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“It was on Friday 3 March that I suddenly coughed up mouthfuls of blood. I phoned the doctor, who said that he would call later in the evening. I gave Mark his tea, put him to bed, did some ironing, had my supper when Dr Henderson [general practitioner] arrived. Said I ought to go to bed and stay there—explained that I had no help, so he said ‘do as little as possible in the morning and go when Bill comes home at 1.30 pm’, and he would come again in the afternoon. Thought I had better have a cook up for Bill. I little knew it would be the last cooking I should do for a year or so!”
Excerpt from the personal diary of a 32-year-old woman with tuberculosis, 1944

Although we are currently in the midst of a global health pandemic, this isn’t the first time that a respiratory disease has wreaked havoc around the world. For centuries, tuberculosis (TB), or consumption, has been considered one of the deadliest diseases in human history, and even now causes around 1.4 million deaths per year – the leading cause of death from a single infectious agent and outstripping even HIV/AIDS. So what causes this disease, and why is it still so hard for us to control, even in an age of vaccines and antibiotics?

To understand this, let’s start by looking at the history of TB. As TB is one of the few infectious diseases that eventually causes skeletal lesions, we can trace it all the way back to Ancient Egypt, with several mummies exhibiting the bone ulcerations and deformities that are typical of long-term infection. Since then, there is widespread evidence of TB being a persistent presence throughout history, though it didn’t really spring to the forefront of public consciousness until the 18thcentury and the dawn of the Industrial Revolution. The birth of industry brought more people than ever before to cities to live in cramped, unhygienic conditions, rife with poverty, pollution and malnutrition. This was an ideal breeding ground for M. tuberculosis, and TB, or consumption as it was then known, exploded, becoming responsible for one in four deaths by the early 19th century. Before the discovery of antibiotics, it was thought that TB could be treated with pure air, good food and plenty of bed rest, leading to the establishment of enormous sanitoriums where patients stayed for months or years at a time… with mixed results. Pneumothorax was also used as a treatment, deliberately collapsing an infected lung to allow the lesions time to heal. Although cases began to decline in the 20th century due to improved public health and the discovery of a vaccine, it wasn’t until 1944 and the discovery of the antibiotic streptomycin, that TB infections could be tackled in full force. Unfortunately, this relief is now mitigated by the rise in multi-drug resistant TB. 

A vaccine for TB is available – the Bacille Calmette-Guérin (BCG) vaccine – and is one of the oldest vaccines still in use. Just 40 years after Robert Koch discovered that the intracellular bacteria M. tuberculosis was responsible for the consumption that ravaged the 19th century, the BCG vaccine was developed in France by Albert Calmette and Camille Guérin, using an attenuated bovine strain of TB. After first testing it in a newborn infant of a woman who died of TB shortly after giving birth (ethics were distinctly looser in the early 20th century) with no adverse effects, Calmette and Guérin went on to test the vaccine successfully on 664 further children before it was declared safe and mass production began in 1924. The BCG vaccine has been used safely for almost 100 years, but controversy has arisen recently about its efficacy. Although it is 70-80% effective against the most severe forms of TB, evidence suggests that it does not protect sufficiently against respiratory TB, and though it is still given to infants deemed at risk, widespread vaccination of children with BCG was halted in 2005 in the UK. 

As with almost all diseases that attack the respiratory system, TB is spread from person to person in aerosol droplets caused by coughing, sneezing or breathing. It takes only a few of the Mycoplasma tuberculosis bacterium behind TB to infect a patient, however, in 85-95% of people, this infection will remain latent, never displaying symptoms. That leaves 5-15% of infected people who will go on to develop TB, more likely those living with compromised immune systems, or other diseases such as malnutrition, HIV and diabetes. Even when an infected person does develop active TB, the symptoms – cough, fever, night sweats – can be relatively mild, delaying medical attention and increasing the risk of transmission to others at a rate of 5-15 people per year. In active TB, the most common form of the disease manifests as a productive, bloody cough, chest pains, muscle weakness, fever and weight loss, and despite the availability of antibiotics, drug resistant strains and poor treatment adherence results in a 3% mortality rate. Severe TB can also move into many other body systems, including the gastrointestinal tract, the genitourinary system and the bones, causing lesions in the long bones, spine and joints and resulting in pain, stiffness and eventually lower-extremity paralysis. 

One of the main factors that continues to make an ongoing threat is its persistent antibiotic resistance, and ability to evade the immune system. The causative bacteria of TB, Mycobacterium tuberculosis, doesn’t have the same basic structure that most bacteria do. While most bacteria can be classified as “gram negative” or “gram positive” due to the structure of their rigid cell walls, M. tuberculosis has an extra, waxy covering called mycolic acid. This acid makes it difficult to gram stain, and enables the bacteria to survive inside the phagocytic white blood cells that would usually attack and destroy bacterial invaders, such as macrophages. Instead, it replicates inside these cells, safe from the rest of the immune system until the thousands of new bacteria burst out of the macrophage. The death of the macrophage recruits more immune cells, which then surround the site of infection, creating a granuloma. Within the granuloma, the bacteria become dormant, entering a persister state, relatively resistant to immune attack and antibiotics. Bacterial escape from these granulomas is possible, and can results in the infection of other body systems described above.

More importantly than its immune evasion capabilities, M. tuberculosis today carries a number of antibiotic resistance genes. While many other bacteria carry antibiotic resistance genes on mobile genetic elements called plasmids that can be passed from cell to cell, M. tuberculosis is unusual in that its drug resistance is present in its permanent, chromosomal DNA. Efficient treatment of TB requires long courses of antibiotics, taking a regimen of 4 different drugs for at least 6 months. This can be expensive and demanding, particularly in developing nations, meaning that adherence rates are often low. Improper prescription can also contribute to poor treatment. Incomplete antibiotic courses leave partial infections behind, and allow for the survival and proliferation of drug-resistant mutants. Strains of TB resistant to at least one for the classic anti-TB medications have been found in most countries around the world, and multi-drug resistant TB (MDR-TB) is now extensive. While MDR-TB is still treatable using second-line, rarer antibiotics, extensively-drug resistant TB (XDR-TB) is now on the rise and is resistant to almost all treatment options, leaving patients in a situation much like those in the pre-antibiotic era.

The World Health Organisation is working hard to reduce the incidence of TB, and is aiming to end the TB epidemic by 2030, by reducing TB related deaths by 90% and new infections by 80%. While TB cases are in decline, this endeavour must still combat a number of roadblocks, including poor public health, an inefficient vaccine, and most importantly, increasing levels of drug resistance. 

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