Tuberculosis develops from infection with Mycobacterium tuberculosis (Mtb), an acid-fast bacillus. Due
to the aerobic nature of the bacillus, it preferentially infects the lungs to cause pulmonary TB. However,
it can also spread and infect other body systems, such as the urinary tract and the cen...
Tuberculosis (TB) is a severe disease that impacts public health globally. From available data, about two
billion individuals are latently infected; 8-10 million TB cases arise yearly. The World Health
Organization (WHO) ranks TB among the top 10 leading causes of mortality worldwide. It is recognised
as the primary cause of mortality globally as a single infectious agent, alongside HIV/AIDS and COVID-
19. The disease has risen to epidemic proportions, particularly in sub-Saharan Africa (SSA), Kenya
ranking among the top 30 countries with the highest TB burden (World Health Organization. Global
Tuberculosis Programme, 2021). A consultative process by the WHO defined lists of high-burden
countries between 2016 and 2020 in three levels: one list was for multidrug-resistant TB (MDR-TB), one
for TB, and one for HIV-associated TB. Kenya is one of the 14 countries that appear on all three lists.
These countries bear an enormous burden of the impact of TB. Global estimates project that about 63%
of the incident TB cases in 2019 occurred in these countries (MacNeil, 2020).
Tuberculosis develops from infection with Mycobacterium tuberculosis (Mtb), an acid-fast bacillus. Due
to the aerobic nature of the bacillus, it preferentially infects the lungs to cause pulmonary TB. However,
it can also spread and infect other body systems, such as the urinary tract and the central nervous system.
Shimeles et al discussed determinant factors associated with TB in adult populations in high-burden TB
areas (Shimeles et al., 2019). These risk factors are likely predictors for tuberculosis and can be broadly
categorised as environmental, socioeconomic and host/pathogen genetics. A distinctive feature of
tuberculosis is the wide variation in the outcome of exposure to the pathogen, which ranges from a latent
stage where individuals are exposed and infected but do not have any clinical symptoms to a more
symptomatic infectious stage. Since only 10% of individuals infected with the bacillus in an HIV-1
negative population often progress to clinically evident active disease, many studies have postulated that
exposure is significantly hinged on several host genetic factors that play a role in regulating disease
expression (Duarte et al., 2018; Selvaraj, 2004; Wu et al., 2013).
Latent tuberculosis state can be identified when Mycobacterium tuberculosis antigens persistently
stimulate the immune system without inducing the clinical symptoms of active TB. Most people who
develop this state are asymptomatic but are more likely to develop active TB eventually (World Health
Organization, 2018b). Although the actual burden of latent tuberculosis globally has not been established,
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,data shows that at least a third of humans have LTBI. Individuals who closely interact with PTB patients
often have a significantly higher risk of getting infected due to prolonged exposure. Studies show that
10% of latent TB patients later progress to clinically symptomatic TB within the first five years of the
initial infection (Kiazik S and Ball TB, 2017; Comstock et al., 1974), with clinical conditions associated
with immune deficiency being the most common predictor for progressing to active TB (Blumberg &
Ernst, 2016). People living with HIV and have LTBI (primary tuberculosis) are 26 times more likely to
progress from latent to active TB (Kiazyk & Ball, 2017; Tilahun et al., 2019).
WHO has recommended a systematic screening approach for high-risk individuals and preventive therapy
as control strategies for eliminating TB (Blumberg & Ernst, 2016). The preventative strategy postulates
that TB elimination programs should incorporate screening for LTBI and prevent its progression to TB as
part of primary care. The updated guidelines on the management of LTBI by the WHO (World Health
Organization, 2018b) propose that children and both HIV-negative and positive adult HHCs of PTB
patients who are living in a country with a high TB incidence should undergo a proper clinical evaluation
to exclude active TB, and after that preventive therapy offered to those who test positive. Knowledge of
LTBI and active TB dynamics in different populations at host and bacteria levels is crucial for controlling
the disease.
Several studies on host genetics have investigated why some individuals are less prone to contracting TB
than others. Infectious diseases such as TB exert much selective genetic pressure on victims because the
genes that evoke immune responses are very diverse (Burgner et al., 2006). Many studies that have
assessed the contributions of specific variations of specific DNA sequences (polymorphism) in the human
genome and resistance or susceptibility to TB have elicited more questions than answers. Findings from
some of these studies suggest that the outcome of exposure to M. tuberculosis and subsequent infection
depends on bacteria, environmental, and host genetic factors, among several other factors (Coscolla &
Gagneux, 2014).
The Human Leukocyte Antigen (HLA) has been studied extensively as a genetic risk factor for infectious
disease transmission, auto-immune diseases and cancers ( Kettaneh et al., 2006; Yim & Selvaraj,
2010Debebe et al., 2020). The nature and localisation of HLA polymorphism observed in populations
would contribute significantly to disease susceptibility because different people express alleles and their
specific extended haplotypes differently (Fernando et al., 2008; Pisanti et al., 2020). Understanding the
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,protective association of HLA in particular populations will be helpful for future studies in developing
new epitope-based vaccines specific to phylogeographical lineages. The HLA class 2 genes, notably the
HLA-DRB and HLA-DQB1 loci, have impacted the mycobacterial antigens presented to T helper cells
for destruction (Bakir-Gungor & Sezerman, 2011).
This work investigates the prevalence of LTBI and socio-demographic dynamics among adult HHCs of
PTB patients in a Kenyan setting. We will also highlight the experiences and challenges faced by the
contacts of the PTB patients at the household level and propose a prototype PTB patient HHC Data card
that can be customised for TB diagnostic centres. Furthermore, we discuss the findings of an exploratory
analysis on the distribution of HLA-DQB and HLA-DRB allele groups among the study participants
grouped as those with active disease (PTB patients), those who are LTBI positive (HHCs who are exposed
and infected but asymptomatic) and those who are LTBI negative (HHCs who are exposed but do not have
immunological evidence of infection). We explore which HLA alleles can be further investigated as
markers for the acquisition and development of PTB in this population.
1.1 THESIS OVERVIEW
This thesis is divided into six chapters. The first chapter gives a general overview of Mycobacterium
tuberculosis and this study's rationale and aims. The second chapter is an in-depth write-up on facts and
emerging issues regarding the diagnosis and treatment of LTBI in various populations and the role of HLA
in TB immunopathogenesis. The third chapter details the protocol used to measure the study's stated
objectives. The findings and discussion of the results are presented in the fourth and fifth chapters. Finally,
the study conclusions, limitations and recommendations are shown in the last chapter.
1.2 STUDY JUSTIFICATION
The HHCs are the TB patients' primary caregivers at home and, subsequently, have a high cumulative
exposure to the infectious agent through close physical and social contact in the shared living space.
Consequently, the HHCs are more likely to acquire M. tb infection. Identifying and treating individuals
with LTBI significantly reduces active TB cases. However, the available data on the prevalence of LTBI
and its associated factors among adults living with PTB patients in Kenya is relatively minimal. Increased
sensitisation on the available testing and treatment options of LTBI among this population and
highlighting the challenges they face while caring for the TB patient within the home setup will
significantly reduce TB cases. Host genetics has been documented as an essential factor in susceptibility
3
, to infectious diseases. The Human Leucocyte Antigen (HLA) class II alleles influence the early immune
response to TB by presenting antigens to CD4+ T cells; hence polymorphisms in the genes can affect the
immune response to infection regulation and progression to active disease. By identifying the
polymorphisms within this population, this study will offer insight into alleles that can be explored as
predictive biomarkers of infection outcomes among individuals exposed to the bacilli. Also, knowledge
of the HLA alleles' contribution to the immunopathogenesis of TB within this population will provide
valuable data for future studies on vaccine candidate development.
1.3 OBJECTIVE
To investigate Latent Tuberculosis Infection and Human Leukocyte Antigen polymorphisms in
Pulmonary Tuberculosis patients and their household contacts in Kenya.
1.3.1 Study Objectives
1. To measure the prevalence of Latent Tuberculosis Infection among Household Contacts of
Pulmonary Tuberculosis patients in Nairobi, Kenya.
2. To identify risk factors for Latent Tuberculosis Infection among the Household Contacts of
Pulmonary Tuberculosis patients in Nairobi, Kenya.
3. To determine the distribution of Human Leukocyte Antigen Class II (HLA-DRB and HLA-DQB)
allele groups in the study population.
4. To evaluate the association between Human Leukocyte Antigen Class II (HLA-DRB and -DQB)
allele group frequencies and the outcome of exposure to Mycobacterium tuberculosis.
1.3.2 Secondary objectives
1. To document challenges experienced by Household Contacts of PTB patients in an urban setting.
2. To design a prototype PTB HHC Data card that can be customised in specific TB diagnostic centres
to follow up on household contacts of PTB patients.
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