Chapter 1: Introduction
1.3 Diagnosis and screening of HIV-associated tuberculosis
In 2020, the gap between the total number tuberculosis cases and number of tuberculosis cases reported was 4.1 million worldwide (Figure 1-6).1 The gap is a result of both underreporting of people diagnosed with tuberculosis and underdiagnosis of tuberculosis.
Although this gap was becoming smaller between 2017 and 2019, the gap widened from 2019 to 2020 because the COVID-19 pandemic resulted in a reduction in the estimated total number of tuberculosis cases reported by 18%.1 In a meta-analysis of facility-based autopsy studies among PLHIV, tuberculosis was estimated to be the cause of death in 37% of all deaths, but 46% of these tuberculosis cases went undiagnosed at time of death.12 Therefore, undiagnosed tuberculosis potentially accounts for approximately 20% of all facility-based deaths in PLHIV.
Figure 1-6: Global number of tuberculosis cases reported (black) and estimated number of total tuberculosis cases (green) from 2000 to 2020 (shaded area represents
uncertainty interval)1
HIV-associated tuberculosis is challenging to diagnose.PLHIV with severe immune suppression typically have disseminated or extrapulmonary tuberculosis, a non-specific clinical presentation, and produce paucibacillary specimens that reduce the accuracy of diagnostic tests.23,24 Furthermore, a large proportion have difficulty producing sputum for diagnostic testing, especially in certain subgroups such as inpatients.18,19,24,25
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Strategies as part of the global response to tuberculosis, from the DOTS strategy to the STOP TB Strategy and now the WHO End TB Strategy, have placed a strong emphasis on early and accurate diagnosis of HIV-associated tuberculosis.26 The current WHO End TB Strategy includes 10 components housed within 3 strategic pillars: 1) integrated, patient-centred tuberculosis care and prevention; 2) bold policies and supportive systems; and 3) intensified research and innovation (Table 1-2).26 The first pillar has 4 components. The first component is early diagnosis of tuberculosis, including systematic screening of high-risk groups such as PLHIV. The third component is collaborative tuberculosis/HIV activities and management of co-morbidities. For this component, WHO has developed a 12-point package on collaborative TB/HIV activities.27 One goal of the package is to reduce the burden of tuberculosis in
PLHIV using the “Three I’s” strategy, which involves intensified tuberculosis case-finding (ICF; which includes systematic screening) and high-quality treatment; isoniazid preventative therapy (IPT) and early ART; and tuberculosis infection, prevention, and control. Effective tuberculosis screening and diagnosis are crucial to ensure effective implementation of each of the “Three I’s”. The third pillar, which includes 2 components, emphasizes intensified
research and innovation, including new tools and strategies to improve screening for and diagnosis of tuberculosis.
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Table 1-2: Pillars and components of the WHO End TB Strategy6 Pillar 1 - Integrated, patient-centred care and prevention
1. Early diagnosis of tuberculosis including universal drug-susceptibility testing, and systematic screening of contacts and high-risk groups
2. Treatment of all people with tuberculosis including drug-resistant tuberculosis, and patient support
3. Collaborative tuberculosis and HIV activities, and management of comorbidities 4. Preventive treatment of persons at high risk, and vaccination against tuberculosis Pillar 2 - Bold policies and supportive systems
1. Political commitment with adequate resources for tuberculosis care and prevention 2. Engagement of communities, civil society organizations, and public and private care providers
3. Universal health coverage policy, and regulatory frameworks for case notification, vital registration, quality and rational use of medicines, and infection control
4. Social protection, poverty alleviation and actions on other determinants of tuberculosis Pillar 3 - Intensified research and innovation
1. Discovery, development and rapid uptake of new tools, interventions and strategies 2. Research to optimize implementation and impact, and promote innovations
In general, there are two approaches to diagnosis of tuberculosis: active case-finding (ACF) and passive case-finding (PCF). PCF involves a person with symptoms suggestive of tuberculosis seeking care and a health worker who is able to correctly identify that the symptoms may be a result of tuberculosis and that the person requires diagnostic evealutation.28,29 PCF is mainly patient-initiated.28
ACF is an alternative approach. ACF is often used synonymously with systematic screening and is mainly provider initiated. Systematic screening for tuberculosis is defined as “the systematic identification of people at risk for tuberculosis disease, in a predetermined target group, by assessing symptoms and using tests, examinations, or other procedures that can be applied rapidly”.28 The aims of screening programmes for both individuals and health systems are to reduce mortality, incidence, and severity, as well as to increase choice by identifying disease earlier when more treatment options are available.30 Screening also has greater economic benefits. For example, screening may reduce costs by preventing
disability.30 Conversely, screening can lead to harms. False positive results can lead to anxiety and individual complications from further investigations.30 Screening may also be resource intensive, particularly when there are many false positive results.30 False negative results may also affect the health system by resulting in legal claims. Furthermore, screening can also result in overdiagnosis and overtreatment.30
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ACF involves identifying those who need confirmatory tuberculosis testing (i.e., those who screen positive) from those who do not (i.e., those who screen negative). Thus, ACF for tuberculosis involves two steps: screening followed confirmatory testing (and other
diagnostic evaluation) for those with a positive screen.28 A single screening tool may be used or screening tools may be combined as a parallel strategy (e.g., two or more screening tests offered at the same time) to improve sensitivity or as a sequential strategy (e.g., second screening test offered only if first screening test is positive) to improve specificity (Table 1- 7).31
Figure 1-7: Screening algorithms that combine screening tools in a parallel or sequential strategy31
ACF can be performed for the whole population or for high-risk groups, such as PLHIV, and can be performed in individuals who seek care (with or without tuberculosis symptoms and signs) or in individuals who do not seek care (e.g., community-based screening).28 The goal of ACF is to identify more PLHIV with tuberculosis at an earlier stage to reduce morbidity, mortality, and community transmission and to identify PLHIV without tuberculosis who would benefit from IPT/tuberculosis preventative therapy (TPT).27,32
The 2011 WHO guidelines for ICF and IPT/TPT in PLHIV recommends that PLHIV be systematically screened for active tuberculosis at each visit to a health facility.27 The 2013 WHO guidelines on systematic screening for active tuberculosis in PLHIV reaffirm this recommendation.28 The WHO screening and diagnostic algorithm for tuberculosis in PLHIV has 2 components: the WHO Xpert algorithm and the WHO AlereLAM algorithm (Table 1-
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3). According to the WHO Xpert algorithm, WHO recommends screening PLHIV at each encounter for the presence of a positive WHO four symptom screen (W4SS) (comprising any one of current cough, fever, night sweats, or weight loss). In those with a positive screen, Xpert MTB/RIF (Xpert) or Xpert MTB/RIF Ultra (Xpert Ultra) confirmatory testing should be performed. According to the WHO AlereLAM algorithm, WHO recommends also screening for the presence of a positive W4SS, CD4 cell count ≤200 cells/µL (in inpatients) or CD4 cell count ≤100 cells/µL (in outpatients), WHO stage 3 or 4, or positive WHO- defined danger sign. In those with a positive screen, Alere Determine TB-LAM (AlereLAM) confirmatory testing should be performed. In those with a negative screen using both
algorithms, IPT/TPT should be provided.
Table 1-3 Summary of initial steps in 2019 WHO tuberculosis screening and diagnostic algorithm for PLHIV33
WHO Xpert algorithm Assess for tuberculosis signs and symptoms*
→ if positive, perform confirmatory testing with Xpert Ultra WHO AlereLAM algorithm
Assess for tuberculosis signs and symptoms*, CD4 cell count ≤ 200 cells/µL (inpatients) or CD4 cell count ≤ 100 cells/µL (outpatients), WHO stage 3 or 4, or a WHO-defined danger sign (i.e., meets seriously ill criteria) †
→ if any positive, perform urine AlereLAM
*Using the WHO four symptom screen, defined as any one of current cough, fever, night sweats, or weight loss.
†WHO-defined danger signs are respiratory rate >30 breaths/min, body temperature >39°C, heart rate >120 beats/min, or unable to walk unaided
The following sections summarize confirmatory tests and screening tools that may be used for active tuberculosis in PLHIV.