Peter Teunis

Norwalk virus: How infectious is it?†

Noroviruses are major agents of viral gastroenteritis worldwide. The infectivity of Norwalk virus, the prototype norovirus, has been studied in susceptible human volunteers. A new variant of the hit theory model of microbial infection was developed to estimate the variation in Norwalk virus infectivity, as well as the degree of virus aggregation, consistent with independent (electron microscopic) observations. Explicit modeling of viral aggregation allows us to express virus infectivity per single infectious unit (particle). Comparison of a primary and a secondary inoculum showed that passage through a human host does not change Norwalk virus infectivity. We estimate the average probability of infection for a single Norwalk virus particle to be close to 0.5, exceeding that reported for any other virus studied to date. Infected subjects had a dose‐dependent probability of becoming ill, ranging from 0.1 (at a dose of 103 NV genomes) to 0.7 (at 108 virus genomes). A norovirus dose response model is important for understanding its transmission and essential for development of a quantitative risk model. Norwalk virus is a valuable model system to study virulence because genetic factors are known for both complete and partial protection; the latter can be quantitatively described as heterogeneity in dose response models. J. Med. Virol. 80:1468–1476, 2008.

Different Epidemic Curves for Severe Acute Respiratory Syndrome Reveal Similar Impacts of Control Measures

Abstract Severe acute respiratory syndrome (SARS) has been the first severe contagious disease to emerge in the 21st century. The available epidemic curves for SARS show marked differences between the affected regions with respect to the total number of cases and epidemic duration, even for those regions in which outbreaks started almost simultaneously and similar control measures were implemented at the same time. The authors developed a likelihood-based estimation procedure that infers the temporal pattern of effective reproduction numbers from an observed epidemic curve. Precise estimates for the effective reproduction numbers were obtained by applying this estimation procedure to available data for SARS outbreaks that occurred in Hong Kong, Vietnam, Singapore, and Canada in 2003. The effective reproduction numbers revealed that epidemics in the various affected regions were characterized by markedly similar disease transmission potentials and similar levels of effectiveness of control measures. In controlling SARS outbreaks, timely alerts have been essential: Delaying the institution of control measures by 1 week would have nearly tripled the epidemic size and would have increased the expected epidemic duration by 4 weeks.

Bordetella pertussis Strains with Increased Toxin Production Associated with Pertussis Resurgence

A more virulent strain of the disease is emerging.

Assessment of the risk of infection by Cryptosporidium or Giardia in drinking water from a surface water source

The significance of the presence in drinking water of the protozoan microparasites Cryptosporidium parvum and Giardia lamblia for public health may be analyzed by means of risk assessment. This requires quantitative knowledge of all the contributing factors, from the concentration of these organisms in the source water to the dose-response relation for the probability of infection or disease in a human host. The major contributing factors are: the concentration of cysts or occysts in raw water, the recovery of the detection method, the viability of recovered cysts or oocysts, the removal of organisms in the treatment process, and the daily consumption of unboiled tap water. To enable analysis of the uncertainty in the calculated risk of infection, each of these factors is treated as a stochastic variable, for which a suitable distribution is proposed. A frequency distribution for the probability of infection is then constructed with standard sampling techniques. This first evaluation of the calculation of the risk of infection due to exposure to Cryptosporidium oocysts and Giardia cysts via drinking water, shows that the uncertainty in the estimated removal efficiency of the treatment process dominates over uncertainities in other contributing factors.

Dose Response Models For Infectious Gastroenteritis

When pathogenic microorganisms enter the human body via ingestion with food or drinking water, they encounter a system of barriers mounted by the host. In order to reach parts of the intestinal tract that are suitable for growth and attachment, each of the barriers must be overcome successfully. The present view on infection states that at least one of the ingested pathogens must survive to start colonization. This is the basis for dose response models, used for quantitative risk assessment. In this paper, the usefulness of the Beta Poisson model for multiple barriers is corroborated. Infection is associated with the presence of elevated numbers of reproducing pathogens in the intestinal tract. This does not necessarily imply illness symptoms: when intestinal microorganisms engage in damaging activities, this may lead to illness symptoms. At the same time, these activities probably elicit defensive measures from the host, promoting the removal of pathogens and terminating infection. The duration of the period of colonization reflects the balance between the colonization potential of pathogens and the strength of host defenses. Starting from the assumption that during infection the host has a certain hazard of becoming ill, a simple dose response relation for acute gastroenteritis is developed. With the use of literature data from volunteer experiments, we show that examples can be found for three possible alternatives: an increase in the probability of illness with increasing dose, a decrease with higher doses, and a probability of illness (given infection) independent of the ingested dose. These alternatives may reflect different modes of interaction between pathogens and host.

Assessment of the dose-response relationship of Campylobacter jejuni

Mathematical relations describing the risk of infection after exposure to enteropathogens are important tools for the evaluation of the potential health risk from exposure via food and water. A quantitative description of the dose-response relation for Campylobacter jejuni with the Beta-Poisson model was fitted to experimental data of infection with Campylobacter jejuni (as determined by shedding of C. jejuni) obtained in human feeding studies performed by Black et al. (1988). The maximum likelihood estimates for the Beta-Poisson model parameters based on these data are: alpha = 0.145 and beta = 7.59. The fit of the model on the experimental data was good: the difference between the likelihood obtained with the Beta-Poisson model and the maximum possible likelihood was not significant. The occurrence of symptoms of intestinal illness did not follow a similar dose-related trend. Overall, 22% of the infected volunteers developed symptoms (diarrhea, fever). The highest illness-to-infection ratio was found at an intermediate dose (9 x 10(4)). The dose-response relation and the illness-to-infection ratio appeared to differ between different C. jejuni isolates. The dose-response relation derived from feeding studies with a single isolate should therefore be considered indicative. The absence of experimental data in the low dose range resulted in a relatively large confidence interval at low doses. However, in cases where the dose-response relation has been applied so far to estimate the health risk of exposure to C. jejuni in water, the uncertainty in the dose-response relation was insignificant compared to the uncertainty in the exposure estimate.

A reconsideration of the Campylobacter dose-response relation.

As a major foodborne pathogen, Campylobacter jejuni receives much attention in quantitative risk assessment. To date, all dose-response assessments have been based on a single human feeding study which unfortunately provides incomplete and possibly biased information on the dose-response relation. An incident at a dairy farm, where several children from a school class became ill as a result of drinking raw milk contaminated with C. jejuni, appeared to show a very clear dose-response relation between the amount of milk consumed and the attack rate. This relation was very nearly exponentially shaped and, therefore, seemed to conflict with the rather slowly rising dose-response relation established in the feeding study. Here we show that both datasets can be reconciled when illness and infection are considered separately. This not only provides new information on the illness dose-response relation for Campylobacter, but also amends the infection dose-response relation because of their conditional dependence.

Incidence and Reproduction Numbers of Pertussis: Estimates from Serological and Social Contact Data in Five European Countries

Analyses of serological and social contact data from several European countries by Miriam Kretzschmar and colleagues show that vaccination against pertussis has shifted the burden of infection from children to adolescents and adults.

Hierarchical dose response of E. coli O157:H7 from human outbreaks incorporating heterogeneity in exposure

The infectivity of pathogenic microorganisms is a key factor in the transmission of an infectious disease in a susceptible population. Microbial infectivity is generally estimated from dose-response studies in human volunteers. This can only be done with mildly pathogenic organisms. Here a hierarchical Beta-Poisson dose-response model is developed utilizing data from human outbreaks. On the lowest level each outbreak is modelled separately and these are then combined at a second level to produce a group dose-response relation. The distribution of foodborne pathogens often shows strong heterogeneity and this is incorporated by introducing an additional parameter to the dose-response model, accounting for the degree of overdispersion relative to Poisson distribution. It was found that heterogeneity considerably influences the shape of the dose-response relationship and increases uncertainty in predicted risk. This uncertainty is greater than previously reported surrogate and outbreak models using a single level of analysis. Monte Carlo parameter samples (alpha, beta of the Beta-Poisson model) can be readily incorporated in risk assessment models built using tools such as S-plus and @ Risk.

Long-Term Inactivation Study of Three Enteroviruses in Artificial Surface and Groundwaters, Using PCR and Cell Culture

ABSTRACT Since the transmission of pathogenic viruses via water is indistinguishable from the transmission via other routes and since the levels in drinking water, although significant for health, may be too low for detection, quantitative viral risk assessment is a useful tool for assessing disease risk due to consumption of drinking water. Quantitative viral risk assessment requires information concerning the ability of viruses detected in drinking water to infect their host. To obtain insight into the infectivity of viruses in relation to the presence of virus genomes, inactivation of three different enteroviruses in artificial ground and surface waters under different controlled pH, temperature, and salt conditions was studied by using both PCR and cell culture over time. In salt-peptone medium, the estimated ratio of RNA genomes to infectious poliovirus 1 in freshly prepared suspensions was about 100. At 4°C this ratio was 103 after 600 days, and at 22°C it was 104 after 200 days. For poliovirus 1 and 2 the RNA/infectious virus ratio was higher in artificial groundwater than in artificial surface water, but this was not the case for coxsackievirus B4. When molecular detection is used for virus enumeration, it is important that the fraction of infectious virus (based on all virus genomes detected) decays with time, especially at temperatures near 22°C.