Tuberculosis

Tuberculosis, also known as TB, occurs all over the world and is one of the most infectious diseases, causing more deaths than HIV/AIDS and Malaria [1] [2]. It is estimated that a quarter of the world’s human population is infected or has been infected with the TB bacteria and at risk of developing the disease [3].

In South Africa, TB is the leading cause of death, and has been for the past two decades [2] . From 1997, reported TB deaths rapidly increased, peaking in 2006 with 76 881 reported deaths (13% of total mortality). The number of TB related deaths then steadily declined to 29 399 (6% of total mortality) in 2016 [2] .

There has been more than 400 000 cases of TB in South Africa every year [4] and more than 300 TB related deaths every day in the country [5]. South Africa is ranked with the 8th highest rate of TB infection in the world, following India, China, Indonesia, the Philippines, Pakistan, Nigeria and Bangladesh [6].

Cause, Risk and Symptoms

TB is caused by airborne bacteria called Mycobacterium Tuberculosis entering into a person's airways, through the nose or mouth, and infecting their lungs. This can occur when a person with lung TB coughs, spits or sneezes and the TB germs in their sputum are inhaled or ingested by another person.

The body’s immune cells, called macrophages, attempt to absorb and break down the bacterial invaders. In many cases this immune system response is enough to remove the bacteria, but in individuals with other medical conditions, such as malnutrition, HIV, diabetes, pregnancy or high risk behaviours such as excessive alcohol use or tobacco smoking, the immune response might not be strong enough, and the mycobacterium will continue to reproduce, and form colonies in the lung tissue.

These bacteria also deploy cell degrading enzymes that destroy affected tissue. This causes chest pain and the coughing up of sputum and blood. The damage to the lungs also causes oxygen deprivation, which can lead to hormonal imbalances, loss of appetite, fatigue and other possible symptoms. The infectious microbes can also continue to spread through the body, infecting areas such as the kidneys, intestines and brain.

Evolution of TB and Treatment

Mycobacterium has evolved with humans for thousands of years and has been traced in humans as far back as 9 000 years ago [7]. TB has been known by many civilizations and referred to by various names. During the Victorian era in England, it was referred to as Tuberculosis or the “White Plague” because of its ashen effects on a human’s skin.

On 24 March we observe World TB Day, the day that German physician Dr. Robert Koch announced that he discovered the bacterial origins of Tuberculosis in 1882. Since then, advents such as the X-Ray machine, the Bacillus Calmette-Guerin (BCG) vaccine and antibiotics have made it increasingly possible to diagnose, treat and cure TB.

In South Africa the BCG vaccine has been mandatory since 1973 [8] and is administered to infants after birth, with the exception of infants showing signs of HIV infection, seriously ill infants, infants suspected to have already been exposed to mycobacterium and infants with allergies to the vaccine [9]. It is still possible for children or adults to develop TB later in life even after having been vaccinated for TB. The developed TB disease can then be treated with antibiotics through a treatment process generally lasting between 6 months to 2 years. TB is thus predominantly considered as a preventable and curable disease [10].

Rate of Infection, Latent TB and Diagnosis

It is also estimated that about 80% of the population of South Africa is or have been infected with the TB bacteria, the vast majority of whom do not show symptoms and carry latent TB rather than the active TB disease [11].  An estimated 70% - 90% of infected persons have latent TB, making it difficult to diagnose. Latent TB carriers are not infectious, but they do run the risk of developing active TB.

TB is also difficult to diagnose because of its ability to access all body organs. Ideally, microbiological proof of the bacteria will confirm diagnosis but as this is not always possible; a diagnosis is often made based on symptoms without proof. HIV/AIDS patients also run the risk of being misdiagnosed, as HIV/AIDS has symptoms similar to TB and the latter infection might not be identified. 

TB Treatment

South Africa has taken major strides in improving access to testing and treatment for TB, in line with the World Health Organization’s (WHO) Global Plan to Stop TB put forth for 2006 - 2015, and to continue reducing TB mortality rates in line with the WHO’s 2016 - 2035 End TB Strategy and the Sustainable Development Goal (SDG) targets [2] .

In South Africa, analysis shows that the vast majority of individuals with tuberculosis are engaged in the public health system [12]. Despite this and the over 90% curability of TB [13], it is estimated that South Africa has a successful TB treatment rate of just over 50% [12] . This is due to various factors, such as testing, with about 5% of individuals with active TB not receiving testing and a further 13% that are receiving tests, but are not receiving their diagnosis [12] . Estimates also show that about 12% of patients who receive a positive TB diagnosis don’t begin treatment, and at least 17% of patients with a positive TB diagnosis begin, but do not complete their treatment [12] . This suggests that urgent efforts are needed to improve the implementation of existing policies and protocols for TB treatments [12] .

Dr Helen Cox, an epidemiologist at the University of Cape Town Institute of Infectious Disease and Molecular Medicine, suggests that treatment literacy and counselling should be improved to better facilitate the TB treatment process [14]. Dr Cox argues that the lives of patients are complex and once patients start to feel better it often isn’t a “high priority” for them to complete their treatment process. This is especially problematic, as patients who don’t finish their course of treatment are at high risk of getting sick again, and developing drug resistant TB.
 

TB Treatment and HIV/AIDS

People with HIV and AIDS are on average 19 more times likely to develop active TB once infected, and are at a much greater risk of dying [15]. South Africa’s high TB mortality rate is directly connected to the HIV and AIDS pandemic that the country is facing.

South Africa has the highest rate of HIV in the world, with 7.7million people (20.4%) estimated to be living with HIV [16]. In 2016, over 80% of the TB related deaths were people also infected with HIV [5] .

There is also a strong correlation between the steady decline of TB and HIV related mortality and the intensive roll out of antiretroviral drugs (ARV) and antiretroviral therapy (ART), that began in 2006 [2] . South Africa now has the world’s largest ART programme. This is a major factor in combating TB mortality.

Patients who have TB and HIV/AIDS are advised to receive treatments for both illnesses.  

Drug Resistant Tuberculosis

Tuberculosis has also evolved strains of Drug Resistant TB (DR TB) also known as Excessive Drug Resistant TB (XDR TB) or Multi Drug Resistant TB (MDR TB). These strands are also contagious when active and they have developed immunity to commonly used TB treatments and do not respond as predictably to developed drug treatments.

There are over 20 000 cases of DR TB in South Africa per year and it appears that the rates of DR TB have been going up [4] . This is a contentious area of scientific development, as new drugs are being brought into circulation, and health care systems need to weigh the risks of using these drugs for treatment and the potential harm they could cause. There is also the risk of the TB bacteria further evolving immunity to drugs if they are not administered correctly.

In 2012, only 19% of XDR TB patients in South Africa were cured even if they completed the intensive two year treatment [17]. This treatment process has lacked standardisation and is a toxic process that can leave patients with severe side effects.
By 2016 67% of XDR TB patients were cured, with the introduction of the bedaquiline treatment; a drug that blocks an enzyme inside the bacteria that causes TB [17] . The latest available data on the bedaquiline-containing nine-month treatment for  MDR TB also shows improvement, with a 73% cure rate and a 9% drop-out rate [17] .

On 14 August 2019, The United States of America Food and Drug Administration (FDA) approved the medicine pretomanid used in combination with other specific medicines for the treatment of XDR TB. This three-medicine regimen, called BPaL, was shown to shorten the treatment duration for XDR TB from the current 18 months or longer to just six months [17] . It also cured around 90% of XDR TB patients in the NixTB trial conducted in South Africa [17] .

The research and testing conditions for the NixTB trial were limited and do not guarantee the same outcome when administered outside of clinical testing conditions. The World Health Organisation (WHO) has not yet approved the wide usage of this pretomanid-combination treatment, and the Global TB Community Advisory Board warned against the low approval standards the FDA used [18]. South Africa still needs to determine when it will adopt this newly FDA approved drug to treat XDR TB.
 

Most of the research has been done in South Africa and clearly we would like to be either the first country, or among the first, to offer it to patients.

- Department of Health Deputy Director-General, Dr Yogan Pillay [17]

TB and Animals

Bovine TB also known as M.Bovine, is a disease caused by a specific strain of bacteria called Mycobacterium Bovis. Bovine TB usually affects animals such as cattle, but it can affect practically all mammals, causing a general state of illness, coughing and eventual death [19].

Bovine TB can be transmitted from animals to humans as well as to other animals. The disease is spread by contact between infected domestic animals such as cattle, and wild animals and humans. The usual route of infection is by animals and humans inhaling infected droplets which are expelled from the lungs by coughing. Infection can also occur from direct contact with a wound or by ingesting raw (unpasteurized) milk and other dairy products from infected cows.

The symptoms of bovine TB can differ from the normal symptoms of TB in humans, with some reporting abdominal infections in young children and swollen and sometimes ulcerated lymph glands in the neck in older patients [19] .

The WHO estimates that up to 10% of TB infections in “developing” countries could be due to bovine TB [20], especially where there are neither schemes for compensation nor government policies of eradication.

A recent study conducted in a resource-poor community in South Africa, that is surrounded by several game parks where M. bovis infection has been previously diagnosed in wildlife, found a 12% - 28% prevalence rate of M.Bovine out of 659 cattle from a total of 192 traditionally managed herds [21]. The widespread presence of M. bovis in this cattle population raises public health concerns and warrants further investigation into the risk factors for M. bovis transmission to cattle and humans, and the need for effective control measures to reduce infection in the communal cattle and prevent its spread to uninfected herds [20] .

A major difficulty in knowing how much human disease is caused by bovine TB is that the most commonly used laboratory processes are unable to distinguish between disease caused by M. bovis and disease caused by M. tuberculosis.

Management of bovine TB occurs through herd skin testing, slaughter, surveillance and monitoring the movement of animals between herds. Vaccinating cattle for the control of bovine TB is not recommended, as it will not be possible to differentiate between cattle that have TB and cattle that have been vaccinated. It is illegal to commercially vaccinate animals with the BCG vaccine in the European Union (E.U.)

[1] World Health Organisation, 2020, “World Tuberculosis Day 2020” ↵

[2] Loveday, et al., 2019, “Figures of the dead,” ↵

[3] Cohen, et al., 2019, “A quarter of the,” ↵

[4] Spotlight, 2017, “10 things to know,” ↵

[5] National Institute for Communicable Diseases, 2019, “World TB Day 2019” ↵

[6] World Health Organisation, 2020, “Tuberculosis” ↵

[7] University College London, 2008, “Earliest known human TB,” ↵

[8] Fourie, 1987, “BCG vaccination and the” ↵

[9] National Institute for Communicable Diseases, 2016, “Vaccine information for parents,” ↵

[10] Donald Gordon Medical Centre, “Tuberculosis in South Africa” ↵

[11] TBfacts.org, “TB Statistics for South Africa,” ↵

[12] Naidoo et al., 2017, “The South African Tuberculosis,” ↵

[13] Copenhagen Consensus, “South Africa Perspective: Tuberculosis,” ↵

[14] GroundUp, 2018, “Why do so many,” ↵

[15] Kwan and Ernst, 2011, “HIV and Tuberculosis,” ↵

[[16] Avert, 2018, “HIV and AIDS in,” ↵

[17] Green, 2018, “Drug-resistant TB breakthrough,” ↵

[18] Global TB Community Advisory Board, “The Global TB Community,” ↵

[19] TBfact, “Bovine TB” ↵

[20] TBfacts, “TB statistics - latest,” ↵

[21] Sichewo, 2019, “Prevalence of Mycrobacterium bovis,” ↵