TB Diagnosis and case finding SAHCS 7Sep20 Final 09 11 - Naidoo, K.pdf · 2020. 9. 23. · TB Burden in Africa, #1 cause of death in SA a Indicates high TB burden countries Source:

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


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


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 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


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




• His sputum Xpert Ultra is trace positive


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




• His sputum Xpert/MTB Rif is positive with Rif resistance


• 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

TB Diagnosis and case finding SAHCS 7Sep20 Final 09 11 - Naidoo, K.pdf · 2020. 9. 23. · TB Burden in Africa, #1 cause of death in SA a Indicates high TB burden countries Source:

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