Screening and prevention of Tuberculosis : the impact of screening policy and practice on public health outcomes

Tuberculosis (TB) is a disease of public health importance due to the associated morbidity and mortality as well as the potential for transmission of infection to uninfected contacts. Tuberculosis can be prevented by screening of high risk groups and targeted prophylaxis with isoniazid (INH). Screening programs with structured guidelines exist for the screening of many groups at risk for TB, including refugees, contacts, health workers and prisoners, with some run by health authorities and others by employers. Screening programs for TB may focus on case finding, prevention or a combination of both, and may differ in their aims, guidelines, practice and resources. The outcomes and effectiveness of such programs may also differ, and may be influenced by a number of factors. These include the nature of screening guidelines and whether such guidelines are evidence based, the consistency between policy and practice of screening by health professionals, and external factors such as structural or political change and financial restrictions. The null hypothesis is that TB screening programs operate under evidence based guidelines, have good implementation of guidelines and have optimal outcomes. Aims To examine screening programs for contacts, refugees and prisoners in selected programs in Australia and the USA. Because of the differences in screening methods and policy outlined above, I aimed to examine the rationale of screening policies and their scientific basis, the efficacy of screening practice, whether screening guidelines are properly implemented by medical and nursing staff, what intrinsic and extrinsic problems may have hindered the implementation of guidelines, and the outcomes of screening programs as measured by the incidence of active TB and skin test conversion, and the prevention of active TB. Methods I undertook a series of separate studies in order to address the aims above. The studies are outlined below. The first chapter presents background and a general literature review, but more specific literature reviews are contained in the subsequent chapters. 1) The first study retrospectively estimates missed opportunities for prevention of TB in notified cases of active TB in Victoria, Australia. All notified cases of active TB in 1991 in Victoria (n=231) were reviewed for any past screening for TB. If such screening or indications for screening were documented, each case was evaluated as to whether appropriate preventive action was taken. Missed opportunities for prevention of TB were quantified for each case. 2) The next chapter is a retrospective cohort study of 1,142 contacts of tuberculosis screened in 1991. This cohort was screened by health authorities in Victoria, Australia, and had two years of follow up for the development of active disease. The study describes the two-year incidence of TB in recent contacts. Skin test reaction sizes were correlated with risk of developing active disease in order to provide data to select appropriate criteria for the interpretation of the test. Preventability of incident cases of TB was quantified retrospectively. 3) The third study is a detailed analysis of each step of screening and prevention in the 1,142 recent contacts described in item (2) above. This study compares recommended guidelines with actual practice. 4) The cost effectiveness of contact screening per case prevented and per case found was estimated for three different models. The first model describes cost effectiveness of contact screening as it was conducted in 1991; the second model describes cost effectiveness of contact screening had the 1991 guidelines been followed closely; and the final model describes the cost effectiveness of contact screening practised according to hypothetical, evidence-based guidelines. 5) This study is a retrospective cohort study of 1,101 Indo-Chinese refugees screened between 1989-1990 in Victoria, Australia. The study included five years of follow up for the development of active disease. Skin test reaction sizes were correlated with risk of developing active disease in order to provide data to select appropriate criteria for the interpretation of the test. Preventability of incident cases was assessed retrospectively. 6) This study is a detailed analysis of each step of screening and prevention in the 1,1 01 refugees, comparing recommended guidelines with actual practice. 7) This study is a comparison of tuberculin skin test distributions in a number of Victorian populations of varying degree of risk for TB. The skin test distributions are used to assess the sensitivity and specificity of the cut-off points used in Victoria at the time for defining a positive reaction. 8) This is a study to determine the incidence of skin test conversion during annual screening of inmates of Maryland prisons, with an analysis of the impact of TB control measures and risk factors on the incidence of skin test conversion. 9) A study of the skin test converters identified in (8) above was then conducted to determine exposure to undetected TB within the correctional system. The movements within the correctional system of skin test converters were matched with those of inmates with documented infectious TB. This was supplemented by a linkage study with the State TB registry to identify cases of active TB which may have been missed within the prison system. 1 0) In the same group, I studied implementation of screening guidelines by prison medical and nursing staff and the utilisation of INH prophylaxis. Results The study of all notified cases of active TB in 1991 identified that nearly half of all notified cases of TB have been screened for TB in the past, and yet this screening had failed to prevent the development of active TB. Over 70% of those screened were found to be at risk for TB, but rates of preventive therapy were low. Nearly 30% of cases may have been prevented. There was evidence that the guidelines for screening and prevention used in Victoria for refugees and contacts required updating. These guidelines emphasise case finding rather than identification of asymptomatic infection and prevention, and rely more on chest radiograph (CXR) screening than skin testing. In addition, the guidelines were poorly implemented . This was partly explained by devolution of TB screening programs in the 1970s and 1980s and lack of resources. In nearly 60% of contacts, the presence or absence of infection could not be determined because a skin test was not done, and a CXR, if done, was clear. The rate of preventive therapy for eligible contacts and refugees was low. The two year incidence of active pulmonary TB was 5311100,000 per year for contacts, and 110/100,000 per year for refugees. Of the incident cases, many were considered "not infected" at the time of screening because of they had received BCG vaccine in the past and had a skin test reaction of 1 0-19mm. In logistic regression models testing various skin test cut-off points, a reading of 15mm or more was the strongest predictor of the development of active TB for contacts. The use of a 20mm cut-off excludes most individuals who are at risk. The incidence of active TB increased with increasing skin test reaction size. The direct cost of contact screening as it was actually performed in 1991 was A$331,610 per case prevented, A$248,708 per case found and A$871 per contact traced. If the guidelines had been followed closely, the respective costs would have been A$81 ,892 per case prevented, A$286,621 per case found and A$1 ,004 per contact traced. In an alternative model which I propose, the costs would be A$47,358 per case prevented, A$319 ,670 per case found and A$793 per contact traced. The guidelines used in Maryland prisons, in contrast, are well supported by the literature. However, I found a poor implementation of guidelines by prison medical and nursing staff, and a low rate of preventive therapy for eligible inmates. Skin test conversions occurred at a rate of 6.3/100 person-years, and the rate of preventive therapy was lowest for this high risk group. Reasons for not giving, or prematurely ceasing INH were largely unfounded. The rate of true side effects was low. There was a wide variation in skin test conversion rates and in rates of giving INH, between different prisons and prison types. The highest risk of conversion was in the intake institution. A strong positive correlation existed between prison crowding and skin test conversion, and a strong negative correlation with rates of INH use and skin test conversion. Exposure to TB was only found for 30% of skin test converters. Linkage with the State TB registry identified cases of TB that occurred in inmates but were undiagnosed during incarceration. Discussion The lack of adherence to screening guidelines and the inadequate use of preventive therapy were problems common to all screening programs. Although under-use of preventive therapy in different settings has been reported in the literature, this is a poorly studied area. The low rates of preventive therapy and the low threshold for discontinuing it once started, suggest that confusion and fear about the use of INH may be prevalent, and that there is a need for education of providers. The guidelines used for contact and refugee screening in Victoria are not well supported by scientific rationale and exclude a large proportion of individuals who are at high risk. This was confirmed by the high incidence of active TB at follow up, and by examining the features of each incident case. It was further confirmed by finding the high rate of preventability of notified cases of active TB. I found a lack of cost effectiveness of the contact screening program, largely because intervention in the form of prevention was an unlikely outcome at the end of a sequence of screening tests. The findings also emphasise that in a low prevalence setting, case finding is an expensive exercise and should not be the main focus of screening. In the Maryland prisons, whilst the guidelines used were well founded, a wide variation was found in adherence to guidelines and in rates of preventive therapy. Evidence was also found that significant transmission ofTB may go undetected in prisons, due to high population turnover. For the Victorian contact and refugee programs, the recommendation that more sensitive skin test criteria be adopted, that age should not be considered for contacts of TB when skin testing or offering preventive therapy, that CXR screening needs to be rationalised, and that contacts of non-infectious TB need not be screened en masse, have been accepted and adopted. These data contributed to significant revision of the screening guidelines in 1994. It would be prudent to conduct a follow up study of the application and impact of these changes. In Maryland prisons, it was recommended that efforts be made to standardise preventive efforts across different prisons, and to prioritize TB control measures according to the level of risk of the prison. Crowding is not a risk factor which is readily amenable to change, but maximal use of preventive therapy can diminish that risk. Guidelines used by screening programs are variable. In the case of Victoria, there was no convincing evidence or data for the use of their screening guidelines. This study provided sound data for decision making and had a favourable impact on the revision of guidelines. This in itself is a public health exercise which proves that long standing policies should be questioned for validity, and if those policies are not supported by evidence, the collection of required evidence for change is indicated. The major problem faced by the screening programs studied, however, is not a lack of policies, but a failure to apply structured guidelines in the practice of prevention. In the case of Victoria, this is partly explained by factors extrinsic to the TB program, such the devolution of TB services in the 1970s and 1980s, and lack of adequate resources and support for TB program staff. There is, nonetheless, considerable opportunity to improve the outcome of screening, which should not be carried out unless there is a commitment to intervention that makes a positive public health impact. Screening without an end point of change in outcome is not good practice. In the case of TB, intervention in the form of INH preventive therapy is available, and as such, should be used

Association of influenza infection and vaccination with cardiac biomarkers and left ventricular ejection fraction in patients with acute myocardial infarction

Aims: The aim of this study was to examine the association of influenza infection and vaccination with extent of cardiac damage during acute myocardial infarctions (AMIs) as measured by serum biomarkers and left ventricular ejection function (LVEF) in patients. Methods: Post-hoc analysis was performed on data from a prospective case-control study of influenza and AMI, conducted in a tertiary care hospital in Sydney, Australia. We included 275 cases of AMI, aged ≥ 40 years admitted to the cardiology during the study period. Results: Mean and median CK-MB levels were significantly higher among unvaccinated group compared to vaccinated group (p value < 0.05). Troponin levels were also higher among unvaccinated group compared to vaccinated group; although not statistically significant. Troponin and CKMB values were not statistically different among influenza positive cases and influenza negative cases. Large size infarcts were less frequent among vaccinated cases compared to unvaccinated cases (25% vs 35.5%) and were more frequent among influenza positive cases compared to influenza negative cases (35.3% vs 31.5%), however differences were not statistically significant. LVEF was lower among vaccinated cases compared to unvaccinated cases (62.5% vs. 52.8%) and influenza positive cases compared to influenza negative cases (58.8% vs 55.4), however differences were not significant. Conclusion: Lower CKMB levels among vaccinated groups showed that influenza vaccine may have a protective effect against large infarcts, therefore influenza vaccination should be recommended for high risk groups. The study suggests an association of larger infarcts with influenza infection, but larger studies are required to confirm this

Mathematical assessment of the impact of non-pharmaceutical interventions on curtailing the 2019 novel Coronavirus

A novel Coronavirus pandemic emerged in December of 2019, causing devastating public health impact across the world. In the absence of a safe and effective vaccine or antiviral, strategies for mitigating the burden of the pandemic are focused on non-pharmaceutical interventions, such as social-distancing, contact-tracing, quarantine, isolation and the use of face-masks in public. We develop a new mathematical model for assessing the population-level impact of these mitigation strategies. Simulations of the model, using data relevant to COVID-19 transmission in New York state and the entire US, show that the pandemic will peak in mid and late April, respectively. The worst-case scenario projections for cumulative mortality (based on the baseline levels of anti-COVID non-pharmaceutical interventions considered in the study) in New York State and the entire US decrease dramatically by 80% and 64%, respectively, if the strict social-distancing measures implemented are maintained until the end of May or June, 2020. This study shows that early termination of strict social-distancing could trigger a devastating second wave with burden similar to that projected before the onset of strict social-distance. The use of efficacious face-masks (efficacy greater than 70%) could lead to the elimination of the pandemic if at least 70% of the residents of New York state use such masks consistently (nationwide, a compliance of at least 80% will be required using such masks). The use of low efficacy masks, such as cloth masks (of efficacy less than 30%), could also lead to significant reduction of COVID-19 burden (albeit, they are not able to lead to elimination). Combining low efficacy masks with improved levels of other anti-COVID-19 intervention measures can lead to elimination of the pandemic. The mask coverage needed to eliminate COVID-19 decreases if mask-use is combined with strict social-distancing

Modelling of optimal vaccination strategies in response to a bioterrorism associated smallpox outbreak

The reemergence of smallpox as a bioterrorism attack is now an increasing and legitimate concern. Advances in synthetic biology have now made it possible for the virus to be synthesized in a laboratory, with methods publicly available. Smallpox introduction into a susceptible population, with increased immunosuppression and an aging population, raises questions of how vaccination should be used in an epidemic situation when supply may be limited. We constructed three modified susceptible-latent-infectious-recovered (SEIR) models to simulate targeted, ring and mass vaccination in response to a smallpox outbreak in Sydney, Australia. We used age-specific distributions of susceptibility, infectivity, contact rates, and tested outputs under different assumptions. The number of doses needed of second- and third-generation vaccines are estimated, along with the total number of deaths at the end of the epidemic. We found a faster response is the key and ring vaccination of traced contacts is the most effective strategy and requires a smaller number of doses. However if public health authorities are unable to trace a high proportion of contacts, mass vaccination with at least 125,000 doses delivered per day is required. This study informs a better preparedness and response planning for vaccination in a case of a smallpox outbreak in a setting such as Sydney

Risk Factors for Tuberculosis

The risk of progression from exposure to the tuberculosis bacilli to the development of active disease is a two-stage process governed by both exogenous and endogenous risk factors. Exogenous factors play a key role in accentuating the progression from exposure to infection among which the bacillary load in the sputum and the proximity of an individual to an infectious TB case are key factors. Similarly endogenous factors lead in progression from infection to active TB disease. Along with well-established risk factors (such as human immunodeficiency virus (HIV), malnutrition, and young age), emerging variables such as diabetes, indoor air pollution, alcohol, use of immunosuppressive drugs, and tobacco smoke play a significant role at both the individual and population level. Socioeconomic and behavioral factors are also shown to increase the susceptibility to infection. Specific groups such as health care workers and indigenous population are also at an increased risk of TB infection and disease. This paper summarizes these factors along with health system issues such as the effects of delay in diagnosis of TB in the transmission of the bacilli

Comparative epidemiology of Middle East respiratory syndrome coronavirus (MERS-CoV) in Saudi Arabia and South Korea

MERS-CoV infection emerged in the Kingdom of Saudi Arabia (KSA) in 2012 and has spread to 26 countries. However, 80% of all cases have occurred in KSA. The largest outbreak outside KSA occurred in South Korea (SK) in 2015. In this report, we describe an epidemiological comparison of the two outbreaks. Data from 1299 cases in KSA (2012–2015) and 186 cases in SK (2015) were collected from publicly available resources, including FluTrackers, the World Health Organization (WHO) outbreak news and the Saudi MOH (MOH). Descriptive analysis, t-tests, Chi-square tests and binary logistic regression were conducted to compare demographic and other characteristics (comorbidity, contact history) of cases by nationality. Epidemic curves of the outbreaks were generated. The mean age of cases was 51 years in KSA and 54 years in SK. Older males (⩾70 years) were more likely to be infected or to die from MERS-CoV infection, and males exhibited increased rates of comorbidity in both countries. The epidemic pattern in KSA was more complex, with animal-to-human, human-to-human, nosocomial and unknown exposure, whereas the outbreak in SK was more clearly nosocomial. Of the 1186 MERS cases in KSA with reported risk factors, 158 (13.3%) cases were hospital associated compared with 175 (94.1%) in SK, and an increased proportion of cases with unknown exposure risk was found in KSA (710, 59.9%). In a globally connected world, travel is a risk factor for emerging infections, and health systems in all countries should implement better triage systems for potential imported cases of MERS-CoV to prevent large epidemics.Emerging Microbes & Infections (2017) 6, e51; doi:10.1038/emi.2017.40; published online 7 June 201

Monitoring the burden of COVID-19 and impact of hospital transfer policies on Australian aged-care residents in residential aged-care facilities in 2020

Abstract Background Residential aged-care facilities in Australia emerged as the high-risk setting the COVID-19 outbreaks due to community transmission. The vulnerable aged-care residents of these facilities suffered due to low hospital transfers and high mortality and morbidity rates. This study aimed to monitor and report the burden of COVID-19 in residential aged-care facilities across Australia and the impact of hospital transfer policies on resident hospitalisation during the first year of the pandemic. Methods We conducted a retrospective cohort study by collecting data from weekly aged-care outbreak reports published by open sources and official government sources between 1st March and 20th November 2020. A comprehensive line list of outbreaks was created using open-source data. The line list included the name of the facility, location, COVID-19 cases among residents, & staff, resident hospitalisations, mode of transmission, number of resident deaths, and state policies involving resident hospitalisation. We also searched the websites of these facilities to collect data on their COVID-19 policies for the residents, staff, and visitors. Statistical analyses were performed on the data obtained. Results 126 aged-care COVID-19 outbreaks were identified in Australia during the study period. The incidence rate of COVID-19 infections among aged-care residents in Australia was (1118.5 per 100,000 resident population) which is 10 times higher than the general population (107.6 per 100,000 population). The hospitalisation rate for aged-care residents in Australia was 0.93 per 100,000 population. The hospitalisation rate of aged-care residents in Victoria was 3.14 per 100,000 population despite having the highest COVID-19 cases. Excluding South Australia, all states followed ad-hoc case-by-case hospital transfer policies for aged-care residents. Conclusion This study documented a higher risk of COVID-19 infection for aged-care residents and workers but found low hospitalisation rates among residents across Australia. The hospitalisation rates in Victoria were higher than the national average but low when considering the COVID-19 infection rates in the state. The hospitalisation rates could have been impacted due to the state hospital transfer policies at that time. Immediate transfer of infected residents to hospitals may improve their survival and reduce the risk of infection to the other residents, as healthcare settings have more advanced infection control measures and are well-equipped with trained staff and resources

Adherence to anti-vectorial prevention measures among travellers with chikungunya and malaria returning to Australia: comparative epidemiology

Abstract Objective Compare the adoption and adherence to health protection behaviours prior to and during travel among international Australian travellers who return to Australia with notified chikungunya or malaria infection. This information could inform targeted health promotion and intervention strategies to limit the establishment of these diseases within Australia. Results Seeking travel advice prior to departure was moderate (46%, N = 21/46) yet compliance with a range of recommended anti-vectorial prevention measures was low among both chikungunya and malaria infected groups (16%, N = 7/45). Reasons for not seeking advice between groups was similar and included ‘previous overseas travel with no problems’ (45%, N = 9/20) and ‘no perceived risk of disease’ (20%, N = 4/20). Most chikungunya cases (65%, N = 13/20) travelled to Indonesia and a further 25% (N = 5/20) visited India, however most malaria cases (62%, N = 16/26) travelled to continental Africa with only 12% (N = 3/26) travelling to India. The majority (50%, N = 10/20) of chikungunya cases reported ‘holiday’ as their primary purpose of travel, compared to malaria cases who most frequently reported travel to visit friends and family (VFR; 42%, N = 11/26). These results provide import data that may be used to support distinct public health promotion and intervention strategies of two important vector-borne infectious diseases of concern for Australia

Effect of statin use on the risk of influenza and influenza vaccine effectiveness

Background: Some studies have shown that statins reduce the efficacy of influenza vaccine. The aim was to examine the impact of statins on influenza and influenza vaccine effectiveness (VE). Methods: This study was a post-hoc analysis of subjects in a prospective case-control study of influenza and acute myocardial infarction, where data on influenza infection, vaccination and statin use was collected. Study participants, aged ≥40 years were recruited from tertiary hospitals in Sydney from 2008 to 2010. Univariate and logistic regression analysis was performed. Results: Of total 559 participants, 276 (49.4%) had been vaccinated and 196 (35.1%) were taking statins. The rate of laboratory confirmed influenza was significantly higher in unvaccinated statin users (adjusted odds ratio (AOR), 2.44; 95% CI: 1.06–5.62) compared to unvaccinated non-users. The VE was 98% overall, and not significantly different between statin users (92.4%) and non-statin users (100%). In adjusted analysis of all subjects, vaccination was significantly protective (AOR, 0.02; 95% CI: 0.01–0.15), and statins remained significantly associated with influenza risk (AOR, 2.47; 95% CI: 1.08–5.64). Conclusion: There was no significant difference in influenza VE by statin use, and vaccine was highly effective in both statin users and non-users. There was a significantly higher risk of influenza among statin users, independent of vaccination. Statins may increase the risk of influenza through immunomodulatory mechanisms, or this may be confounded by other risk factors for influenza. It is important that people on statins should be vaccinated against influenza