Ending Tuberculosis in the Face of Antimicrobial Resistance
In Act 1 of Giacomo Puccini's 1896 opera La Bohème, the main character Mimi, a beautiful but frail woman, knocks on the door of her bohemian poet neighbor, Rodolfo. She is short of breath, cold and faints not long after telling Rodolfo that her candle has burned out. After many months of poverty and weakness, Mimi finally succumbs to her disease. In a heartbreaking final scene, she dies in her lover's arms after a violent coughing fit. Although this may seem like a dramatic love story, La Boheme, and other 19th-century operas, accurately depicted the plight of those living with, and dying of, tuberculosis.
Written just a few years after Robert Koch's discovery of the bacterium that causes tuberculosis (TB), La Boheme contained relevant subject matter that was a part of daily life for Europeans at the time. In the 1880s, TB was responsible for killing 1 out of every 7 people in Europe and the United States, but the history of the disease stretches as far back as 150 million years ago. Today, the burden of TB is immense. Worldwide, TB is the second leading cause of death by infectious diseases (second only to COVID-19), and 1.6 million people died of the disease in 2021. TB remains a global threat and efforts are underway to attempt to end the death and misery caused by the disease once and for all through improved detection, prevention, policy and treatment.
The History of Tuberculosis
It is hypothesized that the causative agent of tuberculosis, Mycobacterium tuberculosis (MTB), originated hundreds of millions of years ago. However, the first written record of TB dates from 3,300 years ago in India. TB was well-described in ancient Greece and was referred to as “phthisis.” Greek and Roman physicians described the symptoms of phthisis as fever, sweating, coughing and the production of bloody sputum. The recommendations for treating this fatal disease included “air, milk and sea voyages."
Over the years, especially before the germ theory of disease was accepted, TB was referred to by many names and believed to be caused by various things. Some of these include:
- The King’s Evil: now known as scrofula, this extrapulmonary form of TB, which affects the lymph nodes, was believed to be a mysterious disease that the touch of a member of royalty could heal.
- Consumption: described in 1679 by Francis Sylvius in Italy as an infectious disease that could cause pulmonary and extrapulmonary manifestations.
- The robber of youth: the disease was given this name due to a high mortality rate (900 deaths per 100,000 infected), predominantly in young people in western Europe, during the 18th century.
- The White Plague: related to the paleness of patients infected with MTB.
- Tuberculosis: coined by Johann Lukas Shoenlein in the mid-19th century.
- Captain of All These Men of Death: used to describe TB during a massive epidemic in Europe and North America in the 19th century that led to death in 1 of every 4 patients with TB.
Discovery of the Causative Agent: Mycobacterium tuberculosis
The most significant progress in defining and fighting TB came when Robert Koch discovered the bacteria that causes the disease, Mycobacterium tuberculosis (MTB), and reported this to the scientific community on March 24, 1882. Using what became known as “Koch’s Postulates,” he was able to identify the bacillus in all individuals with the disease, grow the organism outside of the host and replicate the disease in a susceptible animal host by inducing infection with MTB.
The Current State of TB Globally
Over 10 million people become infected with TB yearly, and over 1 million die. Although the infection can be treated with antibiotics, the treatment course is difficult, and multidrug-resistant (MDR) TB is increasing in frequency. According to the World Health Organization (WHO), nearly half of TB-infected households sustain costs related to their care that are higher than 20% of their household income.
TB spreads easily through the air, and a person can be infected after contact with very few TB organisms. Not everyone who becomes infected with MTB will develop active disease. Although it is currently estimated that 25% of the global population has been infected with MTB, most will not go on to develop active disease. Those infected with the bacteria have a 5-10% risk of developing active disease in their lifetime with higher risk for people with immunosuppressive conditions like HIV/AIDS or diabetes.
Currently, there are guidelines for treating both active and latent TB infections. Four first-line drugs are recommended to treat active TB infection (isoniazid, pyrazinamide, ethambutol and rifampin), and they should be taken for 4 months, followed by at least 2 months of a 2-drug regimen. In recent years, the development of MDR-TB has become a global crisis. MTB is considered multidrug resistant if it does not respond to isoniazid and rifampin. If an MTB isolate is determined to be MDR, the patient must receive second-line drugs for at least 9 months, and potentially up to 20 months, to treat their infection.
Since long-term use of these drugs is associated with adverse events and toxicity, patient monitoring is required. Additionally, patients receiving TB drugs less than 7 days a week are required to have directly observed therapy (DOT), where a healthcare worker or other designated person watches the patient swallow their prescribed TB medications each day.
According to the WHO, only 1 in 3 people infected with MDR-TB accessed treatment, and the success rate in the patients who received treatment was only 60%. In terms of impact, WHO estimates that approximately 500,000 people become sick with MDR-TB each year.
In the rare case that a patient develops extensively drug-resistant TB (XDR TB), which is resistant to isoniazid, rifampin, all fluoroquinolones and at least 1 of 3 injectable second-line drugs, success of the TB control program will depend on the patient's immune system and adherence to treatment, as well as the extent of resistance and severity of disease.
The type of test used to identify patients infected with TB will differ, depending on the presence or absence of symptoms (e.g., active vs. latent infection). In asymptomatic people, there are 2 types of tests used to screen for MTB infection: the TB skin test (e.g., Mantoux, "PPD") and a blood test called an interferon-gamma release assay (IGRA). Both tests can help determine if a person has been infected with MTB but are unable to determine if the person has an active or latent infection.
People with latent TB infection do not have signs or symptoms of the disease and do not feel sick, whereas people with active TB have symptoms and demonstrate disease on other tests, like sputum smear and culture, or on chest X-ray. Therefore, if a person has a positive test, additional testing, such as a chest X-ray, should be performed to confirm whether the infection is active or latent.
For people with signs and symptoms of TB, WHO recommends the use of rapid molecular assays, citing their high diagnostic accuracy and ability to identify infectious patients sooner. Due to the highly infectious nature of TB, earlier diagnosis may help prevent the spread of the disease, which is particularly important in the case of MDR-TB. Mycobacterial smear and culture is a time-consuming and labor-intensive process, but it is used for species identification, susceptibility testing and genotyping. Laboratories that perform culture for MTB must adhere to biosafety level requirements and all appropriate personal protective equipment (PPE) requirements to safely handle this dangerous pathogen.
The Ending TB Strategy
In collaboration with multiple other agencies around the globe, WHO has taken on an ambitious initiative called the “End TB Strategy.” This strategy, led by the Global Tuberculosis Programme, “works towards the goal of a world free of TB, with zero deaths, disease or suffering due to the disease. The team’s mission is to lead and guide the global effort to end the TB epidemic through universal access to people-centered prevention and care, multisectoral action and innovation."
In 2014, the World Health Assembly approved the strategy and aimed to dramatically reduce the burden of TB on the world’s most vulnerable populations. The program is built on 3 key pillars:
- Integrated, patient-centered care and prevention: early diagnosis and screening of high-risk groups, treatment of all patients with TB, preventative treatment and vaccination of those at high risk and management of comorbidities, specifically HIV.
- Bold policies and supportive systems: global political commitments that support TB prevention and treatment, engagement of communities and public health organizations, poverty alleviation, universal health coverage and infection prevention.
- Intensified research and innovation: discovery, development and rapid uptake of new therapies and diagnostic tools, accompanied by research to optimize implementation and impact.
Since 2014, the End TB Strategy has had a significant impact. According to WHO, millions of lives have been saved through effective diagnosis and treatment of TB. HIV-related TB deaths have decreased by 32% and treatment for MDR-TB has increased. The biggest challenges include a large funding gap for implementing programs and research, 3.6 million people with TB missed by healthcare systems each year and the ongoing crisis of MDR-TB.
The Way Forward
Despite thousands of years of dealing with TB, it remains one of the biggest killers globally. The WHO’s End TB Strategy aims to decrease TB incidence in each country by 80% and reduce TB-related deaths by 90% by 2030. Additionally, WHO and colleagues hope to improve the quality of life for those affected by TB by eliminating “catastrophic costs” associated with TB infection. Although perhaps regarded by some as a bygone disease, particularly in high-resource settings, this is not the case. As a global community, it is important that we keep the burden of TB front of mind. Then, it might be possible to envision a future without TB through supportive programs, better diagnostics, effective treatment and addressing inequity.
In honor of World Tuberculosis Day (March 24), and to promote ongoing research efforts to fight TB, ASM Journals presents our World TB Day Collection.