frequently quoted lower threshold is 95%. The idea behind this is the concept of a critical vaccination rate, a threshold needed for elimination of an infection in a large, well-mixed population. In this article we argue why the critical vaccination rate does not offer a scientific basis for a lower threshold to the national vaccination rate.

Outbreak of Arcanobacterium haemolyticum in chronic wounds in The Netherlands.

INTRODUCTION: Aging and comorbidities such as diabetes and vascular problems contribute to the increasing occurrence of chronic wounds. From the beginning of 2016, a marked increase in Arcanobacterium haemolyticum (ARH) in chronic wound cultures was noted among patients visiting a wound expertise centre in The Netherlands. AIM: To report the outbreak investigation of ARH cultured from chronic wounds and describe the implemented infection prevention measures. METHODS: In total, 50 ARH isolates were sent to a reference laboratory for molecular typing. Samples for bacterial culture and ARH polymerase chain reaction were taken from care workers, the environment and items used for wound care. Infection prevention measures were implemented in a bundled approach, involving education, better aseptic wound care conditions and hygienic precautions. Before and after the implementation of infection prevention measures, two screening rounds of ARH testing were performed among all patients receiving home care. RESULTS: ARH isolates from wound care patients were found to be identical by core genome multi-locus sequence typing. No definite outbreak source could be determined by culture. However, three pairs of forceps, used by two nurses on multiple patients, were found to be ARH positive by polymerase chain reaction. In the two screening rounds before and after the implementation of infection prevention measures, the proportion of ARH-positive patients decreased significantly from 20% (20/99) to 3% (3/104). Subsequently, no new cases occurred. CONCLUSION: This first ARH outbreak was likely caused by re-using contaminated instruments. Through the implementation of improved infection prevention measures and re-education of all employees involved, the outbreak was controlled. With the current trend of care transition, infection control must be a major concern.

Epidemiology and control of influenza A(H1N1)v in the Netherlands: the first 115 cases.

Introductions of the new influenza A(H1N1) variant virus in the Netherlands led to enhanced surveillance and infection control. By 24 June 2009, 115 cases were reported, of whom 44% were indigenously acquired. Severity of disease is similar to reports elsewhere. Our point estimate of the effective reproductive number (Re) for the initial phase of the influenza A(H1N1)v epidemic in the Netherlands was below one. Given that the Re estimate is based on a small number of indigenous cases and a limited time period, it needs to be interpreted cautiously.

Measures of disassortativeness and their application to directly transmitted infections.

We propose a measure of disassortativeness to summarize contact patterns relevant to the transmission of directly transmitted infections. We discuss the properties of this measure, describe standardization relative to homogeneous mixing, and generalize it to multivariate contact structures. We explore some of its properties and apply our methods to serological surveys of close contact infections and surveys of self-reported social contacts obtained in several European countries.

Vaccinating children against influenza increases variability in epidemic size.

Seasonal influenza causes a high disease burden. Many influenza vaccination programmes target the elderly and persons at high risk of complications. Some countries have recommended or even implemented a paediatric vaccination programme. Such a programme is expected to reduce influenza transmission in the population, offering direct protection to the vaccinated children and indirect protection to the elderly. We study the impact of a child vaccination programme with an age- and risk-structured transmission model, calibrated to data of 11 influenza seasons in the Netherlands. The model tracks the build-up of immunes and susceptibles in each age cohort over time, and it allows for seasonal variation in vaccine match and antigenic drift. Different vaccination strategies are evaluated for three target age groups (2-3, 2-12 and 2-16 year olds) over the full range of vaccination coverages (0-100%). The results show that the paediatric vaccination programme has only a limited impact on the elderly age groups, which account for most influenza morbidity and mortality. This is due to two notable changes in infection dynamics. First, an age shift is observed: influenza infections are reduced in vaccinated children, but are increased in young adults with limited natural immunity after years of vaccination. These young adults assume the role of driving the epidemic. Second, a year with low influenza activity can be followed by a large epidemic due to build-up of susceptibles. This variation of the infection attack rate increases with increasing vaccination coverage. The increased variability in the infection attack rate implies that health care facilities should be prepared for rare but larger peaks in influenza patients. Moreover, vaccinating the group with the highest transmission potential, results in a larger dependency on a secure vaccine supply. These arguments should be taken into account in the decision to introduce mass vaccination of school-aged children against influenza.

S. typhi Vi capsular polysaccharide vaccine-induced humoral immunity in travellers with immunosuppressive therapy for rheumatoid disease.

INTRODUCTION: Typhoid fever is a global health problem, causing significant morbidity and mortality. Currently, the most widely used vaccine is the typhoid Vi capsular polysaccharide (Vi-PS) vaccine. While epidemiological studies on its efficacy have been performed in children in endemic countries, there are no efficacy studies evaluating its use in travel medicine. Response to vaccination may differ in travellers receiving immunosuppressive therapy. This study investigates the humoral response to Vi-PS vaccination in travellers receiving immunosuppressive therapy for rheumatoid disease. METHODS: We recruited patients from the LUMC rheumatology outpatient clinic and travellers from the travel clinic who had previously received Vi-PS vaccination and also immunosuppressive therapy for rheumatoid disease. We analysed blood samples acquired from 42 patients over a period of 3 years. We estimated the length of persistence of protective titres using the survival analysis using multiple cut-off values for protection and measured titre half-life and the influence of immunosuppressive medication on titre half-life using mixed models. RESULTS: Anti-Vi-PS antibody levels stayed above 10 EU/ml for a mean of 13.3 years, above 15 EU/ml for a mean of 10.1 years and above 20 EU/ml for a mean of 8.6 years after Vi-PS vaccination. Titre half-life was 7.5 years (95% CI 5.0-14.7 years, P < 0.001). No significant influence of medication on titre half-life was found. CONCLUSION: Both persistence of protective antibody titres and titre half-life are longer than expected based on other studies. This warrants further study in adult volunteers, both in healthy individuals and patients suffering from rheumatoid disease.

Optical bleaching front in bedrock revealed by spatially-resolved infrared photoluminescence.

Optically stimulated luminescence (OSL) dating of sediment, based on the accumulation of trapped charge in natural crystals since their last exposure to daylight, has revolutionised our understanding of the late Quaternary period. Recently, a complementary technique called luminescence rock surface dating (RSD), which uses differential spatial eviction of trapped charges in rocks exposed to daylight, has been developed to derive exposure and burial ages, and hard-rock erosion rates. In its current form, the RSD technique suffers from labour intensive sample preparation, uncertainties in the depth and dose rate estimates, and poor resolution of the luminescence-depth profile. Here, we develop a novel, 2D luminescence imaging technique for RSD of large rock slabs (3 × 5 cm) to overcome these challenges. We utilize the recently discovered infrared photoluminescence (IRPL) signal for direct, non-destructive imaging of the luminescence-depth profile in a sub-aerially exposed granitic rock, with an unprecedented spatial resolution of ~140 µm. We further establish a correlation between luminescence and geochemistry using micro X-ray fluorescence (µXRF) spectroscopy. Our study promises a substantial advancement in luminescence imaging and paves the path towards novel applications using 2D dating, micro-dosimetry in mixed composition samples, and portable instrumentation for in-situ luminescence measurements.

The impact of influenza vaccination on infection, hospitalisation and mortality in the Netherlands between 2003 and 2015.

Influenza epidemics annually cause substantial morbidity and mortality. For this reason, vaccination is offered yearly to persons with an elevated risk for complications. Assessments of the impact of vaccination are, however, hampered by year-to-year variation in epidemic size and vaccine effectiveness. We estimate the impact of the current vaccination programme comparing simulations with vaccination to counterfactual simulations without vaccination. The simulations rely on an age- and risk-structured transmission model that tracks the build-up and loss of immunity over successive seasons, and that allows the vaccine match to vary between seasons. The model parameters are estimated with a particle Monte Carlo method and approximate Bayesian computation, using epidemiological data on vaccine effectiveness and epidemic size in the Netherlands over a period of 11 years. The number of infections, hospitalisations and deaths vary greatly between years because waning of immunity and vaccine match may differ every season, which is in line with observed variation in influenza epidemic sizes. At an overall coverage of 21%, vaccination has averted on average 13% (7.2-19%, 95% range) of infections, 24% (16-36%) of hospitalisations, and 35% (16-50%) of deaths. This suggests that vaccination is mainly effective in protecting vaccinees from infection rather than reducing transmission. As the Dutch population continues to grow and age, the vaccination programme is projected (up to 2025) to gain in impact, despite a decreasing infection attack rate.

Managing invasive aspergillosis in haematological patients in the era of resistance polymerase chain reaction and increasing triazole resistance: A modelling study of different strategies.

OBJECTIVES: Triazole resistance in Aspergillus spp. is emerging and complicates prophylaxis and treatment of invasive aspergillosis (IA) worldwide. New polymerase chain reaction (PCR) tests on broncho-alveolar lavage (BAL) fluid allow for detection of triazole resistance at a genetic level, which has opened up new possibilities for targeted therapy. In the absence of clinical trials, a modelling study delivers estimates of the added value of resistance detection with PCR, and which empiric therapy would be optimal when local resistance rates are known. DESIGN: A decision-analytic modelling study was performed based on epidemiological data of IA, extended with estimated dynamics of resistance rates and treatment effectiveness. Six clinical strategies were compared that differ in use of PCR diagnostics (used vs not used) and in empiric therapeutic choice in case of unknown triazole susceptibility: voriconazole, liposomal amphotericin B (LAmB) or both. Outcome measures were proportion of correct treatment, survival and serious adverse events. RESULTS: Implementing aspergillus PCR tests was projected to result in residual treatment-susceptibility mismatches of <5% for a triazole resistance rate up to 20% (using voriconazole). Empiric LAmB outperformed voriconazole at resistance rates >5-20%, depending on PCR use and estimated survival benefits of voriconazole over LAmB. Combination therapy of voriconazole and LAmB performed best at all resistance rates, but the advantage over the other strategies should be weighed against the expected increased number of drug-related serious adverse events. The advantage of combination therapy over LAmB monotherapy became smaller at higher triazole resistance rates. CONCLUSIONS: Introduction of current aspergillus PCR tests on BAL fluid is an effective way to increase the proportion of patients that receive targeted therapy for IA. The results indicate that close monitoring of background resistance rates and adverse drug events are important to attain the potential benefits of LAmB. The choice of strategy ultimately depends on the probability of triazole resistance, the availability of PCR and individual patient characteristics.

Symptoms of influenza virus infection in hospitalized patients.

BACKGROUND: During influenza outbreaks, fever and cough are the most accurate symptoms in predicting influenza virus infection in the community. OBJECTIVE: To determine the usefulness of fever, cough, and other symptoms for diagnosing influenza virus infection in hospitalized patients. DESIGN: Prospective cohort study. SETTING: Three wards (pulmonology, internal medicine and infectious diseases, and geriatrics) of a tertiary care hospital in the Netherlands. PATIENTS: All patients staying in the wards during peak national influenza activity in the 2005-2006 and 2006-2007 influenza seasons. METHODS: During peak influenza activity, the presence of fever, cough, and/or other symptoms possibly associated with influenza was monitored for all patients, and nose and throat swab samples were taken twice weekly for virologic analysis. RESULTS: Of 264 patients, 23 (9%) tested positive for influenza virus. The positive predictive value of fever and cough for the diagnosis of influenza virus infection was 23% (95% confidence interval, 0%-62%), and the sensitivity was 35% (95% confidence interval, 11%-58%). The combination of symptoms with the highest positive predictive value (40%) was that of cough, chills, and obstructed nose or coryza. The combination of cough and chills or fever had the highest sensitivity (60%). None of the combinations of symptoms had both a positive predictive value and a sensitivity higher than 40%. CONCLUSIONS: Both the sensitivity and the positive predictive value of fever, cough, and/or other symptoms for the diagnosis of influenza virus infection in hospitalized patients are low. The use of these common symptoms for treatment decisions and infection control management will probably be insufficient to contain a nosocomial outbreak, because many influenza cases will remain unidentified.

How generation intervals shape the relationship between growth rates and reproductive numbers.

Mathematical models of transmission have become invaluable management tools in planning for the control of emerging infectious diseases. A key variable in such models is the reproductive number R. For new emerging infectious diseases, the value of the reproductive number can only be inferred indirectly from the observed exponential epidemic growth rate r. Such inference is ambiguous as several different equations exist that relate the reproductive number to the growth rate, and it is unclear which of these equations might apply to a new infection. Here, we show that these different equations differ only with respect to their assumed shape of the generation interval distribution. Therefore, the shape of the generation interval distribution determines which equation is appropriate for inferring the reproductive number from the observed growth rate. We show that by assuming all generation intervals to be equal to the mean, we obtain an upper bound to the range of possible values that the reproductive number may attain for a given growth rate. Furthermore, we show that by taking the generation interval distribution equal to the observed distribution, it is possible to obtain an empirical estimate of the reproductive number.