TB Flashcards
TB Susceptible treatment
2HRZE4HR
TB Shorter treatment
Consider in milder disease - no cavitation and smear <2+ BUT stratifying treatment is difficult in a high burden setting
TB MDR treatment
6m BPaLM: bedaquiline, pretomanid, linezolid, and moxifloxacin (cannot be used in pregnancy, <14y or previous exposure to drugs). 9m regimens used in pregnant <14y. Bedaquiline is the cornerstone of the MDRTB treatment, but if you have new drugs - should think about using it in drug susceptible disease (eg DTG in HIV) transition to first line and reduce the chance of needing second line
TB XDR treatment
Last resort regimen, those who failed or not eligible for shorter regimens, individualised based on current recommendations
TB MDR definition
Resistant to isoniazid and rifampicin
TB XDR definition
Resistant to MDR (isoniazid/rifampicin) plus quinolone and another group A drug [bedaquiline or linezolid] (pre-XDR is INH/RIF+quinolone
TB Natural history
Most infection does not lead to disease, infection is a dynamic continuum not a binary state, self-cure is probably common but we cannot test for it, active pulmonary TB is a chronic cavitatory pneumonia. TB further impoverishes the poor
TB Key clinical features of PTB
Cough, fever, weight loss, night sweats are cardinal features
TB Diagnostic approach PTB
Sputum is key sample, microscopy widely used and detects the most infectious cases but misses half. Auramine improves performance over ZN. Xpert MTB/RIF detects MTB DNA. Sputum culture is used less and less, mainly if concerned about drug resistance. CXR useful and automated (CAD) reading of digital imaging increases access
TB Therapeutic principles
Multidrug therapy for 6m remains standard (2HRZE4HR), shorter 4m regimens endorsed but not implemented, TRUNCATE-TB shows we can go shorter if we can find the right regimen
TB Access
TB diagnostic and treatment services are free of charge in the public sector
TB Vaccines
TB vaccine enthusiasts believe no attempt at TB control will work without a new, effective vaccine, BCG is most widely used but efficacy is limited, objective of vaccine design (and thus study population in vaccine trials) vary, particular focus on prevention of infection (POI) and prevention of disease (POD) in those already infected, major hurdle is correlate of protection - there is no Ab level or other biomarker identified that can predict a vaccine will work, so large and long trials are needed. Therapeutic vaccines aim to improve outcome of treatment of active disease (add to standard treatment) tough as standard treatment already works well
TB LTBI Diagnosis
TST and IGRA are tests of immunoreactivity (not viable latent infection). Indeterminate IGRA means no assessment of TB risk can be made - the test is not valid, the PPV ~5% (fewer than 5% with positive result will go on to develop active TB disease)
TB LTBI Treatment
6H or 3HP (weekly) or 1HP (daily) - (P=rifapentine)
TB Epidemiology
Global TB report tracks national and global data on TB diagnosis, treatment, prevention, screening, financing, social determinants and research - also tracks progress against END-TB targets - progress has been glacial, and short on intermediate milestones, 70% TB burden in 8 countries
TB WHO 2030 END-TB Targets
80% reduction in new TB cases, 90% reduction in TB deaths, 100% of TB-affected families protected from catastrophic costs
TB HIV and Diabetes
Predispose to active TB, relative importance of each varies in different parts of the world, HIV is major driver in sub-Saharan Africa but not in Sth America
TB 8 top countries
India 27%, Indonesia 10%, China 7%, Philippines 7%, Pakistan 6%, Nigeria 5%, Bangladesh 4%, DRC 3%
TB Diabetes
Risk of TB is 3x higher in diabetes than non-diabetes in same population, holds true in both low and high TB burden settings. T2DM is rapidly increasing and accounts for vast majority of this effect, risk in T1DM is probably higher but much less common. People diagnosed with TB should be tested for DM as the TB might be the first manifestation of DM (as for HIV). Screening people with DM for TB is low yield and not cost effective. TB in people with DM is not substantially different to TB in people without DM, treatment is the same
TB Natural history
Some clear infection, most control infection and develop latent TB, of those with LTBI 10% will go on to develop active TB in their lifetime (90% don’t), some develop active TB (develops over weeks to months)
TB HIV coinfection
Different natural history, phenotype and diagnosis, HIV increases probability of early progression, and probability of TB reactivation to 10% per year
TB Paediatric TB
Different natural history, phenotype and diagnosis, larger number go on to active disease
TB TB control
Stop transmission, treat adults with pulmonary TB who are the infectious source
TB Empiric antibiotics
Stop giving empiric antibiotics as it does not discriminate between those with TB and those without - broad spectrum Abx are NOT a discriminator
TB Definition PTB
Involves lung parenchyma, includes miliary disease and any PTB with EP manifestations
TB Definition EPTB
Involves any other system than lung parenchyma, includes hilar lymphadenopathy and pleural disease, for EPTB think HIV
TB Median time to culture conversion
37d in fully susceptible disease
TB WHO Vaccine priorities
1 safe effective & affordable TB vaccine for adolescents and adults, 2 affordable TB vaccine for neonates and infants with improved safety & efficacy, 3 therapeutic vaccine to improve TB Rx outcomes
TB Vaccine challenges
Efficacy seems to be different, including how far people are from the equator, gender, important to consider when looking at vaccines
TB BCG
Only licenced TB vaccine, protects children from TB meningitis and miliary disease, non-specific effects, protection from pulmonary TB lowest near the equator
TB Vaccine strategy
Efficacy signals obtained by POI candidates would require a much lower sample size and a shorter duration of follow-up compared to those candidates tested in Prevention of disease (POD) trials. POI vaccine with partial efficacy would likely have an important public health impact
TB Vaccine for PLHIV
Live mycobacterial vaccines like BCG, VPM1002, and MTBVAC might present a safety risk for PLHIV. This risk needs to be evaluated in the context of ART, viral suppression, CD4 recovery, and completion of TPT. Inactivated mycobacterial, viral-vectored and protein-subunit candidate vaccines, including M72/AS01E, might be safer for vaccination of individuals with HIV and other immune-suppressive conditions
TB Paed prevention gap
In 2020 2/3 of 1.1mil eligible contacts <5y did not access TB preventive treatment (TPT) and less than 5% of eligible HIV-uninfected older child/adolescent contacts accessed TPT
TB RF for paed TB
Infectiousness of the index case, age of child, proximity to and duration of contact with index case, immune status of child, children of families living with HIV, other illnesses (HIV, pertussis, malnutrition, post-measles
TB Paed TB clinical features
Persistent unremitting cough >2-3 weeks, intermittent fever, weight loss/failure to gain weight - other common sx loss of appetite, cough, night sweats, reduced energy/playfulness, recent measles, pertussis and not returning to normal health
TB Tuberculin Skin Testing (TST)
Based on delayed-type hypersensitivity reaction to PPD, positive result suggests infection or sensitisation, do not indicate or rule out TB disease, false positive with previous BCG vaccine, NTM and HIV - positive >=10mm regardless of BCG, >=5mm in children with HIV/malnutrition
TB Interferon gamma release assay (IGRA)
Rely on measurement of IFNg released by memory CD4 T cells stimulated with TB antigens ESAT-6 CFP-10 Pro: one visit Con: expensive, sophisticated lab technology, not available in most resource-poor settings, suboptimal sens in children
TB TST/IGRA limitation
Most people will be sensitised from a very early age, so both TST and IGRA have a low positive predictive value – limits use, as knowledge of epidemiology is just as useful. IGRA NNT (no needed to test) ~80 to make one additional diagnosis
TB Xpert MTB/Rif
SEN ~66% (Ultra ~72%); SPE >98%, does not differentiate between viable and non-viable MTB, SEN lower in routine testing compared to research findings. Advantages: sens, fully automated, commercial, minimal expertise, TAT 2h, identifies rif resistance. Disadvantages: needs stable electricity, good maintenance, uninterrupted cartridge supplies, often underutilised because of these issues
TB Paed TB diagnosis
Confirmed Mycobacterial confirmation (smear, Xpert or culture) with or without CXR changes, positive TST/IGRA, improvement on antiTB Rx and no confirmed alternative diagnosis - unconfirmed is same minus micro
TB Paed TB diagnostic challenges
Smear sens <10% Xpert sens lower than adults, Culture pos <30%, CXR changes non-specific, TST/IGRA of limited value in TB-endemic settings
TB Paed TB treatment pulmonary, lymphadenitis
2HRZE4HR - daily in intensive phase, intermittent 3x/wk in continuation phase - shorter treatment for children and adolescents with non-severe/smear neg TB are an option
TB Paed TB treatment meningitis, miliary, bone
2HRZE10HR
TB Paed TB treatment
Fixed dose combinations widely available - ensures accurate dosing, simplifies treatment, improves compliance
TB BCG culture process
M bovis in media with ox bile, gradually lost virulence over 18y
TB BCG first administered
1921 infant of mother who died of TB
TB BCG Lubeck disaster
1929 MTB administered to 250 infants instead of BCG, 72 died
TB BCG explanation for variable efficacy
Differences in methods, genetics, geography (works better away from equator), epidemiology (differences in annual risk of infection), nutrition, BCG strains over time, environmental mycobacterial exposure - cellular immunity may be formed due to NTM exposure which blocks/masks BCG effect
TB BCG NTM exposure
BCG more effective in those who are immunologically naïve than in those with prior mycobacterial sensitivity
TB BCG effects
BCG has very good protection against TB meningitis, whereas it is a mess for pulmonary - BCG is a better vaccine against leprosy than it is against TB – major factor behind the worldwide decline in leprosy
TB BCG WHO policy
Single dose at birth, to protect (primarily ?) against childhood TB disease eg: one case of TB meningitis prevented for each 3,500 doses (c.$200 per year of life saved). This policy has relatively little impact on adult pulmonary tuberculosis, or on transmission of M tuberculosis nb: WHO does not advocate repeat vaccination
TB TB vaccine future
Much interest, several candidates, world is ‘saturated’ with BCG - cannot get BCG-free individuals in high endemic TB regions, major problem is no ‘correlate’ of protection - no Ab level etc - very difficult to design immunologic and/or epidemiologic study
TB TB lymphadenitis
Most frequent form of EPTB, often cervical, hilar, mesenteric. Painless/mild inflammation, if untreated - liquefaction and fistulising, diagnosis by large needle biopsy, no surgery, swelling comes and goes (until months after therapy)
TB TB pleuritis
Classic primary TB (6-12w) may also occur in reactivation, 90% unilateral, 10% bilateral, exudate leuk 0.5-5x10^6, protein >30, pH 7.3, slightly low glucose (seldom real empyema), Micro ZN, culture PCR often negative, pleural biopsy histo/micro most sensitive, different management from bacterial empyema - this usually does not need drainage
TB Miliary TB
Haematogenous spread, primary reactivation, often decreased host defence, sometimes T-cell anergy (TST/IGRA negative), semi-acute (sepsis-like) or more chronic, may involve lung, liver, adrenals, brain, retinae. Lab: cytopaenia, liver, SIADH, low albumin, sterile pyuria. Micro: sputum/BAL, bone marrow, liver, urine, if acutely ill give empiric Rx
TB TB spondylitis
50% of all bone TB, pain, sometimes focal neurology, ‘cold abscess’ psoas, variable inflammation, often TB elsewhere. Diagnosis aspiration (psoas) abscess or bone biopsy - surgery if unstable spinal column (not necessarily with focal neurology. Inflammatory markers often not elevated
TB Ocular TB
Usually posterior uveitis (esp choroiditis in context of miliary TB), also anterior uveitis, retinal abnormalities, neuritis optica. Micro confirmation is difficult - vitreal biopsy, vitrectomy, DDx toxo, syphilis, autoimmune. Consider steroids and treatment. If sight threatening immunosuppress and treat straight away
TB TB meningitis
Rare but most severe form of TB, subacute meningitis, basal meningitis, hydrocephalus, stroke, CN palsy, often, but not always immunocompromised. Often TB outside the brain (lung, miliary, myelitis), micro confirmation is difficult. Elevated opening pressure (like crypto and bacterial), 1/3 will have neutrophil predominance - no test can rule out TB meningitis - have to build story based on clinical, epi, immune, routine CSF markers, imaging, always do chest imaging. TB meningitis is basal - progression is probably not haematogenous, but may be direct progression of TB up the neck 80-90% have myelin lesions. Generally entrapment of 4th ventricle and CN (eye movement) lesions, particularly extremes of age, immunosuppressed. Can have new events during treatment due to enlarging lesions in the brain - stroke, seizure, infarcts
TB TB meningitis adjunctive Rx
Steroids: studies not conclusive, would be reluctant to withhold steroids until further research. Aspirin: inconclusive, studies underway
TB Cutaneous TB
Exogenous inoculation (very rare), TB verrucosa cutis (PB form in a sensitised immunocompetent individual due to exogenous reinfection), scrofuloderma (direct invasion of the skin from TB in an underlying LN or bone), fistula from pleural lesion etc
TB BCG-osis
Early: granulomas in Lungs, liver, bone marrow ; Late: iliopsoas abscess, mycotic aneurysm, osteoarticular (PJI, spondylodiscitis)
TB Histopathology in immunosuppression
Immunosuppression will reduce the chance of developing classic non-necrotising granulomas and may make the diagnosis difficult
TB EPTB Adjuvants
TB meningitis (HIV+), constrictive TB pericarditis, ocular TB, severe immunopathology; and surgery rarely for spondylodiscitis or pericarditis
TB IRIS
HIV typical paradoxical (clinical worsening TB because of immune reconstitution), or HIV unmasking - did not know they had cerebral disease - develop seizures on therapy. Paradoxical worsening can also occur in non-HIV (fever, new or enlarging lesions)
TB Diagnostic interventions
1 Digital CXR and computer-aided diagnostics then sputum PCR at primary care, 2 urine LAM (TB Ag) screening for all hospitalised HIV+ medical patients, 3 community interventions with evidence for affordable impact: digital CXR, symptom and smear-microscopy based
TB Passive case finding
People who attend facility with symptoms consistent with TB - wait for them to come to you
TB Diagnostic problems
Slow, suboptimal TB tests, no one test available that could be scaled up, and whatever you are doing, you should not create disadvantage to those presenting to primary care.
TB Transmission
People can remain infectious for years, this is a big barrier to reducing transmission
TB TB and DM
~500million people, RR 3 fold, disease more severe pulmonary TB, mortality 2 fold, drug resistance 2 fold, post TB more TB recurrence, post-TB lung disease, CVD and deaths, IGRA/TST not affected, no evidence (yet) for TB preventive therapy. If TB screen for DM (not vice versa). Even following TB treatment there is persistent inflammation, T cell anergy, and the immune system does not return to baseline
TB TB and HIV
~40million people, RR 40 fold (depending on CD4, lower with effective ART), fewer cavities & more disseminated disease, mortality 2 fold higher (dependent CD4/ART), no clear association with MDR, IGRA/TST reduced sensitivity if low CD4, existing policy for TB preventive therapy. If TB, screen for HIV, and if HIV screen for TB
TB Practecal
Practecal trial showed effectiveness of 6-month all-oral bedaqualine containing regimens for adults with MDR-TB
TB Prevalence surveys
Go to every house, or every 3 houses, screen for symptoms, then do tests on those with symptoms. There are likely a number of people who have not met their threshold of symptoms so have not found their way to healthcare system, but who contribute to transmission
TB TB vs LTBI
Latent TB is an asymptomatic state (no evaluable clinical sample) where MTB is believed not to be replicating (uncertain). Previously thought of as binary, more recently understood this is a spectrum. Those with limited symptoms in the community and have CXR changes, but if you gave them a pot, asked them to cough - they would. Time is not linear - can go forward and backward. Gradually developed the subclinical active phase and move up and down the continuum
TB TST
Purified protein derivative (cocktail of lots of mycobacterial proteins), cross react with lots of other mycobacteria, exposure to BCG cross reactivity wanes with age, but undermines TST
TB IGRA
Test of immunoreactivity to ESAT-6 CFP-10, need a lab and not practical for widespread use in LMIC - it will only recognise these peptides if you have been exposed to MTB in the past. <0.35 negative >=0.35 positive - calculate the concentration in the test tube minus the background (null) response. How positive it is does not reflect risk of reactivation in the future. Repeating indeterminate test is generally futile. IGRA does not ‘resolve’ to normal following LTBI treatment
TB Omics
Would be great, but not yet predictive - ideally sample of whole blood, look at whole gene expression within that blood sample, which genes are turned on and off and whether there is anything that could predict the development of TB
TB Treatment for LTBI - Who
In all settings - children <15, household contacts, immunosuppressed. In low-burden settings - occupational screening (prevent risk of reactivation in those who move to a setting where reinfection is very low). Under 5yo should have active TB excluded and then offered latent TB treatment as they are the highest risk of progressive disease or reactivation. When rolling out preventive treatment there is a risk of driving resistance - the most important thing is to rule out active TB. In reality TST and IGRA are not available in many settings, and high risk (<5yo) household contacts may be offered treatment without testing prior
TB Treatment for LTBI - What
INH 6-9m, INH/RIF 3m, Rif 4m - Rifapentine/INH 3m probably better than INH 9m. Drug resistance does not increase risk of reactivation, but does render the regimens ineffective. WHO recently recommended levofloxacin LTBI treatment
TB LTBI Key messages
There are emerging insights into the nature of ‘latent’ TB infection and concepts of ‘subclinical’ TB (and ‘incipient’ TB), and these states may potentially be detectable by immunological signatures which might help the targeting of rapidly improving preventive therapy tools
TB Global summary
2022 10.6 million cases, 1.3 million deaths. Of all TB adult men 55%, adult women 33%, children 12%. 6.3% of all people with TB have HIV, MDR TB identified in 3.3% of all new cases, 17% of previously treated TB developed MDR TB subsequently. Global TB and MDR TB epidemiology is slow moving. Ambitious WHO End-TB targets will not be met through current approach. TB affects the economically active age group which disproportionally affects the economy of the country. There are a lot of priorities, and money for TB is money that doesn’t go somewhere else, however because TB costs governments much money, making the economic case that treating TB saves money. Substantial proportion of patients are disabled following treatment of TB as the chronic scarring and consequences of extrapulmonary TB are significant. Men are at risk - likely a combination of factors including smoking, iron deficiency of childbearing women (mycobacteria are iron siderophores), fat distribution and sex hormones
TB National TB Program Needs
Sustained political commitment (money to support it), Case detection with smear microscopy, standardised short-course treatment, uninterrupted supplies of drugs, standardised monitoring and evaluation. Central reference laboratory for culture and drug susceptibility testing (only offered in Malawi to those who have previously been treated)
TB National TB Program Approach
Rely on passive case finding - waiting for patients to present to health facility, need cough 2-3w, fever, night sweats, weight loss = presumptive diagnosis. Sputum for microscopy or Xpert - operational research showed 2 sputums as good as 3. Active case finding identifies more cases but is very labour and resource intensive. Middle ground is to approach easily-identifiable high-risk groups - HIV and household contacts of index cases, plus (resources permitting) - prisons, mines (silicosis), migrants and urban slums.
TB National TB Program EPTB
Pleural - straw coloured pleural effusion TB until proven otherwise, but might miss malignancy. Pericardial - dx made clinically, again can miss malignancy.
TB Global treatment
5-40% of patients diagnosed with bacteriologically confirmed TB fail to start treatment
TB National TB Program Monitoring
TB patient register, TB treatment card, TB patient identity card - having these in place allows for case finding and treatment outcome, but is also necessary for predicting how much drug will be required in the next quarter
TB Operational research
Definition: Research into interventions, strategies or tools that can enhance the quality, effectiveness or coverage of a disease control programme. Six step strategy: 1 Political commitment, incorporate research as part of the five-year plan with fast-tracked ethical approval, dedicated budget line for research. 2 Work with people, partners, institutions. 3 Identify key areas for operational research - treatment regimens, decentralised therapy, traditional healers, 2 vs 3 smears, etc 4 Build/strengthen research capacity (research question>protocol development/ethics approval>secure funding>implementation, collection of data, cleaning of data> data analysis and interpretation> paper writing, submission, peer review, rewriting> translation of findings into policy and practice 5 Provide essential resources: office, computers, internet, transport, costs of ethics approvals, research implementation, conference attendance, Open access publication - pay for publication so everyone can read it 6 Evaluate the research > ultimately aiming for health outcomes to improve
TB 3 approaches to shorten treatment
1 New drug regimens with improved activity (3 new drugs in 10-15y, repurposing drugs), 2 Improve the immune response to clear persistent bacteria (multiple drugs tried have not had any benefit), 3 Innovative treatment strategies (treat everyone with shorter duration needed for the majority, shift resources to ensure early detection and early retreatment of relapses in the minority)
TB Biomarkers
The way forward for trials - ideally measure something at 8w to determine the probability the person has had sufficient treatment, rather than having to do sputum smear and symptoms (these are very imprecise)
TB New treatment key messages
Current 6m regimen for DS-TB is hard to beat. Main focus is on shortening treatment (not the only consideration). Have alternative 4m regimen (RPT/MOX), but low uptake. Treatment shortening to 2m is optimal goal. Healthy (by TB standards) new drug pipeline. Healthy (by TB standards) funding for taking new drugs into phase 2. Innovative trial designs that may enable faster testing. Increasing interest in host-directed therapy. Innovative treatment strategies: TRUNCATE-TB trial shows potential for more personalised approaches to TB treatment
