“Tuberculosis is a social disease with medical complications.”
Sir William Osler, Canadian physician and a founding professor of Johns Hopkins Hospital
“Almost forgotten today, tuberculosis (TB) is still one of the deadliest infectious diseases in the world.”
Ronald Gerste, MD, PhD, American physician, historian, and author
In 2023, tuberculosis (TB) killed 1.3 million people surpassing COVID-19 (less than 1 million deaths) as a cause of death and thereby regained the dubious distinction of being the world’s deadliest infectious disease. Virtually everything about TB is extraordinary—from its place in the history of microbiology to the sneaky pathogenesis of its etiologic agent (the tubercle bacillus), to its immunology (mechanisms of host defense), and, most importantly, to its profound and sustained impact on global health. I recently reviewed TB in my October 18, 2023 Germ Gems post, “Stopping the Tuberculosis Pandemic,” but decided this week to provide my assessment of why TB is once again the leading infectious disease killer in the world or, as I call it, “Public Health Enemy No. 1.”
Historical highlights. TB is an ancient disease. The earliest written mentions of TB were in India and China more than 3 millennia ago. In the 1600-1800s, TB caused 25% of all deaths in Europe; it was called the “White Plague” due to the pale appearance of dying patients.
In 1882, Robert Koch, a German general practitioner and cofounder of the germ theory of disease, announced his discovery of the tubercle bacillus proving that TB was an infectious disease and not hereditary. Koch was awarded the Nobel Prize for medicine in 1905 for his discovery.
What is TB (a synopsis)? TB is a pulmonary infection caused by the bacterium, Mycobacterium tuberculosis. The typical symptoms of TB include a persistent cough that can produce blood-tinged sputum, weight loss, night sweats, fever, loss of appetite, and fatigue. Because tubercle bacilli are spread through the air when infected people cough, sneeze, or spit, TB is highly contagious.
TB most often affects the lungs. It can, however, involve many other organ systems such as the brain, kidneys, bones and joints, peritoneal cavity, skin, and eyes. Moreover, the tubercle bacillus has the capacity to survive in the body in a dormant state (latency) for years, and then reactivate if host defenses become compromised.\
Prevention and treatment. At present, the only TB vaccine is the Bacillus Calmette-Guerin (BCG) vaccine. Developed in 1921, BCG is the most widely used vaccine in the world—predominantly in the developing world. There it is given to children at around 28 days of age and while it does offer some protection against TB meningitis in young children (specifically those under five years of age), it provides little or no protection for adolescents or adults.
In addition to having no effective vaccine to prevent the disease, treating TB is extremely complicated. Under the best of circumstances, a two or three anti-tuberculosis drug regimen taken for 9 to 12 months under direct supervision (called directly observed therapy or DOT) is necessary to eradicate the tubercle bacillus.
But when the tubercle bacillus is resistant to the most commonly used drugs (isoniazid and rifampin), longer duration treatment with newer (more expensive) drugs becomes necessary. Tragically, antimycobacterial resistance is increasing worldwide, and the mortality in such areas is now about 50%—similar to what it was before any anti-TB drugs became available.
In addition to these growing challenges for clinicians, the classification of different states of TB infection, such as “latent TB infection” (LTBI), are undergoing changes. Therefore, keeping up with the latest TB treatment guidelines requires a high level of professional sophistication.
TB epidemiology. In 2014, the World Health Organization (WHO) developed “End TB,” a strategy proposing to end the global TB epidemic by 2035. And from 2014 until 2020, there had been a sustained downward trend in the number of TB cases worldwide. But in 2022, that trend reversed; the WHO reported an estimated total of 10.6 million people fell ill with TB (people living with HIV accounted for 6.3% of these cases). More than 1.6 million people died of the disease—an increase from the more than 1.4 million people who succumbed in 2019.
The Centers for Disease Control and Prevention’s (CDC) March 28, 2024 report “Tuberculosis—United States, 2023,” was also discouraging. According to the CDC, TB cases had increased among all age groups in the U.S. reaching the highest levels since 2013. During 2023, a total of 9,615 TB cases were reported representing an increase of 16% since 2022.
As you might surmise, the disappointing trend in the rising incidence of TB both globally and in the U.S. can be traced to the COVID-19 pandemic. The pandemic complicated many aspects of the WHO’s “End TB” strategy and put an enormous strain on public health officials and health care providers—the people who provide most of the infrastructure for the control of TB.
Impediments to achieving the goal of TB elimination. It is difficult to stay on top of highly contagious microbes let alone eliminate them. Take measles as an example.
In 2000, measles was declared “eliminated” in the U.S. due to a highly effective vaccination program using the measles, mumps and rubella (MMR) vaccine. (Two doses of the MMR vaccine are 97% effective against measles.) Nonetheless, there has been a recent resurgence of measles here due to unvaccinated populations. According to the CDC, in 2024, 100 cases of measles were reported across 18 states as compared to a total of 58 cases in 2023.
In contrast to the measles vaccine (MMR ), there is no effective TB vaccine. One of the highest priorities in the field of vaccinology is the development of such a vaccine. Getting the pharmaceutical industry fully engaged, however, is difficult as most people at risk of TB live in resource poor areas of the world. Simply put, the financial incentives are not there.
A bright spot in TB vaccine development came to light on March 19, 2024 when the Bill & Melinda Gates Medical Research Institute announced commencement of a phase 3 trial of its TB vaccine candidate M72/AS013 (“M72”) in five nations in sub-Saharan Africa. (A phase 2b trial of the M72 vaccine in 2019 showed roughly 50% protection against progression to active pulmonary TB in adults with LTBI.) Most experts agree that if the M72 vaccine is efficacious, it will have a huge impact on the control of TB globally.
TB: “a glaring example of global injustice.” Unless a safe, highly effective, and inexpensive vaccine can be developed for TB, I believe the tubercle bacillus is assured of maintaining its “most deadly pathogen” status for a long time. This is due in large part to what are called the social determinants of health—the economic and social conditions that influence individual and group differences in health status. These conditions include poverty, lack of nutritious food, crowding, and racial/ethnicity disparities. (See “Beyond the Bacillus: Closing Gaps in Tuberculosis Health Disparities Requires Targeting Social Determinants,” Annals of Internal Medicine, April 2, 2024.)
Given TB’s enormous impact on global health, the strategies to dislodge it from its status as Public Health Enemy No. 1 require an “all hands on deck” approach. This involves not only non-governmental foundations like the Gates Foundation working on vaccine development but also public-private partnerships of all kinds. An example of one such partnership is the John Green story. (See Kathleen McPhail’s March 16, 2024 STAT News article, “The latest twist in John Green’s anti-tuberculosis story: working with governments.”)
John Green, a New York Times bestselling author, YouTuber, and philanthropist, sees “global heath as the ultimate social justice issue because…these global health inequities are a form and expression of injustice.” He recently announced joining a public-private funding partnership with USAID and the Philippines. (Total funding $57 million.) Green and his family are contributing up to $4 million to test and treat TB in the Philippines. As for his reason for doing so, Green stated:
“I think I’ve become obsessed with tuberculosis because it’s such a glaring example of global injustice. This is a disease that is curable, it’s preventable. And yet, it remains the deadliest infectious disease in the world. And I didn’t know that. I didn’t understand that tuberculosis is this present-tense catastrophe. Once I came to understand that, I just felt like I had a responsibility to myself and to the people I know and care about who are TB survivors to try to do what I could.”
Green hopes “to see an expansion of private-public funding models to accelerate the fight against TB.” If successful, this could disrupt the reign of TB as Public Health Enemy No. 1.
