The following essay was contributed by public health researcher Jon Servello.

This article presents a brief review of tuberculosis (TB) reduction in Europe and North America, comparing and contrasting the circumstances throughout the 17th - 20th C with present-day countries that have a high incidence of endemic TB. Based on this comparison, the final section attempts to take some lessons from interpretations of historical data and plot a more humane trajectory for TB elimination globally, and what would need to be in place to meet WHO End TB goals — with special attention given to community health approaches, the potential role for new TB vaccines and treatment regimens in the short-term, and theories of economic development in the long-term.

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Tuberculosis is an ancient disease and has been infecting humans at least since the development of agriculture and domestication of bovine animals, some 60-70,000 years ago. At present, it is estimated that around 1.86 billion people have been  infected with M. tuberculosis, and the related bacilli M. bovis and M. africanus. Though exact prevalence can be difficult to gauge, it is more certain that there are at least 10 million new cases per year and 1.5 million deaths caused by TB.

Despite this, the disease is often overlooked in public discourse across Europe, due in part to the steady decline of endemic TB cases since the 19th century, with a clearer reduction in the more accurate records of the 20th century onward. Once referred to as the white plague or the “Captain of All These Men of Death”, incidence has now dropped to 9.6 per 100,000 people per year in Europe, and as low as <5 per 100,000 in northern Europe. This dramatic change has been seen throughout the world’s wealthiest countries, and while the overall picture is complex, incidence remains far lower in what Hans Rosling would refer to as “level 4” populations; those with the highest income.

The World Health Organization End TB Strategy aims to reduce TB incidence by 80% and the number of deaths by 90% by the year 2030. Currently, the global incidence is 127 per 100,000 people per year. Matteelli et al. offer an operational approach on what has worked in reaching TB elimination levels (<10 per 100,000 per year) in different areas of the world, emphasizing centrally coordinated, well-funded TB programs at the national level and the promotion of universal and free-of-cost treatment services.

Fig. 1: Projected trend in the decline of global tuberculosis incidence, from 110 cases per 100,000 in 2015 to 10 cases per 100,000 or less by 2035, reproduced from the World Health Assembly resolution on global strategy and targets for tuberculosis prevention, care and control after 2015

Setbacks from COVID-19 which, by most accounts, have pushed us back to 2013 levels of case detection and care leads me to be far more pessimistic than I would like to be about meeting the 2030 / 2035 targets. That said, I have left a long left-tail on my forecasts just in case one of several upcoming technologies (e.g. vaccine candidates) has a greater effect than I anticipated, or there is a renewed commitment to meeting the TB funding targets set out in the End TB plan.

My forecast is based off of the 2015 World Health Assembly's forecast of TB incidence, which predicts a 2% decrease per year (p. 73 of the report). This may seem pessimistic, but my reasoning is similar to my prediction for TB mortality. Setbacks from COVID-19 will likely play a large role here.

Data from the Institute for Health Metrics and Evaluation / Our World in Data presently indicates a 4% drop in the rate of global TB deaths per 100,000 people from 2018 to 2019. This can be contextualized historically; Europe achieved a 6% reduction in TB mortality rate from the years 1921 - 1939. This number appears even more modest in comparison to the 10% reduction in TB mortality rate achieved from 1947 - 1968. 

This is particularly striking given that streptomycin was discovered in 1943. Isoniazid, rifampicin, ethambutol, pyrazinamide are rightly considered essential medicines by the World Health Organization. Yet, while these powerful antibiotic drugs developed from the mid-20th century onward are invaluable in saving the lives of individual patients with an “active,” symptomatic TB infection, this was clearly not the only factor in achieving dramatic TB reduction in 20th century Europe.

Similarly, the now century-old Bacillus Calmette–Guérin (BCG) vaccine is considered critical for preventing disseminated TB forms and TB meningitis in children in endemic countries. At the same time, some correlates of protection as a result of receiving the BCG are unclear from studies and it may have limited efficacy in certain contexts.

There is a self-evident and urgent need for greater funding and more intensive research in TB drug and vaccine development, as well as improved access to existing tools. Another point to consider, though, is that historical epidemiological studies have shown that TB reduction is also underpinned by other factors, with most arguing that the change relied heavily on improvements to living standards, including better nutrition and housing, in addition to the strategy of isolating sick people in sanatoria.

The McKeown thesis and revisitations

In his 1976 work, The Role of Medicine: Dream, Mirage or Nemesis?, Thomas McKeown examines the efficacy of modern medicine in the history of disease elimination in England and Wales, and argues that the majority of the reduction in TB came about by advances in the average living conditions across the population, particularly improved nutrition and hygiene practices. 

The work has undergone extensive criticism from multiple perspectives, especially in its grouping of incidence statistics of several respiratory diseases from periods before modern microbiological methods allowed us to discern between them. Still, McKeown’s central idea that living standards are the fundamental driving force behind infectious disease reduction remains a compelling one, and has been revisited by contemporary public health researchers and economists including Angus Deaton in The Great Escape. The thesis has also been adaptable depending on current political interests. 

It is understandable, then, that the question would return more frequently as one of the central questions in an age of increasingly high-tech biomedical and life sciences industries. To paraphrase medical historian Vanessa Heggie, it is not immediately obvious how much in the way of resources to allocate to the various approaches in public health and infectious disease control. She identifies three main threads of thought in this area; the ‘progressivist’ approach which focuses on funding drugs and vaccine research, the ‘historian's approach’ which prioritizes sanitary measures and public health interventions, and finally the McKeown-inspired approach which aims to foster the biggest picture change in the form of long-term economic development and subsequently improved standards of living. 

Of course, these approaches are not mutually exclusive and it is counterproductive to treat them as such. What we can derive from historical data, though, is that while medicines were (and are) critical for treating those with symptomatic disease, other changes in society already dramatically reduced mortality from the mid-19th century (fig. 2).

Fig. 2: The original figure produced by McKeown et al. estimating TB mortality from 1850, presented by Danika Berry

Modern data related to the same question appear to show a similar trend, with anti-TB drugs accelerating and perhaps sustaining the decrease, but with a clear and steep reduction in TB mortality taking place well before (fig. 3).

Fig. 3: Lönnroth et al.’s more recent estimate of decline in TB mortality in England and Wales, and its association in time with the two World Wars, and the introduction of chemotherapy against TB

Nutrition and TB

McKeown proposes that the key difference is in the nutritional status of the population. He and more recent researchers have reflected on this and pointed out this was a period of rapid economic growth, but also of social reform and the expansion of public protections in the labour market and in the form of reductions to limit poverty. 

Generally, studies find a consistent log-linear relationship between BMI and TB incidence. This appears to be corroborated in countries with a high endemic TB incidence; Padmapriyadarsini et al. found in 2016 that undernutrition was the single most predisposing factor for TB in India, with an attributable fraction of over 50% in most Indian states. A cohort study in China conducted by Chen et al. confirmed the ‘dose-response’ nature between low BMI and TB, with the authors suggesting that new policies specifically target those at less than 22.5 kg/m² BMI.

This also suggests obvious and practicable complements to medical treatment. Indeed, a form of combined medical and community-based intervention aimed at improving nutritional status alongside TB treatment has indeed already been advocated by many groups working in areas of high endemic TB. Barriers in accessing the care necessary for stemming TB, including nutritional assessments, are a concern in some regions. For prevention of TB, however, nutritional status and food security must improve at a population level.

The question of sanatoria and case detection

Arthur Newsholme’s earlier analyses of the constituent factors leading to the spread of TB has also gained credence among medical historians. He argued that the introduction of the 1834 Poor Law in the UK effectively quarantined TB patients and barred them from entering workhouses, which had the (unintended) effect of allowing a pathway for screening and early detection of diagnosis, preventing its spread among the general population. Newsholme also noted the importance of sanatoria, where they undoubtedly played an important role in reducing TB in Europe and North America.

Fig. 4: Annual number of tuberculosis deaths (5 year average) in Minnesota, US, as presented by Leonard Wilson

The question of hospital-based treatment in a modern setting is a more complex one, however. Not only are the ethics of historical institutions like sanatoria now rightly questioned in some contexts (see later sections of this essay), but counterintuitively, lengthier treatments with the advent of anti-TB drugs led to more patients leaving against medical advice and higher readmission rates.

It seems, then, that the main utility of sanatoria (especially pre-antibiotics) would have been overwhelmingly in the case detection policies that came with their establishment, isolation of contagious individuals, and as diagnostic centers for the surrounding areas. Since current TB medicines render patients as non-infectious within 3 to 4 weeks, there are different concerns regarding containment in the modern world. 

Though we can cover many bases through screening programs (which exist at borders, for example), our newfound ability to treat TB with shorter regimens might best be combined with active case finding. The difference is one of scale; the WHO estimated in 2010 that one third of TB cases go undetected, with COVID-19 interruptions potentially bringing us back to such levels. 

While new TB diagnostic technologies would help, much can be achieved by funding community health workers to act as case-finders in TB hotspots. Potty et al. document an outreach program that detected over 3800 cases of TB over a four year program for the cost of hiring 112 community health workers to undertake a fortnightly visit to urban slum areas of Hyderabad and Bengaluru. Assuming a case fatality rate of around 70% for untreated TB, the program would have averted over 1600 TB deaths with successful treatments.

The modern role of medical solutions

One advantage we possess in the present is a greatly expanded industry aimed specifically at biomedicine. Sadly, this industry has, proportionally, not yet directed much of its growing resources towards TB elimination. After many years with a dearth of new anti-TB drugs, trials of bedaquiline, delamanid, and pretomanid showed their efficacy in the treatment of TB and MDR-TB, even on much shorter regimens. With these promising results, a suite of options could be made available. TB vaccine candidates hold potential for future immunization programs. Recent years have shown our ability to more rapidly develop drugs than in the past, and this has understandably led to a renewed interest in mRNA-based solutions for TB.

My forecast here is optimistic, mainly due to VPM1002; of the five current phase III candidates, it has international support between the Max Planck Institute and the Serum Institute India, has shown better safety and roughly equal efficacy to the traditional BCG in phase II trials, and received a 30 million EUR loan from the European Investment Bank in 2020.

Three trials of VPM1002 are expected to finish between now and mid-2023. Regulatory times for the EMA can take just months. My forecast leaves a 10% chance that all phase III results show no efficacy and regulatory approval isn't pursued at all, and the other vaccine candidates are delayed or lose funding.

For both new and existing tools, universal access is a critical element of TB elimination. Not only is this illustrated historically with the use of the first TB drugs in Europe, but concerns around equity are also demonstrated in the case of antiretroviral drugs; especially relevant here as many places face overlapping epidemics of HIV/TB coinfection.  

Drug-resistant TB

Another critical point of difference between historical Europe and present global counterparts with respect to TB incidence is that we now face the additional burden of increased rates of drug-resistant TB. Even early treatment of TB required a combination of drugs to kill all bacilli; where streptomycin killed many of the bacilli but left some resistant strains, additional drugs such as isoniazid would take care of the remaining bacilli (and vice versa). Just 13 years after their introduction, strains of TB with resistance to streptomycin, para-aminosalicylic acid, and isoniazid were found in patients. 

Over subsequent years, rates of multidrug-resistant TB (MDR-TB) have decreased globally as a result of successful control programs, but spiked specifically in areas of very severe TB incidence, especially in countries of the former Soviet Union, South and central Asia. There is also particular concern for urban areas.

In the future, novel approaches such as biologic therapies may also help to overcome some of the limitations imposed by MDR-TB and extensively drug-resistant TB (XDR-TB). According to Rivas-Santiago et al., antimicrobial peptides “have demonstrated remarkable efficacy to kill mycobacteria in vitro and in vivo in experimental models”. Dijksteel et al. provide an overview of all clinical trials and therapeutic uses of biologic therapies in humans in Table 1 of their article; unfortunately none specifically target TB as of the article publication on February 22nd, 2021.

I find myself less optimistic for this forecast, for several reasons:

• There are no biologic therapies for MTB in humans in the pre-clinical pipeline (update 16 August 2022, FDNR 20364 is a registered pre-clinical study in guinea pigs).
• The track record of drug development for TB has been extremely slow, even in more 'conventional' areas of medicine. There are a number of reasons for this, but most often comes down to funding limitations. TB funding regularly does not reach the stated goals laid out in the WHO Global Plan to End TB strategy, so it is difficult to estimate how much of that funding would be put toward testing novel therapies like this.
• More generally, developing biologic therapies is expensive, even with the push on behalf of regulatory agencies to allow cheaper generics; developing similar biologics costs 100 - 200 million USD, where generic drugs are typically between 1 - 5 million USD.
• While the U.S. NIH and other organizations have recently put up funding for new anti-TB drugs, these appear to be more traditional compounds judging by the level of funding (28.4 million USD total).

Factors working in favor:

• Biologic therapies are a highly profitable area of biotech, with this study by Gazendam et al. pointing out that biologic therapies made up the greatest part of global pharmaceutical sales (presumably prior to COVID-19), and that 29% of these therapies are aimed at infectious diseases.
• There are lots of possible peptides, with some of the most promising being the synthetic types.
• One such synthetic compound was shown to be effective against MDR-TB in mice.
• In vitro studies with a fungal peptide were also effective.

I've given myself a 30% margin for error because of the longer timeframe on this. We have shown that we're capable of developing drugs rapidly, it's mainly about allocation of resources rather than scientific feasibility.

Avoiding repeating ethical catastrophes of the past

In this review of lessons to learn from historical TB elimination, it would be remiss not to also take note of the growing record of previous human rights abuses undertaken in certain infectious disease treatment and control contexts. With regard to TB, there is increasing recognition of the harms caused by historical unethical practice, including lasting generational distrust in health institutions. Examples include the treatment of indigenous populations of North America in the early to mid-20th century, and the execution of people with TB during times of conflict.

Few studies attempt to take into account these historical practices and their potential impact on TB reduction, but understanding their effect may help to gauge the “true effect” of those treatments which are ethically sound. Fortunately, as presented throughout this essay, it appears possible to dramatically reduce TB across much of the world by ethical means. This has been corroborated by modern public health literature, which suggests that ethical practice can help to reinforce standards of infectious disease control and care by building trust in potentially marginalized populations.

Marrying urgent humanitarian need and long-term development

The purpose of this article is not to advocate diverting effort from drug development to non-pharmaceutical efforts. On the contrary; TB is rightly regarded as a neglected disease, and the need for novel, strategic, and rapid medical intervention has only increased, not least to address hotspots of drug-resistant TB. To develop new tools but fail to ensure that these are accessible to the populations that need them would be to repeat historical mistakes, such as the debates around the logic of cost-effectiveness analyses effectively limiting access to second-line drugs to treat drug-resistant TB throughout the 1990s. The point is aptly summarized by previous director of the Global Tuberculosis Program at the World Health Organization, Mario Ravilgione: “We need all of them. Waiting for poverty alleviation without investing in research means accepting deaths and suffering for decades. We need poverty relief, better living conditions and new tools which also means access to them for all and especially those populations and persons most at risk”.

Instead, the aim of this essay has been to emphasize that the urgent need to treat people with TB exists in a social and economic context where TB is allowed to proliferate. Perhaps more than any other infectious disease, TB exemplifies a disease of poverty. The underlying truth of TB epidemiology also hints at the reason for its comparative neglect (especially in pharmaceutical and biomedical industries) among diseases with more continuous research and development funding; the majority of those contracting TB are the world’s poorest and most economically insecure populations. These are both the result of inter- and intra-national inequality. This is, perhaps, why the McKeown thesis persists in spite of its flaws. As McKeown points out, “prosperity, as indicated by the gross national product or per capita income, is not always essential, since in some circumstances the distribution of wealth and the use of resources may be as significant as their creation”.

There is also another economic argument to be made: if mortality is not enough to move policymakers, a study published in 2013 found that TB inflicts annual direct health costs of more than 500 million euros ($670 million) on European governments, and costs another 5.3 billion euros in productivity losses. Selective inattention in important areas of disease burden, particularly those that exacerbate existing problems of inequality, presents a serious drain even in those countries with a lower TB incidence.

Summarizing points

Allowing for differences in context, we can still draw some possible lessons from the historical experiences of Europe and North America with TB:

• Active case-finding is an essential tool to reducing the burden of TB in highly-afflicted areas; this can involve introducing screening programs or employing community health workers to seek and offer treatment
• These treatments must be ethical, equitable, and universally accessible, with history amply demonstrating the potential for inequitable treatment of different populations
• Current standard treatments, even as drug regimens continue to improve, are best accompanied by context-appropriate community health work, and particularly adequate social support programs (including nutrition where needed)
• More equitable funding in TB research would allow us to utilize the advantages of our modern biomedical approach by developing entirely new sets of tools, including improved vaccines, diagnostics, and anti-TB drugs
• Ultimately, our present situation in which we have areas of high TB endemicity is a familiar and rectifiable one which demands increased allocations for both treatment/control programs, and the long-term goal of reducing the conditions of economic inequality which allow TB to persist

Acknowledgements

I would like to extend my sincere thanks to Professor Mario Raviglione for his review, suggestions, and permitting the use of his comments in writing this essay.

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