Studies needed to address public health challenges of the 2009 H1N1 influenza pandemic: insights from modeling.

In light of the 2009 influenza pandemic and potential future pandemics, Maria Van Kerkhove and colleagues anticipate six public health challenges and the data needed to support sound public health decision making.

A simple, valid, numerical score for grading chest x-ray severity in adult smear-positive pulmonary tuberculosis.

BACKGROUND: The grading of radiological severity in clinical trials in tuberculosis (TB) remains unstandardised. The aim of this study was to generate and validate a numerical score for grading chest x-ray (CXR) severity and predicting response to treatment in adults with smear-positive pulmonary TB. METHODS: At a TB clinic in Papua, Indonesia, serial CXRs were performed at diagnosis, 2 and 6 months in 115 adults with smear-positive pulmonary TB. Radiographic findings predictive of 2-month sputum microscopy status were used to generate a score. The validity of the score was then assessed in a second data set of 139 comparable adults with TB, recruited 4 years later at the same site. Relationships between the CXR score and other measures of TB severity were examined. RESULTS: The estimated proportion of lung affected and presence of cavitation, but not cavity size or other radiological findings, significantly predicted outcome and were combined to derive a score given by percentage of lung affected plus 40 if cavitation was present. As well as predicting 2-month outcome, scores were significantly associated with sputum smear grade at diagnosis (p<0.001), body mass index, lung function, haemoglobin, exercise tolerance and quality of life (p<0.02 for each). In the validation data set, baseline CXR score predicted 2-month smear status significantly more accurately than did the proportion of lung affected alone. In both data sets, CXR scores decreased over time (p<0.001). CONCLUSION: This simple, validated method for grading CXR severity in adults with smear-positive pulmonary TB correlates with baseline clinical and microbiological severity and response to treatment, and is suitable for use in clinical trials.

Age-specific risk factors for sporadic Campylobacter infection in regional Australia.

In a case-control study in the Hunter region of New South Wales, Australia, 354 cases and 593 controls were recruited to investigate meat, other food, and environmental exposures as potential risk factors for domestically acquired Campylobacter illness. In a multivariable model, illness was significantly associated with household exposure to diarrheal illness, consumption of restaurant chicken or beef, eating two or more "fast" food meals in a week, and overseas travel. Comparing exposures for the 0- to 4-year and 5-year and older age groups allowed detection of additional risk factors. Eating restaurant-prepared red meat and swimming were significantly associated with Campylobacter illness in the older group only. These findings demonstrate age-specific differences in risk factors for campylobacteriosis.

The role of health care workers and antiviral drugs in the control of pandemic influenza.

Until a vaccine against the new strain becomes available, the response to newly emerged pandemic influenza will consist of the use of antiviral drugs and measures that limit exposure to infectious individuals. These first-line defence measures include isolating cases upon diagnosis, reducing close contacts, the use of personal protective equipment and hygiene, and using antiviral drugs for treatment and prophylaxis. There are significant 'costs' associated with control measures, so to justify such interventions it is important to assess their potential to reduce transmission. In this paper, we determine the effect that a number of different antiviral interventions have on the reproduction number of infectives and the probability that an imported infection fades out, and determine parameter scenarios for which these interventions are able to eliminate an emerging pandemic of influenza. We also assess the role that health care workers play in transmission and the extent to which providing them with antiviral prophylaxis and personal protective equipment modifies this role. Our results indicate that this class requires protection to avoid a greatly disproportionate contribution to early infective numbers, and for the maintenance of a stable health care system. Further, we show that the role children play in increasing transmission is moderate, in spite of closer mixing with other children.

Low-level fluoroquinolone resistance among Campylobacter jejuni isolates in Australia.

BACKGROUND: Ciprofloxacin-resistant Campylobacter jejuni isolates obtained from infected patients in Australia have not been detected in studies of isolates from specific geographic areas. The Australian government has prohibited the use of fluoroquinolone in food-producing animals. To assess the impact of this policy, we have examined the antimicrobial susceptibility of isolates from 5 Australian states. METHODS: We conducted a period-prevalence survey of the susceptibility of C. jejuni isolates to 10 antimicrobial agents. C. jejuni isolates obtained from 585 patients from 5 Australian states (Queensland, South Australia, Tasmania, Victoria, and Western Australia) were identified by means of notifiable disease databases and were systematically selected from September 2001 to August 2002. RESULTS: Among locally acquired infections, only 2% of isolates (range, 0%-8% in different states) were resistant to ciprofloxacin. The locally acquired isolates also exhibited resistance to sulfisoxazole (55%), ampicillin (46%), roxithromycin (38%), tetracycline (7%), nalidixic acid (6%), chloramphenicol (3%), erythromycin (3%), gentamicin (2%), and kanamycin (0.2%). Treatment with antimicrobial agents in the 4 weeks before onset was not associated with ciprofloxacin resistance. CONCLUSIONS: The very low level of ciprofloxacin resistance in C. jejuni isolates likely reflects the success of Australia's policy of restricting use of fluoroquinolones in food-producing animals.

Population-based detection of systolic and diastolic dysfunction with amino-terminal pro-B-type natriuretic peptide.

BACKGROUND: There is limited information regarding the clinical utility of amino-terminal pro-B-type natriuretic peptide (NT-proBNP) for the detection of left ventricular (LV) dysfunction in the community. We evaluated predictors of circulating NT-proBNP levels and determined the utility of NT-proBNP to detect systolic and diastolic LV dysfunction in older adults. METHODS: A population-based sample of 1229 older adults (mean age 69.4 years, 50.1% women) underwent echocardiographic assessment of cardiac structure and function and measurement of circulating NT-proBNP levels. RESULTS: Predictors of NT-proBNP included age, female sex, body mass index, and cardiorenal parameters (diastolic dysfunction [DD] severity; LV mass and left atrial volume; right ventricular overload; decreasing ejection fraction [EF] and creatinine clearance). The performance of NT-proBNP to detect any degree of LV dysfunction, including mild DD, was poor (area under the curve 0.56-0.66). In contrast, the performance of NT-proBNP for the detection of EF < or = 40% and moderate-severe DD was strong with area under the curve of > 0.90 regardless of age and sex; history of hypertension, diabetes, coronary artery disease; or body mass category. The ability of NT-proBNP to detect EF < or = 40% and/or moderate-severe DD was optimized by using age/sex-specific limits. Of "false-positive" tests, 88% (124/141) were explained after considering cardiorenal determinants of NT-proBNP levels. CONCLUSIONS: Amino-terminal pro-B-type natriuretic peptide is a suboptimal marker of mild LV dysfunction, but performs strongly as a marker of EF < or = 40% and/or moderate-severe DD in the community. Most subjects with a positive NT-proBNP test, using age/sex-specific cutoffs, had prognostically significant abnormalities of cardiac structure or function.

Air travel and the risk of deep vein thrombosis.

BACKGROUND: The magnitude of the risk of venous thromboembolism (VTE) following air travel has been difficult to resolve due to a lack of adequate data. We determine the association more precisely by using a large dataset and an improved method of analysis. METHOD: Data on air-travel history for each of 5,196 patients hospitalised for VTE in Western Australia from 1981 to 1999 is analysed using a log-linear regression model for the probability that a flight triggers VTE and for the baseline hazard rate for VTE hospitalisation. RESULTS: The risk of VTE being triggered on the day of an international flight relative to a flight-free day is 29.8 (95% CI 22.4-37.3). Evidence that this relative risk depends on age is weak (p = 0.06), but the absolute risk clearly depends on age. The annual relative risk for an individual taking one international flight, compared with an individual of the same age taking no flight, is estimated to be 1.079. The estimated median time from flight to hospital admission is 4.7 days (95% CI 3.8-5.6) and the estimated 95th percentile is 13.3 (95% CI 10.3-16.8). CONCLUSIONS: Evidence for an association between international air travel and VTE hospitalisation is strong and passengers should be advised on ways to minimise risk during long flights. While 29.8 is a large relative risk, it must be remembered that the baseline risk is very small and the relative risk applies only to the unobserved triggering of a deep vein thrombosis episode on the day of travel; the consequent hospitalisation occurs on one of numerous ensuing days.

Control of transmission with two types of infection.

The effectiveness of a vaccination strategy to control transmission of an infectious disease depends on the way vaccine doses are distributed to individuals in a community of households. Here we show that this dependence is more complicated when acquisition and severity of illness are determined by the size of the infecting dose, as is thought to be the case for measles and varicella. Two alternative formulations for the way vaccination changes an individual's susceptibility and infectivity show that vaccination coverage, the nature of the vaccine response and the distribution of household size also have a big impact on which strategy is more effective. These judgements are made by comparing the post-vaccination reproduction numbers corresponding to different vaccination strategies.

Monitoring measles elimination in Victoria.

OBJECTIVES: To weigh the evidence from outbreak data that Victoria has achieved, and is maintaining, elimination of measles. To identify age groups that measles vaccination has not protected adequately. METHODS: Data on observed measles outbreaks in Victoria since the start of 1998 are used to estimate the reproduction number of cases, and the probability that it is maintained below unity, its threshold value for elimination. The relative susceptibility to measles is estimated as a function of age, with confidence intervals. RESULTS: Seventeen measles introductions led to secondary cases, while 22 were single-case introductions. From these, the probability that the reproduction number for cases exceeds unity is estimated to be 0.044, or less, depending on assumptions made. There is no evidence that the reproduction number increased over time. Those aged between 19 and 32 years were most susceptible, followed by those in the first and second year of life. CONCLUSIONS: The data provide strong evidence that Victoria has maintained elimination of measles over the period 1998 to mid-2003. There is scope to improve the immunisation coverage. It is not clear how much outbreak intervention is contributing to the success in achieving apparent elimination. IMPLICATIONS: To prevent importations from causing a major epidemic of measles, Victoria must maintain its immunisation coverage and outbreak control at current levels, or better. It is important to monitor the control of measles even when elimination is achieved.

Controlling emerging infectious diseases like SARS.

To control emerging infectious diseases like SARS, it is necessary to resort to basic control measures that limit exposures to infectious individuals. These measures include isolating cases at diagnosis, quarantining household members and tracing contacts of diagnosed cases, providing the community with advice on how to reduce exposures, and closing schools. To justify such intervention it is important to understand how well each of these measures helps to limit transmission. In this paper, we determine the effect of a number of different interventions on the effective reproduction number and estimate requirements to achieve elimination of the infectious disease. We find that the strategy of tracing and quarantining contacts of diagnosed cases can be very successful in reducing transmission.

Can antiviral drugs contain pandemic influenza transmission?

Antiviral drugs dispensed during the 2009 influenza pandemic generally failed to contain transmission. This poses the question of whether preparedness for a future pandemic should include plans to use antiviral drugs to mitigate transmission.Simulations using a standard transmission model that allows for infected arrivals and delayed vaccination show that attempts to contain transmission require relatively few antiviral doses. In contrast, persistent use of antiviral drugs when the reproduction number remains above 1 use very many doses and are unlikely to reduce the eventual attack rate appreciably unless the stockpile is very large. A second model, in which the community has a household structure, shows that the effectiveness of a strategy of dispensing antiviral drugs to infected households decreases rapidly with time delays in dispensing the antivirals. Using characteristics of past pandemics it is estimated that at least 80% of primary household cases must present upon show of symptoms to have a chance of containing transmission by dispensing antiviral drugs to households. To determine data needs, household outbreaks were simulated with 50% receiving antiviral drugs early and 50% receiving antiviral drugs late. A test to compare the size of household outbreaks indicates that at least 100-200 household outbreaks need to be monitored to find evidence that antiviral drugs can mitigate transmission of the newly emerged virus.Use of antiviral drugs in an early attempt to contain transmission should be part of preparedness plans for a future influenza pandemic. Data on the incidence of the first 350 cases and the eventual attack rates of the first 200 hundred household outbreaks should be used to estimate the initial reproduction number R and the effectiveness of antiviral drugs to mitigate transmission. Use of antiviral drugs to mitigate general transmission should cease if these estimates indicate that containment of transmission is unlikely.

Estimating antiviral effectiveness against pandemic influenza using household data.

Current estimates of antiviral effectiveness for influenza are based on the existing strains of the virus. Should a pandemic strain emerge, strain-specific estimates will be required as early as possible to ensure that antiviral stockpiles are used optimally and to compare the benefits of using antivirals as prophylaxis or to treat cases. We present a method to measure antiviral effectiveness using early pandemic data on household outbreak sizes, including households that are provided with antivirals for prophylaxis and those provided with antivirals for treatment only. We can assess whether antiviral drugs have a significant impact on susceptibility or on infectivity with the data from approximately 200 to 500 households with a primary case. Fewer households will suffice if the data can be collected before case numbers become high, and estimates are more precise if the study includes data from prophylaxed households and households where no antivirals are provided. Rates of asymptomatic infection and the level of transmissibility of the virus do not affect the accuracy of these estimates greatly, but the pattern of infectivity in the individual strongly influences the estimate of the effect of antivirals on infectivity. An accurate characterization of the infectiousness profile--informed by strain-specific data--is essential for measuring antiviral effectiveness.

The waiting time for inter-country spread of pandemic influenza.

BACKGROUND: The time delay between the start of an influenza pandemic and its subsequent initiation in other countries is highly relevant to preparedness planning. We quantify the distribution of this random time in terms of the separate components of this delay, and assess how the delay may be extended by non-pharmaceutical interventions. METHODS AND FINDINGS: The model constructed for this time delay accounts for: (i) epidemic growth in the source region, (ii) the delay until an infected individual from the source region seeks to travel to an at-risk country, (iii) the chance that infected travelers are detected by screening at exit and entry borders, (iv) the possibility of in-flight transmission, (v) the chance that an infected arrival might not initiate an epidemic, and (vi) the delay until infection in the at-risk country gathers momentum. Efforts that reduce the disease reproduction number in the source region below two and severe travel restrictions are most effective for delaying a local epidemic, and under favourable circumstances, could add several months to the delay. On the other hand, the model predicts that border screening for symptomatic infection, wearing a protective mask during travel, promoting early presentation of cases arising among arriving passengers and moderate reduction in travel volumes increase the delay only by a matter of days or weeks. Elevated in-flight transmission reduces the delay only minimally. CONCLUSIONS: The delay until an epidemic of pandemic strain influenza is imported into an at-risk country is largely determined by the course of the epidemic in the source region and the number of travelers attempting to enter the at-risk country, and is little affected by non-pharmaceutical interventions targeting these travelers. Short of preventing international travel altogether, eradicating a nascent pandemic in the source region appears to be the only reliable method of preventing country-to-country spread of a pandemic strain of influenza.

An analysis for a cross-over cohort study with an application to the study of triggers of Menière's disease.

When studying the effect of a transient exposure on the risk of a rare illness, for time and cost effectiveness it is desirable to follow a cohort of individuals who are 'prone' to the illness over an observation period. In this paper, we present a method of analysis for data arising from such a study. The proposed method can be used to estimate the relative risk of an exposure triggering the illness and the distribution of the time delay from exposure to the onset of illness. The model is extended to include covariate effects and to the situation where there are two types of exposure. For the two types of exposures situation, a model to handle a possible synergism of the exposures is proposed. Finally, the method is applied to study the potential triggers of attacks of Menière's disease.

Analysis of a potential trigger of an acute illness.

Sometimes certain short-term risk exposures are postulated to act as a trigger for the onset of a specific acute illness. When the incidence of the illness is low it is desirable to investigate this possible association using only data on cases detected during a specific observation period. Here we propose an analysis for such a study based on a model expressed in terms of the probability that the exposure triggers the illness and a random delay from a triggered illness until its diagnosis. Both the natural hazard rate for the illness and the probability that the exposure triggers the illness are assumed to be small and possibly dependent on age and covariates such as sex and duration or severity of the exposure. The method of analysis is illustrated with a study of the association between long flights and hospitalization for venous thromboembolism.

Estimating vaccine effects from studies of outbreaks in household pairs.

The traditional way to measure efficacy of a vaccine, with respect to reduced susceptibility and reduced infectivity once infected, is to look at relative attack rates. Although straightforward to apply, such measures do not take disease transmission into account, with the consequence that they can depend strongly on the community setting, the duration of the study period, the way participants are recruited into the study and the virulence of the infection. Sometimes they give a very misleading assessment of the vaccine, as we illustrate by examples. Here measures of vaccine efficacy are considered that avoid these defects, and estimation procedures are presented for studies based on outbreaks in household pairs. Such studies enable estimation of vaccine effects on susceptibility, infectivity and transmission. We propose that the vaccine efficacy measures be estimated, without making any assumptions about the nature of the vaccine response, by consistent estimates of bounds for the measures.

Prevalence of heart failure and systolic ventricular dysfunction in older Australians: the Canberra Heart Study.

OBJECTIVE: To estimate the prevalence of heart failure (HF) and left ventricular (LV) systolic dysfunction in a population-based sample of older Australians. DESIGN, SETTING AND PARTICIPANTS: A cross-sectional survey of 2000 randomly selected residents of Canberra, aged 60-86 years, conducted between February 2002 and June 2003. Participants were assessed by history, physical examination by a cardiologist, and echocardiography. MAIN OUTCOME MEASURES: Age- and sex-specific prevalence rates of clinical HF and LV systolic dysfunction (defined as LV ejection fraction < or = 50%). RESULTS: Of 1846 people eligible for our study, 1388 (75%) agreed to participate and 1275 completed all investigations (mean age, 69.4 years; 50% men). In the study sample, 72 subjects (5.6%; 95% CI, 4.4%-7.1%) had clinical HF that had been previously diagnosed and was confirmed by our assessment. A further 0.6% (95% CI, 0.3%-1.2%) had undiagnosed clinical HF (ie, evidence of structural heart disease and symptoms/signs of cardiac insufficiency without a previous diagnosis of clinical HF). Thus, the overall prevalence of clinical HF in the sample was 6.3% (95% CI, 5.0%-7.7%). Clinical HF increased in prevalence with advancing age (a 4.4-fold increase from the 60-64-years age group to the 80-86-years age group; P < 0.0001). Of the 75 subjects (5.9%; 95% CI, 4.7%-7.3%) with LV systolic dysfunction, 44 (59%) were in the preclinical stage of disease. CONCLUSION: Diagnosed HF cases represent the "tip of the iceberg" for the national burden of HF and LV systolic dysfunction. Clinically identifiable HF cases can remain undiagnosed, and the majority of people with LV systolic dysfunction are in a preclinical stage of the disease.

Spatial dynamics of an epidemic of severe acute respiratory syndrome in an urban area.

OBJECTIVE: To map risk of exposure to severe acute respiratory syndrome (SARS) in an urban area and assess the ability of traditional interventions to control dispersion of the disease. METHODS: Data on the Beijing SARS epidemic were used to map spatial clusters of identified contacts and to estimate transmission of SARS using a model with a time-dependent transmission rate. RESULTS: The estimated transmission rate decreased dramatically from 20 to 30 April 2003. The total number of cases in the epidemic in Beijing was estimated to be 2521. Hierarchical clustering revealed that risk-exposures were widespread, but clustered in a pattern that is distinctly related to the Beijing urban ring roads. CONCLUSION: Traditional control measures can be very effective at reducing transmission of SARS. Spatial patterns of risk-exposures can inform disease surveillance, prediction and control by identifying spatial target areas on which interventions should be focused.

The effect of transient exposures on the risk of an acute illness with low hazard rate.

There are many situations where intermittent short-term exposures of a certain kind are thought to temporarily enhance the risk of onset of an adverse health event (illness). When the hazard rate of the illness is small it is desirable to investigate this possible association using only data on cases occurring in a finite observation period. Here we extend a method for such an analysis by allowing the baseline hazard for the illness to depend on the increasing age over the observation period and using age at the times of exposure, a time dependent variable, as a covariate in the effect of the transient exposure. The method is illustrated with a study of the possible association of long-haul air travel and hospitalization for venous thromboembolism over an observation period of 19 years. It is demonstrated that allowing for aging over the observation period can avoid bias in the estimated effect size when the baseline hazard for the illness increases with age and exposures occur irregularly over time.

Estimating vaccine effects on transmission of infection from household outbreak data.

This article is concerned with a method for making inferences about various measures of vaccine efficacy. These measures describe reductions in susceptibility and in the potential to transmit infection. The method uses data on household outbreaks; it is based on a model that allows for transmission of infection both from within a household and from the outside. The use of household data is motivated by the hope that these are informative about vaccine-induced reduction of the potential to transmit infection, as household outbreaks contain some information about the possible source of infection. For illustration, the method is applied to observed data on household outbreaks of smallpox. These data are of the form needed and the number of households is of a size that can be managed in a vaccine trial. It is found that vaccine effects, such as the mean reduction in susceptibility and the mean reduction in the potential to infect others, per infectious contact, can be estimated with precision. However, a more specific parameter reflecting the reduction in infectivity for individuals partially responding to vaccination is not estimated well in the application. An evaluation of the method using artificial data shows that this parameter can be estimated with greater precision when we have outbreak data on a large number of small households.