Tuberculosis: A Clinical Practice Guide

2020.

Tuberculosis Global Epidemiology

Rafael Laniado-Laborín

Abstract

Globally, tuberculosis is one of the top 10 overall causes of death, the leading cause of death from a single infectious agent, and the principal cause of death among subjects living with human immunodeficiency virus infection.

The United Nations and the World Health Organization (WHO) have set very ambitious goals for the period 2020-2035 that include a 95% reduction in the number of deaths and a 90% reduction in TB incidence by 2035 compared with 2015.

The WHO reported in 2018, an estimated 10 million incident cases of TB (global incidence rate: 133 cases per 10⁵ population), and 1.2 million TB deaths, for a case fatality rate of 15.7%. Incidence rates vary widely among regions of the world; geographically, most TB cases in 2018 were in the WHO regions of South-East Asia (44%), Africa (24%) and the Western Pacific (18%).

Rifampin-resistant (RR-TB) or multidrug-resistant TB (MDR-TB) in 2018 occurred in an estimated half a million cases, and accounted for 3.4% of all new cases and 18% of previously treated cases; an estimated 230,000 persons died of either RR or MDR-TB (case fatality rate: 41%).

Almost a quarter of the world population (1.7 billion people or 23%) are estimated to have latent TB infection and therefore are at risk of developing active TB during their lifetime.

Progress toward global TB elimination during 2018 was very modest, as it has occurred in recent years, and if kept at this current pace, the global targets for the period 2020-2035 will not be accomplished.

Keywords: Epidemiology, Incidence, MDR-TB, Mortality, Tuberculosis, XDR-TB.

INTRODUCTION

Tuberculosis (TB) has affected humans for most of its history and continues to do so even though we have had an effective pharmacological treatment for more than 70 years [1]. TB is a leading cause of death among adults in the most productive age groups, and even those that have been cured can be left with significant irreversible sequelae that will substantially affect their quality of life [2].

Globally, tuberculosis is one of the top 10 overall causes of death, the leading cause of death from a single infectious agent, and the principal cause of death among subjects living with human immunodeficiency virus infection, causing approximately 40% of deaths in this population group [3].

The United Nations (UN) and the World Health Organization (WHO) have set very ambitious goals for the period 2020-2035 (Table 1) that include a 95% reduction in the number of deaths and a 90% reduction in TB incidence by 2035 compared with 2015 [4, 5].

Table 1 The End TB Strategy. A world free of TB: zero deaths, disease and suffering due to tuberculosis*.

*modified from WHO Global Tuberculosis Report 2018 [9].

A Stop TB Partnership target is that by the year 2050, the global incidence of active TB will be less than one case per million population per year. The components of the Stop TB Strategy are:

Pursue high-quality DOTS expansion and enhancement.

Address TB-HIV, MDR-TB, and the needs of poor and vulnerable populations.

Contribute to health system strengthening based on primary health care.

Engage all care providers.

Empower people with TB, and communities through partnership.

Enable and promote research.

Tuberculosis Statistics

TB incidence has never been measured at a country level, since this would require long term prospective studies, including large population cohorts (hundreds of thousands) with very high costs and challenging logistics. As a proxy of real incidence, TB incidence is estimated from case reports included in routine surveillance systems. Unfortunately, in many countries, surveillance systems cannot provide an adequate measure of TB incidence because of underreporting or underdiagnosis of cases [6].

Incidence rates vary widely among regions of the world (Table 2). The lowest rates (<10 per 10⁵) are reported from high-income countries including most countries from Western Europe, Canada, the United States, Australia, and New Zealand; most countries in the Americas (the WHO region with the lowest TB burden) have rates <50 per 10⁵, although some countries like Haiti (181 per 10⁵), Bolivia (111 per 10⁵), and Peru (116 per 10⁵) still have very high rates [7]. The countries with the highest rates are mostly located in Africa.

Table 2 Estimated number of incident tuberculosis (TB) cases, incidence, and percentage of deaths among all TB cases*.

*modified from WHO Global Tuberculosis Report, 2018 [9].

Geographically, most TB cases in 2018 were in the WHO regions of South-East Asia (44%), Africa (24%), and the Western Pacific (18%) [8]. Eight countries account for two-thirds of the world cases: India (27%), China (9%), Indonesia (8%), the Philippines (6%), Pakistan (5%), Nigeria (4%), Bangladesh (4%) and South Africa (3%). On the other hand, only 3% of the global cases are reported by the WHO European Region and 3% by the WHO Americas region [7, 9].

The WHO reported for the year 2018, an estimated 10 million (range 9.0-11.1 million) incident cases of TB (global rate: 133 cases per 10⁵population), and 1.2 million TB deaths (range 1.1 to 1.3 million [8]. This represents a reduction of 1.8% and 3.9% in incident TB cases and TB deaths, respectively, in comparison with the year 2016; 920,000 (9%) of the incident cases and an estimated 300,000 deaths (case fatality rate 32.6%) occurred among persons living with HIV. Of the estimated 10 million cases, there were 5.8 million men, 3.2 million women, and 1 million children. Ninety percent of the cases are reported in adults (≥15 years), and, as mentioned, 9% occurred in people living with HIV, 72% of those living in Africa [9].

Rifampin-resistant (RR-TB) or multidrug-resistant TB (MDR-TB) occurred in an estimated half a million cases (range 417,000-556,000) in 2018, which constitutes 5.6% of all cases. RR/MDR-TB accounted for 3.4% and 18% of new and previously treated cases, respectively, in 2018; an estimated 230,000 persons died of either RR or MDR-TB (case fatality rate: 41%) [9]. Among the RR-TB cases, 78% were MDR [8]; of the MDR-TB cases, 8.5% (CI95% 6.2-11%) were estimated to have extensively drug-resistant TB, also known as XDR-TB. Three countries accounted for almost half of the world cases of RR/MDR-TB: India (24%), China (13%), and the Russian Federation (10%). Although the overall incidence of TB in the WHO European region was only 30 per 10⁵, the proportion of TB cases with RR or MDR-TB in this region (40%) was much higher than that in all the other five regions (range: 3.6%–6.3%) [9].

Almost a quarter of the world population (1.7 billion people or 23%) are estimated to have latent TB infection (LTBI) and therefore are at risk of developing active TB during their lifetime, become infectious, and transmit the disease [10].

Achieving the targets of the End TB strategy (Table 1) for a reduction in TB cases and deaths set for 2020 and 2025 will require to accelerate the current annual decline from 1.5% per year in 2015 to 4-5% per year by 2020, and by 10% per year by 2025. The global proportion of people who die from TB (case fatality ratio) needs to be reduced from 15.7% in 2017 to 10% by 2020 and 6.5% by 2025. This reduction in rates will only be possible if all those with TB can access high-quality health services for early diagnosis and effective treatment.

Reaching the 2030 and 2035 targets will require an average acceleration of the decline rate of 17% per year. Such acceleration will depend on technological developments that could substantially reduce the risk of progression to an active disease of 1.7 billion people with LTBI through an effective post-exposure vaccine [11] or a concise, effective, and safe treatment for LTBI [1, 6].

Despite advances in treatment and prevention, tuberculosis is one of the leading causes of morbidity and mortality and the leading cause of death from an infectious disease globally.

Tuberculosis ceased to be an essential public health issue in economically developed countries as the main determinants of disease -extreme poverty, severe malnutrition, and overcrowding- gradually disappeared. Some public health experts declared that virtual elimination of tuberculosis was in sight [12].

Although the development of antibiotic resistance due to M. tuberculosis was reported almost immediately after the introduction of the first effective regimen in the treatment of tuberculosis in 1944 with streptomycin, the effectiveness of regimens consisting of a combination of several antimicrobials in the treatment of tuberculosis during the decades of the 50’s and 60’s, brought as a consequence, the lack of interest in the development of new anti-tuberculosis drugs; 40 years had to pass between the introduction of rifampicin in the 1960s and the development of two new drugs, bedaquiline and delamanid in the 2010s [13].

However, drug resistance is only one of the factors that favor the persistence of tuberculosis as a serious public health problem. Extreme poverty and co-infection with HIV in economically underdeveloped regions are a very significant contributing factor. Globalization has improved the mobility of the population but also the transmission of tuberculosis.

The control of tuberculosis will require a comprehensive approach to tackle the disease’s socio-cultural determinants in combination with scientific advances in diagnosis [14] and treatment [15] if the disease is to be eradicated one day.

REFERENCES

Microbiology of Tuberculosis

Rafael Laniado-Laborín

Abstract

Mycobacterium tuberculosis (MTB) is the primary etiological agent of tuberculosis in humans (since the disease may be due to other mycobacteria of the MTB complex such as M. bovis). It belongs to the order of the Actinomycetales and the Mycobacteriaceae family. It is a bacillus that lacks capsule or flagella and does not produce spores or toxins; it measures 0.5 by four microns. Its generation time is prolonged (up to 24 hours). It is an aerobic bacillus that, if necessary, can persist under anaerobic conditions.

It has a cell wall of extremely complex composition, with great strength and thickness, constituted up to 60% by lipids, generally known as mycolic acids that form complexes with polysaccharides such as arabinogalactan and peptidoglycan; these lipids determine their resistance to discoloration by alcohol-acid after they have been stained with carbol fuchsin (hence the term acid-fast bacilli acid or AFB). A distinctive feature of the MTB cell wall is its content of N-glycolimuranic acid instead of N-acetylmuramic acid found in most bacteria.

The unusual cell wall of MTB also allows it to survive initially in the macrophage. The cell wall also constitutes a robust and highly impermeable barrier to harmful compounds and drugs. MTB can sense when the local tissue conditions are inadequate for survival (low oxygen tension and nutrient depletion), as in the macrophages and granulomas, responding by the activation of a dormant state, in which the bacilli stop multiplying, down-regulates its metabolism and activates anaerobic metabolism.

Keywords: Acid-fast bacilli, Granulomas, Mycobacterium tuberculosis, Mycolic acids.

INTRODUCTION

The Mycobacterium Tuberculosis Complex (MTC)

Members of the MTC are bacteria that share a genetically identical 16SrRNA sequence and a greater 99.9% nucleotide identity. The four original species of the MTC are M. tuberculosis (affects humans, known as M. tuberculosis sensu stricto), M. africanum (affects humans), M. microti (affects voles) and M. bovis (affects cattle and other bovines). Newer species of the MTC include M. pinnipedii

(affects pinnipeds: seals and sea lions), M. canettii (affects humans? it is the most ancestral recognized MTC member, although rarely isolated), the dassie bacillus (affects the rock hyraxes, [Procavia capensis]), M. caprae (affects goats), Myco bacterium orygis, (associated with various species), Mycobacterium mungi (which infects banded mongooses [Mungos mungo]), Mycobacterium suricattae (which affects meerkats [Suricata suricattae]), and M. bovis-BCG [1, 2]. The most accurate method to distinguish members of the MTC from one another are through genetic markers, single nucleotide polymorphisms (SNPs) in the 16S rDNA and gyrB genes and elsewhere in the genome, as well as extensive sequence polymorphisms referred to as regions of difference [2].

The deciphering of the Mycobacterium tuberculosis (MTB) genome that contains 4,411,529 base-pairs with high guanine-cytosine content [3] has allowed the reconstruction of the evolutionary history of MTB as an infectious agent at a global level. MTB emerged from Africa 70,000 years ago and followed human migrations and was forced to genetically evolve to be able to persist in these low-density migrant populations. The increase in human population density associated with the introduction of agriculture and overall civilization led to the selection and transmission of more virulent MTB strains, which are now known as modern MTB strains [4].

No human remains older than 11,000 years have shown the presence of tuberculosis disease, while the earliest tuberculosis case in animals has been reported in the 17,000-year-old remains of a bison [5].

Human disease by M. bovis strains is a frequent clinical finding, with transmission to the human host occurring via aerosol (in people in contact with livestock) or the consumption of infected milk. There has always been speculation that human TB originally was acquired as a zoonotic disease from cattle; the fact that animal tuberculosis preceded human tuberculosis suggests some causality with the increase in domestication of livestock. It has been hypothesized that contact of animal stocks and humans favored transmission from cattle to humans (in the past, humans shared their home with domesticated animals to protect them from the weather and predators). However, this hypothesis proved to be false when mycobacterial interspersed repetitive unit genotyping and whole-genome sequencing (WGS) provided strong evidence against such a linear explanation [5]; the accumulation of genomic deletions makes it improbable that M. bovis is the precursor of M. tuberculosis and that human TB was associated with the domestication of cattle [1].

Paleopathological studies had proven that mycobacterial disease was present in America in the pre-Columbian era [6] when Mycobacterium tuberculosis DNA was identified in a pre-Columbian Peruvian mummy [7]. It has been suggested that seals were the source of human tuberculosis in South America, predating the entrance of Mycobacterium tuberculosis L4 strains carried by the European Conquistadores. However, M. pinnipedii has been entirely replaced by the L4 lineage in the present day [8].

M. tuberculosis belongs to the order of the Actinomycetales and the Myco bacteriaceae family. It lacks capsule or flagella and does not produce spores or toxins; it stains very weakly as Gram-positive; it measures 0.5 by 4 μ. It is a preferably aerobic bacillus that, if necessary, can persist under anaerobic conditions. A distinctive feature of the M. tuberculosis cell wall is its content of N-glycolimuranic acid instead of N-acetylmuramic acid found in most bacteria. The unusual cell wall of M. tuberculosis allows it to survive inside the alveolar macrophage, a cell that usually destroys the bacteria that phagocytes.

Transmission of tuberculosis usually occurs through aerosols from one diseased host to a contact. Mycobacteria virulence will adapt to the host immunity. However, greater virulence would facilitate transmission, and it would also produce disseminated disease and some forms of TB that are nontransmissible (e.g., TB meningitis), types of disease that would rapidly kill the host stopping the chain of transmission; therefore, excessive virulence could be detrimental to mycobacteria survival. Optimal transmissibility requires enough virulence to produce a disease with a high rate of transmission (e.g., pulmonary disease through aerosols) before killing the host [1].

Mycobacterium tuberculosis is characterized by its slow growth rate (generation time in synthetic media is about 24 hours), dormancy (known clinically as latent TB infection), a sophisticated cell wall, and genetic homogeneity. The state of dormancy reflects metabolic shut down as a response to the cell-mediated immune response of the host, a response that will contain, but not sterilize the lesion. When immunity wanes (e.g., old age) or the host immune response is inadequate (e.g., due to immunosuppressive treatment or HIV co-infection), latent bacteria can reactivate, even decades after the primary infection [9].

One of the host responses to M. tuberculosis infection is the formation of a cluster of macrophages, creating a granuloma surrounding the mycobacteria. Host immune containment by granuloma formation creates a physical micro environment with nutrient limitations, a low pH,