Addressing TB disease, a global burden

Bacteria, fungi, viruses, protozoan parasites; we share our world with countless agents of infectious, disease-causing bugs. Globally, infectious (or ‘communicable’) diseases of various stripes – respiratory infections, HIV/AIDS, diarrheal diseases, malaria, tuberculosis, and meningitis among them – together remain the fourth leading cause of death, with people from lower-income countries being disproportionately more affected. Children form an especially vulnerable group; according to the World Health Organization (WHO), 6.6 million children under 5 years died worldwide in 2012, and over two-thirds of these deaths were attributable to infectious causes.

The scourge of TB

Of all the infectious diseases plaguing humankind, one – tuberculosis (TB), the disease caused by the rod-shaped bacterium, Mycobacterium tuberculosis (Mtb, for short) – has been contributing significantly to the global burden of disease throughout history (even in ancient Egypt, around 600 BCE).

TB is contagious. When a TB patient forcefully exhales (such as during a cough, sneeze, conversation or musical performance), microscopic, bug-laden droplets remain suspended in air, and enter unbeknownst the lungs of others in the vicinity via the nose. As one can imagine, therefore, environmental exposure to TB (and infection) can occur without one’s knowledge. This is especially true for certain parts of the world – called regions ‘endemic’ for TB – where the TB disease burden is very high, such as sub-Saharan Africa, parts of Asia, Central and South America. In 2012, WHO estimated 12 million TB cases in the world (WHO Global Health Observatory data); in the same year, as a point of comparison, close to 10,000 people came down with TB in the United States, even though the rate of TB incidence has been declining in this country.

2010 data: TB incidences globally; source: CDC Yellow book

Interestingly, however, this infection process is not always sufficient to cause disease. Usually, bug-devouring immune cells (a.k.a. phagocytes, the first line of defence in the lungs), gobble incoming bugs, kill and break them apart, and use the bug components to educate and prime other players in the immune system, such as T-cells and B-cells. If, for some reason, the phagocyte is unable to kill the bug inside, other phagocytes and other cells come together and build a wall around it (known as a ‘granuloma’), preventing the bug from escaping.

Unfortunately, Mtb, having been around for a really LONG time, has learned a few tricks of its own: Mtb has developed mechanisms to prevent phagocytes from killing it, to hide within these cells, and – when the environment is propitious – to escape the confinement and spread to neighboring cells, sometimes by subverting the immune cells’ own internal processes.

LTBI and active TB disease

For healthy individuals, the exposure usually does not pose a problem; the immune defence cells come together to restrict the growth and spread of the bacteria, and push it into dormancy (i.e. hiding). This condition is known as a Latent TB Infection (‘LTBI’); many people with LTBI never develop disease, because their immune system can fight back.

However, if, at the time of infection, the immune system of the person is weakened because of other conditions (such as HIV infection/AIDS, cancer, medical treatments that work by suppressing immunity, et cetera), or if the immune cells are unable to fight back adequately (as in children or the elderly), Mtb becomes active and starts multiplying in the lungs and elsewhere. This is an active TB disease, and the host becomes ill, as well as contagious. TB is the leading killer of people living with HIV/AIDS.

Once diagnosed, TB is treated by using a combination of several anti-tubercular drugs, usually for 6-9 months. To ensure all the bugs in the body are dead, it is essential to complete the entire course of all drugs. Treatment of LTBI seeks to kill dormant Mtb and requires fewer drugs, but is used for the same time span.

How do doctors figure out if one has TB?

The active TB disease, which makes a person rather ill, is diagnosed by a combination of:

1. Evaluation of clinical symptoms
2. A skin or blood test that checks if the patient’s immune system recognizes and reacts to Mtb; this indicates prior exposure
3. Chest X-ray that searches for suspicious abnormalities in the lung structure, if any, and
4. Microbiological tests.

Mtb, rod shaped, in a sputum smear; photo courtesy: CDC/Ronald W. Smithwick, 1975

Diagnostic microbiological tests use biological specimens collected from the patient (usually, ‘sputum’, i.e. mucus material coughed out from the throat or upper part of the air canal) to check for the presence of Mtb under the microscope. In parallel, attempt is made to grow (‘culture’) it in an artificial medium. Mtb is notoriously hard to grow outside the body; therefore, some experts have recommended techniques that can use Mtb genetic material (‘DNA’) to accurately identify the bug; however, these techniques are not without their own, significant challenges, both procedural and economic.

In addition, it becomes often necessary to test the bug for inherent or acquired resistance to the anti-tubercular drugs being used; drug-resistant TB (‘MDR’ and ‘XDR’) is a serious problem in TB treatment, which has prompted the search for newer and better drugs. In situations where Mtb cannot be grown, DNA-based molecular techniques may help; this principle forms the basis of a new test, called Xpert MTB-RIF, which detects Mtb and can simultaneously identify if the bug is resistant to Rifampicin, a first-line TB drug. For diagnosis of suspected MDR-TB, TB in HIV-infected people, and TB spread outside the lungs, WHO currently recommends this test and encourages its field implementation.

Since people with LTBI can get sick with active TB years later, if their immunity decreases, the diagnosis of LTBI assumes great importance for public health. It is challenging, because the disease is unrecognizable in individuals who have no tell-tale symptoms, leaving only specialized blood tests as indicators. It has been difficult to gauge accurately the proportion of global population with LTBI, which according to some estimates may be around 2.3 billion; an estimated 1 in every 10 such individuals is likely to have active TB during their lifetime.

The undue burden on children

Globally, children (defined as under 15 years of age) are the hardest hit, even though the full scope and extent of childhood TB is not known. TB in the pediatric age group has often been neglected by collators of health data, since children were not considered to be infectious and high risks for community disease propagation. Global plans to eradicate TB, drawn up by international bodies like WHO and the Stop TB Partnership, often omit any childhood TB-specific goals. In addition, diagnosing childhood TB is subject to many procedural and socio-economic challenges, and the numbers, when reported, are muddied by comorbidities (such as HIV, malnutrition, pneumonia, and meningitis), resulting in severe underestimates.

The 2010 TB data from WHO (published in 2011) reported new TB cases segregated by age group, with 49,000 children all over the world, and a 65% case notification rate. This, too, is likely an underestimate, because it represented only one measure of positive cases (‘smear positive’). However, the 2012 Global TB report (containing 2011 data) represented the first concerted attempt by WHO to address the TB burden in children. At a 66% case notification rate, WHO estimated 490,000 TB cases in children in 2011, with 64,000 deaths from TB in absence of HIV; the 2012 update (2013 Global TB Report) puts these numbers at more than half a million new TB cases, and death of about 74,000 children.

A recent study published in The Lancet Global Health* employed extensive mathematical modeling, and combined official 2011 TB and population data from WHO and the UN bodies, as well as 2010 case notification data, with exposure predictions and natural history of pediatric TB. According to this study, in the 22 countries identified to have a high TB burden (accounting for about 80% of the world’s TB cases), 53 million children under 15 were infected via exposure by 2010, with 7.5 million in 2010 alone, of which 650,000 developed active TB disease.

This model yielded larger numbers compared to the WHO statistics. However, regardless of the calculation methods, these figures highlight the immense burden of TB disease borne by children across the world.

Aggressive public health measures undertaken by various governments around the world since 2000 (the year of the United Nations Millennium Declaration) have achieved a modicum of success in terms of combating tuberculosis, in conjunction with HIV/AIDS and other diseases; in the United States, 2013 statistics show a decrease of 4.2% in annual TB incidence rate (a downward trend since 1992), as well as decrease in TB deaths. However, paucity and poor quality of health data from various parts of the world, especially the lower-income countries, have called into question the achievements reported by global bodies such as the WHO and UNAIDS. In its 2013 Global TB Report, WHO has acknowledged that the set target of 50% reduction in active TB disease worldwide by 2015 may not be achievable due to various reasons, and has laid out steps for progress. The US CDC, WHO, the Stop TB Partnership, and other global bodies continue to work towards bringing more awareness and helping high burden countries inch towards TB elimination.

* NOTE:
For the sake of academic integrity, it needs to be mentioned that this study – as mentioned in the author disclosure – was commissioned as a part of a market research to estimate the market for pediatric TB drugs and formulations for a non-profit body (TB Alliance) that has an interest in TB drug development, and can theoretically benefit from an inflation in its target market size. But from the study published, I have no reason to believe that the authors were motivated by any concern other than scientific or benefit to the countless TB patients across the world.