What We Know About Tuberculosis Transmission: An Overview

Abstract Tuberculosis remains a global health problem with an enormous burden of disease, estimated at 10.4 million new cases in 2015. To stop the tuberculosis epidemic, it is critical that we interrupt tuberculosis transmission. Further, the interventions required to interrupt tuberculosis transmission must be targeted to high-risk groups and settings. A simple cascade for tuberculosis transmission has been proposed in which (1) a source case of tuberculosis (2) generates infectious particles (3) that survive in the air and (4) are inhaled by a susceptible individual (5) who may become infected and (6) then has the potential to develop tuberculosis. Interventions that target these events will interrupt tuberculosis transmission and accelerate the decline in tuberculosis incidence and mortality. The purpose of this article is to provide a high-level overview of what is known about tuberculosis transmission, using the tuberculosis transmission cascade as a framework, and to set the scene for the articles in this series, which address specific aspects of tuberculosis transmission.

Tuberculosis remains a global health problem with an enormous burden of disease, estimated at 10.4 million new cases in 2015.
To stop the tuberculosis epidemic, it is critical that we interrupt tuberculosis transmission. Further, the interventions required to interrupt tuberculosis transmission must be targeted to high-risk groups and settings. A simple cascade for tuberculosis transmission has been proposed in which (1) a source case of tuberculosis (2) generates infectious particles (3) that survive in the air and (4) are inhaled by a susceptible individual (5) who may become infected and (6) then has the potential to develop tuberculosis. Interventions that target these events will interrupt tuberculosis transmission and accelerate the decline in tuberculosis incidence and mortality. The purpose of this article is to provide a high-level overview of what is known about tuberculosis transmission, using the tuberculosis transmission cascade as a framework, and to set the scene for the articles in this series, which address specific aspects of tuberculosis transmission.
Tuberculosis remains a global health problem with an enormous burden of disease, estimated at 10.4 million new cases in 2015, of which 10% were among children and 12% involved human immunodeficiency virus (HIV) coinfection [1]. In 2015, there were an estimated 1.8 million deaths due to tuberculosis, including HIV-associated tuberculosis deaths, making tuberculosis the leading cause of death from an infectious disease [1]. Latent Mycobacterium tuberculosis infection is the reservoir of the tuberculosis epidemic. The global burden of M. tuberculosis infection has recently been reestimated at 24% [2]. The global rate of decline in tuberculosis incidence is currently 1.5% and will need to increase to 4%-5% by 2020 and then to 10% per year by 2025 to meet the World Health Organization End TB Strategy targets ( Figure 1) [3]. Interrupting tuberculosis transmission is central to achieving the reductions in tuberculosis incidence required to meet the End TB targets. A rate of decline of 10% per year is thought to be achievable, as this was observed during the 1950s and 1960s in Western Europe, where comprehensive tuberculosis control efforts, which included infection control and treatment of M. tuberculosis infection and all forms of tuberculosis, were intensified and universal health coverage and socioeconomic development were expanded [1]. Specific examples include declines in tuberculosis mortality and incidence observed after the second world war in England, Wales, and the Netherlands, where improved socioeconomic conditions and better nutrition and living standards were thought to be major factors contributing to improved tuberculosis control [4]. Tuberculosis case notifications among children <5 years of age declined in New York and London but not in Cape Town over the century between 1912 and 2012 despite similar, contemporaneous tuberculosis control strategies, which included the introduction of chemotherapy in the mid-1950s. This observation suggests that socioeconomic development played a greater role than the introduction of chemotherapy in reducing tuberculosis transmission [5]. Mathematical modeling suggests that it is possible to rapidly reduce tuberculosis incidence and mortality in high-burden countries, including those with a high HIV prevalence, if a comprehensive strategy of combination treatment and prevention is implemented at scale, rapidly [6]. Modeling further suggests that development of new drugs, diagnostic assays, and vaccines will be essential to accelerate progress toward tuberculosis elimination [7]. We have a unique opportunity in the era of the United Nations Sustainable Development Goals to address poverty and other social determinants of tuberculosis while simultaneously scaling up currently available effective tuberculosis control interventions to interrupt tuberculosis transmission and thereby maximize impact on reducing tuberculosis incidence and mortality. In addition, we should continue to conduct research to optimize delivery of effective interventions, as well as develop new tools that can maximize interrupting tuberculosis transmission.
In March 2016, the National Institutes of Health convened a workshop aimed at identifying the research needs for halting tuberculosis transmission, with the eventual aim of reducing new M. tuberculosis infections to zero. The purpose of this article is to give a high-level overview of the discussion at the workshop regarding what is known about tuberculosis transmission and to set the scene for the articles that address specific aspects of tuberculosis transmission. The lessons learned from studying tuberculosis transmission are also relevant to reducing transmission of other airborne pathogens.

EPIDEMIOLOGY OF TUBERCULOSIS TRANSMISSION: A BRIEF HISTORY
Robert Koch discovered M. tuberculosis in 1882. William Osler, in 1909, wrote that "all who mix with tuberculosis patients got infected, but remained well so long as they took care of themselves and kept the soil in a condition unfavorable for the growth of the seed" [8]. Over the intervening century of tuberculosis research, our understanding of tuberculosis transmission and disease progression has improved: in 1920, Devoto recognized that healthcare workers were at risk of developing tuberculosis; in 1934, Wells described the falling and evaporation times for droplet nuclei [9]; and Riley, in 1961, described the deposition of airborne bacteria in the lung [10] and, in 1960-1962, described aerial dissemination of M. tuberculosis in a tuberculosis ward [11,12]. Chapman, in 1964, described the social and other factors associated with tuberculosis transmission in tuberculosis-affected households [13].
More recent achievements (circa mid-2000s) in this area include the phylogeographical classification of global M. tuberculosis strains and the advent of whole-genome sequencing for molecular tracking of tuberculosis outbreaks.

TUBERCULOSIS TRANSMISSION CASCADE
In this series, a simple cascade for tuberculosis transmission is proposed in which (1) a source case of tuberculosis (2) generates infectious particles (3) that survive in the air and (4) are inhaled by a susceptible individual (5) who may become infected and (6) who then has the potential to develop tuberculosis. Interventions that target bacterial, host, or behavioral catalysts of transmission will interrupt tuberculosis transmission and accelerate the decline in tuberculosis incidence and mortality [14]. In this article, this cascade of tuberculosis transmission will be used to describe who is transmitting, where transmission is occurring, and who is susceptible to infection and to disease progression. In answering these questions, we can understand what it will take to stop tuberculosis transmission ( Figure 2).

WHO IS TRANSMITTING?
The infectiousness and duration thereof for a person with tuberculosis depend on host and bacterial factors. Persons with smear-positive pulmonary tuberculosis are highly infectious, and the degree of infectiousness is thought to increase with the degree of smear positivity. In a large study of household contacts in Peru, smear-positive index cases were associated with a higher risk of infection among household contacts, compared with smear-negative index cases, regardless of the age of the household contacts [15]. Persons with smear-negative tuberculosis cases may, however, also transmit tuberculosis [16]. Nevertheless, scale-up of sputum smear microscopy has not succeeded in achieving dramatic declines in tuberculosis incidence. Possible reasons for the lack of impact include the poor sensitivity of smear microscopy, particularly among HIV-infected persons and children, and the occurrence of many cases of transmission before people receive a tuberculosis diagnosis and treatment.  coughing, singing, shouting, sneezing, or any other forceful expiratory maneuver that shears respiratory secretions from the airways, with coughing being the most efficient at generating infectious aerosols [16]. Appropriate treatment of individuals with infectious tuberculosis results in a rapid reduction in infectiousness [17]. Individuals with index tuberculosis cases who are HIV infected, particularly those with advanced immunosuppression, were hypothesized to be less likely than HIV-uninfected individuals with tuberculosis to transmit to household contacts, possibly because of a greater likelihood of having smear-negative tuberculosis and a shorter duration of infectiousness due to more rapid progression to death [18,19]. Antiretroviral therapy reduces the risk of tuberculosis among people with HIV infection (PLHIV) by 67% and, if scaled up, may contribute to a reduction in tuberculosis case rates at a population level [20,21]. Although there is preferential mixing of close contacts within age groups and sexes, in Southern Africa most M. tuberculosis infections appear to be associated with contact with adult men [22].

WHERE IS TRANSMISSION OCCURRING?
Robert Koch, in his Nobel Lecture, delivered in 1905, said that "tuberculosis has been called plainly, and quite justly, a disease of accommodation" [23], highlighting transmission of tuberculosis within tuberculosis-affected households. Today there is a wealth of evidence to support transmission of drug-susceptible and drug-resistant tuberculosis in households [15,24,25]. Transmission of tuberculosis to household contacts is most likely to occur when the index case is smear positive and the household contacts are <15 years of age [15,26]. Despite a historical focus on household transmission, the overall proportion of tuberculosis transmissions that occur in households is estimated to be between 8% and 19% in countries with a high HIV prevalence, such as South Africa and Malawi [27]. In settings with a high tuberculosis burden, tuberculosis transmission is therefore more likely to occur outside the household, in schools, public transportation settings, workplaces, healthcare facilities, mines, and prisons [19,[26][27][28][29][30][31][32][33]. Nevertheless, targeting tuberculosis-affected households for tuberculosis screening, HIV testing, and referral for treatment of tuberculosis or M. tuberculosis infection remains a priority because of the high prevalence of tuberculosis and M. tuberculosis infection among household contacts. Transmission within hospitals and clinics can be reduced by using the FAST approach: Finding undiagnosed tuberculosis cases Actively through cough surveillance and use of rapid molecular diagnostics, Separating safely, and providing appropriate Treatment [34]. Geographic areas with increased tuberculosis transmission (so-called hot spots) may be identified using Step 1: Source case Individual with active tuberculosis Step 5: Infection, with potential to progress to disease Step 2: Aerosolization Release of viable airborne bacilli Step 4: Exposure and inhalation Contact: nature, duration, intensity, locations Step 3: Airborne survival Characteristics and factors associated with survival of Mycobacterium tuberculosis in air geospatial mapping, and interventions targeted to these areas may help to interrupt transmission [25]. In a country with a low tuberculosis burden, such as the United States, targeting active, community-based screening and isoniazid preventive therapy to 2 relatively high-burden neighborhoods was effective in eliminating tuberculosis in the intervention neighborhoods [35].

WHO IS SUSCEPTIBLE?
Close contacts of infectious tuberculosis cases are susceptible to becoming infected and, if infected, to progressing to tuberculosis, particularly within the first year after exposure [36]. Among 95 contact investigation studies from countries of low and middle incomes, the prevalence of M. tuberculosis infection among contacts was 51.5%. Contacts who are <5 years of age or HIV infected have the greatest risk of developing tuberculosis [36]. Among countries with high burdens of tuberculosis and HIV infection, such as South Africa and Zambia, HIV-infected household contacts have a risk of progressing to tuberculosis that is almost 5-fold greater than that for HIV-uninfected household contacts [37]. In settings with a high tuberculosis burden, silica-exposed miners, particularly those with silicosis, have a high prevalence of M. tuberculosis infection [38,39]. Many persons who are at high risk of developing tuberculosis can be identified on the basis of their medical history or with simple tests [14]. Currently, it is not possible to identify persons who have an increased risk of infection if exposed.

HALTING TRANSMISSION
Halting tuberculosis transmission is central to stopping the tuberculosis epidemic. As shown in Figure 2, it may be possible to target interventions to reduce the infectiousness or duration of infectiousness of tuberculosis cases, contact rates, and susceptibility of contacts. Contact between an infectious tuberculosis case and a susceptible person may occur because of clustering in space (such as in households, workplaces, and urban slums) or over time (such as in public transportation settings, among migrant workers, and during urbanization or displacement) [14]. Contact rates can be reduced through socioeconomic development leading to reduced crowding. Socioeconomic development also improves nutrition, reducing progression to tuberculosis. Improved infection control also accompanies socioeconomic development, particularly improved ventilation in areas where contact is likely to occur, such as healthcare facilities, public transportation settings, workplaces, and schools [5,14]. Infectiousness and the duration of infectiousness can be reduced through early case detection and treatment by improving access to quality tuberculosis diagnostic and treatment services, use of quicker and more-sensitive diagnostic assays such as Xpert MTB/Rif, active case finding and linkage to care for appropriate treatment, and interventions to reduce attrition before starting treatment [6]. Susceptibility to tuberculosis can be reduced by addressing host factors such as HIV infection, diabetes, anti-tumor necrosis factor treatment, organ transplantation, renal dialysis, silicosis, illicit drug use, malnutrition, harmful alcohol use, and smoking. Susceptibility to tuberculosis can also be reduced by treating the underlying condition (eg, HIV infection and diabetes), by reducing key exposures (eg, silica dust, tobacco smoke, and indoor pollutants), and by providing preventive therapy for latent M. tuberculosis infection.
A number of intervention studies have attempted to reduce tuberculosis transmission at a population level by using combinations of case finding and preventive therapy interventions targeting at-risk groups or communities, with success ranging from no or minimal impact to large and sustained impact ( Table 1) [40][41][42][43][44][45][46][47][48][49][50][51]. The variable success of the interventions in achieving a population-level impact may be due to poor targeting of risk groups, inadequate coverage, implementation of interventions that are not implemented or evaluated long enough to capture mass effect, and use of old tools, such as sputum microscopy.

NEW TOOLS
Advances in technology may allow more-effective targeting of the sources of tuberculosis transmission. The Xpert MTB/RIF test was initially heralded as a "game changer" in the diagnosis of tuberculosis, owing to its greater sensitivity than sputum smear microscopy [52,53]. The roll out of Xpert MTB/RIF, however, has had limited impact on tuberculosis mortality and incidence to date, largely because of health system weaknesses, particularly those due to poor uptake of HIV testing and linkage to care for antiretroviral therapy. This highlights the need to strengthen health systems and develop new tools [54,55]. The next-generation Xpert MTB/Rif (Ultra) cartridge is expected to be even more sensitive and could be a valuable tool to identify active and infectious cases, thereby allowing the prevention of transmission. Modeling suggests that new tuberculosis drugs and regimens for drug-susceptible and drug-resistant tuberculosis that are shorter and more efficacious may have a modest population-level impact [7,56]. New tests for individuals with M. tuberculosis infection that predict who will progress to tuberculosis will allow treatment of infection to be targeted to those at greatest risk of developing tuberculosis [57]. Implementation of new, short-course regimens for treating latent M. tuberculosis infection, such as weekly high-dose isoniazid and rifapentine for 3 months or daily isoniazid and rifampicin for 3 months, potentially could have a profound effect on the tuberculosis epidemic, particularly if implemented at scale and coupled with active case finding and treatment of all forms of tuberculosis. Barriers to scaling up treatment of M. tuberculosis infection should be addressed, and innovative, affordable models of delivery that support scale up of treatment of M. tuberculosis infection should be evaluated [58]. New research tools, such as whole-genome sequencing, could help us understand global and local tuberculosis epidemiology better and thereby target interventions to reduce transmission more effectively [59]. Similarly, tuberculosis vaccines that prevent M. tuberculosis infection or disease among adolescents and adults may have a profound impact on the tuberculosis epidemic [60].

CONCLUSION
Robert Koch, in his Nobel Lecture, said that "amidst the persistently great variety in the ways and means of combating tuberculosis, it is yet necessary to ask what measures do indeed best satisfy the scientific requirements" [23]. More than 100 years later, we are still asking the same question. Although our understanding of tuberculosis transmission has improved substantially, many gaps remain. Subsequent articles in this series aim to identify these gaps and to describe the benefits (and obstacles) to filling them. One thing is certain: if we wish to end tuberculosis by 2035, a massive concerted effort is required today.  Data are adapted and expanded from the article by Kranzer et al [51], which used a nonsystematic literature review and was therefore not comprehensive.