Epidemiological studies on tuberculosis control and respiratory viruses
Sloot, R.
Publication date
2015
Document Version
Final published version
Link to publication
Citation for published version (APA):
Sloot, R. (2015). Epidemiological studies on tuberculosis control and respiratory viruses.
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Chapter
1
Introduction
Introduction
Tuberculosis epidemiology
Tuberculosis (TB) is a major global health problem; it is the second leading cause of death from an infectious agent worldwide, after the human immunodeficiency virus (HIV). The World Health Organization (WHO) estimated that there were 8.6 million new TB cases in 2012 (1). The global burden of TB is fuelled by high rates of HIV/AIDS; 1.1 million (13%) of the people who developed TB in 2012 were HIV positive; 75% of these HIV-positive TB cases were in the African Region. Out of the 1.3 million estimated deaths due to TB, 320,000 (25%) deaths were among HIV-infected people (1).
Since the start of national recording of TB cases in the Netherlands in 1951, the incidence of TB has steadily declined. In 2001-2005 the TB incidence declined 4% annually to 7.1 per 100,000 (2). Reported rates in 2013 were 5.1 per 100,000 population. Among 848 TB patients in 2013 were 74% foreign-born, of which the largest group were of Somalian origin (147/848, 17%) (3). Although the Netherlands is among the countries with the lowest TB incidence worldwide, it has not yet reached the elimination target, defined as less than 1 sputum smear-positive patient per 1,000,000 inhabitants (4). It is expected that, under the current conditions, elimination in the Netherlands will not be reached in the coming decades, mainly because TB incidence among the first generation immigrants will remain high (5).
TB is more common in the largest cities (>250,000 inhabitants) in the Netherlands than in smaller towns or villages. In 2011, the TB incidence in the urban areas Amsterdam, The Hague, Rotterdam and Utrecht was on average 3 times higher (14.1/100,000) than in rural areas (4.7/100,000) (6). In 2013, the highest rate was recorded in Amsterdam (13.3/100,000), and the majority of cases were among foreign-born (79%) (7).
Tuberculosis – transmission, infection and disease
M. tuberculosis is carried in airborne particles, called droplet nuclei. Aerosol droplets
containing M. tuberculosis bacilli are generated when individuals with pulmonary TB cough, sneeze, talk or otherwise exhale (8). In poorly ventilated environments the bacilli can be kept airborne for prolonged periods of time, resulting in dispersion throughout a room. The presence of acid-fast bacilli in the sputum smear is the
Introduction
1
main indicator of potential for transmission and the probability of transmission is increased by the presence of lung cavitation on the chest radiograph. In addition to the infectiousness of the source case, also proximity, frequency and length of exposure can affect transmission of M. tuberculosis.
Infection occurs when an individual inhales droplet nuclei containing M. tuberculosis bacilli that reach the alveoli of the lungs. These bacilli are ingested by alveolar macrophages and dendritic cells and, if not destroyed or inhibited, spread through the lymphatic system or bloodstream to more distant tissues and organs (9) (10). Infection with M. tuberculosis infrequently progresses directly to active disease and is more often contained by the host immune response. The resulting latent infection can be eradicated, or can persist in a dormant state for prolonged periods (latent TB infection). In this state, the immune system prevents active replication but fails to eradicate the bacteria. Any subsequent weakening of the host immune system may result in reactivation of dormant bacilli, causing clinically active disease many years after the infection (reactivation TB) (11). The risk of progression to disease declines steeply with time since infection. About 50%-80% of the individuals who develop TB are believed to do so shortly after infection. When individuals develop active TB more than 2-5 years after infection this is called reactivation (12) (13) (14). Co-infection with HIV and M. tuberculosis is the most important risk factor for both immediate and reactivation TB; the risk of progression to disease for co-infected individuals is 5%-10% each year (15) (16), while in those without HIV co-infection the lifetime risk is believed to be 10% or less.
Molecular fingerprinting as tool for investigating transmission
M. tuberculosis strains recently derived from a common ancestor generally exhibit
an identical DNA fingerprinting pattern. The finding of individuals with identical or highly similar fingerprint patterns suggests epidemiological links between such cases and form a cluster. It is therefore assumed that the proportion of clustered isolates in a population reflects the amount of recent or ongoing transmission of M.
tuberculosis (17). Non-matching, i.e. unique DNA fingerprint patterns, are attributed
to reactivation of infections acquired in the past or recent transmission from patients outside the observed period or geographical area covered by the study (18). In addition to quantification of recent transmission in a population, molecular epidemiological studies have identified risk factors for transmission by comparing characteristics of
clustered and unique patients (19) (20). Knowledge of such risk factors may help to develop strategies to interrupt transmission in high-risk populations. Risk factors identified in molecular epidemiological studies include: male sex, younger age, not being an immigrant, HIV-coinfection, homelessness, injecting drug use and alcohol abuse (21).
In the Netherlands, IS6110 restriction fragment length polymorphism (RFLP) typing has been applied routinely to all M. tuberculosis complex isolates from 1993 until the end of 2008 (22). The analysis of the complex IS6110 RFLP banding patterns is technically demanding, difficult to interpret and unreliable for typing strains with low (<6) IS6110 copy numbers (23). In 2006, 24-locus variable number of tandem repeat (VNTR) typing has gained recognition as the new gold standard for typing of
M. tuberculosis (24) and has been used in the Netherlands since 2008.
Tuberculosis control
In low TB incidence countries (<20 notifications per 100,000 population), which includes most countries in the European Union, TB is concentrated in big cities among risk groups, including immigrants, homeless people and those with drug- or alcohol abuse (25). In contrast to TB control in high-TB burden countries, focussed on the detection and treatment of all TB patients, most low-incidence countries are confronted with very specific challenges as a result of the declining disease incidence in the native population and the increasing relative importance of TB among the immigrant population (26). TB control activities in low-incidence countries include ensuring early detection and treatment of TB patients, reducing the incidence of TB infection by risk group management, prevention of transmission of infection in institutional settings, reducing the incidence of TB through outbreak management, and provision of preventive treatment for specific groups (26).
Diagnosis and treatment
Diagnosis of active TB relies on microscopic examination, chest radiograph and growth of M. tuberculosis on a culture plate or in liquid medium, which are usually performed when individuals are suspected to have pulmonary TB based on clinical symptoms. In the Netherlands, liquid assays, such as Mycobacteria Growth Indicator Tube (MGIT) techniques, are recommended in addition to culture plates, due to the reduced time to detection in liquid medium than in solid medium (27). The most
Introduction
1
common symptoms for pulmonary TB include weight loss, cough, fever, night sweats, haemoptysis and breathlessness (28).
The tuberculin skin test (TST), introduced in 1890, is the oldest test to diagnose latent TB infection. The TST measures the in vivo cell-mediated immune response to a cocktail of M. tuberculosis antigens, known as purified protein derivative (PPD). If the transverse diameter of the resulting induration is 10 mm or more, measured 48 to 72 hours after injection of PPD, this is considered a positive TST result. PPD shares many antigens with
M. bovis Bacille de Calmette et Guérin (BCG), and several non-tuberculous mycobacteria
(NTM). As a result, the TST has a low specificity in individuals from low- and middle income countries with a high prevalence of infection with NTM, or high coverage of BCG vaccination. Responses to BCG generally last for only a few years after vaccination, so these effects are thought to be of limited influence among immigrants from countries with high BCG coverage (29). The sensitivity of the TST may be low in individuals with depressed immunity such as AIDS or malnutrition. In the last decade more specific tests such as cell-mediated immunity-based interferon-gamma (IFN-γ) release assays (IGRAs) have been developed and include M. tuberculosis specific antigens (ESAT-6 and CFP-10) (30). T-cells of individuals infected with M. tuberculosis produce IFN-γ when they are stimulated in vitro by these M. tuberculosis specific antigens.
Both the IGRA and the TST cannot differentiate between recent or old TB infection, nor between latent TB infection and active TB. Furthermore, both tests are unable to predict which latently infected individuals are at risk for progression to TB; which is a major drawback since the risk to develop active TB in latently infected is small and there may be adverse effects of preventive LTBI treatment. Thus, until such predictive tests become available, the risk of not receiving treatment versus the risk of receiving treatment must be weighed for each individual before deciding on whether to start preventive LTBI treatment (31).
Preventive treatment for LTBI generally consists of six months isoniazid, but LTBI can also be treated with 4 months rifampicin or 3 months isoniazid and rifampicin. Treatment for TB requires daily administration for two months of isoniazid, rifampicin, ethambutol and pyrazinamide, followed by four months of isoniazid and rifampicin. This schedule can be adapted to the drug sensitivity of the strain but treatment of multidrug-resistant TB (resistant to at least isoniazid and rifampicin) is more extensive, less effective and more expensive (32).
Source- and contact investigations in the Netherlands
Source- and contact investigation among infectious pulmonary TB patients is an essential component of TB control in most low-incidence countries. The objectives are reducing transmission and morbidity through early detection and adequate treatment of (secondary) source cases, and by reducing incidence through prompt initiation of preventive treatment among recently infected contacts (33). National guidelines recommend the initiation of a contact investigation for each patient with pulmonary TB, to be performed by public health nurses of the Public Health Services (PHSs) under supervision of a TB specialist. Contacts are prioritized for screening based on a risk assessment, which investigates the infectiousness of the index patient, degree of exposure to the index as determined by duration and intensity of exposure, and risk of progression to TB among infected contacts (33) (34). Subsequently contacts are evaluated according to the stone-in-the-pond principle were screening for TB and/or LTBI starts among the high priority contacts and expands to less prioritized contacts until the infection prevalence resembles the background prevalence of infection in the community, or until all identified contacts have been screened (35). Since the introduction of the IGRA, national guidelines recommend that contacts should be screened according to a two-step strategy in which the IGRA is used to confirm a positive TST result (36).
Respiratory viruses
Acute respiratory tract infections (ARTIs) are a leading cause of morbidity. It is estimated that in the Netherlands, based on a population of 16.9 million individuals, about 920,000 persons annually visit their general practitioner for an ARTI (37). A viral cause of respiratory illness is identifiable in up to 95% of the paediatric cases, but the detection rates decrease steadily by age, to 30-40% in the elderly (38). More than 50% of ARTIs are caused by rhinoviruses and coronaviruses (39). Human rhinoviruses are the most common respiratory pathogens in all ages (>50%), and coronaviruses are estimated to account for 7–26% of all upper respiratory tract infections in adults (38, 39). Influenza viruses account for 5–15% of ARTIs and typically cause mid-winter epidemics. The typical respiratory symptoms (cough, fever and sore throat), however, are poorly associated with confirmed influenza illnesses in older adults (39, 40). Etiologic diagnosis solely based on symptoms is impossible because respiratory viral infections are characterized by a wide range of similar respiratory symptoms including cough, sneezing, fever, myalgia and malaise (41). The recent introduction of
Introduction
1
multiplex reverse transcription polymerase chain reaction (RT-PCR)-based methods has greatly improved the diagnostics for respiratory viral infections (42). However, due to its high sensitivity, the clinical interpretation of a positive result is often difficult. PCR detection of viral nucleic acids in asymptomatic individuals is common, which has raised concerns about establishing a causal link between viral infection and respiratory symptoms in individual patients, especially during high prevalence seasons (43). Furthermore, studies on the burden of viral respiratory infections in critically ill patients give conflicting results regarding the associations between the presence of a viral respiratory tract infection and the clinical outcome (44) (45). Understanding the etiologies and clinical profiles of respiratory viral infections are essential for improving preventive and therapeutic strategies. Most etiological studies have focused on patients presenting in health care settings with respiratory illness. Studies including the general population could provide information on the background prevalence of respiratory infections and thereby contribute to our understanding of the clinical interpretation of a positive PCR in patients with respiratory illness who are seeking healthcare.
Outline of the thesis
The general aim of this thesis was to study the epidemiology of TB and respiratory viruses in the Netherlands, which resulted in the following research questions:
1. Is 24-locus VNTR typing suitable to identify recent transmission between TB cases?
2. What is the impact of source- and contact investigation in Amsterdam regarding TB prevention?
3. Can biomarkers be identified that predict which individuals will progress to TB within a high TB risk population?
4. Could viral load estimations aid in the diagnostic interpretation of respiratory viruses detected in the upper airways by multiplex RT-PCR? The first research question is addressed in chapter 2: it describes the population
structure of 3,776 M. tuberculosis isolates from native Dutch and foreign-born TB cases, collected in the period 2004-2008 in the Netherlands, and assesses to what extent clustering based on VNTR typing represents recent transmission. The second research question is addressed by identifying opportunities for improvement of contact
investigation in chapter 3, and by investigating the potential impact of preventive TB treatment among contacts of pulmonary patients in chapter 4. In chapter 3 the success
of TB contact investigations in Amsterdam is evaluated by investigating compliance to national guidelines and by determining its coverage and yield between 2008-2011. Chapter 4 estimates the risk of TB among latently infected contacts according
to initiation of preventive treatment in a low-incidence, high-income setting, using 10 years of follow-up data. The third research question is addressed in chapter 5. We
retrospectively selected blood samples of HIV-infected drug users and compared gene expression profiles in samples of drug users months before clinical TB diagnosis with gene expression in samples of drug users who did not develop TB.
To address the fourth research question, we compared the prevalence, relative distribution and viral load of respiratory viruses among adult populations by approximated illness severity, based on symptom status and health care use. In
chapter 6 we investigated nasopharyngeal samples, collected during the influenza
seasons of 2011-2013, among a random sample of participants in an adult population-based cohort study and compared results to those obtained during the same period from adult patients presenting at or admitted to various departments of a hospital serving the geographical area of the cohort study population.
Chapter 7 provides a general discussion of the findings and their implications in the
context of the literature, and gives some recommendations for TB control in low-incidence high-income settings.
Introduction
1
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