Tuberculosis notification rates in South Africa are as high today as they were in the early 1900s. (Photo: Madelen Cronje) 
The tuberculosis notification rates in South Africa are as high today as they were reported in the early 1900s. When you consider our population and our rates of new TB cases per year, then South Africa is ranked among the 10 highest countries despite more than a century of TB control efforts and 75 years of combination TB therapy. Some would say, therefore, that our TB control is failing
The World Health Organization (WHO) has endorsed an “End TB Strategy” to end the TB global epidemic by 2035. The South African TB control programme is predicated on finding, diagnosing and treating TB cases as the main means for TB control as demonstrated by three strategic pillars: “find and link”, “treat and retain” and “prevent and prepare”. However, there is little precedence for infectious epidemics being controlled by treatment of clinically symptomatic cases alone. Furthermore, the link between TB treatment and transmission is more nuanced. In the early 20th century, before chemotherapy, TB incidence decreased by 75% in New York and London. In contrast, in Cape Town, one of the first cities to introduce compulsory TB notification, it remained high over the early 20th century. While the introduction of TB therapy markedly decreased TB case fatality equally in each setting, it had little impact on the TB notification rate.
Until now, it has been thought that TB transmission is solely linked to sputum-positive TB disease. In other words, a TB patient must be coughing infectious sputum to pass the TB infection to others. However, only a minority of transmission events in high-burdened settings can be linked to identified sputum-positive TB cases, indicating that TB transmission events result from unrecognised sources.
An active TB case-finding programme using mass chest radiography (MMR) to identify asymptomatic TB patients was implemented in Cape Town between 1948 and 1994, when 2.6 million mass chest radiographs were performed. In the 1950s, MMR screening reached 12% of the city’s population annually, identifying disease in 14 people per 1,000 radiographs and contributing up to 20% of annual TB notifications. However, the impact of MMR on transmission was modest, with TB notifications briefly dipping beneath 400 per 100,000 in the 1960s and 1970s. TB notifications returned to levels above 500 per 100,000 in 1980s and 1990s, paralleling the wind-down of MMR with subsequent increases due to the HIV-epidemic. People living with HIV are more susceptible to TB, especially if they are not on antiviral therapy, and this resulted in a surge in TB cases, especially in the early stages of the South African HIV epidemic.
Recent experiences of the HIV and Covid-19 epidemics have highlighted the role of asymptomatic carriage and transmission of infections, making population control of those diseases particularly difficult. The study of asymptomatic TB carriage is technically and ethically challenging. In the pre-treatment era, Mycobacterium tuberculosis (Mtb) was transiently found in gastric washings of adults with normal chest radiographs. “Mirage de tuberculose”, a historically reported condition in which transient positive sputum cultures were observed in clinically well individuals, has been recently reviewed. Several studies using sensitive detection methods identified aerosol shedding of Mtb organisms and DNA sequences from subclinical and asymptomatic individuals in high-burdened settings. A study of patients in a Pretoria hospital detected Mtb genetic material from face mask samples of subclinical TB cases. Mtb was also identified by a gene-based assay from electrostatically captured organisms from cough sampling of 10 randomly selected asymptomatic Brazilian prisoners who remained TB disease free for more than 12 months of follow-up.
Viable Mtb organisms have been found using sensitive detection assays in exhaled breath (bioaerosol) of 30 asymptomatic sputum-negative TB suspects attending TB clinics, who again remained disease free for six months without antitubercular treatment. Interestingly, this latter study showed that Mtb shedding could be controlled in the absence of TB therapy. A study using the same collection and detection system identified persistent low shedding of living Mtb organisms in 80% of randomly selected residents of a high-burdened Cape township. These studies demonstrated shedding of viable Mtb organisms which may explain a portion of TB transmission in high-burdened settings that are not linked with symptomatic TB cases identified in the clinic.
The separation of TB transmission from TB disease raises both challenges and opportunities. Mtb has co-evolved with Homo sapiens for thousands of years and its evolutionary survival is more dependent on successful ongoing transmission rather than an ability to cause disease. Additionally, the finding of asymptomatic Mtb carriage implies that Mtb may be necessary but not sufficient to cause TB disease. Asymptomatic carriage of Mtb may be due to the organism living within a part of the human host that is not subjected to host immune protection, or the organism may undergo a modification to avoid immune recognition. Both host symptoms and lung damage result from immune system activation to TB infection rather than the TB organism per se. Immune reaction has been strongly associated with weight loss and weakness – well-described symptoms of consumptive TB.
Studying what makes Mtb shift from a form that allows asymptomatic carriage to an inflammatory process causing TB disease could give rise to novel diagnostics and targeted therapies. The triggers for the change may be intrinsic, the bacteria or externally driven. Host factors such as diabetes, HIV infection and immune suppression have been recognised as TB risk factors. The Mtb pathogen has also been known to adapt and change in response to its environment. It has been speculated, for example, that the seasonality of TB might be related to other seasonal respiratory infections that could trigger the transition to the inflammatory state.
The change of focus from only identification of asymptomatic, sputum-positive individuals who have not presented to the health system, to include larger populations of potential transmitters will require new programmatic strategies. Finding the individuals who may make up a large population but have a low transmission rate identifies a new and potentially important target population. Low organism shedding from this population could be expected to be highly sensitive to social and environmental conditions. This is illustrated by the longstanding difficulty of TB control in prisons and other overcrowded environments – the overcrowding favouring ongoing infection despite low transmission. The reduction in the amount of Mtb in the breath (bioaerosol) of symptomatic but untreated people suspected of having TB is potentially important in limiting TB prevalence. If our candidate TB vaccines could replicate this host-related clearance of bioaerosol TB shedding this could lead to a vaccine strategy targeting TB transmission control in current endemic settings.
Our understanding of disease is dependent on the assays and tools available to study it. Sputum-based diagnostics have held centre stage over the past century but recent detection of Mtb in bioaerosols challenges the current TB transmission paradigm. Better understanding of TB transmission may help explain past failures and help re-address the greatest infectious disease challenge to our country. DM
Robin Wood and Linda-Gail Bekker, Desmond Tutu HIV Centre, Institute of Infectious Disease and Molecular Medicine, University of Cape Town.