On March 24th 1882 Koch’s announcement in Berlin of the discovery of the microbial
cause of tuberculosis (TB), Mycobacterium tuberculosis, heralded a major breakthrough,
bringing hope for a devastating disease which at that time caused the death of one
in seven people in Europe and the Americas. (Wallstedt and Maeurer, 2015). One hundred
and twenty years later, and despite the availability of effective treatment for the
past 6 decades, 1.4 million people die of TB annually (WHO, 2021a). Over the past
15 months, the unprecedented COVID-19 pandemic has disrupted health services globally
(Cilloni et al., 2020) and has negatively impacted on gains being made in global TB
control efforts to achieve End TB targets (Sahu et al., 2020; STOP TB, 2019).
The theme of this year’s World TB Day March 24th, 2021, ‘The Clock is Ticking’ (WHO,
2021b), conveys the sense of urgency that the world is running out of time to deliver
the commitments to End TB made by global leaders at the United Nations General Assembly
high level meeting on TB (UNGA, 2018). This theme is particularly appropriate and
critical in light of the devastating COVID-19 pandemic which is currently the top
killer from an infectious disease globally, with TB now being shifted to second place
(WHO, 2021a; WHO, 2021c). Since the end of December, 2019, when the WHO was made aware
of several cases of atypical pneumonia in Wuhan, China, caused by the novel severe
acute respiratory syndrome coronavirus 2 (SARS-CoV-2), as of March 15th 2021, there
have been 119,603,761 confirmed COVID-19 cases, with 2,649,722 deaths, reported to
WHO (WHO, 2021c).
In commemoration of World TB Day March 24th, 2021, the International Journal of Infectious
Diseases is once again publishing a specific TB Theme issue of 18 articles covering
a range of topics.
The October 2020 WHO Global TB report and the United Nations (UN) Secretary-General’s
2020 progress report on TB, are reviewed by Chakaya et al. (2021). They reflect on
current TB control strategies in light of the United Nations (UN) targets set in the
political declaration at the September 2018 UN General Assembly high-level meeting
on TB held in New York (UNGA, 2018). Progress in achieving TB control targets has
been very slow. Globally, an estimated 10.0 million people developed TB disease in
2019, and there were an estimated 1.2 million TB deaths among HIV-negative people
and an additional 208,000 deaths among people living with HIV. In addition, preliminary
assessments of how the unprecedented, devastating COVID-19 pandemic is affecting TB
health services, interrupting and slowing down treatment and prevention efforts. It
is anticipated that the End TB strategy target of ending TB by 2035 will not be met.
The WHO 2020 TB Report (WHO, 2021a) states that a 50% drop in the number of people
with TB detected, could result in up to 400,000 additional TB deaths in a year. Innovative
plans are needed to maintain all TB services as well as access to these services,
in the wake of the COVID-19 pandemic and investments in the development of low-cost
rapid diagnostic tests for both COVID-19 and TB are urgently needed. There needs to
be a rejuvenated, sustained, and concerted effort to identify and treat ‘missing people
with TB’. Governments of high TB incidence countries need to ensure there are rapid
TB diagnostic services available in every health facility, so all TB cases can be
reached. Global health inequities that underlie differences in TB disease burden,
as well as daunting environmental health challenges, need to be addressed by multiple
approaches and sectors.
Fox et al. (2021) highlight that latent tuberculosis infection affects one quarter
of the world’s population and that despite effective oral treatment regimens being
available, scale-up and rollout of TB preventive treatment (TPT) remains limited.
They describe strategies to support scale-up of TPT in high-prevalence settings, where
the potential benefit for affected individuals is considerable and emphasise that
patients must be at the centre of TPT policies. Addressing health system requirements
for scale-up will be important to ensure that programs can deliver treatment safely,
efficiently and sustainably.
Nachega et al. (2021a) discuss the negative impact of COVID-19 on TB and HIV health
services. They suggest approaches to mitigate the growing burden of these colliding
epidemics in sub-Saharan Africa, which bear the highest proportions of TB and HIV
cases worldwide. The COVID-19 pandemic has added an additional burden to already overstretched
health systems, which, among many other things, were struggling to deal with the longstanding
dual epidemics of TB and HIV.
Knipper et al. (2021) review the COVID-19 pandemic threat to derailing health services
for forcibly displaced people and migrant populations, populations who face specific
vulnerabilities placing them at increased risk of developing TB if they have LTBI,
or not being diagnosed as having active TB. Highlighting three case studies as examples—from
Peru, South Africa, and Syria—they illustrate the lived experience of forced migration
and mobile populations, and the impact of COVID-19 on TB among these populations.
They indicate that addressing TB, COVID-19 and migration from a syndemic perspective,
not only draws systematic attention to comorbidity and the relevance of social and
structural context, but also helps to find solutions. The true reality of syndemic
interactions can only be fully understood by considering a particular population and
bio-social context and ensuring that they receive the comprehensive care that they
need. It also provides avenues for strengthening and expanding the existing infrastructure
for TB care to tackle both COVID-19 and TB in migrants and refugees in an integrated
and synergistic manner.
Over a quarter of the individuals diagnosed with TB in the European Union region are
born outside the EU and the proportion has been increasing steadily. Over 50% of TB
cases in Italy are foreign born migrants. Goscé et al. (2021) describe the EDETECT-TB
project in Italy which implemented and evaluated active TB screening in the migrant
population and their study confirmed that early case detection is a cost-effective
intervention and that targeted post-arrival early screening ensures that potential
further transmission is averted.
Recurrent pulmonary TB is a growing, important and neglected problem affecting treated
TB patients and TB health services across the world, particularly in sub-Saharan Africa
and Asia. Analyses and identification of differences in clinical features between
recurrent PTB and newly diagnosed PTB may lead to improved management recommendations.
Nagu et al. (2021) performed a prospective case-controlled study of clinical and imaging
features of patients with recurrent pulmonary TB (RPTB) and compared them with those
of newly diagnosed PTB cases. They found that hemoptysis, lung parenchymal damage,
and patients being older than 45 years of age are significant features of RPTB, suggesting
that management of TB cases should focus on risk factors for recurrence, and design
a more holistic model of care to prevent long term lung injury.
Kizny Gordon et al. (2021) review the clinical and public health utility benefits
of M. tuberculosis whole genome sequencing (WGS), including provision of more rapid
and complete information on drug-resistance, detection of transmission clusters, contamination
events, mixed infections, and to differentiate between re-infection and relapse. They
also discuss future advances that have the potential to change the landscape of TB
diagnostics and management, such as culture-free sequencing and surveillance of antimicrobial
resistance to guide precision medicine approaches, as well as some of the challenges
involved. Whole genome sequencing-based differentiation between re-infection and relapse
in TB cases has important implications for public health, especially in patients with
human immunodeficiency virus (HIV) coinfection. Shanmugam et al. (2021) compared Mycobacterial
Interspersed Repeat Unit (MIRU) typing and spoligotyping with WGS to differentiate
between relapse and re-infection and assessed the value of WGS to track acquired drug
resistance in those with relapse after successful treatment. Comparing M. tuberculosis
genomes, they found that 95% of TB recurrences in the HIV-negative cohort were due
to relapse, while the majority of TB recurrences in the HIV-positive cohort were due
to re-infection, highlighting the need for effective infection control in HIV care
setting.
WGS for M. tuberculosis drug resistance detection is now available in diagnostic and
reference laboratories worldwide. Characterizing novel mutations and deletions associated
with drug resistant M. tuberculosis could ultimately lead to better treatment outcomes.
The additional value WGS provides in inferring drug resistance is discussed by Lam
et al. (2021). They sequenced genomes from all M. tuberculosis isolates in NSW, Australia,
collected between 2016 and 2019 and tracked the prevalence of drug resistance and
circulation of predominant M. tuberculosis lineages. They demonstrated that WGS was
able to capture an additional 20% of drug resistance mutations not detected by commercial
diagnostic assays, signaling the additional value that WGS offers over existing genotypic
drug resistance assays in terms of sensitivity.
The Bandim TBscore is a clinical score that predicts treatment outcome in TB patients
and may prove useful as an indicator of which healthcare-seeking adults to refer for
sputum smear microcopy. Rudolf et al. (2021) conducted a stepped wedge cluster-randomized
trial at six health centers in Bissau, Guinea-Bissau, and Gondar, Ethiopia. They conclude
that it is an implementable approach and solution to an old and yet unresolved challenge.
Using the TBscore for triage before smear microscopy may improve case detection and
decrease mortality if there is sufficient laboratory capacity to increase sputum smears.
Marais et al. (2021) discuss new advances to close persistent gaps in the prevention
and diagnosis of childhood TB. Almost all children estimated in the Global TB Report
2020 to have died from TB were never diagnosed or offered TB treatment. Thus new approaches
are required to ensure that effective TB prevention strategies are implemented and
to improve the accuracy of current and new diagnostic (rule-in and rule-out) tests.
Reducing the major gaps in TB preventive treatment (TPT) will require strong political
commitment and concerted effort, with major upscaling of household contact investigation.
While widespread roll-out of Xpert MTB/RIF Ultra® should be supported and could improve
case detection in young children, they caution that specimen collection remains difficult
and test sensitivity low. The use of non-sputum specimens are essential to improve
diagnostic access, but given the limited accuracy of all available tests and the excellent
tolerance of TB drugs in children the global community may have to accept some over-treatment
using the most feasible approaches available; if we are serious about closing the
persistent case detection gap in young children.
Zoonotic TB is evolving in an everchanging global landscape. Despite slow reductions
in the annual burden of active TB cases, Zoonotic TB (zTB) remains a poorly monitored
and poorly addressed global burden. Kock et al. (2021) in their zoonotic TB review
highlight the higher incidence in some specific regions and countries, especially
where close association exists between growing numbers of cattle (the major source
of Mycobacterium bovis (M. bovis) and people, many suffering from poverty and where
milk or dairy products are consumed un-pasteurized. Attention needs to be re-focused
to prevent a rapid increase in zTB disease along with growing intensification of dairy
production. Evidence of new zoonotic mycobacterial strains such as M. orygis, especially
in South Asia and Africa warrants rapid assessment of drivers and risk, and the development
of appropriate interventions. Control of M. bovis in cattle through early detection
of infection and disease, as well as pasteurization of dairy products, remains the
mainstay of reducing zTB risk to humans, while new point of care diagnostics will
help to detect and appropriately treat human cases.
Lipman et al. (2021) highlight that pulmonary disease caused by non-tuberculous mycobacteria
(NTM) is often missed, is difficult to treat successfully in an often frail population
with other chronic conditions such as bronchiectasis and COPD, is on the rise globally,
and results in significant morbidity and even mortality. They identify and discuss
key issues in NTM management. In addition to the need for research into epidemiology,
immunology and treatment, they recommend an 8-point plan including greater use of
patient and clinician networks to educate primary and secondary care clinicians and
promote a multidisciplinary team approach with shared patient-clinician decision making
throughout care. They also call for co-ordinated patient-focused research to improve
what is often a limited evidence base to guide management.
Nachega et al. (2021b) re-ignite the century old controversies on the Bacille Calmette–Guérin
(BCG) vaccine, which is yet again a focus of global attention—this time due to the
global COVID-19 pandemic caused by SARS-CoV-2) Their viewpoint focusses on the assumptions,
knowns, unknowns and need for developing an accurate scientific evidence base for
suggestions of potential cross-protection against SARS-CoV-2 infection. Recent studies
have shown that human CD4+ and CD8+ T-cells primed with a BCG-derived peptide developed
high reactivity to its corresponding SARS-CoV-2-derived peptide. Furthermore, BCG
vaccine has been shown to substantially increase interferon-gamma (IFN-γ) production
and its effects on CD4+ T-cells and these nonspecific immune responses could be harnessed
as cross protection against severe forms of COVID-19. They highlight that there are
numerous clinical trials in progress to determine the effectiveness of BCG vaccination
for prevention of SARS-CoV-2 infection or to reduce morbidity and mortality associated
with COVID-19. Data from ongoing BGG trials may shed light on the mechanisms underlying
BCG-mediated immunity and could lead to improved efficacy, increased tolerance of
treatment, and identification of benefits combining BCG and COVID-19 vaccines, or
other adjunct immunotherapies.
There are several ongoing studies which are defining the interactions between COVID-19
and TB. Petrone et al. (2021) evaluated IFN-γ levels in whole blood after stimulation
with Mtb antigens in the Quantiferon-Plus format or with peptides derived from SARS-CoV-2
spike protein, Wuhan-Hu-1 isolate (CD4-S). They demonstrated for the first time that
COVID-19 patients, either with TB or LTBI, have a low ability to build an immune response
to SARS-CoV-2 while retaining the ability to respond to Mtb-specific antigens. These
results may have important implications for the clinical management of COVID-19 individuals
coinfected with Mtb.
Fatima et al. (2021) focus on TB control in Pakistan and discuss the importance of
a multi-pronged approach for building better TB control systems to cope with the effects
of COVID-19. As in all high-TB endemic countries, COVID-19 is impacting negatively
in Pakistan. The COVID-19 has provided an opportunity in country to introduce some
adaptations to bring TB care closer to communities, increased investments in human
resources and addressing stigma, and implementation of telemedicine systems for follow-up
and consultations. Global health inequities driving TB epidemiology, including the
environment and climate control, gender, age, socio-economic status, and wealth as
well as resource distribution, need to be addressed by multiple approaches and sectors.
The WHO 2020 global TB Report estimates that in 2019 there were an estimated 500,000
cases of multi-drug resistant TB (MDR-TB) of which only 186,772 MDR-TB cases were
diagnosed, and positive treatment outcomes were achieved in 57% of them. These data
highlight the need for accelerating and improving MDR-TB screening, diagnostic, treatment
and patient follow-up services. Maretbayeva et al. (2021) present the first study
from Kazahstan on culture conversion at six months in patients receiving bedaquiline-
and delamanid-containing regimens for the treatment of MDR-TB.
Tiberi et al. (2021) emphasize that the direct and indirect negative impacts of COVID-19
on health services overall, including national TB programs and TB services add further
to longstanding challenges for tackling MDR-TB such as availability of budgets, rollout
of TB diagnostics and TB drugs. Implementation of latest WHO guidelines for MDR-TB,
in light of COVID-19 disruption of TB services will be difficult and, it is anticipated
the numbers of MDR-TB cases will rise in 2021 and 2022 and will affect MDR-TB treatment
outcomes further. Investing more in development of new TB drugs and shorter MDR-TB
treatment regimens is required in anticipation of emerging drug resistance to new
TB drug regimens. These include closely aligning and optimizing COVID-19 and MDR-TB
algorithms and improving clinical capacity to offer rapid diagnosis, quality treatment
and follow up, and ensuring availability of quality, regular supply of cost-free TB
drugs (for both DS-TB and MDR-TB) through improved procurement and distribution of
TB drugs.
Sahu et al. (2021) remind us that it has been over two years since global leaders
signed the UN General Assembly high level meeting on TB (UNGA-HLM-TB) declaration
which committed to mobilize 15 billion USD per annum for TB, 13 billion USD for TB
care and 2 billion USD per annum for TB R&D (UNGA, 2018). They point out that the
follow up October 21, 2020 UN Secretary-General report (UNGA, 2020) on progress towards
implementation of the UNHLM political declaration on TB stresses that although high-level
commitments and targets had galvanized global and national progress towards ending
TB, urgent and more ambitious investments and actions were required, especially in
lieu of the COVID-19 pandemic where associated public health measures and travel restrictions,
have disrupted health services universally. The report sets out 10 priority recommendations
to get the world on track to reach agreed targets by 2022. Importantly, all countries
should signup to these ten priority recommendations and the Global Fund needs to increase
its current commitment to mitigating the impact of COVID-19 on TB services (Global
Fund, 2020). Additional supplementary measures and resources are required to reduce
the accumulating pool of undetected people with TB. These should include ramped-up
active case-finding with intensive community engagement and contact tracing to sustain
awareness of recognizing and responding to symptoms suggestive of TB, using digital
technology and other diagnostic tools, and an uninterrupted supply of quality TB drugs
and care for all people with TB (Stop TB Partnership, 2020).
On World TB Day 2021, every political and community leader, and funding agency must
get the message that it is time to reduce global inequities as we work towards a TB
free world. While there is a continued need to develop new prevention and treatment
tools for TB, obtaining the resources required for implementation of current TB diagnostic
and management tools could significantly advance TB control efforts. World leaders
need to urgently address and reverse the socio-economic and health services impact
of the COVID-19 pandemic. As COVID-19 vaccines and public health measures start to
have an effect on slowing down the COVID-19 outbreak, every effort must be made by
to ensure that health services and prevention programs for TB are not compromised.
The commitment of western governments to the rapid development and rollout of COVID-19
vaccines is commendable, but it is important to ensure that no-one is ‘left behind’.
It’s now time for them to invest with equal commitment to ending the TB epidemic.
Reality showed us that it can be achieved, if there is serious political will which
is translated into measurable, tangible actions resulting in impactful deliverables.