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TB Diagnosis and Case Finding
Kogie Naidoo (MBCHB, PhD)Head: CAPRISA HIV-TB Treatment Research Programme
Honorary Associate Professor UKZN Public Health Medicine
SAHCS Continuing Medical Education Meeting
11 September
Presentation Outline
• Epidemiology
• TB disease burden
• Current performance
• Programmatic Approaches
• Patient Pathway analysis and TB care cascade
• Health system challenges & linkage to care
• TB Pathogenesis & spectrum of disease
• TB testing and diagnosis
Global TB Epidemic –TB Incidence (2018)
• 10 million new TB cases • 8.6 % in PLWASource: WHO Global TB Report 2019
1.5 MILLION TB DEATHSINCLUDING 251 000 TB DEATHS AMONG PEOPLE WITH HIV
TB is the top infectious killer worldwide
TB is also the leading cause of deaths among people with HIV and a major cause of
antimicrobial resistance related deaths
58 million lives saved between 2000 and2018TB deaths fell by 38% in the same period
US$ 3.3
BILLION
GAP
Funding shortfall for TBGap of over US$ 1.2 billion per year
for TB research
Top 8 countries: 66% of New TB cases
HIV Rank Prop of Global
TB BurdenCountry
3rd 27% India
4th 9% China
5th 8% Indonesia
7th 6% Phillipines
6th 6% Pakistan
2nd 4% Nigeria
8th 4% Bangladesh
1st 3% South Africa
DR-TB remains a public health crisis with gaps in detection and
treatment Only 1 in 3 needing treatment were enrolled
on it
GLOBAL TUBERCULOSIS REPORT 2019
66%
TB Burden in Africa, #1 cause of death in SA
a Indicates high TB burden countries
Source: WHO Global TB Report 2019
MDR-TB TB/HIV
Botswana
Cameroon
Chad
Eswatini Ghana
Guinea-Bissau
Malawi
Uganda
Brazil
Central AfricanRepublica
Congoa
Lesothoa
Liberiaa
Namibiaa
URTanzania
Zambiaa
Cambodiaa
Sierra Leonea
Angola
China
DR Congo
Ethiopia India
Indonesia
KenyaMozambique
Myanmar
NigeriaPapua New Guineaa
South Africa
Thailand
Zimbabwea
Bangladesh
DPR Korea
Pakistan
PhilippinesRussian Federation
Viet NamAzerbaijan
Belarus
Kazakhstan
Kyrgyzstan Peru
Republic ofMoldova
Somalia Tajikistan
Ukraine
Uzbekistan
TB
Tuberculosis in SA
Source: WHO Global TB Report 2019
Estimated TB incidence & mortality in SA
Source: Naidoo et al JID 2017
Rate of decline of TB incidence and mortality too slow to meet the SDGs & End TB Strategy targets
THE GLOBAL PLAN TO END TB (2016–2020)
Source: 90(90)90 - The Tuberculosis report for heads of state & governments global plan to end TB 2016 - 2020
Programmatic Approaches to establishing gaps in TB diagnosis & linkage to care
• Two types of care cascades used in evaluating TB care: cascade analysis and patient pathway analysis (PPA)
• Care cascade enumerates losses at each step across care continuum• Provides indirect estimates of disease burden• Based on expert opinion and epidemiologic data. • Facilitates targeted interventions aimed at points of attrition along care continuum
580 000
132 347
64 995
500 000
125 000
68 750
2015
2020
PEOPLE DEVELOPING TB PEOPLE ON TREATMENT PEOPLE TREATED SUCCESSFULLY
100%
23%11%
100%
25% 14%
Current Performance: 90-(90)-90 Targets for DR-TB
Source: 90(90)90 - The Tuberculosis report for heads of state & governments global plan to end TB 2016 - 2020
Only 1 in 10 people developing DR-TB were successfully treated
Establishing gaps in TB diagnosis & linkage to care in the SA TB Programme
• Only 53% of all tuberculosis cases were successfully treated
• Data from NHLS, TB registries & published studies
10 400 000
6 100 000
5 063 000
10 000 000
7 000 000
5 000 000
2015
2020
PEOPLE DEVELOPING TB PEOPLE ON TREATMENT PEOPLE TREATED SUCCESSFULLY
100%
59% 49%
100%
70% 50%
Global Performance: 90-(90)-90 Targets for DS-TB
Source: 90(90)90 - The Tuberculosis report for heads of state & governments global plan to end TB 2016 - 2020
Only 50% of people developing TB are successfully treated
• PPA identifies bottlenecks and assesses alignment: availability of TB diagnostic and treatment services vs patient needs along care continuum
• PPA data sources: qualitative surveillance and survey data incl care seeking behaviour, care access and location,
coverage of diagnostic and treatment services and treatment success
• Limitation: coverage vs quality of diagnostic and treatment services incl ability of healthcare workers to implement guidelines
• PPA from 13 countries that carry 76% of all TB cases & 92% of all “missing” TB cases globally recommends capacitating primary health care networks proper TB testing, treatment, and referral services will reduce costs and save lives
• Low rates of TB screening and testing despite access to services and diagnostics• 39/779 participants tested positive for TB were not tested by clinic staff• 38.5% were never screened and 61.5% were screened but not tested• health system missed 62.9–78.5% of symptomatic TB patients and 89.5–100% of TB in those attending
clinic for other reasons
Health Systems Challenges impeding Finding and Successfully treating TB
CHALLENGES WITH TB
SCREENING
CHALLENGES WITH TB
SCREENING
CHALLENGES IN TB
DIAGNOSIS
CHALLENGES IN TB
DIAGNOSIS
CHALLENGES IN LINKAGE TO TB CARE
CHALLENGES IN LINKAGE TO TB CARE
CHALLENGES WITH TB SCREENING
Non-compliance with TB guidelines
• Failure to:
• Assess for symptoms of TB
• Act on symptomatic patients
• Offer sputum microscopy
• Screen contacts of index TB patients
Healthcare worker skill
• Poor understanding and interpretation of TB symptoms
Source: K Naidoo – in press
CHALLENGES IN TB DIAGNOSIS
Non-compliance with TB guidelines
• Poor Microbiologic coverage for suspected TB
• Failure to request repeat samples from patients that test negative
• Repeat testing with lab requests for additional samples not acceded to
Poorly skilled healthcare workers
• Poor specimen quality: insufficient volume, saliva vs sputum
• Inadequate staff training on sputum collection and new diagnostic algorithms Lack of TB treatment knowledge among healthcare workers
• Poor implementation of new diagnostic algorithms
• Poor healthcare worker attitude in following up on laboratory tests
Weak clinic systems (e.g. patient flow)
• Inefficient patient flow systems through clinics
• Inadequate physical infrastructure Inadequate infrastructure for safe sputum collection
• Lack of patient privacy
Poor/no quality assurance of data collected
• Poorly completed laboratory request forms
CHALLENGES IN LINKAGE TO TB CARE
Lack of patient engagement
• Failure to provide patient education and to engage patients in care
• Lack of provision of follow up appointments for patients to access laboratory results
• Lack of provision of follow up appointments for patients to commence therapy
Poor/no quality assurance of data collected
• Incomplete or failure to collect patient locator information to facilitate tracing attempts
• Lack of unique identifier linking laboratory results to patients
Weak communication systems and infrastructure
• Poor mechanisms of communication of laboratory results to facilities and patients
• Lack of systems for tracing and linking patients to treatment
• Difficulty locating and accessing patients’ homes particularly in rural areas
• Inadequate resources for patient tracing (e.g. lack of telephone, vehicles)
Source: K Naidoo – in press
With acquired immune response
With innate immune response*
Subclinical TB disease
Latent TB infection
ActiveTB disease
TST
IGRA
Culture
Sputum smear
Infectious
Symptoms
Preferred treatment
Positive
Positive
Negative
Negative
No
None
None
Negative
Negative
Negative
Negative
No
None
None
Positive
Positive
Intermittently positive
Usually negative
Sporadically
Mildor none
Multidrug TB therapy
Positive
Positive
Negative
Negative
No
None
Preventive therapy
Usually positive
Usually positive
Positive
Positive ornegative
Yes
Mild to severe
Multidrug TB therapy
or
Infection eliminated
Mycobacterium tuberculosis
GranulomaLung
Heart
TB pathogenesis
Source: Pai et al., Nat Rev .2016
Interventions: Improved TB
Diagnosis
TB SUSPECTSTB and DR-TB contacts, non-contact symptomatic individuals, re-treatment after relapse, failure and default
Collect one sputum specimen at the health facility under supervision
GXP positiveRifampicin susceptible
GXP positiveRifampicin resistant
GXP positiveRifampicin unsuccessful
GXP negative GXP unsuccessful
Treat as TBStart on Regimen 1
Send one specimen for microscopy
Treat as MDR-TBRefer to MDR-TB
Unit
Treat as TB
Start on Regimen 1Collect one specimen for microscopy Culture & DST / LPA
Collect one sputum specimen for a repeat GXP
HIV positive HIV negative
Collect one specimen for culture & LPA or culture & DST (for R and H)Treat with antibiotics and review after 5 daysDo chest x-ray
Treat with antibiotics
Poor response to antibiotics Clinically TB TB on chest x-ray
LPA/ DST results
Resistant to R and H/ R only
Good response
No further follow up
Advise to return
when symptoms recur
Poor response
Consider other diagnosis
Refer for further investigation
Treat as MDR-TB
Refer to MDR-TB Unit
Treat as TBStart on Regimen 1Review culture results
Follow up with microscopy
Collect one specimen for microscopy, culture and DST for Rifampicin, Isoniazid, fluoroquinolone and Aminoglycoside
Follow up with microscopy and culture
Source: National Tuberculosis Management Guidelines 2011
Meta-analysis of Sensitivity & Specificity of XpertMTB/RIF in Pulmonary TB
• Meta-analysis of 27 unique studies with 9,558 participants
Initial diagnostic test replacing AFB smear: Pooled sensitivity 88%; specificity 99%
Add-on test following negative AFB smear: Pooled sensitivity 68%; specificity 99%
Detecting true RIF resistance: pooled sensitivity 95%; specificity 98%
Parameter Pooled Sensitivity 95% CrI
Smear (+)/Culture (+) 98% 97-99%
Smear (-)/Culture (+) 68% 61-74%
HIV (+) 79% 70-86%
HIV (-) 86% 76-92%
Source: WHO Xpert MTB/RIF Policy Update-2014
Meta-analysis of Sensitivity & Specificity of XpertMTB/RIF in Extrapulmonary TB
Specimen Type
Median Pooled Sensitivity (95% CrI)
Median Pooled Specificity (95% CrI)
False Positive (%)
False Negative (%)
CSF 71.1 (60.9 -80.4) 98.0 (97.0 -98.8) 20 3
Pleural Fluid 50.9 (39.7 -62.8) 99.2 (98.2 -99.7) 8 8
Urine 82.7 (69.6 -91.1) 98.7 (94.8 -99.7) 17 1
Rifampicinresistance
95.0 (89.7 -97.9) 98.7 (97.8 -99.4) 9 1
66 unique studies evaluated 16 213 specimens (adult and children) for detection of EPTB and rifampicin resistance, 7% from LMIC
Xpert Ultra Trace Algorithm
Xpert Ultra reduced sensitivity in previous TB: 84% < 2 years vs 96% > 5 years (Lancet ID, 2018)
Xpert Ultra ‘MTB trace detected’ result
Previous TB history
1. Perform clinical assessment2.Collect sputum specimen for TB
culture and DST
Patient is asymptomatic or clinical findings not suggestive
of TB: PH < 5 YRS
Follow up TB culture and DST results
Clinical presentation consistent with TB:PH > 5
YEARS
Commence DS-TB treatment
Follow up TB culture and DST results
Never diagnosed or treated for TB previously
Re-evaluate TB symptom screen and assess clinical condition of patient at the current visit
Clinical presentation consistent with TB:
1. Commence DS-TB treatment
2. Collect sputum specimen for TB culture and DST
3. Follow up TB culture and DST results
Patient is asymptomatic or clinical findings not suggestive of TB:
Refer for further
investigations
Finding TB in HIV co-infection:SA DoH Recommends Urine LAM
• Improved sensitivity for diagnosis of TB among HIV co-infected individuals
• Especially among patients with low CD4 counts
• Recommended by WHO in HIV-positive adults with CD4 counts less than or equal to 100 cells/UL & with signs & symptoms of TB
2019 LF-LAM Guideline
• Sensitivity of the test has been shown to be higher in patients with low CD4 count (CD4 ≤ 200)
• Increased CD4 inclusion criteria to 200 cells/UL
• LF-LAM is recommended for all hospitalized with advanced HIV, irrespective of presumptive TB
• LF-LAM for ambulatory out-patients with TB symptoms and advanced HIV
2020 LF-LAM Guideline (Draft)
Diagnostic Algorithm - Urine LAM
Criteria for Urine LAM use• Seriously ill patients defined on four danger signs:
• respiratory rate > 30/minute• temperature > 39 °C • HR > 120/minute • unable to walk unaided
• Advanced HIV Disease: CD4 cell count < 200 cells/mm3, WHO stage 3 or 4, children with HIV under 5 years - LAM should only be performed in children who can void urine i.e. non catheter-based urine sample
Additional Considerations• ** Culture and DST should also be requested• Seek appropriate consultation if poor response to TB
treatment• Read LAM result using the supplied reference card in the
kit minimise false positive and negative results• Hospitalised HIV infected patients LAM recommended:
• Irrespective of suspicion of TB, available CD4 count, & without the presence of danger signs
• Ambulatory out-patients LAM recommended under specific circumstances:
• TB is suspected based on symptoms &/ or signs & (ii) eligible CD4 count threshold
LAM: Additional Findings
• Compared Determine TB LAM Ag [AlereLAM] with novel Fujifilm SILVAMP TB LAM (FujiLAM)• 968 stored urine samples from 3 cohorts of hospitalized HIV infected patient, 62% with microbiologically-
confirmed tuberculosis• Sensitivity of FujiLAM: 70.4% (95% CI 53 – 83.1) vs AlereLAM 42.3% (31.7 to 51.8) - difference 28.1%• Specificity similar > 90% in both• CD4 ≤100 cells per μL: FujiLAM sensitivity highest (84.2%), which was 26.9% higher than that with
AlereLAM. • Combined with sputum Xpert, FujiLAM could diagnose nearly three-quarters of microbiologically
confirmed tuberculosis within 24 h ofhospital admission.
Urine LAM for TB diagnosis: Impact on mortality
• 2 arm RCT in Edendale and Malawio SOC: Sputum Xpert MTB/RIFo Intervention: Sputum Xpert
MTB/RIF + Urine TB-LAM• 2600 patients• Primary outcome was all-cause
mortality at 56-days
• No significant difference in 56-day all-cause mortality between arms
• Mortality benefit for predefined high-risk groups: low CD4 cell counts, low haemoglobin & in clinically suspected TB
Chest Radiograph in TB• No typical pattern
• Many diseases mimic TB on CXR
• Lung fibrosis from previous TB over diagnosis of active PTB
• Patients with intact immunity: upper-lobe infiltrates, with or without cavities
• Patients with advanced immunosuppression, intrathoracic lymphadenopathy & LL infiltrates
• Radiological manifestations of primary tuberculosis (typically in children) Parenchymal disease
Lymphadenopathy
Miliary disease
Pleural effusion
• Radiological manifestations of post-primary (reactivation) tuberculosis Parenchymal disease (cavitation and consolidation)
Airway involvement (bronchial obstruction, or stenosis lobar pneumonia/collapse and hyperinflation)
Pleural effusion – in 18% of all patients
Cavitatory TB
TB effusion & hilarlymphadenopathy
Clinical and Lab diagnosis of Extrapulmonary TB
Clinical Diagnosis
• High index of suspicion from the treating clinician
• Risk stratify each patient
• Each site requires a unique diagnostic approach
• Definitive microbiological diagnosis not always possible
Laboratory Diagnosis:
• Lymph Node Biopsy / Aspirate (97% yield - TB adenitis)
• CSF/ Blood culture
• Liver Biopsy - (20-60% yield)
• Peritoneal/Pleural Fluid ADA – Sensitivity and specificity 90%
• Bone Marrow Aspirates
• Biopsy with histology, cytology and culture
• Significant features:
Abdominal lymphadenopathy over 1 cm
Ascites
Splenic lesion
Splenic lesion + lymphadenopathy
Splenic lesions + ascites
Splenic lesions + lymphadenopathy + ascites
• Pericardial and abdominal ultrasonography valuable and cost effective- in diagnosing EPTB / disseminated TB
TB Diagnostics in Pleural TB
• Paucibacilliary form of TB• Gold standard: demonstration of TB in pleural fluid• Pleural fluid ADA levels over 40U/L with > 50%
lymphocyte proportion suggest pleural TB• Sensitivity 90.7%, Specificity of 97.7% justifies
treatment initiation in high TB burden settings• False negative: early disease, elderly and smokers• False positive: bacterial empyema, lung cancer,
parapneumonic effusions, haematologic malignancies
Summary: Finding TB in HIV
• Despite being preventable, treatable and curable, TB is the number one cause of death in SA
• TB in SA largely among PLWH
• Half (53%) of all tuberculosis cases in South Africa in 2013 were successfully treated
Substantial losses during tuberculosis diagnosis, linkage to care, and retention in care
• Interrogating the TB Care cascade and analysis of patient pathways offer practical approaches to finding missing TB cases
• Strong policies and guidelines supporting improved TB outcomes yet non-adherence to guidelines continue to undermine programme performance
• Enhanced TB diagnostic capacity yet failure to screen and test for TB due to poor HCW capacity and training, & inadequate infrastructure and resources
• Adaptation of existing TB diagnostics to non-sputum samples offer opportunities to enhance TB diagnosis in EPTB and in advanced HIV
Acknowledgements
TB-HIV studies are funded by:
South African MRC
DAIDS, NIAID, National Institutes of Health
President’s Emergency fund for AIDS Relief (PEPFAR)
US Centers for Disease Control and Prevention (CDC)
Fogarty International Center, NIH
Doris Duke Charitable Foundation (DDCF)
Howard Hughes Medical Institute (HHMI)
The Global Fund to fight AIDS, Tuberculosis and Malaria
EDCTP
MRC - Newton Fund
MRC-SHIPP
USAID through BroadReach Health Care Africa
NRF
Gates Medical Research Foundation
Merck/MSD
UK MRC through Infectious Diseases Institute of Uganda
CAPRISA gratefully acknowledges all study participants
MCQ’s
Which initial TB diagnostic test does WHO recommend for HIV + people with suspected TB?
1. Smear Microscopy
2. Xpert MTB/RIF
3. Culture
Where GeneXpert (GXP) is available, culture may still be required for:
1. HIV positive TB suspects, who have a negative GXP test
2. TB cases diagnosed as Rifampicin(Rif) resistant on GXP for susceptibility testing of other drugs
3. Despite a Rif susceptible result, the patient is failing treatment and treatment adherence is good and thus resistance to drugs other than Rif is suspected
4. All of the above
A test sensitivity correctly identifies those with the disease
1. True
2. False
3. Don’t know
4. This confuses me!!!
Case 1
• A 29 year old man, initiated on TDF/3TC/DTG FDC since July 2019
• Previous TB treatment completed 6 years ago
• He now presents with fever and productive cough
• His sputum Xpert/MTB Rif is positive Rif sensitive
How should he be managed further?
1. Stop the ART, treat TB, then restart ART
2. Start Rifafour and continue ART unchanged
3. Start Rifafour and double the dose of Dolutegrivir
4. Replace Rifampicin with Rifabutin
Case 1 continued
• A 29 year old man, initiated on TDF/3TC/DTG FDC since July 2019
• Previous TB treatment completed 6 years ago
• He now presents with fever and productive cough
• His sputum Xpert Ultra is trace positive
How should he be managed further?
1. Patient symptomatic of TB, and previous TB > 5 years ago, therefore start TB treatment while waiting for culture and DST results
2. Patient symptomatic of TB, therefore do culture and DST and wait for results
3. Request repeat TB test on Ultra platform
4. Ignore Xpert Ultra trace positive, as trace positive likely due to previous TB
Case 1 continued
• A 29 year old man, initiated on TDF/3TC/DTG FDC since July 2019
• Previous TB treatment completed 6 years ago
• He now presents with fever and productive cough
• His sputum Xpert/MTB Rif is positive with Rif resistance
How should he be managed further?
• Stop the ART, treat DR TB, then restart ART
• Start DR TB regimen and continue ART unchanged
• Start DR TB regimen and double the dose of Dolutegrivir
• Start Rifafour and continue ART
• Replace Rifampicin with Rifabutin